Document 8ReKV1zG230K99ZJjVokD1em
AR226-1523
FINAL REPORT
RECEIVED OPPT NCIC
03 SEP 30 PM1:00
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 SCREENINGTEST
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
li
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
iii
SUBJECT Figure 2.
Fo Generation Female Rats
PAGE A-2
Figure 3. Figure 4.
Motor Activity - Number of Movements - Fo Generation Male Rats A-3 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 Bl. 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 ll. Relative Feed Consumption Values (g/kg/day) - Summary Fo Generation Male Rats
B-18
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 B 18. 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 ab led . Table C2.
Clinical Observations - Summary - Fo Generation Female Rats Necropsy Observations - Summary - Fo Generation Female Rats
C-l 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 Cl 1. Maternal Body Weight Changes - Gestation - Summary Fo Generation Female Rats
C-19
Table C12. 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 C16. 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 C19. 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 C2L 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-l 10
Table C44. Pup Body Weights from Birth to Day 22 Postpartum Individual Data - FI Generation Pups
C-l 13
Table C45. Pup Vital Status and Sex from Birth to Day 22 Postpartum Individual Data - FI Generation Pups
C -l25
Table C46. Clinical Observations from Birth to Day 22 Postpartum Individual Data - FI Generation Pups
C -l28
Table C47. Necropsy Observations - Individual Data - FI Generation Pups C -l30
Table C48. Pup Liver Weights - Individual Date - FI Generation Pups
C -l36
APPENDIX D - PROTOCOL AND AMENDMENTS
D-l to D-52
vm
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 to J-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 SCREENINGTEST
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 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, litter sizes and pup viability at birth. Maternal behavior was evaluated on DLs 1, 5, 8, 15 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 liveborn 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. FI generation male and female pup terminal body weights, absolute liver weight and ratio of liver 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
Associate PirectoKof Research 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 2-2
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 the 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 02-16 MAY 02 06 MAY 02 - 09 MAY 02
14 APR 02 12 MAY 02 12 MAY 02 13 MAY 02 -17 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 02 - 23 MAY 02 07 MAY 02 - 20 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.
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2.3.4. 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 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 Substance3
Homogeneity0 (all levels)
1g 2 mL
09 JUN 02 29 MAR 02
Room temperature Refrigerated
Exygenb/ Ambient conditions Sponsor/ Refrigerated
10 JUN 02 01 APR 02
Concentration" (all levels)
2 mL 24 MAY 02e Refrigerated 07 JUN 02f
Exygenb/ Refrigerated
28 MAY 02 10 JUN 02
Stability8
Bulk Test Substance Reserve
2 mL 1g
29 MAR 02 10 JUN 02
Refrigerated Room temperature
Sponsor/ Refrigerated Testing Facility Archives
01 APR 02 10 JUN 02
Vehicle Components Reserve
Carboxymethylcellulose R.O. deionized water
1g 5 mL
10 JUN 02 10 JUN 02
Room temperature Testing Facility Archives
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.
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2.4.2. Analytical Results Results of the analytical analyses are available in APPENDIX G. 2.5. Test System
2.5.1. Rat
Species
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
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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
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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 Guidefor the Care and Use of 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 sacrifice5.
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.
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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.
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2.7. Methods
2.7.1. Dosage Administration
Dosage Number Dosage Dosagea Concentration Volume of Rats
Assigned Numbers
Group (mg/kg/day) (mg/mL) (mL/kg) 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
III 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 + 3d
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.
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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
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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, 7,10,12,15, 18, 20 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)(1013) 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.
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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 APPENDIX I.
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
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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.
2.7.5.2. 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 daily2. 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 1,8,15 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 analysis13. 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.
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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 Thorne 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.
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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.
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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 liveborn, 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 Argus Automated Data Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System, the Coulbourn Instruments Passive Infrared Motor Activity System, the Coulbourn Instruments Auditory Startle System, the Coulbourn Instruments Spatial Delayed Alternation System, and/or the passive avoidance software. All data were tabulated, summarized and/or statistically analyzed using the Argus Automated Data Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System, Microsoft Excel [part of Microsoft Office 97 (version SR-2)] and/or The SAS System (version 6.12).
a. See APPENDK E, item 9.
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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 t0
Type of Test3
II. Nonparametricb
A. Kruskal-Wallis Test
(<.75% ties at any concentration)
Significant at p<.0.001
Not Significant
Significant at p<Q.Q5
Not Significant
Nonparametric
Analysis of Variance
Significant at p<0.05 Dunnett's Test
Not Significant
Dunn's Test
B. Fisher's Exact Test on Proportion of Ties
(>75% ties at any concentration)
B. Analysis of Variance with Repeated Measures
Significant at p<.0.05
Not Significant
I---------
(Dosage) Dunnett's Test
I
(Dosage x Block Interaction) One-way ANOVA for each block
r
Significant at p<Q.05
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 p<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 Variance(15). If that test was significant (p<0.05), the groups given the test substance were compared with the control group using Dunnett's Test(16). If Bartlett's Test was significant (p<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 (p<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 (p<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*45) was used to evaluate the data at each measurement period, and a significant result (p<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^.
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.
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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 /?<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<0.01) 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 FI 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, 11, 13 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. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values (Summaries - Tables C14 through C19; Individual Data Tables C36 through C38)
4.5.1. 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<0.01) 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 diestrus or estrus 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.
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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 liveborn 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 liveborn 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 liveborn 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 liveborn pups per number of pregnant rats), viability index (number of live pups on DL 8 per number of liveborn pups on DL 1) and lactation index (number of live pups on DL 22 per number of liveborn 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 FI 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 corneal 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.
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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 Guidelinefor 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 Standardfor Safety Studies on Drugs, MHW 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). Guidefor the Care and Use of 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: A functional observational battery. J. Amer. Col. Toxicol. 8:85-94.
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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 Statisticsfor 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/STA1TM 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
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.
418-028 :PAGE A-l
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
DAY OF STUDY
DAY OF GESTATION
0 MG/KG/DAY
0.3 MG/KG/DAY
1 MG/KG/DAY
3 MG/KG/DAY
DAY OF LACTATION
10 MG/KG/DAY
a. Last value recorded before cohabitation.
*p<0.05
**p < 0 .0 1
418-028 :PAGE A-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)
MOTOR ACTIVITY - NUMBER OF MOVEMENTS - Fo GENERATION MALE RATS
Figure 3
0 MG/KG/DAY
0.3 MG/KG/DAY
1 MG/KG/DAY
3 MG/KG/DAY
10 MG/KG/DAY
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
0 MG/KG/DAY 0.3 MG/KG/DAY 1 MG/KG/DAY 3 MG/KG/DAY 10 MG/KG/DAY
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
10 MG/KG/DAY
418-028 :PAGE A-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)
MOTOR ACTIVITY - TIME SPENT IN MOVEMENT - Fo GENERATION FEMALE RATS
Figure 6
0 MG/KG/DAY
:A:
0.3 MG/KG/DAY
1 MG/KG/DAY
3 MG/KG/DAY
10 MG/KG/DAY
418-028:PAGE A-6
APPENDIX B REPORT TABLES - Fo GENERATION MALE RATS
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
0/ 0
1/ 1
1/ 1
1/ 1 '
INCISORS: TOTAL MISSING/BROKEN MISALIGNED
2/ 1 2/ 1 0/ 0
0/ 0 0/ 0 0/ 0
0/ 0 0/ 0 0/ 0
13/ 1 6/ 1
13/ 1
CHROMODACRYORRHEA
0/ 0
0/ 0
3/ 1
9/ 1
LACRIMATION
0/ 0
0/ 0
0/ 0
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/ 1
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
-SH9Vdr*8Z0-8W
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE B2 (PAGE 1): NECROPSY OBSERVATIONS - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II III IV V
0 0.3
1 3 10
RATS EXAMINED a
N 15
15
15 15 15
MORTALITY
N0 0 0 0 0
APPEARED NORMAL
N 14
12
15 14 14
KIDNEYS:
BILATERAL, MOTTLED, MOTTLED TAN
AND RED OR MOTTLED DARK RED N
1
2
0 00
LEFT, PELVIS, SLIGHT DILATION N
0
1
0 00
EPIDIDYMIDES:
BILATERAL, SMALL
N0
0
0 10
LEFT CAUDA, SMALL
N0
0
0 10
TESTES :
BILATERAL, SMALL
N0
0
0 10
JEJUNUM:
DIVERTICULUM
N0
0
0 01
a. Refer to the individual clinical observations table (Table B17) for external observations confirmed at necropsy.
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE B3 (PAGE 1) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RATS TESTED
N
TERMINAL BODY WEIGHT
MEAN+S.D.
EPIDIDYMIS LEFT
MEAN+S.D .
CAUDA EPIDIDYMIS LEFT MEANS.D.
TESTIS LEFT
MEANS.D .
SEMINAL VESICLES WITH FLUID
MEANS.D .
SEMINAL VESICLES WITHOUT FLUID
MEANS.D .
EPIDIDYMIS RIGHT
MEANS.D .
TESTIS RIGHT
MEANS.D .
PROSTATE
MEANS.D .
BRAIN
MEAN+S.D .
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
I 0 10 ' 31.6 ; 0.0367 1 0.0294 . 0.0879
I 0.2370
) 0.1038 ; 0.0424 ' 0.0936 ! 0.2968 > 0.11
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
1.5473 0.3182
0.7670 0.1477 0.6106 0.1218 1.6175 0.3393 1.2734 0.1659
2.38 0.09
V 10 10 440.8 12.6 0.6134 0.0472 0.3041 0.0309 1.7483 0.1549
1.4424 0.2669
0.7772 0.1163 0.6261 0.0409 1.7604 0.1447 1.1918 0.2344
2.40 0.10
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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
MEANS.D .
469.7 + 31.6
448.8 + 37.8
LIVER
MEANS.D .
14.63 1.81
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 (p<0.05).
* * Significantly different from the Group I value (p<0.01).
III 1
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
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
MEANS.D .
469.7 + 31.6
EPIDIDYMIS LEFT
MEANS.D .
0.138 0.014
CAUDA EPIDIDYMIS LEFT MEANS.D .
0.068 0.009
TESTIS LEFT
MEANS.D .
0.354 + 0.024
SEMINAL VESICLES WITH FLUID
MEAN+S.D .
0.366 0.064
SEMINAL VESICLES WITHOUT FLUID
MEANS.D .
0.181 0.031
EPIDIDYMIS RIGHT
MEANS.D .
0.143 + 0.016
TESTIS RIGHT
MEANS.D .
0.357 0.030
PROSTATE
MEAN+S.D .
0.276 0.073
BRAIN
MEANS.D .
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 0.13 8 + 0 .Oil 0.068 0.008 0.397 0.041
0.348 0.073
0.359 + 0.063
0.329 0.081
0.326 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.
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1 )
TABLE B4 (PAGE 2) : RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II 0 0 .3
RATS TESTED
N 10
10
TERMINAL BODY WEIGHT
MEANS.D .
469.7 + 31.6
448.8 + 37.8
LIVER
MEANS.D .
3.109 0.264
3.165 0.208
KIDNEY LEFT
MEANS.D .
0.419 0.032
0.415 0.033
KIDNEY RIGHT
MEAN+S.D .
0.428 0.036
0.426 0.044
ADRENAL LEFT a
MEANS.D .
7.419 1.226
7.837 1.573
ADRENAL RIGHT a
MEANS.D .
7.202 1.181
7.587 1.353
SPLEEN
MEANS.D .
0.168 0.025
0.180 + 0.024
THYMUS
MEANS.D .
0.086 0.024
0.099 0.017
HEART
MEANS.D .
0.331 0.021
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^O.Ol).
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
6.680 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.
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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
MEAN+S.D .
2.40 + 0.11
EPIDIDYMIS LEFT
MEANS.D .
27.10 2.14
CAUDA EPIDIDYMIS LEFT MEAN+S.D.
13.83 + 1.28
TESTIS LEFT
MEANS.D .
69.36 4.17
SEMINAL VESICLES WITH FLUID
MEAN+S.D .
71.40 + 11.06
SEMINAL VESICLES WITHOUT FLUID
MEANS.D .
35.34 + 4.98
EPIDIDYMIS RIGHT
MEANS.D .
28.22 + 2.23
TESTIS RIGHT
MEAN+S.D .
70.19 + 5.17
PROSTATE
MEAN+S.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 + 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.
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
MEANS.D .
2.40 + 0.11
2.44 0.11
LIVER
MEANS.D . 611.89 + 79.55
584.43 68.39
KIDNEY LEFT
MEAN+S.D .
82.68 + 9.11
76.46 5.95
KIDNEY RIGHT
MEAN+S.D .
84.22 + 9.20
77.94 6.26
ADRENAL LEFT
MEANS.D .
1.46 + 0.27
1.44 0.31
ADRENAL RIGHT
MEANS.D .
1.41 0.25
1.40 0.26
SPLEEN
MEANS.D .
32.90 5.93
33.34 3.91
THYMUS
MEAN+S.D .
17.22 5.29
18.37 + 4.02
HEART
MEANS.D .
64.91 + 3.78
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
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1 )
TABLE B6 (PAGE 1) : 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
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 S.D. 8.1 0.52
7.9
* Significantly different from the Group I value (p<0.05).
* * Significantly different from the Group I value (p<0.01).
+ 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 3 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
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE B6 (PAGE 2) : 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 III 0.3 1 10 10
IV 3 10
V 10 10
PT (SECONDS)
MEAN S .D. 13.4 0.24
14.2 + 0.27** 13.6 0.23
13.8 0.40*
14.0 0.47**
APTT (SECONDS)
MEAN S.D. 21.0 3.09
22.1 4.41
20.6 2.38
21.2 2.24
21.3 1.43
NRBC COUNT
MEAN S.D. 0
0.0
0 0.0
0 0.0
0 0.0
0 0.0
Lymphocytes (THSN/CU MM) MEAN S.D. 11.9 1.72
11.0 2.68
10.8 2.02
12.1 + 3.57
12.4 2.75
Segmented (THSN/CU MM) MEAN S.D. 2.2 + 0.73
2.9 1.18
2.0 1.06
2.8 0.73
1.6 0.78
Bands (THSN/CU MM)
MEAN S.D. 0.0 + 0.00
0.0 0.00
0.0 0.03
0.0 0.03
0.0 + 0.00
Monocytes (THSN/CU MM) MEAN S.D. 0.8 0.56
0.7 + 0.50
0.6 0.51
0.8 0.67
0.5 0.33
Eosinophils (THSN/CU MM) MEAN + S.D. 0.3 + 0.20
0.3 0.21
0.3 0.21
0.3 0.26
0.2 0.15
Basophils (THSN/CU MM) MEAN S.D. 0.0 0.00
0.0 0.00
0.0 0.00
0.0 0.00
0.0 0.00
Abnormal L (THSN/CU MM) MEAN S.D. 0.1 0.20
0.1 0.14
0.1 0.07
0.2 0.22
0.1 0.21
418-028:PAGE B-10
Other (THSN/CU MM)
MEAN S.D. 0.0 0.00
0.0
* Significantly different from the Group I value (p<0.05).
** Significantly different from the Group I value (p<0.01).
0.00
0.0 0.00
0.0 0.00
0.0 0.00
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE B6 (PAGE 3): HEMATOLOGY - SUMMARY - Fo GENERATION MALE RATS
KEY TO HEMATOLOGY TABLE ABBREVIATION WBC
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
9 3DV<T-8Z0-8H7
Segmented
Segmented Neutrophils
Abnormal L
Abnormal Lymphocytes
Other
Other Cells
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 III 0.3 1 10 10
IV 3 10
V 10 10
TP (G/DL)
MEAN S.D.
6.3 0.36
6.1 0.28
6.3 0.33
6.2 0.28
6.3 0.28
A (G/DL)
MEAN S.D.
4.3 0.22
4.1 0.19
4.3 0.15
4.2 0.17
4.5 0.20**
GLU (MG/DL)
MEAN S.D.
145 16.8
141 26.0
182 58.2
162 25.2
165 33.7
CHOL (MG/DL)
MEAN S.D.
57 8.3
41 11.1**
46 + 11.6*
43 13.1**
33 7.2**
TBILI (MG/DL)
MEAN S.D.
0.2 0.07
0.1 0.05
0.1 0.06
0.1 0.05
0.2 0.06
BUN (MG/DL)
MEAN S.D.
16 1.5
16 0.8
16 + 1.8
17 1.6
21 2.4**
CREAT (MG/DL)
MEAN S.D.
0.3 0.04
0.3 0.05
0.3 0.06
0.3 0.03
0.3 0.05
CK (U/L)
MEAN S.D.
288 172.6
246 111.5
239 112.9
196 53.5
243 117.4
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
60 34.4
95 124.1
45 + 7.0
418-028:PAGEB-12
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 92.6 111 36.9 10.7 0.44 9.4 1.11
117 40.9 100 12.4 11.1 0.44 9.9 2.09
198 + 248.7 115 25.1 11.1 + 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)
MEAN S.D.
98 2.7
99 1.5
100 2.3
100 2.7
100 1.2
G (G/DL)
MEAN S.D.
2.0 0.19
2.0 + 0.16
2.0 0.24
2.0 0.16
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 ABBREVIATION TP 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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
MEANS.D .
342.7 + 12.6
DAY 8
MEANS.D .
382.7 22.2
DAY 14a
MEANS.D .
407.3 25.4
DAY 29b
MEAN+S.D .
456.6 + 38.9
DAY 36
MEANS.D .
480.2 + 38.2
DAY 43
MEANS.D .
490.5 + 37.2
TERMINAL BODY WEIGHT
MEANS.D .
472.5 + 33.9
DAY = DAY OF STUDY a. Last value recorded before cohabitation. b. First value recorded after cohabitation.
II 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
III 1
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
IV 3
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
V 10 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
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST1 (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)
I II 0 0.3
RATS TESTED
N 15
15
BODY WEIGHT CHANGE (G)
DAYS 1 - 8
MEANS.D .
+39.9 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
MEAN+S.D .
+10.3 10.8
+8.7 + 11.2
DAYS 29bTERMINATION
MEANS.D .
+15.9 + 11.7
+3.4 + 7.9**
DAYS 1 TERMINATION
MEAN+S.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 * * Significantly different from the Group I value
(p<0.05). (p<0.01).
III 1
15
+38.5 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**
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE BIO (PAGE 1) : ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I 0
RATS TESTED
N 15
FEED CONSUMPTION (G/DAY)
DAYS 1 - 8a
MEANS.D .
28.4 3.1
DAYS 29b- 36
MEAN+S.D .
30.2 2.6 [ 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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
MEAN+S.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 3.9 62.8 4.5
III 1
15
80.1 6.9 64.1 4.2
IV 3
15
78.2 61.7
4.3 3.7
V 10
15
74.7 63.2
3 .3 3 .6
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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)
15
15(100.0)
15/ 15 (100.0)
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE B13 (PAGE 1): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY) MALE RATS
I 0 N 10
II 0.3 10
III 1 10
IV 3 10
V 10 10
HOME CAGE BEHAVIOR 1 Sleeping 2 Awake, Immobile 3 Normal movement 4 Unusual posture 5 Unusual behavior
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 N N N N N
2 8 0 0 0
9 la 0 0 0 0 0
3 7 0 0 0
10 0 0 0 0 0 0
3 7 0 0 0
10 0 0 0 0 0 0
8** 2 2** 8 00 00 00
10 10 00 00 00 00 00 00
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
418-028:PAGE B-20
REACTION TO HANDLING
(1) No resistance
N 10
10
10
10
10
(2) Vocalization
N0
0
0
0
0
(3) Tense
N0
0
0
0
0
(4) Squirming
N0
0
0
0
0
MEAN SCORE
1.0
1.0
1.0
1.0
1.0
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
a. Excludes a value for rat 19131, which appeared incorrectly recorded.
** Significantly different from the Group I value (p<0.01).
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE B13 (PAGE 2): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS
i> 3 11111111111
11111111111 !j>H rVoi 1111111111
DOSAGE GROUP
I II III
DOSAGE (MG/KG/DAY)
0 0.3
1
MALE RATS
N 10
10
10
10
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
DEFECATION IN OPEN FIELD 1: None 2 : Feces normal 3: Soft or liquid feces
N N N
10 0 0
8 2 0
7 3 0
9 1 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
N 10
10
10
10
2 Stereotyped behavior
N
0
0
0
0
3 Bizarre behavior
N
0
0
0
0
4 Limb twitches/tremor
N
0
0
0
0
5 Whole body tremor/spasm
N
0
0
0
0
6 Unusual posture
N0
0
0
0
7 Tonic-clonic seizure
N
0
0
0
0
n = Category number for descriptive test item
10 0 0 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 B-21
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE B13 (PAGE 3): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS
o < 11111111111
ZZ~R39Vd;80'8It7
DOSAGE GROUP
I II III
DOSAGE (MG/KG/DAY)
0 0.3
1
MALE RATS
N 10
10
10
IV 3 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
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 (1) 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
2 : Exophthalmos
N
3 : Enophthalmos
N
n: = Category number for descriptive test item
10 0 0
10 0 0
10 0 0
10 0 0
10 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
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE B13 (PAGE 4): FUNCTIONAL <OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP
I II III
DOSAGE (MG/KG/DAY)
0 0.3
1
MALE RATS
N 10
10
10
IV 3 10
V 10 10
LACRIMATION
(1) No excess
N
(2) Excess at eyelid margin
N
(3) Margin persistently damp N
(4) Extends beyond margin
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
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 0 1.0
PILOERECTION
N0
0
0
0
0
ABNORMAL RESPIRATION
N
0
0
0
0
0
APPEARANCE
(1) Clean and groomed
N
(2) Unkempt
N
(3) Urine and/or fecal stain 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
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 2.0
0 10 0 0 0 2.0
0 10 0 0 0 2.0
(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 B-23
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE B13 (PAGE 5): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP
I II III
DOSAGE (MG/KG/DAY)
0 0.3
1
MALE RATS
N 10
10
10
IV 3 10 '
V 10 10
TACTILE REACTION
(1) None
N
(2) Orienting
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
0
0
0
0
(2) Orienting
N 10
10
10
10
10
(3) Startle
N0
0
0
0
0
(4) More energetic reaction
N
0
0
0
0
0
(5) Attacks
N0
0
0
0
0
MEAN SCORE
2.0
2.0
2.0
2.0
2.0
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-24
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE B13 (PAGE 6): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP
I II III
DOSAGE (MG/KG/DAY)
0 0.3
1
MALE RATS
N 10
10
10
IV 3 10
V 10 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 0 0 1.0
PUPIL RESPONSE TO LIGHT
N
10
10
10
10
10
FORELIMB GRIP TEST Maximum (G) Average (G)
MEAN+S.D. 444.0 49.6 MEAN+S.D. 410.5 52.7
451.5 57.5 400.6 62.7
456.0 111.1 409.4 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
465.5 36.8
477.1 58.8
493.2 36.6
461.9
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
13.0
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 52.8 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 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:PAGE B-26
PROTOCOL 4 1 8-0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 26.2 33.3 28.5 54.3 44.2 60.8 46.2 68.7 59.5 46.2 56.7 58.7 49.7 45.1 38.5 + 39.6 453.9
201.8 174.4 140.3 138.3 131.1
89.7 90.2 83.7 80.9 86.6 71.4 67.1 86.9 75.7 53.1 55.5 62.5 47.4 1736.6
17.8 32.9 + 63.3 53.0 71.4 52.6 55.5 55.9 40.5 40.3 63.0 + 60.9 82.2 55.9 46.5 + 47.5 56.4 + 46.1 607.9
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
III 1
10
214.8 195.8 172.5 142.4 150.3 118.4 110.2 109.9
93.6 77.4 86.0 91.7 52.1 54.1 68.0 60.3 46.9 56.3 1900.7
13.0 33.8 35.6 + 24.7 20.6 41.2 46.9 52.7 59.3 55.3 49.1 62.1 44.8 47.4 65.3 73.9 53.5 54.7 469.7
IV 3
10
204.6 23.7 180.2 20.9 140.6 27.5 140.9 34.1 119.2 29.0 109.7 + 48.8 118.6 45.9 116.1 50.9 103.6 56.4
83.1 47.0 97.7 61.8 81.1 49.1 80.2 41.2 107.8 40.9 74.2 35.4 87.2 43.5 91.4 49.7 66.9 43.5 2003.1 453.4
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 68.2 51.0 44.8 54.1 41.8 1741.6 463.4
418-028`.PAGE B-27
PROTOCOL 418-0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY
SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
*
TABLE B15 (PAGE 1): SPERM MOTILITY, COUNT AND DENSITY - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP
I II III IV V
DOSAGE (MG/KG/DAY)
0 0.3
1
3 10
RATS TESTED
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
MEAN+S.D . 92.1 3.1
93.3 2.8
92.5 3.4
85.5 22.3
91.1 7.4
STATIC COUNT (NONMOTILE)
MEAN+S.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 MEAN+S.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 count by the volume in the image area (34.3 x 10~6 mL) , multiplying by 2
(dilution factor) and multiplying by 10"6 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.
8-aaDVd80-8lfr
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 . MEANS.D . MEAN+S.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
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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
0.3 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. O bservation confirm ed a t necropsy.
418-028:PAGE B-30
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 . O bservation confirm ed a t necropsy.
418-028:PAGE B-31
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 CHROMORHINORRHEA INCISORS : MISSING/BROKEN CHROMORHINORRHEA NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS
ZttBDV&ZZQ'm
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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.
418-028:PAGE B-33
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 CM X 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 1.4801 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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. W T . % TBW
THYMUS
ABS. REL. WT . % TBW
HEART
ABS. REL. WT. % TBW
19109 19115 19116 19119 19122 19125 19131 19132 19134 19135
438 ., 466.. 490 . 505 . 451.. 508.. 499.. 439.. 419 . 482 .
0.027 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. WT. = ORGAN WEIGHT.
REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100.
418-028:PAGE B-39
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
19102 19106 19108 19110 19113 19120 19129 19136 19138 19139
428 . 476 . 474 . 453 . 444 . 486. 435. 495 . 365. 432 .
EPIDIDYMIS
LEFT
ABS. REL. WT. % TBW
CAUDA EPIDIDYMIS
LEFT
ABS. REL. WT. % TBW
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
TESTIS LEFT
ABS. REL. WT. % TBW
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
SEMINAL VESICLES WITH FLUID
ABS. REL. WT. % TBW
SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % TBW
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
EPIDIDYMIS RIGHT
ABS. REL. WT. % TBW
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. 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
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 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-40
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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. REL. WT. % 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.
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 :FLUID
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
19101 19105 19107 19112 19114 19121 19123 19130 19137 19146
353 . 505 . 437 . 452. 430. 567. 464 . 434 . 443 . 473 .
TESTIS RIGHT ABS. :REL. WT. % TBW
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
PROSTATE
ABS. WT.
REL.
% TBW
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
BRAIN
ABS. REL. WT. % TBW
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
LIVER
ABS. REL. WT. % TBW
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
KIDNEY LEFT
ABS. REL. WT. % TBW
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
KIDNEY RIGHT ABS. REL. WT. % TBW
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. WT. = ORGAN WEIGHT.
a. Damaged during processing (weight not affected).
REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100.
418-028:PAGE B-42
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 . 452 . 430 . 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. WT. = ORGAN WEIGHT.
REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100.
418-028:PAGE B-43
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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.
REL,. % TBW = (ORGAN WEIGHT/TERMINAL BODY 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-44
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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:PAGEB-45
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
19111 19117 19124 19126 19127 19128 19140 19145 19149 19152
432. 462 . 426. 426 . 434 . 445 . 442 . 441. 439. 461.
EPIDIDYMIS LEFT
ABS. REL. WT. % TBW
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
CAUDA EPIDIDYMIS LEFT
ABS. REL.
WT. % TBW
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
TESTIS
LEFT
ABS. REL. WT. % TBW
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
SEMINAL VESICLES WITH :FLUID
ABS. REL. WT. % TBW
SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % TBW
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
EPIDIDYMIS RIGHT
ABS. REL. WT. % TBW
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/TERMINAL BODY WEIGHT) X 100.
418-028:PAGE B-46
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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. WT. % TBW
THYMUS
ABS. REL. WT. % TBW
HEART
ABS. REL. WT. % TBW
19111 19117 19124 19126 19127 19128 19140 19145 19149 19152
432 . 462 . 426. 426. 434. 445 . 442 . 441. 439. 461.
0.025 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
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
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
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-47
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1 )
TABLE B20 (PAGE 1) : 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
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
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 0.7764 0.9312 0.9106 0.8672
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. % 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
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 1.99 2.16 2.26 1.92 2.31 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 d u r in g p r o c e s s in g (w e ig h t n o t a f f e c t e d ) .
REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
418-028:PAGEB-48
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE B20 (PAGE 2): ORGAN WEIGHTS AND RATIOS (%)1 OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP I
0 MG/KG/DAY
RAT NUMBER
BRAIN WEIGHT
ADRENAL RIGHT
ABS. REL. WT. % BRW
SPLEEN
ABS. REL. W T . % BRW
THYMUS
ABS. REL. WT . % BRW
HEART
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
0.027 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
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
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
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.
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 0.046 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 s lig h t d ila t io n o f th e p e lv is o f th e l e f t kidney. See th e in d iv id u a l necropsy o b serv a tio n s ta b le (Table B 1 8 ).
0S"9 39Vd;80'8It7
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY
SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
ADRENAL RIGHT
ABS. REL. WT. % BRW
SPLEEN
ABS. REL. WT. % BRW
THYMUS
ABS. REL. WT. % BRW
HEART
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
0.038 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
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
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
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.
"9 3O V d :860_8lfr
0 /1
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 40.80 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
1.26 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. WT. = ORGAN WEIGHT.
a . Damaged d u rin g p r o c e s s in g (w eight n o t a f f e c t e d ) .
REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
418-028:PAGE B-52
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7 7 0 6 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
ADRENAL RIGHT
ABS. REL. WT. % BRW
SPLEEN
ABS. WT.
REL. % BRW
THYMUS
ABS. REL. WT. % BRW
HEART
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
0.026 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
0.55 0.74 0.69 0.65 0.68 0.92 0.78 0.87 0.91 0.80
24.77 30.83 29.36 26.97 28.81 36.22 32.10 36.71 37.14 35.40
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 12.39
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. WT. = ORGAN WEIGHT .
REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
418-028'.PAGE B-53
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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. %r 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
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
75.83 100.42
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 1.23 1.24 1.74 0.95 1.26 1.54 1.25 1.57
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
ABS. WT. = 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
ADRENAL RIGHT
ABS. REL. WT. % BRW
SPLEEN
ABS. REL. WT. % BRW
THYMUS
ABS. REL. WT. % BRW
HEART
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
0.032 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
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
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
ABS. WT. = ORGAN WEIGHT'.
REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
418-028:PAGE B-55
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 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
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 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
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
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. WT. = ORGAN WEIGHT.
a . Damaged d u r in g p r o c e s s in g (w e ig h t n o t a f f e c t e d ) .
REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 1 0 0 .
1.01 1.23 1.47 1.27 1.18 1.56 1.49 1.42 1.22 1.54
418-028:PAGE B-56
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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. WT. % BRW
SPLEEN
ABS. REL. W T . % BRW
THYMUS
ABS. REL. W T . % BRW
HEART
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
0.024 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. WT. ORGAN WEIGHT.
REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 6 7 8 9 10 11 12 13 14a 15 16
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.
352 . 388 . 378. 394 . 346. 392 . 384 . 356. 356. 391. 358 . 378 . 362 . 411. 365.
357. 385. 385. 400 . 350 . 400. 388. 361. 358. 393 . 363 . 380. 363 . 417 . 372 .
359. 393 . 388. 414 . 354 . 409. 388. 359. 358. 398. 366. 387. 370. 424 . 373 .
355 . 402 . 389. 420 . 358. 414 . 403 . 353 . 366. 395. 365. 389. 369. 425 . 382 .
363 . 408 . 394 . 424 . 366. 420 . 400. 363 . 367. 398. 374 . 392. 377. 416. 382 .
370. 412 . 402 . 431. 372 . 428 . 407. 363 . 370. 408. 381. 400 . 378 . 436. 388.
374 . 417 . 402 . 446 . 379. 431. 407 . 369. 373 . 403 . 381. 404 . 384 . 433 . 391.
380. 423 . 408. 450. 380. 436. 419. 370 . 373 . 416. 387. 407 . 394 . 436. 391.
380. 427. 403 . 454 . 382 . 440 . 417. 376. 380 . 417 . 390. 406. 393 . 446 . 399.
376. 422 . 410. 449. 389. 435. 418. 376. 357. 416. 387. 404 . 384. 449. 396.
384 . 430 . 416. 452 . 396 . 435 . 418 . 376 . 378 . 424 . 388 . 408 . 392 . 457 . 401.
DAY 17 18 19 20 21 22 23 24 25 26 27 28 29b 30 31 32
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 .
398 . 455. 432 . 485. 409. 452 . 440 . 406. 381. 440 . 407. 428 . 409. 499. 378 .
396. 458. 442 . 483 . 413 . 465 . 447 . 407 . 381. 442 . 413 . 430. 411. 502 . 368.
403 . 460. 448 . 492 . 420. 471. 450 . 406. 387. 446. 414 . 434. 420 . 508. 363 .
406. 465. 448 . 494 . 419. 478 . 456. 418. 388. 449 . 417. 446. 424 . 517. 373 .
409. 463 . 452 . 504 . 421. 482 . 458 . 420. 394 . 453 . 426. 445. 429. 518. 389.
420 . 462 . 461. 513 . 426 . 486. 470 . 424 . 396. 464 . 432 . 450. 432 . 532 . 396.
420. 453 . 469. 511. 432 . 489. 470 . 426. 404 . 465. 440 . 452 . 409. 539. 405.
421. 472 . 462 . 504 . 432 . 491. 479 . 428 . 404 . 468. 435. 463 . 438. 546. 406.
427 . 469. 466. 510 . 434 . 493 . 479 . 428. 406. 469. 440 . 461. 434 . 544 . 414 .
430. 479. 476. 518. 440 . 500. 484 . 431. 415. 470 . 444 . 457 . 439. 548. 398.
435 . 472 . 479. 516. 441. 498. 494 . 438 . 419. 477 . 453 . 464 . 441. 555 . 421.
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-58
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 11 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.
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 .
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-60
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE B21 (PAGE 4): BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DOSAGE GROUP II
0.3 MG/KG/DAY
DAY 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47
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 .
455. 499. 489. 462 . 458. 509. 450. 513 . 389. 451. 478 . 495. 501. 470 . 428.
450. 501. 479 . 471. 456. 493 . 440. 504 . 382 . 451. 469. 498. 504 . 473 . 431.
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.
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 .
486. 435. 495 . 396. 464 . 499. 513 . 517. 489. 444 .
365. 432 . 498 . 506. 521. 492 . 453 .
470 . 487 . 484 . 455. 421.
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G).
418-028:PAGEB-61
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 11 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE B21 (PAGE 7): BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DOSAGE GROUP IV
3 MG/KG/DAY
DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14a 15 16
19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166
332 . 363 . 351. 342 . 338. 363 . 334 . 348. 336. 356. 333 . 351. 331. 350. 356.
332 . 363 . 360. 352. 338. 374 . 338. 357. 343 . 360. 330 . 351. 333 . 356. 359.
341. 379. 366. 358 . 339. 382 . 345. 368 . 342 . 372 . 333 . 364 . 334. 364 . 373 .
344 . 386. 375. 362 . 347 . 391. 354 . 378. 355. 377. 337 . 375 . 338. 368. 385.
348. 393 . 383 . 363 . 354 . 396 . 363 . 386. 360. 384 . 346 . 376. 341. 379. 388.
356. 403 . 389. 370 . 357. 406. 368. 393 . 366. 390. 358 . 388 . 344 . 387. 398.
363. 415 . 398. 374 . 362 . 414 . 374 . 405. 376. 391. 361. 395. 347. 393 . 404 .
363 . 417 . 401. 376. 364 . 422 . 379. 410 . 378. 396. 360. 392 . 351. 394. 396.
366. 428 . 405. 380 . 368. 426 . 389. 418. 388 . 399. 368 . 392 . 352 . 401. 415.
366 . 425. 400 . 383 . 372 . 431. 387. 422 . 378 . 395 . 366. 396. 354 . 405. 416 .
378. 434 . 408 . 389. 384 . 438 . 391. 434 . 388. 404 . 384 . 404 . 358 . 418 . 430 .
377. 436. 412 . 394 . 393 . 451. 398 . 436. 389. 407 . 386. 401. 369. 412 . 430.
376. 439. 412 . 397. 393 . 450 . 400 . 430. 393 . 410. 382 . 412 . 366. 410 . 439.
381. 446. 423 . 399. 388. 457 . 410 . 436. 398. 411. 394 . 417 . 369. 422 . 443 .
375 . 435. 426 . 399. 386. 452 . 407 . 434 . 395. 406. 385. 396. 365. 412 . 437.
382 . 441. 432 . 394 . 395 . 466 . 415 . 437 . 403 . 419 . 395 . 417 . 372 . 419 . 447 .
DAY
19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166
17
390. 451. 438. 398. 395. 462 . 420. 435 . 405 . 418. 396. 421. 377 . 429. 456 .
18
391. 458. 439. 406. 404 . 473 . 425 . 451. 412 . 427. 392. 424 . 376. 434 . 460 .
19
396. 457. 436 . 409. 410 . 476 . 431. 444 . 417 . 432 . 402 . 427. 381. 438 . 465 .
20
400. 470 . 452 . 419. 415 . 476 . 435 . 456 . 421. 441. 411. 434 . 382. 453 . 473 .
21
403 . 468 . 454 . 425 . 421. 486. 441. 459 . 421. 440 . 411. 437 . 390. 455. 480 .
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 .
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-64
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE B21 (PAGE 8): BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DOSAGE GROUP IV
3 MG/KG/DAY
DAY 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47
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 .
445. 508 . 497. 457. 457. 556. 510. 539. 482 . 470 . 446. 485. 429. 494 . 519.
447. 513 . 499. 459 . 464 . 557. 497. 533 . 482. 472 . 450. 488 . 427. 492. 525.
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.
449. 511. 502 . 464 . 470 . 567. 500. 547. 485. 478. 452 . 483 . 435. 500. 522 .
454 . 516. 506. 469 . 475 . 564 . 504 . 552 . 486. 481. 457 . 481. 434 . 503 . 523 .
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.
545 . 479. 523 . 495 . 479 . 455 . 493 . 449. 513 . 531.
454 . 448. 460 . 491. 445 . 512 . 537.
433 . 461. 415 . 486. 506.
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G).
418-028:PAGE B-65
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 11 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:PAGE B-66
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE B21 (PAGE 10): BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DOSAGE GROUP V
10 MG/KG/DAY
DAY 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47
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 .
457. 477 . 448. 429. 444 . 473 . 464 . 460 . 453 . 464 . 479 . 461. 417. 485. 460 .
456. 481. 445 . 438. 454 . 463 . 454 . 463 . 460. 463 . 477 . 458 . 423 . 485 . 462 .
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 .
466. 483 . 450. 452 . 470 . 470. 469. 471. 459 . 483 . 496. 469. 416. 486. 457 .
432 . 462 . 426 . 452 . 467. 481. 473 . 473 . 462. 485. 490. 474 . 416. 479 . 459.
426. 434 . 486. 486. 477 . 466. 498 . 496. 461. 421. 477. 463 .
445 . 442 . 466. 468 . 491. 498 . 478 . 421. 482 . 467 .
441. 439. 461. 498 . 471. 425 . 480. 471.
466. 453 . 402 . 448 . 445 .
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G).
418-028:PAGE B-67
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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:PAGEB-68
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE B22 (PAGE 2) : FEED CONSUMPTION VALUES - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DAYS l- 8a :29b-36
RAT #
DOSAGE GROUP III
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:PAGEB-69
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171
4 1 1 2 4 1 2 1 1 4 1 1 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(19036) P(19037) P (19043) P(19047) P(19048) P (19052) P(19055) P (19061) P (19067) P (19071)
418-028:PAGE B-71
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 (19039) P (19040) P (19045) NP (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 1 4 1 4 1 1 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE B24 (PAGE 1) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP I RAT # HOME CAGE BEHAVIOR ALTERATIONS (HOME CAGE) REACTION TO REMOVAL REACTION TO HANDLING REARS IN OPEN FIELD DEFECATION IN OPEN FIELD URINATION IN OPEN FIELD LEVEL OF AROUSAL ALTERATIONS (OPEN FIELD) GAIT PATTERN GAIT ABNORMALITY, SEVERITY PALPEBRAL CLOSURE PROMINENCE OF THE EYE LACRIMATION SALIVATION PILOERECTION ABNORMAL RESPIRATION APPEARANCE VISUAL REACTION TACTILE REACTION AUDITORY REACTION TAIL-PINCH REACTION AIR RIGHTING RESPONSE PUPIL RESPONSE TO LIGHT FORELIMB GRIP TEST #1 (G) FORELIMB GRIP TEST #2 (G) HINDLIMB GRIP TEST #1 (G) HINDLIMB GRIP TEST #2 (G) LANDING FOOT SPLAY #1 (CM) LANDING FOOT SPLAY #2 (CM) BODY WEIGHT (G)
19109 2 1 1 1 2 1 2 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1
355 460 450 415 6.7 6.8 452
19115 2 1 1 1 5 1 1 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1
460 510 320 380 9.8 7.6 487
19116 2 1 1 1 3 1 1 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1
500 420 620 690 8.8 7.7 495
19119 2 1 1 1 4 1 2 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1
360 395 315 220 7.9 7.6 527
19122 2 1 1 1 3 1 1 3 1 1 1 1 1 1 1 0 0 lb 2 2 3 2 1 1
340 375 315 330 4.5 5.7 464
0I MG/KG/DAY
19125
19131
19132
2 12
1 2a 1
1 11
1 11
6 11
1 11
2 12
3 33
1 11
1 11
1 11
1 11
1 11
1 11
1 11
0 00
0 00
1 11
2 22
2 22
3 33
2 22
1 11
1 11
470 315 415
350 465 465
490 255 300
390 255 325
8.5 7.8 8.0
7.1 7.2 6.8
529 507 445
19134 2 1 1 1 8 1 1 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1
295 430 280 250 7.7 7.5 433
VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THeT bAtT eRy".'
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE B24 (PAGE 2) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP II
01.3 MG/KG/DAY
RAT # HOME CAGE BEHAVIOR ALTERATIONS (HOME CAGE)
19102 2 1
19106 2 1
19108 2 1
19110 2 1
19113 2 1
19120 2 1
19129 2 1
19136 1 1
19138 1 1
REACTION TO REMOVAL
1 111 1111 1
REACTION TO HANDLING
1 111 1111 1
REARS IN OPEN FIELD
11 8 3 11 9 4 4 3 4
DEFECATION IN OPEN FIELD 1 1 1 1 2 2 1 1 1
URINATION IN OPEN FIELD
2 1222222 2
LEVEL OF AROUSAL
3 3333333 3
ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1
GAIT PATTERN
1 1111111 1
GAIT ABNORMALITY, SEVERITY
1
1
1
1
1
1
1
1
1
PALPEBRAL CLOSURE
11111111 1
PROMINENCE OF THE EYE
11111111 1
LACRIMATION SALIVATION PILOERECTION
11111111 1 11111111 1 00000000 0
ABNORMAL RESPIRATION APPEARANCE VISUAL REACTION TACTILE REACTION AUDITORY REACTION TAIL-PINCH REACTION
0 0000000 0 11111111 1 2 2222222 2 22222222 2 33333333 3 22222222 2
AIR RIGHTING RESPONSE PUPIL RESPONSE TO LIGHT
11111111 1 11111111 1
FORELIMB GRIP TEST #1 (G) 355 375 395 415 455 245 250a 505 215 FORELIMB GRIP TEST #2 (G) 400 490 360 470 465 410 365 390 465 HINDLIMB GRIP TEST #1 (G) 345 435 610 365 315 250 315 155 435 HINDLIMB GRIP TEST #2 (G) 460 505 575 450 520 550 345b 220 365
LANDING FOOT SPLAY #1 (CM)
11.6
9.5
7.6
8.0
6.8
6.2 12.5 7.6
8.0
LANDING FOOT SPLAY #2 (CM)
9.7
8.4
6.5
7.8
6.5
4.8 12.7 7.8
9.2
BODY WEIGHT (G)
444 489 490 467 464 496 443 517 385
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.
19139 1 1 1 1 5 1 2 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1
435 550 465 335 9.9 11.5 460
418-028:PAGEB-75
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE B24 (PAGE 3) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP III RAT # HOME CAGE BEHAVIOR ALTERATIONS (HOME CAGE) REACTION TO REMOVAL REACTION TO HANDLING REARS IN OPEN FIELD DEFECATION IN OPEN FIELD URINATION IN OPEN FIELD LEVEL OF AROUSAL ALTERATIONS (OPEN FIELD) GAIT PATTERN GAIT ABNORMALITY, SEVERITY PALPEBRAL CLOSURE PROMINENCE OF THE EYE LACRIMATION SALIVATION PILOERECTION ABNORMAL RESPIRATION APPEARANCE VISUAL REACTION TACTILE REACTION AUDITORY REACTION TAIL-PINCH REACTION AIR RIGHTING RESPONSE PUPIL RESPONSE TO LIGHT FORELIMB GRIP TEST #1 (G) FORELIMB GRIP TEST #2 (G) HINDLIMB GRIP TEST #1 (G) HINDLIMB GRIP TEST #2 (G) LANDING FOOT SPLAY #1 (CM) LANDING FOOT SPLAY #2 (CM) BODY WEIGHT (G)
19101 2 1 1 1 3 2 2 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1
215 175 520 545 8.2 6.7 375
19105 2 1 1 1 3 1 2 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1
500 430 480 580 8.7 7.5 532
19107 2 1 1 1 7 2 2 3 1 1 1 1 1 1 1 0 0 la 2 2 3 2 1 1
480 545 540 415 9.7 10.3 459
19112 2 1 1 1 2 1 1 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1
490 400 415 525 6.8 7.5 482
19114 2 1 1 1 2 1 2 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1
270 430 395 395 9.0 8.8 439
1 MG/KG/DAY
19121
19123
22
11
11
11
32
12
11
33
11
11
11
11
11
11
11
00
00
11
22
22
33
2 2b
11
11
550 405
395 395
465 375
475 490
11.8
8.5
10.2
9.5
601 476
19130 1 1 1 1 5 1 1 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1
395 515 280 435 9.7 7.8 457
19137 1 1 1 1 6 1 1 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1
340 330 305 255 11.1 10.7 467
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.
19146 1 1 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 7.6 483
418-028:PAGE B-76
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE B24 (PAGE 4): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP IV RAT # HOME CAGE BEHAVIOR
19100 2
19103 2
19104 2
19118 2
19133 2
3 MG/KG/DAY
19141
19142
21
19144 2
19148 2
ALTERATIONS (HOME CAGE) REACTION TO REMOVAL
1111 1111 1 1111 1111 1
REACTION TO HANDLING
1111 1111 1
REARS IN OPEN FIELD
7614 4267 3
DEFECATION IN OPEN FIELD 1 2 1 1 1 1 1 1 1
URINATION IN OPEN FIELD
2212 2122 2
LEVEL OF AROUSAL
3333 3333 3
ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1
GAIT PATTERN
11111111 1
GAIT ABNORMALITY, SEVERITY
1
1
1
1
1
1
1
1
1
PALPEBRAL CLOSURE
1111 1111 1
PROMINENCE OF THE EYE
1111 1111 1
LACRIMATION
1111 1111 1
SALIVATION
1111 1111 1
PILOERECTION
0000 0000 0
ABNORMAL RESPIRATION
0000 0000 0
APPEARANCE
1111 1111 1
VISUAL REACTION
2222 2222 2
TACTILE REACTION
22222222 2
AUDITORY REACTION
3333 3333 3
TAIL-PINCH REACTION
2222 2222 2
AIR RIGHTING RESPONSE
1 1 1 1 1 1 lb 1 1
PUPIL RESPONSE TO LIGHT
1111 1111 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
2 2 212 2 2 22
ALTERATIONS (HOME CAGE)
1 1 111 1 11 1
REACTION TO REMOVAL
1 1 111 1 11 1
REACTION TO HANDLING
111111 111
REARS IN OPEN FIELD
6 6282 0 65 9
DEFECATION IN OPEN FIELD 1 1 1 1 2 1 1 1 1
URINATION IN OPEN FIELD
22 1221222
LEVEL OF AROUSAL
3 3 333 3 33 3
ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1
GAIT PATTERN
1 1 111 1 11 1
GAIT ABNORMALITY, SEVERITY
1
1
1
1
1
1
1
1
1
PALPEBRAL CLOSURE
1 1 111 1 1 11
PROMINENCE OF THE EYE
1 1 111 1 111
LACRIMATION
11 111 1 111
SALIVATION
1 1 111 1 111
PILOERECTION
0 0 0000 000
ABNORMAL RESPIRATION
0 0 000 0 0 00
APPEARANCE
1 1 111 1 11 1
VISUAL REACTION
2 2 222 2 222
TACTILE REACTION
2 2 222 2222
AUDITORY REACTION
3 3 333 3 33 3
TAIL-PINCH REACTION
2 2 2222 222
AIR RIGHTING RESPONSE
11 1111 111
PUPIL RESPONSE TO LIGHT
11 1111 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 1 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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:PAGEB-!
OO
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 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
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
240 238 223 209 214 157 153 117 116 137 177 146 190 114 28
1 0 2 2462
19136
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
8"9 3QVd:80"8Il7
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 81 111 98 65 138 211 23
1 2426
19146
207 195 206 122 134 135 92 127 76
0 62 110 2 73 1 1 76 97 1716
418-028:PAGE B-84
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 18 136 111 134 127 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
19150
211 183 175 174 145 187 113 161 109 77 148 128 76
153
82 110 79 119 2430
,
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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'.PAGE B-87
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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.)
RAT NUMBER DOSAGE GROUP I 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 DOSAGE GROUP II 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139
NUMBER MOTILE
276 254 323 328 210 256 375 302 235 332
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 COUNT b
166 190 159 178 126 121 271 222 156 112
139 149 232 101 177 220 231 95 148 90
SPERM DENSITY c
1701.6 1598.6 1433.3 1475.8 978.7 1073.7 2496.6 1743.2 1339.9 1101.2
1402.5 1455.1 1916.4 1051.3 1515.3 1983.2 2100.6 853.7 1187.9 836.0
418-028:PAGE B-89
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 19100 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 COUNT b
163 186 121 173 130 248 164 190 114 121
141 171 131 86 143 217 33 88 119 117
SPERM DENSITY C
1575.4 1593.3 1312.4 1564.4 1290.1 2163.4 1401.9 1564.5 951.2 1002.3
1215.7 1700.4 1279.8 823.2 1397.0 2026.2 716.1 1006.6 893.9 1087.9
418-028`.PAGE B-90
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1 )
TABLE B26 (PAGE 3): SPERM MOTILITY, COUNT AND DENSITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT
NUMBER
MOTILE
STATIC COUNT
TOTAL
SPERM
SPERM
NUMBER
MOTILE
PERCENT
(NONMOTILE)
COUNT a
COUNT b
DENSITY C
DOSAGE GROUP V
10 MG/KG/DAY
19111
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 1794.7
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`6 mL), multiplying by 2
(dilution factor) and multiplying by 10`6 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.
418-028:PAGEB
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 1 1 3 3 8 6 3 3 3
NO HEAD
7 4 4 2 5 2 2 4 2 2
4 1 2 3 1 2 4 1 1 2
BROKEN FLAGELLUM
1 0 0 0 0 1 0 0 1 1
2 1 1 2 0 0 1 0 1 0
BENT FLAGELLUM
0 0 0 0 0 0 1 1 0 0
0 1 1 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 8.0 3.0 1.0
418-028:PAGE B-93
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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
1 1 1 2 2 5 1 1 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
to H oO
PERCENT ABNORMAL
1.5 4.0
5.5 4.5 4.5 2.0 4.0 4.5
418-028:PAGE B-94
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
00
00
BROWN PERIORAL SUBSTANCE
0/ 0
0/ 0
0/ 0
0/ 0
RALES
0/ 0
0/ 0
0/ 0
0/ 0
LOCALIZED ALOPECIA: TOTAL HEAD LIMBS
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
0/ 0
0/ 0
0/ 0
0/ 0
COLD TO TOUCH
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 G
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1 )
TABLE Cl (PAGE 2): CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II III IV
0 0.3
13
PRESUMED GESTATION: a
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
7/ 1 0/ 0 0/ 0 0/ 0
418-028 :PAGE C-2
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE Cl (PAGE 3): CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II III IV
0 0.3
13
MAXIMUM POSSIBLE INCIDENCE
330/ 15
330/ 15
286/ 13
286/ 13
LACTATION:
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
"D HOVd:80"8Il7
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C2 (PAGE 1): NECROPSY OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II III IV V
0 0.3
1 3 10
RATS EXAMINED a
N 15
15
15 15 15
MORTALITY
N0 0 0 0 0
APPEARED NORMAL
N 15
15
14 13 14
KIDNEYS:
RIGHT, CORTEX ADHERED TO RIGHT
LATERAL LIVER LOBE
N0
0
1 00
OVARIES: LEFT, SMALL
N0
0
0 10
SPLEEN:
OMENTUM ADHERED TO THE LENGTH
OF THE OUTER CAPSULE
N0
0
0 10
LARGE AND SMALL INTESTINES:
DISTENDED WITH GAS
N0
0
0 01
THYMUS : SMALL
N0 0 0 0 1
SPLEEN: SMALL
N0 0 0 0 1
ADRENALS:
BILATERAL, LARGE
N0
0
0 01
STOMACH:
FUNDIC MUCOSAL SURFACE CONTAINED
APPROXIMATELY 12 BLACK AREAS N
0
0
0 01
a. Refer to the individual clinical observations table (Table C27) for external observations confirmed at necropsy.
418-028:PAGE C-4
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 15
TERMINAL BODY WEIGHT
MEAN+S.D.
306.3 26.0
BRAIN LIVER KIDNEY LEFT KIDNEY RIGHT ADRENAL LEFT ADRENAL RIGHT SPLEEN THYMUS OVARY LEFT
MEAN+S.,D . MEAN+S.,D . MEANS.,D . MEANS.,D. MEANS.D . MEAN+S.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 [ 10] a
0.63 0 .08 C 10] a
0.21 + 0 .07 [ 10] a
0.055 0. 014
OVARY RIGHT
MEAN+S .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 C 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. 011 [ 10] a
0 .60 0 .11 [ 10] a
0 .18 + 0 .04 [ 10] a
0 .053 0. 014
0. 060 0. 021
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 [ 10] a
0. 049 0 .006 [ 10] a
0 .75 0 .31 ( 10] a
0 .20 + 0 .10 ( 10] a
0. 053 0. 012
0. 054 0. 012
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 0. 008 [ 10] a
0 .54 0 .10 [ 10] a
0 .18 + 0 .04 [ 10] a
0. 054 0. 015
0. 054 0. 018
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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. MEAN+S,.D . MEANS.D . MEANS,.D. MEANS,.D. MEANS.D. MEANS .D.
0..711 + 0..062 [ 10] a
4 .703 0..450 C 10] a
0..459 0,.049 [ 10] a
0..482 0 .043 [ 10] a
17..095 2 .132 C 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 rats were tested. b. Value was multiplied by 1000.
II III IV 0.3 1 3
V 10
15 15 15 15
15 13 13 15
324.3 27.1
311.2 + 35.0
319.6 40.4
303.5 37.9
0..659 + 0,.055 [ 10] a
4 .947 0,.703 [ 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
C 10] a 0,.065 0 .018
[ 10] a 17,.632 + 6 .782
0..684 0,.082 [ 10] a
4 .697 + 0,.512 ( 10] a
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 t 10] a
15..743 2 .727 [ 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
c 10] a 0,.181 0 .026
[ 10] a 0 ,.059 0 .016
[ 10] a 17 ,.611 + 3 .620
18 .514 + 5 .844
19 .152 6 .400
17,.025 3 .632
17,.529 5 .247
0 .175 0 .042
0 .162 0 .046
0..198 0 .063
0,.185 + 0 .055
0 .392 0 .057 [ 10] a
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 BRAIN WEIGHT LIVER KIDNEY LEFT KIDNEY RIGHT ADRENAL LEFT
N MEANS.D . MEANS.D . MEANS.D . MEANS.D . MEAN+S.D .
10 2.16 + 0.08
664.58 96.72 64.31 5.18
67.75 + 4.49
2.42 + 0.42
10
2.11 0.09
757.16 127.78
69.72 + 4.89
71.72 6.50 2.40 0.35
ADRENAL RIGHT
MEANS.D .
1.98 0.31
1.95 + 0.46
SPLEEN
MEAN+S.D .
29.20 + 3.42
30.95 4.47
THYMUS
MEANS.D .
9.72 + 3.12
9.96 2.95
OVARY LEFT
MEAN+S.D .
2.68 0.75
2.85 0.84
OVARY RIGHT
MEANS.D .
2.83 + 0.72
3.09 + 0.93
UTERUS WITH CERVIX
MEANS.D .
26.20 + 4.17
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 2.10 + 0.09
10
2.08 0.18
10
2.12 0.10
701.88 155.49
65.73 6.72 68.95 7.09
729.66 165.57
71.48 6.75* 73.35 5.96
641.86 141.49
65.57 3.88 66.53 5.96
2.44 0.39 2.39 0.48
2.54 0.58
2.36 0.40
2.49 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 24.14 6.72
64.03 5.41
2.55 0.57
31.96 7.43 67.44 6.68
2.37 0.89
27.71 6.59 62.58 10.73
RATIOS {%) = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
418-028:PAGE C-8
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C6 (PAGE 1): HEMATOLOGY - SUMMARY - Fo GENERATION FEMALE RATS (See abbreviations on the last page of this table.)
DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED
I 0 N 10
II III 0.3 1 10 10
IV 3 10
V 10 10
WBC (THSN/CU MM)
MEAN S.D. 9.0 3.09
13.8 5.73*
11.1 2 .98
10.8 + 3.14
8.9 3 .48
RBC (MILL/CU MM)
MEAN S.D. 6.51 0.461
6.22 0.423
6.40 0.554
6.39 0.532
6.42 0.538
HGB (GRAMS/DL)
MEAN S.D. 15.5 0.95
15.0 + 0.77
15.2 0.91
15.2 0.90
15.3 0.77
HCT (%)
MEAN S.D. 40.5 + 2.93
39.3 2.72
39.5 3.24
40.1 3.02
40.4 3.15
MCV (CU MICRONS)
MEAN S.D. 62.2 1.19
63.3 2.01
61.8 1.50
62.9 2.04
63.0 1.60
MCH (PICO GRAMS)
MEAN S.D. 23.9 + 0.55
24.2 0.76
23.9 0.88
23.8 1.25
23.8 + 1.05
MCHC (%) PLAT (THSN/CU MM)
MEAN S.D. 38.4 0.76 MEAN S.D. 1419 153.0
38.3 0.94 1240 208.1
38.7 1.29 1274 226.3
37.8 1.22 1305 207.2
37.8 1.37 1355 176.8
MPV (CU MICRONS)
MEAN S.D. 8.3 0.49
8.0
* Significantly different from the Group I value (p<0.05).
0.84
8.3 0.82
8.0 0.63
7.7 0.74
418-028:PAGE C-9
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C6 (PAGE 2) : HEMATOLOGY - SUMMARY - Fo GENERATION FEMALE RATS (See abbreviations on the last page of this table.)
DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED
I 0 N 10
II III 0.3 1 10 10
IV 3 10
V 10 10
PT (SECONDS)
MEAN S.D. 13.2 + 0.41
13.4 0.29
13.2 0.37
13.5 + 0.42
13.8 1.12
APTT (SECONDS)
MEAN S.D. 21.7 2.36
23.9 3.19
23.5 2.35
25.2 2.45
25.2 3.81
NRBC COUNT
MEAN S.D. 0 0.0
0 + 0.0
0 + 0.0
0 + 0.0
0 0.6
Lymphocytes (THSN/CU MM) MEAN S.D. 6.6 2.44
9.8 3.44*
8.4 + 2.60
8.2 + 2.52
6.0 2.77
Segmented (THSN/CU MM) MEAN S.D. 2.2 0.90
3.6 3.69
2.4 0.93
2.4 0.96
2.6 + 0.82
Bands (THSN/CU MM)
MEAN + S.D. 0.0 0.00
0.0 + 0.00
0.0 0.00
0.0 0.09
0.0 0.00
Monocytes (THSN/CU MM)
MEAN S.D. 0 . 1
0.15
0.3 0.49
0.2 0.13
0.2 0.11
0.2 0.14
Eosinophils (THSN/CU MM) MEAN + S.D. 0 . 1 0 . 1 0
0 .1
0.13
0.1 0.13
0.1 0.10
0.1 0.15
Basophils (THSN/CU MM)
MEAN S.D. 0 . 0
0.00
0.0 + 0.00
0.0 0.00
0.0 0.00
0.0 0.00
Abnormal L (THSN/CU MM) MEAN S.D. 0 . 0 0 . 0 5
0.0 0.00
0.1 0.07
0.0 0.10
0.0 0.05
418-028:PAGE C-10
Other (THSN/CU MM)
MEAN S.D. 0 . 0 0 . 0 0
0.0
* Significantly different from the Group I value (p<0.05).
0.00
0.0 0.00
0.0 0.00
0.0 0.00
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
KEY TO HEMATOLOGY TABLE ABBREVIATION WBC
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
Segmented
Segmented NeutrophiIs
Abnormal L
Abnormal Lymphocytes
Other
Other Cells
418-028:
-P ^
OO
i
OO
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C7 (PAGE 1): CLINICAL CHEMISTRY - SUMMARY - Fo GENERATION FEMALE 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
TP (G/DL)
MEAN S.D.
6.1 0.52
5.5 0.50
5.9 0.41
5.8 0.32
5.8 0.29
A (G/DL)
MEAN S.D.
4.1 0.42
4.0 0.34
4.1 + 0.24
4.0 0.29
4.0 0.31
GLU (MG/DL)
MEAN S.D.
152 19.8
162 20.0
155 18.7
146 16.2
140 35.5
CHOL (MG/DL) TBILI (MG/DL)
MEAN + S.D. MEAN S.D.
77 27.8 0.2 0.07
72 14.0 0.2 0.03
71 20.0 0.2 0.05
62 14.2 0.1 0.05
61 19.8 0.1 0.05
BUN (MG/DL)
MEAN S.D.
28 4.4
24 4.7
28 6.7
25 4.4
30 15.4
CREAT (MG/DL) CK (U/L)
MEAN S.D. MEAN S.D.
0.4 0.05 202 54.1
0.4 0.05 250 85.6
0.3 0.05 192 21.7
0.4 0.08 213 80.4
0.3 0.06 252 101.6
ALT (U/L)
MEAN S.D.
129 31.7
133 23.0
142 34.2
127 24.7
145 20.0
418-028:PAGE C-12
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C7 (PAGE 2): CLINICAL CHEMISTRY - SUMMARY - Fo GENERATION FEMALE 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)
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 88.7
159 81.7
136 + 107.3
178 131.0
128 + 44.7
CA (MG/DL)
MEAN S.D. 10.6 0.72
11.2 0.63
10.4 0.87
10.4 0.46
10.4 0.82
PHOS (MG/DL)
MEAN S.D.
8.8 1.33
7.9 1.94
9.0 2.80
8.7 2.88
10.1 + 1.64
TRI (MG/DL)
MEAN S.D.
54 19.9
50 10.2
49 29.4
45 19.5
44 18.3
NA (MMOL/L)
MEAN S.D.
143 6.3
143 2.4
142 2.5
142 2.6
142 2.6
K (MMOL/L)
MEAN S.D.
5.8 0.67
5.6 0.58
5.6 0.32
6.1 0.70
6.2 0.90
CL (MMOL/L)
MEAN S.D.
96 3.4
94 2.7
95 3.8
95 3.4
94 3.1
G (G/DL)
MEAN S.D.
1.9 0.22
1.6 0.26**
1.8 0.21
1.7 0.13
1.8 0.21
A/G (NONE)
MEAN S.D.
2.2 0.28
2.6
** Significantly different from the Group I value (p<0.01).
+ 0.43**
2.2 + 0.21
2.4 0.26
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 ABBREVIATION TP
A
TERMINOLOGY Total Protein
Albumin
GLU CHOL
Glucose Cholesterol
TBILI
Total Bilirubin
BUN CREAT ALT AST ALK CA PHOS TRI NA K CL G A/G
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE C8 (PAGE 1): BODY WEIGHTS - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS
418-028:PAGEC-15
o
CO
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I 0
RATS TESTED
N 15
BODY WEIGHT (G)
DAY 1
MEANS.D .
228.6 +
DAY 2
MEANS.D .
228.2 + 8.7
DAY 3
MEAN+S.D .
233.5 7.2
DAY 4
MEANS.D .
236.6 7.7
DAY 5
MEANS.D .
239.0 + 10.0
DAY 6
MEANS.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
MEAN+S.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.
00 o
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 + 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 + 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C9 (PAGE 1) : BODY WEIGHT CHANGES - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I 0
RATS TESTED
N 15
BODY WEIGHT CHANGE (G)
DAYS 1 - 8
MEAN+S.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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE CIO (PAGE 1): 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 0
MEAN+S.D .
DAY 1
MEANS.D .
DAY 2
MEAN+S.D .
DAY 3
MEAN+S.D.
DAY 4
MEANS.D .
DAY 5
MEANS.D .
DAY 6
MEANS.D .
DAY 7
MEANS.D .
DAY 8
MEAN+S.D .
DAY 9
MEAN+S.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 . 266.9 + 19, 269.1 + 18 , 275.7 + 18 , 277.7 + 20, 280.9 + 19, 283.7 + 19, 287.7 20. 292.2 21, 295.9 + 20. 302.1 22.
418-028:PAGE C-17
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
MEAN+S.D .
DAY 12
MEANS.D .
DAY 13
MEANS.D .
DAY 14
MEANS.D .
DAY 15
MEAN+S.D .
DAY 16
MEANS.D .
DAY 17
MEANS.D .
DAY 18
MEAN+S.D .
DAY 19
MEAN+S.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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
MEAN+S.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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE C12 (PAGE 1) : 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 1
MEANS.D .
313.1 22.6
302.2 16.8
309.5 20.6
304.7 23.2
296.3 19.9
DAY 2
MEANS.D .
313.1 24.6
300.1 17.2
305.4 18.9
304.2 22.2
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 . MEANS.D . MEANS.D. MEANS.D . MEANS.D. MEANS.D . MEAN+S.D . MEAN+S.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 ( 12] a
305.0 23.1 [ 12] a
310.2 22.5 [ 12] a
311.5 23.0 [ 12] a
316.9 16.1 [ 11] a
317.7 21.6** [ 12] a
322.2 21.5*
331.8 21.2
333.5 23.0 C 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 t ] = 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
DELIVEREDiA 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
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
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
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
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
334.2 32.5 [ 14] a
340.1 30.8*
335.2 32.2** [ 13] a
333.4 33.6 [ 14] a
337.8 34.3 [ 14] a
333.0 33.4
340.6 34.3
DAY 19 DAY 20
MEAN+S.D . MEANS.D .
360.1 21.4 359.6 19.0
347.9 15.1 344.6 16.1
355.0 19.6 348.8 20.6
357.5 25.1 352.9 24.0
339.5 32.3 [ 14] a
338.9 34.9
DAY 21 DAY 22
MEANS.D . MEAN+S.D .
350.1 26.9 [ 14] a
306.3 26.0
335.7 18.7 [ 14] a
324.3 27.1
343.4 19.8 311.2 35.0
344.4 25.8 319.6 40.4
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-21
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C13 (PAGE 1) : MATERNAL BODY WEIGHT CHANGES - 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
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 CHANGE (G)
DAYS 1 - 5 DAYS 5 - 8 DAYS 8 - 1 1 DAYS 11 - 15 DAYS 15 - 18 DAYS 18 - 22
MEANS.D . MEANS.D . MEANS.D . MEANS.D . MEAN+S .D. MEANS.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 [ 11] 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 [ 13] a
+12.1 10.8
+3.7 + 11.2 [ 14] a
+7.4 11.4 [ 14] a
-37.1 29.8
DAYS 1 - 2 2
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.
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 1.6
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
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C15 (PAGE 1) : RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II 0 0.3
III 1
RATS TESTED
N 15 15 15
FEED CONSUMPTION (G/KG/DAY)
DAYS 1 - 8
MEANS.D .
86..1 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 10.0
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 Cl6 (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 - 1 0
MEANS.D .
27.7 2.8
DAYS 10 - 12 DAYS 12 - 15
MEANS.D . MEAN+S.D .
32.0 10.5 ( 14] a
28.4 2.8
DAYS 15 - 18
MEANS.D .
25.4 4.0
DAYS 1 8 - 2 0
MEANS.D .
26.6 5.7
DAYS 0 - 2 0
MEANS.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 2.5 26.8 2.8 27.0 3.2 27.5 2.4 26.7 3.1 22.8 6.2 25.9 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 2.7 25.8 2.5 27.0 2.8 27.5 2.6 26.0 3.3 26.1 4.8 25.6 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 Cl7 (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)
DAYS 0 - 7
MEAN+S.D .
88.8 8.4
DAYS 7 - 1 0
MEANS.D.
90.5 7.4
DAYS 10 - 12 DAYS 12 - 15
MEANS.D . MEAN+S.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 - 2 0
MEAN+S.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
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE Cl8 (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 . MEANS.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 8.3*
DAYS 1 - 15
MEANS.D .
59.9 7.0
54.3 7.1
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).
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 C 14] a
52.3 9.0
68.2 9.4**
55.7 8.2
418-028:PAGE C-27
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE Cl9 (PAGE 1) : MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - 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 FEED CONSUMPTION (G/KG/DAY)
DAYS 1 - 5 DAYS 5 - 8 DAYS 8 - 11 DAYS 11 - 15 DAYS 1 - 15
MEAN+S.D . MEANS.D . MEANS.D . MEANS.D . MEAN+S.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 [ 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).
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1 )
TABLE C20 (PAGE 1): MATING AND FERTILITY, ESTROUS CYCLING AND DAYS IN COHABITATION - SUMMARY - Fo GENERATION FEMALE RATS
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
V 10
15 2.1 1.2
1
0
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
MEANS.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(%)
M 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)
K 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)
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1 )
TABLE C21 (PAGE 1): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION FEMALE RATS
, M 1 w <j
DOSAGE GROUP
I II III
DOSAGE (MG/KG/DAY)
0 0.3
1
FEMALE RATS
N 10
10
10
10
V 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
1 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 (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 1.0
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE C21 (PAGE 2): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION FEMALE RATS
j> s 1111111111111
jJH>
DOSAGE GROUP
I II III
DOSAGE (MG/KG/DAY)
0 0.3
1
FEMALE RATS
N 10
10
10
T) ri
10
10
REARS IN OPEN FIELD
MEANS.D . 12.0 3.6
13.0 + 2.7
11.6 3.5
10.7 2.3
10.9 2.6
DEFECATION IN OPEN FIELD 1 : None 2 : Feces normal 3 : Soft or liquid feces
N N N
8 2 0
10 0 0
8 1 1
8 1 1
8 2 0
URINATION IN OPEN FIELD (1) None (2) Normal urination (3) Excess urination
N N N MEAN SCORE
6 4 0 1.4
7 3 0 1.3
7 3 0 1.3
10 0 0 1.0
8 2 0 1.2
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
N 10
2 : Stereotyped behavior
N
0
3 : Bizarre behavior
N
0
4 : Limb twitches/tremor
N
0
5 : Whole body tremor/spasm
N
0
6 : Unusual posture N 0
7: Tonic-clonic seizure
N
0
n : = Category number for descriptive test item.
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
(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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE C21 (PAGE 3): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION FEMALE RATS
,, m j w <!
DOSAGE GROUP
I II III
DOSAGE (MG/KG/DAY)
0 0.3
1
FEMALE RATS
N 10
10
10
10
V 10 10
GAIT PATTERN
1: Apparently normal
N
10
10
10
10
2: Ataxic
N0
0
0
0
3: Limbs splay or drag
N
0
0
0
0
4: Spastic, tip-toe
N
0
0
0
0
5: Duck-walk
N0
0
0
0
6: Scissors gait
N0
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
0
n: = Category number for descriptive test item
10 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-33
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C21 (PAGE 4): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION FEMALE RATS
C '1^ 1 1 1 1 1 1 1 1 1 1 1
1 1 1 1 1 1 1 1 1 1 1
.. M I w <1
DOSAGE GROUP
DOSAGE (MG/KG/DAY) FEMALE RATS
N
LACRIMATION
(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
10 0 0 0 1.0
II 0.3 10
10 0 0 0 1.0
III 1 10
10 0 0 0 1.0
10
10 0 0 0 1.0
OM
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
10
0 0 0
1.0
10
0 0 0
1.0
PILOERECTION
N0
0
0
0
0
ABNORMAL RESPIRATION
N
0
0
0
0
APPEARANCE
(1) Clean and groomed (2) Unkempt
N N
10 0
10 0
9 1
9 0
(3) Urine and/or fecal stain N
0
0
0
1
MEAN SCORE
1.0
1.0
1.1
1.2
1
10 0 0
1.0
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 2.0
0 10
0 0
0
2.0
(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-34
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE C21 (PAGE 5): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY) FEMALE RATS
I 0 N 10
II 0.3 10
III 1 10
IV 3 10
TACTILE REACTION
(1) 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
V 10 10
0 10 0 0 0 2.0
AUDITORY REACTION
(1) None
N0
0
0
0
(2) Orienting
N0
0
0
1
(3) Startle
N 10
10
10
9
(4) More energetic reaction
N
0
0
0
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
(1) 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
418-028:PAGE C-35
MEAN SCORE
2.2
2.1
2.2
2.0
2.1
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
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C21 (PAGE 6): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP
I II III
DOSAGE (MG/KG/DAY)
0 0.3
1
FEMALE RATS
N 10
10
10
IV 3 10
V 10 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 0 0 1.0
PUPIL RESPONSE TO LIGHT
N
10
10
10
10
10
FORELIMB GRIP TEST Maximum (G) Average (G)
MEAN+S.D. 509.5 161.7 MEAN+S.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 MEAN+S.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
1to 1 !
9"0H9Vd;80~8It7
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
347.2 14.8
350.6 + 22.8
345.2
328.3
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
44.7
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 -770S.1)
TABLE C22 (PAGE 1) : MOTOR ACTIVITY - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II 0 0.3
NUMBER OF FEMALE 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 MEAN MEAN MEAN MEAN MEAN 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 7.6 53.6 20.8 41.2 + 34.2 30.7 25.5 21.2 23.6 19.4 20.7 17.8 23.2 13.2 + 18.6 10.5 24.3
6.5 7.2 7.0 16.6 5.9 5.3 15.0 22.1 19.0 19.6 13.0 15.7 15.0 16.7 11.7 18.6 10.8 14.7 378.6 202.4
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 9.7 57.1 18.2 49.3 21.4 39.0 25.1 33.9 24.2 35.0 26.8 38.3 29.4 44.5 18.0 34.0 19.0 25.9 23.5 23.5 22.7 21.8 20.4 19.8 25.0 24.4 26.2 19.8 24.9 27.2 29.0 21.9 23.2 19.0 25.3 600.1 292.0
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 4 18-0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C22 (PAGE 2) : MOTOR ACTIVITY - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II m 0 0.3 1
NUMBER OF FEMALE RATS
N
10
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 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
TOTAL = SUM OF BLOCKS ; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
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
154.4 114.4
88.5 70.2 63.4 56.1 69.0 60.7 37.9 38.7 39.7 34.4 38.4 34.5 36.4 36.1 37.8 18.1 1028.7
32.2 24.2 56.9 52.2 42.7 41.1 46.5 36.2 41.2 44.1 44.2 48.6 52.5 48.1 44.5 42.1 48.8 + 23.2 477.6
IV V 3 10
10 10
181.0 119.5
94.4 73.0 52.0 56.7 65.3 70.1 66.6 41.6 37.2 26.6 33.4 33.1 33.0 38.6 34.9 29.3 1086.3
36.4 56.0 55.9 61.1 47.4 47.1 59.7 26.6 58.8 49.9 46.8 25.8 49.6 42.5 54.3 40.7
46.8 48.7 711.3
146.2 96.6 52.3 34.6 27.6 31.0 16.5 41.7 40.1 14.1 24.6 38.7 32.7 25.6 17.3 18.5 21.7 27.6
707.4
26.1 63.6 51.5 45.9 35.5 30.6 29.0 38.3 38.6 16.3 33.0 34.5 43.3 30.6 25.7 23.1 33.6 + 30.1 442.6
418-028:PAGE C-38
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE C23 (PAGE 1): NATURAL DELIVERY OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II III IV
V
0 0.3 1 3 10
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
2 2 . 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
GESTATION INDEX b
% N/N
0( 0.0)
100.0 15/ 15
0( 0.0)
100.0 15/ 15
0( 0.0)
100.0 13/ 13
0( 0.0)
100.0 13/ 13
0( 0.0)
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C24 (PAGE 1): 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
PUPS DELIVERED (TOTAL)
N
MEANS.D .
235 15.7 1.7
214 14.3 3.2
201 15.5 1.4
LIVEBORN
MEANS.D . N (%)
15.7 1.7 235 (100.0)
14.3 3.2 214(100.0)
15. 4 + 1.6 200 ( 99.5)
STILLBORN
MEANS.D . N(%)
0.0 0.0 0( 0.0)
0.0 0.0 0( 0.0)
0.1 0.3 M 0.5)
UNKNOWN VITAL STATUS
N
0
0
0
PUPS FOUND DEAD OR PRESUMED CANNIBALIZED
DAY 1 DAYS 2 - 8 DAYS 9-15 DAYS 16-22
VIABILITY INDEX a
N/N (%) N/N (%) N/N (%) N/N (%)
% N/N
1/235 ( 6/234 ( 0/228 ( 0/228(
0.4) 2.6) 0.0) 0.0)
97.0 228/235
2/214 ( 0.9) 6/212 ( 2.8) 2/206 ( 1.0) 0/204 ( 0.0)
96.3 206/214
0/200 ( 3/200 ( 1/197( 0/196 (
0.0) 1.5) 0.5) 0.0)
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 ( 2/175 ( 1/173 ( 0/172 (
1.1) 1.1) 0.6) 0.0)
97.7 173/177
99.4 172/173
V 10
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
418-028:PAGE C-40
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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
MEAN+S.D .
15.7 1.7
14.3 + 3.2
15.4 + 1.6
DAY 8
MEAN+S.D .
15.2 1.8
13.7 + 2.9
15.2 + 1.5
DAY 15
MEANS.D .
15.2 1.8
13.6 2.8
15.1 + 1.3
DAY 22
MEANS.D .
15.2 1.8
13.6 + 2.8
15.1 + 1.3
PERCENT MALE PUPS PER NUMBER OF PUPS SEXED
DAY 1
MEANS.D .
45.2 12.4
51.9 13.1
51.6 6.8
DAY 8
MEAN+S.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 + 2 14.1 + 2 14.1 2 14.1 2
51.4 13 51.4 13 51.8 14 51.8 14
418-028:PAGE C-
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
MEANS.D .
DAY 8
MEAN+S.D .
DAY 15
MEANS.D .
DAY 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 37.4 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 26.3 3.9 39.3 + 6.9
III 1
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
IV 3
13
13.5 3.3 13.3 3.3 13.2 3.2 13.2 + 3.2
6.5 0.7 14.1 3.1 27.4 + 5.7 40.0 + 7.9
V 10
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 25.1 3.3 36.2 + 7.7
418-028:PAGE C-42
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 III
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE C26 (PAGE 1): NECROPSY OBSERVATIONS - SUMMARY - FI GENERATION PUPS
MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)
I II Ill
0 0.3
1
IV 3
V 10
LITTERS EXAMINED (N)
15 15 13 13
15
TOTAL PUPS STILLBORN, OR FOUND DEAD a,b
STILLBORN FOUND DEAD
N6 N0 N6
5 0 5
24 12 12
3 2 1
NO MILK IN STOMACH C
N(%) 2 ( 33.3)
5 (100.0)
0( 0.0)
1( 50.0)
0( 0.0)
PUPS SACRIFICED AND NECROPSIED ON DAYS 5 AND 22 POSTPARTUM c
LITTERS EVALUATED PUPS EVALUATED
N 15 15 13 N 228 204 196
13 15 172 211
APPEARED NORMAL LITTER INCIDENCE PUP INCIDENCE
N(%) 15(100.0) N(%) 228(100.0)
14 ( 93.3) 203 ( 99.5)
13(100.0) 196(100.0)
13(100.0) 172(100.0)
15 (100.0) 211(100.0)
KIDNEYS: RIGHT, PELVIS, MODERATE DILATION LITTER INCIDENCE PUP INCIDENCE
N(%) 0( 0.0) N (%) 0( 0.0)
1( 6.7) 1( 0.5)
0( 0.0) 0( 0.0)
0( 0.0) 0( 0.0)
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C27 (PAGE 1): PUP LIVER WEIGHTS - SUMMARY - FI GENERATION PUPS
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
II 0.3
10
40.00 + 8.08 41.57 + 8.53 38.35 + 7.94
III 1
10
38.56 + 4.78 40.27 + 4.60 36.86 + 5.30
IV 3
10
40.11 + 8.35 41.04 + 8.18 39.22 + 8.57
V 10 10
34.70 + 8.26 35.33 + 8.27 34.07 + 8.30
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
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
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) .
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 + 0.47
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C28 (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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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
.
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 i 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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) DG ( 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 ADMINISTERED 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
P
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
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.
418-028:PAGE C-5
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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
III
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
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.
418-028:PAGE C-52
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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
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
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.
418-028'.PAGE C-53
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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.
418-028:PAGE C-54
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE C3 0 (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
BRAIN
ABS. REL. WT. % 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
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.
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
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
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
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
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
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
RAT TERMINAL BODY NUMBER WEIGHT
SPLEEN
ABS. REL. WT. % TBW
THYMUS
ABS. REL. WT. % TBW
OVARY LEFT
ABS. REL. WT. % TBW a
OVARY RIGHT ABS. REL. WT. % TBW a
UTERUS WITH 1CERVIX ABS. REL. WT. % TBW
HEART
ABS. REL. WT. % TBW
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 .
0.78 0.64 0.58 0.58 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
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
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
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
0.48 0.57 0.51 0.53 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
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. WT. = ORGAN WEIGHT,
P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
a . V alue was m u ltip lie d by 1000.
REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100.
418-028:PAGE C-55
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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. WT. % 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. REL. WT. % 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 25.72 0.072 20.81 0.081 25.80 0.068 20.12 0.075 25.34 0.095 26.46 0.046 14.89 0.056 15.73 0.059 18.15 0.026 8.50 0.055 17.19 0.052 . 15.48 0.025 7.94 0.059 20.07 0.058 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 IGRAMS (G).
ABS. WT. = ORGAN WEIGHT.
P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
a. V alue was m u ltip lie d by 1000.
REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100 .
418-028:PAGE C-56
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE C3 0 (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. WT.
REL. % 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
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
SPLEEN
ABS. REL. WT. % TBW
THYMUS
ABS. REL. WT. % TBW
OVARY LEFT
ABS. REL. WT. % TBW a
OVARY RIGHT ABS. REL. WT. % TBW a
UTERUS WITH 1CERVIX ABS. REL. WT. % TBW
HEART
ABS. REL. WT. % TBW
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.
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 0.20 0.18 0.19 0.22
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
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
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
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
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 0.55 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/TERMINAL 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 057
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
3 MG/KG/DAY
RAT TERMINAL BODY NUMBER WEIGHT
BRAIN
ABS. REL. WT. % 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
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 .
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
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
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
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
0.044 0.064 0.055 0.052 0.063 0.041 0.064 0.046 0.067 0.031
15.44 24.52 17.46 17.69 16.36 14.28 18.28 15.86 18.16 10.62
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
RAT TERMINAL BODY NUMBER WEIGHT
SPLEEN
ABS. REL. WT. % TBW
THYMUS
ABS. REL. WT. % TBW
OVARY LEFT
ABS. REL. WT. % TBW a
OVARY RIGHT ABS. REL. WT. % TBW a
UTERUS WITH 1CERVIX ABS. REL. WT. % TBW
HEART
ABS. WT.
REL. % TBW
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.
P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100 .
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).
418-028:PAGE C-58
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1 )
TABLE C3 0 (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. 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
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 12.0 9 14.65 10.53
RAT TERMINAL BODY NUMBER WEIGHT
SPLEEN
ABS. WT.
REL. % TBW
THYMUS
ABS. REL. WT. % 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 19011 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:PAGE C-59
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1 )
T A B L E C 3 1 1[PAGE 1): O R G A N W E I G H T S A N D R A T I O S (%) O F O R G A N W E I G H T TO' B R A I N W E I G H T - I N D I V I D U A L D A T A - Foi G E N E R A T I O N F E M A L E R A T S
DOSAGE GROUP I
0 MG/KG/DAY
RAT NUMBER
BRAIN WEIGHT
LIVER
ABS. WT.
REL. % 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. 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
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
A L L W E I G H T S W E R E R E C O R D E D I N G R A M S (G) .
A B S . WT. = ORGAN WEIGHT.
P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
REL. % T B W = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
418-028:PAGE C-60
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C31 (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
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
LIVER
ABS. REL. WT. % BRW
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
KIDNEY LEFT
ABS. REL. WT. % BRW
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
KIDNEY RIGHT ABS. REL. WT. % BRW
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
ADRENAL LEFT
ABS. REL. WT. % BRW
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
ADRENAL RIGHT
ABS. REL. WT. % BRW
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
SPLEEN
ABS. REL. WT. % BRW
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. 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
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 25.00
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 52.50 55.80
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
ABS. WT. = ORGAN WEIGHT.
P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
418-028:PA
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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
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
LIVER
ABS. WT.
REL. % BRW
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
KIDNEY LEFT
ABS. REL. WT. % BRW
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
KIDNEY RIGHT ABS. REL. WT. % BRW
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
ADRENAL LEFT
ABS. REL. WT. % BRW
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
ADRENAL RIGHT
ABS. REL. WT. % BRW
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
SPLEEN
ABS. REL. WT. % BRW
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/BRAIN 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 necropsy
observations table (Table C28).
418-028'.PAGE C-62
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE C31 (PAGE 4) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TCi BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP IV
3 MG/KG/DAY
RAT NUMBER
BRAIN WEIGHT
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
LIVER
ABS. REL. WT. % BRW
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
KIDNEY LEFT
ABS. REL. WT. % BRW
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
KIDNEY RIGHT ABS. REL. WT. % BRW
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
ADRENAL LEFT
ABS. REL. WT. % BRW
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
ADRENAL RIGHT
ABS. REL. WT. % BRW
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
SPLEEN
ABS. WT.
REL. % BRW
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C31 I!PAGE 5) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TOi BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP V
10 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. 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
OVARY LEFT
ABS. REL. WT. % 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
0.048 0.056 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).
ABS. WT. = 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 #2 21 46 34 36 36 34.6
RAT # 19042
AVERAGE
OVARY #1 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
418-028:PAGE C-65
19023
AVERAGE 19041
AVERAGE
7 14 10 14 11 11.2
7 14 2 5 7 7.0
22 11 13 27 6 15.8
4 3 4 6 9 5.2
19053
AVERAGE 19065
AVERAGE
24 11 27 27 25 22.8
4 3 9 3 14 6.6
3 11 16 20 38 17.6
7 15 11 12 16 12.2
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C32 (PAGE 2): PRIMORDIAL FOLLICLE COUNT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP V RAT # 19001
AVERAGE 19006
AVERAGE
OVARY #1 3 4 9 6 23
9.0
27 11 23 26 21 21.6
OVARY #2 6 5 6 17 20
10.8
10 MG/KG/DAY
5 6 19 20 20 14.0
RAT # 19025
AVERAGE 19027
AVERAGE
OVARY #1 11 12 6 6 7 8.4
6 6 17 13 43 17.0
OVARY #2 4 6 15 25 12
12.4
0 5 8 12 8 6.6
19011
AVERAGE 19020
AVERAGE 19022
AVERAGE
6 16 8 16 37 16.6
5 4 15 8 20 10.4
9 2 5 1 7 4.8
1 0 12 24 8 9.0
2 1 2 12 20 7.4
9 4 11 17 19 12.0
19028
AVERAGE 19030
AVERAGE 19031
AVERAGE
3 2 2 5 7 3.8
9 21 24 22 26 20.4
11 15 11 9 14 12.0
1 7 13 13 10 8.8
3 13 6 7 20 9.8
7 4 14 11 17 10.6
418-028:PAGE C
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 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 #
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 .
228. 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 #
DOSAGE GROUP V
10 MG/KG/DAY
19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
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 .
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 .
245 . 275 . 250. 262 . 259. 281. 268 . 265. 244 . 273 . 269. 277 . 259. 270. 274 .
252. 278 . 258 . 266. 273 . 288 . 274 . 275 . 241. 282 . 262 . 284 . 266. 268. 281.
262 . 281. 260. 269. 273 . 292 . 272 . 274 . 248 . 287. 274 . 289. 264 . 283 . 286.
265. 283 . 266. 278. 285. 296. 280. 278 . 248 . 288. 272 . 294 . 271. 288. 292.
269. 286. 260 . 281. 288 . 301. 287. 285. 251. 291. 285 . 300. 278 . 289. 295.
270 . 291. 269. 286. 290 . 304 . 290 . 295 . 255 . 295 . 288. 306. 278 . 289. 304 .
DAY 13 14 15 16 17 18 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. 321. 299. 326. 336. 343 . 321. 329. 280. 321. 322 . 341. 308. 324 . 339.
320. 321. 310. 332 . 349. 348 . 325. 338 . 289. 329 . 330 . 349. 315. 325. 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.
383 . 326. 361. 391. 418 . 410. 377. 389. 334. 358. 391. 411. 367. 379 . 409.
P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G ).
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 . 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. 288.
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.
11
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 4 1 8 - 0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 . 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.
DAY 13 14 15 16 17 18 19
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
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 .
350. 326. 307. 314 . 343 . 363 . 288.
307. 350. 340. 383 . 321. 404 . 349.
371. 338. 323. 324 . 357. 382. 284 .
304 . 365. 356. 392 . 335 . 413 . 368 .
380. 357. 336. 329. 370. 392. 283 .
316. 383 . 376. 393 . 351. 384 . 380.
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.
11
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 . 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.
320. 422 . 375. 349. 389. 409. 353 . 377. 368. 414 . 404 . 370. 386. 383 . 351.
P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G).
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
11
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 4 1 8 - 0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 . 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 19042 19044 19050 19053 19065 19068 19072 19074 19075
334 . 316. 324 . 302 . 279. 337. 335. 301. 285. 324. 332 . 338 . 311. 313 . 266.
330 . 319. 309. 266. 294 . 347. 334 . 300. 285 . 327. 340 . 344 . 298 . 319. 284 .
332 . 322 . 320. 289. 299. 346. 329. 303 . 285. 338. 337. 349. 300 . 313 . 279.
334 . 327 . 337. 288. 302 . 352 . 340 . 312. 290 . 336. 345. 348. 305. 320. 287.
341. 323 . 337. 310. 310. 358. 338. 321. 300. 339. 343 . 347. 299. 336. 288.
344 . 331. 342 . 272 . 319. 371. 346. 319. 305. 359. 351. 360 . 324 . 345. 303 .
351. 347. 343 . 324 . 316. 363 . 346 . 330. 304 . 367. 362 . 362 . 334 . 352 . 305.
351. 346. 340 . 320. 318. 367. 344 . 340. 313 . 367. 361. 371. 337. 348 . 311.
368. 349. 360. 291. 331. 383. 350. 339. 330. 374. 364. 381. 288.a 358. 321.
353 . 295 .a 360 . 326. 338 . 371. 354 . 341. 327 . 377 . 377 . 366. 340 . 367. 297.a
DAY 14 15 16 17 18 19 20 21 22b
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.
11
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 4 1 8 - 0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 . 1)
TABLE C35 (PAGE 2): MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
RAT #
DOSAGE GROUP II
0.3 MG/KG/DAY
DAY 1 2 3 4 5 6 7 8 9 10
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
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 .
296. 273 . 298. 311. 273 .a 297. 277 . 311. 271. 305. 261.a 320. 297. 311. 335.
301. 251.a 306. 311. 320 . 296. 269. 316. 276. 302 . 264 .a 332 . 293 . 310. 312.
303 . 301. 310 . 318. 314 . 296. 288 . 316. 287 . 307. 285 . 332 . 309. 314 . 329.
317. 312 . 320. 320. 311. 309. 292 . 321. 284 . 315. 315 . 332 . 307. 319. 320 .
310. 324 . 323 . 325 . 326. 319. 296. 332 . 304. 320. 316. 348. 315. 331. 332.
316. 318 . 321. 327 . 331. 303 . 301. 325. 296. 327. 317. 332 . 323 . 335 . 339.
330. 325. 323 . 336. 333. 318. 318. 342. 311. 336. 331. 353. 277.a 346. 342.
331. 331. 318 . 347 . 347 . 334 . 321. 349. 312 . 343 . 330. 363 . 297. 352 . 348.
DAY 14 15 16 17 18 19 20 21 22b
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
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
345. 343 . 336. 341. 356. 356. 332 . 338. 330 . 349. 353 . 363 . 322 . 352 . 369 .
317. 341. 330 . 341. 355. 343 . 312 . 333 . 318 . 338. 349. 366. 348 . 360. 365 .
332 . 345. 327 . 353 . 341. 345. 332 . 344 . 324 . 356. 345 . 372 . 338 . 371. 371.
344 . 349. 329. 349 . 353 . 358. 326. 349. 317 . 365 . 351. 367. 337. 358 . 367.
325. 342. 324. 340. 358 . 344 . 342. 344 . 319. 368. 346. 368. 334 . 343 . 372.
304 . 336. 308. 343 . 360. 351. 321. 348. 308. 350. 346. 350. 327. 308.a 348.
276. 346. 314. 338. 296. 359. 309. 356. 325. 306. 320. 336. 315. 294. 374.
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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.
11
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 19048 19052 19055 19061 19067 19071
132. 156. 126. 137. 144 . 136. 138 . 153 . 110. 131. 123 . 147. 134 . 13 9. 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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. 135. 128. 12 9. 153 . 124 . 153 . 134 .
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G ). a. Last value recorded before coh ab itation .
1 MG/KG/DAY 3 MG/KG/DAY
418-028:PAGE C-81
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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. 14 8. 141. 138. 132 .
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation.
10 MG/KG/DAY
418-028:PAGE C-82
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 . 178 . 188. 182 . 140. 190. 192 . 189. 158. 188 . 203 . 191. 171. 193 . 117 .
85 . 82. 90. 85. 66. 82 . 91. 91. 70. 77 . 92 . 93 . 75 . 89. 78.
50. 55. 82 . 58. 44 . 127. 69. 59. 49. 64 . 73 . 57.
a 63 . 46.
77. 83 . 95. 93 . 76. 81. 101. 93 . 73 . 84 . 94 . 86. 77. 90. 77 .
76. 81. 75. 78 . 47 . 83 . 88. 90. 56. 76. 88. 86. 74 . 82. 65.
53 . 59. 56. 21. 51. 58. 66. 54 . 53 . 58. 68. 55. 58. 51. 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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.
14 9 .
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
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE C37 (PAGE 3): 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 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. 63 . 42 . 71. 70. 41.
165. 74 . 55. 85. 72 . 61.
146. 69. 48. 69. 75. 56.
162 . 77 . 53 . 79.
64 . 51.
185. 75 . 57. 88. 81. 69.
202 .
88.
65.
73 . 64 . 50 .
144 . 73 . 47. 81. 65. 41.
184 .
82.
56.
93 . 84 . 55.
175 .
71.
54 . 78.
73 . 57 .
182 .
91.
59.
94 . 89.
54 .
180.
84 . 59.
93 . 94 . 62 .
164. 82 . 57. 89. 85. 55 .
176. 83 . 54 . 81. 81. 52 .
169. 75. 54 . 84 . 86. 50 .
156. 75. 50. 82. 88. 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C3 8 (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 . 137. 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. S p ille d feed precluded the c a lc u la tio n o f th is valu e.
418-028:PAGE C-86
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1 )
TABLE C38 (PAGE 2): MATERNAL FEED CONSUMPTION VALUES - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DAY 1 - 5 5 - 8 8 - 1 5
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 .
149.
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.
146.
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.
139.
453 .
106.
81. 451.
114 .
167.
523 .
DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G ). a. S p ille d feed precluded th e c a lcu la tio n of th is valu e.
418-028:PAGE C-87
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C38 (PAGE 3): MATERNAL FEED CONSUMPTION VALUES - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
1 00 1
111 1 LO 1
DAY 1 - 5
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.
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1 )
TABLE C3 9 (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
1
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 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
4 3 3 3 1 2 3 4 2 4 2 2 3 3 3
4M 1M 1M 2M 4M 1M 2M 1M 1M 4M 1M 1M 2M 3M 1M
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C3 9 (PAGE 2) : 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 III
1 MG/KG/DAY
19003
3
3
M
19007
3
3
M
19008
3
4
M
19013
3
2
M
19014
4
1
M
19015
2
4
M
19017
3
1
M
19024
3
4
M
19029
3
2
M
19034
3
3
M
19038
3
1
M
19056
4
4
M
19057
4
4
M
19060
4
2
M
19064
4
4
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 21 la 14 33 21 44 32 34 32 31
M M M M M M M DID NOT MATE M M M M M M M
M = MATED C = CONFIRMED P = PREGNANT NP = NOT PREGNANT a. Six or more consecutive days of estrus 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
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 1 4 1 4 1 1 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
418-028 :PAGE C-91
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY
SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
3 2 33 3 3 333
ALTERATIONS (HOME CAGE)
1 1 11 1 1 1 11
REACTION TO REMOVAL
1 1 11 1 1 111
REACTION TO HANDLING
1 1 11 1 1 111
REARS IN OPEN FIELD
10 12 12 19 7 13 15 7 14
DEFECATION IN OPEN FIELD 1 1 1 2 1 1 2 1 1
URINATION IN OPEN FIELD
1 122 12 2 1 1
LEVEL OF AROUSAL
3 3 333 3 333
ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1
GAIT PATTERN
1 1 111 1 111
GAIT ABNORMALITY, SEVERITY
1
1
1
1
1
1
1
1
1
PALPEBRAL CLOSURE
1 1 111 1 111
PROMINENCE OF THE EYE
1 1 111 1 1 11
LACRIMATION
1 1 111 1 1 11
SALIVATION
1 1 111 1 11 1
PILOERECTION
000000000
ABNORMAL RESPIRATION
00 000 0000
APPEARANCE
1 1 la 1 lb 1 1 1 1
VISUAL REACTION
2 2 222 2 222
TACTILE REACTION
222222222
AUDITORY REACTION
33 3333 333
TAIL-PINCH REACTION
2 2 232 3 222
AIR RIGHTING RESPONSE
1 1 111 1 111
PUPIL RESPONSE TO LIGHT
1 1 111 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
VALUES 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 JL 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE C40 (PAGE 2): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP II RAT # HOME CAGE BEHAVIOR ALTERATIONS (HOME CAGE) REACTION TO REMOVAL REACTION TO HANDLING REARS IN OPEN FIELD DEFECATION IN OPEN FIELD URINATION IN OPEN FIELD LEVEL OF AROUSAL ALTERATIONS (OPEN FIELD) GAIT PATTERN GAIT ABNORMALITY, SEVERITY PALPEBRAL CLOSURE PROMINENCE OF THE EYE LACRIMATION SALIVATION PILOERECTION ABNORMAL RESPIRATION APPEARANCE VISUAL REACTION
19004 3 1 1 1 10 1 1 3 1 1 1 1 1 1 1 0 0 1 2
19009 1 1 1 1 12 1 2 3 1 1 1 1 1 1 1 0 0 1 2
19016 3 1 1 1 12 1 1 3 1 1 1 1 1 1 1 0 0 la 2
19018 2 1 1 1 9 1 1 3 1 1 1 1 1 1 1 0 0 1 2
19026 1 1 1 1 11 1 1 3 1 1 1 1 1 1 1 0 0 1 2
0 .3 MG/KG/DAY
19036
19037
19043
32 1
111
111
111
14 14 15
111
112
333
111
11 1
111
111
111
111
111
000
000
111
222
19047 3 1 1 1 18 1 1 3 1 1 1 1 1 1 1 0 0 1 2
TACTILE REACTION
2222 22222
AUDITORY REACTION TAIL-PINCH REACTION
33 3 3 3 333 3 22222 222 3
AIR RIGHTING RESPONSE PUPIL RESPONSE TO LIGHT
11111 111 1 11111 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
LANDING FOOT SPLAY #2 (CM)
7.9
9.0
6.9
6.8
7.4
6.7
7.0
5.4
5.7
BODY WEIGHT (G)
317 356 352 350 334 362 335 356 345
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
3 3 1 313 31 2
ALTERATIONS (HOME CAGE)
1 1 1 11 1 11 1
REACTION TO REMOVAL
1 1 1 111 11 1
REACTION TO HANDLING
1 1 1 1 1 1 1 1 1
REARS IN OPEN FIELD
14 9 10 8 6 13 14 10 16
DEFECATION IN OPEN FIELD 1 1 1 1 1 1 1 3 1
URINATION IN OPEN FIELD
11 112 1112
LEVEL OF AROUSAL
333333333
ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1
GAIT PATTERN
1 1 1 111 11 1
GAIT ABNORMALITY, SEVERITY
1
1
1
1
1
1
1
1
1
PALPEBRAL CLOSURE
11111111 1
PROMINENCE OF THE EYE
1 1 1 11 1 11 1
LACRIMATION
1 1 1 11 1 11 1
SALIVATION
1 1 1 11 1 11 1
PILOERECTION
0 0 0 00 0 00 0
ABNORMAL RESPIRATION
0 0 0 00 0 00 0
APPEARANCE
1 1 la 1 lb 2 1 lc 1
VISUAL REACTION
2 2 222222 2
TACTILE REACTION
2 2 2 22 222 2
AUDITORY REACTION
3 3 3 333 33 3
TAIL-PINCH REACTION
2 2 2 22 3 22 2
AIR RIGHTING RESPONSE
1 1 1 11111 1
PUPIL RESPONSE TO LIGHT
11 1 11111 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
VALUES ARE THE QUANTITY, 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 forepaws and forelimbs (2.8 cm x 0.5 cm) and head (0.3 cm x 0.5 cm).
19056 1 1 1 1 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C40 (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)
1 111 11 11 1
REACTION TO REMOVAL
1 11 111 11 1
REACTION TO HANDLING
1 111 11 11 1
REARS IN OPEN FIELD
11 7 15 12 13 10 10 11 8
DEFECATION IN OPEN FIELD 3 1 1 1 2 1 1 1 1
URINATION IN OPEN FIELD
1 11 1 11 1 1 1
LEVEL OF AROUSAL
3 33333333
ALTERATIONS (OPEN FIELD)
111111111
GAIT PATTERN
1 111 11 1 1 1
GAIT ABNORMALITY, SEVERITY
1
1
1
1
1
1
1
1
1
PALPEBRAL CLOSURE
1 11111 111
PROMINENCE OF THE EYE
111111111
LACRIMATION
111111111
SALIVATION
111111111
PILOERECTION
0 00 0 0 0 0 0 0
ABNORMAL RESPIRATION
000000000
APPEARANCE
1 1 1 1 la 3b 1 lc 1
VISUAL REACTION
2 22 2 22 2 2 2
TACTILE REACTION
2 22 2 22 2 2 2
AUDITORY REACTION
3 332 33 3 3 3
TAIL-PINCH REACTION
2 22 2 22 2 2 2
AIR RIGHTING RESPONSE
1 11 1 1 1 1 1 1
PUPIL RESPONSE TO LIGHT
1 11 1 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)
5.5 5.4 6.5
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
VALUES ARE THE QUANTITY, 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
o 00
o 00
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1 )
TABLE C40 (PAGE 5): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP V
10 MG/KG/DAY
RAT # HOME CAGE BEHAVIOR
19001 2
19006 2
19011 2
19020 3
19022 2
19025 3
19027 1
19028 3
19030 3
ALTERATIONS (HOME CAGE)
1111 1111 1
REACTION TO REMOVAL
1111 1111 1
REACTION TO HANDLING
1111 1111 1
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
11111122 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
1111 1111 1
PROMINENCE OF THE EYE
1111 1111 1
LACRIMATION
1111 1111 1
SALIVATION
11111111 1
PILOERECTION
0 000 0 00 0 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
2222 2 222 2
AUDITORY REACTION
2333 3333 3
TAIL-PINCH REACTION
2222 2 222 2
AIR RIGHTING RESPONSE
1111 1 111 1
PUPIL RESPONSE TO LIGHT
1111 1111 1
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 1 1 14 2 1 3 1 1 1 1 1 1 1 0 0 1 2 2 3 3 1 1
270 440 410 445 10.4 9.2 373
418-028'.PAGE C-96
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 1 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 1 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 1 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 1 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7 7 0 6 .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 11 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 1 2 9 62 69 5 7 1 1 1098
418-028'.PAGE C-100
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
I0I-DaDVd`80-8It7
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 1 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 11 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:PAGE C-102
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 28 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
476
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 0 3 2 4 4 481
418-028:PAGE C-103
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 1 60 56 29 5 24 11 6 1 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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:P
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 1 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C42 (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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
N NN
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
11
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 11 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 = FEMALE ( ) = NUMBER OF PUPS DYING PRIOR TO WEIGHING ON DAY 1 POSTPARTUM. ( ] = 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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
11
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
0 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.
OII'O 39Vd:80"8It7
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE C43 (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 MFT
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.
111"3 30Vd:8ZO"8It7
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 MFT
DAY 8 MFT
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.
ni-D30V<T.8ft)-8It7
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C44 (PAGE 1) : 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 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 #
MATERNAL DOSAGE GROUP II
0.3 MG/KG/DAY
POSTPARTUM DAY 1
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
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.
II"3 HOVd:80"8Il7
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 III
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
1711-3 3OVd*-8l0-8Il7
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.
SI1'3 3OVd:8l0`8Il7
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 15.6 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 13.4 14.0 12.8 15.2 11.7 15.8 12.5 18.2 13.5
13.4 14.8
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
14.8 13.8 13.9
6.4 11.8 13.6 15.6
10.4 MD 1 13.0 13.1 12.5
13.3
15.0 15.8 12.0
8.6 10.7 12.3 16.0
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.
911-3 3OV<T-8Z0-8lt7
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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
11.1 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
11.1 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 #
MATERNAL DOSAGE GROUP IV
3 MG/KG/DAY
POSTPARTUM DAY 8
19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
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
14.2 16.9 15.1 15.3 10.8 12.4
13.9 13.6
9.9 12.8 13.1
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 11.1
UU
10.0
10.1 10.4
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 . 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 1MG/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
14.3 11.5 10.9
10.3 13.1 12.4
9.3 11.9 FD 1
12.8
16.0 11.9
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.
81TO aOVd;8IO_8ll7
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 17 18 19 20
RAT/ LITTER #
MATERNAL DOSAGE GROUP I
0 MG/KG/DAY
POSTPARTUM :DAY 15
19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
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 28.8 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 22.4 FM 2
25.5 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 24.8 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 33.8 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 26.9 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 28.0 30.9 18.7 26.1 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
27.1 28.8 24.0 18.3 17.9 27.8 26.5 33.9 24.8 26.5 MD 3 27.9 24.7
18.7
28.2 26.3 23.9 25.6 19.3 27.9 23.3 33.1 24.3 23.7 24.9 26.8 25.0
21.1
26.3 23.1 25.8 29.0 19.7 27.5 29.0
21.1 27.5 24.3 27.7 18.1
19.0
26.1 28.4 24.9 20.2 15.9 28.3 28.8
24.9 MD 1 24.8 28.6 27.0
21.5
29.0 26.4 22.2 27.3 17.8 28.9 29.3
22.7 25.0 24.1 27.5 26.7
26.8
25.4 24.9 23.6 23.3 19.6 29.3 24.8
23.3 24.4 25.1 28.6 22.7
23.0
17.1 24.6 22.9 FM11 17.5
23.3 23.6
FD 8 27.4
22.6 26.7 21.3 FD 2 15.9
19.3 26.8
23.2
21.8 FD 1 FD15
21.5 25.6
24.6 23.2
FD 5
FM 6 21.7
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.
6Il"0 3OVd:860"8ll7
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C44 (PAGE 8) : 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 15
19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
RAT/ LITTER #
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 FM11
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
28.4 31.3 30.0 MD 1 19.5 27.3
32.4 23.7 22.5 20.6 22.4 22.7
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.
19
20
418-028:PAGE C-120
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 19.2
FS 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-
to
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 1 - 1 7 0 6 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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
35.7 32.8 40.0 32.6 37.1 35.7 45.0 28.6 33.0 36.0
42.1 35.4
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 47.1 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
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
33.3
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
41.3 39.2 29.1 39.2 32.9 45.2 40.5
37.8 MD 1 34.2 37.0 43.3
24.0
45.4 38.1 31.2 30.5 27.9 42.9 33.0
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
25.8 40.6 27.6 FM11 27.0
37.5 34.5
FD 8 31.1
26.4 43.4 34.6 FD 2 24.9
29.9 37.8
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 #
MATERNAL DOSAGE GROUP III
1 MG/KG/DAY
POSTPARTUM DAY 22
19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
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
26.1 27.4
36.4
36.8 34.2 30.3
33.9 29.7 27.5 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
33.0 29.9 28.5 30.0 30.6
45.8 40.4 47.2 42.5 33.0 42.7
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
28.1
27.8 32.1 34.8
39.9 FS FS
32.3 41.2
39.5 33.8
34.5 24.7
UU
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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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
FM 2 27.6
29.9 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C45 (PAGE 1) : 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 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 MA MA MA MA MA FA FA FA FA FA FA MA MA 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 MA MA MA MA MA 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 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 MA MA MA MA 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 M A M A MA MA MA MA FA FA FA FA FA FA FA FA M A M A 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 M A 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 M A M A 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 MA MA 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 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'.PAGE C-126
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 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 M A M A M A 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 FA M A M A MA MA FA FA FA FA FA FA FA FA FA FA MA MA MA MA MA FA FA FA FA FA FA FA F S MA MA MA MA MA 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
FAFD1 FA FA
FS 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-127
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1)
TABLE C4 6 (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.
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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
1 2- 7
1/15 PUPS: RIGHT HINDLIMB, LACERATION. 1/ 5 PUPS: RIGHT HINDLIMB, SCAB (0.1 CM X 1.0 CM).
19058
20-22
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.
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .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 n e c r o p sie s were not perform ed on pups in which a u to ly s is or c a n n ib a liz a tio n p reclu d ed e v a lu a tio n . R efer to th e in d iv id u a l pup c l i n i c a l o b s e r v a tio n s t a b le (T ab le C44) f o r e x te r n a l c l i n i c a l o b s e r v a tio n s con firm ed a t n e c r o p sy .
418-028:PAGE C-130
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .1)
TABLE C47 (PAGE 2): NECROPSY OBSERVATIONS - INDIVIDUAL DATA - FI GENERATION PUPS
MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)
LITTER NUMBER
DAY POSTPARTUM
OBSERVATIONS a
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`.PAGE C-
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 1 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.
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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
19003
22 16 PUPS APPEARED NORMAL.
19007
2 1 PUP FOUND DEAD. ALL TISSUES APPEARED NORMAL 22 17 PUPS APPEARED NORMAL.
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 NORMAL.
22
17 PUPS APPEARED NORMAL.
'
22 14 PUPS APPEARED NORMAL.
22 17 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-133
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -770S WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1 )
TABLE C47 (PAGE 5): NECROPSY OBSERVATIONS - INDIVIDUAL DATA - FI GENERATION PUPS
MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)
LITTER NUMBER
DAY POSTPARTUM
OBSERVATIONS a
19002
1 1 PUP FOUND DEAD. ALL TISSUES APPEARED NORMAL 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 NORMAL.
19063
1 1 PUP STILLBORN. ALL TISSUES APPEARED NORMAL. 22 13 PUPS APPEARED NORMAL.
19066
1 1 PUP FOUND DEAD. NO MILK IN STOMACH. ALL OTHER TISSUES APPEARED NORMAL.
1 PUP STILLBORN. ALL TISSUES APPEARED NORMAL. 22 12 PUPS APPEARED NORMAL.
19069
10 1 PUP FOUND DEAD. NO MILK IN STOMACH. AUTOLYSIS PRECLUDED FURTHER EVALUATION.
22 16 PUPS APPEARED NORMAL.
19073
22 13 PUPS APPEARED NORMAL.
a . Complete n e c r o p sie s were not perform ed on pups in which a u to ly s is or c a n n ib a liz a tio n p reclu d ed e v a lu a tio n . R efer to th e in d iv id u a l pup c l i n i c a l o b s e r v a tio n s t a b le (T able C44) f o r e x te r n a l c l i n i c a l o b s e r v a tio n s con firm ed a t n e c r o p sy .
418-028'.PAGE C-134
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T - 7 7 0 6 .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 APPEARED 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. AUTOLYSIS 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 NORMAL.
a . Complete n e c r o p sie s were n ot perform ed on pups in which a u to ly s is or c a n n ib a liz a tio n precluded e v a lu a tio n . R efer to th e in d i v id u a l pup c l i n i c a l o b s e r v a t io n s t a b l e (T ab le C44) f o r e x t e r n a l c l i n i c a l o b s e r v a t io n s co n firm ed a t n e c r o p s y .
418-028:PAGE C-135
PROTOCOL 4 1 8 -0 2 8 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T -7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T -7 7 0 6 .1 )
TABLE C48 (p age i;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
2*9.18" 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 - 7 7 0 6 .1)
TABLE C48 (PAGE 2): PUP LIVER WEIGHTS - INDIVIDUAL DATA - FI GENERATION PUPS
LITTER
NUMBER
M
GROUP IV
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
19006 19011 19020 19022 19025 19027 19028 19030 19031
1.358 1.290 0.454 1.336 1.098 1.283 1.550 1.594 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 1.646 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 Sheehy Drive, Bldg. A
Horsham, PA 1 9 0 4 4 Telephone: (2 1 5 )4 4 3 - 8 7 1 0 Telefax: (2 1 5 ) 4 4 3 -8 5 8 7
ARGUS RESEARCH
DiscovCerhyaarnledsDReivveelorpLmaebnotrSaetorvricieess
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 o f this study is to provide information on the possible health hazards that may result from repeated exposure o f 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 of the 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 o f 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. In particular, 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, Ph.D., DABT
Associate Director o f 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 CFRPart 58.
Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standardfo 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 o f 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 that portion of the study. The QAU for this 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 die 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-3
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 o f synthesis, strength and activity/purity of the 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:PAGED-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) and bulk 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 of required 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 the 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 o f the prepared formulations will be verified during the course of this study. Quadruplicate samples (2 mL each) will be taken from the top, middle and bottom of each concentration on the first day o f 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 o f duplicate samples (2 mL each) from each concentration will be taken on the first day of preparation. One sample o f 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 o f 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- IB -10 St. Paul, Minnesota 55144-1000 Telephone: (651) 733-2392
418-028:PAGED-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 o f rat has been demonstrated to be sensitive to reproductive and developmental toxins; and 3) historical data and experience exist at the Testing Facility(,'3)
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 o f 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 o f 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 truck from Charles River Laboratories, Inc., to the Testing Facility.
Identification:
Rats are permanently identified using Monel self-piercing ear tags (Gey Band and Tag Co., Inc., No. MSPT 20101). Male and female rats are assigned temporary numbers 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 o f 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 Guidefo r the Care and Use o f Laboratory Animals^. 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 of presumed 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 o f 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%.
Light:
An automatically controlled 12-hour light: 12-hour dark fluorescent light cycle will be maintained. Each dark period will begin at 1900 hours EST. 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 Page 8
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 o f the vaginal contents and/or a copulatory plug observed in situ.
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 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 o f lactation) in the Standard Operating Procedures o f the Testing Facility. Throughout this protocol, the day of birth 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 of physical 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 cohabitation period will consist of a maximum o f 14 days. Female rats with spermatozoa observed in a smear of the vaginal contents and/or a copulatory plug observed in situ will be considered to be at day 0 o f presumed gestation and assigned to individual housing. Female rats not mated within the first seven days of cohabitation will be assigned alternate male rats that have mated (same dosage group) and will remain in cohabitation for a maximum o f seven additional days.
Day 1 of lactation (postpartum) is defined as the day o f 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 die lactation period, because random selection o f 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 o f 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.
A1" DMINIS....T... RATION: 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 o f a maximum 14 days. Dosage will continue through the day before sacrifice, after completion o f 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 o f a maximum of 14 days. Dosage will continue through the day before scheduled sacrifice (day 21 o f 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:PAGED-10
Dosage Levels. Concentrations and Volumes:
Protocol 418-028 Page 10
Dosage Group
Number ofRats Per Sex
Dosage (mg/kg/day)
Concentration* (mg/mL)
Dosage Volume (mL/kg)
Argus BatchNumber
I 15+ 3b
0
0
10 B-418-028-A(Day.Month.Year)
11 15+ 3b
0.3
0.03
10 B-418-028-B(Day.Month.Year)
III 15+ 3"
1
0.1
10 B-418-028-C(Day.Month.Year)
IV 15 + 3b
3
0.3
10 B-418-028-D(Day.Month.Year)
V 15+ 3b
10
1
10 B-418-028-E(Day.Month.Year)
The testsubstancewillbe considered 100% pureforthepurposeofdosagecalculations. b. Three additionalratspersexperdosagegroupwillbe assignedtotoxicokineticsamplecollection.
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 o f dosage, postdosage observations will be recorded at approximately hourly intervals for the first four hours 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 o f 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 respiratory pattern). Changes in gait, posture
418-028:PAGED-11
Protocol 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 feed jar, replenishment o f the feed jars 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 o f the study (3 pei group).
On day 14 of study and day 21 of presumed gestation, blood samples (approximately 1 mL 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 o f study. The time of each blood collection will be recorded in the raw data.
418-028-.PAGED-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 (<-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 o f 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 Study:
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.
418-028'.PAGE D-13
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 o f 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)(5'8) 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 o f the rat, will assess the following parameters:
1. Lacrimation, salivation, palpebral closure, prominence o f 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:PAGED-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 o f 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 o f blood will be 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 Coipuscular Volume (MCV) Leukocyte Count, Total (WBC) Leukocvte^B^mt. 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 o f 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-.PAGED-15
Protocol 418-028 Page 15
(within 30 minutes o f 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 o f 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 o f 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 o f the test substance.
418-028:PAGE 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 o f male rats will be conducted on day 42 of study. Scheduled sacrifice o f 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 an initial 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 Veterinary Pathologist.
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 after being pressed between glass plates to confirm the absence of implantation sites, and retained in neutral buffered 10% formalin.
418-028-.PAGED-17
Sperm Evaluations of Male Rats:
Protocol 418-028 Page 17
To assess the potential toxicity o f 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 o f the left cauda epididymis will be used to manually evaluate sperm morphology. Sperm morphology evaluations will include the following: 1) determination o f 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 of presumed gestation. Gross necropsy, examination and tissue retention will be conducted as described previously for rats at scheduled sacrifice.
Pams 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-.PAGED-18
Rats Found Dead or M oribund:
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 o f 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 o f 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 and presence 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 Dav 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 Davs 2 to 4 Postpartum:
Pups found dead or sacrificed because of moribundity will be examined for gross lesions and for the cause o f 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 o f the frontal-parietal suture and examination of the crosssectioned brain for apparent hydrocephaly.
Blood samples will be collected from each selected pup (5 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:PAGE D-20
PROPOSED STATISTICAL TESTS(9 16): The following schematic represents statistical analyses of the data.
Protocol 418-028 Page 20
I. Parametric
A. Bartlett's Testc
Type of Test3 II. Nonparametricb
A. Kruskal-Wallis Test
(<75% ties atany concentration)
Significant at p<0.001
Not Significant
Significant at p<0.05
Not Significant
Nonparametric
Analysis of Variance
Significant at p<0.05
Not Significant
Dunn's Test
B. Fisher's Exact Test on Proportion of Ties
(>75% ties at any concentration)
Dunnett's Test
B. Analysis ofVariance with Repeated Measures
Significant at p<0.05
Not Significant
(Dosage) Dunnett's Test
(Dosage x Block interaction) One-way ANOVA for each block
r
Significant atp<0.05
1
Not Significant
Dunnett's Test
III. Test for Proportion Data
Variance Test for Homogeneity of the Binomial Distribution
Statistically significant probabilities are reported as eitherp < 0.05 or/? <0.01. Proportion data are not included in this category, c. Test for homogeneity of variance.
P* F
418-028-.PAGED-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 o f 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*11*. If Bartlett'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 Nonoarametric heading o f 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 o f 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 Nonnarametric 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 Automated Data Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System, the Coulboum Instruments Passive Infrared M otor Activity System, the Coulboum 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 Automated Data Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System, M icrosoft Excel [part o f Microsoft Office 97 (version SR-2)] and/or The SAS 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 o f 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 o f 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 o f 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. Leam, 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 Staff Veterinarian). 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 Director will 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 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.
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 Reproductive and Mutagenicity 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). 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.)
4. Institute of Laboratory Animal Resources (1996). Guidefo r the Care and Use o f Laboratory Animals. 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. O'Donoghue, 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 of homogeneity of variances. Biometry, W.H. Freeman and Co., San Francisco, pp. 370-371.
418-028-.PAGED-25
Protocol 418-028 Page 25
10. Snedecor, G.W. and Cochran, W.G. (1967). Analysis o f Variance. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 258-275.
11. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1121.
12. Sokal, R.R. and Rohlf, F.J. (1969). Kruskal-Wallis Test. Biometry, W.H. Freeman and Co., San Francisco, pp. 388-389.
13. Dunn, O J. (1964). Multiple comparisons using rank sums. Technometrics 6(3):241-252.
14. Siegel, S. (1956). Nonparametric Statisticsfo r the Behavioral Sciences, McGraw-Hill, New York, pp. 96-104.
15. SAS Institute, Inc. (1988). Repeated measures analysis o f 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 Methods, 6th Edition, Iowa State University Press, Ames, pp. 240-241.
PROTOCOL APPROVAL:
FOR THE TESTING FACILITY
ljei- u
--- --
Alan M. Hobennan, Ph.D., DABT Director of Research
C J 2 - 'U -
Art Thesa H. Woodard, D.' Member, Institutional Animal Care and
Use Committee
FOR THE SPONSOR
John Butenhoff, PhD ., DABT, CIH Study Monitor and Sponsor's Representative
418-028:PAGE D-26
Protocol 418-028 Page 26
~l_
Date
r*'
^ ~v-
__2-G> Wfrih 2-00?-
Date
Date
t / p ^ s 2 .0 0 Z-
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 o f Test Substance D osage
M ale R ats
Fem ale R ats
Last Day o f Test Substance Dosage6
Last Day o f Test Substance D osagee
N atural D elivery
Presumed G estation
Postpartum Period
3 Weeks
Day 21 Day 22e
M otor A ctivity/F O B d
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 evaluation. 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 o f3
SCHEDULE"
26 MAR 02 01 APR 02
01 APR 02 - 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 o f lactation).
Cohabitation Period (Maximum of 14 days). Male 1 (7 days) Male 2 (7 days)
Day 14 Toxicokinetic Sample Collection
First Possible Day 0 o f Presumed Gestation. Last Possible Day 0 of Presumed Gestation.
First Possible Day 21 of Presumed Gestation Toxicokinetic Sample Collection and Sacrifice Toxicokinetic Study Female Rats Last Possible Day 21 of Presumed Gestation Toxicokinetic Sample Collection and Sacrifice Toxicokinetic Study Female Rats
FOB and Motor Activity Evaluation -1 0 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 of birth is 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, as described above the protocol section, "Day Numbering System."
418-028:PAGED-30
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 f3
First Possible Delivery (Day 21 of presumed gestation). Last Possible Delivery (Day 25 of presumed gestation).
First Possible Day 25 o f 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 - 10 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:PAGE D-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:... PH:..... ........... VISCOSITY:......... MELTING POINT:.....
N/A Negligible N/A Negligible slight ca. 1.0 Water=1
(Bulk) Negligible N/A N/D N/O
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
MSOS: L-9051 DEVELOPMENTAL PRODUCT December 07, 1999
PAGE 2
3. FIRE AND EXPLOSION HAZARD DATA
K A S H PUlNf:...................> 212 t Setafiash 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: May 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
USDS: 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 K20 & Exempt Solvents: N/D.
Since regulations vary, consult applicable regulations or authorities before disposal. U.S. EPA Hazardous Waste 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 Mith 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'.PAGE D-35
MSDS: 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 naterial(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 wellventilated 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 mes 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. Nash exposed areas thoroughly with soap and water. Nash 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
POTASSIUM PERFLUOROHEXANE SULFONATE........................ .. 0.1 MG/M3
RESIDUAL ORGANIC FLUOROCHEMICALS... .. 0.1 MG/M3
TWA 3M TWA 3M
* SKIN NOTATION: Listed substances indicated with `V under SKIN refer to
Abbreviations: N/D - Not Determined N/A - Not Applicable CA Approximately
418-028 :PAGE D-36
MSOS: L-9051 DEVELOPMENTAL PRODUCT December 07, 1999
EXPOSURE LIMITS
(continued)
PAGE 5
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 orf more particularly, by direct contact with the substance. Vehicles can alter skin absorption.
SOURCE OP 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, may cause:
Irritation (upper respiratory): signs/symptoms can include soreness of the nose and throat, coughing and sneezing.
IF SWALLOWED: Ingestion is not a likely route of exposure to this product.
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/0 - Not Determined N/A - Not Applicable CA - Approximately
418-028'.PAGE D-37
MSDS: L-9051 DEVELOPMENTAL PRODUCT December o7, 1999
PAGE 6
8. HEALTH HAZARD DATA
(continued)
effects fro anticipated exposure to these organic fluorochemicals when used as intended and instructed.
OTHER HEALTH HAZARD INFORMATION: This product may contain one or more organic fluorochemicals that have the potential to be absorbed and remain in the body for long periods of time, either as the parent molecule or as metabolites, and nay accumulate with repeated exposures. There are no known human health effects from anticipated exposure to these organic fluorochemicals when used as intended and instructed.
The presence of organic fluorochemicals 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. 3M MAKES NO WARRANTIES, EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OR COURSE OF PERFORMANCE OR USAGE OF TRADE. User is responsible for determining whether the 3M product is fit for a particular purpose and suitable for user's method of use or application. Given the variety of factors that can affect the use and application of a 3M product, some of which are uniquely within the user's knowledge and control, it is essential that the user evaluate the 3M product to determine whether it is fit for a particular purpose and suitable for user's method of use or application.
3M provides information in electronic form as a service to its customers. Due to the remote possibility that electronic transfer may have resulted in errors, omissions or alterations in this information, 3M makes no representations as to its completeness or accuracy. In addition,
information obtained from a database may not be as current as the
information in the MSDS available directly from 3M.
418-028'.PAGE D-38
ATTACHMENT 3 TEST SUBSTANCE PREPARATION PROCEDURE
418-028'.PAGE D-39
ATTACHMENT 3
Protocol 418-028 Version: 418-028(19 MAR 02)
Page 1 of 2 T E S T S U B S TA N C E PR E P A R A TIO N P R O C E D U R E
T est Substance: T -77 0 6
Vehicle:
Aqueous 0.5% CMC (medium viscosity)
A. Purpose:
T h e purpose o f this procedure is to provide a m ethod fo r the preparation o f dosage suspensions o f T -7 7 0 6 for oral (gavag e) adm inistration to rats on A rgus R esearch Study num ber 418-028.
B. G eneral Inform ation:
1. All suspension containers will be labeled and color-coded. E ach label will specify th e protocol num ber, test substance identification, A rgus batch num ber, concentration, dosage level, preparation d ate, expiration d ate and storage conditions.
2. Suspensions will be prepared:
__ D aily
X W eekly
_ For_ days of use
_ Approxim ately every ten days
__ By S ponsor
3. Suspensions will be adm inistered at a final dosage volum e o f 10 m L/kg.
4 . Safety: X G loves, uniform /lab coat, goggles or safety glasses w ith side shields X D ust-m ist/H EPA -filtered M ask ___ H a lf-F ace Respirator if not used in a chem ical fum e hood ___ F u ll-F ace Respirator/Positive Pressure Hood ___ Tyvek S u it or tyvek apron and sleeves
5. D osage suspensions adjusted for % Activity/Purity or Correction Factor:
__ Y es
_X _ N o (C alculations based on 1 00 % )
__ % A ctivity
__ % P u r ity ___ C orrection Factor
6. Sam pling requirem ents: Cited in protocol
7. Storage: Cited in protocol
418-028:PAGE D-40
ATTACHMENT 3
Protocol 418-028 Version: 418-028(19 MAR 021
Page 2 of 2
T E S T S U B S TA N C E P R E P A R A TIO N P R O C E D U R E
Prior to test substance preparation accurately m easure th e required am ount o f th e appropriate vehicle (R .O . deionized w ate r should be used fo r calibration purposes) in a gradu ated cylinder, pour th e required am ount o f veh icle into a beaker. C arefu lly m ark each b ea ker a t th e m eniscus. This m ark will be used during the preparation to bring th e test sub stance slurry up to volum e.
C . Dosage Suspension Preparation:
1. W eig h th e required am ount o f test substance on a piece o f w eig h pap er or
into an app ro priately sized m ortar (s e e P R E P A R A T IO N C A L C U L A T IO N S ).
2. If w eigh p ap er is used, transfer th e te s t substance to an appropriately
sized m ortar. If necessary, grind th e test substance into a fin e pow der. S low ly add a sm all am ount o f veh icle and grind. C ontinue to add vehicle slow ly and grind th e vehicle and th e test substance tog eth er to form a fine slurry. T ra n s fe r the veh icle/test substance slurry to a m arked beaker.
3. R inse th e m ortar and pestle w ith additional vehicle to rem ove any
rem aining test substance. T ran s fer rinse to beaker.
4. Add additional veh icle to the b eaker to bring volum e up to th e m ark. P lace
on m agnetic stir plate and agitate prior to and during sam pling, aliquotting an d /o r adm inistration.
5. R e p e a t steps (1 ) through (4 ) for each concentration.
W ritten E
D a te :
Y e s [see attached clarification form ]
In itia l/D ate : C (l~
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
urinary bladder
bone marrow (sternum)
testes*
ovaries
prostate
uterus
seminal vesicles (with coagulating gland) vagina
mammary gland (female rats only)
Testes will be fixed in Bourn's solution for 48 to 96 hours before being retained in neutral buffered 10% formalin.
Additionally, the remaining portion 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 f2
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.
The postlactional ovary should contain primordial and growing follicles as well as the large corpora 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 o f 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 Drive, Bldg. A Horsham, PA 19044 Telephone: (215) 4 4 3 -8 7 1 0 Telefax: (215) 4 4 3 -8 5 8 7
ARGUS RESEARCH
C harles 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:PAGE D-45
3. Estrous Cycling and Mating (page 12 o f 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 of the 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 - Toxicokinetic Study (page 16 of 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 of the protocol):
[Effective Date: 27 March 2002] The number of implantation sites will be recorded, rather than the number o f implantation sites and corpora lutea will be recorded.
Reason o f Change:
The number of corpora lutea 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 of the 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 must be made by subsequent amendment.
418-028'.PAGE D-46
Protocol 418-028 Amendment 1 Page 3
Reason for Change:
This change clarifies the protocol by removing an extraneous word.
uUL
Alan M. Hoberman, Ph.D., DABT
Director o f Research
Date Raymd Associate Director i Study Director
, DABT Date esearch
4 (i)m ^ n - 6 , .
1
Theresa H. Woodard, D.V.M. Member, Institutional Animal Care and Use Committee
Date John Butenhoff, Ph.D., DABT, CIH Date Study Monitor and Sponsor's Representative
Any revisions made to this finalized amendment must be made by subsequent amendment.
418-028 :PAGE D-47
905 Sheehy Drive, Bfdg: A
Horsham, PA 1 9 0 4 4 Telephone: (215) 4 4 3 4 7 1 0 Telefax: ( 2 / 5 ) 4 4 3 -8 5 8 7
ARGUS RESEARCH
C harles R iver L ab oratories 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- 15 July 2002
1. Safety Precautions (page 3 of 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 of 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 1page 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.
Ian Mloberman, Ph.D., DABT Director o f Research
Raymond G. Yor] Associate Director Study Director
L, DABT Date search
____ Theresa H. Woodard, DiV.M. Member, Institutional Animal Care and Use Committee
'7
Date John ButenhofF, Ph.D., DABT, CIH Date Study Monitor and Sponsor's Representative
2&s>.
Any revisions to this finalized amendment must be made by subsequent amendment.
418-028 :PAGE D-49
905 Sheehy Drive, Bldg. A Horsham, PA 19 0 4 4 Telephone: (215) 443-8710 Telefax: ( 2 / 5 ) 4 4 3 -8 5 8 7
ARGUS RESEARCH
Chartes R iver L a b 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. 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)
[Effective Date: 29 May 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 of the protocol) Stability (page 5 of the protocol) Plasma toxicokinetic samples (page 11 to 12 and page 16 of the protocol) Plasma samples, rather than serum samples, were retained. Liver toxicokinetic samples (pages 12 and 16 of the protocol) Pooled fetal serum toxicokinetic samples (pages 12 and 16 of the protocol) Pooled fetal liver toxicokinetic samples (pages 13 and 16 of the protocol) Pooled pup serum toxicokinetic samples (page 19 of the protocol) Pup liver toxicokinetic samples (page 19 of the protocol)
The analyses will 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 of 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 of the inspections and report submissions will 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 of the Sponsor because 3M is not able to complete the formulation analysis with their current staffing.
1 L .___
Theresa H. Woodard, D.V.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-51
905 SheehyDrive. Bldg. A Horsham, PA 19044 Telephone*(2IS) 443-8710 Telefax: (215) 443-8587
ARGUS RESEARCH
Chartes R iver L a b 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 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, 12,13,16 and 19, respectively of the protocol) and Amendment 3. Item 1: Bulk Test Substance Sampling. Shipping Instructions. Shipping Instructions. Caesarean-Sectioning - Toxicokinetic Study. Scheduled Sacrifice - Toxicokinetic Study, and Scheduled Sacrifice (page 1 of 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 amendment.
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.
Alan M. foberman, Ph.D., DABT Director Research
Date Study Director
2 & c?2_
f.D., DABT Date "Research
D&iigla^B. 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-l
DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY
The following rats were not fasted overnight prior to necropsy.
Dosage Group
I
Dosage (mg/kg/day)
0
II 0.3
III 1 IV 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.
Postdosage observations were performed out of the range of 60 10 minutes on the following dates.
Dosage Dosage Group (mg/kg/day)
I0
IV 3
Date 09 APR 02 03 JUN 02 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.
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.
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
12. 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.
Study Director
APPENDIX F CERTIFICATE OF ANALYSIS
418-028:PAGEF-1
Certificate of Analysis
Nominal Product: Potassium perfluorohexanesulfonate: C6Fi3S 0 3w K(+) Product Code: PFHS; 127498-80 April 15, 2002 Tom Kestner and Joel Miller
The sample o f 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 1H-NMR Analyses
Component Identities *
Relative Wt.% Concentrations
(single trial measurements, excluding any water)
CF3CF2CF2CF2CF2CF2S03('>k (+)
88.93% (NMR)
(CF3)2-CF-(CF2)3-S03(-) k (+)
6.83% (NMR)
CF3CF2-CF(CF3)-CF2CF2-S03t') K(+)
2.75% (NMR)
CF3CF2CF2CF2-CF(CF3)-S03(') k (+)
0.83% (NMR)
CF3CF2CF2CF(CF3)-CF2-S03() k (+)
0.56% (NMR)
(CF3)3-C-CF2-CF2S 0 3h k {+)
0.078% (NMR)
C gF ^H SO ^ K(+)
0.009% (LCMS)
C7Fi5S 0 3(') Ki+)
0.006% (LCMS)
C4F9S03(', K(+)
0.004% (LCMS)
Probable C,,H2n+2 hydrocarbons
0.0034% (NMR)
Other components
Sum o fC 6F13S 0 3(') K(+) 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 & 19F-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-S03WKi+) (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 o f the sample (~400 mg) was totally dissolved in deuterated dimethylsulfoxide (DMSO-dg) and then the solution was spiked with a small amount o f 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 (# 02537.GDD.401) were acquired at room temperature using a Varian UNITYplus 400 FT-NMR spectrometer. The p-HFX was used as a lH/19F-NMR cross integration standard to permit the cross correlation o f the relative *H and 19F signal intensities for evaluation o f the overall sample composition.
RESULTS:
The combined NMR spectral data indicated the sample of 127498-80 consisted o f a high purity form of the nominal isomeric product mixture, CnF2n+i-S03(') M(+), where `n' was mainly 6 and where the metal cation [`M(+)'] was assumed to be K(+). Trace-levels o f probable aliphatic hydrocarbon impurity components were also observed and quantified.
The qualitative and quantitative compositional results that were derived from the single trial 'H/^F-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
File Reference: dh32537.GID.doc/93
Page 1 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/^F-NMR Cross Integration Analysis
Identified Components *
^ F /'H-NM R Relative Wt.% Concentrations
(single trial measurement)
CF3CF2CF2CF2CF2CF2S 03H k (+)
88.94%
(CF3)2-CF-(CF2)3-S03(`) k (+)
6.83%
CF3CF2-CF(CF3)-CF2CF2- S 0 3{') k <+)
2.75%
CF3CF2CF2CF2-CF(CF3) - S 0 3(') k (+)
0.83%
CF3CF2CF2CF(CF3)-CF2-S03(-) k (+)
0.56%
(CF3)3-C-CF2-CF2S 0 3(-) k (+)
0.078%
Probable CnH2n+2 hydrocarbons
0.0034%
* Trace amounts of other unassigned components were also detected in the NMR spectra.
Study No. FACT-TCR008
Page 2 o f 2
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 of 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.
2J
John Flaherty Principal Investigator Exygen Research
7 /j// Z
Date
Z YJ&t- 2 003
Date
John Butenhoff Study Monitor 3M Corporate Toxicology
Date
Exygen Research
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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 of 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 Insoected
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
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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:
7 A /A S
Date
Exygen Research Facility Management:
Date
Study Monitor, 3M: John Butenhoff 3M Corporate Toxicology
Exygen Research
y j'dL
Date
ZB TUL~
Date
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418-028:PAGE G-5 Exygen Study No.: 023-072
STUDY IDENTIFICATION
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
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
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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 of 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
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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 of 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
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Table I.
LIST OF TABLES Page
Summary of PFHS in Control Rat Plasma Samples.....................................21
Table II. Summary of PFHS in Control Rat Serum Samples......................................21
Table III. Summary of PFHS in Control Rat Liver Samples........................................ 21
Table IV. Summary of PFHS Fortification Recoveries in Rat Plasma......................... 22
Table V. Summary of 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 of PFHS Residues in Homogeneity Samples................................42
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LIST OF FIGURES Page
Figure 1. Typical Calibration Curve for PFHS........................................................... 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 C ontrol, Data Set: 100202A )........................................ 48
Figure 6. Chromatogram Representing Control Rat Plasma Sample Fortified with 10 ppb of PFHS (Exygen ID: 0202913 Spk A, Data Set: 091602B).....49
Figure 7. Chromatogram Representing Control Rat Serum Sample Fortified with 10 ppb of PFHS (Exygen ID: 0202987 Spk A, Data Set: 091902B).....50
Figure 8. Chromatogram Representing Control Rat Liver Sample Fortified with 10 ppb of PFHS (Exygen ID: 0202877 Spk A, Data Set: 100202A)....51
Figure 9. Chromatogram Representing Rat Plasma Sample Analyzed for PFHS (Exygen ID: 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
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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
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1.0 SUMMARY
Exygen Resarch extracted and analyzed rat liver, serum, and plasma samples for the determination of perfluorohexanesulfonate (PFHS) according to Exygen Method ExM023-071 Revision 1 (Appendix B).
The limit of 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 OBJECTIVE
The objective of the analytical part of this study was to determine levels of perfluorohexanesulfonate (PFHS) in specimens of 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 of 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 of 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.
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4.0 ANALYTICAL TEST SAMPLES
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.
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5.0 REFERENCE MATERIAL
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 of test substance is given below:
Name: PFHS Chemical Name: Perfluorohexanesulfonate Molecular Weight: 399
6.0 DESCRIPTION OF ANALYTICAL METHOD
The analytical method ExM-023-071 Revision 1 was used for this study.
6.1. Extraction Procedure
A 1 mL aliquot of the serum and plasma and 1 g of 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 of 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 of 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 of 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 of the bulk test substance was weighed and brought to volume with methanol in a 100-mL volumetric flask. The
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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 of 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.
6.3 Chromatography
Quantification of PFHS was accomplished by LC/MS/MS electrospray. The retention time of 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 of 0.0001 pg/mL of PFHS.
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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 C8(Jones Chromatography), 2.1 mm x 50 mm, 4ju
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 (mL/mini 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
Approximate
Transition Monitored Retention Time (mini
399 --^ 80
~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 of analyte found (in ng/mL, based on peak area) using the standard curve (linear regression parameters) generated by the Masslynx software
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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 (mLl sample volume (mL) or sample weight (g) Where: FV = Final Volume
For samples fortified with known amounts of PFHS prior to extraction, Equation 3 calculated the percent recovery.
Equation 3: Recovery (%) =
((analvte found (ppb) - analvte in control (ppbfi 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 ppb added (fort level)
1
10
avg. amt in controls
0 (Not Detected)
final volume
2 mL
aliquot factor
10
sample weight
1.0 g
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From equation 1: Analyte found (ng/mL)
From equation 2: Analyte found (ppb)
From equation 3: % Recovery
From equation 4: Analyte Found Corrected (ppb)
2125-41.03651 x 1 x 10 4728.12
4.41 ng/mL
(4,41 ng/mL x 2 mLl 0-0 g)
8.82 ppb
((8.82 nob - Oppbl x 100% 10 ppb
88%
8.82 ppb x 0.91
8.03 ppb
7.0 EXPERIMENTAL DESIGN
Each set of samples (liver, serum or plasma) consisted of 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.
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8.0 RESULTS
The PFHS found in the control rat plasma, serum, and liver samples are listed in Tables I-III. Peaks were not detected in any of 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 of 10 ppb.
Fortification recoveries for PFHS in the rat plasma, serum, and liver samples are detailed in Tables IV-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 VIII. 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% of 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% of their known concentrations. The results are listed in Table XII.
9.0 CONCLUSIONS
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.
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10.0 RETENTION OF DATA AND SAMPLES
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 of 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 of 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.
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TABLES
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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 III. Summary of PFHS in Control Rat Liver Samples
Sponsor ID
LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824
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 ID
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 SpkC 0202913 Spk A 0202913 SpkB 0201816 SpkC 0202912 Spk A 0202912 SpkB 0201846 SpkC 0202913 Spk A 0202913 SpkB 0201831 SpkC
Set Number
Amount Added (ppb)
091602A
10
091602A
50
091602A 091602B 091602B
5000 10 50
091602B
5000
091802A 091802A 091802A 091902A
10 50 5000 10
091902A 091902A
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 of PFHS Fortification Recoveries in Rat Serum
Sponsor ID
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 ID
0202987 Spk A 0202987 SpkB 0201861 SpkC 0202987 Spk A 0202987 SpkB 0201875 SpkC 0202987 Spk A 0202987 Spk B 0201890 SpkC 0202987 Spk A 0202987 SpkB 0201905 SpkC 0202987 Spk A 0202987 SpkB
Set Number
Amount Added (ppb)
091902B
10
091902B 091902B 092002A
50 5000
10
092002A 092002A 092002B
50 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 m
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 I, Male 1 LOT 21824 LOT 21824 19018 GROUP II, Male 1 LOT 21824 LOT 21824 19041 GROUP I, Male 1 LOT 21824 LOT 21824 19036 GROUP II, Male 1 LOT 21824 LOT 21824 19003 GROUP m , Male 1 LOT 21824 LOT 21824 19008 GROUP III, Male 1 LOT 21824 LOT 21824 19015 GROUP III, Male 1 LOT 21824 LOT 21824 19035 GROUP IV, Male 1 LOT 21824 LOT 21824 19040 GROUP IV, Male 2 LOT 21824 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 Spk A 0202877 SpkB 0201788 Spk C 0202877 Spk A 0202877 SpkB 0201925 Spk C 0202877 Spk A 0202877 SpkB 0201945 Spk C 0202877 Spk A 0202877 SpkB 0202050 Spk C 0202877 Spk A 0202877 SpkB 0201965 Spk C 0202877 Spk A 0202877 SpkB 0202070 Spk C 0202877 Spk A 0202877 SpkB 0202119 Spk C 0202877 Spk A 0202877 SpkB 0202139 Spk C 0202877 Spk A 0202877 SpkB 0202159 Spk C 0202877 Spk A 0202877 SpkB 0202229 Spk C 0202877 Spk A 0202877 SpkB 0202249 Spk C 0202877 Spk A 0202877 SpkB 0202320 Spk C 0202877 Spk A 0202877 SpkB 0202340 Spk C 0202877 Spk A 0202877 SpkB 0202360 Spk C
Exygen Research
Set Amount Number Added (ppb)
092802A
10
092802A
50
092802A
5000
092602A
10
092602A
50
092602A
5000
092602B
10
092602B
50
092602B 092702A
5000 10
092702A 092702A
50 5000
092702B
10
092702B
50
092702B
5000
100202A
10
100202A
50
100202A 100102A 100102A
5000 10 50
100102A
5000
100302A 100302A
10 50
100302A 100402A
5000 10
100402A 100402A
50 5000
100402BR
10
100402BR 100402BR 100902AR
50 5000
10
100902AR 100902AR 100902BR
50 5000
10
100902BR 100902BR
50 5000
101002A
10
101002A
50
101002AR
5000
101002B
10
101002B 101002BR
50 5000
101102AR
10
101102AR
50
101102AR
25000
101402A
10
101402A
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
Sponsor ED
19176 GROUP I 19176 G R O U P I* 19177 GROUP I 19177 G R O U P I* 19178 GROUP I 19178 G R O U P I* 19179 GROUP n 19179 G R O U P II* 19180 GROUP n 19180 G R O U P II* 19181 GROU P H 19181 G R O U P II* 19182 GROUP ffl 19182 GROUP HI* 19183 GROU P III 19183 GROUP ffl* 19184 G R O U P in 19184 GROUP HI* 19185 G R O U P T V 19185 GROUP IV* 19186 G R O U P IV 19186 G ROUP IV* 19187 G R O U P IV 19187 GROUP IV* 19188 GROU P V 19188 GROU P V* 19189 GROU P V 19189 GROUP V* 19190 GROUP V 19190 GROUP V* 19176 GROUP I 19176 G R O U P I* 19177 GROUP I 19177 G R O U P I* 19178 G ROUP I 19178 G R O U P I* 19179 GROUP II 19179 G R O U P D* 19180 GROUP II 19180 G R O U P II* 19181 GROUP D 19181 G R O U P II* 19182 GROUP III 19182 GROUP in * 19183 GROUP in 19183 GROUP HI* 19184 GROUP ffl 19184 GROUP III* 19185 G R O U P IV 19185 GROUP IV* 19186 G R O U P IV 19186 GROUP IV* 19187 GR O U P IV 19187 GROUP IV* 19188 GROUP V 19188 GROUP V* 19189 GROUP V 19189 GROUP V* 19190 GROUP V 19190 GROUP V*
Exygen ID
0201801 0201801 Dup Inj.
0201802 0201802 D up Inj.
0201803 0201803 Dup Inj.
0201804 0201804 D up Inj.
0201805 0201805 D up Inj.
0201806 0201806 D up Inj.
0201807 0201807 D up Inj.
0201808 0201808 Dup Inj.
0201809 0201809 Dup Inj.
0201810 0201810 Dup Inj.
0201811 0201811 Dup Inj.
0201812 0201812 Dup Inj.
0201813 0201813 Dup Inj.
0201814 0201814 Dup Inj.
0201815 0201815 D up Inj
0201816 0201816 D up Inj
0201817 0201817 D up Inj
0201818 0201818 D up Inj
0201819 0201819 D up Inj
0201820 0201820 D up Inj
0201821 0201821 D up Inj
0201822 0201822 D u p Inj
0201823 0201823 D up Inj
0201824 0201824 D u p Inj
0201825 0201825 D up Inj
0201826 0201826 D up Inj
0201827 020 827 D u p Inj
0201828 0201828 D u p Inj
0201829 0201829 D up Inj
0201830 0201830 D up Inj
Matrix
PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 4 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 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 PD 42 PLASMA
CoUection Date
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 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02
Set Number
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 091602B 091602B 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR
PFHS Found (ng/mL)
182 172 103 108 4 6 .5 "' 4 3 . 3 AA 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 7 4 .7 " 6 5 .4 " 57400 60200 35700 36400 37100 38500 91000 85900 90300 87500 90700 89300 119000 119000 137000 142000 128000 127000 188000 188000 224000 225000 191000 193000
AAA lthough die m ethod u sed allow s for alternate sample volum es or w eights and all the peak area responses are within the calibration curve limits, the precision for the 0.1 m L or 0.1 g samples below 100 ppb has not been validated. * Duplicate Injection
Exygen Research
Page 24 of 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 GROUP I 19076 GROUP I* 19077 GROUP I 19077 GROUP I* 19078 GROUP I 19078 GROUP I* 19079 G ROU P II 19079 G ROU P II* 19080 GROUP II 19080 GROUP H* 19081 GROUP n 19081 G R O U P 11* 19082 GROUP i n 19082 GROUP n i* 19083 GROUP III 19083 GROUP III* 19084 GROUP III 19084 GROUP III* 19085 GROUP IV 19085 GROUP IV* 19086 GROUP IV 19086 GROUP IV* 19087 GROUP IV 19087 GROUP IV* 19088 GROUP V 19088 GROUP V* 19089 GROUP V 19089 GROUP V* 19090 GROUP V 19090 GROUP V* 19076 GROUP I 19076 GROUP I* 19077 GROUP I 19077 GROU P I* 19078 GROUP I 19078 GROUP I* 19079 GROU P II 19079 G ROU P II* 19080 G R O U P II 19080 G R O U P 11* 19081 G ROU P II 19081 G R O U P II* 19082 GROU P III 19082 GROUP III* 19083 GROU P ID 19083 GROUP III* 19084 GROUP III 19084 GROU P III* 19085 GROUP IV 19085 GROUP IV* 19086 GROUP IV 19086 G ROU P IV* 19087 GROUP IV 19087 GROUP IV* 19088 GROUP V 19088 GROUP V* 19089 GROUP V 19089 GROUP V* 19090 GROUP V 19090 GROUP V*
* Duplicate Injection
Exygen ID
0201846 0201846 D up Inj
0201847 0201847 Dup Inj
0201848 0201848 Dup Inj
0201849 0201849 D up Inj
0201850 0201850 D up Inj
0201851 0201851 D up Iiy
0201852 0201852 D up Inj
0201853 0201853 Dup by
0201854 0201854 D up Inj
0201855 0201855 D up Inj
0201856 0201856 Dup Inj
0201857 0201857 Dup Inj
0201858 0201858 Dup Inj
0201859 0201859 Dup Inj
0201860 0201860 D up Inj
0201831 0201831 Dup Inj
0201832 0201832 Dup Inj
0201833 0201833 Dup Inj
0201834 0201834 D up Inj
0201835 0201835 Dup Inj
0201836 0201836 D up Inj
0201837 0201837 D up Inj
0201838 0201838 Dup Inj
0201839 0201839 D up Inj
0201840 0201840 D up Inj
0201841 0201841 D up Inj
0201842 0201842 Dup Inj
0201843 0201843 D up Inj
0201844 0201844 Dup Inj
0201845 0201845 D up Inj
Matrix
GD 21 PLASMA GD 21 PLASMA GD 21 PLASM A GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA G D 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA G D 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA PD 14 PLASM A PD 14 PLASM A PD 14 PLA SM 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 PLA SM A PD 14 PLASM A PD 14 PLA SM A PD 14 PLA SM A PD 14 PLASM A PD 14 PLA SM A PD 14 PLA SM A PD 14 PLASM A PD 14 PLASM A PD 14 PLASM A PD 14 PLASM A PD 14 PLA SM 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 PLA SM A PD 14 PLA SM A PD 14 PLASM A
Collection 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 091802A R 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091902A 091902A 091902A 091902A 091902A 091902A 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR
PFHS Found (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 o f 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
Sponsor
ID
19076 GROUP I 19076 GROUP I* 19078 GROUP I 19078 GROUP I* 19079 GROUP n 19079 GROUP D* 19080 GROU P II 19080 GROUP II* 19081 G R O U P II 19081 GROUP II* 19082 GROUP ffl 19082 GROUP ID* 19083 G R O U P HI 19083 GROUP ffl* 19084 GROUP ffl 19084 GROUP ffl* 19085 GROUP IV 19085 GROUP IV* 19086 GROUP IV 19086 GROUP IV* 19087 GROUP IV 19087 GROUP IV* 19088 GROUP V 19088 GROUP V* 19089 GROUP V 19089 GROUP V* 19090 GROUP V 19090 GROUP V* 19012 GROUP I 19012 GROUP I* 19019 GROUP I 19019 GROUP I* 19021 GROUP I 19021 GROU P I* 19023 GROUP I 19023 GROU P I* 19041 GROU P I 19041 GROUP I* 19042 GROUP I 19042 GROUP I* 19044 GROUP I 19044 GROUP I* 19050 GROUP I 19050 GROUP I* 19053 GROUP I 19053 GROUP I* 19065 GROUP I 19065 GROUP I* 19004 G R O U P II 19004 GROUP n* 19009 GROUP n 19009 GROUP n* 19016 GROUP n 19016 GROUP II* 19018 GROUP n 19018 GROUP R* 19026 G R O U P 11 19026 GROUP H* 19036 GROUP n 19036 GROUP II*
Exygen
ID
0201861 0201861 Dup Inj
0201862 0201862 Dup Inj
0201863 0201863 Dup Inj
0201864 0201864 Dup Inj
0201865 0201865 Dup Inj
0201866 0201866 Dup Inj
0201867 0201867 Dup Inj
0201868 0201868 Dup Inj
0201869 0201869 Dup Inj
0201870 0201870 Dup Inj
0201871 0201871 Dup Inj
0201872 0201872 Dup Inj
0201873 0201873 Dup Inj
0201874 0201874 Dup Inj
0201875 0201875 Dup Inj
0201876 0201876 Dup Inj
0201877 0201877 Dup Inj
0201878 0201878 Dup Inj
0201879 0201879 Dup Inj
0201880 0201880 Dup Inj
0201881 0201881 Dup Inj
0201882 0201882 Dup Inj
0201883 0201883 Dup Inj
0201884 0201884 Dup Inj
0201885 0201885 Dup Inj
0201886 0201886 Dup Inj
0201887 0201887 Dup Inj
0201888 0201888 Dup Inj
0201889 0201889 Dup Inj
0201890 0201890 Dup Inj
M atrix
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 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 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 Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled P up Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled P up Serum Pooled P up Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled P up Serum Pooled Pup Serum Pooled P up Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum
C ollection
Date
5/9/02 5/9/02 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 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 Num ber
091902B 091902B 091902B 091902B 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002AR. 092002A R 092002AR 092002A R 092002AR 092002AR 092002AR 092002AR 092002AR 092002AR 092002BR 092002BR
PFHS F ound (ng/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 6 5 . 3 AA 6 8 . 9 AA 8 1 .1 ^ 86.0** 4 5 .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 of 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 II 19037 GROUP H* 19043 GROUP II 19043 GROUP n * 19047 GROUP II 19047 GROUP H* 19048 GROUP H 19048 GROUP n * 19003 GROUP III 19003 GROUP III 19007 GROUP m 19007 GROUP m * 19008 GROUP HI 19008 GROUP HI* 19013 GROUP i n 19013 GROUP HI* 19015 GROUP III 19015 GROUP III* 19017 GROUP HI 19017 GROUP m * 19024 GROUP IH 19024 GROUP HI* 19029 GROUP m 19029 GROUP in * 19034 GROUP HI 19034 GROUP III* 19056 GROUP m 19056 GROUP HI* 19005 GROUP IV 19005 GROUP IV* 19035 GROUP IV 19035 GROUP IV* 19039 GROUP IV 19039 GROUP IV* 19040 GROUP IV 19040 GROUP IV* 19045 GROUP IV 19045 GROUP IV* 19054 GROUP IV 19054 GROUP IV* 19058 GROUP IV 19058 GROUP IV* 19062 GROUP IV 19062 GROUP IV* 19063 GROUP IV 19063 GROUP IV* 19066 GROUP IV 19066 GROUP IV* 19001 GROUP V 19001 GROUP V* 19006 GROUP V 19006 GROUP V* 19011 GROUP V 19011 GROUP V* 19020 GROUP V 19020 GROUP V* 19022 GROUP V 19022 GROUP V* 19025 GROUP V 19025 GROUP V* 19027 GROUP V 19027 GROUP V* 19028 GROUP V 19028 GROUP V* 19030 GROUP V 19030 GROUP V* 19031 GROUP V 19031 GROUP V*
* Duplicate Injection
Exygen
n>
0201891 0201891 Dup Inj
0201892 0201892 Dup Inj
0201893 0201893 Dup Inj
0201894 0201894 Dup Inj
0201895 0201895 Dup Inj
0201896 0201896 Dup Inj
0201897 0201897 Dup Inj
0201898 0201898 Dup Inj
0201899 0201899 Dup Inj
0201900 0201900 Dup Inj
0201901 0201901 Dup Inj
0201902 0201902 Dup Inj
0201903 0201903 Dup Inj
0201904 0201904 Dup Inj
0201905 0201905 Dup Inj
0201906 0201906 Dup Inj
0201907 0201907 Dup Inj
0201908 0201908 Dup Inj
0201909 0201909 Dup Inj
0201910 0201910 Dup Inj
0201911 0201911 Dup Inj
0201912 0201912 Dup Inj
0201913 0201913 Dup Inj
0201914 0201914 Dup Inj
0201915 0201915 Dup Inj
0201916 0201916 Dup Inj
0201917 0201917 Dup Inj
0201918 0201918 Dup Inj
0201919 0201919 Dup Inj
0201920 0201920 Dup Inj
0201921 0201921 Dup Inj
0201922 0201922 D ip Inj
0201923 0201923 Dup Inj
0201924 0201924 Dup Inj
Matrix
Pooled Pup Serum Pooled Pup Serum Pooled Pup Seram Pooled Pup Serum Pooled P ip Seram Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Seram Pooled Pup Seram Pooled Pup Seram Pooled Pup Serum Pooled Pup Serum Pooled Pup Seram Pooled Pup Seram Pooled Pup Seram Pooled Pup Seram Pooled Pup Seram Pooled Pup Serum Pooled Pup Seram Pooled Pup Serum Pooled Pup Serum Pooled Pup Seram Pooled Pup Serum Pooled Pup Serum Pooled Pup Seram Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Seram Pooled Pup Serum Pooled Pup Seram Pooled Pup Seram Pooled Pup Seram Pooled Pup Seram Pooled Pup Serum Pooled Pup Serum Pooled Pup Seram Pooled Pup Serum Pooled Pup Serum Pooled Pup Seram Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Seram Pooled Pup Seram Pooled Pup Serum Pooled Pup Serum Pooled Pup Seram Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Seram Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Seram Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum
Collection Date
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 5/29/02 5/31/02 5/31/02 5/28/02 S/28/02 5/31/02 5/31/02 5/29/02 5/29/02 5/30/02 5/30/02 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 5/13/02 5/13/02 5/14/02 5/14/02 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 Number
092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002 BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002 BR 092002BR 092002BR 092002BR 092002BR 092002BR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR
PFHS Found (ng/mL)
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
Sponsor ID
19176 GROUP 1 19176 GROUP I* 19177 GROUP I 19177 GROUP I* 19178 GROUP I 19178 GROUP I* 19179 GROUP U 19179 GROUP II* 19180 GROUP II 19180 GROUP n* 19181 GROUP n 19181 GROUP II* 19182 GROUP III 19182 GROUP m* 19183 GROUP 111 19183 GROUP IH* 19184 GROUP m 19184 GROUP ffl* 19185 GROUP IV 19185 GROUP IV* 19186 GROUP IV 19186 GROUP IV* 19187 GROUP IV 19187 GROUP IV* 19188 GROUP V 19188 GROUP V* 19189 GROUP V 19189 GROUP V* 19190 GROUP V 19190 GROUP V* 19076 GROUP I 19076 GROUP I* 19077 GROUP I 19077 GROUP I* 19078 GROUP I 19078 GROUP I* 19081 GROUP n Female 1 19081 GROUP IIFemale 1* 19079 GROUP II 19079 GROUP II* 19080 GROUP II 19080 GROUP U* 19082 GROUP ffl 19082 GROUP HI* 19083 GROUP III 19083 GROUP ffl* 19084 GROUP III 19084 GROUP III* 19085 GROUP IV 19085 GROUP IV* 19086 GROUP IV 19086 GROUP IV*
Exygen LD
0201759 0201759 Dup Inj
0201760 0201760 Dup Inj
0201761 0201761 Dup Inj
0201762 0201762 Dup Inj
0201763 0201763 Dup Inj
0201764 0201764 Dup Inj
0201765 0201765 Dup Inj
0201766 0201766 Dup Inj
0201767 0201767 Dup Inj
0201768 0201768 Dup Inj
0201769 0201769 Dup Inj
0201770 0201770 Dup Inj
0201771 0201771 Dup Inj
0201772 0201772 Dup Inj
0201773 0201773 Dup Inj
0201774 0201774 Dup Inj
0201775 0201775 Dup Inj
0201776 0201776 Dup Inj
0203650 0203650 Dup Inj
0201777 0201777 Dup Inj
0201778 0201778 Dup Inj
0201779 0201779 Dup Inj
0201780 0201780 Dup Inj
0201781 0201781 Dup Inj
0201782 0201782 Dup Inj
0201783 0201783 Dup Inj
M atrix
Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe
Collection Date
5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/9/02 5/9/02 5/19/02 5/19/02 5/7/02 5/7/02 5/10/02 5/10/02 5/9/02 5/9/02 5/9/02 5/9/02 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
Set Number
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 092602AR 092602AR 092602AR 092602AR 092602A R 092602AR 092602AR 092602AR 092602A R 092602AR 092602AR 092602AR 092602AR
PFHS Found (ng/mL)
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 82.2TM 82.4TM 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 o f 153
418-028:PAGE G-29
Exygen Study No.: 023-072
Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples
Sponsor ID
Exygen ID
19087 GROUP IV 19087 GROUP IV* 19088 GROUP V
0201784 0201784 Dup Inj
0201785
19088 GROUP V* 19089 GROUP V 19089 GROUP V* 19090 GROUP V 19090 GROUP V*
0201785 Dup Inj 0201786
0201786 Dup Inj 0201787
0201787 Dup Inj
19076 GROUP I 19076 GROUP I* 19078 GROUP I 19078 GROUP I* 19081 GROUP n Female 2 19081 GROUP IIFemale 2* 19079 GROUP II 19079 GROUP H* 19080 GROUP II
0201788 0201788 Dup Inj
0201789 0201789 Dup Inj
0203651 0203651 Dup Inj
0201790 0201790 Dup Inj
0201791
19080 GROUP II* 19082 GROUP HI 19082 GROUP EH* 19083 GROUP IU 19083 GROUP ffl* 19084 GROUP ffl 19084 GROUP 111* 19085 GROUP IV 19085 GROUP IV* 19086 GROUP IV 19086 GROUP IV* 19087 GROUP IV 19087 GROUP IV* 19088 GROUP V 19088 GROUP V* 19089 GROUP V 19089 GROUP V* 19090 GROUP V 19090 GROUP V* 19012 GROUP I,Male 1 19012 GROUP I,Male 1* 19012 GROUP I,Male 2 19012 GROUP I,Male 2*
0201791 Dup Inj 0201792
0201792 Dup Inj 0201793
0201793 Dup Inj 0201794
0201794 Dup Inj 0201795
0201795 Dup Inj 0201796
0201796 Dup Inj 0201797
0201797 Dup Inj 0201798
0201798 Dup Inj 0201799
0201799 Dup Inj 0201800
0201800 Dup Inj 0201925
0201925 Dup Inj . 0201926 0201926 Dup Inj
19012 GROUP I,Male 3 19012 GROUP I,Male 3* 19012 GROUP I,Male 4 19012 GROUP I,Male 4*
0201927 0201927 Dup Inj
0201928 0201928 Dup Inj
19012 GROUP I,Male 5
0201929
19012 GROUP I,Male 5* 19012 GROUP I,Female 7 19012 GROUP I,Female 7* 19012 GROUP I,Female 8 19012 GROUP I,Female 8* 19012 GROUP I,Female 14 19012 GROUP I,Female 14*
0201929 Dup Inj 0201930
0201930 Dup Inj 0201931
0201931 Dup Inj 0201932
0201932 Dup Inj
M atrix
Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Median LiverLobe Fooled FetalLiver Pooled FetalLiver Pooled FetalLiver Pooled FetalLiver Pooled FetalLiver Pooled FetalLiver Pooled Fetal Liver Pooled FetalLiver Pooled Fetal Liver Pooled FetalLiver Pooled FetalLiver Pooled FetalLiver Pooled Fetal Liver Pooled FetalLiver Pooled FetalLiver Pooled FetalLiver Pooled FetalLiver Pooled FetalLiver Pooled FetalLiver Pooled FetalLiver Pooled Fetal Liver Pooled FetalLiver Pooled FetalLiver Pooled FetalLiver Pooled FetalLiver Pooled FetalLiver Pooled FetalLiver Pooled FetalLiver
Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers
CoUecton Date 5/6/02 5/6/02 5/9/02 5/9/02 5/9/02 5/9/02 5/9/02 5/9/02 5/9/02 5/9/02 5/7/02 5/7/02 5/10/02 5/10/02 5/9/02 5/9/02 5/9/02 5/9/02 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 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02
Set Number
092602AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602B 092602B 092602B 092602B 092602B 092602B 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A
PFHS Found (ng/mL)
7500 7210 19000 20000 15100 15300 14700 15100 27 y A A
25.7/'A 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
^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 29 o f 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
19012 GROUP I,Female 15 19012 GROUP I,Female 15* 19012 GROUP I,Female 16 19012 GROUP I,Female 16*
19019 GROUP I,Male 1 19019 GROUP I,Male 1* 19019 GROUP I,Male 2 19019 GROUP I,Male 2* 19019 GROUP I,Male 3 19019 GROUP I,Male 3* 19019 GROUP I,Male 7 19019 GROUP I,Male 7* 19019 GROUP I,Male 8 19019 GROUP I,Male 8* 19019 GROUP I,Female 11 19019 GROUP I,Female 11* 19019 GROUP I,Female 12 19019 GROUP I,Female 12* 19019 GROUP I,Female 13 19019 GROUP I,Female 13* 19019 GROUP I,Female 14 19019 GROUP I,Female 14* 19019 GROUP I,Female 15 19019 GROUP I,Female 15* 19021 GROUP I,Male 1 19021 GROUP I,Male 1* 19021 GROUP I,Male 2 19021 GROUP I,Male 2* 19021 GROUP I,Male 6 19021 GROUP I,Male 6* 19021 GROUP I,Male 8 19021 GROUP I,Male 8* 19021 GROUP I,Male 9 19021 GROUP I,Male 9* 19021 GROUP I,Female 11 19021 GROUP I,Female 11* 19021 GROUP I,Female 12 19021 GROUP I,Female 12* 19021 GROUP I,Female 13 19021 GROUP I,Female 13* 19021 GROUP I,Female 14 19021 GROUP I,Female 14* 19023 GROUP I,Male 1 19023 GROUP I,Male 1* 19023 GROUP I,Male 2 19023 GROUP I,Male 2* 19023 GROUP I,Male 3 19023 GROUP I,Male 3* 19023 GROUP I,Male 6 19023 GROUP I,Male 6* 19023 GROUP I,Male 7 19023 GROUP I,Male 7*
Exygen ID
0201933 0201933 Dup Inj
0201934 0201934 Dup Inj
0201935 0201935 Dup Inj
0201936 0201936 Dup Inj
0201937 0201937 Dup Inj
0201938 0201938 Dup Inj
0201939 0201939 Dup Inj
0201940 0201940 Dup Inj
0201941 0201941 Dup Inj
0201942 0201942 Dup Inj
0201943 0201943 Dup Inj
0201944 0201944 Dup Inj
0201945 0201945 Dup Inj
0201946 0201946 Dup Inj
0201947 0201947 Dup Inj
0201948 0201948 Dup Inj
0201949 0201949 Dup Inj
0201951 0201951 Dup Inj
0201952 0201952 Dup Inj
0201953 0201953 Dup Inj
0201954 0201954 Dup Inj
0201955 0201955 Dup Inj
0201956 0201956 Dup Inj
0201957 0201957 Dup Inj
0201958 0201958 Dup Inj
0201959 0201959 Dup Inj
M atrix
Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers
Collection Date 5/29/02 5/29/02 5/29/02 5/29/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02
Set Number
092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 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 21.7TM 18.3TM 20.5TM 18.9TM ND ND ND ND ND ND 34.0TM 30.6TM ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND 50.6TM 53.5TM 34.0TM 37.0TM 19.6TM 24.1TM ND ND 30.8TM 34.0TM
^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
Sponsor ID
Exygen ID
9 0201960
19023 GROUP I,Female 8* 0201960 Duplnj
19023 GROUP I,Female 9
0201961
19023 GROUP I,Female 9* 0201961 Duplnj
19023 GROUP I,Female 10
0201962
19023 GROUP I,Female 10* 0201962 Duplnj
19023 GROUP I,Female 11
0201963
19023 GROUP I,Female 11* 0201963 Duplnj
19023 GROUP I,Female 12
0201964
19023 GROUP I,Female 12* 0201964 Duplnj
19021 GROUP I.Female 10
0201950
19021 GROUP I,Female 10* 0201950 Dup Inj
19041 GROUP I,Male 1
0201965
19041 GROUP I,Male 1* 0201965 Dup Inj
19041 GROUP I,Male 2
0201966
19041 GROUP I.Male 2* 0201966 Dup Inj
19041 GROUP I,Male 3
0201967
19041 GROUP I,Male 3* 0201967 Dup Inj
19041 GROUP I,Male 4
0201968
19041 GROUP I,Male 4* 0201968 Dup Inj
19041 GROUP I,Male 5
0201969
19041 GROUP I,Male 5* 0201969 Dup Inj
19041 GROUP I,Female 8
0201970
19041 GROUP I,Female 8* 0201970 Dup Inj
19041 GROUP I,Female 9
0201971
19041 GROUP I.Female 9* 0201971 Duplnj
19041 GROUP I,Female 15
0201972
19041 GROUP I,Female 15* 0201972 Dup Inj
19041 GROUP I,Female 16
0201973
19041 GROUP I,Female 16* 0201973 Dup Inj
19041 GROUP I,Female 17
0201974
19041 GROUP I,Female 17* 0201974 Dup Inj
19004 GROUP H, Male 2
0202025
19004 GROUP n , Male 2* 0202025 Dup Inj
19004 GROUP II,Male 3
0202026
19004 GROUP II,Male 3* 0202026 Dup Inj
19004 GROUP II,Male 4
0202027
19004 GROUP n , Male 4* 0202027 Dup Inj
19004 GROUP II,Male 5
0202028
19004 GROUP H, Male 5* 0202028 Dup Inj
19004 GROUP II,Male 6
19004 GROUP II,Male 6*
n,19004 GROUP Female 9
0202029 0202029 Dup Inj
0202030
19004 GROUP II,Female 9* 0202030 Dup Inj
19004 GROUP II,Female 11
0202031
19004 GROUP n , Female 11* 0202031 Dup Inj
19004 GROUP U, Female 15
0202032
n,19004 GROUP Female 15* 0202032 Dup Inj
19004 GROUP II,Female 16
0202033
19004 GROUP II,Female 16* 0202033 Dup Inj
19004 GROUP II,Female 17
0202034
19004 GROUP D, Female 17* 0202034 Dup Inj
Matrix
Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers
Collection Date
5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/29/02 5/29/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02
Set Number
092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702BR 092702BR 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR
PFHS Found (ng/mL)
ND ND ND ND ND ND ND ND ND ND ND ND ND ND 24.4TM 26.6TM 26.0TM 24.7TM ND ND ND ND ND ND 30.6TM 30.8TM 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 die 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
Sponsor ID
Exygen ID
19018 GROUP II,Male 1
0202050
19018 GROUP II,Male 1* 0202050 Dup Inj
19018 GROUP II,Male 4
0202051
19018 GROUP H, Male 4* 0202051 Dup Inj
19018 GROUP II,Male 5 19018 GROUP n , Male 5* 19018 GROUP II,Male 6 19018 GROUP II,Male 6*
0202052 0202052 Dup Inj
0202053 0202053 Dup Inj
19018 GROUP H, Male 7 19018 GROUP H,Male 7* 19018 GROUP II,Female 9 19018 GROUP II,Female 9*
0202054 0202054 Dup Inj
0202055 0202055 Dup Inj
19018 GROUP II,Female 10
0202056
19018 GROUP II,Female 10* 0202056 Dup Inj
19018 GROUP H, Female 11
0202057
19018 GROUP H, Female 11* 0202057 Dup Inj
19018 GROUP II,Female 12 19018 GROUP n , Female 12* 19018 GROUP II,Female 14 19018 GROUP n, Female 14*
19026 GROUP 0,Male 5 19026 GROUP H, Male 5* 19026 GROUP n, Male 1
0202058 0202058 Dup Inj
0202059 0202059 Dup Inj
0202063 0202063 Dup Inj
0202060
19026 GROUP II,Male 1* 19026 G ROUP n , Male 3 19026 GROUP n , Male 3* 19026 G ROUP n , Male 4 19026 GROUP II,Male 4* 19026 GROUP n , Male 7 19026 GROUP II,Male 7* 19026 GROUP II,Female 12 19026 GROUP n , Female 12* 19026 GROUP II,Female 13 19026 GROUP II,Female 13*
0202060 Dup Inj 0202061
0202061 Dup Inj 0202062
0202062 Dup Inj 0202064
0202064 Dup Inj 0202065
0202065 Dup Inj 0202066
0202066 Dup Inj
19026 GROUP II,Female 14
0202067
19026 GROUP II,Female 14* 0202067 Dup Inj
19026 GROUP II,Female 15
0202068
19026 GROUP II,Female 15* 0202068 Dup Inj
19026 GROUP II,Female 18
0202069
19026 GROUP n , Female 18* 0202069 Dup Inj
19036 GROUP II,Male 1
0202070
19036 GROUP II,Male 1* 19036 GROUP II,Male 2 19036 GROUP R, Male 2* 19036 GROUP n , Male 4 19036 GROUP H, Male 4* 19036 GROUP II,Male 5
0202070 Dup Inj 0202071
0202071 Dup Inj 0202072
0202072 Dup Inj 0202073
19036 GROUP II,Male 5* 19036 GROUP n, Male 6 19036 GROUP n, Male 6* 19036 GROUP II,Female 7 19036 GROUP II,Female 7*
0202073 Dup Inj 0202074
0202074 Dup Inj 0202075
0202075 Dup Inj
M atrix
Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers
Collection Date 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02
Set Number
100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A R 100202AR 100202AR 100202AR 100202AR 100202A R 100202A R 100202A R 100202AR 100202AR 100202AR 100202AR 100202AR 100202AR 100202AR 100202AR 100202A R 100202A R 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A
PFHS Found (ng/mL)
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
N D = N ot Detected (Area less than lowest 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
Sponsor ID
Exygen ID
19036 GROUP II,Female 8 19036 GROUP II,Female 8* 19036 GROUP II,Female 11 19036 GROUP H, Female 11* 19036 GROUP II,Female 12 19036 GROUP II,Female 12* 19036 GROUP II,Female 13 19036 GROUP H, Female 13*
19037 GROUP II,Male 6 19037 GROUP U, Male 6* 19037 GROUP II,Female 15 19037 GROUP II,Female 15* 19037 GROUP H, Male 2 19037 GROUP n, Male 2* 19037 GROUP n , Male 3 19037 GROUP II,Male 3* 19037 GROUP n , Male 7 19037 GROUP II,Male 7* 19037 GROUP H, Male 8 19037 GROUP H, Male 8* 19037 GROUP II,Female 10 19037 GROUP II,Female 10* 19037 GROUP II,Female 11 19037 GROUP H, Female 11* 19037 GROUP II,Female 13 19037 GROUP II,Female 13* 19037 GROUP II,Female 14 19037 GROUP n , Female 14*
0202076 0202076 Dup Inj
0202077 0202077 Dup Inj
0202078 0202078 Dup Inj
0202079 0202079 Dup Inj
0202082 0202082 Dup Inj
0202089 0202089 Dup Inj
0202080 0202080 Dup Inj
0202081 0202081 Dup Inj
20831983 0202083 Dup Inj
0202084 0202084 Dup Inj
0202085 0202085 Dup Inj
0202086 0202086 Dup Inj
0202087 0202087 Dup Inj
0202088 0202088 Dup Inj
19003 GROUP HI,Male 1 19003 GROUP IE,Male 1* 19003 GROUP n i, Male 3 19003 GROUP III,Male 3* 19003 GROUP m , Male 5 19003 GROUP in , Male 5* 19003 GROUP III,Male 7 19003 GROUP III,Male 7*
0202119 0202119 Dup Inj
0202120 0202120 Dup Inj
0202121 0202121 Dup Inj
0202122 0202122 Dup Inj
19003 GROUP III,Male 8
0202123
19003 GROUP III,Male 8* 0202123 Dup Inj
19003 GROUP III,Female 9
0202124
19003 GROUP ffl,Female 9* 0202124 Dup Inj
19003 GROUP in , Female 10
0202125
19003 GROUP III,Female 10* 0202125 Dup Inj
19003 GROUP HI, Female 11
0202126
19003 GROUP III,Female 11* 0202126 Dup Inj
19003 GROUP III,Female 15
0202127
19003 GROUP HI,Female 15* 0202127 Dup Inj
19003 GROUP ffl,Female 16
0202128
19003 GROUP HI, Female 16* 0202128 Dup Inj
19007 GROUP ffl,Male 1
0202129
19007 GROUP ffl,Male 1* 0202129 Dup Inj
19007 GROUP 111,Male 2
0202130
19007 GROUP ffl,Male 2* 0202130 Dup Inj
M atrix
Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers
Collection Date
5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02
Set Number 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302AR 100302AR 100302AR 100302AR 100302A R 100302AR 100302A R 100302AR 100302AR 100302AR 100302AR 100302AR 100302A R 100302AR 100302AR 100302AR 100402A R 100402A R 100402A R 100402A R 100402AR 100402A R 100402A R 100402AR 100402A R 100402A R 100402A R 100402AR 100402A R 100402A R 100402AR 100402A R 100402A R 100402AR 100402A R 100402AR 100402A R 100402A R 100402A R 100402A R
PFHS Found (ng/mL)
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
* Duplicate Injection
ND = N ot Detected (Area less than lowest calibration standard o f 0.1 ng/mL)
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
Sponsor ID
Exygen ID
19007 GROUP HI,Male 3 19007 GROUP III,Male 3* 19007 GROUP HI,Male 6
0202131 0202131 Duplnj
0202132
19007 GROUP ID, Male 6* 19007 GROUP HI,Male 7 19007 GROUP ffl,Male 7* 19007 GROUP III,Female 9 19007 GROUP ffl,Female 9*
0202132 Duplnj 0202133
0202133 Dup Inj 0202134
0202134 Dup Inj
19007 GROUP HI,Female 11
0202135
19007 GROUP ffl,Female 11* 0202135 Dup Inj
19007 GROUP ffl,Female 12
0202136
19007 GROUP ffl,Female 12* 0202136 Dup Inj
19007 GROUP ffl,Female 13
0202137
19007 GROUP ffl,Female 13* 0202137 Dup Inj
19007 GROUP ffl,Female 16
0202138
19007 GROUP ffl,Female 16* 0202138 Dup Inj
19008 GROUP III,Male 1
0202139
19008 GROUP ffl,Male 1* 0202139 Dup Inj
19008 GROUP ffl,Male 3
0202140
19008 GROUP ffl,Male 3* 19008 GROUP III,Male 4 19008 GROUP ffl,Male 4* 19008 GROUP HI, Male 6
0202140 Dup Inj 0202141
0202141 Dup Inj 0202142
19008 GROUP III,Male 6* 19008 GROUP III,Male 7 19008 GROUP ffl,Male 7* 19008 GROUP ffl,Female 9
0202142 Dup Inj 0202143
0202143 Duplnj 0202144
19008 GROUP ffl,Female 9* 0202144 Dup Inj
19008 GROUP ffl,Female 10
0202145
19008 GROUP HI, Female 10* 0202145 Dup Inj
19008 GROUP ffl,Female 11
0202146
19008 GROUP III,Female 11* 0202146 Dup Inj
19008 GROUP ffl,Female 12
0202147
19008 GROUP ffl,Female 12* 0202147 Dup Inj
19008 GROUP III,Female 13
0202148
19008 GROUP ffl,Female 13* 0202148 Dup Inj
19013 GROUP ffl,Male 1
0202149
19013 GROUP III,Male l* 0202149 Dup Inj
19013 GROUP III,Male 4
0202150
19013 GROUP ffl,Male 4* 0202150 Dup Inj
19013 GROUP ffl,Male 5
0202151
19013 GROUP III,Male 5* 0202151 Duplnj
19013 GROUP III,Male 6
0202152
19013 GROUP ffl,Male 6* 0202152 Dup Inj
19013 GROUP HI, Male 9
0202153
19013 GROUP ffl,Male 9* 0202153 Dup Inj
19013 GROUP III,Female 11
0202154
19013 GROUP III,Female 11* 0202154 Dup Inj
19013 GROUP ffl,Female 12
0202155
19013 GROUP ffl,Female 12* 0202155 Dup Inj
19013 GROUP ffl,Female 13
0202156
19013 GROUP ffl,Female 13* 0202156 Dup Inj
M atrix
Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers
CoIIection Date
5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02
Set Number
100402AR 100402A R 100402AR 100402AR 100402AR 100402A R 100402A R 100402A R 100402A R 100402AR 100402A R 100402AR 100402A R 100402AR 100402A R 100402A R 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR
PFHS Found (ng/mL)
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
N D = N ot Detected (Area less than lowest 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 GROUP HI, Female 14
0202157
19013 GROUP III,Female 14* 0202157 Duplnj
19013 GROUP ffl,Female 15
0202158
19013 GROUP ffl,Female 15* 0202158 Dup Inj
19015 GROUP ffl,Male 1
0202159
19015 GROUP ffl,Male 1* 0202159 Dup Inj
19015 GROUP ffl,Male 3
0202160
19015 GROUP ffl,Male 3* 0202160 Dup Inj
19015 GROUP ffl,Male 6
0202161
19015 GROUP ffl,Male 6* 0202161 Dup Inj
19015 GROUP ffl,Male 7
0202162
19015 GROUP ffl,Male 7* 0202162 Dup Inj
19015 GROUP ffl,Male 8
0202163
19015 GROUP ffl,Male 8* 0202163 Dup Inj
19015 GROUP ffl,Female 10
0202164
19015 GROUP ffl,Female 10* 0202164 Duplnj
19015 GROUP ffl,Female 12
0202165
19015 GROUP III,Female 12* 0202165 Dup Inj
19015 GROUP ffl,Female 13
0202166
19015 GROUP ffl,Female 13* 0202166 Dup Inj
19015 GROUP ffl,Female 14
0202167
19015 GROUP ffl,Female 14* 0202167 Dup Inj
19015 GROUP ffl,Female 15
0202168
19015 GROUP ffl,Female 15* 0202168 Dup Inj
19005 GROUP IV,Male 1
0202219
19005 GROUP IV, Male 1* 0202219 Dup Inj
19005 GROUP IV, Male 2
0202220
19005 GROUP IV, Male 2* 0202220 Dup Inj
19005 GROUP IV, Male 3 19005 GROUP IV,Male 3* 19005 GROUP IV, Male 5
0202221 0202221 Duplnj
0202222
19005 GROUP IV, Male 5* 0202222 Dup Inj
19005 GROUP IV, Male 6
0202223
19005 GROUP IV, Male 6* 0202223 Dup Inj
19005 GROUP IV,Female 8
0202224
19005 GROUP IV, Female 8* 0202224 Dup Inj
19005 GROUP IV,Female 10
0202225
19005 GROUP IV, Female 10* 0202225 Dup Inj
19005 GROUP IV, Female 11
0202226
19005 GROUP IV, Female 11* 0202226 Dup Inj
19005 GROUP IV,Female 12
0202227
19005 GROUP IV, Female 12* 0202227 Dup Inj
19005 GROUP IV, Female 15
0202228
19005 GROUP IV,Female 15* 0202228 Dup Inj
19035 GROUP IV,Male 1
0202229
19035 GROUP IV,Male 1* 0202229 Dup Inj
19035 GROUP IV,Male 2
0202230
19035 GROUP IV, Male 2* 0202230 Dup Inj
19035 GROUP IV, Male 4
0202231
19035 GROUP IV, Male 4* 19035 GROUP IV,Male 5 19035 GROUP IV, Male 5*
0202231 Duplnj 0202232
0202232 Dup Inj
M atrix
Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers
Collection Date 5/29/02 5/29/02 5/29/02 5/29/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02
Set Number
100402BR 100402BR 100402BR 100402BR 100902A R 100902A R 100902AR 100902AR 100902AR 100902A R 100902AR 100902A R 100902AR 100902AR 100902AR 100902A R 100902A R 100902AR 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902AR 100902AR 100902AR 100902AR 100902A R 100902A R 100902AR 100902A R 100902AR 100902AR 100902A R 100902AR 100902A R 100902AR 100902AR 100902AR 100902AR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR
PFHS Found (ng/mL)
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 Detected (Area less than lowest calibration standard o f 0.1 ng/mL)
Exygen Research
Page 35 of 153
418-028:PAGE G-36 Exygen Study No.: 023-072
Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples
Sponsor ID
Exygen ID
19035 GROUP IV, Male 6
0202233
19035 GROUP IV, Male 6* 0202233 Dup Inj
19035 GROUP IV, Franale 8
0202234
19035 GROUP IV, Female 8* 0202234 Dup Inj
19035 GROUP IV, Female 10
0202235
19035 GROUP IV, Female 10* 0202235 Dup Inj
19035 GROUP IV, Female 11
0202236
19035 GROUP IV, Female 11* 0202236 Dup Inj
19035 GROUP IV, Female 12
0202237
19035 GROUP IV, Female 12* 0202237 Dup Inj
19035 GROUP IV, Female 13
0202238
19035 GROUP IV, Female 13* 0202238 Dup Inj
19039 GROUP IV, Male 1
0202239
19039 GROUP IV, Male 1* 0202239 Dup Inj
19039 GROUP IV,Male 2
0202240
19039 GROUP IV, Male 2* 0202240 Dup Inj
19039 GROUP IV,Male 3
0202241
19039 GROUP IV, Male 3* 0202241 Dup Inj
19039 GROUP IV, Male 4
0202242
19039 GROUP IV, Male 4* 0202242 Dup Inj
19039 GROUP IV,Male 5
0202243
19039 GROUP IV, Male 5* 0202243 Dup Inj
19039 GROUP IV, Female 8
0202244
19039 GROUP IV, Female 8* 0202244 Dup Inj
19039 GROUP IV,Franale 11
0202245
19039 GROUP IV, Female 11* 0202245 Dup Inj
19039 GROUP IV, Female 12
0202246
19039 GROUP IV,Female 12* 0202246 Dup Inj
19039 GROUP IV, Female 14
0202247
19039 GROUP IV, Female 14* 0202247 Dup Inj
19039 GROUP IV, Female 15
0202248
19039 GROUP IV,Female 15* 0202248 Dup Inj
19040 GROUP IV, Male 2
0202249
19040 GROUP IV, Male 2* 0202249 Dup Inj
19040 GROUP IV, Male 3
0202250
19040 GROUP IV, Male 3* 0202250 Dup Inj
19040 GROUP IV, Male 4
0202251
19040 GROUP IV, Male 4* 0202251 Dup Inj
19040 GROUP IV, Male 5
0202252
19040 G R O U P IV , M ale 5* 0202252 D up Inj
19040 GROUP IV, Male 7
0202253
19040 GROUP IV, Male 7* 0202253 Dup Inj
19040 GROUP IV, Female 11
0202254
19040 GROUP IV, Female 11* 0202254 Dup Inj
19040 GROUP IV, Female 12
0202255
19040 GROUP IV, Female 12* 0202255 Dup Inj
19040 GROUP IV, Female 13
0202256
19040 GROUP IV, Female 13* 0202256 Dup Inj
19040 GROUP IV, Female 15
0202257
19040 GROUP IV, Female 15* 0202257 Dup Inj
19040 GROUP IV, Female 16
0202258
19040 GROUP IV, Female 16* 0202258 Dup Inj
M atrix
Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers
P up Livers
Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers
Collection Date
5/31/02 5/31/02 5/31/02 5/31/02 . 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02
Set Number
100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 101002A R 101002AR 101002AR 101002A R 101002AR 101002A R 101002AR 101002AR 101002AR 101002A R 101002AR 101002A R 101002AR 101002A R 101002A R 101002AR 101002AR 101002A R 101002A R 101002AR
PFHS Found (ng/mL)
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
N D = Not Detected (Area less than lowest 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
Sponsor ID
Exygen ID
19045 GROUP IV, Male 1 19045 GROUP IV, Male 1* 19045 GROUP IV, Male 2 19045 GROUP IV, Male 2* 19045 GROUP IV, Male 4 19045 GRO U P IV, Male 4* 19045 GROUP IV, Male 5 19045 GROUP IV, Male 5* 19045 GROUP IV, Male 6 19045 GROUP IV, Male 6* 19045 GROUP IV, Female 8 19045 GROUP IV, Female 8* 19045 GROUP IV, Female 9 19045 GROUP IV, Female 9*
0202259 0202259 Dup Inj
0202260 0202260 Dup Inj
0202261 0202261 Dup Inj
0202262 0202262 Dup Inj
0202263 0202263 Dup Inj
0202264 0202264 Dup Inj
0202265 0202265 Dup Inj
19045 GROUP IV, Female 10
0202266
19045 GROUP IV, Female 10* 0202266 Dup Inj
19045 GROUP IV, Female 11
0202267
19045 GROUP IV, Female 11* 0202267 Dup Inj
19045 GROUP IV, Female 14
0202268
19045 GROUP IV, Female 14* 0202268 Dup Inj
19006 GROUP V, Male 1
0202320
19006 GROUP V, Male 1* 0202320 Dup Inj
19006 GROUP V, Male 2
0202321
19006 GROUP V, Male 2* 0202321 Dup Inj
19006 GROUP V, Male 3
0202322
19006 GROUP V, Male 3* 0202322 Dup Inj
19006 GROUP V, Male 4
0202323
19006 GROUP V, Male 4* 0202323 Dup Inj
19006 GROUP V, Male 5
0202324
19006 GROUP V, Male 5* 0202324 Dup Inj
19006 GROUP V, Female 8 19006 GROUP V, Female 8* 19006 GROUP V, Female 10 19006 GROUP V, Female 10* 19006 GROUP V, Female 11 19006 GROUP V, Female 11*
0202325 0202325 Dup Inj
0202326 0202326 Dup Inj
0202327 0202327 Dup Inj
19006 GROUP V, Female 13 19006 GROUP V, Female 13* 19006 GROUP V, Female 18 19006 GROUP V, Female 18*
19011 GROUP V, Male 2 19011 GROUP V, Male 2* 19011 GROUP V, Male 3 19011 GROUP V, Male 3* 19011 GROUP V, Male 4 19011 GROUP V, Male 4*
0202328 0202328 Dup Inj
0202329 0202329 Dup Inj
0202330 0202330 Dup Inj
0202331 0202331 Dup Inj
0202332 0202332 Dup Inj
19011 GROUP V, Male 5 19011 GROUP V, Male 5* 19011 GROUP V, Male 6 19011 GROUP V, Male 6*
0202333 0202333 Dup Inj
0202334 0202334 Dup Inj
19011 GROUP V, Female 9
0202335
19011 GROUP V, Female 9* 0202335 Dup Inj
M atrix
Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers
Collection Date
5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02
Set Number
101002AR 101002A R 101002AR 101002A R 101002AR 101002A R 101002AR 101002A R 101002AR 101002A R 101002AR 101002A R 101002AR 101002A R 101002AR 101002AR 101002A R 101002A R 101002AR 101002A R 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR
PFHS Found (ng/mL)
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
* Duplicate Injection
N D = Not Detected (Area less than lowest 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 GROUP V, Female 10
0202336
19011 GROUP V, Female 10* 0202336 Dup Inj
19011 GROUP V, Female 11
0202337
19011 GROUP V, Female 11* 0202337 Dup Inj
19011 GROUP V, Female 12
0202338
19011 GROUP V, Female 12* 0202338 Dup Inj
19011 GROUP V, Female 13
0202339
19011 GROUP V, Female 13* 0202339 Dup Inj
19020 GROUP V, Male 2 19020 GROUP V, Male 2* 19020 GROUP V, Male 4
0202340 0202340 Dup Inj
0202341
19020 GROUP V. Male 4* 19020 GROUP V, Male 5 19020 GROUP V, Male 5*
0202341 Dup Inj 0202342
0202342 Dup Inj
19020 GROUP V, Male 7
0202343
19020 GROUP V, Male 7* 0202343 Dup Inj
19020 GROUP V, Male 8
0202344
19020 GROUP V, Male 8* 0202344 Dup Inj
19020 GROUP V, Female 9
02021345
19020 GROUP V, Female9* 0202345 Dup Inj
19020 GROUP V, Female 10
0202346
19020 GROUP V, Female 10* 0202346 Dup Inj
19020 GROUP V, Female 11
0202347
19020 GROUP V, Female 11* 0202347 Dup Inj
19020 GROUP V, Female 12
0202348
19020 GROUP V, Female 12* 0202348 Dup Inj
19020 GROUP V, Female 13
0202349
19020 GROUP V, Female 13* 0202349 Dup Inj
19022 GROUP V, Male 1
0202350
19022 GROUP V, Male 1* 0202350 Dup Inj
19022 GROUP V, Male 4
0202351
19022 GROUP V, Male 4* 0202351 Dup Inj
19022 GROUP V, Male 5
0202352
19022 GROUP V, Male 5* 19022 GROUP V, Male 7 19022 GROUP V, Male 7*
0202352 Dup Inj 0202353
0202353 Dup Inj
19022 GROUP V, Male 8
0202354
19022 GROUP V, Male 8* 0202354 Dup Inj
19022 GROUP V, Female 11
0202355
19022 GROUP V, Female 11* 0202355 Dup Inj
19022 GROUP V, Female 12
0202356
19022 GROUP V, Female 12* 0202356 Dup Inj
19022 GROUP V, Female 13
0202357
19022 GROUP V, Female 13* 0202357 Dup Inj
19022 GROUP V, Female 14
0202358
19022 GROUP V, Female 14* 0202358 Dup Inj
19022 GROUP V, Female 15
0202359
19022 GROUP V, Female 15* 0202359 Dup Inj
19025 GROUP V, Male 2
0202361
19025 GROUP V, Male2* 0202361 Dup Inj
19025 GROUP V, Male 7
0202362
19025 GROUP V, Male 7* 0202362 Dup Inj
M atrix
Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers
Collection Date
5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/30/02 5/30/02 5/30/02 5/30/02
Set Number 101002BRR 101002BRR 101002BRR 101002BRR 101002BRR 101002BRR 101002BRR 101002BRR 101102AR 101102AR 101102AR
101102A R
101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101402A R 101402AR 101402AR 101402AR
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 Detected (Area less than lowest calibration standard o f 0.1 ng/mL)
Exygen Research
Page 38 of 153
418-028:PAGE G-39 Exygen Study No.: 023-072
Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples
Sponsor ID
Exygen ID
19025 GROUP V, Male 8
0202363
19025 GROUP V, Male 8* 0202363 Dup Inj
19025 GROUP V, Male 13
0202364
19025 GROUP V, Male 13* 0202364 Dup Inj
19025 GROUP V, Female 14 02021365
19025 GROUP V, Female 14* 0202365 Dup Inj
19025 GROUP V, Female 15
0202366
19025 GROUP V, Female 15* 0202366 Dup Inj
19025 GROUP V, Female 18
0202367
19025 GROUP V. Female 18* 0202367 Dup Inj
19025 GROUP V, Female 19
0202368
19025 GROUP V, Female 19* 0202368 Dup Inj
19025 GROUP V, Female 20
0202369
19025 GROUP V, Female 20* 0202369 Dup Inj
19025 GROUP V, Male 1
0202360
19025 GROUP V, Male 1* 0202360 Dup Inj
M atrix
Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers
Collection Date
5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02
Set Number
101402A R 101402AR 101402AR 101402AR 101402AR 101402A R 101402AR 101402A R 101402AR 101402AR 101402AR 101402A R 101402A R 101402AR 101402ARR 101402ARR
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 Research
Page 39 of 153
418-028:PAGE G-40 Exygen Study No.: 023-072
Table X. Summary of PFHS Residues in Dosing Solutions
Sample D e scrip tio n
B-418-028-A (07.Jua.02) 0 mg/mL 1 of4 B-418-028-A (07.Jim.02) 0 mg/mL 1 of4 B-418-028-B (24.May.02) 0.03 mg/mL 1of4 B-418-028-B (24.May.02) 0.03 mg/mL 1 of4 B-418-028-C (24.May.02) 0.1 mg/mL 1of4 B-418-028-C (24.May.02) 0.1 mg/mL 1of4 B-418-028-D (07.Jun.02)0.3mg/mL 1of4 B-418-028-D (07.Jun.02)0.3mg/mL 1of4 B-418-028-E (24.May.02) 1mg/mL 1 of4 B-418-028-E (24.May.02) 1 mg/mL 1of4
Bulk TA/S Sample (09.Jun.02)
B u lk T A /S S am ple (09.Jun.02)
Set
PFHS
PFHS
PFHS
N um ber Known Concentration (ng/mL) Found (ng/mL) Recovery (% )
110702C
0
ND -
110702C
0
ND -
110702C 110702C
30000 30000
26500 27300
88 91
110702C 110702C
100000 100000
88900 91000
89 91
110702C 110702C 110702CR 110702CR 110702C 110702C
300000 300000 1000000 1000000 100000 100000
268000 278000 1010000 1000000 125000 122000
89 93 101 100 125 122
ND = Not Detected (Area less than lowest calibration standard of 0.1 ng/mL)
Exygen Research
Page 40 of 153
418-028:PAGE G-41 Exygen Study No.: 023-072
Table XI. Summary of PFHS Residues in Stability Samples
3M ID
E 0 2 - 0 5 14-38611 E 0 2 -0 5 14-38611* E 0 2 -0 5 14-38612 E 0 2 -0 5 14-38612* E 0 2 -0 5 14-38613 E02-0514-38613* E 0 2 - 0 5 14-38614 E 0 2 -0 5 14-38614* E 0 2 -0 5 14-38615 E02-0514-38615* E 0 2 -0 5 14-38616 E02-0514-38616* E 0 2 -0 5 14-38617 E 0 2 -0 5 14-38617* E 0 2 -0 5 14-38618 E 0 2 -0 5 14-38618* E 0 2 -0 5 14-38619 E 0 2 -0 5 14-38619* E 0 2 -0 5 14-38620 E02-0S14-38620*
Exygen ID
0203923 0203923 Dup Inj
0203924 0203924 D ap Inj
0203925 0203925 D up Inj
0203926 0203926 Dup Inj
0203927 0203927 Dup Inj
0203928 0203928 Dup Inj
0203929 0203929 Dup Inj
0203930 0203930 D up Inj
0203931 0203931 Dup log
0203932 0203932 Dup Inj
Sample Description
B -418-028 A (29 M ar 02) 0 mg/mL 1 o f 4 B-418-028 A (29 M ar 02) 0 mg/mL 1 o f 4 B -418-028 A (29 M ar 02) 0 mg/mL 2 o f 4 B-418-028 A (29 M ar 02) 0 mg/mL 2 o f 4 B-418-028 B (29 M ar 02) 0.03 mg/mL 1 o f 4 B-418-028 B (29 M ar 02) 0.03 mg/mL 1 o f 4 B-418-028 B (29 M ar 02) 0.03 mg/mL 2 o f 4 B-418-028 B (29 M ar 02) 0.03 mg/mL 2 o f 4 B-418-028 C (29 M ar 02) 0.1 mg/mL 1 o f 4 B-418-028 C (29 M ar 02) 0.1 mg/mL 1 o f 4 B-418-028 C (29 M ar 02) 0.1 mg/mL 2 o f 4 B-418-028 C (29 M ar 02) 0.1 mg/mL 2 o f 4 B-418-028 D (29 M ar 02) 0.3 mg/mL 1 o f 4 B-418-028 D (29 M ar 02) 0.3 mg/mL 1 o f 4 B-418-028 D (29 M ar 02) 0.3 mg/mL 2 o f 4 B-418-028 D (29 M ar 02) 0.3 mg/mL 2 o f 4 B-418-028 E (29 M ar 02) 1 mg/mL 1 o f 4 B-418-028 E (29 M ar 02) 1 mg/mL 1 o f 4 B-418-028 E (29 M ar 02) 1 mg/mL 2 o f 4 B-418-028 E (29 M ar 02) 1 mg/mL 2 o f 4
Set Number
110502A 110502A 110502A 110502A 110502A 110502A 110502A 110502A 110502A 110502A 110502A 110502A 110502A 110502A U0502A 110502A 110702AR 110702AR 110702AR 110702AR
PFHS Known Cone.
(ng/mL)
0
0
0 0 30000 30000 30000 30000 100000 100000 100000 100000 300000 300000 300000 300000 1000000 1000000 1000000 1000000
PFHS Found (ng/mL)
ND ND ND ND 29700 29600 29700 29500 122000 117000 100000 100000 308000 316000 326000 324000 910000 919000 1030000 1010000
PFHS Recovery
(% >
-
-
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
E02-0514-38621 E02-0514-38621* E02-0514-38622 E02-0514-38622* E02-0514-38623 E02-0514-38623* E02-0514-38624 E02-0514-38624* E02-0514-38625 E02-0514-38625* E02-0514-38626 E02-0514-38626* E02-0514-38627 E02-0514-38627* E02-0514-38628 E02-0514-38628* E02-0514-38629 E02-0514-38629* E02-0514-38630 E02-0514-38630* E02-0514-38631 E02-0514-38631* E02-0514-38632 E02-0514-38632* E02-0514-38633 E02-0514-38633* E02-0514-38634 E02-0514-38634* E02-0514-38635 E02-0514-38635* E02-0514-38636 E02-0514-38636* EQ2-0514-38637 E02-0514-38637* E02-0514-38638 E02-0514-38638* E02-0514-38639 E02-0514-38639* E02-0514-38640 E02-0514-38640* E02-0514-38641 E02-0514-38641* E02-0514-38642 E02-0514-38642* E02-0514-38643 E02-0514-38643* E02-0514-38644 EQ2-0514-38644* E02-0514-38645 E02-0514-38645* E02-0514-38646 E02-0514-38646* E02-0514-38647 E02-0514-38647* E02-0514-38648 E02-0514-38648* E02-0514-38649 E02-0514-38649* E02-0514-38650 E02-0514-38650*
Exygen ID
Sample Description
Set Number
0203933
B-418-028-A (29Mar02) 0 mg/mL 1 of 12T 110702A
0203933 Dup Inj B-418-028-A (29Mar02) 0 mg/mL 1 of 12T 110702A
0203934
B-418-028-A (29Mar02) 0 mg/mL 2 of12T 110702A
0203934 Dup Inj B-418-028-A (29Mar02) 0 mg/mL 2 of12T 110702A
0203935
B-418-028-A (29Mar02) 0 mg/mL 5 of12M 110702A
0203935 Dup Inj B-418-028-A (29Mai02) 0 mg/mL 5 of 12M 110702A
0203936
B-418-028-A (29Mai02) 0 mg/mL 6 of12M 110702A
0203936 Dup Inj B-418-028-A (29Mai02) 0 mg/mL 6 of12 M 110702A
0203937
B-418-028-A (29Mar02) 0 mg/mL 9 of 12B 110702A
0203937 Dup Inj B-418-028-A(29Mar02) 0 mg/mL 9 of 12B 110702A
0203938
B-418-028-A (29Mar02) 0 mg/mL 10 of 12B 110702A
0203938 Dup Inj B-418-028-A(29Mar02)0mg/mL lOof 12B 110702A
0203939 B-418-028-B (29Mar02) 0.03 mg/mL 1of12T 110702A
0203939 Dup Inj B-418-028-B (29Mar02) 0.03 mg/mL 1 of12T 110702A
0203940 B-418-028-B (29Mar02) 0.03mg/mL 2 of 12T 110702A
0203940 Dup Inj B-418-028-B (29Mar02) 0.03mg/mL 2 of12T 110702A
0203941 B-418-028-B (29Mar02) 0.03mg/mL 5 of 12M 110702A
0203941 Dup Inj B-418-028-B (29Mar02) 0.03mg/mL 5 of 12M 110702A
0203942 B-418-028-B (29Mar02) 0.03 mg/mL 6 of12M 110702A
0203942 Dup Inj B-418-028-B (29Mai02) 0.03mg/mL 6 of 12M 110702A
0203943 B-418-028-B (29Mar02) 0.03 mg/mL 9 of 12B 110702A
0203943 Dup Inj B-418-028-B (29Mai02) 0.03 mg/mL 9 of12B 110702A
0203944 B-418-028-B (29Mar02) 0.03 mg/mL 10 of 12B 110702A
0203944 Dup Inj B-418-028-B (29Mar02) 0.03 mg/mL 10 of 12B 110702A
0203945
B-418-028-C (29Mar02) 0.1 mg/mL lof 12T 110702A
0203945 Dup Inj B-418-028-C (29Mar02) 0.1 mg/mL 1of 12T 110702A
0203946
B-418-028-C (29Mar02) 0.1 mg/mL 2 of 12T 110702A
0203946Dup Inj B-418-028-C (29Mai02) 0.1 mg/mL 2 of 12T 110702A
0203947
B-418-028-C (29Mar02) 0.1 mg/mL 5 of 12M 110702AR
0203947 Dup Inj B-418-028-C (29Mar02) 0.1 mg/mL 5 of 12M 110702AR
0203948
B-418-028-C (29Mar02) 0.1 mg/mL 6 of 12M 110702A
0203948 Dup Inj B-418-028-C (29Mar02) 0.1 mg/mL 6 of 12M 110702A
0203949
B-418-028-C (29Mar02) 0.1 mg/mL 9 of 12B 110702A
0203949 Dup Inj B-418-028-C (29Mar02) 0.1 mg/mL 9 of 12B 110702A
0203950 B-418-028-C (29Mar02) 0.1 mg/mL 10 of 12B 110702AR
0203950Dup Inj B-418-028-C (29Mar02) 0.1 mg/mL 10 of 12B 110702AR
0203951
B-418-028-D (29Mar02) 0.3mg/mL 1of 12T 110702A
0203951 Dup Inj B-418-028-D (29Mar02) 0.3mg/mL 1 of 12T 110702A
0203952
B-418-028-D (29Mar02) 0.3 mg/mL 2 of12T 110702A
0203952 Dup Inj B-418-028-D (29Mar02) 0.3 mg/mL 2 of 12T 110702A
0203953
B-418-028-D (29Mar02) 0.3mg/mL 5 of 12M 110702B
0203953 Dup Inj B-418-028-D (29Mar02) 0.3mg/mL 5 of 12M 110702B
0203954 B-418-028-D (29Mar02) 0.3mg/mL 6 of 12M 110702B
0203954 Dup Inj B-418-028-D (29Mar02) 0.3mg/mL 6 of 12M 110702B
0203955
B-418-028-D (29Mar02) 0.3mg/mL 9 of12B 110702B
0203955 Dup Inj B-418-028-D (29Mar02) 0.3mg/mL 9 of12B 110702B
0203956 B-418-028-D (29Mar02) 0.3mg/mL 10 of 12B 110702B
0203956 Dup Inj B-418-028-D (29Mai02) 0.3mg/mL 10 of12B 110702B
0203957
B-418-028-E (29Mar02) 1mg/mL 1 of 12T 110702B
0203957 Dup Inj B-418-028-E (29Mar02) 1mg/mL 1of 12T 110702B
0203958
B-418-028-E (29Mar02) 1mg/mL 2 of 12T 110702B
0203958 Dup Inj B-418-028-E (29Mar02) 1mg/mL 2 of 12T 110702B
0203959
B-418-028-E (29Mai02) 1mg/mL 5 of12M 110702B
0203959 Dup Inj B-418-028-E (29Mar02) 1mg/mL 5 of 12M 110702B
0203960
B-418-028-E (29Mar02) 1mg/mL 6 of 12M 110702B
0203960 Dup Inj B-418-028-E (29Mar02) 1mg/mL 6 of12M 110702B
0203961
B-418-028-E (29Mar02) 1mg/mL 9 of 12B 110702B
0203961 Dup Inj B-418-028-E (29Mar02) 1mg/mL 9 of 12B 110702B
0203962
B-418-028-E (29Mar02) 1mg/mL 10 of 12B 110702B
0203962 Dup Inj B-418-028-E f29Mar02) 1 mg/mL 10 of 12B 110702B
PFHS Known Cone.
(ng/mL)
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
PFHS Found (ng/mL)
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 1100000 1110000 1070000
PFHS Recovery _ (%)
-
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
* Duplicate Injection
ND = Not Detected (Area less than lowest 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
Exygen Research
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. Chromatogram Representing a 0.1 ng/mL standard for PFHS
C082002-6,0.1 ng/mL Standard 091902B-2012 Sm (Mn. 2x3)
21-Sep-2002 10:34:30 LC/MS/MS #7
MRM of 1 Channel ES-
Exygen Research
Page 45 of 153
418-028:PAGE G-46
E xygen Study N o.: 0 23 -0 7 2
Figure 3. Chromatogram Representing a Control Rat Plasma Sample for PFHS (Exygen ID 0202913 Control, Data Set: 091602B)
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 Control, Data Set: 100202A)
0202877 Control
03-0ct-2002 08:12:19
Exygen Research
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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-208 Sm (Mn, 2x3)
17-Sep-2002 23:14:44 LC/MS/MS m
MRM of 1 Channel ES
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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 Sm (Mn, 2x3)
21-Sep-2002 09:29:14
LC/MS/MS #7 MRM of 1 Channel ES-
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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/MS/MS #7
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Figure 9. Chromatogram Representing Rat Plasma Sample Analyzed for PFHS (Exygen ID: 0201816, Sponsor ID: 19176 GROUP I, Data Set: 091602B)
0201816 091602B-212 Sm (Mn, 2x3)
18-Sep-2002 00:41:24 LC/MS/MS #7
MRM of 1 Channel ES-
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Figure 10. Chromatogram Representing Rat Serum Sample Analyzed for PFHS, DF=10 (Exygen ID: 0201863, Sponsor ID: 19079 GROUP II, Data Set: 091902BR)
0201863, DF-10
-,091902BR-308 Sm (Mn, 2x3)
100
8.80 2488'
24-Sep-2002 02:50:15 LC/MS/MS #7
MRM of 1 Channel ES399 >80 3.91 e4 Area
0 I. .T l-I Il- 'III,,I,1 T p . .1-1 n r i I I... I .I IT r II 1.00 2.00 3.00 4.00
5.00
6.00
, i , 1 1 1 1 11 W -fy f, n - r, 1 11..... 111 iv i 1 11 ........ i Time 7.00 8.00 9.00 10.00 11.00 12.00
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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)
100
B.28 21849
03-0ct-2002 10:00:52 LCyMS/MS #7
MRM of 1 Channel ES399 >80 1.19e5 Area
%-
0-
1.00
4.00
5.00
6.00 Too
B.00
9.00 1 i!o
Hloo
r-^n Time 12.00
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APPENDIX A
Study Protocol 418-028
(Exygen Study No. 023-072) and
Amendments, Deviation and
Note to File
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90S Sheehy Drive, Bldg- A
Hontem,M 19044 Telephone;(2 15) 443-8710
Telefax: (215) 443-BS87
QiarAieRsGRUiveSrRLEabSoErAatRoCrieHs
Discovery and D evelopm ent Services
PROTOCOL 418-028
SPONSOR'S STUDY NUMBER: T-7706.1
STUDY TITLE: Oral (Gavage) Combined Repeated Dose Toxicity Study o f T-7706 with the Reproduction/Developmental Toxicity Screening Test
PURPOSE:
The purpose of this study is to provide information on die 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 o f 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., gnnadal function, mating behavior, conception, development o f die conceptus and parturition). The study also places emphasis on neurological effects as a specific endpoint and should identify die neurotoxic potential o f a test substance, which may warrant further in-depth investigation.
TESTING FACILITY:
Because o f the selectivity ofthe endpoints and the short duration ofthe study, the screening test will not provide evidence for definitive claims of no reproduction/developmental effects. In particular, it offers only limited
means o f detecting postnatal manifestations ofprenatal exposure or effects that maybe 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, Ph.D., 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
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STUDY MONITOR:
John ButenhofL Ph.D., DABT, CIH
3M Corporate Toxicology
3M Medical Department
Telephone: (651)733-1962
Telefax: (651) 733-1773
Email:
jlbutenhoif@ninim.com
Protocol418-028 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 o f Good Laboratory Practices [C(97)186/Final].
U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFRPart 58.
Japanese Ministry ofHealth and Welfare (1997). Good Laboratory P ractice Standardfo r Safety Studies on D rugs, MHW Ordinance Number 21, March 26, 1997.
REGULATORY COM PLIANCE:
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 o fthe study conducted at die 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 o f the study and that all
applicable GLP regulations were followed in the conduct ofthe 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 ofthe study.
Should any portion of the study be conducted by a subcontractor or by die Sponsor, the Study Director will ensure that a qualified Principal Investigator is identified by the facility conducting that portion of the study. The QAU for this 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
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to the Testing Facility for inclusion in the final report, hi 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:
T-7706 [Perfluorohexanc Sulfonate Potassium Salt (PFHS)] Lot identification will be documented in the raw data.
The Sponsor will provide to the Testing Facility documentation or certification ofthe identity, composition, method of synthesis, strength and activity/purity of the test substance. This documentation will be included in the final report.
Vehicle:
Aqueous 0.5% caiboxymethlycellulose (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 o f 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 umfoim/lab coat to be worn during formulation preparation and dosage. The Material Safety Data Sheet (MSDS) is attached to foe 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 o f Julian Gulbinski, Manager of Formulation Laboratory, at the previously cited Testing Facility address and telephone number.
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Shipments should include information concerning storage conditions and shipping cartons should be labeled appropriately. The recipient should be notified in advance of shipment.
FO R M U L A T IO N :
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 o f dosage calculations.
Testing Facility Reserve Samples:
The Testing Facility will reserve a sample of each lot of bulk test substance (approximately 1 g) and bulk vehicle components (approximately 1 g or 5 mL) used during the course ofthe 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 ofthe study. Additional analyses, if required, will be documented by protocol amendment.
Bulk Test Substance Sampling:
A sample of approximately 1 g o f the test substance will be taken on the last day oftreatment 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.
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Analyses of P repared Form ulations:
Concentration and Homogeneity:
Concentration and homogeneity o f die prepared formulations will be verified during the course of this 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 o f 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 ofthe Sponsor.
Stability:
Stability of the prepared formulations will be documented during this study. Two sets o f duplicate samples (2 mL each) from each concentration will be taken on the first day of preparation. One sample ofeach duplicate set will be shipped on the day ofpreparation. 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
D IS P O S IT IO N :
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-IB-10 St. Paul, Minnesota 55144-1000 Telephone: (651)733-2392
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TEST SYSTEM:
Species/Strain and Reason for Selection:
The Crl:CD(SD)lGS 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 o frat has been demonstrated to be sensitive to reproductive and developmental toxins; and 3) historical data and experience exist at the Testing Facility*1'3*
N um ber:
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 pa*
dosage group).
Body W eight and Age:
Male rats will be ordered to weigh fiom 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 o f each 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 truck from Charles River Laboratories, Inc., to the Testing Facility.
Identification:
Rats are permanently identified using Monel self-piercing ear tags (Gey Band and Tag Co., Inc., No. MSPT 20101). Male and female rats are assigned temporary numbers 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 o f the litter.
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ANIMAL HUSBANDRY:
All cage sizes and housing conditions are in compliance with the Guidefo r the Care and Use o f Laboratory A nim als^. 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 ofrats will be housed in the male rat's cage. Beginning no later than day 20 of presumed gestation, Fo generation female rats will be individually housed in nesting boxes. Each Asm and delivered litter will be housed in a common nesting box during the postpartum period.
Nesting M aterial:
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. Tem perature 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 a d 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.
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C ontam inants:
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 die 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.
Hie day ofbirth 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 o f lactation) in the Standard Operating Procedures of the Testing Facility. Throughout this protocol, the day o f birth will be designated day 1postpartum (day 1 o f 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 o f 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 of physical 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 cohabitation period will consist o f a maximum o f 14 days. Female rats with spermatozoa observed in a smear of the vaginal contents and/or a copulatory plug observed in situ will be considered to be at day 0 ofpresumed gestation and assigned to individual housing. Female rats not mated within the first seven days of cohabitation will be assigned alternate male rats that have mated (same dosage group) and will remain in cohabitation for a maximum of seven additional days.
Day 1 of lactation (postpartum) is defined as the day ofbirth and is also the first day on which all pups in a litter are individually weighed (pup body weights will be recorded after aUpups in a litter are delivered and groomed by the dam).
Litters will not be culled during the lactation period, because random selection o fpups for culling could result in potential biases in pup viabilities and body weight gains over this period.
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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 o frandom 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.
A D M IN ISTR A TIO N :
Ronte and Reason fo r Choice:
The oral (gavage) route was selected for use because: 1) in comparison with the dietary route, the exact dosage can be accurately administered; and 2) it is one o f the possible routes for environmental exposure.
M ethod and Frequency:
Dosages will be adjusted daily for body weight changes and given at approximately the same time each day. The first day o f 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 o f a maximum 14 days. Dosage will continue through foe day before sacrifice, after completion of foe cohabitation period, after a minimum o f 42 days of administration.
Female rats will be given foe test substance once daily beginning 14 days before a cohabitation period that consists o f a maximum of 14 days. Dosage will continue through foe day before scheduled sacrifice (day 21 of lactation).
Rationale fo r Dosage Selection:
Dosages were selected by foe 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 notmortality or obvious suffering. The descending sequence of the lower dosage levels will be selected for foe purpose of demonstrating any dosage-related response, with no adverse effects expected at the lowest level.
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Dosage Levels. Concentrations and Volumes:
Dorage Group
I a
in IV
V
Number ofRan PerSex 15+3* 15+3* 15+3* 15+3* 15+3*
Dorage fmg/kottay)
0
0.3 1 3 10
Concentration* (mofad.) 0 0.03 0.1
0J 1
Dorage Volume (mUkg)
10 10
10
10 10
AnusBuchNumber B-418-02B-A(Diy.Month.Yetr) B-418-028-B(Dty.Manth.Yew) B-418-028-C(Diy.Manm.Yeir) B-418-028-D(Dty.Month.Yetr)
B-418-028-E(Diy.Month.Yeu)
b. Threeadditionalratipersexperdougegroupwillbeasrigncdtotoxicakineticsunplecollection.
TESTS. ANALYSES AND MEASUREMENTS - Fo GENERATION:
Viability - Male and Female Rats:
All Periods:
At least twice daily.
rriniral Observations and/or General A ppearance - M ale and Fem ale Rats:
Acclimation Period:
Weekly.
Dosage Period:
Daily before dosage. On the first day of dosage, postdosage observations will be recorded at approximately hourly intervals for the first four hours and at the end o f 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 o f 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 respiratory pattern). Changes in gait, posture
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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 W eights - 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 Wats (recorded and tohnlatefi):
Dosage Period:
Weekly to cohabitation.
Gestation Period:
Days 0,7 ,1 0 ,1 2 ,1 5 ,1 8 ,2 0 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 die 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.
Toxicokfnetic 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 per group).
On day 14 o f study and day 21 o f presumed gestation, blood samples (approximately 1 mL each) will be collected from each female rat assigned to the toxicokinetic sample collection portion of
the study (3 par group). Samples will be collected prior to dosage on day 14 o f study. The time of each blood collection will be recorded in the raw data.
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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 tabes labeled with the protocol number, Sponsor study number, animal number, sex, group number, dosage level, day o f study, collection interval, date o f collection, species, generation and storage conditions. All samples will be immediately frozen on dry ice and maintained frozen (<-706C) until shipment for analysis.
After the last blood sample collection, rats will be sacrificed and samples ofthe 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 M ating:
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 ofthe vaginal contents and/or a copulatory plug is observed in situ during the cohabitation period.
Caesarean-Sectioning - Toxicokinetic Study.
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 weightwill 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.
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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.
N atural Delivery:
Female rats will be evaluated for:
Adverse Clinical Signs Observed During Parturition.
Duration of Gestation (day 0 ofpresumed gestation to die time the first pup is observed).
Litter Size (defined as all pups delivered).
Pup Viability at Birth.
Functional O bservational Battery;
On one occasion during the course of die study, a functional observational battery (FOB)(5'8)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 o f die 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 hmdbxnb 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 die eyes, nose or mouth.
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Evidence o f 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.
M otor Activity Test:
Motor activity will be evaluated on 10 male and 10 female rats per group once during the course of die study. This assessment will be conducted shortly before scheduled sacrifice, but prior to blood sample collection.
The movements o f 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 o f 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 fire test system is capable of detecting increases in activity produced by positive control substances (Testing Facility Positive Control Data).
HEM ATOLOGY 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 ofblood will be collected and processed as described below. Determinations additional to those described below may be conducted if the known properties o f 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).
H em atology:
Approximately 1 mL o fblood will be collected into EDTA-coated tubes and maintained on wet ice or refrigerated until shipment for analysis o f the following hematologic parameters:
Erythrocyte Count (RBC) Hematocrit (HCT) Hemoglobin (HGB) Mean Corpuscular Hemoglobin (MCH) Mean Corpuscular Hemoglobin Concentration (MCHC)
Mean Corpuscular Volume (MCV) Leukocyte Count, Total (W BQ Leukocyte Count, 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 foe tubes are centrifuged
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Protocol418-028 Page IS
(within 30 minutes o f 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 ofprothrombin time (PT) and activated partial thromboplastin time (APTT).
Clinical Chem istry:
Approximately 2 mL o f blood will be collected into serum separator tubes and centrifuged. The resulting sera samples will be immediately frozen on dry ice and maintain! frozen (<-70C) until shipment for analysis o f the following parameters:
Total Protein (TP) Triglycerides (TRI) Albumin (A) Globulin (G) Albumin/Globulin Ratio (A/G) Glucose (GLU) Cholesterol (CHOL) Total Bilirubin (TBIL1) 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. Shinning Instructions:
Samples will be shipped to arrive on Monday through Friday according to the r.nnHitjpTije 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.
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METHOD OF SACRIFICE:
Protocol418-028 Page 16
Fo generation rats will be sacrificed by carbon dioxide asphyxiation.
GROSS NECROPSY AND H1STOPATHOLOGY - Fo GENERATION RATS:
Scheduled Sacrifice - Toxicokinetic Study:
Scheduled sacrifice o f male rats will be conducted on day 42 of study. Scheduled sacrifice of female rats will be conducted on day 21 ofpresumed 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 - M ain 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 an initial physical evam m atinn 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 o f 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 histppafhology will be performed under the supervision of or by a Board-Certified Veterinary Pathologist.
The ovaries and the uterus with cervix o f 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 after being pressed between glass plates to confirm the absence of implantation sites, and retained in neutral buffered 10% formalin.
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Sperm Evaluations of Male Rats:
Protocol418-028 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 (spam per gram of tissue weight). The remaining portion o f the left cauda epididymis will be used to manually evaluate sperm morphology. Sperm morphology evaluations will include the following: 1) determination of the percentage ofnormal sperm in a sample ofat 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 R ats that Do Not Deliver L itters:
Rats that do not deliver a litter will be sacrificed on day 25 ofpresumed gestation. Gross
necropsy, examination and tissue retortion will be conducted as described previously for rats at scheduled sacrifice.
Dams with No Surviving Pups:
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.
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Rats Found Dead or M oribund:
Protocol418-028 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 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 Bourn'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 o f apparently nonpregnant rats will be examined after being pressed between glass plates to confirm the absence o f implantation sites. Ovaries and uteri will be retained in neutral buffered 10% formalin.
TESTS, ANALYSES AND MEASUREMENTS - F I GENERATION:
V iab ility :
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 A ppearance:
Preweaning Period:
Once daily.
Pups will be observed if they are warm and dean, for evidence o f 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 and presence 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 W eights:
Preweaning Period:
Days 1 (birth), 8,15 and 22 postpartum.
Sacrifice:
Terminal weight
Feed Consumption Values (recorded and tabulated):
Preweaning Period:
Not recorded.
M ETHOD OF SACRIFICE - FI GENERATION PUPS:
FI generation pups will be sacrificed by carbon dioxide asphyxiation.
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Protocol418-028 Page 19
NECROPSY - F I 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.
Puns Found Dead on Dav 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 presaved in Bourn's solution for possible future evaluation.
P ups F o u n d D ead o r M o rib u n d on Devs t to 4 P o stp a rtu m :
Pups found dead or sacrificed because o f 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 Bourn'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 o f 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 (5 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.
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PR O PO SE D S T A T IS T IC A L T E S T S(9~l6): The following schematic represents statistical analyses ofthe data.
Protocol418-028 Page 20
I. Parametric
Type of Test"
II. Nonparametriob
A. BartMfa Taat
A. MnwkaMAMKa Teat ( 75%>n >tm t eoncanMIon)
Significant at pgp.001
Not Significant
I
Significant at p<0.05
Not Significant
A n alysis o fVariance
r1
Significantat pKO.05
Not Significant
Dunnetre Teat
B. Fisher's Exact Teat on Proportion ofTies
pfS% a MycoaanMon)
B. Analysis o f Variance with Repeated M easures
___________ |___________
II
Significant at p<0.05
Not Significant
(Dosage) DunnatraTeat
(Dosage x Block Interaction) Ona-wsy ANOVA fbr each block
Significant at<0.05
I
Ourmatfs Test
Not Significant
III. Test for Proportion Data Variance TestforHomogeneity
ofthe Binomial Distribution
a. Statistically significant probabilities are reported as eitherp < 0.05 or/j <0.01. b. Proportion data are not included in this category. c. Test for homogeneity of variance.
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Protocol418-028 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 ofthe schematic. Bartlett's Test ofHomogeneity of Variances*91will be used to estimate the probability that foe groups had different variances. A nonsignificant result (p>0.001) will indicate that an assumption ofhomogeneity of variance is not inappropriate, and the data will be compared using the Analysis ofVariance Test*101. If that test is significant (p<0.05), the groups exposed to foe test article/substance will be compared with foe control group using Dunnett's Test*1'1. If Bartlett's Test is significant (<0.001), foe Analysis of Variance Test is not appropriate, and the data will be analyzed as described under foe Nonparametric heading of the schematic. When 75% or fewer o f foe scores in all foe groups are tied, the Kruskal-Wallis Test*121will be used to analyze the data, and in the event o f a significant result (<0.05), Dunn's Test*131will be used to compare the groups exposed to foe test article/substance with foe control group. When more than 75% o f the scores in any group are tied, Fisher's Exact Test*141will be used to compare the proportion o f ties in foe groups.
Data from the motor activity test, with repeated measurements within a session, will be analyzed using an Analysis o f Variance with Repeated Measures*131, as described under that heading in foe schematic. A significant effect (p<0.05) in that test can appear as effect of Concentration (a difference between groups in foe total across all measurements in a session) or as an interaction between Concentration and Block (a difference between groups at specific measurement periods). If foe Concentration effect is significant, foe totals for foe control group and foe groups given foe test article/substance will be compared using Duimetfs Test. If foe Concentration x Block interaction is significant, an Analysts o fVariance Test will be used to evaluate foe data at each measurement period, and a significant result (<0.05) will be followed by a comparison of the groups using Dunnett's Test.
Test items in foe FOB having graded or count scores will be analyzed using the procedures described under foe Nonnarametric heading of the schematic.
Clinical observation incidence data, as well as the descriptive and quantal data from foe FOB, will be analyzed as contingency tables using foe Variance Test for Homogeneity o f foe Binomial Distribution*161.
Alternate or additional statistical evaluations may be performed if deemed necessary or appropriate.
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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 R elative H um idity M onitoring System, the Coulboum Instruments P assive Infrared M otor A ctivity System , the Coulboum Instrum ents Auditory Startle System , the Coulboum Instrum ents Spatial D elayed Alternation System, and/or the passive avoidance software. All data will be tabulated, summarized and/or statistically analyzed using die Argus Autom ated D ata Collection and M anagement System , the Vivarium Temperature and Relative H um idity M onitoring System, M icrosoft Excel [part o f Microsoft Office 97 (version SR-2)] and/or The SAS System (version 6.12).
Records will be reviewed by the Study Director and/or appropriate management personnel within 21 days after generation. Ail original records will be stored in the archives o f 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 o f the draft final report, after which time die Sponsor will be contacted to determine the disposition ofthese materials.
KEY PERSONNEL:
Executive Director of Research: Mildred S. Christian, Ph.D., Fellow, ATS Director of Research: Alan M. Hoberman, Ph.D., DABT Associate Director o fResearch and Study Director: Raymond G. York, Ph.D., DABT Director of 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 of Animal Operations: Dena C. Lebo, V.M.D. Chairperson, Institutional Animal Care and Use Committee: Douglas B. Leam, Ph.D. Consultant, Veterinary Pathology: W. Ray Brown, D.V.M., PhJD., ACVP
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RECORDS TO BE MAINTAINED:
Protocol418-028 Page23
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 Director will provide periodic updates o f 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 mid Method. Evaluation o fTest 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 o f 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 o f the Testing Facility. All original data will be bound and indexed. A copy o f 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 o f the draft final report, after which time the Sponsor will be contacted to determine the disposition ofthese materials.
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Protocol418-02S Page24
INSTITUTIONAL ANIMAL CARE AND USE COM M ITTEE STATEM ENT:
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 ofNaltrexone Symposium, New York Academy of Sciences, November 7, 1983), J. Clin. Psychiat. 45(9):7-10.
3. Lang, P.L. (1988). Embryo and F etal D evelopm ental Toxicity (Teratology) Control D ata in the Charles River 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 Animals. 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 o f 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. ODonoghue, 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 o f homogeneity o f variances. Biometry, W.H. Freeman and Co., San Francisco, pp. 370-371.
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Protocol418-028 Page 25
10. Snedecor, G.W. and Cochran, W.G. (1967). Analysis ofVariance. Statistical M ethods, 6th Edition, Iowa State University Press, Ames, pp. 258-275.
11. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1121.
12. Sokal, R Jl. 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). N onparam etric Statisticsfo r the Behavioral Sciences, McGraw-Hill, New York, pp. 96-104.
15. SAS Institute, Inc. (1988). Repeated measures analysis o f 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 ofthe binomial distribution. Statistical M ethods, 6th Edition, Iowa State University Press, Ames, pp. 240-241.
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PROTOCOL APPROVAL: FOR THE TESTING FACILITY
Alan M. Hoberman, PhD ., DABT Director of Research
&L
Theresa H. Woodard,, Devivi. t- Member, Institutional Animal Care and
Use Committee
FOR THE SPONSOR
John Butenhof PhD ., DABT, CIH Study Monitor and Sponsor's Representative
418-028:PAGE G-81 Exygen Study No.: 023-072
Protocol418-028 Page 26
1_
Date
2 -fa tf . 3 -0 0 1 -- Date
AL, P L r
Date
a
Date
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ATTACHMENT 1 SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE
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ATTACHMENT I
STUDY SCHEMATIC
Protocol418-028 Page 1of3
COMBINED REPEAT DOSE AND REPRODUCTIVE/DEVELOPMENTAL TOXICITY SCREEN*
FitstDay of Test Substance
LastDay ofTest Substance
Male Rats
Cohabitation
LastDay ofTest Substance
1 2 Weeks | 2 Weeks
Natural Delivery
Female
Rats
Acdvity/FOBb
Presumed I Gestation
2 Weeks
2 Weeks
3 Weeks
Postpartum Period
Day 21 Day 22*
Motor Activity/FOBd
O* P
Dosage Period
For additional details see "Tests, Analyses and Measurements" section o f the protocol. FOB and motor activity evaluations conducted on ten.males per group. c. Male rats sacrificed after completion o f 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 evaluation. e. Ten female rats per group and their fitters 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.
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ATTACHMENT l
Protocol418-028 Page2 of3
SCHEDULE*
26 MAR 02 01 APR 02
01 APR 0 2 -1 2 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 of Dosage Period - Male Rats (14 days before cohabitation and through a 14-day cohabitation period until the day before sacrifice alter 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 o f Presumed Gestation. Last Posable Day 0 of Presumed Gestation.
First Possible Day 21 o f Presumed Gestation Toxicokinetic Sample Collection and Sacrifice Toxicokinetic Study Female Rats Last Possible Day 21 of Presumed Gestation Toxicokinetic Sample Collection and Sacrifice Toxicokinetic Study Female Rats
FOB and Motor Activity Evaluation - 10 Male Rats per Group
The start date o f the study is the day the Study Director signs the protocol. Throughout this schedule, the day o fbirth is designated day 1postpartum (day 1 of lactation) and all subsequent ages o f the FI generation rats and days of the lactation period will be determined and cited accordingly, as described above the protocol section, "Day Numbering System."
O* pi
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ATTACHMENT 1
06 MAY 02 23 MAY 02 10 MAY 02 23 MAY 02 12 MAY 02
13 MAY 02
23 MAY 0 2-09 JUN 02 27 MAY 02 - 13 JUN 02
24 SEP 02
Protocol418-028 Page3 of3
First Possible Delivery (Day 21 o f presumed gestation). Last Possible Delivery (Day 25 o f presumed
First Possible Day 25 ofPresumed Gestation Female Sacrifice. Last Possible Day 25 of Presumed Gestation Female Sacrifice.
Day 42 Toxicokinetic Sample Collection and Scheduled Sacrifice - Toxicokinetic Study Male
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 - 10 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
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ATTACHMENT 2 MATERIAL SAFETY DATA SHEET
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MATERIAL SAFETY DATA SHEET (Experimental)
3M 3M Center St. Paul, Minnesota 55144-1000 1-800-364-3577 or (651) 737-6501 (24 hours)
T
Copyright, 1999, Minnesota Mining and Manufacturing Company. All rights reserved. Copying and/or downloading of this information for the purpose of properly utilizing 3H 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
m
1. INGREDIENT
C.A.5. NO.
PERCENT
POTASSIUM PERFLUOROHEXANE SULFONATE.... 3871-99-6 RESIOUAL ORGANIC FLUOROCHEMICALS...... Mixture
100.0 Unknown
This material is not listed on the TSCA inventory and should bo 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 HATER: SPECIFIC GRAVITY:...
PERCENT VOLATILE:... PH:............... VISCOSITY:......... MELTING POINT:..... .
N/A Negligible N/A Negligible slight ea. 1.0 Water-1
(Bulk) Negligible N/A N/D
N/D
APPEARANCE AND ODOR: Off-white crystalline solid, sharp odor.
fp
-
Abbreviations: N/O - Not Determined N/A - Not Applicable CA - Approximately
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MSDS: L-9051 DEVELOPMENTAL PRODUCT December 07, 1999
PAGE 2
3. FIRE AND EXPLOSION HAZARD DATA
FLASH POINT.................. > 212 F Setaflash
Setaflash Closed Cup FLAMMABLE LIMITS - LEL:...... N/A FLAMMABLE LIMITS - UEL:...... N/A AUTOIGNITION TEMPERATURE:.....N/D
EXTINGUISHING MEOIA: Hater, Carbon dioxide, Dry cheeieal, Foam
SPECIAL FIRE FIGHTING PROCEDURES:
Hear full protective clothing, including helmet, self'contained,
positive pressure or pressure deaand breathing apparatus, bunker coat
and pants, bands around anas, waist and legs, face aaek, 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: May 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 cosaercial facility in the presence of a combustible material. Combustion products will include HF. Disposal alternative: Dispose ef waste product in a facility permitted to accept chemical waste.
Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately
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MSDS: L-9051 DEVELOPMENTAL PRODUCT December 07, 1999
PAQE 3
5. ENVIRONMENTAL INFORMATION
(continued)
ENVIRONMENTAL DATA: Not determined.
REGULATORY INFORMATION: Volatile Organic Compounds: N/O. 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 sore organic fluorochemieals 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 SHALLOWED: If swallowed, call a physician lamedlately. 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 bs worn alone or in combination, as appropriate, to prevent eye contact: Hear vented goggles.
Abbreviations: N/D - Not Determined N/A - Not Applicable CA Approximately
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MSDS: L-9051 DEVELOPMENTAL. PRODUCT December 07, 1999
PAGE 4
7. PRECAUTIONARY INFORMATION
(continued)
SKIN PROTECTION:
Avoid skin contact. Hear appropriate gloves when handling this eaterial. A pair of gloves Bade f r o m the following eaterial(s) are recommended: butyl rubber, polyethylene/polyvinylidene chloride (Saranex). Use one or Bore of the following personal protection items as necessary to prevent skin contact: head covering, coveralls. Protective garaents (other than gloves) should be Bade 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 recoanended exposure liaits. If exhaust ventilation
is not adequate, use appropriate respiratory protection. Provide
ventilation adequate to control vapor concentrations below
recoanended exposure liBits and/or control spray or mist.
Local exhaust ventilation is recoaaended where the aes airborne.
aaterial beco
RESPIRATORY PROTECTION: Avoid breathing of airborne aaterial. Select one of the following NIOSH approved respirators based on airborne concentration of contaainants 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 snoke when using this product. Hash exposed areas thoroughly with soap and water. Hash hands after handling and before eating.
RECOMMENDED STORAGE: Store at rooa tesperature. Keep container dry. Keep container closed when not in use.
FIRE AND EXPLOSION AVOIDANCE: Not determined.
EXPOSURE LIMITS
INGREOIENT
POTASSIUM PERFLUOROHEXANE SULFONATE........................ .
RESIDUAL ORGANIC FLUOROCHEMICALS.....
VALUE UNIT
0.1 MG/M3 0.1 MG/M3
TYPE AUTH SKIN*
TWA 3M TWA 3M
Y Y
* SKIN NOTATION: Listed substances indicated with under SKIN refer to
Abbreviations: N/D - Not Oeterained N/A - Not Applicable CA - Approxiaately
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MSDS: L-9051 DEVELOPMENTAL PRODUCT Oecember 07, 1999
pare 5
EXPOSURE LIMITS
(continued)
INGREDIENT
VALUE UNIT
TYPE AUTH SKIN*
the potential contribution to the overall exposure by the cutaneous route including mucous aeabrane and eye, either by airborne or, core particularly, by direct contact with the substance. Vehicles can alter skin absorption.
SOURCE OP EXPOSURE LIMIT DATA: - 3M: 3M Recommended Exposure Guidelines
.
8. HEALTH HAZARD DATA
EYE CONTACT: No infonaation was found regarding effects froa eye contact.
Single exposure aay cause:
Mild Eye Irritation: signs/syMptons can include redness, swelling, pain, and tearing.
SKIN CONTACT: No information was found regarding effects froe skin contact.
May be absorbed through the skin and persist in the body for an extended time.
Single exposure nay cause:
Moderate Skin Irritation: signs/syaptoes can include redness, swelling, itching, end dryness.
INHALATION: No information was found regarding effects froa inhalation exposure.
May be absorbed by inhalation and persist in ths body for an extended time.
Single overexposure, above reeoaasnded guidelines, aay cause:
Irritation (upper respiratory): signs/syaptoas 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 froa swallowing.
Animal studies conducted on organic fluoroeheaicals which aay be present in this product indicate effects including liver disturbances, weight loss, loss of appetite, lethargy, and neurological, pancreatic, adrenal aRd hematologic effects. There are no known human health
Abbreviations: N/0 - Not Deterained N/A Not Applicable CA - Approximately
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USDS: L-9051 DEVELOPMENTAL PRODUCT December 07, 1999
PAGE 6
8. HEALTH HAZARD DATA
(continued)
effects from anticipated exposure to these organic fluorocheaicala when used as intended and instructed.
OTHER HEALTH HAZARD INFORMATION: This product may contain one or aora organic fluorochemicals that have the potential to be absorbed and raaain in the body for long periods of time, either as the parent aoleeule or as metabolites, and nay accumulate with repeated exposures. There are no known human health effects from anticipated exposure to these organic fluorochemicals when used as intended and instructed.
The presence of organic fluorochemicals in the blood of the general population and subpapulations, 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 OATES
PRECAUTIONARY INFO. SECTION CHANGED SINCE Nay 17, 1999
ISSUE
Abbreviations: N/O Not Oeterained 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, soae 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 custoaers. Due to the remote possibility that electronic transfer may haya 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 nay not bs as current as the information in the MSDS available directly from 3M.
Exygen Research
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ATTACHMENT 3 TEST SUBSTANCE PREPARATION PROCEDURE
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ATTACHMENT 3
Protocol 418-028
Version: 418-028/19 MAR 021
TEST SUBSTANCE PREPARATIONPROCEDURE
Pagel of2
Test Substance: T-7706
Vehicle:
Aqueous 0.5% CMC(mediumviscosity)
A. Purpose:
The purposeofthisprocedureistoprovidea methodforthe preparationof dosage suspensionsofT-7706fororal (gavage) administrationto ratsonArgus Research Studynumber418-028.
B. General Information:
1. All suspensioncontainerswill be labeledandcolor-coded. Each label will specifythe protocol number, test substanceidentification, Argusbatch number, concentration, dosage level, preparationdate, expiration date and storage conditions.
2. Suspensionswill beprepared:
_ Daily
X Weekly _ For_daysof use
_ Approximatelyeverytendays
_ BySponsor
3. Suspensionswill be administered at a final dosagevolumeof 10 mL/kg.
4. Safety: X Gloves, uniform/labcoat, gogglesorsafetyglasseswith side shields X Dust-mist/HEPA-filteredMask
__ Half-Face Respiratorif not used ina chemical fume hood __ Full-Face Respirator/PositivePressure Hood __ TyvekSuitortyvekapronand sleeves
5. Dosage suspensionsadjustedfor %Activity/Purityor CorrectionFactor.
_ Yes
X No(Calculations basedon 100%)
_ %Activity
_%Purity__ Correction Factor
6. Sampling requirements: Citedinprotocol
7. Storage: Cited inprotocol
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ATTACHMENT 3
Protocol 418-028
Version: 418-02BH9 MAR 021
TEST SUBSTANCE PREPARATION PROCEDURE
Page 2 o f2
NOTE:
Priortotest substance preparation accuratelymeasurethe required
amount of the appropriatevehicle(R.O. deionizedwatershould be used torcalibration purposes) ina graduated cylinder, pourthe required amount ofvehicle intoa beaker. Carefully markeach beaker atthe meniscus. This markwill be usedduringthe preparationto bringthetest substance slurry up to volume.
C. DosageSuspension Preparation:
1. Weigh the required amountoftest substance ona piece ofweigh paperor intoan appropriatelysized mortar(see PREPARATION CALCULATIONS).
2. Ifweigh paper isused, transferthe test substanceto an appropriately sizedmortar, if necessary, grindthetestsubstance intoa fine powder. Slowlyadd a small amountofvehicle andgrind. Continueto add vehicle slowlyand grindthe vehicle and thetest substancetogethertoforma fine slurry. Transferthe vehicleftest substanceslurryto a marked beaker.
3. Rinsethe mortarand pestlewith additional vehicleto removeany remainingtest substance. Transfer rinseto beaker.
4. Addadditional vehicletothe beakerto bringvolumeuptothe mark. Place onmagnetic stir plate and agitate priorto and duringsampling, aliquotting and/or administration.
5. Repeat steps (1) through (4) for each concentration.
?U /.AWritten By:
TAJU'4^-
Approved by:
0 Clarification
c Date: Z 4 A H i-O Z --
No Yes [see attached clarificationform]
Initial/Date :
'fv
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ATTACHMENT 4 TISSUES TO BE WEIGHED, RETAINED AND EXAMINED HISTOLOGICALLY
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ATTACHMENT 4
Protocol418-028 Page 1of2
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 histnlngip.^l 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
urinary bladder
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 remaining portion of file left epididymis (corpus and caput), as well as the right epididymis will be fixed in neutral buffered 10% formalin.
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ATTACHMENT 4
Protocol418-028 Page 2 of2
Histological Examination:
Histological examination ofretained 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 o f quantitative evaluation, scheduled report date and prices will be adjusted accordingly.
The postlactional ovary should contain primordial and growing follicles as well as the large corpora ltea of lactation. Histopathological examination may detect qualitative depletion of the primordial follicle population. A quantitative evaluation o fprimordial follicles will be conducted for Fo generation female rats; the number o f rats, ovarian section selection and section sample size will be statistically appropriate for the evaluation procedure used. Examination will include enumeration o f 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
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9 0 5 Shcehy Drive. BfcfeA - Horsham. PA 1 9 0 4 4
Telephone flI S ) 443-8710 Telefax: (2 1 5 ) 4 4 3 -8 5 8 7
ARGUS RESEARCH
O taries 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 -1 7 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 of 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 o f 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 of feed consumption will be available from die rats assigned to the main study.
Any revisions m ade to this finalized amendm ent must be n u d e by subsequent amendm ent.
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3. Estrous Cycling and Mating (page 12 of the protocol):
Protocol418-028 Amendment 1
Page 2
[Effective Date: l 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 - Toxicokinetic Study (page 16 of 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 o f Change:
This change was made in order to provide more information about possible toxicity of the test substance in pregnant rats.
5. Scheduled Sacrifice - Main Study fpage 16 of die protocol):
[Effective Date: 27 March 2002] The number o f implantation sites will be recorded, rather than the number of implantation sites and corpora lutea will be recorded.
Reason of Change:
The num b o f corpora lutea 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 o f the protocol):
[Effective Date: 4 April 2002] The liver from each selected pup will be excised and die 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 m ost be made by subsequent am endm ent
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Protocol418-028 Amendment 1
Reason for Change: This change clarifies the protocol by removing an extraneous word. `
Alan M. Hoberman, Ph.D., DABT Director o f Research
Date Raymdgn G. York, fh.D ., DABT Date Associate Director oTltesearch Study Director
M(VjU j
w e t.
Theresa H. Woodard, D.V.M.
Date John Butenhoff, Ph.D., DABT, CIH Date
Member, Institutional Animal Care
Study Monitor and
and Use Committee
Sponsor's Representative
Any revisions m ade to this finalized am endm ent m ust b e m ade by subsequent am endm ent
Exygen Research
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905 SfeefyOrne, Bldg. A Wo/shom,PA 19044
Telephone: (215) 443 -8 7 0
Telefax: (215} 4 43S 5B 7
ARGUS RESEARCH
Charles R iver Laboratories Discovery and Developm ent Services
PROTOCOL 418-028
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTTON/DEVELOPMENTAL TOXICITY SCREENING TEST
SPONSOR'S STUDY NUMBER: T-7706.1
Amendment 2 - 15 July 2002
1. Safety Precautions (page 3 of 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 unifomi/lab coat during formulation preparation of 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 mast be made by subsequent amendment
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Protocol418-028 Amendment 2 Page 2
Reason for Change: This change was made because more time is needed to evaluate animals aw ig r^ to FOB and motor activity evaluations.
Date Raymond G. YorkfPh-U., DABT Date Associate Director ofKesearch Study Director
. jkki^
__ /
p^There H. Woodard, D&M . Member, Institutional Animal Care and Use Committee
' 7 7U L
Date John Butenhoff, Ph.D., DABT, CIH Date Study Monitor and Sponsor's Representative
Any revisions to this finalized amendment mnst be made by subsequent amendment.
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905 Sheehy Drive,Bldg. A H orsham . PA 19044 Telephone:(215)443-fl710 Telefax: (2 1 5 ) 4 4 3 * 5 9 7
ARGUS RESEARCH
Chartes River Laboratories
Discovery and Development Services
PROTOCOL 418-028
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE EEPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
SPONSOR'S STUDY NUMBER: T-7706.1
Amendment 3-1 7 July 2002
1. Bulk Test Substance Sampling Shipping Instructions. Shipping Instructions. Caesarean-Sectioning - Toxicokinetic Study. Scheduled Sacrifice - Toxicokinetic Study, and Scheduled Sacrifice, (pages 4, S, 12,13,16 and 19, respectively of the protocol)
[Effective Date: 29 May 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.
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Protocol418-028 Amendment 3 Page 2
These samples include: Bulk test substance sampling (page 4 of the protocol) Concentration and homogeneity (page 5 of the protocol) Stability (page 5 of the protocol) Plasma toxicokinetic samples (page 11 to 12 and page 16 of the protocol) Plasma samples, rather than serum samples, were retained. Liver toxicokinetic samples (pages 12 and 16 of the protocol) Pooled fetal serum toxicokinetic samples (pages 12 and 16 of the protocol) Pooled fetal liver toxicokinetic samples (pages 13 and 16 of the protocol) Pooled pup serum toxicokinetic samples (page 19 of the protocol) Pup liver toxicokinetic samples (page 19 of the protocol)
The analyses will 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 of 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 of the inspections and report submissions will 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 of the Sponsor because 3M is not able to complete the formulation analysis with their current staffing.
_________--
Theresa H. Woodard, D.V.M. Member, Institutional Animal Care and Use Committee
/P J2- ZCktn.
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.
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I I!
. PROTOCOL 418-028
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTTON/DEVELOPMENTAL TOXICITY SCREENING TEST
SPONSOR'S STUDY NUMBER: T-7706.1
Amendment 4 - 2 0 March 2003
1, B ulk T est Substance Sampling. Shipping Instructions. Shipping Tnstructirms. Cagsarean-Sactirmin[>- Toxicokinetic Study. Scheduled Sacrifice - ToxicnViriptir. Study, and Scheduled Sacrifice, (pages 4, 5, 12,13,16 and 19, respectively of the protocol) and Amendment 3. Item 1: Bulk Test Substance Sam nling. Shipping Instructions. Shipping Instructions. Caesarean-Sectioning - Toxicokinetic Study Scheduled 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), ' Perfluorooctanesulfonatc (PFOS) and Pentadecafluorooctanoic Acid (PFOA) in Rat Liver, Serum and Urine Revision 1".
I Any revisions to this finalized amendment must be made by subsequent am endm ent
l.
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Protocol 418-028 Amendment4 Page 2
Reason for Change:
This change was made at the request of the Exygen Research in order to clarify the method of analysis.
Alan M. {ioberman, PhD ., DABT Director fResearch
Date
ond G. Y
Associate Direct
Study Director
DSglaS'B. Lem, PhD. Chair, Institutional Animal Care and Use Committee
John Butenhoff, Ph.D., DABT, CIH D ate Study M onitor and
i iI
Exygen Research
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RESEARCH
.Precise Research. \ Proven Results.
PROTOCOL DEVIATION
deviation Number: 1____ Date of Occurrence: 10/14/02
1 of 1
Exygen Study Number: 023-072
Protocol Number: 418-028
DESCRIPTION OF DEVIATION A recovery rif 62% for PFHS is being accepted for the 5000 ppb spike (0202119 Spk C) in data set 100402A. \
Deviation Issued.
ACTIONS TAKEN
far example - deviation issued. S O P revision, etc.
Recorded By:{
:Date: urlisi
IMPACT ON STUDY The 10 ppb and 50 ppb control matrix spikes Included with the set gave acceptable recoveries.
M anagem en tS ignature (Sponsor) Study Monitor
____ y . -- _
U:\Forms\PROTOCO^_DEVIATION.doc p
. y D ate o7 / n D ate
Exygen QAU Review fi*-^ ^/f^/o3
9/25/2002/5
VitatamsteJiWOisEiufrfE-issiN me to s&reaehus&of ori&inw. . toi|iir/c3
A g i3058 Research Drive State College, PA 16B01, USA
\J: 800.281.3219 F: 814.272.1019 exygen.com
Exygen Research
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3058 Research Drive State College, PA 16801
Phone: 814-272-1039 Fax: 814-231-1580
NOTE TO FILE
Date: 01/14/03
Exygen Research Study # 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 data associated with this study, the concentrations of fortification and calibration solutions listed throughout the raw data were left uncorrected for the salt content. The final PFHS values recorded were corrected to reflect the difference in PFHS concentration due to the salt content. The correction was performed by multiplying the final ppb value found by 0.91.
Exygen Research
July 31, 2001/0
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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)
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TITLE Method of Analysis for the Determination of Perfluorohexanesulfonate (PFHS), Perfluorooctanesulfonate (PFOS) and Pentadecafluorooctanoic Acid (PFOA) in Rat
Liver, Seram and Urine Revision 1
AUTHORS John Flaherty, Karen Risha, and Emily Decker
DATE ISSUED November 20,2002
SPONSOR 3M Medical Department Corporate Toxicology
3M Center, Building 220-2E-02 St. Paul, MN 55144-1000
PERFORMING LABORATORY Exygen Research
3058 Research Drive State College, PA 16801
METHOD NUMBER ExM-023-071 Revision 1
TOTAL NUMBER OF PAGES 43
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ExygenMethod No: ExM-023-071 Revision 1
MANAGEMENT APPROVAL
Z
/lo h n Flaherty ' Laboratory Manager
Exygen Research
Date
John L. Butenhoff
Date
Sponsor Representative
3M Medical Department Corporate Toxicology
Exygen Research
Exygen Research
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ExygenMethod No: ExM-023-071 Revision 1
TABLE OF CONTENTS
T IT L E .............................................................................................................................................. i
MANAGEM ENT A PPRO VAL....................................................................................................2
TABLE O F CO N TEN TS....................................................................................................... 3
LIST OF T A B L E S .......................................................................................................................... 4
LIST OF FIG U RES......................................................................................................................... 5
1. SU M M A R Y ...............................................................................................................................7
2. EXPERIM ENTAL COM POU NDS.......... ............................................................................ 8
3. CHEMICALS AND SU PPLIES............................................................................................ 9
3.1. CHEMICALS.......................................................................................................................9
3.2. Sta n da rd s...................................................................................................................... 9
3.3. E quipment and Supplies............................................................................................. 9 3.4. Solutions...................................................................................................................... 10
3.5. Preparation of Standard Solutions...........................................
10
3.5.1. Stock solution................................................................................................... 11
3.5.2. Fortification Solutions.....................................................................................n
3.5.3. Calibration Standards...................................................................................... 11
4. M ETHOD..................................................................................................................................12
4.1. F low Dia gra m ............................................................................................................. 12
4 .2. Sample Pro cessing.................................................................................................... 12 4.3. Batch Se t u p .................................................................................................................13
4.4. Sample Extraction................................................................................................... 13
4.4.1. L iver Extraction................................................................................................13
4.4.2. Serum and Urine Extraction...........................................................................13
4.4.3. SPE Column Conditioning............................................................................. 14
4.5. Qu an titatio n .............................................................................................................. 14
4.5.1. LC/M S/M S System and Operating Conditions........................................... 14
4.5.2. Calibration Curve Procedures........................................................................15
4.5.3. Sam ple A nalysis...............................................................................................16
4.6. Acceptance Criteria..................................................................................................17
4.7. Performance Criteria...............................................................................................17
4.8. Time Required for Analysis....................................................................................18
5. CA LCU LA TIO N S..................................................................................................................18
6. SA FETY....................................................................................................................................19
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LIST OF TABLES
Table 1. Recovery Summary of PFHS in Rat Liver and Serum...................................... 20 Table 2. Recovery Summary of PFOS in Rat Liver, Serum and Urine..........................21 Table 3. Recovery Summary of PFOA in Rat Liver, Serum and Urine.......................... 22
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LIST OF FIGURES
Figure 1. Calibration Curve for PFHS..........................................................................23
Figure 2. Calibration Curve for PFOS..........................................................................24
Figure 3. Calibration Curve for PFOA.........................................................................25
Figure 4. Representative Chromatogram of a 0.1 ng/mL Standard Containing PFHS...........................................................................................26
Figure 5. Representative Chromatogram of a 0.1 ng/mL Standard Containing PFOS...26
Figure 6. Representative Chromatogram of a 0.1 ng/mL Standard Containing PFOA.. 27
Figure 7. Representative Chromatogram of a 0.5 ng/mL Standard Containing PFHS... 27
Figure 8. Representative Chromatogram of a 0.5 ng/mL Standard Containing PFOS... 28
Figure 9. Representative Chromatogram of a 0.5 ng/mL Standard Containing PFOA.. 28
Figure 10. Representative Chromatogram of a 5.0 ng/mL Standard Containing PFHS... 29
Figure 11. Representative Chromatogram of a 5.0 ng/mL Standard Containing PFOS...29
Figure 12. Representative Chromatogram of a 5.0 ng/mL Standard Containing PFOA.. 30
Figure 13. Representative Chromatogram of a Reagent Blank Sample Analyzed for PFHS............................................................................................................ 30
Figure 14. Representative Chromatogram of a Reagent Blank Sample Analyzed for PFOS............................................................................................................ 31
Figure 15. Representative Chromatogram of a Reagent Blank Sample Analyzed for PFOA............................................................................................................ 31
Figure 16. Representative Chromatogram of a Control Liver Sample Analyzed for PFHS....................................................................................................... 32
Figure 17. Representative Chromatogram of a Control Liver Sample Analyzed for PFOS....................................................................................................... 32
Figure 18. Representative Chromatogram of a Control Liver Sample Analyzed for PFOA...................................................................................................... 33
Figure 19. Representative Chromatogram of a Control Serum Sample Analyzed for PFHS..................................
33
Figure 20. Representative Chromatogram of a Control Serum Sample Analyzed for PFOS....................................................................................................... 34
Figure 21. Representative Chromatogram of a Control Serum Sample Analyzed for PFOA...................................................................................................... 34
Figure 22. Representative Chromatogram of a Control Urine Sample Analyzed for PFOS....................................................................................................... 35
Figure 23. Representative Chromatogram of a Control Urine Sample Analyzed for PFOA...................................................................................................... 35
Figure 24. Representative Chromatogram of a Control Liver Sample Fortified at 10 ng/g with PFHS.................................................................................... 36
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LIST OF FIGURES (continued)
Figure 25. Representative Chromatogram of a Control Liver Sample Fortified at 10 ng/g with PFOS......................................................................................
Figure 26. Representative Chromatogram of a Control Liver Sample Fortified at 10 ng/g with PFOA....................................................................................37
Figure 27. Representative Chromatogram of a Control Liver Sample Fortified at 50 ng/g with PFHS....................................................................................37
Figure 28. Representative Chromatogram of a Control Liver Sample Fortified at 50 ng/g with PFOS....................................................................................38
Figure 29. Representative Chromatogram of a Control Liver Sample Fortified at 50 ng/g with PFOA....................................................................................38
Figure 30. Representative Chromatogram of a Control Serum Sample Fortified at 10 ng/mL with PFHS................................................................................ 39
Figure 31. Representative Chromatogram of a Control Serum Sample Fortified at 10 ng/raL with PFOS................................................................................ 39
Figure 32. Representative Chromatogram of a Control Serum Sample Fortified at 10 ng/mL with PFOA................................................................................40
Figure 33. Representative Chromatogram of a Control Serum Sample Fortified at 50 ng/mL with PFHS.................................................................................40
Figure 34. Representative Chromatogram of a Control Serum Sample Fortified at 50 ng/mL with PFOS.................................................................................41
Figure 35. Representative Chromatogram of a Control Serum Sample Fortified at 50 ng/mL with PFOA................................................................................41
Figure 36. Representative Chromatogram of a Control Urine Sample Fortified at 10 ng/mL with PFOS.................................................................................42
Figure 37. Representative Chromatogram of a Control Urine Sample Fortified at 10 ng/mL with PFOA................................................................................42
Figure 38. Representative Chromatogram of a Control Urine Sample Fortified at 50 ng/mL with PFOS.................................................................................43
Figure 39. Representative Chromatogram of a Control Urine Sample Fortified at 50 ng/mL with PFOA................................................................................43
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1. SUMMARY
This report details a method of analysis for residues of Perfluorohexanesulfonate (PFHS), Perfluorooctanesulfonate (PFOS) and Pentadecafluorooctanoic Acid (PFOA) in Rat Liver, Serum and Urine.
Residues of PFHS, PFOS and PFOA are extracted from each matrix with acetonitrile. The acetonitrile extract is added to water and loaded onto a conditioned Cl 8 solid phase extraction (SPE) cartridge. Analyte residues are eluted with 2 mL of methanol. Quantification of PFHS, PFOS and PFOA is accomplished by liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis using multiple reaction monitoring (MRM).
The proposed limit of quantitation (LOQ; the lowest fortification specified by the method which gives adequate recovery according to EPA guidelines) for this method is 10 ng/g (parts-per-billion) each for PFHS, PFOS and PFOA.
The theoretical limit of detection (LOD) will be based on the signal to noise ratio and will be at least greater than 3 times the level of noise, based on the instrumentation system used. For all analytes, the lowest analytical standard corresponds to 0.1 ng/mL.
This method was developed using rat liver, serum and urine. Typical percent recoveries standard deviations (at 10 and SOng/g) are shown below:
Fortification Level (ng/g)
10 50
PFHS RecoveryinRat Liver
115% 9.9% (n=3) 98% 3.5%(n=3)
Fortification Level(ng/mL)
10
50
PFHS RecoveryinRat Serum
108% 4.7% (ii=3) 111% 9.6% (n=3)
Fortification Level (ng/g) 10
50
PFOS Recovery inRatLiver
96% 8.5% (n=3) 88% 1.5%(n=3)
Fortification Level (ng/mL) 10 50
PFOS Recovery in Rat Serum
88% 9.8% (n=3) 120% 2.1% (n=3)
PFOS Recoveryin Rat Urine
93% 4.7% (n=3) 79% 1.2% (n=3)
Fortification Level (ng/g) 10 50
PFOA Recovery inRatLiver
98%3.1%(n=3) 94% 2.5% (n=3)
Fortification Level (ng/mL) 10
50
PFOA Recovery in Rat Serum
117%1.5%(n=3) lll%4.0%(n=3)
PFOA Recoveryin Rat Urine
89% 2.5% (n=3) 87% 2.1% (n=3)
Representative calibration curves are shown in Figures 1-3. Representative chromatograms are shown in Figures 4 to 39.
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2. EXPERIMENTAL COMPOUNDS
The structures for PFHS, PFOS and PFOA are given below.
PFHS Chemical Name = Molecular weight -
Perfluorohexanesulfonate 399, as shown
PFHS is supplied as the potassium salt (QFuSOa'K*), molecular weight = 438
PFOS Chemical Name Molecular weight
Perfluorooctanesulfonate 499, as shown
FFF
PFOS is supplied as the potassium salt (CgFnSOs'K*) molecular weight = 538
PFOA Chemical Name Molecular weight
= =
Pentadecafluorooctanoic Acid 413, as shown
F F0
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3. CHEMICALS AND SUPPLIES
3.1. Ch em ica ls
Chemical
Methanol (MeOH) Ammonium Acetate Water Acetonitrile
Grade
HPLC Reagent Type I HPLC
Source
EM Science JT Baker Exygen
EM Science
Catalog No.
MX0475-1 0596-01 NA AX0145-1
Type I water = electrical resistivity, minimum of 16.67 M2/cm at 25 C, from a Labconco WaterproTM workstation.
St a n d a r d s
Standard
Perfluorohexanesulfonate (PFHS) Perfluorooctanesulfonate (PFOS) Pentadecafluorooctanoic Acid (PFOA)
TCR Number SE-036
SD-018
Lot No: 08316DO
Purity (%) 99.99 all isomers. 84.36 straight chain
86.9
96
Source 3M
3M
Aldrich Chem
E q u ipm en t and Su pplie s
Equipment
Balance, analytical (display at least 0.0001 g) 125-mL LDPE narrow mouth bottles Disposable glass micropipets (50-100 & 100-200 pL) Tissumizer Wrist action shaker Sorvall RC 5C plus Centrifuge 50 mL disposable polypropylene centrifuge tubes 15 mL disposable polypropylene centrifuge tubes Visiprep vacuum manifold Sep Pak Vac 6 cc (lg) tC18 cartridges (part # WAT 036795 2-raL clear HPLC vial Kit (cat # 5181-3400) Class A pipets and volumetric flasks Standard lab equipment (graduated cylinders, disposable tubes etc.) Stand-alone drop-in guard cartridge holder (part #844017-400) Hypercarb drop-in guard column (4 mm) (part # 844017-400) HPLC Pump (LC-10AD) LGMS/MS and HPLC systems
Supplier Mettler Nalgene Drummond (VWR) Tekmar Burrell Scientific Dupont VWR VWR Supelco Waters
Hewlett-Packard various suppliers various suppliers
Keystone Scientific
Keystone Scientific
Shimadzu As described in
section 4.5.
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Notes: 1. In order to avoid contamination, the use of disposable labware (containers, tubes, pipettes, etc.) is highly recommended. 2. Teflon or Teflon-lined containers or equipment should not be used. 3. It may be necessary to check the solvents (acetonitrile, methanol) for the presence of contaminants (especially PFO) by LC/MS/MS before use. Certain lot numbers have been found to be unsuitable for use. 4. Use disposable micropipettes or pipettes to aliquot standard solutions when preparing standards and samples for extraction. 5. Equivalent materials may be substituted for those specified in this method.
3.4. So lu tio n s
(1) 2 mM ammonium acetate in water is prepared by weighing 0.154 g of ammonium acetate and dissolving in 1 L of water.
(2) Hypercarb filtered type I water is prepared by filtering type I water through a Hypercarb guard column using a HPLC pump at ~2-3 mL/min. Before use, wash the guard cartridge with ~25 mL of HPLC grade acetonitrile, then - 25 mL of type I water, then begin collecting the filtered type I water eluate for use in the extraction. Repeat the wash after filtering ~2L of water.
Note: The aforementioned example is provided for guidance, alternative volumes may be prepared as long as the appropriate ratios of the solvent to solute are maintained.
3 .5 . P r e p a r a t i o n o f St a n d a r d So l u t i o n s
Analytical standards are used for three purposes: 1. Calibration Standards - These standards are prepared in methanol and are used to calibrate the response of the detector used in the analysis. 2. Laboratory Control Spikes - These fortifications are prepared at concentrations corresponding to the LQQ and Sx LOQ and are used to determine analytical recovery. Laboratory control spikes are prepared in control matrix. 3. Matrix Spikes - These fortifications are prepared by spiking into the field samples at a known concentration. Matrix spikes are used to evaluate the effect of the sample matrix on analytical recovery and are prepared at the client's request.
The analyst may vary the absolute volumes of the standards as long as the correct proportions of solute to solvent are maintained.
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3.5.1. Stock solution
Prepare individual stock solutions at 100 pg/mL for PFHS, PFOS and PFOA by weighing out 10 mg of each analytical standard (corrected for purity and if necessary, salt content) and dilute to 100 mL with methanol in separate 100-mL volumetric flasks. The stock solutions (in 125-mL LDPE bottles) are to be stored in a refrigerator at 2C to 6C and are stable for a maximum period of one year from the date of preparation.
3.5.2. Fortification Solutions
a. Prepare a mixed fortification standard at 1.0 pg/mL (1000 ng/mL) of PFHS, PFOS and PFOA by adding 1.0 mL of each of the 100 pg/mL stock solutions into a 100-mL volumetric flask and bring up to volume with methanol.
b. Prepare a mixed fortification standard at 0.1 pg/mL (100 ng/mL) of PFHS, PFOS and PFOA by diluting 10.0 mL of the 1.0 pg/mL mixed fortification solution to 100 mL with methanol in a volumetric flask.
Example: one hundred microliters of the 0.1 pg/mL solution spiked into 1 g of liver or 1 mL of serum/urine is equivalent to a 10 ppb (10 ng/mL or ng/g) fortification.
Store all fortification standard solutions in a refrigerator (in 125-mL LDPE bottles) at 2C to 6C for a maximum period of one year from the date of preparation. Note also that additional concentrations may be prepared if necessary.
3.5.3. Calibration Standards LC/MS/MS calibration standards containing PFHS, PFOS and PFOA are prepared at 0.1,0.2,0.5,1.0,2.0 and 5.0 ng/mL in methanol via dilution of the 0.1 pg/mL mixed fortification solution (section 3.5.2.b).
The following is a typical example; additional concentrations may be prepared as needed.
Initial Cone. (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
Diluted to (mL) 100 100 100 100 100 100
Final Cone. (ng/mL) 5.0 2.0 1.0 0.5 0.2 0.1
The standards may be used for a period of one year (in 125-mL LDPE bottles) when stored refrigerated (at 2C to 6C).
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4. METHOD
4.1. F lo w Dia g ra m
The flow diagram of the method is given below, followed by a detailed description of each step.
Method Flow Diagram
Weigh appropriate amount of liver or measure appropriate volume of serum or urine (fortify samples designated as matrix spikes and laboratory control spikes)
J*
Add water to liver for a final volume of 10 mL, add water to serum and urine for a final volume of 20 mL, homogenize
4
Remove 1 mL and add S mL of ACN, shake
4
Centrifuge
4
Decant supernatant into 35 mL of water
4
Load onto conditioned SPE
4
Elute with 2 mL methanol
4
LC/MS/MS Analysis
4.2. Sa m ple P r o c essin g
For liver samples, place frozen samples in a food processor and homogenize with dry ice. Then place samples in containers and leave open in frozen storage overnight to allow for COz sublimation. Seal and place the samples in frozen storage below -10C until time of extraction. Alternately, if there is an insufficient amount of sample (~ less than 5 g), then no processing is necessary and the sample can be used as supplied. No sample processing is needed for serum and urine samples. However, frozen serum and urine samples must be allowed to completely thaw to room temperature before use.
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4.3. B a tch Se t u p
a. A batch of samples should not contain more than 20 field samples.
b. Each batch of samples analyzed must include at least one control (method blank using control matrix) and two matrix controls fortified at known concentrations (typically 10 and SO ng/g for liver or ng/mL for serum and urine) to verify procedural recovery for the batch.
c. At least one field sample in each batch must also be separately fortified at a known concentration and carried through the procedure to verify recovery. Additional samples in the batch may also be fortified if desired.
d. All samples require duplicate injections.
4.4. Sa m ple E x tra ctio n
4.4.1. Liver Extraction
a. Weigh 1 g of liver sample into a SO mL disposable centrifuge tube and fortify, if appropriate. Note that alternate weights of liver may be measured depending on the sample size available for use.
b. Add water to the sample for a final volume of 10 mL. Cap tightly. c. Homogenize sample using a tissuemizer for ~1 minute. d. Transfer 1 mL of the sample using a disposable pipette into 15 mL
disposable centrifuge tubes. Add 5 mL of ACN and shake for ~20 minutes on a wrist action shaker. e. Centrifuge tubes at -3000 rpm for - 5 minutes. Carefully decant supernatant into a 50 mL disposable centrifuge tube and add 35 mL of water. f. Load the sample onto a conditioned SPE column (for conditioning details, see section 4.4.3.). Discard the eluate. Any analyte residues will be trapped on the SPE column at this point. g. Elute with 2 mL of methanol. Collect 2 mL of elute into a graduated 15 mL centrifuge tube. h. Analyze samples using electrospray LC/MS/MS.
4.4.2. Serum and Urine Extraction
a. Measure 1 mL of serum or urine sample into a 50 mL disposable centrifuge tube and fortify, if appropriate. Note that alternate volumes of serum and urine may be measured depending on sample size available for use.
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b. Add water to sample for a final volume of 20 mL. Cap tightly and vortex for -1 minute. Then continue with steps d-h in section 4.4.1.
4.4.3. SPE Column Conditioning
Place the unconditioned SPE columns on the vacuum manifold. Condition the SPE columns by passing ~ 10 mL of methanol through the column followed by - 5 mL of water. Hie washes may be pulled through the SPE column using vacuum at a flow rate of -1 drop/sec or may be allowed to pass through the column unaided. Discard all washes. Do not allow the column to dry.
4.5. Q u a n t i t a t i o n
4.5.1. LC/MS/MS System and Operating Conditions
Mass Spec: Interface:
Computer: Software:
Micromass Quattro Ultima (Micromass) Electrospray (Micromass) Harvard infusion pump (Harvard Instruments), for tuning COMPAQ Professional Workstation AP200 Windows NT, Masslynx 3.3
HPLC:
Hewlett Packard (HP) Series 1100
HP Quat Pump
HP Vacuum Degasser
HP Autosampler
HP Column Oven
Note: A 4 x 10 mm hypercarb drop in guard cartridge is attached on-line after
the purge valve and before the sample injector port to trap any residue
contaminants that may be in the mobile phase and/or HPLC system.
HPLC Column: Genesis Cg (Jones Chromatography), 2.1 mm x 50 mm, 4p
Column Temperature: 35 C
Injection Volume: 15 pL
Mobile Phase (A): 2 mM Ammonium Acetate in Type I water
Mobile Phase (B): Methanol
Tim e 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 R ate im L /m inl 10 0.3 10 0.3 90 0.3 90 0.3 100 0.3 100 0.3 10 0.3 10 0.3
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It may be necessary to adjust the HPLC gradient in order to optimize instrument performance. Columns with different dimensions (e.g. 2.1 x 30) and also columns from different manufacturers (Keystone Betasil Cia etc.) could be used, provided equivalent chromatography is obtained.
Ions monitored:
Analvte FFHS PFOS PFOA
Mode Negative Negative Negative
Transition Monitored 399 - 8 0 499 -> 99 413--369
Approximate Retention Time
-8.2 min. - 8.8 min - 8.6 min
The retention times may vary, on a day to day basis, depending on the batch of
mobile phase etc. Drift in retention times (up to 4 %) is acceptable within an analytical run, as long as the drift continues through the entire analysis and the standards are included at the beginning and end of the analytical run.
Note: An alternative LC/MS/MS system may be used once demonstrated to be equivalent.
The mass spectrometer is tuned for each analyte by infusing a - 1.0 pg/mL standard solution (at 10 fiL/min, using an infusion pump) via a "T" into a stream of mobile phase containing 50% methanol and 50% 2mM ammonium acetate in water at 0.2 mL/min flow rate. Each analyte is initially tuned for the parent ion and then tuned for the product ion. Once the instrument is tuned, the optimized parameters are saved as a tune file. This tune file is then used during routine analysis.
4.5.2. Calibration Curve Procedures
a. Inject the same aliquot (between 10 to 50 pL) of each calibration standard (ranging from the lowest level standard to the highest level prepared), into the LC/MS/MS.
b. Use weighted linear standard curves for quantitation. Linear standard curves are generated for each analyte by linear regression using 1/x weighting of peak area versus calibration standard concentration using Masslynx (or equivalent) software system. Any calibration standard found to be a statistical outlier by using an appropriate outlier test, may be excluded from the calculation of the calibration curve. However, the total number of calibration standards that may be excluded must not exceed 20% of the total number of standards injected.
c. The correlation coefficient (R) for calibration curves generated must be >0.9925 (R2 0.985). If calibration results fall outside these limits, then appropriate steps must be taken to adjust instrument operation, and the standards or the relevant set of samples should be reanalyzed.
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Typical calibration curves for PFHS, PFOS and PFOA can be found in Figures 1 3.
4.5.3 Sample Analysis
a. Inject die same aliquot (between 10 to SO pL) of each standard, sample, recovery, control, etc. into the LC/MS/MS system.
b. Standards corresponding to at least five or more concentration levels (starting with the LOQ level or below) must be included in an analytical set.
c. An entire set of calibration standards should be injected at the beginning of a set followed by calibration standards interspersed approximately every 5-10 samples (to account for a second set of extracted standards). As an alternative, an entire set of calibration standards may be included at the beginning and at the end of a sample set. hi either case, calibration standards must be the first and last injection in a sample set.
d. The concentration of each sample/fortification/contiol is determined from the standard curve, based on the peak area of each analyte. The standard responses should bracket responses of the residue found in each sample set. Results may be quantitated up to 10% outside the curve by extrapolation. If necessary, dilute the samples to give a response within the standard curve range.
e. Fortification recoveries falling within 70 to 130% are considered acceptable.
f. Samples must be stored refrigerated between 2C to 6C until analysis.
g. Samples in which either no peaks are detected or peaks less than the lowest concentration of the calibration standards are detected at the corresponding analyte retention time will be reported as ND (not detected). Samples in which peaks are detected at the corresponding analyte retention time that are less than the LOQ and greater than or equal to the lowest concentration of the calibration standards will be reported as NQ (not quantifiable).
The analysis performed during the method development included fortifications at 10 and 50 ng/g of PFHS in rat liver, 10 and 50 ng/mL of PFHS in serum, 10 and 50 ng/g of PFOS and PFOA in rat liver and 10 and 50 ng/mL of PFOS and PFOA in serum and urine. Typical chromatograms can be found in Figures 4-39.
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4.6. A c c e p t a n c e C rit eria
The following criteria must be met to ensure the presence of PFHS, PFOS and PFOA:
1. The chromatogram must show a peak of a daughter ion at 80 amu from a parent of 399 amu for PFHS, a daughter ion at 99 amu from a parent of 499 amu for PFOS, and a daughter ion at 369 amu from a parent of 413 amu for PFOA.
2. Method blanks must not contain analyte at levels greater than the LOQ. If a blank contains the analyte at levels greater than 10 ng/mL, then a new blank sample must be obtained and the entire set must be re-extracted.
3. Recoveries of control spikes and matrix spikes (if any) must be between 70-130% of their known values. If a control spike falls outside the acceptable limits, the entire set of samples should be re-extracted. Any matrix spike outside 70-130% should be evaluated by the analyst to determine if re-extraction is warranted.
4. Any calibration standard found to be a statistical outlier by using the Huge Error Test, may be excluded from the calculation of the calibration curve. However, the total number of calibration standards that could be excluded must not exceed 20% of the total number of standards injected.
5. The correlation coefficient (R) for calibration curves generated must be >0.9925 (R2 >0.985). If calibration results fall outside these limits, then appropriate steps must be taken to adjust instrument operation, and the standards or the relevant set of samples should be reanalyzed.
6. Retention times between standards and samples must not drift more than 4 % within an analytical run. If retention time drift exceeds this limit within an analytical run then the set must be reanalyzed.
4.7. P e r f o r m a n c e C rit eria
The following two criteria must be performed once as a system suitability test, before the commencement of analysis, when using an instrumentation set-up that has not been used for this method.
First Criterion:
.
Run a standard solution on LC/MS/MS corresponding to the estimated LOQ
(10 ng/mL) in matrix and obtain a signal to noise ratio for the analyte transition of
at least 9:1, compared to a reagent blank. If this criterion cannot be met, optimize
and change instrument operating parameters (or increase the injection volume, if
appropriate).
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Second Criterion: Run a set of standards of five or more concentration levels, from at or below the LOQ, up to the highest concentration level to be included in the analysis. Generate a calibration curve for the analyte and obtain a linear regression with a coefficient of determination (R2) of at least 0.98S for the analyte. Once this criterion is met, samples may be analyzed with standards interspersed.
4 .8 . T im e R eq u ir ed f o r Analysis One person can take a set of 20 samples through the sample preparation procedure in approximately 4 hours. The LC/MS/MS analysis of the set (containing 20 field samples, 1 matrix blank, 2 laboratory control spikes, 1 matrix spike and 12 standard injections) will take approximately 14 hours.
5. CALCULATIONS
a. Use Equation 1 to calculate the amount of analyte found (in ng/mL, based on peak area) using the standard curve (1/x weighted linear regression parameters) generated by the Masslynx software program.
Equation 1:
Analyte found (ng/mL) = /peak area - intercept! x DF x aliquot factor slope
DF = factor by which the final volume was diluted, if necessary. Aliquot facton= 10 for liver, 20 for serum and urine b. For samples fortified with known amounts of analyte prior to extraction, use Equation 2 to calculate the percent recovery. Equation 2:
Recovery (%) =
[ total analyte found (ng/mL) - analyte found in control (ng/mL)] analyteadded (ng/mL)
Note: Subtract analyte found in control (ng/mL) from analyte found (ng/mL), if ng/mL in control is greater than LOQ.
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c. Use Equation 3 to calculate the amount of analyte found (in ppb)
Equation 3:
Analytefound(ng/gorng/tnL)= fanalvtefound (na/mLlx FV fmLl sampleweight(g)orsample volume (mL)
FV = final volume
For reporting purposes, samples in which either no peaks are detected or peaks less than the lowest concentration of the calibration standards are detected at the corresponding analyte retention time will be reported as ND (not detected). Samples in which peaks are detected at the corresponding analyte retention time that are less than the LOQ and greater than or equal to the lowest concentration Of the calibration standards will be reported as NQ (not quantifiable).
6. SAFETY
The analyst should read the material safety data sheets for all standards and reagents before performing this method. Use universal precautions when handling standards and reagents, including working in fume hoods and wearing laboratory coats, safety glasses, and gloves.
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Table 1. Recovery Summary of PFHS in Rat Liver and Serum
Recovery Summaryof PFHS In Rat Liver
Sample ID 0201684 Spk A 0201684 Spk B 0201684 SokC
Sample ID 0201684 Spk D 0201684 Spk E 0201684 Sok F
Analyte Added (nq/q)
10 10 10
Average: Standard Deviation:
Percent Recovery (%)
108 110 126
115 9.9
Analyte Added (no/q)
50 50 50
Average: Standard Deviation:
Percent Recovery (%)
101 98 94
98 3.5
RecoverySummaryof PFHS in Rat Serum
Sample ID
0201682 Spk A 0201682 Spk B 0201682 Sok C
Analyte Added (nq/mL)
10 10 10
Average: Standard Deviation:
Percent Recovery (%)
112 103 110
108 4.7
Sample ID
0201682 Spk D 0201682 Spk E 0201682 Spk F
Analyte Added (nq/mL)
50 50 50
Average: Standard Deviation:
Percent Recovery (%)
107 104 122
111 9.6
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Table 2. Recovery Summary of PFOS in Rat Liver, Serum and Urine
RecoverySummaryof PFOSInRat Liver
Samla ID
02016S4 Spk A 0201684 SpkB 0201684 Spk C
AnalyteAdded (ng/g)
10 10 10
Average: Standard Deviation:
Percent Recovery (%)
88 95 105
96
8.5
Sample ID
0201684 Spk D 0201684 Spk E 0201684 Spk F
Analyte Added (ng/g)
SO SO
so
Average: Standard Deviation:
Percent Recovery (%)
90 88 87
88
1.5
RecoverySummaryof PFOSInRatSerum
Sample ID
0201682 Spk A 0201682 Spk B 0201682 SDkC
AnalyteAdded (ng/mL)
10 10 10
Average: Standard Deviation:
Percent Recovery (%)
80 85 69
88
9.8
Sample ID
0201682 Spk 0201682 Spk E 0201682 Spk F
AnalyteAdded (ng/mL)
50 50 SO
Average: Standard Deviation:
Percent Recovery (%)
118 122 121
120 2.1
RecoverySummaryof PFOSin Rat Urine
Sample ID
0201682 Spk A 0201682 Spk B 0201682 Spk C
Analyte Added (ng/mL)
10 10 10
Average: Standard Deviation:
Percent Recovery (%)
98 69 91
93 4.7
Sample ID
0201682 Spk D 0201682 Spk E 0201682 SpkF
AnalyteAdded (ng/mL)
50 50 50
Average: Standard Deviation:
Percent Recovery (%)
80 78 78
79 1.2
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Table 3. Recovery Summary of PFOA in Rat Liver, Serum and Urine
RecoverySummaryofPFOAIn Rat Liver
Sample ID
02016B4 Spk A 0201684 Spk B 0201684 SDk C
Anelyte Added (ng/g)
10 10 10
Average: Standard Deviation:
Percent Recovery (%)
95 101 99
98 3.1
Sample ID 0201684 Spk D 0201684 Spk E 0201684 Sok F
AnalyteAdded (ng/g)
50 50 50
Average: Standard Deviation:
Percent Recovery (%)
97 92 94 94 2.5
RecoverySummaryofPFOAInRat Serum
Sample ID
0201682 Spk A 0201682 Spk B 0201682 Spk C
Analyte Added (ng/mL)
10 10 10
Average: Standard Deviation:
Percent Recovery (%)
118 117 115 117 1.5
Sample ID
0201682 Spk D 0201682 Spk E 0201682 Spk F
AnalyteAdded (ng/mL)
50 50 50
Average: Standard Deviation:
Percent Recovery (%) 107 112 115 111 4.0
RecoverySummaryof PFOAin Rat Urine
Sample ID 0201682 Spk A 0201682 Spk B 0201682 Spk C
Analyte Added (ngAnL)
10 10 10
Average: Standard Deviation:
Percent Recovery (%)
86 91 89
89 2.5
Sample ID
0201682 Spk D 0201682 Spk E 0201682 Spk F
AnalyteAdded (ng/mL)
50 50 50
Average; Standard Deviation:
Percent Recovery (%)
89 68 85 87 2.1
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Figure 1. Calibration Curve for PFHS
Compound 1 name: PFHS C08fflotent of Determination: 0.996465 Calibration curve: 1918.28 * x + 9.14134 Response type: External Std, Area
Curve type: Unear, Origin: Exclude, Weighting: 1/x, Ards trans: None
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Figure 2. C alibration Curve for PFOS
Compound 2 name: PFOS CoefficientofDetermination: 0.997009 Calibration curve: 3211.30 *x + 48.9285 Response type: External Std, Area Curve type: Linear, Origin: Exclude, Weighting: 1/x,Axis trans: None
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Figure 3. C alibration Curve for PFOA
Compound 1 name: PFOA Coefficientof Determination: 0.995945 Calibration curve: 31270.9 x +3675.36 Response type; External Sid. Area Curve type: Linear, Origin: Exclude, Weighting: 1/x, Axistrans: None
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Figure 4. Representative Chromatogram of a 0.1 ng/mL Standard Containing PFHS
C0621OS-6,0.1 ngftnL PFHS OSZTQZA'IOI SmtMn,2)(2)
24-Jitn-20Q 216:02:60
LC /M S/M S67
MRMof 1ChannelES* 399 > BO 2.78a3
%
1.00 Z.00 3.00 4.00 5.00 5.00 7.00 0.00 9.00 10.00 11.00 12.00
Figure 5. Representative Chromatogram of a 0.1 ng/mL Standard Containing PFOS
0002503-0,0.1 ng/m L PFO * and PFOS
M -Jul-20Q 210:25:20
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Figure 6. Representative Chromatogram of a 0.1 ng/mL Standard Containing PFOA
C082502-6,0.1 ng/fflL PFOA WKIPFOS
01 JuMQQl 32:17:42
Figure 7. Representative Chromatogram of a 0.5 ng/mL Standard Containing PFHS
CM 2102-4,0.9 ng/m L PFHS
0621OEA-13 Sm(Mn.2x2) 100i
Mm7i -,
2 4 Ju n -2 0 0 3 16:49:11
LC/MS/MS #7
MfiMe l 1 ChannelES 300 >S0
V
JUr
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Figure 8. Representative Chromatogram of a 0.5 ng/mL Standard Containing PFOS
C0625D2-4,0.5 n|m L PFO A.nd PFOS
W JuF S K fi1S :07:17
Figure 9. Representative Chromatogram of a 0.5 ng/mL Standard Containing PFOA
C M 2502-4,0.5 n tfm L PFOA nd PFOS
O frJul-200210:07:37
Lcmsmsfr
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Figure 10. Representative Chromatogram of a 5.0 ng/mL Standard Containing PFHS
C0621Q2-1,5.0 nsftiO . m s OEBItOMOBSift (Mn,2x2)
2*-Jun-20 217:51:31
LC /M SJM 3#7 W M or 1Channel ES
sn > n 1.13*5
%
1.00 2.00 3.00 4.00 5.00 5.00 7.00 5.00 9.00
Figure 11. Representative Chromatogram of a 5.0 ng/mL Standard Containing PFOS
CO*2SOS-1,S.O n o ta li PFO A.ndPFO S
M -JuM O M 20:10:50 LCMSfM9#7
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Figure 12. Representative Chromatogram of a 5.0 ng/mL Standard Containing PFOA
CW 2502-1, 5.0 ngftnL PFOA and PFOS
Figure 13. Representative Chromatogram of a Reagent Blank Sample Analyzed for PFHS
R M gultB IW IkA
i4 -J u n -2 0 0 2 11 :3 4 :4 0
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Figure 14. Representative Chromatogram of a Reagent Blank Sample Analyzed for PFOS
R ugentB U nkA
OW ukHKH 20:53:11
Figure 15. Representative Chromatogram of a Reagent Blank Sample Analyzed for PFOA
R ugantB lankA
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Figure 16. Representative Chromatogram of a Control Liver Sample Analyzed for PFHS
0BO16M U m r B lin k A
S U u n jU B 18:17:57
Figure 17. Representative Chromatogram of a Control Liver Sample Analyzed for PFOS
02D1SS4 U vw B lank A
O a-Jul-200221:35:27
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Figure 18. Representative Chromatogram of a Control Liver Sample Analyzed for PFOA
0201644 U var B lank A
00-4(11-200221:35:27
Figure 19. Representative Chromatogram of a Control Serum Sample Analyzed for PFHS
0201B02 Swum Blank A
24-Jun-2QQ2 23:36:22
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Figure 20. Representative Chromatogram of a Control Serum Sample Analyzed for PFOS
0201M2 Swum Hank A
fli iliiHOOd 01:49:00
Figure 21. Representative Chromatogram of a Control Serum Sample Analyzed for PFOA
0201682 Saruin Blank A
OO-JuMOOZ 01'.49:00
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Figure 22. Representative Chromatogram of a Control Urine Sample Analyzed for PFOS
0201803 (Irin a Blank A
Sfeli*am08:02.-21
Figure 23. Representative Chromatogram of a Control Urine Sample Analyzed for PFOA
0201003 U rli B lank B
OSJul-2002 06:23:33
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Figure 24. Representative Chromatogram of a Control Liver Sample Fortified at 10 ng/|g with PFHS
Q2Q16S4 U vtr Spk A , 10ppb
2Uun-2002 20:23:00
Figure 25. Representative Chromatogram of a Control Liver Sample Fortified at 10 ng/g with PFOS
02O1RB4 U ln rSp k A, 10ppb
M-Jul-2002 22:3*51
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Figure 26. Representative Chromatogram of a Control Liver Sample Fortified at 10 ng/g with PFOA
Q 201lM U w SpkA it& pp b
Mtlul-2002 22:30:51
Figure 27. Representative Chromatogram of a Control Liver Sample Fortified at 50 ng/g with PFHS
OZOtSMUW fSpkD. M ppb
2*Jun-2D02 21:28:01
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Figure 28. Representative Chromatogram of a Control Liver Sample Fortified at 50 ng/g with PFOS
0201*8 U w r Spk 0,90 ppb
0-Jul-2002 23:42:12
Figure 29. Representative Chromatogram of a Control Liver Sample Fortified at 50 ng/g with PFOA
02016*4 Uvor Spk D, 50 ppb
08-Jul-20Q2 23:42:12 LCM SM S7
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Figure 30. Representative Chromatogram of a Control Serum Sample Fortified at 10 ng/mL with PFHS
0201082 Strum Spk B, 10ppb 082102*128 8m (Mn,S B )
tflfh
25-Jucv20Q2 01:05:10 LC/MS/MS7
MOMof 1CtametES*
2 7.>86M0
%
fro-Na^SWf
10.00 11.00 12.00
Figure 31. Representative Chromatogram of a Control Serum Sample Fortified at 10 ng/mL with PFOS
0201682 Stram Spk B , 10 ppb
OMutOOOZ 03:13:27 LO M S/M SS7
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Figure 32. Representative Chromatogram of a Control Serum Sample Fortified at 10 ng/mL with PFOA
88018B* SwumSpk A,10ppB
08-JuHHXB 02:1301 LCM SM S87
Figure 33. Representative Chromatogram of a Control Serum Sample Fortified at 50 ng/mL with PFHS
0201882 Swum SpkD, 30 ppb
iSJun-2002 01:48:38 LCM S/M S87
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Figure 34. Representative Chromatogram of a Control Seram Sample Fortified at 50 ng/mL with PFOS
<001882 Scram Spit 50 ppb
WJuWOOa 03:55:41
Figure 35. Representative Chromatogram of a Control Serum Sample Fortified at 50 ng/mL with PFOA
0201682 Swum SpK E, 30 ppb
OO-JuHMB 0*-.15:S1 LG M S/M SC 7
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Figure 36. Representative Chromatogram of a Control Urine Sample Fortified at 10 ng/mL with PFOS
02018*3l*tn SpfcA, 10ppb
SfehittH B 07:0S:tt
Figure 37. Representative Chromatogram of a Control Urine Sample Fortified at 10 ng/mL with PFOA
noinsUrlnpSpkB, 10 ppb
OPJuMO 07:28:3
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Figure 38. Representative Chromatogram of a Control Urine Sample Fortified at 50 ng/mL with PFOS
Figure 39. Representative Chromatogram of a Control Urine Sample Fortified at 50 ng/mL with PFOA
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APPENDIX H TEMPERATURE AND RELATIVE HUMIDITY REPORTS
ARGUS
418-028:PAGE H-l
Tem perature and Relative Hum idity Report Location: Room 05
Protocol Num ber: 418-028
Range o f Dates: 26-M ar-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-Jun-2002 at 13:26
COMMENTS:
REVIEWED BY:
DATE: h W 2
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
In-Life Start
Test Substance
Dosage Information
Number o f mg/kg mL/kg Dosages
012-006 - Validation o f Functional Observational Battery and Motor Activity Measure Using Positive Test Substances
12/89
acrylamide
50 1
7
physostigmine
0.75
1.5
1
DDT
75 1
1
012-014 - Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats
9/91 acrylamide
40 1
9
IDPN
200 1
3
carbaryl
75 5
1
DDT
75 5
1
triadimefon 200 5
1
012-0IS - Neurotoxicity Evaluation of DDT in Crl:CDBR VAF/Plus Rats
3/92
DDT
75 1
1
012-017 - Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats
012-022 - Neurotoxicity Evaluation of Carbaryl in Crl:CDBR VAF/Plus Rats 012-031 - Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats
5/92 10/92
acrylamide IDPN carbaryl DDT
d-amphetamine
40 200 40 75 4.0
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 - Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats
012-075 - Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats
012-081 - Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats
418-028:PAGE 1-3
11/95
acrylamide IDPN carbaryl DDT
d-amphetamine
45 250 40 75 4.0
1 1 1 1 1
3/98 acrylamide 30 1
trimethyltin 8 1
MK-801
0.3 1
carbaryl
100 4
DDT 100 2
11/01
acrylamide IDPN
-amphetamine carbaryl DDT
30 250 40 100 100
1 1 1 4 2
10 5 1 1 1
17 1 1 1 1
10 1 1 1 5
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418-028:PAGE 1-4
Summary Information for Motor Activity
Study - Title
In-Life Start
012-011 - The Assessment of Motor Activity in Neonatal and Adult Rodents using Passive Infrared Sensors
5/91
012-014 - Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats
9/91
012-016 - Motor Activity Evaluation in Crl:CDBR VAF/Plus Rats Administered Chlorpromazine and dAmphetamine (Positive Control Study)
012-058 - Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats
4/96
Test Substance
Dosage Information
mg/kg
mL/kg
Number of Dosages
d-amphetamine chlorpromazine
0 .7 5 ,1 .5 ,4 1 ,2,4
1 1
1 1
acrylamide 40 1
IDPN
200 1
carbaryl
75 5
DDT
75 5
triadimefon 200 5
9 3
1 1
l
d-amphetamine chlorpromazine
0 .5 ,1 ,4 1 ,2 ,4
1 1
1 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 SERVICESf 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
SUBMITTED BY:
W. Fay Brown, D.V.M., PhlD. 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 SPONSOR'S STUDY NUMBER T-7706.1
HISTOPATHOLOGY REPORT
TABLE OF CONTENTS
REPORT
Page
Method.................................................................................................................................. 1
Results................................................................................................................................... 3
Sum m ary................................................................................................................................ 5
Quality Assurance Unit Statement.....................................................................................6
Good Laboratory Practice Compliance Statement.......................................................... 7
TABLE
1. Incidence and Degree of Severity of Histomorphologic Observations.....................8
APPENDICES
I. Histomorphologic Observations.................................................................... M 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 ats................................ I-4 I-3. Histomorphologic Observations - Group III Male R ats............................... 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 Rats............................. I-9 I-7. Histomorphologic Observations - Group V Female Rats........................... 1-11
II. Individual Animal Gross and Histomorphology Data................................11-1 to II-70
III. Histomorphologic Observations in the Liver - F1 Generation Pups.......111-1 to III-2
Tables
MI-1. MI-2.
Histomorphologic Observations in the Liver - Group I F1 Generation Pups.......................................................................................MI-2 Histomorphologic Observations in the Liver - Group V F1 Generation Pups....................................................................................... MI-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 SPONSOR'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
I
NUMBER OF RATS PER SEXa
15 + 3C
DOSAGE (mg/kg/day)
0
CONCENTRATION15 (mg/ml_)
0
DOSE VOLUME (mL/kg)
10
II 15 + 3C
0.3
0.03
10
III 15 + 3C
1
0.1
10
IV 15 + 3
3
0.3
10
V 15 + 3
10
1
10
aTen male and ten female rats of Groups I and V were assigned for histopathologic evaluation. bThe test substance was considered to be 100% active for the purpose of dosage calculations. cThree additional rats per sex per dosage group were assigned to toxicokinetic sample 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 SPONSOR'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, Peyer's 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.
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PROTOCOL 418-028 SPONSOR'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.
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PROTOCOL 418-028 SPONSOR'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.
There were a few other microscopic changes observed in the various organs 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
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ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL 418-028 SPONSOR'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.
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PROTOCOL 418-028 SPONSOR'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.
Organisation for Economic Cooperation and Development (1996). OECD Guideline for 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 Cooperation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Final].
US Food and Drug Administration. Good Laboratory Practice Regulations: Final Rule. 21 CFR Part 58.
Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26,1997.
Quality assurance unit study-based inspections were performed as shown below. There were no devia
tions from the 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 in the final report sub
mitted to the study director on July 3, 2003.
Dates of
Dates Reported to
Date Reported
Inspection
Study 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 02/28/03 02/28/03 02/28/03 02/28/03 07/03/03
Research Pathology Services, Inc.
Karen W. Harkins, BS Quality Assurance Unit
(y> cf.
f'S- Date
-6
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PROTOCOL 418-028 SPONSOR'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. were conducted according to:
Organisation for Economic Cooperation and Development (1996). OECD Guideline for 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 Cooperation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Final]. US Food and Drug Administration. Good Laboratory Practice Regulations: Final Rule. 21 CFR Part 58. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26,1997.
No deviations were noted that had any significant impact on the validity of the study.
Veterinary Pathologist
Date
Research Pathology Services, Inc.
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SPONSOR'S STUDY NUMBER T-7706.1
TABLE 1
Incidence and Degree of Severity of Histomorphologic Observations
Dose Group: Sex: Number of Animals/Grouo:
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] [0] [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 80009
-inflammation, mucosa, chronic mild moderate
[2] [0] [0] [0] [1] 00001 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] [0] 10000
DUODENUM: NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 10
EPIDIDYMIDES: NO. EXAMINED NO. NORMAL
10 0 0 1 10 60009
[ ] = Total incidence of sp ecified lesion , all grades.
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 C2] [0] 10 10
10 10 10 10 [0] [0] 00
10 10 10 10
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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/Group:
EPIDIDYMIDES (Continued):
I II III IV V MMMMM 10 10 10 10 10
-exfoliated spermatogenic cells moderate
-hypospermi a marked
-infi 1tration, mononuclear-cell, focal minimal
[0] [0] [0] [1] [0] 00010 CO] [0] [0] [1] [0] 0 0 0 10 [4] [0] [0] [0] [1] 40001
HEART: NO. EXAMINED NO. NORMAL
10 0 0 0 10 80009
-inflammation, chronic, focal minimal mild
[2] [0] [0] [0] [1] 10001 10000
ILEUM: NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 10
JEJUNUM: NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 9
-diverticulurn
00001
KIDNEYS: NO. EXAMINED NO. NORMAL
10 3 0 0 10 71007
-basophilia/degeneration, cortical tubules, focal/multi focal minimal
[0] [0] [0] [0] [1] 00001
-cyst(s), medulla
10002
-dilatation, pelvis minimal mild
[0] [2] [0] [0] [0] 0 10 0 0 01000
-infi1trati on, mononuclear-cell, focal/multi focal minimal
[2] [0] [0] [0] [2] 20002
-mineralization, multifocal minimal
[0] [0] [0] [0] [0] 00000
IV FF 10 10
10 10 10 10 [0] [0] 00 00
10 10 10 10
10 10 10 10 00
10 10 98
[0] [0] 00 00 [0] [0] 00 00 [0] [0] 00 [0] [1] 01
[ ] = Total incidence of sp ecified lesio n , all grades.
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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/Group:
KIDNEYS (Continued):
I II III IV V MMMMM 10 10 10 10 10
-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] 00084
000 15
00001
-inflammation, chronic, focal/multifocal minimal mild
-lipidosis, tension, focal
[8] [6] [7] C6] [5] 54 765 32000
02000
-necrosis, focal minimal
[0] [0] [0] [0] [0] 00000
-vacuolation, hepatocellular, midzonal mild
[0] [0] [1] [0] [0] 0 0 10 0
-vacuolation, hepatocellular, multifocal minimal mild
[0] [1] Cl] [0] [0] 01000 00100
LUNG: NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 10
-infiltration, polymorphonuclear, peri vascular/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
-congestion minimal
8 0 0 0 10 70008
[0] [0] [0] [0] [0] 00000
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 sp ecified lesio n , all grades.
-10
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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/Group:
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
[13 [0] [0] [0] [2] 10002
LYMPH NODE. SUBMANDIBULAR: NO. EXAMINED NO. NORMAL
10 0 0 0 10 50004
-hyperplasi a , 1ymphocyti c/plasmacyti c minimal mild moderate
[5] [0] [0] [0] [6] 10002
20000 20004
MAMMARY GLAND: NO. EXAMINED NO. NORMAL
-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] 00001
PROSTATE: NO. EXAMINED NO. NORMAL
10 0 0 0 10 60006
IV FF 10 10
[1] [0] 10 [1] [0] 10
10 9 43
[6] [6] 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 sp ecified lesio n , all grades.
-11
418-028:PAGE J-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/Group:
I II III IV V MMMMM 10 10 10 10 10
PROSTATE (Continued):
-atrophy, focal/multifocal minimal moderate
[1] [0] [0] [0] [2] 10001 00001
-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
Cl] [0] [0] [0] [1] 00001 10000
SEMINAL VESICLES: NO. EXAMINED
NO. NORMAL
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: NO. EXAMINED NO. NORMAL
10 0 0 0 10 80009
[ ] = Total incidence of sp ecified lesio n , all 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
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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/Group:
I II III IV V MMMMM
10 10 10 10 10
STOMACH (Continued):
-dilatation, mucosal glands minimal
[1] [0] [0] [0] [0] 10000
-edema/inflammation, submucosa, forestomach mild
[1] [0] [0] [0] [1] 10001
-edema/inflammation, submucosa, glandular area minimal
mild moderate
[2] [0] [0] [0] [0] 10000
00000 10000
-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] 000 10
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] 01120
22 123
00004
-ultimobranchial body/cyst
34422
TRACHEA: NO. EXAMINED NO. NORMAL
10 0 0 0 10 60009
[ ] = Total incidence of sp ecified lesio n , all grades.
IV FF 10 10
Cl] [1] 11 [0] [1] 01 [2] [3] 00 13 10 [0] Cl] 01
10 10 99 [1] [1] 10 01
10 10 55 [0] [0] 00 00 00 55
10 10 10 9
-13
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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/Group:
I II III IV V MMMMM 10 10 10 10 10
TRACHEA (Continued):
-inflammation, chronic, focal minimal mild
URINARY BLADDER: NO. EXAMINED NO. NORMAL
-inflammation, chronic, focal minimal
[4] [0] [0] [0] [1] 20000 20001
10 0 0 0 10 10 0 0 0 10
[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] [8] 10
22 75
01
10 10 10 10
[ ] = Total incidence of sp ecified lesio n , all grades.
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 SPONSOR'S STUDY NUMBER T-7706.1
HISTOPATHOLOGY REPORT
APPENDIX I
HISTOMORPHOLOGIC OBSERVATIONS
418-028:PAGE J-18
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PROTOCOL 418-028 SPONSOR'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
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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 MMMMMMMMMM 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
---2------
DUODENUM:
----------
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/multi focal
- - <-> - - - - - P - - <-> 1 - - - - - 1
LIVER: -inflammation, chronic, focal/multifocal
- 112 1122 -1
LUNG:
LYMPH NODE, MEDIASTINAL: -mastocytosis
---------1---*--*--
LYMPH NODE. SUBMANDIBULAR: -hyperplasi a, 1ymphocyti c/plasmacyti c
3-2-132---
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/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
TABLE 1-1 (Continued)
Histomorphologic Observations
Dose Group: Animal Number: Sex: Death Tvoe:
IIIIIIIIII 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135
M MM MMMM M M M SS SS SS SS SS SS SS SS SS SS
PROSTATE (Continued): -inflammation, chronic, focal/multifocal
1_ _ - _ - 1 __ 1
RECTUM: -inflammation, mucosa, chronic
---2------
SEMINAL VESICLES:
----------
SPINAL CORD. CERVICAL:
----------
SPINAL CORD. LUMBAR:
----------
SPINAL CORD. THORACIC:
----------
SPLEEN:
----------
STOMACH:
-dilatation, mucosal glands
1
-edema/inflanimation, submucosa, forestomach - - - - - - - - 2 -
-edema/inflammation, submucosa, glandular
area
- - - - - - - 3 1-
TESTIS (H&E):
--- -- - - - - -
TESTIS (PAS):
----------
THYMUS:
----------
THYROID: -hypertrophy/hyperplasi a , fol1icular
epithelium
-ultimobranchial body/cyst
22 -P---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:
'H
T 1 fi T F 0
Animal Number:
19102 19106 19108 19110 19113 19120 19129 19136 19138 19139
Sex:
MMMMMMMMMM
Death Type: _______________________________ SS SS SS SS SS SS SS SS SS SS
KIDNEYS: -dilatation, pelvis
LIVER: -inflammation, chronic, focal/multifocal -lipidosis, tension, focal -vacuolation, hepatocellular, multifocal
THYROID: -hypertrophy/hyperplasia, fol 1icular
epithelium -ultimobranchial body/cyst
< 2>
11 P-
1 P
-
<1>
1--
-1
PP
2
1-P
-2 P-
1-4
418-028:PAGE J-22
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
TABLE 1-3
Histomorphologic Observations
Dose Group: Animal Number: Sex: Death T y p e : _________________________
LIVER: -inflammation, chronic, focal/multifocal -vacuolation, hepatocellular, midzonal -vacuolation, hepatocellular, multifocal
THYROID: -hypertrophy/hyperplasia, fol 1icular
epithelium -ultimobranchial body/cyst
III III H I III III III III III III III 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146
MMMMMMMMMM SS SS SS SS SS SS SS SS SS SS
- 11111 2- - - - -
2
1PP
-
P
2- P--
1-5
418-028:PAGE J-23
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 1-4
Histomorphologic Observations
Dose Group: Animal Number: Sex: Death Tvoe:
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 -hypospermia
<3> <4>
LIVER:
-hypertrophy, hepatocellular, centrilobular 1 1 2 1 1 1 1
11
-inflammation, chronic, focal/multifocal
1-11--111-
TESTIS (H&El: -dgnrtion, multifocal
<2>
TESTIS (PAS): -degeneration, multifocal
<2>
THYROID: -hypertrophy/hyperplasia, foilicular
epi theli urn
-ultimobranchial body/cyst
1- - - 1- - -22 ----PP----
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:
VVVVVV V V V V
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
BONE MARROW STERNUM1:
----2--------------
BRAIN:
----------
CECUM: -inflammation, mucosa, chronic
-----2----
COAGULATING GLAND:
----------
COLON:
----------
DUODENUM:
----------
EPIDIDYMIDES: -infiltration, mononuclear-cell, focal
-- 1- - - - - --
HEART: -inflammation, chronic, focal
-------- - 1
ILEUM:
- -- -- --- - -
JEJUNUM: -diverticul urn
<P> - - - - - - - - -
KIDNEYS:
-basophilia/degeneration, cortical tubules,
focal/multi focal -cyst(s), medulla
1 P-P----___
-infi1trati on, mononuclear-cel 1,
focal/multi focal -nephritis, chronic, focal
11 --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
- 1 1 -------
LYMPH NODE. SUBMANDIBULAR: -hyperplas ia , 1ymphocyt ic/plasmacyt ic
13 --1 3 -3 -3
NERVE. SCIATIC:
----------
PARATHYROID:
----------
PEYER'S PATCH: -mineralization, focal
1 """""-"-
1-7
418-028:PAGE J-25
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
TABLE 1-5 (Continued)
Histomorphologic Observations
Dose Group: Animal Number: Sex: Death TvDe:
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/multifocal -inflammation, chronic, focal/multifocal
31 1--1----"1
RECTUM: -inflammation, mucosa, chronic
-------1--
SEMINAL VESICLES:
----------
SPINAL CORD, CERVICAL:
----------
SPINAL CORD. LUMBAR:
----------
SPINAL CORD. THORACIC:
----------
SPLEEN:
----------
STOMACH: -edema/inflammation, submucosa, forestomach - 2 - - - - - - - -
TESTIS (H&El:
----------
TESTIS (PAS):
----------
THYMUS:
----------
THYROID:
-hypertrophy/hyperplasia, foilicular epi theli urn
-ultimobranchial body/cyst
3 2 233 32
P- - - - - - - P-
TRACHEA: -inflammation, chronic, focal
-------2--
URINARY BLADDER:
----------
1-8
418-028:PAGE 1-26
ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELQPMENTAL 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:
IIIIIIIIII 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 (STERNUM!:
----------
BRAIN:
----------
CECUM: -inflammation, mucosa, chronic
--------32
COLON:
----------
DUODENUM:
----------
HEART:
----------
ILEUM:
----------
JEJUNUM:
----------
KIDNEYS: -nephritis, chronic, focal
------1---
LIVER: -inflammation, chronic, focal/multifocal
-- 1- - - - - - 1
LUNG: -infiltration, polymorphonuclear,
peri vascular/peri bronchi al
__2 _ _ _ _
LYMPH NODE. MEDIASTINAL: -congestion -hyperplasia, lymphocytic/plasmacytic -mastocytosi s
1 1. ------2--" -1"" """
LYMPH NODE. SUBMANDIBULAR: -hyperplasi a , 1ymphocyti c/plasmacyti c
-2--3 -3 122
MAMMARY GLAND:
----------
NERVE. SCIATIC:
----------
OVARIES: -cyst(s), intraovari an
--
---P----
PARATHYROID:
----------
PEYER'S PATCH:
----------
RECTUM:
----------
SKIN (GROSS LESION): -dermatitis, chronic, focal
<2>
1-9
418-028'.PAGE J-27
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
TABLE 1-6 (Continued)
Hi stomorphologi c Qbservat ions
Dose Group: Animal Number Sex: Death Type:
II
II
I
IIIII
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/inflanimation, submucosa, glandular
area
---23-----
THYMUS: -atrophy
--------3-
THYROID: -ultimobranchial body/cyst
P-P-PP--P-
TRACHEA:
__________
URINARY BLADDER: -inflammation, chronic, focal
UTERUS: -macrophages, pigmented
--*------1 3231333332
VAGINA:
418-028:PAGE J-28
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
Histomorphologic Observations
Dose 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
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
1 ---1-----1
LUNG: -inflammation, interstitial, focal -macrophages, alveoli, focal
1 1-- - - - - - --
LYMPH NODE. MEDIASTINAL:
----------
LYMPH NODE. SUBMANDIBULAR: -hyperplasi a , 1ymphocyti c/plasmacyti c
-2-22-23*2
MAMMARY GLAND: -necrosis, focal
NERVE. SCIATIC:
----1--
---
------* ---
OVARIES:
----------
PARATHYROID:
----------
PEYER'S PATCH:
----------
RECTUM:
- - - <-> - - - - -
1-11
418-028:PAGE J-29
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
TABLE 1-7 (Continued)
Histomorphologic Observations
Dose Group: Animal Number: Sex: Death Tvoe:
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
<1>
SPINAL CORD. CERVICAL:
SPINAL CORD. LUMBAR:
SPINAL CORD. THORACIC:
SPLEEN: -atrophy
- - - <2> - - - - -
-
STOMACH:
-dilatation, mucosal glands
-edema/inflanimation, submucosa, forestomach - - - <2> - - - - -
-edema/inflanimation, submucosa, glandular
area
- - - <2> - 2 2 - - -
-erosion(s), glandular mucosa
- - - <3> - - - - - -
THYMUS: -atrophy
- - - <4> - - - - - -
THYROID: -ultimobranchial body/cyst
- P-PP-P-P-
TRACHEA: -inflammation, chronic, focal
URINARY BLADDER:
1- - - - - - - -
-
UTERUS: -distention, lumen -macrophages, pigmented
2 --------
3
323423-33-
VAGINA:
1-12
418-028:PAGE J-30 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1
HISTOPATHOLOGY REPORT
APPENDIX II
INDIVIDUAL ANIMAL GROSS AND HISTOMORPHOLOGY DATA
418-028:PAGE J-31
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: 19109
SEX:
M
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONfS1: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION^! : 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 TISSUEfSl 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/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: 19115
SEX:
M
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONfS): 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 inflammation, chronic, focal (mild)
THE FOLLOWING TISSUEfS) 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
End of Record- 19115
COAGULATING GLAND JEJUNUM LYMPH NODE, SUBMANDIBULAR PROSTATE SPINAL CORD, LUMBAR TESTIS (H&E)
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 NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19116
SEX:
M
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONfS1: KIDNEYS: Mottled tan and red, bilateral.
HISTOMORPHOLOGIC OBSERVATIONfS): 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:PAGE J-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 OBSERVATIONfS): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION(Si : 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
11-4
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 Histomorphology Data
ANIMAL NUMBER: 19122
SEX:
M
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONS): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION!Si : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
EPIDIDYMIDES: LIVER: LYMPH NODE, SUBMANDIBULAR: TRACHEA:
infiltration, mononuclear-cell, focal (minimal) inflammation, chronic, focal/multifocal (minimal)
hyperplasia, lymphocytic/plasmacytic (minimal) inflammation, chronic, focal (minimal)
THE FOLLOWING TISSUEfS) 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
TISSUEfST 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 OBSERVATION!Si : 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
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTIQN/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: 19131
SEX:
M
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONS: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONS! : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
ADRENAL GLANDS: EPIDIDYMIDES: HEART: LIVER: LYMPH NODE, SUBMANDIBULAR: PROSTATE: TRACHEA:
vacuolation, cortex, diffuse (mild) infiltration, mononuclear-cell, focal (minimal) inflammation, chronic, focal (mild) inflammation, chronic, focal/multifocal (mild) hyperplasia, lymphocytic/plasmacytic (mild) inflammation, chronic, focal/multifocal (minimal) inflammation, chronic, focal (mild)
THE FOLLOWING TISSUE(S) 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:PAGEJ-38
ORAL (6AVAGE) 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: 19132
SEX:
M
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONf S): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfS: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: STOMACH: THYROID:
inflammation, chronic, focal/multifocal (mild) edema/infiammati on, submucosa, glandular area (moderate) ultimobranchial body/cyst
THE FOLLOWING TISSUEfS) 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
TISSUEfSl NOT AVAILABLE FOR EVALUATION: LYMPH NODE, MEDIASTINAL End of Record- 19132
11-8
418-028:PAGE J-39
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: 19134
SEX:
M
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONfS: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfSi : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
EPIDIDYMIDES: KIDNEYS: STOMACH:
THYROID: TRACHEA:
infiltration, mononuclear-cell, focal (minimal) cyst(s), medulla
dilatation, mucosal glands (minimal) edema/infiammaiion, submucosa, glandular area (minimal) edema/infiammati on, submucosa, forestomach (mild) hypertrophy/hyperplasia, follicular epithelium (mild) inflammation, chronic, focal (minimal)
THE FOLLOWING TISSUE(Sl 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
11-9
418-028:PAGE J-40
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: 19135
SEX:
M
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONS): GENERAL: No qross chancles.
HISTOMORPHOLOGIC OBSERVATIONS) : 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 TISSUES) 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
THE FOLLOWING TISSUES) WERE WITHIN NORMAL LIMITS: KIDNEYS End of Record- 19102
11-11
418-028'.PAGE J-42
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: 19106 SEX M
DOSE GROUP: DEATH TYPE:
II Sacrifice-Scheduled
GROSS OBSERVATIONfSl: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfSl: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: THYROID:
End of Record- 19106
inflammation, chronic, focal/multifocal (mild) ultimobranchial body/cyst
11-12
418-028:PAGE J-43
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: 19108
SEX:
M
DOSE GROUP: DEATH TYPE:
II Sacrifice-Scheduled
GROSS OBSERVATIONfS): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION(S): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER:
lipidosis, tension, focal inflammation, chronic, focal/multifocal (minimal)
THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19108
11-13
418-028:PAGE J-44
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: 19110 SEX M
DOSE GROUP: DEATH TYPE:
II Sacrifice-Scheduled
GROSS OBSERVATION(S): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfS: 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 (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: 19113 SEX M
DOSE GROUP: DEATH TYPE:
II Sacrifice-Scheduled
GROSS OBSERVATIONfST; KIDNEYS: Left- pelvis, slight dilation.
HIST0M0RPH0L06IC OBSERVATIONS! : dilatation, pelvis
HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS:
dilatation, pelvis (mild)
THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS:
LIVER
THYROID
End of Record- 19113
11-15
418-028 :PAGE J-46
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTIQN/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 OBSERVATIONfS^: GENERAL: No gross changes.
HISTOMQRPHOLOGIC OBSERVATION(S1: Not applicable
HISTOMQRPHOLOGIC OBSERVATIONS: LIVER:
inflammation, chronic, focal/multifocal (minimal) lipidosis, tension, focal
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19120
11-16
418-028:PAGE J-47
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: 19129 SEX M
DOSE GROUP: DEATH TYPE:
II Sacrifice-Scheduled
GROSS OBSERVATIONfS): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION(S): 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 REPRODUCTIQN/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 OBSERVATIONS: KIDNEYS: Bilateral- mottled.
HISTOMORPHOLOGIC OBSERVATIONfS): dilatation, pelvis
HISTOMORPHOLOGIC OBSERVATIONS:
KIDNEYS: LIVER: THYROID:
End of Record- 19136
dilatation, pelvis (minimal) vacuo!ation, hepatocellular, multifocal (minimal) ultimobranchial body/cyst
11-18
418-028:PAGE J-49
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: 19138
SEX:
M
DOSE GROUP: DEATH TYPE:
II Sacrifice-Scheduled
GROSS OBSERVATION(S): GENERAL: No gross changes.
HISTOMORPHOLQGIC OBSERVATIONfSi : Not applicable
HISTOMORPHOLQGIC OBSERVATIONS: THYROID:
ultimobranchial body/cyst
THE FOLLOWING TISSUEfSl 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
DOSE GROUP: DEATH TYPE:
II Sacrifice-Scheduled
GROSS OBSERVATION(S): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfSY: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: THYROID:
hypertrophy/hyperplasia, follicular epithelium (mild)
THE FOLLOWING TISSUEfS) 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 OBSERVATIQN(S): GENERAL: No gross changes.
HISTOMORPBOLOGIC OBSERVATION?S): 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 GROUP: DEATH TYPE:
III Sacrifice-Scheduled
GROSS OBSERVATION(S): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION!Si : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER:
inflammation, chronic, focal/multifocal (minimal)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19105
11-22
418-028:PAGE J-53
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: 19107 SEX M
DOSE GROUP: DEATH TYPE:
III Sacrifice-Scheduled
GROSS OBSERVATIONS): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION(S) : 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 (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: 19112 SEX M
DOSE GROUP: DEATH TYPE:
III Sacrifice-Scheduled
GROSS OBSERVATIONS! : GENERAL: No gross changes.
HIST0M0RPH0L06IC OBSERVATION!Si : Not applicable
HIST0M0RPH0L06IC OBSERVATIONS:
LIVER: THYROID:
End of Record- 19112
inflammation, 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/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: 19114 SEX M
DOSE GROUP: DEATH TYPE:
III Sacrifice-Scheduled
GROSS OBSERVATION!Si: GENERAL: No gross changes.
HISTQM0RPH0L06IC OBSERVATION(S): 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 OBSERVATIONfS): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfST: 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:PAGE J-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 OBSERVATION (S): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONS! : 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 J-58
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: 19130 SEX M
DOSE GROUP: DEATH TYPE:
III Sacrifice-Scheduled
GROSS OBSERVATIONS) : GENERAL: No gross changes.
HIST0M0RPHQL06IC 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:PAGEJ-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 OBSERVATIONfSI: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION!SI: Not applicable
THE FOLLOWING TISSUEfSl 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 OBSERVATION!Si: GENERAL: No gross changes.
HISTQMORPHOLOGIC OBSERVATION!S): Not applicable
HISTQMORPHOLOGIC 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 OBSERVATIONfS^: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATI0N(Si : 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(Si: GENERAL: No gross changes.
HIST0M0RPH0L06IC OBSERVATION(Si : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER:
hypertrophy, hepatocellular, centrilobular (minimal)
THE FOLLOWING TISSUE(S) 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 OBSERVATION(Si: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION(S): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER:
inflammation, chronic, focal/multifocal (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 (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: 19118 SEX: M
DOSE GROUP: DEATH TYPE:
IV Sacrifice-Scheduled
GROSS OBSERVATION(ST : GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION(S) : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER:
inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal)
THE FOLLOWING TISSUES! WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19118
11-34
418-028:PAGE J-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 OBSERVATION^! ; GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION^) ; Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID:
End of Record- 19133
hypertrophy, hepatocellular, centrilobular (minimal) hypertrophy/hyperplasia, follicular epithelium (minimal)
ult imobranchi al 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 OBSERVATIONfS^: GENERAL: No gross changes.
HIST0M0RPH0L06IC OBSERVATIONS): 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 QBSERVATIONfSl:
EPIDIDYMIDES: Bilateral- small; cauda epididymis, left, small.
TESTES: Bilateral- small.
HIST0MQRPH0L06IC OBSERVATION ISi :
hypospermia exfoliated spermatogenic cells degeneration, multifocal, TESTIS (PAS) degeneration, multifocal, TESTIS (H&E)
HIST0M0RPH0L0GIC OBSERVATIONS:
EPIDIDYMIDES:
LIVER:
TESTIS (H&E): TESTIS (PAS):
hypospermia (marked) exfoliated spermatogenic cells (moderate) inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal) degeneration, multifocal (mild) degeneration, multifocal (mild)
THE FOLLOWING TISSUE(S) 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 SCREENING TEST PROTOCOL NUMBER 418-028 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 OBSERVATION(S): GENERAL : No gross changes.
HIST0M0RPH0L06IC OBSERVATIONfSi : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER:
inflammation, chronic, focal/multifocal (minimal)
THE FOLLOWING TISSUE(S) 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^! : GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION!Si : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19148
inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal)
hypertrophy/hyperplasia, follicular epithelium (mild)
11-39
418-028:PAGE J-70
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: 19150 SEX M
DOSE GROUP: DEATH TYPE:
IV Sacrifice-Scheduled
GROSS OBSERVATIONS): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfS) : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: THYROID:
End of Record- 19150
hypertrophy, hepatocellular, centrilobular (minimal) hypertrophy/hyperplasia, follicular epithelium (mild)
11-40
418-028:PAGE J-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 OBSERVATIONfST:
GASTROINTESTINAL TRACT: Jejunum- diverticulum, 1.5x0.6x0.4cm.
HIST0M0RPH0L06IC OBSERVATIONfST: 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) inflammation, 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 (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: 19117
SEX:
M
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATIONS!: GENERAL: No gross changes.
HISTOMORPHQLOGIC OBSERVATIONfSl: Not applicable
HISTOMORPHQLOGIC OBSERVATIONS:
LIVER: LYMPH NODE, MEDIASTINAL: LYMPH NODE, SUBMANDIBULAR: STOMACH:
hypertrophy, hepatocellular, centrilobular (minimal) mastocytosis (minimal) hyperplasia, lymphocytic/plasmacytic (moderate) edema/inflanimation, 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 (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: 19124 SEX: M
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATION(S): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION!S): 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 REPRODUCTIQN/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: 19126
SEX:
M
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATIONS): GENERAL: No gross changes.
HIST0M0RPH0L06IC OBSERVATION!Si : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER: PROSTATE:
inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (mild)
inflammation, chronic, focal/multifocal (minimal)
THE FOLLOWING TISSUEfSl 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 (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTIQN/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 OBSERVATION(ST: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfS): 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 TISSUE(S) 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 (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: 19128
SEX:
M
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATIONS) : GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfS): 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(S1 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 OBSERVATIONS): GENERAL: No gross changes.
HIST0M0RPH0L06IC OBSERVATION^! : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID:
inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal)
hypertrophy/hyperpl asi a , folli cular epithelium (moderate)
THE FOLLOWING TISSUE(S) 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-.PAGE J-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 OBSERVATION!Si: GENERAL: No gross changes.
`
HISTOMORPHOLOGIC OBSERVATION(Si : 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 TISSUE(S) 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 (GAVAGE) 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 OBSERVATIONfST: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION(S): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: THYROID:
hypertrophy, hepatocellular, centri lobular (minimal) ultimobranchial body/cyst hypertrophy/hyperplasia, follicular epithelium (moderate)
THE FOLLOWING TISSUEiSl 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 OBSERVATIONfS): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION(Si : 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 (H&E) URINARY BLADDER
11-50
418-028:PAGE J-81
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTIQN/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: 19012
SEX:
F
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONS): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION!S): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
STOMACH: THYROID: UTERUS:
dilatation, mucosal glands (minimal) ultimobranchial body/cyst
macrophages, pigmented (moderate)
THE FOLLOWING TISSUE(S) 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 (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: 19019
SEX:
F
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONfS): GENERAL: No gross changes.
HISTOMQRPHOLOGIC OBSERVATIONfSi : Not applicable
HISTOMQRPHOLOGIC OBSERVATIONS:
LYMPH NODE, SUBMANDIBULAR: UTERUS:
hyperplasia, lymphocytic/plasmacytic (mild) macrophages, pigmented (mild)
THE FOLLOWING TISSUE(S) 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 OBSERVATION!Si : HEAD: Head- scab, 0.2cmx0.4cm.
HISTOMORPHOLOGIC OBSERVATION!Si : 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 CORD, 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 gross changes.
HISTOMORPHOLOGIC OBSERVATION(S): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LUNG:
LYMPH NODE, MEDIASTINAL: STOMACH: UTERUS:
infiltration, polymorphonuclear, perivascular/peribronchi al
(mild) mastocytosis (minimal) edema/infiammati on, submucosa, glandular area (mild) macrophages, pigmented (minimal)
THE FOLLOWING 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 OBSERVATIONfS1: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LYMPH NODE, SUBMANDIBULAR: STOMACH: THYROID: UTERUS:
hyperplasia, lymphocytic/plasmacytic(moderate) edema/inflanimation, submucosa, glandular area (moderate) ultimobranchial body/cyst macrophages, pigmented (moderate)
THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COLON JEJUNUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR TRACHEA
BONE MARROW (STERNUM) DUODENUM KIDNEYS
MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC URINARY BLADDER
BRAIN HEART
LIVER NERVE, SCIATIC RECTUM SPLEEN VAGINA
End of Record- 19041
CECUM ILEUM
LUNG OVARIES SPINAL CORD, CERVICAL THYMUS
11-55
418-028:PAGE J-86
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTIQN/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 OBSERVATIONfST: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfS^: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
OVARIES: THYROID: UTERUS:
cyst(s), intraovarian ultimobranchial body/cyst macrophages, pigmented (moderate)
THE FOLLOWING TISSUEfS) 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 REPRODUCTIQN/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): 6ENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONS : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
KIDNEYS: LYMPH NODE, MEDIASTINAL:
LYMPH NODE, SUBMANDIBULAR: UTERUS:
nephritis, chronic, focal (minimal) congest ion (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
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 OBSERVATIONfSI: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION fS1: 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
BRAIN HEART
LIVER
NERVE, SCIATIC RECTUM SPLEEN TRACHEA
CECUM
ILEUM
LUNG OVARIES SPINAL CORD, CERVICAL STOMACH URINARY BLADDER
End of Record- 19050
COLON
JEJUNUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR THYMUS VAGINA
11-58
418-028:PAGE J-89
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: 19053
SEX:
F
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONS!: GENERAL: No gross changes.
HISTOMORPHQLOGIC OBSERVATIONS): Not applicable
HISTOMORPHQLOGIC OBSERVATIONS:
ADRENAL GLANDS: CECUM: LYMPH NODE, SUBMANDIBULAR: THYMUS: THYROID: UTERUS:
vacuolation, zona glomerulosa (mild) inflammation, mucosa, chronic (moderate)
hyperplasia, lymphocytic/plasmacytic (mild) atrophy (moderate) ultimobranchial body/cyst macrophages, pigmented (moderate)
THE FOLLOWING TISSUEiS) 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
End of Record- 19053
DUODENUM KIDNEYS
MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC URINARY BLADDER
11-59
418-028-.PAGE J-90
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: 19065
SEX:
F
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATION!SI: GENERAL: No gross changes.
HISTQMORPHOLOGIC OBSERVATIONS! : Not applicable
HISTQMORPHOLOGIC 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 TISSUE(S) 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
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATION'S): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfS): 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 (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: 19006
SEX:
F
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATION(S): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION(S): 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 OBSERVATION(S): GENERAL: No aross chanaes.
HISTOMORPHOLOGIC OBSERVATIONfSl: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
ADRENAL GLANDS: LIVER: UTERUS:
necrosis, cortex, focal (mild) Not remarkable 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
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 OBSERVATIONfS):
ADRENAL GLANDS: Bilateral- large. GASTROINTESTINAL TRACT: Abdominal distention,
large and small intestines distended with gas.
SPLEEN: Smal1. STOMACH: Fundic mucosa surface contains approximately 12 black areas ranging in size
from pinpoint to 0.3cm in diameter. THYMUS: Smal1.
HISTOMORPHOLOGIC OBSERVATIONfS):
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/infiammati on, submucosa, glandular area edema/infiammati on, submucosa, forestomach erosion(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/inflammation, submucosa, glandular area (mild) edema/inflanimation, submucosa, forestomach (mild) atrophy (marked) ultimobranchial body/cyst macrophages, pigmented (marked)
THE FOLLOWING TISSUEfSl 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
GROSS OBSERVATION(S): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION!Si : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: THYROID: UTERUS:
inflammation, chronic, focal/multifocal (minimal) hyperplasia, lymphocytic/plasmacytic (mild) necrosis, focal (minimal) ultimobranchial body/cyst
macrophages, pigmented (mild)
THE FOLLOWING TISSUEfS) 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-9<5
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: 19025
SEX:
F
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATIONfSi: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfS): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
ADRENAL GLANDS: KIDNEYS: STOMACH: UTERUS:
hypertrophy/vacuolation, cortex, multifocal (mild) nephritis, chronic, focal (minimal)
edema/inflanimation, submucosa, glandular area (mild) macrophages, pigmented (moderate)
THE 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 (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: 19027
SEX:
F
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATION(Si: GENERAL: No aross chanaes.
HISTOMORPHOLOGIC OBSERVATION Si : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
KIDNEYS: LYMPH NODE, SUBMANDIBULAR: STOMACH: THYROID:
mineralization, multifocal (minimal) hyperplasia, lymphocytic/plasmacytic (mild) edema/infiammaiion, submucosa, glandular area (mild) ultimobranchial body/cyst
THE FOLLOWING TISSUEfSl 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
TISSUEfSl 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 REPRQDUCTIQN/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
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATION!SI: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION(S): 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 GLANDS 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 OBSERVATIONS!: HEAD: Head- scab. 0.3cm x 0.3cm.
HISTOMORPHOLOGIC OBSERVATION(S): 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
TISSUES) NOT AVAILABLE FOR EVALUATION: LYMPH NODE, SUBMANDIBULAR End of Record- 19030
11-69
418-028'.PAGE MOO
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
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATION(S): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION!Si : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: LYMPH NODE. SUBMANDIBULAR: UTERUS:
necrosis, focal (minimal) hyperplasia, lymphocytic/plasmacytic (mild)
distention, lumen (moderate)
THE FOLLOWING TISSUEfS) 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) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1
HISTOPATHOLOGY REPORT
APPENDIX III
HISTOMORPHOLOGIC OBSERVATIONS IN THE 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
Dose Group: Dam Number: Pud Number:
LIVER:
T a b le 111-1 Histomorphologic Observations in the Liver - Group I - F1 Generation Pups
IIIIIIIIII 19012 19012 19012 19012 19012 19012 19012 19012 19012 19012 1 2 3 4 5 7 8 14 15 16
__.
.
Dose Group: Dam Number: Pud Number: LIVER:
Dose Group: Dam Number: Pud Number: LIVER:
Dose Group: Dam Number: Pud Number: LIVER:
IIIIIIIIII 19019 19019 19019 19019 19019 19019 19019 19019 19019 19019 1 2 3 7 8 11 12 13 14 15
- -------- -
IIIIIIIIII 19021 19021 19021 19021 19021 19021 19021 19021 19021 19021 1 2 6 8 9 10 11 12 13 14
- ---- ---- -
IIIIIIIIII 19023 19023 19023 19023 19023 19023 19023 19023 19023 19023 1 2 3 6 7 8 9 10 11 12
--------- -
Dose Group: Dam Number: Pud Number:
LIVER:
IIIIIIIIII 19041 19041 19041 19041 19041 19041 19041 19041 19041 19041 1 2 3 4 5 8 9 15 16 17
----------
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
Dose Group: Dam Number: Pud Number:
LIVER:
Table 111-1 (Continued) Histomorphologic Observations in the Liver - Group I - F1 Generation Pups
IIIIIIIIII 19042 19042 19042 19042 19042 19042 19042 19042 19042 19042 1 2 4 5 6 7 8 10 12 13
_-
__
_
Dose Group: Dam Number: Pud Number:
LIVER:
IIIIIIIIII 19044 19044 19044 19044 19044 19044 19044 19044 19044 19044 1 2 5 6 7 9 11 12 13 14
___
__
.
Dose Group: Dam Number: Pud Number:
LIVER:
I 1I I I I I I I I 19050 19050 19050 19050 19050 19050 19050 19050 19050 19050 1 2 3 4 5 6 7 8 13 14
-- - - - - - -
--
Dose Group: Dam Number: Pud Number:
LIVER:
Dose Group: Dam Number: Pud Number:
LIVER:
IIIIIIIIII 19053 19053 19053 19053 19053 19053 19053 19053 19053 19053 1 3 4 5 6 10 I I 12 13 14
-- ------ - -
IIIIIIIIII
19065 19065 19065 19065 19065 19065 19065 19065 19065 19065
3
4
5
7
8
10 I I
14 15 17
----------
III-2
418-028-.PAGEJ-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 HistomorphologicObservations Inthe Liver- GroupV - F1 Generation Pups
Dose Group: Dam Number: Pud Number:
LIVER :
VVVVVVVVV 19001 19001 19001 19001 19001 19001 19001 19001 19001 1 2 3 4 5 6 7 9 11
_.
Dose Group: Dam Number: 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: Dam Number: 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: Dam Number: 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: Dam Number: Pud Number:
LIVER :
VVVVVVVVVV 19022 19022 19022 19022 19022 19022 19022 19022 19022 19022 1 4 5 7 8 11 12 13 14 15
- --- --- - - -
III-3
418-028:PAGE J-105
ORAL (GAVAGE) COMBINED REPEATED DOSE STUDY OF T-7706 W ITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-028 S P O N S O R 'S STU D Y NUM BER T -7 7 0 6 .1
Table III-2 (Continued) Histomorphologic Observations in the Liver - Group V - F1 Generation Pups
Dose Group: Dam Number: Pud Number:
LIVER :
VVVVVVVVVV 19025 19025 19025 19025 19025 19025 19025 19025 19025 19025 1 2 7 8 13 14 15 18 19 20
_ _.
.
Dose Group: Dam Number: Pud Number:
LIVER :
VVVVVVVVV 19027 19027 19027 19027 19027 19027 19027 19027 19027 1 2 3 4 5 6 7 13 14
_.
.
Dose Group: Dam Number: Pud Number:
LIVER :
VVVVVVVVVV 19028 19028 19028 19028 19028 19028 19028 19028 19028 19028 1 2 3 4 5 6 7 10 11 12
____ _ .
.
Dose Group: Dam Number: Pud Number:
LIVER :
Dose Group: Dam Number: Pud Number:
LIVER :
VVVVVVVVVV 19030 19030 19030 19030 19030 19030 19030 19030 19030 19030 1 2 4 5 6 8 9 11 12 13
_ __ _
.
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
INDIVIDUAL ANIMAL REPORT BY GROUP
PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
WBC
THSN/CU MM
RBC MILL/CU MM
GROUP: 1-M 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167
13.5 15.9 15.1 12.7 16.4 17.6 17.7 14.9 15.0 14.3
-- --
-- -- --
7.10 8.58 6.95 7.16 6.77 7.61 7.37 7.45 7.43 8.71
--
--
-- --
--
MEAN SD N
15.3 1.63
10
7.51 0.648
10
HGB GRAMS/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
HCT MCV MCH % CU MICRONS PICO GRAMS
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
-- -- -- --
--
22.0 0.87
10
418-028:PAGE K-l
SEX: MALE
MCHC %
PLT THSN/CU MM
37.9 38.0 38.3 38.5 38.7 39.1 39.2 37.6 36.5 36.6
-- --- --
--
38.0 0.93
10
1219 1072
964 1354 1074 1322 1049 1264 1269 1203
-- --- --
--
1179 130.9
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
INDI'VIDUAL ANIMAL REPORT BY GROUP PERIOD; TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
WBC
THSN/CU MM
RBC MILL/CU MM
GROUP: 2-M 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171
10.9 17.0 12.7 13.1 15.7 18.4 14.7 10.5 17.2 19.0
--
--- -- --
7.55 6.93 7.02 8.20 6.80 7.42 7.29 7.32 7.53 7.20
-- -- -- --
--
MEAN SD N
14.9 3.03
10
7.33 0.396
10
HGB GRAMS/DL
16.2 15.2 16.1 15.9 16.1 16.4 15.9 15.4 16.4 15.5
-- -- ---
--
-
15.9 0.42
10
HCT MCV MCH % CU MICRONS PICO GRAMS
43.6 39.6 40.3 43.9 42.0 44.4 43.2 41.3 42.2 41.7
-- --
--
--
--
42.2 1.57
10
57.7 57.1 57.4 53.5 61.8 59.8 59.3 56.4 56.0 57.9
-- -- -- --
--
57.7 2.27
10
21.5 21.9 22.9 19.4 23.7 22.1 21.8 21.0 21.8 21.5
--- --
--
--
21.8 1.13
10
418-028:PAGE K-2
SEX: MALE
MCHC %
PLT THSN/CU MM
37.2 38.4 40.0 36.2 38.3 36.9 36.8 37.3 38.9 37.2
--- -- --
--
37.7 1.15
10
926 970 959 1468 1170 1382 1184 1183 1069 994
-- --- --
--
1131 183.7
10
(-- ) - Data Unavai table LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-3
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
SEX: MALE
Animal ID
WBC
THSN/CU MM
RBC MILL/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
HGB GRAMS/DL
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
HCT MCV MCH % CU MICRONS PICO GRAMS
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
MCHC %
PLT THSN/CU MM
37.7 37.7 36.3 38.4 36.9 38.0 38.4 37.4 36.2 37.9
-- -- --- --
37.5 0.79
10
958 960 993 1002 1253 1340 1143 1123 1046 1336
-- -- --
-- --
1115 149.2
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-4
Study Report for Hematology
INDIVIDUAI ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
WBC
THSN/CU MM
RBC MILL/CU MM
GROUP: 4-M 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166
12.6 21.0 18.1 12.0 22.0 17.4 12.8 19.6 15.6 11.1
-- -- -- -- --
6.59 6.73 6.75 6.83 7.50 7.07 6.87 7.37 6.97 6.62
-- -- -- -- --
MEAN SD N
16.2 3.97
10
6.93 0.305
10
HGB GRAMS/DL
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
HCT MCV MCH % CU MICRONS PICO GRAMS
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
SEX: MALE
MCHC %
PLT THSN/CU MM
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
Animal ID
UBC
THSN/CU MM
RBC MILL/CU MM
HGB GRAMS/DL
HCT MCV MCH % CU MICRONS PICO GRAMS
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
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
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 Unavailable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-6
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 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 %
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
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD : TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
WBC
THSN/CU MM
RBC MILL/CU MM
HGB GRAMS/DL
HOT MCV MCH % CU MICRONS PICO GRAMS
SEX: FEMALE
MCHC %
PLT THSN/CU MM
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 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
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 % 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
418-028:PAGE K-8
SEX: FEMALE
MCHC %
PIT 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 A N I M A L R E P O R T B Y G R O U P
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
Study Report for Hematology
418-028:PAGE K-10
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 : 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 % 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 %
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 Unavai table 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-M 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 2.0 0.0 1.1
0 11.4
2.7
0.0
1.6
0 11.6
3.0
0.0
0.3
0 9.1 2.2 0.0
1.3
0 14.1 1.5 0.0 0.2
0 14.3 1.4 0.0
1.1
0 13.1 2.7 0.0 1.6
0 12.7
1.5
0.0
0.4
0 11.0
3.5
0.0
0.5
0 12.2 1.6 0.0 0.3
-- -- -- -- --
-- -- -- -- _ _
-- --
--
--
--
-- -- -- -- --
-- -- -- -- .--
0 11.9 2.2 0.0 0.8 0.0 1.72 0.73 0.00 0.56
10 10 10 10 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 0.0
0 12.1 2.9 0.0
0 10.9 1.4 0.0
0 10.0 2.0 0.0
0 11.1 3.6 0.0
0 13.4 3.1 0.0
0 9.4 4.0 0.0
0 8.6 1.4 0.0
0 11.4 5.2 0.0
0 16.3 2.5 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 Unavai table 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
Animat ID
MPV
CU MICRON
PT seconds
GROUP: 3-M 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174
8.0 7.4 8.0 9.9 8.3 8.3 8.1 8.9 7.8 7.6
-- -- -- ---
13.9 13.7 13.6 13.6 13.5 13.2 13.7 13.7 13.4 14.0
--- -- -- --
MEAN SD N
8.2 0.72
10
13.6 0.23
10
APTT seconds
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
SEX: MALE
NRBC COUNT
Lymphocyte THSN/CU MM
Segmented THSN/CU MM
Bands THSN/CU MM
Monocytes THSN/CU MM
0 0 0 0 0 0 0 0 0 0 -- --- --
. ------
0 0.0
10
10.1 8.8 9.8
11.0 7.8
14.8 10.4 11.7 10.6 13.1
-- -- -- --
--
10.8 2.02
10
2.1 1.9 0.6 1.3 2.7 4.0 3.4 1.7 1.1 1.4
--- ---
--
2.0 1.06
10
0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0
-- -- --
__
--
0.0 0.03
10
0.5 0.2 1.5 0.5 0.6 1.5 0.1 0.4 0.2 0.3
-- --- --
--
0.6 0.51
10
(-- ) - Data Unavai table LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-14
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: 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
APTT seconds
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
SEX: MALE
NRBC COUNT
Lymphocyte THSN/CU MM
Segmented THSN/CU MM
Bands THSN/CU MM
Monocytes THSN/CU MM
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 ---- ---- ---- -- -----
4.0 0.0 2.3 0.0 3.1 0.0 1.4 0.0 2.9 0.0 3.7 0.0 2.8 0.1 2.7 0.0 3.1 0.0 2.4 0.0
---- -- --- -- ---- ----
0.6 1.7 2.2 0.5 0.7 0.5 1.0 0.6 0.0 0.2
~ -- --
__
--
0 12.1 2.8 0.0 0.8 0.0 3.57 0.73 0.03 0.67
10 10 10 10 10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-15
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: 5-M 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170
7.7 7.5 7.3 9.0 8.8 8.6 8.0 7.5 7.8 8.2
--- -- -- --
13.9 15.1 13.8 13.7 14.1 13.5 13.9 14.3 13.5 13.7
-- -- -- -- --
MEAN SD N
8.0 0.59
10
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: MALE
NRBC COUNT
Lymphocyte THSN/CU MM
Segmented THSN/CU MM
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 ---- -- --- -----
----
1.4 0.0 0.6
1.7 0.0 0.9
0.3 0.0 0.2
1.1 0.0 0.9
2.4 0.0 0.2
1.4 0.0
0.3
2.1 0.0 0.2
2.5 0.0 0.8
2.2 0.0 0.0
0.4 0.0
0.4
---- --
-- --
--
-- -- . --
---- --
-- '--
--
0 12.4 0.0 2.75
10 10
1.6 0.78
10
0.0 0.00
10
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 KM
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
MEAN 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 2.7 0.0 0.5
0 4.4 2.0 0.0 0.2
0 5.7 1.4 0.0 0.0
0 6.1 0.9 0.0 0.1
0 5.0 2.9 0.0 0.1
0 5.3 1.5 0.0 0.0
0 7.3 3.1 0.0 0.1
0 6.1 1.8 0.0 0.2
0 4.7 1.8 0.0 0.0
0 8.4 3.8 0.0 0.1
-- -- ~ __ --
------ -- --
-- -- -- -- --
-------- -
--
----
0 6.6 2.2 0.0 0.1 0.0 2.44 0.90 0.00 0.15
10 10 10 10 10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-02S:PAGE K-17
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD; TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
SEX: FEMALE
Animal ID
MPV
CU MICRON
GROUP: 2-F 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
9.6 7.2 8.8 8.2 8.4 7.8 8.1 8.0 6.9 7.0
-- -- -- --
--
MEAN SD
N
8.0 0.84
10
PT seconds
13.3 13.8 13.3 13.7 12.8 13.5 13.3 13.2 13.5 13.1
-- -- -- -- --
13.4 0.29
10
APTT seconds
27.5 21.3 29.2 22.6 20.3 24.3 20.0 26.8 25.3 22.1
-- -- --- --
23.9 3.19
10
NRBC COUNT
Lymphocyte THSN/CU MM
Segmented THSN/CU MM
Bands THSN/CU MM
Monocytes THSN/CU MM
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 13.7
0 9.6 3.5
0 6.2 4.6
0 5.4 1.6
------
------
-- --
--
------
-- ----
0.0 0.1 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.4 0.0 1.6 0.0 0.3 0.0 0.2 0.0 0.0
---- ---- __ -- __ -- -- .--
0 9.8 0.0 3.44
10 10
3.6 3.69
10
0.0 0.00
10
0.3 0.49
10
C-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-18
Study Report for Hematology
INDIVIDUAI,, ANIMAL REPORT BY GROUP PERIOD; TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
MPV
CU MICRON
PT seconds
GROUP: 3-F 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
7.2 7.3 9.3 8.5
-- 9.0 7.8 8.8 7.4 8.1
-- 9.3
--
-- --
12.9 12.9 12.8 13.7
-- 13.6 13.3 12.9 13.3 12.7
-- 13.6
--- --
MEAN SD N
8.3 0.82
10
13.2 0.37
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 COUNT
Lymphocyte THSN/CU MM
Segmented THSN/CU MM
Bands THSN/CU MM
Monocytes THSN/CU MM
0 6.5 4.0 0.0 0.3 0 5.7 2.0 0.0 0.2 0 5.0 1.9 0.0 0.0 0 12.3 3.8 0.0 0.3 -------- -- 0 5.7 1.6 0.0 0.1 0 9.8 2.6 0.0 0.1 0 7.4 2.6 0.0 0.2 0 10.3 2.1 0.0 0.0 0 10.9 1.0 0.0 0.1 -- -- -- -- -- 0 10.2 2.2 0.0 0.4 -- -- -- -- ' -- ------ -- -- --- -- -- -- --
0 8.4 2.4 0.0 0.2 0.0 2.60 0.93 0.00 0.13
10 10 10 10 10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-19
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: 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 0.63
10
13.1 13.4 13.4 12.9 13.0
-- -- 14.1 13.5 13.9 14.0 13.5 -- --
13.5 0.42
10
APTT seconds
21.4 24.5 23.7 27.9 21.9
--
__
27.1 25.7 25.2 26.2 28.9
_ --
25.3 2.45
10
SEX: FEMALE
NRBC COUNT
Lymphocyte THSN/CU MM
Segmented THSN/CU MM
Bands THSN/CU MM
Monocytes THSN/CU MM
0 7.7 1.6 0.0 0.1 0 7.1 2.3 0.0 0.1 0 9.6 2.8 0.0 0.3 0 7.7 2.2 0.0 0.1 0 5.4 3.8 0.3 0.2 -- -- -- -- __ -- -- -- __ -- 0 12.2 1.9 0.0 0.4 0 11.5 3.9 0.0 0.2 0 4.8 1.4 0.0 0.1 0 9.8 2.6 0.0 0.3 0 6.0 1.0 0.0 0.1 -- ---- -- -- -- ---- ----
o 8.2 2.4 0.0 0.2 0.0 2.52 0.96 0.09 0.11
10 10 10 10 10
(-- ) - Data Unavaitable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-20
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: 5-F 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
6.9 9.2 7.4 7.0 7.6 8.3 7.3 8.1 7.9 6.8
-- -- -- -- --
13.8 12.8 12.9 16.8 13.7 13.5 13.2 13.6 13.7 13.5
-- -- -- -- --
MEAN SD N
7.7 0.74
10
13.8 1.12
10
APTT seconds
30.4 22.1 22.3 27.6 21.6 25.3 27.5 22.2 31.5 21.6
-- -- -- ---
25.2 3.81
10
SEX: FEMALE
NRBC COUNT
Lymphocyte THSN/CU MM
Segmented THSN/CU MM
Bands THSN/CU MM
Monocytes THSN/CU MM
0 10.1 4.2 0.0 0.5 0 4.6 2.7 0.0 0.2 0 4.4 1.8 0.0 0.1 2 2.2 1.9 0.0 0.1 0 3.1 2.0 0.0 0.2 0 5.2 2.0 0.0 0.1 0 10.2 2.0 0.0 0.1 0 7.1 2.8 0.0 0.3 0 5.2 2.8 0.0 0.1 0 8.2 3.7 0.0 0.0 ------ -- -- ---- -- -- -- -- -- -- -- ~ -- -- -- -- -- -- ---- ----
0 6.0 2.6 0.0 0.2 0.6 2.77 0.82 0.00 0.14
10 10 10 10 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: 060-069
Animal ID Eosinophi L BasophiIs THSN/CU MM THSN/CU MM
Abnormal L THSN/CU MM
Other THSN/CU MM
GROUP: 1-M
19109
0.7 0.0 0.0 0.0
19115
0.2 0.0 0.0 0.0
19116
0.2 0.0 0.0 0.0
19119
0.1 0.0 0.0 0.0
19122
0.2 0.0 0.5 0.0
19125
0.5 0.0 0.4 0.0
19131
0.2 0.0 0.2 0.0
19132
0.0 0.0 0.3 0.0
19134
0.2 0.0 0.0 0.0
19135
0.3 0.0 0.0 0.0
19143 -- -- -- --
19151 -- _ _ -- --
19157 -- -- -- --
19161 -- -- -- --
19167 -- -- -- --
MEAN SD N
0.3 0.20
10
0.0 0.00
10
0.1 0.20
10
0.0 0.00
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 Eosinophil THSN/CU MM
BasophiIs THSN/CU MM
Abnormal L THSN/CU MM
Other THSN/CU MM
GROUP: 2-M 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171
MEAN 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 0.00
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: MALE
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-23
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD; TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
SEX: MALE
Animal ID Eosinophil THSN/CU MM
BasophiIs THSN/CU MM
Abnormal L THSN/CU MM
Other THSN/CU MM
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 0.00
10
0.1 0.1 0.0 0.1 0.0 0.2 0.1 0.0 0.0 0.0
-- -- ----
0.1 0.07
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-2002
418-028:PAGE K-24
Study Report for Hematology
INDIVIDUAI. ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID Eosinophil THSN/CU MM
Basophils THSN/CU MM
Abnormal L THSN/CU MM
Other THSN/CU MM
SEX: MALE
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 0.26
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
0.1 0.6 0.4 0.5 0.2 0.2 0.1 0.0 0.0 0.0
-- -- ---
--
0.2 0.22
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-2002
Study Report for Hematology
418-028:PAGE K-25
IN D IV ID U A L ANIMAL REPORT BY' GROUP PER IO D : TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
SEX: MALE
Animal ID Eosinophil THSN/CU MM
Basophils THSN/CU MM
Abnormal L THSN/CU MM
Other THSN/CU MM
GROUP: 5-M
19111
0.2 0.0 0.5 0.0
19117
0.4 0.0 0.0 0.0
19124
0.1 0.0 0.0 0.0
19126
0.4 0.0 0.0 0.0
19127
0.1 0.0 0.2 0.0
19128
0.1 0.0 0.0 0.0
19140
0.3 0.0 0.5 0.0
19145
0.2 0.0 0.0 0.0
19149
0.0 0.0 0.0 0.0
19152
0.0 0.0 0.0 0.0
19154 -- -- -- --
19158 -- -- -- --
19168 -- -- -- --
19169 __ ~ -- --
19170 -- -- -- --
MEAN SD N
0.2 0.15
10
0.0 0.00
10
0.1 0.21
10
0.0 0.00
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
418-028:PAGE K-26
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD; TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID Eosinophil THSN/CU MM
BasophiIs THSN/CU MM
Abnormal L THSN/CU MM
Other THSN/CU MM
GROUP: 1-F 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
0.2 0.0 0.3 0.1 0.0 0.0 0.1 0.1 0.0 0.1
-- --- --
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.1
-- . ----- ---- ----
0.0 0.0 0.0 0.0 0.0 0.0 0,0 0.0 0.0 0.0
--
-- ---
MEAN SD N
0.1 0.10
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
418-028:PAGE K-27
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animat ID Eosinophil THSN/CU MM
BasophiIs THSN/CU MM
Abnormal L THSN/CU MM
Other 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 0.13
10
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
-- --- --
--
0.0 0.00
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
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
-- -- -- -- --
0.0 0.00
10
(-- ) - Data Unavaitable 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 418-028 STUDY NO: 060-069
SEX: FEMALE
Animal ID Eosinophil THSN/CU MM
BasophiIs THSN/CU MM
Abnormal L THSN/CU MM
Other THSN/CU MM
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 0.00
10
0.1 0.1 0.1 0.2
-- 0.0 0.0 0.1 0.0 0.0
-- 0.0
--
--
--
0.1 0.07
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-2002
418-028:PAGE K-29
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD; TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
SEX: FEMALE
Animal ID Eosinophil THSN/CU MM
BasophiIs THSN/CU MM
Abnormal L THSN/CU MM
Other THSN/CU MM
GROUP: 4-F
19002
19005
0.1 0.0 0.0 0.0
19035
0.0 0.0 0.1 0.0
19039
0.1 0.0 0.0 0.0
19040
0.0 0.0 0.0 0.0
19045
0.0 0.0 0.0 0.0
19046 -- -- _ _ ~
19051
-- --
-- --
19054
0.0 0.0 0.3 0.0
19058 19062
0.2 0.0 0.0 0 0 0.0 0.0 0.0 0.0
19063 19066
0.3 0.0 0.0 0.0 0.0 0.0 0.1 0.0
19069 -- -- -- --
19073
--
------
MEAN SD N
0.1 0.11
10
0.0 0.00
10
0.1 0.10
10
0.0 0.00
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028 :PAGE K-30
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PER IO D ; TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
SEX: FEMALE
Animal ID Eosinophil BasophiIs Abnormal L
Other
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
0.3 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.4
-- -- -- --
--
0.1 0.15
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
0.0 0.0 0.1 0.0 0.0 0.1 0.0 0.0 0.1 0.0
-- --- --
--
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-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: MALE
TEST(s): UNITS:
WBC RBC THSN/CU MM MILL/CU MM
HGB GRAMS/DL
HCT MCV MCH % 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
14.9 3.03
10
7.33 0.396
10
15.9 0.42
10
42.2 1.57
10
57.7 2.27
10
21.8 1.13
10
37.7 1.15
10
1131 183.7
10
7.9 0.54
10
Group: 3-M MEAN
SD N
13.8 2.84
10
7.32 0.441
10
15.7 0.59
10
42.0 2.22
10
57.4 1.78
10
21.5 0.75
10
37.5 0.79
10
1115 149.2
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-M 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 from Control P < .05 LABCAT HE4.43
**-Significant Difference from Control P < .01 27-JUN-2002
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
418-028:PAGE K-32
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS 0F VARIANCE F0LL0WED BY DUNNETT'S PROCEDURE
SEX: MALE
TEST(s): UNITS:
PT seconds
APTT seconds
Group: 1-M MEAN
SD N
13.4 0.24
10
21.0 3.09
10
Group: 2-M 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-M MEAN
SD N
13.8* 0.40
10
21.2 2.24
10
Group: 5-M MEAN
SD N
14.0** 0.47
10
21.3 1.43
10
NRBC Lymphocyte Segmented
Bands Monocytes Eosinophil Basophi Ls
COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM
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 2.68 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
ANALYSIS OF VARIANCE F0LL0WED BY DUNNETT'S PROCEDURE
TEST(s) : Abnormal L
Other
UNITS:
THSN/CU MM 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-M 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
418-028 :PAGE K-33
SEX: MALE
LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
418-028:PAGE K-34
SUMMARY REPORT P E R IO D : TERMINAL
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.
D U N N E T T 1'S 't'
DUNNETT'S RANGES
LO -95%- HI
L0 -99%- HI
Degree
Source
Fdm
Sum of Squares
Mean Square
1-M
10 153.1
15.3
1.63
TREATMENTS
4
32.41
8.10
2-M
10 149.2
14.9
3.03
0.29
11.9
18.7
11.1
19.5
ERROR 45
406.23
9.03
3-M
10 137.6
13.8
2.84
1.15
11.9
18.7
11.1 19.5 -----------------------
-- -----
4-M
10 162.2
16.2
3.97
0.68
11.9
18.7
11-1
19.5
TOTAL 49
438.64
5-M
10 146.6
14.7
3.07
0.48
11.9
18.7
11.1
19.5
F Ratio =
Co e f f . Var. % =
0.90 20.065
' F* table values Dunnett' s 'T 1 table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
Red Blood Count
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
8.16 --------------------
2.834 -- M
10 69.30
6.93
0.305
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 C o e f f . Var. % =
2.88 6.381
Hemoglobin
*F ` table values Dunnett's 1T 1 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
17.6
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 = C o e f f ., 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-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
418-028:PAGE K-35 Study Report for Hematology
SUMMARY REPORT PERIO D; TERMINAL
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: MALE
Group
1-M 2-M 3-M 4-M 5-M
N Total
Mean
TO 434.6 10 422.2 10 419.9 TO 401.7 10 406.7
43.5 42.2 42.0 40.2 40.7
Std. DUNNETT'S
Dev.
't 1
3.48 1.57 2.22 2.29 1.81
1.17 1.39 3.11 2.64
DUNNETT'S RANGES
LO -957.- HI
L0 -997.- HI
Degree
Source
Fdm
40.8 40.8 40.8 40.8
46.1 46.1 46.1* 46.1*
40.2 40.2 40.2 40.2
46.8 46.8 46.8 46.8
TREATMENTS ERROR
TOTAL
4 45
49
Sum of Squares
68.54 252.15
320.69
Mean Square
17.13 5.60
F Ratio = Coef f. Var. % =
3.06 5.676
'F 1 table values Du n n e t t 's 'T'1 table values
M e an C o r p u s c u l a r Volume
F.01 = P. 01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
1-M
10 579.1
57.9
1.89
2-M
TO 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
C o e f f . Var. % =
0.34 3.006
1F 1 table values Dunnett's 'T'1 table values
F.01 = P.01 =
Mean Corpuscular Hemoglobin
55.5 55.5 55.5 55.5
60.3 60.3 60.3 60.3
TREATMENTS ERROR
TOTAL
4 45
49
3.78 3.12
F.05 = P.05 =
2.58 2.51
4.07 136.05
140.12
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. % =
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 from 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 PERIODS TERMINAL
418-028 :PAGE K-36
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS 0F VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
M ean
Group
N
C o rp u sc u la r
Total
Mean
Hem. C o n e .
Std. DUNNETT'S
Dev.
1t *
DUNNETT' S RANGES
LO -95%- HI
L0 -99%- HI
Degree
Source
Fdm
1-M
10 380.4
38.0
0.93
TREATMENTS
4
2-M
10 377.2
37.7
1.15
0.80
37.0
39.0
36.8
39.3
ERROR 45
3-M
10 374.9
37.5
0.79
1.38
37.0
39.0
36.8
39.3 -
4-M
10 383.7
38.4
0.80
0.83
37.0
39.0
36.8
39.3
TOTAL 49
5-M
10 383.1
38.3
0.70
0.68
37.0
39.0
36.8
39.3
F Ratio = C o e f f . Var. % =
1.81 2.343
*F ' table values D u nn et t1s 'T' table values
F.01 = P. 01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
P la te le ts
1-M
10 11790
1179
130.9
TREATMENTS
4
2-M
10 11305
1131
183.7
0.74
1015
1343
975 1383
ERROR 45
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
5-M
10 11483
1148
159.9
0.47
1015
1343
975 1383
F Ratio = C o e f f . Var. % =:
0.40 12.888
'F* table values D u nn et t's 'T' table values
MEAN P L A T E L E T 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
2-M
10 78.6
7.9
0.54
0.92
7.4 8.8
7.2 9.0
ERROR 45
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
5-M
10 80.4
8.0
0.59
0.28
7.4 8.8
7.2 9.0
F Ratio == C o e f f . Var. % ==
0.56 7.823
'F' table values D u nn et t1s 'T' table values
F.01 = P.01 =
3.78 3.12
F.05 = P. 05 =
2.58 2.51
SEX: MALE
Sun of Squares
Mean Square
5.72 35.64
1.43 0.79
41.36
34523 963815
998339
8631 21418
0.90 18.03
18.94
0.23 0.40
Error-within groups Source-Source of Variation
LABCAT HE4.43
Treatments-between groups
27-JUN-2002
Study Report for Hematology
SUMMARY REPORT PERIO D; TERMINAL
418-028:PAGE K-37
STUDY ID: A R G U S 418-028 STUDY NO: 060-069
Prothrombin
Group
N Total
Mean
1-M
10 133.8
13.4
2-M
10 142.3
14.2
3-M
10 136.3
13.6
4--M
10 137.9
13.8
5-M
10 139.5
14.0
ANALYSIS OF VARIANCE F0LL0WED BY DUNNETT'S PROCEDURE
SEX: MALE
Std. DUNNETT'S
Dev.
't'
0.24 0.27 0.23 0.40 0.47
5.63 1.66 2.71 3.77
DUNNETT'S RANGES
L0 -95%- HI
L0 -99Z- HI
Degree
Source
Fdm
Sum of Squares
13.0 13.0 13.0 13.0
13.8* 13.8 13.8* 13.8*
12.9 12.9 12.9 12.9
TREATMENTS
4
13.9**
ERROR 45
13.9 --------------------
13.9
TOTAL 49
13.9**
4.13 5.13
9.26
Mean Square
1.03 0.11
F Ratio = Coeff. Var. % =
9.05 2.448
*F* table values Dunn et t`s 'T' table values
A c t . P a r t . T h r o m b o p la s tin T im e
F.01 = P.01 *
3.78 3.12
F.05 = P.05 =
2.58 2.51
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 =
N u c le a te d Red C e lls
17.0 17.0 17.0 17.0
25.0 25.0 25.0 25.0
TREATMENTS
4
ERROR 45
--------------------
TOTAL 49
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 = C o e f f .. Var. % =
0 0 0.0 0 0 0.0 0.00 0 0 0.0 0.00 0 0 0.0 0.00 0 0 0.0 0.00
00 00 00 00
0.00 0.000
'F ' table values Dunn et t`s 'T ' table values
F.01 = P.01 =
TREATMENTS
4
0.00000
0.00000
00
ERROR 45
0.00000
0.00000
0 o --------------------
00 00
TOTAL 49
0.00000
3.78 3.12
F.05 = P.05 =
2.58 2.51
-Significant Difference from Control P < .05 -S ignificant Difference from Control P < .01 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-38
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Lymphocytes
Group
N Total
Mean
1-M
10 119.2
11.9
2-M
10 109.7
11.0
3-M
10 108.1
10.8
4-M
10 120.8
12.1
5-M
10 123.6
12.4
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: MALE
Std. DUNNETT'S Dev.
1.72 2.68 2.02 3.57 2.75
0.81 0.94 0.14 0.37
DUNNETT* S RANGES
LO -957.- HI
LO -997.- HI
Degree
Source
Fdm
9.0 14.9 9.0 14.9 9.0 14.9 9.0 14.9
TREATMENTS
4
8.3 15.6
ERROR 45
8.3 15.6 -
8.3 15.6
TOTAL 49
8.3 15.6
Sum of Squares
19.27 311.29
330.56
Mean Square
4.82 6.92
F Ratio = C o e f f . Var. % =
0. 70 22.619
'F' table values D u n n e t t 1s 1T ' table values
Segmented Neutrophils
F.01 = P. 01 =
3.78 3.12
F.05 = P.05 =
2. 58 2. 51
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 = C o e f f .. Var. % =
3.79 39.885
'F' table values D u n n e t t 1s 'T' table values
F.01 = P.01 =
Bands
TREATMENTS
4
0.9 3.5
ERROR 45
0.9 3.5 ---
0.9 3.5
TOTAL 49
0.9 3.5
3.78 3.12
F. 05 = P.05 =
2.58 2.51
12.77 37.87
50.64
3.19 0.84
1-M 1 0 0.0 0.0 0 . 0 0
TREATMENTS
4
0 .0 0 1 2
0.0003
2-M
10
0.0 0.0
0 .0 0
0 .0 0
0.0 0.0
0.0 0.0
ERROR 45
0.0180
0.0004
3-M
10
01
0.0
0.03
1.12
0.0 0 Q
0.0 0.0 -
4-M
1 0 0 .1
0.0
0.03
1.12
0.0 0.0
0.0 0.0
TOTAL 49
0.0192
5-M
10
0.0
0.0
0 .0 0
0 .0 0
0.0 0.0
0.0 0.0
F Ratio = C o e f f ., Var. Z =
0.75 500.000
'F' table values D u n n e t t 's 'T1 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 PERIO D ; TERMINAL
418-028 :PAGE K-39
STUDY 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 -95%- HI
L0 -99%- 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
3-M '
10
5.8
0.6
0.51
1.11
4-M
10
8.0
0.8
0.67
0.17
5-M
10
4.5
0.5
0.33
1.66
0.2 1.4 0.2 1.4 0.2 1.4 0.2 1.4
TREATMENTS
4
0.1 1.6
ERROR 45
0.1 1.6
0.1 1.6
TOTAL 49
0.1 1.6
1.03 12.43
13.46
0.26 0.28
F Ratio = C o e f f . Var. % =
0.93 78.222
Eosinophils
'F' table values Dunn et t's 'T' table values
F.01 = P.01 =
3.78 3.12
F..05 * P..05 =
2.58 2.51
1-M 10 2.6 0.3 0.20
2-- M
10
3.0
0.3
0.21
0.43
0.0 0.5
3-M
10
2.5
0.3
0.21
0.11
0.0 0.5
4-M
10
2.7
0.3
0.26
0.11
0.0 0.5
5-M
10
1.8
0.2
0.15
0.86
0.0 0.5
F Ratio = C o e f f .. Var. % =
0.46 82.096
'F* table values Dunnett *s *T* table values
F.01 = P. 01 =
Basophils
1-M 10 0.0 0.0 0.00
2-M
10
0.0
0.0
0.00
0.00
0.0 0.0
3-M
10
0.0
0.0
0.00
0.00
0.0 0.0
4-M
10
0.0
0.0
0.00
0.00
0.0 0.0
5-M
10
0.0
0.0
0.00
0.00
0.0 0.0
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
'
TREATMENTS
4
0.0 0.0
ERROR 45
0.0 0.0 ------------
0.0 0.0
TOTAL 49
0.0 0.0
0.08 1.93
2.00
0.02 0.04
0.00000 0.00000
0.00000 0.00000
0.00000
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-2002
Study Report for Hematology
SUMMARY REPORT PE R IO D : TERMINAL
418-028 :PAGE K-40
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
Abnormal Lymphocytes
Std. DUNNETT'S
Group
N Total
Mean
Dev.
't'
DU NN ET T1S RANGES
LO -'95%- HI
LO -99%- HI
Degree
Source
Fdm
1-M 10 1.4 0.1 0.20
TREATMENTS
4
2-M
10
1.1
0.1
0.14
0.38
-.1 0.3
-.1 0.4
ERROR 45
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
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 Dunn et t1s '1r 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
2-M
10
0.0
0.0
0.00
0.00
0.0 0.0
0.0 0.0
ERROR 45
3-M lU
nn
0.00
0.00
nn nn
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
5-M
10
0.0
0.0
0.00
0.00
0.0 0.0
0.0 0.0
F Ratio = C o e f f ., Var. % =
0.00
0.000
'F' table values D u nn et t1s 'T' table values
F.01 = P.01 =
3.78 3.12
F.05 = P. 05 =
2.58 2.51
SEX: MALE
Sum of Squares
Mean Square
0.12 1.40
1.52
--
0.03 0.03
0.00000 0.00000
0.00000 0.00000
0.00000
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 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: FEMALE
TEST(s): UNITS:
UBC RBC THSN/CU MM MILL/CU MM
HGB GRAMS/DL
Group: 1-F MEAN
SD N
9.0 3.09
10
6.51 0.461
10
15.5 0.95
10
Group: 2-F MEAN
SD N
13.8* 5.73
10
6.22 0.423
10
15.0 0.77
10
Group: 3 - F MEAN
SD N
11.1 2.98
10
6.40 0.554
10
15.2 0.91
10
Group: 4-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 3.48
10
6.42 0.538
10
15.3 0.77
10
HCT MCV MCH % CU MICRONS PICO GRAMS
40.5 2.93
10
62.2 1.19
10
23.9 0.55
10
39.3 2.72
10
63.3 2.01
10
24.2 0.76
10
39.5 3.24
10
61.8 1.50
10
23.9 0.88
10
40.1 3.02
10
62.9 2.04
10
23.8 1.25
10
40.4 3.15
10
63.0 1.60
10
23.8 1.05
10
MCHC PLT MPV % THSN/CU MM CU MICRON
38.4 0.76
10
1419 153.0
10
38.3 0.94
10
1240 208.1
10
8.3 0.49
10
8.0 0.84
10
38.7 1.29
10
1274 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 0.74
10
-Significant Difference from Control P < .05
LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
418-028 :PAGE K-42
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNN ET T1S PROCEDURE
SEX: FEMALE
TEST(s): UNITS:
PT seconds
APTT seconds
NRBC Lymphocyte Segmented
Bands Monocytes Eosinophil BasophiIs
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
13.2 0.41
10
13.4 0.29
10
21.7 2.36
10
23.9 3.19
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
Group: 3-F MEAN
SD N
13.2 0.37
10
23.5 2.35
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
Group: 4 - F MEAN
SD N
13.5 0.42
10
25.3 2.45
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
Group: 5-F MEAN
SD N
13.8 1.12
10
25.2 3.81
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 Di fference from Control P < .05 LABCAT HE4.43
27-JUN-2Q02
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
TEST(s): UNITS:
Abnormal L
Other
THSN/CU MM 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-2002
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
Mean
Dev.
DUNNETT'S *t 1
DUNNETT'S RANGES
LO -95%- HI
LO -99%- HI
Degree
Source
Fdm
1-F 2-F 3-F 4-F 5-F
10 89.9 10 137.8 10 110.7 10 108.4 10 88.9
9.0 13.8 11.1 10.8
8.9
3.09 5.73 2.98 3.15 3.48
2.80 1.22 1.08 0.06
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
F Ratio = Coeff. Var. % =
2.70 35.721
'F ' table values Dunnett's 'T 1 table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
Red Blood Count
Sum of Squares
158.42 659.12
817.54
Mean Square
39.61 14.65
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
6.40
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 = C o e f f .. Var. % =
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 7.21 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 = C o e f f . 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-within groups
LABCAT HE4.43
Source-Source of Variation Treatments-between groups
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
418-028 :PAGE K-45
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: FEMALE
Group
N Total
Mean
Std. DUNNETT'S
Dev.
't '
DUNNETT'!3 RANGES
L0 -95%- HI
L0 -99%- HI
Degree Source Fdm
1-F
10 404.9
40.5
2.93
TREATMENTS 4
2-F
10 393.4
39.3
2.72 0.85
37.1 43.9
36.3 44.7
ERROR 45
3-F
10 395.1
39.5
3.24 0.73
37.1
43.9
36.3 44.7 -
4-F
10 401.4
40.1
3.02 0.26
37.1
43.9
36.3 44.7
TOTAL 49
5-F
10 404.1
4 0 .4
3.15
0 .0 6
37.1
43.9
36.3 44.7
F Ratio =: Coeff. Var. % =!
0.30 7.548
1F 1 table values Dunnett's 1T* table values
Mean Corpuscular Volume
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
1-F
10 622.3
62.2
1.19
TREATMENTS 4
2-F
10 633.3
63.3
2.01
1.45
60.3 64.1
59.9 64.6
ERROR 45
3-F
10 618.2
61.8
1.50 0.54
60.3 64.1
59.9 64.6 -
4-F
10 629.1
62.9
2.04 0.90
60.3 64.1
59.9 64.6
TOTAL 49
5-F
10 629.7
63.0
1.60 0.97
60.3 64.1
59.9 64.6
F Ratio -= Coeff. Var. % ==
1. 30 2.709
'F 1 table values Dunnett's 1T * table values
Mean Corpuscular Hemoglobin
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
1-F
10 239.0
23.9
0.55
TREATMENTS 4
2-F
10 242.4
24.2
0.76 0.82
22.9 24.9
22.6 25.2
ERROR 45
3-F
10 238.9
23.9
0.88 0.02
22.9 24.9
22.6 25.2 -
4-F
10 237.9
23.8
1.25 0.26
22.9 24.9
22.6 25.2
TOTAL 49
5-F
10 238.3
23.8
1.05 0.17
22.9 24.9
22.6 25.2
F Ratio =: Coeff. Var. % ==
0.37 3.886
'F' table values Dunnett's 'T ' table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
Sum of Squares
11.01 409.80 420.81
14.98 129.67 144.64
1.28 38.92 40.21
Mean Square
2.75 9.11
3.74 2.88
0.32 0.86
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-46
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: FEMALE
Mean Corpuscular Hem. Cone.
Std. DUNNETT'S
Group
N Total
Mean
Dev.
t '
DUNNETT' S RANGES
LO -95%- HI
L0 -99%- HI
Degree Source Fdm
1-F
10 384.2
38.4
0.76
TREATMENTS 4
2-F
10 382.9
38.3
0.94 0.26
37.1
39.7
36.8 40.0
ERROR 45
3-F
10 386.6
38.7
1.29 0.47
37.1
39.7
36.8 40.0 ---
4-F
10 378.3
37.8
1.22 1.16
37.1
39.7
36.8 40.0
TOTAL 49
5-F
10 378.4
37.8
1.37 1.14
37.1
39.7
36.8 40.0
Sum of Squares
5.34 58.25
63.60
Mean Square
1.34 1.29
F Ratio = Coeff. Var. % =
1. 03 2.978
Platelets
'F 1 table values Dunnett's 'T 1 table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2. 58 2. 51
1-F
10 14189
1419
153.0
2-F
10 12396
1240
208.1 2.05
1199 1639
3-F
10 12735
1274
226.3 1.66
1199 1639
4-F
10 13048
1305
207.2 1.30
1199 1639
5-F
10 13554
1355
176.8 0.72
1199 1639
F Ratio = Coeff.. Var. % =
1.29 14.868
'F 1 table values Dunnett's *T' table values
F.01 = P.01 =
MEAN PLATELET VOLUME
1145 1145 1145 1145
1692 1692 1692 1692
TREATMENTS 4 ERROR 45
-----------------TOTAL 49
198797 1729216
1928012
3.78 3.12
F.05 = P.05 =
2.58 2.51
49699 38427
1-F 10 83.4 8.3 0.49
TREATMENTS 4
2.95
0.74
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 0.22
7.5 9.1
7.3 9.3 -------------------
4-F
10 80.3 8.0 0.63 0.97
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 Ratio = Coeff.. Var. % =
1.44 8.894
'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-47
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: FEMALE
Prothrombin
Group
N Total
Mean
Std. DUNNETT'S
Dev.
't *
DUNNETT'SI RANGES
L0 -95%- HI
L0 -99%- HI
Degree Source Fdm
Sum of Squares
Mean Square
1-F
10 131.8
13.2
0.41
TREATMENTS 4
2.32
0.58
2-F
10 133.5
13.4
0.29 0.63
12.5 13.9
12.3 14.0
ERROR 45
16.48
0.37
3-F
10 131.7
13.2
0.37 0.04
12.5
13.9
12.3 14.0 -
4-F
10 134.8
13.5
0.42 1.11
12.5 13.9
12.3 14.0
TOTAL 49
18.80
5-F
10 137.5
13.8
1.12 2.11
12.5
13.9
12.3 14.0
F Ratio = Coeff. Var. % =
1.58 4.521
1F 1 table values Dunnett's 'T' table values
Act. Part. Thromboplastin Time
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
1-F
10 217.3
21.7
2.36
2-F
10 239.4
23.9
3.19 1.71
18.5 25.0
3-F
10 234.5
23.5
2.35 1.33
18.5 25.0
4-F
10 252.5
25.3
2.45 2.72
18.5 25.0*
5-F
10 252.1
25,2
3.81 2.69
18.5 25.0*
F Ratio = Coeff. Var. % =
2.53 12.081
*F * table values Dunnett's *T ' table values
F.01 P.01
17.7 17.7 17.7 17.7
25.8 25.8 25.8 25.8
TREATMENTS ERROR
TOTAL
4 45
49
3.78 3.12
F.05 P.05
2.58 2.51
84.50 375.66
460.17
21.13 8.35
Nucleated Red Cells
1-F 10 2-F 10 3-F 10 4-F 10 5-F 10
F Ratio = Coeff.. Var. % =
0 0 0 0 2
1.00 707.107
0 0.0 0 0.0 0.00 0 0.0 0.00 0 0.0 0.00 0 0.6 1.58
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 ERROR 45 0 --------------------
0 TOTAL 49 0
0.32 3.60
3.92
F.05 = P.05 =
2.58 2.51
0.08 0.08
-Significant Difference from 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 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY IDUNNETT'S PROCEDURE
SEX : FEMALE
Lymphocytes
Group
N Total
Mean
Std. DUNNETT'S
Dev.
'f
DUNNETT'S RANGES
LO -95%- HI
LO -99%- HI
Degree Source Fdm
1-F 10 65.6 6.6 2.44
TREATMENTS 4
2-F
10 98.0 9.8 3.44 2.61
3.4 9.7* 2.7 10.4
ERROR 45
3-F
10 83.8 8.4 2.60 1.46
3.4 9.7
2.7 10.4 -
4-F
10 81.8 8.2 2.52 1.30
3.4 9.7
2.7 10.4
TOTAL 49
5-F
10 60.3 6.0 2.77 0.43
3.4 9.7
2.7 10.4
F Ratio = Coeff. Var. % =
2.96 35.677
*F ' table values Dunnett's 'T 1 table values
F .01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.!58 2.!51
Segmented Neutrophils
Sum of Squares
91.51 347.60
439.11
Mean Square
22.88 7.72
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 Ratio = Coeff., Var. % =
0.95 70.025
'F1 table values Dunnett's 'T* table values
F.01 = P.01 =
Bands
TREATMENTS 4
12.77
-.4 4.8
ERROR 45
151.70
-.4 4.8 -------------------
-.4 4.8
TOTAL 49
164.47
-.4 4.8
3.78 3.12
F.05 = P.05 =
2.58 2.51
3.19 3.37
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
0.0018
3-F
10 0.0 0.0 0.00 0.00
0.0 0.0
-.1 0.1 -------------------
4-F
10 0.3 0.0 0.09 1.58
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 Ratio = Coeff., Var. % =
1.00 707.107
*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 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-49
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: FEMALE
Monocytes
Group
N Total
Mean
Std. DUNNETT'S
Dev.
't'
DUNNETT' S RANGES
LO -'95%- HI
L0 -99%- HI
Degree Source Fdm
Sum of Squares
Mean Square
1-F 10 1.3 0.1 0.15
TREATMENTS 4
0.11
0.03
2-F
10 2.7 0.3 0.49 1.26
-.1 0.4
-.2 0.5
ERROR 45
2.79
0.06
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 0.54
-.1 0.4
-.2 0.5
TOTAL 49
2.90
5-F
10 1.7 0.2 0.14 0.36
-.1 0.4
-.2 0.5
F Ratio = Coeff. Var. % =
0.43 133.942
*F 1 table values Dunnett 's ''r' table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2. 58 2. 51
Eosinophils
-F 10 0.9 0.1 0.10
l-F
10 1.2 0.1 0.13 0.54
0.0 0.2
i-F
10 0.9 0.1 0.13 0.00
0.0 0.2
-F
10 0.7 0.1 0.11 0.36
0.0 0.2
-F
10 0.8 0.1 0.15 0.18
0.0 0.2
F Ratio = Coeff.. Var. % =
0.23 137.686
'F ' table values Dunnett' s 'T' table values
F.01 = P.01 =
TREATMENTS 4
-.1 0.3
ERROR 45
-.1 0.3 -------------------
-.1 0.3
TOTAL 49
-.1 0.3
3.78 3.12
F.05 = P.05 =
2.58 2.51
0.014 0.691
0.705
0.004 0.015
Basophils
-F 10 0.0 0.0 0.00
TREATMENTS 4
0.00000 0.00000
!-F
10 0.0 0.0 0.00 0.00
0.0 0.0
0.0 0.0
ERROR 45
0.00000 0.00000
-F
10 0.0 0.0 0.00 0.00
0.0 0.0
0.0 o.o ------------------
-F
10 0.0 0.0 0.00 0.00
0.0 0.0
0.0 0.0
TOTAL 49
0.00000
-F
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-2002
418-028:PAGE K-50 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
Abnormal Lymphocytes
Std. DUNNETT'S
Group
N Total
Mean
Dev.
't '
DUNNETT' S RANGES
L0 -95%- HI
L0 -99%- HI
Degree Source Fdm
1-F 10 0.3 0.0 0.05
2-F
10 0.0 0.0 0.00 1.09
0.0 0.1
3-F
10 0.6 0.1 0.07 1.09
0.0 0.1
4-F
10 0.5 0.1 0.10 0.73
0.0 0.1
5-F
10 0.3 0.0 0.05 0.00
0.0 0.1
F Ratio = Coeff. Var . % =
1.39 181.306
'F* table values Dunnett's ''T1 table values
F.01 = P.01 =
TREATMENTS 4
-.1 0.1
ERROR 45
-.1 0.1 --
-.1 0.1
TOTAL 49
-.1 0.1
3.78 3.12
F.05 =* P.05 =*
2.58 2.51
Other
1-F 10 0.0 0.0 0.00
2-F
10 0.0 0.0 0.00 0.00
0.0 0.0
3-F
10 0.0 0.0 0.00 0.00
0.0 0.0
4-F
10 0.0 0.0 0.00 0.00
0.0 0.0
5-F
10 0.0 0.0 0.00 0.00
0.0 0.0
F Ratio = Coeff.. Var. % =
0.00 0.000
*F ' tabte values Dunnett's 'T ' table values
F.01 = P.01 =
TREATMENTS 4
0.0 0.0
ERROR 45
0.0 0.0 ---
0.0 0.0
TOTAL 49
0.0 0.0
3.78 3.12
F.05 = P.05 =
2.58 2.51
Sum of Squares
0.021 0.171 0.192
0.00000 0.00000 0.00000
Mean Square
0.005 0.004
0.00000 0.00000
Error-within groups Source-Source of Variation
LABCAT HE4.43
Treatments-between groups
27-JUN-2002
418-028:PAGE K-51
Study Report for Hematology
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 1-M
19109 19115 19116
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs 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
BasophiIs
Abnormal Lymphocytes
Other
WBC
TERMINAL CNT ABS
0 72 9.7 15 2.0
0 0.0 8 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
15.9
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 HE4.43
27-JUN-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-52
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 1-M
TERMINAL CNT ABS
SEX: MALE
19119 19122 19125
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 NeutrophiIs Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
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 14.3
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
418-028:PAGE K-53
Study Report for Hematology
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 1-M
TERMINAL CNT ABS
SEX: MALE
19131 19132 19134
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 BasophiIs Abnormal Lymphocytes Other UBC
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
17.7
0 85 12.7 10 1.5
0 0.0 3 0.4 0 0.0 0 0.0 2 0.3 0 0.0
14.9
0 73 11.0 23 3.5
0 0.0 3 0.5 1 0.2 0 0.0 0 0.0 0 0.0
15.0
LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-54
Study Report for Hematology WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 1-M
TERMINAL CNT ABS
SEX: MALE
19135 19143
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 UBC
0 85 12.2 11 1.6
0 0.0 2 0.3 2 0.3 0 0.0 0 0.0 0 0.0
14.3
0 o 0 o 0 0 0 0 0
19151
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
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-55
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
GROUP: 1-M
SEX: MALE
Animal ID
TERMINAL CNT ABS
19157
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other MBC
0 0 -0-- 0-- 0-- 0-- 0-- 0-- 0--
--
19161 19167
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs 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--
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-56
Study Report for Hematology WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 2-M
19102 19106 19108
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 BasophiIs Abnormal Lymphocytes Other 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 12.1 17 2.9
0 0.0 8 1.4 3 0.5 0 0.0 1 0.2 0 0.0
17.0
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
12.7
SEX: MALE
LABCAT HE4.43
27-JUN-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-57
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
GROUP: 2-M
SEX: MALE
Animal ID
TERMINAL CNT ABS
19110
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
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
19113 19120
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
0 71 11.1 23 3.6
0 0.0 5 0.8 1 0.2 0 0.0 0 0.0 0 0.0
15.7
0 73 13.4 17 3.1
0 0.0 8 1.5 2 0.4 0 0.0 0 0.0 0 0.0
18.4
LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-58
Study Report for Hematology WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 2-M
TERMINAL CNT ABS
SEX: MALE
19129 19136 19138
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 WBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
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 HE4.43
27-JUN-2002
418-028:PAGE K-59
Study Report for Hematology WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 2-M
TERMINAL CNT ABS
SEX: MALE
19139 19147 19153
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 BasophiIs Abnormal Lymphocytes Other WBC
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 Unavailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 2-M
19164 19165 19171
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs Bands Monocytes Eosinophils BasophiIs 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
418-028:PAGE K-60
SEX: MALE
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-61
Study Report for Hematology WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 3-M
19101 19105 19107
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
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
11.0
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-JUN-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-62
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 3-M
19112 19114 19121
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 EosinophiIs Basophils Abnormal Lymphocytes Other UBC
TERMINAL CNT ABS
0 83 11.0 10 1.3
0 0.0 4 0.5 2 0.3 0 0.0 1 0.1 0 0.0
13.3
0 70 7.8 24 2.7
0 0.0 5 0.6 1 0.1 0 0.0 0 0.0 0 0.0
11.2
0 71 14.8 19 4.0
0 0.0 7 1.5 2 0.4 0 0.0 1 0.2 0 0.0
20.9
SEX: MALE
LABCAT HE4.43
27-JUN-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-63
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 3-M
19123 19130 19137
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
BasophiIs
Abnormal Lymphocytes
Other
WBC
TERMINAL CNT ABS
0 74 10.4 24 3.4
0 0.0 1 0.1 0 0.0 0 0.0 1 0.1 0 0.0
14.1
0 84 11.7 12 1.7
0 0.0 3 0.4 1 0.1 0 0.0 0 0.0 0 0.0
13.9
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 HE4.43
27-JUN-2002
418-028:PAGE K-64
Study Report for Hematology
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 3-M
TERMINAL CNT ABS
SEX: MALE
19146 19155
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
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
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
~
19159
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-65
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
GROUP: 3-M
SEX: MALE
Animal ID
TERMINAL CNT ABS
19172
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
0 0-- 0-- 0-- 0-- 0 -0-- 0-- 0--
--'
19173
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
0 0-- 0-- 0-- 0-- 0-- 0 -0-- 0--
--
19174
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
Study Report for Hematology
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
GROUP: 4-M
Animal ID
TERMINAL CNT ABS
19100 19103
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
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
12.6
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
21.0
19104
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
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
418-028:PAGE K-66
SEX: MALE
LABCAT HE4.43
2 7 - JUN-2002
418-028:PAGE K-67
Study Report for Hematology WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 4-M
TERMINAL CNT ABS
SEX: MALE
19118 19133 19141
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 BasophiIs Abnormal Lymphocytes Other WBC
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
22.0
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
LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
418-028:PAGE K-68
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
GROUP: 4-M
SEX: MALE
Animal ID
TERMINAL CNT ABS
19142
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
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
19144 19148
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
0 81 15.9 14 2.7
0 0.0 3 0.6 2 0.4 0 0.0 0 0.0 0 0.0
19.6
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
15.6
LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-69
Study Report for Hematology WHITE DIFFERENTIAL DATA
----
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 4-M
TERMINAL CNT ABS
SEX: MALE
19150
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
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
19156
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
~
19160
Nucleated Red Cells
Lymphocytes
Segmented NeutrophiIs
Bands
Monocytes
'
EosinophiIs
BasophiIs
Abnormal Lymphocytes
Other
WBC
0 0-- 0-- 0-- 0 --' 0-- 0-- 0-- 0--
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-70
Study Report for Hematology WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 4-M
TERMINAL CNT ABS
SEX: MALE
19162 19163
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs 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~
--
19166
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-71
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
GROUP: 5-M
SEX: MALE
Animal ID
TERMINAL CNT ABS
19111
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
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 19124
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segment ed Neut rophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other 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
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-2002
418-028:PAGE K-72
Study Report for Hematology WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 5-M
19126 19127 19128
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs 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 NeutrophiIs Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
TERMINAL CNT ABS
0 81 10.1
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
SEX: MALE
LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
WHITE DIFFERENTIAL DATA
418-028:PAGE K-73
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 5-M
TERMINAL CNT ABS
SEX: MALE
19140 19145
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
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
19149
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
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
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
Animal ID
GROUP: 5-M
TERMINAL CNT ABS
SEX: MALE
19152
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
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 Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
0 o 0 o 0 0 0 0 0
19158
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
0 0 0 0 0 0 0 0 0
(-- ) - 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: 5-M
Animal ID
TERMINAL CNT ABS
19168 19169 19170
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
UBC
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0~ 0-- 0-- 0--
418-028:PAGE K-75
SEX: MALE
'
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
WHITE D IFFER E N T IA L DATA
418-028:PAGE K-76
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 1-F
TERMINAL CNT ABS
SEX: FEMALE
19010
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
0 0-- 0-- 0~ 0-- 0-- 0-- 0-- 0--
--
19012 19019
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
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
LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-77
Study Report for Hematology
WHITE D IFFERENTIA L 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 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 Eosinophils Basophils 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
GROUP: 1-F
SEX: FEMALE
Animal ID
TERMINAL CNT ABS
19042
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
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
19044
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs Basophils Abnormal Lymphocytes Other UBC
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
19050
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
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
LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-79
Study Report for Hematology
WHITE DIFFERENTIA L DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 1-F
TERMINAL CNT ABS
SEX: FEMALE
19053
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
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
19065
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
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
19068
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
0 0 -0-- 0-- 0-- 0-- 0-- 0-- 0--
(-- > - Data Unavai Lable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
WHITE DIFFERENTIAL DATA
GROUP- 1-F 1r
TERMINAL CNT ABS
19072
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
0 o 0 g o o o o g
19074
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
o o 0 o o o o 0 o
19075
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
0 o 0 o o o o 0 o
418-028:PAGE K-80
_ SEX: FEMALE
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
WHITE DIFFER E N T IA L DATA
418-028:PAGE K-81
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
GROUP: 2-F
SEX: FEMALE
Animal ID
TERMINAL CNT ABS
19004 19009
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
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
19016
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
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
LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-82
Study Report for Hematology
WHITE DIFFERENTIA L DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal 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 BasophiIs Abnormal Lymphocytes Other WBC
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-2002
418-028:PAGE K-83
Study Report for Hematology
WHITE DIFFER E N T IA L DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 2-F
19037 19043 19047
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 UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs 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
418-028:PAGE K-84
Study Report for Hematology
WHITE D IFFERENTIA L DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
GROUP: 2-F
SEX: FEMALE
Animal ID
TERMINAL CNT ABS
19048
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs 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
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
0 0-- 0-- 0 -0-- 0-- 0-- 0-- 0--
--
19055
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
0 0 -0-- 0 -0-- 0-- 0-- 0-- 0--
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
WHITE D IFFERENTIA L DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
GROUP: 2-F
Animal ID
TERMINAL CNT ABS
19061 19067
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
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
19071
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
0 0-- 0-- 0-- 0-- 0-- 0 -- 0-- 0--
418-028:PAGE K-85
SEX: FEMALE
'
C-- ) - 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
Animal ID
TERMINAL CNT ABS
19003
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs 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 EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
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 UBC
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
Animal ID
TERMINAL CNT ABS
19013
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
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
19014
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
19015
Nucleated Red Cells
Lymphocytes
Segmented Neutrophils
Bands
Monocytes
'
EosinophiIs
BasophiIs
Abnormal Lymphocytes
Other
WBC
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 WHITE DIFFERENTIAL DATA
418-028:PAGE K-88
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 3-F
TERMINAL CNT ABS
SEX: FEMALE
19017 19024 19029
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
BasophiIs
Abnormal Lymphocytes
Other
UBC
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
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
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-2002
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
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs Bands Monocytes EosinophiIs 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
19038 19056
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
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-2002
Study Report for Hematology
418-028:PAGE K-90
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 3-F
TERMINAL CNT ABS
SEX: FEMALE
19057 19060
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
0 0-- 0-- 0-- 0-- 0-- 0 -0-- 0 --
--
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
.
19064
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
0 0-- 0-- 0 -0 -0-- 0-- 0-- 0--
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
418-028:PAGE K-91
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 4-F
TERMINAL CNT ABS
SEX: FEMALE
19002
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
19005
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs Basophils Abnormal Lymphocytes Other WBC
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
19035
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
0 74 7.1 24 2.3
0 0.0 1 0.1 0 0.0 0 0.0 1 0.1 0 0.0
9.6
LABCAT HE4.43
27-JUN-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-92
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 4-F
TERMINAL CNT ABS
SEX: FEMALE
19039 19040 19045
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 BasophiIs Abnormal 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
C-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
418-028:PAGE K-93
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
GROUP: 4-F
SEX: FEMALE
Animal ID
TERMINAL CNT ABS
19046
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
0 0 0 0 0 0 0 0 0
19051
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
0 0 0 0 0 0 0 0 0
19054
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
0 82 12.2 13 1.9
0 0.0 3 0.4 0 0.0
0 0.0 2 0.3
0 0.0
14.9
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
418-028:PAGE K-94
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 4-F
TERMINAL CNT ABS
SEX: FEMALE
19058 19062 19063
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
BasophiIs
Abnormal Lymphocytes
Other
WBC
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
LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-95
Study Report for Hematology
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 4-F
TERMINAL CNT ABS
SEX: FEMALE
19066
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
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
19069
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
0 0 0 0 0 0 0 0 0
19073
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
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-96
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
GROUP: 5-F
SEX: FEMALE
Animal ID
TERMINAL CNT ABS
19001 19006 19011
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other MBC
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
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
LABCAT HE4.43
27-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 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 EosinophiIs 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 HE4.43
27-JUN-2002
Study Report for Hematology
418-028 :PAGE K-98
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 5-F
TERMINAL CNT ABS
SEX: FEMALE
19027
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
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
19028 19030
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
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
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
GROUP: 5-F
SEX: FEMALE
Animal ID
TERMINAL CNT ABS
19031
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
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
19032
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
0 0-- 0-- 0-- 0-- 0-- 0-- 0~ 0--
--
19033
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs 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-100
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
19049 19059
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
0 0 .0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0
" --
-- -- -- -- -- --
--
-- -- -- -- -- -- -- --
--
19070
Nucleated Red Cells
Lymphocytes
Segmented Neutrophils
Bands
Monocytes
'
EosinophiIs
BasophiIs
Abnormal Lymphocytes
Other
WBC
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal 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 0.36
10
418-028:PAGE K-101 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: MALE
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 0.22
10
164 165 119 134 140 169 128 141 140 153
-- -- -- --
--
145 16.8
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
263
19 0.4
164
16 0.3 330
14 0.3
105
15 0.3 177
15 0.4 260
18 0.3 15 0.3 15 0.3 15 0.3 ~--
385 250 722 221
--
--~
--
----
--
~-- --
----
--
16 0.3 288
1.5
0.04
172.6
10 10 10
(-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 2-M 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171
TP g/dL
6.1 6.2 5.8 6.1 5.6 6.5 5.7 6.2 6.3 6.1
-- -- -- ---
MEAN SD N
6.1 0.28
10
418-028:PAGE K-102 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: MALE
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 0.19
10
172 166 152 104 157 115 149 123 108 165
-- -- -- -- --
141 26.0
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
169
17 0.3
151
15 0.3 235
16 0.3
307
16 0.3 133 17 0.4 350
17 0.3 292
17 0.3
134
15 0.4 478
16 0.4 213
----
--
----
--
---- --
---- --
-- -- . --
16 0.3 246
0.8
0.05
111.5
10 10 10
(-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS A18-028 STUDY NO: 060-069
Animal ID
TP g/dL
GROUP: 3-M 19101 19105 19107 19112 1911A 19121 19123 19130 19137 191A6 19155 19159 19172 19173 1917A
6.2 H 6.1 5.8 6.3 6.3 6.6 6.2 5.7 6.7 6.6
-- -- -- ~. --
MEAN SD N
6.3 0.33
10
418-028:PAGE K -103 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: MALE
ALB g/dL
GLU mg/dL
CHOL mg/dL
T-BIL mg/dL
BUN mg/dL
CREAT mg/dL
CK U/L
A.O H A.3 A.1 A.3 A.3 A.A A.A A.1 A.A A.A
-- -- -- --
--
A.3 0.15
10
30A H 25A 198 137 1A2 121 156 1A9 158 20A
-- ~ -- -- --
182 58.2
10
27 H 52 50 A6 65 A5 A6 3A 59 35 -- -- -- --
--
A6 11.6
10
0.3 H 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1
-- -- -- --
--
0.1 0.06
10
18 H 16 15 12 16 18 17 17 17 16 --- -- --
--
16 1.8
10
O.A H 0.3 0.3 0.3 0.3 0.4 0.2 0.3 0.3 0.3
-- -- -- -- --
0.3 0.06
10
129 H 118 132 286 250 289 329 A80 200 175
--
__
---
--
239 112.9
10
(-- ) - Data Unavailable LABCAT CCA.A3
H - Hemolyzed
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
TP g/dL
GROUP: 4-M 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166
MEAN SD N
6.0 5.7 5.9 6.0 6.3 6.2 6.6 6.2 6.5 6.4
-- -- -- -- --
6.2 0.28
10
418-028:PAGE K-104 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: MALE
ALB g/dL
GLU mg/dL
CHOL mg/dL
T-BIL mg/dL
BUN mg/dL
CREAT mg/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 0.17
10
175 202 167 131 179 147 132 130 175 181
-- -- -- -- --
162 25.2
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 20 0.3 16 0.3 20 0.4 17 0.3 16 0.3 17 0.3 18 0.3 16 0.3 18 0.3 -- -- -- ----- -- -----
111 145 196 187 146 182 270 242 267 218
-- -- -- -- --
17 0.3
196
1.6 0.03
53.5
10 10 10
(--) - Data Unavailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
TP g/dL
GROUP: 5-M 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170
MEAN SD 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 0.28
10
418-028:PAGE K -105
Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: MALE
ALB g/dL
4.6 H 4.3 H 4.8 4.6 4.6 4.8 4.3 4.5 4.5 4.2
-- -- -- -- --
4.5 0.20
10
GLU mg/dL
173 H 177 H 226 165 156 181 110 134 195 132
-- -- -- -- --
165 33.7
10
CH0L mg/dL
38 H 37 H 25 29 47 35 24 27 38 31 --- -- --
--
33 7.2
10
T-BIL mg/dL
0.2 H 0.3 H 0.1 0.1 0.2 0.2 0.2 0.2 0.2 0.2
-- -- ~ -- --
0.2 0.06
10
BUN mg/dL
26 H 23 H 20 20 22 21 18 19 19 19 -- --~ --
21 2.4
10
CREAT mg/dL
CK U/L
0.4 H 0.3 H 0.4 0.3 0.3 0.4 0.3 0.3 0.3 0.3
-- -- ~ -- --
0.3 0.05
10
211 H 269 H
94 156 379 472 304 239 175 128 --
-- -- -- --
243 117.4
10
(-- ) - Data Unavailable LABCAT CC4.43
H - Hemolyzed
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal 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
GLU mg/dL
CHOL mg/dL
T-BIL mg/dL
BUN mg/dL
CREAT mg/dL
CK U/L
3.7 4.3 4.9 4.3 4.3 4.3 4.4 3.9 3.7 3.5
-- -- ---
4.1 0.42
10
149 139 157 156 165 155 144 184 108 163
-- -- -- --
152 19.8
10
63 92 136 85 62 77 93 78 43 40 --- --
--
77 27.8
10
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
32 0.4 166
29 0.3 212
33 0.4 210
26 0.4 222 28 0.3 201
25 0.4 178
27 0.4 332
34 0.3 198
28 0.3 123
19 0.3 175
-- --
--
-- -- . --
-- --
~
------
28 0.4 202 4.4 0.05 54.1
10 10 10
(-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal 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 SD N
5.5 0.50
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 mg/dL
T-BIL mg/dL
BUN mg/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 0.34
10
178 166 173 152 170 203 153 149 135 142
-- -- -- --
--
162 20.0
10
56 62 83 77 85 84 54 92 57 73 -- -- -- -- "
72 14.0
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
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
TP g/dL
GROUP: 3-F 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
5.6 5.3 5.7 5.8
-- 5.6 5.8 6.7 5.8 6.4
-- 6.1
-- -- --
MEAN SD N
5.9 0.41
10
418-028:PAGE K-108 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: FEMALE
ALB g/dL
GLU mg/dL
CHOL mg/dL
T-BIL mg/dL
BUN mg/dL
CREAT mg/dL
CK U/L
3.9 3.8 4.0 4.1
-- 3.7 4.1 4.5 4.0 4.3
-- 4.2
-- -- --
4.1 0.24
10
179 121 171 146
-- 155 164 140 142 151
-179
-- -- --
155 18.7
10
54 45 56 59 -- 61 87 96 79 105 -63 -- -- --
71 20.0
10
0.1 0.1 0.1 0.2
-- 0.2 0.2 0.2 0.2 0.1
-- 0.1
~ -- --
0.2 0.05
10
36 0.3
199
41 0.3
159
20 0.3
206
24 0.4 ----
160
--
28 0.3
212
22 0.4
190
33 0.4
215
26 0.3
212
23 0.4 ----
169 --
28 0.3 ----
197 --
----
--
-- -- .--
28 0.3 6.7 0.05
10 10
192 21.7
10
(-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
TP g/dL
GROUP: 4-F 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
6.1 5.7 5.5 5.8 5.6
-- --
6.3 5.6 6.0 5.2 5.9
-- --
MEAN SD N
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 mg/dL
CHOL mg/dL
T-BIL mg/dL
BUN mg/dL
CREAT mg/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 0.29
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 14.2
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 0.4 259
27 0.4
193
26 0.4
160
20 0.3
233
25 0.5 398
---- ----
-- --
25 0.4 124
20 0.3 267
34 0.3
176
23 0.4 172
22 0.2 ----
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 418-028 STUDY NO: 060-069
Animal ID
TP g/dL
GROUP: 5-F 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
5.5 5.7 5.8 5.6 5.8 5.8 5.5 5.9 6.3 6.3
-- -- -- -- --
MEAN SD N
5.8 0.29
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 mg/dL
CHOL mg/dL
T-BIL mg/dL
BUN mg/dL
CREAT mg/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 35.5
10
55 58 48 33 60 49 71 70 58 108 --- -- -- --
61 19.8
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 15.4
10
0.3 0.3 0.4 0.2 0.3 0.4 0.3 0.3 0.3 0.3
-- -- --
__
--
0.3 0.06
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 418-028 STUDY NO: 060-069
Animal ID
ALT U/L
GROUP: 1-N 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167
36 38 40 33 51 49 39 42 49 43 -- -- -- --
--
MEAN SD N
42 6.0
10
418-028:PAGE K'-l 11 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
mg/dL
mg/dL
mg/dL
mmol/L
mmol/L
78 77 93 83 86 113 116 80 146 85 -- -- -- -- --
96 22.4
10
91 77 102 112 103 115 107 98 126 119 -- -- -- -- --
105 14.3
10
10.6 11.8 10.3 10.8 11.3 10.6 11.1 11.1 10.4 11.4
-- -- -- -- --
10.9 0.48
10
12.0 11.6
9.7 7.9 9.4 8.7 7.9 9.8 8.5 9.2
~ -- -- -- --
9.5 1.40
10
23 48 59 43 28 65 93 45 36 76 -- -- -- -- --
52 21.8
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 Unavai table LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animat ID
ALT U/L
GROUP: 2-M 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171
MEAN SD N
37 38 37 57 40 46 48 34 261 33 -- -- -- ~ --
63 69.9
10
418-028:PAGE K-112 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
mg/dL
mg/dL
mg/dL
mmol/L
mmol/L
84 77 81 116 91 111 104 80 382 87 -- -- -- -- --
121 92.6
10
101 70 99
141 130
91 99 88 199 95 -- --- -- --
111 36.9
10
10.5 11.6 10.3 10.3 11.2 10.7 10.6 10.7 10.3 11.1
-- -- --
--
--
10.7 0.44
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 17.2
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 Unavai table LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
ALT U/L
GROUP: 3-M 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174
60 H 35 35 45 141 42 101 55 44 42 -- -- -- -- --
MEAN SD N
60 34.4
10
418-028:PAGE K-113 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 mg/dL
mg/dL
mg/dL
mmol/L
mmol/L
124 H 70 82 99
197 92
171 140 102
94 -- ~ -- --
--
117 40.9
10
101 H 107
97 92 108 88 80 124 108 96 -- -- -- --
100 12.4
10
11.5 H 11.5 11.5 10.2 10.8 10.7 11.2 10.7 11.3 11.3
-- --- -- --
11.1 0.44
10
10.4 H 9.5
15.6 8.8 9.9 9.0 9.4 9.4 8.3 8.8 --- -- -- --
9.9 2.09
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 1.27
10
(-- ) - Data Unavailable LABCAT CC4.43
H - Hemolyzed
27-JUN-2002
418-028:PAGE K-114 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
SEX: MALE
Animal ID
ALT U/L
GROUP: 4-M 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166
51 37 50 439 54 46 45 48 138 46 -- -- -- -- --
MEAN SD N
95 124.1
10
AST U/L
91 83 107 887 106 91 108 119 277 107 -- -- -- -- --
198 248.7
10
iCMn
ALP U/L
122 76 98
154
93 98 124 112 123 -- ----
--
115 25.1
10
CA mg/dL
10.9 11.0 11.5 10.8 11.7 10.7 10.7 11.2 11.2 11.3
-- -- ~ -- "
11.1 0.34
10
PHOS mg/dL
8.3 13.3
8.6 9.8 9.3 10.7 8.8 9.8 9.2 9.3
-- --- --
--
9.7 1.43
10
TRIG mg/dL
14 19 35 23 32 113 35 30 28 32 -- -- -- -- --
36 27.9
10
NA mmol/L
146 147 148 148 147 145 148 147 147 146
--
--- -- --
147 1.0
10
K mmol/L
5.5 6.6 5.6 6.9 5.3 6.4 5.3 5.5 6.1 6.5
--
-- -- -- .--
6.0 0.60
10
(-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
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
418-028:PAGE K -l 15 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
mg/dL
mg/dL
mg/dL
mmol/L
mmol/L
86 H 114 H
76 88 104 112 95 125 87 87 -- --- ---
97 15.6
10
115 H 153 H 204 159 182
83 169 137 140
99 -- -- -- -- --
144 37.5
10
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 - Hemolyzed
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
ALT U/L
GROUP: 1-F 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
144 136 177 115 142 104 153 156
87 80 -- -- -- --
MEAN SD N
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 PROS TRIG
NA
K
U/L
U/L
mg/dL
mg/dL
mg/dL
mmol/L
mmol/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
C-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal 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:PAGE K^l 17 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
mg/dL
mg/dL
mmol/L
mmol/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 Unavai table 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
182 90
107 137
-178 166 121 189 124
-- 130
--- --
MEAN SD N
142 34.2
10
418-028:PAGE K-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
mg/dL
mg/dL
mmol/L
mmol/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 CCA.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal 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-119 Study Report for Clinical Chemistry
IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: FEMALE
AST ALP
CA PHOS TRIG
NA
K
U/L
U/L
mg/dL
mg/dL
mg/dL
mmol/L
mmol/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
SEX: FEMALE
Animal ID
GROUP: 5-F 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
MEAN SD N
ALT AST U/L U/L
116 160 132 151 143 113 149 179 156 148
-- -- -- ---.
133 149 131 263 167 141 138 127 177 138
-- --- .-- --
145 20.0
10
156 40.7
10
ALP U/L
135 71
131 138 101 142
58 122 171 211
-- -- --- --
128 44.7
10
CA mg/dL
10.1 10.1 10.3
9.8 10.3
9.6 9.6 12.0 10.9 11.6
-- --- -- --
10.4 0.82
10
PHOS mg/dL
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
TRIG mg/dL
37 49 53
7 38 30 44 45 77 57 -- -- -- -- --
44 18.3
10
NA mmol/L
141 138 142 143 145 142 141 147 139 143
--
-- -- ---
142 2.6
10
K mmol/L
6.8 6.8 5.2 6.9 6.4 5.4 7.6 5.1 6.3 5.1
-- -- -- -- .--
6.2 0.90
10
(-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
418-028:PAGE K-121 Study Report for Clinical Chemistry
IN D IV ID U A L ANIMAL REPORT BY GROUP PERIO D : TERMINAL
SEX: MALE
Animal ID
CL mmol/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 9/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 Unavai table LABCAT CC4.43
27-JUN-2002
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: MALE
Animal ID
CL mmol/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
Animal ID
CL mmol/L
GROUP: 3-M 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174
MEAN SD N
101 H 96
105 100
99 99 100 100 98 99 --- -- ---
100 2.3
10
GLOB 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 - Hemolyzed
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: MALE
Animal ID
CL mmol/L
GROUP: 4-M 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 -- -- -- -- --
MEAN 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
(-- ) - Data Unavai Lable LABCAT CC4.43
27-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: MALE
Animal ID
CL mmol/L
GROUP: 5-M 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 2.4 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 - Hemolyzed
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
418-028:PAGE K-126 Study Report for Clinical Chemistry
IN D IV ID U A L ANIMAL REPORT BY GROUP PERIO D : TERMINAL
SEX: FEMALE
Animal ID
CL mmol/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 CCA.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: FEMALE
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/G 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
C-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
418-028:PAGE K 429 Study Report for Clinical Chemistry
IN D IV ID U A L ANIMAL REPORT BY GROUP PE R IO D : TERM INAL
SEX: FEMALE
Animal ID
CL mmol/L
GROUP: 4-F 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
_
90 96 101 91 97 ~ ~ 94 97 98 97 93 -- --
MEAN SD N
95 3.4
10
GLOB g/dL
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
A/G none
_
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
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
418-028:PAGE K-130 Study Report for Clinical Chemistry
IN D IV ID U A L ANIMAL REPORT BY GROUP P E R IO D : TERMINAL
SEX: FEMALE
Animal ID
CL mmol/L
GROUP: 5-F 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
91 . 93 92 91 100 94 96 95 95 89 ~ -- --- --
MEAN SD N
94 3.1
10
GLOB g/dL
1.5 1.7 1.5 2.1 1.7 2.1 1.7 1.9 1.8 1.9
--
~ -- ~ --
1.8 0.21
10
A/G none
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 PE R IO D : TERM INAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE F0LL0WED BY DUNNETT1S PROCEDURE
SEX: MALE
TEST(s): UNITS:
Group: 1-M MEAN
SD N
Group: 2-M MEAN
SD N
Group: 3-M MEAN
SD N
TP g/dL
6.3 0.36
10
6.1 0.28
10
6.3 0.33
10
ALB 9/dL
GLU mg/dL
CHOL mg/dL
T-BIL mg/dL
BUN mg/dL
CREAT mg/dL
CK U/L
4.3 0.22
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
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
4.3 0.15
10
182 58.2
10
46 11.6
10
0.1 0.06
10
16 0.3 239
1.8
0.06
112.9
10 10 10
ALT U/L
42 6.0
10
63 69.9
10
60 34.4
10
Group: 4-M MEAN
SD N
Group: 5-M MEAN
SD N
6.2 0.28
10
6.3 0.28
10
4.2 0.17
10
162 25.2
10
4.5** 0.20
10
165 33.7
10
43* 13.1
10
0.1 0.05
10
33** 7.2
10
0.2 0.06
10
17 0.3 196
95
1.6
0.03
53.5
124.1
10 10 10 10
21** 2.4
10
0.3 0.05
10
243 117.4
10
45 7.0
10
-Significant Difference from Control P < .05 LABCAT CC4.43
**-Significant Difference from Control P < .01 27-JUN-2002
418-028:PAGE K-132 Study Report for Clinical Chemistry
SUMMARY REPO R T P E R IO D : TERM INAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT1S PROCEDURE
SEX: HALE
TEST(s): UNITS:
AST ALP
CA PHOS TRIG
NA
K CL GLOB
U/L
U/L
mg/dL
mg/dL
mg/dL
mmol/L
mmol/L
mmol/L
g/dL
Group: 1-M HEAN
SD N
Group: 2-M HEAN
SD N
96 22.4
10
121 92.6
10
105 14.3
10
111 36.9
10
10.9 0.48
10
10.7 0.44
10
9.5 1.40
10
9.4 1.11
10
52 21.8
10
47 17.2
10
146 6.6 1.4 2.10
10 10
146 6.1 1.3 0.89
10 10
98 2.0 2.7 0.19
10 10
99 2.0 1.5 0.16
10 10
Group: 3-H HEAN
SD N
117 40.9
10
100 12.4
10
11.1 0.44
10
9.9 2.09
10
36 13.8
10
147 6.5 1.6 1.27
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 from Control P < .01 LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
418-028:PAGE K -133 Study Report for Clinical Chemistry
SUMMARY REPORT P E R IO D ; TERMINAL
SEX: MALE
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT1S PROCEDURE
TEST(s): UNITS:
A/G none
Group: 1-M MEAN
SD N
2.1 0.18
10
Group: 2-M MEAN
SD N
2.1 0.16
10
Group: 3-M MEAN
SD N
2.2 0.26
10
Group: 4-M MEAN
SD N
2.2 0.15
10
Group: 5-M MEAN
SD N
2.5** 0.17
10
**-Significant Difference from Control P < .01 LABCAT CC4.43
27-JUN-2002
418-028:PAGE K-134 Study Report for Clinical Chemistry
SUMMARY REPORT P E R IO D : TERMINAL
STliDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE F0LL0WED BY DUNNETT1S PROCEDURE
SEX: MALE
Total Protein
Group
N Total
Mean
Std. DUNNETT'S
Dev.
't '
DUNNETT'S RANGES
LO -95%- HI
L0 -99%- HI
Degree Source Fdm
Sum of Squares
Mean Square
1-M 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
O.OS
3-M
10 62.5 6.3 0.33 0.22
5.9 6.6
5.9 6.7 -
4-M
10 61.8 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. % =
1. 16 4.948
Albumin
*F' table values Dunnett's 'T 1 table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2. 58 2. 51
1-M 10 42.5 4.3 0.22
2-M
10 41.1 4.1 0.19 1.66
4.0 4.5
3-M
10 42.7 4.3 0.15 0.24
4.0 4.5
21 t
O
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 4.399
''F table values ' 'Dunnett's T table v a lues
F.01 = P.01 =
Glucose
1-M 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 21.988
'F ' table values Dunnett's 'T' table values
F.01 =
P.01 =
TREATMENTS 4
0.90
4.0 4.5
ERROR 45
1.59
4.0 4.5 --- ------- --
--
4.0 4.5
TOTAL 49
2.49
4.0 4.5**
3.78 3.12
F.05 = P.05 =
2.58 2.51
TREATMENTS 4
10942
96 194
ERROR 45
55071
96 194 -----------
96 194
TOTAL 49
66013
96 194
3.78 3.12
F.05 =
P.05 =
2.58 2.51
0.22 0.04
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 P E R IO D ; TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: MALE
Cholesterol
Group
N Total
Mean
1-M
10 569
57
2-M
10 413
41
3-M
10 459
46
4-M
10 427
43
5-M
10 331
33
Std. DUNNETT'S
Dev.
't '
8.3 11.1 11.6 13.1
7.2
3.32 2.34 3.03 5.07
DUNNETT'S RANGES
LO -95%- HI
LO -99%- HI
Degree Source Fdm
Sum of Squares
TREATMENTS 4
2978.08
45
69*
42
72**
ERROR 45
4954.90
45 69
42 72 -------------------
45 69* 42 72
TOTAL 49
7932.98
45 69* 42 72**
Mean Square
744.52 110.11
F Ratio = Coeff. Var. % =
6.76 23.859
F ' table values 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-M
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. % =
2.25 39.527
'F' table values Dunnett`s 'T' table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
Blood Urea Nitrogen
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 18 --------------
4-M
10 174 17 1.6 2.11
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 9.821
'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 CC4.43
Source-Source of Variation Treatments-between groups
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY N0: 060-069
418-028:PAGE K-136 Study Report for Clinical Chemistry
SUMMARY REPORT P E R IO D : TERMINAL
ANALYSIS 0F VARIANCE F0LL0UED BY DUNNETT1S PROCEDURE
SEX: MALE
Group
1-M 2-M 3-M 4-M 5-M
N Total
Mean
10 3.2 0.3 10 3.3 0.3 10 3.1 0.3 10 3.1 0.3 10 3.3 0.3
Std. DUNNETT'S
Dev.
't '
0.04 0.05 0.06 0.03 0.05
0.48 0.48 0.48 0.48
DUNNETT'S RANGES
LO -95%- HI
L0 -99%- HI
Degree Source Fdm
Sum of Squares
0.3 0.4 0.3 0.4 0.3 0.4 0.3 0.4
TREATMENTS 4
0.0040
0.3 0.4
ERROR 45
0.0960
0.3 0.4 -------------------
0.3 0.4
TOTAL 49
0.1000
0.3 0.4
Mean Square
0.0010 0.0021
F Ratio = Coeff. Var. % =
0.47 14.434
'F' table values Dunnett's *T ` table values
Creatine Kinase
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
1-M
10 2877
288 172.6
TREATMENTS 4
41956
10489
2-M
10 2462
246 111.5 0.78
153 422
121 455
ERROR 45
644538
14323
3-M
10 2388
239 112.9 0.91
153 422
121 455 -------------------
4-M
10 1964 196 53.5 1.71
153 422
121 455
TOTAL 49
686494
5-M
10 2427
243 117.4 0.84
153 422
121 455
F Ratio = Coeff. Var. % =
0.73 49.381
F' table values Dunnett's 'T' table values
Alanine Aminotransferase
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
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 = Coeff. Var. % =
1.05 107.598
'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 CC4.43
Treatments-between groups
27-JUN-2002
418-028:PAGE K -137 Study Report for Clinical Chemistry
SUMMARY REPORT P E R IO D : TERM INAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE F0LL0WED BY DUNNETT'S PROCEDURE
SEX: HALE
Aspartate Aminotransferase
Std. DUNNETT'S
Group
N Total
Mean
Dev.
*t '
DUNNETT1S RANGES
LO -95%- HI
LO -99%- HI
Degree Source Fdm
Sum of Squares
Mean Square
1-M
10 957
96 22.4
TREATMENTS 4
69637
17409
2-M
10 1213 121 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-M
10 974
97 15.6 0.03
-40 231
-73 264
F Ratio = Coeff. Var. % =
1.20 95.916
'F ' table values Dunnett's 'T 1 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
2-M
10 1113 111 36.9 0.51
74 136
67 143
ERROR 45
33780
3-M
10 1001 100 12.4 0.40
74 136
67 <143 -------------------
4-M
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. % =
3.94 23.795
`F ' table values Dunnett's 'T' table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
Calcium
1-M
10 109.4
10.9
0.48
TREATMENTS 4
3.45
2-M
10 107.3
10.7
0.44 1.12
10.5 11.4
10.4 11.5
ERROR 45
7.97
3-M
10 110.7
11.1
0.44 0.69
10.5 11.4
10.4 11.5
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. % =
4.87 3.800
'F ' table values Dunnett's *T ' table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
2956 751
0.86 0.18
-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-138 Study Report for Clinical Chemistry
SUMMARY REPORT P E R IO D ; TERM INAL
STUDY ID: ARGUS 418-028 STUOY NO: 060-069
ANALYSIS 0F VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: MALE
Phosphorus
Group
N Total
Mean
Std. DUNNETT'S
Dev.
't '
DUNNETT1S RANGES
LO -95%- HI
LO -99%- HI
Degree Source Fdm
Sum of Squares
Mean Square
1-M 10 94.7 9.5 1.40
TREATMENTS 4
4.80
1.20
2-M
10 93.7
9.4
1.11
0.15
7.8 11.2
7.4 11.6
ERROR 45
102.32
2.27
3-M
10 99.1 9.9 2.09 0.65
7.8 11.2
7.4 11.6 -
4-M
10 97.1 9.7 1.43 0.36
7.8 11.2
7.4 11.6
TOTAL 49
107.12
5-M
10 102.3
10.2
1.33 1.13
7.8 11.2
7.4 11.6
F Ratio = Coeff. Var. % =
0.53
15.485
'F' table values Dunnett's 'T 1 table values
Triglycerides
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2. 58 2. 51
1-M
10 516
52 21.8
TREATMENTS 4
7188
1797
2-M
10 469
47 17.2 0.55
30 73
25 78
ERROR 45
16244
361
3-M
10 364
36 13.8 1.79
30 73
25 78 -------------------
4-M
10 361
36 27.9 1.82
30 73
25 78
TOTAL 49
23432
5-M
10 168 17 8.0 4.10
30 73* 25 78**
F Ratio = Coeff. Var. % =
4.98 50.584
*F* table values Dunnett's 'T ' table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
Sodium
1-M
10 1459
146
1.4
TREATMENTS 4
9.60
2.40
2-M
10 1457
146
1.3 0.29
144 148
144 148
ERROR 45
108.40
2.41
3-M
10 1465
147
1.6 0.86
144 148
144 148 -------------------
4-M
10 1469
147
1.0 1.44
144 148
144 148
TOTAL 49
118.00
5-M
10 1460
146
2.2 0.14
144 148
144 148
F Ratio = Coeff.. Var. % =
1.00 1.062
'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 CC4.43
Source-Source of Variation Treatments-between 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
Dev.
't '
DUNNETT'S RANGES
LO -95%- HI
LO -99%- HI
Degree Source Fdm
Sum of Squares
Mean 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-M
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. % =
0.73 21.633
'F* table values
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
2-M
10 988 99 1.5 0.62
96 101
3-M
10 997 100
2.3 1.54
96 101
4-M
10 1000
100
2.7 1.85
96 101
5-M
10 998 100
1.2 1.64
96 101
F Ratio = Coeff.. Var. % =
1.25 2.190
'F ' table values Dunnett's 'T ' table values
F.01 = P.01 =
Globulin
TREATMENTS 4
23.60
95 101
ERROR 45
212.90
95 101 -------------------
95 101
TOTAL 49
236.50
95 101
3.78 3.12
F.05 = P.05 =
2.58 2.51
5.90 4.73
1-M 10 20.3 2.0 0.19
TREATMENTS 4
0.27
0.07
2-M
10 19.5 2.0 0.16 0.99
1.8 2.2
1.8 2.3
ERROR 45
1.46
0.03
3-M
10 19.8 2.0 0.24 0.62
1.8 2.2
1.8 2.3 --------------------
4-M
10 19.5 2.0 0.16 0.99
1.8 2.2
1.8 2.3
TOTAL 49
1.72
5-M
10 18.1 1.8 0.13 2.73
1.8 2.2* 1.8 2.3
F Ratio = Coeff., Var. % =
2.06 9.253
'F* table values Dunnett's 1T* table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
-Significant Difference from Control P < .05 Error-within groups
LABCAT CC4.43
Source-Source of Variation Treatments-between groups
27-JUN-2002
418-028:PAGE K-140
Study Report for Clinical Chemistry
SUMMARY REPORT P E R IO D : TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS 0F VARIANCE F0LL0WED BY DUNNETT1S PROCEDURE
SEX: HALE
Albumin/Globulin Ratio
Std. DUNNETT'S
Group
N Total
Mean
Dev.
*t '
DUNNETT'S RANGES
L0 -95%- HI
L0 -99%- HI
Degree Source Fdm
Sum of Squares
Mean Square
1-M 10 21.2 2.1 0.18
TREATMENTS 4
1.02
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. % =
7.31 8.368
*F ' table values Dunnett's ''P 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 CC4.43
Source-Source of Variation Treatments-between groups
27-JUN-2002
418-028:PAGE K-141 Study Report for Clinical Chemistry
SUMMARY REPORT P E R IO D : TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT' S PROCEDURE
SEX: FEMALE
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 g/dL
GLU mg/dL
CHOL mg/dL
T-BIL mg/dL
BUN mg/dL
CREAT mg/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
252 101.6
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 P E R IO D : TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT' S PROCEDURE
SEX: FEMALE
TEST(s): UNITS:
AST ALP
CA PHOS TRIG
NA
K CL GLOB
U/L
U/L
mg/dL
mg/dL
mg/dL
mmol/L
mmol/L
mmol/L
g/dL
Group: 1-F MEAN
SD N
Group: 2-F MEAN
SD N
142 22.8
10
135 21.6
10
145 88.7
10
159 81.7
10
10.6 0.72
10
11.2 0.63
10
8.8 1.33
10
7.9 1.94
10
54 19.9
10
50 10.2
10
143 5.8 6.3 0.67
10 10
143 5.6 2.4 0.58
10 10
96 1.9 3.4 0.22
10 10
94 1.6** 2.7 0.26
10 10
Group: 3 - F MEAN
SD N
137 11.8
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
Group: 4-F MEAN
SD N
124 12.1
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
Group: 5-F MEAN
SD N
156 40.7
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 1.8 3.1 0.21
10 10
**-Significant Difference from Control P < .01 LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
418-028:PAGE K-143
Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
SEX: FEMALE
ANALYSIS OF VARIANCE FOLLOUED BY DUNNETT'S PROCEDURE
TEST(s): UNITS:
A/G none
Group: 1-F MEAN
SD N
Group: 2-F MEAN
SD N
2.2 0.28
10
2.6* 0.43
10
Group: 3-F MEAN
SD N
2.2 0.21
10
Group: 4-F MEAN
SD N
Group: 5-F MEAN
SD N
2.4 0.26
10
2.3 0.37
10
-Significant Difference from Control P < .05 LABCAT CC4.43
27-JUN-2002
418-028:PAGE K-144
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: FEMALE
Total Protein
Group
N Total
Mean
Std. DUNNETT'S
Dev.
't*
DUNNETT'S RANGES
LO -95%- HI
LO -99%- HI
Degree Source Fdm
Sum of Squares
Mean Square
1-F 10 60.7 6.1 0.52
TREATMENTS 4
1.70
0.43
2-F
10 55.0 5.5 0.50 3.04
5.6 6.5* 5.5 6.7
ERROR 45
7.91
0.18
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 0.32 1.60
5.6 6.5
5.5 6.7
TOTAL 49
9.62
5-F
10 58.2 5.8 0.29 1.33
5.6 6.5
5.5 6.7
F Ratio = Coeff. Var. % =
2.42 7.220
'F 1 table values Dunnett's *'r1 table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
Albumin
1-F 10 41.3 4.1 0.42
2-F
10 39.5 4.0 0.34 1.24
3.8 4.5
3-F
10 40.6 4.1 0.24 0.48
3.8 4.5
4-F
10 40.4 4.0 0.29 0.62
3.8 4.5
5-F
10 40.3
4.0
0.31
0.69
3.8 4.5
F Ratio = Coeff.. Var. % =
0.39 8.059
'F ' table values Dunnett's 'T* table values
F.01 = P.01 =
Glucose
TREATMENTS 4
3.7 4.6 7 7 /.A
ERROR 45 -
3.7 4.6 3.7 4.6
TOTAL 49
3.78 3.12
F.05 = P.05 =
2.58 2.51
0.17 4.78
4.94
0.04 0.11
1-F 10 1520 152 19.8
TREATMENTS 4
2750
687
2-F
10 1621 162 20.0 0.98
126 178
120 184
ERROR 45
24006
533
3-F
10 1548 155 18.7 0.27
126 178
120 184 -------------------
4-F
10 1461 146 16.2 0.57
126 178
120 184
TOTAL 49
26756
5-F
10 1404 140 35.5 1.12
126 178
120 184
F Ratio = Coeff.. Var. % =
1.29 15.288
'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 Error-within groups
LABCAT CC4.43
Source-Source of Variation Treatments-between groups
27-JUN-2002
418-028:PAGE K-145
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
Cholesterol
Group
N Total
Mean
Std. DUNNETT'S
Dev.
't '
DUNNETT'S RANGES
L0 -95%- HI
LO -99%- HI
Degree Source Fdm
1-F 10 2-F 10 3-F 10 4-F 10 5-F 10
F Ratio = Coeff. Var. % =
769 77 27.8 723 72 14.0 0.52 705 71 20.0 0.72 621 62 14.2 1.67 610 61 19.8 1.79
55 99 55 99 55 99 55 99
1.18 28.929
'F* table values Dunnett's 1T* table values
F.01 = P.01 =
TREATMENTS 4
49 105
ERROR 45
49 105 -
49 105
TOTAL 49
49 105
3.78 3.12
F.05 = P.05 =
2.58 2.51
Total Bilirubin
SEX: FEMALE
Sum of Squares
Mean Square
1862 17702
19564
--
465 393
1-F 10 1.6 0.2 0.07
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
4-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 Ratio = Coeff. Var. % =
2.33 33.974
'F ' table values Dunnett's 'T' table values
F.01 = P.01 =
Blood Urea Nitrogen
1-F 10 2-F 10 3-F 10 4-F 10 5-F 10
F Ratio = Coeff. Var. % =
281 28 4.4 241 24 4.7 1.08 281 28 6.7 0.00 252 25 4.4 0.78 298 30 15.4 0.46
19 37 19 37 19 37 19 37
0.79 30.672
'F ' table values Dunnett's 'T * table values
F.01 = P.01 =
TREATMENTS 4
0.1 0.2
ERROR 45
0.1 0.2 -
0.1 0.2
TOTAL 49
0.1 0.2
3.78 3.12
F.05 = P.05 =
2.58 2.51
0.025 0.120
0.145
TREATMENTS 4
17 40
ERROR 45
17 40 -
17 40
TOTAL 49
17 40
3.78 3.12
F.05 = P.05 =
2.58 2.51
218.92 3099.90
3318.82
0.006 0.003
54.73 68.89
Error-within groups Source-Source of Variation
LABCAT CC4.43
Treatments-between groups
27-JUN-2002
418-028:PAGE K-146
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: FEMALE
Creatinine
Group
N Total
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
Std. DUNNETT'S
Dev.
't '
0.05 0.05 0.05 0.08 0.06
0.00 0.37 0.37 1.47
DUNNETT1S RANGES
LO -95%- HI
L0 -99%- HI
Degree Source Fdm
Sum of Squares
Mean Square
0.3 0.4 0.3 0.4 0.3 0.4 0.3 0.4
TREATMENTS 4
0.015
0.004
0.3 0.4
ERROR 45
0.167
0.004
0.3 0.4 -
----
0.3 0.4
TOTAL 49
0.182
0.3 0.4
F Ratio = Coeff. Var. % =
1.00 17.813
'F' table values
Dunnett's ''r 1 table values
Creatine Kinase
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2. 58 2. 51
1-F 10 2017 202 54.1
TREATMENTS 4
30624
7656
2-F
10 2495 250 85.6 1.44
118 285
98 305
ERROR 45
247619
5503
3-F
10 1919 192 21.7 0.30
118 285
98 305 -------------------
4-F
10 2129 213 80.4 0.34
118 285
98 305
TOTAL 49
278244
5-F
10 2521
252 101.6 1.52
118 285
98 305
F Ratio = Coeff.. Var. % =
1.39 33.472
'F* table values Dunnett's 'T' table values
Alanine Aminotransferase
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
1-F 10 1294 129 31.7
2-F
10 1334 133 23.0 0.33
99 160
3-F
10 1424 142 34.2 1.07
99 160
4-F
10 1265 127 24.7 0.24
99 160
5-F
10 1447 145 20.0 1.26
99 160
F Ratio = Coeff.. Var. % =
0.86 20.138
'F ' table values Dunnett's 'T' table values
F.01 = P.01 =
TREATMENTS 4
91 167
ERROR 45
91 167 -------------------
91 167
TOTAL 49
91 167
3.78 3.12
F.05 = P.05 =
2.58 2.51
2546 33396
35942
637 742
Error-within groups Source-Source of Variation
LABCAT CC4.43
Treatments-between groups
27-JUN-2002
418-028:PAGE K -147
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: FEMALE
Aspartate Aminotransferase
Std. DUNNETT'S
Group
N Total
Mean
Dev.
*t '
DUNNETT'S RANGES
LO -95%- HI
LO -99%- HI
Degree Source Fdm
Sum of Squares
Mean Square
1-F 10 1423 142 22.8
TREATMENTS 4
5587
1397
2-F
10 1351 135 21.6 0.67
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 1.69
115 169
109 176
TOTAL 49
31946
5-F
10 1564 156 40.7 1.30
115 169
109 176
F Ratio = Coeff. Var. % =
2.38 17.422
'F ' table values Dunnett's 'T* table values
Alkaline Phosphatase
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
1-F 10 1448 145 88.7
TREATMENTS 4
15762
3941
2-F
10 1586 159 81.7 0.32
38 252
12 277
ERROR 45
406995
9044
3-F
10 1363
136 107.3 0.20
38 252
12 277 -------------------
4-F
10 1784
178 131.0 0.79
38 252
12 277
TOTAL 49
422757
5-F
10 1280 128 44.7 0.40
38 252
12 277
F Ratio = Coeff. Var. % =
0.44 63.733
Calcium
*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-F
10 105.5
10.6
0.72
TREATMENTS 4
3.99
1.00
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
10.4
0.87 0.37
9.7 11.4
Q 5 11.6 -
4-F
10 104.4
10.4
0.46 0.34
9.7 11.4
9.5 11.6
TOTAL 49
27.11
5-F
10 104.3
10.4
0.82 0.37
9.7 11.4
9.5 11.6
F Ratio = Coeff.. Var. % =
1.94 6.760
*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 CC4.43
Treatments-between groups
27-JUN-2002
418-028 :PAGE K-148
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: FEMALE
Phosphorus
Group
N Total
Mean
Std. DUNNETT'S
Dev.
't '
DUNNETT'S RANGES
LO -95%- HI
LO -99%- HI
Degree Source Fdm
Sum of Squares
Mean Square
1-F 10 87.5 8.8 1.33
TREATMENTS 4
24.53
6.13
2-F
10 79.3 7.9 1.94 0.83
6.3 11.2
5.7 11.8
ERROR 45
219.09
4.87
3-F
10 90.0 9.0 2.80 0.25
6.3 11.2
5.7 11.8 -------------------
4-F
10 87.0 8.7 2.88 0.05
6.3 11.2
5.7 11.8
TOTAL 49
243.62
5-F
10 101.0
10.1
1.64 1.37
6.3 11.2
5.7 11.8
F Ratio = Coeff., Var. % =
1.26 24.803
'F' table values Dunnett's 'T1 table values
Triglycerides
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
1-F
10 544
54 19.9
TREATMENTS 4
693 173
2-F
10 495
50 10.2 0.54
32 77
26 83
ERROR 45
18711
416
3-F
10 490
49 29.4 0.59
32 77
26 83
4-F
10 453
45 19.5 1.00
32 77
26 83
TOTAL 49
19404
5-F
10 437
44 18.3 1.17
32 77
26 83
F Ratio = Coeff.. Var. % =
0.42 42.148
Sodium
*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-F
10 1434
143
6.3
TREATMENTS 4
10.92
2.73
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 Ratio = Coeff.. Var. % =
0.21 2.534
'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 CC4.43
Treatments-between groups
27-JUN-2002
418-028:PAGE K-149
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
Potassium
Group
N Total
Mean
Std. DUNNETT'S
Dev.
't '
DUNNETT'S RANGES
L0 -95%- HI
L0 -99X- HI
Degree Source Fdm
1-F 10 58.1 5.8 0.67
TREATMENTS 4
2-F
10 55.8 5.6 0.58 0.78
5.1 6.6
4.9 6.7
ERROR 45
3-F
10 55.5 5.6 0.32 0.88
5.1 6.6
4.9 6.7
4-F
10 61.0
6.1
0.70 0.98
5.1 6.6
4.9 6.7
TOTAL 49
5-F
10 61.6 6.2 0.90 1.18
5.1 6.6
4.9 6.7
F Ratio = Coeff. Var. % =
1.84 11.322
1F ' table values Dunnett's 'T' table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
Chloride
1-F 10 956 96 3.4
TREATMENTS 4
2-F
10 941 94 2.7 1.01
92 99
91 100
ERROR 45
3-F
10 949 95 3.8 0.47
92 99
91 100
4-F
10 954 95 3.4 0.14
92 99
91 100
TOTAL 49
5-F
10 936 94 3.1 1.35
92 99
91 100
F Ratio =
Coeff. Var. X =
0.66 3.494
Globulin
'F* table values
Dunnett's *T' table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
SEX: FEMALE
Sum of Squares
Mean Square
3.23 19.67
22.90
--
0.81 0.44
29.08 493.00
522.08
7.27 10.96
1-F 10 19.4 1.9 0.22
2-F
10 15.5 1.6 0.26 4.12
1.7 2.2*
3-F
10 18.2
1.8
0.21
1.27
1.7 2.2
4-F
10 17.3 1.7 0.13 2.22
1.7 2.2
5-F
10 17.9
1.8
0.21
1.59
1.7 2.2
F Ratio = Coeff., Var. % =
4.56 11.982
'F' table values Dunnett's 'T' table values
F.01 = P.01 =
TREATMENTS 4
1.6 2.2**
ERROR 45
1.6 2.2 --------------------
1.6 2.2
TOTAL 49
1.6 2.2
3.78 3.12
F.05 = P.05 =
2.58 2.51
0.82 2.02
2.83
0.20 0.04
-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 -150
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
Albumin/Globulin Ratio
Std. DUNNETT'S
Group
N Total
Mean
Dev.
't *
DUNNETT'S RANGES
LO -95%- HI
LO -997.- HI
Degree Source Fdm
1-F 10 21.7 2.2 0.28
TREATMENTS 4
2-F
10 26.1 2.6 0.43 3.07
1.8 2.5* 1.7 2.6
ERROR 45
3-F
10 22.3 2.2 0.21 0.42
1.8 2.5
1.7 2.6
4-F
10 23.7 2.4 0.26 1.39
1.8 2.5
1.7 2.6
TOTAL 49
5-F
10 23.0 2.3 0.37 0.91
1.8 2.5
1.7 2.6
F Ratio = Coeff. Var. % =
2.83 13.734
F' table values Dunnett's 'T 1 table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2. 58 2. 51
SEX: FEMALE
Sum of Squares
Mean Square
1.16 4.63
0.29 0.10
5.80
-Significant Difference from Control P < .05 Error-within groups
LABCAT CC4.43
Source-Source of Variation Treatments-between groups
27-JUN-2002
APPENDIX L STATEMENT OF THE STUDY DIRECTOR
9 0 S Sheehy Drive, Bldg. A Horsham , PA 1 9 0 4 4 Telephone: (2 1 5 ) 4 4 3 -3 7 1 0 Tehfbx: (21 5 ) 443-B 587
418-028:PAGE L-l
ARGUS RESEARCH
Charles 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
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 Rulea, the Japanese Ministry of Health and Welfare (MHW) Good Laboratory Practice Standardfor Safety Studies on Drugs0, 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 Chemicals0occurred that affected the quality or integrity of the study.
Raymond G. York, Ph^D, DABT Associate Director of Research Study Director Argus Research
Date
a. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58.
b. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance No. 21, March 26, 1997.
c. Organisation for Economic Co-operation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Final].
d. Organisation for Economic Co-operation and Development (1996). OECD Guidelinefor Testing of 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
905 Sheehy D rive, Bldg. A /H o rs h a m , PA 9 0 4 4
Telephone: (2 1 5 ) 4 4 3 - 8 7 iO
Telefax: (2 1 5 ) 4 4 3 -8 5 8 7
ARGUS RESEARCH
Charles River Laboratories Discovery and Development 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 for 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 Date(s)
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
Manager of Regulatory Compliance
