Document YGQwG8abk0nm1OXREOLK4paoV
AR226-3184
DuPont-4739
TRADE SECRET
Study Title H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
Volume 1 of 5
Laboratory Project ED: DuPont-4739
TEST GUIDELINES: U.S. EPA Health Effects Test Guidelines OPPTS 870.3100 (1998)
AUTHOR: Don A. Delker, Ph.D. STUDY COMPLETED ON: October 23, 2001
PERFORMING LABORATORY:
E.I. du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050
WORK REQUEST NUMBER: UBB 1
SERVICE CODE NUMBER: jmj
SPONSOR STUDY NUMBER:!----^B 1
irf
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H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-4739
GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT
This study was conducted in compliance with U.S. EPA TSCA (40 CFR part 792) Good Laboratory Practice Standards except for the items documented below. None of the items listed impact the validity of the study.
1. The characterization of the test substance that was conducted prior to the initiation of the study provided the percentage of solids in the test substance. This information was used to
calculate the dose levels, based on percent active ingredient, for the study. Additional
chemical characterization of the test substance was conducted after the completion of the study and provided analysis of the solids in the test substance. Samples of the test substance were collected on the first day of dosing, during the 90-day dosing period, and on the last day of dosing and were analyzed; these analyses provided confirmation of the percentage of solids and documented the test substance stability and uniformity over the course of the study. None of the aforementioned analyses were performed under Good Laboratory Practice Standards; however, the analyses were conducted in compliance with IS09002 regulations. All of the analyses are considered valid and sufficient for the purposes of this study.
2. Gross observations on five F[ weanlings, not more than two from any treatment group, were
inadvertently not documented at the time of necropsy. Due to the large number of pups that received gross observations on postnatal day 21, this lack of data will not affect the validity of the study.
Submitter / Sponsor:
E.I. du Pont de Nemours and Company Wilmington, Delaware 19898
U.S.A.
Study Director:
TVl/^/I-F)^.----
'Don~A.Delker,Ph.D.
Research Scientist
%7 Oc^- Z<(
Date
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H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
QUALITY ASSURANCE STATEMENT
__DuPont-4739
Haskell Sample Number(s): 24616
Dates of Inspections:
Conduct: September 6, 2000; November 13, 15, 22, 2000; December 6,14, 18,2000
Records, Reports:
March 5-9, 2001; April 10-12,15,16, 27, 30, 31, 2001; May 1-4, 610, 13-14, 17-18, 21-25, 28-31, 2001; June 1,4, 2001; August 6-10, 13, 30, 2001; September 11-14, 17, 2001
Dates Findings Reported to:
Study Director: November 14, 2000; March 12, 2001; April 16, 2001; May 14, 2001; June 18, 2001; August 30, 31, 2001; September 17, 2001
Management: December 3, 2000; March 12, 2001; April 16, 2001; June 18, 2001; August 30, 31, 2001; September 17, 25,2001; October 18, 2001
Reported by:
ChLJ^
Joseph C. Hamill Sr. Quality Assurance Auditor
23-^-2^f Date
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H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
CERTIFICATION
We, the undersigned, declare that this report provides an accurate evaluation of data obtained
from this study.
Neurological Evaluations Reported by:
^^u^. ^k^f Linda A. Malley, Fb.D.,<b.^.B.^.
Senior Research Scientist
J?3 -^a^- J?fa^ Date
Reproductive Evaluations Reported by:
Qjiw Mthreest, Ph.D.
Research Scientist
Clinical Pathology Evaluations Reported by:
< % - . ^ 9 Nancy EJEvcrds. D.V.M.
Diplomate A.C.V.P. Principal Research Scientist
Pathological Evaluations Reported by:
J^te^/J.----G. Tracy Makovec, D.V.M Diplomate A.C.V.P. Senior Research Scientist
Pathological Evaluations Peer Review Reported by:
-Cy&LAj^. ^'"'^f^--^-<-
Steven R. Frame, D.V.M., Ph.D. Diplomate A.C.V.P.
Director, Anatomic Pathology
23 oj-. 2oai
Date
23 0t7^\
Date
^3-0^-^0v\ Date
^?3 GJ-^6) Date
O^W^^fe/Ax (/// Judith CStadler. Ph.D., D.A.B.T. Director, General Toxicology
ss-cxir-^wi
Date
^V^- f),AA A
/
fldnA'belker.Pfa.D.
Research Scientist
23 Oc^zw}
Date
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H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-4739
TABLE OF CONTENTS
Page
GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT.................................. 2 QUALITY ASSURANCE STATEMENT...................................................................................3
CERTIFICATION........................................................................................................................4
LIST OF TABLES ........................................................................................................................8
LIST OF FIGURES .................................................................................................................... 11
LIST OF APPENDICES............................................................................................................. 12
STUDY INFORMATION........................................................................................................... 14
STUDY PERSONNEL................................................................................................................ 15
SUMMARY.................................................................................................................................. 16
INTRODUCTION....................................................................................................................... 19
OBJECTIVE................................................................................................................................ 19
MATERIALS AND METHODS ............................................................................................... 19
A. Test Guidelines.................................................................................................................. 19
B. Test Substance................................................................................................................... 19
C. Test Species....................................................................................................................... 19
D. Animal Husbandry............................................................................................................ 20
E. Quarantine and Pretest Period....,..........................:.....................:......................::............. 21
F.
Study
22
Design.....................................................................................................................
G. Assignment to Groups and Study Start ............................................................................. 22
H. Test Substance Administration and Sampling .................................................................. 23
I. Body Weights.................................................................................................................... 23
J. Food Consumption and Food Efficiency........................................................................... 23
K. Detailed Clinical Observations and Mortality................................................................... 24
L. Ophthalmological Evaluations......................................................................................... 24
M. Neurotoxicity Evaluations................................................................................................. 25
N. Clinical Pathology............................................................................................................. 25
0. Serial Blood Collection (Satellite Group)......................................................................... 27
P. Anatomic Pathology - Rats Designated for Subchronic Toxicity and Recovery.............. 27
Q. Reproductive Assessment .................................................................................................29 R. Anatomical Pathology - Rats Designated for Reproductive Evaluations.......................... 30 S. Statistical Analyses............................................................................................................ 33
RECORDS AND SAMPLE STORAGE ...................................................................................35
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TABLE OF CONTENTS (Continued)
Page
RESULTS AND DISCUSSION ............................................................................................... 36 ANALYTICAL EVALUATIONS.............................................................................................. 36
A. Test Substance Stability.................................................................................................... 36 B. Test Substance Concentration Verification....................................................................... 36 C. Iodine Analysis.................................................................................................................. 36 D. Analytical Conclusions...................................................................................................... 37
SUBCHRONIC TOXICITY EVALUATIONS........................................................................ 38 IN-LIFE TOXICOLOGY........................................................................................................... 38
A. Dosage Data ......................................................................................................................38 B. Mean Body Weights and Body Weight Gains................................................................... 38 C. Food Consumption and Food Efficiency........................................................................... 39 D. Clinical Observations, Ophthalmology Evaluations, and Survival................................... 39 E. to-Life Toxicology Conclusions........................................................................................ 39
NEUROBEHAVIORAL TOXICOLOGY................................................................................ 40
A. Functional Observational Battery (FOB).......................................................................... 40 B. Motor Activity (MA)......................................................................................................... 40 C. Neurobehavioral Toxicity Conclusions............................................................................. 41
CLINICAL PATHOLOGY........................................................................................................ 42
A. Hemato logy/Coagulation............................................................................ r...................... 42 B. Clinical Chemistry............................................................................................................. 43 C. Urinalysis........................................................................................................................... 46 D. Clinical Pathology Conclusions........................................................................................ 47
ANATOMICAL PATHOLOGY................................................................................................ 48
A. Subchronic Toxicity and Recovery................................................................................... 48 B. Anatomical Pathology Conclusions for Subchronic Toxicity Evaluation......................... 52
REPRODUCTIVE TOXICOLOGY EVALUATIONS........................................................... 53 REPRODUCTIVE FUNCTION................................................................................................ 53
A. Pi Generation..................................................................................................................... 53 B. Offspring Data................................................................................................................... 53 C. Fi Generation................................................................................................................... 54 D. Reproductive Function Conclusions ................................................................................. 54
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TABLE OF CONTENTS (Continued)
Page
ANATOMICAL PATHOLOGY................................................................................................ 55
A. Organ Weight Data............................................................................................................ 55
B. Gross Observations ...........................................................................................................55
C. Microscopic Observations................................................................................................. 55
D.
55 Mortality............................................................................................................................
E. Anatomical Pathology Conclusions for Reproductive Toxicity........................................ 55
CONCLUSIONS......................................................................................................................... 56
REFERENCES............................................................................................................................ 57
TABLES (Tables 1-41)................................................................................................................ 59
VOLUME 2 TABLES (Tables 42-74)............................................................................................................ 297
FIGURES...................................................................................................................................394
APPENDICES (Appendices A-E)............................................................................................ 406
VOLUME 3 (Appendices F-L)................................................................................................. 607
VOLUME 4 (Appendices L-JJ) ............................................................................................... 937
VOLUME 5 (Appendices KK-00)........................................................................................ 1197
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H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
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TABLE 1 TABLE 2 TABLES TABLE 4 TABLE 5 TABLE 6 TABLE 7 TABLES TABLE 9 TABLE 10 TABLE 11 TABLE 12 TABLE 13 TABLE 14 TABLE 15 TABLE 16 TABLE 17 TABLE 18 TABLE 19
TABLE 20
TABLE 21
TABLE 22
TABLE 23
TABLE 24
TABLE 25 TABLE 26 TABLE 27 TABLE 28
LIST OF TABLES
Page
MEAN DAILY DOSE VOLUMES FOR MALE RATS ........................................................
63
MEAN DAILY DOSE VOLUMES FOR FEMALE RATS....................................................
64
MEAN BODY WEIGHTS OF MALE RATS ........................................................................
65
MEAN BODY WEIGHTS OF FEMALE RATS...................................................................
67
MEAN BODY WEIGHT GAINS OF MALE RATS.............................................................
69
MEAN BODY WEIGHT GAINS OF FEMALE RATS.........................................................
71
MEAN DAILY FOOD CONSUMPTION BY MALE RATS ................................................ 73
MEAN DAILY FOOD CONSUMPTION BY FEMALE RATS............................................
75
MEAN DAILY FOOD EFFICIENCY OF MALE RATS.......................................................
77
MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS .................................................
79
SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS....................................
81
SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS...............................
84
SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR MALE RATS............
87
SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR FEMALE RATS
88
PERCENT SURVIVAL OF MALE RATS.............................................................................
89
PERCENT SURVIVAL OF FEMALE RATS........................................................................
90
MEAN FORELIMB GRIP STRENGTH: MEAN OF THREE TRIALS...............................
91
MEAN HINDLIMB GRIP STRENGTH: MEAN OF THREE TRIALS...............................
92
SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS
FOR MALE RATS..................................................................................................................
93
SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS
FOR FEMALE RATS............................................................................................................
95
MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS FOR MALE RATS.................................................................................................................. 97
MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS FOR FEMALE RATS............................................................................................................. 99
MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR MALE RATS.................................................................................................................. 101
MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR FEMALE RATS............................................................................................................. , 103
SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS......................................... 105
SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS.................................... 109
SUMMARY OF COAGULATION VALUES FOR MALE RATS........................................ 113
SUMMARY OF COAGULATION VALUES FOR FEMALE RATS ................................... 113
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H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
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TABLE 29 TABLE 30 TABLE 31 TABLE 32 TABLE 33 TABLE 34 TABLE 35 TABLE 36 TABLE 37
TABLE 38
TABLE 39
TABLE 40
TABLE 41
TABLE 42
TABLE 43 TABLE 44
TABLE 45
TABLE 46
TABLE 47 TABLE 48
TABLE 49 TABLE 50 TABLE 51 TABLE 52 TABLE 53
LIST OF TABLES (Continued)
Page
SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS........... 114
SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS...... 118
SUMMARY OF URINALYSIS VALUES FOR MALE RATS................................................... 122
SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS............................................... 124
MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS....................................... 126
MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS.................................. 133
INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS................................................ 140
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS........................................... 155
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS..................................
..176
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS.......................................
,.185
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS- NON-NEOPLASTIC LESIONS...............................................
,.203
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS- NON-NEOPLASTIC LESIONS ..........................................
..217
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED- NEOPLASTIC AND NON-NEOPLASTIC LESIONS ..........................................247
MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED- NEOPLASTIC AND NON-NEOPLASTIC LESIONS ..........................................297
MEAN BODY WEIGHTS AND BODY WEIGHT GAINS OF P, MALE RATS ......................357
MEAN BODY WEIGHTS AND BODY WEIGHT GAINS OF P, FEMALE RATS DURING
358 GESTATION.............................................................................................................................
MEAN BODY WEIGHTS AND BODY WEIGHT GAINS OF P, FEMALE RATS DURING
LACTATION.
..359
MEAN DAILY FOOD CONSUMPTION AND FOOD EFFICIENCY BY Pi FEMALE RATS} DURING GESTATION...............................................................................................................,..360
SUMMARY OF CLINICAL OBSERVATIONS IN P, RATS.......................................................361
MEAN ESTROUS CYCLE PARAMETERS AND PRECOITAL INTERVAL P, FEMALE RATS..............................................................................................
,.362
SUMMARY OF SPERM PARAMETERS IN P| MALE RATS..........................
..363
SUMMARY OF REPRODUCTIVE INDICES: P, GENERATION...................
,.364
MEAN PUP NUMBERS AND SURVIVAL: Fi GENERATION.......................
,.365
MEAN PUP WEIGHTS: F| GENERATION....................................................... SUMMARY OF PUP CLINICAL OBSERVATIONS DURING LACTATION.
..366 ,.367
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H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
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TABLE 54 TABLE 55 TABLE 56
TABLE 57
TABLE 58 TABLE 59 TABLE 60 TABLE 61 TABLE 62 TABLE 63 TABLE 64 TABLE 65 TABLE 66 TABLE 67 TABLE 68 TABLE 69 TABLE 70 TABLE 71
TABLE 72
TABLE 73
TABLE 74
LIST OF TABLES (Continued)
Page
MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF F, MALE RATS..........368 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF F, FEMALE RATS .....369 MEAN DAILY FOOD CONSUMPTION AND MEAN FOOD EFFICIENCY BY F| MALE RATS .....................................................................................................................370 MEAN DAILY FOOD CONSUMPTION AND MEAN FOOD EFFICIENCY BY F| FEMALE RATS.................................................................................................................371 SUMMARY OF CLINICAL OBSERVATIONS IN F, RATS.....................................................372 SUMMARY OF DEVELOPMENTAL LANDMARKS IN F, RATS..........................................373 MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS - P, ADULTS............374 MEAN FINAL BODY AND ORGAN WEIGHTS FROM FEMALE RATS - Pi ADULTS .......375 MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS - F, ADULTS ............376 MEAN FINAL BODY AND ORGAN WEIGHTS FROM FEMALE RATS - F, ADULTS .......378 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - P[ ADULTS........................380 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS-P, ADULTS...................381 INCIDENCES OF GROSS OBSERVATIONS IN RATS - F, PUPS..........................................382 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - F, WEANLINGS................385 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - F, WEANLINGS ...........386 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - F, ADULTS........................387 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - F, ADULTS ...................388 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS-P, ADULTS...................................................................................................389 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS - Pi ADULTS...............................................................................................391 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS - F| ADULTS ...................................................................................................392 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS - F| ADULTS ..............................................................................................393
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H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
LIST OF FIGURES
FIGURE 1 FIGURE 2 FIGURE 3 FIGURE 4 FIGURE 5 FIGURE 6 FIGURE?
FIGURE 8
FIGURE 9
FIGURE 10
MEAN BODY WEIGHTS OF MALE RATS ........................... MEAN BODY WEIGHTS OF FEMALE RATS....................... MEAN FORELIMB GRIP STRENGTH OF MALE RATS......
MEAN FORELIMB GRIP STRENGTH OF FEMALE RATS.
MEAN HINDLIMB GRIP STRENGTH OF MALE RATS......
MEAN HINDLIMB GRIP STRENGTHOF FEMALE RATS ..
MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS FOR MALE RATS.................................................................................................... MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS FOR FEMALE RATS.............................................................................................. MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR MALE RATS................................................................................................ MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR FEMALE RATS...........................................................................................
Page
..396 ..397 ..398 ..399 ..400 -.401
..402
..403
..404
..405
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H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
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LIST OF APPENDICES
Page
APPENDIXA APPENDIXB APPENDIX C APPENDIX D
APPENDIX E APPENDIX F APPENDIX G APPENDIX H APPENDIX I APPENDIX J APPENDIX K. APPENDIX L APPENDIX M APPENDIX N. APPENDIX 0 APPENDIX P APPENDIX Q APPENDIX R APPENDIX S
APPENDIX T APPENDIX U
APPENDIX V
APPENDIX W
APPENDIX X
APPENDIX Y APPENDIX Z
INDIVIDUAL DOSE VOLUMES................................................................................................407 INDIVIDUAL BODY WEIGHTS................................................................................................497 INDIVIDUAL FOOD CONSUMPTION DATA..........................................................................531 INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA...................................................................................................................549 OPHTHALMOLOGICAL EXAMINATION REPORTS.............................................................603 INDIVIDUAL FORELIMB AND HINDLIMB GRIP STRENGTH ASSESSMENTS ...............608 INDIVIDUAL FUNCTIONAL OBSERVATIONAL BATTERY ASSESSMENTS...................619
INDIVIDUAL MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENT............628 INDIVIDUAL MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS .............639 INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA......................................................650 INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS ..........................................769 INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS ............................786 INDIVIDUAL BODY WEIGHTS OF P, MALE RATS ..............................................................969 INDIVIDUAL BODY WEIGHT GAINS OF P, MALE RATS ...................................................975 INDIVIDUAL BODY WEIGHTS OF P| FEMALE RATS DURING GESTATION..................981 INDIVIDUAL BODY WEIGHT GAINS OF P, FEMALE RATS DURING GESTATION....... 9 87
INDIVIDUAL BODY WEIGHTS OF P, FEMALE RATS DURING LACTATION .................993 INDIVIDUAL BODY WEIGHT GAINS OF P| FEMALE RATS DURING LACTATION....... 999
INDIVIDUAL DAILY FOOD CONSUMPTION BY P, FEMALE RATS DURING
GESTATION..............................................................................................................................1005
INDIVIDUAL CLINICAL OBSERVATIONS IN P, MALE RATS.......................................... 1011 INDIVIDUAL CLINICAL OBSERVATIONS IN P| FEMALE RATS DURING
GESTATION..............................................................................................................................1020
INDIVIDUAL CLINICAL OBSERVATIONS IN P, FEMALE RATS DURING
LACTATION..............................................................................................................................1026
INDIVIDUAL ANIMAL ESTROUS CYCLE PARAMETERS DURING PREMATING AND COHABITATION IN P| FEMALE RATS.................................................................................1035 INDIVIDUAL ANIMAL ESTROUS CYCLE STAGES DURING PREMATING AND COHABITATION IN P| FEMALE RATS.................................................................................1041 INDIVIDUAL ANIMAL SPERM MOTILITY DATA IN P) MALE RATS............................. 1047 INDIVIDUAL ANIMAL SPERM MORPHOLOGY DATA IN P, MALE RATS..................... 1050
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____
LIST OF APPENDICES (Continued)
Page
APPENDIX AA INDIVIDUAL ANIMAL SPERM AND SPERMATID COUNTS IN P) MALE RATS............ 1054
APPENDIX BB INDIVIDUAL MATING DATA AND GESTATION LENGTH: P, GENERATION............. 1057
APPENDIX CC INDIVIDUAL IMPLANTATION SITE DATA AND IMPLANTATION EFFICIENCY........ 1063
APPENDIX DD INDIVIDUAL PUP SURVIVAL: F| GENERATION...............................................................1069
APPENDIX EE INDIVIDUAL PUP WEIGHTS: F| GENERATION................................................................. 1095
APPENDIX FF INDIVIDUAL LITTER CLINICAL OBSERVATIONS: F, GENERATION........................... 1145
APPENDIX GG INDIVIDUAL BODY WEIGHTS: F, GENERATION............................................................. 1151
APPENDIX HH INDIVIDUAL BODY WEIGHT GAINS: F, GENERATION..................................................1161
APPENDDC II INDIVIDUAL FOOD CONSUMPTION: F, GENERATION................................................... 1171
APPENDDCJJ INDIVIDUAL CLINICAL OBSERVATIONS: F, GENERATION .........................................1181
APPENDIX KK INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS........................................ 1198
APPENDIX LL
INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS
FOR P| ADULTS........................................................................................................................1215
APPENDIX MM INDIVIDUAL ANIMAL GROSS OBSERVATIONS FOR F| PUPS........................................ 1377
APPENDIX NN INDIVIDUAL ANIMAL GROSS OBSERVATIONS FOR F, WEANLINGS.......................... 1382
APPENDIX 00 INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS
FOR F| ADULTS.............................................................;............................................:.............1404
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H-24616: Subchronic Toxic ity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
STUDY INFORMATION
Substance Tested: IB^^^H J
Synonyms/Codes: H-24616 Haskell Number: 24616
Known Impurities:
DuPont-4739
Physical Characteristics:
Sponsor:
E.I. du Font de Nemours and Company Wilmington, Delaware 19898
U.S.A.
Study Initiated/Completed: September 14, 2000/ (see report cover page)
In-Life Initiated/Completed: September 18, 2000 / March 19, 2001
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H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
STUDY PERSONNEL
Study Director: Management:
Primary Technician:
Don A. Delker, Ph.D. Judith C. Stadler, Ph.D., D.A.B.T. Nancy C. Chromey, Ph.D., D.A.B.T. Janice L. Connell, M.S., B.A., C.I.H. Janine A. Britton, B.S.
Reproductive Toxicologist: Eve Mylchreest, Ph.D.
Management: Robert M. Parker, Ph.D.
Clinical Pathologist: Nancy E. Everds, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D.
Pathologist:
Management: Peer Review Pathologist:
G. Tracy Makovec, D.V.M. Steven R. Frame, D.V.M., Ph.D. Steven R. Frame, D.V.M., Ph.D.
Neurotoxicologist: Linda A. Malley, Ph.D. Management: Robert M. Parker, Ph.D.
Toxicology Report Preparation: Mary K. LaRoe Cecilia R. Kee, B.S.
Ophthalmologist:
Nancy M. Bromberg, V.M.D., M.S.
6119 Massachusetts Avenue
Bethesda, Maryland 20816
Laboratory Veterinarians: William Singleton, D.V.M., A.C.L.A.M. Wanda L. West, D.V.M., A.C.L.A.M.
DuPont-4739
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\J
H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739
SUMMARY
Four groups of young adult male and female Crl:CD(SD)IGSBR rats were administered neat
H-24616 by gavage at dosages ofO, 50, 250, or 1000 mg/kg/day based on the active ingredient. Selected animals from each group were designated for subchronic toxicity or reproductive evaluations.
In the subchronic study, body weights, food consumption, and clinical signs were evaluated
weekly. Clinical pathology endpoints were evaluated during weeks 7 and 13 of the 90-day
exposure period and 1-month postdosing. Neurobehavioral assessments were also performed prior to dosing, during week 12, and near the end of the 1-month recovery period. After 90 days of dosing, ten rats/sex/dose were sacrificed and given a gross and microscopic pathological examination. One month after the 90-day dosing period, 10 animals/sex in the control and high dose group were examined for recovery of toxic effects. An additional five animals/sex/dose were evaluated for recovery 3 months following the end of the dosing period.
The average daily volumes of H-24616 given to male rats over the 90-day exposure period were 0.09, 0.45, and 1.74 mL H-24616 for the 50, 250, and 1000 mg/kg/day dosage groups, respectively. The average daily volume given to female rats over the 90-day exposure period were 0.05, 0.28, and 1.08 mL H-24616 for the 50, 250, and 1000 mg/kg/day dosage groups,
respectively.
In-Life and Neurotoxicology Parameters: No test substance-related mortality occurred in the study. No adverse clinical signs of toxicity or changes in neurobehavioral parameters were observed in male or female rats in any dose group. Statistically significant lower body weight, body weight gain, food consumption, and food efficiency were observed in male rats administered 1000 mg/kg/day when compared to controls. There were no adverse effects on these parameters at any dose level in female rats at 90 days and no adverse effects in males and females dosed with 1000 mg/kg/day by the end of the one-month recovery period.
Clinical Pathology: Potentially adverse findings of elevated liver enzymes (ALKP, AST, ALT, and/or SDH) were observed after treatment and/or a one month recovery in males and/or females dosed with 250 or 1000 mg/kg/day. Other changes in clinical pathology parameters, during
treatment or after a one-month recovery, were considered treatment-related but non-adverse
because the magnitude of change was small, transient, and/or in a direction not associated with
toxicity. The noteworthy parameters thus affected were red cell mass, red cell shape, urea nitrogen, cholesterol, triglycerides, bilirubin, albumin, globulin, and urine fluoride.
Anatomical Pathology (Subchronic Toxicity): Test-substance related and statistically significant
increases in liver weight parameters occurred in male rats of all dose groups and female rats in
the high-dose group after the 90-day exposure period. Histopathologically, hepatocellular hypertrophy was also observed in male rats of all dose levels but not in female rats. Nasal olfactory epithelium degeneration/necrosis was observed in male and female rats at all dose
levels and inflammation of the olfactory epithelium in male rats in the 250 and 1000 mg/kg/day
dose level. Thyroid hypertrophy and increased alterations in colloid were observed in male and
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H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
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female rats in the 250 and 1000 mg/kg/day dose groups. No thyroid hypertrophy was observed in
rats dosed with 50 mg/kg/day.
After one month of recovery, rats dosed with 1000 mg/kg/day showed some reversibility of
effects. Hepatocellular hypertrophy was present in male rats (less severe than at 90 days) and nasal epithelium degeneration/necrosis also persisted in male rats at a lower incidence and severity than observed at the end of the dosing period. Inflammation of the nasal epithelium was no longer seen in male rats and nasal epithelium degeneration/necrosis was not observed in female rats. Treatment-related thyroid hypertrophy and increased colloid alterations persisted in
male and female rats.
After the 3-month recovery period, hepatocellular hypertrophy was observed only in male rats in the 250 and 1000 mg/kg/day dose groups. Nasal epithelium degeneration/necrosis or inflammation was not observed in male or female rats at any dose level. Thyroid hypertrophy occurred in one female rat in the 1000 mg/kg/day dose group and increased colloid alterations were observed in male rats in the 250 and 1000 mg/kg/day dose groups.
Reproduction: Twenty male and female rats from each dose group were designated for reproductive evaluations. Parental rats (Pi generation) were dosed daily for 70 days prior to cohabitation, during the cohabitation period (mating), during gestation, and during lactation, until the weaning of the F) offspring. The following parameters were conducted on Pi rats: body weights, food consumption, clinical signs, gross pathology, sperm parameters, estrous cyclicity and reproductive performance. The Fi offspring were evaluated during the lactation period for growth and survival and given a gross pathological examination at weaning. A subset ofFi rats (Fi generation) were retained at weaning, and the following parameters evaluated for 6 weeks: body weights, food consumption, clinical signs, and age at onset of vaginal opening and preputial separation. After 6 weeks, the Fi generation rats were given a gross pathological examination,
selected reproductive organs were weighed and histopathology evaluation of the thyroid was
conducted.
No test substance-related effects on reproductive parameters were observed. There were no adverse effects at any dose level on estrous cycle or sperm parameters, or reproductive indices. There were no test substance-related changes in Fi litter size, pup weights or survival during lactation. There were no test substance-related changes in body weights, food consumption, or developmental landmarks in the Fi generation.
Mean thyroid organ weight was significantly lower in the 250 and 1000 mg/kg/day dose groups in the Fi generation, but not in the P] generation. However, there were no histopathological changes in the thyroid of the Fi generation rats. There were no other test substance-related gross pathology findings in Pi or Fi generation rats.
l<C
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H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
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NOEL for Subchronic Toxicity and Recovery: Target organs identified in this 90-day subchronic
toxicity study included liver, nose and thyroid. Based on the olfactory nasal epithelium necrosis
observed after 90 days of treatment in male and female rats at all dose levels, a no-observed-
effect level (NOEL)3 cannot be determined for the subchronic toxicity evaluation. However, the
nasal olfactory epithelium effects observed after the 90-day exposure period were completely
reversible by the end of the 3-month recovery period.
NOEL for Reproductive Evaluations: Although there were no test substance-related effects observed on reproductive function, a NOEL of 50 mg/kg/day was determined for reproductive evaluations based on decreased thyroid weights in both male and female F[ adults at dosages of
250 mg/kg/day and above.
The NOEL for this study is defined as the highest dose at which lexicologically important effects attributable to the test substance were not detected. Thus, for this study, the NOEL is equivalent to the NOEL as defined by the United States Environmental Protection Agency (1985) and to the no-observed-adverse-effect level (NOAEL) as defined by the European Union (1994).
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H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
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INTRODUCTION
I^k-^^^K Thetest substance, H-24616, contains am^^^^^^^^H
fl|H^^----l^--------Hha 2-week rmge^indingstudy conducted with H-24616 in rats,
thei^wasnoobservables^temic toxicity observed up to the limit dosage of 1000 mg/kg/day active ingredient. Dosages of 50, 250 and 1000 mg/kg/day were selected for this 90-day subchronic toxicity with one generation reproduction study based on the ability of rats to tolerate the upper limit dosage of 1000 mg/kg/day in the range-finding study.
OBJECTIVE
The objective of this study was to evaluate the potential subchronic and reproductive toxicity of H-24616 when administered by gavage to male and female rats. The oral route of administration was selected as the most efficient way to deliver an accurate dosage.
MATERIALS AND METHODS
A. Test Guidelines The subchronic toxicity study design complies with the United States Environmental Protection
Agency (EPA), Office of Prevention, Pesticides, and Toxic Substances (OPPTS) Health Effects Test Guidelines, OPPTS 870.3100 90-Day Oral Toxicity in Rodents (AUG-1998). The onegeneration reproduction study includes many endpoints of reproductive function but does not
comply with a specific guideline.
B. Test Substance The test substance, H-24616, was supplied by the sponsor as
agBBBB^_________________ ^BS^BSBjThe test substance is
^^^Hmestability analysis of the test substance before and during the study was conducted by
Regional Analytical Services (RAS), Jackson Laboratories, Deepwater, New Jersey. A reserve sample of the test substance was collected and retained by Haskell Laboratory.
C. Test Species
On August 31, 2000, 176 male and 176 female Crl:CD(SD)IGS BR rats, with an assigned birth date of July 31, 2000, were received from Charles River Laboratories, me., Raleigh, North
Carolina for use on this study.
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H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739 The rat was selected because it is the recommended species specified in the subchronic toxicity
guidelines and is extensively used in reproduction studies. The Crl:CD(SD)IGSBR strain was
chosen because extensive background information is available from the literature, the supplier, and previous studies at Haskell Laboratory. This species/strain also is considered suitable relative to longevity, hardiness, sensitivity to the test substance, and low incidence of spontaneous diseases.
D. Animal Husbandry
1. Housing
With the exception of some portions of the reproductive study, all rats were housed one per cage,
sexes separate, in stainless steel, wire-mesh cages suspended above cage boards. Animal rooms were maintained on a 12-hour light/dark cycle (fluorescent light) and at a temperature of 23 3C and a relative humidity of 50% 20%. Occasional excursions outside the accepted ranges were minor and did not affect the study.
Rats designated for reproductive toxicity evaluations were housed as breeding pairs during the cohabitation period. During the gestation period, female rats designated for reproductive toxicity evaluations were housed individually until gestation day 20. Beginning on gestation day 20 for mated females, or at the end of the cohabitation period for females without evidence of copulation, female rats were housed individually in polycarbonate pans with bedding. During the lactation period, adult female rats were housed with their litters in polycarbonate pans.
During the 70-day premating period for Pi adults and the 42-day postweaning period for Fi weanlings, cage racks were relocated within the animal room each week and cages were repositioned on the racks every 2 weeks.
2. Feed and Water Tap water was provided ad libitum. All rats were fed PMI Nutrition International, me. Certified Rodent LabDiet 5002 ad libitum.
3. Identification Prior to assignment to groups, each rat was temporarily identified by either the presence or absence of a colored tail mark and cage identification. After assignment to groups, an individual
identification number was tattooed on the tail of each rat. The information on the cage labels
included the unique 6-digit Haskell animal number and the individual identification number assigned to each rat.
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4. Health Monitoring Program As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to ensure that contaminant levels are below
those that would be expected to impact the scientific integrity of the study: Water samples are analyzed for total bacterial counts, and the presence ofcoliforms, lead,
and other contaminants. Feed samples are analyzed for total bacterial, spore and fungal counts. Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation
by the cagewashers. Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional
requirements and not to exceed stated maximum concentrations of key contaminants, including
specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence of these contaminants below the maximum concentration stated by the manufacturer
would not be expected to impact the integrity of the study. The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian. Evaluation of these data did not indicate any conditions that affected the validity of the study.
E. Quarantine and Pretest Period
Upon arrival at Haskell Laboratory, the rats were quarantined for 10 days of the 17-day pretest period. The rats were observed daily for any clinically apparent signs of disease or injury, weighed 4 times, and examined by a veterinary ophthalmologist to identify animals with
preexisting ocular lesions. Prior to study start, one female rat (animal no. 641270) was found dead prior to grouping and
was necropsied to check for the presence of disease. No disease was found; death was due to
spontaneous urinary obstruction.
On the basis of acceptable body weight gains and clinical observations, all surviving rats were released from quarantine on test day -7 by the laboratory animal veterinarian.
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F. Study Design
Groups
Male Female
I
n
ffl
IV
V
VI
vn vm
No./ Group
Dietary Dosages
Male Female____(mg/kg/day)
45
45
0 (Control)
35
35
50
35
35
250
45
45
iooo
a
Weight of test substance animal body weight.
(adjusted
" w fbi^^Hjictive ^^,1
ingredient)/kg
The first ten rats in each group were designated for the 90-day exposure evaluation. The next five rats in each group were designated as a satellite subset for serial blood collection and
evaluation of selected tissues following a 3-month recovery period. The next 20 animals in each
group were designated for reproductive evaluations. The last 10 male and female rats in the control and high dose groups were designated for 1-month recovery evaluations.
Male and female rats designated for the 90-day exposure evaluation were dosed for 91 and 92 days, respectively, and necropsied the following day. Male and female rats designated for the one- and three- month recovery evaluations were dosed for 90 days and necropsied 33-34 days and 92 days postdosing, respectively.
Neurobehavioral evaluations were conducted on control and high dose animals designated for the one-month recovery (predose, week 13, one-month post'dose) and on male and female animals designated for the 90-day exposure evaluation (predose and week 13). Clinical pathology evaluations were conducted on animals designated for the 90-day exposure evaluation on weeks 7 and 13 and on animals designated for the one-month recovery evaluation immediately prior to
necropsy.
G. Assignment to Groups and Study Start
Rats were selected for study use on the basis of adequate body weight gain, freedom from any ophthalmological abnormalities or clinical signs of disease or injury, and a body weight within 20% of the mean within a sex. The selected rats were distributed by computerized, stratified randomization so that there were no statistically significant differences among group body weight means within a sex.
Oral administration of H-24616 began on test day 0. The rats were approximately 49 days of age on test day 0. Prior to the start of the test substance administration, rats with body weights that were not within 20% of the mean within a sex, were replaced and discarded without gross or microscopic evaluations. Replacement rats were selected on the basis of freedom from any clinical signs of disease or injury and a body weight 20% of the mean within a sex.
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H. Test Substance Administration and Sampling The test substance as received from the sponsor was administered to the study animals by oral gavage to achieve dosage levels of 50, 250, or 1000 mg active ingredient/kg body weight/day, based on the most recently recorded body weight. The neat liquid was not diluted prior to dosing but was given to the animals in varying volumes depending on the targeted dose and amount (grams) of active ingredient in the test substance preparation. Dose volumes did not exceed 20 mL/kg. Animals designated for subchronic toxicity were dosed daily by gavage for 90 days. Animals designated for reproductive evaluations were dosed daily by gavage for 70 days, and
then daily during cohabitation until evidence of copulation was found or until the 14-day
cohabitation period ended. Pregnant females were dosed during the 3-week gestation period. From gestation day 18 until delivery, dose volumes were based on the gestation day 18 body
weights. Pregnant females in the process of delivery or showing signs of delivery were not dosed. Lactating females were dosed until pups were weaned on day 21. Pi females with no evidence of copulation continued to be dosed until sacrifice. Following the cohabitation period,
PI males were dosed until sacrifice.
The test substance was supplied by the sponsor in multiple-gallon containers. To determine the stability of the test substance over the 90-day exposure period, an analytical sample was taken from gallon container #1 on test day 0 and from gallon container # 6 on test day 91. Analytical samples for homogeneity and concentration verification were also taken. To verify proper
mixing and homogeneity of the test substance over the course of the daily dosing period, an
additional analytical sample was taken from the dosing container after dosing on test day 0. To verify proper mixing and homogeneity of the test substance in gallon container #1, an additional analytical sample was taken from gallon container # 1 prior to the last day of use on test day 17.
All male and female control animals were treated with deionized water at the same dose volume
as used in the high-dosage groups, respectively.
I. Body Weights
All rats were weighed once per week during the 90-day feeding phase of the study. In addition,
the rats designated for neurobehavioral evaluations, undergoing functional observational battery
and motor activity assessments, were weighed on the days of those observations. During the reproduction substudy, male rats were weighed on a weekly schedule and female rats were weighed during gestation on days 0, 7, 14, and 21, and lactation days 0, 7, 14, and 21. Pi female rats with no evidence of copulation or that did not deliver a litter continued to be weighed weekly. Weaned Fi rats were weighed weekly until postnatal day 63.
J. Food Consumption and Food Efficiency
The amount of food consumed by each rat over each weighing interval was determined throughout the study. Each rat's feeder was weighed at the beginning and end of the interval and the final weight of the feeder and the amount of spillage from the feeder during the interval was subtracted from the initial feeder weight. From these measurements, mean daily food
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consumption over the interval was determined. From the food consumption and body weight data, the mean daily food efficiency was calculated.
Mean daily food consumption was determined for all animals designated for subchronic toxicity evaluations during the 90-day exposure period. Food consumption was also determined for onemonth postdosing for animals designated for one- and three-month recovery evaluations. The only exception is that food consumption was not determined for animals designated for 3-month recovery during the urine and feces collection period on test days 84-91.
During the reproductive assessment, food consumption was determined for each female rat designated for reproductive assessment as follows:
Premating Dosing period - individual food consumption was determined weekly, ending test day 69.
Cohabitation period, beginning test day 69 - food consumption was not determined. Gestation period - individual food consumption was determined on gestation days 0, 7, 14,
and 21 (not reported). Lactation period - food consumption was not determined. Postweaning Fi rats - individual food consumption was determined weekly, ending on
postnatal day 63.
K. Detailed Clinical Observations and Mortality
During the test period, cage-site examinations to detect moribund or dead rats and abnormal behavior and/or appearance among rats were conducted at least twice daily throughout the study, except for test day 36 when the rats were checked only once. One male animal in the 250 mg/kg/day dosage group was euthanized on test day 51 due to a large open wound under the neck. At every weighing, each rat was individually handled and examined for abnormal behavior and appearance. Detailed clinical observations in a standardized arena were also evaluated on rats designated for the 90-day exposure and one-month recovery periods. The detailed clinical
observations included (but were not limited to) evaluation of far, skin, eyes, mucous membranes, occurrence of secretions and excretions, autonomic nervous system activity (lacrimation,
piloerection, and unusual respiratory pattern), changes in gait, posture, response to handling,
presence ofclonic, tonic, stereotypical, or bizarre behavior.
L. Ophthalmological Evaluations
Three Ophthalmological examinations were conducted by a veterinary ophthalmologist. Both eyes were examined by focal illumination and indirect ophthalmoscopy. The examinations were conducted under subdued lighting after mydriasis had been produced with a 1% tropicamide solution.
On test day -10, the initial examination was performed on all rats received for the study, prior to selection and grouping. On test day 88, all surviving rats designated for the 90-day exposure and one-month recovery were examined again. On test day 116, all surviving rats designated for recovery evaluation were given a final examination.
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M. Neurotoxicity Evaluations
1. Sensory Function Evaluation
Prior to test substance administration, during week 12 of test substance administration, and following an approximately one-month recovery period, assessments of responses to approach/touch, sharp auditory stimulus, and tail pinch were made while the animal was in a
standard arena. These assessments were conducted on 10 animals per group for the baseline and week 12 evaluations. The recovery evaluation was conducted on the 10 animals per group designated for recovery (control and high-dose groups only). Fore- and hindlimb grip strength
were measured by a strain gauge device (ChatillonDigital Force gauge). Pupillary constriction
was measured immediately prior to removing the rats from the motor activity chambers (Section 2. below) because the darkened room in which the apparatus was located facilitated observing the response. The presence or absence of pupillary constriction was assessed after a beam of light was directed into each eye. For all these assessments, the experimenter was unaware of the group designation of the animal.
2. Motor Activity (MA)
Following the evaluation of grip strength and sensory function, assessment of motor activity (MA) was conducted. Rats were individually tested in 1 of 30 nominally identical, automated activity monitors (CoulboumInfrared Motor Activity System). Group and gender were counterbalanced across the monitors and time of day to the fullest extent possible. The infrared monitoring device enables measurement of 2 dependent variables: duration of movement and number of movements. A continuous movement was counted as 1 movement regardless of
duration. Each test session was 60 minutes in duration, and the results were expressed for the total session as well as for 6 successive 10-minute blocks.
Presence of defecation and urination on the cageboards below the motor activity monitor were also recorded following each motor activity session.
3. Test Facility Positive Control Data
Data on the effects of acrylamide, carbaryl, d-amphetamine, and trimethyltin are described in four separate reports.0'213>4T) hese positive control studies are the basis of training certification for the individuals making judgments in the neurobehavioral and neuropathology tests. The data also document that the equipment and procedures are capable of detecting effects that may be seen in neurotoxicity studies of this type.
N. Clinical Pathology
Clinical pathology evaluations were conducted on the first 10 male and 10 female rats per group in all groups on test days 45 (male) or 44 (female) and either 91 (male) or 92 (female). The rats were fasted overnight (approximately 16 hours) and urine was collected during this interval. Blood samples for hematology and clinical chemistry measurements were collected from the orbital sinus of each fasted rat while the rat was under light carbon dioxide anesthesia. Blood samples for coagulation (end of dosing only) were collected from the abdominal vena cava while
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H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations____________DuPont-4739
the rat was under carbon dioxide anesthesia, immediately prior to sacrifice. All blood samples were examined visually and observations recorded. A clinical pathology evaluation (hematology,
clinical chemistry, and urinalysis, but not coagulation) was also conducted on all recovery rats
(control and rats dosed with 1000 mg/kg/day) from blood and urine collected after a month of recovery (test day 123, male, or 124, female).
1. Hematology/Coagulation
Complete blood counts (including reticulocytes) were determined on a BayerAdvia 120 hematology analyzer and determined from microscopic evaluation of the blood smear. Wrightstained blood smears from all rats were examined microscopically for confirmation of automated results and evaluation of cellular morphology. Coagulation times were determined on a BCS Behring Coagulation Analyzer. New methylene blue-stained blood smears were prepared from
each rat undergoing hematology evaluation but were not needed for evaluation.
The following hematology and coagulation parameters were determined:
Erythrocyte count (RBC) Hemoglobin concentration (HGB) Hematocrit (HCT) Mean corpuscular volume (MCV) Mean corpuscular hemoglobin (MCH) Mean corpuscular hemoglobin concentration (MCHC)
Red cell distribution width (RDW) Absolute reticulocyte counts (ARET) Total leukocyte count (WBC) Differential leukocyte count Platelet count (PLT)
Microscopic blood smear examination
Prothrombin time (PT) Activated partial thromboplastin time (APTT)
2. Clinical Chemistry
Clinical chemistry parameters were measured or calculated on a Roche Diagnostics
(BMC)/Hitachi917 clinical chemistry analyzer. Plasma fluoride concentration was determined using a phi/I 2 pH meter with a fluoride-selective electrode.
The following serum chemistry parameters were determined:
Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Sorbitol dehydrogenase (SDH) Alkaline phosphatase (ALKP) Total bilimbin (BILI) Urea nitrogen (BUN) Creatinine (CREA) Cholesterol (CHOL) Triglyceride (TRIG) Glucose (GLUC)
Total protein (TP) Albumin (ALB) Globulin (GLOB)
Calcium (CALC) Inorganic phosphorus (IPHS) Sodium (NA) Potassium (K) Chloride (CL) Plasma fluoride (PFLU)
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3. Urinalysis The following urinalysis parameters were determined:
Appearance (quality, clarity, and color) Volume (VOL) Osmolality (OSMO) Specific gravity (SG)
pH Glucose (UGLU) Ketones (KET)
Bilimbin (UBIL) Blood (BLD) Urobilinogen (URO) Urine fluoride (UFLU) Protein (UMTP) Microscopic examination of sediment
Urine volume and appearance were measured and evaluated visually, respectively. Urine constituents were semi-quantitatively measured on a Bayer Clinitek AtlasTM Automated Urine Chemistry analyzer. Urine volume and appearance were measured and evaluated visually, respectively. Urine constituents were semi-quantitatively measured on a Bayer Clinitek AtlasTM Automated Urine Chemistry analyzer. Urine protein was measured on a Roche Diagnostics (BMQ/Hitachi 717 clinical chemistry analyzer. Urine osmolality was determined using an Advanced Osmometer 3900. Urine fluorides were determined by multiplication of measured urine volume by urine fluoride concentration (measured using a phi/I 2pH meter and a fluoride
selective electrode). Sediments from all urine specimens were evaluated microscopically.
0. Serial Blood Collection (Satellite Group)
On test day 1 (males only), and test days 4,10, 21, 36, 57, 78, and 90 (males and females) blood (approximately 0.5 - 1 mL) was collected from the orbital sinus of designated animals (5 rats/sex/dose) while the animals were under light carbon dioxide anesthesia. On the day of blood collection, blood was collected from the animals prior to dosing. The blood was collected in glass tubes containing EDTA while the tubes were on ice and then stored frozen. For each bleeding, blood was collected at approximately the same time of day. During the last week of the 90-day exposure period urine and feces were collected daily at 24-hour intervals from each animal. The animals were placed in metabolism cages for collection of feces and urine. The exact time period of collection of urine and feces was documented along with the total volume of urine obtained. Urine and feces were stored frozen. Blood was also collected 3, 9,16, 29, 43, 64, and 85 days postdosing for both male and female animals of each dose group. Animals were sacrificed at the end of the 3-month recovery period. Blood, urine, and feces samples were not
analyzed during the course of this study but may be analyzed, if needed, at a later date. Any data
generated from these analyses will be archived in the study records and reported separately.
P. Anatomic Pathology - Rats Designated for Subchronic Toxicity and Recovery
On test days 91/92, the first 10 male/female rats from the 0, 50, 250, and 1000 mg/kg/day groups were sacrificed and necropsied. Thirty-day recovery rats from 0 and 1000 mg/kg/day were sacrificed and necropsied on test days 122 and 123 for males and females, respectively. Male and female satellite animals (90-day recovery) from each group were sacrificed and necropsied on test day 182. Rats were euthanatized by carbon dioxide anesthesia and exsanguination. Rats
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DuPont-4739
scheduled for sacrifice were fasted overnight on the afternoon before their scheduled sacrifice. Gross examinations were performed on all male and female rats.
The following tissues were collected from rats designated for the 90-day exposure and onemonth recovery that were found dead, accidentally killed, or sacrificed by design.
Digestive System Liver Esophagus Stomach Duodenum Jejunum Ileum Cecum Colon Rectum Salivary glands Pancreas
Urinary System Kidneys Urinary bladder
Respiratory System Lungs Trachea Nose Larynx Pharynx
Cardiovascular System Heart Aorta
Hematopoietic System Spleen Thymus Mandibular lymph node Mesenteric lymph node Bone Marrow3
Endocrine System Pituitary gland Thyroid gland Parathyroid glands Adrenal glands
Nervous System Brain (including cerebrum, cerebellum, medulla/pons)
Spinal Cord (3 levels: cervical, mid-thoracic, lumbar)
Sciatic Nerve
Musculoskeletal System Skeletal Muscle Femur/Knee Joint Sternum
Reproductive System Male Testes Epididymides Prostate Seminal Vesicles Female Ovaries Uterus Mammary Gland
Miscellaneous Skin Eyes (including optic nerve) gross observations
a Bone marrow was collected with the femur and sternum.
The liver, kidneys, adrenal glands, brain, spleen, thymus, heart, ovaries, uterus, epididymides, and testes were weighed at necropsy, and organ weight/final body weight and organ weight/brain weight ratios were calculated. Due to elevated liver weights observed at the one-month recovery sacrifice, liver was also collected and weighed from 3-month recovery animals designated for blood collection.
Gross lesions which were diagnosed at necropsy and for which microscopic examination was not appropriate (e.g., fluid accumulation, ruffled fur, missing anatomic parts) were generally not collected. Gross lesions for which a microscopic diagnosis would not be additive (e.g., osteoarthritis, pododermatitis, chronic dermatitis of the tail, urinary calculi, and deformity of the teeth, toe, tail, or pinna) were saved but were generally not processed for microscopic
evaluation.
Testes, epididymides, and eyes were fixed in Bouin's solution. All other tissues were fixed in 10% neutral buffered formalin. Processed tissues were embedded in paraffin, cut at a nominal thickness of 5 micrometers, stained with hematoxylin and eosin (H&E), and examined
microscopically.
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H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739
All collected tissues from rats sacrificed on test days 91/92 from control, and 1000 ing/kg/day
rats and all found dead or accidentally killed rats were processed and received a full histopathological examination. Liver, thyroid gland, and nose were collected and processed from 50 and 250 mg/kg/day 90-day exposure rats and from all one-month and 3-month recovery (satellite) rats and were examined microscopically. The key to Appendix G describes the lesion grading system used in this study.
Liver, kidney, testes, and approximately one gram of fat were collected from all satellite animals designated for blood collection (90-day recovery) and placed in plastic freezer bags and stored in
the freezer for future analysis.
Q. Reproductive Assessment
1. Breeding
After approximately 10 weeks of exposure to the test substance, on test day 69, each female was continually housed on a 1:1 basis with a randomly selected male of the same dose concentration
level in the male's cage. On the day copulation was confirmed, the female was transferred back
to individual cage housing. Mating pairs were cohoused until evidence of copulation was observed (designated as day 0 of gestation), or until 2 weeks elapsed. The presence of an intravaginal or extruded copulation plug was considered evidence of copulation.
2. Estrous Cycle Evaluation
Vaginal smears were collected from all Pi female rats in order to determine the stages of the
estrous cycle. Vaginal smears were collected daily beginning 3 weeks prior to mating, and continuing until copulation was confirmed, or the cohabitation period ended.
Vaginal smears were also collected from all Pi parental female rats at the time of sacrifice to determine the stage of estrous cycle.
3. Gestation Procedures
Female rats were transferred to polycarbonate pans (on day 20 of gestation for mated females or at the end of the cohabitation period for female rats without evidence of copulation), and were observed at least twice daily for signs of delivery and pups.
4. Lactation Procedures
The day when delivery was complete was designated day 0 postpartum. At each examination period, pups were individually handled and examined for abnormal behavior and appearance; any dead, missing, or abnormal pups were recorded.
a.
Day 0 Postpartum
Live and dead pups in each litter were counted as soon as possible after delivery was completed. Live pups in each litter were individually weighed.
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b.
Day 4 Postpartum
__ DuPont-4739
Litters were culled randomly to 8 (4/sex when possible). Extra pups were euthanatized (by decapitation) and discarded without pathological examination. Litters of 8 pups or less were not reduced. Litter counts were determined prior to and after culling, and individual pup weights
were determined prior to culling.
c.
Days 7 and 14 Postpartum
Pups in each litter were counted by sex and individually weighed.
d.
Day 21 Postpartum (Weaning)
Pups in each litter were counted by sex and individually weighed (3 of4/sex/litter were then sacrificed and grossly examined on postnatal day 21). Randomly selected weanlings (one/sex/litter) were placed in individual cages, monitored for attainment of developmental landmarks, and weighed and food consumption determined weekly until developmental landmark
criteria were met.
At each examination period, offspring were individually handled and examined for abnormal behavior and appearance; any dead, missing, or abnormal pups were recorded.
5. Post Weaning and Developmental Landmarks
Developmental landmarks in the Fi generation male and female rats (one/sex/litter) were monitored on a daily basis until criterion was achieved. Body weight and food consumption were determined until postnatal day 63.
a.
Vaginal Patency
Female rats were examined beginning on test day 0 (postpartum day 21).
b.
Preputial Separation
Male rats were examined beginning on test day 14 (postpartum day 35).
R. Anatomical Pathology - Rats Designated for Reproductive Evaluations
1. Pi Adults
All Pi parental rats were sacrificed by carbon dioxide asphyxiation and exsanguination, and subjected to gross pathological examination, including the females that died and those for which mating did not result in a production of offspring. The sacrifices were on test days 107 through 110 for male rats and on test days 113 through 118 for female rats.
The uteri of all cohabited females were examined for the presence and number of implantation
!
sites.
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The testes of each male rat were weighed. Sperm parameters for the first 10 male animals sacrificed by design in each treatment group were evaluated. The right cauda epididymis was weighed. Sperm was collected from the right cauda epididymis and percent motility and morphology was determined. The left epididymis and testis were frozen in liquid nitrogen and stored between -65 and -85 C for sperm and spermatid counts, respectively. The right testis and epididymis from these 10 rats were saved and placed in fixative.
The following table lists tissues that were collected:
Tissues Collected from Pi Adults
_______Male_____________Female____________Both Sexes_____
Testes/Testis" Epididymides/Epididymis3
Prostate
Ovaries Uterus (with oviducts) Vagina
Thyroid Gland1'
Gross Observations0 Pituitary Gland
Seminal Vesicles Coagulating
Gland________________________________________
a The testes/testis and epididymides/epididymis collected from male rats were placed in Bourn's solution. All other tissues (reproductive and non-reproductive) collected from male and female rats were placed in formalin.
b Thyroid glands were weighed after fixation. c Gross lesions observed at necropsy for which histopathology was not appropriate or would not be
additive were generally not collected.
Reproductive organs from animals with impaired reproductive performance were evaluated microscopically.
2. Offspring Offspring that were found dead during the lactation period underwent a gross pathological evaluation.
3. F) Weanlings
Three Fi weanlings/sex/litter (randomly selected), litter size permitting, were sacrificed by carbon dioxide asphyxiation and underwent a gross pathological evaluation on postnatal day 21. Gross lesions were preserved.
4. Fi Adults
All Fi generation rats were sacrificed by carbon dioxide asphyxiation and exsanguination, and subjected to a gross pathological examination. Selected tissues and gross lesions were preserved.
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The following table lists tissues that were collected and/or weighed:
Male
Tissues Collected from F( Adults Female
Both Sexes
Testes Epididymides
Prostate Seminal Vesicles Coagulating Gland
Ovaries Uterus (with oviducts) Vagina
Thyroid Gland Gross Observations Pituitary
Male
Tissues Weighed from F) Adults Female
Both Sexes
Testes Epididymides Seminal Vesicles (with coagulating glands)
Uterus (with oviducts and cervix)
Thyroid Gland (after fixation) Liver Brain
Prostate________________________________________________
Processed tissues for histopathological examination were embedded in paraffin, cut at a nominal
thickness of 5 micrometers, and stained with hematoxylin and eosin (H&E). Selected gross
lesions were evaluated microscopically. Selected gross observations, for which a microscopic diagnosis would not be additive (e.g., osteoarthritis, pododermatitis, tail chronic dermatitis,
calculus, and deformities of the teeth, toe, tail, or ear pinnae) were saved, but not processed for
microscopic evaluation.
Thyroid glands from all Fi adults were processed for microscopic examination. Thyroid glands from Fi control and 1000 mg/kg/day males and females were examined microscopically.
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S. Statistical Analyses
Except for Bartlett's test (p < 0.005), significance was judged at p < 0.05. Separate analyses
were performed on the data for each gender.
Parameter
Body Weight Body Weight Gain Food Consumption Food Efficiency Organ Weight
Preliminary Test
Test for lack of trend^'
Levene's test for homogeneity and
Shapiro-Wilk testator normality11
Method of Statistical Analysis
If preliminary test is not If preliminary test is
significant
significant
Sequential application16'
of the Jonckheere-
Preliminary tests for pairwise comparison
Terpstra trend test^
OR2
One-way analysis of variance00' followed
with Dunnett's test00
Kruskall-Wallis test02'
followed with Dunn's test03'
Motor Activity0 Grip Strength Clinical Pathology'1
Levene's test for homogeneity and Shapiro-Wilk testator normality1'
Bartlett's test06' for
homogeneity of
variances
Levene's test for homogeneity and Shapiro-Wilk test'9' for normality1'
Repeated measures
analysis of variance04' followed by contrasts05'
Sequential application^'
of the JonckheereTerpstra trend test"
One-way analysis of
variance00' followed
with Dunnett's test0"
Kruskall-Wallis test02'
followed with Dunn's
test03'
One-way analysis of variance00' followed with Dunnett's test'7'
Kruskall-Wallis test02'
followed with Dunn's test03'
Survival Incidence of Clinical
Observations
Incidence of FOB Descriptive Parameters
Incidence of Microscopic Lesions
None None
Cochran-Armitage test for trend00'6 None
a Pairwise comparisons and associated preliminary tests were only conducted if the test for lack of trend was
significant.
b If the Shapiro-Wilk test was not significant but Levene's test was significant, a robust version of Dunnett's test
was used. c Test day and block (10-minute EPOCH) was used as repeated-measure factors. d When an individual observation was recorded as being less than a certain value, calculations were performed
on half the recorded value. For example, ifbilirubin was reported as O.I, 0.05 was used for any calculations
performed with that bilirubin data.
e If the incidence was not significant, but a significant lack of fit occurred, then Fisher's Exact test07' with a
Bonferroni correction was used.
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The following table lists the indices of reproductive function that were calculated for the Pi and
Fi adults.
Parameter
Mean Number of Pups Per Litter Percent Bom Alive Vaginal Patency Preputial Separation
Preliminary Test
Test for lack of trend^
Levene's test for homogeneity^'and Shapiro-Wilk test
^for normality1'
Method of Statistical Analysis
If preliminary test is
If preliminary test is
not significant
significant
Sequential
application^ofthe
Jonckheere-Terpstra
Preliminary tests for pairwise comparison
trend test^
OR"
One-way analysis of variance0^ followed with Dunnett's test00
Kruskall-Wallis test C^followed with Dunn's test031
Body Weight Body Weight Gain Food Consumption Food Efficiency Gestation Length
Implantation Site Numbers Implantation Efficiency Precoital Interval Estrous Cycle Length Sperm Parameters
None None
One-way analysis of variance0 0) followed with Dunnett's test00
Jonckheere-Terpstra trend test^
Incidence of Clinical
Observations Mating Index Fertility Index
Gestation mdex Viability Index Lactation Index
None
Cochran-Armitage test for trend0010
Sex Ratio Mean Pup Weights (Covariates: litter size, sex ratio)
None
Linear contrast of
least squares means0^
Dunn's test03'
a Pairwise comparisons and associated preliminary tests were only conducted if the test for lack of trend was
significant.
b If the Shapiro-Wilk test was not significant but Levene's test was significant, a robust version of Dunnett's test
was used.
c If the incidence was not significant, but a significant lack of fit occurred, then Fisher's Exact test071 with a
Bonferroni correction was used.
For each parameter analyzed with a trend test, the test was applied to the data sequentially. If a
significant dose-response was detected, data from the top dose group were excluded and the test repeated until no significant trend was detected. For litter parameters, the proportion of affected fetuses per litter or the litter mean was used as the experimental unit for statistical
evaluation.09' The level of significance selected was p < 0.05.
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90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739 Where the data are tied and the standard large sample version ofjonckheere's test is not applicable, exact p values were calculated using permutation methodology/20^
RECORDS AND SAMPLE STORAGE
Laboratory-specific or site-specific raw data, such as personnel files and equipment records will be retained by the facility where the work was done. A sample of the test substance was collected for archive purposes and retained at Haskell
Laboratory. Specimens (if applicable), raw data, and the final report will be retained at Haskell
Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware. Clinical pathology slides and raw data will be retained at Haskell Laboratory, Newark, Delaware. Characterization data will be stored at Regional Analytical Services (RAS), Jackson Laboratories, Deepwater, New Jersey
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RESULTS AND DISCUSSION
ANALYTICAL EVALUATIONS
A. Test Substance Stability
To determine the stability of the test substance over the duration of the study, H-24616 (Lot # 436) was analyzed on the first and last day of dosing of the 90-day exposure period. The
percent solids of the test substance on test day 0 (predose) and test day 91 werefH^----^^l
variabilityjIHIII^H^----------Would not significantly impact the targeted dose given
to the test animals. Therefore, under the conditions of this study, the test substance was considered stable over the course of the study.
B. Test Substance Uniformity Analyses
H-24616 was administered neat to the test animals. No dosing preparations were made. However, uniformity of the test substance was determined in the daily dosing container, the first gallon container used for the study, and across multiple gallon containers.
1. Daily Dosing Container
On te^stday 0, percent soljds prior todosing (predose)^and after dosing (postdose) were^------R
ThisHJI|BIHUUBover ^Kjrespectively.
the course of the daily dosing period
may be due to evaporatiorTof water from the test substance. ThiHmBm------------V
would not significantly impact the targeted dose given to the testTlhimals. Therefore, the tes?"
substance was considered uniform during the daily dosing period.
2. First Gallon Container
On test day 0 and on test day 17 analytical samples were taken from the first gallon container used for the study. The percent solids ofthejtest substance taken from the first gallon container
on test day 0 (predose) and test day 17 wereflHj^^B^jrespectively. Based on these
results, the test substance was considered uniform in the first gallon container used for the study.
3. Across Gallon Containers
Analytical samples were taken from the first and last gallon container used for the 90-day study.
The percent solids of the test substance from gaUpn container #1 (test day 0, predose) and gallon
container #6 (test day 91) wer^BBBBBHyespectively. Other test substance analyses of
percent solids from a concurregtiy run developmental study with H-24616, showed percent solids
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^maximum difference in percent solids from samples from each of the three gallon containers was
^^^^l^lllBased on these results, the test substance was considered uniform across
contamerssupplied by the sponsor.
Test Day
Container
% Solids
C. Analytical Conclusions
Data from the stability and uniformity checks of the test substance, H-24616
, during
the study, suggest that the test substance was stable and uniform throughout i Te 90-day exposure
period.
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SUBCHRONIC TOXICITY EVALUATIONS
IN-LIFE TOXICOLOGY
A. Dosage Data (Tablesl-2, Appendix A)
The amount of test substance administered to each animal was calculated using individual body weights, the density of the test substance and the design dosage (50, 250, and 1000 mg/kg/day). Tables 1 and 2 depict the average amount of test substance (mL) administered by gavage for a given test day. The average daily amounts given to male rats over the 90-day exposure period were 0.09,0.45, and 1.74 mL H-24616 for the 50,250, and 1000 mg/kg/day dosage groups, respectively. Based on individual body weights, these amounts equated to dose ranges of 46-55, 236-255, and 932-1036 mg/kg/day for the 50,250, and 1000 mg/kg/day dosage groups,
respectively. The average daily amounts given to female rats over the 90-day exposure period were 0.05, 0.28, and 1.08 mL H-24616 for the 50,250, and 1000 mg/kg/day dosage groups, respectively. Based on individual body weights, these amounts equated to dose ranges of 43-57, 241-258, and 934-1044 mg/kg/day for the 50, 250, and 1000 mg/kg/day dosage groups, respectively.
On test day 28,1.18 mL (4 times the correct amount of 0.29 mL) of test material was inadvertently administered to one female rat in the 250 mg/kg/day dosage group. On test day 45, 0.5 mL (10 times the correct amount of 0.05 mL) of test material was inadvertently administered to two female rats in the 50 mg/kg/day dosage group. These errors in dosing will not affect the validity of the study.
B. Mean Body Weights and Body Weight Gains (Tables 3-6, Figures 1-2, Appendices B-C)
Body weight and weight gain in male rats fed 1000 mg/kg/day were statistically lower than control rats after week 4 and throughout the remainder of the 90-day exposure period. At the end of the 90-day exposure period, mean body weights were approximately 20 % (day 90, exposure animals) and 8 % (day 91, recovery animals) lower in male rats given 1000 mg/kg/day compared to control rats. The overall weight gains were approximately 34 and 15 % lower, respectively. This reduction in body weight gain was considered lexicologically adverse.
After a 30-day recovery period, the mean body weights of male rats that received 1000 mg/kg/day H-24616 were similar to controls ( 2%) indicating that the effects on body weight were reversible.
There were no adverse, test substance-related effects on body weight or body weight gain in female rats.
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(Tables 7-10, Appendix D)
Compared to male control rats overall, food consumption and food efficiency was statistically lower in male rats that received 1000 mg/kg/day H-24616 after week 4 and throughout the
remainder of the 90-day exposure period. At the end of the 90 day exposure period, food consumption was approximately 16 % (day 90, exposure animals) and 2 % (day 91, recovery
animals) lower in male rats given 1000 mg/kg/day compared to control rats. The overall food efficiency was 21 and 20 % lower, respectively. Based on the parallel reduction in body weight gain in male rats given 1000 mg/kg/day, this reduction in food efficiency was considered lexicologically adverse.
After a 30-day recovery period, food consumption and food efficiency in male rats given 1000 mg/kg/day H-24616 were similar to or greater than that observed in control rats. Therefore, the test substance-related effects on food consumption and food efficiency were reversible.
There were no adverse, test substance-related effects on food consumption or food efficiency in female rats.
D. Clinical Observations, Ophthalmology Evaluations, and Survival (Tables 11-16, Appendix E-F)
No test substance-related clinical or ophthalmological signs oftoxicity were observed in male or female rats. Clinical signs observed were incidental, i.e., hair loss, exo/enophthalmus as the result of orbital sinus bleeding, etc.
One male rat in the 250 mg/kg/day group was sacrificed in extremis on test day 51 due to a large, open wound under the neck of the animal. One female rat in the 1000 mg/kg/day dose group was found dead on test day 121. These deaths were considered not to be treatment related but of a spontaneous nature.
E. In-Life Toxicology Conclusions Based on the decrements in body weight gain and food efficiency in males dosed with 1000 mg/kg/day H-24616 for 90 days, the NOEL for in-life parameters for male rats is 250 mg/kg/day. The NOEL for female rats is 1000 mg/kg/day since no adverse in-life effects were observed in female rats during the 90-day dosing period.
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NEUROBEHAVIORAL TOXICOLOGY
A. Functional Observational Battery (FOB)
1. Forelimb Grip Strength (Table 17, Figures 3-4, Appendix G)
There were no test substance-related effects or statistically significant differences on forelimb grip strength in males or females administered any dosage of H-24616. Males administered 250 or 1000 mg/kg/day had slightly lower (14% and 13% lower than the control value, respectively) forelimb grip strength at week 12, however, a linear dose response-relationship was not present,
and the values were within the range of normal variation for this measurement. In addition, there were no effects in females for forelimb grip strength, and no effects on hindlimb grip strength.
Therefore, this slight difference was not considered to be test substance-related.
2. Hindlimb Grip Strength (Table 18, Figures 5-6, Appendix G)
There were no test substance-related effects or statistically significant differences in hindlimb
grip strength for either males or females administered any dosage of H-24616.
3. Sensory Function Observation
(Table 19-20, Figures 7-8, Appendix H)
There were no test substance-related changes in neurobehavioral parameters in males or females
administered any dosage of H-24616. During the baseline evaluation, females assigned to the 1000 mg/kg/day group had a significantly lower incidence of defecation in the motor activity monitor compared to control. However, since test substance administration had not been
initiated, this statistical difference was considered to be spurious. During the week 12 evaluation, females administered 50, 250 or 1000 mg/kg/day had a significantly higher incidence
of defecation in the motor activity monitor compared to the control value. However, a dose response-relationship was not present, and the incidences of the females treated with 50, 250, or
1000 mg/kg/day were similar to the control incidence during the baseline evaluation. Therefore, these statistically significant differences were considered to be spurious. There were no statistically significant differences in males for any parameter.
B. Motor Activity (MA)
(Tables 21-24, Appendices I-J)
There were no test substance-related effects on duration of movement or number of movements
for males or females for any dosage concentration tested. Males assigned to the 1000 mg/kg/day
group had significantly lower total duration of movement during the baseline evaluation and during the week 12 evaluation (20% and 26% lower, respectively, compared to control). In addition, mean total number of movements was significantly lower for 1000 mg/kg/day males compared to control during the week 12 evaluation. However, the values for total duration of
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movement and total number of movements for 1000 mg/kg/day males were similar between their
baseline, week 12, and recovery evaluations. Since there was no increase or decrease from their baseline performance with respect to either duration of movement or number of movements, the statistically significant differences compared to control were not considered to be test substance
related, hi addition, total duration of movement for males in the 1000 mg/kg/day group was 20% lower compared to control during the baseline evaluation and 26% lower compared to control
during the week 12 evaluation. Therefore the percentage change from control between baseline and week 12 for the 1000 mg/kg/day males was not biologically relevant. Duration of movement
and number of movements for males in the 1000 mg/kg/day group was also significantly lower compared to control during the third 10-minute interval for the week 12 evaluation. These statistical differences contributed to the significantly lower total duration of movement and total number of movements; however, as discussed above, they are not considered to be test substance
related.
There were no statistically significant differences in either duration of movement or number of movements for females administered any dosage of the test substance.
C. Neurobehavioral Toxicity Conclusions
Under the conditions of the study, the NOEL for neurobehavioral parameters was 1000 mg/kg/day in males and females, the highest concentration tested.
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CLINICAL PATHOLOGY
A. Hematology/Coagulation (Tables 25-28, Appendix K)
There were no lexicologically significant changes in hematology parameters in rats dosed with 50, 250, or 1000 mg/kg/day
All statistically significant changes in hematology parameters were considered unrelated to treatment and/or non-adverse (not lexicologically significant). These changes are detailed below.
Hemoglobin and hematocrit were transiently decreased in males dosed with 1000 mg/kg/day at test day 44. These decreases were considered to be non-adverse because the changes were minor (96% and 95% of control group mean, respectively) and transient.
Acanthocytes were minimally increased in some males dosed with 1000 mg/kg/day at test day 44. Although this change was possibly related to treatment, acanthocytes were not considered adverse because the effect was mild, variable, transient, and in affected individual animals was not associated with any other measured changes in red blood cells.
Absolute reticulocytes were mildly decreased (77% of control group mean) in males dosed with 1000 mg/kg/day at test day 91. For individual animals, there was no correlation between decreased reticulocytes and decreased RBC mass. Decreased reticulocytes were considered to be unrelated to treatment, because mildly decreased reticulocytes in the absence of relevant alterations in red cell mass have no significance. After one month of recovery, reticulocytes of rats previously dosed with 1000 mg/kg/day were similar to control group
values.
Platelets were minimally decreased (82% of control group mean) in males dosed with 1000 mg/kg/day at test day 91 only. This change was considered unrelated to treatment and non-adverse, because the change was very minor (clinically insignificant) and individual counts did not follow a dose relationship. After one month of recovery, platelet counts in rats
previously dosed with 1000 mg/kg/day were statistically similar to control group values.
White blood cells were transiently increased due to increased lymphocytes in male rats dosed with 1000 mg/kg/day at test day 44. This change was considered unrelated to treatment. The increases were minimal for both white blood cell counts and lymphocytes compared to the normal variability of these cell counts. Additionally, although the cell counts were increased, individual values for rats dosed with 1000 mg/kg/day were both above and below the minimum and maximum values for individual control animals. Due to the magnitude and transient nature of the responses, these changes were not considered adverse.
The following statistically significant changes in hematology parameters were considered to be unrelated to treatment because they did not occur in a dose-related manner:
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Minimally decreased red cell mass parameters (red blood cell, hemoglobin, and hematocrit) in females dosed with 50, 250, or 1000 mg/kg/day at test days 44 and 92. The decreases were variable and unrelated to dose (varying from 93-97% of control group means; variable statistical significance). Therefore, these changes were considered to be unrelated to treatment, and therefore non-adverse. After one month of recovery, red cell mass parameters in rats previously dosed with 1000 mg/kg/day were similar to control values.
Increased MCHC in females dosed with 250 mg/kg/day at test day 44
Increased monocytes in males (day 44) and decreased eosinophils in females (day 92) dosed with 50 mg/kg/day
At the end of treatment (test days 91/92), there were no alterations in coagulation parameters; therefore, coagulation parameters were not measured at the end of recovery (test days 123/124).
B. Clinical Chemistry (Tables 29-30, Appendix K)
Rats dosed with 250 (males only) or 1000 mg/kg/day (males and females) had changes in liver enzymes indicating possible adverse effects. Males dosed with 1000 mg/kg/day had increased ALKP (an indicator ofcholestasis or enzyme induction) at mid-study, at the end of treatment, and after one month of recovery. Most males and some females previously dosed with 1000 mg/kg/day had increased enzyme activity indicating hepatocellular injury (AST, ALT, SDH) after one month of recovery. Although many of these changes, in isolation, could likely be
considered non-adverse, the constellation of changes and the persistence of changes into the recovery period suggest potential adverse effects in light of continued liver weight changes even after recovery. Thus the NOEL for liver effects was conservatively determined to be
50 mg/kg/day in males and 250 mg/kg/day in females.
ALT activity was minimally increased (137% of control group means) in males dosed with
1000 mg/kg/day at test day 91. The increase was consistent among all animals in the group. ALT activity was also minimally increased in males dosed with 250 mg/kg/day and possibly 50 mg/kg/day.
After one month of recovery, mean ALT (males and females), and AST and SDH (females
only) activities were increased in rats previously dosed with 1000 mg/kg/day. The increased mean activities were primarily due to lexicologically significant increases in the enzymes of 3 animals (Animal No. 641203 - male, Animal No. 641366 - female, and Animal No. 641399
- female). Histologically, 2 of these rats (Animal No. 641203 - male and Animal No. 641366 - female) had minimal to multiple small areas of hepatic necrosis. Excluding the outliers, the remainder of the recovery males still had minimally increased AST and ALT. The remainder of the females actually had decreased AST, ALT, and SDH activities (of no toxicologic significance). The fact that 3 of 20 rats had toxicologically significant increases in hepatocellular injury enzymes after one month of recovery suggests an ongoing process and is
potentially adverse.
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ALKP activity was minimally to mildly increased (124-229% of control group mean) in male rats dosed with 1000 mg/kg/day at mid-study and at the end of dosing. The changes were more prominent at test day 91 compared to test day 44. Anatomic pathology changes included increased liver weights and hepatocellular hypertrophy; these changes might have contributed to the ALKP increase. After recovery, ALKP activity was still minimally increased. Excluding rat Animal No. 641203 (see discussion under ALT above), mean ALKP activity after one month of recovery was 126 U/L (158% of control group mean).
Statistically significant increased ALKP in male rats dosed with 250 mg/kg/day was considered to be of equivocal relationship to treatment because the difference from control
was very slight.
The following statistically significant changes were considered unrelated to treatment and/or non-adverse (not lexicologically significant):
Urea nitrogen was mildly increased in males (250 or 1000 mg/kg/day) and in females (1000 mg/kg/day) at test days 91/92. The magnitude of change was similar in both dose groups. Increased urea nitrogen was probably related to treatment. The cause of increased urea nitrogen was not determined. Generally, increased urea nitrogen indicates decreased glomemlar filtration due to dehydration or renal damage. However, individual animals with increased urea nitrogen did not have indicators of dehydration (increased sodium, chloride, or albumin). Additionally, individual rats with increased serum urea nitrogen maintained urinary concentrating ability (as indicated by urine osmolality and specific gravity) indicating normal functioning kidneys. There were no changes in other markers of decreased renal function (phosphorus or creatinine) and no renal histologic lesions were observed in rats dosed with H-24616 at any dose. After one month of recovery, urea nitrogen values in treated animals were similar to controls. For the above reasons, the change in urea nitrogen was not considered to be adverse.
Cholesterol and triglyceride concentrations were mildly decreased in rats dosed with 250 or 1000 mg/kg/day (variable statistical significance, variable across sexes and time-points).
Cholesterol was decreased in males and females dosed with 250 or 1000 mg/kg/day (Clinical Pathology Text Table). The changes were generally similar at test days 44 and 91/92, and were more pronounced in males. After one month of recovery (test days 123/124), cholesterol concentrations in rats previously dosed with 1000 mg/kg/day were only minimally less than those in control group rats.
Triglyceride concentrations were decreased in rats dosed with 1000 mg/kg/day. Triglyceride concentrations in males were decreased at all time-points, including recovery, but were only decreased at test day 44 in females.
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The above decreases in cholesterol and triglycerides were considered to be treatment-related because they are part of a dose-response and are consistent within treatment groups. The changes in cholesterol and triglycerides indicate alteration oflipid processing. However, changes of this magnitude in cholesterol and triglycerides are not associated with adverse
effects.
Clinical Pathology Text Table: Cholesterol and Triglyceride changes
(expressed as percent of control group mean)
TEST CHOL (mg/dL)
Dose (mg/kg/day) Day 44 Day 91 Day 123
50 87% 87%
ND
Males 250 73% 70%
ND
1000 63% 64% 81%
TRIG (mg/dL)
Day 44 Day 91 Day 123
119% 127%
ND
76% 88%
ND
56% 54% 55%
Females
CHOL (mg/dL) Day 44
86%
82%
74%
"h
Day 92
90%
80%
75%
Day 124
ND
ND
94%
TRIG (mg/dL)
Day 44 Day 92 Day 124
85% " 93%
ND
74% 102% ND
63% 82% 90%
Statistical significance indicated by bold italicized font ND: Not done
Decreased bilirubin concentrations in females dosed with 1000 mg/kg/day at test days 44, 92, and 124 were considered treatment-related, but were not considered adverse because
decreased bilirubin is not an indicator of disease. The persistence of this change during recovery is correlated with persistence of increased liver weights.
Mildly increased albumin and decreased globulins occurred in males dosed with 250 or 1000 mg/kg/day at all time-points, including recovery (except albumin at test day 44 in rats dosed with 250 mg/kg/day). The changes compared to controls were similar at all timepoints. These changes were probably treatment-related, but were not considered adverse because the magnitude of change was small compared to the normal variability of the parameter. Additionally, mild changes in these parameters are not associated with adverse
effects.
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Calcium was minimally decreased in males dosed with 1000 mg/kg/day at test day 91. This change is possibly treatment-related, but was considered non-adverse because of the extremely small change in the parameter.
Chloride was minimally and transiently increased in females dosed with 1000 mg/kg/day at test day 44. This change was possibly treatment-related, but was considered non-adverse
because of the transient nature of the change and the extremely small magnitude of the change (103% of control group mean).
The following statistically significant changes in clinical chemistry parameters were considered to be unrelated to treatment because they did not occur in a dose-related manner, or only occurred
after one month of recovery:
Decreased creatinine in males dosed with 50 mg/kg/day at test day 91, and in females dosed with 250 mg/kg/day at day 44
Decreased total protein in males and females dosed with 250 mg/kg/day at test day 44
Decreased globulins in females dosed with 250 mg/kg/day at test day 44
Decreased calcium in females dosed with 250 mg/kg/day at test day 44
Increased sodium in females previously dosed with 1000 mg/kg/day at test day 124
Increased inorganic phosphorus in males previously dosed with 1000 mg/kg/day at test day 123
C. Urinalysis
(Tables 32-32, Appendix K)
There were no lexicologically significant changes in urinalysis parameters in rats dosed with 50, 250, or 1000 mg/kg/day. All statistically significant changes were considered unrelated to treatment and/or non-adverse. These changes are detailed below.
Urine volume was decreased in females dosed with 50 mg/kg/day (test day 92) or 1000 mg/kg/day (test days 44 and 92). These changes were considered to be unrelated to treatment because they did not occur in a dose-related manner. Additionally, decreased urine volume in animals with normal hydration is of no biologic or toxicologic significance.
Urine fluoride was increased in males and females dosed with 250 or 1000 mg/kg/day at test days 91/92. The change occurred in a dose-related manner, and males were minimally more
affected than females. After one month of recovery (test days 123/124), urine fluoride was still mildly increased in males and females previously dosed with 1000 mg/kg/day (not
statistically significant in females). Although increased urine fluoride was treatment-related, it was not considered adverse because there were no adverse effects on any parameters relating to renal glomerular or tubular function.
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Decreased urine protein concentration in males dosed with 1000 mg/kg/day at test day 91 is possibly treatment-related, but was not considered adverse because increased urine protein, rather than decreased urine protein, is indicative oftoxicity.
D. Clinical Pathology Conclusions
Under the conditions of this study, the NOEL for males was 50 mg/kg/day and the NOEL for females was 250 mg/kg/day. These were based on the findings of elevated liver enzymes at 90 days and/or recovery in males dosed with 250 or 1000 mg/kg/day and females dosed with
1000 mg/kg/day. There were no adverse findings for hematologic, coagulation or urinalysis
parameters at any dose.
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ANATOMICAL PATHOLOGY
A. Subchronic Toxicity and Recovery
1. Organ Weight Data (Tables 33-34, Appendix L)
Test substance-related and statistically significant increases, compared to controls, in liver weight parameters occurred in male rats sacrificed on test day 91. Liver weight relative to body weight was increased in 50, 250, and 1000 mg/kg/day males. Absolute and relative to body weight liver weights were increased in one-month recovery and 3-month recovery (satellite) males at 1000 mg/kg/day. At all dose levels, the increased liver weights in males correlated with microscopic hepatocellular hypertrophy (see discussion under Microscopic Findings).
Liver weight relative to body weight was statistically significantly increased in 1000 mg/kg/day females on test day 92. This increased weight was most likely test substance-related, however, there were no correlative microscopic findings present in female livers.
Increased absolute spleen weights (not statistically significant) and statistically significant relative to body weight and relative to brain weight spleen weights were present in 250 and 1000 mg/kg/day females on test day 92. There were no microscopic findings in spleens from 1000 mg/kg/day females, male spleen weights were not affected, and clinical pathology parameters were within normal limits. Therefore, the increased spleen weights were considered to be test substance-related but not lexicologically significant.
There were no other test substance-related organ weight effects. All other statistically significant
organ weight changes in subchronic and recovery groups were secondary to decreases in body weight. In 1000 mg/kg/day male rats, these included decreases in absolute organ weight and/or organ weight relative to brain weight for heart, spleen (90-day exposure and one-month recovery groups), thymus and adrenal glands. There were no weight changes in these organs when adjusted to final body weight, and no test substance-related microscopic changes were present. Also in 1000 mg/kg/day male rats, organ weights relative to body weight were increased in brain, testes (90-day exposure and one-month recovery groups), epididymides and kidney (250 and 1000 mg/kg/day exposure groups) without correlative effects in other weight parameters or microscopic changes in these organs. Weights for these latter organs are generally maintained despite body weight loss, and thus this pattern of organ weight change is also consistent with effects occurring secondary to decrements in body weight.
2. Gross Observations
(Tables 35-36, Appendix M)
Gross observations noted were sporadic across groups and were not test substance-related.
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3. Microscopic Findings
(Tables 37-42, Appendix M)
Test substance-related microscopic findings were present in nose and thyroid gland from male and female rats and in liver from male rats.
____________Summary of Test substance-Related Microscopic Findings____________
0
50
250
1000
mg/kg/day
mg/kg/day
mg/kg/day
mg/kg/day
Males 90-day Exposure (Day 91)
Nose: Degeneration/necrosis, olfactory epithelium
Inflammation, subacute/chronic
0/10" 0/10
8/10(0.9)" 0/10
10/10(1.7) 5/10(0.5)
10/10(2.1) 6/10(0.6)
Thyroid gland: Hypertrophy, follicular Alteration, colloid
0/10 8/10(0.8)
0/10 8/10(1.1)
5/10(0.5) 10/10(1.4)
10/10(1.8) 10/10(2.8)
Liver: Hypertrophy, hepatocellular
0/10
1/10(0.1)
10/10(1.8)
10/10(2.0)
Males One-Month Recovery (Day 122)
Nose:
Degeneration/necrosis, olfactory
0/10
NA
epithelium
NA
3/10(0.3)
Thyroid gland: Hypertrophy, follicular Alteration, colloid
0/10 6/10(0.7)
Liver: Hypertrophy, hepatocellular
0/10
Males Three-Month Recovery (Satellite) (Day 182)
Thyroid gland: Alteration, colloid
5/5(1.2)
Liver:
Hypertrophy, hepatocellular
0/5
NA . NA NA
4/5(1.2)
0/5
NA
8/10(1.1)
NA
10/10(2.9)
NA
10/10(1.0)
4/4(2.3) 3/4(0.8)
5/5(2.6) 4/5(0.8)
i
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Summary of Test substance-Related Microscopic Findings
50
250
mg/kg/day
mg/kg/day
mg/kg/day
Females 90-day Exposure (Day 92)
1000 mg/kg/day
Nose: Degeneration/necrosis, olfactory epithelium
0/10
2/10 (0.2)
4/10( 0.5)
8/10(1.0)
Thyroid gland:
Hypertrophy, follicular Alteration, colloid
0/10 3/10(0.3)
Females One-Month Recovery (Day 123)
Thyroid gland: Hypertrophy, follicular Alteration, colloid
0/10 6/10 (0.6)
Females Three-Month Recovery (Satellite) (Day 182)
Thyroid gland: Hypertrophy, follicular Alteration, colloid
0/5 3/5 (0.6)
0/10 5/10 (0.5)
NA NA
0/5 5/5 (1.0)
2/10 (0.2) 6/10 (0.6)
7/10(1.0) 10/10(1.1)
NA
5/10 (0.6)
NA
7/10(1.0)
0/5 4/5 (0.8)
1/5 (0.2) 3/5 (0.8)
a Numerator indicates incidence of rats with microscopic lesion. Denominator indicates number of rats in group.
b Number in parentheses indicates group average severity of lesion. NA Tissue not available
Test substance-related nose lesions in 50, 250, and 1000 mg/kg/day test day 91 male and female
rats consisted of degeneration and or necrosis of olfactory epithelium, which was most prominent along the endoturbinates and nasal septum of levels 3 and 4. Incidence and severity of this lesion
increased in a dose dependent manner. Subacute to chronic inflammation was also present in male noses at 250 and 1000 mg/kg/day. m male one-month recovery rats the nasal
degeneration/necrosis of olfactory epithelium was still present, however, the incidence and
severity were decreased. Test substance-related nose lesions were not present in female onemonth recovery rats or in male and female 3-month recovery (satellite) rats.
Follicular hypertrophy was present in thyroid glands of male and female rats in the 250 and 1000 mg/kg/day 90-day exposure and one-month recovery groups, and in 1 female rat in the 1000 mg/kg/day 3-month recovery (satellite) group. Follicular hypertrophy was characterized by tall columnar follicular epithelium with a finely granular or vacuolated cytoplasm. Thyroid hypertrophy was minimal and unassociated with proliferative thyroid lesions. However, this hypertrophy indicates possible disruption of thyroid homeostasis and thus was considered
potentially adverse.
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Follicles containing altered colloid were found in thyroids from controls as well as treated, one-
month recovery, and 3-month recovery (satellite) rats. However, an increase in the number of
affected follicles, and thus grade, was treatment related. The diagnosis of "alteration, colloid"
was used to diagnose stippled, granular, clumped, and/or diffusely basophilic colloid. A 4 level
grading scheme was applied based on an estimate of the percentage of follicles that contained
altered colloid. A grade of 1 was applied when 1 follicle to about 25% of the follicles were
involved, with grades 2,3, and 4 applied for each 25% increase in follicular involvement. The size, density, or staining intensity of stipples, granules, clumps, or diffuse basophilia within
individual follicles did not impact the grading. In this study, there was only a treatment-related
increase in grade and not an appreciable increase in the overall incidence of the observation.
There was no apparent association between the presence or absence of altered colloid with
follicles that were lined by hypertrophic or non-hypertrophic follicular cells.
Altered colloid described as clumped or granular has been reported to occur spontaneously in
Sprague-Dawley rats with increasing incidence correlating to increasing age/21^Because altered
colloid occurs spontaneously in healthy Sprague-Dawley rats, and since increases in its grading score did not consistently correlate with other morphologic alterations, altered colloid was interpreted in the present study as not biologically meaningful and not adverse.
There was minimal to mild diffuse hepatocellular hypertrophy in 50, 250, and 1000 mg/kg/day male 90-day exposure rats, the male 1000 mg/kg/day one-month recovery group, and 250 and 1000 mg/kg/day male 3-month recovery (satellite) group. Microscopically, hepatocellular
hypertrophy was characterized by an increased amount of finely granular eosinophilic cytoplasm within hepatocytes. There was no histomorphologic evidence of hepatocellular damage. The severity of hepatocellular hypertrophy was less in one-month recovery and three-month recovery (satellite) rats then in 90-day exposure rats, however, complete reversibility of the hypertrophy
was not evident by test day 182. The hepatocellular hypertrophy (and the associated increase in liver weights) was considered a test substance-related physiologic response to a xenobiotic and not toxicologically adverse/22'23'2^
All other microscopic observations noted are known to occur spontaneously in rats of this strain and age and were not present in a dose response fashion in either incidence or severity.
4. Cause of Death (Appendix M)
There were no test substance-related deaths. One male 250 mg/kg/day rat (Animal No. 641090) was sacrificed in extremis on test day 51 due to a large, open wound under the neck of the animal. One female 1000 mg/kg one-month recovery rat (Animal No. 641356) was found dead on test day 121. Cause of death was a brain tumor (mixed glioma).
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90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739 B. Anatomical Pathology Conclusions for Subchronic Toxicity Evaluation Exposure to 50, 250, and 1000 mg/kg/day of the test substance for up to 91/92 days produced degeneration/necrosis of olfactory epithelium in the noses of male and female rats and thyroid gland hypertrophy in 250 and 1000 mg/kg/day males and females. Increased liver weights and microscopic hepatocellular hypertrophy were also present in males in the 50,250, and 1000 mg/kg/day groups. These liver changes were considered to represent a physiologic response to metabolism of a xenobiotic and thus were not considered to be lexicologically significant. The severity of altered colloid in thyroid glands increased beyond control level as the dose increased, however, it was not consistently correlated with any morphologic alterations and was not considered biologically adverse. Under the conditions of this study, the NOEL for pathology for male and female rats could not be determined based on nose lesions at the lowest dose tested (50 mg/kg/day).
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REPRODUCTIVE TOXICOLOGY EVALUATIONS
DuPont-4739
__
REPRODUCTIVE FUNCTION
A. Pi Generation
1. Mean Body Weights and Body Weight Gains
(Table 43-45, Appendices 0-T) Body weights of Pi adult male rats administered 1000 mg/kg/day H-24616 were statistically lower (10-11% of control mean) than male control body weights during and after the cohabitation
period. Although this finding was test substance-related, it was not considered lexicologically significant since there was no concomitant reduction in body weight gain in Pi males during that period. There were no test substance-related effects on body weight or body weight gain in Pi female rats during gestation or lactation.
2. Food Consumption and Food Efficiency During Gestation (Table 46, Appendix U)
There were no test substance-related effects on food consumption and food efficiency in Pi female rats during gestation.
3. Clinical Observations
(Tables 47, Appendices V-X)
There were no test substance-related clinical signs in Pi male rats during or after the cohabitation period, or in Pi female rats during cohabitation, gestation or lactation.
4. Reproductive Indices
(Tables 48-50, Appendices Y-EE) There were no test substance-related effects on estrous cycle or sperm parameters, or
reproductive indices in the Pi generation.
B. Offspring Data
1. Litter Size, and Pup Weights, and Survival (Table 51-52; Appendix FF-HH)
Mean number of pups per litter, pup weights at birth, and pup weights and survival during the
lactation period were not affected by test substance administration. There were no test substance-related clinical signs in pups during lactation.
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C. Pi Generation
___ DuPont-4739
1. Mean Body Weights and Body Weight Gains (Table 54-55, Appendices n-JJ)
There were no test substance-related effects on body weight or body weight gain during the postweaning period.
2. Food Consumption and Food Efficiency
(Table 56-57, Appendix KK)
There were no test substance-related effects on food consumption or food efficiency during the post-weaning period.
3. Clinical Observations (Tables 58, Appendices LL)
There were no test substance-related clinical signs during the post-weaning period.
4. Developmental Landmarks
(Tables 59, Appendices LL)
The age at onset of vaginal opening in F) female rats was similar across groups. The age at onset ofpreputial separation in F] male rats was similar across groups. However, the mean day of
preputial separation for the control group in this study (48.8) was outside the range for other
studies at Haskell Laboratory.3 Thus, some of the sensitivity of the assay may have been lost
because the criteria for preputial separation was more rigid in this study compared to previous
studies.
D. Reproductive Function Conclusions
For the reproductive toxicity parameters evaluated under the condition of this study, the NOEL was 1000 mg/kg/day, the highest dose tested. The NOEL was based upon the absence of test
substance-related effects on reproductive function.
' Historical control data for preputial separation was collected between April and August, 1999. For these studies, the mean day ofpreputial separation ranged from 42.2-43.9 days.
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REPRODUCTIVE TOXICOLOGY EVALUATIONS
ANATOMICAL PATHOLOGY
A. Organ Weight Data Parental Pi Adults and Fi Adults
(Tables 60-63; Appendix MM) There were no test substance-related weight effects on the thyroid gland ofPi adults. Thyroid
gland absolute weight, relative to body weight, and relative to brain weight were decreased in F] males and females at 250 and 1000 mg/kg/day dose levels. There were no correlating microscopic changes seen in males or females at 1000 mg/kg/day.
B. Gross Observations
Parental Pi Adults (Tables 64-65, Appendix NN) Fi Pups, Weanlings, and Adults (Tables 66-70, Appendix 00-QQ)
There were no test substance-related gross observations. Observations occurred in low incidences and were randomly distributed across control and treatment groups.
C. Microscopic Observations
Parental Pi Adults (Tables 71 -72, Appendix NN) Fi Adults (Tables 73-74, Appendix QQ)
There were no test substance-related microscopic findings. Lesions occurred in low incidences without a relevant dose-response relationship and were considered incidental occurrences of spontaneous lesions in rats of this strain and age.
D. Mortality Parental Pi Adults and Fi Adults (Appendices NN and QQ)
There were no test substance-related effects on mortality. One P] female rat (Animal No. 641392) from the 250 mg/kg/day dose group was found dead. The cause of death was urinary calculi and obstruction. There were no test substance-related effects on mortality in Fi
adults.
E. Anatomical Pathology Conclusions for Reproductive Toxicity For pathology, the NOEL, based upon the decreased thyroid gland weights in F| adults, was 50 mg/kg/day for both male and female rats.
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90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739
CONCLUSIONS
No test substance-related mortality or clinical signs oftoxicity were observed in male or female rats. Statistically significant and lexicologically adverse lower body weights, weight gain, and food efficiency were observed in male rats administered 1000 mg/kg/day compared to controls. Food consumption was also significantly lower in male rats administered 1000 mg/kg/day. After a 30-day recovery period these parameters were similar to controls. No effects on body weight, weight gain, food consumption, or food efficiency were observed in female rats at any dose level.
Potentially adverse findings of elevated liver enzymes (ALKP, AST, ALT and/or SDH) were observed after the 90-day exposure period and/or after one month of recovery in some male rats
dosed with 250 and 1000 mg/kg/day and some female rats dosed with 1000 mg/kg/day.
Increased liver weights and/or hepatocellular hypertrophy were observed in male rats of all dose levels and female rats administered 1000 mg/kg/day. These latter changes were considered a test substance-related physiologic response to a xenobiotic and not lexicologically adverse. After three months of recovery, hepatocellular hypertrophy was observed only in male rats administered 250 and 1000 mg/kg/day and not in female rats.
Thyroid hypertrophy was observed after 90 days in male and female rats administered 250 and 1000 mg/kg/day. These changes were considered test substance-related and toxicologically adverse. After three months of recovery, thyroid hypertrophy was not observed in male rats and seen in only one female rat in the 1000 mg/kg/day dose group.
Test substance-related and toxicologically adverse olfactory epithelium degeneration / necrosis was observed in male and female rats in all dose groups. Incidence and severity of the lesion occurred in a dose dependent manner. Incidence and severity of the lesions decreased after one
month of recovery. Nose lesions were not observed in male or female rats at any dose level after
a 3-month recovery period.
There were no test substance-related effects on reproductive function. However, the F) offspring of Pi adults administered 250 and 1000 mg/kg/day had statistically significant lower thyroid
weights compared to control F) rats. These effects on Fl thyroid organ weight were considered
toxicologically adverse.
Based on the nasal epithelium necrosis observed in male and female rats of all dose levels, a no-observed-effect-level (NOEL)' cannot be determined for the 90-day exposure period. Although there were no test-substance related effects observed on reproductive function, a NOEL of 50 mg/kg/day was determined for reproductive evaluations based on decreased thyroid weight observed in both male and female Fi adults at dosages of 250 mg/kg/day and above.
The NOEL for this study is defined as the highest dose at which toxicologically important effects attributable to the test substance were not detected. Thus, for this study, the NOEL is equivalent to the NOEL as defined by the United States Environmental Protection Agency(25)and to the no-observed-adverse-effect level (NOAEL) as
defined by the European Union(26).
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REFERENCES
1.^ DuPont (1995). Neurotoxicity Equation ofTrimethyltin in Rats (Positive Control Study).
21. DuPPoonntt((1997). Neurotoxicity Evaluattiicon of Amphetamine in Rats (Positive Control Study).
3. DuPont (1997). Neurotoxicity Evaluation ofCarbaryl in Rats (Positive Control Study).
4. DuPont (1996). Neurotoxicity Evaluation ofAcrylamide in Rats (Positive Control Study).
5. Draper, N.R. and Smith, H. (1981). Applied Regression Analysis, 2nd edition, pp 266-273. Wiley, New York.
6. Selwyn, M.R. (1995). The use of trend tests to determine a no-observable-effect level in animal safety studies. Journal of the American College of Toxicology 14(2), 158-168.
7. Jonckheere, A.R. (1954). A distribution-free K-sample test against ordered alternatives. Biometrika 41, 133-145.
8. Levene,H. (1960). Robust test for equality of variances. Contributions to Probability and
Statistics (J. Oikin, ed.), pp 278-292. Stanford University Press, Palo Alto.
9. Shapiro, S.S. and Wilk., M.B. (1965). An analysis of variance test for normality (complete samples). Biometrika 52, 591-611.
10. Snedecor, G.W. and Cochran, W.G. (1967). Statistical Methods, 6th edition, pp 246-248 and 349-352. The Iowa State University Press, Ames.
11. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Statist. Assoc. 50, 1096-1121.
12. Kruskal, W.H. and Wallis, W.A. (1952). Use of ranks in one-criterion analysis of variance. J. Amer. Statist. Assoc. 47, 583-621.
13. Dunn, O.J. (1964). Multiple contrasts using rank sums. Technometrics 6, 241-252.
14. Milliken, G.A. and Johnson, D.A. (1984). Analysis of Messy Data, Volume 1.: Designed Experiments. Lifetime Learning Publications, Belmont.
15. Hocking, R.A. (1985). The Analysis of Linear Models. Brooks/Cole, Monterey.
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H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739 16. Bartlett, M.S. (1937). Some examples of statistical methods of research in agriculture and
applied biology. J. Royal. Statis. Soc. Suppl. 4,137-170. 17. Fisher, R.A. (1985). Statistical Methods for Research Workers, 13th edition. Haffiier,
New York. 18. Dempster, A.P., Selwyn, M.R., Patel, C.M., and Roth, A.J. (1984). Statistical and
computational aspects of mixed model analysis. The Journal of the Royal Statistical Society, Series C (Applied Statistics) 33(2), 203-214.
19. Haseman, J.K. and Hogan, M.D. (1975). Selection of the experimental unit in teratology studies. Teratology, 12, 165-171.
20. Patefield, W. (1982). Exact tests for trends in ordered contingency tables. Applied Statistics 31,32-43.
21. Rao-Rupanagudi, S., Heywood, R., and Gopinah, C, (1991). Age-related changes in thyroid structures and function in Sprague-Dawley rats. Vet. Pathol. Vol. 29, No. 4, 278-287.
22. Sipes, G. I. and Gandolfi, A. J. (1991). Biotransformation of toxicants. In Casearett and Doull's Toxicology: The Basic Science of Poisons (M. 0. Amdur, J. Doull, and C. D. Klaassen, Eds.), pp. 88-126. Pergamon Press, New York.
23. Paynter, 0. E., Harris, J. E., Burin, G. J. and Jaeger, R. B. (1985). Guidance for analysis of evaluation of subchronic exposure studies. United States Environmental Protection Agency,
P/4-540/9-85-020.
24. Greaves, P. (1990). Digestive system 2. In Histopathology ofPreclinical Toxicity Studies: Interpretation and Relevance in Drug Safety Evaluation (P. Greaves, Ed.), pp. 393-496, Elsvier, Amsterdam.
25. Hazard Evaluation Division, Standard Evaluation Procedure, Toxicity Potential: Guidance
for Analysis and Evaluation of Subchronic and Chronic Exposure Studies Paynter, 0. E. et al., United States Environmental Protection Agency, Office of Pesticide Programs,
Washington, D.C., 20406. EPA-540/9-85-020. (June 1985). 26. Risk Assessment of Notified New Substances. Technical Guidance Document (XI/283/94-
EN), Chapter I, Sections 2.24 and 2.25. 1994.
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TABLES
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TABLES
EXPLANATORY NOTES
DuPont-4739
Critical Dates
Day 69
Male and female rats designated for reproduction evaluations were cohoused. Body weight and clinical observation data recorded during the cohabitation and post-mating periods are reported in the Reproductive Toxicology section. Dose volumes administered during the cohabitation and post-mating periods are documented in study records.
Day 90 >
Last day of test substance administration for male rats designated for the
90-day exposure and one-month and 3-month recovery periods, and female rats designated for one-month and 3-month recovery periods.
> Last day of non-fasted body weight and food consumption data collection for male rats designated for the 90-day exposure period.
Day 91 > Last day of test substance administration for female rats designated for
the 90-day exposure period.
> Last day of non-fasted body weight and food consumption data collection
for female rats designated for the 90-day exposure period.
> Male rats designated for the 90-day exposure period were sacrificed.
> Recovery period begins for rats designated for the one-month and 3-month recovery periods.
Days 84-91
Rats designated for the 3-month recovery period were temporarily housed in metabolism cages for urine and feces collection. Food consumption data was not collected for these animals during this period.
Day 92 Female rats designated for 90-day exposure period were sacrificed.
Day 119 Last day of food consumption data collection for animals designated for the
one-month and 3-month recovery periods.
Days 122 and 123 Male and female rats designated for the one-month recovery period were
sacrificed, respectively.
Days 126-182 Body weight and clinical observation data for rats designated for the 3-month recovery period are provided in the appendix.
Day 182 Male and female rats designated for the 3-month recovery period were
sacrificed.
60
company SanHbed. Dees not eoKWte TSIRA Cflt
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLES
ABBREVIATIONS:
EXPLANATORY NOTES
Summary ofHematology Values
RBC - red blood cell count
HGB - hemoglobin
HCT - hematocrit
MCV MCH -
mean corpuscular volume mean corpuscular hemoglobin
MCHC - mean corpuscular hemoglobin concentration
RDW - red cell distribution width
ARET - absolute reticulocyte count
WBC - white blood cell count
ANEU - absolute neutrophil (all forms)
ANPR - absolute neutrophil precursor
ALYM - absolute lymphocyte
AMON - absolute monocyte
AEOS - absolute eosinophil
ABAS - absolute basophil
ALUC - absolute large unstained cell
ABLT - absolute blast leukocyte
AMSC - absolute miscellaneous leukocyte
PLT - platelet count
Summary of Coagulation Values PT - prothrombin time
APTT - activated partial thromboplastin time
DuPont-4739
61
'company Sanitized. Does mot esntals T&SA eat
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLES
DuPont-4739
ABBREVIATIONS:
EXPLANATORY NOTES
Summary of Serum and Plasma Chemistry Values AST - aspartate aminotransferase
ALT - alanine aminotransferase
SDH - sorbitol dehydrogenase
ALKP - alkaline phosphatase
BILI - total bilirubin
BUN CREA -
urea nitrogen creatinine
CHOL - cholesterol
TRIG - triglycerides
GLUC - glucose
TP - total protein
ALB - albumin
GLOB - globulin
CALC - calcium
IPHS - inorganic phosphorous
NA - sodium
K - potassium
CL - chloride
PFLU - plasma fluoride
Summary of Urinalysis Values VOL - volume
UOSM - urine osmolality
SG - specific gravity
pH URO -
the logarithm of the reciprocal of the hydrogen ion concentration
urobilinogen
UFLU - urine fluoride
UMTP - urine protein
Notes for Clinical Pathology data:
When an individual observation was recorded as being less than a certain value, calculations
were performed on half the recorded value. For example, if bilirubin was reported as O.I, 0.05
was used for any calculations performed with that bilirubin data.
62
eompanySanltteed. Does not confab TfteA eft)
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 1
MEAN DAILY DOSE VOLUMES (mL) FOR MALE RATS
Group I 0 mg/kg/day
I I I Group
50 mg/kg/day
DAY 0 - DAY 6
1.04 0.08 (45)
0.05 0.00 (35)
DAY 7 - DAY 13
1.26 0.10 (45)
0.06 0.00 (35)
DAY 14 - DAY 20
1.45 0.12 (45)
0.07 0.01 (35)
DAY 21 - DAY 27
1.62 0.14 (45)
0.08 0.01 (35)
DAY 28 - DAY 34
1.77 0.16 (45)
0.09 0.01 (35)
DAY 35 - DAY 41
1.88 0.16 (45)
0.09 0.01 (35)
DAY 42 - DAY 48
1.97 0.18 (45)
0.10 0.01 (35)
DAY 49 - DAY 55
2.05 0.19 (45)
0.10 0.01 (35)
DAY 56 - DAY 62
2.13 0.21 (45)
0.10 0.01 (35)
DAY 63 - DAY 69
2.18 0.22 (45)
0.11 0.01 (35)
DAY 70 - DAY 76
2.25 0.21 (25)
0.11 0.01 (15)
DAY 77 - DAY 83
2.32 0.22 (25)
0.11 0.01 (15)
DAY 84 - DAY 89
2.36 0.25 (25)
0.11 0.02 (15)
DAY 90
Data summarized as:
2.37 0.24 (25)
0.11 0.02 (15)
Mean
Standard Deviation (n)
Group V
250 mg/kg/day
0.26 0.02 (35)
0.31 0.02 (35)
0.36 0.02 (35)
0.40 0.03 (35)
0.43 0.03 (35)
0.46 0.03 (35)
0.47 0.04 (35)
0.49 0.04 (35)
0.52 0.04 (34)
0.53 0.04 (34)
0.54 0.04 (14)
0.55 0.04 (14)
0.55 0.04 (14)
0.55 0.04 (14)
Group VII
1000 mg/kg/day
1.03 0.08 (45)
1.23 0.09 (45)
1.42 0.12 (45)
1.57 0.14 (45)
1.67 0.17 (45)
1.77 0.19 (45)
1.84 .0.20 (45)
1.90 0.22 (45)
1.95 0.22 (45)
2.00 0.23 (45)
2.06 0.27 (25)
2.10 0.27 (25)
2.05 0.28 (25)
2.05 0.28 (25)
63
ompany Sanitized. Does not contafn TSCA CBI
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
__
TABLE 2
MEAN DAILY DOSE VOLUMES (mL) FOR FEMALE RATS
I I Group
0 mg/kg/day
Group IV 50 mg/kg/day
DAY 0 - DAY 6
0.76 0.04 (45)
0.04 0.00 (35)
DAY 7 - DAY 13
0.85 0.05 (45)
0.04 0.00 (35)
DAY 14 - DAY 20
0.92 0.06 (45)
0.04 0.01 (35)
DAY 21 - DAY 27
0.99 0.08 (45)
0.05 0.00 (35)
DAY 28 - DAY 34
1.08 0.09 (45)
0.05 0.01 (35)
DAY 35 - DAY 41
1.10 0.09 (45)
0.05 0.01 (35)
DAY 42 - DAY 48
1.14 0.10 (45)
0.06 0.01 (35)
DAY 49 - DAY 55
1.17 0.10 (45)
0.06 0.01 (35)
DAY 56 - DAY 62
1.20 0.10 (45)
0.06 0.01 (35)
DAY 63 - DAY 69
1.24 0.10 (45)
0.06 0.01 (35)
DAY 70 - DAY 76
1.27 0.11 (25)
0.06 0.00 (15)
DAY 77 - DAY 83
1.28 0.11 (25)
0.06 0.01 (15)
DAY 84 - DAY 90
1.30 0.13 (25)
0.06 0.01 (15)
DAY 91
Data summarized as:
1.37 0.15 (10)
0.06 0.00 (10)
Mean
Standard Deviation (n)
Group VI 250 mg/kg/day
0.19 0.01 (35)
0.21 0.02 (35)
0.23 0.02 (35)
0.25 0.02 (35)
0.27 0.03 (35)
0.28 0.03 (35)
0.29 0.03 (35)
0.30 0.03 (35)
0.30 0.03 (35)
0.31 0.03 (35)
0.30 0.03 (15)
0.32 0.04 (15)
0.33 0.04 (15)
0.34 0.04 (10)
Group VIII
1000 mg/kg/day
0.76 0.05 (45)
0.85 0.06 (45)
0.93 0.07 (45)
0.99 0.09 (45)
1.05 0.09 (45)
1.08 0.10 (45)
1.12 0.11 (45)
1.15 0.12 (45)
1.17 0.11 (45) 1.21 0.12 (45) 1.25 0.14 (25)
1.26 0.15 (25)
1.28 0.15 (25)
1.26 0.20 (10)
64
Company SanRteed. Does not contain TSCA CB(
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLES MEAN BODY WEIGHTS (g) OF MALE RATS
Group I 0 ing/kg/day
III Group
50 mg/kg/day
Group V 250 mg/kg/day
Group VII
1000 mg/kg/day
Dosing Period for Subchronic Toxicity and Reproduction Evaluations
DAY 0
255.1 16.9(45 )
254.7 15.6(35 )
253.0 15.6(35 )
252.9 16.9(45 )
DAY 7
308.5 22.2(45 )
305.6 21.5(35 )
305.9 20.3(35 )
300.5 20.6(45 )
DAY 14
352.8 27.0(45 )
353.2 28.2(35 )
352.5 24.0(35 )
344.8 26.8(45 )
DAY 21
394.2
31.9(45 )
396.6 34.4(35 )
392.2 28.0(35 )
382.7 35.2(45 )
DAY 28
431.7 37.6(45 )
427.1 39.8(35 )
421.2 32.5(35 )
407.1# 40.9(45 )
DAY 35
457.5 40.3(45 )
459.9 41.4(35 )
446.4 33.2(35 )
431.9# 44.4(45 )
DAY 42
481.4 44.5(45 )
482.3 43.8(35 )
464.7 41.5(35 )
448.5# 46.3(45 )
DAY 49
499.6 46.5(45 )
505.0 45.1(35 )
483.8 43.8(35 )
465.1# 50.9(45 )
DAY 56
520.7 51.1(45 )
520.6 47.9(35 )
508.0 40.4(34 )
476.5ft 51.8(45 )
DAY 63
532.7 53.3(45 )
533.0 47.9(35 )
520.1 41.5(34 )
487.41 56.5(45 )
DAY 69 a
551.2 60.1(20 )
551.7 39.6(20 )
540.4 43.3(20 )
498.6ft
51.2(20 )
65
Company Sanitized. Does not cwWit w* ^"nf
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 3 (CONTINUED)
MEAN BODY WEIGHTS (g) OF MALE RATS
Group I 0 nig/kg/day
I I I Group
Group V
Group VII
50 mg/kg/day 250 mg/kg/day 1000 mg/kg/day
Dosing Period for Subchronic Toxicity Evaluation (Continued)
DAY 70
548.5 52.5(25 )
542.0 60.5(15 )
524.5 37.3(14 )
DAY 77
565.1 55.5(25 )
552.9 66.3(15 )
536.3 39.9(14 )
DAY 84
574.2 60.2(25 )
562.8 68.7(15 )
538.9 42.3(14 )
DAY 90 b
592.9 57.3(10 )
577.0 66.1(10 )
549.6 35.0(10 )
503.1ft 63.4(25 )
513.0# 65.9(25 )
500.7ft
69.0(25 )
474.7ft 27.4(10 )
Recovery Period for Subchronic Toxicity Evaluation
DAY 91 c
571.6 61.1(15 )
559.1 87.7(5 )
521.5 54.7(4 )
DAY 99
573.9 62.5(15 )
562.5 84.2(5 )
528.6 61.0(4 )
DAY 106
580.9 64.2(15 )
570.1 89.6(5- )
545.4 61.3(4 )
DAY 112
592.4 71.8(15 )
581.1 87.3(5 )
561.7 67.2(4 )
527.6 85.0(15 )
542.9 82.6(15 )
560.3 79.2(15 )
572.1 85.0(15 )
DAY 119
601.5 73.4(15 )
588.9 91.6(5 )
573.8 64.8(4 )
588.2 85.9(15 )
Data summarized as:
Mean
Standard Deviation (n)
Statistical Methods: Trend test (Jonckheere-Terpstra). ft Statistically significant difference at p < 0.05.
a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 69; subsequent data are reported as part of the reproduction
evaluation. b. Rats designated for the 90-day sacrifice (10 rats/group) only; rats were
sacrificed on test day 91. c. Rats designated for recovery evaluation.
day 91.
Recovery period began on test
66
Company Sanftfeed. Does not contain TSCA CBI
H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-4739
TABLE 4 MEAN BODY WEIGHTS (g) OF FEMALE RATS
I I Group
0 mg/kg/day
Group IV 50 mg/kg/day
Group VI 250 mg/kg/day
Group VIII
1000 mg/kg/day
Dosing Period for Subchronic Toxicity and Reproduction Evaluations
DAY 0
187.3 10.1(45 )
184.7 11.8(35 )
187.2 13.6(35 )
186.7 11.6(45 )
DAY 7
208.4 12.0(45 )
205.5 14.8(35 )
208.7 16.9(35 )
208.5 14.0(45 )
DAY 14
227.5 15.5(45 )
227.8 15.7(35 )
229.5 19.1(35 )
227.0 16.4(45 )
DAY 21
244.0 18.0(45 )
244.5 18.7(35 )
249.8 24.4(35 )
241.6 20.6(45 )
DAY 28
265.2 20.2(45 )
265.2 22.5(35 )
265.1 25.1(35 )
258.8 21.7(45 )
DAY 35
272.3 21.8(45 )
271.7 21.6(35 )
274.2 25.8(35 )
266.3 22.5(45 )
DAY 42
281.9 23.5(45 )
285.0 23.0(35 )
283.4 26.3(35 )
277.4 26.0(45 )
DAY 49 DAY 56
289.2 22.8(45 )
296.4 23.6(45 )
289.4 24.3(35 )
297.8 24.7(35 )
290.5 27.5(35 )
298.7 28.6(35 )
284.2
26.4(45.)
288.9 26.9(45 )
DAY 63
300.1 24.6(45 )
301.3 26.5(35 )
303.0 27.8(35 )
294.2 29.1(45 )
DAY 69 a
304.2 22.9(20 )
312.9 29.4(20 )
306.1 27.2(20 )
296.7 28.4(20 )
67
Company SanHteed. Does not contain TSCA CQ\
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 4 (CONTINUED)
MEAN BODY WEIGHTS (g) OF FEMALE RATS
I I Group
0 mg/kg/day
Group IV 50 mg/kg/day
Group VI 250 mg/kg/day
Group VIII
1000 mg/kg/day
Dosing Period for Subchronic Toxicity Evaluation (Continued)
DAY 70
307 .7 27 .4(25 )
299 .5 19 .2 (15 )
309 .0 32 .9 (15 )
DAY 77
311 .0
27 .1(25 )
304 .6 18 .9 (15 )
312 .2 37 .4 (15 )
DAY 84
316 .6 30 .1(25 )
306 .2 18 .0 (15 )
320 .0 40 .5 (15 )
DAY 91 b
330 .8
37 .2(10 )
309 .3 17 .5 (10 )
328 .2 41 .0 (10 )
Recovery Period for Subchronic Toxicity Evaluation
DAY 91 c
308 .6
24 .9(15 )
301 .7 15 .9 (5 )
304 .8 40 .0(5 )
DAY 99
317 .5 22 .1(15 )
307 .7 16 .7 (5 )
313 .6 42 .9 (5 )
DAY 106
322 .2
24 .6(15 )
313 .0 15 .7 (5 )
316 .6 44 .9 (5 )
DAY 112
326 .2
23 .4(15 )
.316 .3 13 .2 (5 )
323 .4 44 .1 (5 )
DAY 119
327 .5 26 .1(15 )
320 .2 10 .1 (5 )
331 .8 45 .6 (5 )
303 .6 33 .5 (25 )
309 .3 36 .9 (25 )
312 .7 36 .5 (25 )
308 .0 45 .7 (10 )
318 .6 31 .2 (15 )
328 .1 31 .9 (15 )
337 .8 33 .5 (15 )
337 .7 34 .5 (15 )
341 .7 34 .3 (15 )
Data summarized as:
Mean
Standard Deviation (n)
Statistical Methods: Trend test (Jonckheere-Terpstra). There were no statistically significant differences at p < 0.05.
a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 69; subsequent data are reported as part of the reproduction
evaluation. b. Rats designated for the 90-day sacrifice (10 rats/group) only; rats were
sacrificed on test day 92. c. Rats designated for recovery evaluation.
day 91.
Recovery period began on test
68
eompam. Sanded. Do.. no, contain TSCA C^
H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739
TABLES MEAN BODY WEIGHT GAINS (g) OF MALE RATS
III Group I
Group
0 mg/kg/day 50 mg/kg/day
Group V
Group VII
250 mg/kg/day 1000 mg/kg/day
Dosing Period for Subchronic Toxicity and Reproduction Evaluations
DAY 0 - DAY 7
'53.4
8.7(45 )
50.9 10.0(35 )
52.9 9.9(35 )
47.5# 8.7(45 )
DAY 7 - DAY 14
44.3 8.3(45 )
47.7 9.5(35 )
46.5 6.6(35 )
44.3 9.4(45 )
DAY 14 - DAY 21
41.4 8.9(45 )
43.3 9.1(35 )
39.7 10.4(35 )
37.9 11.6(45 )
DAY 21 - DAY 28 DAY 28 - DAY 35
37.5 9.0(45 )
25.8 8.1(45 )
30.5# 10.4(35 )
32.8 12.6(35 )
29.1# 12.3(35 )
25.2 6.9(35 )
24.4ft 11.7(45 )
24.9 9.1(45 )
DAY 35 - DAY 42 DAY 42 - DAY 49 DAY 49 - DAY 56 DAY 56 - DAY 63 DAY 63 - DAY 69 a
23.9 8.8(45 )
18.2 7.6(45 )
21.1 8.9(45 )
12.0 11.5(45 ) 12.8
4.9(20 )
22.4 7.9(35 )
22.7 10.5(35 )
15.6 9.1(35 .)
12.4 9.7(35 )
11.3 6.8(20 )
18.3 19.9(35 )
19.1 13.4(35 )
20.5 9.6(34 )
12.0 8.7(34 )
10.7 8.4(20 )
16.6ft
8.1(45 )
16.6 11.6(45 )
11.4# - 8.5(45 )
10.8 8.4(45 )
9.8 9.8(20 )
DAY O - DAY 69 a
294.6 46.4(20 )
295.8 37.7(20 )
285.0 36.2(20 )
246.8# 41.7(20 )
^
69
ewnpany SanHbed. Does not contain TSCA (^
H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739
TABLE 5 (CONTINUED)
MEAN BODY WEIGHT GAINS (g) OF MALE RATS
III Group I
Group
0 ing/kg/day 50 mg/kg/day
Group V
Group VII
250 mg/kg/day 1000 mg/kg/day
Dosing
DAY 63
Period for
- DAY 70
Subchronic Toxicity
20.4 14.1(25 )
Evaluation
18.9 6.1(15 )
(Continued) 18.0 6.9(14 )
DAY 70 - DAY 77
16.6 6.2(25 )
10.9 8.5(15 )
11.8 6.7(14 )
DAY 77 - DAY 84
9.1 9.5(25 )
9.9 7.5(15 )
2.7S 9.4(14 )
DAY 84 - DAY 90"
6.9 6.1(10 )
10.0 4.0(10 )
5.1 6.7(10 )
DAY 84 - DAY 91 c
5.3 15.8(15 )
4.4 8.3(5 )
-3.6 8.1(4 )
16.9 8.1(25 ) 9.9ft
10.8(25 ) -12.3#
17.0(25 )
2.5 7.8(10 ) 7.9 10.6(15 )
DAY O - DAY 90 b
338.2 52.3(10 )
322.5 62.8(10 )
297.5 30.5(10 )
DAY 0 - DAY 91 c
318.2 51.6(15 )
308.8 76.6(5 )
273.1 36.8(4 )
Recovery Period for Subchronic Toxicity Evaluation
DAY 91 - DAY 99
2.2 8.0(t5 )
3.4 8.6(5 ).
7.1 13.4(4 )
DAY 99 - DAY 106
7.0 7.7 (15 )
7.6 7.0(5 )
16.7ft 2.6(4 )
DAY 106 - DAY 112
11.5 11.6(15 )
11.0 5.0(5 )
16.3 6.4(4 )
DAY 112 - DAY 119
9.1 6.3(15 )
7.7 7.8(5 )
12.2 4.3(4 )
224.2ft 28.7(10 )
271.6# 73.7(15 )
15.2# 14.2(15 )
17. 5# 12.3(15 )
11.8 12.0(15 )
16.1# 5.1(15 )
DAY 91 - DAY 119 c
29.9 20.4(15 )
29.8 10.8(5 )
52.3 19.9(4 )
60.6# 22.5(15 )
Data summarized as: Mean Standard Deviation (n)
Statistical Methods: Trend test (Jonckheere-Terpstra). ft Statistically significant difference at p < 0.05.
a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 69; subsequent data are reported as part of the reproduction
evaluation. b. Rats designated for the 90-day sacrifice (10 rats/group) only; rats were
sacrificed on test day 91. c. Rats designated for recovery evaluation.
day 91.
Recovery period began on test
!
70
| Company Sanitized. Does not contain TSCA CBt
CompanyganBfeerf n^o, ,,,,, ,,
H-24616; Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 6 MEAN BODY WEIGHT GAINS (g) OF FEMALE RATS
II Group
Group IV
0 mg/kg/day 50 mg/kg/day
Group VI
Group VIII
250 mg/kg/day 1000 mg/kg/day
Dosing Period for Subchronic Toxicity and Reproduction Evaluations
DAY 0 - DAY 7
21 .2
6 .5(45 )
20 .9
9 .4(35 )
21 .5 8 .0(35 )
21 .7
6 .6(45 )
DAY 7 - DAY 14
19 .1 9 .3(45 )
22 .3
7 .6(35 )
20 .9 8 .3(35 )
18 .6 6 .3(45 )
DAY 14 - DAY 21
16 .5 7 .3(45 )
16 .7
6 .7(35 )
20 .2
9 .8(35 )
14 .6 7 .9(45 )
DAY 21 - DAY 28
21 .3 9 .2(45 )
20 .6 8 .7(35 )
15 .3 8 .9(35 )
17 .2ft
8 .2(45 )
DAY 28 - DAY 35
7 .0
10 .8(45 )
6 .5 7 .8(35 )
9 .1
7 .1(35 )
7 .4 7 .7 (45 )
DAY 35 - DAY 42
9 .6 8 .5(45 )
13 .3 7 .3(35 )
9 .2 6 .7(35 )
11 .2
9 .4(45 )
DAY 42 - DAY 49
7 .3
10 .5(45 )
4 .3
6 .2(35 )
7 .1
7 .7(35 )
6 .8 8 .1(45 )
DAY 49 - DAY 56
7 .2 9 .0(45 )
8 .4 8 .8(35 )
8 .2
6 .5(35 )
4 .6 7 .9(45 )
DAY 56 - DAY 63
3 .7
8 .0(45 )
3 .5 8 .0(35 )
4 .3 6 .1(35 )
5 .3
7 .0(45 )
DAY 63 - DAY 69 a
4 .0
6 .7(20 )
4 .4 5 .7(20 )
2 .3
5 .3(20 )
5 .6
6 .8(20 )
DAY 0 - DAY 69 "
116 .6
20 .6(20 )
125 .7
23 .5(20 )
117 .8 22 .3(20 )
109 .8
24 .1(20 )
71
Company Sanitized. Pw""'c""'-'- -*"'* "^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 6 (CONTINUED)
DuPont-4739
MEAN BODY WEIGHT GAINS (g) OF FEMALE RATS
II Group
Group IV
0 mg/kg/day 50 mg/kg/day
Group VI 250 mg/kg/day
Dosi ng
DAY 63
Priod for
- DAY 70
Siibchron;ic Tcixicit.y
7 .5 5 .3(25 )
Ev'aluaf:ion
7 .7
8 .1(15 )
((:onitinued)
7 .0 9 .9(15 )
DAY 70 - DAY 77
3 .4 7 .4(25 )
5 .1 10 .2(15 )
3 .3 9 .5(15 )
DAY 11 - DAY 84 DAY 84 - DAY 91 b
5 .6
6 .6(25 )
0 .2 9 .7(10 )
1 .6 7 .7(15 ) -0 .8 6 .9(10 )
7 .7 10 .2(15 )
1 .6 3 .8(10 )
DAY 84 - DAY 91 c
1 .3
5 .1(15 )
3 .3
10 .2(5 )
-1 .9 8 .4(5 )
Group VIII
1000 mg/kg/day
6 .9 7 .2(25 ) 5 .7 8 .3(25 ) 3 .4 8 .2(25 ) 0 .7 9 .4(10 ) 2 .3 6 .7(15 )
DAY 0 - DAY 91
130 .4 28 .5(25 )
125 .5 16 .2(15 )
134 .7 28 .4(15 )
Recovery Period for Subchronic Toxicity Evaluation
DAY 91 - DAY 99
8 .9 7 .2(15 )
6 .0
11 .7(5 )
DAY 99 - DAY 106
4 .7 7 .6(15 )
5 .3
- 5 .5(5 )
8 .8 7 .5(5 ) 3 .0 3 .4(5 )
DAY 106 - DAY 112
4 .0
5 .9(15 )
3 .4
7 .3(5 )
6 .8 5 .5(5 )
DAY 112 - DAY 119
1 .3
11 .9(15 )
3 .9 5 .8(5 )
8 .4 5 .9(5 )
127 .7 28 .8(25 )
9 .5 4 .2(15 ) 9 .7
6 .8(15 ) -0 .0 21 .2(15 )
4 .0
6 .9(15 )
DAY 91 - DAY 119 c
18 .9 11 .7(15 )
18 .5 18 .5(5 )
27 .0 9 .2(5 )
23 .2
17 .0(15 )
Data summarized as:
Mean
Standard Deviation (n)
Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p < 0.05.
a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 69; subsequent data are reported as part of the reproduction evaluation.
b. Rats designated for the 90-day sacrifice (10 rats/group) only; rats were sacrificed on test day 92.
c. Rats designated for recovery evaluation. Recovery period began on test
day 91.
72
Sompany Sanitized. Does not contain TSCA CBI
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE? MEAN DAILY FOOD CONSUMPTION (g) BY MALE RATS
III Group I
Group
0 nig/kg/day 50 mg/kg/day
Group V
Group VII
250 mg/kg/day 1000 mg/kg/day
Dosing E'erioid for Sub chron:i-c Toxicit y
DAY 0 - DAY 7
28 .7
3 .0(44 )
DAY 7 - DAY 14
30 .4
3 .1(45 )
DAY 14 - DAY 21
32 .1 3 .3(45 )
DAY 21 - DAY 28
32 .6
3 .5(45 )
DAY 28 - DAY 35
31 .2
3 .4(45 )
DAY 35 - DAY 42
32 .1 3 .5(45 )
DAY 42 - DAY 49
31 .3
3 .4(45 )
DAY 49 - DAY 56
32 .8 3 .7(45 )
DAY 56 - DAY 63
32 .4 4 .3(45 )
DAY 63 - DAY 69 -
33 .2
4 .5(20 )
an.d Reprodu<:tioin Evaluati ons
28 .7 2 .3(35 )
27 .6 2 .5(35 )
27 .9 2 .9(45 )
30 .7
3 .2(35 )
30 .5 2 .7(35 )
29 .8 3 .2(45 )
32 .4 3 .3(35 )
31 .6 2 .6(35 )
31 .2
4 .1(45 )
32 .6 3 .5(35 )
30 .5# 2 .6(35 )
29 .2# 4 .0(45 )
31 .5 3 .4(35 )
30 .2
2 .3(35 )
29 .5ft
3 .9(45 )
31 .4 3 .3(35 )
29 1#
4 .6(35 )
28 .7S
3 .5(45 )
31 .1 3 .3(35 )
29 .3# 3 .5(35 )
28 .8 3 .9(45 )
31 .6 2 .9(35 )
31 .5
3 .1(34 )
29 -5# 3 .5(45 )
31 .3 3 .1(35 )
31 .2
2 .9(34 )
29 .S
3 .7(45 )
33 .4 3 .0(20 )
31 .8 2 .7(20 )
31 .1 4 .2(20 )
DAY 0 - DAY 69
32 .03 3 .651(19 )
31 .75 2 .444(20 )
30 .80 2 .391(20 )
29 62# 2 .788(20 )
73
Company Sanitized. Does not contafn TSCA CB1
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 7 (CONTINUED)
MEAN DAILY FOOD CONSUMPTION (g) BY MALE RATS
III Group I
Group
0 mg/kg/day 50 mg/kg/day
Group V 250 mg/kg/day
Dosirig Peiriod for
DAY 63 - DAY 70
Siibchron ic Tcixicil;y E-v'alua t ion
32 .5 3 .6(25 )
32 .0 2 .7(15 )
(C:ontinued) 30.1 2.2(14 )
DAY 70 - DAY 77 DAY 77 - DAY 84 b
DAY 84 - DAY 90 "^
DAY 84 - DAY 91 l'd
32 .3
3 .5(25 )
31 .7
3 .4(20 ) 32 .4
4 .2(10 )
30 .9
2 .3(10 )
32 .0 3 .4(15 )
32 .2
2 .8(10 ) 31 .7
3 .1(10 )
30.2 2.2(14 )
29.1# 2.6(10 )
28.3ft
2.3(10 )
Group VII
1000 mg/kg/day
30 .5 4 .1(25 )
30 .1ft
4 .2(25 )
27 .6ft
3 .7(20 )
25 .5ft
2 .1(10 )
26 .4ft
6 .2(10 )
DAY 0 - DAY 90 "^ DAY 0 - DAY 91 ''''
32 .43 3 .296( 10 )
31 .28 1 .517(10 )
31 .35 2 .627( 1 0 )
29.99 1.674(10 )
Recovery Period for Subchronic Toxicity Evaluation
DAY 91 - DAY 99
29 .2
2 .6(15 )
29 .7
)'
3 .1(5
27.6 3.6(4 )
DAY 99 - DAY 106
30 .3 3 .6(15 )
30 .3
4 .2(5 )
29.5 4.0(4 )
DAY 106 - DAY 112
29 .6
4 .0(15 )
29 .0
4 .1(5 )
30.9 3.4(4 )
DAY 112 - DAY 119
31 .2 3 .8(15 )
30 .4 3 .7(5 )
32.3 2.8(4 )
27 .34tt 0 .890(]LO )
30 .70 3 .117(10 )
31 .3 4 .7 (15 )
31 .9
4 .5(15 )
31 .4
4 .2(15 )
32 .5
3 .8(15 )
DAY 91 - DAY 119 d
30 .06 3 .313( 15 )
29 .88 3 .704(5 )
29.94 3.422(4 )
31 .79 4 .120CIL5 )
Data summarized as: Mean Standard Deviation (n)
Statistical Methods: Trend test (Jonckheere-Terpstra). ft Statistically significant difference at p < 0.05. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused
on test day 69; food consumption data were not collected during the cohabitation and postmating periods. b. Food consumption data for rats designated for the 3-month recovery (5 rats/group) were not determined for test days 84 through 91. c. Rats designated for the 90-day sacrifice (10 rats/group) only; rats were sacrificed on test day 91. d. Rats designated for recovery only. Recovery period began on test day 91.
74
eompany sanmzed-D^ "t co^h, TSCA CB
H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739
TABLES MEAN DAILY FOOD CONSUMPTION (g) BY FEMALE RATS
I I Group
0 mg/kg/day
Group IV
Group VI
Group VIII
50 mg/kg/day 250 mg/kg/day 1000 mg/kg/day
Dosing Period for Sub(:hron:ic Toxicit y anci Rep>rodu<:tion Evaluati ons
DAY 0 - DAY 7
20 .4 2 .5(45 )
19. 9 1. 7(35 )
20. 3 2. 0(35 )
20. 1 1. 8(45 )
DAY 7 - DAY 14
22 .5 5 .7(45 )
21. 8 2. 0(35 )
21. 6 2. 5(35 )
21. 5 2. 1(45 )
DAY 14 - DAY 21
22 .4 2 .5(45 )
21. 9 1. 9(35 )
22. 3 2. 4(35 )
21. 6 2. 6(45 )
DAY 21 - DAY 28
23 .3
2 .5(45 )
23. 9 2. 4(35 )
23. 6 2. 6(33 )
22. 7 2. 7(44 )
DAY 28 - DAY 35
22 .3 2 .4(45 )
22. 5 2. 0(35 )
22. 1 2. 1(35 )
21. 1# 2. 8(45 )
DAY 35 - DAY 42
23 .1 2 .5(45 )
23. 7 2. 0(34 )
23. 3 2. 2(35 )
22. 6 2. 4(45 )
DAY 42 - DAY 49
21 .2
2 .4(45 )
22. 8 2. 1(35 )
21. 5 2. 6(35 )
21. 9 2. 4(45 )
DAY-49 - DAY 56
21 .9 2 .3(45 )
21. 8 3. 0(35 ) :
22. 3 2. 4(35 )
21. 2 2'. 7(45 )
DAY 56 - DAY 63
22 .3 2 .4(45 )
23. 1 2. 6(35 )
22. 0 2. 3(35 )
22. 0# 5. 3(45 )
DAY 63 - DAY 69 a
22 .65 1 .717(20 )
23. 50 2. 278(20 )
22. 16 2. 109(20 )
21. 66 2. 450(20 )
DAY 0 - DAY 69 a
21 .79 1 .299(20 )
22. 93 1. 802(20 )
22. 53 1. 682(18 )
21. 46 1. 742(20 )
75
Company SanUfzed. Does not contain TSCA CB)
H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739
TABLE 8 (CONTINUED)
MEAN DAILY FOOD CONSUMPTION (g) BY FEMALE RATS
Group II
0 mg/kg/day
Group IV
Group VI
50 mg/kg/day 250 ing/kg/day
Dosi ng P erio<a for s\ibchron:i.C T03ticilty Evaluation (C:on tinuec1)
Group VIII
1000 mg/kg/day
DAY 63 - DAY 70 DAY 70 - DAY 77 DAY 77 - DAY 84 "^
DAY 84 - DAY 91 "^
DAY 84 - DAY 91 bd
22 .8 2 .3(25 )
22 .1 2 .4(25 )
23 .0 2 .1(20 )
22 .4 3 .4(10 )
21 .6
1 .6(10)
22 .3
1 .8(15 ) 22 .8
1 .9(15 )
22 .3
1 .4(10 )
21 .2
1 .2(10 )
22 .6 2 .6(15 )
22 .8 2 .8(15 )
22 .1 3 .2(10 )
21 .5
3 .0(10 )
22 .5 2 .6(25 )
22 .8 3 .2(25 )
22 .6 3 .4(20 )
22 .4 2 .5(10 )
21 .6 2 .3(10 )
DAY 0 - DAY 91 b<:
22 .77 2 .404(2 0 )
21 .83 0 .884(9 )
21 .94 2 .386(1 0 )
Recovery Period for Subchronic Toxicity Evaluation
DAY 91 - DAY 99
23 .2
2 .2(15 )
22 .2
2 .6(5 )
21 .9 3 .3(5 )
DAY 99 - DAY 106
22 .9
2 .0(15 )
20 .8
3 .0(5 )
23 .1
1 .6(5 )
DAY 106 - DAY 112 DAY 112 - DAY 119
22 .6 1 .9(15 )
22 .3
2 .6(15 )
21 .5
3 .7(5 )
21 .6
2 .1(5 )
23 .8
1 .6(5 )
24 .4
2 .0(5 )
21 .62 2 .146(19 )
24 .7
3 .3(15 ) 24 .1 .- 3 .2(15 ) 22 .5
4 .9(15 )
23 .3
3 .8(15 )
DAY 91 - DAY 119 d
22 .80 1 .571(1 5 )
21 .55 2 .364(5 )
23 .25 1 .735(5 )
23 .70 2 .988(15 )
Data summarized as:
Mean
Standard Deviation (n)
Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p < 0.05.
a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 69; data were not collected during the cohabitation and postmating periods.
b. Pood consumption data for rats designated for the 3-month recovery (5 rats/group) were not determined for test days 84 through 91.
c. Rats designated for the 90-day sacrifice (10 rats/group) only; rats were sacrificed on test day 92.
d. Rats designated for recovery only. Recovery period began on test day 91.
76
eompany Sanitized. Does not contain TSCACB1
H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-4739
TABLE 9
MEAN DAILY FOOD EFFICIENCY OF MALE RATS (g body weight gain/g food consumed)
III Group I
Group
0 mg/kg/day 50 mg/kg/day
Group V
Group VII
250 mg/kg/day 1000 mg/kg/day
Dosing Period for Subchronic Toxicity and Reproduction Evaluations
DAY 0 - DAY 7 DAY 7 - DAY 14 DAY 14 - DAY 21 DAY 21 - DAY 28 DAY 28 - DAY 35 DAY 35 - DAY 42 DAY 42 - DAY 49 DAY 49 - DAY 56 DAY 56 - DAY 63 DAY 63 - DAY 69 "
0 .265 0 .029(44 )
0 .207 0 .028(45 )
0 .184 0 .029(45 )
0 .163 0 .034(45 )
0 .118 0 .034(45 )
0 .105 0 .032(45 )
0 .082 0 .032(45 )
0 .090 0 .033(45 )
0 .052 0 .048(45 )
0 .064 0 .025(20 )
0 .252 0 .038(35 )
0 .221 0 .031(35 )
0 .190 0 .028(35 )
0 .133S 0 .038(35 )
0 .148 0 .061(35 )
0 .102 0 .035(35 )
0 .104 0 .047 (-35 ->
0 .070 0 .040(35 )
0 .055 0 .042(35 )
0 .056 0 .032(20 )
0 .272 0 .036(35 )
0 .217 0 .023(35 )
0 .179 0 .041(35 )
0 133# 0 .053(35 )
0 .119 0 .033(35 )
0 .054 0 .276(35 )
0 .091 0 .064(35 )
0 .092 0 .039(34 )
0 .054 0 .037(34 )
0 .056 0 .041(20 )
0 .243S 0 .034(45 )
0 .211 0 .029(45 )
0 .171 0 .039(45 )
0 -116ft
0 .048(45 )
0 .120 0 .040(45 )
0 .082# 0 .036(45 )
0 .079 0 .050(45 )
0 .054# 0 .039(45 )
0 .049 0 .038(45 )
0 .049 0 .048(20 )
DAY 0 - DAY 69 a
0 .134 0 .009(19 )
0 .135 0 .013(20 )
0 .134 0 .013(20 )
0 -120f
0 .012(20 )
77
Company Sanlthed. Does not contain TSCA C8
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 9 (CONTINUED)
MEAN DAILY FOOD EFFICIENCY OF MALE RATS (g body weight gain/g food consumed)
Dosi ng
DAY 63
Period for
- DAY 70
III Group I
Group
0 mg/kg/day 50 mg/kg/day
Group V 250 mg/kg/day
;3ubchronic Tcixici ty Bv'aluat i on i[Cont inued)
0 .087 0 .047(25 )
0. 084 0. 025(15 )
0 .085 0 .031(14 )
Group VII
1000 mg/kg/day
0 .079 0 .034(25 )
DAY 70 - DAY 77 DAY 77 - DAY 84 b
0 .073 0 .025(25 )
0 .046 0 .040(20 )
0. 047 0. 036(15 ) 0. 043 0. 034(10 )
0 .055 0 .030(14 )
0 011# 0 .032(10 )
0 044ft
0 .047(25 )
-0 .'077# 0 .106(20 )
DAY 84 - DAY 90 b':
DAY 84 - DAY 91 "^
0 .035 0 .032(10 )
0 .043 0 .039(10 )
0. 052 0. 019(10 )
0 .029 0 .040(10 )
0 .018 0 .049(10 )
0 .044 0 .063(10 )
DAY 0 - DAY 90 ''c
0 .115 0 .009(10 )
0. 114 0. 016(10 )
0 .110 0 .006(10 )
DAY 0 - DAY 91 bd
0 .119
-
-
0 .008(10 )
One-Mon th Recovery Period for Subchronic Toxicity Evaluation
DAY 91 - DAY 99
0 .008 0 .032(15 )
0. 015 0. 037(5 )
0 .028 0 .051(4 )
DAY 99 - DAY 106
0 .032 0 .037(15 )
0. 033 0. 032(5 )
0 .082# 0 .016(4 )
DAY 106 - DAY 112
0 .060 0 .050(15 )
0. 066 0. 036(5 )
0 .086 0 .024(4 )
DAY 112 - DAY 119
0 .041 0 .028(15 )
0. 034 0. 035(5 )
0 .054 0 .020(4 )
0 .091# 0 .010(10 )
0 .095# 0 .015(10 )
0 058tt
0 .051(15 )
0 080ft
0 .066(15 )
0 .057 0 .066(15 )
0 .072# 0 .023(15 )
DAY 91 - DAY 119 d
0 .034 0 .021(15 )
0. 035 0. 011(5 )
0 .061 0 .017(4 )
0 .068# 0 .021(15 )
Data summarized as: Mean Standard Deviation (n)
Statistical Methods: Trend test (Jonckheere-Terpstra). tt Statistically significant difference at p < 0.05.
a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 69; data were not collected during the cohabitation and postmating periods.
b. Food consumption data for rats designated for the 3-month recovery (5 rats/group) were not determined for test days 84 through 91.
c. Rats designated for the 90-day sacrifice (10 rats/group) only; rats were sacrificed on test day 91.
d. Rats designated for recovery only. Recovery period began on test day 91.
78
Company SanHTzed. Does not contain TSCA CBI
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 10
MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (g body weight gain/g food consumed)
1000 mg/kg/day
II Group
0 mg/kg/ day
Group IV
(3roup VI
(3roup VIII
50 mg/kg/clay :250 mg/kg/d,ay
Dosi ng Period for Sulachronic Tc)xici ty and Repr-oduc'tion Evalugitionis
DAY 0 - DAY 7
0.148 0.042(45 )
0.147 0.059(35 )
0.149 0.048(35 )
DAY 7 - DAY 14
0.121 0.052(45 )
0.145 0.046(35 )
0.137 0.054(35 )
DAY 14 - DAY 21
0.103 0.042(45 )
0.108 0.040(35 )
0.127 0.056(35 )
DAY 21 - DAY 28
0.132 0.058(45 )
0.122 0.047(35 )
0.091ft 0.052(33 )
0.153 0.041(45 )
0.122 0.036(45 )
0.095 0.048(45 )
0.106ft 0.050(44 )
DAY 28 - DAY 35
0.042 0.065(45 )
0.041 0.048(35 )
0.058 0.044(35 )
0.046 0.060(45 >
DAY 35 - DAY 42 DAY 42 - DAY 49 DAY 49 - DAY 56
0.058 0.050(45 )
0.047 0.070(45 )
0.045 0.058(45 )
0.080 0.040(34 )
0.026 0.038(35 )
0.055 0.054(35 )
0.055 0.041(35 )
0.046 0.049(35 )
0.052 0.040(35 )
0.068 0.057(45 )
0.043 0.052(45 )
0.029 0.051(45 )
DAY 56 - DAY 63 DAY 63 - DAY 69 a
0.023 0.052(45 )
0.028 0.049(20 )
0.019 0.050(35 )
0.032 0.038(20 )
0.028 0.041(35 )
0.015 0.038(20 )
0.034 0.043(45 )
0.041 0.052(20 )
DAY 0 - DAY 69 a
0.077 0.012(20 )
0.079 0.009(20 )
0.077 0.010(18 )
0.074 0.012(20 )
79
company Sanitized. Does not contain TSCA C6l
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 10 (CONTINUED)
MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (g body weight gain/g food consumed)
1 000 mg/kg/dciy
Group I]
0 mg/kg/'iday
Grouip IV
Grou]:? VI
50 n ig/kg/clay 250 rng/kg/d,ay
Dosing Period for iiubchronic T CxiciLty Ev'aluati.on (Cont inued)
DAY 63 - DAY 70
0.048 0.035(25 )
0. 048 0. 053(15 )
0 .042
0 .062(15 )
DAY 70 - DAY 77 DAY 77 - DAY 84 b DAY 84 - DAY 91 "^ DAY 84 - DAY 91 l'd
0.020 0.048(25 )
0.041 0.038(20 )
-0.001 0.051(20 )
-0.004 0.067(10 )
0. 030 0. 062(15 ) 0. 006 0. 038(10 )
-0. 006
0. 047(10 )
-0. 006
0. 047(10 )
0 .018 0 .060(15 )
0 .046 0 .056(10 )
0 .009 0 .025(10 )
0 .009 0 .025(10 )
Grout3 VIII
0 .042 0 .043(25 ) 0 .033 0 .054(25 ) 0 .025 0 .043(20 ) 0 .009 0 .050(20 ) 0 .005 0 .060(10 )
DAY 0 - DAY 91 ''c
0.064 0.009(20 )
0. 062 0. 004(9 )
0 .069 0 .007(10 )
One-Month Recovery Period for Subchronic Toxicity Evaluation
DAY 91 - DAY 99
0.046 0.037(15 )
0. 029 0. 071(5" ).
0 .048 0 .038(5 )
DAY 99 - DAY 106
0.028 0.047(15 )
0. 035 0. 035(5 )
0 .017 0 .021(5 )
DAY 106 - DAY 112
0.028 0.045(15 )
0. 022 0. 053 (5 )
0 .047 0 .041(5 )
DAY 112 - DAY 119
-0.000 0.093(15 )
0. 027 0. 037(5 )
0 .048 0 .033(5 )
0 .062 0 .011(19 )
0 .048 0 .020(15 )
0 .056 0 .037(15 )
-0 .055 0 .351(15 )
0 .026 0 .050(15 )
DAY 91 - DAY 119 d
0.029 0.018(15 )
0. 029 0. 031(5 )
0 .041 0 .013(5 )
0 .034 0 .023(15 )
Data summarized as: Mean Standard Deviation (n)
Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p < 0.05.
a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 69; data were not collected during the cohabitation and postulating periods.
b. Food consumption data for rats designated for the 3-month recovery (5 rats/group) were not determined for test days 84 through 91.
c. Rats designated for the 90-day sacrifice (10 rats/group) only; rats were sacrificed on test day 92.
d. Rats designated for recovery only. Recovery period began on test day 91.
80
inoteorrta?nTSCACai
^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 11 SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS
Treatment Group
Dose
Number Animals at Study Start
I
0 mg/kg/day
45
50
III
mg/kg/day
35
V
250 mg/kg/day
35
Eye Observations Corneal Opacity
Incidence Mean onset (Days)
Exophthalmus
Incidence Mean onset (Days)
Enophthalmus
Incidence Mean onset (Days)
General Teeth Observations Absent
Incidence Mean onset (Days)
Breathing Observations Noise
Incidence Mean onset (Days)
103
-
-
0
91
21 00 0 0
106
-
1 , 0 -
-
0
-
-
-
0 0000 81
\Qy
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABUill (CONTINUED)
SUMMARY OF CLINICAI. OBSERVATIONS FOI1 MALE RATS
Treatment Group
Dose
Number Animals at Study Start
i
0 mg/kg/day
45
50
in
mg/kg/day
35
V
250 mg/kg/day
35
Discharge Eyes
Incidence
2
Mean onset (Days)
77
0
1
-
63
Nose
Incidence
1
0
Mean onset (Days)
77
-
-
Hair Loss
Incidence
5
4
4
Mean onset (Days)
44
35
26
Wound
g
Deep (Neck, Tail)
1 W
Incidence
1
Mean onset (Days)
69
0
1
-
51
ST
&
Superficial (Nose, Neck, Lumbar, Forepaw)
?
Incidence
3
(D
w
Mean onset (Days)
47
1
0
1
-
21
0
1
o*
3"
C-?
g
v
0 CO
82
^assf
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 11 (CONTINUED)
SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS
Treatment Group
Dose
Number Animals at Study Start
I
0 mg/kg/day
45
III
50 mg/kg/day
35
V
250 mg/kg/day
35
Hyperreac t ive
Incidence
1
Mean onset (Days)
49
Vocalization
Incidence
1
Mean onset (Days)
14
0
0
Incidence - The number of animals for which an observation was recorded.
Mean onset (Days) - The mean of the first test day an observation was recorded for that grou
Statistical Methods: Trend test (Cochran-Armitage). There were no statistically significant differences at p < 0.05.
83
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 12 SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS
Treatment Group
Dose
Number Animals at Study Start
II
0 mg/kg/day
45
Mass Side Right
Mass #1
Not Ulcerated
Incidence
1
Mean onset (Days)
63
Eye Observations Corneal Opacity
Incidence
0
Mean onset (Days)
Exophthalmus
Sj
Incidence
0
^
Mean onset (Days)
"<
Enophthalmus
w
s
y
Incidence
0
R"
Mean onset (Days)
p.
0
8
0)
I
o o
S_
5"
^ s
{ --------------------------
EB
IV
50 mg/kg/day 35
VI 250 mg/kg/day
35
1
106
1
1
99
106
1
119
84
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 12 (CONTINUED)
SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS
Treatment Group Dose
Number Animals at Study Start
Abnormal Gait Hindlimb
Incidence Mean onset (Days)
Breathing Observations Noise
Incidence Mean onset (Days)
Discharge Eyes
Incidence Mean onset (Days)
Nose
Incidence Mean onset (Days)
II0 mg/kg/day 45 0
0
1
77
0
IV 50 mg/kg/day
35
VI 250 mg/kg/day
35
4
1
90
14
1
84
85
^LY
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS
Treatment Group
Dose
Number Animals at Study Start
II
0 ing/kg/day
45
Hair Loss
Incidence
8
Mean onset (Days)
51
Wound
Superficial (Neck, Side< Forelimb)
Incidence
1
Mean onset (Days)
99
IV 50 mg/kg/day
35
7
41
0
VI 250 mg/kg/day
35
6
39
1
49
Incidence - The number of animals for which an observation was recorded.
Mean onset (Days) - The mean of the first test day an observation was recorded for that group
Statistical Methods: Trend test (Cochran-Armitage). There were no statistically significant differences at p < 0.05.
86
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 13 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR MALE RATS
Treatment Group Dose
0 mg/kg/day
Examination Day: Test Day 88 Number of Rats Examined
Retina Retinal Degeneration Focal
Incidence
20 0 ( 0%)
50
III
mg/kg/day
10
V
250 mg/kg/day
10
1 ( 10%)
0 ( 0%)
Examination Day: Test Day 116
Number of Rats Examined
10
Retina Retinal Degeneration Focal
Incidence
1 ( 10%)
Incidence - The number of animals (percent of animals examined) for which an observation was
Statistical Methods: Trend test (Cochran-Armitage). There were no statistically significant differences at'p < 0.05.
87
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 14 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR FEMALE RATS
Treatment Group Dose Number of Rats Examined
II
0 mg/kg/day
25
IV 50 mg/kg/day
15
VI 250 mg/kg/day
14
Examination Day: Test Day 88
Number of Rats Examined
20
10
10
There were no ophthalmological abnormalities detected.
Examination Day: Test Day 116
Number of Rats Examined
10
There were no ophthalmological abnormalities detected.
H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739
TABLE 15
PERCENT SURVIVAL OF MALE RATS
Treatment Group Dose (mg/kg/day)
Animal Count at Study
DAYS ON TEST
Start
III I
V
VII
0
50
250
1000
45
35
35
45
0
7
14 21 28 35 42 49 56 63 70 77 84
9113
99 106 112 119
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
97
100
100
100
97
100
100
100
93
100
100
100
93
100
100
100
93
100
100
100
93
100
100
100
80
100
100
100
80
100
100
100
80
100
100
100
80
100
Number at study start
45
35
35
45
Sacrificed in extremis
0
0
-
1
0
Removed from study (test day 69)a
20
20
20
20
Sacrificed by design (test day 91) 10
10
10
10
Alive on test day 119
15
5
4
15
Percent Survival = Number of rats from study -
a. Rats designated b. Recovery period
(AE/Number of rats at risk)*100 at risk = Number at study start number sacrificed by design.
for reproduction evaluation were began on test day 91.
number of rats removed cohoused on test day 69.
Statistical Method: Cochran-Armitage trend test. There were no statistically significant decreases in survival at p < 0.05.
89
ompany Sanitized. Does not contain TSCA Cfii
H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739
TABLE 16 PERCENT SURVIVAL OF FEMALE RATS
II Treatment Group
Dose (mg/kg/day)
0
Number Animals at Study Start
45
IV
VI
VIII
50
250
1000
35
35
35
DAYS ON
0
7
14 21 28 35 42 49 56 63 703 77 84 91" 99 106 112 119
TEST
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
.
.
100
100
100
Number at study start
45
: 35
35
45
Accidentally killed
1
0
0
0
Removed from study (test day 69)"
20
20
20
20
Sacrificed by design (test day 92)
9
10
10
10
Alive on test day 119
15
5
5
15
Percent Survival = Number of rats from study -
a. Rats designated b. Recovery period
(AE/Number of rats at risk)*100 at risk = Number at study start - number of rats removed number sacrificed by design - accidentally killed.
for reproduction evaluation were cohoused on test day 69. began on test day 91.
Statistical Method: Cochran-Armitage trend test. There were no statistically significant decreases in survival at p < 0.05.
90
KompanySanitized. Does not contain TSCA CBt
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 17 MEAN FORELIMB GRIP STRENGTH (kg): MEAN OF THREE TRIALS
Male Rats Group:
Concentration: N:
0 mg/kg/day
10
ffl 50 mg/kg/day
10
V
250 mg/kg/day 10
vn
1000 mg/kg/day 10
Baseline Week 12 Recovery
0.71 (0.14) 1.42(0.33) 1.49(0.43)
0.65 (0.06) 1.32(0.36)
NM
0.73 (0.10) 1.22(0.39)
NM
0.67(0.12) 1.24(0.34) 1.42(0.26)
Female Rats Group:
Concentration: N:
n 0 mg/kg/day
10
IV
50 mg/kg/day 10
VI
250 mg/kg/day 10
Vffl
1000 mg/kg/day 10
Baseline Week 12 Recovery
0.66(0.08) 1.09(0.26) 1.01(0.34)
0.63 (0.11) 0.94 (0.24)
NM
0.70(0.16) 1.01 (0.41)
NM
0.68(0.13) 1.06 .(0.31) 0.93 (0.24)
Data arranged as:
Mean (Standard Deviation).
NM = Not measured.
Statistical Methods: Bartlett's test for homogeneity, followed by Analysis of Variance and Dunnett's test.
There were no statistically significant differences from control at p<0.05.
IpanSaynded. Does not eonlah, TSCA CB.
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 18 MEAN fflNDLIMB GRIP STRENGTH (kg): MEAN OF THREE TRIALS
Male Rats Group:
Concentration: N:
0 mg/kg/day
10
ffl 50 mg/kg/day
10
V
250 mg/kg/day 10
vn
1000 mg/kg/day
10
Baseline Week 12 Recovery
0.32 (0.07) 0.57(0.14) 0.78(0.15)
0.28 (0.06) 0.54 (0.13)
NM
0.36 (0.05) 0.69(0.16)
NM
0.32 (0.07) 0.60(0.12) 0.66 (0.07)
Female Rats Group:
Concentration: N:
n
0 mg/kg/day 10
IV
50 mg/kg/day 10
VI
250 mg/kg/day 10
vm
1000 mg/kg/day 10
Baseline Week 12 Recovery
0.31 (0.06) 0.51 (0.07) 0.58(0.12)
0.30 (0.05) 0.46 (0.09)
NM
0.35(0.07) 0.52(0.11)
NM
0.33 (0.06) 0.47 (0.09) 0.60 (0.14)
Data arranged as:
Mean (Standard Deviation).
NM = Not measured.
Statistical Methods: Bartlett's test for homogeneity, followed by Analysis of Variance and Dunnett's test.
There were no statistically significant differences from control at p<0.05.
^^
92
Company Sanitized. Does not contain TSCA CBI
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 19
SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR MALE RATS
BASELINE
WEEK 12
R
GROUP:
I
CONCENTRATION (mg/kg/day):
0
NUMBER EXAMINED:
10
III
V
VII
50
250
1000
10
10
10
I
III
V
VII
0
50
250 1000
10
10
10
10
APPROACH & TOUCH:
-1 no reaction 0 normal 1 increased reaction
(jumps away or attacks)
AUDITORY STIMULUS:
CT
-1 no reaction
J 0 normal reaction (rat flinches or flicks ear)
<S
1 exaggerated reaction
<B
(rat jumps, flips)
0010 0010 109 109
0 0 0 0 10
10
10
9
0
0
0
1
^
TAIL PINCH:
a,
-1 no response
0
0 normal (turns toward site)
<D
1 exaggerated response
3
2.
PUPILLARY RESPONSE:
3
1 absent
I'
O present
10
10
10
9
00000010 O
0
0 0 10
10
10
10
-4
DEFECATION IN MOTOR ACTIVITY MONITOR:
0
0 absent
>
1 present
a
D diarrhea
460370370190
93
0010 0010 0010 0010
00201000 10
8
9
10
208109280280 010 010 010 010
460640550460
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 19 (CONTINUED)
SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR MALE RATS
BASELINE
WEEK 12
R
GROUP:
I
CONCENTRATION (mg/kg/day):
0
NUMBER EXAMINED:
10
HI
V
VII
50
250
1000
10
10
10
I
III
V
VII
0
50
250 1000
10
10
10
10
URINATION IN MOTOR ACTIVITY MONITOR:
0
____1
abse
pre
nt
se
n
t
_
_
_
_
_
_
_
_
_
_
_
_
_
_
_
_
_
010
010
19_
0___10
19 19 010 19
There were no statistically significant differences by Cochran-Armitage test for trend at p < 0.05.
94
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 20
SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR FEMALE RAT
BASELINE
WEEK 12
GROUP:
II
CONCENTRATION (mg/kg/day):
0
NUMBER EXAMINED:
10
IV
VI VIII
50
250
1000
10
10
10
II
IV
VI VIII
0
50
250 1000
10
10
10
10
APPROACH & TOUCH:
-1 no reaction 0 normal 1 increased reaction
(jumps away or attacks)
0
0
0
0
10
9
10
10
0
1
0
0
AUDITORY STIMULUS:
-1 no reaction 0 normal reaction
(rat flinches or flicks ear) 1 exaggerated reaction
(rat jumps, flips)
0
0
0
0
10
8
10
9
0
2
0
1
TAIL PINCH:
-1 no response 0 normal (turns toward site) 1 exaggerated response
1
0
1
0
9
9
9
10
0
1
0
0
PUPILLARY RESPONSE:
1 absent 0 present
0
0
0
0
10
10
10
10
DEFECATION IN MOTOR ACTIVITY MO)NITOR:
0 absent
7
7
5
3*
1 present
3
3
5
7
D diarrhea
0
0
0
0
0
0
0
0
10
9
10
10
0
1
0
0
0
0
10
9
0
0
10
10
0
1
0
0
1
1
1
0
9
9
9
10
0
0
0
0
0
0
0
0
10
10
10
10
1
9# 6* 7*
9
1
4
3
0
0
0
0
95
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 20 (CONTINUED) SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR FEMALE RAT
BASELINE
WEEK 12
GROUP:
II
CONCENTRATION (nig/kg/day):
0
NUMBER EXAMINED:
10
IV
VI VIII
50
250 1000
10
10
10
II
IV
VI Vffl
0
50
250
1000
10
10
10
10
URINATION IN MOTOR ACTIVITY MONITOR:
0001 0111 0 absent
1
10
10
9
9
9
present_________________10
9_________10
#
Statistically significant difference by Fisher's exact test at p < 0.05.
*
Statistically significant difference by Cochran-Annitage test for trend at p < 0.05.
96
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 21 MOTOR ACTIVITY ASSESSNIENT: DURATION OF MOVEMENTS (sec) FOR MALE RAT
DOSAGE GROUP (mg/kg/day)
I
0
III
50
V
250
VII
1000
1
397 (54) 408 (33) 373 (33) 378 (57)
DOSAGE GROUP (mg/kg/day)
I
0
III
50
V
250
VII
1000
1
415 (57) 409 (37) 390 (53) 417 (58)
2
349 (87) 332 (56) 287 (50) 293 (69)
2
344 (70) 343 (67) 293 (78) 271 (93)
BASELINE
SUCCESSIVE 10-MINUTE INTERVALS
3
262 (95)
4
173(115)
5
57 (99)
170(101)
77 (102)
43 (77)
166 (137)
101 (115)
74 (99)
227 (74)
65 (93)
35 (93)
1
WEEK 12
SUCCESSIVE 10-MINUTE INTERVALS
3
288 (81)
4
220 (92)
5
152 (127)
265 (107)
208(119)
133(117)
243 (90)
126(106)
80 (92)
152(139)*
135 (135)
106(138)
6
T
23 (37)
1
7(13)
1
40 (95)
1
16 (46)
1
6
120 (83)
1
89 (76)
1
84 (87)
1
62 (102)
1
97
\^/
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 21 (CONTINUED)
MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS (sec) FOR MALE RAT
RECOVERY
DOSAGE GROUP (mg/kg/day)
SUCCESSIVE 10-MINUTE INTERVALS
123456 I
0
VII
1000
Data arranged as:
393 (74) 351(48)
283 (69) 233(79)
Mean (Standard Deviation).
215 (86) 161(59)
151 (76) 131(36)
129 (141) 114(77)
T
98 (107)
12
89(54)
10
Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Jonckheere's trend test or repeated measures analysis of variance was used to identify which dosage groups, if any, were significantly different from the control group. These tests were applied to bin data
* Statistically significant difference from control at p < 0.05.
98
\^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
0
g
|
.?
0
8
?
ST 3'
3 2
^
0 CO
TABLE 22
Men"OR ACTIWFY ASSESSMIiNT: DURATIC)N OF M<y/EMEN1FS (sec) FORFEMAL12 RA
DOSAGE GROUP (mg/kg/day)
II
0
IV
50
VI
250
vnl
1000
i 379 (63) 384 (85) 391 (50) 373 (48)
DOSAGE GROUP (mg/kg/day)
II
0
iv
50
250
VIII
1000
1 392 (43) 391 (46) 380 (74) 378 (43)
2
284 (52) 323 (94) 258(121) 257 (54)
2
312 (67) 322 (64) 274 (71) 266 (92)
BASELINE
SUCCESSIVE 10-MINUTE INTERVA.LS
3
146 (83)
4
91 (86)
C
77 (73)
274 (106)
193 (140)
170 (145)
167(119)
192 (140)
141 (123)
184(115)
105 (85)
95 (126)
WEEK 12
SUCCESSIVE 10-MINUTE INTERVALS
3
207 (70)
4
138 (94)
J
132 (105)
226 (96)
184 (97)
105 (88)
158(81)
176 (124)
114 (95)
133 (99)
112(103)
115 (90)
6
46 (76)
1
119(140)
1
75(114)
1
53 (78)
1
6
99 (77)
1
63 (84)
1
43 (44)
1
86 (95)
1
99
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 22 (CONTINUED)
MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS (sec) FOR FEMALE RA
DOSAGE GROUP (mg/kg/day)
II
0
VIII
1000
1
351 (46) 361 (61)
2
203 (56) 172 (45)
RECOVERY
SUCCESSIVE 10-MINUTE INTERVALS
3
136 (45)
4
172 (70)
5
104 (71)
128(51) ,
106 (52)
93 (61)
6
T
107 (54)
10
114(87)
9
Data arranged as:
Mean (Standard Deviation).
Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Jonckheere's trend test or repeated measures analysis of variance was used to identify which dosage groups, if any, were significantly different from the control group. These tests were applied to bin data
There were no statistically significant differences from control at p < 0.05.
100
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 23
MOTOR AC TIVITY ASSE;SSMENT: NUMBER OF MOiVEMENTS FC)RMALERA'TS
DOSAGE GROUP (mg/kg/day)
I
0
III
50
V
250
VII
1000
1 119 (20) 122 (19) 128(11) 133 (14)
2
117(20) 125 (21) 136(10) 132 (19)
BASELINE
SUCCESSIVE 110-MINUTE IN TERVALS
3
119(27)
4
85 (36)
5
27 (37)
95 (42)
47 (59)
30 (43)
89 (56)
67 (60)
47 (54)
120 (19)
42 (36)
25 (53)
6
17 (24) 8(12) 26 (46) 16 (41)
ff
WEEK 12
^
DOSAGE GROUP (mg/kg/day)
SUCCESSIVE lO-MDMUTE INTERVALS
I w
1
2
3
4
5
6
I
0
130(19)
128 (20)
125 (17)
110(33)
78 (59)
68 (41)
&
III
50
124 (9)
129 (14)
119(45)
94 (39)
66 (55)
59 (41)
1 250
133 (17)
136 (24)
118(30)
74 (57)
59 (53)
55 (44)
S
VII
1000
130 (22)
118(24)
71 (58) *
67 (54)
58 (62)
38 (46)
a
57
-r
,4
:
i
uj
101
\^
^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 23 (CONTINUED) MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR MALE RATS
DOSAGE GROUP (mg/kg/day)
I
0
VII
1000
i 122 (25)
136(14)
2
126 (25) 122 (33)
RECOVERY
SUCCESSIVE 10-MINUTE INTERVALS
3
99 (36)
4
80 (40)
5
54 (45)
100(31)
81 (19)
72 (37)
6
T
49 (37)
5
71 (36)
5
Data arranged as:
Mean (Standard Deviation).
Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis of variance with linear contrasts was dosage groups, if any, were significantly different from the control group. These tests were applied to bin data and total data.
* Statistically significant difference from control at p < 0.05.
102
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 24 MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR FEMALE RATS
DOSAGE GROUP (mg/kg/day)
II
0
IV
50
VI
250
VIII
1000
; L
130 (18) 120 (24) 129 (22) 132 (18)
DOSAGE GROUP (mg/kg/day)
II
0
IV
50
VI
250
VIII
1000
1
134(14) 133 (16) 134(19) 141 (12)
136 (14) 124 (23) 109 (41) 129 (13)
2
140 (14) 137(16) 129(15) 132(26)
BASELINE
SU(:CESSIVE 10-MINUTE IN TERVALS
5
4
5
91 (37)
62 (49)
56 (45)
118 (25) 85 (47)
92 (49) 89 (60)
80 (60) 78 (53)
100 (53)
76(51)
59 (67)
WEEK 12
SUCCESSIVE 10-MINUTE INTERVALS
3
4
5
119(25) 119(33) 101 (40)
88 (46)
96 (52) 108 (42) 100(47)
73 (50)
89 (56) 73 (53) 79 (47) 79 (54)
6
T
36(51)
5
61 (55)
5
45 (49)
5
48 (63)
5
6
T
71 (51)
6
48 (60)
6
36 (28)
5
57 (49)
5
103
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 24 (CONTINUED)
MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR FEMALE RATS
RECOVERY
DOSAGE
GROUP (mg/kg/day)
SUCCESSIVE 10-MINUTE INTERVALS
123456 II
0
vm
1000
143(15) 144(14)
126(11) 121(20)
Data arranged as:
Mean (Standard Deviation).
93(21) 91(30)
112(30) 82(32)
84(32) 77(41)
84(30)
6
82(48)
5
Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis of variance with linear contrasts wa dosage groups, if any, were significantly different from the control group. These tests were applied to bin data and total data.
There were no statistically significant differences from control at p < 0.05.
104
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 25
TEST/ PERIOD
SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS
Group I Omg/kg
Group m 50mg/kg
Group V 250 mg/kg
Group Vn
1000 mg/kg
RBC (xlO%iL) DAY 45 DAY 91
DAY 123 HGB (g/dL)
DAY 45 DAY 91
DAY 123 HCT (%)
DAY 45
DAY 91
DAY 123 MCV (fl)
DAY 45 DAY 91 DAY 123 MCH (pg) DAY 45
DAY 91
DAY 123
8.18 0.27(9) 8.74 0.23(10) 8.65 0.29(10)
15.0 0.5(9)
15.8 0.5(10)
15.0 0.5(10)
48.9 1.5(9)
49.5 1.3(10)
46.3 1.3(10)
59.8 1.2(9)
56.7 1.2(10)
53.6 1.5(10)
18.4 0.6(9)
18.1
0.6(10)
17.3
0.6(10)
8.07 0.32(10) 8.84 0.57(10)
a
14.9 0.4(10)
15.8 0.9(10)
a
-48.0 1.6(10)
49.5 3.1(10)
a
59.6 1.3(10)
56.0 1.4(10)
a
18.5 0.9(10)
17.9 0.7(10)
a
7.83 0.33(10) 8.73 0.37(10)
a
14.7 0.6(10)
15.8 0.6(10)
a
47.4 2.5(10)
49.7 2.5(10)
a
60.5 2.1(10)
56.9 1.9(10)
a
18.7 0.7(10)
18.1
0.6(10)
a
7.86 0.31(10) 8.50 0.44(10) 8.47 0.35(10)
14.4* 0.4(10) 15.2 0.6(10) 14.6 . 0.7(10)
46.5* 1.1(10)
47.8 2.1(10)
45.5 2.3(10)
59.2 1.6(10)
56.2 1.4(10)
53.7 2.1(10)
18.3 0.6(10)
17.9 0.6(10)
17.3 0.5(10)
105
0fflpany Sanitized. Does nol contain TSCA CBl
H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
__
DuPont-4739
TABLE 25 (Continued)
TEST/ PERIOD
SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS
Group I Omg/kg
Group ffl 50mg/kg
Group V 250 mg/kg
Group Vn
1000 mg/kg
MCHC (g/dL) DAY 45
DAY 91
DAY 123 RDW (%)
DAY 45 DAY 91
DAY 123 ARET (xlOV/xL)
DAY 45
DAY 91
DAY 123 WBC (xlOV/iL)
DAY 45 DAY 91 DAY 123 ANEU (xlOV^L) DAY 45 DAY 91 DAY 123
30.7 0.5(9)
31.8 0.5(10)
32.3 0.5(10)
11.5 0.5(9)
12.3 0.7(10)
13.4 0.4(10)
223 33(9)
192
36(10)
183
21(10)
14.08 2.83(9)
11.26 1.97(10)
13.85 2.80(10)
1.73 0.54(9) 1.45 0.27(10) 1.84 0.55(10)
31.1 1.0(10)
31.9 0.8(10)
a
11.5
0.5(10) 12.3
0.6(10)
a
216 27(10)
205 27(10)
a
16.84 2.73(10)
13.05 1.39(10)
a
2.02 0.36(10) 1.93 0.49(10)
a
31.0 0.7(10)
31.8 0.5(10)
a
11.5 0.5(10)
12.1
0.5(10)
a
208 33(10)
159 33(10)
a
16.43 2.68(10)
12.72 2.62(10)
a
1.85 0.64(10) 1.45 0.29(10)
a
30.9 0.6(10)
31.8 0.5(10)
32.2 0.4(10)
12.1
0.8(10) 12.6 0.8(10) 13.7 0.8(10)
219 50(10)
147* 40(10)
177
24(10)
18.67* 5.47(10)
13.54 3.41(10)
13.35 1.52(10)
2.04 0.76(10) 1.62 0.68(10) 2.16 0.79(10)
106
eompany sanm2ed- Does not co^In TSCA ^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 25 (Continued)
TEST/ PERIOD
SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS
Group I Omg/kg
Group in 50mg/kg
Group V 250 mg/kg
Group VH 1000 mg/kg
ANPRCxIOV/iL)
DAY 45
b
b
b
b
DAY 91
b
b
b
b
DAY 123
b
a
a
b
ALYM (xlOV/iL) DAY 45
DAY 91
DAY 123
AMON (xlOV^iL) DAY 45
DAY 91
DAY 123
AEOS (xlOV^L) DAY 45
DAY 91
DAY 123 ABAS (xlOV/xL)
DAY 45 DAY 91
DAY 123
11.55 3.00(9)
9.18 2.00(10)
11.16 2.29(10)
13.95 2.82(10)
10.36 1.48(10)
a
0.26 0.09(9)
0.31
- .-.
0.08(10)
0.32 0.11(10)
0.38@ 0.11(10)
.0.37
.
.
0.11(10)
a
0.18 0.15(9)
0.14 0.06(10)
0.15 0.09(10)
0.15 0.05(10)
0.17 0.05(10)
a
0.12 0.04(9) 0.08 0.03(10) 0.14 0.06(10)
0.10 0.05(10) 0.09 0.04(10)
a
13.84 2.28(10)
10.63 2.43(10)
a
0.32 0.08(10)
0.30
0
.
0
6
(
.
1
0.).
-
a
0.10 0.04(10)
0.15 0.09(10)
a
0.12 0.04(10) 0.08 0.04(10)
a
15.68* 4.78(10) 11.23 2.99(10) 10.34 1.93(10)
0.36 0.17(10) 0.32 0.08(10) 0.33 0.04(10)
0.15 0.13(10) 0.12 0.04(10) 0.15 0.08(10)
0.15 0.07(10) 0.11 0.05(10) 0.20 0.12(10)
107
Oompany SanIHzed. Does nol conia'n TSCA '^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 25 (Continued)
SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS
TEST/
Group I
Group m
Group V
PERIOD_________Omg/kg_____50mg/kg____250mg/kg
ALUC (xlOV^L) DAY 45
DAY 91
DAY 123
ABLT (xlOV^L) DAY 45 DAY 91 DAY 123
0.24 0.14(9) 0.11 0.05(10) 0.23 0.15(10)
b b b
0.24 0.07(10) 0.12 0.03(10)
a
b b
a
0.20 0.06(10) 0.10 0.04(10)
a
b b
a
Group VH
lOOOmg/kg
0.31 0.27(10) 0.15 0.06(10) 0.17 0.08(10)
b b b
AMSC (xlOV/AL)
DAY 45
b
b
b
b
.
DAY 91
b
b
b
b
DAY 123
b
a
a
b
PL^xlO3//^) DAY 45
DAY 91
DAY 123
1158
76(5)
1131
117(8) 1060
128(7)
1186
99(6)
1056
55(7)
a
1002 144(8) 972 188(9)
a
"
1068
116(9) 929* 122(8) 926 132(9)
Data arranged as:
Mean Standard deviation (Number of values included in calculation)
a Measurements for this group at this timepoint were not taken or not performed. b Measurements for these cells are determined either by instrument or microscopic examination. Microscopic
slide review indicated no cells of this type; therefore, the instrument count was accepted and no manual count was performed. Individual data are reported in the Clinical Pathology appendix.
* Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett).
@ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's).
108
Offlpany Sanitized. Does nolconSaIn TSCA C3^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 26
TEST/ PERIOD
SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS
Group n Omg/kg
Group IV 50mg/kg
Group VI
250 mg/kg
Group Vm
1000 mg/kg
RBC (xlO^L)
DAY 44
DAY 92
DAY 124 HGB (g/dL)
DAY 44
DAY 92
DAY 124 HCT (%)
DAY 44
DAY 92
DAY 124 MCV (fl)
DAY 44
DAY 92
DAY 124
MCH (pg) DAY 44
DAY 92
DAY 124
8.12 0.34(10) 8.51 0.22(10) 8.12 0.37(10)
15.3
0.3(10) 15.9 0.4(10) 15.0 0.4(10)
49.4 1.4(10)
50.0 1.4(10)
45.8 1.3(10)
60.9 2.0(10)
58.8 1.5(10)
56.5 2.1(10)
18.9 0.5(10) 18.7 0.5(10) 18.5 0.7(10)
7.83 0.27(10)
8.23* 0.16(10)
a
7.71* 0.41(10)
8.29 0.45(10)
a
14.7* 0.7(10)
15.4 0.6(10)
a
14.6* 0.5(10)
15.4 0.5(10)
a
47.2*
45.7*
2.0(10) '-
1.9(10)
48.1*
48.5
1.6(10)
2.3(10)
a
a
60.4 1.5(10)
58.5 1.5(10)
a
59.4 1.4(10)
58.6 1.0(10)
a
18.8 0.6(10)
18.8 0.6(10)
a
18.9 0.6(10)
18.6 0.5(10)
a
7.70* 0.18(10) 8.15* 0.15(10)
8.11 0.46(9)
14.9 0.4(10)
15.7 0.5(10)
15.1
0.7(9)
47.0* 1.5(10)
48.4, 1.4(10)
46.0 2.4(9)
61.1 1.5(10)
59.3 1.1(10)
56.8 2.0(9)
19.3
0.5(10) 19.2
0.5(10) 18.6 0.6(9)
109
0ffipany SanRbed. Do^ ^} cwta'n TSCA CB\
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 26 (Continued)
TEST/ PERIOD
SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS
Group n Omg/kg
Group IV 50mg/kg
Group VI
250 mg/kg
Group Vffl
1000 mg/kg
MCHC (g/dL) DAY 44
DAY 92
DAY 124 RDW (%)
DAY 44 DAY 92 DAY 124 ARET (xlOV/xL) DAY 44 DAY 92
DAY 124
WBC (xlOV^L) DAY 44
DAY 92 DAY 124
ANEU(xlOV^L) DAY 44
DAY 92
DAY 124
31.1
0.7(10) 31.8
0.4(10) 32.8
0.4(10)
11.0 0.3(10)
10.8 0.4(10)
12.0 0.5(10)
212 47(10)
153
41(10)
176 20(10)
13.87 2.94(10) 8.68 1.26(10)
11.10 2.66(10)
1.39 0.49(10) 0.93 0.36(10) 1.00 0.24(10)
31.2 0.6(10)
32.1 0.6(10)
a
11.4 0.6(10)
10.6 0.4(10)
a
222 43(10)
.
146 29(10)
a
13.20 2.48(10) 8.84 1.49(10)
a
1.13 0.48(10) 0.93 0.31(10)
a
31.8* 0.8(10)
31.7 0.5(10)
a
11.2 0.8(10)
10.6 0.4(10)
a
226 29(10)
173
13(10)
a
13.32 3.68(10)
10.29 2.21(10)
a
1.50 0.32(10) 1.33 1.23(10)
a
31.6 0.6(10)
32.3 0.6(10)
32.7 0.3(9)
11.3 0.3(10)
10.7 0.3(10)
11.9 0.3(9)
241
37(10)
173
34(10)
167
31(9)
13.70 3.63(10)
10.14 3.04(10)
10.83 2.50(9)
1.58
0.63(10)
1.15
0.41(10)
1.11
0.42(9)
110
Company SanKteed. Does not cwa'" ^WA c^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 26 (Continued)
SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS
TEST/
Group n
Group?/
Group VI
PERIOD_________Omg/kg_____50mg/kg____250mg/kg
ANPR(xlOV/AL)
DAY 44 DAY 92
b
b
b
b
c
c
DAY 124
c
a
a
Group Vffl
lOOOmg/kg
b
c c
ALYM(xlOV^L) DAY 44
DAY 92
DAY 124 AMON (xlO'//xL)
DAY 44
DAY 92
DAY 124 AEOS (xlO'//xL)
DAY 44
DAY 92
DAY 124 ABAS (xlOV/xL)
DAY 44
DAY 92
DAY 124
11.68 2.71(10) 7.20 1.25(10) 9.35 2.48(10)
0.28 0.05(10) 0.23 0.07(10) 0.31 0.08(10)
0.17 0.06(10) 0.16 0.05(10) 0.16 0.12(10)
0.11 0.03(10) 0.08 0.03(10) 0.09 0.05(10)
11.41 2.54(10) 7.51 1.46(10)
a
0.27 0.12(10) 0.19 0.04(10)
a
0.12 0.06(10) 0.09* 0.04(10)
a
0.09 0.05(10) 0.05 0.03(10)
a
11.11 3.50(10) 8.35 2.01(10)
a
0.25 0.10(10) 0.25 0.10(10)
a
0.18 0.09(10) 0.13 0.04(10)
a
0.09 0.05(10) 0.10 0.07(10)
a
11.43 3.17(10) 8.44 2.65(10) 9.04 2.24(9)
0.22 0.09(10) 0.21 0.08(.10) 0.31 0.13(9)
0.19 0.23(10) 0.13 0.04(10) 0.12 0.03(9)
0.10 0.05(10) 0.08 0.05(10) 0.09 0.07(9)
ill
ompany Sanitized. Does not contain TSCA CB'5
H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739
TABLE 26 (Continued)
SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS
TEST/
Group n
Group IV
Group VI
PERIOD_________Omg/kg_____50mg/kg____250mg/kg
ALUC (xlO'/^L) DAY 44
DAY 92
DAY 124
ABLT(xlO//xL) DAY 44 DAY 92 DAY 124
0.25 0.14(10) 0.09 0.03(10) 0.19 0.10(10)
b b
c
0.18 0.09(10) 0.08 0.05(10)
a
b
c a
0.19 0.12(10) 0.13 0.09(10)
a
b
c a
Group Vffl
lOOOmg/kg
0.20 0.08(10) 0.13 0.12(10) 0.16 0.10(9)
b
c c
AMSC(xlO//AL)
DAY 44
b
b
b
b
DAY 92
b
c
c
c
DAY 124
c
a
a
c
PLT (xlOV/xL) DAY 44
DAY 92
DAY 124
1055
259(5)
1123
164(7) 954 138(7)
1084 153(8)
1050 69(6)
a
1054 129(6)
1043 107(9)
a
1161
218(7)
1050
152(9) 985 111(9)
Data arranged as:
Mean Standard deviation (Number of values included in calculation)
a Measurements for this group at this timepoint were not taken or not performed. b Measurements for these cells are determined either by instrument or microscopic examination. Microscopic
slide review indicated no cells of this type; therefore, the instrument count was accepted and no manual count was performed. Individual data are reported in the Clinical Pathology appendix. c When this analysis was performed, valid measurements were taken on only 1 animal from the group. Data
from this small sample size did not add value to this summary table. Individual data are reported in the Clinical Pathology appendix.
* Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett).
112
0np6ny Sandhod. Doex nnt c^-w WM* ^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPonM739
TABLE 27
SUMMARY OF COAGULATION VALUES FOR MALE RATS
TEST/
Group I
Group ffl
Group V
PERIOD_________Omg/kg_____50mg/kg____250 mg/kg
PT (seconds)
DAY 91
APTT (seconds) DAY 91
15.1 0.4(10)
20.1 3.8(10)
15.1 0.5(10)
19.9 3.0(10)
15.7 0.7(9)
19.8 1.7(9)
Group VH
1000 mg/kg
15.7 0.6(10)
19.5
2.6(10)
Data arranged as:
Mean Standard deviation (Number of values included in calculation)
There were no statistically significant differences from control at p < 0.05.
TABLE 28
SUMMARY OF COAGULATION VALUES FOR FEMALE RATS
TEST/
Group n
Group?/
Group VI
PERIOD_________Omg/kg_____50mg/kg____250 mg/kg
PT (seconds)
DAY 92
APTT (seconds) DAY 92
15.3 0.3(9)
19.8 1.2(9)
15.2 0.7(10)
19.6 1.9(10)
15.2 0.7(10)
18.3 1.1(10)
Group Vffl
1000 mg/kg
15.2
0.5(10)
18.3 1.5(10)
Data arranged as:
Mean Standard deviation (Number of values included in calculation)
There were no statistically significant differences from control at p < 0.05.
^
113
Company Sanitized. Does not contain TSCA CBI
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 29
SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS
TEST/ PERIOD
Group I Omg/kg
Group ffl 50mg/kg
Group V 250 mg/kg
Group Vn
1000 mg/kg
AST (U/L) DAY 45
DAY 91
DAY 123 ALT (U/L)
DAY 45 DAY 91 DAY 123 SDH (U/L) DAY 45
DAY 91 DAY 123 ALKP(U/L) DAY 45
DAY 91
DAY 123 BILI (mg/dL)
DAY 45 DAY 91
DAY 123
91
17(10) 84 10(10) 79 10(10)
38
6(10)
35
5(10) 34
7(10)
20.4 3.5(10)
23.4 5.6(10)
19.4 3.8(10)
127 17(10) 80 13(10) 80 15(10)
0.09 0.04(10) 0.14 0.01(10) 0.08 0.03(10)
86
19(10) 92 22(10)
a
39 7(10)
46 17(10)
a
24.2 6.4(10)
27.1 8.4(10)
a
130
24(10) 100 24(10)
a
0.07 0.03(10) 0.14 0.04(10)
a
85
14(10)
91
27(10)
a
37
7(10)
50
26(10)
a
23.7 5.0(10)
24.0 7.1(10)
a
115
20(10) 110* 26(10)
a
0.06 0.02(10) 0.12 0.04(10)
a
88
11(10) 94 17(10)
131
116(10)
44
10(10) 48@
9(10) 98@ 158(9)
20.5 3.7(10)
22.4 4.4(10)
32.7 36.2(10)
158* 31(10)
183* 28(10) 135* 37(10)
0.06 0.02(10) 0.12 0.02(10) 0.06 0.02(10)
114
Company Sanitized. Does not contain TSCA CB^
H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739
TABLE 29 (Continued)
SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS
TEST/ PERIOD
Group I Omg/kg
Group ffl 50mg/kg
Group V 250 mg/kg
Group Vn
1000 mg/kg
BUN (mg/dL) DAY 45
DAY 91
DAY 123 CREA (mg/dL)
DAY 45 DAY 91
DAY 123 CHOL (mg/dL)
DAY 45
DAY 91
DAY 123 TRIG (mg/dL)
DAY 45
DAY 91 DAY 123
GLUC (mg/dL) DAY 45 DAY 91
DAY 123
15
2(10)
15
1(10)
14
1(10)
0.37 0.02(10) 0.42 0.04(10) 0.30 0.06(10)
75 16(10) 77 19(10) 79 24(10)
75
28(10)
81
29(10) 210
62(10)
104
7(10)
113 6(10)
122 11(10)
15
2(10)
16
2(10)
a
0.36 0.05(10) 0.37* 0.05(10)
a
65 12(10) 67 19(10)
a
89
47(10)
103
43(10)
a
104
6(10)
118 13(10)
a
15
3(10) 19* 2(10)
a
0.33 0.06(10) 0.42 0.03(10)
a
55* 12(10) 54* 14(10)
a
57
41(10)
71
25(10)
a
100
6(10)
117
6(10)
a
16
2(10) 19* 2(10)
15
2(10)
0.34 0.06(10) 0.40 0.05(10) 0.30 0.05(10)
47* 13(10) 49* 15(10) 64 16(10)
42@ 22(10) 44@ 11(10) 115* 53(10)
109
10(10)
121
8(10)
122
8(10)
115
ICompany Sa^ed. Does not contain TSCA CBI
H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739
TABLE 29 (Continued)
SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS
TEST/ PERIOD
Group I Omg/kg
Group ffl 50mg/kg
Group V 250 mg/kg
Group VH 1000 mg/kg
TP (g/dL) DAY 45
DAY 91 DAY 123 ALB (g/dL) DAY 45 DAY 91 DAY 123 GLOB (g/dL) DAY 45
DAY 91
DAY 123 CALC (mg/dL)
DAY 45
DAY 91
DAY 123
IPHS (mg/dL)
DAY 45 DAY 91 DAY 123
6.7 0.2(10) 7.2 0.2(10) 6.9 0.2(10)
4.2 0.1(10) 4.3 0.2(10) 4.2 0.1(10)
2.5 0.2(10) "" 3.0 0.2(10) 2.7 0.2(10)
10.7 0.3(10)
10.7 0.2(10)
11.1
0.3(10)
8.6 0.6(10) 7.4 0.2(10) 7.0 0.3(10)
6.8 0.2(10) 7.2 0.2(10)
a
4.3 0.1(10) 4.3 0.2(10)
a
2.5 0.2(10) 2.9 0.2(10)
a
10.8 0.3(10)
10.7 0.3(10)
a
8.7 0.5(10) 7.2 0.5(10)
a
6.4* 0.3(10)
7.2 0.4(10)
a
4.2 0.2(10) 4.5* 0.2(10)
a
2.2* 0.3(10) 2.7* 0.3(10)
a
10.7 0.4(10)
10.8 0.3(10)
a
8.9 0.7(10) 7.7 0.5(10)
a
6.8 0.3(10) 7.1 0.3(10) 7.0 0.3(10)
4.6* 0.2(10) 4.7* 0.2(10) 4.5* 0.2(10)
2.2* 0.1(10) 2.4*' 0.2(10) 2.5@ 0.2(10)
10.7 0.2(10)
10.3@ 0.2(10) 11.0 0.3(10)
9.1
0.5(10) 7.7 0.9(10) 7.5* 0.4(10)
116
Company Sanitized. Does not contain TSCA RBit
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 29 (Continued)
SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS
TEST/ PERIOD
Group I
Group in
Group V
Omg/kg_____50mg/kg____250mg/kg
Group VII
IQOOmg/kg
NA (mmol/L) DAY 45
DAY 91
DAY 123
K (mmol/L)
DAY 45
DAY 91
DAY 123
CL (mmol/L) DAY 45
DAY 91
DAY 123
PFLU (^g/mL)
DAY 45 DAY 91
DAY 123
148.0 1.6(10)
146.5 0.9(10)
146.5 1.0(10)
6.45 0.35(10) 6.25 0.34(10) 6.05 0.24(10)
99.3 1.1(10)
101.6 1.2(10)
98.9 1.2(10)
0.1 0.0(10)
148.1 0.9(10)
146.6 0.9(10)
6.29 0.18(10) 5.97 0.31(10)
"
98.1 0.9(10)
100.5 1.7(10)
0.1 0.0(9)
148.5 0.7(10)
147.3 1.0(10)
6.31 0.23(10) 6.07 0.30(10)
98,9 1.0(10)
100.9 1.1(10)
a
0.1 0.0(8)
147.8 0.7(10)
145.4 1.5(10)
147.0 0.9(10)
6.54 0.43(10) 6.15 0.45(10) 6.19 0.28(10)
99.7 1.9(10)
101.7 1.0(10)
99.5 1.3(10)
a
0.1
0.0(10)
Data arranged as:
Mean Standard deviation (Number of values included in calculation)
a Measurements for this group at this timepoint were not taken or not performed.
# Statistically significant difference from control at p < 0.05 by trend test (Jonckheere-Terpstra). * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett).
117
Company Sanitized. Does not contain TSCA Cffl
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 30
SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS
TEST/ PERIOD
Group n Omg/kg
Group IV
50mg/kg
Group VI
250 mg/kg
Group Vm
1000 mg/kg
AST (U/L) DAY 44 DAY 92
DAY 124 ALT (U/L)
DAY 44
DAY 92 DAY 124
SDH (U/L) DAY 44 DAY 92 DAY 124
ALKP(U/L) DAY 44
DAY 92 DAY 124
BILI (mg/dL) DAY 44
DAY 92
DAY 124
82
7(10)
88
19(9)
101
19(10)
35
3(10)
36
14(9)
64 30(10)
22.4 5.9(10)
21.8 4.8(9)
26.1 5.4(10)
81
25(10)
51
21(9) 40 13(10)
0.12 0.03(10) 0.18 0.03(9) 0.15 0.04(10)
107 47(9)
113
40(10)
a
49 29(9) 62 38(10)
a
24.1 12.9(10) 26.4 11.1(10)
a
91
14(9)
58
22(10)
a
0.09 0.04(9) 0.16 0.04(10)
a
82 6(10)
87 23(10)
a
36
5(10)
45
23(10)
a
18.6 5.0(10)
22.0 4.5(10)
a
81
17(10) 50 12(10)
a
0.08 0.04(10) 0.16 0.03(10)
a
91
20(10)
91
30(10)
152
176(9)
39
9(10)
39
12(10)
124
192(9)
20.3 6.1(10)
'
20.1 3.3(10)
45.4 68.7(9)
82
20(10)
58
17(10) 44 15(9)
0.06* 0.03(10) 0.10* 0.03(10) 0.09@ 0.04(9)
118
ompany Sanitized. Does not contain TSCA C61
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 30 (Continued)
SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS
TEST/ PERIOD
Group n Omg/kg
Group IV 50mg/kg
Group VI
250 mg/kg
Group Vffl 1000 mg/kg
BUN (mg/dL) DAY 44
DAY 92 DAY 124
CREA (mg/dL)
DAY 44 DAY 92
DAY 124 CHOL (mg/dL)
DAY 44 DAY 92 DAY 124 TRIG (mg/dL) DAY 44
DAY 92
DAY 124 GLUC (mg/dL)
DAY 44
DAY 92
DAY 124
16
2(10)
15
2(9)
15
2(10)
0.44 0.04(10) 0.46 0.08(9) 0.41 0.03(10)
102 18(10)
104 12(9)
105
29(10)
46 11(10) 57 27(9) 62 20(10)
97 12(10) 117 18(9) 107 10(10)
16
1(10)
17
3(10)
a
16
2(10)
16
2(10)
a
0.39 0.04(10) 0.47 0.06(10)
a
'
88 12(10) 94 15(10)
a
0.37* 0.05(10) 0.47 0.05(10)
a
84* 18(10) 83 29(10)
a
39 16(9) 53 21(10)
a
34 12(10) 58 47(10)
a
99 10(10) 111 13(10)
a
104 9(10)
109 9(10)
a
17
2(10) 18* 2(10)
15
2(9)
0.39 0.04(10) 0.46 0.05(10) 0.45 0.07(9)
.
75* 9(10)
78@ 11(10)
99 32(9)
29* 9(10)
47 15(10) 56 22(9)
103
12(10)
133
26(10)
104 11(9)
119
eompanyswmzels- D^ not contain T8CA CBl
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 30 (Continued)
SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS
TEST/ PERIOD
Group n Omg/kg
Group IV 50mg/kg
Group VI
250 mg/kg
Group Vm
1000 mg/kg
TP (g/dL) DAY 44
DAY 92 DAY 124
ALB (g/dL)
DAY 44 DAY 92 DAY 124
GLOB (g/dL)
DAY 44 DAY 92
DAY 124 CALC (mg/dL)
DAY 44 DAY 92 DAY 124
IPHS (mg/dL) DAY 44
DAY 92 DAY 124
7.4 0.3(10) 8.0 0.3(9) 8.3 0.6(10)
5.0 0.2(10) 5.2 0.3(9) 5.6 0.5(10)
2.4 0.1(10) 2,8 0.1(9) 2.7 0.2(10)
11.0 0.3(10)
11.1
0.4(9) 11.7
0.5(10)
8.0 0.6(10) 5.1 0.9(8) 6.3 0.6(10)
7.2 0.5(9) 8.0 0.5(10)
a
4.9 0.3(9) 5.3 0.4(10)
a
2.3 0.3(9) 2.6 0.2(10)
a
10.7 0.3(10)
11.2 0.3(10)
a
7.8 0.8(9) 5.4 0.6(10)
a
7.0* 0.3(10) 7.7 0.6(10)
a
4.8 0.3(10) 5.2 0.3(10)
a
2.1* 0.2(10) 2.5 0.3(10)
a
10.5* 0.4(10)
11.2 0.5(10)
a
7.5 1.1(10) 5.7 0.7(10)
a
7.5 0.4(10) 8.1 0.6(10) 8.2 0.3(9)
5.3 0.4(10) 5.5 0.4(10) 5.5 0.3(9)
2.2 0.2(10) 2.6 0.3(10) 2.6 0.3(9)
10.7 0.4(9)
11.2 0.4(10)
11.6 0.3(9)
7.9 0.5(10) 5.6 0.5(10) 6.5 0.4(9)
120
Company Sanfllzed. Does not contain TSCA crit
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 30 (Continued)
SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS
TEST/ PERIOD
Group n Omg/kg
Group IV 50mg/kg
Group VI
250 mg/kg
Group Vffl
1000 mg/kg
NA (mmol/L) DAY 44
DAY 92
DAY 124
K (mmol/L)
DAY 44
DAY 92
DAY 124
CL (mmol/L)
DAY 44
DAY 92
DAY 124
PFLU (/-ig/mL)
DAY 44 DAY 92
DAY 124
146.2 1.6(10)
147.7 1.2(9)
145.7
0.7(10)
6.25 0.38(10) 5.67 0.26(9) 5.67 0.56(10)
98.6 2.1(10)
103.1 1.7(9)
97.8 1.8(10)
a
0.2 0.1(8)
a
146.2 1.4(9)
147.6 1.0(10)
a
6.01 0.34(9) 5.67 0.27(10)
a
99.6 1.7(9)
103.8 1.2(10)
a
a
0.2 0.0(10)
a
145.9 1.4(10)
148.1 1.7(10)
a
6.01 0.31(10) 5.67 0.46(10)
a
100.6 1.7(10)
103.7 1.8(10)
a
a
0.2 0.1(10)
a
146.2 1.4(10)
147.6 1.1(10)
146.9* 1.1(9)
6.13 0.33(10) 5.82 0.41(10) 5.41 0.24(9)
101.4@ 1.3(10)
104.2 1.9(10)
98.4 2.2(9)
a
0.2 0.0(10)
a
Data arranged as:
Mean Standard deviation (Number of values included in calculation)
a Measurements for this group at this timepoint were not taken or not performed.
* Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett).
@ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's).
121
Company Sanitized. Does not contain TSCA CB1
H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739
TABLE 31
TEST/ PERIOD
SUMMARY OF URINALYSIS VALUES FOR MALE RATS
Group I Omg/kg
Group m 50mg/kg
Group V 250 mg/kg
Group Vn
1000 mg/kg
VOL (mL) DAY 45 DAY 91 DAY 123
UOSM (mOsm) DAY 45
DAY 91 DAY 123
SG
DAY 45 DAY 91
DAY 123
pH DAY 45
DAY 91
DAY 123 URO (EU/dL)
DAY 45
DAY 91 DAY 123
9.4 5.3(10) 8.5 7.8(10) 4.4 2.0(10)
1143
380(9)
1275
384(10)
1823
723(10)
1.035 0.012(10) 1.040 0.011(10) 1.054 0.018(10)
6.6 0.6(10) 6.7 0.3(10) 6.5 0.9(10)
0.2 0.0(10) 0.4 0.3(10) 0.3 0.3(10)
11.9 4.6(10) 11.4 5.6(10)
a
945 333(10) 990 464(10)
a
1.030 0.010(10) 1.031 0.013(10)
a
6.9 0.2(10) 6.4 0.5(10)
a
0.2 0.0(10) 0.3 0.3(10)
a
8.5 5.4(9) 5.7 2.9(10)
a
1435 873(9)
1848
741(10)
a
1.043 0.024(9) 1.051 0.019(10)
a
6.7 0.4(9) 6.6 0.5(10)
a
0.4 0.4(9) 0.4 0.4(10)
a
12.1
9.3(10) 9.4 5.5(10) 5.4 2.9(10)
1277 882(10)
1075 472(10)
1891
795(10)
1.039 0.025(10) 1.036 0.015(10) 1.055 0.020(10)
6.9 0.3(10) 6.6 0.6(10) 7.1 0.8(10)
0.4 0.3(10)
0.4 0.3(10) 0.4 0.3(10)
122
Company Sanitized. Does not contain TSCA CB8
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 31 (Continued)
TEST/ PERIOD
SUMMARY OF URINALYSIS VALUES FOR MALE RATS
Group I Omg/kg
Group m 50mg/kg
Group V 250 mg/kg
Group Vn
1000 mg/kg
UFLU (Mg) DAY 45 DAY 91
DAY 123
UMTP (mg/dL) DAY 45
DAY 91
DAY 123
a
12.2 3.5(9)
10.3
4.9(10)
89 48(10) 93
36(10)
141
64(10)
a
14.1
3.4(10)
a
60 38(10) 57 38(10)
a
a
24.9@ 4.3(9)
a
83
68(9)
86 34(9)
a
a
42.7@ 14.1(10) 14.8* 4.4(10)
79
71(10) 45* 21(10)
129
66(10)
Data arranged as:
Mean
Standard deviation (Number of values included in calculation)
a Measurements for this group at this timepoint were not taken or not performed.
* Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's).
123
Company Sanitized. Does not confitn TSCA CBt
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 32
TEST/ PERIOD
SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS
Group n Omg/kg
Group IV
50mg/kg
Group VI
250 mg/kg
Group Vffl
1000 mg/kg
VOL(mL) DAY 44
DAY 92 DAY 124
UOSM (mOsm) DAY 44 DAY 92
DAY 124
SG
DAY 44 DAY 92
DAY 124
pH DAY 44
DAY 92
DAY 124 URO (EU/dL)
DAY 44
DAY 92 DAY 124
12.6 6.3(9) 8.6 3.6(10) 6.5 3.9(10)
713
265(9) 860 303(10)
1291
699(10)
1.022 0.008(9) 1.026 0.009(10) 1.040 0.019(10)
6.4 0.4(9) 6.1 0.6(10) 5.7 0.7(10)
0.2 0.0(9) 0.2 0.0(10) 0.2 0.0(10)
9.7 5.2(9) 4.3@ 1.3(10)
a
763 338(8) 1255 419(10)
a
1.027 0.015(9) 1.038 0.012(10)
a
6.4 0.2(9) 5.9 0.2(10)
a
0.2 0.0(9) 0.3 0.3(10)
a
6.9 4.9(9) 5.8 3.1(10)
a
1038
515(8)
1168
572(10)
a
1.035 0.018(9) 1.035 0.016(10)
a
6.3 0.4(9) 6.0 0.4(10)
a
0.2 0.0(9) 0.3 0.3(10)
a
6.8* 3.3(10) 5.8@ 5.4(9)
5.2 1.7(9)
1066
455(10)
1354
662(9)
1227 ,376(9)
1.032 0.013(10) 1.041 0.019(9) 1.039 0.011(9)
6.3 0.4(10) 5.9 0.3(9) 5.8 0.3(9)
0.2 0.0(10) 0.4 0.4(9) 0.2 0.0(9)
124
ompany SanKbed. Does not cnntaiin rtinfl rq(
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 32 (Continued)
TEST/ PERIOD
SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS
Group n Omg/kg
Group IV
50mg/kg
Group VI
250 mg/kg
Group Vm
1000 mg/kg
UFLU (^g) DAY 44 DAY 92
DAY 124
UMTP (mg/dL) DAY 44
DAY 92
DAY 124
a
9.5 2.2(10) 9.2 3.6(9)
12
7(9)
19
10(10) 35 21(10)
a
8.2 2.4(10)
a
18
16(9)
25
8(10)
a
a
14.0* 4.4(9)
a
22 14(9) 57 124(10)
a
a
23.7* 8.1(7)
10.7 2.3(9)
21
12(10)
33
27(9) 30 13(9)
Data arranged as:
Mean
Standard deviation (Number of values included in calculation)
a Measurements for this group at this timepoint were not taken or not performed.
* Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's).
125
company Sanitized. Does not contain TSCA CBt
H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739
TABLE 33
MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS
(90-DAY EXPOSURE EVALUATION)
MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams)
Group I 0 ing/kg/day
I I I Group
50 nig/kg/day
Group V
Group VII
250 mg/kg/day 1000 mg/kg/day
LIVER
16.29990 2.37854(10)
16.87220 2.61074(10)
17.17570 1.42650(10)
17.73860 1.69212(10)
KIDNEYS
4.11790 0.46383(10)
4.07140 0.44324(10)
4.29670 0.30710(10)
4.14600 0.50094(10)
HEART
1.72150 0.18011(10)
1.63930 0.09797(10)
1.60160' 0.15360(10)
1.45190# 0.15909(10)
SPLEEN
0.81060 0.13297(10)
0.81960 0.13467(10)
0.75140 0.04046(10)
0.62300# 0.06573(10)
BRAIN
2.11630 0.11666(10)
2.09420 0.05678(10)
2.10710 0.07523(10)
2.08770 0.10561(10)
THYMUS
0.39550 0.10511(10)
0.35220 0.10652(10)
0.35900 0.07574(10)
0.29070# 0.08475(10)
ADRENAL GLANDS
0.05420 0.00819(10) -
0.05070 0.00766(10)
0.05590 0.00565(10)
0.04540 0.00759(10)
TESTES
3.55240 0.26647(10)
3.44250 0.28401(10)
3.47420 0.21284(10)
3.63750 0.46281(10)
EPIDIDYMIDES
1.52290 0.13239(10)
1.46590 0.10031(10)
1.44610 0.07824(10)
1.44300 0.12745(10)
FINAL BODY WEIGHT
571.20001 54.34041(10)
553.88000 64.04053(10)
525.24000 32.58446(10)
453.54000# 27.10724(10)
126
eompany Sanllzed. Does no! conlatn TSCA CB^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 33 (CONTINUED)
MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (90-DAY EXPOSURE EVALUATION)
MEAN RELATIVE ORGAN WEIGHTS (% of body weight)
Giroup I
0 nig/kg /day
II G roup I
5 0 mg/kg/day
GIroup V 2 50 mg/ kg/da:y
Group VII
10 00 ing/kg/day
LIVER/ FINAL BODY * 100
2 .84282 0 .18604 (10)
3 .03802 ^ 0 .21348 (10)
3 .26805 ^ 0 .13073 (10)
3 .90847# 0 .24375(10)
KIDNEYS/ FINAL BODY * 100
0 .72142 0 .04767 (10)
0 .73746 0 .05458 (10)
0 .81838ft 0 .03911 (10)
0 .91438# 0 .09585(10)
HEART/ FINAL BODY * 100
-
0 .30162 0 .01735 (10)
0 .29831 0 .02690 (10)
0 .30476 0 .02003 (10)
0 .32005 0 .02896(10)
SPLEEN/ FINAL BODY * 100
0 .14146 0 .01571 (10)
0 .14759 0 .01234 (10)
0 .14355 0 .01190(10)
0 .13746 0 .01303(10)
BRAIN/ FINAL BODY * 100
0 .37329 0 .03801 (10)
0 .38195 0 .03860 (10)
0 .40251 0 .02774 (10)
0 .46124ft
0 .02746(10)
THYMUS/ FINAL BODY * 100
0 .06894 0 .01543 (10)
0 .06381 0 .01967 (10)
0 .06850 0 .01460 (10)
0 .06376 " 0 .01674(10)
ADRENAL GLANDS/ FINAL BODY * 100
0 .00952 0 .00147 (10)
0 .00919 0 .00117 (10)
0 .01066 0 .00100(10)
0 .01000 0 .00146(10)
TESTES/ FINAL BODY * 100
0 .62419 0 .04177 (10)
0 .62763 0 .07394 (10)
0 .66300 0 .04622 (10)
0 .80306ft 0 .10131(10)
EPIDIDYMIDES/ FINAL BODY * 100
0 .26700 0 .01067 (10)
0 .26813 0 .03744 (10)
0 .27582 0 .01536 (10)
0 .31857ft
0 .02711(10)
127
Sompany SanHtsed. Does not contain TSCA CB^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 33 (CONTINUED)
MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS
(90-DAY EXPOSURE EVALUATION)
MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio)
Group I
0 mg/kg/day
I I I G r o u p
50 mg/kg/day
Group V
250 mg/kg/day
Group VII
1000 mg/kg/day
LIVER/
BRAIN * 100
770.15709 104.54656(10)
805.01169 115.90201(10)
815.55517 67.73836(10)
849.17608 61.67427(10)
KIDNEYS/ BRAIN * 100
194.75542 20.46963(10)
194.18409 17.86388(10)
203.90854 12.59494(10)
198.79654 23.95776(10)
HEART/ BRAIN * 100
81.49513 9.02494(10)
78.26848 3.91573(10)
76.02567 6.96468(10)
69.57323# 7.11744(10)
SPLEEN/ BRAIN * 100
38.35205 6.39417(10)
39.03931 5.59356(10)
35.69114 2.14067(10)
29.85103# 2.88927(10)
THYMUS/ BRAIN * 100
18.75573 5.19498(10)
16.85615 5.23759(10)
17.02594 3.49770(10)
13.92191# 3.97262(10)
ADRENAL GLANDS/ BRAIN * 100
2.57297 0.43823(10)
2.41939 0.34590(10)
2.65955 0.32621(10)
2.16774# 0.29613(10)
TESTES/ BRAIN * 100
168.21509 14.61825(10)
164.39229 12.67559(10)
165.02970 10.88670(10)
174.03435 18.18484(10)
EPIDIDYMIDES/ BRAIN * 100
72.06007 6.34437(10)
70.09865 5.95636(10)
68.65294 3.39848(10)
69.12080 5.03411(10)
128
Sompany Sar'n'^p'' n""^ ^t cwla'n TSCA CBl
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 33 (CONTINUED)
MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS
(ONE-MONTH RECOVERY EVALUATION)
MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams)
Group I
0 mg/kg/day
Group VII
1000 mg/kg/day
LIVER
18.08270 1.47750(10)
21.60940# 3.55199(10)
KIDNEYS
4.45450 0.47991(10)
4.36820 0.56393(10)
HEART
1.79860 0.16518(10)
1.71710 0.17531(10)
SPLEEN
0.85170 0.09574(10)
0.77160# 0.07517(10)
BRAIN
2.21690 0.08271(10)
2.12510 0.14088(10)
THYMUS
0.40740 0.08460(10)
0.33660 0.06047(10)
ADRENAL GLANDS
0.05500 0.00790(10)
0.05570 0.00983(10)
TESTES
3.50310 0.15626(10)
3.62410 0.34573(10)
EPIDIDYMIDES
1.56120 0.11432(10)
1.53520 0.13761(10)
FINAL BODY WEIGHT
614.23000 31.93733(10)
575.99000 75.57794(10)
129
Company Sanitized. P"- -"ft--a"- ""^A C^l
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 33 (CONTINUED)
MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS
(ONE-MONTH RECOVERY EVALUATION)
MEAN RELATIVE ORGAN WEIGHTS (% of body weight)
Group I 0 mg/kg/day
Group VII
1000 mg/kg/day
LIVER/ FINAL BODY * 100
2.94443 0.19349(10)
3.74065# 0.17971(10)
KIDNEYS/ FINAL BODY * 100
0.72426 0.05939(10)
0.76003 0.06052(10)
HEART/ FINAL BODY * 100
0.29257 0.01864(10)
0.29998 0.02662(10)
SPLEEN/ FINAL BODY * 100
0.13879 0.01514(10)
0.13549 0.01764(10)
BRAIN/ FINAL BODY * 100
0.36188 0.02412(10)
0.37309 0.04080(10)
THYMUS/ FINAL BODY * 100
0.06621 0.01259(10)
0.05842 0.00695(10)
ADRENAL GLANDS/ FINAL BODY * 100
0.00896 0.00130(10)
0.00974 0.00167(10)
TESTES/ FINAL BODY * 100
0.57159 0.03732(10)
0.63583# 0.07408(10)
EPIDIDYMIDES/ FINAL BODY * 100
0.25424 0.01435(10)
0.26847 0.02279(10)
130
ompany Sanitized. Does not cii"^'- '""* r>ei
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 33 (CONTINUED)
MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS
(ONE-MONTH RECOVERY EVALUATION)
MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio)
Group I 0 ing/kg/day
Group VII
1000 mg/kg/day
LIVER/ BRAIN*100
KIDNEYS/ BRAIN*100
HEART/ BRAIN*100
SPLEEN/ BRAIN*100
THYMUS/ BRAIN*100
ADRENAL GLANDS A BRAIN * 100
TESTES/ BRAIN*100
EPIDIDYMIDES/ BRAIN * 100
816.87669 76.65974(10)
200.98135 21.27432(10)
81.24372 8.38089(10)
38.41308 3.88576(10)
18.39074 3.84886(10)
2.47677 0.31243(10)
158.21602 9.14123(10)
70.55650 6.38733(10)
1015.9066# 144.74869(10)
205.35810 21.95910(10)
80.73190 5.51430(10)
36.51872 4.85835(10)
15.82333 2.53299(10)
2.63760 0.52852(10)
170.75088 14.77783(10)
72.33118 6.05327(10)
131
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 33 (CONTINUED)
MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS
(3-MONTH RECOVERY EVALUATION)
MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams)
Group I 0 mg/kg/day
III Group
50 mg/kg/day
Group V
250 mg/kg/day
Group VII
1000 mg/kg/day
LIVER
16.02880 3.59419(5)
17.89020 5.71336(5)
17.80925 2.72291(4 )
19.89400 4.91210(5)
FINAL BODY WEIGHT
570.94001 115.89048(5)
613.46000 90.47218(5)
614.80000
628.34000
66.22251(4 ) 122.14361(5)
LIVER/ FINAL BODY *
MEAN RELATIVE ORGAN WEIGHT ( % organ to body weight)
100 2.80261 0.13585(5)
2.86633 0.46688(5)
2.88670 0.16631(4 )
3.15405 0.33800(5)
Data summarized as:
Mean
Standard Deviation (n)
Statistical Methods: Trend test (Jonckheere-Terpstra) # Statistically significant difference at p < 0.05.
132
company Sanitized. Does nol contain T8CA CBI
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 34
MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS
(90-DAY EXPOSURE EVALUATION)
MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams)
I I Group
0 mg/kg/day
Group IV 50 mg/kg/day
Group VI
Group VIII
250 mg/kg/day 1000 mg/kg/day
LIVER
8.84878 0.88178(9)
8.70190 0.37828(10)
9.13210 1.55337(10)
9.61140 1.45116(10)
KIDNEYS
2.32156 0.13554(9)
2.37890 0.13760(10)
2.43270 0.32086(10)
2.41310 0.20469(10)
HEART
1.13467 0.11533(9)
1.03470 0.09322(10)
1.08350 0.12105(10)
1.05610 0.15199(10)
SPLEEN
0.47933 0.06135(9)
0.51200 0.08004(10)
0.54790 0.08040(10)
0.54350 0.11346(10)
BRAIN
1.95533 0.04179(9)
1.93720 0.05827(10)
1.94880 0.04951(10)
1.94110 0.11203(10)
THYMUS
0.30811 0.06008(9)
0.27820 0.05904(10)
0.32100 0.08173(10)
0.32000 0.07946(10)
ADRENAL GLANDS
0.06756 0.01454(9)
0.07030 0.01046(10)
0.07790 0.02075(10)
0.07380 0.00860(10)
OVARIES
0.13444 0.03048(9)
0.12380 0.02466(10)
0.11550 0.01848(10)
0.12490 0.02469(10)
UTERUS
0.48856 0.08202(9)
0.62250 0.14580(10)
0.64920 0.10251(10)
0.61880 0.16651(10)
FINAL BODY WEIGHT 313.86000 33.38430(10)
294.51000 17.61934(10)
311.33000 38.77024(10)
293.62000 46.15103(10)
133
Company Sanitized. Does not contain TSCA CBf
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 34 (CONTINUED)
MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION)
MEAN RELATIVE ORGAN WEIGHTS (% of body weight)
Group II
0 mg/kg/day
Group IV 50 mg/kg/day
Group VI
Group VIII
250 mg/kg/day 1000 mg/kg/day
LIVER/ FINAL BODY * 100
2.87266 0.19054(9)
2.96392 0.21436(10)
2.92590 0.20524(10)
3.28260# 0.18650(10)
KIDNEYS/ FINAL BODY * 100
0.75624 0.05892(9)
0.80964 0.05663(10)
0.78343 0.06553(10)
0.83304 0.09834(10)
HEART/ FINAL BODY * 100
0.36786 0.01744(9)
0.35204 0.03400(10)
0.34870 0.01585(10)
0.36162 0.03160(10)
SPLEEN/ FINAL BODY * 100
0.15582 0.01949(9)
0.17458 0.03057(10)
0.17637# 0.01806(10)
0.18582# 0.03162(10)
BRAIN/ FINAL BODY * 100
0.63885 0.06119(9)
0.66028 0.04991(10).
0.63323 0.06670(10)
0.67437 0.09883(10)
THYMUS/ FINAL BODY * 100
0.10020 0.01888(9)
0.09442 0.01909(10)
0.10210 .0.01577(10)
0.10923 0.02110(10)
ADRENAL GLANDS/ FINAL BODY * 100
0.02200 0.00471(9)
0.02391 0.00358(10)
0.02509 0.00590(10)
0.02573 0.00502(10)
OVARIES/ FINAL BODY * 100
0.04364 0.00931(9)
0.04227 0.00945(10)
0.03746 0.00667(10)
0.04275 0.00772(10)
UTERUS/ FINAL BODY * 100
0.15839 0.02151(9)
0.21128 0.04737(10)
0.21164 0.04491(10)
0.21888 0.08174(10)
134
Company Sanitized. Does nol contain TSCA CBI
TABLE 34 (CONTINUED)
MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION)
MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio)
I I Grouip
0 mgr/kg/day
Group IV 50 nig/kg/day
Group VI 250 mg/kg/day
Group VIII
1000 mg/kg /day
LIVER/ BRAIN * 100
453. 16871 51. 53255(9)
KIDNEYS/ BRAIN * 100
118. 82351 8. 13654(9)
HEART/ BRAIN * 100
58. 04840 6. 01775(9)
SPLEEN/ BRAIN * 100
24. 52604 3. 19572(9)
THYMUS/ BRAIN * 100
15. 78026 3. 20325(9)
ADRENAL GLANDS/ BRAIN * 100
3. 45494 0. 72733(9)
OVARIES/ BRAIN * 100
6. 88661 1. 60341(9)
UTERUS/ BRAIN * 100
24. 99779 4. 19207(9)
449.40303
467.75182
496.43390
19.98274(10)
70.86370(10)
79.13478 (10)
122.86286 7.29982(10)
124.72456 14.96060(10)
124.65330 12.56924 (10)
53.39885 4.26402(10)
55.56214 5.64538(10)
54.52115 8.21116 (10)
26.43428 4.08542(10)
28.06953ft 3.72366(10)
27.90773# 4.88065 (10)
14.37108 3.07053(10)
16.43012 3.95870(10)
16.50275 4.12823 (10)
3.62641 0.50714(10)
3.98493 0.98532(10)
3.81032 0.47299 (10)
6.40432 1.30463(10)
5.92383 0.91033(10)
6.41872 1.17561 (10)
32.08705 7.23638(10)
33.35351 5.50293(10)
32.04322 9.03999 (10)
135
Company Sanfflzed. Does nol conta'n TSCA CBI
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 34 (CONTINUED)
MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (ONE-MONTH RECOVERY EVALUATION)
MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams)
I I Group
0 mg/kg/day
Group VIII
1000 mg/kg/day
LIVER
9.28370 1.09118(10)
9.81700 1.02818(9)
KIDNEYS
2.49660 0.13680(10)
2.49433 0.25909(9)
HEART
1.18130 0.12273(10)
1.16611 0.06908(9)
SPLEEN
0.53490 0.06089(10)
0.53133 0.06821(9)
BRAIN
1.92700 0.06756(10)
1.90700 0.07682(9)
THYMUS
0.27040 0.06344(10)
0.26578 0.08276(9)
ADRENAL GLANDS
0.06720 0.00930(10)
0.07433 0.01158(9) .
OVARIES
0.11380 0.01923(10)
0.13044 0.03080(9)
UTERUS
0.69240 0.15493(10)
0.64000 0.14365(9)
FINAL BODY WEIGHT
319.89000 29.45560(10)
319.46667 39.20315(9)
136
eompany sanf"^. Does not co.tarn TSCA CBt
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 34 (CONTINUED)
MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (ONE-MONTH RECOVERY EVALUATION)
MEAN RELATIVE ORGAN WEIGHTS (% of body weight)
I I Group
0 mg/kg/day
Group VIII
1000 mg/kg/day
LIVER/ FINAL BODY * 100
2.90965 0,31572(10)
3.08176 0.17865(9)
KIDNEYS/ FINAL BODY * 100
0.78454 0.06459(10)
0.78462 0.07204(9)
HEART/ FINAL BODY * 100
0.37077 0.04110(10)
0.36727 0.02209(9)
SPLEEN/ FINAL BODY * 100
0.16798 0.02111(10)
0.16684 0.01593(9)
THYMUS/ FINAL BODY * 100
0.08434 0.01769(10)
0.08194 0.01357(9)
BRAIN/ FINAL BODY * 100
0.60627 0.05176(10)
0.60309 0.06179(9)
ADRENAL GLANDS/ FINAL BODY * 100
0.02115 0.00335(10)
0.02332 0.00303(9)
OVARIES/ FINAL BODY * 100
0.03554 0.00488(10)
0.04080 0.00830(9)
UTERUS/ FINAL BODY * 100
0.21976 0.05912(10)
0.20282 0.05408(9)
137
Company Sanitized. Does not contain TSCA CBl
H-24616: Subchronic Toxicity 90-Day Gavage Study m Rats with One-Generation Reproduction Evaluations
DuPont-4739
TABLE 34 (CONTINUED)
MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS
(ONE-MONTH RECOVERY EVALUATION)
MEAN RELATIVE ORGAN WEIGHTS (% of organ to brain weight ratio)
I I Group
0 ing/kg/day
Group VIII
1000 mg/kg/day
LIVER/ BRAIN*100
481.41153 51.16500(10)
514.77685 48.35577(9)
KIDNEYS/ BRAIN*100
129.58552 6.03970(10)
130.84378 12.62861(9)
HEART/ BRAIN*100
61.30509 6.13495(10)
61.16895 3.06644(9)
SPLEEN/ BRAIN*100
27.72580 2.69809(10)
27.85508 3.32437(9)
THYMUS/ BRAIN*100
14.02984 3.15456(10)
13.92129 4.13240(9)
ADRENAL GLANDS/ BRAIN * 100
3.47982 0.39498(10)
3.90318 0.63048(9)
OVARIES/ BRAIN*100
5.90446 0.97360(10)
6.83405 1.57365(9)
UTERUS/ BRAIN*100
35.91140 7.83175(10)
33.68099 8.06631(9)
138
Company Sanitized. Does not conlain TSCA CBt
H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739
TABLE 34 (CONTINUED)
MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (3-MONTH RECOVERY EVALUATION)
MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHT (grams)
I I Group
0 mg/kg/day
Group IV 50 mg/kg/day
Group VI
Group VIII
250 mg/kg/day 1000 mg/k.g/day
LIVER
9.78580 1.03445(5)
9.09420 1.03757(5)
10.15800 1.14344(5)
10.94320 1.05921(5)
FINAL BODY WEIGHT
321.19999 15.12316(5)
329.13999 14.29032(5)
345.69999 45.08364(5)
371.77999ft 33.74221(5)
MEAN RELATIVE ORGAN WEIGHT ( % organ to body weight)
LIVER/ FINAL BODY * 100
3.05923
2.75646
2.95270
2.95638
_______________0.42653(5)_____0.19747(5)______0.25319(5)_____0.33569(5)
Data summarized as: Mean
Standard Deviation (n)
Statistical-Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p < 0.05.
- i )^""-\
139
company Sanitized. Does not contain TSCA CBl
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 35
INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION)
LESION INCIDENCE
LESIONS
LIVER NO ABNORMALITY DETECTED
TREATMENT
(nig/kg/day)
0
I
(10) 10
Males
50
250
III V
(10) (10)
10
10
KIDNEYS NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
LUNGS NO ABNORMALITY DETECTED
(10)
10
(10) 10
(10)
10
HEART NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
SKELETAL MUSCLE NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
SPLEEN NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
AORTA NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
BRAIN NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
140
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 35 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION)
LESION INCIDENCE
LESIONS
SPINAL CORD NO ABNORMALITY DETECTED |STOMACH NO ABNORMALITY DETECTED
TREATMENT
(nig/kg/day)
0
I
(10) 10
(10) 10
Males
50
250
III V
(10) (10)
10
10
(10) (10)
10
10
DUODENUM NO ABNORMALITY DETECTED
JEJUNUM NO ABNORMALITY DETECTED
(10) (10) (10)
10
.10
10
(10) (10) (10)
10
10
10
ILEUM NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
PANCREAS NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
CECUM NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
COLON |NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
141
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 35 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDENCE
LESIONS
RECTUM NO ABNORMALITY DETECTED
TREATMENT
(mg/kg/day)
0
I
(10) 10
Males
50
250
III V
(10) (10)
10
10
MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
SALIVARY GLANDS NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
THYMUS NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
ADRENAL GLANDS NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
SCIATIC NERVE
NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
PITUITARY GLAND NO ABNORMALITY DETECTED
(10) (10) (10
10
10
10
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
142
W'y^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 35 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDENCE
LESIONS
THYROID GLAND NO ABNORMALITY DETECTED
TREATMENT
(ing/kg/day)
0
I
(10)
10
Males
50
250
III V
(10) (10)
10
10
PARATHYROID GLANDS NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
TRACHEA NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
ESOPHAGUS
i
NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
5
PHARYNX/LARYNX
i
NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
(0
5
EYE(S) WITH OPTIC NERVE
3
NO ABNORMALITY DETECTED
8
(10) (10) (10)
10
10
10
0.
SKIN
00 NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
S
3
|PROSTATE
(10) (10) (10)
2.
|NO ABNORMALITY DETECTED
8
10
10
10
S
Figures in parentheses is the number of animals grossly examined for this tissue
2.
The absence of a number indicates the finding specified was not identified
(3
0 >
0
143
<^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 35 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDENCE
LESIONS
SEMINAL VESICLES NO ABNORMALITY DETECTED
TREATMENT
(mg/kg/day)
0
I
(10)
10
Males
50
250
III V
(10) (10)
10
10
URINARY BLADDER NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
TESTES NO ABNORMALITY DETECTED LARGE, RIGHT.
EPIDIDYMIDES
NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
(10) (10) (10)
10
10
10
FEMUR/KNEE JOINT NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
STERNUM NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
NOSE NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
144
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 35 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
Males
LESIONS
LIVER NO ABNORMALITY DETECTED KIDNEYS NO ABNORMALITY DETECTED
TREATMENT
0
(nig/kg/day)
I
50
250
III V
(10)
10
t
(10) 10
LUNGS NO ABNORMALITY DETECTED
(10)
10
HEART NO ABNORMALITY DETECTED
(10)
10
SKELETAL MUSCLE NO ABNORMALITY DETECTED
(10)
10
SPLEEN NO ABNORMALITY DETECTED
(10)
10
AORTA NO ABNORMALITY DETECTED
(10)
10
BRAIN NO ABNORMALITY DETECTED
(10)
10
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
145
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 35 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION)
LESION INCIDENCE (N
LESIONS
SPINAL CORD NO ABNORMALITY DETECTED
TREATMENT
(ing/kg/day)
0
I
(10) 10
Males
50
250
III V
STOMACH NO ABNORMALITY DETECTED
(10)
10
DUODENUM NO ABNORMALITY DETECTED
(10) 10
JEJUNUM NO ABNORMALITY DETECTED
(10) 10
ILEUM NO ABNORMALITY DETECTED
(10)
10
PANCREAS NO ABNORMALITY DETECTED
(10) 10
CECUM NO ABNORMALITY DETECTED
(10)
10
COLON NO ABNORMALITY DETECTED
(10) 10
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
146
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 35 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
LESIONS
RECTUM NO ABNORMALITY DETECTED
TREATMENT
0
(ing/kg/day) | | I
(10)
10
Males
50
250
III V
MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED
(10)
10
SALIVARY GLANDS NO ABNORMALITY DETECTED
(10) 10
s
MANDIBULAR LYMPH NODE
I NO ABNORMALITY DETECTED
'5 THYMUS
NO ABNORMALITY DETECTED
1 ^
ADRENAL GLANDS
(2*-
NO ABNORMALITY DETECTED
SCIATIC NERVE
1
NO ABNORMALITY DETECTED
(10)
10
(10) 10
(10)
10
(10)
10
| PITUITARY GLAND
S
NO ABNORMALITY DETECTED
f--n
(10) 10
Figures in parentheses is the number of animals grossly examined for this tissue
es
S9
The absence of a number indicates the finding specified was not identified
>
-.">?
sss
147
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 35 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS
(ONE-MONTH RECOVERY EVALUATION)
LESION' INCIDENCE
LESIONS
THYROID GLAND NO ABNORMALITY DETECTED
TREATMENT
(mg/kg/day)
0
I
(10) 10
Males
50
250
III V
PARATHYROID GLANDS NO ABNORMALITY DETECTED
(10) 10
TRACHEA NO ABNORMALITY DETECTED
(10)
10
ESOPHAGUS NO ABNORMALITY DETECTED
(10) 10
PHARYNX/LARYNX NO ABNORMALITY DETECTED
(10) 10
EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED
(10) 10
SKIN [NO ABNORMALITY DETECTED
(10)
10
PROSTATE NO ABNORMALITY DETECTED
(10)
10
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
148
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 35 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
LESIONS
SEMINAL VESICLES NO ABNORMALITY DETECTED
| TREATMENT | (mg/kg/day)
0
I
(10)
10
Males
50
250
III V
URINARY BLADDER NO ABNORMALITY DETECTED
(10) 10
TESTES NO ABNORMALITY DETECTED
(10) 10
EPIDIDYMIDES NO ABNORMALITY DETECTED
(10) 10
FEMUR/KNEE JOINT NO ABNORMALITY DETECTED
(10)
10
STERNUM NO ABNORMALITY DETECTED
(10) 10
NOSE NO ABNORMALITY DETECTED
(10)
10
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
149
H-24616: Subchronic Toxicity 90-Day Gavage Study m Rats with One-Generation Reproduction Evaluations
TABLE 35 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS
(3-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
Males
LESIONS
LIVER NO ABNORMALITY DETECTED DISCOLORATION, TAN, MANY. KIDNEYS NO ABNORMALITY DETECTED
TREATMENT
0
(nig/kg/day)
I
50
250
III V
(5)
(5)
(4
5
4
4
1
(5)
(5)
(4
5
5
4
LUNGS NO ABNORMALITY DETECTED
(5)
(5)
(4
5
5
4
HEART NO ABNORMALITY DETECTED
(5)
(5)
(4
5
5
4
SKELETAL MUSCLE NO ABNORMALITY DETECTED
(5)
(5)
(4
5
5
4
SPLEEN NO ABNORMALITY DETECTED
(5)
(5)
(4
5
5
4
AORTA NO ABNORMALITY DETECTED
(5)
(5)
(4
5
5
4
BRAIN NO ABNORMALITY DETECTED
(5)
(5)
(4
5
5
4
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
150
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 35 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS
(3-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
.
LESIONS
SPINAL CORD NO ABNORMALITY DETECTED
TREATMENT
(mg/kg/day)
0
I
(5)
5
Males
50
250
III V
(5)
(4)
5
4
STOMACH |NO ABNORMALITY DETECTED
(5)
(5)
(4)
5
5
4
DUODENUM NO ABNORMALITY DETECTED
(5)
(5)
(4)
5
5
4
JEJUNUM NO ABNORMALITY DETECTED
(5)
(5)
(4)
5
5
4
ILEUM NO ABNORMALITY DETECTED
(5)
(5)
(4)
5
5
4
PANCREAS
1
NO ABNORMALITY DETECTED
CECUM
a
NO ABNORMALITY DETECTED
a
0
COLON
s
NO ABNORMALITY DETECTED
(5)
(5)
(4)
5
5
4
(5)
(5)
(4)
5
5
4
(5)
(5)
(4)
5
5
4
'
Figures in parentheses is the number of animals grossly examined for this tissue
d
The absence of a number indicates the finding specified was not identified
3"
^ 2
y
2o - ------------------------------------------------------------15--1 --
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 35 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (3-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
LESIONS
RECTUM NO ABNORMALITY DETECTED
| TREATMENT [ (mg/kg/day) 1
0
I
(5)
5
Males
50
250
III V
(5)
(4)
5
4
MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED
(5)
(5)
(4)
5
5
4
SALIVARY GLANDS NO ABNORMALITY DETECTED
(5)
(5)
(4)
5
5
4
MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED
(5)
(5)
(4)
5
5
4
THYMUS NO ABNORMALITY DETECTED
(5)
(5)
(4)
5
5
4
W
13 ADRENAL GLANDS
s
NO ABNORMALITY DETECTED
SCIATIC NERVE
0
NO ABNORMALITY DETECTED
0
(5)
(5)
(4)
5
5
4
(5)
(5)
(4)
5
5
4
(D
W
3
PITUITARY GLAMD
(5)
(5)
(4)
0
NO ABNORMALITY DETECTED
5
5
4
g
^
F-i-g-u-re-s--i-n--p-ar-e-n-th-e-s-e-s--is--t-h-e--nu-m-b-e-r--of--a-n-im--al-s--g-ro-s-s-l-y-e-x-a-m-i-ne-d--f-o--r th-i-s--ti-s-s-u-e-----
93*. The absence of a number indicates the finding specified was not identified
^
0 >
0
152
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 35 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (3-MONTH RECOVERY EVALUATION)
LESION INCIDENCE (
Males
LESIONS
THYROID GLAND NO ABNORMALITY DETECTED
TREATMENT
(mg/kg/day)
0
I
(5)
5
50
III
(5)
5
250
V
(4)
4
PARATHYROID GLANDS NO ABNORMALITY DETECTED
(5)
(5)
(4)
5
5
4
TRACHEA NO ABNORMALITY DETECTED
'
(5)
(5)
(4)
5
5
4
ESOPHAGUS NO ABNORMALITY DETECTED
(5)
(5)
(4)
5
5
4
PHARYNX/LARYNX NO ABNORMALITY DETECTED
(5)
(5)
(4)
5
5
4
EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED
(5)
(5)
(4)
5
5
4
SKIN |NO ABNORMALITY DETECTED
(5)
(5)
(4)
5
5
4
PROSTATE NO ABNORMALITY DETECTED
(5)
(5)
(4)
5
5
4
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
153
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 35 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS
(3-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
LESIONS
SEMINAL VESICLES NO ABNORMALITY DETECTED
TREATMENT
(mg/kg/day)
0
I
(5)
5
Males
50
250
III V
(5)
(4
5
4
URINARY BLADDER NO ABNORMALITY DETECTED
(5)
(5)
(4
5
5
4
TESTES NO ABNORMALITY DETECTED
(5)
(5)
(4
5
5
4
EPIDIDYMIDES NO ABNORMALITY DETECTED
(5)
(5)
(4
5
5
4
FEMUR/KNEE JOINT NO ABNORMALITY DETECTED
(5)
(5)
(4
5
5
4
STERNUM NO ABNORMALITY DETECTED
(5)
(5)
(4
5
5
4
NOSE |NO ABNORMALITY DETECTED
(5)
(5)
(4
5
5
4
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
154
^
H-24616: Subchronic Toxicity 90-Day Gavage Study m Rats with One-Generation Reproduction Evaluations
TABLE 36
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION)
LESION INCIDENCE
LESIONS
'LIVER
NO ABNORMALITY DETECTED
TREATMENT
(nig/kg/day)
0
II
(10) 10
Females
50
250
IV
VI
(10) (10)
10
10
KIDNEYS
(10) (10) (10)
NO ABNORMALITY DETECTED
10
10
10
LUNGS
(10) (10) (10)
NO ABNORMALITY DETECTED DISCOLORATION, DARK, DIFFUSE.
HEART
9 1
(10)
10
(10)
10 (10)
NO ABNORMALITY DETECTED
10
10
10
SKELETAL MUSCLE
(10) (10) (10)
NO ABNORMALITY DETECTED
10
10
10
SPLEEN NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
Figures in parentheses is the number of animals grossly examined for this tissue. The absence of a number indicates the finding specified was not identified
155
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION)
LESION INCIDENCE
LESIONS SPLEEN
TREATMENT
(mg/kg/day)
0
II
(10)
Females
50
250
IV
VI
(10) (10)
DISCOLORATION, BROWN.
AORTA
(10) (10) (10)
NO ABNORMALITY DETECTED
10
10
10
BRAIN NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
SPINAL CORD
(10) (10) (10)
NO ABNORMALITY DETECTED
10
10
10
STOMACH
(10) (10) (10)
NO ABNORMALITY DETECTED
10
10
10
| DUODENUM
|
NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
156
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDENCE
Females
LESIONS JEJUNUM
TREATMENT
(mg/kg/day)
0
II
(10)
50
IV (10)
250
VI
(10)
NO ABNORMALITY DETECTED
10
10
10
ILEUM
(10) (10) (10)
NO ABNORMALITY DETECTED
I PANCREAS
1 NO ABNORMALITY DETECTED
(ft
CECUM
1t MO ABNORMALITY DETECTED
?
COLON
s NO ABNORMALITY DETECTED
10
(10)
10
(10) 10 (10)
10
10 (10)
10
(10)
10
(10)
10
10 (10) 10 (10)
10
(10)
10
0
RECTUM
0
(10) (10) (10)
1
NO ABNORMALITY DETECTED
10
10
10
5}
Figures in parentheses is the number of animals grossly examined for this tissue
S
The absence of a number indicates the finding specified was not identified
0 0
157
^)
v
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDENCE
Females
LESIONS MESENTERIC LYMPH NODE
TREATMENT
(mg/kg/day)
0
II
(10)
50
IV
(10)
250
VI
(10)
NO ABNORMALITY DETECTED
10
10
10
SALIVARY GLANDS
(10) (10) (10)
NO ABNORMALITY DETECTED
10
10
10
1s?
MANDIBULAR LYMPH NODE
NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
THYMUS
CO
NO ABNORMALITY DETECTED
a
p. ADRENAL GLANDS
0
0
NO ABNORMALITY DETECTED
<&
I'O
(10) (10) (10
10
10
10
(10) (10) (10
10
10
10
a ;:
SCIATIC NERVE
i
0
Ki
NO ABNORMALITY DETECTED
(10) (10) (10
10
10
10
fc"3
?1
3
Figures in parentheses is the number of animals gros sly examined for this tissue
Sl
The absence of a number indicates the finding specif ied was not identified
P
0 S-i
158
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION)
LESION INCIDENCE
LESIONS
PITUITARY GLAND NO ABNORMALITY DETECTED
TREATMENT
(mg/kg/day)
0
II
(10)
10
Females
50
250
IV (10)
VI
(10)
10
10
THYROID GLAND
(10) (10) (10)
NO ABNORMALITY DETECTED
1(A
PARATHYROID GLANDS
1 NO ABNORMALITY DETECTED
&
0
TRACHEA
10
10
10
(10) (10) (10)
10
10
10
(10) (10) (10)
S
NO ABNORMALITY DETECTED
ESOPHAGUS
J1 NO ABNORMALITY DETECTED
5"
o!
PHARYNX/LARYNX
10
10
10
(10) (10) (10
10
10
10
(10) (10) (10
>
NO ABNORMALITY DETECTED
?
10
10
10
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
159
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDENCE
LESIONS
EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED
SKIN
TREATMENT
(mg/kg/day)
0
II
(10)
10 (10)
Females
50
250
IV
VI
(10) (10)
10
10
(10) (10)
NO ABNORMALITY DETECTED
10
10
10
MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED
(10) (10) (10)
10
10
10
OVARIES
(10) (10) (10)
NO ABNORMALITY DETECTED
10
10
10
UTERUS NO ABNORMALITY DETECTED
(10) (10) (10
10
10
10
URINARY BLADDER
(10) (10) (10
NO ABNORMALITY DETECTED
10
10
10
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
160
H-24616: Subchronic Toxicity 90-Day Gavage Study m Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDENCE (
Females
LESIONS FEMUR/KNEE JOINT
TREATMENT
(ing/kg/day)
0
II
(10)
50
IV
(10)
250
VI
(10)
NO ABNORMALITY DETECTED
10
10
10
STERNUM
(10) (10) (10)
NO ABNORMALITY DETECTED
10
10
10
NOSE
(10) (10) (10)
NO ABNORMALITY DETECTED
10
10
10
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
161
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
LESIONS
LIVER
NO ABNORMALITY DETECTED HERNIA.
TREATMENT
(mg/kg/day)
0
II
(10)
9 1
Females
50
250
IV
VI
KIDNEYS
(10)
NO ABNORMALITY DETECTED
10
LUNGS
(10)
NO ABNORMALITY DETECTED
10
HEART
(10)
NO ABNORMALITY DETECTED
10
SKELETAL MUSCLE
(10)
NO ABNORMALITY DETECTED
10
SPLEEN
(10)
NO ABNORMALITY DETECTED
10
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
162
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
LESIONS AORTA
TREATMENT
(mg/kg/day)
0
II
(10)
Females
50
250
IV
VI
NO ABNORMALITY DETECTED
10
BRAIN
(10)
NO ABNORMALITY DETECTED
10
SPINAL CORD
(10)
NO ABNORMALITY DETECTED
10
STOMACH
(10)
NO ABNORMALITY DETECTED
10
DUODENUM
(10)
NO ABNORMALITY DETECTED
10
JEJUNUM
(10)
NO ABNORMALITY DETECTED
10
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
163
^
^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
LESIONS ILEUM
TREATMENT
(mg/kg/day)
0
II
(10)
Females
50
250
IV
VI
NO ABNORMALITY DETECTED
10
PANCREAS
(10)
NO ABNORMALITY DETECTED
10
CECUM
(10)
NO ABNORMALITY DETECTED
10
COLON
(10)
NO ABNORMALITY DETECTED
10
RECTUM
(10)
NO ABNORMALITY DETECTED
10
MESENTERIC LYMPH NODE
(10)
NO ABNORMALITY DETECTED
10
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
164
1^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
LESIONS SALIVARY GLANDS
TREATMENT
(nig/kg/day)
0
II
(10)
Females
50
250
IV
VI
NO ABNORMALITY DETECTED
10
MANDIBULAR LYMPH NODE
(10)
NO ABNORMALITY DETECTED
10
THYMUS
(10)
NO ABNORMALITY DETECTED
10
ADRENAL GLANDS
(10)
NO ABNORMALITY DETECTED
10
SCIATIC NERVE
(10)
NO ABNORMALITY DETECTED
10
PITUITARY GLAND
(10)
NO ABNORMALITY DETECTED
10
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
165
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
LESIONS THYROID GLAND
TREATMENT
(mg/kg/day)
0
II
(10)
Females
50
250
IV
VI
NO ABNORMALITY DETECTED
10
PARATHYROID GLANDS
(10)
NO ABNORMALITY DETECTED
10
TRACHEA
(10)
NO ABNORMALITY DETECTED
10
ESOPHAGUS
(10)
NO ABNORMALITY DETECTED
10
PHARYNX/LARYNX
(10)
NO ABNORMALITY DETECTED
10
EYE(S) WITH OPTIC NERVE
(10)
NO ABNORMALITY DETECTED
10
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
166
H-24616: Subchronic Toxicity 90-Day Gavage Study m Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
LESIONS SKIN
TREATMENT
(mg/kg/day)
0
II
(10)
Females
50
250
IV
VI
NO ABNORMALITY DETECTED
10
MAMMARY GLAND (FEMALE)
(10)
NO ABNORMALITY DETECTED
10
OVARIES
(10)
NO ABNORMALITY DETECTED
10
UTERUS
(10)
NO ABNORMALITY DETECTED
10
URINARY BLADDER
(10)
NO ABNORMALITY DETECTED
10
FEMUR/KNEE JOINT
(10)
NO ABNORMALITY DETECTED
10
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
167
^-M ,
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
LESIONS STERNUM
TREATMENT
(mg/kg/day)
0
II
(10)
Females
50
250
IV
VI
NO ABNORMALITY DETECTED
10
NOSE
(10)
NO ABNORMALITY DETECTED
10
Figures in parentheses is the number of animals-grossly examined for this tissue The absence of a number indicates the finding specified was not identified
168
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (3-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
LESIONS
LIVER
1
NO ABNORMALITY DETECTED
TREATMENT
(ing/kg/day)
0
II
(5)
5
Females
50
250
IV
VI
(5)
(5)
5
5
KIDNEYS
1 NO ABNORMALITY DETECTED
1 LUNGS
(0 NO ABNORMALITY DETECTED
(A
0
HEART
NO ABNORMALITY DETECTED
IS
5"
SKELETAL MUSCLE
^
g
NO ABNORMALITY DETECTED
0
5
SPLEEN
NO ABNORMALITY DETECTED
(5)
(5)
(5)
5
5
5
<5)
(5)
(5)
5
5
5
(5)
(5)
(5)
5
5
5
(5)
(5)
(5)
5
5
5
(5)
(5)
(5)
5
5
5
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
169
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (3-MONTH RECOVERY EVALUATION)
LESION INCIDENCE (
Females
LESIONS
'^
AORTA
TREATMENT
(nig/kg/day)
0
II
(5)
50
IV
(5)
250
VI
(5)
< w
s
N
^
a
a (D (0 3
a
c 0 3
& 3"
5J
0 >
0
S.
NO ABNORMALITY DETECTED BRAIN
NO ABNORMALITY DETECTED SPINAL CORD
NO ABNORMALITY DETECTED STOMACH
NO ABNORMALITY DETECTED DUODENUM
NO ABNORMALITY DETECTED JEJUNUM
5
5
5
(5)
(5)
(5)
5
5
5
(5) . (5) (5)
5
5
5
(5)
(5)
(5)
5
5
5
(5)
(5)
(5)
5
5
5
(5)
(5)
(5)
NO ABNORMALITY DETECTED
5
5
5
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
170
f
|
OS
SB
1 M
?
0
1
1 S
ff
0
a-
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS EN FEMALE RATS (3-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
LESIONS ILEUM
TREATMENT
(mg/kg/day)
0
II
(5)
Females
50
250
IV
VI
(5)
(5
NO ABNORMALITY DETECTED
5
5
5
PANCREAS
(5)
(5)
(5
NO ABNORMALITY DETECTED
5
5
5
CECUM
|
NO ABNORMALITY DETECTED
(5)
(5)
(5
5
5
5
COLON
(5)
(5)
(5
NO ABNORMALITY DETECTED
5
5
5
RECTUM
(5)
(5)
(5
NO ABNORMALITY DETECTED
5
5
5
MESENTERIC LYMPH NODE
(5)
(5)
(5
NO ABNORMALITY DETECTED
5
5
5
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
171
^y
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (3-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
LESIONS
j
SALIVARY GLANDS
^
NO ABNORMALITY DETECTED
|(A MAMDIBULAR LYMPH NODE
H"
.&
NO ABNORMALITY DETECTED
0 THYMUS
TREATMENT
(mg/kg/day)
0
II
(5)
5
(5)
5
(5)
Females
50
250
IV
VI
(5)
(5)
5
5
(5)
(5)
5
5
(5)
(5)
1
NO ABNORMALITY DETECTED
|
ADRENAL GLANDS
aT
3"
NO ABNORMALITY DETECTED
^
SCIATIC NERVE
>
a NO ABNORMALITY DETECTED
PITUITARY GLAND
5
5
5
(5)
(5)
(5)
5
5
5
(5)
(5)
(5)
5
5
5
(5)
(5)
(5)
NO ABNORMALITY DETECTED
5
5
5
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
172
^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS
(3-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
Females
LESIONS THYROID GLAND
TREATMENT
(nig/kg/day)
0
II
(5)
50
IV
(5)
250
VI
(5)
NO ABNORMALITY DETECTED
5
5
5
PARATHYROID GLANDS
(5)
(5)
(5)
NO ABNORMALITY DETECTED
5
5
5
TRACHEA
(5)
(5)
(5
NO ABNORMALITY DETECTED
5
5
5
ESOPHAGUS
(5)
(5)
(5
NO ABNORMALITY DETECTED
5
5
5
PHARYNX/LARYNX
(5)
(5)
(5
NO ABNORMALITY DETECTED
5
5
5
EYE(S) WITH OPTIC NERVE
(5)
(5)
(5
NO ABNORMALITY DETECTED
5
5
5
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
173
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS EN FEMALE RATS (3-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
Females
LESIONS SKIN
TREATMENT
(ing/kg/day)
0
II
(5)
50
IV
(5)
250
VI
(5)
NO ABNORMALITY DETECTED
5
5
5
MAMMARY GLAND (FEMALE)
(5)
(5)
(5)
NO ABNORMALITY DETECTED
5
5
5
OVARIES
(5)
(5)
(5)
NO ABNORMALITY DETECTED
5
5
5
UTERUS
(5)
(5)
(5)
NO ABNORMALITY DETECTED
5
5
5
URINARY BLADDER
(5)
(5)
(5)
NO ABNORMALITY DETECTED
5
5
5
FEMUR/KNEE JOINT
(5)
(5)
(5)
NO ABNORMALITY DETECTED
5
5
5
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
174
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 36 (CONTINUED)
INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS
(3-MONTH RECOVERY EVALUATION)
LESION INCIDENCE
LESIONS
STERNUM
TREATMENT
(nig/kg/day)
0
II
(5)
Females
50
250
IV
(5)
VI
(5)
NO ABNORMALITY DETECTED
5
5
5
NOSE
(5)
(5)
(5)
NO ABNORMALITY DETECTED
5
5
5
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
175
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 37
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDE
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(mg/kg/day)
I
III
LIVER NO ABNORMALITY DETECTED
NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCELLULAR. HYPERPLASIA, BILE DUCT. FATTY CHANGE, PERI PORTAL. FATTY CHANGE, MEDIAN CLEFT. FATTY CHANGE, CENTRILOBULAR.
(10)
1 2 9
1
(10)
2
10
1 1 3 1
PANCREAS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. ATROPHY.
(10)
6 4
1
ESOPHAGUS NO ABNORMALITY DETECTED
FIBROSIS.
(10)
9
1
STOMACH NO ABNORMALITY DETECTED
(10) 10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
176
m
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 37 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESION INCIDE
LESIONS DIGESTIVE SYSTEM
'
TREATMENT
0
50
(mg/kg/day)
I
III
DUODENUM NO ABNORMALITY DETECTED
(10)
10
JEJUNUM NO ABNORMALITY DETECTED
(10)
10
ILEUM NO ABNORMALITY DETECTED
(10) 10
CECUM NO ABNORMALITY DETECTED
(10) 10
COLON NO ABNORMALITY DETECTED
(10)
10
RECTUM NO ABNORMALITY DETECTED
(10)
10
SALIVARY GLANDS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC.
(10) 10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesi6n specified was not identified
177
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 37 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESION INCIDE
LESIONS URINARY SYSTEM
TREATMENT
0
50
I I I (nig/kg/day) I
KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. INFLAMMATION, SUBACUTE/CHRONIC.
(10)
5
4
1
URINARY BLADDER
'
NO ABNORMALITY DETECTED
(10) 10
RESPIRATORY SYSTEM
LUNGS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC.
(10)
5
5
TRACHEA NO ABNORMALITY DETECTED
(10)
10
PHARYNX/LARYNX NO ABNORMALITY DETECTED
(10) 10
NOSE
NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. HYPERPLASIA/HYPERTROPHY, TRANSITIONAL
CELL,
EPITHELIUM.
(10)
10
(10)
2
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified '
178
w
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 37 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS RESPIRATORY SYSTEM
TREATMENT
0
50
(mg/kg/day)
I
III
NOSE
DEGENERATION/NECROSIS, OLFACTORY, EPITHELIUM.
(10) (10)
8
CARDIOVASCULAR SYSTEM
HEART NO ABNORMALITY DETECTED CARDIOMYOPATHY.
(10)
5
5
AORTA NO ABNORMALITY DETECTED
(10)
10
LYMPHATIC AND HEMATOPOIETIC SYSTEM
SPLEEN NO ABNORMALITY DETECTED
(10)
10
THYMUS NO ABNORMALITY DETECTED
(10) 10
MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED
(10)
10
MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED
(10) 10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
179
)
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 37 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDE
LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM
TREATMENT
0
50
(nig/kg/day)
III
BONE MARROW NO ABNORMALITY DETECTED
(10)
10
ENDOCRINE SYSTEM
PITUITARY GLAND NO ABNORMALITY DETECTED CYST.
THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID.
(10) 10
(10)
2
8
(10)
2
8
PARATHYROID GLANDS
(6)
NO ABNORMALITY DETECTED
6
ADRENAL GLANDS NO ABNORMALITY DETECTED
(10)
10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
180
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 37 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDE
LESIONS NERVOUS SYSTEM
TREATMENT
0
50
(rag/kg/day)
I
III
BRAIN NO ABNORMALITY DETECTED
(10) 10
SPINAL CORD NO ABNORMALITY DETECTED
(10) 10
SCIATIC NERVE
NO ABNORMALITY DETECTED
(10) 10
MUSCULAR AND SKELETAL SYSTEM
SKELETAL MUSCLE NO ABNORMALITY DETECTED
(10)
10
FEMUR/KNEE JOINT NO ABNORMALITY DETECTED
(10)
10
STERNUM NO ABNORMALITY DETECTED
(10)
10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
181
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 37 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDE
LESIONS REPRODUCTIVE SYSTEM
TREATMENT
0
50
(mg/kg/day)
I
III
TESTES NO ABNORMALITY DETECTED DILATATION, SEMINIFEROUS TUBULES,
'
UNILATERAL.
EPIDIDYMIDES NO ABNORMALITY DETECTED
(10)
10
(10) 10
PROSTATE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC.
SEMINAL VESICLES NO ABNORMALITY DETECTED
(10)
9 1
(10) 10
CUTANEOUS SYSTEM
SKIN NO ABNORMALITY DETECTED
(10) 10
SPECIAL SENSES SYSTEM
EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT. FOLD/ROSETTE, RETINAL.
(10)
9
1
1
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
182
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 37 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(mg/kg/day)
I
III
LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCELLULAR. FATTY CHANGE, MEDIAN CLEFT.
,
RESPIRATORY SYSTEM
(10)
1
9
1
NOSE NO ABNORMALITY DETECTED DEGENERATION/NECROSIS, OLFACTORY,
EPITHELIUM.
(10) 10
ENDOCRINE SYSTEM
THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID.
(10)
4
6
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
183
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 37 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS
(3-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(mg/kg/day)
I
III
LIVER NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC.
HYPERTROPHY, HEPATOCELLULAR.
HYPERPLASIA, BILE DUCT. FATTY CHANGE, PERIPORTAL. FATTY CHANGE, MEDIAN CLEFT.
FATTY CHANGE, CENTRILOBULAR.
(5)
(5)
1
5
5
1
1
1
1
2
RESPIRATORY SYSTEM
NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC.
(5)
(5)
5
5
ENDOCRINE SYSTEM
THYROID GLAND NO ABNORMALITY DETECTED ALTERATION, COLLOID.
(5)
(5)
1
5
4
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
184
B^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 38
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(ing/kg/day)
II IV
LIVER
(10) (10)
NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. FATTY CHANGE, MEDIAN CLEFT.
1
9
10
1
1
PANCREAS
(10)
NO ABNORMALITY DETECTED
6
ATROPHY.
4
ESOPHAGUS
(10)
NO ABNORMALITY DETECTED
9
FIBROSIS.
1
STOMACH
(10)
NO ABNORMALITY DETECTED
9
CYST, KERATIN.
1
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
185
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 38 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESION INCIDE
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(nig/kg/day)
II IV
DUODENUM NO ABNORMALITY DETECTED
(10)
10
JEJUNUM
(10)
NO ABNORMALITY DETECTED
10
ILEUM NO ABNORMALITY DETECTED
(10)
10
CECUM
(10)
NO ABNORMALITY DETECTED
10
COLON
(10)
NO ABNORMALITY DETECTED
10
RECTUM
(10)
NO ABNORMALITY DETECTED
10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
186
H-24616: Subchronic Toxicity 90-Day Gavage Study m Rats with One-Generation Reproduction Evaluations
TABLE 38 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
SALIVARY GLANDS NO ABNORMALITY DETECTED
(10)
10
URINARY SYSTEM
KIDNEYS
(10)
NO ABNORMALITY DETECTED
8
NEPHROPATHY, CHRONIC PROGRESSIVE.
1
INFLAMMATION, SUBACUTE/CHRONIC.
HYDRONEPHROSIS, UNILATERAL.
1
URINARY BLADDER
(10)
NO ABNORMALITY DETECTED
10
RESPIRATORY SYSTEM
LUNGS
(10)
NO ABNORMALITY DETECTED
10
INFLAMMATION, SUBACUTE/CHRONIC.
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
,187
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 38 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS RESPIRATORY SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
TRACHEA
(10)
NO ABNORMALITY DETECTED
10
PHARYNX/LARYNX
(10)
NO ABNORMALITY DETECTED
10
NOSE
(10) (10)
NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM. DEGENERATION/NECROSIS, OLFACTORY, EPITHELIUM.
10
8
2
CARDIOVASCULAR SYSTEM
HEART
(10)
NO ABNORMALITY DETECTED
8
CARDIOMYOPATHY.
2
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
188
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 38 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS CARDIOVASCULAR SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
AORTA
(10)
NO ABNORMALITY DETECTED
10
LYMPHATIC AND HEMATOPOIETIC SYSTEM
SPLEEN
? NO ABNORMALITY DETECTED 1 PIGMENT INCREASED.
THYMUS
w
1
NO ABNORMALITY DETECTED
N"
0
a.
MANDIBULAR LYMPH NODE
a
a <o
NO ABNORMALITY DETECTED
w
1
MESENTERIC LYMPH NODE
1
NO ABNORMALITY DETECTED
(10)
9 1
(10) 10 (10)
10 (10)
10
1
^
Figure in parentheses is number of animals microscopicallyy examined for this tissue The absence of a number indicates the lesion specified was not identified
1
) 3
189
T^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 38 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM
| TREATMENT
0
50
| (mg/kg/day)
II IV
BONE MARROW
(10)
NO ABNORMALITY DETECTED
10
ENDOCRINE SYSTEM
PITUITARY GLAND
(9)
NO ABNORMALITY DETECTED
9
THYROID GLAND
(10) (10)
NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID.
PARATHYROID GLANDS
7
5
3
5
(8)
NO ABNORMALITY DETECTED
8
ADRENAL GLANDS
(10)
NO ABNORMALITY DETECTED
10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
190
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 38 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
| LESION INCIDE
LESIONS NERVOUS SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
BRAIN
(10)
NO ABNORMALITY DETECTED
10
SPINAL CORD
(10)
NO ABNORMALITY DETECTED
10
SCIATIC NERVE
NO ABNORMALITY DETECTED
(10) 10
MUSCULAR AND SKELETAL SYSTEM
SKELETAL MUSCLE
(10)
NO ABNORMALITY DETECTED
10
FEMUR/KNEE JOINT
(10)
NO ABNORMALITY DETECTED
10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
191
-^ ^
^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 38 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESION INCIDE
LESIONS MUSCULAR AND SKELETAL SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
STERNUM
(10)
NO ABNORMALITY DETECTED
10
REPRODUCTIVE SYSTEM
OVARIES
(10)
NO ABNORMALITY DETECTED
10
UTERUS
(10)
NO ABNORMALITY DETECTED
DILATATION, LUMEN.
MAMMARY GLAND (FEMALE)
10
(10)
NO ABNORMALITY DETECTED
10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
192
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 38 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESION INCIDE
LESIONS CUTANEOUS SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
SKIN
(10)
NO ABNORMALITY DETECTED
10
SPECIAL SENSES SYSTEM
EYE(S) WITH OPTIC NERVE
(10)
NO ABNORMALITY DETECTED
9
OPTIC NERVE NOT PRESENT.
1
FOLD/ROSETTE, RETINAL.
1
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
193
'''
^ _
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 38 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION)
LESION INCIDE
LESIONS
DIGESTIVE SYSTEM LIVER
NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. FATTY CHANGE, MEDIAN CLEFT. PANCREAS
TREATMENT
0
50
(mg/kg/day)
II IV
(10)
10
3
NO ABNORMALITY DETECTED
ESOPHAGUS
NO ABNORMALITY DETECTED
STOMACH
NO ABNORMALITY DETECTED
DUODENUM
NO ABNORMALITY DETECTED
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
194
n^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 38 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
JEJUNUM
NO ABNORMALITY DETECTED
ILEUM
AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED.
CECUM
AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED.
COLON
AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED.
RECTUM
NO ABNORMALITY DETECTED
SALIVARY GLANDS
NO ABNORMALITY DETECTED
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
195
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 38 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS URINARY SYSTEM
TREATMENT
0
50
(ing/kg/day)
II
IV
KIDNEYS
NO ABNORMALITY DETECTED
URINARY BLADDER
NO ABNORMALITY DETECTED
RESPIRATORY SYSTEM
LUNGS
NO ABNORMALITY DETECTED
TRACHEA
NO ABNORMALITY DETECTED
PHARYNX/LARYNX
NO ABNORMALITY DETECTED
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
196
tj
H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 38 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION)
LESIONS RESPIRATORY SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDE
0
50
II IV
NOSE NO ABNORMALITY DETECTED
(10)
10
CARDIOVASCULAR SYSTEM
HEART
NO ABNORMALITY DETECTED
AORTA
|
NO ABNORMALITY DETECTED
LYMPHATIC AND HEMATOPOIETIC SYSTEM
SPLEEN
NO ABNORMALITY DETECTED
THYMUS
NO ABNORMALITY DETECTED
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
197
t)
H-24616: Subchronic Toxicity
90-Day Gavage Study m Rats with One-Generation Reproduction Evaluations
TABLE 38 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION)
LESION INCIDE
LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM
TREATMENT
0
50
(nig/kg/day)
II IV
MANDIBULAR LYMPH NODE
NO ABNORMALITY DETECTED
MESENTERIC LYMPH NODE
NO ABNORMALITY DETECTED
BONE MARROW
NO ABNORMALITY DETECTED
ENDOCRINE SYSTEM
PITUITARY GLAND NO ABNORMALITY DETECTED
THYROID GLAND
(10)
NO ABNORMALITY DETECTED
4
HYPERTROPHY, FOLLICULAR.
ALTERATION, COLLOID.
6
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
198
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 38 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION)
LESION INCIDE
LESIONS ENDOCRINE SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
THYROID GLAND
(10)
AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED.
PARATHYROID GLANDS
NO ABNORMALITY DETECTED
ADRENAL GLANDS
NO ABNORMALITY DETECTED
NERVOUS SYSTEM
BRAIN
MIXED GLIOMA [M]. SPINAL CORD
NO ABNORMALITY DETECTED
[M] Malignant tumor Figure in parentheses is number of animals microscopically examined for this tissue
The absence of a number indicates the lesion specified was not identified
199
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 38 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDE
LESIONS NERVOUS SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
SCIATIC NERVE
'
NO ABNORMALITY DETECTED
MUSCULAR AND SKELETAL SYSTEM
SKELETAL MUSCLE
NO ABNORMALITY DETECTED
FEMUR/KNEE JOINT
NO ABNORMALITY DETECTED
STERNUM
NO ABNORMALITY DETECTED
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
200
~ v -- H-24616: Subchronic Toxicity
90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 38 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS REPRODUCTIVE SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
OVARIES
NO ABNORMALITY DETECTED
UTERUS
NO ABNORMALITY DETECTED
SPECIAL SENSES SYSTEM
EYE(S) WITH OPTIC NERVE
AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED.
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
201
^^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 38 (CONTINUED)
INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (3-MONTH RECOVERY EVALUATION)
LESIONS DIGESTIVE SYSTEM
LESION INCIDEN
'
TREATMENT
0
50
(mg/kg/day)
II IV
LIVER
(5)
(5)
NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. FATTY CHANGE, MEDIAN CLEFT. FATTY CHANGE, FOCAL.
2
1
3
4
1
RESPIRATORY SYSTEM
NOSE
(5)
(5)
NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. ATROPHY, UNILATERAL, NASAL GLANDS.
2
4
2
1
1
ENDOCRINE SYSTEM
THYROID GLAND
(5)
(5)
NO ABNORMALITY DETECTED HYPERTROPHY. FOLLICULAR. ALTERATION, COLLOID.
2
3
5
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
202
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 39
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
| TREATMENT
. 0
50
| (mg/kg/day)
1
I
III
LIVER NO ABNORMALITY DETECTED
NECROSIS, FOCAL.
minimal
Total observations per lesion
INFLAMMATION, SUBACUTE/CHRONIC.
minimal
Total observations per lesion
HYPERTROPHY, HEPATOCELLULAR.
minimal mild Total observations per lesion HYPERPLASIA, BILE DUCT. minimal Total observations per lesion
FATTY CHANGE, PERIPORTAL.
minimal Total observations per lesion
FATTY CHANGE, MEDIAN CLEFT.
minimal mild Total observations per lesion
(10)
1 2 2 9 9
1 1
(10)
2 2
10 10
1
1
1 1
3 3
1
1
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
203
^1
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 39 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(ing/kg/day)
I
III
LIVER FATTY
CHANGE, CENTRILOBULAR.
minimal
Total observations per
lesion
PANCREAS
NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC.
minimal Total observations per
ATROPHY.
minimal Total observations per
lesion lesion
ESOPHAGUS NO ABNORMALITY DETECTED
FIBROSIS. minimal
Total observations per lesion
STOMACH NO ABNORMALITY DETECTED
(10) (10)
(10)
6
4 4
1 1
(10)
9
1 1
(10) 10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
204
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 39 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(mg/kg/day)
I
III
DUODENUM NO ABNORMALITY DETECTED
(10) 10
JEJUNUM NO ABNORMALITY DETECTED
(10) 10
ILEUM NO ABNORMALITY DETECTED
(10)
10
CECUM NO ABNORMALITY DETECTED
(10) 10
COLON NO ABNORMALITY DETECTED
(10)
10
RECTUM NO ABNORMALITY DETECTED
(10)
10
SALIVARY GLANDS NO ABNORMALITY DETECTED
INFLAMMATION, SUBACUTE/CHRONIC.
minimal
Total observations per lesion
(10) 10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
205
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 39 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDE
LESIONS URINARY SYSTEM
TREATMENT
0
50
(mg/kg/day)
I
III
KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE.
minimal Total observations per lesion
INFLAMMATION, SUBACUTE/CHRONIC. minimal
Total observations per lesion
URINARY BLADDER NO ABNORMALITY DETECTED
(10)
5
4 4
1 1
(10)
10
RESPIRATORY SYSTEM
LUNGS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC.
minimal Total observations per lesion
TRACHEA NO ABNORMALITY DETECTED
(10)
5
5 5
(10) 10
Figure in parentheses is number of animals 'microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
206
^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 39 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
| LESION INCIDE
LESIONS RESPIRATORY SYSTEM
TREATMENT
0
50
(mg/kg/day)
I
III
PHARYNX/LARYNX NO ABNORMALITY DETECTED
(10)
10
NOSE
NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC.
minimal Total observations per lesion HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM. minimal Total observations per lesion DEGENERATION/NECROSIS, OLFACTORY, EPITHELIUM. minimal mild moderate Total observations per lesion
CARDIOVASCULAR SYSTEM
(10) (10)
10
2
7 1
8
HEART NO ABNORMALITY DETECTED CARDIOMYOPATHY.
minimal Total observations per lesion
(10)
5
5 5
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
207
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 39 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS CARDIOVASCULAR SYSTEM
TREATMENT
0
50
(mg/kg/day)
I
III
AORTA NO ABNORMALITY DETECTED
(10)
10
LYMPHATIC AMD HEMATOPOIETIC SYSTEM
SPLEEN NO ABNORMALITY DETECTED
(10) 10
THYMUS NO ABNORMALITY DETECTED
(10) 10
MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED
(10) 10
MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED
(10) 10
BONE MARROW NO ABNORMALITY DETECTED
(10)
10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
208
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 39 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS ENDOCRINE SYSTEM
TREATMENT
0
50
(mg/kg/day)
I
III
PITUITARY GLAND NO ABNORMALITY DETECTED
CYST.
minimal Total observations per lesion
THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR.
minimal mild
Total observations per lesion
ALTERATION, COLLOID.
minimal mild moderate severe Total observations per lesion
PARATHYROID GLANDS NO ABNORMALITY DETECTED
(10) 10
(10)
2
(10)
2
8
5
3
8
8
(6)
6
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
209
V_y
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 39 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS ENDOCRINE SYSTEM
TREATMENT
0
50
(ing/kg/day)
I
III
ADRENAL GLANDS NO ABNORMALITY DETECTED
(10) 10
NERVOUS SYSTEM
BRAIN NO ABNORMALITY DETECTED
(10) 10
i
SPINAL CORD
NO ABNORMALITY DETECTED
i
SCIATIC NERVE NO ABNORMALITY DETECTED
5s
&
MUSCULAR AND SKELETAL SYSTEM
00 SKELETAL MUSCLE
S
NO ABNORMALITY DETECTED
(10) 10
(10) 10
(10)
10
0
FEMUR/KNEE JOINT
NO ABNORMALITY DETECTED
(10) 10
oT
3"
STERNUM
NO ABNORMALITY DETECTED
(10)
10
CO
rt
&>
FI, igure in parentheses is number of animals microscopicall''y examined for this tissue
0;10 The absence of a number indicates the lesion specified was not identified
210
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 39 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS REPRODUCTIVE SYSTEM
TREATMENT
0
50
(mg/kg/day)
I
III
TESTES NO ABNORMALITY DETECTED DILATATION, SEMINIFEROUS TUBULES, UNILATERAL.
mild Total observations per lesion
EPIDIDYMIDES NO ABNORMALITY DETECTED
(10) 10
(10) 10
PROSTATE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC.
minimal
Total observations per lesion
SEMINAL VESICLES NO ABNORMALITY DETECTED
(10)
9
1 1
(10) 10
CUTANEOUS SYSTEM
SKIN NO ABNORMALITY DETECTED
(10) 10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
211
^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 39 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDE
LESIONS SPECIAL SENSES SYSTEM
TREATMENT
0
50
(ing/kg/day)
I
III
EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED
OPTIC NERVE NOT PRESENT. FOLD/ROSETTE, RETINAL.
minimal Total observations per lesion
(10)
9 1
1 1
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
212
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 39 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(mg/kg/day)
I
III
LIVER
(10)
NO ABNORMALITY DETECTED
1
NECROSIS, FOCAL.
minimal
Total observations per lesion
INFLAMMATION, SUBACUTE/CHRONIC.
minimal
9
Total observations per lesion
9
HYPERTROPHY, HEPATOCELLULAR.
minimal
Total observations per lesion
FATTY CHANGE, MEDIAN CLEFT.
minimal
1
Total observations per lesion
1
RESPIRATORY SYSTEM
NOSE
NO ABNORMALITY DETECTED
DEGENERATION/NECROSIS, OLFACTORY, EPITHELIUM. minimal
Total observations per lesion
(10)
10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
213
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 39 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS ENDOCRINE SYSTEM
TREATMENT
0
50
(mg/kg/day)
I
III
THYROID GLAND
(10)
NO ABNORMALITY DETECTED
4
HYPERTROPHY, FOLLICULAR.
minimal mild
Total observations per lesion
ALTERATION, COLLOID.
minimal
5
mild
1
moderate
severe
Total observations per lesion
6
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
214
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 39 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS
(3-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
I I I (nig/kg/day) I
LIVER
NECROSIS, FOCAL.
mild
moderate
Total observations per
INFLAMMATION, SUBACUTE/CHRONIC.
minimal Total observations per
HYPERTROPHY, HEPATOCELLULAR.
minimal Total observations per HYPERPLASIA, BILE DUCT. minimal Total observations per
FATTY CHANGE, PERI PORTAL.
minimal mild Total observations per
FATTY CHANGE, MEDIAN CLEFT.
minimal mild
Total observations per
lesion lesion lesion lesion lesion lesion
(5)
(5)
1 1
5
5
5
5
1 1
1
1
1
1
2
1
1
2
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
215
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 39 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS
(3-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(mg/kg/day)
I
III
LIVER
FATTY
CHANGE,
mild Total
CENTRILOBULAR.
observations per
lesion
RESPIRATORY SYSTEM
(5)
(5)
NOSE NO ABNORMALITY DETECTED
INFLAMMATION, SUBACUTE/CHRONIC.
minimal
Total observations per lesion
ENDOCRINE SYSTEM
(5)
(5)
5
5
THYROID GLAND
NO ABNORMALITY DETECTED
ALTERATION, COLLOID.
minimal mild moderate severe Total observations per lesion
(5)
(5)
1
4
2
1
2
5
4
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
216
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
LIVER
(10) (10)
NO ABNORMALITY DETECTED NECROSIS, FOCAL.
minimal Total observations per lesion
INFLAMMATION, SUBACUTE/CHRONIC.
minimal Total observations per lesion
FATTY CHANGE, MEDIAN CLEFT.
minimal
Total observations per lesion
PANCREAS
1
9
10
9
10
1
1
1
1
(10)
NO ABNORMALITY DETECTED ATROPHY.
minimal Total observations per lesion
ESOPHAGUS
6
4 4
(10)
NO ABNORMALITY DETECTED
9
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
217
w
H
^
J
a
8
2, 3"
^
2
^
3
&
i
3
^
a
3
sT S.
?
(D W
1
3
^
&
f
3-
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(ing/kg/day)
II IV
ESOPHAGUS
(10)
FIBROSIS.
minimal
1
Total observations per lesion
1
STOMACH
(10)
NO ABNORMALITY DETECTED CYST, KERATIN.
minimal
Total observations per lesion
DUODENUM
9
1 1
(10)
NO ABNORMALITY DETECTED
10
JEJUNUM
(10)
NO ABNORMALITY DETECTED
10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
218
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
ILEUM
(10)
NO ABNORMALITY DETECTED
10
CECUM
(10)
NO ABNORMALITY DETECTED
10
COLON
(10)
NO ABNORMALITY DETECTED
10
RECTUM
(10)
NO ABNORMALITY DETECTED
10
SALIVARY GLANDS
(10)
NO ABNORMALITY DETECTED
10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
219
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS URINARY SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
KIDNEYS
(10)
,
NO ABNORMALITY DETECTED
8
NEPHROPATHY, CHRONIC PROGRESSIVE.
minimal
1
Total observations per lesion
1
INFLAMMATION, SUBACUTE/CHRONIC.
minimal
Total observations per lesion
HYDRONEPHROSIS, UNILATERAL.
minimal
1
Total observations per lesion
1
URINARY BLADDER
(10)
NO ABNORMALITY DETECTED
10
RESPIRATORY SYSTEM
LUNGS
(10)
NO ABNORMALITY DETECTED
10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
220
^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS RESPIRATORY SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
LUNGS
(10)
INFLAMMATION, SUBACUTE/CHRONIC.
minimal
Total observations per lesion
TRACHEA
(10)
NO ABNORMALITY DETECTED
10
PHARYNX/LARYNX
(10)
NO ABNORMALITY DETECTED
10
NOSE
(10) (10)
NO ABNORMALITY DETECTED
INFLAMMATION, SUBACUTE/CHRONIC.
minimal mild Total observations per lesion
HYPERPLASIA/HYPERTROPHY, TRANSITIONAL
minimal
CELL,
EPITHELIUM.
10
8
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
221
H-24616: Subchronic Toxic ity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS RESPIRATORY SYSTEM
LESION INCIDEN
'
TREATMENT
0
50
(ing/kg/day)
II IV
NOSE
(10) (10)
HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM.
Total observations per lesion
DEGENERATION/NECROSIS, OLFACTORY, EPITHELIUM.
minimal
2
mild
Total observations per lesion
2
CARDIOVASCULAR SYSTEM
HEART
(10)
NO ABNORMALITY DETECTED CARDIOMYOPATHY.
minimal
Total observations per lesion
AORTA
8
2 2
(10)
NO ABNORMALITY DETECTED
10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
222
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
SPLEEN
(10)
NO ABNORMALITY DETECTED PIGMENT INCREASED.
mild Total observations per lesion
THYMUS
9
1 1
(10)
NO ABNORMALITY DETECTED
10
MANDIBULAR LYMPH NODE
(10)
NO ABNORMALITY DETECTED
10
MESENTERIC LYMPH NODE
(10)
NO ABNORMALITY DETECTED
10
BONE MARROW
(10)
NO ABNORMALITY DETECTED
10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
223
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS ENDOCRINE SYSTEM
; | TREATMENT 0 50
| (mg/kg/day)
1
II IV
PITUITARY GLAND
(9)
NO ABNORMALITY DETECTED
9
THYROID GLAND
(10) (10)
g
NO ABNORMALITY DETECTED
3
HYPERTROPHY, POLLICULAR.
S
minimal
<3
mild
o
Total observations per lesion
ALTERATION, COLLOID.
a
minimal
mild
^Ob Total observations per lesion
3
PARATHYROID GLANDS
i NO ABNORMALITY DETECTED
i ADRENAL GLANDS
7
5
3
5
3
5
(8)
8
(10)
?
<^ NO ABNORMALITY DETECTED
10
Figure in parentheses is number of animals microscopically examined for this tissue
0
The absence of a number indicates the lesion specified was not identified
224
Y^'
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rate with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS NERVOUS SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
BRAIN
(10)
NO ABNORMALITY DETECTED
10
SPINAL CORD
(10)
NO ABNORMALITY DETECTED
10
SCIATIC NERVE
(10)
NO ABNORMALITY DETECTED
10
MUSCULAR AND SKELETAL SYSTEM
SKELETAL MUSCLE
(10)
NO ABNORMALITY DETECTED
10
FEMUR/KNEE JOINT
(10)
NO ABNORMALITY DETECTED
10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
225
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RAT NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS MUSCULAR AND SKELETAL SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
STERNUM
(10)
NO ABNORMALITY DETECTED
10
REPRODUCTIVE SYSTEM
OVARIES
(10)
NO ABNORMALITY DETECTED
10
UTERUS
(10)
NO ABNORMALITY DETECTED
10
DILATATION, LUMEN.
minimal mild
Total observations per lesion
MAMMARY GLAND (FEMALE)
(10)
NO ABNORMALITY DETECTED
10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
226
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDE
LESIONS CUTANEOUS SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
SKIN
(10)
NO ABNORMALITY DETECTED
10
SPECIAL SENSES SYSTEM
EYE(S) WITH OPTIC NERVE
(10)
NO ABNORMALITY DETECTED
9
OPTIC NERVE NOT PRESENT.
1
FOLD/ROSETTE, RETINAL.
minimal
1
Total observations per lesion
1
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
227
^3-'
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE. 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
'
TREATMENT
0
50
(mg/kg/day)
II IV
LIVER
(10)
NO ABNORMALITY DETECTED
NECROSIS, FOCAL.
minimal
Total observations per lesion
INFLAMMATION, SUBACUTE/CHRONIC.
minimal
10
Total observations per lesion
10
FATTY CHANGE, MEDIAN CLEFT.
minimal
2
mild
1
|
Total observations per lesion
3
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
228
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(ing/kg/day)
II IV
PANCREAS
NO ABNORMALITY DETECTED
ESOPHAGUS
NO ABNORMALITY DETECTED
STOMACH
NO ABNORMALITY DETECTED
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
229
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDE
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
DUODENUM
NO ABNORMALITY DETECTED
JEJUNUM
NO ABNORMALITY DETECTED
ILEUM
AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED.
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
230
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
CECUM
AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED.
COLON
AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED;
RECTUM
NO ABNORMALITY DETECTED
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
231
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(ing/kg/day)
II IV
SALIVARY GLANDS
NO ABNORMALITY DETECTED
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
232
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
| LESION INCIDEN
LESIONS URINARY SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
KIDNEYS
NO ABNORMALITY DETECTED
URINARY BLADDER
NO ABNORMALITY DETECTED
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
233
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS RESPIRATORY SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
LUNGS
NO ABNORMALITY DETECTED
TRACHEA
NO ABNORMALITY DETECTED
PHARYNX/LARYNX
NO ABNORMALITY DETECTED
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
234
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS RESPIRATORY SYSTEM
| TREATMENT
0
50
| (ing/kg/day)
II IV
NOSE
;
(10)
NO ABNORMALITY DETECTED
10
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
235
^
H-24616: Subchronic Toxicity 90-Day Gavage Study m Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS CARDIOVASCULAR SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
HEART
NO ABNORMALITY DETECTED
AORTA , NO ABNORMALITY DETECTED
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion .specified was not identified
236
H-24 616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS LYMPHATIC AND HEMATOPOIETZC SYSTEM
TREATMENT
0
50
(ing/kg/day)
II IV
SPLEEN
NO ABNORMALITY DETECTED
THYMUS
NO ABNORMALITY DETECTED
MANDIBULAR LYMPH NODE
NO ABNORMALITY DETECTED
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
237
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
MESENTERIC LYMPH NODE
NO ABNORMALITY DETECTED
BONE MARROW
NO ABNORMALITY DETECTED
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
238
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDE
LESIONS ENDOCRINE SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
PITUITARY GLAND
NO ABNORMALITY DETECTED
THYROID GLAND
(10)
NO ABNORMALITY DETECTED
4
HYPERTROPHY, FOLLICULAR.
minimal mild Total observations per lesion ALTERATION, COLLOID.
minimal
6
mild
moderate
Total observations per lesion
6
AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED.
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
239
^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
| LESION INCIDE
LESIONS ENDOCRINE SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
PARATHYROID GLANDS
NO ABNORMALITY DETECTED
ADRENAL GLANDS
NO ABNORMALITY DETECTED
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
240
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDE
LESIONS NERVOUS SYSTEM
TREATMENT
0
50
(ing/kg/day)
II IV
SPINAL CORD
NO ABNORMALITY DETECTED
SCIATIC NERVE
NO ABNORMALITY DETECTED
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
241
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDE
'
LESIONS
MUSCULAR AND SKELETAL SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
SKELETAL MUSCLE.
NO ABNORMALITY DETECTED
FEMUR/KNEE JOINT
NO ABNORMALITY DETECTED
STERNUM
NO ABNORMALITY DETECTED
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
242
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS REPRODUCTIVE SYSTEM
TREATMENT
0
50
(mg/kg/day)
II IV
OVARIES
NO ABNORMALITY DETECTED
UTERUS
NO ABNORMALITY DETECTED
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
243
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RAT NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS SPECIAL SENSES SYSTEM
TREATMENT
0
50
(mg/kg/day)
II
IV
EYE(S) WITH OPTIC NERVE
AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED.
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
244
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RAT NON-NEOPLASTIC LESIONS
(3-MONTH RECOVERY EVALUATION)
LESION INCIDENC
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(ing/kg/day)
II IV
LIVER
(5)
(5)
NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC.
minimal Total observations per lesion
FATTY CHANGE, MEDIAN CLEFT.
minimal mild
Total observations per lesion
FATTY CHANGE, FOCAL.
mild Total observations per lesion
RESPIRATORY SYSTEM
2
1
3
4
3
4
1
1
NOSE
(5)
(5)
NO ABNORMALITY DETECTED
INFLAMMATION, SUBACUTE/CHRONIC.
minimal Total observations per lesion
2
4
2
1
2
1
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
245
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 40 (CONTINUED)
INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RAT NON-NEOPLASTIC LESIONS
(3-MONTH RECOVERY EVALUATION)
LESION INCIDEN
LESIONS RESPIRATORY SYSTEM
TREATMENT
0
50
.
(mg/kg/day)
II IV
NOSE
(5)
(5)
ATROPHY, UNILATERAL, NASAL GLANDS.
severe
1
Total observations per lesion
1
ENDOCRINE SYSTEM
THYROID GLAND
(5)
(5)
NO ABNORMALITY DETECTED
HYPERTROPHY, FOLLICULAR.
minimal
|
Total observations per lesion
ALTERATION, COLLOID.
minimal mild
Total observations per lesion
2
3
5
3
5
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
246
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESION INCIDEN
LESIONS DIGESTIVE SYSTEM
TREATMENT
0
50
(ing/kg/day)
I
III
LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC.
HYPERTROPHY, HEPATOCELLULAR.
(10) (10) 641094 641149 641081 641172 641198 641069 641055 6 641070 641056 6 641147 641073 6 641149 641081 6 641155 641144 6 641172 641146 6 641206 641178 641214 641198 641222 641218
641224
641081
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
247
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS
DIGESTIVE SYSTEM LIVER
HYPERTROPHY, HEPATOCELLULAR.
HYPERPLASIA, BILE DUCT. FATTY CHANGE, PERIPORTAL.
FATTY CHANGE, MEDIAN CLEFT. FATTY -CHANGE, CENTRILOBULAR.
TREATMENT
(mg/kg/day)
LESION INCIDEN
0
50
I
III
(10) (10) 6
641172 641081 641144 641198 641224 641218 6 6
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
248
\c/
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS DIGESTIVE SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDEN
0
50
I
III
PANCREAS NO ABNORMALITY DETECTED
(10) 641069 641094 641147 641155 641172 641222
INFLAMMATION, SUBACUTE/CHRONIC. ATROPHY.
641070 641149 641206 641214 641214
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
249
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS DIGESTIVE SYSTEM
TREATMENT
(ing/kg/day)
LESION INCIDEN
0
50
I
III
ESOPHAGUS NO ABNORMALITY DETECTED
FIBROSIS.
(10) 641069 641070 641094 641147 641149
641155 641206 641214 641222
641172
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
250
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS DIGESTIVE SYSTEM
| TREATMENT | (mg/kg/day) 1
LESION INCIDE
0
| 50
|
I | III
STOMACH NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
251
D
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS DIGESTIVE SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDE
0
50
I
III
DUODENUM NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
252
^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS DIGESTIVE SYSTEM
TREATMENT
(ing/kg/day)
LESION INCIDEN
0
50
I
III
JEJUNUM NO ABNORMALITY DETECTED
(10) 641069
641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
253
Bh
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS DIGESTIVE SYSTEM
| TREATMENT | (nig/kg/day) 1
LESION INCIDEN
0
50
I
III
ILEUM NO ABNORMALITY DETECTED
(10) 641069 641070 641094
641147 641149 641155 641172 641206
641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
254
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS DIGESTIVE SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDEN
0
50
I
III
CECUM
NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206
641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
255
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS DIGESTIVE SYSTEM
| TREATMENT | (mg/kg/day) 1
LESION INCIDEN
0
50
I
III
COLON NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
256
w
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS DIGESTIVE SYSTEM
| LESION INCIDEN
TREATMENT
0
50
(mg/kg/day)
I
III
RECTUM NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
257
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS DIGESTIVE SYSTEM
| TREATMENT | (mg/kg/day) 1
| LESION INCIDEN
0
50
I
III
SALIVARY GLANDS NO ABNORMALITY DETECTED
INFLAMMATION, SUBACUTE/CHRONIC.
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214
641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
258
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS URINARY SYSTEM
TREATMENT
(mg/kg/day)
I LESION INCIDEN
0
| 50
1
I | III
KIDNEYS NO ABNORMALITY DETECTED
NEPHROPATHY, CHRONIC PROGRESSIVE.
INFLAMMATION, SUBACUTE/CHRONIC.
(10) 641069 641155 641172 641214 641222 641070 641147 641149 641206
641094
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
259
^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS URINARY SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDEN
0
50
I
III
URINARY BLADDER NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
260
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS RESPIRATORY SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDEN
0
50
I
III
LUNGS NO ABNORMALITY DETECTED
INFLAMMATION, SUBACUTE/CHRONIC.
(10) 641094 641147 641149 641214 641222
641069 641070 641155 641172 641206
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
261
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS RESPIRATORY SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDEN
0
50
I
III
TRACHEA NO ABNORMALITY DETECTED
(10) 641069 641070 641094
641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
262
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS RESPIRATORY SYSTEM
TREATMENT
(ing/kg/day)
LESION INCIDE
0
50
I
III
PHARYNX/LARYNX NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
263
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS RESPIRATORY SYSTEM NOSE
NO ABNORMALITY DETECTED
INFLAMMATION, SUBACUTE/CHRONIC.
TREATMENT
(mg/kg/day)
LESION INCIDEN
0
50
I
III
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
(10) 641178 641198
HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM. DEGENERATION/NECROSIS. OLFACTORY, EPITHELIUM.
641055 641056 641073 641081 641144
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
264
s^ --^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS RESPIRATORY SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDE
0
50
I
III
NOSE
DEGENERATION/NECROSIS, OLFACTORY, EPITHELIUM.
(10) (10) 641146
641218 641224
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
265
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS CARDIOVASCULAR SYSTEM
| LESION INCIDEN
TREATMENT
0
50
(ing/kg/day)
I
III
HEART NO ABNORMALITY DETECTED
CARDIOMYOPATHY.
(10) 641070 641094 641155 641172 641222
641069 641147 641149 641206 641214
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
266
^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS CARDIOVASCULAR SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDEN
0
50
I
III
AORTA NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
267
^-l
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDE
0
50
I
III
SPLEEN NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155
641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
268
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDEN
0
50
I
III
THYMUS NO ABNORMALITY DETECTED
(10) 641069 641070 641094
641147 641149 641155 641172 641206 641214 641222
Figure in. parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
269
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM
| LESION INCIDE
TREATMENT
0
50
(ing/kg/day)
I
III
MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
270
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS LYMPHATIC AMD HEMATOPOIETIC SYSTEM
| LESION INCIDEN
TREATMENT
0
50
(ing/kg/day)
I
III
MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147
641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
271
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDE
0
50
I
III
BONE MARROW NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
272
w ^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS ENDOCRINE SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDEN
0
50
I
III
PITUITARY GLAND NO ABNORMALITY DETECTED
CYST.
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
273
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS
ENDOCRINE SYSTEM THYROID GLAND
NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR.
TREATMENT
(mg/kg/day)
LESION INCIDEN
0
50
I
III
(10) (10) 641069 641218 641070 641224
ALTERATION, COLLOID.
641094 641147 641149 641155 641172 641206 641214 641222
641055 641056 641073 641081 641144 641146 641178 641198
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
274
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS ENDOCRINE SYSTEM
| LESION INCIDEN
TREATMENT
0
50
(mg/kg/day)
I
III
PARATHYROID GLANDS NO ABNORMALITY DETECTED
(6) 641070 641147 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
275
^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS ENDOCRINE SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDEN
0
50
I
III
ADRENAL GLANDS NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
276
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS NERVOUS SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDEN
0
50
I
III
BRAIN NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214
641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
277
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS NERVOUS SYSTEM
TREATMENT
(ing/kg/day)
LESION INCIDE
0
50
I
III
SPINAL CORD NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
278
^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS NERVOUS SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDE
0
50
I
III
SCIATIC NERVE NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
279
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS MUSCULAR AND SKELETAL SYSTEM
| LESION INCIDEN
TREATMENT
0
50
(mg/kg/day)
I
III
SKELETAL MUSCLE NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
280
<9
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS MUSCULAR AND SKELETAL SYSTEM
| LESION INCIDEN
TREATMENT
0
50
(ing/kg/day)
I
III
FEMUR/KNEE JOINT NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
281
H-24616: Subchronic Toxicity 90-Day Gavage Study inRats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS MUSCULAR AND SKELETAL SYSTEM
| LESION INCIDEN
TREATMENT
0
50
(mg/kg/day)
I
III
STERNUM NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
282
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS REPRODUCTIVE SYSTEM
| LESION INCIDE
TREATMENT
0
50
(mg/kg/day)
I
III
TESTES NO ABNORMALITY DETECTED
DILATATION, SEMINIFEROUS TUBULES, UNILATERAL.
(10) 641069
641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates 'the lesion specified was not identified
283
w^
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS REPRODUCTIVE SYSTEM
| LESION INCIDE
TREATMENT
0
50
(mg/kg/day)
I
III
EPIDIDYMIDES NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
284
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS REPRODUCTIVE SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDEN
0
50
I
III
PROSTATE NO ABNORMALITY DETECTED
INFLAMMATION, SUBACUTE/CHRONIC.
(10) 641069 641094
641147 641149 641155 641172 641206 641214 641222
641070
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
285
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS REPRODUCTIVE SYSTEM
| TREATMENT | (mg/kg/day) 1
LESION INCIDEN
0
50
I
III
SEMINAL VESICLES NO ABNORMALITY DETECTED
(10) 64L069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
286
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION)
LESIONS CUTANEOUS SYSTEM
| LESION INCIDE
TREATMENT
0
50
(mg/kg/day)
I
III
SKIN NO ABNORMALITY DETECTED
(10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
287
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(90-DAY EXPOSURE EVALUATION)
LESIONS SPECIAL SENSES SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDE
0
50
I
III
EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED
OPTIC NERVE NOT PRESENT. FOLD/ROSETTE, RETINAL.
(10) 641069 641070 641094 641147 641149 641155 641206 641214 641222
641069 641172
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
288
^
w
H-24616: Subchronic Toxicity 90-Day Gavage Study m Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECT NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION)
LESIONS
DIGESTIVE SYSTEM LIVER
NO ABNORMALITY DETECTED NECROSIS, FOCAL.
TREATMENT
(mg/kg/day)
LESION INCIDENC
0
50
I
III
(10) 641083
INFLAMMATION, SUBACUTE/CHRONIC.
|
HYPERTROPHY, HEPATOCELLULAR.
641084 641085 641101 641105 641123 641154 641159 641165 641215
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
289
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION)
LESIONS DIGESTIVE SYSTEM
| LESION INCIDEN
TREATMENT
0
50
(ing/kg/day)
I
III
LIVER HYPERTROPHY, HEPATOCELLULAR.
FATTY CHANGE, MEDIAN CLEFT.
(10) 641159
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
290
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION)
LESIONS RESPIRATORY SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDEN
0
50
I
III
NOSE NO ABNORMALITY DETECTED
DEGENERATION/NECROSIS, OLFACTORY, EPITHELIUM.
(10) 641083
641084 641085 641101 641105 641123 641154 641159 641165 641215
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
291
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECT NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(ONE-MONTH RECOVERY EVALUATION)
LESIONS
ENDOCRINE SYSTEM THYROID GLAND
NO ABNORMALITY DETECTED
HYPERTROPHY, FOLLICULAR.
TREATMENT
(mg/kg/day)
LESION INCIDENC
0
50
I
III
(10) 641083 641084 641165 641215
ALTERATION, COLLOID.
641085 641101 641105 641123
641154 641159
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
292
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECT NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(3-MONTH RECOVERY EVALUATION)
LESIONS DIGESTIVE SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDENC
0
50
I
III V
LIVER NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC.
HYPERTROPHY, HEPATOCELLULAR.
HYPERPLASIA, BILE DUCT. FATTY CHANGE, PERIPORTAL. FATTY CHANGE, MEDIAN CLEFT. FATTY CHANGE, CENTRILOBULAR.
(5)
(5)
641113
641066 641059 6 641098 641113 6 641104 641160 6 641115 641194 641220 641225
6 6 6
641115 641098
641113 641113 641059
641113
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
293
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS
(3-MONTH RECOVERY EVALUATION)
LESIONS RESPIRATORY SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDEN
0
50
I
III
NOSE NO ABNORMALITY DETECTED
INFLAMMATION, SUBACUTE/CHRONIC.
(5)
(5)
641066 641059 6
641098 641113 6
641104 641160 6
641115 641194 6
641220 641225
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
294
H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations
TABLE 41 (CONTINUED)
MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (3-MONTH RECOVERY EVALUATION)
LESIONS ENDOCRINE SYSTEM
TREATMENT
(mg/kg/day)
LESION INCIDEN
0
50
I
III
THYROID GLAND NO ABNORMALITY DETECTED
ALTERATION, COLLOID.
(5)
(5)
641194
641066 641059 6
641098 641113 6
641104 641160 6
641115 641225 6
641220
Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified
295