### Harlan StudyNumber: 41205015 Report



## Appendix 1 (continued) IndividualDaily Clinical Observations Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign

1(F) 13 No Abnormalities Detected Scheduled kill 14 No Abnormalities Detected Scheduled kill 15 No Abnormalities Detected Scheduled kill 16 No Abnormalities Detected Scheduled kill 17 No Abnormalities Detected Scheduled kill 18 No Abnormalities Detected Scheduled kill 19 No Abnormalities Detected Scheduled kill 20 No Abnormalities Detected Scheduled kill 21 No Abnormalities Detected Scheduled kill 22 No Abnormalities Detected Scheduled kill 23 No Abnormalities Detected Scheduled kill 24 No Abnormalities Detected Littering

X

## =Present Not Observed Due to Littering Scheduled kill 52 1h 

### 52 5h 53 

### A.M. 53 

### Pre 53 

### Post 53 1h



### Dose Levels: Group 1 - 

## o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day 54 

### A.M.

Group 4 - 750 mg/kg bw/day 

### Page 148

### HarlanStudyNumber: 

### 41205015 Report Page 149



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date Group Animal 1 1 1 1 2 2 2 2 3 3 3 3 4 4 4 (Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h

2(F) 37 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 38 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 39 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 40 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 41 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 42 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 43 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 44 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 45 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 46 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 47 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 48 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill

X = Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan

### StudyNumber: 

### 41205015 Report Page 150



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 5 5 5 6 6 6 6 7 7 7 7 8 8 8 8 (Sex) Number Clinical Sign Pre Post 1h Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Sh

2(F) 37 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 38 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 39 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 40 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 41 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 42 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 43 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 44 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 45 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 46 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 47 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 48 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill

X

## =Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 151



## Appendix 1 (continued) IndividualDaily Clinical Observations Day Numbers Relative to Start Date (continued) Group Animal 9 9 9 9 10 10 10 10 11 11 11 12 12 12 13 (Sex) Number Clinical Sign Pre Post 1 h 5h Pre Post 1h 5h Pre Post 1h Pre Post 1h Pre

2(F) 37 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 38 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 39 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 40 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 41 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 42 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 43 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 44 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 45 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 46 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 47 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 48 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill

X = Present Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 152



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 13 13 13 14 14 14 14 15 15 15 15 16 16 16 16 (Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h

2(F) 37 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 38 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 39 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 40 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 41 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 42 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 43 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 44 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 45 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 46 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 47 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 48 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill



## x 

## =Present Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 153



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 17 17 17 17 18 18 18 19 19 19 20 20 20 20 21 (Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h Pre Post 1h Pre Post 1h 5h Pre

2(F) 37 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 38 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 39 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 40 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 41 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 42 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 43 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 44 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 45 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 46 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 47 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 48 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill

X

## =Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan

### StudyNumber: 

### 41205015 Report Page 154



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 21 21 21 22 22 22 22 23 23 23 23 24 24 24 24 (Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h

2(F) 37 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 38 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 39 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 40 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 41 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 42 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 43 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 44 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 45 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 46 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 47 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 48 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill

X

## = Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 155



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 25 25 25 26 26 26 27 27 27 27 28 28 28 28 29 (Sex) Number Clinical Sign Pre Post 1h Pre Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre

2(F) 37 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 38 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 39 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 40 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 41 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 42 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 43 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 44 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 45 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 46 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 47 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 48 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill

X

## = Present Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page 156



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 29 29 29 30 30 30 30 31 31 31 31 32 32 32 33 (Sex) Number Clinical Sign Post 1h Sh Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Pre

2(F) 37 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 38 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 39 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 40 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 41 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 42 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 43 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 44 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 45 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 46 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 47 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 48 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill

X

## =Present Dose Levels: Group 1 - 

## o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 157



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 33 33 34 34 34 34 35 35 35 35 36 36 36 36 37 (Sex) Number Clinical Sign Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre

2(F) 37 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 38 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 39 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 40 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 41 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 42 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 43 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 44 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 45 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 46 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 47 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 48 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill

X

## = Present Dose Levels: Group 1 - 

## o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page 158



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 37 37 37 38 38 38 39 39 39 40 40 40 41 41 41 (Sex) Number Clinical Sign Post 1h 5h Pre Post 1h Pre Post 1h Pre Post 1 h Pre Post 1h

2(F) 37 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 38 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 39 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 40 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 41 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 42 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 43 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 44 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 45 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 46 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 47 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 48 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill

X = 

### Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page 159



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 42 42 42 42 42 43 43 43 43 43 44 44 44 44 44 (Sex) Number Clinical Sign A.M. Pre Post 1h 5h A.M. Pre Post 1 h 5h A.M. Pre Post 1h 5h

2(F) 37 No Abnormalities Detected 

### x x x x x x x x x Scheduled kill 

### x 38 No Abnormalities Detected 

### x x x 

## x x x x x x x x x Scheduled kill 39 No Abnormalities Detected 

## x x 

## x x x Scheduled kill 

## x 40 No Abnormalities Detected 

## x x x x x Scheduled kill 

## x 41 No Abnormalities Detected 

## x Scheduled kill 

## x 42 No Abnormalities Detected 

## x Scheduled kill 

## x 43 No Abnormalities Detected 

## x x x 

## x x x x 

## x x x x 

## x Scheduled kill 44 No Abnormalities Detected 

## x x x x 

## x x x 

## x x x x x Scheduled kill 45 No Abnormalities Detected 

### x 

## x x x x Scheduled kill 

## x 46 No Abnormalities Detected 

## x x x x x Scheduled kill 

## x 47 No Abnormalities Detected 

## x x x x x x 

## x x 

## x Scheduled kill 

### x 48 No Abnormalities Detected 

## x x x x x x x x x Scheduled kill 

### x

X

## =Present Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan

### StudyNumber: 41205015 Report



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign

2(F) 37 No Abnormalities Detected Scheduled kill 38 No Abnormalities Detected Scheduled kill 39 No Abnormalities Detected Scheduled kill 40 No Abnormalities Detected Scheduled kill 41 No Abnormalities Detected Scheduled kill 42 No Abnormalities Detected Scheduled kill 43 No Abnormalities Detected Scheduled kill 44 No Abnormalities Detected Scheduled kill 45 No Abnormalities Detected Scheduled kill 46 No Abnormalities Detected Scheduled kill 47 No Abnormalities Detected Scheduled kill 48 No Abnormalities Detected Scheduled kill

X

## = Present Dose Levels: Group 1 - o (Control) 45 45 45 45 45 46 46 46 46 47 47 47 48 48 48 A.M. Pre Post 1h 5h A.M. Pre Post 1h Pre Post 1h Pre Post 1h



### x x

x x x x

Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 

### Page 160

### HarlanStudyNumber: 

### 41205015 Report



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign

2(F) 37 No Abnormalities Detected Scheduled kill 38 No Abnormalities Detected Scheduled kill 39 No Abnormalities Detected Scheduled kill 40 No Abnormalities Detected Scheduled kill 41 No Abnormalities Detected Scheduled kill 42 No Abnormalities Detected Scheduled kill 43 No Abnormalities Detected Scheduled kill 44 No Abnormalities Detected Scheduled kill 45 No Abnormalities Detected Scheduled kill 46 No Abnormalities Detected Scheduled kill 47 No Abnormalities Detected Scheduled kill 48 No Abnormalities Detected Scheduled kill

X

## = Present Dose Levels: Group 1 - O (Control) 48 49 49 49 49 50 50 50 50 51 51 51 51 52 52 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post

Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 

### Page 161

### HarlanStudyNumber: 

### 41205015 Report



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign

2(F) 37 No Abnormalities Detected Scheduled kill 38 No Abnormalities Detected Scheduled kill 39 No Abnormalities Detected Scheduled kill 40 No Abnormalities Detected Scheduled kill 41 No Abnormalities Detected Scheduled kill 42 No Abnormalities Detected Scheduled kill 43 No Abnormalities Detected Scheduled kill 44 No Abnormalities Detected Scheduled kill 45 No Abnormalities Detected Scheduled kill 46 No Abnormalities Detected Scheduled kill 47 No Abnormalities Detected Scheduled kill 48 No Abnormalities Detected Scheduled kill

X

## = Present 52 1h 

### 52 5h 53 

### A.M. 53 

### Pre 53 

### Post 53 1h



### Dose Levels: Group 1

- 

## o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day 54 A.M.

Group 4 - 750 mg/kg bw/day 

### Page 162

### HarlanStudyNumber: 

### 41205015 Report Page 163



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date Group Animal 1 1 1 1 2 2 2 2 3 3 3 3 4 4 4 (Sex) Number Clinical Sign Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h

3(F) 61 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 62 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 63 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 64 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 65 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 66 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 67 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 68 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 69 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 70 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 71 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 72 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill

X

## =Present Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page 164



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 5 5 5 6 6 6 6 7 7 7 7 8 8 8 8 (Sex) Number Clinical Sign Pre Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h

3(F) 61 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 62 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 63 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 64 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 65 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 66 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 67 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 68 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 69 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 70 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 71 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 72 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill

X = 

### Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 165



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 9 9 9 9 10 10 10 10 11 11 11 12 12 12 13 (Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h Pre Post 1h Pre

3(F) 61 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 62 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 63 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 64 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 65 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 66 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 67 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 68 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 69 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 70 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 71 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 72 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill

X

## =Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan

### StudyNumber: 

### 41205015 Report Page 166



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 13 13 13 14 14 14 14 15 15 15 15 16 16 16 16 (Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h

3(F) 61 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 62 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 63 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 64 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 65 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 66 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 67 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 68 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 69 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 70 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 71 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 72 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill

X

## =Present Dose Levels: Group 1 - 

## o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 167



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 17 17 17 17 18 18 18 19 19 19 20 20 20 20 21 (Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h Pre Post 1h Pre Post 1h 5h Pre

3(F) 61 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 62 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 63 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 64 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 65 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 66 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 67 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 68 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 69 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 70 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 71 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 72 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill

X

## = Present Dose Levels: Group 1

- O (Control) Group 2

- 50 mg/kg bw/day Group 3

- 250 mg/kg bw/day Group 4

- 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 168



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 21 21 21 22 22 22 22 23 23 23 23 24 24 24 24 (Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h

3(F) 61 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 62 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 63 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 64 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 65 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 66 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 67 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 68 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 69 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 70 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 71 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 72 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill

X = 

### Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 169



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 25 25 25 26 26 26 27 27 27 27 28 28 28 28 29 (Sex) Number Clinical Sign Pre Post 1h Pre Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre

3(F) 61 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 62 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 63 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 64 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 65 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 66 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 67 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 68 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 69 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 70 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 71 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 72 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill

X

## = Present Dose Levels: Group 1 - 

## o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page 170



## Appendix 1 (continued) IndividualDaily Clinical Observations Day Numbers Relative to Start Date (continued) Group Animal 29 29 29 30 30 30 30 31 31 31 31 32 32 32 33 (Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h Pre

3(F) 61 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill 62 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill 63 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill 64 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill 65 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill 66 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill 67 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill 68 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill 69 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill 70 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill 71 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill 72 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill

X

## =Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page 171



## Appendix 1 (continued) IndividualDaily Clinical Observations Day Numbers Relative to Start Date (continued) Group Animal 33 33 34 34 34 34 35 35 35 35 36 36 36 36 37 (Sex) Number Clinical Sign Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre

3(F) 61 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill 62 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill 63 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill 64 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill 65 No Abnormalities Detected 

### x x x x x 

## x x x x 

## x x x x x x Scheduled kill 66 No Abnormalities Detected 

### x x x x x x 

## x x x x x x x x x Scheduled kill 67 No Abnormalities Detected 

### x x x x x x x x x x x x x x 

## x Scheduled kill 68 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill 69 No Abnormalities Detected 

### x x x 

## x x x x x 

## x x x x x x x Scheduled kill 70 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill 71 No Abnormalities Detected 

### x x x x x x x x x x x x x x 

## x Scheduled kill 72 No Abnormalities Detected 

### x x x x x x 

## x x x x x x x x x Scheduled kill

X = Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 41205015 Report Page 172



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 37 37 37 38 38 38 39 39 39 40 40 40 41 41 41 (Sex) Number Clinical Sign Post 1h 5h Pre Post 1h Pre Post 1h Pre Post 1h Pre Post 1h

3(F) 61 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 62 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 63 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 64 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 65 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 66 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 67 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 68 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 69 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 70 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 71 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 72 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill

X = Present Dose Levels: Group 1

- 

## o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 173



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 42 42 42 42 42 43 43 43 43 43 44 44 44 44 44 (Sex) Number Clinical Sign A.M. Pre Post 1h Sh A.M. Pre Post 1h Sh A.M. Pre Post 1h Sh

3(F) 61 No Abnormalities Detected 

## x x x x x x x x x Scheduled kill 

## x 62 No Abnormalities Detected 

## x x x x x x x x x x x x Scheduled kill 63 No Abnormalities Detected 

## x x x x x Scheduled kill 

## x 64 No Abnormalities Detected 

## x x x x x x x x x Scheduled kill 

## x 65 No Abnormalities Detected 

## x x x x x x x x x Scheduled kill 

## x 66 No Abnormalities Detected 

## x Scheduled kill 

## x 67 No Abnormalities Detected 

## x x x x x x x x x x x x Scheduled kill 68 No Abnormalities Detected 

## x Scheduled kill 

## x 69 No Abnormalities Detected 

## x x x x x x x x x Scheduled kill 

## x 70 No Abnormalities Detected 

## x x x x x Scheduled kill 

## x 71 No Abnormalities Detected 

## x x x x x x x x x Scheduled kill 

## x 72 No Abnormalities Detected 

## x x x x x x x x x x x x Scheduled kill

X

## = Present Dose Levels: Group 1

- 

## o (Control) Group 2

- 50 mg/kg bw/day Group 3

- 250 mg/kg bw/day Group 4

- 750 mg/kg bw/day

### Harlan

### StudyNumber: 

### 41205015 Report Page 174



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 45 45 45 45 45 46 46 46 46 47 47 47 48 48 48 (Sex) Number Clinical Sign A.M. Pre Post 1h Sh A.M. Pre Post 1h Pre Post 1h Pre Post 1h

3(F) 61 No Abnormalities Detected Scheduled kill 62 No Abnormalities Detected 

### x x x x x Scheduled kill 

### x 63 No Abnormalities Detected Scheduled kill 64 No Abnormalities Detected Scheduled kill 65 No Abnormalities Detected Scheduled kill 66 No Abnormalities Detected Scheduled kill 67 No Abnormalities Detected 

### x Scheduled kill 

### x 68 No Abnormalities Detected Scheduled kill 69 No Abnormalities Detected Scheduled kill 70 No Abnormalities Detected Scheduled kill 71 No Abnormalities Detected Scheduled kill 72 No Abnormalities Detected 

### x x x x x Scheduled kill 

### x

X

## =Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign

3(F) 61 No Abnormalities Detected Scheduled kill 62 No Abnormalities Detected Scheduled kill 63 No Abnormalities Detected Scheduled kill 64 No Abnormalities Detected Scheduled kill 65 No Abnormalities Detected Scheduled kill 66 No Abnormalities Detected Scheduled kill 67 No Abnormalities Detected Scheduled kill 68 No Abnormalities Detected Scheduled kill 69 No Abnormalities Detected Scheduled kill 70 No Abnormalities Detected Scheduled kill 71 No Abnormalities Detected Scheduled kill 72 No Abnormalities Detected Scheduled kill

X = 

### Present 48 49 49 49 49 50 50 50 50 51 51 51 51 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h 52 52 Pre Post

Dose Levels: Group 1

- 

## o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 

### Page 175

### HarlanStudyNumber: 

### 41205015 Report



## Appendix 1 (continued) IndividualDaily Clinical Observations Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign

3(F) 61 No Abnormalities Detected Scheduled kill 62 No Abnormalities Detected Scheduled kill 63 No Abnormalities Detected Scheduled kill 64 No Abnormalities Detected Scheduled kill 65 No Abnormalities Detected Scheduled kill 66 No Abnormalities Detected Scheduled kill 67 No Abnormalities Detected Scheduled kill 68 No Abnormalities Detected Scheduled kill 69 No Abnormalities Detected Scheduled kill 70 No Abnormalities Detected Scheduled kill 71 No Abnormalities Detected Scheduled kill 72 No Abnormalities Detected Scheduled kill

X

## =Present 52 1h 52 5h 53 

### A.M. 53 

### Pre 53 

### Post 53 1h



### Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day 54 

### A.M.

Group 4 - 750 mg/kg bw/day 

### Page 176

### HarlanStudyNumber: 

### 41205015 Report Page 177



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date Group Animal 1 1 1 1 2 2 2 2 3 3 3 3 4 4 4 (Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h

4(F) 85 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 86 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 87 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 88 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 89 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 90 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 91 No Abnormalities Detected 

## x 

# x x x x x x x x x x x x x x Scheduled kill Increased salivation 92 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 93 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 94 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation

X

## =Present Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 178



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 5 5 5 6 6 6 6 7 7 7 7 8 8 8 8 (Sex) Number Clinical Sign Pre Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h

4(F) 85 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 86 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 87 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 88 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 89 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation


# .. 90 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 91 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 92 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 93 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 94 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation

X = 

### Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 

### Report Page 179



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 9 9 9 9 10 10 10 10 11 11 11 12 12 12 13 (Sex) Number Clinical Sign Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Pre Post 1h Pre

4(F) 85 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 86 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 87 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 88 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 89 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 90 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 91 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 92 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 93 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 94 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation

X

## = Present Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 180



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 13 13 13 14 14 14 14 15 15 15 15 16 16 16 16 (Sex) Number Clinical Sign Post 1h Sh Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Sh

4(F) 

### 85 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 86 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 87 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 88 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 89 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 90 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 91 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 92 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 93 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 94 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation

X

## =Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 181



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued} Group Animal 17 17 17 17 18 18 18 19 19 19 20 20 20 20 21 (Sex} Number Clinical Sign Pre Post 1h 5h Pre Post 1h Pre Post 1h Pre Post 1h 5h Pre

4(F} 85 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 86 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 87 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 88 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 89 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 90 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 91 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 92 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 93 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 94 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation

X

## = Present Dose Levels: Group 1 - O (Control} Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 182



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 21 21 21 22 22 22 22 23 23 23 23 24 24 24 24 (Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h

4(F) 85 No Abnormalities Detected 

## x x x x x x x x x x x x x x Scheduled kill Increased salivation 

## x 86 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 87 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 88 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 89 No Abnormalities Detected 

## x x x x x x x x x x x x x x Scheduled kill Increased salivation 

## x 90 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 91 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 92 No Abnormalities Detected 

## x x x x x x x x x x x x x Scheduled kill Increased salivation 

## x x 93 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 94 No Abnormalities Detected 

## x x x x x x x x x x x x x Scheduled kill Increased salivation 

## x x

X

## = Present Dose Levels: Group 1

- 

## o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 183



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 25 25 25 26 26 26 27 27 27 27 28 28 28 28 29 (Sex) Number Clinical Sign Pre Post 1h Pre Post 1h Pre Post 1h Sh Pre Post 1h Sh Pre

4(F) 85 No Abnormalities Detected 

## x x x x x x x x x x x x x x Scheduled kill Increased salivation 

## x 86 No Abnormalities Detected 

## x x x x x x x x x x x x x Scheduled kill Increased salivation 

## x x 87 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 88 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 89 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 90 No Abnormalities Detected 

## x x x x x x x x x x x x x Scheduled kill Increased salivation 

## x x 91 No Abnormalities Detected 

## x x x x x x x x x x x x Scheduled kill Increased salivation 

## x x x 92 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 93 No Abnormalities Detected 

## x x x x x x x x x x x x x x Scheduled kill Increased salivation 

## x 94 No Abnormalities Detected 

## x x x x x x x x x x i< 

## x x x x Scheduled kill Increased salivation

X

## =Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 184



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 29 29 29 30 30 30 30 31 31 31 31 32 32 32 33 (Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h Pre

4(F) 85 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 86 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 87 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 88 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 89 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 90 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 91 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 92 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 93 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 94 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation

X

## = Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 185



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 33 33 34 34 34 34 35 35 35 35 36 36 36 36 37 (Sex) Number Clinical Sign Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre

4(F) 85 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 86 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 87 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 88 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 89 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 90 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 91 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 92 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 93 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 94 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation

X

## = Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 186



## Appendix 1 (continued) IndividualDaily Clinical Observations Day Numbers Relative to Start Date (continued) Group Animal 37 37 37 38 38 38 39 39 39 40 40 40 41 41 41 (Sex) Number Clinical Sign Post 1h 5h Pre Post 1h Pre Post 1h Pre Post 1h Pre Post 1h

4(F) 85 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 86 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 87 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 88 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill 89 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 90 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 91 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 92 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 93 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 94 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation

X = 

### Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 187



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 42 42 42 42 42 43 43 43 43 43 44 44 44 44 44 (Sex) Number Clinical Sign A.M. Pre Post 1h 5h A.M. Pre Post 1h 5h A.M. Pre Post 1h 5h

4(F) 85 No Abnormalities Detected 

### x Scheduled kill 

### x Increased salivation 86 No Abnormalities Detected 

### x x x x x x x x x Scheduled kill 

### x Increased salivation 87 No Abnormalities Detected 

### x Scheduled kill 

### x 88 No Abnormalities Detected 

### x Scheduled kill 

### x 89 No Abnormalities Detected 

### x x x x x Scheduled kill 

### x Increased salivation 90 No Abnormalities Detected 

### x x x x x x x x x x x x Scheduled kill Increased salivation 91 No Abnormalities Detected 

### x x x x x x x x x Scheduled kill 

### x Increased salivation 92 No Abnormalities Detected 

### x Scheduled kill 

### x Increased salivation 93 No Abnormalities Detected 

### x x x x x x x x x x x x Scheduled kill Increased salivation 94 No Abnormalities Detected 

### x Scheduled kill 

### x Increased salivation

X

## = Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 41205015 Report Page 188



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 45 45 45 45 45 46 46 46 46 47 47 47 48 48 48 (Sex) Number Clinical Sign A.M. Pre Post 1h 5h A.M. Pre Post 1 h Pre Post 1h Pre Post 1h

4(F) 85 No Abnormalities Detected Scheduled kill Increased salivation 86 No Abnormalities Detected Scheduled kill Increased salivation 87 No Abnormalities Detected Scheduled kill 88 No Abnormalities Detected Scheduled kill 89 No Abnormalities Detected Scheduled kill Increased salivation 90 No Abnormalities Detected 

### x x x x x x x x x x x x x Scheduled kill Increased salivation 91 No Abnormalities Detected Scheduled kill Increased salivation 92 No Abnormalities Detected Scheduled kill Increased salivation 93 No Abnormalities Detected 

## x x x x x x x x x x x x x Scheduled kill Increased salivation 94 No Abnormalities Detected Scheduled kill Increased salivation

X

## =Present Dose Levels: Group 1

- o (Control) Group 2

- 50 mg/kg bw/day Group 3

- 250 mg/kg bw/day Group 4

- 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 

### Report Page 189



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 48 49 49 49 49 50 50 50 50 51 51 51 51 52 52 (Sex) Number Clinical Sign 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post

4(F) 85 No Abnormalities Detected Scheduled kill Increased salivation 86 No Abnormalities Detected Scheduled kill Increased salivation 87 No Abnormalities Detected Scheduled kill 88 No Abnormalities Detected Scheduled kill 89 No Abnormalities Detected Scheduled kill Increased salivation 90 No Abnormalities Detected 

## x x x x x x 

## x x x x x x x x x Scheduled kill Increased salivation 91 No Abnormalities Detected Scheduled kill Increased salivation 92 No Abnormalities Detected Scheduled kill Increased salivation 93 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 94 No Abnormalities Detected Scheduled kill Increased salivation

X = 

### Present Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan

### StudyNumber: 

### 41205015 Report Page 190



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 52 52 53 53 53 53 54 (Sex) Number Clinical Sign 1h 5h A.M. Pre Post 1h A.M.

4(F) 85 No Abnormalities Detected Scheduled kill Increased salivation 86 No Abnormalities Detected Scheduled kill Increased salivation 87 No Abnormalities Detected Scheduled kill 88 No Abnormalities Detected Scheduled kill 89 No Abnormalities Detected Scheduled kill Increased salivation 90 No Abnormalities Detected 

### x x x x x x Scheduled kill 

### x Increased salivation 91 No Abnormalities Detected Scheduled kill Increased salivation 92 No Abnormalities Detected Scheduled kill Increased salivation 93 No Abnormalities Detected 

### x x x Scheduled kill 

### x Increased salivation 94 No Abnormalities Detected Scheduled kill Increased salivation

X

## =Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 191



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date Group Animal 1 1 1 1 2 2 2 2 3 3 3 3 4 4 4 

### (Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h

4(F) 

### 95 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 96 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation

X

## =Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 41205015 Report Page 192



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 5 5 5 6 6 6 6 7 7 7 7 8 8 8 8 

### (Sex) Number Clinical Sign Pre Post 1h Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Sh

4(F) 

### 95 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill Increased salivation 96 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill Increased salivation

X

## = Present Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page 193



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 9 9 9 9 10 10 10 10 11 11 11 12 12 12 13 (Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h Pre Post 1h Pre

4(F) 

### 95 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 96 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation

X

## = Present Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 41205015 Report Page 194



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 13 13 13 14 14 14 14 15 15 15 15 16 16 16 16 (Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h

4(F) 95 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 96 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation

X = 

### Present Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 195



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 17 17 17 17 18 18 18 19 19 19 20 20 20 20 21 (Sex) Number Clinical Sign Pre Post 1h 5h Pre Post 1h Pre Post 1h Pre Post 1h 5h Pre

4(F) 

### 95 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 96 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation

X

## = Present Dose Levels: Group 1

- 

## o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan

### StudyNumber: 

### 41205015 Report 

### Page 196



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 21 21 21 22 22 22 22 23 23 23 23 24 24 24 24 (Sex) Number Clinical Sign Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h

4(F) 95 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 96 No Abnormalities Detected 

## x x x x x x x x x x x x x Scheduled kill Increased salivation 

## x x

X

## = Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 197



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 25 25 25 26 26 26 27 27 27 27 28 28 28 28 29 (Sex) Number Clinical Sign Pre Post 1h Pre Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre

4(F) 

### 95 No Abnormalities Detected 

## x x x x x x x x x x x x x Scheduled kill Increased salivation 

## x x 96 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation

X

## = Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 198



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 29 29 29 30 30 30 30 31 31 31 31 32 32 32 33 (Sex) Number Clinical Sign Post 1h Sh Pre Post 1h Sh Pre Post 1h Sh Pre Post 1h Pre

4(F) 

### 95 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill Increased salivation 96 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill Increased salivation

X

## = Present Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 41205015 Report 

### Page 199



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 33 33 34 34 34 34 35 35 35 35 36 36 36 36 37 (Sex) Number Clinical Sign Post 1h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1 h 5h Pre

4(F) 95 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation 96 No Abnormalities Detected 

## x x x x x x x x x x x x x x x Scheduled kill Increased salivation

X

## =Present Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page200



## Appendix 1 (continued) IndividualDaily Clinical Observations Day Numbers Relative to Start Date (continued) Group Animal 37 37 37 38 38 38 39 39 39 40 40 40 41 41 41 (Sex) Number Clinical Sign Post 1h 5h Pre Post 1h Pre Post 1h Pre Post 1h Pre Post 1h

4(F) 95 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill Increased salivation 96 No Abnormalities Detected 

### x x x x x x x x x x x x x x x Scheduled kill Increased salivation

X = 

### Present Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan

### StudyNumber: 

### 41205015



## Appendix 1 (continued) Report



## IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal 42 42 42 42 42 43 43 43 43 43 44 44 44 44 44 

### (Sex) Number Clinical Sign

4(F) 

### 95 No Abnormalities Detected Scheduled kill Increased salivation 96 No Abnormalities Detected Scheduled kill Increased salivation

X

## = Present Dose Levels: Group 1 - O (Control) A.M. Pre Post 1h 5h A.M. Pre Post 1h 5h A.M. Pre Post 1h 5h 

### x x 

## x

x x 

## x

Group 2 - 50 mg/kg bw/day 

### x

x x 

## x x x

Group 3 - 250 mg/kg bw/day

### x x 

## x x 

## x

Group 4 - 750 mg/kg bw/day 

## x Page201

### HarlanStudyNumber: 

### 41205015 Report



## Appendix 1 (continued) IndividualDailyClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign

4(F) 

### 95 No Abnormalities Detected Scheduled kill Increased salivation 96 No Abnormalities Detected Scheduled kill Increased salivation

X

## = Present Dose Levels: Group 1 - O (Control) 45 45 45 45 45 46 46 46 46 47 47 47 48 48 48 A.M. Pre Post 1h 5h A.M. Pre Post 1h Pre Post 1h Pre Post 1h



## x x

Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 

### Page202

### Harlan StudyNumber: 

### 41205015 Report



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign

4(F) 95 No Abnormalities Detected Scheduled kill Increased salivation 96 No Abnormalities Detected Scheduled kill Increased salivation

X = 

### Present 48 49 49 49 49 50 50 50 50 51 51 51 51 5h Pre Post 1h 5h Pre Post 1h 5h Pre Post 1h 5h 52 52 Pre Post

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day 

### Page203

### HarlanStudyNumber: 

### 41205015 Report



## Appendix 1 (continued) IndividualDaily ClinicalObservations Day Numbers Relative to Start Date (continued) Group Animal (Sex) Number Clinical Sign

4(F) 95 No Abnormalities Detected Scheduled kill Increased salivation 96 No Abnormalities Detected Scheduled kill Increased salivation

X

## =Present 52 1h 52 5h 53 

### A.M. 53 

### Pre 53 

### Post 53 1h



### Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day 54 

### A.M.

Group 4 - 750 mg/kg bw/day Page204

### Harlan StudyNumber: 

### 41205015 Report Page205



## Appendix2 Individualand GroupMeanBodyWeights Body Weights (g) Day Numbers Relative to Start Date Group Animal (Sex) Number 1 8 15 22 29 36 43 1(M) 1 319 336 349 365 375 385 391 2 310 325 344 347 358 372 387 3 310 320 336 343 354 378 385 4 315 334 355 373 393 400 409 5 318 332 343 365 378 391 406 6 316 332 344 353 362 369 379 7 328 347 362 369 384 392 405 8 306 317 329 339 345 345 346 9 325 346 363 374 391 405 417 10 312 323 338 344 353 366 374 11 331 355 372 363 387 397 410 12 315 331 342 350 369 381 391

- 

### --- --- --- --- --- --- -- Mean 317.1 333.2 348.1 357.1 370.8 381.8 391.7 S.D. 7.6 11 . 5 12.6 12.5 16.3 17.0 19.7 N 12 12 12 12 12 12 12

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report 

### Page206



## Appendix2 (continued) Individualand GroupMeanBodyWeights Body Weights (g) Day Numbers Relative to Start Date Group Animal (Sex) Number 1 8 15 22 29 36 43 2(M) 25 316 336 346 361 378 381 389 26 313 334 354 362 374 390 403 27 308 320 327 334 348 357 374 28 303 310 316 323 332 343 349 29 327 352 371 386 387 404 417 30 316 337 345 355 367 378 393 31 298 307 317 334 347 348 358 32 336 353 360 365 379 390 414 33 326 350 367 381 386 387 390 34 327 339 352 342 366 385 404 35 306 330 338 329 357 372 383 36 317 333 340 339 355 369 371

- 

### -- -- 

## -- -- -- -- -- Mean 316.1 333.4 344.4 350.9 364.7 375.3 387.1 S.D. 11.3 15.1 17.9 20.5 17.2 18.3 21.2 N 12 12 12 12 12 12 12

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page207



## Appendix2 (continued) Individualand GroupMeanBodyWeights Body Weights (g) Day Numbers Relative to Start Date Group Animal (Sex) Number 1 8 15 22 29 36 43 3(M) 49 320 330 332 343 348 341 348 50 325 338 355 367 374 375 387 51 326 345 360 376 381 381 393 52 350 370 388 399 424 436 440 53 323 345 361 372 394 406 424 54 316 336 343 359 369 376 384 55 316 332 348 357 372 378 386 56 314 329 343 350 367 378 389 57 314 325 334 347 362 373 382 58 305 317 323 330 342 351 357 59 310 329 339 350 366 368 378 60 320 334 353 364 386 399 408



### --- 

## -- 

## --- --- -- -- -- --- Mean 319.9 335.8 348.3 359.5 373.8 380.2 389.7 S.D. 11.3 13.3 17.0 18.0 21.5 24.8 25.4 N 12 12 12 12 12 12 12

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page208



## Appendix2 (continued) Individualand GroupMeanBodyWeights Body Weights (g) Day Numbers Relative to Start Date Group Animal (Sex) Number 1 8 15 22 29 36 43 4(M) 73 300 319 312 326 346 358 368 74 323 335 342 343 351 357 365 75 323 331 353 352 367 367 383 76 312 321 332 338 351 357 366 77 313 317 330 348 369 385 394 78 327 330 341 354 364 383 401 79 311 323 333 342 348 358 370 80 335 356 372 376 382 391 401 81 316 331 324 335 347 358 370 82 302 300 309 324 340 337 349 83 320 335 338 357 359 362 374 84 319 323 345 360 359 367 386



### --- --- --- --- --- --- --- Mean 316.8 326.8 335.9 346.3 356.9 365.0 377.3 S.D. 10.0 13.4 17.2 14.8 12.0 15.0 15.9 N 12 12 12 12 12 12 12

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015



## Appendix2 (continued) Report



## Individualand GroupMeanBodyWeights Body Weights (g) Day Numbers Relative to Start Date Group Animal (Sex) Number 1 8 15 1(F) 13 210 218 225 14 202 208 213 15 199 202 211 16 218 219 223 17 208 206 215 18 218 220 221 19 219 225 230 20 215 214 227 21 211 217 227 22 204 216 220 23 209 216 221 24 207 209 210



## --- --- --- --- Mean 210.0 214.2 220.3 S.D. 6.5 6.6 6.7 N 12 12 12

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day 

### Page209

Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015



## Appendix2 (continued) Report



## Individualand GroupMeanBodyWeights Body Weights (g) Day Numbers Relative to Start Date Group Animal (Sex) Number 1 8 15 2(F) 37 210 213 217 38 206 209 205 39 204 213 223 40 210 215 219 41 212 211 222 42 201 198 204 43 214 217 221 44 217 226 234 45 210 219 232 46 215 224 229 47 202 209 217 48 215 220 222



### --- --- 

## --- -- Mean 209.7 214.5 220.4 S.D. 5.3 7.6 9.2 N 12 12 12

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day 

### Page210

Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015



## Appendix2 (continued) Report



## Individualand GroupMeanBodyWeights Body Weights (g) Day Numbers Relative to Start Date Group Animal (Sex) Number 1 8 15 3(F) 61 206 206 211 62 210 215 218 63 209 205 216 64 205 206 210 65 205 207 211 66 199 200 208 67 214 219 223 68 211 204 212 69 204 205 209 70 209 213 220 71 212 220 226 72 206 211 213

- 

## --- --- --- Mean 207.5 209.3 214.8 S.D. 4.1 6.3 5.8 N 12 12 12

Dose Levels: Group 1

- 

## o (Control) Group 2 - 50 mg/kg bw/day Group 3

- 250 mg/kg bw/day 

### Page211

Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page212



## Appendix2 (continued) Individualand GroupMeanBodyWeights Body Weights (g) Day Numbers Relative to Start Date Group Animal (Sex) Number 1 8 15 4(F) 85 222 220 229 86 211 211 216 87 206 202 203 88 198 194 201 89 201 204 208 90 215 214 213 91 213 216 221 92 220 222 230 93 212 207 204 94 212 212 225 95 206 208 208 96 217 224 232



### --- --- --- --- Mean 211 .1 211.2 215.8 S.D. 7.3 8.8 11 . 3 N 12 12 12

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page213



## Appendix2 (continued) Individualand Group MeanBodyWeights Body Weights (g) Day Group Animal After Mating (Sex) Number Lactation 0 7 14 20 1 4 1(F) 13 225 250 276 334 234 256 14 212 237 258 316 235 240 15 NP 210 234 230 244 16 227 257 286 357 248 266 17 214 247 275 344 239 251 18 235 269 290 368 263 281 19 236 254 277 339 252 275 20 225 258 284 336 254 266 21 227 246 268 329 230 252 22 223 248 272 323 258 272 23 218 244 267 330 218 245 24 211 236 258 321 218 245 Mean 223.0 249.6 273.7 336.1 240.8 259.0 S.D. 8.5 9.6 10.6 15.6 15.4 13.7 N 11 11 11 11 11 11

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page214



## Appendix2 (continued) Individualand GroupMeanBodyWeights Body Weights (g) Day Group Animal After Mating Lactation (Sex) Number 0 7 14 20 1 4 2(F) 37 219 246 271 347 252 260 38 219 256 275 341 252 260 39 NP 223 252 257 249 40 218 252 281 331 255 259 41 NP 218 252 246 245 42 203 234 255 326 229 220 43 224 248 274 350 237 262 44 231 277 314 389 292 304 45 231 265 301 372 294 287 46 231 262 279 352 243 268 47 NP 215 240 243 237 48 222 257 276 338 239 257 Mean 222.0 255.2 280.7 349.6 254.8 264.1 S.D. 9.0 12.3 17.2 19.9 23.2 22.9 N 9 9 9 9 9 9

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page215



## Appendix2 (continued) Individualand GroupMeanBodyWeights Body Weights (g) Day Group Animal After Mating (Sex) Number Lactation 0 7 14 20 1 4 3(F) 61 216 244 273 323 252 260 62 229 258 281 352 247 262 63 210 246 264 315 241 258 64 210 246 266 336 245 251 65 213 234 265 327 244 246 66 208 233 253 307 287 241 67 229 263 285 358 262 281 68 208 238 262 324 235 241 69 207 238 256 315 236 250 70 219 244 273 337 234 260 71 232 263 291 345 278 285 72 218 241 263 324 245 259 Mean 216.6 245.7 269.3 330.3 250.5 257.8 S.D. 9.0 10.4 11 . 6 15.6 16.9 13.9 N 12 12 12 12 12 12

Dose Levels: Group 1

- O(Control) Group 2

- 50 mg/kg bw/day Group 3

- 250 mg/kg bw/day Group 4

- 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page216



## Appendix2 (continued) Individualand GroupMeanBodyWeights Body Weights (g) Day Group Animal (Sex) Number After Mating Lactation 0 7 14 20 1 4 4(F) 85 225 258 279 341 270 266 86 212 250 280 339 255 268 87 NP 202 224 232 228 88 201 235 270 336 256 253 89 211 231 255 328 241 250 90 257 276 315 385 272 293 91 225 252 283 348 258 259 92 230 261 290 359 272 265 93 245 258 279 343 262 265 94 224 258 284 357 266 274 95 204 233 256 311 226 239 96 224 259 285 349 251 250 Mean 223.5 251.9 279.6 345.1 257.2 262.0 S.D. 16.8 13.8 16.4 18.8 14.1 14.4 N 11 11 11 11 11 11

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page217



## Appendix3 Individualand GroupMean BodyWeight Gains
Increase in Body Weight (g) Day Numbers Relative to Start Date Group Animal From: 1 8 15 22 29 36 (Sex) Number To: 8 15 22 29 36 43 1(M) 1 17 13 16 10 10 6 2 15 19 3 11 14 15 3 10 16 7 11 24 7 4 19 21 18 20 7 9 5 14 11 22 13 13 15 6 16 12 9 9 7 10 7 19 15 7 15 8 13 8 11 12 10 6 0 1 9 21 17 11 17 14 12 10 11 15 6 9 13 8 11 24 17 -9 24 10 13 12 16 11 8 19 12 10



### -- 

## -- -- 

## -- -- -- Mean 16.1 14.9 9.0 13.7 11 

## .o 9.9 S.D. 4.3 3.2 7.9 5.4 5.7 4.1 N 12 12 12 12 12 12

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg,bw/day

### Harlan StudyNumber: 

### 41205015 Report Page218



## Appendix

## 3 (continued) Individualand Group MeanBodyWeightGains Increase in Body Weight (g) Day Numbers Relative to Start Date Group Animal From: 1 8 15 22 29 36 (Sex) Number To: 8 15 22 29 36 43 2(M) 25 20 10 15 17 3 8 26 21 20 8 12 16 13 27 12 7 7 14 9 17 28 7 6 7 9 11 6 29 25 19 15 1 17 13 30 21 8 10 12 11 15 31 9 10 17 13 1 10 32 17 7 5 14 11 24 33 24 17 14 5 1 3 34 12 13 -10 24 19 19 35 24 8 -9 28 15 11 36 16 7 -1 16 14 2



### -- -- -- -- 

### -- - Mean 17.3 11.0 6.5 13.8 10.7 11.8 S.D. 6.2 5.0 9.0 7.3 6.2 6.5 N 12 12 12 12 12 12

Dose Levels: Group 1

- 

## o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page219



## Appendix

## 3 (continued) Individualand GroupMeanBodyWeight Gains Increase in Body Weight (g) Day Numbers Relative to Start Date Group Animal From: 1 B 15 22 29 36 (Sex) Number To: 8 15 22 29 36 43 3(M) 49 10 2 11 5 -7 7 50 13 17 12 7 1 12 51 19 15 16 5 0 12 52 20 18 11 25 12 4 53 22 16 11 22 12 18 54 20 7 16 10 7 8 55 16 16 9 15 6 8 56 15 14 7 17 11 11 57 11 9 13 15 11 9 58 12 6 7 12 9 6 59 19 10 11 16 2 10 60 14 19 11 22 13 9



### -- -- -- -- -- 

### -- Mean 15.9 12.4 11.3 14.3 6.4 9.5 S.D. 4.0 5.5 2.9 6.7 6.2 3.6 N 12 12 12 12 12 12

Dose Levels: Group 1 - o (Control) Group 2

- 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page220



## Appendix

## 3 (continued) Individualand GroupMeanBodyWeightGains Increase in Body Weight (g) Day Numbers Relative to Start Date Group Animal From: 1 8 15 22 29 36 (Sex) Number To: 8 15 22 29 36 43 4(M) 73 19 -7 14 20 12 10 74 12 7 1 8 6 8 75 8 22 -1 15 0 16 76 9 11 6 13 6 9 77 4 13 18 21 16 9 78 3 11 13 10 19 18 79 12 10 9 6 10 12 80 21 16 4 6 9 10 81 15 -7 11 12 11 12 82 -2 9 15 16 -3 12 83 15 3 19 2 3 12 84 4 22 15 -1 8 19



### -- -- -- -- 

### -- - Mean 10.0 9.2 10.3 10.7 8.1 12.3 S.D. 6.9 9.4 6.6 6.8 6.3 3.6 N 12 12 12 12 12 12

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page221



## Appendix3 (continued) Individualand GroupMeanBodyWeightGains Increase in Body Weight (g) Day Numbers Relative to Start Date Group Animal From: 1 8 (Sex) Number To: 8 15 1 (F) 13 8 7 14 6 5 15 3 9 16 1 4 17 -2 9 18 2 1 19 6 5 20 -1 13 21 6 10 22 12 4 23 7 5 24 2 1



### -- Mean 4.2 6.1 S.D. 4.0 3.6 N 12 12

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page222



## Appendix3 (continued) Individualand GroupMeanBodyWeightGains Increase in Body Weight (g) Day Numbers Relative to Start Date Group Animal From: 1 8 (Sex) Number To: 8 15 2(F) 37 3 4 38 3 -4 39 9 10 40 5 4 41 -1 11 42 -3 6 43 3 4 44 9 8 45 9 13 46 9 5 47 7 8 48 5 2



### -- -- Mean 4.8 5.9 S.D. 4.0 4.5 N 12 12

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page223



## Appendix

## 3 (continued) Individualand GroupMeanBodyWeightGains Increase in Body Weight (g) Day Numbers Relative to Start Date Group Animal From: 1 8 (Sex) Number To: 8 15 3(F) 61 0 5 62 5 3 63 -4 11 64 1 4 65 2 4 66 1 8 67 5 4 68 -7 8 69 1 4 70 4 7 71 8 6 72 5 2



### - Mean 1.8 5.5 S.D. 4.2 2.6 N 12 12

Dose Levels: Group 1 - 

## o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page224



## Appendix3 (continued) Individualand Group Mean BodyWeightGains Increase in Body Weight (g) Day Numbers Relative to Start Date Group Animal From: 1 8 (Sex) Number To: 8 15 4(F) 85 -2 9 86 0 5 87 -4 1 88 -4 7 89 3 4 90 -1 -1 91 3 5 92 2 8 93 -5 -3 94 0 13 95 2 0 96 7 8



### -- - Mean 0.1 4.7 S.D. 3.5 4.7 N 12 12

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page225



## Appendix3 (continued) Individualand GroupMeanBodyWeightGains Increase in Body Weight (g) Cumulative Body Weight Change (g) Days Days After Mating Lactation After Mating Group Animal From: 0 7 14 1 0 0 (sex) Number To: 7 14 20 4 14 20
1(F) 13 25 26 58 22 51 109 14 25 21 58 5 46 104 15 NP 24 -4 14 20 34 16 30 29 71 18 59 130 17 33 28 69 12 61 130 18 34 21 78 18 55 133 19 18 23 62 23 41 103 20 33 26 52 12 59 111 21 19 22 61 22 41 102 22 25 24 51 14 49 100 23 26 23 63 27 49 112 24 25 22 63 27 47 110



### --- Mean 26.6 24.1 62.4 18.2 50.7 113.1 S.D. 5.4 2.8 8.0 6.9 7.0 12.2 N 11 11 11 11 11 11

Dose Levels: Group 1

- O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page226



## Appendix

## 3 (continued) Individual and Group MeanBodyWeightGains Increase in Body Weight (g) Cumulative Body Weight Change (g) Days Days After Mating Lactation After Mating Group Animal From: 0 7 14 1 0 0 (sex) Number To: 7 14 20 4 14 20 2(F) 37 27 25 76 8 52 128 38 37 19 66 8 56 122 39 NP 29 5 -8 34 26 40 34 29 50 4 63 113 41 NP 34 -6 - 1 28 27 42 31 21 71 -9 52 123 43 24 26 76 25 50 126 44 46 37 75 12 83 158 45 34 36 71 -7 70 141 46 31 17 73 25 48 121 47 NP 25 3 -6 28 22 48 35 19 62 18 54 116



### --- Mean 33.2 25.4 68.9 9.3 58.7 127.6 S.D. 6.3 7.4 8.5 12.3 11.4 13.9 N 9 9 9 9 9 9

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page227



## Appendix

## 3 (continued) Individualand GroupMeanBodyWeightGains Increase in Body Weight (g) Cumulative Body Weight Change (g) Days Days After Mating Lactation After Mating Group Animal From: 0 7 14 1 0 0 (sex) Number To: 7 14 20 4 14 20 3(F) 61 28 29 50 8 57 107 62 29 23 71 15 52 123 63 36 18 51 17 54 105 64 36 20 70 6 56 126 65 21 31 62 2 52 114 66 25 20 54 -46 45 99 67 34 22 73 19 56 129 68 30 24 62 6 54 116 69 31 18 59 14 49 108 70 25 29 64 26 54 118 71 31 28 54 7 59 113 72 23 22 61 14 45 106



### -- Mean 29.1 23.7 60.9 7.3 52.8 113.7 S.D. 4.9 4.5 7.7 18.1 4.5 9.2 N 12 12 12 12 12 12

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page228



## Appendix3 (continued) Individualand GroupMeanBodyWeightGains Increase in Body Weight (g) Cumulative Body Weight Change (g) Days Days After Mating Lactation After Mating Group Animal From: 0 7 14 1 0 0 (sex) Number To: 7 14 20 4 14 20 4(F) 85 33 21 62 -4 54 116 86 38 30 59 13 68 127 87 NP 22 8 -4 30 26 88 34 35 66 -3 69 135 89 20 24 73 9 44 117 90 19 39 70 21 58 128 91 27 31 65 1 58 123 92 31 29 69 -7 60 129 93 13 21 64 3 34 98 94 34 26 73 8 60 133 95 29 23 55 13 52 107 96 35 26 64 -1 61 125 Mean 28.5 27.7 65.5 4.8 56.2 121 .6 S.D. 7.9 5.7 5.6 8.7 10.1 11.3 N 11 11 11 11 11 11

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page229



## Appendix4 Individual and Group MeanFood ConsumptionValuesforFemalesFollowingMatingandDuringLactation

Mean Food Consumption (g/rat/day) After Mating Lactation Group Animal From: 0 7 14 1 (Sex) Number To: 7 14 20 4 1 (F) 13 18 20 23 25 14 17 20 22 22 15 NP 19 18 17 16 18 22 24 23 17 18 22 25 20 18 19 23 24 31 19 17 19 23 29 20 19 21 23 21 21 17 20 22 27 22 18 20 22 31 23 16 19 20 26 24 18 20 22 34 Mean 18.0 20.6 22.6 26.3 S.D. 0.8 1.6 1.9 4.5 N 11 11 11 11

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page230



## Appendix4 (continued) Individualand GroupMeanFood ConsumptionValuesforFemalesFollowingMatingandDuring Lactation Mean Food Consumption (g/rat/day) After Mating Lactation Group Animal From: 0 7 14 1 (Sex) Number To: 7 14 20 4 2(F) 37 19 21 26 24 38 19 24 25 26 39. NP 18 22 15 40 18 23 22 17 41 NP 20 17 15 42 17 21 22 11 43 19 21 25 37 44 22 28 27 32 45 22 26 27 21 46 20 22 25 33 47 NP 17 19 16 48 18 21 22 25 Mean 19.6 22.9 24.5 25.0 S.D. 1.7 2.5 2.0 8.3 N 9 9 9 9

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page231



## Appendix4 (continued) Individualand Group Mean Food ConsumptionValuesforFemales Following MatingandDuring Lactation Mean Food Consumption (g/rat/day) After Mating Lactation Group Animal From: 0 7 14 1 (Sex) Number To: 7 14 20 4 3(F) 61 19 24 25 23 62 20 24 23 28 63 20 20 21 30 64 20 22 25 24 65 15 21 21 20 66 16 19 21 18 67 19 21 26 34 68 16 19 23 19 69 17 21 22 26 70 17 21 23 23 71 20 23 25 27 72 17 22 25 30 Mean 18.0 21.3 23.2 25 .1 S.D. 1.9 1.8 1.8 5.0 N 12 12 12 12

Dose Levels: Group 1

- O(Control) Group 2

- 50 mg/kg bw/day Group 3

- 250 mg/kg bw/day Group 4

- 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page232



## Appendix4 (continued) Individualand Group MeanFood ConsumptionValues forFemales FollowingMatingandDuring Lactation Mean Food Consumption (g/rat/day) After Mating Lactation Group Animal From: 0 7 14 1 (Sex) Number To: 7 14 20 4 4(F) 85 19 22 23 21 86 18 21 22 25 87 NP 15 18 12 88 18 23 25 19 89 14 21 23 25 90 20 25 26 37 91 19 23 25 26 92 20 25 24 18 93 16 21 24 29 94 21 22 26 30 95 16 19 20 25 96 20 21 23 17 Mean 18.5 21.9 23.7 24.6 S.D. 2.8 3.6 5.1 6.0 N 11 11 11 11

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page233



## Appendix5 IndividualMatingPerformance,Fertilityand GestationLengths Group: 1 Dose Level: o (Control)

Paired Animal Number Pre-Coital Interval (Days) Copulation Plug Count Sperm Reading Score Pregnancy Status Gestation Length (Days) 13 F 1 M 2 5 PT 3+ p 22:\, 14 F 2 M 2 5 PT H 3+ p 22:\, 15 F 3 M 2 4 PT H 1+ NP 16 F 4 M 3 6 PT H 3+ p 23\ 17 F 5 M 1 3 PT 3+ p 22:\, 18 F 6 M 4 4 PT 2+ p 22:\, 19 F 7 M 3 3 PT H PV 3+ p 23:\, 20 F 8 M 1 5 PT H 3+ p 22\ 21 F 9 M 2 4 PT 3+ p 22:\, 22 F 10 M 2 5 PT H 2+ p 23:\, 23 F 11 M 2 6 PT H 3+ p 23 24 F 12 M 3 6 PT H 3+ p 23

### Harlan StudyNumber: 41205015 Report Page234



## Appendix5 (continued) IndividualMatingPerformance,Fertilityand GestationLengths Group: 2 Dose Level: 50 mg/kg bw/day

Paired Animal Number Pre-Coital Interval (Days) Copulation Plug Count Sperm Reading Score Pregnancy Status Gestation Length (Days) 37 F 25 M 3 4 PT H 3+ p 22\ 38 F 26 M 4 5 PT 1+ NP 22\ 39 F 27 M 2 1 PT H 3+ p 40 F 28 M 2 5 PT H 3+ p 22\ 41 F 29 M 1 3 PT 2+ NP 42 F 30 M 1 1 PT H 1+ p 22\ 43 F 31 M 3 4 PT 1+ p 23\ 44 F 32 M 3 4 PT H 3+ p 23\ 45 F 33 M 2 7 PT H 3+ p 22\ 46 F 34 M 2 6 PT 3+ p 22\ 47 F 35 M 3 6 PT H 3+ NP 48 F 36 M 3 3 PT H PV 3+ p 22\

### HarlanStudyNumber: 

### 41205015 Report Page235



## Appendix5 (continued) IndividualMatingPerformance,Fertilityand GestationLengths Group: 3 Dose Level: 250 mg/kg bw/day

Paired Animal Number Pre-Coital Interval Copulation Plug Count (Days) Sperm Reading Score Pregnancy Status Gestation Length (Days) 61 F 49 M 3 6 PT H 3+ p 

### 221r; 62 F 50 M 4 7 PT H 3+ p 

### 231r; 63 F 51 M 1 3 PT 3+ p 

### 23 64 F 52 M 3 4 PT H 3+ p 

### 221r; 65 F 53 M 3 5 PT H 3+ p 

### 221r; 66 F 54 M 1 3 PT 3+ p 

### 221r; 67 F 55 M 4 7 PT 3+ p 

### 221r; 68 F 56 M 1 4 PT 3+ p 

### 22 69 F 57 M 3 5 PT 3+ p 

### 221r; 70 F 58 M 2 3 PT 3+ p 

### 221r; 71 F 59 M 3 3 PT 3+ p 

### 221r; 72 F 60 M 4 8 PT H 2+ p 

### 231r;

### HarlanStudyNumber: 

### 41205015 Report 

### Page236



## Appendix5 (continued) IndividualMatingPerformance,Fertilityand GestationLengths Group: 4 Dose Level: 750 mg/kg bw/day

Paired Animal Number Pre-Coital Interval Copulation Plug Count Sperm Reading Score Pregnancy Status Gestation Length (Days) (Days) 85 F 73 M 1 1 PT H 3+ p 

### 221:; 86 F 74 M 3 3 PT 3+ p 

### 221:; 87 F 75 M 1 4 PT H 2+ NP 88 F 76 M 1 2 PT 2+ p 

### 221:; 89 F 77 

### M 2 2 PT 2+ p 

### 221:; 90 F 78 M 13 3 PT H 2+ p 

### 221:; 91 F 79 M 3 5 PT H 3+ p 

### 221:; 92 F 80 M 1 4 PT H 3+ p 

### 231:; 93 F 81 M 12 6 PT H 3+ p 

### 221:; 94 F 82 M 1 3 PT H 2+ p 

### 221:; 95 F 83 M 3 6 PT H 3+ p 

### 231:; 96 F 84 M 2 5 PT 3+ p 

### 221:;

### HarlanStudyNumber: 

### 41205015 Report 

### Page237



## Appendix6 Individualand GroupMeanLitterSizeandLitterWeights Group: 1 Dose Level: O(Control) Number of Live Litter Weight Mean Offspring Weight Mean Offspring Number Total Body Weight Change Number of Offspring (g) (g) Animal/Litter of Implantation Number of (g) Number Corpora Sites Offspring Day 1 Day 4 Days 1-4 Lutea Born Day 1 Day 4 Day 1 Day 4 Males Females Males Females Males Females 13 12 12 12 11 11 62.4 91.6 5.7 5.6 8.4 8.3 2.7 2.6 14 17 13 11 11 11 58.9 78.8 5.6 5.2 7.4 7.0 1.9 1.8 15 NP 4 16 14 14 12 12 12 76.3 100.8 6.4 6.3 8.4 8.4 2.0 2.2 17 14 13 13 13 12 74.0 95.9 6.0 5.3 8.2 7.6 2.2 2.3 18 16 16 15 15 15 81.1 114.3 5.5 5.3 7.6 7.6 2.2 2.3 19 12 12 11 11 10 71.4 92.5 6.7 6.2 9.3 9.2 2.6 3.0 20 12 11 10 9 9 53.3 79.3 6.6 5.7 9.0 8.8 2.5 3.0 21 15 15 13 13 13 67.5 95.6 5.3 5.1 7.5 7.3 2.2 2.2 22 11 10 9 9 9 58.4 88.7 6.6 6.4 9.8 10.0 3.2 3.6 23 15 15 13 12 11 59.3 85.6 5.1 4.8 8.0 7.5 2.9 2.7 24 16 13 13 13 13

- 72.4 101 .4 5.6 5.6 7.8 7.9 2.2 2.3 Mean 14.0 13.1 12.0 11.7 11.5 66.82 93.14 5.90 5.59 8.30 8.14 2.40 2.54 S.D. 2.0 1.8 1.7 1.8 1.8 8.89 10.32 0.57 0.52 0.77 0.89 0.42 0.50 N 11 11 11 11 11 11 11 11 11 11 11 11 11 

### I

### Harlan StudyNumber: 

### 41205015 Report Page238



## Appendix6 (continued) Individualand GroupMean LitterSize andLitterWeights Group: 2 Dose Level: 50 mg/kg bw/day Number of Live Litter Weight Mean Offspring Weight Mean Offspring Number Total Body Weight Change Number of Offspring (g) (g) Animal/Litter of Implantation Number of (g) Number Corpora Sites Offspring Day 1 Day 4 Days 1-4 Lutea Born Day 1 Day 4 Day 1 Day 4 Males Females Males Females Males Females 37 14 12 12 12 12 73.8 103.0 6.4 6.0 9.0 8.3 2.6 2.3 38 14 13 12 12 12 71.4 91.8 6.0 5.9 7.8 7.5 1 . 8 1.6 39 NP 5 40 11 10 10 10 10 54.2 75.3 5.3 5.5 7.4 7.6 2.1 2.1 41 NP 42 14 14 14 14 11 70.9 67.2 5.3 4.9 6.4 5.9 1 . 1 1.0 43 14 14 14 14 14 82.6 126.7 5.9 5.9 9.0 9.1 3.1 3.2 44 15 15 14 14 14 88.6 132.0 6.5 6.0 9.7 9.0 3.2 2.9 45 12 12 12 11 11 66.7 89.5 6.2 5.9 8.4 7.7 2.2 1.9 46 15 15 15 15 14 74.9 103.6 5.4 4.7 7.8 7.0 2.4 2.4 47 NP 48 13 12 12 12 12 69.8 94.2 5.9 5.7 7.8 7.9 1.9 2.2 Mean 13.6 13.0 12.8 12.7 12.2 72.54 98.14 5.87 5.60 8.14 7.77 2.27 2.17 S.D. 1.3 1.7 1.6 1.7 1.5 9.67 21.29 0.46 0.50 1.00 0.97 0.67 0.65 N 9 9 9 9 9 9 9 9 9 9 9 9 9

### HarlanStudyNumber: 

### 41205015 Report Page239



## Appendix6 (continued) Individualand GroupMeanLitterSize andLitterWeights Group: 3 Dose Level: 250 mg/kg bw/day Number of Live Litter Weight Mean Offspring Weight Mean Offspring Number Total Body Weight Change Number of Offspring (g) (g) Animal/Litter of Implantation Number of (g) Number Corpora Sites Offspring Day 1 Day 4 Days 1-4 Lutea Born Day 1 Day 4 Day 1 Day 4 Males Females Males Females Males Females 61 14 13 8 8 8 50.5 75.1 6.5 6.3 9.6 9.3 3.1 3.1 62 14 13 13 13 13 87.6 108.5 6.9 6.2 8.5 8.0 1.6 1.7 63 15 12 10 10 10 68.9 101 .8 7.2 6.7 10.8 9.8 3.7 3.1 64 14 14 12 12 12 67.0 95.1 5.7 5.4 8.0 7.9 2.3 2.5 65 16 15 13 13 13 68.8 94.8 5.3 5.3 7.4 7.2 2.0 2.0 66 12 11 10 10 10 59.6 79.2 6.1 5.7 8.0 7.8 1.9 2.1 67 15 13 13 13 13 78.6 116.3 6.2 5.9 9.6 8.6 3.3 2.6 68 13 13 11 11 11 60.0 82.3 5.6 5.2 7.6 7.3 2.0 2.1 69 14 14 11 11 11 62.7 95.2 6.0 5.6 9.3 8.5 3.3 2.9 70 12 12 12 12 12 63.7 91 .9 5.4 5.1 7.8 7.4 2.4 2.3 71 15 14 9 9 9 55.3 81.8 6.2 6.1 9.2 9.1 3.0 2.9 72 14 13 11 11 10 74.6 102.1 7.1 6.5 10.3 10.1 3.3 3.6



### --- --- Mean 14.0 13. 1 11.1 11.1 11.0 66.44 93.68 6.18 5.84 8.83 8.40 2.65 2.56 S.D. 1.2 1 . 1 1.6 1.6 1.7 10.28 12.44 0.62 0.53 1.12 0.97 0.69 0.56 N 12 12 12 12 12 12 12 12 12 12 12 12 12

### Harlan

### StudyNumber: 

### 41205015 Report Page240



## Appendix6 (continued) Individualand GroupMeanLitterSize andLitterWeights Group: 4 Dose Level: 750 mg/kg bw/day Number of Live Litter Weight Mean Offspring Weight Mean Offspring Number Total Body Weight Change Number of Offspring (g) (g) Animal/Litter of Implantation Number of (g) Number Corpora Sites Offspring Day 1 Day 4 Days 1-4 Lutea Born Day 1 Day 4 Day 1 Day 4 Males Females Males Females Males Females 85 13 13 10 10 10 57.3 85.8 6.1 5.6 8.8 8.5 2.8 2.9 86 15 14 13 13 13 72.5 97.1 5.7 5.5 7.6 7.4 1.9 1.9 87 NP 88 13 12 12 12 11 62.3 89.0 5.4 5.0 8.3 7.9 2.9 2.9 89 13 12 · 12 12 12 66.1 89.4 5.7 5.0 7.6 7.0 1.9 2.0 90 18 18 18 18 18 92.0 129.6 5.0 5.1 6.4 7.5 1.4 2.3 91 14 14 14 14 14 73.5 102.6 5.3 5.2 7.4 7.3 2.1 2.1 92 12 12 12 12 12 68.7 91.8 5.9 5.6 7.8 7.6 1.9 2.0 93 14 14 13 13 13 75.8 110.1 6.0 5.7 8.6 8.4 2.6 2.7 94 13 13 13 13 13 73.3 98.1 5.7 5.5 7.6 7.4 1.9 1.9 95 14 12 11 11 11 68.4 97.6 6.4 6.1 9.2 8.6 2.9 2.5 96 16 14 14 14 13 74.8 72.3 5.5 5.2 5.6 5.5 0.2 0.3 Mean 14.1 13.5 12.9 12.9 12.7 71.34 96.67 5.69 5.41 7.73 7.53 2.04 2.12 S.D. 1.7 1.8 2.1 2.1 2.1 8.89 14.66 0.39 0.33 1.04 0.87 0.79 0.72 N 11 11 11 11 11 11 11 11 11 11 11 11 11

### HarlanStudyNumber: 

### 41205015 Report Page241



## Appendix7 IndividualandGroupMeanImplantationLossesand SurvivalIndices

Pre- Post

- Live Group Litter Implantation Implantation Birth Viability (Sex) Number Loss (%) Loss (%) Index Index (%) (%) 1 (F) 13 0 0 92 100 14 24 15 100 100 15 NP 16 0 14 100 100 17 7 0 100 92 18 0 6 100 100 19 0 8 100 91 20 8 9 90 100 21 0 13 100 100 22 9 10 100 100 23 0 13 92 92 24 19 0 100 100



### -- Mean 6.1 8.2 97.6 97.7 S.D. 8.4 5.9 4.1 3.9 N 11 11 11 11

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page242



## Appendix7 (continued) Individualand GroupMeanImplantationLossesand SurvivalIndices
Pre- Post

- Live Group Litter Implantation Implantation Birth Viability (Sex) Number Index Index 

### (%) Loss 

### (%) Loss 

### (%) (%) 2(F) 37 14 0 100 100 38 7 8 100 100 39 NP 100 40 9 0 100 100 41 NP 42 0 0 100 79 43 0 0 100 100 44 0 7 100 100 45 0 0 92 100 46 0 0 100 93 47 NP 48 8 0 100 100



### -- Mean 4.2 1.6 99.1 96.9 S.D. 5.4 3.2 2.8 7.2 N 9 9 9 9

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page243



## Appendix7 (continued) Individualand GroupMeanImplantationLosses and SurvivalIndices
Pre- Post

- Live Group Litter Implantation Implantation Birth Viability (Sex) Number Loss (%) Loss (%) Index Index (%) (%) 3(F) 61 7 38 100 100 62 7 0 100 100 63 20 17 100 100 64 0 14 100 100 65 6 13 100 100 66 8 9 100 100 67 13 0 100 100 68 0 15 100 100 69 0 21 100 100 70 0 0 100 100 71 7 36 100 100 72 7 15 100 91



### -- Mean 6.3 15.0 100.0 99.2 S.D. 6.0 12.6 0.0 2.6 N 12 12 12 12

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page244



## Appendix7 (continued) Individualand GroupMeanImplantationLosses and SurvivalIndices
Pre- Post

- Live Group Litter Implantation Implantation Birth Viability (Sex) Number Loss 

### (%) Loss 

### (%) Index Index 

### (%) (%) 4(F) 85 0 23 100 100 86 7 7 100 100 87 NP 88 8 0 100 92 89 8 0 100 100 90 0 0 100 100 91 0 0 100 100 92 0 0 100 100 93 0 7 100 100 94 0 0 100 100 95 14 8 100 100 96 13 0 100 93



### -- Mean 4.4 4.2 100.0 98.6 S.D. 5.5 7.2 0.0 3.1 N 11 11 11 11

Dose Levels: Group 1 - O(Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page245



## Appendix8 Individualand GroupMean SexRatio ValuesforOffspring Group: 1 Dose Level: o (Control) Sex Ratio 

### (Post Partum) Day: Litter Number At birth 1 4 Male Female %Male Male Female %Male Male Female %Male 13 6 6 50 5 6 45 5 6 45 14 4 7 36 4 7 36 4 7 36 15 NP 16 7 5 58 7 5 58 7 5 58 17 8 5 62 8 5 62 8 4 67 18 10 5 67 10 5 67 10 5 67 19 6 5 55 6 5 55 6 4 60 20 3 7 30 2 7 22 2 7 22 21 6 7 46 6 7 46 6 7 46 22 5 4 56 5 4 56 5 4 56 23 7 6 54 6 6 50 6 5 55 24 8 5 62 8 5 62 8 5 62 Mean 52.2 50.8 52.1 S.D. 11. 1 12.9 13.6 N 11 11 11

### Harlan StudyNumber: 

### 41205015 Report Page246



## Appendix8 (continued) Individual and GroupMean SexRatio Values forOffspring Group: 2 Dose Level: 50 mg/kg bw/day Sex Ratio 

### (Post Partum) Day:

Litter Number At birth 1 4 Male Female %Male Male Female % Male Male Female %Male 37 5 7 42 5 7 42 5 7 42 38 6 6 50 6 6 50 6 6 50 39 NP 40 3 7 30 3 7 30 3 7 30 41 NP 42 6 8 43 6 8 43 5 6 45 43 8 6 57 8 6 57 8 6 57 44 9 5 64 9 5 64 9 5 64 45 7 5 58 7 4 64 7 4 64 46 7 8 47 7 8 47 7 7 50 47 NP 48 6 6 50 6 6 50 6 6 50 Mean 49.0 49.6 50.2 S.D. 10.3 11 . 0 10.8 N 9 9 9

### Harlan

### StudyNumber: 41205015 Report 

### Page247



## Appendix8 (continued) Individualand GroupMean SexRatioValues forOffspring Group: 3 Dose Level: 250 mg/kg bw/day Sex Ratio 

### (Post Partum) Day:

Litter Number At birth 1 4 Male Female %Male Male Female %Male Male Female %Male 61 2 6 25 2 6 25 2 6 25 62 10 3 77 10 3 77 10 3 77 63 4 6 40 4 6 40 4 6 40 64 7 5 58 7 5 58 7 5 58 65 7 6 54 7 6 54 7 6 54 66 7 3 70 7 3 70 7 3 70 67 5 8 38 5 8 38 5 8 38 68 6 5 55 6 5 55 6 5 55 69 2 9 18 2 9 18 2 9 18 70 8 4 67 8 4 67 8 4 67 71 2 7 22 2 7 22 2 7 22 72 6 5 55 6 5 55 6 4 60 Mean 48.2 48.2 48.7 S.D. 19.4 19.4 19.6 N 12 12 12

### HarlanStudyNumber: 

### 41205015 Report Page248



## Appendix8 (continued) Individualand GroupMean SexRatio Valuesfor Offspring Group: 4 Dose Level: 750 mg/kg bw/day Sex Ratio 

### (Post Partum) Day:

Litter Number At birth 1 4 Male Female %Male Male Female %Male Male Female % Male 85 3 7 30 3 7 30 3 7 30 86 6 7 46 6 7 46 6 7 46 87 NP 88 5 7 42 5 7 42 5 6 45 89 9 3 75 9 3 75 9 3 75 90 5 13 28 5 13 28 5 13 28 91 4 10 29 4 10 29 4 10 29 92 6 6 50 6 6 50 6 6 50 93 5 8 38 5 8 38 5 8 38 94 9 4 69 9 4 69 9 4 69 95 5 6 45 5 6 45 5 6 45 96 8 6 57 8 6 57 8 5 62 Mean 46.3 46.3 47.1 S.D. 15.8 15.8 16.0 N 11 11 11

### HarlanStudyNumber: 

### 41205015



## Appendix9 Individual Clinical Signsfor Offspring Group: 1 Dose Level: 

## o (Control)

Litter Number 13 14 15 

### NP 16 17

18 19 20

21 22 23

24 

### Affected Offspring Sex and Identity 1M



### Female 13



### Female 7 1M

1M 

### Female 10 

### Report

Clin.ical Observation Found dead No Abnormalities Detected
No Abnormalities Detected Cold, weak, no milk in stomach Missing No Abnormalities Detected Missing

Small Found dead No Abnormalities Detected No Abnormalities Detected Found dead

Missing No Abnormalities Detected 

### Page249

Day Post Partum 

### Pre Day 1

2

4 

### Pre Day 1



### Pre Day 2

### HarlanStudyNumber: 

### 41205015 Report



## Appendix9 (continued) IndividualClinicalSigns for Offspring Group: 2 Dose Level: 50 mg/kg bw/day

Litter Number 37 38 39 

### NP 40 41 

### NP 42

43 44 45 46

47 

### NP 48 

### Affected Offspring Sex and Identity

Female 13 

### Female 14 

### Male 5 

### Female 7

1F 

### Female 

### a Female 11 

### Clinical Observation No Abnormalities Detected No Abnormalities Detected
No Abnormalities Detected
Small Missing Missing Physical injury to tail No Abnormalities Detected No Abnormalities Detected Found dead Bruised snout

Found dead
No Abnormalities Detected Page250

Day 

### Post Partum

Pre day 1 - 1 2 3 3-5



### Pre Day 1-2 3

### Harlan StudyNumber: 

### 41205015 Report



## Appendix9 (continued) Individual ClinicalSigns for Offspring Group: 3 Dose Level: 250 mg/kg bw/day

Litter Number 61 62 63 64 65 66 67 68 69 70 71 72 

### Affected Offspring Sex and Identity

Female 12

Female 9 

### Page251

Clinical Observation Day Post Partum No Abnormalities Detected No Abnormalities Detected No Abnormalities Detected No Abnormalities Detected No Abnormalities Detected No Abnormalities Detected Small 4-5 

### No Abnormalities Detected No Abnormalities Detected No Abnormalities Detected No Abnormalities Detected Missing 4

### HarlanStudyNumber: 

### 41205015 Report



## Appendix9 (continued) Individual ClinicalSigns for Offspring Group: 4 Dose Level: 750 mg/kg bw/day

Litter Number 85 86 87 NP 88 89 90 

### 91 92 93 94 95 96 

### Affected Offspring Sex and Identity

Female 11

Female 12 BM 6F (Whole Litter) Female 11 BM SF (Whole Litter) Clinical Observation No Abnormalities Detected No Abnormalities Detected Missing No Abnormalities Detected No Abnormalities Detected No Abnormalities Detected No Abnormalities Detected No Abnormalities Detected No Abnormalities Detected No Abnormalities Detected Cold Small Missing

Small 

### Page252

Day 

### Post Partum

2

2 3 4 4-5

### HarlanStudyNumber: 

### 41205015 Report



## Appendix 10 Individualand GroupMean ReflexologicalResponses for Offspring Group: 1 Dose Level: o (Control)

Litter Number

13 14 15 NP 16 17 18 19 20 21 22 23 24



### - Mean S.D. N Surface righting (Day 1 

### Post Partum) Number of offspring % passed examined passed 11 11 100 11 11 100
12 12 100 13 13 100 15 15 100 11 10 91 9 8 89 13 13 100 9 9 100 12 12 100 13 13 100 98.2 4.1 11 

### Page253

### HarlanStudyNumber: 

### 41205015 Report



## Appendix 10 (continued) Individualand Group Mean ReflexologicalResponses for Offspring Group: 2 Dose Level: 50 mg/kg bw/day

Litter Number

37 38 39 NP 40 41 NP 42 43 44 45 46 47 NP 48

- Mean S.D. N Surface righting (Day 1 

### Post Partum) Number of offspring % passed examined passed 12 12 100 12 10 83
10 10 100
14 13 93 14 14 100 14 13 93 11 11 100 15 15 100
12 12 100 96.6 5.8

9 

### Page254

### Harlan StudyNumber: 41205015 

### Report Page255



## Appendix 10 (continued) Individualand GroupMean ReflexologicalResponses for Offspring Group: 3 Dose Level: 250 mg/kg bw/day Surface righting Litter (Day 1 

### Post Partum) Number Number of offspring examined % passed passed 61 8 8 100 62 13 13 100 63 10 9 90 64 12 12 100 65 13 13 100 66 10 10 100 67 13 13 100 68 11 11 100 69 11 11 100 70 12 12 100 71 9 9 100 72 11 11 100 Mean 99.2 S.D. 2.9 N 12

### HarlanStudyNumber: 

### 41205015 Report



## Appendix 10 (continued) Individualand GroupMeanReflexologicalResponses for Offspring Group: 4 Dose Level: 750 mg/kg bw/day

Litter Number

85 86 87 NP 88 89 90 91 92 93 94 95 96

- Mean S.D. N Surface righting (Day 1 

### Post Partum) Number of offspring %passed examined passed 10 9 90 13 13 100
12 10 83 12 12 100 18 16 89 14 14 100 12 11 92 13 13 100 13 11 85 11 11 100 14 14 100 94.4 6.8 11 

### Page256

### HarlanStudyNumber: 

### 41205015 Report



## Appendix 11 IndividualNecropsyFindingsfor Offspring Group: 1 Dose Level: o (Control)

Interim Deaths Litter Number Necropsy Day (Post 

### Offspring Sex 

### & Macroscopic Observation
13 

### 14 15 NP 16 17 18 19 

### 20 21 22 23 

### 24 Partum) 

### Pre Day 1

Pre Day 1 Number 1M Autolytic changes detected

1M Autolytic changes detected 

### Page257

Terminal kill
Total Number Macroscopic Observation of Offspring 5M 6F No abnormalities detected 4M 7F No abnormalities detected

7M 5F No abnormalities detected SM 4F No abnormalities detected 10M 5F No abnormalities detected 6M 4F No abnormalities detected 2M 7F No abnormalities detected 6M 7F No abnormalities detected 5M 4F No abnormalities detected 6M 5F No abnormalities detected SM 5F No abnormalities detected

### HarlanStudyNumber: 

### 41205015 Report



## Appendix 11 (continued) IndividualNecropsyFindingsforOffspring Group: 2 Dose Level: 50 mg/kg bw/day

Litter Number

37 38 

### 39 NP 40 41 

### NP 42


### 43 44 

### 45 46 47 NP 48 

### Interim Deaths Necropsy Day (Post Offspring Sex 

### & Partum) Number

Pre Day 3 1F 

### Female 11 

### Macroscopic Observation

Autolytic changes detected Autolytic changes detected 

### Page258

Terminal kill
Total Number Macroscopic Observation of Offspring 5M 7F No abnormalities detected 6M 6F No abnormalities detected

3M 7F No abnormalities detected
Female 7 Physical injury to tail

5M 5F No abnormalities detected SM 6F No abnormalities detected 9M 5F No abnormalities detected 7M 4F No abnormalities detected 7M 7F No abnormalities detected

6M 6F No abnormalities detected

### HarlanStudyNumber: 

### 41205015 Report



## Appendix 11 (continued) IndividualNecropsyFindingsfor Offspring Group: 3 Dose Level: 250 mg/kg bw/day

Litter Number

61 62 63 64 65 66 67

68 69 70 71 72 Interim Deaths Necropsy Day 

### (Post Offspring Sex 

### & Partum) Number Macroscopic Observation 

### Page259

Terminal kill
Macroscopic Observation Total Number of Offspring 2M 6F No abnormalities detected 9M 4F No abnormalities detected 4M 6F No abnormalities detected 7M SF No abnormalities detected 7M 6F No abnormalities detected 7M 3F No abnormalities detected Female 12 Small

SM 7F No abnormalities detected 6M SF No abnormalities detected 2M 9F No abnormalities detected 8M 4F No abnormalities detected 2M 7F No abnormalities detected 6M 4F No abnormalities detected

### HarlanStudyNumber: 

### 41205015 Report



## Appendix 11 (continued) IndividualNecropsyFindingsforOffspring Group: 4 Dose Level: 750 mg/kg bw/day

Litter Number

85 86 87 NP 88 89 90 91 92 93 94 95 96 

### Interim Deaths Necropsy Day 

### (Post Offspring Sex 

### & Partum) Number Macroscopic Observation Total Number of Offspring 3M 7F 6M 7F

5M 

### 6F 9M 3F 5M 13F 4M 10F 

### 6M 6F 5M 

### BF 9M 4F 5M 

### 6F BM 5F 

### Page260

Terminal kill



## ~- Macroscopic Observation No abnormalities detected No abnormalities detected

No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Small

### HarlanStudyNumber: 

### 41205015 Report Page261



## Appendix 12 IndividualNecropsyFindings Group: 1 Dose Level: o (Control) Sex: Male

Animal Death No. Mode Of Death Day (Week) Observation(s)
SCHEDULED KILL 43 (7) 

### No abnormalities detected 2 SCHEDULED KILL 43 (7) 

### No abnormalities detected 3 

### SCHEDULED KILL 43 (7) 

### Epididymides; Small Testes; Small Testes; Flaccid All remaining tissues had no abnormalities detected 4 

### SCHEDULED KILL 43 (7) 

### No abnormalities detected 5 

### SCHEDULED KILL 43 (7) 

### Lungs (With Bronchi); Reddened All remaining tissues had no abnormalities detected
6 

### SCHEDULED KILL 43 (7) 

### No abnormalities detected 7 

### SCHEDULED KILL 43 (7) 

### No abnormalities detected 8 

### SCHEDULED KILL 43 (7) 

### No abnormalities detected
9 

### SCHEDULED KILL 43 (7) 

### No abnormalities detected 10 SCHEDULED KILL 43 (7) 

### No abnormalities detected 11 SCHEDULED KILL 43 (7) 

### No abnormalities detected 12 SCHEDULED KILL 43 (7) 

### No abnormalities detected

### HarlanStudyNumber: 

### 41205015 Report Page262



## Appendix 12 (continued) IndividualNecropsyFindings Group: 1 Dose Level: O (Control) Sex: Female

Animal Death No. Mode Of Death Day (Week) Observation(s)

13 SCHEDULED KILL 43 (7) No abnormalities detected 14 SCHEDULED KILL 43 (7) No abnormalities detected 15 SCHEDULED KILL 43 (7) No abnormalities detected 16 SCHEDULED KILL 45 (7) No abnormalities detected 17 SCHEDULED KILL 42 (6) No abnormalities detected 18 SCHEDULED KILL 45 (7) No abnormalities detected 19 SCHEDULED KILL 45 (7) No abnormalities detected 20 SCHEDULED KILL 42 (6) No abnormalities detected 21 SCHEDULED KILL 43 (7) No abnormalities detected 22 SCHEDULED KILL 44 (7) No abnormalities detected 23 SCHEDULED KILL 44 (7) No abnormalities detected 24 SCHEDULED KILL 45 (7) No abnormalities detected

### HarlanStudyNumber: 

### 41205015 Report Page263



## Appendix 12 (continued) IndividualNecropsyFindings Group: 2 Dose Level: 50 mg/kg bw/day Sex: Male

Animal Death No. Mode Of Death Day (Week) Observation(s)

25 SCHEDULED KILL 43 (7) No abnormalities detected 26 SCHEDULED KILL 43 (7) No abnormalities detected 27 SCHEDULED KILL 43 (7) Lungs (With Bronchi); median lobe; Mass: Fibrous mass 7mm x 7mm x7mm. All remaining tissues had no abnormalities detected 28 SCHEDULED KILL 43 (7) No abnormalities detected 29 SCHEDULED KILL 43 (7) Epididymides; Small Testes; Small Testes; Flaccid All remaining tissues had no abnormalities detected 30 SCHEDULED KILL 43 (7) No abnormalities detected 31 SCHEDULED KILL 43 (7) No abnormalities detected 32 SCHEDULED KILL 43 (7) No abnormalities detected 33 SCHEDULED KILL 43 (7) No abnormalities detected 34 SCHEDULED KILL 43 (7) No abnormalities detected 35 SCHEDULED KILL 43 (7) No abnormalities detected 36 SCHEDULED KILL 43 (7) No abnormalities detected

### Harlan StudyNumber: 

### 41205015 Report Page264



## Appendix 12 (continued) IndividualNecropsyFindings Group: 2 Dose Level: 50 mg/kg bw/day Sex: Female

Animal Death No. Mode Of Death Day (Week) Observation(s)

37 SCHEDULED KILL 44 (7) Kidneys; Increased Pelvic Space All remaining tissues had no abnormalities detected 38 SCHEDULED KILL 45 (7) No abnormalities detected 39 SCHEDULED KILL 43 (7) No abnormalities detected 40 SCHEDULED KILL 43 (7) No abnormalities detected 41 SCHEDULED KILL 42 (6) No abnormalities detected 42 SCHEDULED KILL 42 (6) No abnormalities detected 43 SCHEDULED KILL 45 (7) No abnormalities detected 44 SCHEDULED KILL 45 (7) No abnormalities detected 45 SCHEDULED KILL 43 (7) No abnormalities detected 46 SCHEDULED KILL 43 (7) No abnormalities detected 47 SCHEDULED KILL 44 (7) No abnormalities detected 48 SCHEDULED KILL 44 (7) No abnormalities detected

### HarlanStudyNumber: 

### 41205015 Report Page265



## Appendix 12 (continued) IndividualNecropsyFindings Group: 3 Dose Level: 250 mg/kg bw/day Sex: Male Animal Death No. Mode Of Death Day (Week) Observation(s)

49 SCHEDULED KILL 43 (7) No abnormalities detected 50 SCHEDULED KILL 43 (7) No abnormalities detected 51 SCHEDULED KILL 43 (7) No abnormalities detected 52 SCHEDULED KILL 43 (7) No abnormalities detected 53 SCHEDULED KILL 43 (7) No abnormalities detected 54 SCHEDULED KILL 43 (7) No abnormalities detected 55 SCHEDULED KILL 43 (7) No abnormalities detected 56 SCHEDULED KILL 43 (7) Kidneys; left; Increased Pelvic Space Kidneys; left; Fluid Filled All remaining tissues had no abnormalities detected 57 SCHEDULED KILL 43 (7) No abnormalities detected 58 SCHEDULED KILL 43 (7) No abnormalities detected 59 SCHEDULED KILL 43 (7) No abnormalities detected 60 SCHEDULED KILL 43 (7) No abnormalities detected

### Harlan StudyNumber: 

### 41205015 Report Page266



## Appendix 12 (continued) IndividualNecropsyFindings Group: 3 Dose Level: 250 mg/kg bw/day Sex: Female

Animal Death No. Mode Of Death Day (Week) Observation(s)

61 SCHEDULED KILL 44 (7) No abnormalities detected 62 SCHEDULED KILL 46 (7) No abnormalities detected 63 SCHEDULED KILL 43 (7) No abnormalities detected 64 SCHEDULED KILL 44 (7) No abnormalities detected 65 SCHEDULED KILL 44 (7) No abnormalities detected 66 SCHEDULED KILL 42 (6) No abnormalities detected 67 SCHEDULED KILL 45 (7) No abnormalities detected 68 SCHEDULED KILL 42 (6) No abnormalities detected 69 SCHEDULED KILL 44 (7) No abnormalities detected 70 SCHEDULED KILL 43 (7) No abnormalities detected 71 SCHEDULED KILL 44 (7) No abnormalities detected 72 SCHEDULED KILL 46 (7) No abnormalities detected

### HarlanStudyNumber: 

### 41205015 Report 

### Page267



## Appendix 12 (continued) IndividualNecropsyFindings Group: 4 Dose Level: 750 mg/kg bw/day Sex: Male

Animal Death No. Mode Of Death Day (Week) Observation(s)

73 SCHEDULED KILL 43 (7) No abnormalities detected 74 SCHEDULED KILL 43 (7) No abnormalities detected 75 SCHEDULED KILL 43 (7) No abnormalities detected 76 SCHEDULED KILL 43 (7) No abnormalities detected
77 

### SCHEDULED KILL 43 (7) No abnormalities detected 78 SCHEDULED KILL 43 (7) No abnormalities detected 79 SCHEDULED KILL 43 (7) No abnormalities detected 80 SCHEDULED KILL 43 (7) No abnormalities detected 81 SCHEDULED KILL 43 (7) No abnormalities detected 82 SCHEDULED KILL 43 (7) No abnormalities detected 83 SCHEDULED KILL 43 (7) No abnormalities detected 84 SCHEDULED KILL 43 (7) No abnormalities detected

### HarlanStudyNumber: 

### 41205015 Report Page268



## Appendix 12 (continued) IndividualNecropsyFindings Group: 4 Dose Level: 750 mg/kg bw/day Sex: Female

Animal Death No. Mode Of Death Day (Week) Observation(s)

85 SCHEDULED KILL 42 (6) No abnormalities detected 86 SCHEDULED KILL 44 (7) No abnormalities detected 87 SCHEDULED KILL 42 (6) Lungs (With Bronchi); Reddened All remaining tissues had no abnormalities detected 88 SCHEDULED KILL 42 (6) No abnormalities detected 89 SCHEDULED KILL 43 (7) No abnormalities detected 90 SCHEDULED KILL 54 (8) No abnormalities detected 91 SCHEDULED KILL 44 (7) No abnormalities detected 92 SCHEDULED KILL 42 (6) No abnormalities detected 93 SCHEDULED KILL 53 (8) No abnormalities detected 94 SCHEDULED KILL 42 (6) No abnormalities detected 95 SCHEDULED KILL 45 (7) No abnormalities detected 96 SCHEDULED KILL 43 (7) No abnormalities detected

### Harlan StudyNumber: 

### 41205015 Report Page269



## Appendix 13 Individualand GroupMean OrganWeights

Group Animal Epididy- Seminal (Sex) Number Day Adrenals Brain mides Heart Kidneys Liver Pituitary Prostate vesicles Spleen Testes Thymus Thyroid Number g g g g g g g g g g g g g 1(M) 1 43 0.0736 2.1443 1.4940 1.2439 2.3877 12.1858 0.0100 0.5812 2.8611 0.6730 3.8686 0.3656 0.0276



### --- --- 2 43 0.0680 1.9421 1.5261 0.9843 2.2134 12.0389 0.0102 0.5557 2.5679 0.6864 3.3255 0.4154 0.0241



### - -- --- 3 43 0.1279 2.0185 1.2462 1.1672 2.1771 12.1619 0.0136 0.4816 1.9744 0.7279 1 .4766 0.3658 0.0244



### - -- 4 43 0.0809 1.9138 1.1778 1.1769 2.0426 11 .2170 0.0128 0.4564 1.9959 0.7478 3.0325 0.3491 0.0173



### - -- 5 43 0.0754 2.0263 1.5456 0.8496 2.0681 12.3641 0.0113 0.5986 2.3326 0.7056 3.6573 0.4467 0.0212



### - -- 6 43 0.0705 2.0012 1.5446 0.9900 2.2715 10.3368 0.0110 0.7359 2.4901 0.7093 3.4676 0.3074 0.0239 7 43 0.0607 2.0341 1.5998 1.2737 2.4294 12.8814 0.0139 0.5442 2.3946 0.6227 4.1127 0.4841 0.0243



### - -- 8 43 0.0771 2.1103 1 .3971 0.9357 1.9344 9.9041 0.0105 0.6238 2.7761 0.5463 3.9675 0.2342 0.0219



### - -- 9 43 0.0743 2. 1149 1.6719 1.1991 2.5142 14.2513 0.0106 0.7472 2.2484 0.8426 3.9337 0.4929 0.0164

- 10 43 0.0777 1.9897 1.7239 1.1464 2.2224 10.2537 0.0129 0.8584 2.2013 0.7152 3.7348 0.3806 0.0169



### -- 11 43 0.0802 2.0377 1.6414 1.1506 2.3054 12.3507 0.0118 0.6588 2.8309 0.8130 3.4745 0.4182 0.0315



### -- 12 43 0.0616 2.1334 1.5274 0.8582 2.1964 10.3659 0.0116 0.6017 1.9933 0.6981 3.6252 0.3914 0.0250

Dose Levels: Group 1

- 

### o (Control) Group 2

- 50 mg/kg bw/day Group 3

- 250 mg/kg bw/day Group 4

- 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page270



## Appendix 13 (continued) Individualand GroupMeanOrganWeights

Group Animal Epididy- Seminal (Sex) Number Day Adrenals Brain mides Heart Kidneys Liver Pituitary Prostate vesicles Spleen Testes Thymus Thyroid Number g g g g g g g g g g g g g 2(M) 25 43 0.0875 2.0035 1.8649 1.1475 2.3813 12.9192 0.0145 0.7236 2.2860 0.7231 3.6791 0.2826 0.0242



### --- -- --- 26 43 0.0757 2.0694 1.4551 0.9043 2.4173 12.2344 0.0124 0.4008 2.1948 0.7079 3.5921 0.3787 0.0196



### - --- 27 43 0.0628 1.8753 1.2123 1.1013 2.1266 11 .4197 0.0142 0.6806 2.2072 0.7285 3.2621 0.3196 0.0395



### - 

## -- 28 43 0.0615 1.7988 1.2107 0.9803 1.9301 10.9231 0.0086 0.4876 1.9801 0.5820 3.0692 0.2827 0.0275

- 

### -- 29 43 0.0674 2.0119 0.8928 0.9939 2.3214 13.1545 0.0150 0.4764 2.1718 0.9492 1.4548 0.4512 0.0296

- 

### -- 30 43 0.0955 2.2611 1.6604 1 .3158 2.0938 12.2628 0.0104 0.5563 1.1491 0.7522 3.8503 0.5966 0.0330

- 

### -- 31 43 0.0803 1.9452 1.4068 0.9876 2.2339 12.1215 0.0140 0.5618 2.0187 0.6332 3.5725 0.3464 0.0234

- 

### -- 32 43 0.0789 2.1016 1.5483 1.3879 2.5332 12.4895 0.0137 0.8106 2.5730 0.7481 3.9314 0.4924 0.0341

- 

### -- 33 43 0.0798 2.1508 1.5558 0.9680 2.4574 11.3828 0.0126 0.7192 3.1667 0.7188 3.7988 0.2083 0.0232

- 

### -- 34 43 0.0672 2.1281 1.6618 1 .1171 2.2860 12.9702 0.0156 0.6383 2.8861 0.9066 4.2510 0.3923 0.0308

- 

### -- 35 43 0.0761 2.2631 1.4487 1.0494 2.3848 12.1641 0.0123 0.6549 2.6317 0.8614 3.7279 0.2401 0.0338

- 

### -- 36 43 0.0945 2.0333 1.4904 1.1287 2.3065 11.0239 0.0120 0.5692 2.6081 0.6316 3.4233 0.4037 0.0299

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page271



## Appendix 13 (continued) Individualand GroupMeanOrganWeights

Group Animal Epididy- Seminal (Sex) Number Day Adrenals Brain mides Heart Kidneys Liver Pituitary Prostate vesicles Spleen Testes Thymus Thyroid Number g g g g g g g g g g g g g 3(M) 49 43 0.0775 2.1013 1.4179 1.1313 2.2968 11.3304 0.0114 0.7106 2.7581 0.7223 3.7224 0.5021 0.0247



### --- -- 50 43 0.0824 1.9016 1.4986 1.0498 2.2243 11.0820 0.0102 0.4866 2.5935 0.7424 3.3671 0.3302 0.0253

- 

### -- 51 43 0.0795 2.0461 1.5288 0.8636 2.4806 12.1867 0.0138 0.5073 2.5646 0.7185 3.4557 0.3434 0.0220

- 

### -- 

### --- 52 43 0.0806 1.9861 1.7080 1.3436 2.5481 12.6608 0.0136 0.6591 2.5520 0.7565 4.0138 0.4224 0.0251

- 

### -- 53 43 0.0910 2.0995 1.8133 1.1728 2.4602 12.4525 0.0117 0.7811 2.0150 0.7713 4.3082 0.6322 0.0218

- 

### -- 54 43 0.0723 2.0355 1.4961 1.1566 2.3709 11.8185 0.0118 0.5946 2.3869 0.8240 3.8903 0.3544 0.0278



## - -- 55 43 0.0689 2.0504 1.7580 1.1284 2.3975 12.4809 0.0122 0.6569 2.4268 0.6961 4.1806 0.2860 0.0206



### - 

## -- 56 43 0.0656 1.9370 1.4497 0.9519 2.4370 9.8506 0.0124 0.5523 2.2490 0.7230 3.6106 0.4463 0.0280

- 

### -- 57 43 0.0658 1.9630 1.3793 0.9529 2.1449 11.3742 0.0108 0.4605 1.9256 0.6806 3.2586 0.5183 0.0275



### - 

## -- 58 43 0.0700 2.0068 1.3669 0.9975 2.2084 12.3900 0.0116 0.4742 1.8138 0.7538 3.2351 0.3914 0.0240

- 

### -- -- 59 43 0.0716 2.0851 1.4760 1.1567 2.2838 10.3656 0.0097 0.5056 1.9690 0.6905 3.7863 0.4933 0.0214

- 

### -- 60 43 0.0925 1.8664 1.5854 1.0741 2.2777 11 .1209 0.0122 0.5275 2.4804 0.7126 3.2182 0.3909 0.0188

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page272



## Appendix 13 (continued) Individualand GroupMean OrganWeights

Group Animal Epididy- Seminal (Sex) Number Day Adrenals Brain mides Heart Kidneys Liver Pituitary Prostate vesicles Spleen Testes Thymus Thyroid Number g g g g g g g g g g g g g 4(M) 73 43 0.0790 2.0810 1.4803 1.0887 2.1537 11.2632 0.0126 0.5446 2.1671 0.5809 3.7906 0.3159 0.0210



### --- -- --- 74 43 0.0713 2.0526 1.4434 0.9612 2.2329 11 .8855 0.0100 0.5525 1.7961 0.6862 3.4164 0.2740 0.0183 75 43 0.0767 2.0701 1 .5631 1.0837 2.2347 12.0591 0.0130 0.4875 1.8697 0.7670 3.9498 0.5553 0.0399



### - - 76 43 0. 1018 2.0086 1.8102 1.2994 2.3852 12.1008 0.0108 0.6022 1.5484 0.8051 3.9440 0.3996 0.0196



### - -- --- 77 43 0.0591 1 .9513 1.5445 1.0396 2.1592 12.0304 0.0123 0.5242 1.9308 0.7378 4.2019 0.4769 0.0285



### - -- 78 43 0.0875 2.0697 1.5487 1.0271 2.4757 13.0204 0.0135 0.6825 2.3596 2.3572 3.7466 0.3713 0.0283



### - -- 79 43 0.0724 1.8640 1.3790 0.9453 2.2822 12.1129 0.0108 0.5590 1.9389 0.5743 3.1607 0.4654 0.0224



### - -- 80 43 0.0760 2.1132 1.5510 1

.0891 2.4096 12.4719 0.0136 0.5918 1.8694 0.7304 3.5134 0.3391 0.0277



### - -- 81 43 0.0894 2.1994 1.6582 1.0834 2.4868 12.7299 0.0100 0.7308 2.1337 0.8089 3.7753 0.2840 0.0429



### -- 82 43 0.0604 2.0721 1.4407 1.0953 2.1053 11 .1856 0.0084 0.5520 1.8294 0.6321 3.8489 0.4420 0.0251



### - 83 43 0.0801 2.1304 1.7593 1

. 1107 2.3421 12.1240 0.0109 0.5144 2.0534 0.6537 4.3291 0.4838 0.0309



### - -- 84 43 0.0806 1.9730 1.4229 1 .0541 2.1621 12.1255 0.0097 0.5514 2.1653 0.6628 3.7596 0.3764 0.0366

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page273



## Appendix 13 (continued) Individual and GroupMean OrganWeights

Group Animal (Sex) Number Day Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Thyroid Number g g g g g g g g g g 1(F) 13 43 0.0809 2.0555 0.7697 1.5335 10.6504 0.1152 0.0184 0.6798 0.2364 0.0237



### --- -- --- 14 43 0.0773 1.9568 0.8107 1.5453 8.9510 0.1224 0.0159 0.6148 0.1536 0.0171

- 

### -- --- 15 43 0.0917 1.8494 0.9580 1 .5819 7.7741 0.1070 0.0145 0.5441 0.4196 0.0200

- 

### -- 16 45 0.0917 1.9509 0.8166 1.3770 10.1651 0.1204 0.0178 0.6570 0.2858 0.0192

- 17 42 0.1147 1.9588 0.9421 1.6107 10.6019 0.1169 0.0185 0.5508 0.2709 0.0219

- 

### -- -- 18 45 0.0855 1.7760 0.7262 1 .7179 10.5511 0.1276 0.0182 0.7322 0.1605 0.0254

- 

### -- 19 45 0.0892 1.9389 0.8107 1.5598 11.0369 0.0946 0.0101 0.7796 0.3251 0.0234



### - 20 42 0.0828 1.9386 0.8647 1.6030 10.1411 0.1280 0.0147 0.5497 0.2796 0.0229



### - -- --- 21 43 0.0987 1

.7419 0.6424 1.4842 9.0193 0.1224 0.0136 0.7061 0.1652 0.0225



### - 22 44 0.0896 1.7925 0.8887 1.5797 10.1758 0.1140 0.0180 0.6451 0.2663 0.0284



### -- 23 44 0.1005 1.9213 0.8364 1.4839 11.4961 0.1159 0.0152 0.6646 0.2853 0.0270



### - -- 24 45 0.0861 1.8841 0.6778 1.6222 9.6888 0.1120 0.0137 0.6945 0.1475 0.0243

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page274



## Appendix 13 (continued) Individualand GroupMeanOrganWeights

Group Animal (Sex) Number Day Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Thyroid Number g g g g g g g g g g 2(F) 37 44 0.0811 1.8942 0.8321 1.6274 9.8862 0.1002 0.0102 0.6684 0. 1671 0.0303



### --- -- 38 45 0.0888 1.8236 0.7249 1.6216 10.8586 0.1195 0.0203 0.7601 0.2095 0.0206



### - -- --- 39 43 0.0786 1 .8921 0.8054 1 .6617 8.0144 0.1032 0.0159 0.6010 0.3652 0.0285



### - -- 40 43 0.1139 2.0114 0.8508 1.5344 10.1269 0.1166 0.0196 0.7315 0.2883 0.0270



### - -- - 41 42 0.0846 1.9680 0.7620 1.5162 9.5310 0.1567 0.0189 0.6237 0.3819 0.0253 42 42 0.0708 1 .8351 0.7871 1.4458 9.3228 0.1265 0.0178 0.5334 0.1402 0.0330



### -- 43 45 0.0898 1.9324 0.8481 1.6295 11.1036 0.1362 0.0185 0.7430 0.2272 0.0218



### -- 44 45 0.1076 1.8565 0.8033 1.8195 12.8538 0.1412 0.0172 0.9088 0.2971 0.0322



### -- 45 43 0.1090 1.9647 0.9410 1.7325 11.9074 0.1299 0.0190 0.5890 0.1942 0.0367



### -- -- 46 43 0.1010 1.9435 0.8176 1.6368 11.5265 0.1496 0.0220 0.5655 0.2457 0.0234



### - -- 47 44 0.0639 1.8582 1.0478 1.5509 7.6501 0.1307 0.0160 0.5144 0.4547 0.0313



### -- 48 44 0. 1016 2.0029 0.9185 1.5961 10.0023 0. 1101 0.0158 0.6631 0.1935 0.0268

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan 

### StudyNumber: 

### 41205015 Report Page275



## Appendix 13 (continued) Individualand Group Mean OrganWeights

Group Animal (Sex) Number Day Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Thyroid Number g g g g g g g g g g 3(F) 61 44 0.0724 1.9707 O.BBB3 1.5420 10.1BB6 0.1112 0.0151 0.4744 0.2115 0.0255



### --- -- 62 46 0.0954 2.0012 0.8774 1.8198 12.8351 0.1754 0.0182 0.7778 0.2634 0.0244



### - 63 43 0.0713 1.8697 0.7065 1.4845 10.0909 0.0958 0.0127 0.5410 0.1888 0.0235



### - -- 64 44 0.0886 2.0670 1.0379 1 .4951 10.9938 0.1310 0.0175 0.7738 0.1953 0.0140



### - -- 65 44 0.0821 1 .8721 0.8317 1.5518 10.2238 0.1048 0.0158 0.5543 0.2879 0.0202



### - -- 66 42 0.0959 1.7434 0.8787 1.5797 10.7115 0.1025 0.0168 0.6110 0.1524 0.0201



### --- 67 45 0.1014 1.9068 0.8142 1.6682 12.5421 0.1331 0.0163 0.6463 0.2934 0.0236



### - -- 68 42 0.0702 1 .7137 0.6481 1.4049 9.7140 0.0844 0.0155 0.5067 0.1538 0.0199



### - -- 69 44 0.1256 1.8532 0.8521 1.5179 11.5033 0.1619 0.0150 0.6142 0.1736 0.0177



### -- 70 43 0.0809 1 .8391 0.8074 1.6746 9.9322 0.1219 0.0192 0.4561 0.1890 0.0267

-- 71 44 0.0641 1 .9166 0.8554 1.7906 11.5848 0. 1271 0.0174 0.6719 0.3382 0.0177



### - 72 46 0.0868 1.9647 0.8569 1 .6185 10.7423 0.1230 0.0165 0.6127 0.2083 0.0248

Dose Levels: Group 1

- 

### o (Control) Group 2

- 50 mg/kg bw/day Group 3

- 250 mg/kg bw/day Group 4

- 750 mg/kg bw/day

### HarlanStudyNumber: 41205015 Report Page276



## Appendix 13 (continued) Individualand GroupMean OrganWeights

Group Animal (Sex) Number Day Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Thyroid Number g g g g g g g g g g 4(F) 85 42 0.0947 1.7772 1.0737 1.7782 10.7660 0.1257 0.0153 0.7424 0.2118 0.0333



### --- -- --- 86 44 0.1062 1 .8831 1

.0311 1.6272 12.5462 0.1533 0.0132 0.7066 0.3215 0.0221



### - -- 87 42 0.0612 1 .7941 0.6404 1.6171 8.0528 0.0910 0.0104 0.6126 0.3139 0.0208



### - -- 88 42 0.0767 1.7075 0.7134 1.4525 10.4177 0.0987 0.0157 0.5508 0.1843 0.0295



### - -- 89 43 0.0981 1.8277 0.7765 1.4655 10.9969 0. 1191 0.0143 0.6402 0.2144 0.0288



### - --- 90 54 0.0914 1.7577 0.9646 1.5262 13.6323 0.1275 0.0141 0.7798 0.1693 0.0125



### - -- 91 44 0.0826 1.8669 0.9074 1 .5716 12.7620 0.1307 0.0134 0.6291 0.3767 0.0250



### - -- 92 42 0.1038 1.9405 0.9895 1.6807 12.0545 0.1068 0.0169 0.6246 0.2641 0.0278



### - -- 93 53 0.0839 1.6978 0.9477 1.6562 11 .2473 0.1116 0.0153 0.6922 0.1773 0.0136



### -- 94 42 0.1029 1.8902 0.8126 1.7963 12.3259 0.1366 0.0148 0.6667 0.2545 0.0312



### - -- -- 95 45 0.0887 1.9012 0.7628 1.4633 10.2295 0.0921 0.0120 0.5413 0.2136 0.0195



### - -- 96 43 0.0746 1.8675 0.6853 1.5423 10.6476 0.1190 0.0154 0.6650 0.1727 0.0356

Dose Levels: Group 1

- O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page 277



## Appendix 14 Individualand GroupMeanRelative OrganWeights
Group Animal Relative Relative Relative Relative Relative Relative Relative (Sex) Number Day Bodywt Adrenals Brain Epididys Heart Kidneys Liver Pituitary Number g % % % % % % % 1(M) 1 43 391 0.0188 0.5484 0.3821 0.3181 0.6107 3.1166 0.0026

--- 

### -- 2 43 387 0.0176 0.5018 0.3943 0.2543 0.5719 3.1108 0.0026



### -- 3 43 385 0.0332 0.5243 0.3237 0.3032 0.5655 3.1589 0.0035 4 43 409 0.0198 0.4679 0.2880 0.2878 0.4994 2.7425 0.0031



### - --- --- 5 43 406 0.0186 0.4991 0.3807 0.2093 0.5094 3.0453 0.0028



### - -- --- 6 43 379 0.0186 0.5280 0.4075 0.2612 0.5993 2.7274 0.0029 7 43 405 0.0150 0.5022 0.3950 0.3145 0.5999 3.1806 0.0034



### --- 8 43 346 0.0223 0.6099 0.4038 0.2704 0.5591 2.8625 0.0030



### - --- 9 43 417 0.0178 0.5072 0.4009 0.2876 0.6029 3.4176 0.0025

- 

### -- --- 10 43 374 0.0208 0.5320 0.4609 0.3065 0.5942 2.7416 0.0034

- 

### -- --- 11 43 410 0.0196 0.4970 0.4003 0.2806 0.5623 3.0124 0.0029

- 

### --- 12 43 391 0.0158 0.5456 0.3906 0.2195 0.5617 2.6511 0.0030

Dose Levels: Group 1 - 

### o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page278



## Appendix 14 (continued) Individualand GroupMean Relative Organ Weights (continued) Group Animal Relative Relative Relative Relative Relative Relative (Sex) Number Day Prostate Sem.Ves. Spleen Testes Thymus Thyroid Number % % % % % % 1(M) 1 43 0.1486 0.7317 0.1721 0.9894 0.0935 0.0071



### --- -- 2 43 0.1436 0.6635 0.1774 0.8593 0.1073 0.0062



### - -- 3 43 0.1251 0.5128 0.1891 0.3835 0.0950 0.0063



### - 4 43 0.1116 0.4880 0.1828 0.7414 0.0854 0.0042



### - -- 5 43 0.1474 0.5745 0.1738 0.9008 0.1100 0.0052



### -- -- 6 43 0.1942 0.6570 0.1872 0.9149 0.0811 0.0063



### - -- 7 43 0.1344 0.5913 0.1538 1 .0155 0.1195 0.0060



### - -- 8 43 0.1803 0.8023 0.1579 1.1467 0.0677 0.0063



### - -- 9 43 0.1792 0.5392 0.2021 0.9433 0.1182 0.0039

- 

### -- 10 43 0.2295 0.5886 0.1912 0.9986 0.1018 0.0045

- 

### -- 11 43 0.1607 0.6905 0.1983 0.8474 0.1020 0.0077

- 

### -- 12 43 0.1539 0.5098 0.1785 0.9272 0.1001 0.0064

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 

### 41205015 Report Page279



## Appendix 14 (continued) Individualand GroupMeanRelative OrganWeights Group Animal Relative Relative Relative Relative Relative Relative Relative (Sex) Number Day Bodywt Adrenals Brain Epididys Heart Kidneys Liver Pituitary Number g % % % % % % % 2(M) 25 43 389 0.0225 0.5150 0.4794 0.2950 0.6122 3.3211 0.0037



## --- -- -- --- 26 43 403 0.0188 0.5135 0.3611 0.2244 0.5998 3.0358 0.0031



### - 

## -- -- 27 43 374 0.0168 0.5014 0.3241 0.2945 0.5686 3.0534 0.0038

- 

### -- -- 28 43 349 0.0176 0.5154 0.3469 0.2809 0.5530 3.1298 0.0025

- 

### -- -- 29 43 417 0.0162 0.4825 0.2141 0.2383 0.5567 3.1546 0.0036

- 

### -- -- 30 43 393 0.0243 0.5753 0.4225 0.3348 0.5328 3.1203 0.0026

- 

### -- -- 31 43 358 0.0224 0.5434 0.3930 0.2759 0.6240 3.3859 0.0039

- 

### -- -- 32 43 414 0.0191 0.5076 0.3740 0.3352 0.6119 3.0168 0.0033

- 

## -- -- 33 43 390 0.0205 0.5515 0.3989 0.2482 0.6301 2.9187 0.0032



### - 

## -- 

## -- -- 34 43 404 0.0166 0.5268 0.4113 0.2765 0.5658 3.2104 0.0039

- 

### -- 

## -- 35 43 383 0.0199 0.5909 0.3783 0.2740 0.6227 3.1760 0.0032

- 

### -- 

## -- 36 43 371 0.0255 0.5481 0.4017 0.3042 0.6217 2.9714 0.0032

Dose Levels: Group 1

- 

## o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page280



## Appendix 14 (continued) Individualand GroupMeanRelativeOrganWeights (continued) Group Animal Relative Relative Relative Relative Relative Relative (Sex) Number Day Prostate Sem.Ves. Spleen Testes Thymus Thyroid Number % % % % % % 2(M) 25 43 0.1860 0.5877 0.1859 0.9458 0.0726 0.0062



### --- -- 26 43 0.0995 0.5446 0.1757 0.8913 0.0940 0.0049



### - -- 27 43 0.1820 0.5902 0.1948 0.8722 0.0855 0.0106



### - -- 28 43 0.1397 0.5674 0.1668 0.8794 0.0810 0.0079

- 

### -- - 29 43 0.1142 0.5208 0.2276 0.3489 0.1082 0.0071



### - -- --- 30 43 0.1416 0.2924 0.1914 0.9797 0.1518 0.0084



### - 31 43 0.1569 0.5639 0.1769 0.9979 0.0968 0.0065



### - -- 32 43 0.1958 0.6215 0.1807 0.9496 0.1189 0.0082



### - -- 33 43 0.1844 0.8120 0.1843 0.9741 0.0534 0.0059

- 34 43 0.1580 0.7144 0.2244 1.0522 0.0971 0.0076

- 

### -- 35 43 0.1710 0.6871 0.2249 0.9733 0.0627 0.0088



### - -- 36 43 0.1534 0.7030 0.1702 0.9227 0.1088 0.0081

Dose Levels: Group 1

- o (Control) Group 2

- 50 mg/kg bw/day Group 3

- 250 mg/kg bw/day Group 4

- 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page281



## Appendix 14 (continued) Individualand GroupMeanRelative Organ Weights Group Animal Relative Relative Relative Relative Relative Relative Relative (Sex) Number Day Bodywt Adrenals Brain Epididys Heart Kidneys Liver Pituitary Number g % % % % % % % 3(M) 49 43 348 0.0223 0.6038 0.4074 0.3251 0.6600 3.2559 0.0033



### --- --- 50 43 387 0.0213 0.4914 0.3872 0.2713 0.5748 2.8636 0.0026



### -- --- --- 51 43 393 0.0202 0.5206 0.3890 0.2197 0.6312 3.1009 0.0035



### - -- --- 52 43 440 0.0183 0.4514 0.3882 0.3054 0.5791 2.8775 0.0031



### - -- --- 53 43 424 0.0215 0.4952 0.4277 0.2766 0.5802 2.9369 0.0028



### -- --- --- 54 43 384 0.0188 0.5301 0.3896 0.3012 0.6174 3.0777 0.0031



### - --- 55 43 386 0.0178 0.5312 0.4554 0.2923 0.6211 3.2334 0.0032



### - -- --- 56 43 389 0.0169 0.4979 0.3727 0.2447 0.6265 2.5323 0.0032



### - -- --- 57 43 382 0.0172 0.5139 0.3611 0.2495 0.5615 2.9775 0.0028



### - -- --- --- 58 43 357 0.0196 0.5621 0.3829 0.2794 0.6186 3.4706 0.0032



### - -- --- 59 43 378 0.0189 0.5516 0.3905 0.3060 0.6042 2.7422 0.0026



### - -- --- 60 43 408 0.0227 0.4575 0.3886 0.2633 0.5583 2.7257 0.0030

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan

### StudyNumber: 

### 41205015 Report 

### Page282



## Appendix 14 (continued) Individualand GroupMeanRelativeOrganWeights (continued) Group Animal Relative Relative Relative Relative Relative Relative (Sex) Number Day Prostate Sem.Ves. Spleen Testes Thymus Thyroid Number % % % % % % 3(M) 49 43 0.2042 0.7926 0.2076 1.0697 0.1443 0.0071



### -- -- 50 43 0.1257 0.6702 0.1918 0.8701 0.0853 0.0065

- 

## -- 51 43 0.1291 0.6526 0.1828 0.8793 0.0874 0.0056

- 

## -- 52 43 0.1498 0.5800 0.1719 0.9122 0.0960 0.0057

- 

## -- 53 43 0.1842 0.4752 0.1819 1 .0161 0.1491 0.0051

- 

### -- 54 43 0.1548 0.6216 0.2146 1 .0131 0.0923 0.0072

- 

## -- 55 43 0.1702 0.6287 0.1803 1.0831 0.0741 0.0053



## - -- 56 43 0.1420 0.5781 0.1859 0.9282 0.1147 0.0072

- 

### -- 57 43 0.1205 0.5041 0.1782 0.8530 0.1357 0.0072

- 

### -- 

## --- 58 43 0.1328 0.5081 0.2111 0.9062 0.1096 0.0067



## - -- 59 43 0.1338 0.5209 0.1827 1.0017 0.1305 0.0057

- 

## -- 60 43 0.1293 0.6079 0.1747 0.7888 0.0958 0.0046

Dose Levels: Group 1 - o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page283



## Appendix 14 (continued) Individualand GroupMean Relative OrganWeights Group Animal Relative Relative Relative Relative Relative Relative Relative (Sex) Number Day Bodywt Adrenals Brain Epididys Heart Kidneys Liver Pituitary Number g % % % % % % % 4(M) 73 43 368 0.0215 0.5655 0.4023 0.2958 0.5852 3.0607 0.0034

--- 

### -- --- --- 74 43 365 0.0195 0.5624 0.3955 0.2633 0.6118 3.2563 0.0027



### - --- --- 75 43 383 0.0200 0.5405 0.4081 0.2830 0.5835 3.1486 0.0034



### - -- --- 76 43 366 0.0278 C>".5488 0.4946 0.3550 0.6517 3.3062 0.0030



### - -- --- 77 43 394 0.0150 0.4953 0.3920 0.2639 0.5480 3.0534 0.0031



### - -- --- 78 43 401 0.0218 0.5161 0.3862 0.2561 0.6174 3.2470 0.0034



### - -- --- 79 43 370 0.0196 0.5038 0.3727 0.2555 0.6168 3.2738 0.0029



### - -- --- --- 80 43 401 0.0190 0.5270 0.3868 0.2716 0.6009 3.1102 0.0034



### - -- --- 81 43 370 0.0242 0.5944 0.4482 0.2928 0.6721 3.4405 0.0027



### - -- --- 

### --- 82 43 349 0.0173 0.5937 0.4128 0.3138 0.6032 3.2050 0.0024



### - -- --- --- 83 43 374 0.0214 0.5696 0.4704 0.2970 0.6262 3.2417 0.0029



### - -- --- 84 43 386 0.0209 0.5111 0.3686 0.2731 0.5601 3.1413 0.0025



### Dose Levels: Group 1 - o (Control) Group 2 - 50 

### mg/kg bw/day Group 3 - 250 

### mg/kg bw/day Group 4 - 750 

### mg/kg bw/day

### Harlan StudyNumber: 41205015 Report Page 284



## Appendix 14 (continued) Individualand GroupMeanRelative OrganWeights (continued) Group Animal Relative Relative Relative Relative Relative Relative (Sex) Number Day Prostate Sem.Ves. Spleen Testes Thymus Thyroid Number % % % % % % 4(M) 73 43 0.1480 0.5889 0.1579 1

.0301 0.0858 0.0057



### -- 74 43 0.1514 0.4921 0.1880 0.9360 0.0751 0.0050



### - -- 75 43 0.1273 0.4882 0.2003 1.0313 0.1450 0.0104



### -- 76 43 0.1645 0.4231 0.2200 1.0776 0.1092 0.0054



### - -- 77 43 0.1330 0.4901 0.1873 1.0665 0.1210 0.0072



### - -- --- 78 43 0.1702 0.5884 0.5878 0.9343 0.0926 0.0071



### - -- 79 43 0.1511 0.5240 0.1552 0.8542 0.1258 0.0061



### - -- 80 43 0.1476 0.4662 0.1821 0.8762 0.0846 0.0069



### - -- 81 43 0.1975 0.5767 0.2186 1.0204 0.0768 0.0116



### - 82 43 0.1582 0.5242 0.1811 1.1028 0.1266 0.0072



### - -- 83 43 0.1375 0.5490 0.1748 1.1575 0.1294 0.0083



### - 84 43 0.1428 0.5610 0.1717 0.9740 0.0975 0.0095

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page285



## Appendix 14 (continued) Individualand GroupMean Relative OrganWeights

Group Animal Relative Relative Relative Relative Relative Relative Relative Relative Relative Relative (Sex) Number Day Bodywt Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Thyroid Number g % % % % % % % % % % 1 (F) 13 43 259 0.0312 0.7936 0.2972 0.5921 4. 1121 0.0445 0.0071 0.2625 0.0913 0.0092



### --- -- --- 14 43 247 0.0313 0.7922 0.3282 0.6256 3.6239 0.0496 0.0064 0.2489 0.0622 0.0069

- 

### -- --- 15 43 238 0.0385 0.7771 0.4025 0.6647 3.2664 0.0450 0.0061 0.2286 0.1763 0.0084

- 

### -- --- 16 45 267 0.0343 0.7307 0.3058 0.5157 3.8072 0.0451 0.0067 0.2461 0.1070 0.0072

- 

### --- 17 42 257 0.0446 0.7622 0.3666 0.6267 4.1253 0.0455 0.0072 0.2143 0.1054 0.0085

- 

### -- --- 18 45 288 0.0297 0.6167 0.2522 0.5965 3.6636 0.0443 0.0063 0.2542 0.0557 0.0088



### -- --- 19 45 272 0.0328 0.7128 0.2981 0.5735 4.0577 0.0348 0.0037 0.2866 0.1195 0.0086

- 

### --- --- 20 42 271 0.0306 0.7154 0.3191 0.5915 3.7421 0.0472 0.0054 0.2028 0.1032 0.0085



### - -- --- 21 43 254 0.0389 0.6858 0.2529 0.5843 3.5509 0.0482 0.0054 0.2780 0.0650 0.0089



### - -- --- 

### --- 22 44 270 0.0332 0.6639 0.3291 0.5851 3.7688 0.0422 0.0067 0.2389 0.0986 0.0105



### - -- --- 23 44 254 0.0396 0.7564 0.3293 0.5842 4.5260 0.0456 0.0060 0.2617 0.1123 0.0106



### - -- --- 24 45 243 0.0354 0.7753 0.2789 0.6676 3.9872 0.0461 0.0056 0.2858 0.0607 0.0100

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 

### Report Page286



## Appendix 14 (continued) Individualand GroupMean Relative OrganWeights

Group Animal Relative Relative Relative Relative Relative Relative Relative Relative Relative Relative (Sex) Number Day Bodywt Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Thyroid Number g % % % % % % % % % % 2(F) 37 44 259 0.0313 0.7314 0.3213 0.6283 3.8171 0.0387 0.0039 0.2581 0.0645 0.0117

--- 

### -- --- 38 45 270 0.0329 0.6754 0.2685 0.6006 4.0217 0.0443 0.0075 0.2815 0.0776 0.0076



### - -- --- 39 43 246 0.0320 0.7691 0.3274 0.6755 3.2579 0.0420 0.0065 0.2443 0.1485 0.0116



### - -- --- 40 43 261 0.0436 0.7707 0.3260 0.5879 3.8800 0.0447 0.0075 0.2803 0.1105 0.0103



### - -- --- --- 41 42 251 0.0337 0.7841 0.3036 0.6041 3.7972 0.0624 0.0075 0.2485 0.1522 0.0101



### - -- 42 42 232 0.0305 0.7910 0.3393 0.6232 4.0184 0.0545 0.0077 0.2299 0.0604 0.0142



### - -- --- 

### -- 43 45 269 0.0334 0.7184 0.3153 0.6058 4.1277 0.0506 0.0069 0.2762 0.0845 0.0081



### -- --- --- 44 45 310 0.0347 0.5989 0.2591 0.5869 4.1464 0.0455 0.0055 0.2932 0.0958 0.0104



### - -- --- 45 43 296 0.0368 0.6637 0.3179 0.5853 4.0228 0.0439 0.0064 0.1990 0.0656 0.0124



### -- --- 46 43 280 0.0361 0.6941 0.2920 0.5846 4.1166 0.0534 0.0079 0.2020 0.0878 0.0084



### - -- --- 47 44 243 0.0263 0.7647 0.4312 0.6382 3.1482 0.0538 0.0066 0.2117 0.1871 0.0129



### - -- --- 48 44 258 0.0394 0.7763 0.3560 0.6186 3.8769 0.0427 0.0061 0.2570 0.0750 0.0104

Dose Levels: Group 1 - 

### o (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page 287



## Appendix 14 (continued) Individualand GroupMean Relative OrganWeights

Group Animal Relative Relative Relative Relative Relative Relative Relative Relative Relative Relative (Sex) Number Day Bodywt Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Thyroid Number g % % % % % % % % % % 3(F) 61 44 262 0.0276 0.7522 0.3390 0.5885 3.8888 0.0424 0.0058 0. 1811 0.0807 0.0097



### --- -- --- -- 62 46 272 0.0351 0.7357 0.3226 0.6690 4.7188 0.0645 0.0067 0.2860 0.0968 0.0090



### - -- --- -- 63 43 264 0.0270 0.7082 0.2676 0.5623 3.8223 0.0363 0.0048 0.2049 0.0715 0.0089



### - -- --- 64 44 251 0.0353 0.8235 0.4135 0.5957 4.3800 0.0522 0.0070 0.3083 0.0778 0.0056



### - -- --- 65 44 247 0.0332 0.7579 0.3367 0.6283 4.1392 0.0424 0.0064 0.2244 0.1166 0.0082



### - -- --- 66 42 250 0.0384 0.6974 0.3515 0.6319 4.2846 0.0410 0.0067 0.2444 0.0610 0.0080



### -- 67 45 285 0.0356 0.6691 0.2857 0.5853 4.4007 0.0467 0.0057 0.2268 0.1029 0.0083



### - --- 68 42 250 0.0281 0.6855 0.2592 0.5620 3.8856 0.0338 0.0062 0.2027 0.0615 0.0080



### - --- 69 44 250 0.0502 0.7413 0.3408 0.6072 4.6013 0.0648 0.0060 0.2457 0.0694 0.0071



### - -- --- 70 43 264 0.0306 0.6966 0.3058 0.6343 3.7622 0.0462 0.0073 0.1728 0.0716 0.0101



### - -- --- 71 44 287 0.0223 0.6678 0.2980 0.6239 4.0365 0.0443 0.0061 0.2341 0.1178 0.0062



### - -- --- - 72 46 270 0.0321 0.7277 0.3174 0.5994 3.9786 0.0456 0.0061 0.2269 0.0771 0.0092

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### Harlan StudyNumber: 

### 41205015 Report Page288



## Appendix 14 (continued) Individualand GroupMean Relative OrganWeights

Group Animal Relative Relative Relative Relative Relative Relative Relative Relative Relative Relative (Sex) Number Day Bodywt Adrenals Brain Heart Kidneys Liver Ovaries Pituitary Spleen Thymus Thyroid Number g % % % % % % % % % % 4(F) 85 42 271 0.0349 0.6558 0.3962 0.6562 3.9727 0.0464 0.0056 0.2739 0.0782 0.0123



### --- -- --- 86 44 279 0.0381 0.6749 0.3696 0.5832 4.4968 0.0549 0.0047 0.2533 0.1152 0.0079



### - --- 87 42 227 0.0270 0.7904 0.2821 0.7124 3.5475 0.0401 0.0046 0.2699 0.1383 0.0092



### - -- --- 88 42 253 0.0303 0.6749 0.2820 0.5741 4.1177 0.0390 0.0062 0.2177 0.0728 0.0117



### - -- --- 89 43 256 0.0383 0.7139 0.3033 0.5725 4.2957 0.0465 0.0056 0.2501 0.0838 0.0113



### - -- --- 90 54 293 0.0312 0.5999 0.3292 0.5209 4.6527 0.0435 0.0048 0.2661 0.0578 0.0043



### -- --- 91 44 267 0.0309 0.6992 0.3399 0.5886 4.7798 0.0490 0.0050 0.2356 0.1411 0.0094



### -- 92 42 270 0.0384 0.7187 0.3665 0.6225 4.4646 0.0396 0.0063 0.2313 0.0978 0.0103



### - -- --- 93 53 274 0.0306 0.6196 0.3459 0.6045 4.1049 0.0407 0.0056 0.2526 0.0647 0.0050



### -- 94 42 284 0.0362 0.6656 0.2861 0.6325 4.3401 0.0481 0.0052 0.2348 0.0896 0.0110



### - -- --- 95 45 239 0.0371 0.7955 0.3192 0.6123 4.2801 0.0385 0.0050 0.2265 0.0894 0.0082



### - -- --- 96 43 261 0.0286 0.7155 0.2626 0.5909 4.0795 0.0456 0.0059 0.2548 0.0662 0.0136

Dose Levels: Group 1 - O (Control) Group 2 - 50 mg/kg bw/day Group 3 - 250 mg/kg bw/day Group 4 - 750 mg/kg bw/day

### HarlanStudyNumber: 41205015 Report



## Appendix 15 HistopathologyPhaseReport

PATHOLOGYPHASEREPORT

TestFacilityStudy

### No.:41215015 TestSite

### ReferenceNo.: 155-023 Page289



### PMDAH\:1>R.OL\:'ZEDTOP~IA: ORAL (GAVAGE)

### COMBINED REPR.ODUCTIONJDE\"ELOPMEl\"TALTOXICITYSCREL"«NGTESTINTHERAT (OECD421)



### P.M.Milar

11115

### Harlan StudyNumber: 41205015 Report



## Appendix 15 (continued) HistopathologyPhaseReport 

## PATHOLOGYPHASEREPORT

Test flllitDHy Study

### No.:41205815 

### TestSheReferenceNo.: 155-W Page290

PMDAHYDROLYZEDTOPMA:ORAL(GAV AGE)COMBINED 

### REPRODUCTION/DEVELOPMENTALTOXICITYSCREENINGTESTINTHERAT(OECD4ll)


## GLPCOMPUANCESTATBMENT

I. the undersigned. declare that 

### this histopalhology repon contribution 

### consdnnes a 

### true record

### of

### theactions undertaken and die results obtained in the 

### above 

## stUdy. I

### accept re.spoulbility for die validity ofthe da!a

## am oontinn that 

### this -,ectofthe stud)I was 

### conducted in compliance wilh 

### Good Laboratory Practice (GLP) as 

### required by 

### the United Kingdom OLP Regulations 1999 (SI 1999

### No. 3l06)whichare ht accordanc:e 

### with the o,ganisation ofEconmnic Co-operation and Deveklpment (OECD) Principles ofGood Laboratory Practice (1982

### andsubsequentrevisions).



### P.M.MIU.AR8.V.M.S.,M.V.M.•

### M.R.C.V.S••Dlplom1teA.C.V.P. {Principal 

### Investigator

- Histopathology)

21115

### Harlan StudyNumber: 41205015 Report



## Appendix 15 (continued) HistopathologyPhaseReport PATHOLOGY PHASE REPORT



### TestFaelUtyStudy

### No.:41285015 THf

### Site

### Reftff1m1 No.: 155-023 Page291



### PMDA HYDROLYZEDTOPMA:ORAL

### (GAVA~E)COMBINED REPRODUCTION/DEVELOPMENTALTOXICITY SCREENINGTESTIN THERAT(OECD421)


### QUALITYASSURANCESTATEMENT

I

## cm1nrmchat 1lliis 

### repon gives an accume a«ollfll

### of

### 1bc 

### methods used, 

### alkl the 

### rcponed results accurately 

### reflectthe ,aw

### data. 

### Thedatesmt

### whichvarious

### phases of

### lhe study wen: 

### inspectedand on which reports

### ofthese 

### inspcclion.s were 

### submitted 10

### lhepathorogist,

### wereasfollows:

Date

### Inspected Dale

### Reported DateReponed loPJ to

### Study Director 

### Rel'iew ofStudy

### Plan& Amendmenl5 

### 08103120EJ 08l03120l3 

### 23!0812013 ReviewofStudy

### Docwnents 

### 23/08l20.3 23J08/2013 U/0812013 Revic,,v

### ofDraft

### Report 23/08/2013 

### 23/fl8/2013 231tl8f2013 Reviewof

### Final

### Repon 23/08l2013 

### 23/08/2013 23/08l2013



### Pn.:icessMdfacility based inspections

### arc performed

### atregularincervaJs(everythree

### monlhsand six monshs. n:spcctively)incompliancewidlStandardOperatingProcedure(SOP8).Thefindings ofthoseinspectionsand


### meresponses of

### the

### Principal Jnvestigaklr

### (TestSiteManagement)arean:hivcd.The

# msaprocess-based inspection(slid&M':cadins:.slidelabeling.receiptof

### materials,datatransfercheck)wascarriedouton I &h 

### August2013.

TheStudy

### Di.ectorwu

### advikd ina 

### timelymonnetof

### any signirlCIWfindings

### f'or 1he

### wmtconductedatthis ·restSile

### datmishthave

### affeaedthe

### OLPcomplianceofthe

### study.

# ~~

# ......~~.t~l1~

JANELAWRENCEB.Sc.,Ph.D. (Quality

### Assurance Inspector)

J/115

### HarlanStudyNumber: 41205015 Report



## Appendix 15 (continued) HistopathologyPhaseReport
TestFadlbySmd.yNe.41205015 TestSileRefRmftNo.155-023 PMDA.llydnlyzedtoPMA.:Oral(Ga-ce)R.eprodndioa.lDevelopmeomlTtnidtyScreeningTestinthe Rat(OECD421)

CONTENTS

SUMMARY&:CONCLUSION
INTRODUcnON
STUDYDESIGN
MATERIALS
METHODS
RESULTS

TABLES



### TableI
Table2 His1:opatboloay

### SmyIDcicleoce
lndiulualAnimalPathologyFindings 

### 5
5
6
7 8
8

10 

### 20

41115

### Page292

### Harlan StudyNumber: 41205015 Report



## Appendix 15 (continued) HistopathologyPhaseReport

TestFadluyStwlyNo.41205015 TestSiteReferaceNo.155-823 Pl-IDAhydrelyzedtoPt.IA:Oral(Gavage)Reprodudio11.IDevelopmentalToxicitySn-eeoiagTestintire Rat{OECD421}

SUMMARY& CONCLUSION

The oral (gavage) adminismti.on ofPyromellitic dianb.ydride (PMDAhydmlyzedtoPMA) to HanWistarnts fur at least twenty-eight days at dosages of 50, 250 or 750 mg/kg bw/day produced no treatment-related !Justcpatboloeicalfimtings.

All of the :lmtlopathologicall fiodiings encountmed were considered to have arisen spontanecmslly or at post modem.

INTRODUCTION



### Three

### groupsof12maleand 

### 12femaJe

### HaoWistarrats

### wereadministeredPMDAhydrolyzedto

### P.MA,byoral 

### gavage,atdosages

### of50, 250

### or750 mg/kg

### bw/day. Animalswere

### treated,

### oncedaily,for

### up

### toeightweeks, starting

### fourteendays

### prior

### topairingand

## comummgthroughoutthe

### matingperiod.

### gestationand

### lactation.A 

### similarlycoostimkdgroup\V3S

### gi'Vell

### vebicl.ealoneandserved

### topro,.>idecontrol

### data.

### Attheend

### ofthe 

### treatmentperiod(Day

### 43foe

### malesandDay

### 5post-partumfor

### females) allthe 

### animals

### wereeuth.aniza:l 

### hnmanelyandsubjected

### toafull

### necropsyexammatioawith

### specialattentionpaid

### tothe

### reproductiveorgans. Thetisn.es

### of

### five males

### and

### .fivefemaleswere

### processedand

### exami:nf.ld

### mstologically, in

### accordancewith 

### procedures laiddown

### inthe

### study

## pmamlamendments.

Thisreportcontaimdie.resu1ts of1lbepathologicaJI a.aminatimlofallanimals ass,ecifiedinthe studyplanand amelldmeuts.

51115 

### Page293

### HarlanStudyNumber: 41205015



## Appendix 15 (continued)

TestFad&lyStudyNo.41205815 TestSiteReferenceNo.ISS-Ol.l 

### Report



## HistopathologyPhaseReport

RIDAbydnlyzedtoPMA: Oral(Gavage)ReprodudionlDevelopmeotalTou:itySaeeoiugTestinthe Rat(OECD411)

STUDYDESIGN
ExperimentalDeri,:n Thedosagele,,elsuedland1lhe

## mmmerofamm.alspergroupwereasfoDows:

Group l l 3 4

Dosa~ 0 50 250 750 mglkabwlday M.aleAnimal 1-12 25-36 49..(j() 73-84

Numbers

FemaleAnimal 13-24 37-48 61-72 85-96 Numbea

Thefollowme;bSS'lleSwere

### ez.ammedfromthefirstfivelDillesofthecontco]andhighestdosagegroups,and fromthefirstfivefemalesinthese gronpstureara &ImtoDay

### 5post-panum:


### All Gron Lesions, Adrentil Gla:11.ds, Bram (Cerebral & Cerebellllffl & Medulla/Pons), 

### Caecum, Colon. Dttoda111m, Epiditfymides, Heart, llemn, Jejunum. Kidney'S, Liver • .Lun&s (+ Bronchi). Lymph Notks (Mandibular&: Mesmtenc), Manamary Gland, Owuies, Paradrpoid Gland, Prostate 

### Gland, Pituitary 

### Gland. Recmm, Sciatic Nerve, Seminal Vesicles (witll Coqulalil'l& Glands), Spinal Cmd (Cervical, Lumbar & 

### 17aarv.tctej, Spleen, Stomach, Te,stes, Tlaymm, Thyroid Glands, Trachea. Urmary Bladder, Uterus, Uterine Cenu. 

### Vqma. 

### ~realeuminationwas alsoeaniedoat mi1lhefollowingtissuesImmthe DITTP1ining 

### mam study animals ofthe COEl'Ol and highr.st dosage groups, imemle males

## am al females that did not give birth: All Gross 

### Lesi-.s, Epididymides, CoaguJamrg Glands. Mammary Gland, Ovaries, Pituitary Gland. Prostate Gland, Semmal Venf'les, Te.i:tes, lltena, Uterine Cenitt:and Vagina.



### 61115 

### Page 294