**,....""~** () \......; '_._" 

### Table 16-4 Hematology of female rats 

### treated orally with for 28 

### days

- 14-day of recovery ­ Group-No. Dose

.(mg/kg)

..................... 

### 00 Control

### o 01 Vehicle

### 0 04 1000 MCH--.-" MCHC**~th:UlDcyte** 

### Pla-hlet (pg) 

## ( s ) (%0) (x1 0 4 /**~l)** 3 5 5 

### 5 

### 19.9 35.0 13 

### 115.8 0.5 0.4 3 

### 9.9 5 5 5 5 19.9 34.7 17 

### 104.1 0.6 0.4 5 9.5 5 5 5 5 

### 20.3 35.0 16 81.0

. 1.0 0.7 4 40.2 N 

### Mean S.D.­ N Mean S.D. N Mean S. O. -Rer**(xl04/~L)**

........_.__...............................­ 5 

### 823

53

5 804



### 25

5 803

49 

### Ht (S) 

### 5 46.6

2.1 5 46.3

2.0 5 46.5

1.5 Hb (g/dL) 5 

### 16.3

1.

### 0 5 16.0

0.8 5 16.3 0.4 MeV (fL) 5 

### 56.1

1.

### 0



### 5 51.5

1. 1 5 58.0

1.9

-'" If: No.

### of animals ..J 

### PROJECT 

### No.



# o o o N**~** 

### -J 

# -t**~**

### TabIe 

### 16';'5 Hematology of female rats treated orally with 

### 'or 28 days

- 14-day of recovery ­ Group-No. PT APTT WBe 0

### i

### fferentfiT 

### count 11) 

### Dose (mg/kg) 

### 00 

### Control0 N 

### Mean S.O. 

### ( sec.)5 15.6

1.0 ( sec.)5 

### 18.3

1.2 (x

### 1 ot/**~L)** 

### 5 

### 54

. 10 lympho

## 5 84.5



### 5.0 Eosino 5 

### 1.6 0.8 

### .Mono 5 4.7 2.9 Baso 

### 5 0.0 0.0 Stab 5 

### 0.3 0.4 01 

### Vehicle0 N 

### Mean S.

### D. 5 15.'3 0.3 5 

### 18.0

1.9 

### 5 67 

### 21 5 

### 80.4

6.8 5 2.0 1.2 5 4.8 2.3 5 

### 0.0 0.0 5 

### 0.4 0.4 04 1000 N 

### Mean S.D. 5 15.0 0.4 5 18.5

1.1 5 68 18 5 87.9

5.4 5 0.6* 0.4 5 5.5 3.3 5 

### 0.0 0.0 5 O. 

### 1 0.2
.r;. 00 

### Group-No. Dose (mg/kg) 

### 00 Control0 N 

### Mean 

### S.D. Seg 5 

### 8.9 

### 2.6 01 

### Vehicle0 N 

### Mean 

### S.D. 5 

### 12.5 

### 6.6 OA 1000 N 

### Mean S.D. 5 

### 5.9 

### 4.7 

### N : No.of animals**~** 

## *: Significantly different from control, p(0.05 

# o N PROJECT 

### No. 

## o



# .t\**~** .r'''' 

### r--.
, ) '........,.t 

### 00-...:..**'~ I~**  \,-) 

### Table 17-1 Blood biochemistry of male rats treated orally with 

### for 28 

### days

- 28-day of treatment

­ Group-No. AST 

### ALT r-GTP ALP thE 

### Total Total Triglyceride Dose bilirubin cholesterol (mg/kg) ( lUll ) ( lUlL) ( lUll) ( lUll) ( lUll) 

### (mg/dL) (mg/dL) (mg/dl) 00 N 5 5 

### 5 5 5 5 5 5 

### Control Mean 98 32 0.09 447 392 0.02 44.9 46.0 0 S.D. 21 5 O. 

### 15 137 25 0.02 5.4 5.2 01 N 5 

### 5 

### 5 5 

### 5 5 5 

### 5 Vehicle Mean 

### 91 41 O. 

### 16 

### 420 444 0.03 51.

### 2 58.7 0 S. D. 

### 14 26 0.22 92 91 0.01 7.8 18.2 02 N 5 

### 5 5 5 

### 5 5 5 5 Mean 104 34 0.03 383 438 0.03 58.6

# * 69.7 10 S.D. 9 3 

### 0.06 47 76 0.01 11.0 28.4

.;.. \0**O~** N 5 5 

### 5 5 5 

### 5 5 5 Mean 115 30 0.37 418

- 396 0.03 43.7 30.6 100 S.D. 11 

### 4 0.46 88 44 0.01 7.8 10.0 04 N 5 

### 5 5 5 5 5 5 5 Mean 111 31 0.08 417 

### 440 0.02 56.7 55.9 1000**S.~.** 

### 8 3 0.15 48 87 0.01 6. 1 18.9 N : 

### No.of animals 

# *: Significantly different from control, p(0.05
PROJECT No.



# o o 

# o N \.0 \.0

# ~

### Table 17-2 Blood biochemistry of male rats treated orally with: for 28 days

- 28-dal of treatment

­ Group';;'No. BUN Creatinine Glucose Total AI6umin 

### A/G Ca Inorganic Dose protein phosphorus (mg/kg) (lIg/dl) 

### " " 

### (mg/dl) (mg/dl) ( g/dl ) ( g/dl ) (ratio) (mg/dl) (mg/dl) 00 N 

### 5 5 5 

### 5 5 5 5 

### 5 

### Control Mean 13. 1 0.23 146.3 5.8 4.5 3.6

. 10.0 8.6 0 S.D. 

### 0.5 0.02 21.0 0.2 O. 1 0.6 0.4 0.4 01 N 

### 5 S 

### 5 5 5 5 5 5 

### Vehicle Mean 14

..2 0.23 150.6 5.6 4.3 3.6 10.0 8.5 0 S.D

.. 

### 1.6 0.02 17.2 O. 1 0.2 .0.8 0.3 0.2 02 N 

### 5 5 5 5 5 5 

### 5 5 Mean 

### 12.9 0.22 148.8 5.7 4.4 

### 3.3 10.0 8.8 10 S.D. 

### 0.8 0.03 18.5 0.2 0.2 O.7 0.2 0.4

\J\ 0 

### 03 N 5 5 

### 5 5 5 

### 5 5 5 

### Mean 11.5 0.24 127.6 5.5 4.3 3.6 9.7 8.5 100 S.D. 

### 1.6 0.03 6.5 O. 1 0.2 O.7 O. 1 

### 0.5 Od 

### N 5 5 5 5 5 5 5 

### 5 Mean 14. 1 0.23 150.9 5.8 4.5 3.7 10.2 8.5 1000 S.D. 

### 1.5 0.02 24. 1 0.2 O. 1 0.9 0.3 0.5 N : No.of animals
PROJECT No.



# o o 

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# o 

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# '­

### Table 17-3 Group-No. Dose (me/kg) 

### 00 N 

### Control Mean 0 S.D. 01 N 

### Vehicle 

### Mean 0 S.D. 02 N 

### Mean 10 S.D.
V\ 

### 03 N



### .... Mean 100 S.D. p' N 

### Mean 1000 S.D. N : No.of animals



# o o o GJ 

# o


# ... r"'­ ' ; \.."/ 

# 0
Blood biochemistry of male rats treated orally with for 28 days

- 28-day of treatment

- Na K 

### CI (mEq/L) (mEQ!L) (IIIEQ!L) 5 

### 5 143.4 4.39

0.4 0.39 5 5 

### 143.2 4.60

\,4 0.30

5 5 142.2 

### 4.79

1. 1 0.30

5 5 

### 143. 1 4.64

0.6 0.37 5 5 

### 142.9 4.79 1.9 0.19 -S 

### 107.3 1.2

5 

### 107.5

0.9 5 105.9

2. 1 5 

### 107.8

0.9 5 

### 106.4 1.9

PROJECT No.'



# b

## o o o c:.J 

## o N

# ~ ,1'

......'

.... /.,....\
i •••J,,"

.... ,,-) 

### Table 17-5 Blood biochemistry of male rats treated orally with' for 28 

### days

- 14-day of recovery ­ Group-No. BUN- --Creatinine Glucose Total Dose protein (mg/kg) 

### (mg/dL) (mg/dL) (mg!dl) ( g/dl ) 

### 00 N 

### 5 5 5, 5 

### Control Mean 16.3 0.25 128.3 5.8 

## o S. D. 

### 1.1 0.02 6.5 O. 1 

### 01 N 

### 5 5 

### 5 5 

### Vehicle Mean 13.·8

# * 0.24 133.5 5.8 

## o S.D. 1.3 0.02 17.0 

### O. 1 

### 04 N 5 5 5 5 

### Mean 13.9

# * 0.22 147.4

# * 5.8 

### 1000 S.D. .1.7 

### 0.02 11.0 0.2 

### N : No.of an ma s U\ W i 

### Significantly different from control, p(O.OS 

## i* : Significantly different from control, p(O.Ol



# o o o CJ 

# o CJ Albumin ( C/dL )5 

### 4.3 O. 1 

### 5 4.6** O. 1 5 

### 4.6** O. t 

### -xlG (rati0)5 

### 3.0 0.3 5 

### 3.7 0.6 5 

### 3.9** 0.3 

### Ca (mg/dl)5 

### 9.7 0.2 5 

### 9.7 0.2 5 

### 9.8 

### 0.2 

### norcan 

### c phosphorus

(mg/dl)5 

### 7.5 0.4 5 

### 7.3 0.6 5 

### 7.0 0.8

PROJECT No.

# ~

### Table 17-6 Blood biochemistry of male rats treated orally with for 28 days

. - 14-day of recovery ­
<-_......_..­ 

### Group-No. Dose (la/kg) 

### 00 

### Control0 N Mean S.D. 01 Vehicle0 N 

### Mean 

### S.D. OA 1000**~** 

### -Mean S.D. Na K CI (mEq/L) :'(mEq/l) (mEq/l) 5 

### 5 

### 144.3 4.80 1.8 O. t

### 4

5 5 

### 143•.g 

### 4.79 1.2 

### 0.43

5 5 144.2 

### 4.58

1.3 0.31 5 

### 108.6 1.5

5 

### 107.5 1.4

5 

### 108.2 1.8 N : No.of animals 1.1\ 

# "" PROJECT No



# o o o CJ 

## o**~** 

## (')

# ~

< • ...,; "".'".' r···'. 

### h

'...•..."'" 

### \.J 

### TabI

### e 18-1 Blood biochemistry of female rats treated orally with for 28 days



### - 28-day of treatment

­ Group-No. 

### AST All r-GTP ALP ChE 

### Total Total Trighceride Dose bilirubin cholesterol (lIi/kg) ( lUll ) 

### t lUll) ( lUlL) 

### ( lUlL) ( lUll) (lIg/dL) (lIIg/dL) (lIg/dL) 00 N 

### 5 5 5 5 

### 5 

### 5 5 5 

### Control Mean 108 22 0.43 227 1885 0.05 62.2 13.5 

### 0 S.D. 

### 23 5 

### 0.33 32 324 0.02 6.6 2.9 01 N 

### 5 5 

### 5 5 5 5 5 

### 5 Vehicle Mean 1Hi 25 0.27 215 2363 0.06 57.7 11.7 

### 0 S.D. 

### 25 7 0.24 73 1189 0.03 

### 4.6 2. 1 02 N 5 

### 5 5 

### 5 5 5 5 

### 5 Mean 125 24 0.17 291 2523 0.06 62.2 12.6 

### 10 S. O. 

### 34 3 

### 0.24 39 739 0.01 13. 1 2. 1

VI VI**O~** N 

### 5 5 5 5 5 5 5 

### 5 .Aean 117 25 0.33 301 1644 0.06 69.5 10.2 100 S.D. 28 3 0.40 77 

### 454 0.00 lS.2 2.3 04 N 

### 5 5 

### 5 5 5 5 5 5 Mean 102 25 0.38 257 2222 0.05 63.3 8. 1

# ** 1000 S.D. 25 5 0.37 51 840 0.02 4.2 1.4 

### N : No.of animals 

# ** :Significantly different from control. p(O.Ol
PROJECT No.



## o 

## o CJ 

## o CJ1

# ~ c

# -- . --
. .

-, 

### Table 18-2 Blood biochemistry of female rats treated orally with: for 28 days

- 28-day of treatment

­ Group-No. 

### BUN Creatinine Glucose Total Albumin 

## AlG Ca Inorganic Dose protein phosphorus (mg/kg) (mg/dL) '(mg/dL) (mg/dL) ( g/dL ) ( g/dL ) (ratio) (mg/dL) (mg/dl) 00 N 5 5 5 

### 5 5 

### 5 5 5 Control Mean 12.5 0.24 143.9 6.0 5.0 5.2 9.8 7.8 0 S.D. 

### 1.6 0.01 31.3 0.2 0.3 0.6 0.3 0.3 01 N 5 

### 5 5 

### 5 5 5 5 5 Vehicle Mean 

### 11.·2 0.23 124.9 6. 1 5.0 4.8 9.8 7.5 0 S.D. 

### 1.5 

### 0.02 22.9 0.3 0.3 0.8 0.3 0.5 02 N 

### 5 5 5 5 

### 5 5 5 5 Mean 14.0 0.25 128.0 6.0 5.0 5.2 9.7 7.7 10 S.D. 

### 1.6 0.02 14.2 0.2 0.2 0.6 0.2 0.4

U\ 

### 03 N 5 

### 5 5 5 5 5 5 

### 5 0'1 

### Mean 13. 1 0.23 122.8 6.0 4.9 4.6 9.8 7.9 100 S.D. 

### 1.1 0.01 24.2 0.3 0.2 1.1 0.2 0.9 

### nA N 5 5 5 5 

### . 5 5 5 5 Mean 12.6 0.24 123.8 6.2 5.3 5.4 10. 1 8.2 1000 S.D. 1.7 

### 0.02 14.2 0.4 0.4 0.6 0.5 1.2 N : No.of animals
PROJECT No.

(....,; 

# - o 

# o Col 

# o (1) ,.-...,

# ~**:~,_,., .',~** **/'~'. .~**  

### 'V


### Table 18-3 Blood biochemistry of female rats treated orally with. for 28 days

- 28-day of treatment

­ Group-No. Na K CI 

### Dose (mg/kg) (mEQ/l)**·~(mEQ/l)** 

### (mEQIL) 00 N 

### 5 5 5 

### Control Mean 143.0 4.57 108.8 0 S.D. 1.0 

### 0.49 0.8 01 N 

### 5 5 

### 5 Vehicle Mean 142:3 4.50 IDS. 1 0 S.D. 

### 0.4 0.39 1.4 02 N 5 5 5 

### Mean 142.8 4.73 108.7 10 S.D. 

### 1.3 

### O.28 0.8

VI 5 N 

### 5 -..J 

### 03 5 

### Mean 143.4 4.59 109.2 100 S.D. 

### 1.4 0.28 1.4**O~** N 5 

### 5 5 

### Mean 143.9 4.95 108.7 1000 S.D. 2.7 1. 36 1.0 

### N : No.of animals
PROJECT No.



# o o o Co.) 

## o 4IJ

# ~:·1"

Table 

### 18-4 

### Blood**bioche~istry** 

### of female rats treated orally with for 28 

### days

- 14-day of recovery ­ Group

.....No. AST----- ALT--- r-GTP --ALP -------ChE

- Total-Total-Triglyceride Dose bilirubin 

### cholesterol (llig/kg) ( lUll 

### )t IU/L ) ( lUll) ( lUll ) ( lUll) (mg/dL) (mg/dL) (mg/dL) 

### 00 N 

### 5 5 5 5 55 5 

### 5 Control Mean 

### 114 21 2.08 206 2350 0.01 66.0 11.4 0 S.D. 

### 10 6 0.33 41 556 0.01 10.2 1.5 01 N 5 

### 5 5 5 5 5 5 5 Vehicle 

### Mean HI 

### 25 2.26 188 2231

. 0.08 51.9 11.9 0 S.D. 

### 24 5 0.32 30 402 0.01 2.9 5.5 04 N 5 5 

### 5 5 5 5 5 5 Mean 95 28 

### 2.28 115

.2505 0.08 67.3 14.5 1000 S.D. 

### 26 4 0.58 37 125 0.02 11.4 8. 1 N-: No.of**ani~als** VI QO PROJECT No.



# o o o c.J 

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Table 18-5 Blood biochemistry of female rats treated orally with for 28 days

- 14-day of recovery ­ Group-No.**BU~** 

### Creatinine Glucose Total Albumin -f../fJ. Ca 

### Inorgan c 

### Dose . protein phosphorus (mg/kg) (mg/dO :img/dl) (mg/dl) ( g/dl ) ( g/dl ) 

### (ratio) (mg/dl) (mg/dl) 

### 00 N 5 5 5 5 • 5 5 

### 5 

### 5 Control 

### Mean 15.3 0.26 126.7 6.4 5.2 4.4 9.9 

### 6.7 0 S.D. 

### 2.0 0.01 8. 1 O. 3 

### 0.2 0.6 0.5 0.6 01 N 5 

### 5 5 

### 5 5 5 5 5 Vehicle Mean 15:4 0.28 135.3 6. 1 S. 

### 1 5.3 9.9 6.4 0 S.D. 

### 1.8 0.02 15.9 0.3 0.4 1.7 

### 0.3 0.6 04 N 5 

### 5 5 5 5 5 5 5 

### Mean 14.6 0.26 127.2 6.4 5.3 5.5 9.8 6.7 

### 1000 S.D. 

### 1.0 0.04 15.7 O. 1 

### 0.3 2.4 O. t 

### 1.1 N : 

### No.of animals VI \Q 

### PROJECT No.



# o o o C.J 

# o <.D**~** 

# -.....

### Table 18-6 Blood biochemistry of female rats treated orally with :or 28 days

- 14-day of recovery ­ Group-No. Na K CI 

### Dose (mg/kg) (mEQ/l) c{mEQ/l) (mEQ/l) 

## 00 N 5 5 5 

### Control Mean 143.2 4.52 109.7 0 S.D. 

### 1.3 0.37 1.3 01 N 5 5 5 

### Vehicle Mean 144.·3 4.38 110.6 0 S.D. 

### 1.1 0.27 0.9 04 N 

### 5 5 5 

### Mean 143.8 4.28 110.4 1000 S.D. 

### 1.1 0.55 1.5 

### N : No.of animals 0\ <:> PROJECT No.



# o o o Co.) 

# .. o 

# o N 

# "

"---'

### (''\ "-.../ 

### Table 19-1 Absolute Jnd relative organ weights of male rats treated orally with for 28 days.

- 28-day ef treatment

­ Group-No. 00 01 

### O? 03 04 Dose Centrol Vehicle (milki) 

### 0 0 10 100 1000 Final N 

### 5 5 5 5 

### 5 body weight (g) 

### 388 

### ± 22 395 

### ± 11 

### 374 

### ± 33 362 

### ± 22 374 

### ± 13 Brain N 

### 5 5 5 5 5 (g) 

### 2.13 

### ± O. 11 2. 15 

### ± 0.07 2.09 

### ± 0.07 2.10 

### ± 0.05 2. 11 

### ± 0.04 Re I. 

### 0.55 

### ± 0.03 0.54 

### ± 0.01 0.56 

### ± 0.04 0.58 

### ± 0.03 0.57 

### ± 0.02 liver N 

### 5 5 5 5 5 (g) 

### 12.26 

### ± 0.77 11.95 

### ± 0.74 11.53 

### ± 1.

### 45 10.43 

### ± 0.83 11.59 

### ± 1.45 Re I. 

### 3.16 

### ± 

## o. 1'6 3.03 

### ± 0.15 3.08 

## ± O. 14 2.88 

### ± 0.09 3.09 

## ± 0.32

..... 0\ 

### Spleen N 

### 5 5 5 5 

### 5 (mg) 

### 727 

### ± 83 723 

### ± 85 760 

### ± 74 768 

### ± 93 707 

### ± 78 Re I. 

### 187 

### ± 12 183 

### ± 23 203 

### ± 12 212 

### ± 25 189 

## ± 17 

### Kidney(R) N 5 

### 5 5 5 5 (g) 

### 1.42 

### ± 0.09 1.44 

### ± 0.05 1.37 

### ± 0.15 1.

### 29 

### ± 0.11 1.

### 31 

### ± 0.09 Re I. 

### 0.37 

### ± 0.03 0.37 

### ± 0.01 0.37 

### ± 0.02 0.36 

## ± 0.02 0.35 

### ± 0.02 Kidney (L) 

### 5 5 5 5 5 (g) 1.

### 39 

### ± 0.0,9 1.44 

### ± 0.09 1.35 

### ± O. 12 1.

### 33 

### ± 0.11 1.31 

### ± 0.09 Re I. 

### 0.36 

### ± 0.03 0.37 

### ± 0.02 0.36 

### ± 0.02 0.37 

### ± 0.02 0.35 

## ± 0.02 ReI. : Relative organ weight (g or mg 

## 7 100g final body weight) N : No.of animals
PROJECT No., 

## c o 

# o CJ 

### t-""


# ... 

# c

### Table 19-2 Absolute and relative organ weights of male rats treated or_lly with

. for 28 days.

- 28-day of treatment

­ Group-No. 00 01 02 03 04 Dose Control Vehicle (mg/kg) 0 0 10 100 1000 Adrenal (R) N 

### 5 5 5 5 5 

### (mg) 29. 1 

### ± 1.7 30.5 

### ± 1.5 24.8 

### ± 2.3 

# * 24.7 

### ± 1.9 

# * 26.2 

### ± 3.9 ReI. 7.5 

### ± 0.4 7.8 

### ± 0.4 6.7 

### ± 0.8 6.8 

### ± 0.6 7.0 

### ± 1. 1 . 5 Adrenal (l) N 

### 5 5 5 5 (mg) 

### 30.7 

### ± 2.7 31.5 

### ± 1.9 26.2 

### ± 1.9 27.1 

### ± 2.2 27.6 

### ± 4.6 Re I. 

### 7.9 

### ± 0.5 8.0 

### ± 0.6 7.0 

### ± 0.7 7.5 

### ± 0.8 7.4 

### ± 1.3 Testi

### s(R) N 

### 5 5 

### 5 5 5 (g) 1.

### 60 

### ± 0.08 1.60 

### ± 

## o. 11 

### 1.53 

### ± 0.17 1.56 

### ± 0.05 1.57 

## ± O. 12 Re I. 

### 0.41 

## ± 0.03 0.41 

### ± 0.03 0.41 

### ± 0.05 0.43 

## ± 0.02 0.42 

### ± 0.04 0\ t-l 

### Testi

### s(l) N 

### 5 5 5 5 5 (g) 1.

### 61 

## ± 0.08 1.65 

## ± O. 19 1.

### 54 

### ± 0.22 1.

### 57 

## ± 0.05 1.56 

## ± O. 11 Rel. 

### 0.42 

## ± 0.03 0.42 

### ± 0.04 0.41 

## ± 0.{)7 0.43 

## ± 0.03 0.42 

## ± 0.04 Prostate N 

### 5 5 5 5 5 (mg) 547 

## ± 105 545 

## ± 47 491 

## ± 161 484 

## ± 109 431 

## ± 55 Re I. 

### 142 

## ± 33 138 

### ± 10 131 

## ± 42 134 

## ± 32 '15 

## ± 13 Rei. : Relative organ weight (g or mg'/ 100g final body weight) N : No.of animals 

## *: Significantly different from control, p(0.05 PROJECT No.



## o 

# o 

# o CJ

### ~**~** /'**'~**..... 

# r'i N \....-. .".......**/~'~** ...... I ' \

......r" 

# o

Table 19-3 

### Absolute and relative organ weights of male rats treated orally with for 28 days



### - 14-day of recovery ­ Group-No. 00 01 

### 04 

### Dose Control Vehicle (mg/kg) 0 

### 0 1000 

### Final N 5 

### 5 

### 5 body weight (g) 413 ± 15 436 ± 44 410 ± 37 

### Brain N 5 5 

### 5 (g) 2.17 ± 0.07 2.18 ± O. 15 2.17 

### ± 0.09 ReI. 0.53 ± 0.01 0.50 

### ± 0.02

# * 0.53 

### ± 0.04 

### liver N 5 5 5 (g) 11.68 ± 0.71 12.71 ± 1.67 11. 85 ± 1.32 Re I. 2. 83 ± 0.08 2.91 ± O. 13 2.89 ± O. 13

w 5 5 0- 

### Spleen N 5 (mg) 744 

### ± 106 842 ± 112 812 ± 148 Re I. 180 ± 23 193 

### ± 14 197 ± 24 

### K I dney(R) N 

### 5 5 5 (g) 1.

### 42 ± O. 14 1.47 ± O. 14 1.41 ± O. 14 

### Re I. 0.34 ± 0.03 0.34 ± 0.01 0.34 ± 0.01 

### Kidney(L) 5 5 5 (g) 1.40± 0.20 1.53± 0.11 1.43± 0.15 ReI. 0.34 

### ± 0.04 0.35 ± 0.02 0.35 ± 0.02 

### Rei. : Relative organ weight (g or mg 

## 7 100g final body weight) 

### N : No.of animals

. 

# *:Significantly 

### different from 

### control. p(0.05 

### PROJECT No 

# o o o c.J**~** 

### t.J

# ~Table 19-4 Absolute and relalive organ weights of male rats treated orally with

. for 28 days_

- 14-day of recovery ­ Group-No. 00 01 04 

### Dose Contr-ol Vehicle 

### (milkg) 0 0 1000 

## AdronaI(R' N 

## 5 5 5 (lIg) 27.6 

## ± 3.5 28.2 

## ± 2.0 26.2 

## ± Re I. 6.7 

## ± 0.9 6.5 

## ± 0.5 6.5 

## ± Adrena' (L) N 5 5 5 (mg) 29.0 

## ± 3.9 29.2 

## ± 3.3 27.2 

## ± ReI. 7.0 

## ± 0.8 

### 6.8 

## ± 1.1 6.7 

## ± TestiS(R) N 

### 5 5 5 (g) 1.56 

## ± O. 18 1.72 

## ± O. 14 1.60 

## ± Ret. 0.38 

## ± 0.03 0.40 

## ± 0.02 0.39 

### ±**~** Testis(L) N 

### 5 

### 5 5 (g) 1.58 

## ± 0.18 1.72 

## ± 0.17 1.59 

## ± Re I. 0.38 

## ± 0.04 0.40 

### ± 0.03 0.39 

### ± Prostate N 5 5 5 (mg) 503 

### ± 92 565 

### ± 93 436 

### ± ReI. 122 

### ± 22 129 

## ± 13 107 

### ± 4.5 1.6
3.9 1.4
0.05 0.04
0.09 0.03
32 15 ReI. : Relative organ weight (g or mg 

## 7 100g final body weight) N : No.of animals


### PROJECT No.


# o o o c.J**~ ~** **~ ~**  (u.•.. 

## ()("", \..,.,,/ 

# '0
Table 20-1 Absolute and relative organ weights of female rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. 00 01 02 03 04 Dose Contro,1 ' Vehicle (alg/kg) 0 

### 0 

### 10 100 lOUD 

### Final N 

### 5 

## 5 5 5 5 body 

### weight (g) 

### 217 

## ± 14 230 ± 22 215 

## ± 10 217 

## ± 10 216 

## ± 15 Brain N 

### 5 5 

### 5 5 5 (g) 1.

### 95 

## ± 0.01 2.00 

## ± 0.08 1.

### 95 

## ± 0.05 1.99 

## ± 0.03 1.96 

## ± 0.05 Re I. 

### 0.90 

## ± 0.03 0.87 

## ± 0.07 0.91 

## ± 0.01 0.92 

## ± 0.03 0.91 

## ± 0.06 Liver N 

### 5 5 5 5 5 (g) 6.31 

## ± O.72 6.17 

## ± 0.68' 6.11 

## ± 0.49 6.35 

### ± 0.49 6.64 ± 0.53 Re1. 

### 2.91 

## ± 0.19 2.95 

## ± 0.24 2.84 

## ± O. 15 2.92 

## ± 0.23 3.08 

## ± 0.26
0­ VI 

### Spleen N 

### 5 5 5 5 5 

### (mg) 449 

### ± 27 484 

## ± 82 483 

## ± 55 444 

## ± 72 431 ± 64 Re I. 

### 208 

## ± 8' 210 

## ± 21 224 

## ± 20 204 

## ± 29 198 

## ± 18 Kidney(R) N 

### 5 5 

### 5 5 5 (g) 

### 0.82 ± 0.07 0.86 

## ± 0.01 0.19 

## ± 0.02 0.84 

## ± 0.06 0.84 

## ± 0.06 Re I. 

### 0.38 

## ± 0.04 0.38 

## ± 0.03 0.31 

## ± 0.01 0.39 

## ± 0.02 0.39 

## ± 0.02 K Idnay(l) 

### 5 5 

### 5 5 5 (g) 0.80 

### ± 0.06 0.81 

## ± 0.03 0.78 

## ± 0.03 0.83 

### ± 0.05 0.83 

### ± 0.08 ReI. 0.31 

## ±- 0.04 0.38 

## ± 0.02 0.36 

## ± 0.01 0.38 

### ± 0.02 0.39 

### ± 0.03 ReI. : 

### Relative organ weight (g 

### or mg 

## 7 100g 

### final body weight) 

### N : No.of animals
PROJECT 

### No. 

# o o 

# o c,..)**~** 

# " '-l CI1

### Table 20-2 Absolute and relative organ weights of female rats treated orally with for 28**da~$**



### - 28-day of treatment

­ Group-No. 00 01 02 

### 03 04 Dose Contr-ol Vehicle (illg/kg) 

### 0 0 10 100 1000 Adrenat

### (R) N 

### 5 5 

## 5 5 5 -(mg) 

### 32.0 

### ± 4.0 31.5 

### ± -2.4 31.0 

### ± 3.2 34.4 

### ± 5.2 33.2 

### ± 1. 1 ReI. 

### 14.8 

## ± 1.4 

### 13.9 

### ± 1.8 14.4 

## ± 1.1 

### 15.9 

## ± 3.0 15.4 

### ± 0.8 . 5 Adrenar(L) 

### N 5 5 5 5 (ma) 

### 33.9 ± 5.4 32.9 

### ± 3.6 33.8 

### ± 2.9 36.9 

## ± 6.4 35.5 

### ± 2.4 Re I. 

### 15.6 

### ± 2.1 

### 14.4 

### ± 1.8 15.7 

### ± 0.8 17.1 

### ± 3.3 16.4 

### ± 0.8 Ovary(R) N 5 5 

### 5 5 5 (mg) 

### 39.9 

### ± 8.3 34.3 

### ± 18.2 39.9 

### ± 7.5 39.5 

### ± 9.3 43.7 

### ± 7.6 0\ 

### (ReI.) 

### 18.3 

## ± 2.8 15.5 

### ± 8.4 18.6 

### ± 3.4 18. 1 

### ± 4.2 20.4 

### ± 4. 1 0\ 

### Ovary(l) N 

### 5 5 5 5 5 (mg) 

### 35.8 

### ± 4.5 32.3 

### ± 18.6 38.5 

### ± 6.0 39.0 

### ± 6.2 41.7 

### ± 7.8 (Re I.) 

### 16.5 

### ± 1.2 14.5 

### ± 8.3 17.9 

### ± 2.9 17.9 

### ± 2.7 19.3 

### ± 3.4 Uterus N 5 5 

### 5 5 5 (g) 

### 0.55 

### ± 

# o. 13 0.42 

### ± 0.35 0.46 

### ± 0.20 0.50 

### ± O. 14 0.70 

### ± 0.23 (Re I.) 

### 0.25 

### ± 0.07 0.19 

### ± O. 16 0.21 

### ± 0.09 0.23 

### ± 0:07 0.33 

### ± O. 12 Rei. : Rela tive organ weicht (g or mg 

# 7100g final body weight) N : No.of animals
PROJECT No.



## o 

# o 

# o**~** 

### c.J

## ~**~** ,r""

........ (f) 

# o**',-.~.**r",", 

# o ,"" Table 20-3 

### Absolute and relative organ weights of female 

### rats treated orally with for 28 da,ys

- 14-day of recovery­ 

### Group-No. 00 01 04 

### Dose Control Vehicle (mg/kg) 

### 0 0 1000 final N 5 5 5 body 

### weight (g) 248 

## ± 16 231 

### ± 18 236 

### ± 13 . N 5 5 5 Bra

### In (8) 1.

### 99 

## ± 0.05 

### 2.01 

### ± 0.04 

### 1.

### 99 

### ± 0.03 ReI. 0.80 

### ± 0.06 0.85 

### ± 0.06 0.85 

### ± 0.03 N 5 5 5 liver (g) 6.45 

### ± 0.25 

### 6.15 

### ± 0.41 6.40 

### ± 0.55 Rei. 2.60 

## ± 0.13 2.59 

### ± 0.09 2.12 

### ± 0.15**~** Spleen N 5 5 5 (mg) 512 

## ± 13 483 

### ± 19 483 

### ± 42 Rei. 

### 206 

## ± 24 202 

## ± 19 206 

## ± 25 Kldney(R) N 5 5 5 (g) 0.87 

### ± 

### 0.06 0.81 

### ± 0.08 

### 0.86 

### ± 0.08 Re1. 0.35 

## ± 0.02 0.34 

### ± 0.02 0.31 

### ± 0.03 Kldney{l) 5 5 5 (g) 0.86 

### ± 0.06 0.19 

### ± 0.09 0.83 

### ± 0.01 Re I. 0.35 

### ± 0.03 0.33 

### ± 0.01 0.35 

## ± 0.03 ReI. : ReLative organ weight (g or mg 

## 7 100g final body 

### weight) 

### N : No.of animals
PROJECT No. 

# o 

# o o**~** c..J

### ~**~** 

### ...J

### Table 20-4 

### Absolute and relative organ weights of female rats treated orally with for 28 

### days

- l-i-day of r'ecovery

­ Group-No. 00 

### 01 04 

### Dose Control Vehicle (me/kg) 

### 0 0 

### 1000 

### AdrenaI(R) N 5 5 5 (mg)· 

### 32.0 

## ± 3.0 

### 30.3 

### ± 2.6 

### 32.6 

### ± 4.3 ReI. 13.0 

### ± 

### 1.1 12.8 

### ± 1.4 

### 13.8 

### ± 1.6 

### Adrenal (l) N 

### . 5 

### 5 5

. (me) 

### 35.1 

### ± 

### 4. 1 32.6 

### ± 6.4 35.2 

### ± 5.0



### ReI. 14.3 

### ± 2.7 13.7 

### ± 2.4 15.0 

### ± 2. 1 

### Ovary(R) N 

### 5 5 

### 5 (mg) 

### 37.9 

### ± 9.9 

### 36.3 

### ± 6.2 

### 35.9 

### ± 4.4 

### (ReI.) 15.3 

## ± 4. 1 15.3 

### ± 2.3 15.2 

### ± 1.9 0\ co Ovary(l) N 5 5 5 (mg) 

### 34.6 

## ± 6. 1 42.9 

## ± 11.2 

### 34.9 

### ± 5.5 (Re I.) 

### 13.9 

### ± 2.0 18.0 

### ± 4. 1 14.8 

### ± 1.7 

### Uterus N 5 

### 5 5 (g) 

### 0.58 

### ± 0.31 0.49 

### ± O. 19 0.48 

### ± O. 14 (Re I.) 

### 0.23 

### ± O. 12 0.20 

### ± 0.07 0.20 

### ± 0.07 

## Rei. : Relative organ weight (g or mg 

# 7100g final body weight) N : No.of animals
PROJECT No.



# o o**~** 

## o Co,) 

### .c::::>**~** /;:'>'.**~** .......",: 

# o

# --- (--...,

... .,./ 

# o

Table 21-1 Necropsy Qf male rats treated orally with for 28 days 28-day of treatment

­ Group-No. 00 01 02 03 OA 

### Control Vehicle Dose(mg/kg) 0 0 10 100 1000 Oruns : No. of animals 5 

### 5 5 5 

### 5 FIndings Epididymis (caudal region) nodule 0 0 0 0

0\ \0 

### PROJECT No.



## o o o c.J**~**

### ~**~**('-, 

# o

Table 21-2 Necropsy of 

### male rats treated orally with for 28 

### days

.-' 

### 14-day of recov,ry -­ Group-No. 00 01 

### 04 Control Vehicle Dose(me/kg) 0 0 

### 1000 Organs : No. of anllals 5 

### 5 5 Findings
abnormal change 0 0 0



### PROJECT No. 

### 2S



## o 

# o c.,) 

### N 

# o

# ~ c

### lable 

### 22-1 Necropsy of female rats treatad orally wIth

. for 28 days

- 28-day of treatment

­ 

# . Group-No. 00 01 02 03 04 

### Control Vehicle Dose(mg/kg) 0 0 10 100 1000 Organs : 

### No. of animals 5 

### 5 

### 5 5 5 Findings
Ovary :



## -..**-~~~'!!-** 

## .....-...--...--..---.-....---..----....**~----** 

## ______.....__.._.......___.._____......

## _!

_____....__.__**-.~---.---------** 

## ...

## P---

...**----~.** 

### Uterus : atrophy 

### o o o o swe II

### ing 2 4 ...J



### ....
PROJECl No.



# o o o Co.) 

# <N N 

# .. r"··". 

## r <..J 

## -....l

### r-;'''"', ,I"'''''

,**.~.,**.. 

### U

Table 22-2 Necropsy of female rats treated orally with for 28 

### days 14-day of recovery -­ Group-No. 00 01 

### 04 

### ControI 

### Vehicle Dose(mg/kg) 

## o 

## o 1000 

### Organs : No. of animals 5 5 5 Findings


### abnormal change 

## o o o

PROJECT 

### No. t:j



# o o 

# o c..,) 

### N N

## ~ 

# -t:..Table %3-1 HistopathololY of fats treated orally wjtb for 28 days

- 28-day 

### DC treatment

­ Sex (---- IiIale ----) (, Female ----------) Group-No. Dose (mg/kg) 00 Control 01 Vehicle 04 1000 00 Control OJ Vehicle 02 

### l.!!.­ 03 100 04 .-l.Q.!!Q Organs : No. of animals 5 5 5 5 5 555

Findings Liver: 1 1 IIIOnbnuc\ear cell infiltration 1 % 

### s 1 

### s microaranuloma 0 % I 1 

### o vacuolatIon In**~_c!pB**toclte 0 0 0 0 

## o fOrestoDl::a:.:c:!:.h.:....:

_____ ____.._ ....___ _ 0 1-_....__ 1 n n
....

9.

................ ..._---'0:...-

__

### -=-

____-=-

__........:::...-

__....!- 

### o**.~J.!ndula!** stomach: 

### o _...L 0 0 0 1



### .._L

___,_9

.._._. puodenllm: 

## o 0 0 0 0 1 

### o _".1 Heart: 1 1**~** mononuclear cell infiltration 1 0 0 0 

### o n JIIyocardlaJ.....:f

.... i,::;br:..,:o"'s.:,;i s"--

_________

## --=:_ 0 0 

### •.

_ ......._9._-_

......._. 0



### ____.."

......"1

..........."

..".,,.

M

....................... Kidney: 1 1

mononuclear cell infiltration 2 0 1 1 0 

### o basopbilic tubule 2 2 I 0 1 

## o fibrosis 0 0 Z 0 0 

### o Cyst 1 0 Z 0 1 

### o calcification 0 0 0 0 1 

## o vacuolar**deg~_~eration** of tubular epithelium 0 0 I 0 0 

### o Spleen: 1 1 n

__ 0**~~_~.~.~** extramedu**118TX.Jl~~ill.o** I**e~J!.__** 3

___. __....

### ,,_1

___. ___"'--_ 

## o Sternal bone**JII~!!.~!.;** ___________ 

### JL.

__.... 0 0 

### L_

.._ ......._._Q 

### L

...___ I



### __._...9.

.._.__ n 0 

### o 0 1 

### _L o Femoral bone marrow:_.

____________-=--

__

### •.--I!.. Adrenal: 0 0 0

__._Q

____,_--=-O

__---' 

### o t_". 1 Testis: 

### •

__..._9.

........... 0 0 

## ._----_....

## _._---­ 

# o o Prostate: Dlononuclear cell Infiltration 4 

## o c.,) 

# G\ 1 : Not examined (contloucd.) 

### N PROJECT No. 

### tJ r;..... {" '-/ . ....../"-' " ( 

# o

Table 23-2 HistopatholoaY of rats treated orally with for %8 days

- 28-day of treatment

­ Sex 

## < -: liIale ) 

## < - Fellale ) Group-Ho. 00 01 04 00 01 02 03 04 Dose big/kg) :' Control Vehicle 1000 Control Vehicle 10 !QL 1000 --5 Organs : No. of animals 5 5 5 5 5 

# -, 5

Pindings Ovary: / /

atrophy

_ .•_.__._.... 0 0 Uterus: (1) (}) 1 . dilated lumen 2 1 1 4 squamous metaplasia of 1 

### o 

## o 0 0

epitheIium ce11**_.-!lliR.~:Y..** ..._........, .............., ......_.... _ .._._._............_._.............._. 

### 9 1

..._._..

### Jl

. L

.....___ O Sternal bone: 0

....

### 9..-."

.....__ 0 DOL I



### ....**!.-~** 

### ...."-

..., !.!!lora**1.!2P:~.;..** 0 0 Q

.........._.... 0 0 / / 0**~** Bpidldymls: (1) spermatic granuloma 1 () : No. o[ animals examined. / : Hot examined PROJECT No.



# o o 

# o Co) 

### N**~** 

## .....:) c-.....

### PUBLIC VERSTON PMN P-04-635 Table ofContents 

### CompanySanitized I. Revised 28-day Repeated DoseToxicityStudy:
a. Translation Statement

......................................................1 b. Final Report

..................................................................2 c. Figures and Tables

........................................................39 d. Appendix
.....................................................................114 II. Acute Oral Toxicity in Rats

......................................................215 III. A SimplifiedAcuteToxicity Study by Nose-Only Inhalation Exposure in Rats

................................................243 IV. Partition Coefficient(1-octanollwater) Study

.............................271

",' f \JJ 

## ..

# 111~l~lll~I~~ 

# ,III,llljlllllll!**I~**

# 11II1 f- 

# 64-**-u~** l't)0325

# /

TranslationStatement

Thefollowing study was conducted in the: The original study report was written in Japanese. I hereby declare that this translation report faithfully reflects the original study report as accurately aspossibleto myknowledge.

Informationofthe originalstudy Sponsor:

Title: 2S-dayRepeatedDoseToxicityStudyof .nMammals ProjectNo.

Informationofthe translation study Sponsor:

OrderNo.:

Translator: Date:

## !J~ I 

# f,**~"y**



## OU0326"28-Day Repeated Dose Toxicity Study of .' in Mammals" PROJECT No. Sponsor Order'

Final Report

May 8, 2000



## OU0327

# 3 Quality Assurance Statement Study Title: 28-Day Repeated Dose Toxicity Study of

. in Mammals PROJECT No.:



# _...

Type of audit/inspection Date of audit/inspection Date reported to Study Director Date reported to Management Study protocol (Draft) January 11 and 12, 2000 January 13, 2000 January 13. 2000

(Final) January 14.2000 January 14, 2000 January 14. 2000 Conduct of study Animal receipt and body weight measurement at receipt January 14, 2000 January 14. 2000 January 14, 2000 Ophthalmoscopy (before the start of administration) January 20. 2000 January 20, 2000 January 20, 2000 Group assignment January 21, 2000 January 24, 2000 January 24, 2000 Body weight measurement. test substance preparation. administration. clinical observations. determination of food consumption and water intake 

## I January 25. 2000 

## I January 25, 2000 January 27, 2000 Analysis of dosing solution [homogeneity, concentration, stability (4 hours in
i airtight containers at room temperature and protected from light)] 

# I January 31, 2000 

## I February 1. 2000 

## I January 31, 2000 Ophthalmoscopy (Week 4 of administration) 

## I February 18. 2000 

## I February 18, 2000 

# I February 18, 2000 Delivery of metabolic cages and urinalysis (fresh urine) 

# IFebruary 21, 2000 

## I February 23. 2000 

## I February 23, 2000 Blood collection. hematology. blood biochemistry. necropsy. determination of organ weights. and isolation and storage of organs and tissues (at the end of administration period)

2 

## 000328 i22, 2000 

# IFebruary 23, 2000 

# lFebruary 23, 2000 

# r---------,,- ebruary

Preparation of histopathologicaI specimens (excision) February 24. 2000 

# IFebruary 24, 2000 

# IFebruary 24, 2000 Necropsy. determination of organ weights. and isolation and storage of organs and tissues (at the end of recovery period) March 7. 2000 

# I March 8. 2000 

# IMarch 8, 2000 Identification of histopathological specimens (all specimens) 

# IApril 27, 2000 

# IApril 27, 2000 

# IApril 27. 2000

3 

## OU0329Study Title: 28-day Repeated Dose Toxicity Study of in Mammals PROJECT No.: Type of Date of Date reported to Date reported to audit/inspection audit/inspection Study Director Management Raw data April 28, May 1 and May 8, 2000 May 8, 2000 2, 2000 Final report (Draft) April 28, May 1 and May 8, 2000 May 8, 2000 2, 2000 (Final) May 8, 2000 May 8, 2000 May 8, 2000

It was confirmed by the above audits and inspections that this study was conducted in accDrdance with GLP. study protocol and the standard operating procedures established by that the methods and procedures used in the study were faithfully described in this final report, and that the raw data generated in the course of the study were exactly reflected in the study results.
May 8, 2000
(Signature)

Director,

4 

## OU0330Statement Study Title: 28-Day Repeated Dose Toxicity Study of in Mammals PROJECT No.:

The above study was conducted in accordance with the "Testing facilities specified in the Ordinance. Article 4. defining the study concerning new chemical substances and the test items of adverse events concerning the designated chemical substances (GLP for chemical sUbstances)" (Kan-Ki-Ken Notification No. 233. Eisei Notification No. 38 and 63 Kikyoku Notification No. 823: revised on November 18. 1988).

(Signature)
Management.
May 8. 2000

5 

## 000331.

# 7

Study Title: 28-day Repeated Dose Toxicity Study of : n Mammals PROJECT No.:
Objectives As a part of the safety evaluation of this substance was orally administered repeatedly to rats for 28 days to examine its toxicity. In addition. for some of the animals. a 14-day recovery period was established to examine the recovery.
Sponsor Name

Address

Study assignee Name

Address

Testing )acility Name

Address

Name

6 

## 000332Address
Facility management

Storage of records, documents and specimens (0 Storage period: The period specified in Article 32-1 of GLP (2) Matters to be stored and the storage place 

## CD Study protocol, raw data, final report (original): Store Room of Raw Data Archives. 

## ® Specimens: Specimen Archives.

@ Documents and the tt"st substance storage samples: Document Archives.

7 

## 000333

# 'f

Study Title: 28-Day Repeated Dose Toxicity Study of n Mammals PROJECT No.:
Study period Study initiation: January 14. 2000 Approval of study protocol: January 14. 2000 Receipt of animals: January 14. 2000 Group assignment: January 21. 2000 End of quarantine and acclimatization: January 24. 2000 Start of administration: January 25. 2000 Necropsy (at the end of administration period): February 22. 2000 Start of recovery: February 22. 2000 Necropsy (at the end of recovery period): March 7. 2000 Preparation of final report (draft): March 15. 2000 Preparation of final report: May 8. 2000 Study termination: May 8. 2000

8 

### 000334

# /0

Study Title: 28-Day Repeated Dose Toxicity Study of n Mammals PROJECT No.:

The above study was conducted on the responsibility of the researcher shown below in accordance with the "Testing facilities specified in the Ordinance. Article 4. defining the study concerning new chemical substances and the test items of adverse events concerning the designated chemical substances (GlP for chemical substances)" (Kan-Ki-Ken Notification No. 233. Eisei Notification No. 38 and 63 Kikyoku Notification No. 823: revised on November 18. 1988) and "[Partial revision (establishment of the screening toxicity study method) of the "test methods concerning new chemical substances]" (Kan-Ho-Gyo Notification No. 700. Notification No.1039 issued by Pharmaceutical Affairs Bureau, 61 Kikyoku Notification No.1014; dated December 5, 1986).
Study director (Signature)
May 8. 2000

9 

## 000335

# /1

Study Title: 28-Day Repeated Dose Toxicity Study of

. in Mammals PROJECT No.: Work responsibility and testing staff Study director. preparation of protocol. direction and control ofworks. and preparation of final report:
. Evaluation of health status of animals: Control of test substance: Test substance Preparation:
Analysis of prepared test substance:

Administration of test substance. clinical observations, and determination of body weights. food consumption and water intake:

.

Ophthalmolscopy: Urinalysis. hematology and blood biochemistry:

Blood collection. Necropsy: Autopsy: Hashizume Identification of the isolated organs: Determination of organ weights:

.

to 

## 000336

# J;J....
Preparation of histopathological specimens:

Histopathology: Statistics:

.

Table of contents 1. Summary 11. Objectives III.Test materials and methods 1. Test substance 2. Preparation of test substance 3. Animals and environmental conditions for feeding 4. Group composition and doses 5. Reason for doses selection 6. Route. method, frequency and period of administration. and recovery period 7. Observation. determination and examinations 8. Statistical analysis 9. Environmental factors considered to have influenced on the reliability of study results and deviations from study protocol IV. Results 1. Mortality and clinical signs 2. Body weights 3. Food consumption 4. Food efficiency 5. Water intake 6. Ophthalmoscopy 7. Urinalysis 8. Hematology

II 

## 000337

# 13
9, Blood biochemistry 10, Organ weights 11. Necropsy 12. Histopathology V. Discussion and conclusion VI. References

12 

## 000338

# I~ Figures 1. Body weight changes (male) 2. Body weight changes (female) 3. Food consumption (male) 4. Food consumption (female) 5. Water intake (male) 6. Water intake (female)

Tables 1. Clinical signs (male) 2. Clinical signs (female) 3. 'Body weights (male) 4. Body weights (female) 5. Food consumption (male) 

### 6. Food consumption (female) 7. Food efficiency (male) 8. Food efficiency (female) 

### 9. Water intake (male) 10. Water intake (female) 11. Ophthalmoscopy (male) 12. Ophthalmoscopy (female) 13. Urinalysis (male) 14. Urinalysis (female) 15. Hematology (male) 16. Hematology (female) 17. Blood biochemistry (male) 18. Blood biochemistry (female) 19. Absolute and relative organ weights (male) 20. Absolute and relative organ weights (female) 21. Necropsy (male)

13 

## 00033922. Necropsy (female) 23. Histopathology
Appendices 1. Clinical signs (male) 2. Clinical signs (female) 3. Body weights (male) 4. Body weights (female) 5. Food consumption (male) 6. Food consumption (female) 7. Food efficiency (male) 8. Food efficiency (female) 9. Water intake (male) 10. Water intake (female) 11. Ophthalmoscopy (male) 12. Ophthalmoscopy (female) 13. Urinalysis (male) 14. Urinalysis (female) 15. Hematology (male) 16. Hematology (female) 17. Blood biochemistry (male) 18. Blood biochemistry (female) 19. Absolute and relative organ weights (male) 20. Absolute and relative organ weights (female) 21. Necropsy (male) 22. Necropsy (female) 23. Histopathology (male) 24. Histopathology (female)

14 

## 000340

# It
Attachment 1. Results of the stability of the test substance in the dosing solutions 2. Results of determination of the homogeneity and concentration of the test substance in the dosing solutions

15 

## 000341

# 17
I. Summary
was orally administered repeatedly to Sprague-Dawley rats [Crj:CD{SD)IGS] at doses levels of 0 (water for injection JP control group). 

## o (vehicle control group). 10. 100 and 1000 mg/kg for 28 days to examine its toxicity. Number of animals was 10 each of males and females in the 0 (water for injection JP control group). 0 (vehicle control group) and 1000 mg/kg groups and 5 each of males and females in the 10 and 100 mg/kg groups. For 5 each of males and females in the 0 (water for injection JP control group). 0 (vehicle control group) and 1000 mg/kg groups. the drug
was withdrawn for 14 days after the end of administration period to examine the recovery. In addition. water for injection JP and Macrogol 400
were administered in a similar manner in the water for injection JP control group and the vehicle control group. respectively.

There was no toxicological change due to administration of the test substance in clinical signs. body weights. food consumption. food efficiency. water intake. ophthalmolscopy. urinalysis. hematology. blood biochemistry, organ weights, necropsy and histopathology.

As shown the above. since no toxrcological change was observed in this study even after administration of , at a dose of 1000 mg/kg, the No Observed Adverse Effect Level of Nas considered as 1000 mg/kg for both males and females.

16 

## 000342

# I¥

II. Objectives As a part of the safety evaluation of this substance was orally administered repeatedly to rats for 28 days to examine its toxicity. In addition, for some animals. a 14-day recovery period was established to examine the recovery.

III. Test materials and methods 1. Test substance In this study ethane supplied by the

was used as the test substance. This substance is a clear liquid having the molecular weight of 200.05. the boiling point of 56.22°C. the specific gravity of 1.4789 g/cm3 (23°C) and the vapor pressure of 28.4 kPa (25°C), and its molecular formula is (rational formula' In this study, the test substance, Lot No. 991224 (purity of 99.82%), was used and stored in airtight containers at
room temperature while protecting from light. After the end of administration period, the sample for storage (about 5 mL) was collected. and the residual test substance was returned to the Sponsor. When the purity of this substance was analyzed by the Sponsor before the start of administration and after the end of administration period. it was confirmed that there was no difference in the analytical values between before and after the study. The results showed that the test substance was stable throughout the administration period.

2. Preparation of test substance A predetermined amount of ;/as weighed before use and dissolved in Macrogol 400 JP (Lot No. EF-7. EI-1, Kozakai Pharmaceutical Co

.. Ltd.) to prepare a 500-mg/mL solution. In addition. this solution was diluted stepwise with the vehicle to prepare a 50-mg/mL solution and a

17 

## 0003435-mg/mL solution. At weighing. however. no conversion of purity was conducted. The preparations were stored at room temperature under airtight conditions and protected from light and used for administration within 4 hours after preparation. For the water for injection JP control group, water for injection JP (Lot No. 9040'ID. Fuso Pharmaceutical Industries. Ltd.) was administered. and for the vehicle control group. Macrogol 400 JP was administered.

The stability of the test substance in the Macrogol 400 JP solution was analyzed in parallel with administration. The analysis was conducted according to the analytical procedures (13-03-74) prepared based on the results obtained after establishing and validating the analytical method by high performance liquid chromatography (LC1OA system. Shimadzu Corporation) at this institution. That is. when the stability in airtight containers protected from light at room temperature for 4 hours was examined on the concentrations of 5 and 500 mg/mL. it was confirmed that the preparations were stable (Attachment 1). The analysis of homogeneity and concentration of the preparations was conducted on the preparation
on Day 7 of administration by the analytical method as shown the above. As a result. for the homogeneity. the CV value was 0.5 to 1.7% for the 5-. 50- and 500-mg/mL solutions. The concentration was determined to be 94.2 to 98.6% of the nominal concentration. showing that all the preparations were within the acceptable range (+ 10% ofthe nominal value; Attachment 2).

18 

## 0003443. Animals and environmental conditions for feeding Fifty (50) each of male and female Sprague-Dawley rats [Crj:CD{SD)IGS] aged 5 weeks were purchased from Atsugi Breeding Center. Charles River Japan. Inc. (795. Shimofurusawa. Atsugi. Kanagawa) and quarantined and acclimatized for 11 days. During the quarantine and acclimatization periods. the health conditions of animals were evaluated, and 40 each of male and female animals were selected from healthy ones and assigned to each group by stratified randomization of body weight. The age at the start of administration was 6 weeks. and the body weight ranged from 216 to 245 g for males and 155 to 184 g for females.

Animals were housed and kept individually in stainless steel bracket cage for rats (260W

### x 380D

### x 180H mm) in the animal room (Room No. 3 of Building A) where the temperature set at 22+ 3°e (measured values: within the range from 19 to 25°e). the humidity at 50+ 20% (measured values: within the range from 30 to 70%), ventilation at more than 10 times/hour (all fresh air system) and lighting for 12 hours/day (from 6:00 to 18:00, illuminance of 150 to 300 lux). As a food. a chow for experimental animals CE-2 (Lot No. E2109. E2129. Clea Japan. Inc.: 20-14. Aobadai 2-chome. Meguro-ku. Tokyo) was given with feeders. and as a drinking water. domestic tap water was given

### t~rough polycarbonate water bottles. both
were given ad libitum.
Cages. feeders, saucers and water bottles were used after autoclaving (121°e, 30 minutes). cages and feeders were changed more than once every 5 weeks, and saucers and water bottles were changed more than twice a week. In addition. the animal room was cleaned daily after the end of work. and the floor was wiped and disinfected with a 400-fold diluted solution of benzethonium chloride (Hyamine solution, Sankyo Co

.. Ltd.).

19 

## 000345

# 11

Animals were identified with tattoos describing the abbreviation of animal number on the root of the tail. and cages were identified by attaching the color labels describing the study numbers and the route of administration.

For the analysis of contaminants/pollutants in food. Tokyo Kenbikyoin Foundation (44-1. Nihonbashi Hakozaki-cho. Chuo-ku. Tokyo). which undertook the work entrusted by the manufacturer. conducted on the same lot as used in the test, and the copy of the results of analysis were obtained from the foundation. For the analysis of contaminants/pollutants in drinking water, this institution sampled the water regularly and requested the Environmental Hygiene Testing Center. Gunma Pharmaceutical Association (5-18-36. Nishi-Katakai-cho. Maebashi. Gunma) for the following examinations: Examinations of the reference items concerning water purification (including trihalomethane test) (water sampling: August 3. 1999). the whole item examination based on the Building Management Law (water sampling: February 15. 2000) and the omitted item examination based on the Building Management Law (water sampling: January 11 and March 7. 2000). As a result. in all the examinations mentioned above. the results were within the range of the reference values in the acceptance criteria specified by this institution and the reference values specified in the ministerial ordinance concerning the water quality standards. and there
was no abnormal value considered to affect the study.

4. Group composition and doses A total of 5 groups. including the water for injection JP control group. the vehicle control group. and the 10 mg/kg group. 100 mg/kg group and 1000 mg/kg group of Here established. Each group consisted of 5 males and 5 females. As the recovery group. 5 each of animals were added to the water for injection JP control group. the vehicle control group and

20 

## 000346the 1000 mg/kg group of The doses. the number of animals and animal numbers are shown in the table below. (1) Dose. dosing volume. concentration of dosing solution. and the number of animals used Dosing Concentration Number of animals substance Dose Group Test (mg/kg) of dosing used (mLlkg) volume solution (mg/mU Male Female 00 5"+5 b 5"+5 b 0 2 0 Water for 1 injection JP (Control) 5a+5 b 5"+5 b (Control) 02 0 0 2 Vehicle 01

5­ 10 5 5" 2

e 100 5" 2 50 5' 04 03 1000 5°+5 b 5"+5 b Total 2 500 40 ' 40

, a: Administration for 28 days b: Administration for 28 days with recovery period for 14 days (2) Animal No. Group Test substance Dose (mg/kg) Animal number Male Female 00 Water for injection JP 0 OOMO 1-00M 1 0 00F01-00F10 (Control) 01 In?

03 Vehicle (Control)

I 0 10 100 01M 01-01M 1 0 102M01-02M05

03MO 1-03M05 01F01-01F10 02F01-02F05 03F01-03F05 04 1000 04M01-04Ml0 04F01-04Fl0

The animal Nos. 6 to 10 were used as the recovery group.

21 

## OU03475. Reason for doses selection As a result of a preliminary 7-day repeated dose toxicity study ll (dose: 10. 100 and 1000 mg/kg) conducted prior to the main study. since no toxic change was observed even in the 1000 mg/kg group. 1000 mg/kg. the limit dose in the Guidelines for the Law Concerning Examination and Regulation of Manufacture and Handling of Chemical Substances (1986). was used as the high dose in this study. 100 mg/kg and 10 mg/kg were set as the mid-dose and the low dose in a geometrical ratio of 10, respectively.

6. Route. method, frequency and period of administration, and recovery period The oral ro.ute by gavage was selected for administration because oral ingestion was considered as the possible route of exposure in humans.

For administration. the dosing volume was calculated from the most recent body weight. and the dosing solution was administered once a day using a disposable syringe equipped with an oral sound for rats. For the water for injection JP control group and the vehicle control group, water for injection JP and Macrogol 400 were administered in a similar manner, respectively.
According to the Guidelines for the Law Concerning Examination and Regulation of Manufacture and Handling of Chemical Substances (1986). the administration period was established as once a day for 28 days. and the recovery period was established as 14 days.

7. Observations, determinations and examinations The starting date of administration was considered as Day 1 of administration, and the starting date of recovery was considered as Day 1 of recovery. Unless otherwise specified, the following observations,

22 

## OU0348determinations and examinations were conducted on all animals.

(1) CIinical signs Clinical signs including death and moribund animals were observed more than once a day before and after administration during the administration period and once a day during the recovery period.
(2) Body weight Body weight was determined once before administration at the start of administration and once a week during the administration period and the recovery period using an electronic balance (Sartorius K.K.), and the data
was collected automatically with the safety study system.
(3) Food consumption The amount of food supplied on the previous day and the amount of residual food on the day were measured once before the start of administration and once a week during the administration period and the recovery period using an electronic balance (Sartorius K.K.), and the data
was collected automatically with the safety study system.

The daily food consumption was calculated from the fed amount and the amount of residual food. In addition. the food efficiency was calculated by the equation shown below. Body weight gain (g/period) Food efficiency

# = x 100 Food consumption (g/period)
(4) Water intake The amount of water supplied on the previous day and the amount of residual water on the day were determined once before the start of administration and once a week during the administration period and the

23 

## 000349recovery period using an electronic balance (Sartorius K.KJ, and the data

was collected automatically with the safety study system. The daily water intake was calculated from the water supplied and the amount of residual water.
(5) Ophthalmoscopy The anterior segment of the eye (cornea and conjunctiva) and the intermediate optic media (pupil. lens and vitreous body) were observed

once before the start of administration and once each at Week 4 of administration and Week 2 of recovery using an ophthalmoscope (Beta 200, Heine), and mydriasis was produced with a mydriatic (Mydrin8 P: Santen Pharmaceutical Co., Ltd.) to observe the eyegrounds. Since no abnormality
was observed in the eyegrounds. however. no photo was taken.
(6) Urinalysis Five (5) mL of water for injection JP was administered orally by gavage to each animal for scheduled necropsy at the end of administration period (the day before necropsy) and at the end of recovery period (the day before necropsy). then urine was collected for about 3 hours using metabolic cages under fasting and prohibition of drinking water. This urine
was considered as the fresh urine to conduct examinations on the following items:

Occult blood (POD action of hemoglobin), ketone body (application of Lange reaction), glucose [GOD-POD chromogen (KJ) reaction]. protein (protein error reaction of indicator). pH (combined indicator method). urobilinogen (application of Ehrlich reaction). bilirubin (diazo-coupling reaction) (for the above. MultistickslHl. Bayer·Sankyo). and color tone (the method using the color tone table. standard color card 230. Japan Color Enterprise Co

.. ltd.).

24 

## 000350(7) Hematology At the end of administration period and recovery period. the respective animals for scheduled necropsy were opened under anesthesia with ether after fasting for about 20 hours from the previous day. and blood was collected from the abdominal aorta. Using the blood anticoagulated with EDTA-2K or 3.8% sodium citrate. the following parameters were determined:

EDTA-2K-treated blood: Red blood cell count (RBC). white blood cell count (WBC) and platelet count (Platelet; for the above. DC detection method). hematocrit (Ht; detection of the pulse height of red blood cell). hemoglobin (Hb; SLS-Hb method). mean corpuscular volume (MCV; Ht/RBC 

### x 1000). mean corpuscular hemoglobin (MCH; Hb/RBC 

### x 1000) and mean corpuscular hemoglobin concentration (MCHC; Hb/Ht 

### x 100; for the above. multiparameter automatic hemocytometer K-4500. Sysmex Corporation). Differential white blood cell count (Lympho. Eosino. Mono. Baso. Stab. Seg; Wright staining) and reticulocyte count (Reticulocyte; Brecher method; for the above. automatic blood cell analyzer HEG-120A. Omrcin Corporation). 3.8% sodium citrate-treated blood: Prothrombin time (PT) and activated partial thromboplastin time (APTT; magnetic sensor method; for the above. automatic blood coagulation monitor KC-4A. Amelung).
(8) Blood biochemistry The blood for blood biochemistry was collected simultaneously with and in
a similar manner to that for hematology. Using the serum obtained by centrifuging (3000 rpm. 15°C. about 10 minutes) the collected blood. the following parameters were determined: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT; for

25 

## 000351the above. formulation conforming to JSCC). alkaline phosphatase (ALP; p-nitrophenyl phosphate substrate method). 

### r -glutamyl transpeptidase 

### ( r -GTP; L- 

### r -glutamyl-3- hydroxymethyl4-nitroanilide substrate method). choline esterase (ChE; DTNB method), total protein (biuret method). albumin (BCG method), glucose (hexosokinase-G-6-PDH method). total cholesterol (cholesterol oxidase·DAOS method), triglyceride (GPO·DAOS method, glycerin elimination method). total bilirubin (vanadic acid oxidation method). urea nitrogen (BUN; urease·GLDH method). creatinine (creatininase·F·DAOS method), inorganic phosphorus (PNP'XOD method), calcium (Ca; MXB method), sodium**(N~).** potassium (K) and chlorine (CI; for the above. ion selective electrode method; for the above, model 7070 automatic analyzer, Hitachi Ltd.), and A/G ratio (calculated from TP and ALB).
(9) Necropsy At the end of administration period and recovery period, the animals were opened under ether anesthesia, the blood was collected, then, the animals
were exsanguinated to death by cutting the abdominal aorta.**~**The body surface and various intracranial, intrathoracic and intraperitoneal organs and tissues were observed macroscopically.
(10) Organ weights After necropsy, the following organs were excised and weighed with an electronic balance (Sartorius K.KJ, and the data was collected automatically with a safety study system. In addition, the relative weights
were calculated from the body weight on the day of necropsy. Brain, liver, kidneys,* spleen, adrenals,* testes.* prostate. ovaries* and uterus. Bilateral organs marked with * were determined individually for the right and left sides.

26 

## O()03S2(11) Histopathology 1) Excision. fixation and preservation of organs and tissues The following organs and tissues (after having determined the organ weights for the above designated organs) were excised, and all the organs and tissues were fixed and preserved in 10% neutral buffered formalin solution. The eyeballs and harderian gland were, however, prefixed in glutaraldehyde-formalin solution and testes in Bouin solution, and then preserved in 10% neutral buffered formalin solution. The lung was injected 10% neutral buffered formalin solution through the trachea and immersed in this solution. Brain. pituitary. thyroid gland (including parathyroid), thymus, salivary gland (submandibular gland. sublingual gland), heart, trachea and lungs. liver, stomach, duodenum. kidneys. spleen. adrenals, testes, prostate. epididymidis. seminal vesicles. ovaries. uterus, urinary bladder, bone and bone marrow (sternum. femur). eyeballs (right and left. including optic nerve). harderian gland (right and 'eft). and the organs and tissues with macroscopic abnormalities. Carcasses were discarded.
2) Preparation of histopathological specimens and histopathological examination At the end of administration period, microscopic examinations were conducted on the organs and tissues in the water for injection JP control group. the vehicle control group and the 1000 mg/kg group after having excised. embedded in paraffin. sectioned. and stained with hematoxylin and eosin. The organs and tissues examined were heart, liver. spleen. kidneys. adrenals. testes. prostate. ovaries. uterus, stomach. duodenum. bone

marrow and bone (femur. sternum) and the organs and tissues with macroscopic abnormalities [epididymidis in one male (No. 01 MOS) in the

27 

## 000353vehicle control group and the uteri in one each offemale in the 10 and 100 mg/kg/day groups (No. 02F02 and 03F03)]. Since there was no effect of the test substance in the histopathological examination at the end of administration period. no histopathological examination of organs and tissues was conducted in the mid-dose group. the low-dose group and the recovery group.

8. Statistical analysis The measured values obtained were compared with the water for injection JP control group using the following test methods and described at the possibility of less than 5% and less than 1". In the 2a-day treatment group. Bartlett's test for homogeneity of variance was conducted, and if the homogeneity of variance was observed, one-way analysis of variance was conducted. As a result. if there was
some significant difference between groups. a paired comparative test of

mean values was conducted with the water for injection JP control group using Dunnett's method. If the variance was not uniform. Kruskal-Wallis' s H-test was conducted. and if there was some significant difference between groups, a paired comparative test of mean rank was conducted with the water for injection JP control group using Dunnett's method. In the 14-day recovery group. F-test was conducted, and if uniformity of variance was observed, Student's t-test was conducted, and if no uniformity of variance was observed, Aspin-Welch' s t-test was conducted to compare with the water for injection JP control group. For clinical signs and the results of ophthalmoscopy, urinalysis. necropsy and histopathology, no statistical analysis was conducted.

9. Environmental factors considered to have influenced on the reliability of study results and deviation from study protocol (1)Deviation from the study protocol

28 

## 000354

## CD In the protocol. the name of the test substance was described as but in the final report. the IUPAC name,
was used. 

## ® In the protocol. only bone marrow (femur. sternum) was to be examined in the histopathological examination. but bone tissues (femur, sternum) were also examined. 

## ® In the protocol. the storage period of records, documents and specimens was set to 5 years. In the final report, however. it was described as the period specified in Article 32-1 of the GlP.

(2) Unforeseeable matter Since a female No. 04F03 died due to excessive ether anesthesia at blood collection, no blood for hematology could be collected. and hematology could not be conducted.
(3) Effects on the reliability of study results For (1) above. there was no effect on the reliability of study results for all of (1), 

## ® and 

### ®. For (2) above, reasonable evaluation could be made from the test values of other 4 cases, and there was no effect on the reliability of study results.

IV. Results 1. Mortality and clinical signs (Tables 1 and 2. Appendices 1 and 2) Throughout the administration and recovery periods. no death was observed. For clinical signs. salivation was sporadically observed in 1 to 3 animals per day on and after 10 days of administration for males and on and after 9 days of administration for females in the 1000 mg/kg group. No other clinical signs were observed in any of males and females in any group throughout the administration period and recovery period.

29 

## 000355

# 3)

2. Body weights (Figures 1 and 2, Tables 3 and 4, Appendices 3 and 4) Throughout the administration period and the recovery period, no difference was observed in any of males and females in any treatment group compared with the water for injection JP control group.

3. Food consumption (Figures 3 and 4, Tables 5 and 6, Appendices 5 and 6) Throughout the administration period and the recovery period, no difference was observed in any of males and females in any treatment group compared with the water for injection JP control group.

4. Food efficiency (Tables 7 and 8, Appendices 7 and 8) Throughout the administration period, no difference was observed in any of males and females in any treatment group compared with the water for injection JP control group. A significant increase was observed in males in the vehicle control group on Day 17 of administration.

5. Water intake (Figures 5 and 6, Tables 9 and 10, Appendices 9 and 10) Throughout the administration period and the recovery period, no difference was observed in any of males and females in any treatment group compared with the water for injection

...IP control group.

6. Ophthalmoscopy (Tables 11 and 12. Appendices 11 and 12) In the examinations before the start of administration and at the end of the administration period and the recovery period, there was no abnormality in any of males and females in any group.

7. Urinalysis (Tables 13 and 14. Appendices 13 and 14) In the examination at the end of the administration period and the recovery period. no difference was observed in any ofmales and females in

30 

## OU035Gany treatment group compared with the water for injection JP control group.

8. Hematology (Tables 15 and 16. Appendices 15 and 16) In the examination at the end of administration period. significantly shortened activated partial thromboplastin time was observed in males in the 1000 mg/kg group, and significantly decreased reticulocyte count in females in the 10 mg/kg group, compared with the water for injection JP control group. In the examination at the end of recovery period. a significant decrease in the eosinophil ratio was observed in females in the 1000 mg/kg group, compared with the water for injection JP control group. In addition, a significant decrease in the band nucleic neutrophil ratio was observed in males in the vehicle control group compared with the water for injection JP control group.

9. Blood biochemistry (Table 17 and 18. Appendices 17 and 18) In the examination at the end of administration period, a significant increase in total cholesterol was observed in males in the 10 mg/kg group, and a significant decrease in triglyceride in females in the 1000 mg/kg group. compared with the water for injection JP control group. In the examination at the end of recovery period, significant decreases in 

### r -GTP and BUN and significant increases in triglyceride. glucose, albumin and A/G ratio were observed in males in the 1000 mg/kg group compared with the water for injection JP control group. In addition, significant decreases in ALT and BUN and a significant increase in albumin were observed in males in the vehicle control group compared with the water for injection JP control group.

10. Organ weights (Tables 19 and 20, Appendices 19 and 20)

31 

## 000357

# J3

In the examination at the end of administration period. a significant decrease in the absolute weight of right adrenal was observed in males in the 10 and 100 mg/kg groups compared with the water for injection JP control group.

In the examination at the end of recovery period, no change was observed in males and females in the 1000 mg/kg group. A significant decrease in the relative brain weight was observed in males in the vehicle control group compared with the water for injection JP control group.

11. Necropsy {Tables 21 and 22. Appendices 21 and 22) In the examination at the end of administration period, swollen uteri were observed in 1 to 4 females in all treated groups, but there was no difference in its incidence compared with the water for injection JP control group. In addition. nodes at the cauda epididymidis were observed in one male in the vehicle control group, and atrophied ovaries and uterus
were observed in one female in the vehicle control group. In the examination at the end of recovery period, no abnormality was observed in any group.

12. Histopathology (Table 23. Appendices 23 and 24) ]n the examination at the end of administration period, infiltration of mononuclear cells and microgranulomas in the liver, infiltration of mononuclear cells, basophilic tubules, fibrosis and cysts in the kidneys. increased extramedullary hematopoiesis in the spleen, infiltration of mononuclear cells in the prostate and dilated lumen of uterus were observed in males or females in the 1000 mg/kg group. which were similarly observed in the water for injection JP control group or the vehicle control group.

32 

## 000358V. Discussion and conclusion

. was repeatedly administered orally to Sprague-Dawley rats [Crj:CD(SD)IGS] at dose levels of 0 (water for injection JP control group. 

### o (vehicle control group). 10. 100 and 1000 mg/kg for 28 days to examine its toxicity. Number of animals was 10 each ofmales and females per group in the 0 (water for injection JP control group). 0 (vehicle control group) and 1000 mg/kg groups, and 5 each of males and females per group in the 10 and 100 mg/kg groups. For 5 each of males and females in the 0 (water for injection JP control group), 0 (vehicle control group) and 1000 mg/kg group. administration was withdrawn for 14 days after the end of administration period to examine the recovery. Water for injection JP and Macrogol 400 were administered fn a similar manner in the water for injection JP control group and the vehicle control group. respectively. For clinical signs. salivation was sporadically observed in 1 to 3 animals per day after administration on and after 10 days of administration in males and on and after 9 days of administration in females in the 1000 mg/kg group. It was a transient finding not observed before administration

on the next day. which was considered as a reflective response induced by stimulation of the test substance. Since no macroscopic or histopathological change was observed in the oral cavity. salivary gland and stomach. this finding was considered to be of no toxicological significance. Significantly shortened activated partial thromboplastin time and significantly decreased triglyceride observed in the hematology and blood biochemistry at the end of administration period were both mild changes. Since there was no histopathologically related change in the liver. these changes were considered to be of no toxicological significance. For the significantly decreased reticulocyte count and significantly increased total cholesterol, there was no relationship to doses, and these changes

were not considered to be attributable to administration of the test

33 

## OU0359substance. Significantly decreased eosinophil ratio observed at the end of recovery period was a mild change and considered as a physiological change. Also. since the change was not observed at the end of administration period. it was considered to be of no toxicological significance. Significantly decreased 

### r -GTP and BUN and significantly increased triglyceride. glucose. albumin and A/G ratio observed at the end of administration period were the changes not different from the vehicle control group. Therefore, all the changes were inferred as the changes not related to administration of the test substance. For the organ weights, significantly decreased absolute weight of the right adrenal observed at the end of administration period was not a dose-dependent change. and there was no change in the relative weight. Therefore, it was considered as the change not related to administration of the test substance. In addition. there was no abnormality attributable to administration of the test substance in body weight. food consumption. food efficiency. water intake. ophthalmoscopy. urinalysis. necropsy and histopathology. As shown the above. since no toxic change was observed even after administration of at a dose of 1000 mg/kg. the No Observed Adverse Effect Level of nder the conditions of this study
was considered to be 1000 mglkg for both males and females.

VI. Reference 1)Kouichi Neda. et al. Preliminary acute oral dose toxicity study and preliminary 7-day repeated oral dose toxicity study of

. in rats. Final report of (PROJECT No.

34 

## OU0360Attachment 1 Test Result (StabilityTest)

Analytical ChemistryOffice Februaryl, 2000

Testsubstancename HFE-347pc-f PROJECTNo. Analyzed sample Preparation of LotNo. 

### -_..-""-----""..._ ....-.-......

# _ ...... name

. PreparingSection Safety No.2 research date January3l.2000 section Usedbaseproduct LotNo Baseproduct LotNo.991224 Usedmedium macrogol400 LotNo.EI-1

Analysisdate January3I, 2000 Analytical method SOPNo.1 3-03-74 Analyticalresult Storagecondition Atroom temp. protected from light. airtight Storageperiod Start After4hours Nominal concentration 5mglmL Observed 4.77 4.69 4.58 4.75 4.63 4.65 value 4.81 4.71 4.67 Determined 4.71(94.2%) 4.68(93.6%) value Residual 100% 99.4% ratio 500mglmL Observed 494 496 494 489 486 476 value 493 491 489 Determined 493(98.6%) 484(96.8%) value Residual 100% 98.2% ratio l)Unitofthe observedvalue andthedeterminedvalue ismg/mL 2) ( )ofthe determinedvalue isrecoveryagainstthe nominalconcentration 3)Theobservedvalueinstartofstorageare obtainedonesfromconcentrationanalysis and homogeneitytest. Judgment Acceptable Acceptablerange Residual ratio>=90%

Theparsonincharge ofAnalysisTest AnalysisTestDirector Date February 1,2000 Manager 

## 000361.

# 31 Attachment2 Test Result <concentration analysis, homogeneitytest)

Analytical ChemistryOffice Feburlyl,2000 

### ITest substancename ..
I Analyzed sample HFE-347pc-f Preparation of**~--** PROJECTNo. LotNo. 

### I"

. -,--­ ..**-~.-,--**

..

-----------.......................-----­ name -. Preparing Section SafetyNo.2 research date January31,2000 section UsedLotNo LotNo.991224

. Usedmedium macrogol 400 LotNo.EI-l

Analytical date January31,2000 Analytical method SOPNo.13-03-74 Analyticalresult



### I nominal Sampling

concent­ point ration
.0mglmL Center layer 5mglmL Upper layer Center I layer

Lower layer 50mglmL Upper layer Center layer Lower layer 500mglmL Upper layer Center layer Lower layer I Observed value(mglmL) 1 2 Averag
e

N.D. N.D. N.D.

4.77 4.81 4.79

4.69 4.71 4.70

4.58 4.67 4.63

48.5 49.2 48.9

47.9 49.1 48.5

48.4 48.2 48.3

494 493 494

496 491 494

494 489 492 Determined Observe Observe CV value vs vs % (mglmL) nominal determine % % N.D. 

### --­ --­ 

## --­
4.71 94.2 102 1.7

99.8

98.3

48.6 97.2 101 1.0

·99.8

99.4

493 98.6 100

. 0.5

100

99.8

I)Thedeterminedvalue is obtainedby average of6 observedvalues. 

## 04.10362

# 33 2)Observevsdetermine meanspercentoftheaverage ofobservedvalues/determinedvalue. 3)CV(%)is obtainedby average of6observed values. 4)N.D. meanslessthanidentification limit. Judgment Acceptable Acceptable Concentration:+-l0%ofthe nominal value (concentration range Homogeneity: +-10%ofthenominalvalue ,homogeneity)

Theparsonincharge ofAnalysisTest AnalysisTestDirector Date February 1,2000 Manager



## 0003G3Figure 1, 2 3, 4 5, 6

Table 1, 2 3, 4 5, 6 7, 8 9,10 11,12 13,14 15,16 17,18 19,20 21,22 23 Body weight changes 1

........ 2 Food consumption 3

........ 4 Water intake 5

........ 6

Clinical signs B6dy weights 7

........ 14 15

........ 18 

# C)

Food consumption 19

........ 22 Food efficiency 23

........ 26 Water intake 27

........ 30 Ophthalmoscopy 31

........ 32 Urinalysis 33-38 Hematology 39-48 Blood biochemistry 49

...... 60 Absolute and relative organ weights 61-68 Necropsy 69-72 Histopathology 73-74 ;' \. \"



## 000364/"""\

./ 

### \..

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# - tlD


### .....,



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# .,. 500

400

300 --0- 

### Control

-­ Vehicle -fr- HFE-' ----;6;- HFE­-o-HFE

## omgl/kg 

# omg kg 10 mg/kg 100**m!~kg** 

### 1000 

### ·m61kg

..... "0 » 

### 200 0 a:I



### 100
(-------------------------------- Treatment -------------------------------) (------------- Recovery ------------)


# o 8 

### 15 22 28 1 8 

### (Days) 

# e Fig.l 

### Body weight changes of male rats treated orally with for 28 days 

## o C.J QI) PROJECT No. 

### CIt 

# -t:.**~** 

## c 14

### 500 --0- Contro I 

## omg/kg e-- 

### Vehicle 

# amgjkg --tr-- 

### 10 mi/kg 100 mg/kg --0- 

### 1000 mg/kg 400

,.... bD 

### 300



# -

...... ..c bD I\) jI: 

# L**~~ ~** **~~** N**~** 

### 200 . c co

# ~

100 (-------------------------------- Treatment -------------------------------) (------------- Recovery ------------)


# a 8 15 22 28 1 8 

### 14 

# c (Days) 

# c o Fi,g.2 Body weight changes of female rats treated orally with for 28 days G.J**~** 

### a-J PROJECT No. 

## ..J:: /,,'-'..... ,""

## ...' \....-) 

# -

### 50 

# o**~Control** 

# omg/kg

-- Vehicle ,- 

# omg/kg -Cr-' 

### 10 

### mg/kg 

# .- 100 mg/kg --0---

. 

### 1000 mg/kg 40



### ,.... CIO
......, s::: o 30

...... c.

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## 8 e ::I ." s::: o U "0 (.j.J o**~** 

### 20

10 

### (----------------------------- Treatment -----------------------------) (----- Recovery -----)



# o 3 

### 10 17 

### 24 

### 3 10 (Days) 

## o Fig.3 Food consumption of male rat. treated orally with. for 28 

### days 

# o c.J PROJECT ",**~**

# ~ c50 --0- 

### Control 

# omg/kg


### .- Vehicle 

# omg/kg



# ..**~** " ' 

### , 10 mg/kg 

# ..-- 100 mg/kg -0- 

### 1000 mg/kg 40

,.... bQ

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### 20

### ~ 

# 8 u. 

# t**~** ::::;:::: 

### -cQ" Q=:**~** 

# .- 0 

### =

10

### <---------------------~------- 

### Treatment**--------------------~---------)** 

### (----- Recovery -----)



# o 3 10 17 

### 24 3 (Days) 

# e o Fig.4 Food consumption of female rats treated orally with for 

### 28 days c.J 

### a"J 

### PROJECT No.**~ ("'~""**  

# o**~J** 

## c 10r" 

# o
./


### 60 -0- Control 

# omg/kg

- Vehiclp 

# omg/kg -fs-- 

### 10 mi/.kg 

# .-. 100 mg/kg 50**~** -{)--

# . 1000 mg/kg

----0 0-­ 40 

# _------0 • 

# . '"' -l E
......, II.)**~** «S 

### 30

..... C
VI**~** II.) «S !ill 

### 20

10 

# <---------------------------- Treatment**-----------------~---------)** 

# <---- Recovery -----)



# o 3 

### 10 17 24 3 

### 10**(Da~s)** 

### Fig.5 

### Water intake of male rats treated orally with. for 28 days 

# o c 

# o Co.) PROJECT No,**~** 

### r.:J

# ~.60 -0- 

### Control 

# omg/kg

-- Vehicle 

# omg/kg**~** 

### 10 mg/kg k- 

### 100 mg/kg 50**~** -0-, 

### 1000 mg/kg

40 

# - ...J E



### ...... Q,) .:.t!.



## ....

# 30~¥~ 

# :

!'OS C


# - Q\ '­ Q,)


## .... 

# • !'OS 

### 20

10 

### (---------------------------- Treatment ---------------------------) (---- Recovery -----)



# o 3 10 

### 17 24 3 

### 10 

## o (Days) 

# e­ Fig.6 

### Water intake of female rats treated orally with for 28 days O G.J "'\1**~** PROJECT No, 

### -b**~** ...."**~** 

# ,**\~ r~'** **~** ',-)

Table**'~l** Clinical Signs of male rats treated orally with for 28 days
Group-No. Dose (llg/kg) 00 flndings No.of animals**----------------------------------------~s** of trea

## tunt 1 2 3 4 5 6 1 8 A 6 10 10 A B 10 10 A B 10 10 A B 10 10 A 6 -A-B10 10 10 10 A 6 10 10 A B 10 10 

# )=---------------------------------------------­ 9 10 11 12 13 14 A B 10 10 A B 10 10 A B 10 10 A B 10 10 A B 10 10 A B 10 10 Contro I no abnorllalities 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 

### o 01 No.of anillals 10 10 TO 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 Vehicle no abnorl1alities 10 

### to 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 

### o 02 No.of aniliaI $ 5 5 5 5 5 5 5 S 5 5 5 5 5 5 5 5**~** 5 5 5 5 5 5 5 5 5 5 5 no abnormalIties 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 10 03 No.of aniaals 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 -..J no abnorDalitias 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 100 04 No. of animals 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 .10 10 10 10 10 10 10 10 no abnormalities 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 9 10 10 10 10 10 9 10 8 1000 salivation 2 A : Bafore adl1inistration 6 After adlilinistrillon PROJECT No



# c e 

## o GJ '.!

# ~**~**Tab!e 1-2 CIinica! signs of lIale rats treated orally with

. for 2& days
Group-No. 00$1 (lie/kg) Findings 15 A B 16 A B 17 A B 18 A B 19 A B ---(Days-oftreatill9n-t 20 21 22 A B A B A B**~--------------------** 23 24 25 A B A B A B 26 A B 27 A B 28 A B 00 Ho.of anillals 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 Control no abnormalities 10 10 10 10 10 10 10 10 lQ 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 TO 

### o 01 No.of animals 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 Vehicle no abnormalltles 10 1'0 1010' 1010 1010 1010 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 

### o 02 No.of anlilais 5 5 5 5 5 5 5 5 S 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 no abnormalities 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 10 03 No.of anlilais 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 S co no abnormalities 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 S 5 S 5 100 04

A No.of anl.als no abnorllalities 1000 salivation Before adainistration 10 10 10 10 10 10 8 10 9, 10 2 B : After administration 10 9 I' 10 10 10 9 10 10 10 9 10 10 10 9 10 10 10 8 2 10 10 10 8 2 10 10 10 9 10 10 10 8 2 10 10 10 9 10 10 10 T 3 10 10 10 7 3 10 10 10 8 2

PROJECT No



# o o o c.J**~** 

### N

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. 

# C)

. / Table 1-3 Clinical signs of male rats**tr~attd** orally with for 28 days
Group-No. Dose (I,/kl) Flndinls 

### ------------­ n -C-­**-----------------~sot** treatment -}-----­

00 No.of animals Control no abnorDaIitias 0 01 Ho.of aniDals Yetlic:le no abnorlll!lities 0 02 No.of animals no abnorll1alities 10
\0 03

04


## t No.of anillais no abnorllaIItias 100 No.of anilals no abnor!!al ities 1000 salivation Before autopsy
PROJECT Ho



## o c 

# o Co,) 

### ..J Co,) 

## -!::::.**~**',:

Table 1-4**~fini,al** siens of male rats treated orally with for 28 days
GtGup-No. Dose - 

### -------­ - 2 3 4 ----------------------------------( Dars of recovery 5 6 7 8 9 10 11 12 13 14 15**~--------------------------------------------------- ~·I/ki)**  FIndings 00 No.of animals 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 Control no**abnor~alities** 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 0 01 No.ol anillals 5 5 5 5 '5 5 5 5 5 5 5 5 5 5 5 Vehicle no abnorullties 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 0 04 No.of an!1Il1s 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 no**abnor~aiities** 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5

__ 1_000



### .... 0 PROJECT Ne



## e 

# o Col**~ ~**  

## ..t::

/

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### ~ ',---I 

# c!"c"­ 

# () "" ,J';
Table H Clinical signs of felur. rats treated orally with for 28 days
Group-No. Dose (III/kg) Findings A B 2 A B 3 --A----S-­ ------------------------( 4 5 6 A B A B A B Days of treatment 7 8 A B 

### r B 

### >--------------------------------­ 9 10 11 12 A B A B A B A B 13 A B 14 A B 00 No.of animals 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 Control no abnorilialities 10 10 10 10. 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 

### o 01 No. a f ani IIIIs 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 Vehicle no abnorrtlllties 10 1'0 10 10 10 10 10 10 to 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 

### o 02 No.of anil1als 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5

, no abnormalities 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 10 03 Ho.of anlililis 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5



### .... no abnorlaI Ities 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

# - 100 04

A No.of animals

. no abnorma Iities 1000 salivation Befor. adrtlnlstratlon B 10 10 10 10 10 10 10 10 10 10 After administration 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 9 10 10 10 9 10 10 10 9 10 10 10 9 10 10 10 9 10 10 10 8 2

PROJECT No,



# o 

# e o CJ 

### -J CII

# ~Table 2-2 Clinical signs of female rat, treated orally with for 28 days
Group-No. Dose (miLkr} 00 Findings Ho.of animals 15-A-B10 10 16 A 8

.10 10 ---------------------------------( 17 18 19 20 A B A 8 10 10 10 10 A 8 10 10 A B 10 10 Days of treatllenn..:

.....:- ......:......:-------------------------------------------­ 21 22 23 24 2S 26 21 28 A 8 10 10 A B 10 10 A . B 10 10 A 8 10 10 A 8 10 10 A B 10 10 A 8 10 10 A 8 10 10 Control no abnorillI 1 tIas 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 

### o 01 Ho.of animals 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 Vehicle no abnorlllaIities 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 

### o 02 No.of animals 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 no abnormal itias 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 10 03 No.of animals 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 l-' N no abnor.aI itillS 5 5 5 5, 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 100 04 No.of anillals 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 no abnorlll I itIes 10 9 10 9 10 10 10 9 10 9 10 9 10 7 10 9 10 9 10 9 10 8 10 9 10 8 10 9 1000 salivation 1 3 1 2 2 A Before ad.lnlstratlon B : After administration
PROJECT No



# c 

# e o t.J "".l 

# '-"

­ a'J /''', i I , J '--'

# o

Table 2-3 Clinical signs 

### of female rlts treated orilly with for 28 days
Group-No.**--~-s-----------------------------------------------<** Days 

### oflfreatmenf )-------------------­--------------------------------­ 00$8 (1II1/kg) FIndIngs C 00 No.of animals 5 Control no abnorlllal Itles 5 0 01 No.of anllllais 5 Yehlcle no abnormalIties 5 0 02 

### No.of animals no abnormalities 5

___ 10 03 No.of anImals 5 i-l I.H no abnorllla rIIIes 5 100 04 No. of Inimlls no abnormalIties 1000 salivation C-;- Before autopsy 5 5

PROJECT Ne



# o o C.J**~ ~**  

# p cTable 2-4 CI inleal signs of fellale rats treated orally with .or 28 days
Group-No. Dose**(Ig/k~)** 00 Control Findings No.•of anillais

no abnormalities 

### ------------------------­ 2 3 4 5 6 7

5 5 5 5 5 5 5 5 5 5 5 5 5 5 

## -­ ---­ 8 9 10

5 5 5 5 5 5 11

5 5 12

5 5 

# - -< Days of 13 14 15

5 5 5 5 5 5 recovery 

### )=-----------------------------------------------­

0 Ot No.of anillals 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 Vehicle no abnormalities 5 S 5 5 5 5 5 5 5 5 5 5 5 5 5 0 04 No.of anillals 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 no abnormall ties 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 1000



## .... .;. PROJECT No.



# e o tJ ".l 

### ell ,"-.:."""'. 

# 'lJ c(""'" 

## u
Table 3-1 

### Body weights 

### of male rats treated orally with. for 28 

### days 

### Group-No.**-------------------------------------------~s**

## or-frealmerit--;---------------------------------­ Dose (mg/kg) 

### 1 8 15 22 28 

## 00 N 

### 10 10 10 10 10 Contro Mean 231 289 340 379 410 0 S. O. 

### 8 14 

### 18 21 23 01 N 

### 10 10 10 10 

### 10 Vehicle Mean 233 296 347 392 424 0 S.D. 

### 7 12 14 21 27 02 N 

### 5 5 5 5 5 Mean 231 290 337 374 403 10 S.D. 

### 11 18 24 31 34



# ... V\ 

### 03 N 

### 5 5 5 5 5 Mean 232 286 329 365 391 100 S.D. 

### 8 10 15 22 25
(lA N 

### 10 10 10 10 10 

### Mean 232 288 335 372 399 1000 S.O. 

### 8 12 18 22 23 Unit: g N : 

### No.of animals
PROJECT 

### No.


# c c 

# o t.J 

### <oJ (J)

# ~

### Table 3-2 Body 

### weights of male rats treated orally with for 28 days 

### Group-No. Dose**-------------------------------------------<~ays** 

## of recovery )---------------------------------­ (mg/kg) 1 

### 8 14**~** N 5 5 5 

### Control Mean 401 430 449 0 S.O. 

### 17 

### 18 18 01 N 

### 5 5 5 

### Vehicle Mean 418 448 473 0 S.D. 

### 38 44 50 

### 04 N 

### 5 5 5 

### Mean 396 423 

### 442 1000 S.O. 

### 33 37 38 

### Unit: g 

### N : No.of animals 

# - 0\ 

### PROJECT No.



# o e 

# o C.J

/"P

...... 

## o 

# b.

# ,**,-"'~'** 

### 00

# o
Table 4-1 Body weights' of female rats treated orally with for 28 days 

### Group-No. Dose (mg!kg) 

## 00-­ Control 0 N 

### Mean S.D. 

## --------------------=----------..:-----------( Days of trea.tment L­ 

### 8 15 22 28 10 10 10 10 10 168 194 215 231 243

7 12 11 

### 15 17 

### -)---------------------------------­

01 Vehicle 0 N 

### Mean S.D. 

### 10 168

8 10 196

12 10 215

18 10 233

21 10 246

20 02 10 N 

### Mean S.D. 

### 5 167

5 5 

### 188

5 5 206 5 5 224

10 5 235

10 03 100 N 

### Mean S.D. 

### 5 167

9 5 194

9 5 211

11 5 

### 228

12 5 235

12 04 1000 Unit: g N 

### 10 

### Mean 167 S.D. 

### 7 

### N : No.of animals 10 190

9 

### 10 208

12 10 222

14 10 236

11

PROJECT No.



# e 

# c o CJ**~ ~** 

# ~

### Table 4-2 Body weights of female rats treated orally with. 'or 

### 28 

### days Group-No. -------------------------------------------( Days 

### of recovery )---------------------------------­ Dose (mg/kg) 1 8 14 

### 00 N 5 5 5 

### Control Mean 247 259 273 

### 0 S.D. 

### 12 18 17 01 N 5 

### 5 5 VehicIe 

### Mean 242 253 264 0 S.D. 

### 16 15 

### 23 

### 04 N 5 5 5 

### Mean 238 251 257 1000 S.D. 10 9 

### 16 N No. of 

## anirna Is**~--~~-** Unit: g

..... 00 

### PROJECT No.



## c 

# e o C.J 

### 00 

### N 

# 4 /,"", 

### \--.,.J 

## ----.l/"". ("""\1

..-,/**~~** ../ 

### Table 5-1 

### Food consumption of male rats treated orally with for 28 

### days Group-No.**------------7-------------~----------------<** 

### Days of treatment )---------------------------------­ Dose -1 2 9 16 23 (mg!kg) ...... 

### 1 -17 

### - 3 - 10

- 24 00 N 

### 10 10 10 10 10 

### Control 

### Mean 26.3 27.3 28.7 30.0 30.3 0 S.D. 

### 1.4 3.3 

### 1.8 2.8 3. 1 01 N 

### 10 10 10 10 10 

### Vehicle 

### Mean
.26.2 26.9 28.6 29.8 29.0 0 S.D. 

### 1.7 1.9 2.7 2.5 3.5 02 

### N 5 5 5 

### 5 5 

### Mean 26.3 26.3 28.6 30.4 29.3 10 S.D. 

### 1.4 2.2 2.3 3.0 2.9

.­

. .J:>**O~** N 

### 5 5 5 

### 5 5 

### Mean 25.7 25.9 27.3 27.6 27.5 100 S.D. 

### 1.1 1.4 2.2 1.4 2.7 0.4 N 

### 10 10 10 10 10 

### Mean 25.5 24.9 26.7 27.4 28.8 1000 S.D. 

### 2.0 1.9 

### 2. 1 1.9 

### 1.4 Uni

### t : g 

### N No.ofanimals
PROJECT 

### No.



## o 

# o GJ Q)

# ~ t.) 

# c

### Table 5-2 Food consumption of male rats treated orally wi 

### th for 28 

### days Group-No. -------------------------------------------(- Days of recovery )---------------------------------­ Dose 2 9 (mg/kg)

-- 3 ,.." 10 00 N 5 5 . 

### Control Mean 29. 1 29.4 0 S.D. 2.0 1. 1 01 N 5 5 

### Vehicle Mean

.27.9 

### 28.8 0 S.D. 4.3 3.6 04 N 5 5 

### Mean 28. 9 28.8 1000 S.D. 2.0 2.2
N 

### Unit: g 

### N No.of animals 0 

### PROJECT No.



# e 

# o c.J 

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# o J

# ~

-._.-' 

## c

# o
Table 6-1 

### Food consumption of female rats treated orally with. ilr 28 

### days Group-No. -------------------------------------------{ Days of**treatme~---------------------------------** 

### Dose -1 2 9 16 23 (mg!kg) - 1

-- 3 - 10

- 17

-- 24 N 10 10 -,0-----10----- -{0 00 

### Control Mean 16.5 19.3 19.7 18.0 20.3 0 

### S.D. 2.5 

### 2.0 3.2 2.8 

### 2.9 01 

### N 10

- 10 10 10 10 

### Vehicle Mean

. 17.7 18.0 19.4 19.3 20.4 0 S.O. 2.0 2. 1 2.3 2. 1. 1.4 02 N 5 5 5 5 5 

### Mean 18.7 18. 1 20. 1 19. 1 20.2 10 

### S.D. 2.0 1.4 2.2 1.6 2.2 I'..> 

### ""' 

### 03 N 5 5 5 5 5 

### Mean 17.5 19.0 19.0 ' 19.8 20.2 100 

### S.D. 1.2 1.0 1.4 2.2 2.5 04 

### N 10 10 10 

### 10 10 

### Mean 17.7 17.5 17.9 19.3 20.8 1000 

### S.D. 1.0 1.6 2.7 1.7 0.8 Uni t : g 

### N No.of animals
PROJECT 

### No.



# o 

# e o c.J ell**~ ~** **~**

### Table 6-2 

### Food consumption of 

### female rats treated orally with 

### for 28 days Group-No. 

### -------------------------------------------( Days of recovery )---------------------------------­ Dose 2 9 (mg/kg) "" 3 ,.", 10 00 N 

### 5 5 

### Control Mean 21.5 21.0 0 S.D. 

### 2.7 

### 2. 9 01 N 

### 5 5 

### Vehicle Mean '18.4 19.4 0 S.D. 3.0 

### 2.2 

### 04 N 5 5 

### Mean 20.4 19.7 

### 1000 S.D. 2.9 4.3 Unit g N 

### No.of an ma s 1:3 

### PROJECT No



# o o C.J

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## U 

# "'"' 

# - c"


### .. 

# o

Table 7-1 

### Food efficiency of male rats treated orally with for 28 days 

### Group-No. Dose (mg!kg) 00 N 

### Control Mean 0 S.D. 01 N 

### Vehicle Mean 0 S. D. 

### 02 N 

### Mean 10 S. D. N (;.l 

### 03 N 

### Mean 100 S.D. 

### 04 N 

### Mean 1000 S.D. -------------------------------------------( DaYSof t

### reatment 2

...... 3 

### 10 30.8

2.6 9

..... 

### 10 10 25.5

2.3 16

..... 17 

### 10 18.2

2.2 10 33:8

2.9 10 

### 2S.4

3.6 10 

### 21. 8

# *

3.4 5 31.6

2.0 5 23.4

1.7 5 17.4

2.6 5 29.8

1.6 5 22.3

2.9 5 18.5

3.5 10 31.9

4.3 10 24.9

3.4 10 19.7

3.2 23

..... 

### 24 10 17.4 2.9

10 17.8

4.0 5 16.6

1.3



### 5 15.6 0.6

10 15.Z

3.4 

### )---------------------------------­

Unit X N : 

### No.of an ma s 

# *: Significantly different from control, 

### p(O.OS PROJECT 

### No.



# o e 

# o C.J 

### C1J**~**

# ~

### Table 7-2 Group-No. Dose (mg/kg) 

### 00·­ 

### Control 0 01 

### Vehicle 0 

### 04 1000 

### Food efficiency of male rats treated orally with 

### for 28 

### days

----------------------- ....::::=::...:- ...-------------,

## DaYs I)f recov

## eiY -):.:

......

## = ...=:.:
...-------------:...-----------­ 

### Z 9

,..., 3 ...., 10 N 5 

### Mean 14.1 

### S.D. 1.5 N 5 

### Mean

.15.4 S.D. 

### Z.O N 5 

### Mean 13.4 S.D. Z. 1 5 10.7



### 2.8 5 14.3



### 2.3 5 11.1

1.5 Unn :

# r N NI).ofanimals**~** 

### PROJECT No.



# o e 

## o t..J**~** 

## ........ Cll 

# () U**/-:.~~'"''**{'''­ 

# o -' 

### Table 8-1 

### Food efficiency of female rats 

### treated orally 

### with for 28 days 

### Croup-No.**-------------------------------------------~ays** 0

# rtr

### sa-liliant 

# >---------------------------------­ Dose 2 9 

### 16 23

­ (mgJkg) ....., 3 ....., 

### 10 ....., 17 ....., 

### 24 00 N 

### 10 10 10 10 

### Control Mean 19.0 15.6 12.0 9.5 0 S.D. 

### 4.0 3.2 3.3 5.1 01 N 

### 10 10 10 10 

### Vehicle Mean 21: 9 

### 13.7 13.4 10.3 0 S.D. 

### 4.3 

### 4.5 3.6 4.0 

### O? N 5 

### 5 5 

### 5 

### Mean 16.2 12.8 13.7 9.3 10 S.D. 

### 3. 1 

### 2.3 4. 1 

### 3.0**~** 

### 03 N 5 

### 5 5 

### 5 

### Mean 19.9 

### 13.3 12.0 5.7 100 S.D. 1.8 

### 1.8 1.8 1.9 

### 04


### Uni t 

### 1000 % N 

### 10 

### Mean 19.5 S.O. 2.2 

### N No.of 

### animals 10 14.0

3.7 10 10.5

3.8 10 11.2

3.9



### PROJECT Nc



# o c o CJ**~** (.(,)**~** 

## -t..

### Table 8-2 Food efficiency of female rats treated orally with for 28 

### days Group-No. 

## -------------------------------------------< Days of**recover~---------------------------------** 

### Dose 2 9 (mg/kg) - 3 "" 

## to 00 N 

### Control Mean 7. 7 11.6 0 

### S.D. 5.9 2.9 01 N 

### 5 5 

### Vehicle Mean 

### 8.0 9.7 0 S.D. 

### 2.0 6.3 04 N 5 5 

### Mean 9.4 3.3 1000 

### S.D. 2.9 8.2 tv Unit :**~** 

### N No.of an 

### mals Q\ 

### PROJECT 

### No.



## o 

## e· 

# o CJ

# ~ ;"f

__!'. 

# i,**~**

......,/ V 

## \-,,,,..,­ 

# o

Table 9-1 Water intake,of male rats**~reated** 

### orally with for 28 

### days 

### Group-No. -------------------------------------------,- Days of 

### treatment )---------------------------------­ 

### Dose -1 2 9 16 23 (mg!kg) 

### "" 1 - 3 "" 10 ,.." 17

- 

### 24 00 N 

### 10 10 

### ---10 ----10 

### 10 Control 

### Mean 37.1 38.6 42.5 46.5 45.6 0 

### S.D. 6.2 8.4 8.7 15.7 11.4 01 

### N 10 10 10 10 10 

### Vehicle Mean 33.5 37.0 39.9 42.4 41.2 0 S.D. 

### 3.2 3.6 4. 1 

### 4.3 4.8 02 N 5 5 5 5 5 Mean 33.8 37.9 39.3 41. 8 

### 42.3 10 

### S.D. 3.5 3. 1 4.0 3.

### 7 4.9

rv -.J 

### 03 N 5 

### 5 5 5 5 Mean 36.3 37.6 41. 1 43.8 45.5 100 S.D. 

### 4.5 2.9 5.9 5.7 11.6 04 

### N 10 10 , 10 10 10 Mean 34.8 34.3 39.4 40.7 41.7 1000 

### S.D. 3.6 3.4 3.3 3.8 3;9 Un it; mL 

## N No.of animals 

### PROJECT No



# o 

# e 

# o c.J toO**~** 

# .... .........

### Table 9-2 Water intake of male rats treated orally with 

### for 28 days 

### Group-No.**---~~----------------------------------<** 

### Days of recovery**>-~-------------------------------** 

### Dose 2 9 (mg/kg) - 3 - 10 00 N 5· 5 

### Control Mean 43.1 45.4 

## o S.D. 4.0 8.2 01 N 5 5 

### Vehicle Mean

.37.5 39. 1 

### 0 S. O. 4.0 

### 6.0 04 N 

### 5 5 

### Mean 39.3 40.4 

### 1000 

### S.D. 2.0 5.6
tv 

### Un it: ml 

### N : No.of animals 0:> 

### PROJECT 

### No



## o 

# e o c.J**~** 

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### ~ /'':'''",," 

### N () '-./(' (-­ 

# v Table 10-1 Water intake of female rats treated orally with for 28 days 

### Croup-No. 

## -------------------------------------------<-oiys 0

### ft-

### reat

## lI1ent )---------------------------------­ Dose -1 2 9 16 23 (mg/kg) - 1 - 3 ,..., 

### 10 ,..., 11 ,..., 

### 24 N - 

### 10- 

### fO----- 10- 

### --10 10 00 

### Control Mean 24. 1 27.8 28.0 26.6 29.9 0 

### S.D. 6.6 4.6 6.3 9.4 8.5 01 

### N 10 10 10 10 10 

### Vehicle Mean

.25.6 28.4 30.2 31. 5 

### 33.7 0 S. O. 

### 3.9 4. 1 4.8 5.6 7.7 02 

### N 5 5 5 4 4 Mean 32.4 32.5 40.2 35.0 35. 1 10 S. O. 

### 9.5 7.7 16.6 9.0 -8.0
t-.J v:> 

### 03 N 5 

### 5 5 

### 5 5 

### Mean 29.2 33.6 33.9 35.0 39.5 100 S.O. 

### 5.6 10.6 9.4 10.4 20.7 04 N 

### 10 10 10 10 10 Mean 25.9 27.6 26.5 28.3 30.3 1000 S.O. 3. 1 

### 3. 1 6.0 3.8 3.7 

### Unit : IIIL 

### N No.of animals
PROJECT 

### No.



# e o GJ 

### CD 

### G.J**~** 

## c

### Table 10-2 Water intake of female rats treated orally with for 28 days Group-No.**------------~------------------------------<** 

### Days 

### of**recoyery-~---------------------------------** 

### Dose 2 9 (mg/kg) ...., 3 ...., 10 

### 00 N 5 5 

### Control Mean 35.0 33.5 0 

### S.D. 6.5 8.6 01 N 5 5 

### Vehicle Mean

.32.4 32. 1 0 S.D. 

### 12.8 6.4 04 N 5 5 

### Mean 32. 1 29.9 1000 S.D. 3.8 8.0 

### Un

### it: mL N 

### No.of animals w 0 

### PROJECT No.



## o 

# e o ..oS) (..) 

# " (.Q**I""I~** i ,**~** \

..-1/,,"C,.

, '. 

### Table 11 

### Ophthalmoscopy of**mal~** 

### rats treated orally with
Before 4-week Group Dose treatment treatment No. (mg/kg)

.___-.Bight Left 

### Right Left -_
..._--­ 

## 00 Control 0 

### 01 

### Vehicle0 02 10 03 100

lJ.) 

### 04**~** 

### 1000 0/10 0/10
0/10 0/10
0/ 5 0/5
0/ 5 0/ 5
0/10 0/10 0/10 0/10
0/10 0/10
0/ 5 0/ 5
0/ 5 0/ 5
0/10 0/10 

# 0**~or** 

### 28 days
2-week recovery Right Left 0/ 5 0/ 5
0/ 5 0/ 5

0/ 5 0/ 5 

### No.of animals with abnormality 

### 7No.of**an~mals** 

### examined
PROJECT No.



## e 

# e 

# o CJ CJ) 

# '-l**~** C)

# -- Table 12 

### Ophthalmoscopy of female rats treated orally with for 28 days
Before 4-week 2-week Croup Dose treatment treatment recovery No. (mg/kg) Right Left Right Left Right Left 00 

### Control0 0/10 0/10 0/10 0/10 0/ 5 0/ 5 01 

### Vehicle0 0/10 0/10 0/10 

### O/tO 0/ 

### 5 ' 0/ 5 02 10 0/ 5 0/ 5 0/ 5 0/ 5 03 100 0/ 5 0/ 5 0/ 5 0/ 5

w N 

### 04 1000 0/10 0/10 0/10 0/10 

### 01 5 0/ 5 

### No.of animals with abnormality 

### I No.of animals examined
PROJECT No.



## o 

## e 

# o c.J CoD CJ')

,-\ '\_-) 

## .....l/

Table 13-1 Urinalysis of male'rats treated orally with )r 28 days

- 28-day of treat ment

­ Group-No. Occult Ketone Glucose Protein pH Urobilinogen Bilirubin Color Dose blood body (mg/kg) Grade Grade Grade Grade Grade Grade 00 5 5 5 0 5.0 0 O. 1 5 5 A -S Control 

### ± 0 

### ± 0 0 5 6.0 0 1.0 0 

### + 0 B 0 0 

### + 0 

### + 0 0 0 6.5 0 2.0 0 2+ 0 C 0 2+ 0 2+ 0 0 0 1.0 1 4.0 0 3+ 0 0 0 3+ 0 3+ 0 0 0 1.5 3 8.0 0 4+ 0 0 0 8.0 1 8.5 0 01 5 2 5 0 5.0 0 O. 1 5 5 A 5 Vehicle ± 0 

### ± 3 0 2 6.0 0 1.0 0 

### + 0 B 0 0 

### + 0 

### + 0 0 3 6.5 0 2.0 0 2+ 0 C 0 2+ 0 2+ 0 0 0 1.0 0 4.0 0 3+ 0 0 0 3+ 0 3+ 0 0 0 1.5 5 8.0 0**~** 4+ 0 0 0 8.0 0**~** 8.5 0

.. 5 01 4 5 0 5.0 0 O. 1 5 5 A 5 1: 0 

### ± 1 0 3 6.0 0 1.0 0 

### + 0 B 0 10 

### + 0 

### + 0 0 2 6.5 0 2.0 0 2+ 0 

### C 0 2+ 0 21' 0 0 0 1.0 0 4.0 0 3+ 0 D 0 3+ 0 3+ 0 0 0 1.5 4 8.0 0 4+ 0 0 0 8.0 1 8.5 0 Color A ; pale yellow B ; yeIlow C ; yellowish brown D; other


### PROJECT No.



## c 

# e



# - CJ 

### f.D 

# .....J. --J

# ~Table 13-2 Urinalysis of male rats lreated orally with for 28 days

- 28-day of treatment

­ Group-No. Occult Ketone Glucose Protein pH UrobiIInogen Bilirubin Color Dose blood body (mg/kg) Grade Grade Crade Grade Grade ---Crade --5 0' 5 3 5 0 

### 5.0 0 O. 1 5 5 A 

### '± 0 

### ± 2 0 2 6.0 0 1.0 0 

## + 0 B 0 )00 

## + 0 

## + 0 0 3 6.5 0 2.0 0 2+ 0 C 0 

# , 2+ 0 2+ 0 0 0 7.0 4.0 0 3+ 0 0 0 3+ 0 3+ 0 0 0 7.5 3 8.0 0 4+ 0 0 0 8.0 1 8.5 0 04 5 1 5 0 5.0 0 O. 1 5 5 A 5 

### ± 0 

### ± 4 0 1 6.0 0 1.0 0 

## + 0 B 0 1000 

## + 0 

### + 0 0 3 6.5 0 2.0 0 2+ 0 C 0 

# , 2+ 0 2+ 0 0 1 7.0 4.0 0 3+ 0 0 0 3+ 0 3+ 0 0 0 7.5 3 8.0 0**~** 4+ 0 0 0 8.0 1 .;.. 8.5 0 Color: A : pale yellow 8 ; yellow C ; yellowish brown 

## o ; other
PROJECT No.



# c c 

# o 

# d CoJ 'D**./".~""** r"""\**~** I \"-"",r:"" ("''''-. J
Table 13-3 Urinalysis of male rats treated orally with ror 28 days

- 14-day of recovery ­ GraiIP-Ho. Occult Ketone Glucose Protein pH Urobilinogen Bilirubin Color Dose blood body (mg/kg) Grade Grade Grade Grlide Graae Gride 00 

# --=- 4 2 5 t 5.0 0 

### O. 1 5 5 A 5 Control 

### ± 1 

### ± 3 0 3 6.0 0 1.0 0 

### + 

## o B 

## o 

## o + 0 

### + 0 0 1 6.5 0 2.0 0 

### 2+ 

## o C 

## o 2+ • 0 2+ 0 0 0 7.0 0 4.0 0 3+ 

## o o 

## o 3+ 0 3+ 0 0 0 7. 5 3 8.0 0 4+ 0 0 0 8.0 1 8.5 1 01 5 3 5 0 5.0 0 O. t 5 5 A 5 Vehicle 

### ± 

## o ± 2 0 5 6.0 0 1.0 

## o + 

## o B 

## o 0 

### + 

## o + 

## o 0 0 6.5 0 2.0 

## o 2+ 

## o C 

### o 2+ 

## o 2+ 

## o 0 0 7.0 1 4.0 

## o 3+ 

### o 

### o 

## o 3+ 

## o 3+ 

## o 0 0 7.5 2 8.0 

## o Vol 4+ 

## o 0 0 8.0 1 VI 8.5 t (lA 5 3 5 3 5.0 0 O. t 5 5 A 5 l:: 

## o ± 2 0 2 6.0 0 1.0 

## o + 

## o B 

## o tOOu 

### + 

## o + 0 0 0 6.5 0 2.0 

### o 2+ 

## o C 

## o 2+ 

## o 2+ 0 0 0 7.0 0 4.0 

## o 3+ 

## o o o 3+ 

## o 3+ 0 0 0 7.5 3 8.0 

## o 4+ 0 0 0 8.0 t 8.5 t Color 

### A pale yellow B : yellow 

### C ; yellowish brown 

### D : other
PROJECT No


## o e 

# o GJ 

### C.D .....) 

### C.D 

# -.c::

# o e 

# o**~** 

## o <:>

# ~0.4**/';~,** 

### , f"'''." I, j '-'.
Table 14-2 UrinalysIs of female rats treated orally with for 28 days

- 28-day of treatment

­ Group;;'No. occurt Ketone Glucose Protein pH Urobilinogen Bilirubin

-----.. Color Dose blood body (mg/kg) Grade Grade Grade Grade Grade Grade 

## or 5 5 5 5 5.0 0 

### O. 1 5 5 A 5 

### ± 0 ± 0 0 0 6.0 0 I.0 0 

### + 0 B 0 100 

### + 0 

### + 0 0 0 6.5 0 2.0 0 2+ 0 C 0 2+ 0 2+ 0 0 0 7.0 2 4. 0 0 3+ 0 0 0 3+ 0 3+ 0 0 0 7.5 3 8.0 0 4+ 0 0 0 8.0 0 8.5 0 5 5 5 4 5.0 0 O. 1 5 5 A 5 

### ± 0 ± 0 0 1 6.0 0 1.0 0 

### + 0 B 0 1000 

### + 0 

### + 0 0 0 6.5 1 2.0 0 2+ 0 C 0 2+ 0 2+ 0 0 0 7.0 1 4.0 0 3+ 0 0 

## a 3+ 0 3+ 0 0 0 7.5 3 8.0 0 \.;J 4+ 0 0 0 8.0 0 -.J 8.5 0 Color: A ; pale yellow B ; yellow C ; yellowish brown 

## o ; other
PROJECT No.



## o e 

# o**~** 

# o

# ~**~**Table 14-3 Urinalysis of female rats treated orally with for 28 days

- 14-day of recovery ­ Group-No. Occult Ketone Glucose Protein pH Urob IIInogen Bilirubin Color Dose blood body (mg/kg) Grade Grade Grade Grade Grade Grade 

### 00 5 5- 5 5 5.

### 0 0 O. 1 5 5 A 5 Control 

### ± 0 

### ± 0 0 0 6.0 0 1.0 0 

## + 0 B 0 0 

## + 0 

## + 0 0 0 6.5 0 2.0 0 2+ 0 C 0 2+ 0 2+ 0 0 0 7.0 0 

### 4.0 0 3+ 0 

## o . 0 3+ 0 3+ 0 0 0 7.5 1 

### 8.0 0 4+ 0 0 0 8.0 4 8.5 0 01 5 5 5 5 5.0 

## o . O. 1 5 5 A 5 Vehicle 

### ± 0 

### ± 0 0 0 

### 6.0 0 1.0 0 

### + 0 B 0 0 

### + 0 

### + 0 0 0 6.5 0 2.0 0 2+ 0 C 0 2+ 0 2+ 0 0 0 7.0 2 4.0 0 3+ 0 0 0 3+ 0 -3+ 0 0 0 7.5 2 8.0 0 u..l 4+ 0 0 0 8.0 1 00 8.5 0 04 5 5 5 5 5.0 0 O. 1 5 5 A 5 

### ± 0 ± 0 0 0 

### 6.0 0 1.0 0 

### + 0 B 0 1000 

### + 0 

### + 0 0 0 6.5 0 2.0 0 2+ 0 C 0 2+ 0 2+ 0 0 0 7.0 2 

### 4.0 0 3+ 0 0 0 3+ 0 3+ 0 0 0 7.5 1 8.0 0 4+ 0 0 0 8.0 2 8.5 0 Co or A ; pale yei low B ; yellow C ; yellowish brown 

## o ; other
PROJECT No.


## o 

# e o**~** 

## o N 

## ......;:,**/;::,~** .... ".­ 

### '-l i.,--/ )

### Table 15-1 Hematology of male rats treated orally with 'or 28 days

- 28-day of treatment

­ Group-No. RBC Ht Hb 

### MeV MCH MCHC Reticulocyte Platelet Dose (mg/kg) 

### (x10'/Ul) 

### ( % ) ( g/dl ) ( fl ) ( pg ) 

### ( % ) (%0) (x10'/U,l) 00 N 

### 5 5 5 5 5 5 5 5 

### Control Mean 798 47.9 16.6 60. 1 20.8 34.6 20 107.0 0 S.D. 

### 21 0.9 0.3 1.4 0.6 0.4 4 18.8 01 N 

### 5 5 5 5 5 5 5 5 Vehicle 

### Mean 823 48.7 16.6 59.2 20.2 34.2 20 110.5 0 S.O. 

### 42 0.9 0.2 2.0 0.9 0.6 5 11.5 02 N 

### 5 5 5 5 

### 5 5 

### 5 5 

### Mean 813 48.3 16.6 59.5 20.4 34.2 24 108.6 10 S.D. 

### 13 O.7 0.2 1.3 0.6 0.4 4 12.7**~** 10 

### 03 N 

### 5 5 5 5 5 

### 5 5 5 

### Mean 807 47.5 16.3 58.9 20.2 34.2 20 108. 1 100 S.D. 

### 26 1.4 0.4 0.6 0.2 0.3 6 7.4 04 N 

### 5 5 5 5 5 5 

### 5 5 

### Mean 811 48.4 16.6 59.7 20.4 34.2 22 112. 1 1000 S.O. 

### 24 1.6 0.5 0.9 0.2 0.3 4 14.7 N : No.of animals
PROJECT Ne



# o '-, 

# - o ,.::. 

## <:> '-oJ C.J**~**

# -- Table 15-2 Hematology of male rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. PT 

### APTT 

## wac Differential count 

### (X) Dose (mg/kg) 

### ( sec.) ( sec.) (x102

### 1tLL) 

### lYDlPho Eoslno Mono Baso Stab 00 N 5 

### 5 5 

### 5 5 5 

### 5 5 Control Mean 17. 1 25.2 126 87.9 1.3 3.8 0.0 0.5 0 S.D. 2.9 1.0 14 3.4 1.0 0.9 0.0 0.4 01 N 5 

### 5 5 5 5 5 5 5 Vehicle Mean 17. 1 24. 1 116 86.3 1.5 4.4 0.0 0.9 

### 0 S.D. 1.6 1.9 12 3.3 0.8 2.4 0.0 O.7 02 N 5 

### 5 5 

### 5 5 5 

### 5 5 

### Mean 16.4 22.7 140 87.5 0.8 1.5 0.0 0.4 10 S.D. 2.0 1.1 23 4.9 0.6 1.1 0.0 0.5



# ... 0 

### 03 N 

### 5 5 

### 5 5 5 

### 5 5 

### 5 

### Mean 18.2 24.7 125 89.0 0.4 2.7 0.0 0.4 100 S.D. 

### 3.3 1.9 18 1.3 

### O.7 1.6 

### 0.0 0.5 

### O} N 

### 5 5 5 5 5 5 5 5 

### Mean 15.3 22. 1

# * 125 88.6 0.9 2.0 0.0 0.3 1000 

### S.D. 0.8 2.2 30 2.9 

### 0.7 1.1 0.0 0.4 N : No.of animals 

# *: Significantly different from control. p(0.05 PROJECT 

### No.



## o c**~** 

# o .......Q**~** 

# o**~** ,/''''''\ 

# I)

............/.,r<""' 

### f""" '-.-J 

### Table 15-3 Hematology of male rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. Dose (DIg/kg) 

### Seg 00 N 5 

### Control Mean 6.5 0 

### S.D. 2.4 01 N 5 

### Vehicle Mean 7.0 0 

### S.D. 1.3 

### 02 N 5 

### Mean 9.8 

### 10 

### S.D. 3.9



### ,... 03 N 5 

### Mean 7.5 100 

### S.D. 1.6 

### 04 N 

### 5 Mean 

### 8.2 1000 S.D. 

### 2.4 N : No.of animals

PROJECT 

### No.



# o 

# c 

# o o**~** 

### CJ1

# ~------ 

### Table 15-4 Hematology of male rats treated orally with for 28 'days

- 14-day of recovery ­ Group-No. RSC Ht Hb 

### MCV MCH 

### MCHC Reticulocyte Platelet Dose (mg/kg) (x10"/J,tl) ( % ) 

### ( g/dl ) ( fl ) ( pg ) ( % ) 

### (%0) 

### (x10"/J,tl) 00 N 

### 5 5 

### 5 5 

## 5 5 5 5 

### Control Mean 846 47.9 16.6 56.S 19.6 34.6 20 104.7 0 S.O. 

### 30 0.9 0.4 1.1 0.4 0.3 6 

### 7.8 01 N 5 5 5 5 5 5 5 5 

### Vehicle 

### Mean 850 48.4 16.1 57.0 19.6 34.5 21 112.6 0 S.O. 

### 31 1.6 0.6 1.8 

### O. 1 0.5 3 14.9 

### Od N 5 5 

### 5 5 

### 5 

### 5 5 

### 5 

### Mean 861 48.6 16.7 56.4 19.4 34.3 17 

### 99.0 1000 S.D. 

### 30 1.0 0.2 

### 1.0 0.7 0.6 5 17.5 

### N : No.of animals


# ... N 

### PROJECT No.



# c 

# e 

# o .:. Q (1)**r"~** : /,=-""


## .

# ~ \,

__.1/ 

### '" '"--,, 

### Table 15-5 Hematology of male rats treated orally with for 28 

### days

- 14-day 

### 01 recovery ­ Group-No. 

### PT 

### APTf WBC Differential coun (%) 

### Dose (mg/kg) 

## 00-­ Control0 N 

### Mean S. D. 

### ( sec.)5 16.4

1.6 ( sec.)5 22.9

2.9 (x1

### 0 2 / PoL) 

### 5 121 24 Lympho 5 

### 82.7



### 5.2 Eoslno

## 5 0.8 O.7 

### Mono 5 

### 7. 1 

### 1.3 Baso 5 0.0 0.0 Stab 5 O.7 

### 0.3 01 Vehicle0 N 

### Mean S.D. 

### 5**18.~** 

### 4.3 5 23.2'

3.5 5 108 24 5 81. 3

6.2 5 1.5 0.9 5 5.3 2.0 5 0.0 0.0 5 

### 0.2

# * 0.3 04 1000 N**,~ean** S.D. 5 17.8 

### 3.0 5 

### 23.4

2.3 ' 5 110

29 5 83.3

5.3 5 1.4 1.0 5 

### 6.5 2. 1 5 0.0 0.0 5 0.6 0.5
01:1­ w 

### Group-No. Dose (mg/kg) 

### 00 Control0 N 

### Mean 

### S.D. Seg8.7 

### 3.6 _._. ­**~'---'-**



### 01 Vehicle0 N 

### Mean 

### S.D. 5 

### 11.8 

### 5.0 04 1000 N**~ean** 

### S.D. 5 

### 8.2 3'.0 N No.of animals 

# * Significantly different from control. p(0.05 

# o 

# e PROJECT Ne 

# o**~** 

### C>**~**

# ~

### Table 16-1 Hematology of female rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. RSe Ht Hb 

### MCV MCH MCHC Reticulocyte Platelet Dose (mg/kg) (xl04/ ttl) 

### ( %) 

### ( g/dL ) ( fL ) ( pg ) ( %) 

### (%0) (xl04/ ttL) 

### 00 N 

### 5 5 5 5 5 

### 5 5 5 

### Control Mean 800 46.7 16.6 58.5 20.7 35.4 18 104.8 0 S.D. 

### 34 

### 0.9 0.3 1.7 0.9 0.6 1 

### 11.5 01 N**~** 

### 5 5 5 

### 5 5 5 5 Vehicle Mean 799 46.7 16.4 58.5 20.6 35:2 15 110.0 0 S.D. 

### 45 1.9 0.7 1.4 0.5 O. 1 5 14,.8 02 N 

### 5 5 5 5 5 

### 5 5 5 

### Mean 821 47.5 16.6 57.9 20.3 35.0 11 

# * 103.6 10 S.D. 

### 12 1.4 0.7 1.0 0.5 0.3 4 9.5**~ ~**  

### 03 N 5 5 

### 5 5 5 

### 5 5 5 Mean 793 46.8 16.3 59.0 20.6 34.9 16 111.5 100 S.D. 

### 19 1.6 0.5 1.0 0.4 0.3 6 5.3 04 N 4 4 4 4 4 4 4 4 Mean 786 45.5 16.0 57.9 20.3 35. 1 18 112.5 1000 S.D. 

### 22 1.1 0.3 1.2 0.5 0.3 1 6.3 N : No.of animals 

# *: Significantly different from control, p(0.05 PROJECT No



# - 

# - C 

# o**~** 

# c**~** 

## () , !


### ...... 

# Y9/«'<
',,,/ 

### Table 16-2 Hematology of female rats treated orally with

. for 28 days

- 28-day of treatment

­ Group-No. PT APTT WBC Differential count (X> Dose (mg/kg:) ( sec.) 

### ( sec.) 

### (xl02 / ttL) 

### lympho Eoslno Mono Baso Stab < 00 N 5 5 5 5 5 5 

### 5 5 

### Control Mean 14.6 17.9 77 

### 87.6 1.9 1.6 0.0 

### 0.6 0 

### S.D. 1.0 1.2 23 3.9 O.7 O.7 0.0 0.8 01 N 

### 5 5 5 5 5 5 5 5 Vehicle Mean 14.

### S 18.2 81 90.7 1.0 

### 1.8 0.0 O. 1 0 S.D. 0.3 1.3 15 2.5 0.4 0.4 0.0 0.2 

# a? N 

### 5 5 5 5 5 5 5 5 

### Mean 15.4 18.4 72 83.2 1.0 2.0 0.0 0.6 10 S.D. 0.4 0.6 33 5.3 0.9 1.8 0.0 0.8

VI 

### """ 03 N 

### 5 5 5 5 5 5 5 5 Mean 15.

## a 18.4 74 89.6 0.5 1.3 0.0 0.3 100 S.D. 0.8 0.5 14 2.3 0.4 0.3 0.0 0.3 04 N 

### 4 4 4 4 4 4 4 4 .:ean 14.6 17.6 54 86.2 1.3 4.5 0.0 0.4 1000 S.D. 0.6 0.5 8 2.4 1.0 3.9 0.0 0.5 N : No.of animals PROJECT No.



# o 

# e o .::. c,:, \D

# ~

### Table 16-3 Hematology of female rats treated orally with


### . for 28 

### days

- 28-day of treatment

­ 

### Group-No.**--~** -­ 

### Dose ---Seg (mg/kg) 00 

### N Control Mean 0 S.O. 

### 01 N 

### Vehicle Mean 0 S.D. 

### 02 N 

### Mean 10 S.D.

C\ 0':1 

## "'" N 

### Mean 100 S.O.
n.4 N 

### Mean 1000 S.O. 

### N ; NO.of animals



# o 

# e o**~** 

### t-I'**~** 

### 5 8.3 4. 1 

### 5 

### 6.4 2.0 5 13.2 4.2 5 

### 8.3 2.5 4 

### 1.7 

### 2.6
PROJECT 

### No.

"'-;'" 

# (, 

# f\/"'''', f"""', '-....J 

### Table 16-4 Hematology of famale rats treated orally with for 28 days

- 14-day of recovery ­ Group-No. RSC Ht 

### Hb 

## Mev MCH MCHC Reticulocyh Platelet Dose

.(mg/kg) 

### (x10"/J,l.l) 

### (**~** 

### ) ( g/dl ) ( fl ) ( pg ) 

### ( % ) 

### (%0) (x1 0 4 / J,I.

### L) 00 N 

### 5 5 

### 5 5 5 

### 5 

### 5 5 

### Control Mean 823 46.6 16.3 56.7 19.9 35.0 13 115.8 0 S.D," 

### 53 2.7 1.0 

### 1.0 0.5 0.4 3 9.9 01 N 5 

### 5 5 

### 5 

### 5 5 

### 5 5 

### Vehicle Mean 80'4 46.3 16.0 

### 57.5 19.9 34.7 17 

### 104.7 0 S.D. 

### 25 2.0 0.8 1.1 

### 0.6 0.4 

### 5 9.5 

### 04 N 5 

### 5 5 

### 5 5 

### 5 5 5 

### Mean 803 46.5 16.3 58.0 20.3 35.0 16 81.0 lUUO S.D. 

### 49 1.5 

### 0.4 1.9 1.0 O.7 4 40.2

..... 

### N : No.of animals ....;j 

### PROJECT No,



## o 

# e o**~** 

# ... ...**~**

### Table 16':'5 Hematology of female rats treated orally with for 28 days**~** 

### 14-day gf recovery ­ Group-No. PT 

### APTT WBC Oifferential count (t) 

### Dose (mg/kg) ( sec.) ( sec.) (x1 0 2 / /.LL) 

### lympho Eosino
.Mono Baso Stab 

### 00 N 

### 5 5 5 5 

### 5 5 5 5 

### Control Mean 15.6 18.3 54 84.5 1.6 4. 1 0.0 0.3 0 S.D. 1.0 1.2 10 5.0 0.8 2.9 0.0 0.4 01 N 

### 5 

### 5 5 

### 5 5 

### 5 5 5 

### Vehicle Mean 15:3 18.0 61 80.4 2.0 4.8 0.0 0.4 0 S.D. 

### 0.3 1.9 21 6.8 1.2 2.3 0.0 0.4 04 N 

### 5 5 5 5 

### 5 5 

### 5 5 • Mean 

### 15.0 18.5 68 81.9 0.6

# * 5.5 0.0 O. 1 

### 1000 S.O. 

### 0.4 1.1 18 5.4 0.4 3.3 0.0 0.2**~** 

### Group-No. Dose (mg/kg) Seg 00 N 5 

### Control Mean 8.9 0 S.D. 

### 2.6 01 N 5 

### Vehicle Mean 12.5 0 S.O. 

### 6.6 04 N 5 

### Mean 5.9 1000 S.D. 4.1 

# o N 

### No.of animals 

# * Significantly different from control, p(0.05 

# o 

# ,.. PROJECT 

### No. 

### N

### ~ /''''',

## .**{~ ~**  '--./ 

# c-- · ..."... "


### Table 17-1 Blood biochemistry of male rats tr.eated orally with' for 28 days

- 28-day of treatment

­ Group-No. AST ALT r-GTP ALP ChE Total Total Triglyceride Dose bilirubin cholesterol (mg!kg) ( lUll ) ( IU!L ) ( lU!l ) ( lU!l ) ( IU!L ) (mg!dL) (mg!dl) (mg!dl) 00 N 5 

### 5 

### 5 5 5 5 

### 5 5 Control Mean 98 32 0.09 447 392 0.02 44.9 46.0 0 S.

### D. 21 5 0.15 137 25 0.02 5.4 5.2 01 N 5 5 

### 5 5 

### 5 5 

### 5 5 Vehicle Mean 9-1 41 O. 16 420 444 0.03 51. 2 58.7 0 S.O. 14 26 0.22 92 91 0.01 7.8 18.2 02 N 5 

### 5 5 5 

### 5 5 5 5 Mean 104 34 0.03 383 438 0.03 58.6

# * 69.7 lU 

### S.D. 9 

### 3 0.06 47 76 0.01 11.0 28.4



### ..... \0 

### 03 N 5 

### 5 5 

### 5 5 5 5 

### 5 Mean 115 30 0.37 418
. 396 0.03 43. 7 30.6 100 S.O. 11 

### 4 0.46 88 44 0.01 7.8 10.0 04 N 5 

### 5 5 

### 5 5 

### 5 5 5 Mean 111 31 0.08 417 440 0.02 56.7 55.9 1000 S.D. 

### 8 3 0.15 48 87 0.01 6. 1 18.9 N : No.of animals 

# *: Significantly different from control, p(0.05
PROJECT No.



## c 

# c o**~ ~**  

### CJ

# ~

### TabIe 17-2 Blood biochemistry of male rats treated orally with' for 28 days

- 28-day of treatment

­

- ATC-­ 

### Group-N!i-:- BUN 

### Creatinine Glucose Total Albumin Ca Inorganic Dose protein phosphorus (mg/kg) (mg/dL) 

### (mg/dL) (mg/dL) ( g/dL ) ( g/dL ) (ratio) (mg/dL) (mg/dL) 00 N 5 5 5 

### 5 5 5 5 

### 5 Control Mean 13. 1 0.23 146.3 5.8 4.5 3.6 10.0 8.6 0 S.D. 

### 0.5 0.02 21.0 0.2 O. 1 0.6 0.4 0.4 01 N 

### 5 5 5 5 

### 5 5 5 5 

### Vehicle Mean 14

..2 0.23 150.6 5.6 4.3 3.6 10.0 8.5 0 S.D. 1.6 

### 0.02 17.2 O. 1 0.2 0.8 0.3 0.2 02 N 5 5 5 

### 5 5 5 5 5 Mean 12.9 

### 0.22 148.8 5.7 4.4 3.3 10.0 8.8 10 S.D. 

### 0.8 0.03 18.5 0.2 0.2 O.7 0.2 0.4

VI 0 

### 03 N 5 5 5 

### 5 5 5 5 5 Mean 11.5 0.24 127.6 5.5 4.3 3.6 9.7 8.5 100 S. O. 

### 1.6 0.03 6.5 O. 1 0.2 O.7 O. 1 0.5 04 N 

### 5 5 

### 5 5 5 

### 5 5 5 Mean 14. 1 0.23 150.9 5.8 4.5 3.7 10.2 8.5 1000 

### S.D. 1.5 0.02 24.1 0.2 O. t 0.9 0.3 0.5 N : 

### Ho.of animals
PROJECT No.



# o e o**~** 

# ...**~**

# ~ ,r) 

# '­

# 0
Table 17-3 Blood biochemistry of male rats treated orally with for 28 days

_**----=-28-d~y** 

### of treatment

­ Group-No. Na K CI 

### Dose (mg!kg) (mEQ!L) (mEQ!L) (mEQ!L) 

### 00 N 

### 5 5 

### 5 Control Mean 143.4 4.39 107.3 0 S.

### D. 0.4 0.39 1.2 01 N 5 5 5 

### Vehicle Mean 143.,2 4.60 107.5 0 S.

### D. 1.4 

### 0.30 0.9 02 N 5 5 5 

### Mean 142.2 4.79 105.9 10 S. D. 1.1 

### 0.30 2. 1

VI 1-1 

### 03 N 

### 5 5 5 

### Mean 143.\ 4.64 107.8 100 S.D. 

### 0.6 0.37 0.9 04 N 5 5 

### 5 ..,ean 142.9 4.

### 79 106.4 1000 S.D. 

### 1.9 O. 

### 19 1.9 

### N : No.of animals



# o o 

# o .:.


# ... CIt PROJECT 

### No.



# "-' t::::j

### TabI e 17-4 Blood biochemistry of male rats treated orally with for 28 days

VI N



# e

o**~** 

### t-.a. C1) 

### - 14-day of recovery ­ Group-No. 

### AST ALl r-GTP ALP ChE 

### Total Total Triglyceride Dose bilirubin cholesterol (mg/kg) ( lUlL) ( lUlL) ( lUll ) .( lUlL) ( lUlL) (mg/dL) (mg/dL) (mg/dL) 00 N 5 

### 5 

### Control Mean 128 35 0 S.D. 

### 19 4 01 N 

### 5 5 Vehicle Mean 128 28

# * 0 S.D. 

### 16 4 04 N 

### 5 5 Mean 

### 110 33 1000 S.O. 

### 24 3 

### 5 2.03 O. 19 5 1.96 

### 0.36
1.31 5

# ** 0.38 5 340

32

5 

### 321

41

5 307

51 5 467

42

5 414

85

5 489 114 5 0.03 0.02 5 0.03 0.02 5 0.05 0.02 5 

### 5 57.4 26.6 10.0 8.8 5 

### 5 54.5 41.7 10.9 12.8 5 54.0 5 49.6 

# * 8.5 

### 16.0 N : No.of animals 

# * : Significantly different from control, p(0.05 

## ** : Significantly different from control, p(O.01
PROJECT No.



## ..&)

,....-.....

, \ 

### r'" '. I '-' 

# ­ c!' /'.'''1**\~i** 

### Table 17-5 Blood biochemistry of male rats treated orally with

.or 28 days



### - 14-day 

### of recovery ­ Group-No. 

### BUN Creafinine Glucose Total Albumin A7G Ca Inorganic Dose protei

### n phosphorus (mg/kg) (mg/dL) 

### (mg/dL) (mg/dL) ( g/dL ) ( g/dL ) 

### (ratio) (mg/dL) 

### (mg/dl.) 00 N 5 5 5. 5 5 5 5 5 

### Control Mean 16. 3 

### 0.25 

### 128.3 5.8 

### 4.3 3.0 9.7 

### 7.5 0 

### S.D. 1.1 

### 0.02 

### 6.5 O. 1 O. 1 

### 0.3 0.2 0.4 01 N 5 5 5 5 5 5 

### 5 5 

### Vehicle Mean 13.·8

# * 0.24 133.5 5.8 

### 4.6 

# ** 3.7 9.7 7.3 0 

### S. D. 1.3 

### 0.02 

### 17.0 O. 1 

### O. 1 0.6 0.2 0.6
OJ! N 5 5 5 5 5 5 5 5 

### Mean 13.9

# * 0.22 

### 141.4

# * 5.8 

### 4.6

# ** 3.9 

## ** 9.8 7.0 1000 

### S.D. 1.7 

### 0.02 11.

### 0 0.2 O. t 

### 0.3 0.2 0.8 

### N : No.oT animals VI W 

# * Significantly different from control. p<0.05 

# ** : Significantly different from control. p<O.Ol
PROJECT 

### No.



## e 

# o**~** 

### f-IIo**~**

# ~ c

### TabI e 17-6 Blood biochemistry of male rats treated orally with for 28 days

. - 14-day of recovery ­ _._....._ .._ ...­ 

### Group-No. Na K CI 

### Dose (mg!kg) (mEQ!l). (mEQ!l) (mEQ!l) 

### 00 N 5 5 5 Control Mean 144.3 4.80 108.6 0 

### S.D. 1.8 

### O. 14 1.5 01 N 

### 5 5 5 Vehicle Mean 143.'9 4.79 107.5 0 

### S.D. 1.2 

### 0.43 1.4
IlJ 

### N 5 5 5 ·Mean 144.2 4.53 108.2 1000 

### S.D. 1.3 0.31

._ ..

### 1.8

_ ..­ 

### N : No.of animals U\**~** 

### PROJECT No.



# o o 

# .. e ""'" Cl) 

## .....Q 

# W ()

'

### .. ' . ..."

# o o**~ ~**  (.Q 

### .......Q 

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## --
Table 18-2 Blood biochemistry of female rats treated orally with. 

### .or 28 days

- 28-day of treatment

­ Group-No. 

### BUN Creatinine Glucose Total Albumin 

## AlG Ca Inorganic Dose protei

### n phosphorus (mg/kg) (mg/dl) (mg/dl) (mg/dL) ( g/dl ) ( g/dL ) (ratio) (mg/dL) (mg!dl) 00 N 5 5 5 5 5 5 5 5 Control 

### Mean 12.5 0.24 143.9 6.0 5.0 5.2 9.8 7.8 0 S.O. 1.6 0.01 31. 3 0.2 0.3 0.6 0.3 0.3 01 N 5 5 5 

### 5 5 5 5 5 

### Vehicle Mean 11.·2 0.23 124.9 6. 1 5.0 4.8 9.8 7.5 0 S.O. 1.5 0.02 22.9 0.3 0.3 0.8 0.3 0.5 

### 02 N 5 

### 5 5 5 5 5 

### 5 5 

### Mean 14.0 0.25 128.0 6.0 5.0 5.2 9.7 7.7 10 S.D. 1.6 0.02 14.2 0.2 0.2 0.6 0.2 0.4

IJI 

### 5 5 

### 5 03 N 5 5 5 5 5 

# '" Idean 13. 1 0.23 122.8 6.0 4.9

. 4.6 9.8 7.9 100 S.O. 1.1 0.01 24.2 0.3 0.2 1.1 

### 0.2 0.9 04 N 5 5 5 5 . 5 5 5 5 Mean 12.6 0.24 123.8 6.2 5.3 5.4 10. 1 8.2 1000 S.O. 1.7 0.02 14.2 0.4 0.4 0.6 0.5 1.2 N : No.of animals
PROJECT No.



# c c 

# o .:a. N 

### C 

# () 

# t\

### Table 18-3 Group-No. Dose (mg/kg) 

### 00 N 

### Control Mean 0 S.D. 01 N Vehicle Mean 0 S.O. 

### 02 N 

### Mean 10 S. O.
V\ 

### 03 N -...l 

### Mean 100 S.D. 04 N 

### Mean 1000 S.D.**/,,-~,**


### Blood biochemistry of female rats treated orally with
Na K CI (mEQ/L) 

### 5 143.0

1.0 (mEQ/l) 

### 5 4.57 0.49 (mEQ/l) 

### 5 108.8

0.8 5 

### 142:3

0.4 5 4.50 0.39 5 

### 108. 1 1.4 5 

### 142.8

1.3 5 

### 4.73 0.28 5 

### 108.7

0.8 5 

### 143.4 1.4 5 4.59 0.28 5 109.2 1.4 5 

### 143.9

2.7 5 

### 4.95 1.

### 36 5 

### 108.7 1.0 

### U**~**


### for 28 days

- 28-day of treatment

­

N : No.of animals
PROJECT No.



# c c o**~** 

### N 

## .....g


# ...**~**«,



### Table 18-4 Blood biochemistry of female rats treated orally with for 28 days

- 14-day of recovery ­ Group-No. AST ALT r-GTP ALP 

### thE Total Total Triglyceride Dose bi Ii

### rubi

### n cholesterol (mg/kg) ( lUll) ( lUll ) ( lUlL) ( lUlL) ( lUll ) (mg/dL) (mg/dL) (mg/dL) 00 N 

### 5 5 5 5 5 

### 5 5 5 Control Mean 114 27 2.08 206 2350 0.07 66.0 17.4 0 S. D. 

### 10 6 0.33 41 556 0.01 10.2 7.5 01 N 

### 5 5 

### 5 5 5 5 5 5 Vehiele Mean HI 

### 25 2.26 188 2237 0.08 57.9 11.9 0 

### S.D. 

### 24 5 0.32 30 402 < 

### 0.01 2.9 5.5 

### 04 N 

### 5 

### 5 5 

### 5 5 5 5 

### 5 Mean 95 

### 28 2.28 115 2505 0.08 67.3 14.5 1000 S.D. 

### 26 4 

### 0.58 37 125 0.02 11.4 

### 8. 1 N : No.of animals VI <Xl 

### PROJECT No.·



# o 

# o o .:. 

# :j N N**.,01['!~',** -' 

### "C)"'

... ,/ 

# 0
Table 18-5 Blood biochemistry of female rats treated orally with for 28 days

- 14-day of recovery ­ Group-No. BUN Creatinine Glucose Total Albumin 

## A1G Ca 

### Inorganic Dose protein phosphorus (mg/kg) 

### (mg/dl) (mg/dl) (mg/dl) ( g/dl ) ( g/dl ) (ratio) (mg/dl) (mg/dl) 00 N 5 5 5 5 • 5 5 5 5 

### Control Mean 15.3 0.26 126.1 6.4 5.2 4.4 9.9 6.7 0 S.D. 

### 2.0 0.01 8. 1 0.3 0.2 0.6 0.5 0.6 01 N 

### 5 5 5 5 

### 5 5 5 5 

### Vehicle Mean 15;4 0.28 135.3 6. 1 5. 1 5.3 9.9 6.4 0 S.O. 1.8 

### 0.02 15.9 0.3 0.4 1.7 0.3 0.6 04 N 

### 5 5 5 5 5 5 5 5 

### Mean 14.6 0.26 127.2 6.4 5.3 5.5 9.8 6.7 1000 S.D. 

### 1.0 0.04 5.7 O. 1 0.3 

### 2.4 O. t 

### 1.1
---_

........_ ..­ 

### N : No.of animals VI 1,0 

### PROJECT No.



## o 

# e o .:. N GJ

# ~--- --- 

### Table 18-6 Blood biochemistry of female rats treated orally with for 28 days**_~** 

### ___ -_14-day of recovery ­ Group-No. Na K 

### CI Dose (mg/kg) 

### (mEQ/L) (mEQ/L) (mEQ/L) 00 N 5 

### 5 5 

### Control Mean 143.2 4.52 109.7 0 S.D. 

### 1.3 0.37 1.3 01 N 

### 5 5 5 

### Vehicle Mean 144.·3 4.38 ltO.6 

### 0 S.O. 

### 1.1 0.27 0.9 04 N 

### 5 5 

### 5 

### Mean 143.8 4.28 110.4 1000 S.D. 1.1 

### 0.55 

### .5 N : 

### No.of animals 0\ 0 PROJECT 

### No.



# c 

# e 

# o**~** 

### N**~** 

# .:R 

# o/.0::"",,: 

### ("\

......."'"**.~** Table 19-1 Absolute**~nd** relative organ weights of male rats treated orally with for 28 days_

- 28-day of treatment

­ Group-No. Dose (mg/kg) 00 01 02 Control Vehicle 0 0 10 Final N body we ight (g) 5 5 5 388 

### ± 22 395 

## ± 11 374 

## ± 33 03 100

5 362 

## ± 22 

### 04 1000

5 374 

## ± 13 8rai

### n N (g) Re I. 5 5 5 2.13 

## ± O. 11 2.15 

## ± 0.07 2.09 

## ± 0.55 

## ± 0.03 0.54 

## ± 0.01 0.56 

## ± 0.07 0.04 5 2.10 

## ± 0.58 

## ± 0.05 0.03 5 2.11 

## ± 0.04 0.57 

### ± 0.02 N Liver (g) Re I. 5 5 5 12.26 

## ± 

## o.77 11.95 

## ± 0.74 11. 53 

## ± 3.16 

## ± 0.16 3.03 

## ± O. 15 3.08 

## ± 1.45 O. 14 5 10.43 

## ±

2.88 

## ± 0.83 0.09 5 11. 59 

## ± 1.45

3.09 

## ± 0.32
C\**~** Spleen N (mg) ReI. 5 5 5 727 

## ± 83 723 

## ± 85 760 

## ± 187 

## ± 12 183 

### ± 23 203 

## ± 74 12 5 768 

### ± 212 

## ± 93 25 5 707 

### ± 78 189 

### ± 17 Kidney(R) N (g) ReI. 5 5 5 1.42 

### ± 0.09 1.44 

### ± 0.05 1.37 

## ± 0.37 

### ± 0.03 0.37 

### ± 0.01 0.37 

### ± O. 15 0.02 5 1.29 

### ± 0.36 

## ± O. 11 0.02 5 1. 31 

### ± 0.09 0.35 

## ± 0.02 Kidn ey(L) 5 5 5 (g) 1.39 

## ± 0.0·9 1.44 

## ± 0.09 1. 35 

## ± ReI. 0.36 

### ± 0.03 0.37 

### ± 0.02 0.36 

## ± ReI. : Relative organ weight (g or mg!l1.lOg"final body weight)

- 

### N : No.of animals O. 12 0.02 5 1.33 

### ± 0.37 

## ±

- ---­ 

## o. 11 0.02 5 1. 31 

### ± 0.09 0.35 

### ± 0.02



# - "'-' 

# e o PROJECT No.**~** 

### N CIT

## ~ 0­Table 19-2 Absolute and relative organ weights of male rats treated orally with for 28 days.

- 28-day of treatment ­ Group-No. 00 01 02 03 04 Dose Control Vehicle (mg/kg) 0 

## a 10 100 1000 Adrenal{fn N (mg) ReI. 5 29.1 

## ±

7.5 

## ± 1.7 0.4 30.5 7.8 5 

## ± ± 1.5 0.4 24.8 6.7 5 

## ± ± 2.3 0.8 

# * 24.7 6.8 5 

## ± ± 1. 9 0.6 

# * 26.2 7.0 5 

## ± ± 3.9 1.1 Adrenal (l) N (lIIg) Re I. . 5 30. 7 

## ±

7.9 

## ± 2.7 0.5 31. 5 8.0 5 

## ± ± 1.9 0.& 26.2 7.0 5 

## ± ± 1.9 

### O.7 5 27.1 

## ±

7.5 

## ± 2.2 0.8 27.6 7.4 5 

## ± ± 4.6 1.3

C\ N TestIs(R) N (g) Re I. 5 1.60 

## ± 0.41 

## ± 0.08 0.03 5 1.60 

## ± 0.41 

## ± O. 11 0.03 5 1.53 

## ± 0.41 

## ± 0.17 0.05 5 1.56 

## ± 0.43 

## ± 0.05 0.02 5 1.57 

## ± 0.42 

## ± O. 12 0.04 Testis(L) N (g) ReI. 5 1.61 

## ± 0.42 

## ± 0.08 0.03 5 1.65 

## ± 0.42 

## ± O. 19 0.04 5 1.54 

## ± 0.41 

## ± 0.22 

### O.tl7 5 1.57 

## ± 0.43 

## ± 0.05 0.03 5 1.5& 

## ± 0.42 

## ± 0.11 0.04 Prostate N 5 5 (mg) 547 

## ± 105 545 

## ± ReI. 142 

## ± 33 138 

## ± ReI. : Relative organ weight (g or 

### II1g7 100g final 

### N : No.of animals 

## *: Significantly different from control, p(O.OS 47 10 body 5 491 

## ± 161 131 

## ± 42 we ight}-··­ 484 134 5 

## ± 109 

### ± 32 431 115 5 

## ± ± 55 13

PROJECT No. 

# o o o**~** 

### N Q') r" 

# c 

# , c:,:,


# -

### f"1 

### I...J
Table 19-3 

### Absolute and relative 

### organ weights of male 

### rats treated 

### orally with for 28 days 

### -14-day of 

### recovery ­ Group-No. 00 01 04 Dose 

### Control Vehicle (mg/kg) 0 0 1000 

### Final N 5 5 

### 5 

### body weight (g) 413 

### ± 15 436 

## ± 44 410 

## ± 37 

### Brain N 5 5 5 (g) 2.17 

## ± 0.07 2.18 

## ± 0.15 2.17 

## ± 0.09 Re I. 0.53 

## ± 0.01 0.50 

## ± 0.02

# * 0.53 

## ± 0.04 N 5 5 5 

### liver (g) 11.68 

### ± 0.71 12.71 

## ± 1.67 11.85 

## ± 1. 32 ReI. 2.83 

## ± 0.08 2.91 

## ± 

## o. 13 2.89 

## ± 0.13 

# e Spleen N 5 5 5 (mg) 744 

## ± 106 842 

### ± 112 812 

### ± 148 Re I. 180 

### ± 23 193 

### ± 14 197 

## ± 24 

### Kldney(R) N 5 

### 5 5 (g) 1.42 

### ± O. 14 1.47 

### ± O. 14 1.41 

## ± O. 14 ReI. 0.34 

## ± 0.03 0.34 

### ± 0.01 0.34 

## ± 0.01 

### Kldney(L) 5 5 5 (g) 1.40 

## ± 

## o. 20 1.53 

## ± 

## o. 11 1.43 

## ± O. 15 Re I. 0.34 

### ± 0.04 O. 35 

### ± 0.02 0.35 

### ± 0.02 

### ReI. : Relative organ weight (g or me 

### 7 100e flnal-bo-dy-Y'-elgnt) N : No.ot 

### animals '**~** 

# *: Significantly different from control. p(0.05 

### C­ 

### PROJECT No. O**~** 

### N ".l 

# '-­ C> 

# '-'

### TabIe 19-4 Absolute and relative organ weights of male 

### rats treated orally with for 28 days.



### - 14-day of recovery ­ Group-No. 00 01 04 Dose Control Vehicle (milkg) 

### 0 0 

### 1000 

### Adronal(R) N 

### 5 5 5 (mg) 

### 27.6 

### ± 3.5 28.2 

### ± 2.0 26.2 

### ± 4.5 Re I. 

### 6.7 

### ± 0.9 6.5 

### ± 0.5 6.5 

### ± 1.6 

### AdrenaI (L) N 5 

### 5 5 (mg) 

### 29.0 

### ± 3.9

. 29.2 

### ± 3.3 27.2 

### ± 3.9 Rei. 7.0 

### ± 0.8 6.8 

### ± 1.1 6.7 

### ± 1.4 TestIs(R) N 5 

### 5 5 (g) 1.56 

### ± O. 

### 18 1.

### 72 

### ± 0.14 1.60 

### ± 0.05 Re I. 

### 0.38 

### ± 0.03 0.40 

### ± 0.02 0.39 

### ± 0.04**~** 

### TestI

### s(L) N 

### 5 5 5 (g) 1.58 

### ± 

### O. 18 1.72 

### ± 0.17 1.59 

### ± 0.09 ReI. 

### 0.38 

### ± 0.04 0.40 

### ± 0.03 0.39 

### ± 0.03 Prostate N 5 

### 5 5 (mg) 

### 503 

### ± 92 565 

### ± 93 436 

### ± 32 ReJ. 122 

### ± 22 129 

### ± 13 107 

### ± 15 ReI. : Relative organ weight (g 

### or mg 

## 7 100g final body weight) 

### N : No.of animals
PROJECT 

### No. 

# o 

# o**~** 

### N**~**


### ........

pIA,;"\. 

# U 

# ce, c

# 0
Table 20-1 Absolute and relative organ weights of female rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. 00 01 02 03 04 Dose Control' Vehicle (mg/kg) 

### 0 0 10 100 1000 Final N 5 

### 5 5 5 5 body weight (g) 

### 217 

### ± 14 230 

### ± 22 215 

### ± 10 217 

### ± 10 216 

### ± 15 Brain N 

### 5 5 5 5 5 (g) 1. 95 

### ± 0.07 2.00 

### ± 0.08 1.95 

### ± 0.05 1.

### 99 

### ± 0.03 1.96 

### ± 0.05 Re I. 

### 0.90 

### ± 0.03 0.87 

### ± 0.07 0.91 

### ± 0.07 0.92 

### ± 0.03 0.91 

### ± 0.05 li

### ver N 5 

### 5 5 

### 5 

### 5 (g) 6.31 

### ± O.72 6.71 

### ± 0.68' 6.11 

### ± 0.49 6.35 

### ± 0.49 6.64 

### ± 0.53 ReI. 2.91 

### ± O. 19 

### 2.95 

### ± 0.24 2.84 

### ± O. 

### 15 2.92 

### ± 0.23 3.08 

### ± 0.26
0\ VI 

### Spleen N 5 5 5 5 

### 5 (mg) 449 

### ± 27 484 

### ± 82 483 

### ± 55 444 

### ± 72 431 

### ± 64 ReI. 

### 208 

### ± 8' 210 

### ± 21 224 

### ± 20 204 

### ± 29 198 

### ± 18 KI

### dney(R) N 

### 5 5 5 5 

### 5 (g) 

### 0.82 

### ± 0.07 0.86 

### ± 0.01 0.79 

### ± 0.02 0.84 

### ± 0.06 0.84 

### ± 0.06 Re I. 

### 0.38 

### ± 0.04 0.38 

### ± 0.03 0.37 

### ± 0.01 0.39 

### ± 0.02 0.39 

### ± 0.02 Kidney (L) 5 

### 5 

### 5 5 5 (g) 

### 0.80 

### ± 0.06 0.87 

### ± 0.03 0.78 

### ± 0.03 0.83 

### ± 0.05 0.83 

### ± 0.08 Re I. 

### 0.37 

### ± 0.04 0.38 

### ± 0.02 0.36 

### ± 0.01 0.38 

### ± 0.02 0.39 

### ± 0.03 ReI. : Relative organ weight (g 

### or mg 

## I 100g final body weight) N : 

### No.of animals
PROJECT No 

# o 

# e o 

# , N**~** 

### <:> 

## -t:. ClJ

### Table 20-2 Absolute and relative organ weights of female rats treated orally with for 28**da~s**



### - 28-day of treatment

­ Group-No. 00 

### 01 02 O:t 0.4 

### Dose Control Vehicle (Jllg/kg) 0 0 

## to 100 1000 AdrenaI

### (R) N 

### 5 5 

## 5 5 5 (mg) 

### 32.0 

### ± 4.0 31.5 

### ± .2.4 3t.0 

### ± 3.2 34.4 

### ± 5.2 33.2 

### ± 1. 1 Rei. 14.8 

### ± 1.4 13.9 

### ± 1.8 14.4 

### ± 1.1 15.9 

### ± 3.0 15.4 

### ± 0.8 . 5 Adrenal (L) N 

### 5 5 

### 5 5 (mg) 33.9 

### ± 5.4 32.9 

### ± 3.6 33.8 

### ± 2.9 36.9 

### ± 6.4 35.5 

### ± 2.4 Rel. 

### 15.6 

### ± 2.1 14.4 

### ± 1.8 15.7 

### ± 0.8 17.1 

### ± 3.3 16.4 

### ± 0.8 Ovary(R) N 5 5 

### 5 5 

### 5 (mg) 39.9 

### ± 8.3 34.3 

### ± 18.2 39.9 

### ± 7.5 39.5 

### ± 9.3 43.7 

### ± 7.6
0'1 

### (Rei.) 18.3 

### ± 2.8 15.5 

### ± 8.4 18.6 

### ± 3.4 18.1 

### ± 4.2 20.4 

### ± 4. 1 0'1 

### Ovary (L) N 5 

### 5 5 5 5 (mg) 

### 35.8 

### ± 4.5 32.3 

### ± 18.6 38.5 

### ± 6.0 39.0 

### ± 6.2 41.7 

### ± 7.8 (ReI.) 

### 16.5 

### ± 1.2 14.5 

### ± 8.3 17.9 

### ± 2.9 17.9 

### ± 2.

### 7 19.3 

### ± 3.4 Uterus N 

### 5 

### 5 5 5 5 (g) 0.55 

### ± 0.13 0.42 

### ± 0.35 0.46 

### ± 0.20 0.50 

### ± O. 14 0.70 

### ± 0.23 (Re I.) 

### 0.25 

### ± 0.07 0.19 

### ± 

## o. 16 0.21 

### ± 0.09 0.23 

### ± 0:07 0.33 

### ± 

### O. 12 

### RiL : Relative organ weight (g or mg 

## 7lOOg final body weight) N : No.of animals
PROJECT No. 

## o 

## --.' 

# - o**~** 

### CJ 

## '­ 

# o

# ~ ".,"",./ 

# \(;"".

</ 

# v Table 

### 20-3 Absolute and relative organ weights of female rats treated orally with for 28 days

- 14-day of 

### recovery ­ 

### Group-No. 00 01 04 Dose Control Vehicle (mg/kg) 

### 0 0 

### 1000 Final N 

### 5 5 5 body 

### weight (g) 

### 248 

### ± 16 237 

### ± 18 236 

### ± 13 Brain N 

### 5 5 5 (g) 1.

### 99 

### ± 0.05 2.

### 01 

## ± 0.04 1.

### 99 

## ± 0.03 ReI. 

### 0.80 

### ± 0.06 0.85 

### ± 0.06 0.85 

### ± 0.03 liver N 

### 5 5 5 (g) 6.45 

### ± 0.25 6.15 

### ± 0.41 6.40 

### ± 0.55 ReI. 

### 2.60 

### ± O. 13 2.59 

### ± 0.09 2.72 

### ± O. 15

.....:a 0\ 

### Spleen N 

### 5 5 

### 5 (mg) 

### 512 

### ± 73 483 

### ± 79 483 

### ± 42 ReI. 

### 206 

### ± 24 202 

### ± 19 

### 206 

## ± 25

< 

### KJdney(R) N 5 

### 5 5 (g) 

### 0.87 

### ± 0.06 0.81 

## ± 0.08 0.86 

## ± 0.08 Re I. 

### 0.35 

### ± 0.02 0.34 

### ± 0.02 0.37 

### ± 0.03 Kidney(l) 

### 5 5 

### 5 (g) 0.86 

### ± 0.06 0.79 

### ± 0.09 0.83 

### ± 0.07 Re I. 

### 0.35 

### ± 0.03 0.33 

### ± 0.01 0.35 

### ± 0.03 ReI. :Rel.ative organ weight (g 

### or mg 

## 7 100g final body weight) N : No.of animals
PROJECT Ne 

### C 

# e 0**~** 

# "­ C>o. 

### Col


# ... C"'

### Table 20-4 

### Absolute and relative organ weights of female rats treated orally with 'r 28 

### days

- 14-day of recovery ­ Group-No. 00 01 04 

### Dose Control Vehicle (mg/kg) 0 0 

### 1000 Adrenal (R) N 5 5 5 

### (mg)- 32.0 

### ± 3.0 30.3 

### ± 2.6 32.6 

### ± 4.3 ReI. l3.0 

### ± 1.1 12.8 

### ± 1.4 13.8 

### ± 1.6 

### AdrenaI (l) N 

### . 5 5 

### 5 (mg) 

### 35.1 

## ± 4. 1 32.6 

### ± 6.4 35.2 

### ± 5.0 ReI. 

### l4.3 

### ± 2.7 13.7 

### ± 2.4 15.0 

### ± 2. 1 

### Ovary(R) N 5 

### 5 5 (mg) 37.9 

### ± 9.9 36.3 

## ± 6.2 35.9 

### ± 4.4 (Re I.) 

### 15.3 

### ± 4. 1 15.3 

## ± 2.3 15.2 

## ± 1.9 0'1 OQ 

### Ovary(L) N 5 

### 5 5 

### (mg) 34.6 

## ± 6. 1 42.9 

## ± 11.2 34.9 

### ± 5.5 

### (Re I.) 13.9 

### ± 2.0 18.0 

### ± 4. 1 14.8 

## ± 1.7 

### Uterus N 5 

### 5 5 (g) 

### 0.58 

### ± 0.31 0.49 

### ± O. 19 

### 0.48 

### ± O. 14 

### (ReJ.) 0.23 

## ± O. 12 0.20 

## ± 0.07 

### 0.20 

## ± 0.07 Ref: : RelatIve organ weight (gor mg 1100g final body weight) N : No.of animals
PROJECT No.



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# e o 

# "­**~** 0­**/~"'.** 

## ..........s

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### Table 21-1 Necropsy 9f male rats treated orally with .•H 

### 28 days 28-day of treatment Group-No. 00 01 02 O:l 04 

### Control Vehicle Dos

### e(mg!kg) 0 0 10 100 IUUU 

### Organs : No. of animals 5 

### 5 5 5 5 

### Findings EpIdidymis (caudal region) nodule 0 0 0 0**~** 

### PROJECT No.



# o 

# e Q 

# ti**~** 

## "'­ o**~**()
./ 

### ......J

Table 21-2 Necropsy of male rats treated orally with for 28 days I 

### 14-day of recov(jry

­ Group-No. 00 01 

### 04 Control Vehicle Dose(mg/kg) 0 

### 0 1000 Organs : No. of anillais 

### 5 

### 5 5 Findings
abnormal change 0 

### 0 0



### PROJECT No.**~**



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# ~

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## c

### Table 22-1 Necropsy of 

### female rats treated orally with for 28 days

- 28-day of treatment n') 

### Group-No. 00 01 03 04 

### Control Vehicle Dose(mg!kg) 0 0 10 100 IUull 

### Organs : No. of animals 5 

### 5 

### 5 5 

### 5 Findings Ovary ; atrophy 0 1 0 0 0



# --
...

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........

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Table 

### 22-2 Necropsy of female rats treated orally with for 28 days 14-day of recavery Group-No. 00 01 04 ControI 

### VehIcle Dose(mg/kg) 0 0 1000 

### Organs : No. 

### of animals 

### 5 5 5 Findings
abnorlllal change 0 0 0



### PROJECT No.**~**



# o e o**~** 

### CJ Cf')



### ...........


# .......**~**Table 23-1 Histopathology of rats treated orally with ,or 28 days

- 28-day of treatment

­ Sex (---- Male ----) ( Female ----------) Group-No. 00 01 04 00 01 02 03 04 Dose (mg/kg) Control Vehicle 1000 Conlrol Vehicle 10 100 1000 -5-- 5 ---5­ Organs : No. of animals 5 5 5 5 5

Findings Liver: / /

mononuclear cell infiltration 1 2 3 1 3 microgranuIoma 0 2 1 1 

### o vacuoIation In**~.~J.l?£ll:.:e~** _______-=.

___--.::.-.-­ n 0 0 0

...

## _ ................

# - o**£~~!=ma~c~h~:** __________ 0 0 0 0 /

..**_~/_** _=-0

__**.,-,-,,~,**

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# -

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# ----....9

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### --= n



### ____ I



### _...9"•.
_ 0 Q 0



### - ....

## -....**,.-~**

### ,_'----

__.....1.

....9.

.., ......_, .Duodenum: 0 0 0 0 0 (

__....,./.... 0

..................... Heart: / / 

### ;:;l mononuclear cell infiltration 1 0 0 0 n IIIYOC8Td I**a.L..:f~i**b:,:r:.,;::o.::.s1=.:· s:....-

__________...::....

......................... 0 0


### .._ .......,,_2,

..__......,_•.

__1 ---,-,.,.."

......

# ° Q,

..,,_.......,''''''

.. Kidney: / /

mononuclear cell infIltration 2 0 1 1 0 

### o basophilic tubule 2 2 1 0 I 

### o fibrosis 0 0 Z 0 0 

### o cySt 1 0 2 0 1 calcirication 0 0 0 0 1 

# ° vacuolar**deg~~eration** of tubular epithelium 0 0 J 0 0 

# ° Spleen: / / 

# °**--.l.lli~!ed extramedullar1..,,~!!lJ~.,W!oi.!!.!.t~**  3

..__, __, .......

### 1_

..,_ 0 0

__ 0"--

__ Sternd bone 1Ii!!.!!!!.; 0,

......,... 0 

# ° 0

..............

### _J....... / /

...,.9.

...___ Femoral bone marrow: 

# °

..JL 0 0 0

............./ •..1...... 0 Adrenal:

.....'_,

....._'.

__..._.....__._......_ 0 0 0 _.___ Q._,.•_. 

# ° 1..

...."... /

__ 0::.......

__ resIis: ._"•

### .JL.

........__.;..O

_____ 0'--

________ 

# ._--_............

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# o mononuclear cell infiltration 4 

# e o / : Not examined (continued.)**~** PROJSCT No. 

### CoJ ,,...,-"":"'", 

## ........ !-"""'\**~** 

# r 'J'", --' 

## r)

Table 23-2 Histopathology of rats treated orally with .or 28 days

- 28-day of treatment

­ Sex (---- Male ) (--­

- Pemale ---------) Group-No. 00 01 Ot 00 01 02 OS 04 Dose (DIg/kg) Control Vehicle 1000 Control Vehicle 10 100 1000 Organs: No. of animals 5 5 5 5 5 5 5 -5­

Findings Ovary: / /

atrophy

________.............._._....._ 0 0 Uterus: (I) (l)

dilated lumen 2 1 1 I 4 squamous metaplasia of I 0 0 0 0

epitheljum cell

__**!!!JJl.e.~.Y.**............................................_...... _ ............................................._. ___.!l.

___-=-_ Sternal bone: 0

..

### J

............._._-!.O

___**--.:O~** __**___!~** __.....!. /

................... /

-.........Q

....................... n 

### l!!1o r**.!l.J!.9.g~.:..** 0 0 

### .9

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# o 

# e 

# o**~.** 

### CJ**~** 

# ..... {;:j

# /1'/

Appendix 1, 2 3, 4 5, 6 7, 8 9,10 , 11,12 13,14 15,16 17,18 19,20 21,22 23,24 

## • .f*}JII

## SJlJt3**~** a. V(uaJet Ct

### ~,

## e (; ndiv ;

### du'"

### I )

Clinical signs Body weights Food consumption Food efficiency Water intake Ophthalmoscopy Urinalysis Hematology Blood biochemistry Absolute and relative organ weights Necropsy Histopathology 1

....... 14 15- 20 21- 26 27- 32 33- 38 39- 42 43- 46 47- 64 65

..... 82 83

..... 94 95

..... 98 99

..... 100 

# ()

to \..



## 000439',r"\, '. I ''-'" Appendix 1-1 Clinical signs of male rats treated orally with :or 28 days
Group-No. Dose Animal ------------------------------------, 1 2 3 4 5 6 Days 0f treatment 7 8 )---------------------------------------­ 9 10 11 12 13 14 (mg/kg) No. 

### A B A B A B A B A B A 8 A 8 A B A B A B A B A B A B 

### A B 00 O,OMOI Control 0010102 

## o 001403 00M04 00&105 OOMOS 00M07 001.108 0010109 0010110 01 011401 Vehitle OlM02 

## o 01,.03
.­ 01&104 OlMOS OlMOS OUI07 0110108 01&109 OtMl0 - : no abnormal fty A Before administration

. -8 : After adlllil'llStraffon
PROJECT No.



# o e 

## o**~ ~**  

## <:>

........



## ....... Lo..,Appendix 1-2 Clinical signs of male rats treated orally with for 28 days
Group-No. Dose (.g/kg) Animal No. A B 

### ------------------------------------< 2 3 4 5 6 A B A B A B 

### A B A B Days of treatment 7 8 A B A B 9 

### AB 10 11 

### i\B -A-B 12 AS 13 

### A B 14 

### A B 02 02M01 il2M02 10 02"03 02M04 02M05**n~-** ­ 031101 1l3M02 100 03M03 03M04 03M05 04

- 04M-ui 04M02 a a a 1000 04103 N 04M04 041105 041106 04M07 04M08 04M09 a 04M10 - : no abnormality A Before admlnis{ration- -8: After administration a : salivation 

### PROJECT No.



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# ...**,~** ........... : ........)

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# C)
Appendix 1-3 Clinical sigos of male rats treated orally wIth for 28 days ,Days oftreafment ) :-------­ Group-No. 15 16 11 18 19 20 21 22 23 24 25 26 27 28 Dose Animal (mg/kg)**~o.** A B A B A B A B -I:-B- A B A 8 -AIr -A-a- -A- B·

- A-a-· -A B A 8 A 

### a ITO
- - OOM01----;" Control 001102 

### o 00M03 00104 

### OOMOS 00M06 00M07 

### OOMOa 00109 OOM10 01 01Mllf --_. ­ Vehicle 011102 

## o 01&103**~** 01

..04 

### OlMOS 01M06 01M07 01M08 011109 

## onno - : no abnormality A 

### Before adrilTnlsfrafion B :ATfir a dillInTifratlon
PROJECT No,



# c 

# e o**~ ~**  

# ::::::­ N

## ~Appendix 1-4 Clinical slens of male rats treated orally with for 28 days ,-'--

- -'**~** -Pays**oftreafmerit~** Croup-No. 15 16 17 18 19 20 21 22 23 24 2S 26 27 28 Dose Animal (Illuke) No, A B - A 8- -A-

### e- A 8 A B A B -A-T A B --AT A B -AB 

### A B A B A B 02 

## Gaor --:. ­ 021&02 10 02M03 02"'04 021105 01- ---OlMll1
- - ":' -::- - -,-- - -- -- ­ .)3,.02 100 031103 03,.04 03M05 04 04MOI 04M02 a a a a a a a a a ..: i a a a a 1000 041103 a a 0411104 a a a 

### """ 041105 04M06 04,.01 04,.08 04M09 a 041110

- a - a a - : no abnorlllafHY- --A-: Before aamll1istratioll B:-After adriilllistration a : saljvation 

### PROJECT No.



# o e Q**~ ~**  

# ::::­**~** r"",\ 

## "'''.**~** 

### \...J/""'''., 'r"""\ \...J Appendix 1-5 Clinical silns of male rats treated orally with for 28 days Group-No. 

# ---2-;---------------- .----......;.:....**=-...::::-~<** 

### Days of treafment )-­ Dose Animal (mg/kg) No. 

### C 00 OOUOI Control 001.102 o 00M03 001104 001.105 001.106 00107 00M08 001.109 00M1o**~.'~-** Olliin Vehicle 011.102 o 011.103 VI 01M04 01M05 011106 011.107 01M08 011.109 011.110 no abnormailly C Before autopsy 

### PROJECT No



## o 

# e o**~** ,.0.**~**



### ........

## ~Appendix 1-6 Clinical signs of male rats treated orally with for 28 days 

### ---------=( Days of treatment )--­ Group-No. 29 Dose Animal (mg/kg) No, 

### --C 02 OlMlll 02lt02 10 02U03 021.104 02'105 03 03MOI ·03U02 100 031.103 03M04 03MOS 04 -D4ImI D4lt02 1000 04lt03 0\ 04M04 04M05 04106 041.107 041.108 041.109 041.110 no abnormal ity 

### c: Before autopsy···

--­ 

### PROJECT No.



# e o**~** 

# '"**~**
/_P

....,\ f\ 

### "­ \J

### ~ 

# c. 

# c/'" :;"'\ 

# '0 ./ Appendix 1-7 Clinical signs of male rats treated orally with for 28 days
Group-No. Dos. Animal**----------------------------------~-----------------~ayi** 

### of**recoyeri-~---------------------------** 2 3 4 5 6 7 8 9 TO 11 12 13 14 15 (mg!kg) 0-0­ No. 

### oDJmo------­
---­ Control 00U07

- - - - - - - - - - - - - 

## o 00M08

- - - - - - - - 001109
- - - - - - - - - - 001110

- - - - - - - - - - - - - - - 01 OIUO-&

- - - - - - - - - - - Vehicle 01M07

- - - - - - Q 01M08

- - - - - - - 01M09
- - - - - - - - - - - 011110 04 041106
- - - - - - - - - - - - - - ­ 04M07

- - - - - ­ 1000 04M08
- - - ­ 04U09 -....l 041110
- - - ­ no abnormality
PROJECT No



# o 

# e o**~ ~** **~** 

## ........ 

# ,.., -Appendix 2-1 Clinical signs of female rats treated orally with lor 28 days 

# ---------------------------< Days 

### ot treatment

-

# j=:-------------------------­ Group-No. 2 3 4 5 S 7 8 9 10 II 12 13 14 Dose Animal (l11(/kg) No. A B A B AS 

### A B A B 

### A B 

### A B A B A B A B A B 

### A B A B A B 

### 00 OOFOI Control OOF02 

## o OOF03 OOF04 OOFOS OOFOS OOF07 OOF08 OOF09 OOF10 01 OIFOI Vehicle 0lF02 '­ 

### o 0lF03
)0 01F04 OIFOS 0lF06 0lF07 01F08 OlF09 01fl0 - :no abnormality 

### A Before aalllfnTSTratlon B After administration


### PROJECT No.



# o 

# e o**~ ~**  

### ...J

.......... /

.........

## , \..)

... ' ........ 

# o }--l

# o
Appendix 2-2 Clinical signs of female rats treated orally with

. for 28 days
Group-No. Z 3 4**--------~ays** 

## onriatment**.~-------------** 5 6 7 8 9 10 11 12 13 .14 Dose (mg/kg) Animal No. A B A 8 AS 

### A B A B 

### AD A II 

### A B A B A- B 

### A B A B A B 

### A-a 0' OZFOI

, 02FOZ 10 02F03 02F04 02FOS 03 03FOl**~3F02** 100 03F03 03F04 OlFOS 04 1l4f!OT 04FOZ 1000 04F03 v:> 04F04 04F05 04F06 04F07 04f08 

### a 04F09 a 04FIO a a a a a no abnorlnality- A Before adininTstraTIon B After administration a saIivation PROJECT No.



# o o Q**~ ~**  

# en """"­ 

# tAppendix 2-3 Clinical signs of female rats treated orally with for 28 days**----------------~I)ays** of treatlllent/----­ Group-No. IS 16 17

. 18 19 20 21 22 23 24 25 26 27 28 Dose Animal**~<mi/kg)** No. A 

### a A B A 8 

### AB 

### A 

## a A B 

### A B A 8 A 

### B A-a- -A-S 

### AB A-S- -A-S 

### 00 OOFOI Control OOF02 

## o OOF03 OOF04 OOFOS OOF06 OOF07 OOFOa OOF09 OOF10 01 

## InFor

- 

# ---=- :;---­ Vehicle 01F02 

## o 01F03

..... 01F04 Q OlF05 01F06 01FOl 01F08 OlF09 01F10 no abnormaIIty A : Before aaminlstratlon B : After administration
PROJECT No.



# c 

# o o**~ ~**  ............**~ /~**  ......,. /""',**~** :"-) 

## -J:.("'> 

# o "- ,,/ Appendix 2-4 Clinical signs of female rats treated orally with tor 28 days



## ....
.... Group-No. Dose Animal (Ill/kg) No. 

### 02 02FOI

,02F02 10 02F03 02FD4 02F05 

## oJ' 03FOl 03F02 100 03F03 03F04 03FOS 04 o:4FDl 04F02 1000 04F03 04FD4 04FOS 04F06 04FOl 04F08 04F09 04FI0 no abnorlllliity a salivation 15 16 11 A B A B A B

- :­

- a

- a

A : Before administration 18 A B

- a B -----------( Days of t.reatlllent) 19 20 21 22 23 A 8 A B A B A B A B

- a - a a a a a a AfteraaliiTnistration 24 A B

a 25 A B

a a 26 A B

a 27 28 A B A B

a

a a

PROJECT No



## o 

# e 

# o .:. 

# '"
........**~**

# ~\

# -

--- ,.­
Appendix 2-5 Clinical signs of female rats treated orally with for 28 days 

## ------------------------< Days of treatment Group-No. 29 Dose Animal (mg/kg) No. C 00 OOF(ff Control OOF02 

### o OOF03 OOF04 OOFOS OOF06 OOFOT 00FD8 00F09 ODFID 010fFIH Vehicle 01F02 

## o 01F03


# - tv 01F04 01FOS 01F06 01FOT 01F08 OlF09 OlF10

- .no abnormal ity C : Before autopsy
PROJECT No.



## o**;~ ~**  

# en ,",**~** 

# o \;

..........,",j 

# o
Appendix 2-6 Clinical signs of female,rats treated orally with for 28 days -(-Days of 

## treatment**~-------** Group-No. 29 

### Dose Anilllal (mg/kg) 

### No. C 02 IItl=Ol 02F02 lU 02F03 02F04 02F05 1Jr' 03FU't 03F02 100 03F03 03F04 03F05 

### 04 04FOl 04F02 1000 04F03



### .... 04F04 <..l**04F~** 04F06 04F07 04F08 04F09 04FIO - : no abnormality 

### C Before autopsy PROJECT No



## o 

# e 

# o**~** 

## ....... 

# en N t-.I 

### -...l04 Appendix 2-7 Clinical signs of female rats treated orally with for 28 days
Group-No. Dose Animal**---------------------------------------------------~-** DayiIQf 2 3 4 5 6 7 8 9 10 11 12 13 14 15 recovery )------------­ (IIi/kg) 00 No. 

### OlWns Control OOF07 

## o OOF08 OOF09 OOFIO 01 Vehicle l)1FOo 01F07 -

- -

- - ..: -

- -

- -

- -

- - - 

## o 0lF08

- - - - - - - - - - - OlF09

- - - - - - - - - 01FIO

- - - - - - - - - - - 04F06

- - - - - - ­ :l4F07

- - - - - - - - - - ­ luuO 04F08

- - - - ­

..... 04F09

- - - - ­ .&;. 04FIO

- - - - - - ­ no abnormality
PROJECT No.



# o o 

# o**~** 

# en 

# \:; c." t',..'

...**~,** r''''''**~** 

## \,J**',~,-'**

# o Appendix 

### 3-1 Body weights of male rats treated orally with' for 

### 28 days 

### Croup=No. 

## -------------------------------------------=< Days 

### of treatment 

## >----------------------------------------------­ Dose Animal (lIg/kg) 

### No.8' 15 22 28**Olf~** 

### 00M01-

-**~** 

### 224 281 327 364 398 Control 

### 00M02 234 289 341 377 413 

## o 00M03 235 300 359 402 444 001.104 245 321 373 421 451 00M05 220 284 340 379 408 OOMOS 226 284 335 376 409 00M07 22j 

### 272 312 345 373 00M08 235 292 347 378 409 OOM09 223 274 322 368 390 OOM10 240 295 348 377 

### 407 N 10 10 

### to 10 10 

### Mean 231 289 ' 340 379 410 S.D. 

### 8 14 18 21 23 

### "'"' 01 01MOI 236 306 358 406 438 VI 

### VehIcle 01M02 241 308 357 405 436 

## o 01M03 242 305 353 397 428 01M04 243 311 364 409 442 01M05 224 286 336 380 412 01M06 229 304 363 424 462 0lM07 226 278 332 370 399 01M08 224 286 331 375 388 01M09 234 288 327 356 383 

### OHIlO 228 290 347 402 447 N 

### 10 10 ' 10 10 10 Mean 

### 233 296 347 392 424 S.D. 

### 7 12 14 

### 21 27 Unit: g



# o o 

# o .::. CJl N No.of animals


### PROJECT No.



### "­ 

# ""**~** 

### -.D

### Appendix 3-2 Body weights of 

### male rats treated orally with (or 28 days Group-No.



## ---- ------ -------- --------------------< Days of treatment 

## >-
------------------------­ Dose Animal (lIIg/kg) 

### No. 1 

### 8 15 22 28 02 021.101 216 263 303 335 360 02N02 237 306 357 404 432 10 02M03 243 305 359 398 433 021.104 235 294 344 387 417 021.105 225 280 320 346 374 N 

### 5 5 5 5 5 lIean 231 290 337 374 403 S.D. 11 

### 18 24 31 34 03 03MOI 237 297 353 403 434 031.102 221 272 316 347 371 100 03M03 236 289 324 359 384 031104 227 279 320 353 377 03M05 240 294 332 363 388

..... 0\ N 

### 5 5 5 5 5 Mean 232 286 329 365 391 S.D. 8 

### 10 15 22 25 04 041.101 232 292 354 396

. 420 041102 241 299 342 373 406 

### tOOO 04M03 225 282 334 381 407 041.104 244 298 341 371 394 041.105 236 288 332 364 400 04U06 222 283 327 368 398 04"'07 241 300 351 396 424 041.108 226 285 334
. 373 390 041109 236 292 341 384 407 04MI0 221 259 289 317 339 

### N 10 10 10 10 10 lIean 232 288 335 372 399 S.O. 

### 8 12 18 22 23 Unit: g 

### N : 

### No.of anilllais 0 

# e PROJECT No. 

### 0**~** 

## en

# ~ , /- " 

## en 0'

### ('~

.**~,.** "..,' '-.../ 

### Appendix 3-3 

### Body weights of male rats treated orally with for 28 

### days Group-No. 

# -------------------------------------=( 0

### ays 0f r

### ecovery ..

## r:;....::=-.===------------------­ Dose AnimaI 8 14 (lig/kg) 

### No. 00 00M06 414 443 468 

### Control 001.107 381 409 428 

## o 00M08 413 445 456 001109 385 412 431 00M10 412 439 460 N 5 5 5 

### Mean 401' 430 449 S.D. 17 18 18 

### Of 011106 470 506 536 

### Vehicle 01M07 396 425 445 

## o 01M08 391 414 439 011109 385 411 428 011'" 0 448 484 517 

### .­ N 

### 5 5 5 ...J 

### Mean 418 448 473 S.D. 38 44 50 04 04U06 398 427 445 041107 431 466 489 1000 04"'08 400 425 447 04t.109 407 432 446 041110 342 364 383 N 5 5 5 

### lean 396 423 442 S.D. 33 37 38 

### Uni t 

### g N : No.of animals


### PROJECT No.



# o e 

# o**~**



### ...........

# ~ W


# -

### Appendix 4-1 Body weights of female rats treated orally with 

### for 28 

### days Group-No. 

## -------------------------------------------=( Days 

### of**treatm~--------------------------** 

### Dose Animal (lig/kg) No. 8 15 22 28 00

- OOF01 162 181 203 213 219 Control OOF02 176 205 225 240 254 

## o 00F03 160 179 197 208 220 00F04 172 191 217 240 237 00F05 168 201 217 233 252 00F06 162 198 214 233 243 00F07 175 212 232 249 267 OOF08 158 176 202 208 226 OOF09 173 199 226 246 258 00F10 175 199 220 236 249 N -1'0-· -TO

- 10 10 fO 

### Mean 168 194 215 231 243 S.O. 7 12 11 15 17



# - 00 

### 01------ 01FOt -114-196 21

### 0 233 

### -247 Vehltle 01F02 184 222 253 277 288 

## o 01F03 169 195 207 226 248 OtF04 158 178 197 209 225 01F05 162 192 219 235 248 01F06 174 198 224 239 243 01F07 167 199 222 239 249 01F08 165 t89 200 215 227 0lF09 170 206 226 252 261 01FIO 161 185 193 207 221 H 10-

- - 10 10 10'

- 10 Mean 168 196 215 233 246 S.D. 8 12 18 21 20 Unit i I 

### :-No.of anImals


### PROJECT No. 

## o 

# e o**~**


### ........ 

### CIt**~** ,....,'-', 

## W 

# ()**~**02 /,"\ 

# o

........./ Appendix 4-2 Body weights of female rats treated orally with for 28 days Group-No. 

# -----------------------------------,-08y$ 0f treatment 

## ;>=------------------------­ Dose Animal (mi/kg) No. 8 15 22 28 02FOI 

### lfO 192 211 

### 23T 250 02F02 170 188 203 22t 237 10 02F03 172 189 202 212 224 02F04 162 179 202 222 221 02F05 161 190 210 226 239 N -5 -5**~---** 5 5**~5~--** Mean 

### 161 188 206 224 235 S.D. 5 5 5 10 10 03 03FOI 169 196 219 230 237 03F02 168 192 210 226 235 100 03F03 162 193 206 225 235 03F04 156 181 1"97 214 217 03F05 181 206 225 246 252

..... 1.0 

### NUS 5 5 5 --S Mean 167 194 211 228 235 S.D. 9 9 11 12 12 04 04FOI 155 178 199

-- 208 224 04F02 176 199 224 244 251 1000 04F03 161 183' 196 204 222 , 04F04 178 206 216 230 249 04F05 161 185 t99 209 228 04F06 164 183 206 220 230 04F07 171 198 229 239 251 04F08 165 186 198 215 234 04F09 170 198 214 231 238 04Fl0 164 187 201 221 234 N 10**-~10** --fO 10 10 Mean 167 190 208 222 236 S.D. 7 9 12 14 11 Unit g N No.of animals 

# o PROJECT No. 

# o o """­**~** 

### CI1 ClI**~**

# --- Appendix 4-3 

### Body weights of fenale rats treated orally with for 28 

### days Group-No. 

## --------------------------------------------< Days of recovery /--------------------------------------­ Dose AnI iliaI (lig/kg) 

### No. 1 8 14 00 00F06 244 262 274 

### Control 00F07 254 277 286· 0 OOF08 228 229 244 OOF09 258 264 283 00F10 252 262 280 N 5 5**~** 

### Mean 247 259 273 S.D. 

### 12 18 17 

### 01 01F06 249 264 284 

### Vehicle 01F07 251 257 271 0 01F08 230 240 243 01F09 259 268 287 01FtO 222 234 237 0 tv 

### N 5 5 5 

# • Mean 242 253. 264 S.D. 

### 16 15 23 04 04F06 234 244 258 04F07 253 261 266 1000 04F08 227 244 238 04F09 241 261 278 04Fl0 234 246 243 N 5 

### 5 5 

### Mean 238 251 257 S.D. 

### 10 9 16 

### Unit: g N : No.of animals
PROJECT No. 

### 0 

## e <:>**~** 

# w en**~** /',.f

...... 

## -t: ("L"\

.......... \J**/",,~.} ~:**  I ; \.",./' Appendix 5-1 Food consumption of male rats treated orally with tor 28 days Group-No. Oou (mg/kg) 00 AnlllIal No. 001.101 --------------------------------------------( -1 2 9 16 23



# - 1 - 3

- 10 -17
...... 24 25. 1 24.6 28.2 28.7 29.9 Control 00M02 26.7 25.8 29.4 29.2 30.0 0 00M03 26.4 28.7 30.2 33.6 34.2 001104 28.3 31.3 31.7 35.4 35.9 00M05 26.7 33.8 29.4 31.5 31.9 00M06 23.**~** 24.4 25.5 27.7 25.5 001107 25.3 24.6 26.4 26.3 30.4 OOMOS 27.5 2S.1 28.8 28.4 29.0 00M09 25.4 24.0 28.6 30.4 21. 1 001.110 27.9 27.5 29. 1 2S.9 29.4 Days of treatment )---------------------------------------­

N 10 10 10 10 10 Uean 26.3 27.3 28.7 30.0 30.3 S.D. 1.4 3.3 t.8 2.S 3. 1 N

...... 01 0llla1 27.1 30.3 32.6 32.6 31. 1 Vehicle 011.102 2S.7 26.8 33.3

. 32.3 30.5 0 0lM03 26.6 25.5 28.1 2S.7 2S.4 OtM04 27. 1 28.6 28.3 32.3 30.7 OlMOS 26.2 28.7 2S.S 29.4 30.4 01M06 25.5 27.6 29.7 32.4 33.4 01M01 22.4 24. 1 24.5 27.4 26.2 OlMOS 24.8 25.5 27.3 26.5 26.5 OUI09 26.4 26.4 26.3 26.7 21.5 01Ml0 26. I . 25. 1 27.5 29.5 31.4

UniT 

### :g. N 10 Mean 26.2 S.O. 1.7 N : .No.lIf animals 10 26.9

1.9 10 28.6

2. 1 10 29.8

2.5 10 29.0

3.5

PROJECT No 

# o e o**~** 0') Q 

### ......... t.,..:)



# "\

### Appendix 5-2 Food consumption of male rats treated orally with for 28 days Group-No. 

## -------------------------------------------=< Days of treatment 

## >----------------------------------------------­ Dose Animal -1 2 9 16 23 (rag/kg) 

### No. -1 

### ...., 3

..... 10 -17 

### ...., 24 02 02MOl 24.8 22.6 25.8 26.7 25.3 02M02 26.9 28.4 30.2 34.6 28.9 10 021.103 28. 1 

### 27.2 29.7 30.7 31.2 02M04 26.8 27.3 30.8 31.7 32.9 021.105 25.0 26.0 26.4 28.5 28.0 N 

### 5 5 5 5 5 Mean 26.3 26.3 28.6 30.4 29.3 S.D. 

### 1.4 2.2 2.3 3.0 2.9 03 

### 03MOI 25.3 27.0 30.

### 8 29.5 32. 1 031.102 24.4 23.4 25.8 27.6. 25.5 100 031.103 26.2 26. 1 27.0 25.6 27.6 031.104 27.2 26.5 27.6 27.6 26.8 031.105 25.4 26.6 25.3 27.9 25.7 '.,) .,) N 

### 5 5 5 5 5 Mean 25.7 25.9 27.3 27.6 27.5 S.O. 

### 1.1 1.4 2.2 1.4 2.7 

# or-- 04MOI 23.9 24.2 29. 1 30.3 30.6 041.102 26. 1 28.5 27.0 28.6 27.6 1000 041103 24.3 23. I 25.5 28.2 29.8 04M04 25.3 26.6 25.0 26.4 27.4 04"'05 28.0 23.8 26.2 25.8 28.1 04M06 22.1 23.0 

### 26.9 24.9 2B.4 041.107 26.7 26.9 26.7 30.2 31.2 04MOB 23.5 23.8 27.2 26.0 28.3 04M09 28.5 25.7 30.6 28. 1 29.2 041.110 26.3 23.6 22.8 25.5 27.2 N 

### 10 10 10 

### 10 10 Mean 25.5 24.9 26.7 27.4 28.8 S.D. 

### 2.0 1.9 2. 1 1.9 

### 1.4 Unit: g N : No.of animals 

### 0 PROJECT No. 

# e 0



# ........**~** 

### r'"' ("', \

# ~ " '-".-/ 

## ....... "

__•.r'

### r-'
"'-"'
...... 

### r''''''': V Appendix 5-3 Food consumption of male rats treated ora1 Iy with or 28 days Group-No. Dose (mg/kg) 00 Control 

## o Animal 

### No. 00M06­ 00N07 

## oouoa OOM09 00U10 N Mean S.D. -------;---------9---------------------------<

## ~ 3

## ~ 10

-25.8 29.7 28.5 27.7 30. 3 29. 5 30.4 29.6

_ 30.5 30.6 --5 --5 29.

### l' 29.4

2.0 1. 1 Days recovery )-----------------------------­

--------­

01 01M06 32.7 32.;{ Vehicle 01M07 24.

## a 27.9 

## o 01M08 27.6 27.1 01M09 22.7 24.3 01Ml0 31.8 32.5 tv W N 5 5 Mean 27.9 28.8 S.D. 4.3 3.6 04 04M06 27.3 28.9 04M07 31.0 32.4 1000 04M08 30.1 28.8 04"09 29.9 26.6 04Ml0 26.4 27.4 N**~** 5 Mean 28.9 28.8 S.D. 2.0 2.2 Un!t : g 

### N:INo.of animals
PROJECT No. 

# o e 

# o**~** (J'} 

### N

# ~**~**

### Appendix 6-1 Food consumption of female rats treated orally with n 28 

### days "Group"-No. 

# ------------------------------< Days of 

### treatment 

# r-------------­ Dose AnimaI -1 2 9 16 23 (Dur/kg) No.

..... 1

..... 3 """ 10

..... 17

..... 24 00 OOFOI 12.9 17.1 15.4 n.l 11: 1 

### Control 00F02 15.1 22.3 21.0 17.8 25.3 

## o 00F03 17.1 17.3 14.4 16.4 18.0 00F04 19.4 18.4 21. 1 18.4 17. 1 OOFOS 17.4 20.5 20.5 20.7 22.7 00F06 12.8 20.0 17.6 19.4 19.8 00F07 15.6 21.3 21.0 16.0 23.2 00F08 15.9 16.0 18.8 15.6 21. 2 00F09 20.5 20.4 24.7 22.8 21. 3 00F10 18.1 19.7 22.4 20.0 17.3 N -10-**-~--10-TO** - - 

## ro Mean 16.5 19.3 19.7 18.0 20.3 S.D. 2.5 2.0 3.2 2.8 2.9 01

- lflFOI---20-:1 16.8 19.8 19.-5**~20.8** - ---- -- ----- -- -**-~- ~**  

### Vehicle 01F02 19.3 20.5 21.9 21.8 21.4 

## o 01F03 17.8 19.6 18.0 20.0 20.2 01F04 15.8 15.6 17.3 17.8 18.4 01FOS 20. 1 20.0 22.0 23.0 21.7 01F06 17.9 19.0 20.2 20.6 18.8 01F07 15.2 18.0 20.5 18.8 20.7 01F08 16.3 14.2 17.7 16.1 18.4 01F09 15.1 17.3 21. 2 17.5 21. 5 01Fl0 19.2 19.4 15.0 18.1 21.9 N 

### to
- -'0 --10
- fO 10

- -- - ­ 

### llean 17.7' 18.0 19.4 19.3 20.4 S.O. 2.0 2. 1 2.3 2. 1 1.4 Unit: 

### a N : No.of 

### animals
PROJECT No. 

# c 

# c:­ O



## ........**~** (1') 

# W C-J. 

# n 'c ',--"**~** 1--.) 

### Appendix

### &-2 Food consumption of female rats treated orally with (or 28 days
GrOIlP=-rro:- 

## --------------------------------------------< Days of treatment )----

- ---- --------------------------------­ Dose 

### Animal -1 2 9 16 23 (mg/kg) No. 

# - 1 - 3

- 10 -17

- 24 02 02FOI 19.4 17.5 

### 21.6 

### 21.6 21.7 02F02 21.8 18.4 17.0 19.4 21.4 10 02F03 17.6 16.2 18.9 18.8 17.7 02F04 18.4 18.4 20.2 17.8 17.9 

### 02FOS 16.5 20. 1 22.6 17.7 22. 1 N**~** 5 5 5 5 

### Mean 18.7 18. 1 20. 1 19. I 20.2 

### S.D. 2.0 1.4 2.2 1.6 2.2 03 03FOl 17.2 19.

### 3 20.6 17.2 19.5 03F02 18. 1 19.6 19.8 20.0 21.1 100 03F03 17.2 19.9 16.8 19.9 21. 6 03F04 15.8 17.3 18.5 18.9 16. 1 03F05 19.0 18.7 19.3 23.2 22.5 N VI N 

### 5 5 5 5 

### 5 

### Mean 17.5 

### 19.0 19.0 19.8 20.2 S.D. 

### 1.2 1.0 1.4 2.2 2.5 04 04FOl 16.3 

### 15.6 16.8 18.7 20. 1 04F02 19.0 18.7 21. 3 20.8 19. 1 1000 04F03 17.7 17.1 15.5 20.0 20.2 04F04 19.3 19. 1 17.6 21.1 21. 2 04F05 17.6 15.8 15.3 19.3 21.3 04F06 18.7 16.8 20.4 18.9 20.7 04F07 16.8 18.2 21.6 21.7 21.4 04F08 16.4 18.9 14.4 17.9 20.9 04F09 17.6 19.8 20.4 15.9 22.1 04FIO 17.3 

### 15.4 15.9 18.8 21.0 N 

### 10 10 10 10 10 

### Mean 17.7 

### 17.5 ' 17.9 19.3 20.8 S.D. 

### 1.0 1.6 2.7 1.7 0.8 

### Unit-: g N : No.of 

### animals 0 PROJECT No. 

### C 

### 0


## ........ 

# .:a.**~ ~**  

# .:a.**~**

### Appendix 6-3 Food consumption of female rats treated orally with for 28 days 

### Group=No.
---- ----------------------------------------( Days of recovery 

# >-----­ Dose Animal 2 9 (mg/kg) No. - 3 - 

### 10 OOOOFOl

-- 

### 19.0 18.8 Control 00F07 23.3 20.8 

## o 00F08 18.2 17.7 OOF09 24.1 22.7 OOF10 22.7 24.8 N**~-** 5 

### Mean 21.S 21.0 S.D. ,2.7 2.9 01 OtFOS- 

### -2IT -n.4 Vehicle 01F07 15.6 18.2 

## o 01F08 14.9 18.2 01F09 20.1 21.0 01Fl0 19.5 17.0 N
--- S---- 

## ---s**~** 

### Mean 18.4 19.4 S.D. 3.0 2.2 04 04F06 

### T7.0--- 23:1 04F07 22.7 18.0 1000 04F08 20.0 13.5 04F09 23.9 23.4 04Fl0 IS.S 19.7 N 5 5 

### Mean 20.4 19.7 S.D. 2.9 4.3**U~:** g 

### N :No.

### of anfiiiih


### PROJECT No. 

# o e 

# o 

# ,**~** 

### a"l 

## ---t:.
"".'''\ 1'",\ 

# "" \,J

.....**~..,./** 

## c/" " 

# r" \

. ,/ ,-",) Appendix 7-1 Food efficiency of male rats treated orally with for 28 days Group-No. --------------------------------------------( Days;of treatment )----------------------------------------------­ Dose Animal 2 9 16 23 (alg/kg) No.

- 10 -17

- 24 - 3 00 OOMOI
. 33.I 23.3 18.4 19.0 Control DOYOZ 30.5 25.3 17.6 20.0 0 00Ll03 32.4 27.9 18.3 20.5 OOM04 34.7 23.4 19.4 13.9 001.105 27.0 27.2 17.7 15.2 OOMOS 34.Q 28.6 21. 1 21.6 00M07 28.5 21.6 17.9 15.4 00U08 29.0 27.3 15.6 17.8 001.109 30.4 24.0 21.6 13.5 001.110 28.6 26.0 14.3 17.0 N 10 10 10 10 

### Mean 30.8 25.5 18.2 17.4 S.D. 2.6 2.3 2.2 2.9 N -.J 01 01L101 33.0 22.8 21.0 17.1 Vehicle 011102 35.7 21.0 21.2 16.9 0 0lM03 35.3 24.4 21.9 18.2 0lM04 34.0 26.8 19.9 17.9 OlMOS 30.9 24.8 21.4 17.5 01M06 38.8 28.4 26.9 19.0 01U07 30.8 31.5 19.8 18.4 01M08 34.7 23.5 23.7 8.2 011.109 29.2 21. 2 15.5 20.9 011.110 35.3 29.6 26.6 23.9 N 10 10 10 10 Mean 33.8 25.4 21.8 17.8 S.D. 2.9 3.6 3.4 4.0 Unit: , 

### H: No.of animals

PROJECT No.


## o 

# e '­ 

# o 

# -t..**~** 

# - IJ') IJ')

### Appendix 7-2 Food efficiency of male rats treated orally with for 28 days Group-No.**------------------------------------~-------<** 

### Days of treatment 

## 5=---------------------------------------------­ Dose Animal 

### 2 9 16 23 {mg/kg} 

### No. 

### ..... 3

..... 10

..... 17

..... 24 02 D2M01 29.7 22. 1 17. 1 16.5 D2M02 34.7 24. 1 19.4 16. 1 10 021103 32.6 26.0 18. 1 18.7 021.104 30.9 23.2 19.4 15.2 02"05 30.2 21.6 13.0 16.7 N 

### S 5. 5 5 Mean 31.

### 6 23.4 17.4 16.6 S.D. 

### 2.0 1.7 2.6 1.3 03 031.101 31.7 26.0 24.2 16. 1 03M02 31. 1 24.4 16.0 15.7 100 03M03 29.0 18.5 19.5 15. 1 031.104 28.0 21.2 17.1 14.9 03UOS 29.0 21.5 15.9 16.2 N 00 N 

### 5 5 5 5 Mean 29.8 22.3 18.5 15.6 S.D. 

### 1.6 2.9 3.5 0.6 04 04MOI 3S.4 30.4 19.8 13.1 04M02 29. 1 22.8, 15.5 19.9 1000 04M03 35.3 29.1 23.8 14.S 041104 29.0 24.6 16.2 14.0 04UOS 31.2 24.0 17.7 21.4 041.106 37.9 23.4 23.5 17.6 041.107 31.3 27.3 21.3 15.0 04M08 35.4 25.7 21.4 10.0 041.109 31. 1 22.9 21.9 13. 1 04Ml0 23.0 18.8 15.7 13.5 N 

### 10 10 10 10 Mean 31.9 24.9 19.7 15.2 S.D. 

### 4.3 3.4 3.2 3.4 Uiilt : , N : No.of animals 

### C PROJECT No. 

# e
......... 0 

## ..t:..**~** /'**f~"'\ ~** 

## ~

............,..,/ ..Ji"'" 

# o
,,,,.,/' 

### Appendix 7-3 

### Food efficiency of male rats treated orally with 

### for 2S 

### days**GrouP~No.** 

### Dose**~~d** 

### Anllllal No.**--~-----------------------------------------<** 2

..., 3 9

..., 10 

### Days of recovery )----------------------------------------------­
00 001.106 16. 1 14.0 

### Control OOLl07 14.0 11.4' 

## o 001.108 15. I 6.2 001.109 12.7 10.7 OOM10 12.6 11.4 N 5 5 

### Mean 14.

### i 10.7 S.D. 1.5 2.8 01 

## o Ul06 15.7 15.4 

### Vehicle 011.107 16.7 11.9 0 OlMOS 11.9 15.4 0lN09 16.4 11.7 OUlI0 16.2 16.9 tV 

### N 5 5, \0 

### Uean 15.4 14.3 S.D. 2.0 2.3 04 041.106 15.2 10.4 041.107 16. 1 11.8 1000 04MOS 11.9 12.7 04M09 11.9 8.S 041.110 11.9 11.6 N 5 5 

### Mean 13.4 11. 1 S.D. 2. I 1.5 

### Uni t : 

### S N : No.of animals
PROJECT 

### No.



## o c

........ IA 

# o 

# t, C1') 

### ellAppendix B-1 Food efficiency of female rats treated orally with for 28 days**Group~No.** -------- 

## ---------------------------------------------=( Days of treatment 

## >----------------------------------------------­ Dose Animal 2 9 16 23 (llg/kg) No.

...... 3 ...., 10

...... 17 ...., 24 

### 00 llOFOl

- -**~-** 

### ff.T 20.4 10.9 5.8

---**~-** --- -**~-** --, Control 00F02 IB.6 13.6 12.0 9.2 

## o 00F03 15.7 17.9 9. 6 11. 1 00F04 14.B 17.6 17.9 -2.9 00F05 23.0 11.1 11.0 14.0 00F06 25.7 13.0 14.0 B.4 00F07 24.8 13.6 15.2 12.9 OOFOB 16.1 19.B 5.5 14.2 00F09 lB.2 15.6 12.5 9.4 00FI0 17.4 13.4 11.4 12.5 N -**----10~** -- -10-

-- -, If
- 

### -10 Mean 19.0 15.6 12.0 9.5 S.D. 4.0 3.2 3.3 5. 1**~** 01 01FOI lB.7 10.1 16.B 11.2 Yehicle 01F02 26.5 20.2 15.7 8.6 

## o 01F03 19.0 9.5 13.6 18.2 0lF04 18.3 15.7 9.6 14.5 01F05 21.4 17.5 9.9 10.0 01F06 IB.O IS.4 10.4 3.5 01F07 25.4 16.0, 12.9 S.1 01FOS 24. I S.9 13.3 10.9 OlF09 29.7 13.5 21.2 7.0 01FI0 17.7 7.6 11.0 10.7 N-­ 

### --10**~** -10­ 10. 10 Mean 21.9 13.7 13.4 10.3 S.D. 4. 3 4.5 3.6 4.0 Unit 

### X N No.of animals



# c e o**~** (1) 

### c.Q /',-1<

....,

.**~~""",'** PROJECT No.


## """"­ 

## ....t:. 

# ....r:.. '1"""'" i 1 ,----)

# o Appendix 8-2 Food efficiency of female rats treated orally with for 28 days
G

roup-No. 

## -------------=---:=::::.--::=-....:...----------------( 0ays 0f treatment 

# r-----------------------------------­ Dose Animal 2 9 16 23 (llg/kg) No.

-- 3

-- 10

-- 17

-- 24 

## or- 02FOI 18.0 12.6 18.5 8.4 02F02 14.0 12.6 13.3 12.5 10 02F03 15.0 9.S 1.6 11.3 02F04 13.2 16.3. 16.1 4.7 02F05 20.6 12.6 12.9 9.S N -S-**-5-~** 5 --5 Mean 16.2 12.S 13.7 9.3 S.D. 3. 1 2. 3 '4. 1 3.0 0' 

### UFOI 20.0 16.0 

### 9. 1 6.

### 0 03F02 11.5 13.0 11.4 7.1 100 03F03 22.3 11.1 13.6 7.7 03F04 20.6 12.4 12.S 3. 1 03F05 19.1 14.1 12.9 4.4 VJ N

..**~~** .. -5 5 5 

# - Mean 19.9 13.3 12.0 5.7 S.D. 1.8 1.8 I.S 1.9 04 04F01 21.1 17.9 6.9 11:3 04F02 17.6 16.8 13.7 6.1 1000 04F03 18.4 12.0 5.7 14.9 04F04 20.9 8.1 9.5 14.9 04F05 21.7 13.1 7.4 14.9 04F06 16.2 16.1 10.6 8.1 04F07 21. 2 20.5 6.6 9.3 04FOS 15.9' 11.9 13.6 15.2 04F09 20. 2 11. 2 1S. 3 5. 3 04Fl0 21.3 12.6 15.2 10.3 N 10 10 , 10 10 Mean 19. 5 14.0 10. 5 11.2 S.D. 2.2 3.7 3.8 3.9 Unit: , N :

### No.of animals
PROJECT No. 

# o Q**~** 

### ........... "\l 

# ,**~'** 

# c

### Appendix 8-3 Food efficiency of female rats treated orally with**fo~** 

### 28 days Croup-No. Dose 

### Animal 

## -------;-------;--------------------------'-OIYS of 

## recovery No. 3

### ~ 10 

## )----------------------­

----------------------­ (mg/kg) 

### 00 Control 

## o 00F06 13.5 10.6 00F07 14.I 7.2 00F08 0.8 14.I OOF09 3.6 

### 14.0 OOF10 6.3 

### 12.1 N 5 5


### 01 Vehicle 

## o Mean 7. '( 11.6 S.D. 

### 5.9 2.9 OIF069.8**~;9** 

### 01F07 5.5 

### 12.S OIFOS 9.6 2.7 01F09 6.4 15.1 

### 01FIO S.8 2. 9**~** N 5 !.tean 

### 8.0 9:7 S.D. 

### 2.0 6.3 04 04F06 8.4 9.S 04F07 5.0 4.6 1000 04FOS 12.1 -7.4 04F09 12.0 12.1 04FIO 9.3 -2.5 N 5 5 

### Mean 9.4 3.3 S.D. 2.9 8.2 

### Unit :**~** 

### N No.of animals
PROJECT 

### No.


## o 

# o**~** 

# :t ...J 

# ... /t'_',. 

### <" 

# o**'~-** ...... 

# c("'. 

# o ".,,-/ Appendix 9-1 Water Intake of male rats treated orally with for 28 days


### CrouP=No. 

## ------------------------------------------_=( Days of 

### treatment 

## >----------------------------------------------­ Dose Animal -1 2 9 16 23 (III/kg) No. ...., 1 ,.., 3 ...., 10 "'" 17 "'" 24 

# uo-- - 00'101 31.4 32.9 37.

### 3 37.4 41.0 Control OOM02 35.5 35.9 38.2 37.5 37.8 

## o 00M03 48.6 60.2 63.4 88.0 75.7 DON04 40.7 44.2 48.1 52.0 52.6 OOMOS 28.3 30.1 35.5 38.9 43.7 00M06 33.5 34.4 37.7 50.0 45.3 00M07 35:4 3S.6 35.1 33.9 40.9 00M08 37.6 37.0 40.6 42.8 38.6 00M09 34.8 36.8 47.9 40.3 40.1 OOM10 45.0 38.2 41.0 43.8 40.1 N 

## to**---nr~'**

## - 10 10 10 Mean 37.1 38.6 42.5 46.5 45.6 

### S.D. 6.2 8.4 8.7 15.7 11.4 IoU 01

- - - 011l0T 3S.4 41.5 46.1 49.3 4f:l IoU Vehicle 01M02 35.9 37.3 47.2 46.9 42.8 

## o 01M03 31.9 37.6 36.5 42.3 46.0 OlM04 36.7 40.1 40.8 46.2 46.1 OlMOS 33.2 37.a 39.4 42.1 40.4 OlM06 32.4 34.9 40.1 '40.5 41.6 0lM07 29.8 30.3 37.1 42.1 39.6 0lM08 27.8 33.9 35.6 33.9 29.6 0lM09 37.9 41.8 41.0 39.5 38.5 D1Y1D 32.8 35.7 35.5 41.3 45.0 N 10 10 10 1010 

### Mean 33.5 37.0 39.9 42.4 41.2 

### S.D. 3.2 3.6 4.1 4.3 4.8 Unit :IIlL N 

### No:orammals-**~** 

### PROJeCT No.


## e

........... 

## o .t..**~** 

## -.J -.J 

### N 

# cAppendix 9-2 Water intake of male rats treated orally with for 28 days Group-No. Dose (mg/kg) 02­ 10 Animal No. 021401 02U02 02M03 02M04 02U05 --------------------------------------( Days 0f trsa**tmeo~------------------------------** -1 2 9 16 23

.­ 1 .­ 3 .- 10 .- 17 "" 24

- 28. 5 32.9 35.

### 3 38.2 34.4 36.7 41.4 43.6 46.5 44.6 36.6 39.1 42.5 39.7 46.9 35.2 31.8 40.1 45.0 44.7 32.0 38.1 34.9 39.5 41.0 N 5 5 5 Mean 33:8 31.9 39.3 41.8 42.3 S.D. 3.5 3. 1 4.0 3.7 4.9 

### 03--

- 031401 35.2 39.1 41.

### 9 46.5 44.7 03M02 31.9 32.8 35.1 38.5 37.6 100 03M03 31.0 38.5 40. 1 41.7 45.8 03M04 43.7 39.9 46.4 52.4 64.5 03MOS 33.8 36.9 35.8 39.7 34.9 I.H N - -5- 5 5 5 5**~** Mean 36.3 37.6 41.1 43.8 45.5 S.D. 4.5 2.9 5.9 5.1 11.6 04

--- 04MOI

- 33.7 33.9 40.4 42.2 39.1 04U02 37.7 43.0 44.4 46.6 46.5 1000 04M03 33.0 33. 1 35.2 40.0 39.5 04M04 38.6 33.6 44.6 40.6 48.5 04MOS 37.3 35.4 38.5 39.3 43.0 04M06 30.5 33.1 37.3 36.7 40.5 04M07 36.0 33.6 36.9 42.4 40.7 04M08 27.5 31.2 37.5 35.0 39.0 04M09 38.1 35.1 42.2 46.6 44.9 04Ml0 35.2 30.6 36.9 38.0 35.7 N·- 10

- 10 10 10 10 Mean 34.8 34.3 39.4 40.7 41.7 S.O. 3.6 3.4' 3.3 3.8 3.9 Unit I1IL-·- N No. of animals 

# o PROJECT No, 

## e

......... 

# o -t:**~ ~**  

### 0Cl r':"'\ 

### CJ 

## """'" t-.J/"" 

# o

'..-..-. ."., 

### Appendix 9-3 

### Water Intake of male rats treated orally with 

### for 28 

### days Group-No. Dose Ani

### rnaI**-------~-------;-------------------------\Oay** soTrecove

### ry )---­ (lIIg/kg) 00 

### Control No. DOMOS OOM07 

### - 3 - 10 4-9.-'-- ---;r5:l 44.9 41.3 

## o OOM08 41.S 44.3 00M09 39.4 59.1 001.110 40.3 37.3 N 5 5 

### Mean 43.

# r 45.4 

## or -­ S.D. OlMOS 4.0 3S.S 8.2 40.8 Vehicle OlM07 37.1 37.S 

## o 01M08 32.0 30.0 01M09 38.5 40.5 0lM1D 43. 1 4S. 5 t....l VI N 

### Mean 5 37.5 5 39.1 S.D. 4.0 S.D 04 04MOS 39.3 41.4 04M07 40.4 48.5 1000 041.108 3S.5 35.8 041.109 41.7 41.8 041.110 38.5 34.3 N 5 5 

### Mean 39.3 40.4 S.O. 2.0 5. S 

### Unit: IL 

### N No.of animals
PROJECT 

### No.



# c c 

# '" o**~** 

# -J:::.. ..J -S>**~**Appendix 10-1 Water Intake of female rats treated orally with Group-No. Dose Animal 

## --------­ -1 

### ----­ 2 -------------------( 9 16 23 (mg/kg) No. 

### ..... 1
..... 3

- 10 -17

- 24 00 OOFOI 18.0 23.6 24.7 17.1 21.9 Control 00F02 23.3 32.5 30.6 21.9 32.2 0 00F03 23.4 23.9 19.0 25.0 26.3 00F04 31.7 26.7 31.5 29.2 20.3 00F05 31.3 29.4 26.7 33.2 34.3 00F06 15.9 31.5 24.8 28. 1 30.2 00F07 19

..3 28.6 28.6 19.2 27.9 00F08 18.0 22. 1 22.9 17.8 47.4 00F09 34.6 36.2 42.6 48.9 37.7 OOFIO 25.5 23.7 28.7 25.7 20.3 N 10 10 10 10 10 Mean 24.1 27.8 28.0 26.6 29.9 S.D. 6.6 4.6 6.3 9.4 8.5 w Q\ 01 OtFOI 31.7 26.5 28. 1 29. 1 29.8 Vehicle 01F02 28.7 33.8 35.8 36.7 40.4 0 01F03 22. 1 30.0 23.5 31. 1 28.2 01F04 24.2 23.4 29. 1 28.6 31.7 01F05 30.9 31.2 37.2 38.7 33.9 01F06 25.6 29.3 33.3 37.2 26.8 0lF07 20.2 28.1 29.8 30.5 30.3 0lF08 24.5 20. 1 26.9 22.9 30.3 01F09 21.6 29.7 34.5 23.6 32. 1 01Fl0 26.5 32.1 24. 1 36. 1 53.0 N 10 10 

### 10 10 10 Mean 25.6 28.4 30.2 31.5 33.7 S.D. 3.9 4. 1 4.8 5.6 7.7

- _ ..........._ .._­ Unit: 

### mL N : No.of animals



# o 

# e o**~** 

### "'.l 

# err**/~.~-'-..** 'or 28 days Days of**treat~ent** 

## >=-------------------------------------------­

PROJECT No. 

# (; 

# d**r~"** , \ 'J....**~.,.**...:. ("u_" ;\.....) Appendix 10-2 Water intake of female rats treated orally with for 28 days Group-No.

------ -- -------------- ---------------- 

## < Days of treatment 

## >=-----------­ Dose AnimaI -I 2 9 16 23 (mg/kg) No.

....... 1 ...., 3 ...., 10 ...., 11
- 24 02 o2FOl 33.0 29.6 37.5 44.6 47.0 02F02 47.6 44.1 68.7 183.51) 227.0" 10 02F03 26.6 23.3 25.6 29.7 32.6 02F04 32.1 34.9 35.3 40.3 29.7 02F05 22.8 30.7. 33.7 25.3 31.1 N 5 

### 5 S 4 4 Mean 32:4 32.5 40.2 35.0 35.1 S.D. 9.5 7.7 16.6 9.0 8.0 OJ--

-- 03FOI 22.3 28.3 29.9 23.3 25-:4 03F02 37.5 52.4 49.7 51.9 76.0 100 03F03 30.3 31.6 24.-9 31.7 32.9 03F04 26.8 28.8 32.8 33.4 29.2 03FOS 29.2 27.0 32.1 34.S 33.9 W N 5 5 -...1 Mean 29.2 33.6 33.9 35.0 39.5 

### S.D. 5.6 10.6 9.4 10.4 20.7 0404FOI----- 21.9 25.4 22.

### 8 25.3 29.1 04F02 26.7 27.4 29.1 30.3 25.1 10UO 04F03 25.1 28.0 22.4 31.2 29.9 04F04 24.8 25.2 18.9 26.5 25.3 04F05 23.8 23.2 21.0 25.1 28.6 04F06 30.9 32.6 32.5 29.3 30.3 04F01. 29.4 31.7 34.2 33.3 34.0 04F08 23.0 27.5 20.3 25.7 32.1 04F09 23.9 29.7 33.3 22.6 31.0 04FI0 29.6 24.a 30.6 34.0 37.3 N - -'0 10 10 10 --10 Mean 25.9 27.6 26.5 28.3 30.3 S.O. 3. 1 3. 1 6.0 3.8 3.7 

### Un1T: IIIL
- N: No.of animals 

# o a} : Excluded the data from calculation of lIIeao 

### ± S.D. to be abnormal**~alue** due to spill of water 

# o o PROJECT No.**~ ~** 

# ~ (!)

### Appendix 10-3 

### Water Intake of female rats treated orally with ;or 28 days 

### Group-No. Dose 

### (mg/kg) 00 

### Control Animal No. OQF06 OOF07 

## --------------------------------------------< 2 9



# - 3 ,.., to'

32. I 23.5 31. 5 2B.6 

### Days of recovery 

## 5=----------------------------------­

0 OOF08 33.7 40.8 OOFOS 46.5 44.0 OOFIO 31. 1 30.4 N 

### Mean 5 35.O' 5 33.5 S. D. 6.5 8.6 01 OlF06 30.3 34.4 

### Vehicle OlF07 21. 3 24.7 0 01FOB 22.S 2S.2 01F09 34.4 30.4

w OQ OIFIO N 

### Mean 53.2 5 32.4 41.7 5 32. 1 S.D. 12.8 6.4 OT 04F06 27.2 36.2 04F07 37.3 26.2 1000 04F08 32. 1 tB.O 04F09 33.8 31.5 04FIO 29.9 37.7 N 

### Mean 5 32.1 5 29.9 S. D. 3.8 8.0 

### Unit: 

### mL N : No.of animals
PROJECT 

### No. 

# o 

# o o 

## ..::.**~ ~**  .'/"r,..,

..,,\**;~** 

# (; 0_"",. J 

## \J'/,C.,.,

"'-...•,/ 

# () Appendix 11-1 Ophthalmoscopy of male rats treated orally with for 28 days Group-No. Before 4-week 2-week Dose Animal treatment treatment recovery (mg/kg) No.

... Right left Right left Right left 00 00M01 Contro I 

### 00M02 0 00Y03 00M04 OOMOS OOMOS 00M07 00M08 00M09 00M10 

## In 01M01
w 

### Vehicle 01M02 IJj 

### 0 01M03 01M04 OlMOS -; 

### 01M06 01M01 

### OlMOS 01M09 01M10 no 

### abnormality
PROJECT No.



## o 

# c 

# o**~ ~**  

### ClJ

# ~

### Appendix 11-2 

### Ophthalmoscopy of male rats treated orally with for Z8 

### days Group-No. 

### Before 4-week 2-week Dose Animal treatment treatment recovery (llg/kg) 

### No. Right Left Right Left "Rig'ht Left 

### 02- 

### -OZMOr 02M02 10 02M03 

### OZM04 02M05 03**-~-03MOl** 

### 03M02 100 03M03 03M04 031.105 

### 04 04M01 04M02**~** 

### 1000 04M03 04M04 04M05 04M06 04M07 04M08 04M09 041.110 

### no abno

### rmaIi

### ty
PROJECT No.



# c 

# c o**~** 

### "\I**/~"".**

# ~**~** !"''''''**\"~** 

## -Cl . '"- /:.,

"' 

# C5 Appendix 12-1 Ophthalmoscopy of female rats treated orally with (or 28 

### days Group-No. Before 4-week 2-week Dose 

### Animal treatment treatment recovery (mg/kg) 

### No. .RIght--' Litt Rigfil -Lett Right Left 

### 00 OOF01 Control 

### OOF02 

### o OOF03 OOF04 OOFOS OOF06 OOF07 OOFOS OOF09 OOF10 

### Of 01FOl Vehicle 

### 01F02

..... 

## "'" 

# o 01F03 01F04 01FOS 01F06 01F07 01F08 01F09 01Fl0 no abnormality
PROJECT No.



# o 

# o o**~** 

# o**~**

# ~**~**1'"""­**.~ \.~** .. 

### '\.....J Appendix 12-2 Ophthalmoscopy of 

### female rats treated orally with 

### for 28 days 

### Croup=No. 

### Before 4-week 

### 2-week Dose Animal treatment 

### treatment recovery (mg/kg) 

### No.**~gkt** Left 

### Right left 

### Right lelt 02 02FOt 02F02 10 

### 02F03 02F04 02F05**O~** 

### 03FOI 03F02 100 03F03 03F04 03F05 04 04FOl 04F02**~** 

### lUOO 04F03 04F04 04F05 04F06 04F07 04F08 04F09 04F10 

### no abnormality
PROJECT No.



# o c 

# o**~** (Jj

# ~ 

# ... ""AppendI x 13-1 Urinalysis of male rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. Occult Ketone Glucose Protein pH Urobll inogen BiI irubln Color Dose Animal blood body (mg/kg) No. 00 001.101 O. 1 A Control 00M02 

### ± 7.5 O. 1 A 0 00M03 

### ± 7.5 O. 1 A 00M04 

### ± 7.0 0.1 A OOMOS 

### ± 8.0 O. 1 A N 5 5 5 5 5 5 5 5 01 01MOI 

### ± 7.5 O. 1 A Vehicle 01"'02 

### ± + 7.5 O. 1 A 0 01M03 

### ± + 7.5 O. 1 A 0lM04 

### ± 7.5 O. 1 A OIUOS 

### ± + 7.5 O. 1 A N 5 5 5 5 5 5 5 5 02 02MOI ± 7.5 O. 1 A**~** 02M02 

### ± 7.5 O. 1 A \,0.) 10 02M03 

### + 7.5 O. 1 A 02"'04 

### ± + 7.5 O. 1 A 02MOS 

### ± 8.0 O. 1 A N 5 5 5 5 5 5 5 5 03 03MOI 

### + 1.5 O. 1 A 03M02 

### ± ± 7.5 O. 1 A 100 03U03 

### ± + 7.0 O. 1 A 03M04 ± 8.0 O. 1 A 03MOS 

### + 7.5 O. 1 A N 5 5 5 5 5 5 5 5 04 04MOI 

### ± 

### 2+ 7.5 O. 1 A 04M02 

### ± + 7.5 O. 1 A 1000 04M03 

### + 7.5 O. 1 A 04M04 

### ± + 7.0 O. 1 A 04MOS ± 

### ± 8.0 O. 1 A N 5 5 5 5 5 5 5 5 C N : No.of animals C Color: A; pale yellow 

### 0



## .. 

# t;**~** PROJECT No 

### C¥J 

## ......l N

"

....c\,::.::-,\ 

### () \,"-"",

### (') '-,,./



### . Appendix 13-2 Urinalysis of male 

### rats treated orally with for 28 

### days

- I4-day of recovery ­

Group-No. Occult Ketone Glucose Protein pH 

### Urobilinogen Bilirubin Color Dose Animal blood body (mg/kg) 

### No. 00 

### Control OOMOo 

### OOM07 ± ± ± 

## + ± 8.5 

### 8.0 0.1 O. 1 A A 

## o 00M08 

### ± 

### 7.5 O. 1 A 

### OOM09 ± ± 7.5 O. 1 A 

### OOMIO 7.5 O. 1 A N 5 5 5 5 5 5 5 5 

### 01 OlM06 

### ± . 7.0 

### Vehicle 01M07 

### ± ± 

### S.O 

## o OlMOS ± 

### 8.5 OlM09 ± 

### 7.5 

### OlYIO ± 

### 7.5 5

- -5. 5 N 5 5 5 .j:>. 

### 04 04MOS 8;0 

### """ 04M07 

### ± 8.5 1000 04M08 

### ± ± 7.5 04M09 

### 7.5 

### 04MIO ± 7.5 O. 1 O. 1 O. 1 O. 1 O. 1 A A A A A O. 1 O. 1 O. 1 O. 1 O. 1 A A A A A N 

### 5 5 5 

### 5 5 5 5 5**~No.of** 

### animals 

### Color: A; pale yellow



# e o**~** (Jj 

### CJ PROJECT 

### No.



# (;**~** 

# cAppendix 14-1 Urinalysis of female rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. Occult Ketone Glucose Protein pH Urobilinogen Bilirubin Color Dose Animal blood body (mg/kg) No. 00 OOFOl 8.0 O. 1 A Control 00F02 7.0 0.1 A 0 00F03 7.5 0.1 A 00F04 6.5 O. 1 D 00F05 7.0 O. 1 A N 5 ' 5 5 5 5 5 5 5 

## n---­ 01FOl 7.5 O. 1 0 Vehicle 01F02 7.5 O. 1 A 0 01F03 7.5 O. 1 A 01F04 7.5 O. 1 A 01F05 7.0 O. 1 A N 5 5 5 5 5 , 5 5 5**02-~** 02FOl 7.5 O. 1 A .;.. VI ..2F.02 7.5 O. 1 A 10 02F03 8.0 O. 1 A, 02F04 8.0 0.1 A 02F05 7.5 O. 1 A N 5 5 5 5 5 5 5 5 03 03FOl 7.5 0.1 A 03F02 7.0 0.1 A 100 03F03 7.5 O. 1 A 03F04 7.5 O. 1 A 03F05 7.0 O. 1 A N 5 5 5 5 5 5 5 5 04 04FOl 

### 7.0 0.1 A 04F02 

### ± 6.5 O. 1 A 1000 04F03 7.5 O. 1 A 04F04 7.5 0.1 A 04F05 7.5 O. 1 A 

### 0 N 5 5 5 5 5 5 5 5 

### C N : Ho.of animals 

### 0 Color: A; pale yellow 

## o ; almost colorlessness**~** (1j PROJECT No.**~**

# ~ /'_.•.. r-"'l**~** \_//'''<**t''''~~",",** \.....,./ 

### Appendix 14-2 Urinalysis of female rats treated orally with for 28 

### days Group-No. Dose 

### Animal (mg/kg) 

### No. Occult Ketone blood b'ody Glucose Protein pH 

### Urobilinogen Si I irubin - 14-day of Color recovery -

00 00F06 8.0 O. 1 A 

### ControI 00F07 8.0 O. 1 A 

### 0 00F08 8.0 O. 1 A 

### OOF09 7.5 O. 1 A 

### 00F10 8.0 O. 1 A N 

### 5 

### 5 5 5 6 

### 5 5 5 

### 01 01F06 Vehicle 01F07 0 01F08 01F09 01F10 7.5 O. 1 A 

### 7.0 O. 1 A 

### 7.0 O. 1 A 

### 8.0 O. 1 A 7.5 O. 1 A N 

### 5 5 5 5 5 5 

### 5 5**~** 0\ 

### 04 04F06 04F07 1000 04F08 04F09 04Fl0 8.0 O. 1 A 

### 7.0 O. 1 A 

### 7.0 O. 1 A 

### 8.0 O. 1 A 

### 7.5 O. 1 A 

### N 5 5 5 

### 5 5 5 

### 5 5 

### N : No.of animals Color: A; pale yel low



# o e o**~** (1j 

### CI1 PROJECT No.

# ~ 0.

### Appendi

### x 15-t 

### Hematology of male rats treated orally with cor 28 days

- 28-day of treatment

­ Group-No. RBe Ht Hb MeV MCH MCHC Reticulocyte Platelet Dose Animal (mg/kg) No. (x1 0·/J.L

### L) ( l ) 

### ( g/dL ) ( fL ) ( pg ) 

### ( % ) (%0) 

### (xl0·/**~L)** 

### 00 

### OOMOl 807 47.8 16.3 59.2 20.2 34. 1 15 131.5 Control 00M02 821 49.4 17.0 60.2 20.7 34.4 20 87.6 0 00M03 766 47.9 16.7 62.5 21.8 34.9 18 96.6 00M04 790 47.2 16.5 59.7 20.9 35.0 23 97. 1 00M05 804 47.4 16.5 ,59.0 20.5 34.8 26 122.4 N 

### 5 5 5 5 5 5 5 5 Mean 798 47.9 16.6 60. 1 20.8 34.6 20 107.0 S.D. 

### 21 0.9 0.3 1.4 0.6 .0.4 4 18.8
-_

........ _­ 

### 01 01MOl 765 47.2 16.5 61.7 21.6 35.0 13 103.6 Vehicle 01M02 810 48.6 16.4 60.0 20.2 33.7 20 129.4 0 01M03 815 48.7 16.8 59.8 20.6 34.5 20 103.9
.;:. 

### 01M04 879 49.5 16.8 56.3 19. 1 33.9 26 113.2 -.J 

### 01M05 844 49.3 16.6 58.4

.19.7 33.7 23 102.2 N 

### Mean S.D. 

### 02 02M01 02M02 10 02M03 02M04 02M05 N Mean S.D. 

### N : No.of animals 5 823

42 834 801 809 805 816 5 B13

13 

### 5 48.7

0.9 47.9 47.7 4B.0 49.2 48.9 5 4B.3

O.7 5 16.6 0.2 16.3 16.6 16.5 16.9 16.5 5 16.6 0.2 5 59.2

2.0 57.4 59.6 59.3 61. 1 59.9 5 59.5 '1.3 5 . 20.2

0.9 19.5 20.1 20.4 21.0 20.2 5 20.4

0.6 5 34.2

0.6 34.0 34.8 34.4 34.3 33.7 5 34.2

0.4 5 20

5 26 27 19 21 27

5 24

4 5 110.5

11.5 99.7 120.9 92.5 121. 1 108.6 5 10B.6

12.7


### 0 

# e 0 PROJECT No.**~** CXJ C1') 

### ......... 

# - ('''"'.**.~** 

### ' . .J" 

# 0 Appendix 15-2 Hematology of male rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. PT 

### APTT 

## wac Differential count 

### (X) Dose Animal (mg!kg) No. ( sec.) ( sec.) (xl0!!tLL) Lympho Eoslno Mono Baso Stab 

### 00 OOMOl 14.8 24. 1 131 91.

### 6 0.5 2.5 0.0 0.5 Control 001.102 15. 1 25. 1 124 88.6 0.5 3.5 0.0 0.5 0 001.103 15.2 25. 1 105 87.2 3.0 4.9 0.0 0.5 00M04 20.6 24.9 145 89.6 1.0 3.5 0.0 0.0 OOMOS 19.9 26.8 127 82.6 1.5 4.5 0.0 1.0 N 5 5 5 5 5 5 5 5 

### Mean 17.1 25.2 126 87.9 , 1.3 3.8 0.0 0.5 S.D. 

### 2.9 1.0 14 3.4 1.0 0.9 0.0 0.4 01 01MOl 15.5 22.7 134 87.5 0.5 4.5 0.0 1.5 Vehicle 01M02 18.5 27. 1 113 89.6 2.0 2.5 0.0 0.5 0 01M03 15.3 23.6 115 86.5 2.5 2.5 0.0 0.0
.;.. 

### 011.104 17.6 22.4 101 87.0 1.0 4.0 0.0 1.0 00 

### OlMOS 18.4 24.8 117 80.7 1.5 8.4 0.0 1.5 N 5 5 5 5 5 5 

### 5 5 Mean 17. 1 24. 1 116 86.3 1.5 4.4 0.0 0 .•9 S.D. 

### 1.6 1.9 12 3.3 0.8 2.4 0.0 O.7 O?
---­ 

### 02MOl 18.7 24.0 146 92.5 0.5 1.5 0.0 0.0 02M02 14. 1 21. T 

### 172 82.0 1.0 3.0 0.0 1.0 10 02M03 18.2 22.8 112 93.0 1.0 0.5 0.0 0.0 02M04 16.0 23.2 144 84.6 1.5 0.5 0.0 1.0 02M05 15.2 22.6 126 85.6 0.0 2.0 0.0 0.0 N 5 5 5 5 5 5 5 5 Mean 16.4 22.7 140 87.5 0.8 1.5 0.0 0.4 S.D. 

### 2.0 1.1 23 4.9 0.6 1.1 0.0 0.5 N : No.of animals C 

### PROJECT No. 

# e 0**~** 

### 00

............ 

### ...J**~**

## ~

### Appendix 15-3 Hematology of male rats treated orally wi

### th' for 28 days

- 28-day of treatment

­ Group-No. Dose Animal (mg/kg) No. Seg 00 

### OOMOl 4.9 Control 00M02 6.9 0 00M03 4.4 00M04 5.9 OOMOS 10.4 

### N 5 Mean 6.S S.D. 

### 2.4 01 OlMOl 6.0 Vehicle 

### 01M02 5.4 0 01M03 8.5
.jlIo. 

### 01M04 7.0 \0 

### OlMOS 7.9 N 

### 5 Mean 1.0 S.D. 

### 1.3 02 02MOl 5.5 02M02 13.0 10 02M03 5.5 02M04 12.4 02M05 12.4 N 

### 5 

### Mean 9.8 S.D. 

### 3.9 N : No.of animals PROJECT No. C 

# e 0**~** CJj 

## '""'­ (Jj 

# 'C

/"-, r"'\ '."..../ I

# C5 Appendix 15-4 Hematology of male rats treated orally with .or 28 days

- 28-day of treatment

­ Group-No. RSC Ht

. Hb MCV MCH MCHC Reticulocyte Platelet Dose Animal (mg/kg) No. (xl04 / 

### ILL) 

### (**~** 

### ) ( g/dL ) ( fL )' ( pg ) 

## ( X ) (%0) (xl04 / 

### ILL) 03 03MOl 781 46.5 15.8 59.5 20.2 34.0 28 

### 112.4 03M02 836 49.4 16.8 59. 1 20. 1 34.0 13 95.8 100 03M03 831 48.4 16.5 58.2 19.9 34. 1 20 112.8 03M04 802 41.6 16.4 59.4 20.4 34.5 17 

### 106.4 03MOS 183 45.8 15.8 58.5 20.2 34.5 24 112.9 N 

### 5 5 5 5 5 5 5 5 Mean 801 41.5 16.3 58.9 20.2 34.2 20 108. 1 S.O. 

### 26 1.4 0.4 0.6 0.2 0.3 6 7.4 04 04MOl 792 41.9 16.5 60.5 20.8 34.4 24 126.7 04M02 840 50.0 17. 1 59.5 20.4 34.2 23 101.9 1000 04M03 783 45.8 15.8 58.5, 20.2 34.5 24 119.8
fJl 

### 04M04 826 48.9 16.7 59.2 20.2 34.2 14 120.S Q 

### 04M05 815 49.4 16.7 60.6 20.5 33.8 23 91.6 N 5 5 5 5 5 

### 5 5 5 Mean 811 48.4 16.6 59.7 20.4 34.2 22 112. 1 S.D. 

### 24 1.6 0.5 0.9 0.2 0.3 4 14.7 N:--No.of animals PROJECT No.



## c 

# e o**~ ~**  U') 

# ""'­**~** 

## ...J:::..

### Appendix 15-5 Hematology of male rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. 

### PT APTT WBC 

### Differential count 

### (%) Dose Anima (mg/kg) 

### No. ( sec.) ( sec.) (xl0!/**~l)** 

### lympho Eoslno Mono Baso, Stab 

### 03 03MO! 17. 1 22.2 149 88. 1 0.0 5.0 0.0 0.0 03M02 16.2 24.6 122 88.0 0.5 2.0 0.0 1.0 100 03M03 23.8 27. 1 102 88.5 1.5 2.0 0.0 1.0 03M04 18.2 25.9 115 89.5 0.0 1.0 0.0 0.0 03MOS 15.5 23.6 135 91. 1 0.0 3.5 0.0 0.0 N 5 5 5 5 5 5 5 5 Mean 18.2 24.1 125 89.0 0.4 2. 1 0.0 0.4 S.D. 

### 3.3 1.9 

### 18 1.3 0.1 1.6 0.0 0.5 04 04MOI 14.7 21.7 151 84.7 2.0 1.0 0.0 1.0 04M02 15.7 21. 3 113 92.6 0.0 2.0 0.0 0.0 1000 04M03 14.9 22.2 95 87.5 0.5 3.5 0.0 0.0
VI 

### 04M04 16.4 25.6 162 88.0 1.0 1.0 0.0 0.5



## .... 04M05 14.6 19.5 105 90.0 1.0 2.5 0.0 0.0 N 

### 5 

### 5 5 5 5 5 5 5 Mean 15.3 22. 1 125 88.6' 0.9 2.0 0.0 0.3 S.D. 

### 0.8 2.2 30 2.9' O.7 1.1 0.0 0.4**---~.--** 

### N : No.of animals**---~** 

### PROJECT No.



# o c 

# o**.~** 

# '­ CD 

# " o 

# "
("J,\ \_1r"""**~)** 

### Appendix 15-6 Hematology of male rats treated orally with 

### for 28 

### days

- 28-day of treatment

­ Group-No. Dose 

### Animal (mg/kg) No. Seg 03

. 

### 03MOl 6.9 03M02 

### 8.5 100 03N03 1.0 

### 03M04 9.5 

### 03MOS 

### 5.4 N 

### 5 

### Mean 1.5 S.D. 1.6 

### 04

. 04MOl 11.3 

### 04M02 5.4 1000 04M03 

### 8.5
U\ 

### 04M04 9.5 N 

### 04M05 6.5



### N N 

### Mean S.D. 

### No.of animals 5 

### 8.2 2.4


### PROJECT No.



## o 

# e o**~** (l) 

### t-A 

## ........ 

# "

.........

### Appendix 15-7 Hematology of male rats treated orally with or 28 days

- 14-day of recovery ­ Group-No. RSC Ht Hb MeV. 

### MCH MCHC Reticulocyte Platelet Dose Animal (mg/kg) No. (xl041

### p,l) 

## ( X ) ( g/dl ) ( fL ) ( pg ) 

### (

# ") (%0) (xl0"1

### p,L) 00 OOMOS 815 46. 1 16.3 51.3 20.0 34.9 22 108. 1 Control OOMOI 843 48.4 16.8 51.4 19.9 34.7 17 113.5 0 00M08 881 48.9 17.

## a 55. 1 19.2 34.8 10 109.0 00M09 864 48. 1 16.1 55.7 19.3 34.1 25 96.3 00M10 823 41.2 16. 1 57.4 19.6 34. 1 24 96.7 N 

### 5 5 5 5 5 5 5 5 Mean 846 41.9 16.6 56.6 19.6 34.6 20 104.7 S.D. 

### 30 0.9 0.4 1.1 0.4 0.3 6 7.8 01 OlM06 829 41.1 16.8 51.5 20.3 35.2 20 124.8 Vehicle 01MOI 852 50.6 17.5 59.4 20.5 34.6 18 91.9 0 01M08 836 46.6 16. 1 55.7 19.3 34.5 19 111.0
1II 

### 01M09 903 49.4 16.9 54. 1 18.7 34.2 24 106.4 w 

### 01Ml0 829 47.7 16. 1 57.5 19.4 33.8 23 129. 1 N 5 5 

### 5 5 

### 5 5 5 5 Mean 850 48.4 16.1 51.0 19.6 34.5 21 112.6 S.D. 

### 31 1.6 O.S 1.8 0.1 0.5 3 14.9 04 04M06 828 41.1 16.5 56.9 19.9 35.0 22 114.5 04M07 895 49.4 16.6 55.2 18.5 33.6 19 78.4 1000 04M08 835 48. 1 16.6 51.6 19.9 34.5 9 119.8 04M09 888 49.3 16.7 55.5 18.8 33.9 17 89.3 04Ml0 860 49.0 17.0 57.0 19.8 34.7 16 93.0 N 

### 5 5 

## 5 5 5 5 5 5 Mean 861 48.6 16.7 56.4 19.4 34.3 17 99.0 

### S.D. 30 1.0 0.2
. 1.

## a O. 1 0.6 5 17.5 N

### :No.of animals PROJECT No. 

### 0 

# e 0**~** 

### .......... C.Q



### ......... N 

## -.......l /-'
.. /-"" \ ) '-'./ 

# 0 Appendix 15-8 Hematology of male rats treated orally with for 28 days

- 4-day of recovery ­ Group-No. PT APTT 

### WBC Differential count (i) 

### Dose Animal (mg/kg) No. ( sec.) ( sec.) (xl02 / ttL) 

### Lympho Eosino Mono Baso Stab 00 00M06 14.9 19.6 158 80. 1 1.9 7.3 0.0 1.0 Control 00M07 17.7 25.9 114 84.5 0.0 7.0 0.0 1.0 

## a 00M08 18.4 25.9 123 89.5 0.5 5.5 0.0 0.5 00M09 15.9 22.6 91 75.5 1.0 9.0 0.0 0.5 00M10 t

### 5.0 20.7 121 84.0 0.5 6.5 0.0 0.5 N 5 5 5 5 5 5 5 5 Mean 16.4 22.9 121 82.7 0.8 7. 1 0.0 O.7 S.D. 

### 1.6 2.9 24 5.2 O.7 1.3 0.0 0.3 01 01M06 16.5 23.5 142 90.0 0.5 2.5 0.0 0.5 Vehicle 01M07 24.6 27.4 104 80.6 1.0 6.5 0.0 0.5 0 01M08 14.7 19.3 109 73.5 2.5 4.5 0.0 0.0 VI 

### 01M09 21. 1 25.5 75 78.2 1.0 7.9 0.0 0.0 

## "'" 01Ml0 14.9 20. 

### t 112 84.0 2.5 5.0 0.0 0.0 N 5 5 5 5 5 5 5 5 Mean 18.4 23.2 108 81.3 1.5 5.3 0.0 0.2 S.D. 

### 4.3 3.5 24 6.2 0.9 2.0 0.0 0.3 

### 04

--­ 04M06 18.4 24.9 84 78. 1 3.0 7.0 0.0 1.5 04M07 22.0 25.6 150 79.6 1.0 9.7 0.0 0.5 1000 04M08 18.7 24.6 126 87.0 1.0 6.5 0.0 0.0 04M09 14.6 21.4 110 90.5 0.5 4.0 0.0 0.5 04Ml0 15. 1 20.4 80 81.3 1.5 5.4 0.0 0.5 N 5 5 5 5 5 5 5 5 Mean 17.8 23.4 110 83.3 1.4 6.5 0.0 0.6 S.D. 3.0 2.3 29
.5.3 1.0 2. 1 0.0 0.5 N : No.of animals PROJECT No. C 

# "­ C**~** 

### 0

### ~**~** 

### C.D Co.),**;~:.:** ,:,.,


### Appendix 15-9 Hematology of male rats treated orally with 

### for 28 days

- 14-day of recovery ­ Group-No. Dose Animal (mg!kg) No. 

### Seg 00 OOM06 9.7 Control OOM07 7.5 0 

### OOM08 4.0 OOM09 14.0 

### OOM10 8.5 -N­ 5 

### Mean 8.7 S.D. 

### 3.6 

### 01 

### 01M06 6.5 

### Vehicle 01M07 11. 4 

### 0 

### OlM08 19.5 VI 

### 01M09 12.9 VI 

### 01M10 8.5 

## ;r- 5 

### Mean 11. 8 S.O. 

### 5.0 04 04M06 10.4 04M07 

### 9.2 1000 04M08 5.5 

### 04M09 4.5 04M1O 11. 3 -N­ 

### S 

### Mean 8.2 S.D. 

### 3.0 

### N : No.of animals PROJECT No. 

## o 

# c 

# '"" o**~ ~**  CJ) /""'.**r~"" ~**  , \ \.J

- .... ./

### r'\**~)** 

### Appendix 16-1 Hematology of female rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. RBC Ht Hb MCV MCH MCHC Reticulocyte Platelet Dose Animal (mg/kg) No. (x10·/p.l) 

### (**~** 

### ) ( g/dl ) ( fl ) ( Pi ) 

### ( % ) (%0) 

### (x10·/p.l) 00 OOFOl 774 45.5 16.2 58.8 20.9 35.6 16 95.7 Control 00F02 777 46.8 16.8 60.2 21.6 35.9 20 90.7 

## a OOF03 822 46.7 16.3 56.8 19.8 34.9 18 116.6 00F04 777 46.6 16.8 60.0 21.6 36. 1 19 106.0 00F05 848 48. 1 16.7 56.7 19.7 34.7 18 115.0 N 

### 5 5 5 5 5 5 5 5 Mean 800 46.7 16.6 58.5 20.7 35.4 18 104.8 S.D. 

### 34 0.9 0.3 1.7 0.9 0.6 1 11.5 

### 01 01FOl 826 48.2 16.9 58.4 20.5 35. 1 12 114. 1 Vehicle 01F02 864 49.2 17.4 56.9 20. 1 35.4 15 110.5 0 0lF03 755 45.5 16.0 60.3 21.2 35.2 23 100. 1 01F04 775 44.6 15.6 57.5 20. 1 35.0 12 131.9 0\ 

### 01F05 773 46.0 16.2 59.5. 21.

## a 35.2 15 93.3 N 

### 5 5 5 5 5 5 5 5 

### Mean 799 46.7 16.4
.58.5 20.6 35.2 15 110.0 U'I



### S.D. 

### 45 1.9 O.7 1.4 0.5 O. 1 5 14.8 0-2 02F01 821 47.6 16.6 58.0 20.2 34.9 11 

### 107.0 02F02 816 47.0 16.4 57.6 20. 1 34.9 9 

### 113.8 10 02F03 826 48.9 17.3 59.2 20.9 35.4 5 105.7 02F04 836 48.8 17.2 58.4 20.6 35.2 15 103.6 02F05 804 45.4 15.7 56.5 19.5 34.6 15 88.0 N 

### 5 5 5 5 5 5 5 

### 5 Mean 821 47.5 16.6 57.9 20.3 35.0 11 103.6 S.D. 

### 12 1.4 O.7
. 1.

### 0 0.5 0.3 4 

### 9.5 N : No.of animals PROJECT No. 

### C C



### .......... 0 

## "'-l ,:;. c;;::,. 

### c.D CI1

### Appendix 16-2 Hematology of female rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. PT APTT WBC Differential count 

## (%) Dose Animal (lIIg/kg) No. ( sec.) ( sec.) (xl02 / 

### iLL) Lympho Eosino Mono Baso Stab 00 OOFOI 13.5 19. 1 89 88. 1 2.0 1.0 0.0 O. S Control 00F02 15.4 18.2 82 83.6 2.0 2.0 0.0 0.0 

## a OOF03 14.4 17.4 57 85.5 1.0 1.5 0.0 0.5 00F04 14.0 18.6 107 87.0 3.0 1.0 0.0 2.0 00F05 15.8 16. 1 51 94.0 1.5 2.5 O.

## a 0.0 N 

### 5 5 5 5 5 5 5 5 Mean 14.6 17.9 77 

### 87.6 1.9 1.6 0.0 0.6 S.O. 

### 1.0 t.2 23 3.9 0.7 O.7 0.0 0.8 Ot 

### 01FOI 14.4 18.2 58 92.5 0.5 1.5 0.0 0.0 Vehicle 01F02 14.9 17.9 92 89.5 1.5 2.5 0.0 0.0 

## a 01F03 14.2 16.5 85 94.0 1.0 1.5 0.0 0.0 VI 

### 01F04 14.8 18.6 75 88.0 1.0 2.0 0.0 0.5 -..l 

### OlF05 14.8 20.0 97 89.5 1.0 1.5 0.0 0.0 N 5 5 5 

## 5 5 5 5 5 t.!ean 14.6 18.2 81 90.7 1.0 1.8 0.0 O. 1 S.D. 0.3 1.3 15 2.5 0.4 0.4 0.0 0.2 02 02FOI 16.0 18.4 122 83.6 1.0 1.0 0.0 2.0 02F02 15.0 18.0 34 83.0 0.5 2.0 0.0 0.5 10 02F03 15.6 17.9 56 89.5 1.0 1.5 0.0 0.0 02F04 15.4 19.4 78 85.0 2."5 0.5 0.0 0.0 02FOS 14.9 18.4 69 75.0 0.0 5.0 O.

## a 0.5 N 

### 5 5 5 5 5 5 5 5 Mean 15.4 18.4 72 83.2 1.0 2.0 0.0 0.6 S.D. 0.4 0.6 33
. 5.3 0.9 1.8 0.0 0.8 N : No.of animals 0 

### PROJECT No. 

# e 0 

## .:. ""­ t.f) 

## '-ol (1) 

# --...

/

.....:" r", 

### \,....J.,,,,,,.,...r' 

# o Appendix 16-3 

### Hematology of female rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. 

### Dose Animal (alg/kg) No. Seg 

### 00 OOFOl 8.4 

### Control 00F02 12.4 

## o 00F03 11.5 

### 00F04 

### 7.0 OOF05 2.0 N 

### Mean 5 

### 8.3

VI 00 

### 01 

### Vehicle

## o S.D. 

### 01FOl 01F02 01F03 01F04 01F05 4. 1 

### 5:5 6.5 

### 3.5 8.5 

## 8.0 N 

### Mean S.D. 5 

### 6.4 2.0 02 02FDl 12.4 02F02 14.0 10 02F03 8.0 

### 02F04 12.0 02F05 19.5 N 

### Mean S.D. 

### 1f:No.()f 

### animals 5 13.2 4.2



# o o PROJECT No. 

## o**~ ~**  

### -J 

## ........ 

## --J**~**Appendix 16-4 Hematology of female rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. RBe Ht Hb 

### MeV**M~** MCHC Reticulocyte Platelet Dose Animal (mg/kg) No. (x19'/p.L) ( X) ( g/dl ) ( fl ) ( pg ) (%0) (xl0'/p.l) 

### (

# ") 

# o-r---- 03F01 

### 770 44.7 15.

### 6 58.1 20.3 34.9 11 108.3 03F02 789 45.7 16.0 57.9 20.3 35.0 25 120.0 100 03F03 817 48.0 16.7 58.8 20.4 34.8 16 110.7 03F04 809 48.4 16.7 59.8 20.6 34.5 17 106.3 03F05 782 47.1 16.6 60.2 21. 2 35.2 12 112. 3 N - --5-----5

-- 5 5 5 5 5 Mean 793 46.8

_ 16.3 59.

# a 20.6 34.9 16 111. 5 S.D. 19 1.6 0.5 1.0 0.4 0.3 6 5.3 04 04FOl 770 45.5 15.9--59.1 20.6 34.9 17 105.2 04F02 769 44.9 16.0 58.4 20.8 35.6 17 110.1 1000 04F03 a) a) a) a) a) a) a) a) V1 04F04 787 44.4 15.6 56.4 19.8 35. 1 19 113.6 \0 04F05 817 47.0 16.4 57.5 20. 1 34.9 17 120.3 N 4 4- 4 4 4 4 4 Mean 786 45.5 16.0 57.9 20.3 35. 1 18 112.5 S.D. 22 1. 1 0.3 1.2 0.5 0.3 1 6.3 

### N : No.of animals a) : Sampl ing miss due to excess anesthesia death PROJECT No.



# o c

......... 

## o**~** CJ)

# ~ (,;r,

/.C', f"­ l.,..)/"'''­ ("\ "",j 

### Appendix 16-S Hematology of female rats treated orally with for 28 days

- 28-day of tre'atment ­ Group-No. PT 

### APTT 

## wee Differential count 

### (%) --­ 

### Dose Animal (mg!kg) No. ( sec.) ( sec.) (xl02

### !ttl) 

### Lympho Eoslno Mono Baso Stab 03 03FOl 14. S 18.7 62 89.0 0.0 1.0 0.0 O.S 03F02 14. 1 19.0 96 86.0 0.5 1.5 0.0 0.0 100 03F03 15.5 18.0 77 

### 91.5 0.5 1.5 0.0 0.5 03F04 15.0 18.3 64 91.5 1.0 1.0 0.0 0.5 03FOS

. 16.0 17.9 72 90.0 0.5 1.5 

### 0.0 0.0 N 

### 5 5 5 5 5 5 

### 5 5 Mean 15.0 18.4 74 89.6 0.5 1.3 0.0 0.3 S.D. 0.8 0.5 14 2.3 0.4 0.3 0.0 0.3**~** 

### 04FOl 14.5 18.2 57 83.0 0.5 10.0 0.0 1.0 04F02 15.2 17.6 

### S7 88.0 2.5 4.0 0.0 0.0 1000 04F03 a) a) a) 

### a) a) a) a) a) C\ 0 

### 04F04 14.7 17.1 58 88. 1 0.5 1.0 0.0 O.S 04FOS 13.8 17.4 42 85.5 1.5 3.0 0.0 0.0 N 

### 4 4 4 4 4 

### 4 4 4 Mean 14.6 17.6 54 86.2 1.3 4.5 0.0 0.4 S.O. 0.6 0.5 8 

### 2.4 1.0 3.9 0.0 0.5 N : No.of animals a) : Sampling miss due to excess anesthesia death PROJECT No.



## o 

# o o**~** 

### ......... 

# c.o ......::J 

# c.o -t:.

### Appendix 16-6 Hematology of female rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. 

### Dose Animal (mg/kg) No. 

### Seg 03 03FOl 9.5 

### 03F02 12.0 100 03F03 6.0 03F04 

### 6.0 03FOS 8.0 N 

### Mean S 

### 8.3 S.D. 2. S

0'1 

# - 04 

### 1000 04FOl 

### 04F02 04F03 04F04 

### 04FOS S. S 

### 5.5

a) 9.9 

### 10.0 N 

### Mean 4 7.7 S.D. 

### N : No.of animals 2.6 a) : Sampling 

### miss due to excess anesthesia death PROJECT No.



# o 

# e o 

# '"
............ 

# o o**~** 

# v.,

t"'"'\ ._--' '--.Jir"
\."",,,,/ 

# o Appendix 16-7 

### Hematology of female rats treated orally with for 28 

### days

- 14-day 

### of recovery ­ Group-No. 

### RBe Ht Hb 

### MCV Meli 

### MeHC Reticulocyte Platelet Dose Animal (mg/kg) 

### No. (x10',ttl) ( % ) ( g/dL ) ( fL ) ( pg ) ( % ) (%0) (x104/ 

### ttL) 00 OOFOS 805 45.9 16.4 57.0 20.4 35.7 16 112.7 

### Control 00F07 862 47.4 16.5 55.0 19.1 34.8 13 113.7 

## o 00F08 741 42.3 14.7 57.1 19.8 34.8 13 123.0 OOF09. 873 49.5 17.2 56.7 19.7 34.7 8 102.1 00F10 832 48.0 16.9 57.7 20.3 35.2 15 127.6 N 

### 5 5 ---·-5- 5 5 5 5 5 Mean 823 46.6 16.3 56.7 19.9 35.0 13 115.8 S.D. 53 2.7 1.0 1.0 0.5 0.4 3 9.9 0-1

- 01F06 810 46.8 16.2 57.8 20.0 34.6 18 117.3 

### Vehicle 01F07 760 43.2 15.0 56.8 19.7 34.7 15 97.2 

## o 01F08 823 48.116.8 58.4 20.4 34.9 24 111.7 0\ 01F09 815 47.7 -16.7 58.5 20.5 35.0 14 102.0 N 01Fl0 814 45.5 15.5 55.9 19.0 34.1 12 95.2 N 5 5 

# ----s-. ---1 

### Mean 804 46.3 16.0 57.5 19.9 34.7 

### 17 104.7 S.D. 25 2.0 0.8 1. 1 0.6 0.4 5 9.5 0.4 04F06 828 

### 46.8- 16.3 56.5 19.7 34.8 15**105~7** 04F07 831 47.4 16.8 57.0 20.2 35.4 17 103.3 lUOO 04F08 848 48.2 16.6 56.8 19.6 34.'4 13 98.6 04F09 727 44.4 16.0 61.1 22.0 36.0 22 10.2 04F10 782 45.7 15.8 58.4 20.2 34.6 14 87.1 N 5 5 

### --5-

- 5 5- 5 Mean 803 46.5 16.3 58.0 20.3 35.0 16 81.0 S.D. 49 1. 5 0.4

. 1.9 1.0 O.7 4 40.2 

### N No.of animals 

### PROJECT No 

## o 

# o o CIt



### ......... 

# o .......:t**~ ~** 

### Appendix 16-8 

### Hematology of female rats treated orally with 

### , for 28 

### days

- 14-day of recovery ­ Grou-p-No.**PT~·** 

### APTT WBC Differential count 

### 00 Dose 

### Animal (mg/kg) 00 No. 00F06 ( sec.) 16. 1 (sec.) 16.9 (x102 /lLL) 67 Lympho**78~** Eoslno 

### --T.O Mono 9.0 .Baso 0.0 

### Stab0.0 Control 00F07 15.0 18.6 55 85.0 1. 5 5.0 O.0 0.0 

# a 00F08 14. 1 20.0 38 81.6 1.0 4.0 O.0 0.5 OOF09 16.4 17.7 52 92.0 1.0 1.0 0.0 0.0 00F10 N 

### Mean 16.4 5 15.6 18.5

,**S~·** 18.

### 3 57 S 54 85.5 5 84. 

### S 1.5 5 1.

### 6 4.5 S 4.7 0.0 5 0.0 1.0 

### 5 0.3 

### S.D. 1.0 1.2 10 5.0 0.8 2. 9 0.0 0.4 01 01F06 

### 15.5 18.1 63 69.

### 9 1. 06. 

### 9-·**O~** 1.0 Vehicle 01F07 15.6 16.8 95 85.5 3.0 7.0 0.0 0.0 

## o 01F08 14.8 21. 2 40 79.8 1.5 4.4 0.0 0.0 

### $ 01F09 01Fl0 N 

### Mean 15. 1 15.3 5 15.3 17.4 16.5 5 18.0 80 58 --5-· 67 87.1 79.5 T 80.4 1.0 3.5 2.0 4.0 1.S 4.8 0.0 0.0 0.0 0.5 0.5 5 0.4 04 S.D. 04F06 0.3 15.3 1.9 17.1 21

- 

### 59-· 6.8 -84. 1 1.2 

### .0 2.3 0.0 

### ·0-0.0 0.4 0.0 04F07 14.4 19.3 86 80.6 0.5 10.9 0.0 0.0 1000 04F08 15.4 19.6 87 91.5 1.0 5.0 0.0 0.5 04F09 14.9 17.4 46 93. 5 0.0 5.0 0.0 0.0 04Fl0 14.8 19.0 60 90.0 O. 5 4.5 0.0 0.0 N 

### Mean 5 15.0 5 18.5 5 68 5 87.9 5 0.6 5 5.5 5 0.0 

### 5 O. 1 S.D. 0.4 1.1 18 ·5.4 0.4 3.3 0.0 0.2 N : No.of animals PROJECT No. 

## o 

# o 

# o C/l 

# o N /" /"""\ \

## ..,) 

# """'" ....;:, "-.l

## h .' \....,.I 

### Appendix 16-9 Hematology of female rats treated orally with for 28 days

- 14-day of recovery ­ Group=No. Dose Animal (mg/kg) No. Seg 00 OOFOG**9~**

### 5 

### Control OOF07 8.5 

# o OOFOS 

### 12.9 00F09 6.0 00F1d 7.5 

### N

- 5 Mean 8.9 

### S.D. 2.6 01 01F06 21.2 

### Vehicle 01F07 4,5 

## o OtFOS t4.3 01F09 7,4**~** 

### 01Fl0 15.0 N 5 

### Mean 12,5 

### S,O. 6.6 04 04F06 12.9 04F07 8.0 1000 04F08 2,0 04F09 1,5 04F10 5.0 

### N 5 Mean 5.9 S,O. 4,7 

### N No.of animals PROJECT NI

,-. 

# - o**~** 

### CIT 

# o**~**

### ~ 

### CJ 

# c

### Appendi

### x 17-1 Blood biochemistry of male rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. AST AlT r-GTP ALP ChE 

### Total Total TriglycerIde Dose Animal bilirubin cholesterol (ulg/kg) No. ( lUll ) ( IU/L ) ( lUll ) ( IU/L ) ( IU/l ) (mg/dL) (mg/dL) (mg/dL) 00 OOMOl 135 39 0.34 347 408 0.00 49.6 47.8 Control 00LlO2 85 29 0.00 571 377 0.05 39.3 54.0 0 00M03 88 29 0.01 593 408 0.02 47.0 40.8 00M04 86 29 0.08 448 356 0.03 38.9 43.0 00M05 98 35 0.00 277 413 0.02 49.7 44.2 N 

### 5 5 5 5 

### 5 5 

### 5 5 Mean 98 32 0.09 447 392 0.02 44.9 46.0 S.D. 

### 21 5 O. 15 137 25 0.02 5.4 5.2 01 01MOl 107 86 0.00 456 577 0.02 51.0 63.0 Vehicle 01M02 90 28 0.45 382 404 0.04 39.0 55.9 0 01M03 89 27 0.00 564 494 0.04 50.3 49.5 01M04 70 25 0.36 356 353 0.03 59.5 87.0 

# e: OlMOS 100 38 0.00 341 391 0.01 56.4 38.2 N 5 5 5 5 5 5 5 5 Mean 91 41 O. 16 420 444 0.03 51.2 58.7 S.O. 

### 14 26 0.22 92 91 0.01 7.8 18.2 

# or-­**~** 

### 02MOl 115 38 0.01 342 385 0.05 53.9 57.3 02M02 105 34 O. 13 362 544 0.04 77.9 68. 1 10 02M03 101 32 0.00 408 372 0.01 54.4 84.2 02M04 91 35 0.00 348 396 0.03 56.8 107.3 02M05 106 31 0.00 453 492 0.03 50.1 31.6 N 

### 5 5 5 5 

### 5 5 5 

### 5 Mean 104 34 0.03 383 438 0.03 58.6 69.7 S.D. 

### 9 3 0.06 47 76 0.01 11.0 28.4 N : No.of animals
PROJECT No.



# - e """­ 

### 0 

# --­ ..::J CIt -£\ 

### 0**~** r·..... 

# 0 Appendi

### x 17-2 Blood biochemistry of male rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. BUN 

### Creatinine Glucose Total Albumin AIG Ca Inorganic Dose Animal protein phosphorus (mg/kg) 

### No. (mg/dl) (mg/dl) (mg/dl) ( g/dl ) ( g/dl ) (ratio) (mg/dL) (mg/dL) 00 001.101 12.4 0.21 123.5 5.8 4.4 3. 1 9.4 8. 1 Control 00M02 13.7 0.25 148.8 5.9 4.6 3.5 10.3 9. 1 0 00M03 12.8 0.25 128.9 5.6 4.6 4.6 10.2 8.7 00M04 13. 1 0.23 154.9 5.6 4.3 3.3 9.8 8.9 00M05 13.4 0.21 175.6 5.9 4.6 3.5 10. 1 8.2 N 5 5 5 5 5 5 5 5 Mean 13. 1 0.23 146.3 5.8 4.5 3.6 10.0 8.6 S.D. 0.5 0.02 21.0 0.2 O. 1 0.6 0.4 0.4 01 01MOI 12.8 0.21 132.3 5.4 4. 1 3.2 9.6 8.3 Vehicle 01M02 16.5 0.26 136.3 5.7 4.3 3. 1 10. 1 8.4 0 01M03 12.5 0.21 147.6 5.6 4.3 3.3 9.9 8.4 01M04 14.0 0.23 168.9 5.5 4.6 5. 1 10.3 8.8aa- 

### OlMOS 15.0 0.24 167.9 5.7 4.4 3.4 10.3 8.4 N 5 5 5 5 5 5 

### 5 5 Meln 14.2 0.23 150.6 5.6 4.3 3.-6 10.0 8.5 S.D. 1.6 0.02 17.2 O. 1 0.2 0.8 0.3 0.2 02 02MOI 12.3 0.26 126.6 5.6 4.6 4.6 9.8 8.4 ; 021.102 12.0 0.23 139.9 5.8 4.4 3. 1 9.9 9. 1 10 02M03 12.8 0.19 172.4 5.5 4. 1 2.9 10.2 9.3 021.104 13.3 0.20 142.2 5.7 4.3 3. 1 9.9 8.4 02M05 14.0 0.22 162.9 6. 1 4.5 2.8 10. 1 9.0 N 

### 5 5 5 

### 5 5 . 5 5 5 Mean 12.9 0.22 148.8 5.7 4.4 3.3 10.0 8.8 S.D. 0.8 0.03 18.5 0.2 0.2 0.7 0.2 0.4 N: No.of animals PROJECT No. 

### 0 0 0 CIt 

# =**~** 

### CIt



# ----­ 

# '"

### Appendix 17-3 Blood biochemistry of male rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. Na K 

### CI DolO Animal (mg/kg) No. (mEQ/L) (mEq/L) (mEq/l) 

### 00 OOMOl 143.8 5.07 107.5 Control 00M02 143.0 4. 19 106.S 0 00M03 143.2 4.28 10S.4 00M04 143.8 4.30 109.2 00M05 143.2 4.11 106.7 N 5 

### 5 

### 5 Mean 143.4 4.39 107:3 S.D. 

### 0.4 0.39 1.2 01 01MOI 142.2 5. 11 10S.2 Vehicle 01M02 145.5 4.4S 108. 1 0 01M03 143.2 4.54 108.4 01M04 142.2 4.57 107.4**~** 0'\ 

### OlMOS 142.7 4.34 107.3 N 

### 5 5 5 

### Mean 143.2 4.S0 107.5 S.D. 

### 1.4 0.30 0.9 

### 02 02MOI 142.5 5.08 107.3 02M02 140.5 4.37 102.2 10 02M03 142.9 4.S4 106.5 02M04 143.2 4.83 10S.7 02MOS 142.0 5.05

.lOS.6 N 5 5 5 

### Mean 142.2 4.79 105.9 S.D. 

### 1.1 0.30 2. 1 N : 

### No.of animals PROJECT No. 

# e C 

### 0

............. 

## "<.\ 

# '" Q (1) 

# - ,"'.''', 

# C)r-'··**'.~,.-./** 

# o Appendix 17-4 Blood biochemistry of male rats treated orally with for 28 days



### - 28-day 

### of treatment

­ Group-No. AS-T

-- - 

### AU r-GTP ALP 

### ChE Total Total Triglyceride Dose 

### Animal bilirubin cholesterol (mg/kg) 

### No. ( lUlL) ( lUll) ( lUll) (lUlL) ( lUlL) (mg/dL) (mg/dL) (mg/dL) 03 03[01 132 29 

### O. 13 489 432 0.04 51.6 

### 42.-S 03M02 109 27 0.89 450 446 0.02 37.7 31.8 100 03M03 118 37 0.85 451 376 0.01 51.7 34.0 03M04 105 28 0.00265 387 0.04 34.8 29.6 03M05 109 30 0.00 437 338 0.02 42.9 14.9 N 

### --5 5 5 ---·5 5 -_. 

# -r .--0 5 Mean 115 

### 30 0.31 418 396 0.03 43.7 30.6 S.D. 

### 11 4 0.46 88 

### 44 0.01 7.8 '10.0 04 04M01 107 34 0.34·-340 462 0.01 63.5 55.9 04M02 125 29 0.00 422 418 0.02 48.9 63.9 1000 04M03 108 27 0.00 463 578 0.01 57.7 83.2 04M04 103 34 0.00 450 353 0.03 52.2 36.5**~** 

### 04M05 111 33 0.08 412 391 0.01 61. 3 40. 1 N 5 -5 5 5-

_ .. -S. 5 Mean 

### 111 31 0!08 417 440 0.02 56.7 55.9 S.D. 

### 8 3 0.15 48 87 0.01 6.1 18.9 

### N:-No.of animals 

### PROJECT No.



# c 

# c 

# o
.......... 

# o**~** 

# '" --J 

# ""'Appendix 17-5 

### Blood biochemistry of 

### male rats treated orally with for 28 

### days

- 28-day 

### of treatment

­ Group-No. 

### BUN Cr-eatinine Glucose Total AIbumIn- A/G 

### Ca

- - 

### Inorganic Dose Animal protein 

### phosphorus (mg!kg) No. (mg/dl) (mg/dL) (mg/dL) ( g/dL ) ( g/dL ) 

### (rat10) 

### (mg/d L) 

### (mg/d L) 

# or - 03MOl 12.2 0.2& 122-:4 5.5 4.

### ! 

### 3.2**9~&** 9. 1 

### 03M02 12.5 0.27 133.1 5.5 

### 4.4 

### 4.0 9.7 

### 8.6 100 03M03 11.9 0.25 131.2 5.5 4. 1 

### 2.9 9.5 8.7 

### 03M04 8.& 0.21 132.5 5.& 4.6 4.6 9.9 7.8 03M05 12.2 0.21 118.9 5.4 4. 1 

### 3.2 9.7 

### 8.2 N -. 5 

### 5 

### 5 5 

### 5 5 

### Mean 11.5 0.24 127.& 5.5 

### 4.3 3.& 9.7 8.5 S.D. 1.

### 6 0.03 &.5 O. 1 

### 0.2 O.7 O. 1 

### 0.5 04 04MOl 14.4 

### -0.23-

- 16&.7 &. 1 

### 4.6 3. 1 

### 10.0 8.4 04M02 13.4 0.21 124.3 5.5 

### 4.& 5. 1 

### 10. 1 8.5 1000 04M03 15.8 0.2& 183.& 5.8 4.3 2.9 10.3 8. 1 

### 04M04 11.9 0.20 134.& 5.7 

### 4.5 3.8 9.8 8.2 1.0 0'\ 

### 04M05 15.2 0.24 145.3 5.7 4.4 

### 3.4 10.7 9.4 N 

### 5-·**~.--s** 

### 0 5 

# o 5 

### 5 5 

### Mean 14. 1 0.23 150.9 5.8 

### 4.5 3.7 

### 10.2 8.5 S.O. 1.

### 5 0.02 24. 1 0.2 O. 1 

### 0.9 0.3 0.5 

### N : No.of animals PROJECT No.



# o ,-. 

# - o CIl 

# o (lj 

### """'­**~** 

# W

/.-:, {\ t..
......J

# o AppendIx 17-6 Blood biochemistry of male rats treated orally wIth for 28 days

- 28-day of**tr~atment** ­ Group-No. Na K CI Dose Animal (me/kg) No. (mEq/L) (mEq/l) (mEq/l) 

### III
- 03MOl 143.2 4.50 106.9 03M02 142.4 4.76 t08.8 100 03M03 142.8 4.88 106.9 03M04 144.0 4.07 107.8 03MOS 143. 1 4.99 108.7 N 5 5 

### ----5 Mean 143.1 4.64 107.8 S.D. 0.6 0.37 0.9 04 04MO

## r 04M02 1000 04M03 04M04**~** 04M05 N Mean S.D. 140. t 4.11

- 

### -fOT.I 143.2 5.07 107.3 142.8 4.55 105.3 143.3 4.80 107.7 145.3 4.74 108.1 5 5 

### 5 142.9 4.79 106.4 1.9 0.19 1.9 N : No.of animals 

### PROJECT No.·



# o o o CIt 

# o c.D 

## ......... 

# ao --l:**".~** 

### AppendI x 17-7 Blood biochemistry of male rats treated orally with for 28 

### days

- 14-day 

### of 

### recovery ­ Group-No. AST 

### ALl

- - r-':'GTP ALP 

### ChE Total Total Triglyceride 

### Dose Animal bilirubin cholesterol (mg/kg) No. 

### ( lull ) ( lUll) ( lUlL) ( lUll) ( lUll) (mg/dL) (mg/dL) (mg/dL) 

### 00 OOM06 156 30 2. 15

- 319- S13 0-:05 67.3

- --19:-2 

### Control OOM07 132 39 1.92 344 413 0.04 56.0 35.4 

## a OOM08 106 32 2.28 298 452 0.05 41. 1 34.0 OOM09 114 39 2.02 357 506 0.01 60.0 28.9 OOMIO 133 35 1.80 380 452 0.02 62.7 15.7 -5-- 5 5 S N 5 

### Mean 128 35 2.03 340 467 0.03 57.4 26.6 S.O. 

### 19 4 0.19 32 42 0.02 10.0 8.8 01M06 137 21 1.96 -373-

-**3~1-** 

### O:Of

- 47.1 61.1 

### Vehicle OlM07 116 30 2.24 351 545 0.05 51.3 26.3 

## o 0lM08 106 32 1.65 311 323 0.01 67.5 35.5
-..l 

### OlM09 137 28 2.38 268 441 0.04 42.3 42.4 I-" 

### 01MI0 142 30 1.55 304 369 0.03 64.3 43.0 N 

### 5**-~** 5 5 55 

### Mean 128 28 1.96 321 414 0.03 54.5 41.7 S.O •. 

### 16 4 0.36 41 85 0.02 10.9 12.8 04 04M06 135 35 1.60 277 384
- 

### 0-:-05 ·-59-:-7- 44.-4 04M07 108 34 1.32 361 642 0.08 54.8 70.7 1000 04M08 82 29 0.65 288 384 0.05 39.8 62.0 04M09 93. 35 1.55 249 468 0.05· 54.3 35.8 04MI0 134 30 1.42 360 565 0.04 61.4 35.0 -5

--- 5 5 5 5 5 5 N 5 

### Mean 110 33 1.31 307 489 0.05 54.0 49.6 S.D. 

### 24 3 

### 0.38 51 114 0.02 8.5 16.0 

### N : No.of animals 

## o PROJECT No. 

# c 

# o

......... CI1


# ... o f'

# ~ \

, ) ',.-'r'",' i '

....../ 

# o Appendix 11-8 Blood biochemistry of male rats treated orally with for 28 days

- 14-day of recovery ­ Group-No. 

### BUN Creatinine Glucose Total Albumin A/G Ca Inorganic Dose 

### Animal protein phosphorus (mg/kg) No. (mg/dl) (lI1g/dL) (mg/dL) ( g/dL ) ( g/dL ) (ratio) (mg/d L) (mg/d L) 

### 00 00M06 11.3 0.26 120.9 5.8 4.3 2.9 9.5 7.8 Control 00M07 14.5 0.25 138.3 5.7 4.3 3. 1 9.6 7. 1 0 00M08 17.0 0.27 124.6 5.6 4.3 3.3 9.7 7.5 00M09 16.3 0.24 128.0 5.8 4.2 2.6 9.9 8.0 00M10 16.2 0.22 129.5 6.0 4.5 3.0 9.9 7.2 N 

### 5 5 5 5 5 5 

### 5 5 Mean 16.3 0.25 128.3 5.8 4.3 3.0' 9.7 7.5 S.D. 

### 1.1 0.02 6.5 O. 

### 1 O. 1 0.3 0.2 0.4 01 01M06 14.6 0.26 145.2 5.9 4.5 3.2 9.7 7. 1 Vehicle 01M07 15.5 0.26 149.5 5.8 4.4 3. 1 9.5 8.2 0 01M08 13.4 0.22 122.0 5.9 4.6 3.5 9.9 6.7 01M09 12. 1 0.24 141.3 5.7 4.7 4.7 9.6 7.0 N 

### 01M10 13.5 0.22 109.5 5.8 4.6 3.8 9.8 7.5 N 5 

### 5 5 5 5 5 5 5 Mean 13.8 0.24 133.5 5.8 4.6 3.7 9.7 7.3 -.,J

S.O. 

### 1.3 0.02 17.0 

### O. 1 O. 1 0.6 0.2 0.6 (fA -_. ­ 

### 04M06 15.7 0.23 132.

### 9 5.8 4.6 3.8 9.6 8.0 04M07 11.4 0.21 159.9 5.7 4.6 4.2 10.2 6.8 1000 04M08 12.9 0.21 148.6 6.0 4.8 4.0 9.7 6.7 04M09 15. 1 0.26 155.4 5.9 4.6 3.5 9.7 6. 1 . 04Ml0 14.3 0.21 140.3 5.6 4.5 4. 1 9.7 7.6 N 5 5 5 5 5 5 5 5 

### Mean 13.9 0.22 147.4 5.8 4.6 3.9 9.8 7.0 S.O. 

### 1.7 0.02 11.0 0.2 O. 1 0.3 0.2 0.8

..........-..­ 

### N : No.of animals**-~**


### 0 

### PROJECT No. 

# e 0 CIl 

# --­ -0 !J­ c;;-...... 

### !J­**~, ~.** **~,** 

### Appendi

### x 17-9 Blood biochemistry of male rats treated orally with for 28 

### days

- 14-day 

### of recovery ­ Group-No. 

### Na K CI 

### Dose Animal (mg/kg) 

### No. (mEQ/l) (mEQ/l) (mEQ/l) 00 OOMOS 142.4 4.85 106.9 

### Control 00M07 143.2 4.99 107.S 0 

### 00M08 143.5 4.S8 108.4 00M09 146.8 4.84 109.4 00M1O 145.7 4.S5 110.7 N 

### 5 5 5 

### Mean 144.3 4.S0 10S.6 S.D. 

### 1.S O. 14 1.5 01 OlMOS 142.4 5.31 10S.S 

### Vehicle 01M07 144.S ·4.44 107.7 

## a OlMOS 145.5 4.S3 109.8 01M09 143.2 4.30 107.4 (j 

### 01M10 143.8 5.09 106. 1 N 

### 5 5 5 

### Mean 143.9 4.79 107.5 S.D. 

### 1.2 0.43 1.4 04 04M06 143.4 4.97 10S.S 04M07 142.6 4.21 10S.9 1000 04MOS 145.2 4.76 107.5 04M09 143.9 4.32 109.2 04MI0 145.8 4.64 110.9 N 

### 5 5 5 

### Mean 144.2 4.58 10S.2 S.O. 

### 1.3 0.31 1.8 N: 

### No.of animals
0 

### PROJECT No. 

# e 0


## ........ C/I 

### 00. 

# ... ........J N ."

..,"'

..... 

## () \,

..,.........

### (--­ 

## .-..J ,/ 

### Appendix 18-1 

### Blood biochemistry of female rats treated orally with for 28 

### days

- 28-day of treatment

­ Group-No. AST ALT r-GTP AlP ChE Total Total 

### Triglyceri

### de Dose Animal bi II

### rubin cholesterol (mg!kg) 

### No. ( 

### IU!l ) ( IU!L ) ( IU!L ) ( IU!l ) ( IU!L ) (mg!dL) (mg!dL) (mg!dL) 00 OOFOl 96 21 0.16 260 1532 0.03 -b[1 12. 1 

### Control OOFOt 91 22 0.00 201 2316 0.01 65.1 13.6 

## a 00F03 86 17 0.16 259 2126 0.05 65.1 9.9 OOF04 145 30 0.51 225 1141 0.06 51.4 17.6 OOFOS 115 22 0.68 190 1712 0.06 61.9 14.5 

### N 5 5 55 5 

### 5 Mean 108 22 0.43 221 1885 0.05 62.2 13.5 

### S.D. 23 5 0.33 32 324 0.02 6.6 2.9 01 01FOl 96 22 0.43 181 3421 0.08 -58.9 13:6 

### Vehicle 01F02 109 20 0.46 353 912 0.04 63.4 12.6 

## a 01F03 108 38 O.00 317 3632 0.06 59.5 9. 1 01F04 160 24 0.45 208 2318 0.08 55.4 10.0**~** 01F05 101 23 0.00 310 1464 0.02 51.1 13.4 

### N -----5- 5 5 

### 5 5 5 5 5 Mean 116 25 0.21 215 2363 0.06 51.1 11.7 S.D. 25 1 0.24 13 1189 0.03 4.6 

### 2. 1 02 02FOl 83 24 0.00 270 1437 0.05 72.1 14.5 02F02 114 21 0.33 297 2737 0.01 80.3 14.3 10 02F03 138 24 0.52 241 3112 0.07 54.

# a 9.5 02F04 174· 29 0.00 300 2127 0.06 51.8 13. 1 02F05 116 24 O.00 346 3200 0.06 53.0 11.8 N 

### -5 5 5 5 5 5 --5 5 

### Mean 125 24 0.17 291 2523 0.06 62.2 12.6 S.D. 34 3 0.24 39 739 0.01 13.1 2. 1 

### N : No:of animals 

# o PROJECT No. 

# o o Vl**~** 

### ........... Col**~**

### ~

### Appendix 18-2 

### Blood biochemistry of female rats treated orally with for 28 

### days

- 28-day of treatment

­ Group-No. -------sON 

### Creatinine Glucose Total Albumin A/G Ca Inorganic Dose 

### Animal protein phosphorus (mg/kg) 

### No. (mg/dL) (mg/dL) (mg/dL) ( g/dL ) . ( g/dL ) (rati

### o) (lIIg/d L) (mg/d L) 

### 00 

### Control

## o OOF01 14.2 0.25 140.9 5.8-"4.8 4. 5 8.0 00F02 12.1 0.26 187.4 6.3 5.4 6.0 10.1 7.9 OOF03 11.7 0.24 148.1 6.0 5. 1 5.7 10. 1 8. 1 

### OOF04 14.0 0.24 99.1 6.0 5.0 5.0 9.6 7.7 00F05 10.3 0.22 144.2 5.7 4.7 4.7 9.8 7.4 N 5 5 5 5""" 5 5 5 5 

### Mean 12.5 0.24 143.9 6.0 5.0 5.2 9.8 7.8 S.D. 

### 1.6 0.01 31.3 0.2 0.3 0.6 0.3 0.3 01 

### DTF1Jl 11.5 0.23 118.6 6.35.3 5. 10.1 7.9 

### Vehicle 01F02 8.8 0.23 119.2 5.8 4.8 4.8 9.9 8.3 

# o 01F03 11.0 0.22 138.8 5.8 4.7 4.3 9.5 7.3 OtF04 12.7 0.27 93.7 6.2 5.3 5.9 9.5 

### 7;,**~** 

### 01F05 11.9 0.21 154.1 6.3 5.0 3.8 9.9 7. 1 N 5 5 5 5 5 

### Mean 11.2 0.23 124.9 6. 1 5.0 4. 8 9.8 7.5 S.D. 

### 1.5 

### 0.02 22.9 0.3 0.3 0.8 0.3 0.5 02 

### -01FOl 14.9 0.26 121.6 5.7 4.7 4.7 9.4 7.2 02F02 12.6 0.23 135.8 6. 1 5.2 5.8 9. 7 7.6 10 02F03 16.4 0.25 131.8 6.0 4.9 4.5 9.7 7.7 02F04 13.5 0.24 106.9 5.9 5.0 5.6 9.6 8. 1 

### 02F05 12.6 0.28 143.7 6.2 5.2 5.2 10.0 8. 1 

### N 5 5 5 5 -5 

### 5 Mean 14.0 0.25 128.0 6.0 5.0 5.2 9.7 

### 7.7 

### S.D. 1.6 0.02 14.2 0.2 0.2 0.6 0.2 0.4 N 

### No.of animals 

# o o PROJECT No. 

# o CIl**~ ~**  

### ..........**~** 

### -1\

/. ':;,

.... .;J(""" '....**~-,** 

### U Appendix lS-3 Blood biochemistry of female rats treated orally with for 28 

### days

- 28-day of treatment

­ Group-No. Na K CI 

### Dose Animal (mg/kg) No. (mEq/l) (mEQ/L) (mEq/l) 

### 00 OOF01 141. 6 

### 4.57 --109.2 Control 00F02 142.4 3.75 107.7 

## o 00F03 143.6 4;69 109.7 00F04 143. 1 5.04 10S.4 00F05 144. 1 

### 4.S1 109.0 N 5 

### Mean 143.0 4.57 10S.8 S.D. 

### 1.0 0.49 0.8 01 Q1FO1 142. 1 

# 4.rr--·**109~** 

### Vehicle 01F02 142.2 4.22 106.9 

## o 01F03 143.0 4.25 108.7 01F04 142.0 5.09 10S.9 ...J 0\ 

### 01F05 142.0 4.25 106.4 N 

### 5 

### S­ 5 

### Mean 142.3 4.50 108. 1 S.D. 

### 0.4 0.39 1.4 

### 02 02FOl 140.8 4.78 

### 108.0 02F02 144.4 4.37 109.8 10 02F03 142.7 4.77 109. 1 02F04 142.9 5.14 10S.0 02F05 143.2 4.59 10S.5 N 

### Mean S.D. N : 140.01 

## anI

## iliaIs 5 

### 142.S 1.3 

### 5 4.73 0.2S 

### 5 108.7

0.8 

# o 

# e o CI1 

### PROJECT No**~** 

### CI1

........... 

# """"

c:::"

# -- Appendix 18-4 Blood biochemistry- of female rats treated orally with for 28 days

- 28-day of treatment
­ Group-No. Asr- AlT r-GTP ALP ChE Total Total- 

### TrTilyceriae Dose Animal bilirubin cholesterol 

### (mg/kg) No. ( 

### lUll) ( lUll) ( lUll) ( lUll) ( lUll) (mg/dl) (mg/dl) (mg/dl) 03FOl

- -87 28-

- -0:9-7

--- 235 2146**-o.O~ ~··-----s2.8**  

### 03 

### 13.7 03F02 129 23 0.28 342 1725 0.05 51. 9 9.9 100 03F03 120 25 0.40 409 905 0.06 54.7 7.4 03F04 155 28 0.00 296 1656 0.06 87.9 10.8 03F05 94 22 0.01

. 224 1787 0.06 70.4 9.4 N 

### 55- 5 

## r- 5 5 Mean 

### 117 25 0.33 301 1644 0.06 69.5 10.2 S.D. 

### 28 . 3 0.40 77 

### 454 0.00 16.2 2.3 04 

### mOl 72

-

### -23- 0.00 236

- 

### -,789

- 0.00- - .62.2 

### 9-:6 04F02 116 23 0.84 194 1085 0.02 66.4 6. 1 

### lUOO 04F03 83 27 0.51 322 3008 0.05 61.9 9.3 04F04 134 31 0.00 239 3072 0.08 68.4 7.5 ::j 

### 04F05 104 19 0.56 293 2156 0.05 57.8 8.2



### N: No. of N Mean S.O. 

### an mals 5 

### 102

25 5 

### 25

5 5 

### 0.38 0.37 5 

### 257

51 5 

### 2222

840 0.05 0.02 5 

### 63.3

4.2 5 8. 1 

### 1.4
PROJECT No.



### 0­ C 

# o C/l**~** 

### C1>



# .......**~** / .......1"""",\ '-.,/ 

### \

.....J 

### Appendix 18-5 

### Blood biochemistry of female rats treated 

### orally with 

### for 28 days

- 28-day 

### of treatment

­ 

### Group-No. BUN 

### Creatinine ---cTLlcose Total 

### AlbulIIin--· fJC- 

### Ca--· Inorganic Dose 

### Animal protein phosphorus (mg/kg) 

### No. (mg/dL) (mg/dL) (mg/dL) ( g/dL ) ( g/dL ) (ratio) (mg/d L) (mg/d L) (11 03FO} 

### 13.6 0.22 153.6 6.3 5.1 4.3 10.1**-6~8** 03F02 14.9 0.25 136.9 6.1 4.6 3.1 9.7 8.3 100 03F03 12.6 0.24 118.1 5.6 4.8 6.0 9.5 7.5 03F04 

### t2.0 0.22 89.0 5.9 4.8 4.4 9.7 7.8 03F05 12.6 0.23 116.6 6.0 5.0 5.0 9.9 9.3 -N­ 

### 5 5 5 5 

## r-. 5 5 Mean 13. 1 0.23 122.8 6.0 4.9 4.6 9.8 7.9 S.D. 1.1 0.01 24.2 0.3 0.2 1. 1 0.2 0.9 04 04F01 13.6 0.23 143.3 -6-.4-

- 5.5

.-_.6. 1**10~5-··** 

# i: 1 04F02 14. 1 0.27 120.5 5.9 4.8 4.4 9.9 9.0 1000 04F03 13.8 0.23 104.6 6.6 5.6 5.6 10.5 10.0 --.) 04F04 10.6 0.23 129.8 6.5. 5.5 5.5 10.0 .7.4 00 04F05 10.8 0.25 120.6 5.8 4.9 5.4 9.4 7.6 -N­ 5 55 5 5 5- 5 5 

### Mean 12.6 0.24 123.8 6.2 5.3 5.4 10.1 8.2 S.D. 1.7 0.02 14.2 0.40.4 0.6 0.5 1.2 N : 

### No.of animals PROJECT No.



# o o 

# o err 

# "**~**



## ........ .....1\



# '"'------ 

### Appendix 18-6 Blood blochemiltry of female rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. Na K CI 

### Dose Animal (mg/kg) 

### No. (mEQIL) (mEQ/L) (mEQ/L) 03 03F01 141. 1 4.23 109.4 03F02 143.5 4.35 106.9 lUO 

### 03F03 143.3 4.69 110.6 03F04 145.0 4.85 110.2 03F05 143.9 4.82 108.9 N 

### Mean S.D. 0.1 

### 04FOl 04F02 1000 04F03
...,J 

### 04F04 1.0 

### 04F05 N 

### Mean S.D. 

### 5 

### 5 143.4 4.59 1.4 0.28 143.3 4.06 141.0 4.71 148.2 7.33 142.7 4. 14 144.3 4.49 5 5 143.9 4.95

2.7 1.

### 36 5 

### 109.2 1.4 108.7 107.5 109.6 107.9 109.6 5 108.7 1.0 N : 

### No.of animals PROJECT No



# o e o CI1**~** 

### .......... t2) 

## -"\
:'.,;"..... r"'\ (...) 

### \

....J

.**,~..."./'**

# 0 Appendix 18-7 Blood biochemistry of female rats treated orally with .or 

### 28 days

- 14-day of recovery ­ Group-No. AST AlT r-GTP ALP ChE Total Total Triglyceride Dose Animal bi IIrubin cholesterol (mg/kg) No. ( lUll) ( lUll) ( lUlL) ( lUlL) ( lUll) (mg/dl) (mg/dL) (mg/dL) 00 00F06 12t 

### 22**2~** 

### 31 189 3148 0.07 67.8 19.6 ControI 00F07 111 24 2. 14 217 1895 0.06 52.7 '28.9 0 OOFOS 119 36 1.

### 51 144 2720 0.07 60.6 1&.0 00F09 120 29 2. 18 249 1959 0.08 80.2 13. 1 00F10 97 25 2.28 229 2029 0.09 68.& 9.3 N 

### 5 5 5 5 5 5 5 5 Mean 114 27 2.08 20& 2350 0.07 6&.0 17.4 S.D. 10 6 0.33 41 556 0.01 10.2 7.5 01 OtF06 124 27 1.

### 91 153 2289 0.08 58.4 9.3 Vehicle 01F07 110

. 30 2.58 168 1537 0.09 58.3 15.3 0 01F08 144 18 2.55 225 2538 0.07 53.3 S.5
CJ:) 

### 01F09 84 30 1.93 182 2447 0.07 61.4 19.9 0 

### 01Fl0 95 21 2.32 213 2374 O. 10 58.2 6.6 N 

### 5 5 5 

## 5 5 5 5 5 

### Mean 111 25 2.26 188 2237 0.08 57.9 11.9 S.D. 24 5 0.32 30 402 0.01 2.9 5.5 04 04F06 83 

### 35 1.

### 82 178 2299 O. 10 72. 1 19.9 04F07 91 26 1.

### 61 171 2548 0.07 79.6 24.3 1000 04FOS 133 25 2.70 132 2536 0.06 54.5 4.2 04F09 64 25 2.99 234 2507 0.06 74.4 14.9 04Fl0 104 29 2.29 159 2637 0.09 55.8 9. 1 N 

### 5 

## 5 5 5 5 5 5 5 Mean 95 28 2.28 175 2505 0.08 67.3 14.5 S.D. 26 4 -0.58 37 125 0.02 11.4 8. 1 N : No.of animals
PROJECT No. 0 

### 0 0 

### CI1**~** 

### """""'­ c...o

### ~ 

# -t::Appendix 18-8 Blood biochemistry of female rats treated orally with

. for 28 days

- 14-day of recovery ­ Group-No. Dose (lI1g/kg) 00 Animal No. OOFOS BUN (mg/dL) 14.S Creatinine (mg/dL) 0.26 Glucose (mg/dL)

118.5 Total protein (g/dL) 6.0 Albumin ( g/dL ) 5.0 A/G (ratio) 5.0 Ca

. (mg/dL) 9.S Inorganic phosphorus (mg/dL) 6.S Control 00F07 17.7 0.24 120.7 6.5 5.0 3.3 10.7 7.6 

## o OOFOS 16.4 0.2S 132.0 6.6 5.4 4. 5 9.5 5. 9 00F09 12.4 0.26 138.0 6.5 5.3 4.4 9.S 6.9 OOFIO 15.4 0.26 124.5 6.2 5.1 4.6 9.6 6.5 N 5 5 5 5 5 5 5 5 Mean 15.3 0.26 126.7 6.4 5.2 4.4 9.9 6.7 

### S.D. 2.0 0.01 8. 1 0.3 0.2 0.6 0.5 0.6 01 Vehicle 01F06 01F07 16.0 15.2 0.29 0.27 153.25.S 149. 1 5.9 4.8 4.S (S 4.4 9.5 10.0 5.4 6.3 

## o 01FOS 13.90.30 124.7 6.3 5.3 5.3 9.7 6.5
()() 

## ,... 01F09 01Fl0 lS.l 13.7 0.28 0.25 133.9 115.6 6.3 6.4 5.0 5.7 3.8 8.1 10.1 10.0 7.1 6.8

04 N Mean 

### S.D. 04F06 5 15.4

1.8 13.6 5 0.28 0.02 0.20 5 135.3

15.9 142.7 5 6. 1 0.3 6.4 5 

### 5. 1 0.4 5.8 5 5. 3 1.7 9.7 5 9. 9 0.3 9.7 u 5 6.4 0.6 

### U 04F07 13.7 0.24 139. 1 6.4 5.2 4. 3 9. S S. 7 1000 04FOS 15.9 0.27 103.0 6.5 5.2 4.0 9.8 7.2 04F09 14.2 0.28 122.6 6.2 5.0 4.2 9.9 6.6 04FIO 15.4 0.29 128.6 6.3 5.3 5.3 10.0 8.2 N 5 5 5 5 5 5 5 5 Mean 14.6 0.26 127.2 6.4 5.3 5.5 9.8 6.7 S.D. 1.0 0.04 15.7 O. 1 O. 3 2.4 O. 1 1. 1 N No.of animals 

## c c 

# o C/1 

### N 

# o PROJECT No.

.............

,/:'
..".

# ~ 

# \

# o Appendix 18-9 Blood biochemistry of female rats treated orally with .or 28 days

- 14-day of recovery ­ Group-No. Na K CI Dose 

### Animal (mg/kg) No. (mEq/L) (mEq/L) (mEq!L) 

### 00 -OOF06 144.7 5. 11 111.2 Control 00F07 142.2 4.46 108.3 

## o 00F08 142.4 4.16 108.6 OOF09 144.5 4.26 110.6 OOFfO 142.0 4.62 109.9

Ot 

### Vehicle

## o**~**



### 04 1000 N 

### 555 

### Mean 143.2 4.52 109.7 S.D. 

### 1.3 0.37 1.3 01F06 143.9 

### 4:32

- 111.6 01F07 145.7 4.25 110.6 01F08 145.2 4.05 111.

### 4 01F09 143.1 4.76 109.1 01Fl0 143.1 4.50 109.8 N 

### 555 Mean 144.3 4.38 110.6 S.D. 

### 1.1 0.21 0.9 04F06 145.0 4.53 112.2 04F07 142.4 3.92 101.9 04F08 143.9 4.83 110.6 04F09 143.0 3.50 11O.

### 5 04FI0 144.6 4.62 110.6 N 

### 555 Mean 143.8 4.28 110.4 S.D. 1. 

### 1 0.55 1.

### 5 N No.1iT**anj~als** 

### PROJECT No. 

## o o o CI1 

# "'­ N ....Q**~** 

# '"'Appendix 19-1 Absolute and relative organ weights of male rats treated orally with or 28 days**~- ~8-day**  of treatment

­ Group-No. Final Dose Animal body weight Brain Liver Spleen Kidney(R) Kidney(L) AdrenaIeR) (mg/kg) No. ( g ) ( g) ReI. ( g') ReI. ( mg ) Rei. ( g) ReI. ( g) ReI. ( mg ) ReI. 00 

### OOMOI 365 2.08 0.57 11.70 3.21 623 171 1.51 0.41 1.45 0.40 26.6

. 7.3 Control 00M02 381 2.09 0.55 11.22 2.94 747 196 1.33 0.35 1.26 0.33 28.2 7.4 0 001.103 406 2.01 0.50 12.91 3.18 769 189 1.39 0.34 1.38 0.34 29.4 7.2 00M04 417 2.31 0.55 12.96 3.11 832 200 I.52 0.36 1.49 0.36 30.8 7.4 00M05 372 2.17 0.58 12.53 3.37 665 179 1.36 0.37 1.35 0.36 30.5 8.2 N 5 5 5 5 5 5 5 Mean 388 2.13 0.55 12.26 3. 16 727 187 1.42 0.37 1.39 0.36 29. 1 7.5 S.D. 22 0.11 0.03 O.77 0.16 83 12 0.09 0.03 0.09 0.03 1.7 0.4 01 011A0I 399 2.19 0.55 11.75 2.94 677 170 1.52 0.38 1.53 0.38 30.7 7.7 Vehicle 011A02 399 2.17 0.54 13.07 3.28 860 216 1.42 0.36 1.45 0.36 30.5 7.6 0 01M03 393 2.22 0.56 11.37 2.89 649 165 1.46 0.37 1.53 0.39 28. I 7.2 011404 405 2.13 0.53 12.28 3.03 680 168 1.42 0.35 1.36 0.34 32.2 8.0 OlMOS 377 2.04 0.54 11.28 2.99 747 198 1.38 0.37 1.34 0.36 3i.2 8.3 (Xl N 5 5 5 5 5 5 5**~** Mean 395 2.15 0.54 11.95 3.03 723 183 1.44 0.37 1.44 0.37 30.5 7.8 S.D. 11 0.07 0.01 0.74 0.15 85 23 0.05 0.01 0.09 0.02 1.5 0.4 02 02UOI 332 1.99 0.60 9.76 2.94 714 215 1. 15 0.35 1. 1

### S 0.35 22. 1 6.7 021A02 406 2. 13 0.52 12.SO 3.08 861 212 1.38 0.34 1.42 0.35 24.6 6. 1 10 021A03 397 2. 18 0.55 13.05 3.29 815 205 1.56 0.39 1.44 0.36 23.5 5.9 021A04 388 2.07 0.53 12. 11 3. 12 714 184 1.39 O. 36 1.39 0.36 26. 1 6.7 02M05 347 2.10 0.61 10.23 2.95 695 200 1.37 0.39 1.34 0.39 27.9 8.0 N 5 5 5 5 5 5 5 Mean 374 2.09 0.56 11.53 3.08 760 203 I.37 0.37 1.35 0.36 24.8 6.7 S.D. 33 0.07 0.04 1.45 0.14 74 12 O. 15 0.02 O. 12 0.02 2r3 0.8 Rlil.-:Relafive organ weight (g or mg / 100g final body weight)
PROJECT No. C 

### 0 

### 0 CIT



### .......... N N**~** 

## -.J ,/.. ........ 

# 0

............Appendix 19-3 Absolute and relative organ weights of male rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. Final 

### Dose Anilllal body weight Brain Liver Spleen Kldney(R) KIdney (l) Adrenal (R) (mi/kg) No. ( g ) ( g) Rei. ( I) ReI. ( III ) ReI. ( g) ReI. ( g) ReI. ( lUg ) Rei. 03 03MOI 398 2. 10 0.53 11.86 2.98 777 195 1.35 0.34 1.44 0.36 24.9 6.3 031.102 341 2.05 0.60 9.91 2.91 700 205 1.11 0.33 1.20 0.35 22.3 6.5 IUU 03M03 356 2.07 0.58 9.83 2.76 661 186 1.25 0.35 1.27 0.36 27.6 7.8 03M04 353 2. 18 0.62 10.27 2.91 802 227 1.31 0.37 1.31 0.37 24. 1 6.8 031.105 364 2.09 0.57 10.27 2.82 899 247 1.41 0.39 1.44 0.40 24.8 6.8 N 5 5 5 5 5 5 5 Mean 362 2.10 0.58 10.43 2.88 768 212 1.29 0.36 1.33 0.37 24.7 6.8 S.D. 22 0.05 0.03 0.83 0.09 93 25 O. 11 0.02 0.11 0.02 1.9 0.6 04 04MOI 395 2.08 0.53 13.71 3.47 822 208 1.35 0.34 1.38 0.35 23.0 5.8 04M02 374 2. 18 0.58 9.74 2.60 642 172 1.40 0.37 T. 36 0.36 29.7 7.9 IUUO 041o!03 374 2.13 0.57 11.96 3.20 674 180 1. 18 0.32 1. 18 0.32 26.3 7.0 04"04 365 2.11 0.58 11.02 3.02 751 206 1.35 0.37 1.39 0.38 21.8 6.0 04M05 363 2.07 0.57 11.51 3.17 647 178 1.27 0.35 1.24 0.34 30.4 8.4 00 U'l N 5 5 5 5 5 5 

### 5 Mean 374 2. 11 0.57 11.59 3.09 707 189 1.31 0.35 1.31 0.35 26.2 7.0 S.D. 13 0.04 0.02 1.45 0.32 78 17 0.09 0.02 0.09 0.02 3.9 1.1 Ref: : Relative organ weight (g or mg 

### 7100g final body weight)
PROJECT No.



# o o 

# o CI1**~** 

### N**~ ~**  

### -S\ /'"." /'"",,\ 

### U

# o
Appendix 19-4 Absolute and relative organ weights of male rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. 

### Dose Animal Adrenal (L) Testis(R) TestIs(L) Prostate (RIg/kg) No. ( RIg ) ReI. ( g) Rei. ( g) Rei. ( mg ) ReI. 03 031101 28.2 7.1 1.59 0.40 1.57 0.39 441 111 03M02 29.8 8.7 1.51 0.44 1.50 0.44 452 133 100 03M03 27.6 7.8 1.63 0.46 1.60 0.45 675 190 03&104 24.0 6.8 t.55 0.44 1.56 0.44 400 113 031105 26. 1 1.2 1.52 0.42 1.62 0.45 454 125 N 5 5 5 5 Mean 27. 1 7.5 1.56 0.43 1.57 0.43 484 134 S.D. 2.2 0.8 0.05 0.02 0.05 0.03 109 32 04 04MOl 23.9 6. 1 1.41 0.36 1.42 0.36 477 121 0410102 32.8 8

..8 t.56 0.42 1.51 0.40 426 114 1000 04M03 26.3 1.0 1.73 0.46 1.71 0.46 451 121 04M04 22.8 6.2 1.52 0.42 1.52 0.42 338 93 04M05 32. I 8.8 1.65 0.45 1.63 0.45 461 127 co Q\ N 5 5 5 5 Mean 27.6 7.4 1.57 0.42 1.56 0.42 431 115 S.D. 4.6 1.3 0.12 0.04 0.11 0.04 55 13 ReI. : Relative organ weight (g or RIg 

### 7 100g final body weight)
PROJECT No.



# c 

# e o V1**~** 

### N c:::::::r-. 

### Vf oAppendix 19-5 Absolute and relative organ weights of male rats" treated orally with :or 28 days

- 14-day of recovery - Group-No. Dose (lig/kg) Animal No. Final body weight ( g ) Brain ( g) ReI. LIver ( g) ReI. Spleen ( mg ) Kidney (R) ReI. ( g) K idney(L) ReI. ( g) Adrenal (R) Rei. ( mg ) Re I. 00 001.106 429 2.25 0.52 12.25 2."86 738 172 1.50 0.35 "1.42 0.33 24. 1 5.6 Control 00M07 398 2.08 0.52 11.23 2.82 636 160 1.24 0.31 1.20 0.30 24.5 6.2 0 0010108 418 2.20 0.53 11.99 2.87 681 163 1.59 0.38 1.64 0.39 27.7 6.6 00M09 396 2.13 0.54 10.65 2.69 748 189 1.32 0.33 1. 19 0.30 28.8 7.3 00M10 423 2.18 0.52 12.27 2.90 915 216 1.47 0.35 1.54 0.36 32.8 7.8 N 5 5 5 5 5 5 5 Uean 413 2.17 0.53 11.68 2.83 744 180 1.42 0.34 1.40 0.34 27.6 6.7 S.D. 15 0.07 0.01 0.71 0.08 106 23 0.14 0.03 0.20 0.04 3.5 0.9 01 

### OUA06 492 2.31 0.47 14.85 3.02 884 180 1.63 0.33 1.68 0.34 30.6 6.2 Vehicle 011.107 410 2.02 0.49 11.23 2.74 766 187 1.30 0.32 1.38 0.34 29.6 7.2 0 01M08 404 2.11 0.52 12. 19 3.02 743 184 1.41 0.35 1.53 0.38 27.8 6.9 01M09 399 2.09 0.52 11.22 2.81 799 200 1.40 0.35 1.51 0.38 25.3 6.3 

## ouno 473 2.37 0.50 14.08 2.98 1017 215 1. 59 0.34 1.57 0.33 27.8 5.9 00 N 5 5 5 5 5 5 5 -...I Mean 436 2. 18 0.50 12.71 2.91 842 193 1.47 0.34 1.53 0.35 28.2 6.5 S.D. 44 0.15 0.02 1.67 0.13 112 14 0.14 0.01 0.11 0.02 2.0 0.5 04 04M06 419 2. 22 0.53 11.76 2.81 864 206 1.38 0.33 1.39 0.33 19.2 4.6 04M07 456 2.13 0.47 13.00 2.85 882 193 1.60 0.35 1.59 0.35 27.2 6.0 1000 0411\08 414 2.17 0.52 12.74 3.08 935 226 1.48 0.36 1.55 0.37 26.4 6.4 04M09 411 2.28 0.55 12.10 2.94 823 200 1.39 0.34 1.41 0.34 26.5 6.4 04Ml0 352 2.03 0.58 9.67 2.75 558 159 1.21 0.34 1.21 0.34 31.8 9.0 N 5 5 5 5 5 5 5 Uean 410 2.17 0.53 11.85 2.89 812 197 1.41 0.34 1.43 0.35 26.2 6.5 S.D. 37 0.09 0.04 1.32 

### O. 13 148 24 0.14 0.01 O. 15 0.02 4.5 1.6 ReI. : Relative organ weight (g or mg 

### 7 100g final body weight)
PROJECT Ne


## c 

# c o C/I

### ~ N 

# o 

# ­ (1) / .. :.....

..**~".-/.**

# 0
Appendix 19-6 Absolute and relative organ weights of male rats treated orally witt, for 28 days

- 14-day of recovery ­ Group-Ho. -­ Dose Animal AdrenaI(L) Testis(R) Testls(L) Prostate (IIi/kg) No, ( mi ) ReI. ( If) Rei. ( If) ReI. ( mg ) ReI. 00 00M06 30.5 7.1 1.77 0.41 1.81 0.42 388 90 Control 00M07 25. 1 6.3 1.36 0.34 1.41 0.35 510 128 0 00M08 25.9 6.2 1.41 0.34 1.38 0.33 617 148 001.109 28.9 7.3 1.57 0.40 1.59 0.40 439 111 001.110 34.8 8.2 1.70 0.40 1.10 0.40 560 132 N 5 5 5 5 Mean 29.b 1.0 1.56 0.38 1.58 0.38 503 122 S.D. 3.9 0.8 O. 18 0.03 0.18 0.04 92 22 01 011.106 28.2 5

..7 

### 1.88 0.38 1.91 0.39 635 129 VehicIe· 011.107 34.9 8.5 1.52 0.37 1.46 0.36 442 108 0 011.108 27.9 6.9 1.69 0.42 1.80 0.45 526 130 011.109 26.6 6.7 1.67 0.42 1.65 0.41 545 137 011.110 28.6 6.0 1.83 0.39 1.78 0.38 676 141 00 00 N 5 5 5 

### 5 Mean 29.2 6.8 1.72 0.40 1.72 0.40 565 129 S.O. 3.3 1.1 O. 14 0.02 0.17 0.03 93 13 04 041.106 21.6 5.

### 2 1.52 0.36 1.49 0.36 387 92 J4M07 29.3 6.4 1.59 0.35 1.62 0.36 467 102 1000 04"08 26.0 6.3 1.66 0.40 1.70 0.41 424 102 04M09 27.1 6.6 1.62 0.39 1.64 0.40 441 107 04Ml0 32.0 9. 1 1.59 0.45 1.52 0.43 460 131 N 5 5 5 5 Mean 27.2 6.7 1.60 0.39 1.59 0.39 436 107 S.D. 3.9 1.4 0.05 0.04 0.09 0.03 32 15 

### fler:-: Relative organ weight (g or Jag /100g final body weight)
PROJECT No. 

## o 

# e 

# o VI N**~** 

# N

# ~Appendix 20-1 Absolute and relative organ weights of female rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. Final Dose Animal body wellht Brain Liver Spleen Kidney(R) Kldney(l) Adrenal (R) (llg/kll) No. ( g ) (g ) ReI. (g ) ReI. ( mg ) ReI. (g ) Re I. (II ) ReI. (mil ) ReL 00 OOFOl 205 1.94 0.95 6.05 2.95 429 209 0.90 0.44 0.90 0.44 29.8 14.5 Control 00F02 234 2.04 0.87 7.54 3.22 495 212 0.83 0.35 0.81 0.35 36.9 15.8 

## o 00F03 200 1.85 0.93 5.63 2.82 432 216 0.72 0.36 0.72 0.36 29.5 14.8 00F04 220 l.96 0.89 6.26 2.85 451 205 0.83 0.38 0.80 0.36 35.6 16.2 00F05 224 1.98 0.88 6.09 2.72 439 196 0.80 0.36 0.18 0.35 28.0 12.5 N 5 5 5 5 5 5 5 Mean 211 1.95 0.90 6.31 2.91 449 208 0.82 0.38 0.80 0.31 32.0 14.8 S.D. 14 0.07 0.03 0.72 0.19 27 8 ·0.07 0.04 0.06 0.04 4.0 1.4 01 01FOI 226 1.94 0.86 6.70 2.96 452 200 0.88 0.39 0.89 0.39 31-.1- 13.8 Vehicle 01F02 265 2.08 0.78 1.09 2.68 586 221 0.86 0.32 0.92 0.35 28.5 10.8 

## o 01F03 224 2.08 0.93 6.67 2.98 430 192 0.86 0.38 0.81 0.39 33.2 14.8 01F04 205 1.97 0.96 5.77 2.81 399 195 0.84 0.41 0.84 0.41 30.3 14.8 01FOS 229 1.92· 0.84 1.62 3.33 555 242 0.86 0.38 0.85 0.31 34.6 15.1 Q:l N 5 5 5 5 5 5 5 '-0 Uean 230 2.00 0.87 6.11 2.95 484 210 0.86 0.38 0.81 0.38 31.5 13.9 S.D. 22 0.08 0.07 0.68 0.24 82 21 0.01 0.03 0.03 0.02 2.4 1.8 02-·- 02FOI 231 1.9ll" 0.82 6.42 2.78 534 231---0.8Z O:-:rs--O.83

- -0.:-36 

## n.r 14:5 02F02 216 1.89 0.88 6.25 2.89 456 211 0.77 0.36 0.78 0.36 30.9 14.3 10 02F03 203 2.00 0.99 5.44 2.68 401 198 0.77 0.38 0.15 0.31 25.5 12.6 02F04 209 1.98 0.95 5.80 2.18 523 250 0.79 0.38 0.75 0.36 32.6 15.6 02F05 216 1.96 0.91 6.66 3.08 501 232 0.80 0.31 0.19 0.31 32.7 15. 1 N 5 5 5 5 5 5 5 Mean 215 1.9.5 0.91 6.11 2.84 483 224 0.79 0.31 0.78 0.36 31.0 14.4 S.D. 10 0.05 0.07 0.49 0.15 55 20 0.02 0.01 0.03 0.01 3.2 1.1 ReI. : Relat ve orllan

## weiIlfit(j 

### or mg 

### 7 100g f1l111 body welght)-

---- -------­
PROJECT No 

# c 

# e o C/1 

### N Co:::> (Jj 

# l".J f\ V

### M •.**~./** 

### V Appendix 20-2 Absolute and relative organ weights of female rats lrealed orally with for 28 days

- 28-day of treatment

­ Croup-No. Dose Animal Adrenal (L) Ovary(R) Ovary(L) Uterus <. (me/kg) No. ( mg ) ReI. ( mg ) ReJ. (mg ) ReI. (If) Rei. 00 OOFOl 32.6 15.9 35.0 17.1 31.5 15.4 0.46 0.22 Control OOF02 38.5 16.5 52.0 22.2 41.4 17.7 0.51 0.22 

## o OOF03 29.2 14.6 31.8 15.9 31.9 16.0 0.70 0.35 00F04 40.5 18.4 44.7 20.3 39.6 18.0 0.40 0.18 00F05 28.6 12.8 36.0 16.1 34.7 15.5 0.68 0.30 N 5 5 5 5 Mean 33.9 15.6 39.9 18.3 35.8 16.5 0.55 0.25 S.O. 5.4 2. 1 8.3 2.8 4.5 1. 2 O. 13 0.07 01 Vehicle

## o 01FOl 01F02 0lF03 31.7 31.4 33.9 14.0 11.8 15.1 46.4 2.6 34.9 20.5 1.0 15.6 39.4 1.7 35.1 17.4 0.6 15.7 0.43 0.06 1.00 0.19 0.02 0.45 0lF04 01F05 29.0 38.5 14. 1 16.8 43.2 44.3 21. 1 19.3 33.2 52.0 16.2 22.7 0.30 0.31 0.15 0.14 )g Mean S.D. 555 32.9 14.4 34. 3 15.5 32. 3

3.6 La 18.2 8.4 18.6 14.5 8.3 5 0.42 0.35 0.19 

### O. 16 02 02FOI 37.9 16.4 38.2 16.5 33.2 14.4 0.38 0:16 02F02 32.1 14.9 36.6 16.9 37.7 17.5 0.79 0.37 IU 02F03 30.3 14.9 33.4 16.5 34.2 16.8 0.28 O. 14 02F04 34.2 16.4 38.7 18.5 38.9 .18.6 0.34 O. 16 02F05 34.7 16.1 52.8 24.4 48.3 22.4 0.49 0.23 N 5 -5 Mean 33.8 15.7 39.9 18.6 38.5 17.9 0.46 0.21 S.D. 2. 9 0.8 7. 5 3.4 6.0 2. 9 O.20 0.09 ReI. ReJltive orga.n weight 

### (i-or mg 

### TIOOg finarbody weTglll)
PROJECT No.


# o o o**~** CI1 c:> 

### N 

# r­ \D 

# -Appendix 20-3 Absolute and relative organ weights of female rats treated ora)ly with lor 28 days

- 28-day of treatment

­ Group-No. Final Dose Animal body weight Brain liver Spleen Kldney(R) Kldney(l) Adrenal (R) (lIIg/kg) No. (g) (g) Rei. (g) ReI. (!IIg) ReI. (g) ReI. (g) ReI. (rag) Rei. 03 03FOl 222 1.91 0.89 6.13 3.03 380 171 0.90

. 0.41 0.90 0.41 32.

### 0 14.4 03F02 214 2.00 0.93 6.69 3.13 508 231 0.77 0.36 0.79 0.31 41.2 19.3 100 03F03 213 1.95 0.92 5.52 2.59 387 182 0.80 0.38 0.81 0.38 30.3 14.2 03F04 206 1.98 0.96 6.34 3.08 411 200 0.85 0.41 0.81 0.39 38.9 18.9 03F05 232 2.03 0.88 6.48 2.79 533 230 0.90 0.39 0.86 0.37 29.8 12.8 N 5 5 5 5 5 5 5 Mean 21? 1.99 0.92 6.35 2.92 444 204 0.84 0.39 0.83 0.38 34.4 15.9 S.D. 10 0.03 0.03 0.49 0.23 72 29 0.06 0.02 0.05 0.02 5.2 3;0 04 04FOI 205 1.95 0.95 6.24 3.04 413 201 0.16 0.37 0.79 0.39 33.0 16.1 04F02 233 1.92 0.82 7.08 3.04 530 227 0.90 0.39 0.88 0.38 32.8 14.1 1000 04F03 201 1.91 0.95 7.05 3.51 366 182 0.86 0.43 0.81 0.43 32.0 15.9 04F04 232 2.02 0.87 6.92 2.98 452 195 0.89 0.38 0.90 0.39 35. 1 15. 1 04F05 210 2.02 0.96 5.91 2.81 393 181 0.80 0.38 0.12 0.34 33.0 15.7 \0 N 5 5 5 5 5 5 5



## .... Mean 216 1.96 0.91 6.64 3.08 431 198 0.84 0.39 0.83 0.39 33.2 15.4 S.D. 15 0.05 0.06 0.53 0.26 64 18 0.06 0.02 0.08 0.03 1.1 0.8 ReI. Relat ve organ weight (g or mg / 100g final 

### body weight)

PROJECT No.



## o**~** 

## o 

# o**~** 

### C/l CoJ 

# v, o /',-:.:.
........ \ 

# o

.......:,/­

# o
Appendi x 20-4 Absolute and relative organ weights of female rats treated orally with for 28 days

- 28-day of treatment
­ Group-No. Dose Animal Adrenal (I.) Ovary(R) Ovary(L) Uterus (me/kg) No. ( mg ) Rei. ( mg ) Rei. (mg ) ReI. (g) Re I. 

## or 03FOl 35.8 16.1 35.5 16.0 43.3 19.5 0.43 0.19 03F02 46.8 21.9 53.3 24.9 46.5 21.7 0.48 0.22 100 03F03 30.8 14.5 30.1 14.1 36.9 17.3 0.74 0.35 03F04 38.9 18.9 34.1 16.6 30.6 14.9 0.43 0.21 03FOS 32.3 13.9 44.4 19.1 37.7 16.3 0.40 0.17 N 5 Mean 36.9 17.1 39.5 18.1 39.0 17.9 0.50 0.23 S.D. 6.4 3.3 9.3 4.2 6.2 2.7 0.14 0.07 04 04FOl 32.7 16.0 48.1 23.5 31.0 15.1 0.83 0.40 04F02 3S.1 15.5 46.4 19.9 49.4 21. 2 0.33 O. 14 1000 04F03 35.4 17.6 38.8 19.3 40.8 20.3 0.92 0.46 04F04 39.2 16.9 33.1 14.3 38.0 16.4 0.73 0.31 04FOS 34. 1 16.2 52. 1 24.8 49.2 23.4 0.69 0.33 

## t5 N 5 Mean 35.5 16.4 43.7 20.4 41.7 19.3 0.70 0.33 S.D. 2.4 0.8 7.6 4.1 7.8 3.4 0.23 O. 12 ReI. : Relative organ weight (g or mg I 100gtillli body weight)
PROJECT No.



## e 

# o 

# '"**~** 

### CJ**~** <"



# ..... c----------------- Appendix 20-5 Absolute and relative organ weights of female rats treated orally with for 28 days -.14-day of recovery ­ GrouJ)-No. Final Dose Animal body weight Brain Liver Spleen Kidney(R) Kidney(L) Adrenal (R) (mg/kg) No. ( g ) ( g) ReI. ( g) ReI. ( mg ) ReI. ( g) ReI. ( g) ReI. ( mg ) ReI. 00 OOFOG 248 1.93 O.78 6. 18 2.49 584 235 0.85 0.34 0.85 0.34 27.2

. 11.0 Control 00F07 262 2.05 0.18 6.59 2.52 546 208 0.89 0.34 0.88 0.34 32.2 12.3 0 00F08 221 2.02 0.91 6.18 2.80 410 186 0.82 0.37 0.82 0.37 34.6 15.7 00F09 259 1.98 O. 16 6.59 2.54 461 178 0.82 0.32 0.81 0.31 34.3 13.2 00F10 252 1.99 O.79 6.69 2.65 558 221 0.97 0.38 0.96 0.38 31.7 12.6 N 

### 5 5 5 5 5 5 5 Mean 248 1.99 0.80 6.45 2.60 512 206 0.81 0.35 0.86 0.35 32.0 13.0 S.O. 16 0.05 0.06 0.25 0.13 73 24 0.06 0.02 0.06 0.03 3.0 1.7 01 0lF06 252 2.07 0.82 6.58 2.61 523 208 0.92 0.37 0.89 0.35 31. 9 12.7 Vehicle 01F01 246 1.99 0.81 6.14 2.50 490 199 0.80 0.33 0.81 0.33 33. 1 13.5 0 01F08 219 1.91 0.90 5.59 2.55 408 186 0.15 Q.34 0.68 0.31 31. 1 14.2 0lF09 254 2.02 0.80 6.52 2.57 589 232 0.86 0.34 0.86 0.34 26.6 10.5 0lFl0 216 2.01 0.93 5.92 2.74 404 187 0.14 0.34 O.72 0.33 28.7 13.3 N 5 5 5 5 5 5 5 w 

# '" Mean 237 2.01 0.85 6. 15 2.59 483 202 0.81 0.34 0.79 0.33 30.3 12.8 S.D. 18 0.04 0.06 0.41 0.09 79 19 0.08 0.02 0.09 0.01 2.6 1.4 04 04F06 236 2.00 0.85 6.41 2.72 460 195 0.89 0.38 0.87 0.31 27.1 11.5 04F07 244 1.99 0.82 1.20 2.95 507 208 0.98 0.40 0.93 0.38 38.6 15.8 1000 04F08 222 1.97 0.89 5.74 2.59 545 245 0.82 0.37 0.77 0.35 30.7 13.8 04F09 252 2.04 0.81 6.54 2.60 445 177 0.80 0.32 0.79 0.31 34.3 13.6 04FIO 224 1.95 0.87 6.09 2.72 460 205 0.81 0.36 O.77 0.34 32.3 14.4 N 5 5 5 5 5 5 5 Mean 236 1.99 0.85 6.40 2.72 483 206 0.86 0.37 0.83 0.35 32.6 13.8 S.D. 13 0.03 0.03 0.55 0.15 42 25 0.08 0.03 0.07 0.03 4.3 1.6 Rei. : Relative organ weight (g or mg 

### I 100g final body weight)
PROJECT No. 

# e


# - 0 CIT }...J 

### C.J 0 

### l'J 

### -1r"'""'\, --,' 

## V AppendI

### x 20-6 Absolute and relative organ weights of female tats treated orally with for 28 days

- 14-day of recovery ­ Group-No. Dose Animal Adrenal (L) Ovary(R) Ovary(l) Uterus (mg/kg) No. ( IIIII' ) ReI. ( mil' ) ReI. (mg ) ReI. (II' ) ReI. 00 00F06 34.5 13.9 33.3 13.4 35.9 14.5 0.44 0.18 Control OOF07 33.3 12.7 33.7 12.9 35.8 13.7 0.30 0.11 

## o 00F08 42.3 19.1 36.7 16.6 26.0 11.8 0.37 0.17 00F09 33.1 12.8 30.6 11.8 32.3 12.5 0.72 0.28 00F10 32.5 12.9 55.1 21.9 42.8 17.0 1.06 0.42 N5
-- -- - 5 Mean 35. 1 14.3 37.9 15.3 34.6 13. 9 0.58 0.23 S.D. 4.1 2.7 9.9 4.1 6.1 2.0 0.31 

### 0.12 01 01FO&**~-** 33.4 13.3 46.4 18.4 60.4 24.0 0.80 0.32 Vehicle 01F07 41.6 16.9 36.5 14.8 38.4 15.6 0.48 0.20 

### o 01F08 33.0 15.,1 35.8 16.4 44.6 20.4 0.46 0.21 01F09 31.3 12.3 30.7 12.1 41.4 16.3 0.38 O. 15 01Fl0 23.5 10.9 32.1 14.9 29.7 13.8 0.31 0.14 

### 'f N Mean 5 32.6 13.7 36.3 15.3 42.9 18.0 5 0.49 0.20 S.D. 6.4 2.4 6.2 2.3 11.2 4. 1 O. 19 0.07 04 04F06 

### -19.-'-­ -12.3 36.8 15.6 30.6 13.0 -0.61 0.26 04F07 42.9 17.6 41.8 17.1 40.1 16.4 0.40 0.16 1000 04F08 33.6 15. 1 37.6 16.9 28.6 12.9 0.43 0.19 04F09 34.3 13.6 32.6 12.9 41.0 16.3 0.30 O. 12 04FIO 36.3 16.2 30.5 13.6 34.1 15.2 0.64 0.29 N 5 555 Mean 35.2 15.0 35.9 15.2 34.9 14.8 0.48 0.20 S.D. 5.0 2,'1 4.4 1.9 5.5 1.7 0.14 0.07 Rei. Relative organ we ghf(gor mgTlOOg-Tinal body wefgliU
PROJECT No.


# o c o 

# N vr 0­ 

### e..J**~** 

### CJ

# -- Appendix 21-1 

### Necropsy of male 

### rats treated orally with for 28 

### days

- 28-day 

### of treatment

- Group-No. 00 , 01 0' 03 04 

### Control Vehicle Dose (ma/kg) 

### o o 10 100 1000 

### Animal No. 0-0 0 0 0 

### o IT 0 0 0 

## o 0 0 00­ 

## o a u-ou 

## o 0 

## a 0 

## a 00000 1 1 1 1 1 2 2 222 

### 3 3 3 3 3 4 4 444 

### M M U U U II !II U !II U M M M M Y II M lot 1.1 M 

### M M II'U M Organs 

### a 0 0 0 0 

## o 0 0 0 0 

## o 0 0 0 0 

## o 0 0 0 0 000 0 0 

### Findings t 234 5 1 2 3 4 5 12345 1 2 3 4 5 1 2 3 4 5 Epididymis 

### (caudal region)



### ____ +u nodule**~** 

### negative. U: unilateral

PROJECT No.



# o 

# o 

# "-' c;::, 

# o CIT C.J**~** Ir'\, \..J

# o

Appendix 21-2 Necropsy of 

### male rats treated orally with ror 28 

### days 14-day of recovery ­ Group-No. 00 01 04 

### Control Vehicle Dose(Ig/kg) 

## o 

## o 1000 

### Animal No. 

## o 0 0 0 0 

## o 0 0 0- 0 ,0 0 0 0 0 

## o 000 0 1 1 1 1 1 

### 44444 

### M U U N M M M M M N M N MUM Organs : O' 0 0 0 1 

## o 0 001 00001 

### Findings 6 7 8 '9 0 6 7 8 9 0 67890


### abnormal change**~** 

### negative.

PROJECT 

### No.



# o o**~** VT 

### G.J 

# -- o VT 

## c

# -- Appendix 22-1 

### Necropsy of female rats treated orally with for 28 days

- 28-day of treatment

­ Group-No. 00 01 02 03 04 Control Vehicle Dose (Ig/kg) 

### 0 0 10 100 1000 Animal No. 

### 0 0 0 

### 0 0 0 0 

### 0 

### 0 0 0 0 0 0 

### 0 0 0 

### 0 

### 0 0 0 

### 0 0 0 

### 0 0 0 0 

### 0 0 1 1 

### 1 1 1 2 2 2 2 2 3 3 3 3 3 4 4 

### 4 4 4 F F F F F F F F 

### F F F F F 

### F F F F F F F 

### F F 

### F F 

### F Organs : 0 0 0 0 0 

### 0 0 

### 0 0 0 0 0 0 0 0 0 

### 0 0 

### 0 0 0 0 0 

### 0 0 

### Findings 1 2 3 

### 4 5 1 2 3 4 5 1 2 3 4 5 1 2 

### 3 4 5 1 2 3 

### 4 5 

### Ovary : atrophy



### - +1 Uterus : 

# ::s atrophy 

### + ­ swelling 

### + - + 

### + 

### + - 

## + + + +.+ negative. B: bilateral
PROJECT No.



# o e o**~** 

### C..> (!')

### ~ 

# ..... /"','\ 1"''''' 

# U

## ""'

...". 

### I"'''''. '''-oj -'


### Appendix 22-2 Necropsy of female rats treated orally 

### with 

### tor 28 days 14-day of recovery ­ 

### Group-No. 00 01 nA 

### Control Vehicle Dose

### (llg/kg) 

## o o 1000 

### Animal No. 

### {) {) 0 0 0 0-0 0 0 -U 

## o 0 {) 0 0--­ 00000 1 1 1 , 1 4 4 444 

### F F F F F F F F F F F F F F F Organs 00001 

## o 0 001 00001 

### Findings 6 7 8 9 0 6 7 890 67890
abnormal change

\0 00 

### negati

### ve.
PROJECT 

### No.



# e o**~** 

### CJ ".l**~**

......... 

# p cAppendix 23 Histopathology of .ale rats treated orally ,jtb for Z8 days

- Z8-day of trealment

­ Group-No. 00 01 04 Dose (mg/kg) control vellicle 1000 ADilial No. 00000 

### o 0 0 0 0 o 0 0 0 0 00000 I I I I I 4 4

.. .. 4 II iii Ii If Ii iii Ii iii II II K iii iii

.. l( 00000 

### o 0 0 0 0 

### o 0 000 Organs I Pindlngs I 2 345 1 Z 345 I 234 5 Liver:

mononuclear cell infiltration Ilicrogranulo.a vacuolation in lIepalocyte ± - ± - - - ± ± -

- ±,

- ± - ± - ± t - forestomach: Glandular slomach: Duodenum: Heart:

mononuclear cell infiltralion myocardial fibrosis - ± - - ± - - - - - - Kidney:

mononuclear cell infiltralion basopbilic tubule fibrosis Cyst calciHcalion vacuolar degeneration of

tubular epilhelium - ± - ± 

### - ± - ±
± -

-

- - - ± ±
- ± - ± ± - t - -

- ± ± ­ 

### + ­ Spleen:

increased extramedullary hematopoiesis ± 

### - - 

### - ±

## ­ ± ± t 

### - ± Sternal bone marrow: 

### - - 

### - 

### - 

# - Pemoral bone marrow: Adrenal: Testis: 

## - 

# - - ­

- 

## - - ­ -

- (

.'­**~** I

. Prostate:

Ilononuclear cell infiltration ± ± ±

## - ± t 

### - ± 

### ­ Sternal bone: Pemoral bone: 

### - 

### - 

## - - 

# - - 

# -- - - I!pidldyais:

spermatic grauuloma I I / / / / / / / f / / I / I Gradings:

- ;none. ±;very slight. 

### +;sligbt••;moderate••;severe. (continued.) / : Nol examined PROJECT No.



## 000538 99

# )1'1

Appendix 24 Histopathology of female rats treated orally with for %8 days·

- 28-day of treatment

­ Group-No. 00 01 02 03 04 Dose (mg/kg) control vebicle 

### ..l!L 1M. 1000 AniliaI Ko. 

### o 000 0 o 0 0 0 0 

### o 0 00000 o 0 0 0 0 I I 1 I I % 3

.. 4:

.. .. .. F P F F F F P P F F F F F F P F F 

### o 0 0 0 0 

### o 0 0 0 0 

### o 0 

### o 000 0 Organs / Findings 2 3 4: 5 I %3

.. 5 Z 3 I 23.. 5 Liver:

mononuclear cell infiltration microgranuloma vacuolation in hepatocyte ± - - ± ­ ± - - -

- -

- ± - ± - /

Forestomach: / Glandular stoaach: / Duodenum: / Heart:

mononuclear cell infiltration / Kidney:

mononuclear cell infiltration basophilic tubule fibros Is Cyst calcification vacuolar degeneration of tubular epitheliua -

-

- -

-

-

- ±

- -

- -

- - -

-

- ± -

- ± - ± - /

Spleen:

increased extraaedollary hematopoiesis / Sternal bone marroy: / Femoral bone marrow: / Adrenal: / Ovary:

atrophy - f
- / Uterus: dilated lumen squamous metaplasia of

epitbeliDID cell atrophy + - - +

- - - - :t

- i •

- +

Siernal bone: / Femoral bone: / / ± t
- :!:
-
/ / / / /

/ / / / /

+ + - 

### + + +

/ / Gradings:

- ;none. ±;very sligbt. 

### +;slighl. 

## '* ;moderale. I ;severe. / : Not examined PROIECT No.



### 000539 100STUDY CODE:



### FINALREPORT

ACUTE ORALTOXICITYSTUDYOF

INRATS

March 1993



## 000540STATEMENT

J, the undersigned, hereby declare that this report provides correct English translation ofthe final report (StudyCodeAI6-0169, issued on March 22, 1993).

Chemicals Inspection & TestingInstitute,Japan (CITI) fonnally changed its name to Chemicals Evaluation and Research Institute, Japan (CERI)as ofNovember I, 1999.

# ~b. if"{II ?Arb

# Y
Date

### /



## 000541.

# 21'1 GLPSTATEMENT

Sponsor: Title: Acute Oral Toxicity Studyof in Rats Study Code:

I, the undersigned, hereby declare that this study was conducted in compliance with "OECD PrinciplesofGood LaboratoryPractice(May 12, 1981)".

Management: Signed in original March 22, 1993



## 000542QUALITYASSURANCE STATEMENT

Title: Acute Oral Toxicity Studyof in Rats StudyCode:

This study was audited and inspected by Quality Assurance Laboratories, Chemicals Inspection & Testing Institute, Japan. Section of Hita Research The dates audited and/or inspected and the dates reported ofthese results to the study director and management are as follows. Dates ofInspections and Audits DatesofReport to Study Director Dates ofReportto StudyManagement November 12, 1992 November 12, 1992 November 12, 1992

January 12, 1993 January 12, 1993 January 12, 1993 January20, 1993 January20, 1993 January 20, 1993 January28, 1993 January28, 1993 January28, 1993 February3, 1993 February 3, 1993 February 3, 1993 March 18, 1993 March 18, 1993 March IS, 1993 March 19, 1993 March 19, 1993 March 19, 1993 We, the undersigned, hereby declare that this report provides an accurate description ofthe methods and procedures used in this study and that the reported results accurately reflect the
raw data obtained.

Section Staff, QualityAssurance: Signed in original March22, 1993

SectionChief, QualityAssurance: Signed in original March 22, 1993



## 000543TABLEOFCONTENTS

SUMMARY

I. TITLE

.................................................................................. 2 2. SPONSOR

.................................................................................. 2 3. TESTINGFACILITY

.................................................................... 2 4. PURPOSEOF STUDY

.................................................................... 2 5. TESTINGMETHOD

.................................................................... 2 6. GLPCOMPLIANCE

.................................................................... 2 7. PERIODOF STUDY 2 8. LOCATION ANDPERIODFORRETENTION OFRAWDATA 3 9. AUTHORANDPERSONNELCONCERNEDWITH STUDY 3 MATERIALSANDMETHODS

....................................................... RESULTS

.................................................................................. 10. 4 

### II. 7 12. DISCUSSION 7

.................................................................................. 1-6 TABLE 1-4

.................................. 1-8 APPENDIX PHYSICOCHEMICALREPORT



## 000544

# J.).o

SUMMARY

Acute oral toxicity study of was conducted in both sexes ofCrj: CD (SD) rats, 5 weeks ofage at the dosing. A limittest was conducted at 2,000 mg/kg, and the vehiclecontrol groupwas also set.

No death occurred and no abnonnalities were noted in clinical signs, body weight changes and necropsy.
The LDso value of ,as estimated to be more than 2,000 mg/kg for males and females.

-1- 

## 000545FINALREPORT StudyCode:

1. TITLE Acute Oral Toxicity Study of I Rats
2. SPONSOR Name: Address: TEL:
3. TESTINGFACILITY Name:

Address: TEL:
4. PURPOSEOFSTUDY Thepurpose ofthis study is to assessthe singledose oral toxicityofthetest substance.

5. TESTINGMETHOD This study was conducted in accordance with "401, Acute Oral Toxicity (February 24, 1987)" prescribed in "OECDGuidelinesfor TestingofChemicals".

6. GLPCOMPLIANCE This study was conducted in compliance with "OECD Principles ofGood Laboratory Practice (May 12, 1981}".

7. PERIODOFSTUDY CommencementofStudy: November 16, 1992 Animal Receipt: January 12, 1993 Dosing: January 20, 1993 Necropsy: February 3, 1993 Completion ofStudy: March 22, 1993

- 2 	- 

## U005468. LOCATIONAND PERIODFORRETENTIONOFRAWDATA The raw data will be stored in the archive of the ofour organization for 5years following the date ofcompletion ofstudy. After tennination of the retention period, any measures taken will be done sowith the approval ofthe sponsor.
9. AUTHORAND PERSONNELCONCERNEDWITHSTUDY 9.1 AUTHOR StudyDirector: Signed in original March 22, 1993

Head, Animal Expertment UOlt: Signed in original March 22, 1993

Head, Pathology Unit: Signed in original March 22, 1993

9.2 PERSONNELCONCERNEDWITHSTUDY Study Staff:

Staff, MacroscopicExamination:

Staff,Animal Management:

Head, Analytical chemistry Unit:
9.3 PERSONELINCHAEGEOFSTUDY Test SubstanceManagement:

Animal CareManagement:

- 3

- 

## 00054710. :MATERIALSAND METHODS 10.1 TESTSUBSTANCE (INFORMATIONPROVIDEDBY mESPONSOR) 1) Name

CAS No.:
2) OtherName

3) LotNo.

4) Supplier

5) Structural Formula

(MolecularFormula:
6) Purity 99.9% (GC area%) Name and Concentration ofImpurities

7) Physicochemical Properties MolecularWeight: 200.07 Appearance atOrdinaryTemperature: clearand colorlessliquid Stability: The stability test was conducted in our laboratories, and confirmed thatthe test substance was stableduringthe experimental period (see appendix). MeltingPoint: BoilingPoint: 55°C VaporPressure: Partition Coefficient: Solubility:

- 4 

## 000548Degree ofSolubility (measured in ourlaboratories) Water: <0.5% DMSO:**~5%** Acetone:**~5%** Oliveoil: ;;:::5%
8) StorageConditions Stored in a closed containeratthe cold and dark place in the test substance storage
room. 9) Careon Handling Mask, glove, head capand lab coatwere put on.
10.2 Animals Crj: CD(SD) rats at 4weeks old were obtained from Charles RiverJapan, Inc. Clinical condition, body weights and excrements were observed for 8 days. The animals were al10cated to groups using body weight-stratified randomization and identified by saturated piclinic acid. The animals were 5 weeks old at dosing and the body weights
were 104.5-120.7 gfor malesand 100.1-107.5 g forfemales.

10.3 HousingConditions The animals were housed in a barrier-system animal room maintained at a stable temperature of21-25°Cand relativehumidity of45-65% with 10-15 airchangesperhour and artificial light-dark cycle of 12-12 hours (light on: 7:00 and light off: 19:00). The rats were housed in hanging stainless steel cages with wire-mesh floor (260 Wx380 Dx180 H mm, TOKlWA KAGAKU KIKAI) at I animals/cage. The animals had free
access to an MF pelleted diet and chlorinated water from the supply via automatic waterer with sipper tubes. No environmental deviations, which might affect the study results, were noted during the quarantine, acclimation or study periods. The dietand housingmaterials were autoclaved at 121°C for 30min priortouse.
Analysis ofthe dietand waterwas performed and thecontaminantswere insidethe stated ranges.

- 5 	 ­ 

## 00054910.4 DOSING FORMULATION I) Vehicle Oliveoil (Fujisawa-Astra, lotno. 140RKK)
2) Preparation The testsubstancewas mixed with oliveoil. The preparation was conducted prior to use.
The stability and homogeneity of the formulations were performed in our laboratories. Seeappendix.
10.5 ADMINISTRATION 1) Administration Methods All animals were fasted overnight before dosing and for approx. 3-4 hr after treatment. They were dosed once using a Nelaton catheter (TERUMO) and syringe(TERUMO)in the morning.
2) Dosing levels and rational for dosage selection Grouping Dose Volume Concentration No. ofAnimals(AnimalNo.) Group (mg/kg/day) (mUkg) (w/v%) Male Female Test substance 2,000 10 20 5( 1 

### - 5 ) 5 ( I


## - 5 Vehiclecontrol 0 10 0 5 ( 6 - 10 ) 5( 6

- 10 ) Rationale for dosage selection: A preliminary single-dose oral treatment was performed at 2,000, 500, 100 and 20 mg/kg with 7 days observation. No death occurred in all groups. Therefore, dose level of2,000 mg/kg was chosen for the main study. The vehicle control group was given oliveoil only.
10.6 OBSERVATIONS 1) Clinical Signs Mortality and clinical signs were recorded continuously by Ihr after dosing, and every ] hr by 6 hrafter dosing. From next day ofdosing, animals were observed twicedaiJy.

6 ­ 

## 0005502) Body Weights Body weights were measured just before dosing and on days I, 3, 7 and 14 post-dosing.
3) Necropsy All animals were euthanized at the tennination of the observation period by exsanguination underetheranesthesia, and subjectedto adetailed gross necropsy.
10.7 STATICALANALYSIS The mean values and standard deviations ofthe body weights were calculated for males and females.
11. RESULTS 11.1 MORTALITYAND LDso VALUE (TABLE 1) No deaths occurred in both sexes. TheLOso value was estimated to be more than 2,000 mglkg formalesand females.

11.2 CLINICALSIGNS(TABLE2) I) Males Test substance group: No abnonnalitieswere noted. Vehiclecontrol group: Mucose stool (2/5) was noted from 30 min to I hr after dosing.
2) Females Testsubstancegroup: Noabnonnalities were noted. Vehiclecontrol group: Mucose stool (1/5)was noted at30 min afterdosing.

11.3 BODYWEIGHTS(TABLE3) Noabnonnalities were noted in body weightchanges.

11.4 Nl:<.:RUPSY (TAllLl:4) No abnonnalities were observed.

12. DISCUSSION A singleoral toxicity study of. .vas conducted in males and females ofSO rats at2,000and 0mglkg followed by 14-daysobservation.

- 7 	­ 

## 000551.No death occurred and no abnormalities were noted in the clinical observation, body weight changes and necropsy.

In conclusion, the single oral toxicity of for rats was considered to be weak and theLDso valuewasestimated more than 2,000 mg/kgfor males and females.

- 8 - 

## 000552

### r "**\~**



### Table 1 

### Mortality in male and female rats after the single oral administration of

Number of deaths on day Dose 

### Sex 0 Mortality LD50

### values (l118'/kg) 

### 1 2 

### ······U······ 14(day) 

### 0 

### 5 10 30(Ilin) 1 2 

### 3 4 

### 5 6(hr) 

### 2.000 0/511 

### Ilale >2.0001118'/kg 

### Vehicle cOlltrol 0/5



### ..... 2.000 0/5 

### Female >2.000lli/kg 

### Vehicle control 0/5 

### 1) Number of dead animals 

### I Number of animals.



## o o 

# o Vt Vt CJ

# ~**~**,

# '-'

Table 2 Clinical signs in male and female rats after the single oral administration of

Dose (mg/kg) 

### .2.000 Day Signs Sex 

# o 1 

### 2

.........

# n ...... 14(day) 

### 0* 5 

### 10 30(min) 1 2 

### 3 4 5 6(hr)
No 

### lale 

### 1-5** 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5

..··..

### ···U···

..· 1-5

•••••••••••••••**~** ••••••••••••••••••••••••••••••• h •••••••••••••n ••••••••u ••u ..... ................"',.

### .. ....................... • ••••••

_ .. u ••u ••••
.......... _ .................... . .H

..... ••• •••••• n ••••••• t\:) 

### abnormalities Female 1-5 1-5 1-5 1-5 

### 1-5 1-5 1-5

. 1-5 

### 1-5 1-5 1-5 1-5······

..·

### Ii

...... 1-5 detected 

# * Immediately after administration. 

# ** Animal number.



## o 

# e 

# o VI VI**~**

### ~**~** -S.)i.'-"



### Table 2 - Cnotinued

Dose (mg/kg) 

### Vehicle control Day Signs Sex 

# o 1 

### 2

......

# n...... 14(day) 

### 0* 5 

### 10 30(min) 1 

### 2 3 

### 4 5 6(hr)
No 

### Hale 

### 6-10**6-10 6-10 6.8- 7-10 6-10 6-10 6-10 6-10 6-10 6-10 6-10

......Ii

...... 

### 6-10 abnormaIities 

### 10 w 

### detected Female 

### 6-10 6-10 6-10 7-10 6-10 6-10 6-10 6-10 6-10 6-10 6-10 6-10

......

# n...... 6-10

lucous 

### feces lale 7 6 

### Female 6 

# * Immediately aiter administration. 

# ** Animal number.



# c 

# e o C/1 C/1 C/1 

## y 

# '" o

# :J. 'j,

# I Table 3-1 

### Body weight(g) in**~~lp r~+c**  

### aftar the single oral administration of Dose**~m~/kg)** 

### Animal No. 0 1 3 7 14 

### {dax2 1 104.5 123.4 144.0 176.2 233.9 2 113.3 136.6 156.4 204.0 275.7 2,000 3 120.7 142.0 160.7 199.0 259.4 4 113.6 136.8 152.9 186.5 244.1 5 111.4 133.5 156.2 198.8 25B.l 

### Mean 

## is. D. 112.7 

### ±5.B 134.5 ±6.9 154.0 ±6.3 192.9 ±11.3 254.2 ±16.0 6 119.4 141.5 164.1 204.0 264.9 

### Vehicle

control 7 8 9 10 104.9 111.9 10B.7 118.2 124.4 135.9 131.9 142.5 140.3 154.0 154.5 166.5 174.6 191.8 192.2 206.4 228.0 242.9 255.0 272.5 

### Mean 

### is. D. 112.6 ±6.2 135.2 

### ±7.4 155.9 HO.4 193.8 H2.6 252.7 ±l7.7 

## -)

- 4 ­ 

## 000556

# .23.2 Table 3-2 

### Body weight(g) in female rats after the single



## - oral administration of Dose {milk,} 

### Animal No. 1 0 107.2 1 

### 126.8 3 

### 143.6 7 173.5 14 

### {dal2 205.9 2 100.1 119.4 133.7 149.5 177.3 2,000 3 107.1 123.7 141.1 162.9 189.4 4 106.0 126.4 138.8 154.5 182.7 5 103.6 123.4 134.6 157.6 181.0 

### Mean ±S.D. 104.8 

### ±3.0 123.9 

### ±3.0 138.4 

### ±4.2 159.6 ±9.2 187.3 ±11.3


### Vehicle

control 6 7 8 9 

### 10 

### Mean ±S.D. 104.9 107.5 102.9 101.6 105.0 104.4 

### ±2.3 120.3 127.4 121.4 120.5 127.0 123.3 ±3.6 138.5 141.1 137.8 139.4 140.9 139.5 

### ±1.5 153.7 160.8 153.3 160.6 166.3 158.9 

### ±5.5 174.5 184.6 174.7 190.7 203.2 185.5 ±l2.0 

# J

5 

## 000557(\....,/



### Table 4 Acute oral toxicity study of in rats Gross pathological findings
lale Fellale Findings Vehicle Vehicle 2.000 2.000 (mg/kg) 

### control control
ta* ta ta ta

5** 5 5 5
0) 

### No abnormalities detected 5 5 5 5



## *: ta ; terminal autopsy, No. of animals examined. 

# **:

c c 

# o C/l C/l (Jj )v

# ~APPENDIX 

# 2:3'i

PHYSICOCHEMICALREPORT

Head, Analytical ChemistryUnit: Signed in original March 22, 1993

-1- 

### 000559Sponsor:
TestingFacilities:

Test Substance:

Tests:

DateofTest:

Methods: 1) Stability ofTest Substance 2) Stability and HomogeneityofTest Substance in Fonnulations
I) January 13 and February 8, 1993 2) December 16 and 17, 1992
I) StabilityofTestSubstance The test sample was taken (n=l) before and after dosing, and analyzed with infra-red spectrophotometer (JR-470, SHIMADZU). Test substance was stored in aclosedcontaineratthecold and darkplaceduringthetestperiod.
2) Stability and HomogeneityofTest Substance in Fonnulations Fonnulations were prepared prior todosing. (I) StabilityTest Middle layers ofthe fonnulation weretaken (n=3)just afterpreparation and 24 hr after. After pre-treatment, the test substance was quantitatively analyzed by gas chromatography (GC) to confinne the stability of the fonnulation.
(2) HomogeneityTest Upper, middle and bottom layers of the fonnulations were taken (n=3). After pre-treatment, the test substance were analyzed by the GC method to estimate the homogeneity of the test substance in the fonnulation. The preparation and pre-treatment offonnulation and preparation ofthe standard solution are described in page 3, and the analytical conditions and calculation in page 4. The fonnulation was stored at the cold and dark placeduringthetest period.

-2- 

## 000560Results: I) StabilityofTest Substance There were no differences in the IR spectrum patterns between before and after dosing(Figs I, 2). Thetest substancewas stableduringthetest period.
2) Stability and HomogeneityofTestSubstance in Formulations The test results are shown in Table I. The test substance in formulation was stable for 24 hr. Homogeneity was good with a relative standard deviation (R.S.D.%)ofless than 1%.

A typical chromatogram and calibration curve are shown in Fig. 3 and Fig. 4, respectively. PreparationandPre-treatmentofFormulationandPreparationofStandardSolution PreparationofFormulation Thetest substance ofto g wastaken and mixed with oliveoil to make 50 mL. This was mixed well with a magnetic stirrer.

Pre-treatmentofFormulation 20w/v%Formulation Accurate 80 JlL ofthe formulation was added into a headspace-gas vial with 3 mL ofpurified water, shaken well and incubated in a waterbath at 40°C for 10 min. Headspace gas in the vial
was served for GCsample. PreparationofStandardSolution Accurate 2.0 g ofthe test substance was weighed and dissolved with dimethyl sulfoxide to make 10 mL for the standard solution. Accurate 80 JlL ofthis solution was added into a headspace-gas vial with 3 mL of purified water, shaken well and incubated in a water bath at 40°C for 10 min. Concentraiotn oftheheadspacegaswas assumedtobethe same asthat ofthe standard solution.

-3- 

## 000561AnalyticalConditionsand Calculation
AnalyticalConditions Instrument: Gaschromatography (GC-9A, SIMADZU) Column: 20m )( 1.2 mm i.d., glassware Liquid Phase: G-230 (membrancethickness: I Jlm) Temperature: 40°C Eluent: Helium FlowRate: 20mLimin Detector: FlO (hydrogen=air=0.6 kg/cm2) Output: xl04 Temperature: 120°C Injection volume: 1mL Recorder: Chromatopack(C-R5A, SIMADZU) Output: 64mV

Underthe analytical conditionsmentioned above, linearity ofdetectorresponse was confinned in the test substanceconcentration of0-234650Jlg/mL.

Calculation The test substance in each sample was measured by GC to calculate concentration of the test substance in each fonnulation (Cr: Jlg/mL) using the following equation:
Cr

### =CsxAr As

where: Cs: Concentration ofthetestsubstancein standard solution (Jlg/mL) As: Peak area ofthetest substance in standard solution Ar: Peakarea ofthe testsubstance in each GC sample



## 000562Table 

### 1 lllan1cal stability of the test substance in dose formulations



# .. Time point of Ileasuranent

Imm.ediately after N(JIlinated cone.

### (X.w/v) 20.0 Analyzed D cone.(J,lg/I.I) rate



### 182976.1927 181666.4687 ilution M c 

### 1 1 easure:J onc.

### (X.w/v) 18.30 18.17 Kean cone. 

### (X.w/v)

18.21 R.S.D. 

### (X) 0.43 

### a.p. (X)
preparation 

### 181580.3698 176298.8437 1 1 18.16 17.63 

### ,-) 24 h after 

### 20.0 172761.7187 171395.5312 1 1 17.28 17.14 17.35 1.46 95,3 

### a.S.D.(X) : Relative standard deviation R.P.(X) : Rate to the concentration measured immediately after preparation

Table 

### 2 Physical stability of the test substance 1n dose formulations Ncninated conc.(X,w/v) Layer of measuranent Analyzed conc.(,LLg/IllI) Dilution rate Keasured cone.

### (X.w/v) Mean canc. (X,w/v) R.S.D. 

### (X) 185913.4531 1 

### 18.59 top 

### 180627.8750 1 

### 18.06 18.30 18.2387.Z5QO 1 18.24 173588.6406 1 17.36 20.0 Illiddle 

### 182798.4375 1 18.28 18.17 18.21 0.4.3 188612.3281 1 18.86 '-.--' 

### 173869.3593 1 17.39 bott(Jll 

### 180821.6250 1 

### 18.08 18.16 190050.1250 1 19.01 

### a.S.D.(X) : Relative standard deviation

- 5 ­ 

### 000563

# 23~ 

# .

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>J\-.

'--.. .!**.:~** 'I"r ...." Ct .:s;;: fZ! G) 

### "**i~I~';;! E,l.1'I1~** 

e'l**'WJJ~** ,jO,(,

I'YJZ :**Hl~31** ]11:! aal " 401-



## .. ;)on !191M**SS~ l~ijIjH** **'~:;ij** ;111 0'0**~l** (,'((II tr.lIH1:i i)**}!Illl~ j!'lNl~**  1**S~Hl** (0). '€fI'. ool r·' " 

### ,n'eIl'.**(~jt 'i~"**  tOm**f~) ~}~'3~** **j~** N\!)S 1'J3dX! i'llW 'lHt>

### rr.;"**lfil~H** f 3!);>I!lr.:;o:, H!(r,!**'~l~~** 1I'E 6 \1S?1 :j'll\IKI**~11~(i~** Ii: ll;1liu.)il 

## 000564

...**~.-.** ,

### .......**~~,'"**':..'

.:;, .; Q C·} Q 11> G) 

## )

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...... CI:l "- 

## >+

..... <I.)**~:~** c::: 'V' e "0 ." Q,) cr,. ..c: <r
...... IlZr.lIHS'!lflS.rMN "­ Q,)

...... 

### ..... CI:l e :::::I '­

...... u Q,) OJ**'I{I~** 0. <I.) Q::**I~:** HI"31 311J 00'0 ilel**~** '< 

### o.n H9I11**S9~** ';; '!Ii**~~:** 'Sli:I :nU 0'0 llel 0'001 '''Ilill :\:! co 0 }lU ll\lll**311lH1~** c-..t ¥I.. 0 I Sill! \;>I**~** N 00; : 'itfli 00 IX 3U'6tn u....

.....**~** OOOt**·itl'lll~lS** P'>**~** He 3301l9lJlj J.Jij**H~:r; J~Jdll!** **~lf~** a3JdS tfI)S lIIH1K1l**}l~** IN:J!i £.@!R\1 :**'~I((J** IllS 7 !.ISil !Hlt'!O**l1i'!lJ~** 

### n**jl\iNl~**



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"'l:5 .p VI



# - 'S ;:;) 

# "


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... ...0 "It' r:") (,'.1 •



### Fig.3 Typical chromatogram

- 8 ­ 

## 000566x <=>

o Q) en



# o 58662.5 '17325 234650

Concentration (lI8"/ml)

fig.4 

### Calibration curve

9 

## 000567Submittedto:



### FinalReport
( ASimplifiedAcuteToxicityStudyof

. byNose-DnlyInhalationExposurein Rats
(StudyNo.:

January7, 1994



## 000568

### TranslationStatement

The following studywas conducted in the The original study report was written in Japanese. I hereby declarethat this translation report faithfullyreflects the original studyreport as accurately

as possibletomyknowledge. 

## ( } Informationofthe original study Sponsor:
Title: ASimplifiedAcuteToxicityStudyof

. ;yNose-Dn1yInhalationExposureinRats StudyNo.:

Informationofthetranslation**~tudy** Sponsor: StudyNo.:

Translator:



## 000569

### Statement

Sponsor:
Title: A Simplified Acute Toxicity Study of

.by Nose-OnlyInhalation Exposurein Rats 

### ( J StudyNo.:

This study was conductedin this institute. This final report faithfully reflects the study results.

Management: Signed and Sealed Date: January7, 1994 Management



## 000570Title A Simplified Acute Toxicity Study of byNose-Qnly InhalationExposurein Rats (Study No.' Purpose The objective ofthis study was to examine acute toxic effects of bynose-onlyinhalationusingrats.
Guideline 

### ( GuidelineestablishedbyMinistryofHealthandWelfare (No. I Notification No. 24, 1989) Sponsor (Name) (Address)

Organizationundercontract

Studyschedule Studyinitiation August5, 1993 Studycompletion January7, 1994
Retention The studydata will beretained in the archives ofthe. Theretention period will be five years after submission ofthe final report. Further retention will be discussed with the sponsor.



## 000571(StudyNo.: This study was conducted under responsibility of the following contributors. This report faithfully reflects the studyresults. StudyDirector: Signed and Sealed Date: January7. 1994
StudyContributors: Signedand Sealed Date:January7. 1994 

### ( Signed and Sealed Date: January7, 1994

11 

## 000572

### ( J Contents 1. Summary

.......................................................... 1 2. Materials and Implements

............................................. 2 2.1. Test substance'

................................................. 2 2.2. Experimental animals'

...........................................2 2.3. Animal husbandry'

.............................................. 2 3. TestingMethod'

.................................................... 4 3.1. Exposure samplepreparation

...................................... 4 3.2. Clinical observation

............................................. 6 Test substanceexposure .......................................... 4 3.3. Body weight·

.................................................. 6 3.4. Pathological examination'

........................................ 6 3.5. Lethal concentration

............................................. 7 3.6. Assessment ofthe test substance

................................... 7 3.7. 4. Results····························································8 4.1. Exposure······················································8 4.2. Dead animal'

.................................................. 8 4.3. Clinical sign

................................................... 8 4.4. Body weight

................................................... 8 4.5. Pathologicalexamination'

........................................ 9 4.6. Assessment ofthe test substance

................................... 9 5. Discussion and Conclusion'

.......................................... 10 6. Reference························································· 11 Fig. 1 InhalationExposureSystem

...................................... 12 Fig. 2 Gas Chromatogram

............................................. 13 Fig.3 TimeCourseRelative Concentration'

............................... 14 Fig.4 BodyWeight Gain Ratio'

........................................ 16 Table 1 Test SubstanceConcentration'

................................... 17 Table 2 Environmental Conditioninthe Chamber

.......................... 17

iii 

## 000573Table 3 Clinical Sign

................................................. 18 Table4 BodyWeight·

................................................ 19 Table5 BodyWeight Gain'

............................................ 20 Appendix 1 IndividualClinical Sign'

.................................... 21 Appendix 2 ToxicityClassification Criteria

............................... 21



## ( )

iv


## 000574

### ( 1. Summary

A simplified acute toxicity study of
was conducted using five male SD strain rats (SPF) for each group. The animals were exposed to the substance once for four hours bynose-onlyinhalation exposure. The test substance gas was generated by passing through pressurized air into the test substance and was exposed to rats using a small nose-only inhalation chamber with approximately 2 L of inner volume. Exposure concentrations were set at 1,000 and 3,000ppm. As aresult ofthe exposure, actual exposureconcentrations were 970 ± 10ppmand 3,010 ± 10 ppm. The achieved concentrations were almost comparable to the target concentrations and were temporallystable. Two males died in the 3,010 ppm group due to the exposure. There were struggling, increased urine volume, and soiled fur in clinical observation. Body weight of the surviving animals increased normally. The dead animals reveled reddish lung in the necropsy, as well as moderatecongestion and edemain the lungs in thehistopathological examination. All these findings were considered non-specific changes. Additionally, there weredilatation ofatrium, congestion ofcerebellum aperture, and a large number of grayish patches in the kidney on necropsy, as well as focal inflammatory change in the lungin thehistopathological examination. These findings were considered non-specific changes. From the above results, it is concluded that the minimum lethal concentration of
was over 970 ppm and median lethal concentration was over 3,010 ppm. In regard to the acute toxicity by nose-only inhalationexposure, the test substancewas classifiedas a "non-toxicsubstance"

.

1



## 000575

# .lSI

( ) 2. MaterialsandImplements 2.1. Testsubstance (1) Name: (2) Chemical formula: (3) Molecularweight: 200.06 (4) Density: 1.4789glcm3 

### (23°C) (5) Purity: 99.9% (6) Boilingpoint: 56.22°C (7) Storagecondition: In arefrigerator (8) Stability: The lot used in this study was confirmed to be stable by an analysis conductedby the sponsor.


### 2.2. Experimentalanimals SD strain rats were obtained from Charles River Japan, Inc. on August 25, 1993, and were acclimated and quarantined for seven to eight days. Five males for each group were selected from the animals adjudged to be in good health condition. Therats were five weeks old and body weight ranged from 146 to 173 g that was within ±20% ofthe average weight ontheday ofexposure. The animals were identified by a number on their tail using oil base ink. The cages were also identified by labels listing study number, sex, dose, animal number, and name ofthetest substanceetc.


### 2.3. Animalhusbandry 2.3.1. Environmentalcondition This study used an animal room maintained at temperature of 20° to 25°C, relative humidityof40% to 70%, and airventilation ofapproximately 12times perhour (aU fresh air supply) throughout the entire observation period including the acclimation and
2 

## 000576

# ( ) quarantine period (excluding exposure). The lighting period was provided 12 hours a day (7:00to 19:00). 2.3.2. Animalaccommodations The animals in this study were housed at one ortwo per autoclaved polycarbonate cage (265 W x 426 D x 200 H mm, Tokiwa Kagaku Kikai Co., Ltd.) equipped with hardwood chips (Beta Chip, Charles River Japan Inc.) throughout the entire observation period including the acclimation and quarantineperiod (excluding exposure). Afilter cap with clearresin (Tokiwa Kagaku Kikai Co., Ltd.) on its front and back sides was mounted on the cagefrom the dayofexposure. The filter caps were changed bi-weekly, and other equipments were changed weekly. All accommodationsused in this study were autoclaved. 2.3.3. Diet The pellet diet for experimental animals (MF, Oriental Yeast Co., Ltd.) was given ad libitum using a stainless steel feeder (Tokiwa Kagaku Kikai Co., Ltd.). However, feeding was stopped during exposure. Contaminant such as pesticide residues of the diet used in this studywas analyzedby athird party. Accordingly, it was confrrmedthat thecontaminants were underthe permissiblerange inthe standard operatingprocedureof this laboratory. 2.3.4. Watersupply Tap water filtered though a 5 J..lm filter and disinfected by UV irradiation was given ad libitum using polycarbonate resin watering bottle of 700 mL (T-564, Tokiwa Kagaku Kikai Co., Ltd.). However, watersupplywas stopped duringexposure. Thewaterwas analyzed periodically and the analytical value was confirmed to be within the range of the ordinanceNo.56oftheMinistryofHealth andWelfare.

3

### 3. TestingMethod
3.1. Exposuresamplepreparation Thetestsubstancesuppliedbythe sponsorwas used inthis studyas is.


### 3.2. Test substanceexposure 3.2.1. Exposureconcentrationsettings A preliminary study was conducted using three males that were exposed to an average concentration of8,700 ppm (6,500 to 10,500 ppm) for 70 min. As a result, all animals died. There were struggling, increased urine volume, and soiled fur on clinical observation. An additional preliminary study was conducted using two males each that
were exposed to 100 and 530 ppm (520 to 570ppm) for one hour, respectively. There were no dead animals or any abnormalities in clinical observation. From these results, the exposure concentrations in this study were targeted to 1,000 and 3,000 ppm, respectively. 

### 3.2.2. Exposurecondition Fig. 1shows theinhalation exposuresystem. This study used a small stainless steel chamber (RCC type) for nose-only exposure that has volume of approximately 2 L with inner and outer cylinders. The animals were restrained to the animal holder designed perinasal area ofanimals to be open, and were set on the outer cylinder wall ofthe chamber. Exposure was conducted by blowing air containing designated concentration of the test substance from the inner cylinder for inspiration, and by exhausting expiration from the outer cylinder. The exposure was conductedoncefor four hours. 

### 3.2.3. Gasgenerationandexposuremethod Thetestsubstance gas was generatedby abubbling method that was directlyblows air (l kg/cm2) at flow rate of 11.3 to 37.0 mUmin measured by a mass-flow controller (SEC-4400, STEC Co., Ltd.) to the test substance in acylindermaintained at 5.0°C using a constant temperature bath. The generated gas was mixed with pressurized air, measured at a volume of 105 mUmin by a mass-flow controller (SEC-4400, STEC Co., Ltd.), in a primary mixingjar. After that, the mixed gas was supplied to the chamber
4


### 000578after mixing with pressurized air, measured at a volume of 1.1 Umin by a mass-flow controller (SEC-{)10, STEC Co., Ltd.), in a secondary mixingjar. The chamber was ventilated with exhaust volume of 1.2 to 1.35 Umin by a full-ventilation method. The pressure within the chamber after animal placement was set at +0 to +2.5 mmAq compared with thatoftheoutside. Theexposure initiation was designated at the pointofsetting animalto the chamberafter thegas concentrationinsidethechamberachieved equilibrium. 

### 3.2.4. Exposureconcentrationmeasurement The gas in the chamber was collected by an airtight type glass syringe (Dynatech Precision Sampling Corporation) at approximately 0.5, 2.0, and 3.5 hours after commencement of exposure. The sampled gas was analyzed by the following gas chromatograph (abbreviated to GC) method, then, the gas concentration in the air was calculated. A hydrocarbon meter (HCM-IB, Shimadzu Corp.) continuously monitored the gas concentration in the exhausted air in order to confirm temporal concentration variations. (1)Analytical sample The gas of I mLcollected with an airtight type glass syringe was used as the analytical sample. (2) GCoperatingcondition GC: ShimadzuGC-9AM (Detector: FID) Column: G-300, 1 J.l.m film thickness, 40 m length, 1.2 mm inner diameter (Chemicals Inspection &TestingInstitute) Carriergas: He 20mUmin,H2: 0.5 kg/cm2

,Air: 0.5 kg/cm2 Temperature: COL. 40°C, INJ. and DET. 70°C Fig. 2shows chromatogramobtainedunderthe conditiondescribed above. (3) Calibrationcurve Accurately weighed test substance was dissolved into ethyl acetate and was made up to the prescribed volume to prepare the standard solutions. Each 2 J.l.L of the standard solutions was analyzed under the GC condition as described above. Theobtained peak
areaandstandard solutionconcentration (ppm) madethecalibration curve.


### 5 

## 000579

### ( (4) Test substanceconcentration inthe air The analytical sample was analyzed under the GC condition described above, then, the test substanceconcentration (ppm) inthe airwas calculatedfrom the obtainedpeak: area. 

### 3.2.5. Environmentalconditionintheinhalationchambermeasurement The following items were measured at the commencement ofexposure and one hour intervals. (1) Temperature and relative humidity; Toyama type thermo-hygrometer (Toyama Keiki Co., Ltd.) (2) Oxygenconcentration; Oxygen meter (Galvanic cell type)


### 3.3. Clinicalobservation The animals were observed with respect to their mortality, appearance, and behavior from the start ofexposure to two hours after exposure with one-hour intervals. The clinical observation was also conducted once a day from the day after exposure to 14 days after exposure. However, theobservation during exposure was conducted as much
as possible.


### 3.4. Bodyweight All surviving animals were weighed for their body weight at immediately before exposure and 3, 7 and 14 days after exposure (the day ofexposure was designated as 0 day) with abalance (EB-5000, ShimadzuCorp.). However, the animals thatdied during exposurewerenot weighed.


### 3.5. Pathologicalexamination (1)Necropsy The surviving animals after termination ofobservation on 14 days after exposure were subjected to necropsy after euthanasia by severing the abdominal aorta exsanguination underintraperitoneal thiopental sodiumanesthesia (Ravonal®, Tanabe Seiyaku Co., Ltd.). Thedead animals werealso subjectedto necropsy as soon as theywere found dead. (2) Organpreservation The major organs (heart, lung, liver, kidney, spleen, and nasal cavity) were fixed by a 6



## 000580

# ( ) 10% phosphate bufferedformalin and preserved. (3) Histopathologicalexamination The lung ofrepresentative two animals (animal number 3 ofeach group) and kidney of
one animal (animal number 2 of the 970 ppm group) were microscopically examined after preparation of histopathological specimens by paraffin embedding, slice, and stainingwithhematoxylin andeosinin accordance with the ordinarymethod.


### 3.6. Lethalconcentration Median lethal concentration and minimum lethal concentration were estimated from the mortalityat the end ofthe observationperiod and exposure concentration.


### 3.7. Assessmentofthetestsubstance The toxicity ofthe test substance was classified in accordance with "the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labeling ofdangerous substances, EEC Council Directive". Appendix 2 shows the classificationcriteria.

7



## 000581.

# ( ) 4. Results 4.1. Exposure 4.1.1. Exposureconcentration Table 1 shows the test substance concentrations in the air and Fig. 3 shows the time
courserelative concentrations. The average test substance concentrations in the air were 970 ± 10 ppm and 3,010 ± 10 ppm for the targeted concentrations of 1,000 and 3,000 ppm, respectively. Concentrationvariability was within5% for the averageconcentration. Consequently, it was confirmed that the concentration was well controlled. The relative concentration alsorevealed stable

### gas generation. 4.1.2. Environmentalconditioninthechamber Table 2showsenvironmental conditionin thechamberduringexposure. Temperature 

### was 24°C and relative humidity ranged from 60% to 64%. Oxygen concentrationranged from 20.7% to 21.0%.
4.2. Deadanimal Two animals outoffive ofthe 3,010ppmgroup died at onehourafter commencementof exposure.
4.3. Clinicalsign Table 3andAppendix 1showclinical observationresults. Accurate observation was notperformed duringexposuredue to animalrestraint. There were struggling and increased urine volume in the 3,010 ppm group during exposure. Additionally, the observation performed at immediately afterexposurerevealed systemic fur soiled by urine. These findings disappeared by one hour after the exposure, and thereafter, there were no abnormalitiesby thetermination ofobservation.
4.4. Bodyweight Table 4 shows body weight and Table 5 shows body weight gain. Fig. 4 shows body weight gainratio. The surviving animals had normal body weightgainbythetermination ofobservation.

8


## 000582

## ( J 4.5. Pathologicalexamination 

### (1) Necropsy Dead animals revealed reddish lung, dilatation ofatrium, and congestion ofcerebellum aperture. In 

### the surviving animals, one animal of the 970 ppm group indicated large number ofgrayish patches in the kidney. Other surviving animals did not indicate any abnormalities. (2) Histopathologicalexamination In 

### the 970 ppm group, one animal (animal number 3) revealed focal inflammatory change in the lung. In 

### the 3,010 ppm group, one animal (animal number 3) revealed moderate congestion and edema in the lung. There were no abnormalities in the kidney ofoneanimal (animalnumber2).inthe970 ppm group.
4.6. Assessmentofthetestsubstance 

### Two animals died at exposureconcentration of24.8 mglL (3,010 ppm). However, there were no dead animals at exposure concentration of 8.0 mgIL (970 ppm). From the above results, classification ofthe test substance toxicity based on LCso 

### value was not clear in detail, however, the test substance was classified as a "non-toxic substance" in accordancewith the toxicitycriteriainAppendix 2.

9


## 000583

## ( 5. DiscussionandConclusion
The average test substance concentrations in the chamber were 970 ± 10 ppm and 3,010 ± 10 ppm, and temporally stable gas generations were confirmed. Temperature and relative humidity during exposure did not reveal any changes that were considered to influence the study results. Oxygen concentration during exposure was over 16% that is ordinarily concluded not to have an influence on animal physiology, and it was concludedthat oxygen concentration did not influencethe animals!. Fromtheseresults, it is concluded thattheexposurecondition was appropriate. Two animals out offive ofthe 3,010 ppm group died due to the test substance exposure at one hour after commencement ofexposure. Since there were no dead animals in the 970 ppm group, the median lethal concentration (LCso) of the test substance was considered to be over 3,000 ppm by taking in to account the results ofthe preliminary study. In clinical observation, there were increased urine volume that was considered to be effected bythe test substance exposure in the 970 and 3,010ppmgroups. Inthese groups, animals also indicated systemic soiled fur caused by increased urine volume. Additionally, the animals ofthe 3,010 group revealed struggling. The body weight of surviving animals increased normally by the termination ofobservationperiod. In dead animals, there were reddish lung, dilatation of atrium, and congestion of cerebellum aperture in necropsy. Histopathological examination of dead animals revealed moderate congestion and edema in the lung. These abnormal findings were considered non-specific changes that are seen in animals with sudden death due to circulation obstruction. There were no histopathological abnormalities in the kidney that revealed grayishpatches in necropsy. Sincefocal inflammatorychange in the lung was observed in partial lung in aspottedstate, it is concluded thatthis changeis non-specific. From the above results, it is concluded that the minimum lethal concentration of
was over 970 ppm and median lethal concentration was over 3,010ppmunderthe conditionofthepresent study. Inregard to the acute toxicityby nose-only inhalation exposure, the test substance was classified as a "non-toxicsubstance".
10


## 000584

### 6. Reference (1) Araki S, Numata M, Wada I, editors. Environmental Sciences Dictionary, Tokyo: Tokyo KagakuDojin; 1985. p. 299-300



### (

11


## 000585

# -,

Primaly dilutionflow meter Pressuregauge MFC

Pressuregauge MFC

MFC, Mass-flow controller HCM, Hydrocarbonmeter

Recorder I I HCM

Activatecarbonfor exhaust



# o o Secondary exhaustpump 

### CIt**~** Primaryexhaustpump (,1) 

# -

Gas generationflow meter



# -



# -, Buffertank

Constanttemperaturebath

Exhaustflow meter Flow meter
. Pressuregauge**I-----~**

Gas sampling port 

### f

Mixingjar 

# •

Animalholder



# - Manometer 

# \l



# -**~** 

# •

Pressuregauge MFC

Secondaly dilutionflow meter



# -

Fig. 1 InhalationExposureSystem 

# c

# ~ Ethylacetate



### ( I

o. lIff) CL. 1:=1Il
......



## Fig. 2 Gas Chromatogram



## 000587

# -;

100



### Q 

# B 

# 1 & !. o

,.- 

# =**~** '-" 

### 50



## o 

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## Ratio



## OU0590Table 1 Thetest substanceconcentration Time course test substance concentration

.Target concentration

(ppm) Time after commencement ofexposure (hr) 

### Mean±S. D. 0.5 

### 2.0 3.5 

### 1.000 960 910 970 970±10 

## 3.QOO 3.010 3.000 3.010 3.010±10

Table2 EnvironmentalConditionintheChamber


# ( } Target concentration (ppm) Items (unit)
Temperature 

## CC) Timeaftercommencement ofexposure (he) 

### 0 1 2 3 

## 4 ' 24 24 24 24 24 1.

### 000 Relativehumidity Oxygenconc 

### (%) (%) 

### 60 20.9 60 20.9 60 20.8 64 20.9 64 21.0 Temperature 

## CC) 24 24 24 24 24 3.000 Relative humidity 

### (%) 

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### (%) 

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# o : Immediately aftercommencement ofexposure



## 000591Table3 ClinicalSign Timeaftercommencement Afterexposure Target concentration

. 

### (ppm) Finding') ofexposure (hr) Time (hr) Day



# ----­ 1 2 1"'" 14 Increasedinurine 

### 5 

### 1.000 Soiled fur 

### 5 No abnormalities 

### 5**---4~5** 

### 5 

## -------+·5 Death 

### 2 &ruggling 

### 533 

### 3,000 Increasedin urine 

### 3 3 Soiledfur 

### 3 No abnormalities 

### 3 -------+·3 

## ( 0,Immediately aftercommencement ofexposure *, immediately afterexposure



## 000592Table4 Body Weight (g) 

# :;'8' Daysafter exposure Target concentration AnimalNo. (ppm) 

### 0 3 7 

### 14 1 163 185 225 293 2 160 183 215 278 3 160 181 219 280 1.

### 000 4 156 176 212 275 5 

### 146 160 195 259 

## Mean 157 117 213 277 S.D. 

### 7 10 

### 11 

### 12

1 

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## (

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### . 155 181 

### 217 280 5 161 179 208 263 

## Mean 167 188 223 286 S.D. 

### 8 13 19 27
D: Death (): Day afterexposure



### 000593Table5 Body Weight Gain (g)

# .2'~ Days afterexposure Target concentration (ppm) AnimalNo. 

### 3 1 

### 14 1 

### 22 40 

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### 3 21 38 61 4 

### 20 36 63 5 14 35 64 

## Mean 20 36 64 S.D. 

### 4 

### 3 3 ·1 D(Od.) 

### ( J 

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### 3,000 3 D(Od. ) 

### 4 

### 26 S6 63 5 18 

### 29 55 

## Mean 25 35 63 S. D. 

### 6 6 8 D: Death (): Day afterexposure

/ •



## 000594Appendix 1 IndividualClinicalSign Timeaftercommencement Afterexposure Target concentration ofexposure (hr) Time(hr) 

### Day (ppm) Findings Anima1No 

### 4­ 

### 0 1 

### 2 3 

## 1 2 1

-- 14 1 Increased in urine Soiledfur 

### 0 0 

### 2 Increasedin urine Soiledfue 

### 0 0 

### 1.000 3 Increasedin urine Soiledfur 

### 0 0 "

# . 4 Increasedin urine Soiledfur 

### 0 0


## ( } 

### 5
1 Increasedin urine Soiledfur Death 

### 0 0 0

Struggling 

### 0 

### 2 Struggling Increasedin urine Soiledfur 

### 0 0 0 0 0 

### 0 

### 3.000 3 Death 

### 0 Struggling 

### 0 

### 4 Struggling 

### 0 0 0 Increasedin urine 

### 0 0 Soiledfur 

### 0 • • 

### 5 Struggling 

### 0 0 0 Increasedin urine 

### 0 .0 Soiledfur 

### 0 0:Findingpresent .: Findingabsent

a,Immediately aftercommencement ofexposure *, immediately afterexposure

Appendix2 Toxicity ClassificationCriteria Category LC50 Inhalation Rat (mglLl4hr) 

### < 0.5 Very toxic Toxic 

### 0.5

-- 2.0 Harmful 

### 2.0

-- 20 

## 000595

# :1.'71
FINALREPORT

PartitionCoefficient (I-OctanoVWater) Studyof

April4, 2001



## 000596