,....""~ ()

\......; '_._" 

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

- 14-day of recovery ­ Group-No. 

Dose 

.(mg/k g) ..................... 


00 

Control 

o 

01 

Vehicle 

0 

04 

1000 


MCH--.-" MCHC ~th:UlDcyte Pla-hlet 

(pg) ( s ) (%0) (x1 04

/ ~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 


~ 
Tab Ie 16';'5 Hematology of female rats treated orally with 'or 28 days 

- 14-day of recovery ­ Group-No. PT APTT WBe 0i fferent fiT count 11) 

Dose 

(mg/kg) 

00 

Control 

0 

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 

Vehicle 

0 

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 

Control 

0 

N 

Mean 

S.D. 

Seg 

5 

8.9 

2.6 

01 

Vehicle 

0 

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 ) (rat io) (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 

o 

Co.) 

o 

o ..... ',..~,. .0 ~ ....c,..,~ '­
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 

(rat i 0) 


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. 

~ 
Tabl e 17-6 Blood biochemistry of male rats treated orally with for 28 days 

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

Group-No. 

Dose 

(la/kg) 

00 

Control 

0 

N 

Mean 

S.D. 

01 

Vehicle 

0 

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. t4 

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 

Tab Ie 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 ) (rat io) (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\ 

0'1 03 N 5 5 5 5 5 5 5 5

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 N 5
 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 )tIU/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 

o 

Q) () t"'"';.j";, ~ .....-/ ~ 
(---.. 

' ... ,", .... o 

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 
Tabl e 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 


Adrenal . 5
 (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 


Tes ti 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 

Tes ti 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 


Re l. 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 	 ~ ~ /' '~ ..... N 	 r'i 	

\....-. ." ....... 

/~'~ ...... 

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 


Re I. 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 

Re I. 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 

o PROJECT No

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 


Adrona I (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 ± 


Re I. 7.0 ± 0.8 6.8 ± 1.1 6.7 ± 


Test i S (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 ± ~ 

Tes tis (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 

Re 1. 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 I dnay (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 


Adrena t (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 

Re I. 14.8 ± 1.4 13.9 ± 1.8 14.4 ± 1.1 15.9 ± 3.0 15.4 ± 0.8 

. 5 Adrena r(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\ (Re I. ) 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. : Relative organ weicht (g or mg 7 100g 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 


Re i. 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 


Re 1. 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 


Adrena I(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 


Re I. 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 


(Re I.) 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 7 100g 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 

Dos e(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 

Dos e (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 

Cont ro I 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 infil tration 1 % s 1 s 

microaranuloma 0 % I 1 o 

vacuola tIon In ~_c!pB toclte 0 0 0 0 o 

fO res toDl::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 _".1 o

Heart: 1 1 ~ mononuclear cell infiltration 1 0 0 0 o 

JIIyocard laJ.....:f....i,::;br:..,:o"'s.:,;is"--_________--=:_ n M ....................... 


0 0 •._......._9._-_......._. 0 	 ____.."......"1..........."..".,,.


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 ~~_~.~.~ ex t ramedu 118TX.Jl~~ill.o Ie~J!.__ 3 ___.__....,,_1___.___"'--_ n __0 o 

Sternal bone JII~!!.~!.; ___________ JL.__.... 0 0 L_.._......._._Q L ...___ I __._...9..._.__ 

Femoral bone marrow:_.____________-=-- n __•.--I!.. 
 0 o 0 1 _L o

Adrenal: 0 0 0 __._Q____,_--=-O__---' o
 t_". 1 

Testis: •__..._9............ 0 0 	 o ._----_...._._---­

o 	 Pros tate: 


o Dlononuclear cell Infiltration 4


c.,) 	 G\ 1 : Not examined 	 (con t loucd.) 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

Organs --5 : No. of animals 5 5 5 5 5 -, 5 

Pindings 

Ovary: / / 

atrophy _.•_.__._.... 0 0 

Uterus: (1) (}) 

dilated 1 . lumen 2 1 1 4 

squamous metaplasia of 1 o o 0 0 

epithe Ii um ce 11 

_.-!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 of Contents 

Company Sanitized 

I. Revised 28-day Repeated Dose Toxicity Study: 

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 Simplified Acute Toxicity 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 
/ 


Translation Statement 

The following 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 as possible to my knowledge. 

Information of the original study 

Sponsor: 

Title: 2S-day Repeated Dose Toxicity Study of .nMammals 

Project No. 

Information ofthe translation study 

Sponsor: 

Order No.: 

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/i nsp ection 

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 

IJanuary 25. 2000 IJanuary 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)] 

IJanuary 31, 2000 I February 1. 2000 IJanuary 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 

i 
22, 2000 IFebruary 23, 2000 lFebruary 23, 2000 r---------,,- ebruary 

Preparation of histopathologica I 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. 2 000 IMarch 8. 2000 IMarch 8, 2000 

Identification of histopathologi cal specimens (all specimens) 

IApril 27, 2000 IApril 27, 2000 IApril 27. 2000 

3 

OU0329 
Study Title: 28-day Repeated Dose Toxicity Study of in Mammals 

PROJECT No.: 

Type of Date of Date reported to Date reported to 

audit/inspectio n 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 

OU0330 
Statement 

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 

000332 

Address 

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.1 039 issued by Pharmaceutical Affairs Bureau, 61 

Kikyoku Notification No.1 014; 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 of works. 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 

000339 
22. 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 

000343 
5-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 'I D. 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 (LC 1OA 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% of the nominal value; 

Attachment 2). 

18 

000344 
3. 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 

000346 
the 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 

Group Test Dose

(mg/kg) of dosing used 

(mLlkg) 

volume 

solution 

(mg/mU Male Female 


00 
 5"+5 b 5"+5 b Water for 0 2 0

1 

injection JP 

(Control) 

5a +5 b 5"+5 b 


(Control) 


02 


01 Vehicle 0 2 0

10 2 5 5" 5­

e 100 2 50 5" 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 

01 M 01-01 M 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 

OU0347 

5. 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 we ight. 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 

OU0348 
determinations and examinations were conducted on all animals. 

(1) CI inical 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 

000349 
recovery 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 (AL T; for 

25 

000351 
the 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 

000353 
vehicle control group and the uteri in one each of female 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 of males and females in 

30 

OU035G 

any 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 AL T 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 

000358 
V. 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 of males 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 

OU0359 
substance. 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 

OU0360 

Attachment 1 

Test Result (Stability Test) 

Analytical Chemistry Office 

Februaryl, 2000 

Test substance name HFE-347pc-f PROJECT No. 

Analyzed sample Preparation of Lot No. -_..-""-----""... _....-.-...... _...... 

name 

. Preparing Section Safety No.2 research date January3l. 2000 

section 

Used base product Lot No Base product Lot No.99 1224 

Used medium macrogol 400 Lot No.EI-1 

Analysis date J anuary3 I, 2000 Analytical method SOP No. 1 3-03-74 

Analytical result 

Storage condition At room temp. protected from light. airtight 

Storage period Start After 4hours 

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) 	Unit of the observed value and the determined value is mg/mL 

2) 	( )ofthe determined value is recovery against the nominal concentration 

3) 	The observed value in start of storage are obtained ones from concentration analysis 

and homogeneity test. 

Judgment Acceptable Acceptable range Residual ratio >=90% 

The parson in charge ofAnalysis Test 

Analysis Test Director 

Date February 1,2000 

Manager 

000361. 
31 Attachment2 

Test Result <concentration analysis, homogeneity test) 

Analytical Chemistry Office 

Feburlyl,2000 

I Test substance name 

.. 

I Analyzed sample 

HFE-347pc-f 

Preparation of 

~--

PROJECT No. 

Lot No. 

I" . -,--­ ..-~.-,--

.. 

-----------.......................-----­

name -. 

Preparing Section Safety No.2 research date January31,2000 

section 

Used Lot No Lot No.991224 . 

Used medium macrogol 400 Lot No.EI-l 

Analytical date January31,2000 Analytical method SOP No.13-03-74 

Analytical result 

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 )The determined value is obtained by average of6 observed values. 

04.10362 
33 

2)Observe vs determine means per cent ofthe average of observed values/determined value. 


3)CV(%) is obtained by average of 6 observed values. 


4)N.D. means less than identification limit. 


Judgment Acceptable Acceptable Concentration:+-l0% ofthe nominal value 

(concentration range Homogeneity: +-10% ofthe nominal value 

,homogeneity) 

The parson in charge ofAnalysis Test 

Analysis Test Director 

Date February 1,2000 

Manager 

0003G3 

Figure 	 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 

Op h thalmoscopy 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 

/"""\ 

./ \......) 

-tlD 

....., 

..... 

.c 

tlD 

Q)

.,. 

500 

400 

300 

--0- Control -­ Vehicle 

-fr- HFE-' 

----;6;- HFE­

-o-HFEo mgl/kg o mg kg 10 mg/kg 

100 m!~kg 1000 ·m61 kg 

..... "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- Con t ro I o mg/kg 


e-- Vehicle a mgjkg 


--tr-- 10 mi/kg
 100 mg/kg 


--0- 1000 mg/kg 


400 


,.... 

bD 300

-...... 

..c 

bD 

I\) 

N 

co 

~ c 

jI: 

200 	

L 	~ 

. ~~ ~~ ~ 

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 o mg/kg 
 -- Vehicle,- o mg/kg 
 -Cr-' 10 mg/kg

.- 100 mg/kg 

--0--- . 1000 mg/kg 


40 


,.... 

CIO 

......, 

s::: 

o 

...... 30 c. ~ 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 

", 

~ 

~ 

c 
50 

--0- Control omg/kg .-Vehicle omg/kg ~ .. " ' 

, 10 mg/kg

..-- 100 mg/kg 

-0- 1000 mg/kg 


40 


,.... 

bQ 

......... 


c 

'0 

-0. 

30 

e 

:::J 

en 

c 

0 

U 

"'CI 

.;.. 0 0 0 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 10 
r" 

./ o

60 


-0- Control o mg/kg 
 - Vehiclp o mg/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 o mg/kg 
 -- Vehicle o mg/kg 
 ~ 10 mg/kg 


k- 100 mg/kg 


50 ~ -0-, 1000 mg/kg 


40 -...J 

E 

...... 

Q,) 

.:.t!. 

.... 

!'OS 30~¥~ : 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 

fl nd i ngs 

No.of animals 

----------------------------------------~s of t rea 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 

Con t ro I no abno rlla liti es 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 an ilia I$ 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 abnorDa lit i as 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 adlili nis trill on 

PROJECT No 

c 

e 

o 

GJ 

~ 

'.! ~ 
Tab!e 1-2 CI inica! signs of lIale rats treated orally wi th . 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 

---( Day s-oftrea till 9n-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 

f)

V ~ 
r"·

./ 

. 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 abno rDa I it i as 

0 

01 Ho.of aniDals 

Yetlic:le no abnorlll! lit ies 

0 

02 No.of animals 

no abnorll1alities 

10 

\0 

03 

04 

t 

No.of anillais 

no abnorlla II t i as 

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 abnorull ties 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 

0 

04 No. of an !1Il1 s 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:: / .. c~. f","\ 

',---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 abnorilia lit ies 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. af an i III Is 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 abnorrtlll ties 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 abnorla I I ties 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 I i ties 

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 abno rill I 1 tI as 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 abnorllla Ii ties 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 i t i as 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.a I i tillS 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 anillal s 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 itI es 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) FI nd Ings 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 r III es 5 

100 

04 No. of Inimlls 

no abnormal I ties 

1000 salivation 

C-;- Before autopsy 

5 

5 

PROJECT Ne 

o 

o 

C.J 

~ 

~ p 

c 
Table 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 


Tabl e 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 


Veh i cI e 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 


Unit: g N No. of an i rna Is ~--~~- ..... 

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 Un it: g N No.of animals 

0 

PROJECT No. 

e 

o 

c.J 

rJJ 

~ 

('.;:......., 

'. . 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

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


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 

~ r' -"', /"""'-.

(l) 

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 reatmen t 

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 rt rsa-lilian t >---------------------------------­

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 animal s 

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 ~ 

N 

\.Q /'':'''",,"

~ ()

'-./ 
(' (-­ 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 


00 
 N - 10- fO----- 10- --10 10


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 


Uni t : 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 


w Un it: mL N No.of animals

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 Vehicle 

0 

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 7 No.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 Control 


0 0/10 0/10 0/10 0/10 0/ 5 0/ 5 

01 Vehicle 


0 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 treatment ­ 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 

01 	 .. 5 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 ; ye Ilow 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 Urob i II nogen Bilirubin Color 

Dose blood body 

(mg/kg) Grade Grade Crade Grade Grade ---Crade 

0' 5 3 5 0 5.0 0 O. 1 5 5 A --5

'± 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 III nogen 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) (x 10'/ 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

1tL L) 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-­

Control 

0 

N 

Mean 

S. D. 

( sec.) 

5 

16.4 

1.6 

( sec.) 

5 

22.9 

2.9 

(x 102

/ Po L) 

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 

Vehicle 

0 

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 

Control 

0 

N 

Mean 

S.D. 

Seg 

8. 7 

3.6 

_._. ­ ~'---'-

01 

Vehicle 

0 

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 

(mg/kg) ---Seg

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) (x 10"/ J,l.l) ( ~ ) ( g/dl ) ( fl ) ( pg ) ( % ) (%0) (x 1 04

/ 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 Oi fferent ial count (t) 

Dose 

(mg/kg) ( sec.) ( sec.) (x 1 02

/ /.L L) 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 

,.. 

N PROJECT No.

/''''', . ~ {~ 

'--./ ~ 

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 

~ 
Tab Ie 17-2 Blood biochemistry of male rats treated orally with' for 28 days 

- 28-day of treatment ­ Group-N!i-:- - ATC-­ 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 
Tab I 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 prote i 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 
Tab I 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 


....t:. 

c 
--

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 prote i 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 03 N 5 5 5 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\ 

-...l 03 N

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 rub i n chol esterol 

(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 


Vehicl e 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 

~ 

o .:R
/.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 i gh t (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 Li ver (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) 

Re I. 

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 

Kid n e y(L) 5 5 5 

(g) 1. 39 ± 0.0·9 1. 44 ± 0.09 1. 35 ± 

Re I. 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 ~ 0­
Table 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 

Tes tI s(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 

Tes tis (L) N 

(g) 

Re I. 

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 fi nal 

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"1I...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 we i gh t (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 


Re I. 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 


Re I. 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> 

'-' 
Tab Ie 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 


Adrena I (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 


Tes tI s(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 
 ~ 

Tes tI s(L) 	 N 5 5 5 


(g) 1.58 ± O. 18 1.72 ± 0.17 1.59 ± 0.09 


Re I. 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 

Re I. 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 

Re I. 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 


Adrena I (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 

Adrenal . 5 (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 


Re l. 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 


(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 ± 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 7 lOOg 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 


Re I. 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 


Re I. 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 


Adrena I (l) 	 N . 5 5 5 


(mg) 35.1 ± 4. 1 32.6 ± 6.4 35.2 ± 5.0 


Re I. 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. 

o 

e 

o 

~ "­

0­ /~"'. 

~ ..........s
 '.~."",/' o 
r'<',< r'\, ... ,.,/" i"",..1 

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 I for 28 days

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. ~ 

e 

o 

~ 

~ ~ .....£) 

c 
Table 22-1 Necropsy of female rats treated orally with for 28 days 

- 28-day of treatment 

Group-No. n') 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 --... _--------......._.....- ....__.... _.-.....,...,.........__...._--_......_-----------....-~.- ...--...........----.-----...-....--......-...-...........-.... ....-........---.-..........--...~--.--.-~...-.---~....-._._..._..........._......_.... 
 Uterus : 

atrophy o a o o 

swelling 2 1 4 

-...I 

~ 

PROJECT No. 

o 

~ 

Q 

Iota 

ti /", '.'. o ~ o 
~"'", .r'-"" U 

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

14-day of recavery 

Group-No. 00 01 04 

Con tro I 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

Organs -5-- 5 ---5­ : No. of animals 5 5 5 5 5 

Findings 

Liver: / /

mononuclear cell infiltration 1 2 3 1 3 

mi crogranu Ioma 0 2 1 1 o 

vacuo I ati on In ~.~J.l?£ll:.:e~_______-=.n ___--.::.-.-­ 0 0 0 ..._................- o 

£~~!=ma~c~h~:__________ 0 0 0 0 / .. _~/_ _=-0__ .,-,-,,~,...-...-..----....9.........".........­ ,H~!du lar stollac~h.::...:___________--=n____ I 
 _...9"•._ 0 Q 0-....-.... ,.-~,_'----__.....1. ....9...,......_, 

.Duodenum: 0 0 0 0 0 (__....,./.... 0..................... 

Heart: / / ;:;l mononuclear cell infiltration 1 0 0 0 

IIIYOC8T d I a.L..:f~ib:,:r:.,;::o.::.s1=.:· s:....-__________...::.... n ......................... 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 

calciricat ion 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::.......__ 


res Ii s: ._"•.JL.........__.;..O_____0'--________ 
 ._--_............",._-­

Prostate: o mononuclear cell infiltration 4 e 

o / : Not examined (con t i nued.) ~ 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 

epithel jum cell 

__!!!JJl.e.~.Y............................................. _ ...... _............................................._. ___.!l. ___-=-_ 

Sternal bone: 0 ..J............._._-!.O___--.:O~_____!~__.....!./ ................... / -.........Q....................... n 

l!!1or.!l.J!.9.g~.:.. 0 0 .9..........._..... 0 0 / / 0
 ~ Epididymis: (l) 


spermatic granuloma 1 


() : No. of animals examined. 

/ : Not examined 

PROJECT No. 

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 SJl Jt3 ~ 

a. V(uaJetCt ~, e (; n div ; du'" I ) 


Clinical signs 

Body weights 

Food consumption 

Food efficiency 

Water intake 

Ophthalmoscopy 

Urinalysis 

Hematology 

Blood biochemistry 

Absolute and relative organ weights 

Necropsy 

Histop a thology 

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 

Day s 0 f trea tmen t 

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 : sal ivation 

PROJECT No. 

o 

e 

Q 

~ 

~ 

... ,~ ...........
 :.. ......) 

~ 
C) 


Appendix 1-3 Clinical sigos of male rats treated orally wIth for 28 days 

,Days of treafment ) :-------­

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 adill I nTifra tlon 

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 -A B A B A B A B 


02 Gao r --:. ­ 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 : sal jvation 

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 t rea tment )--­

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 i ty 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 - - - - - - - 01 M09 - - - - - - - - - - - 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 sa I i va t i on 

PROJECT No. 

o 

o 

Q 

~ 

~ 

en """"­

t 

Appendix 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 abnorma II ty 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 sal ivation 

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 

-...l 
04 

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 

VI "'"' 01 01MOI 236 306 358 406 438

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. 	 -------------------------------------=( 0ays 0 f recove ry .. r:;....::=-.===------------------­ Dose Ani ma I 	 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 
 .­

...J N 5 5 5

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------ 01 FO t -114-196 21 0 233 -247 

Vehltle 01F02 184 222 253 277 288 

o 	 01 F03 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$ 0 f t reatmen t ;>=------------------------­ 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 

o PROJECT 	 No.

o 

~ """­

CI1 

ClI 	 ~ 
---

Appendix 4-3 Body weights of fenale rats treated orally with for 28 days 

Group-No. --------------------------------------------< Days of recovery /--------------------------------------­ Dose An Iilia I 

(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 

<:> 

en 

~ w ~ /',.f...... 	 -t: ("L"\ 

.......... \J 
/",,~.} ~: 

I ; 

\.",./' 

Appendix 5-1 Food consumption of male rats treated orally with to r 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 

e PROJECT 	 No.

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 

Dose 

"Group"-No. 	

Control 

00 

(Dur/kg) 

o 	

No. 

00F02 

00F06 

An 

00F03 

OOFOI 

OOFOS 

00F04 

00F07 

i ma I 

------------------------------< 

..... 

17.1 

12.9 

17.4 

15.1 

12.8 

15.6 

19. 

-1 

4 

1 ..... 

22.3 

17.3 14.4 

17.1 

20.0 

20.5 

18. 

21.3 

2 9 

4 

3 """ 

15.4 

21.0 

20.5 

21.0 

21. 

17.6 

10 

1 

..... 

n.l 

16.4 

17.8 

18. 

20.7 

19.4 

16.0 

16 

17 

4 

..... 

25.3 


11: 

22.7 


18.0 


19.8 


17. 

23.2 


23 

24 

1 


1 


Days of treatment r-------------­

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. - 3 - 10 -17 - 24


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~"'\

............,..,/
 ~ ..J 
i"'" 	

,,,,.,/' 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 oUl06 15.7 15.4 


Vehicle 011.107 16.7 11. 9 


0 OlMOS 11. 9 15.4 


0lN09 16.4 11. 7 


OUlI 0 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') 

ell 
Appendix 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 

Gro up-No. 	 -------------=---:=::::.--::=-....:...----------------( 0ay s 0 f t rea tmen t 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 

~ 

...J :t ... /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 

c 
Appendix 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 0 f t rsa 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 

Uni t 	 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 

An i rna I -------~-------;-------------------------\OaysoTrecove 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. 

(;

, 

r~" \ 

d

'J 

.... ~.,. ...:. ("u_" 

;\.....) 

Appendix 	 10-2 Water intake of female rats treated orally with for 28 days 

Group-No. ------ -- -------------- ---------------- < Days of treatment >=-----------­

Dose An i ma I -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 


Cont ro 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. Ri ght 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 rma Ii ty 


PROJECT 	 No. 

c 

c 

o 

~ 

"\I 

~ /~"". !"'''''' ~ \"~ -C 
l . 

'"-

/:., 

"' 	 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. .R Igh t--' Lit t 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 	 ~ "" 
Append I 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 i nogen Bi I i rubl n 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 

\,0.) 

~ 02M02 	 ± 7.5 O. 1 A

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 

N 	 5 	 - -5. 5 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. 

(; 


~ 

c 
Append i x 14-1 Urinalysis of female rats treated orally with for 28 days 

- 28-day of treatment ­ Group-No. Occul t 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 i rub in - 14-day of 

Color 

recovery -

00 00F06 8.0 O. 1 A 

Cont ro I 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. 
Append i 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. (x 1 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,\ 

\_1 
r""" 

~) 

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. (xl04

1p,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 t5.0 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) (x 10·/ 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. (x 19'/ 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 t re'a tmen t ­

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"'"'\ 

._--' '--.J 
i

r" 

\."",,,,/ 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

/ tt L) 

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 

Stab 

0.0 

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 
Append ix 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 Tr iglycer Ide 

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 

Append i 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/d L) (mg/d L) 


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 8.8 aa- 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 AI bum In- A/G Ca - - Inorganic 

Dose Animal protein phosphorus 

(mg!kg) No. (mg/dl) (mg/dL) (mg/dL) ( g/dL ) ( g/dL ) (rat 10) (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 


Append Ix 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: 
".~ 

Append I 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 

N 5 -5-- 5 5 	 S

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 

N 5 -5--- 5 5 5 5 5 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 protei n 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
~, ~. ~, 

Append i 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 animal s 

0 	 PROJECT No. 

e 

0 	 ........ 
 C/I 00. ... 

N ........J


.".. ,"'..... ()

\, .., ......... 

(--­ ,/ .-..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 Tri glycer i 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 01 F03 108 38 O. 00 317 3632 0.06 59.5 9. 1 

01 F04 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 ) (ra t i 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 Q1FO 1 142. 1 4.rr--· 109~ 

Vehicle 01F02 142.2 4.22 106.9 

o 01F03 143.0 4.25 108.7 

...J 01F04 142.0 5.09 10S.9

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 an Iilia Is 

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)

03 03FOl - -87 28- - -0:9-7--- 235 2146 -o.O~ ~··-----s2.8 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 ) (ra t i o) (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 II rub in cholesterol 

(mg/kg) No. ( lUll) ( lUll) ( lUlL) ( lUlL) ( lUll) (mg/dl) (mg/dL) (mg/dL) 

00 00F06 12 t 22 2~ 31 189 3148 0.07 67.8 19.6 

Contro I 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 

0 PROJECT 	 No.

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 

01 F07 

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 11 O. 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) Ki dney (L) Adrena I eR)

(mg/kg) No. ( g ) ( g) ReI. ( g ') Re I. ( mg ) Rei. ( g) ReI. ( g) ReI. ( mg ) Re I. 

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. 1S 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) KI dney (l) Adrenal (R) 

(mi/kg) No. ( g ) ( g) Rei. ( I) ReI. ( III ) Re I. ( g) Re I. ( 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 7 100g 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) Tes tis (R) Tes t Is (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 

N 

V1 ~ 

Vf c:::::::r-.

o 
Appendix 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. 

LI ver 

( g) ReI. 

Spleen 

( mg ) 

Kidney (R) 

Re I. ( g) 

Kidney(L) 

Re I. ( 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 Ad rena I (L) Tes t is (R) Testls(L) Prostate 

(IIi/kg) No, ( mi ) ReI. ( If) Rei. ( If) ReI. ( mg ) Re I. 

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 


Vehi c Ie· 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 ) Re I. (g ) Re I. ( mg ) Re I. (g ) Re I. (II ) Re I. (mil ) Re L 

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 wei Ilfit (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 T IOOg finar body 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 

Append i 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 -1 
r"'""'\, 

--,' 	 V 

Append Ix 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 


N5 	 00F10 32.5 12.9 55.1 21.9 42.8 17.0 1.06 0.42
 -- -- - 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

CJ 

e..J ~ 
--

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 "-' 

o c;::,

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 

Dos e(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 nega t i ve. 

PROJECT No. 

e 

o 

~ 

CJ 

".l 

~ 

......... 


p 

c 
Appendix 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 

calci Hcalion 

vacuolar degeneration of 

tubular epilhelium 

- ± - ± 

- ± - ± 

± 

-

-

-

- - ± ± - ± -± 

± -

t -

-

-

± 

± ­

+ ­

Spleen: 

increased extramedullary hematopoiesis ± - - - ± ­ ± ± t - ± 

Sternal bone marrow: - - - - - Pemoral bone marrow: 

Adrenal: 

Test is: 

- - - ­ - - - ­ -

- ( 

.

'­

~ 

I 

. 

Prostate: 

Ilononuclear cell infiltration ± ± ± - ± t - ± ­

Sternal bone: 

Pemoral bone: - - - - - - -- - -

I!pidl dyais: 

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 

An iliaI 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 mar roy: / 

Femoral bone marrow: / 

Adrenal: / 

Ovary: 

atrophy - f -

/ 

Uterus: 

di lated lumen 

squamous metaplasia of 

epitbeli DID cell 

atrophy 

+ -

- + 

- - - -

:t 

- i 

• 

-

+ 

Siernal bone: / 

Femoral bone: / 

/ 

± t - :!: -

/ 

/ 

/ 

/ 

/ 

/ 

/ 

/ 

/ 

/ 

+ + - + + + 

/ 

/ 

Gradings: - ;none. ± ;very sl igbt. +;sl ighl. '* ;moderale. I ;severe. 

/ : Not examined 

PROIECT No. 

100 000539
STUDY CODE: 

FINAL REPORT 

ACUTE ORAL TOXICITY STUDY OF 

IN RATS 

March 1993 

000540 

STATEMENT 

J, the undersigned, hereby declare that this report provides correct English translation of the 

final report (Study Code AI6-0169, issued on March 22, 1993). 

Chemicals Inspection & Testing Institute, Japan (CITI) fonnally changed its name to Chemicals 

Evaluation and Research Institute, Japan (CERI) as of November I, 1999. 

~b. if" {II ?Arb Y 

Date / 

000541. 

21'1 


GLP STATEMENT 


Sponsor: 


Title: Acute Oral Toxicity Study of in Rats 


Study Code: 


I, the undersigned, hereby declare that this study was conducted in compliance with "OECD 


Principles of Good Laboratory Practice (May 12, 1981 )". 


Management: Signed in original March 22, 1993 

000542 

QUALITY ASSURANCE STATEMENT 


Title: Acute Oral Toxicity Study of in Rats 

Study Code: 

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 of these results to the study director and management are as 

follows. 

Dates of Inspections 

and Audits 

Dates of Report to 

Study Director 

Dates of Report to 

Study Management 

November 12, 1992 November 12, 1992 November 12, 1992 

January 12, 1993 January 12, 1993 January 12, 1993 

January 20, 1993 January 20, 1993 January 20, 1993 

January 28, 1993 January 28, 1993 January 28, 1993 

February 3, 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 of the 

methods and procedures used in this study and that the reported results accurately reflect the 

raw data obtained. 

Section Staff, Quality Assurance: Signed in original March 22, 1993 

Section Chief, Quality Assurance: Signed in original March 22, 1993 

000543 

TABLE OF CONTENTS 

SUMMARY 

I. TITLE .................................................................................. 2 


2. SPONSOR .............. .................................................................... 2 


3. TESTING FACILITY .................................................................... 2 


4. PURPOSE OF STUDY .................................................................... 2 


5. TESTING METHOD .................................................................... 2 


6. GLP COMPLIANCE .................................................................... 2 


7. PERIOD OF STUDY 2 


8. LOCA TION AND PERIOD FOR RETENTION OF RAW DATA 3 


9. AUTHOR AND PERSONNEL CONCERNED WITH STUDY 3 


MATERIALS AND METHODS ....................................................... 


RESULTS ................................................................................. . 


10. 4 


II. 7 


12. DISCUSSION 7 


TABLE .................................................................................. 1-6
 1-4 


APPENDIX PHYSICOCHEMICAL REPORT .................................. 1-8


000544 

J.).o 


SUMMARY 

Acute oral toxicity study of was conducted in both sexes of Crj: CD (SD) rats, 5 

weeks of age at the dosing. A limit test was conducted at 2,000 mg/kg, and the vehicle control 

group was 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- 000545 
FINAL REPORT 

Study Code: 

1. 	 TITLE 


Acute Oral Toxicity Study of I Rats 


2. 	 SPONSOR 

Name: 

Address: 

TEL: 

3. 	 TESTING FACILITY 

Name: 

Address: 


TEL: 


4. 	 PURPOSE OF STUDY 

The purpose of this study is to assess the single dose oral toxicity ofthe test substance. 

5. 	 TESTING METHOD 

This study was conducted in accordance with "401, Acute Oral Toxicity (February 24, 

1987)" prescribed in "OECD Guidelines for Testing ofChemicals". 

6. 	 GLP COMPLIANCE 

This study was conducted in compliance with "OECD Principles of Good Laboratory 

Practice (May 12, 1981}". 

7. 	 PERIOD OF STUDY 

Commencement of Study: November 16, 1992 

Animal Receipt: January 12, 1993 

Dosing: January 20, 1993 

Necropsy: February 3, 1993 

Completion ofStudy: March 22, 1993 

- 2 	- U00546 
8. LOCA TION AND PERIOD FOR RETENTION OF RAW DATA 


The raw data will be stored in the archive of the of our 

organization for 5 years following the date of completion of study. After tennination of 

the retention period, any measures taken will be done so with the approval of the sponsor. 

9. 	 AUTHOR AND PERSONNEL CONCERNED WITH STUDY 

9.1 	 AUTHOR 


Study Director: 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 	 PERSONNEL CONCERNED WITH STUDY 


Study Staff: 


Staff, Macroscopic Examination: 

Staff, Animal Management: 

Head, Analytical chemistry Unit: 

9.3 	 PERSONEL IN CHAEGE OF STUDY 

Test Substance Management: 

Animal Care Management: 

- 3 	 - 000547 
10. 	 :MATERIALS AND METHODS 

10.1 	TEST SUBSTANCE (INFORMATION PROVIDED BY mE SPONSOR) 

1) Name 

CAS No.: 

2) 	 Other Name 

3) 	 Lot No. 

4) 	 Supplier 

5) 	 Structural Formula 

(Molecular Formula: 

6) 	 Purity 


99.9% (GC area%) 


Name and Concentration of Impurities 


7) 	 Physicochemical Properties 

Molecular Weight: 200.07 

Appearance at Ordinary Temperature: clear and colorless liquid 

Stability: The stability test was conducted in our laboratories, and confirmed 

that the test substance was stable during the experimental period (see 

appendix). 

Melting Point: 

Boiling Point: 55°C 

Vapor Pressure: 

Partition Coefficient: 

Solubility: 

- 4 

000548 
Degree of Solubility (measured in our laboratories) 

Water: <0.5% 

DMSO: ~5% 

Acetone: ~5% 

Olive oil: ;;:::5% 

8) Storage Conditions 

Stored in a closed container at the cold and dark place in the test substance storage 

room. 

9) Care on Handling 

Mask, glove, head cap and lab coat were put on. 

10.2 	 Animals 

Crj: CD (SD) rats at 4 weeks old were obtained from Charles River Japan, 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 g for males and 100.1-107.5 g for females. 

10.3 	 Housing Conditions 

The animals were housed in a barrier-system animal room maintained at a stable 

temperature of21-25°C and relative humidity of 45-65% with 10-15 air changes per hour 

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 

diet and housing materials were autoclaved at 121°C for 30 min prior to use. 

Analysis ofthe diet and water was performed and the contaminants were inside the stated 

ranges. 

- 5 	 ­

000549 
10.4 	 DOSING FORMULATION 

I) 	 Vehicle 


Olive oil (Fujisawa-Astra, lot no. 140RKK) 


2) 	 Preparation 

The test substance was mixed with olive oil. The preparation was conducted prior 

to use. 

The stability and homogeneity of the formulations were performed in our 

laboratories. See appendix. 

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. of Animals (Animal No.) 

Group (mg/kg/day) (mUkg) (w/v%) Male Female 

Test substance 2,000 10 20 5( 1 - 5 ) 5 ( I - 5 

Vehicle control 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 of 2,000 mg/kg was chosen for 

the main study. The vehicle control group was 

given olive oil only. 

10.6 	 OBSERVATIONS 

1) 	 Clinical Signs 

Mortality and clinical signs were recorded continuously by I hr after dosing, and 

every ] hr by 6 hr after dosing. From next day of dosing, animals were observed 

twice daiJy. 

6 ­

000550 
2) 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 under ether anesthesia, and subjected to a detailed gross necropsy. 

10.7 	 STATICAL ANALYSIS 


The mean values and standard deviations of the body weights were calculated for males 


and females. 


11. 	 RESULTS 

11.1 	 MORTALITY AND LDso VALUE (TABLE 1) 


No deaths occurred in both sexes. The LOso value was estimated to be more than 2,000 


mglkg for males and females. 


11.2 	 CLINICAL SIGNS (TABLE 2) 

I) Males 

Test substance group: No abnonnalities were noted. 

Vehicle control group: Mucose stool (2/5) was noted from 30 min to I hr after 

dosing. 

2) 	 Females 

Test substance group: No abnonnalities were noted. 

Vehicle control group: Mucose stool (1/5) was noted at 30 min after dosing. 

11.3 	 BODY WEIGHTS (TABLE 3) 

No abnonnalities were noted in body weight changes. 

11.4 	 Nl:<.:RUPSY (TAllLl: 4) 

No abnonnalities were observed. 

12. 	 DISCUSSION 

A single oral toxicity study of. .vas conducted in males and females of SO rats 

at 2,000 and 0 mglkg followed by 14-days observation. 

- 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 the LDso value was estimated more than 2,000 mg/kg for 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 	 0/5 11 

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 


abnorma Iities 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 
Table 3-2 Body weight(g) in female rats after the single .23.2 - 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 

PHYSICOCHEMICAL REPORT 

Head, Analytical Chemistry Unit: 

Signed in original March 22, 1993 

-1- 000559 
Sponsor: 

Testing Facilities: 

Test Substance: 

Tests: 

Date of Test: 

Methods: 

1) Stability of Test Substance 

2) Stability and Homogeneity of Test Substance in Fonnulations 

I) January 13 and February 8, 1993 

2) December 16 and 17, 1992 

I) 	 Stability ofTest Substance 

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 a closed container at the cold and dark place during the test period. 

2) 	 Stability and Homogeneity ofTest Substance in Fonnulations 

Fonnulations were prepared prior to dosing. 

(I) 	Stability Test 

Middle layers of the fonnulation were taken (n=3) just after preparation 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) 	 Homogeneity Test 

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 of fonnu lation and preparation of the 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 

place during the test period. 

-2-	 000560 
Results: I) Stability ofTest Substance 

There were no differences in the IR spectrum patterns between before and after 

dosing (Figs I, 2). The test substance was stable during the test period. 

2) 	 Stability and Homogeneity of Test Substance 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.%) of less than 1%. 

A typical chromatogram and calibration curve are shown in Fig. 3 and Fig. 4, 

respectively. 

Preparation and Pre-treatment of Formulation and Preparation of Standard Solution 

Preparation of Formulation 

The test substance of to g was taken and mixed with olive oil to make 50 mL. This was mixed well 

with a magnetic stirrer. 

Pre-treatment of Formulation 

20 w/v% Formulation 

Accurate 80 JlL of the formulation was added into a heads pace-gas vial with 3 mL of purified 

water, shaken well and incubated in a water bath at 40°C for 10 min. Headspace gas in the vial 

was served for GC sample. 

Preparation of Standard Solution 

Accurate 2.0 g of the test substance was weighed and dissolved with dimethyl sulfoxide to make 10 

mL for the standard solution. Accurate 80 JlL of this 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 ofthe headspace gas was assumed to be the same as that of the standard solution. 

-3-	 000561 

Analytical Conditions and Calculation 

Analytical Conditions 

Instrument: Gas chromatography (GC-9A, SIMADZU) 

Column: 20 m )( 1.2 mm i.d., glassware 

Liquid Phase: G-230 (membrance thickness: I Jlm) 

Tem perature: 40°C 

Eluent: Helium 

Flow Rate: 20 mLimin 

Detector: FlO (hydrogen=air= 0.6 kg/cm2 

) 

Output: xl04 

Temperature: 120°C 

Injection volume: 1 mL 

Recorder: Chromatopack (C-R5A, SIMADZU) 

Output: 64mV 

Under the analytical conditions mentioned above, linearity of detector response was confinned in the 

test substance concentration of 0-234650 Jlg/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 ofthe test substance in standard solution (Jlg/mL) 


As: Peak area ofthe test substance in standard solution 


Ar: Peak area of the test substance in each GC sample 


000562 

Table 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~. 


'-.) 

~ 

c: 

~4 o 

>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.;" 

6 lfil~H f 3!);>I! lr.:;o:, H!(r,! '~l~~ 1I'E

\1S?1 : j'll\IKI ~11~(i~ Ii: ll;1liu.)il

000564 ... ~.-. , ....... ~~,'" 
':..' 

.:;, .; Q C·} 

Q 11> 

G) 

) 

A 

c::: 

0 ~ ...... 

CI:l 

"- >+ ..... 

<I.) 

~:~ c::: 

'V' e 

"0 


." 


Q,) cr,. ..c: <r ...... IlZr.lIHS'!lf lS.rMN "­

Q,) 

...... 

..... 

CI:l 

e 

:::::I 

'­

...... 

u 

Q,) 

0. OJ 'I{I~

<I.) 

Q:: I~: HI"31 311J 00'0 ilel ~ '< o.n H9I11 S9~ ';; '!Ii ~~: 'Sli:I :nU 0'0 llel 

0'001 '''Ilill :\:! c-..t co 0 }lU ll\lll 311lH1~ 0 ¥I.. 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~ 

_...-"'-'-{)OO5G5 
(,I.J 

"'l:5 

.p 

VI 

-'S 

;:;) " 


,.•. / ::; 

C!;l 

1.1... 

...0 

"It' 

r:") 

(,'.1 • 

Fig.3 Typical chromatogram 

- 8 ­

000566 
x 

<=> 

o 

Q) 

en 

o 58662.5 '17325 234650 

Concentration (lI8"/ml) 

fig.4 Calibration curve 

9 

000567 
Submitted to: 

Final Report 

( 

A Simplified Acute Toxicity Study of . 

by Nose-Dnly Inhalation Exposure in Rats 

(Study No.: 

January 7, 1994 

000568 

Translation Statement 

The following 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 

as possible to my knowledge. 

( } Information of the original study 

Sponsor: 

Title: A Simplified Acute Toxicity Study of . 

;y Nose-Dn1y Inhalation Exposure in Rats 

Study No.: 

Information of the translation ~tudy 

Sponsor: 


Study No.: 

Translator: 

000569 

Statement 

Sponsor: 

Title: A Simplified Acute Toxicity Study of 

. by Nose-Only Inhalation Exposure in Rats 

( J 

Study No.: 

This study was conducted in this institute. This final report faithfully reflects the study 

results. 

Management: Signed and Sealed Date: January 7, 1994 

Management 

000570 

Title 

A Simplified Acute Toxicity Study of 


by Nose-Qnly Inhalation Exposure in Rats (Study No.' 


Purpose 

The objective of this study was to examine acute toxic effects of 

by nose-only inhalation using rats. 

Guideline 

( 	 Guideline established by Ministry of Health and Welfare 

(No. I Notification No. 24, 1989) 

Sponsor 

(Name) 


(Address) 


Organization under contract 

Study schedule 

Study initiation August 5, 1993 


Study completion January 7, 1994 


Retention 

The study data will be retained in the archives of the. The retention 

period will be five years after submission of the final report. Further retention will be 

discussed with the sponsor. 

000571 

(Study No.: 

This study was conducted under responsibility of the following contributors. This 

report faithfully reflects the study results. 

Study Director: Signed and Sealed Date: January 7. 1994 

Study Contributors: Signed and Sealed Date: January 7. 1994 

( Signed and Sealed Date: January 7, 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. Testing Method' .................................................... 4 


3.1. 	 Exposure sample preparation ...................................... 4 


3.2. 

Clinical observation ............................................. 6 

Test substance exposure .......................................... 4 


3.3. 

Body weight· .................................................. 6 3.4. 

3.5. Pathological examination' ........................................ 6

Lethal concentration ............................................. 7 3.6. 

3.7. Assessment of the test substance ................................... 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. Pathological examination' ........................................ 9 


4.6. Assessment ofthe test substance ................................... 9 


5. Discussion and Conclusion' .......................................... 10 


6. Reference························································· 11 


Fig. 1 Inhalation Exposure System ...................................... 12 


Fig. 2 Gas Chromatogram ............................................. 13 


Fig.3 Time Course Relative Concentration' ............................... 14 


Fig.4 Body Weight Gain Ratio' ........................................ 16 


Table 1 Test Substance Concentration' ................................... 17 


Table 2 Environmental Condition in the Chamber .......................... 17 


iii 


000573 
Table 3 Clinical Sign ................................................. 18 


Table 4 Body Weight· ................................................ 19 


Table 5 Body Weight Gain' ............................................ 20 


Appendix 1 Individual Clinical Sign' .................................... 21 


Appendix 2 Toxicity Classification 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 by nose-only inhalation 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 

3,000 ppm. 

As a result of the exposure, actual exposure concentrations were 970 ± 10 ppm and 3,010 

± 10 ppm. The achieved concentrations were almost comparable to the target 

concentrations and were temporally stable. 

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 moderate congestion and edema in the lungs in the histopathological 

examination. All these findings were considered non-specific changes. Additionally, 

there were dilatation of atrium, congestion of cerebellum aperture, and a large number of 

grayish patches in the kidney on necropsy, as well as focal inflammatory change in the 

lung in the histopathological 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 

inhalation exposure, the test substance was classified as a "non-toxic substance" . 

1 


000575 

.lSI 


( ) 


2. Materials and Implements 

2.1. Test substance 

(1) Name: 

(2) Chemical formula: 

(3) Molecular weight: 

200.06 

(4) Density: 	 1.4789 glcm3 (23°C) 

(5) Purity: 	 99.9% 

(6) 	 Boiling point: 


56.22°C 


(7) 	 Storage condition: 


In a refrigerator 


(8) 	 Stability: The lot used in this study was confirmed to be stable by an analysis 

conducted by the sponsor. 

2.2. Experimental animals 

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. The rats were 

five weeks old and body weight ranged from 146 to 173 g that was within ±20% of the 

average weight on the day of exposure. 

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 

of the test substance etc. 

2.3. Animal husbandry 

2.3.1. Environmental condition 

This study used an animal room maintained at temperature of 20° to 25°C, relative 

humidity of 40% to 70%, and air ventilation of approximately 12 times per hour (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 (7:00 to 19:00). 

2.3.2. Animal accommodations 

The animals in this study were housed at one or two 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 quarantine period (excluding exposure). A filter cap with 

clear resin (Tokiwa Kagaku Kikai Co., Ltd.) on its front and back sides was mounted on 

the cage from the day of exposure. 

The filter caps were changed bi-weekly, and other equipments were changed weekly. 

All accommodations used 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 study was analyzed by a third party. Accordingly, it was confrrmed that 

the contaminants were under the permissible range in the standard operating procedure of 

this laboratory. 

2.3.4. Water supply 

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, water supply was stopped during exposure. The water was 

analyzed periodically and the analytical value was confirmed to be within the range of 

the ordinance No.56 of the Ministry of Health and Welfare. 

3 

3. Testing Method 

3.1. Exposure sample preparation 


The test substance supplied by the sponsor was used in this study as is. 


3.2. Test substance exposure 

3.2.1. Exposure concentration settings 

A preliminary study was conducted using three males that were exposed to an average 

concentration of 8,700 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 570 ppm) 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. Exposure condition 

Fig. 1 shows the inhalation exposure system. 

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 of animals to be open, and were 

set on the outer cylinder wall of the 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 

conducted once for four hours. 

3.2.3. Gas generation and exposure method 

The test substance gas was generated by a bubbling method that was directly blows 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 a cylinder maintained 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 mixing jar. After that, the mixed gas was supplied to the chamber 

4 

000578 
after 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 mixing jar. 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 that of the outside. 

The exposure initiation was designated at the point of setting animal to the chamber after 

the gas concentration inside the chamber achieved equilibrium. 

3.2.4. Exposure concentration measurement 

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 mL collected with an airtight type glass syringe was used as the analytical 

sample. 

(2) GC operating condition 

GC: Shimadzu GC-9AM (Detector: FID) 

Column: G-300, 1 J.l.m film thickness, 40 m length, 1.2 mm inner diameter (Chemicals 

Inspection & Testing Institute) 

Carrier gas: He 20 mUmin, H2: 0.5 kg/cm2

, Air: 0.5 kg/cm2 

Temperature: COL. 40°C, INJ. and DET. 70°C 

Fig. 2 shows chromatogram obtained under the condition described above. 

(3) Calibration curve 

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. The obtained peak 

area and standard solution concentration (ppm) made the calibration curve. 

5 

000579 
( 


(4) Test substance concentration in the air 


The analytical sample was analyzed under the GC condition described above, then, the 


test substance concentration (ppm) in the air was calculated from the obtained peak: area. 


3.2.5. Environmental condition in the inhalation chamber measurement 

The following items were measured at the commencement of exposure and one hour 


intervals. 


(1) Temperature and relative humidity; Toyama type thermo-hygrometer (Toyama Keiki 


Co., Ltd.) 


(2) Oxygen concentration; Oxygen meter (Galvanic cell type) 

3.3. Clinical observation 

The animals were observed with respect to their mortality, appearance, and behavior 

from the start of exposure 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, the observation during exposure was conducted as much 

as possible. 

3.4. Body weight 

All surviving animals were weighed for their body weight at immediately before 

exposure and 3, 7 and 14 days after exposure (the day of exposure was designated as 0 

day) with a balance (EB-5000, Shimadzu Corp.). However, the animals that died during 

exposure were not weighed. 

3.5. Pathological examination 

(1) Necropsy 

The surviving animals after termination of observation on 14 days after exposure were 

subjected to necropsy after euthanasia by severing the abdominal aorta exsanguination 

under intraperitoneal thiopental sodium anesthesia (Ravonal®, Tanabe Seiyaku Co., Ltd.). 

The dead animals were also subjected to necropsy as soon as they were found dead. 

(2) Organ preservation 

The major organs (heart, lung, liver, kidney, spleen, and nasal cavity) were fixed by a 

6 

000580 
( ) 


10% phosphate buffered formalin and preserved. 

(3) Histopathological examination 

The lung of representative two animals (animal number 3 of each 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 

staining with hematoxylin and eosin in accordance with the ordinary method. 

3.6. Lethal concentration 

Median lethal concentration and minimum lethal concentration were estimated from the 

mortality at the end of the observation period and exposure concentration. 

3.7. Assessment of the test substance 

The toxicity of the test substance was classified in accordance with "the approximation 

of the laws, regulations and administrative provisions relating to the classification, 

packaging and labeling of dangerous substances, EEC Council Directive". Appendix 2 

shows the classification criteria. 

7 

000581. 
( ) 


4. Results 

4.1. Exposure 

4.1.1. Exposure concentration 

Table 1 shows the test substance concentrations in the air and Fig. 3 shows the time 

course relative 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. 

Concentration variability was within 5% for the average concentration. Consequently, it 

was confirmed that the concentration was well controlled. The relative concentration 

also revealed stable gas generation. 

4.1.2. Environmental condition in the chamber 


Table 2 shows environmental condition in the chamber during exposure. 


Temperature was 24°C and relative humidity ranged from 60% to 64%. Oxygen 

concentration ranged from 20.7% to 21.0%. 

4.2. Dead animal 

Two animals out of five of the 3,010 ppm group died at one hour after commencement of 

exposure. 

4.3. Clinical sign 

Table 3 and Appendix 1 show clinical observation results. 

Accurate observation was not performed during exposure due to animal restraint. There 

were struggling and increased urine volume in the 3,010 ppm group during exposure. 

Additionally, the observation performed at immediately after exposure revealed systemic 

fur soiled by urine. These findings disappeared by one hour after the exposure, and 

thereafter, there were no abnormalities by the termination of observation. 

4.4. Body weight 

Table 4 shows body weight and Table 5 shows body weight gain. Fig. 4 shows body 

weight gain ratio. 

The surviving animals had normal body weight gain by the termination of observation. 

8 

000582 
( J 


4.5. Pathological examination 

(1) Necropsy 

Dead animals revealed reddish lung, dilatation of atrium, and congestion of cerebellum 

aperture. In the surviving animals, one animal of the 970 ppm group indicated large 

number of grayish patches in the kidney. Other surviving animals did not indicate any 

abnormalities. 

(2) Histopathological examination 

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 

of one animal (animal number 2).in the 970 ppm group. 

4.6. Assessment of the test substance 

Two animals died at exposure concentration of 24.8 mglL (3,010 ppm). However, there 

were no dead animals at exposure concentration of 8.0 mgIL (970 ppm). From the 

above results, classification of the test substance toxicity based on LCso value was not 

clear in detail, however, the test substance was classified as a "non-toxic substance" in 

accordance with the toxicity criteria in Appendix 2. 

9 

000583 
( 


5. Discussion and Conclusion 

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 

concluded that oxygen concentration did not influence the animals!. From these results, 

it is concluded that the exposure condition was appropriate. 

Two animals out of five of the 3,010 ppm group died due to the test substance exposure 

at one hour after commencement of exposure. 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 of the preliminary 

study. In clinical observation, there were increased urine volume that was considered 

to be effected by the test substance exposure in the 970 and 3,010 ppm groups. In these 

groups, animals also indicated systemic soiled fur caused by increased urine volume. 

Additionally, the animals of the 3,010 group revealed struggling. The body weight of 

surviving animals increased normally by the termination of observation period. 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 

grayish patches in necropsy. Since focal inflammatory change in the lung was observed 

in partial lung in a spotted state, it is concluded that this change is 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 3,010 ppm under the condition of the present study. In regard to 

the acute toxicity by nose-only inhalation exposure, the test substance was classified as a 

"non-toxic substance". 

10 

000584 
6. Reference 

(1) 	 Araki S, Numata M, Wada I, editors. Environmental Sciences Dictionary, Tokyo: 


Tokyo Kagaku Dojin; 1985. p. 299-300 


( 

11 


000585 
-, 


Primaly dilution flow meter

Pressure gauge 

MFC 

Pressure gauge 

MFC 

MFC, Mass-flow controller 


HCM, Hydrocarbon meter 


Recorder I I HCM 

Activate carbon for exhaust 

o 

o Secondary exhaust pump CIt 

~ Primary exhaust pump (,1) 

- Gas generation flow meter 

- -

, 

Buffer tank 

Constant temperature bath 

Exhaust flow meter 

Flow meter . 

Pressure gauge 

I-----~ 

Gas sampling port 

f 

Mixing jar 

• 

Animal holder 

- Manometer \l 

-

~ 

• 

Pressure gauge 

MFC 


Secondaly dilution flow meter 

-

Fig. 1 Inhalation Exposure System 


c 
~ Ethyl acetate 

( I 


o. 

lIff) 

CL. 

1:=1 

Il...... 

Fig. 2 Gas Chromatogram 

000587 
-; 


100 


QB 1
 & 

!. 

o 

,.-= 

~ 

'-" 

50 


o 

o 

o 

o 

CIl 

fXj 

fXj 

I 'UI!I ~ . .1. .. II 2 · II' ; i I' ~I! ! I' I
 I I' i I I: : i
 I 
 ! "I i I :: : 
 I
 i 
 I .. '1':'1 8·~- ----~-. I

I 


.. . 1·1 ! i I I; : 
 I 
 U 1
 1I 
• I I; i ~I-' ___1__._. I .-.-.1---... -1.-.. -... -.-.----.81. ; ! '--'-_.-. 


~I, 
 'r"'; +.... c-'. .. _~_.__.t_._._. ___._._.ll I .
 ... . - . I I I'! ;. 
 II' ;' I ----'. '--'---\r--j-So, I i
 I : 
 I , 'I' ...... EXPO~Uretermiriation:;;. ." L'~' .' . TIl - i.-·Res~oo~:ettochamb·er 1 I 

.... , .... - "1' ._., ·t· 

I 

. . --..,. '" ,._.. _-. . . 

I 

... . I . 

r.... j"" ':' .. I : ~ 

-~. -~//. 

I I 1 n I I : I :
 I" r-'\ .---­ 0 . 

.... ···..· . .J. II Ii' I I ····· ~! ..'1' ::. ~'.' ..... : ,., - .! . 'o'! : ....... n - ~-"--'T'--I') I --;:;;::;;:"'rI' . I I I I" : .
 LL I I' t" I i ~... '; --'" 
 .~ .- '- __L-_ -- _ ..0 i I : 
 . I I .. , " . 


"-r~-2-I''--- . . I ~_J -<> I ; 


, 'I r -I I 

1 

. ~- ........._-. ..... . I. ......... _. L. ...___...t.. __._... J... I I ~ f I;: . -:-y--­J 


I 


4 3 o N


2 1 


Time ~ Fig. 3-1 Time Course Relative Concentraion (1,000 ppm) 
-


100 


(') 

o

::s 

"'t 

~ a 

o· 

::s

-
~ '-' 

50 


o 

c 

c 

o 

C/l

00 

c.D 

! ---j- i:1 , 

; 'I ; 

• 

i . . I 

.. 

__J 

: 

.I 

_____________ ., 

I I I L

Exposure, termination 'r-L +-----'-______>-___'-~ 

1---. --___I__l __ 1'\ 


I 
 I·i i Restr~ed animaJ set to chamber 


,I .__..._+_._... __..__:__ ..___.. I I : 


; , • ! ~ I ..! i j -·1 r .i
 l I
 Iii , I
 ; 1'--1----1 - 2- I : ;.- I 1 ' 


! -. . ! I I' /\ ,........... 1 1 


i ". I .- -- . . r'. I . i . " ":, ..:..... I 


.---, l\ _. I' J 
 ..... I Ii! '''', ·.I!I 


I ~,.I ; .. '--. '-- -".,-_'- "j, •• L-..O••,; L .'i .•L m ....... _. J On i _= ._~ ! . 


I 


4 3 
 2 1 o 
 ~ 

~ Time ~ 

"~+--r I! I e I -L I i
! • tl • I 


i I (j): • -; : 
 t • '. i 
 f : • i ; I Ii: ! ; j I 

I
 I I : : . ~ 1 '. 


t 

I 10;; 'i 


I: ...... _... j ii' ,

.~ __. -o--__L____.....L__,.._ _._ i
 I to 

Ii' 

I i \ I
 ,

1 I 

I 


Ii" ! I I :


---+-...-.+----1.-----.,--,2.-'---r--- -···..T-.. ·. --'-r" '-+--1'---' 1 


I j I 


~-! I I I !._ 


Fig. 3-2 Time Course Relative Concentraion (3,000 ppm) 

to 

0 

0­

'< 

~ 

~. 

OQ 

t:r 

..... 

( OQ

S· 

'"1 

~. 0 

-. 

~ '-' 

100 

50 

0 

• : lOOOppm 

6. : 3000ppm 

-50 L.-_.l..-----L----­

o ~ 7 14 

Days after exposure 

Fig. 4 Body Weight Gain Ratio 


OU0590 

Table 1 The test substance concentration 

Time course test substance concentration 

. Target concentration 

(ppm) Time after commencement of exposure (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 


Table 2 Environmental Condition in the Chamber 

( } 

Target concentration 

(ppm) 

Items (unit) 

Temperature CC) 

Time after commencement of exposure (he) 

0 1 2 3 4 ' 

24 24 24 24 24 

1. 000 Relative humidity 

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 (%) 60 60 60 60 60 

Oxygen conc (%) 20.9 20.9 20.8 20.9 20.7 

o : Immediately after commencement of exposure 

000591 

Table 3 Clinical Sign 

Time after commencement After exposure 

Target concentration . 

(p p m) Finding') 

of exposure (hr) Time (hr) Day

----­ 1 2 1"'" 14 

Increased in urine 5 

1.000 Soiled fur 5 

No abnormalities 5 ---4~5 5 -------+·5 

Death 2 

&ruggling 533 

3,000 Increased in urine 3 3 

Soiled fur 3 

No abnormalities 3 -------+·3 ( 

0, Immediately after commencement of exposure *, immediately after exposure 

000592 

Table 4 Body Weight (g) :;'8' 

Days after exposure Target concentration 

Animal No. (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 

1 171 D(Od~) 

2 173 203 244 315 

( -' 3 173 D(Od.) 

3.000 

4 . 155 181 217 280 

5 161 179 208 263 

Mean 167 188 223 286 

S. D. 8 13 19 27 

D: Death 

( ): Day after exposure 

000593 

Table 5 Body Weight Gain (g) 

Days after exposure .2'~ Target concentration 

(ppm) Animal No. 3 1 14 

1 22 40 68 

2 23 32 63 

1.000 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 2 30 41 71 

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 after exposure 

/

• 

000594 

Appendix 1 Individual Clinical Sign 

Time after commencement After exposure 


Target concentration of exposure (hr) 
 Time (hr) Day (ppm) 	 Findings Anima1No 0 1 2 3 4­ 1 2 1 -- 14 

1 Increased in urine 

Soiled fur 

0 

0 

2 Increased in urine 

Soiled fue 

0 

0 

1.000 3 Increased in urine 

Soiled fur 

0 

0 

" . 

4 Increased in urine 

Soiled fur 

0 

0 

( } 

5 

1 

Increased in urine 

Soiled fur 

Death 0 

0 

0 

Struggling 0 

2 Struggling 

Increased in urine 

Soiled fur 

0 0 0 

0 0 

0 

3.000 3 Death 0 

Struggling 0 

4 Struggling 0 0 0 

Increased in urine 0 0 

Soiled fur 0 • • 

5 Struggling 0 0 0 

Increased in urine 0 .0 

Soiled fur 0 

0: 	Finding present .: Finding absent 

a,Immediately after commencement of exposure *, immediately after exposure 

Appendix 2 Toxicity Classification Criteria 

Category LC50 Inhalation Rat (mglLl4hr) 

Very toxic < 0.5

Toxic 0.5 -- 2.0 

Harmful 2.0 -- 20 

000595 

:1.'71 


FINAL REPORT 


Partition Coefficient (I-OctanoVWater) Study of 

April 4, 2001 

000596