B11-0732 

p. 1 

If the variances were not homogeneous, the Kruskal-Wallis's test was used. If 

there was a significant difference in this analysis, the difference between the 

vehicle control group and each of the treatment group was analyzed by the 

nonparametric Dunnett's test . 

FACTORS THAT MIGHT HAVE AFFECTED THE STUDY 

1) There were no unforeseeable circumstances that might have affected the 

reliability of the study . 

2) Deviations from the protocol. 

Concerning the frequency of replacing the housing apparatus and materials in 

the housing environment, although it was prescribed in the protocol that trays 

would be replaced twice weekly after the group allocation, they were replaced 

daily from day 6 to day 2 (recovery) since soft stool was observed on day 6 of 

the dosing period. 

The above-mentioned deviation from the protocol was considered to have no 

effects on the results of the study. 

3) There were no environmental factors that might have affected the reliability of 

the study results . 

RESULTS 

1 . CLINICAL SIGNS (TABLE 1, ADDENDUM 1) 

l .l During Dosing Period 

Males: Salivation (9/12), soft stool (9/12) and diarrhea (6/12) were observed in 

the 1,000 mg/kg group . 

Conditions of the Occurrence of Salivation 

Salivation was sporadically or continuously observed only immediately 

after dosing from day 6 to day 28. 

Conditions of the Occurrence of Soft Stool 

Soft stool was separately or sporadically observed from day 6 to day 28 . 

Conditions of the Occurrence of Diarrhea 

Diarrhea was separately or sporadically observed from day I') to day 2-l . 

00010i 
Females : Salivation (8/12), soft stool (9/12), diarrhea (4/12) and mucous stool 

(1/12) were observed in the 1,000 mg/kg group. Loss of hair (1/6) was 

also observed in the 40 mg/kg group. 

Conditions of the Occurrence of Salivation 

Salivation was sporadically or almost continuously observed only 

immediately after dosing from day 7 to day 28 . 

Conditions of the Occurrence of Soft Stool 

Soft stool was separately or sporadically observed from day 8 to day 28. 

Conditions of the Occurrence of Diarrhea 

Diarrhea was separately or sporadically observed from day 9 to day 24. 

Conditions of the Occurrence of Mucous Stools 

Mucous stool was observed only on day 23 . 

1 .2 During Recovery Period 

No abnormalities were observed in either males or females . 

2. BODY WEIGHTS (FIG. 1, TABLE 2, ADDENDUM 2) 

2.1 During Dosing Period 

No abnormalities were observed in either males or females. 

2 .2 During Recovery Period 

Males : No abnormalities were observed. 

Females: High value was observed in the 1 .000 mg/kg group on day 1 (recovery). 

3 . FOOD lNTAKES (FIG.2, :'ABLE 3, ADDENDUM 3) 

3 .1 During Dosing Period 

No abnormalities were observed in either males or females. 

3 .2 During Recovery Period 

No abnormalities were observed in either males or females . 

4. HEMATOLOGICAL EXAMINATIONS (TABLE 4, ADDENDUM 4) 

4.1 At Termination of Dosing Period 

Males : Prolonged APTT was observed in the 40 mg/kg group. 

Females : No abnormalities were observed. 

r ~ 1j :r-~ r-~ 000102 

- 13 - 
4 .2 At Termination of Recovery Period 

No abnormalities were observed in either males or females . 

5 . BLOOD CHEMICAL EXAMINATIONS (TABLE 5, ADDENDUM 5) 

5 .1 At Termination of Dosing Period 

Males: Decreased y-GTP in the 40 mg/kg group and increased cholinesterase in 

the 40 and 1,000 mg/kg groups were observed. 

Females: Increased glucose in the 40 and 200 mg/kg groups and decreased total 

bilirubin in the 40 and 1,000 mg/kg groups were observed. 

5 .2 At Termination of Recovery Period 

No abnormalities were observed in either males or females. 

6 . URINALYSES (TABLE 6, ADDENDUM 6) 

6 .1 At Termination of Dosing Period 

No abnormalities were observed in either males or females. 

6.2 At Termination of Recovery Period 

No abnormalities were observed in either males or females. 

7. ORGAN WEIGHTS (TABLES 7, 8, ADDENDA 7,8) 

7.1 At Termination of Dosing Period 

No abnormalities were observed in either males or females . 

7.2. At T;rmination of Recovery Period 

Males: No abnormalities were observed. 

Females : Decreased absolute and relative weights of adrenal glands were 

observed in the 1,000 mg/kg group. 

8. NECROPSY (TABLE 9, ADDENDUM 9) 

8 .1 At Termination of Dosing Period 

Males: Blackish region of the mucosa in the glandular stomach (1/6) was 

observed in the 1,000 mg/kg group. Whitish region was also observed 

in the liver (1/6) in the 200 mg/kg group . 

Females: Loss of hair (1/6) was observed in the 40 mg/kg group. 

8.2 At Termination of Recovery Period 

No abnormalities were observed in either males or females. 000103 

- 14 - ~ ; .~, 
B11-0r3l 

9. 

9.1 

HISTOPATHOLOGICAL EXAMINATIONS (TABLE 10, ADDENDUM 9) 

At Termination of Dosing Period 

Males: Necrosis of the fundic mucosa in the glandular stomach (+, 1/6) was 

observed in the 1,000 mg/kg group. Focal necrosis of hepatocytes (++, 

1/1) was also observed in the 200 mg/kg group. 

Females: Microgranuloma in the liver (+, 1/6) was observed in the vehicle control 

group . 

9 .2 At Termination of Recovery Period 

No abnormalities were observed in either males or females . 

DISCUSSION 

-Vas orally administered by gavage to Crj : CD (SD) IGS rats at doses of 1,000, 

200 and 40 mg/kg/day to perform a 28-day toxicity study followed by a 14-day recovery 

study . 

In the present study, neither deaths nor any adverse effects of the treatment with the test 

substance were observed in the body weight or food intakes during the dosing period or 

in the hematology, urinalysis or organ weights at completion of the dosing period . 

Concerning the general condition, soft stool and diarrhea were observed in males and 

females and mucous stool in females in the 1,000 mg/kg groups, and these signs were 

attributable to the effects of the test substance on the gastrointestinai tract. Salivation in 

males and females in the 1,000 mg/kg group was transiently observed only immediately 

after dosing and was considered to be of little toxicological significance . 

Concerning the blood chemistry, increased cholinesterase was observed in males and 

decreased total bilirubin in females in the 40 and 1,000 mg/kg groups . However, since 

no dose-dependency was observed in either change, and since these changes were also 

within the histological control data of our laboratory 1), these were considered to be 

accidental changes. 

In the necropsy, blackish region of the mucosa in the glandular stomach was observed in 

males in the 1,000 mg/kg group, and necrosis of the fundic mucosa was observed in 

- 15 - 

-t !~3093 oooi04 
B11-~752 

accord with lesion site in the histopathology . However, this finding was observed only 

in one animal and this lesion is sporadically observed as a spontaneous lesion, it was 

considered to have no relation to the treatment with the test substance. 

Other changes observed at completion of the dosing period besides the above-mentioned 

ones were sporadic and showed no dose-dependency, and they were considered to be 

accidental changes. 

The changes in the appearance of stool observed during the dosing period were not 

observed in the recovery study. Although new changes in some test items were 

sporadically observed only in the recovery study, they were considered to be accidental 

changes since they were not observed at completion of the dosing period and no related 

changes were observed either . 

The above-mentioned results showed that I ]exerted effects on the gastrointestinal 

tract, but the effects were not observed in the recovery study . The NOEL of I I in 

rats under the present study conditions is estimated to be 200 mg/kg/day since soft stool 

and diarrhea were observed in males and females and mucous stool in females in the 

1,000 mg/kg groups . 

1) Historical control data at the termination of the dosing period : vehicle/distilled water 

(including 0.5 w/v% CMC-Na aqueous solution) 

Item Sex n Minimum - maximum 

Cholinesterase (IU/L) Male 227 28-80 

Total bilirubin (mg/dL) Female 222 0.06-0 .18 

l ~'~~1®® Q0010S 
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000109 
IA-1 IA732 

Table I Twenty-eight-day repeated-dose oral toxicity study in rats 

Summary of cl inical signs - - 

Sex Signs Administration Period Recovery Period 

mg/kg/day VC VC 40 200 1,000 1,000 VC 1,000 

(R) (R) 

Male ta ta ta ta ta ta ta ta 

6') 6 6 6 6 6 6 6 

No abnormalities detected 6 6 6 6 1 6 6 

Salivation 

Soft stool 

Diarrhea 

4 

5 4 

4 2 

Female ta ta ta ta ta ta ta ta 

6') 6 6 6 6 6 6 6 

No abnormalities detected 6 6 5 6 2 6 6 

Salivation 

Soft stool 

Diarrhea 

Mucous stool 

Loss of hair 1 

4 4 

6 3 

3 1 

a) Number of animals examined . 

VC, Vehicle control ; (R), Recovery . 

ta, terminal autopsy. 
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Addendum 1-1 Twenty-eight-day repeated-dose oral toxicity study in rats 

Clinical signs of individual animals 

Vehicle control 

Administration Recovery 

Si gns Sex 1 2 3 4 1 2 (week) 

1,2,3,4,') 1,2,3,4, 1,2,3,4, 1,2,3,4, 

No abnorrnalities detected Male 5,6,7,8, 5,6,7,8, 5,6,7,8, 5,6,7,8, 7,8,9,10, 7,8,9,10, 

9,10,11, 9,10,11, 9,10,11, 9,10,11, 11,12 11,12 

12 12 12 12 

37,38,39, 3 7,38,39, 37,38,39, 37,38,39, 

Female 

40,41,42, 40,41,42, 40,41,42, 40,41,42, 43,44,45, 43,44,45, 

43,44,45, 43,44,45, 43,44,45, 43,44,45, 46,47,48 46,47,48 

__ 46.4 7.48 46.47 .48 46.47 .48 46,47.48 

a) Animal number . 
pB A60732 

Addendum I-2 Twenty-eight-day repeated-dose oral toxicity study in rats 

Clinical signs of individual animals 

40 mg/kg/day 

Sex 

No abnormalities detected Male 

Female 

Loss of hair (forelimb) Male 

Female 

I 

Administration Recovery 

2 3 4 1 2 

13,14,15," 13,14,15, 13,14,15, 13,14,15, 

16,17 .18 16,17,18 _L6,17,18 16,17,18 

49,50,51, 49,50,51, 49,50,51, 49,50,51, 

52,53,54 52,53,54 52,53 52,53 

54 54 

(week) 

a) Animal number. 
~~1 ?70732 

Addendum 1-3 Twenty-eight-day repeated-dose oral toxicity study in rats 

Clinical signs of individual animals 

200 mg/kg/day 

Administration Recovery 

SiQns Sex f 2 3 4 f 2 (week) 

No abnormalities detected Male 19,20,21,'~ 19,2Q21, I9,20,21, 19,20,21, 

22,23 .24 22,23,24 22,23,24 22,23,24 

Female 55,56,57, 55,56,57, 55,56,57, 55,56,57, 

58 59 60 58 59 6 0 58,59,60 58,59,60 

a) Animal number 

" 00012'7 
01 rD732 

Addendum 1-4 Twenty-eight-day repeated-dose oral toxicity study in rats 

Clinical signs of individual animals 

1,000 mg/kg/day 

Administration Recovery 

Sins Sex 1 2 _ 3 4 1 2 

- 25,26,27,a) 27,31,32, 31,32,33, 31,32,33, 

No abnormalities detected Male 31,32,35, 31,32,36 27,31 36 34,35,36 34,35,36 

Salivation 

36 

61,63,64, 

Female 65,66,67, 66,69,70 69,70,72 

63,66,69, 67,68,69, 67,68,69, 

68,69,70, 70,72 70,71,72 70,71,72 

71 .72 

28 

25,26,28, 25,26,28, 25,26,28, 

Male '3~'33' 

29,30,33, 29,30,33, 29,30,33, 

34 34.35,36 34,35 

62,64,65, 61,62,64, 61,62,64, 

Female 62 67,68,71, 65,67,68, 65,67,68, 

72 71 71 

Soft stool Male 

Female 

29,34 27,30,35 

26,28,29, 26,28,29, 

32,33,34 33 

61,62,63, 61,62,63, 62,64,65, 

72 66,68 67,68 

27 

28,29,30, 

28,33 33,34 

Diarrhea Male 

Female 61,62 61,66 67 

Mucous stool Male 

Female 67 

(week) 

a) Animal number. 
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p. 49 

B 11-0732 

Addendum 9-1 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals 

Sex Exp.group 

Animal No. Fate Macroscopic findings Histopathological findings a) 

Male Vehicle control 

1 ta No abnormalities detected No abnormalities detected 

------------=------ . . .----------------------------- . . .-------------------------------------- . . . . . . .-- 

ta No abnormalities detected No abnormalities detected 

-----------------------------------------------------------------------------------------------------

3 ta No abnormalities detected No abnormalities detected 

--------------------------------------- " -----

. . .----------------------------------------------------- 4 ta No abnormalities detected No abnormalities detected ..-------------------------------------------------- . . . .--------------------------- . . .-------- . . .---- 

5 ta No abnormalities detected No abnormalities detected 

----------------------------------------------------------------------------------------------------- 6 ta No abnormalities detected No abnormalities detected 

a) Organs/tissues examined as follows: forestomach, glandular stomach, duodenum, jejunum, ileum, cecum, colon, rectum, 

liver, heart, kidneys, spleen and adrenals . 

ta, terminal autopsy. 
p. 50 

B 11-0732 

Addendum 9-2 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals - - - 

Sex Exp.group No al Fate Macroscopic findings Histopathological fmdingsa~ 

7 ta No abnormalities detected No abnormalities detected 

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

8 ta No abnormalities detected No abnormalities detected 

---------------------------------------------------------

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

Male 

Vehicle control 9 ta No abnormalities detected No abnormalities detected 

------------ . . .------------------------------------. . . .------------------------ . . . . . . . . .------------- (Recovery group) 10 ta No abnormalities detected No abnormalities detected 

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

11 ta No abnormalities detected No abnormalities detected 

------------------------------------------------------------------------------- . . . . .----------------- 12 ta No abnormalities detected No abnormalities detected 

a) Organs/tissues examined as follows: glandular stomach . 

ta, terminal autopsy. 
BPI-"32 

Addendum 9-3 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals 

Sex Exp.group Animal 

- _ /a ,. .,~ Fate Macrosco pic findings Histopathological findings 

(m No. 

13 ta No abnormalities detected Not examined 

----------------------------------------------------------------------------------------------------- 

Male 40 

14 ta' No abnormalities detected Not examined 

----------------------------------------------------------------------------------------------------- 

15 ta No abnormalities detected Not examined 

----------------------------------------------------------------------------------------------------- 

16 ta No abnormalities detected Not examined 

----------------------------------------------------------------------------------------------------- 

17 ta No abnormalities detected Not examined 

----------------------------------------------------------------------------------------------------- 

18 ta No abnormalities detected Not examined 

ta, terminal autopsy. 
ER-1!R32 

Addendum 9-4 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals 

Sex Exp~a oup Animal 

- 

Fate Macroscopic findings Histopathological findings') 

(

m day) _ No. 

Male 200 

19 ta No abnormalities detected No abnormalities detected 

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

20 ta No abnormalities detected No abnormalities detected 

----------------------------- .. . .-------------------------- . . . .-------------------- . . .--------------- 21 ta No abnormalities detected No abnormalities detected 

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

22 ta Liver Liver 

Whitish region (quadrate lobe, Focal necrosis of hepatocytes ++ 

linear, 5 mm) 

------------------------------ . . . . . .------------------------------------------------------------ 23 ta No abnormalities detected No abnormalities detected 

------------------------------------------------------------------------------------------------

24 ta No abnormalities detected No abnormalities detected 

a) Organs/tissues examined as follows: glandular stomach and macroscopic lesion . 

ta, terminal autopsy. 

++, moderate . 
p. 53 

B11-0732 

Addendum 9-5 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals 

Exp.group Animal 

Sex o da No. 

Fate Macroscopic findings Histopathological fmdings') 

(m_.~~ Y) -_ 

Male 1,000 

25 ta No abnormalities detected No abnormalities detected - . . . . .-------- . . . .--------------------------------------- . . . .----- . . . . .------------. . . . . . . .---------- 

26 ta No abnormalities detected No abnormalities detected 

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

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

27 ta No abnormalities detected No abnormalities detected 

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

28 ta Glandular stomach Glandular stomach 

Blackish region of mucosa Necrosis of fundic mucosa + 

(2 regions, linear, 3 mm, 2 mm) -------,---------

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

29 ta No abnormalities detected No abnormalities detected . . . . . . .------------------------------------------------------------------ . .-------------------------- 

30 ta No abnormalities detected No abnormalities detected 

a) Organs/tissues examined as follows: forestomach, glandular stomach, duodenum, jejunum, ileum, cecurn, colon, rectum, 

liver, heart, kidneys, spleen and adrenals . 

ta, terminal autopsy. 

+, slight . 
p. 54 

B 11-0732 

Addendum 9-6 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals 

Sex Exp~group Animal Fate Macroscopic findings Histopathological findings') (melk da ) No. 

-- -- ------ --- - ---- -- 

31 ta No abnormalities detected No abnormalities detected 

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

32 ta No abnormalities detected No abnormalities detected 

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

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

Male 

1,000 33 ta No abnormalities detected No abnormalities detected 

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

(Recovery group) 34 ta No abnormalities detected No abnormalities detected 

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

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

35 ta No abnormalities detected No abnormalities detected 

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

36 ta No abnormalities detected No abnormalities detected 

a) Organs/tissues examined as follows: glandular stomach. 

ta, terminal autopsy. 
p. 55 

B11-0732 

Addendum 9-7 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological fi ndings of indi vidual animals - -- 

Sex Exp.group No . Fate Macroscopic findings Histopathological findings') Animal 

37 ta No abnormalities detected No abnormalities detected 

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

38 ta No abnormalities detected No abnormalities detected 

----------------------------------------------------------------------------------------------------- 

39 ta No abnormalities detected No abnormalities detected 

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

Female Vehicle control 40 ta No abnormalities detected No abnormalities detected 

-----------------------------------------

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

41 ta No abnormalities detected No abnormalities detected 

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

42 ta No abnormalities detected Liver 

Microgranuloma + 

a) Organs/tissues examined as follows: forestomach, glandular stomach, duodenum, jejunum, ileum, cecum, colon, rectum, 

liver, heart, kidneys, spleen and adrenals . 

ta, terminal autopsy. 

+, slight . 
p. 56 

B 11-0732 

Addendum 9-8 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findin gs of individual animals 

Sex Exp.group 

Animal No. Fate Macroscopic findings Histopathological findingsa~ 

43 ta No abnormalities detected No abnormalities detected 

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

44 ta No abnormalities detected No abnormalities detected 

----------------------------------------------------------------------------------------------------- 

Female Vehicle control 45 ta No abnormalities detected No abnormalities detected 

----------------------------------- . . .. . . ..---------------------------------------------------------- (Recovery group) 46 ta No abnormalities detected No abnormalities detected 

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

47 ta No abnormalities detected No abnormalities detected 

. . .

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

48 ta No abnormalities detected No abnormalities detected 

a) organs/tissues examined as follows: adrenals . 

ta, terminal autopsy. 

"00, 1 ! -11 " 000156 
p. 57 

B11-0732 

Addendum 9-9 Twenty-eight-day repeated-dose oral toxicity study in rats 

-- -- Pathologic al findings of individual animals 

Sex Exp.group Animal Fate Macroscopic findings Histopathological findings') (mg/kg/day) -- No. 

49 ta No abnormalities detected Not examined 

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

50 ta No abnormalities detected Not examined 

-------------------------------------------------

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

51 ta No abnormalities detected Not examined 

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

Female 40 52 ta No abnormalities detected Not examined 

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

53 ta No abnormalities detected Not examined 

----------------------------------------------------------------------------------------------------- 

54 ta Skin Skin 

Loss of hair (forelimbs) No abnormalities detected 

a) Organs/tissues examined as follows: macroscopic lesion, 

ta, terminal autopsy. 

000157 
p. 58 

B11-0732 

Addendum 9-10 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological fmdings of individual animals 

Sex Exp .group Animal 

Fate Macroscopic findings Histopathological findings 

(mg/kg/day) No. 

Female 200 

ta, terminal autopsy . 

55 ta No abnormalities detected Not examined 

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

56 ta No abnormalities detected Not examined 

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

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

57 ta No abnormalities detected Not examined 

---------

. . .---------------------- .- . .- . . . ._ . . . .----------------------------------------------------- 

58 ta No abnormalities detected Not examined 

---------

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

59 ta No abnormalities detected Not examined 

---------------------- ._ . . .-------------------------------------------------------------------------- 

60 ta No abnormalities detected Not examined 

00015S 
p. 59 

BI1-0732 

Addendum 9-11 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals 

Sex 

Exp.group Animal Fate Macroscopic findings Histopathological findings') 

(melk da ) No. 

Female 1,000 

61 ta No abnormalities detected No abnormalities detected 

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

62 ta No abnormalities detected No abnormalities detected 

-------------------------------------------------

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

63 ta No abnormalities detected No abnormalities detected 

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

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

64 ta No abnormalities detected No abnormalities detected 

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

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

65 ta No abnormalities detected No abnormalities detected 

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

. . . .-- 

66 ta No abnormalities detected No abnormalities detected 

a) Organs/tissues examined as follows: forestomach, glandular stomach, duodenum, jejunum, ileum, cecum, colon, rectum, 

liver, heart, kidneys, spleen and adrenals . 

ta, terminal autopsy. 

000159 
F$ P90732 

,um 9-12 Twenty-eight-day repeated-dose oral toxicity study in rats 

Pathological findings of individual animals 

Sex Exp~group Animal 

( mg/kg/day) No . 

Fate Macroscopic findings Histopatholo gical findings 

Female 

a) Organs/tissues examined as follows: adrenals . 

1,000 _-- 

--

69- 

-----_--

ta No abnormalities detected No abnormalities detected --------- . .

(Recovery group) .-------------------------------------------------------------------------- 70 ta No abnormalities detected No abnormalities detected --------------------------------------------- . . .--------------------- 

67 ta No abnormalities detected No abnormalities detected ------------------------------------------------------ . . . .-------------------------------- . . .---- . . . . 68 ta No abnormalities detected_ .- .------ .--- .No-abnormalities detected- 

------------------------- . . . . . tes e ec e 

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

71 ta No abnormalities detected No abnormalit' d t t-d 

72 ta No abnormalities detected No abnormalities detected 

ta, terminal autopsy. 
B 11-0732 

p. 61 

APPENDIX 

PHYSICOCHEMICAL REPORT 

Person in charge of Chemical Analysis : 

Sianed in original July 25, 2003 

Takeharu Wada, M.S . 

000161 

-1- 
B11-0732 

OBJECTIVE 

The purpose of this study is to determine the stability of the test substance during the 

dosing period, and homogeneity and stability of the test substance formulations in 

"Twenty-Eight-Day Repeated-Dose Oral Toxicity Study of E 3in Rats (B11-0732)". 

STUDY ITEMS 

Stability of Test Substance 

Homogeneity and Stability of Test Substance Formulations 

MEASUREMENT DATE 

Stability of Test Substance : February 5, 2003 (before dosing period) 

May 1, 2003 (after dosing period) 

Stability of Test Substance Formulations : March 11, 2003 to March 18, 2003 

Homogeneity of Test Substance Formulations : March 11, 2003 

RESULTS 

The test substance of the "Twenty-Eight-Day Repeated-Dose Oral Toxicity Study of 

3in Rats (B11-0732)" was stable during the dosing period . 

The test substance in formulations was stable for 7 days after preparation and showed good 

homogeneity with a relative standard deviation of less than 5% in each layer. 

1 . MATERIALS 

1 .1 Test Substance 

1) Name 

L 

2) Lot No . 

0-6182 

3) Supplier 

L 

4) Storage Conditions 

Stored in the dark place at room temperature (cabinet no. 1 in the test substance 

storage room) . 

1 .2 Test Substance Formulations 

1) Concentrations 

10.0 and 0.05 w/v% 

2) Vehicle 

0 .5 w/v% CMC-Na aqueous solution ooossz 

p. 62 
B11-0732 

p. 63 

3) Storage Conditions 

Stored at room temperature (test substance storage room). 

2 . METHODS 

2.1 Stability of Test Substance 

Stability of the test substance during the dosing period was confirmed with IR spectrum 

before and after dosing period . 

The infrared absorption spectrum was measured in the range of 4,000 cm ~ to 400 cm I 

using the Fourier transform infrared spectrophotometer (FTS 135, Japan Bio-Rad 

Laboratories, Inc.), before dosing to determine the identity of the test substance . After 

the dosing period, the test substance was also analyzed with infrared spectrophotometer 

to confirm the stability. 

2 .2 Homogeneity and Stability of Test Substance Formulations 

In the homogeneity test, top, middle and bottom layers of 10.0 and 0.05 w/v% 

formulations were taken (n=3) just after preparation. The samples were mixed with 

tetrahydrofuran and filtrated (DISMIC 13JP, Tokyo Roshi Kaisha), and quantitatively 

analyzed by high performance liquid chromatography (HPLC). The homogeneity of 

formulations was confirmed with a relative standard deviation in each layer. In the 

stability test, the homogeneity samples were stored at room temperature. Middle layer 

of the sample was taken (n=3) after 3 days and 7 days. These samples were diluted 

with tetrahydrofuran and filtrated (DISMIC 13JP, Tokyo Roshi Kaisha), and the samples 

were quantitatively analyzed by HPLC to confirm the stability as compared to the 

concentrations immediately after preparation (results of the homogeneity study) . 

2 .3 Preparation of Standard Solution 

Exactly 0.1058 g of the test substance was precisely weighed and dissolved in 

tetrahydrofuran and the volume was correctly adjusted to 100 mL to prepare the stock 

standard solution (1,058 pg/mL) . This stock solution was appropriately diluted with 

tetrahydrofuran to prepare standard solutions for measurement of the test substance 

concentrations in prepared suspensions . 

Standard solutions : 10 .6, 26.5 and 52.9 pg/mL 
p. 64 

B11-0732 

2 .4 Pre-treatment 

1) Stability of Test Substance 

(1) 

The test substance formulations 

treated as follows . 

Sample preparation: KBr tablet 

Homogeneity and Stability of Test Substance Formulations 

were mixed well using a magnetic stirrer and 

Accurate 0.25 mL of test substance formulation was filled to volume of 25 

mL with tetrahydrofuran . Accurate 0 .5 mL of this solution was filled to 

volume of 20 mL with tetrahydrofuran. This solution was filtrated 

(DISMIC-13JP, Tokyo Roshi Kaisha) and served as a HPLC sample (dilution 

10 .0 w/v% formulation 

ratio : 4,000) . 

(2) 0.05 w/v% formulation 

Accurate 0.5 mL of test substance formulation was filled to volume of 10 mL 

with tetrahydrofuran . This solution was filtrated (DISMIC-13JP, Tokyo 

Roshi Kaisha) and served as a HPLC sample (dilution ratio : 20) . 

2.5 Analytical Conditions 

1) Infrared Spectroscopy 

(1) Instrument 

Infrared spectrophotometer: 

(2) Condition 

Wave Number: 

FTS 135 (Japan Bio-Rad Laboratories, Inc.) 

4,000 cm-1 - 400 cm-1 

HPLC 

(1) Instruments (HPLC I ) 

Interface: 

Pump : 

Auto Sampler: 

UV-VIS Detector : 

Column Oven: 

Data Analyzer : 

(2) Condition 

Column: 

Column Temperature : 

Mobile Phase : 

Flow Rate : 

Wave Length: 

Injection Volume: 

Model D-7000IF, Hitachi, Ltd. 

Model L-7100, Hitachi, Ltd. 

Model L-7200, Hitachi, Ltd . 

Model L-7400, Hitachi, Ltd . 

Model L-5020, Hitachi, Ltd . 

Model D-7000 HPLC System manager, Hitachi, Ltd. 

Shodex Asahipak GF-310HQ 7 .6 mm I .D.X300 mm 

40°C 

Tetrahydrofuran 

1 mL/min 

254 rim 

10 pL 0-1 .

.f!_-0q 000164 
3 . DATA PROCESSING IN HOMOGENEITY AND STABILITY TESTS 

3 .1 Detection Value 

Peak area of the test substance in each sample was measured as a detection value . 

3 .2 Generation of Calibration Curve 

The standard solutions were measured according to section 2 .5 2), and the calibration 

curve was constructed by plotting the results for each standard solution against their 

respective nominal concentration. The calibration curve was a straight line, which 

passes through the origin of the coordinates . The concentrations of analytical samples 

were determined by single level calibration using intermediate concentration of the 

standard solutions . 

3 .3 Calculation of Test Substance Concentration in Formulations 

Concentration of the test substance in each sample (C : w/v%) was calculated using a 

following equation, and the results were showed in significant figures of three: 

C_ CsxAxD 

As x 10,000 

where : 

Cs : Test substance concentration in the standard solution (ELg/mL) 

As : Total peak area of test substance in standard solution 

A: Total peak area of test substance in each HPLC sample 

D: Dilution rate in each HPLC sample 

4 . RESULTS 

4 .1 Stability of Test Substance 

IR spectrum of the test substance provided from the sponsor (Fig. 1) was identical with 

that measured prior to dosing in our laboratory (Fig . 2). There were no differences in 

the IR spectrums between before and after dosing period (Fig. 3). 

4.2 Quantitative Analysis 

Calibration curve and typical chromatogram are shown in Fig . 4 and Fig. 5, respectively. 

Calibration curve was the straight line, which passed through the origin of the 

coordinates and obtained linearity with a correlation coefficient of 0 .999. 

" 0001GS I'at'sf) 
B 11 pa U2 

4.3 Stability of Test Substance Formulations 

The results of stability test in formulations are shown in Table 1 . 

Concentration of the test substance in 10.0 and 0 .05 w/v% immediately after preparation 

was within 100±10% of each nominal concentration . The test substance in 

formulations was stable (within 100t10%) for') days and 7 days after preparation. 

Table 1 Chemical stability of test substance in test substance formulations 

Nominal Mean conc. (w/v%) R.P. 

conc. (w/v%) Immediately* 3 days* 7 days* (%) 

10 .0 9 .70 9 .85 9.83 101 

0.05 ~ 0.0520 ~ 0.0520 0.0517 99 . 4 

* After preparation 

R.P. : Rate of the final concentration to the concentration measured 

immediately after preparation . 

4.4 Homogeneity of Test Substance Formulations 

The results of homogeneity test are shown in Table 2 . 

Homogeneity of 10.0 and 0 .05 w/v% after preparation was good with a relative standard 

deviation of less than 5% . 

Nominal conc . 

(w/v%) 

Layer of 

measurement 

Actual conc. 

(w/v%) 

Mean conc . 

(w/v%) 

R.S .D. 

(%) 

I Top ~ 9.65 

10 .0 Middle 9.57 9.70 1 .6 

Bottom 9 .07 

Top 0 .0527 

0.05 Middle 

_ _ 

- 0.0516 0 .0520 1 .2 

Bottom 0.0516 

Table 2 Physical stability of test substance in test substance formulations 

R.S .D.(%) : Relative standard deviation 
B 11-0732 

60.0 

XT -! 

40 .0 - 

20.0 - 

) 

0 .0 .~. r.-r- .---r-----r---i---r-- ~ -r-- ~ 

+1000.0 3500.0 3000.0 - 2500.0 2000 .0 1750.0 1500.0 1250.0 1000.0 750.0 500.0 

1 /cm 

Fig. I IR spectrum provided by the sponsor 

70-I 

1,00 3 , 2 5 S 

sa-~ 

2sbo 2000 1sao 

Wavenumber (an-1) 

p. 67 

Fig-2 IR spectrum measured prior to the administration period 

OC 016'7 

- 
1TI16~732 

2ea3 . S, / 

s 

. 

E 

e C 

4 

FWavenumCer (crrrt) 

Fig.3 IR spectrum measured after the end of the administration period 

1,500,000 

°_' 1,000,000 

v 

a 

° 500,000 

y = 28088x 

R = 0.999 

0.0 25 .0 50.0 

Concentration (p-E/mL) 

Fib .4 Calibration curve 

Concentration (pg,/mL) Total Peak Area 

10 .6 291,198 

26 .5 744,835 

52 .9 1,486,937 

0O0168 
B11-0732 p.69 

!Q 

Fig .5 Typical chromatogram 
Accepted number 

Study number 

S02-4019 

14019 

FINAL REPORT 

Biodegradation study off 3 by microorganisms 

March 7, 2003 

Kurume Laboratory 

Chernicals Evaluation and Research Institute, Japan 

II 91fis 
14019 p' 71 

STATEMENT 

Kurume Laboratory 

Chemicals Evaluation and 

Research Institute, Japan 

Sponsor 

Title 

C . 

Biodegradation study of ~ jby microorganisms 

Study number 14019 

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

the Final Report (Study No . 14019, issued on March 7, 2003) . 

Date 

Study Director 

. ~i~plific 

MaX /S , Zcc~ .3 

Takak Kayashima 

0001'71 
GLP S TATEMENT 

Kurume Laboratory 

Chemicals Evaluation and 

Research Institute, Japan 

Sponsor C 

Title Biodegradation study of E ]by microorganisms 

Study number 14019 

This study was performed in compliance with Good Laboratory Practice Standards for 

industrial chemicals, "Standard Concerning Testing Facility Provided in Article 4 of 

Ministerial ordinance Prescribing Test Items Relating to New Chemical Substances and 

Toxicity Research of Designated Chemical Substances" (March 31, 1984, Revised March l, 

2000, No.39, Planning and Coordination Bureau, Environment Agency; No.229, 

Pharmaceutical Affairs Bureau, Ministry of Health and Welfare; and No.85, Basic Industries 

Bureau, Ministry of International Trade and Industry, Japan) and "OECD Principles of Good 

Laboratory Practice" (November 26, 1997). 

This final report reflects the raw data accurately and it has been confirmed that the test 

data are validity . 

Date March 7, 2003 

Study Director Signed in original 

Takakazu Kayashima 

0 11G7 

oooa.72 
14019 p. 73 

QUALITY ASSURANCE STATEMENT 

Kurunte Laboratory 

Chemicals Evaluation and 

Research Institute, Japan 

Sponsor 

Title 

Study number 

C 1 

Biodegradation study of E 7 by microorganisms 

14019 

The inspections in this study were carried out and the results were reported to the test 

facility management and the Study Director by Quality Assurance Unit of Kurume Laboratory, 

Chemicals Evaluation and Research Institute, Japan as follows. 

Item of inspection Date of inspection Date of report to 

Study Director 

Date of report to test 

facility management 

Study plan ~ January 17, 2003 January 17, 2003 January 17, 2003 

January 22, 2003 January 22, 2003 January 22, 2003 

T t C d t 

February 5, 2003 February 20, 2003 February 20, 2003 

es on uc 

February 19, 2003 February 20, 2003 February 20, 2003 

February 20, 2003 February 20, 2003 February 20, 2003 

Raw Data and 

Final Report March 7, 2003 March 7, 2003 March 7, 2003 

I guarantee that the final report describes accurately the test method used, that details 

in the report are in compliance with the study plan and Standard Operating Procedures and that 

the final report reflects the raw data accurately. 

Date March 7, 2003 

Quality Assurance Unit, Head Signed in original 

Kyoshiro Hori 

Oa0173 
CONTENTS 

Title 

Sponsor 

Test facility 

Objective 

Test method 

Applied GLP 

Dates 

Storage of test item, raw data, etc. 

Personnel 

Approval of final report 

SUMMARY 

1 . Test item 

2. Item supplied by sponsor 

3 . Activated sludge 

4. Performance of biodegradation test 

5. Validity of test conditions 

6 . Factors possibly affecting accuracy 

7. Results 

8. Remarks 

T"T'I P59 
Contents of tables and figures 

Contents of tables 

Table-1 Calculation table for percentage biodegradation by BOD 

Table-2 Calculation table for recovery rate by HPLC 

Table-3 Calculation table for percentage biodegradation by HPLC 

Contents of figures 

Fig. 1 Chart of BOD 

Fig . 2 Chromatograms of HPLC analysis for calibration curve and 

calibration curve 

Fig. 3 Chromatograms of HPLC analysis for recovery test 

Fig. 4 Chromatograms of HPLC analysis for test solution 

Fig. 5 UV spectrum of test item 

Fig. 6-1 IR spectrum of test item measured before experimental start 

Fig. 6-2 IR spectrum of test item measured after experimental completion 

Reference IR spectrum supplied by sponsor 

000175 
Study No. 14019 

Title 

Biodegradation study of I I by microorganisms 

Sponsor 

Test facility 

1 

Kurume Laboratory 

Chemicals Evaluation and Research Institute, Japan 

19-14 Chuomachi, Kurume, Fukuoka 830-0023, Japan 

Objective 

This study was performed to evaluate the biodegradability of ~ ~ by 

microorganisms . 

Test method 

This study was performed according to the "Method for Testing the Biodegradability 

of Chemical Substances by Microorganisms" stipulated in the "Testing Methods for New 

Chemical Substances" (July 13, 1974, No .5, Planning and Coordination Bureau, 

Environment Agency; No .615, Pharmaceutical Affairs Bureau, Ministry of Health and 

Welfare; and No.392, Basic Industries Bureau, Ministry of International Trade and Industry, 

Japan), and "Ready Biodegradability : Modified MITI Test (1) (Guideline 301C, Revised 

July 17, 1992)" in the OECD Guideline for Testing of Chemicals. 
Applied GLP 

(1) Chemical GLP 

This study complied with "Standard Concerning Testing Facility Provided in 

Article 4 of Ministerial ordinance Prescribing Test Items Relating to New Chemical 

Substances and Toxicity Research of Designated Chemical Substances" (March 31, 

1984, Revised March 1, 2000, No .39, Planning and Coordination Bureau, 

Environment Agency; No.229, Pharmaceutical Affairs Bureau, Ministry of Health 

and Welfare; and No-85, Basic Industries Bureau, Ministry of International Trade and 

Industry, Japan) . 

(2) OECD-GLP 

This study complied with "OECD Principles of Good Laboratory Practice" 

(November 26, 1997). 

Dates 

Study initiation date January 17, 2003 

Experimental starting date January 22, 2003 

Experimental completion date February 19, 2003 

Study completion date March 7, 2003 

Storage of test item, raw data, etc. 

(1) Test item 

About 5 g of the item supplied by the sponsor is sealed in a storage vessel and 

stored in archives in this laboratory for ten years after the receipt of notice that the test 

item comes under No . 1, No .2 or No .3 in Clause 1, Article 4 of "Law Concerning 

Examination and Regulation of Manufacture, etc. of Chemical Substances" . 

Treatment of the item supplied by the sponsor after the storage period is discussed 

with sponsor. If it is not stable for the storage period, it is stored while it is kept 

stable and then disposed of with approval of the sponsor. 

(2) Raw data and materials, etc. 

Raw data, the study plan, documents about the study presented by the sponsor, 

the final report and necessary materials are stored in archives in this laboratory for the 

same term as the test item. Treatment of raw data and materials, etc. after the 

storage period is discussed with sponsor. 

'~"~1'~~ 000177 

- 
14uiy 

p. 78 

Personnel 

Study Director Takakazu Kayashima 

Study personnel Kaoru Kondo 

(Operation of biodegradation test) 

Staff for cultivation of activated sludge Yasuko Matsunobu 

Approval of final report 

Study Director Date March 7, 2003 

Signature Signed in original 

Takakazu Kayashima 
14019 p~79 

SUMMARY 

Title 

Biodegradation study of [ ]by microorganisms 

Conditions of cultivation 

(1) Concentration of test item 100 mg/L 

(2) Concentration of activated sludge 30 mglL 

(as the concentration of suspended solid) 

(3) Volume of test solution 300 ML 

(4) Cultivation temperature 25f1 °C 

(5) Cultivation duration 28 days 

Measurement and analysis for percentage biodegradation 

(1) Measurement of biochemical oxygen demand (BOD) by means of a closed system 

oxygen consumption measuring apparatus 

(2) Determination of test item by means of high-performance liquid chromatography 

(HPLC) 

Results 

(1) Percentage biodegradation by BOD 0%, 0%, 0 % average 0 % 

(2) Percentage biodegradation by HPLC 0%, 1 %, 0 % average 0 % 

Conclusion 

The test item was not biodegraded by microorganisms under the present test 

conditions. 

0001'79 
1 . Test item 

In this report,~ ]has the following chemical name, etc. 

1 .1 Chemical name* 1 

1 .2 Chemical structure, etc. ' ~ 

Structural formula 

Molecular weight 

* 1 Information supplied by the sponsor 

. 
2 . Item supplied by sponsor 

2.1 Supplier and lot number* I 

(1) Supplier 

(2) Lot number 0-6182 

2.2 Purity*' 

(1) Test item 99.9 wt% 

(2) Impurity Water 0.1 wt% 

The test item was treated as 100 % in purity . 

2.3 Confirmation of test item 

Two infrared (IR) spectra of the test item provided by the sponsor and measured at 

this laboratory were confirmed to be identical (see Fig. 6 and Reference) . 

2 .4 Physicochemical properties*l 

Appearance Tawny solid 

Melting point 48 °C (DSC) 

Solubility Water c 1 mg/L 

Dimethylsulfoxide >-_ 10 % 

Acetone ? 10 % 

Chloroform ? 10 % 

* 1 Information supplied by the sponsor 

2.5 Storage and stability 

(1) Storage condition 

Dark storage place at room temperature 

(2) Stability 

The test item was stable under the storage conditions, as shown by the finding 

that IR spectra of the test item before the experimental start and after the 

experimental completion were identical (see Fig. 6). 
3 . Activated sludge 

3.1 Sludge sampling sites and date 

(1) Sampling sites 

On-site sludge sampling was carried out at the following l O locations in Japan. 

Fushikogawa city sewage plant (Sapporo-shi, Hokkaido) 

Fukashiba industrial sewage plant (Kashima-gun, Ibaraki) 

Nakahama city sewage plant (Osaka-shi, Osaka) 

Ochiai city sewage plant (Shinjuku-ku, Tokyo) 

Kitakarni River (Ishinomaki-shi, Miyagi) 

Shinano River (Niigata-shi, Niigata) 

Yoshino River (Tokushima-shi, Tokushima) 

Lake Biwa (Otsu-shi, Shiga) 

Hiroshima Bay (Hiroshima-shi, Hiroshima) 

Dookai Bay (Kitakyushu-shi, Fukuoka) 

(2) Date December, 2002 

3 .2 Sludge sampling 

(1) City sewage 

Return sludges from sewage plants were collected. 

(2) Rivers, lake and sea 

Surface water and surface soil which were in contact with the atmosphere were 

collected. 

3 .3 Preparation of activated sludge 

Activated sludge was prepared as follows to maintain its uniformity. 

The filtrate (5 L) of the supernatant of the activated sludge*2 cultivated about for 3 

months was mixed with the mixed filtrate (5 L) of the supernatant of a sludge collected 

newly at each location. The mixed filtrate (10 L) was aerated *3 after the pH value of the 

mixture was adjusted to 7.0±1 .0 . 

*2 The activated sludge cultivated the mixed filtrate (10 L) of the supernatant of sludge 

collected at the ten locations. 

*3 Prefiltered open air was used. 

d r. _. 71 

0 00182 
14019 p. 83 

3 .4 Cultivation 

Roughly 30 minutes after ceasing aeration of the sludge mixture, supernatant 

corresponding to about 1/3 of the whole volume was removed. Dechlorinated water 

was added to the remaining portion so that the total volume reached 10 L. This mixture 

was aerated, and then a predetermined amount of synthetic sewage 

*4 was added to the 

mixture so that the concentration of the synthetic sewage was 0.1 wt°lo in the volume of 

dechlorinated water added. This procedure was repeated once every day. Cultivation 

was carried out at 25±2 °C . 

*4 Synthetic sewage 

Glucose, peptone and potassium dihydrogenphosphate were dissolved in 

dechlorinated water to obtain 50 g/L of the solution for each component. The pH 

of the solution was adjusted to 7.0±1 .0 with sodium hydroxide. 

3 .5 Control and use 

During cultivation, the appearance of the supernatant, sedimentation of the sludge, 

formation of flock, pH, dissolved oxygen concentration in the solution and temperature 

were checked to maintain a normal state of sludge . It was confirmed that these were 

within the scope of the control standard stipulated in the "Testing Methods for New 

Chemical Substances", and these results were stored as raw data. Microflora in the 

activated sludge was microscopically observed and sludge with no abnormal symptoms 

was used for the test . 

3.6 Inspection of activity and date of initiation of use of activated sludge 

(1) Inspection of activity 

Activity of the sludge was assessed using a reference item. 

(2) Date of initiation of use January 21, 2003 
4. Performance of biodegradation test 

4 .1 Preparations for test 

(1) Measurement of concentration of suspended solid 

The concentration of suspended solid was measured to determine the amount of 

activated sludge to add. 

Method In accordance with Japanese Industrial Standards (JIS) K 

0102-1998 Section 14 .1 

Date January 21, 2003 

Result Concentration of suspended solid in the activated sludge was 3500 

mg/L. 

(2) Preparation of basal culture medium 

3 mL each of solutions A, B, C and D, which are prescribed in JIS K 0102-1998 

Section 21, was made up to 1000 mL with purified water (Takasugi Seiyaku Co., 

Ltd.), and then the pH of this solution was adjusted to 7 .0 . 

(3) Reference item 

Aniline (reagent grade, Showa Chemicals Inc. Lot No . SN-23 31 M) was used 

as a reference item to confirm that the sludge was sufficiently active . 

This test is effective when the percentage biodegradation calculated from the 

BOD of aniline after 7 and 14 days exceeds 40 % and 65 %, respectively, according 

to regulations of "Testing Methods for New Chemical Substances" and the OECD 

Guideline for Testing of Chemicals . 

17? ~U, 179 

000184 
14019 p. $5 

4 .2 Preparation of test solutions 

The following test solutions were prepared and cultured under the conditions 

described in Section 4.3 . 

(1) Addition of test item or aniline ' 

(a) Test solution (water + test item) (n=l, Vessel No. 1) 

In one test vessel, 30 mg of the item supplied by the sponsor was accurately 

weighed and added to 300 mL of purified water, so that the concentration of the 

test item reached 100 mg/L . 

(b) Test solution (sludge + test item) (n=3, Vessel No.2, 3 and 4) 

In each test vessel, 30 mg of the item supplied by the sponsor was accurately 

weighed and added to the basal culture medium (the volume was less than 300 mL 

by the volume (2.57 mL) of activated sludge inoculated), so that the concentration 

of the test item reached 100 mg/L. 

(c) Test solution (sludge + aniline) (n=1, Vessel No.6) 

In one test vessel, 29.5 ~tL [30 mg = 29.5 ~iL X 1 .022 g/cm3 (density)] of 

aniline was added into the basal culture medium (the volume was less than 300 

mL by the volume (2.57 mL) of activated sludge inoculated), so that the 

concentration reached 100 mg/L. 

(d) Test solution (control blank) (n=1, Vessel No.5) 

In one test vessel, nothing was added to the basal culture medium (the 

volume was less than 300 mL by the volume (2 .57 mL) of activated sludge 

inoculated). 

(2) Inoculation of activated sludge 

The activated sludge cultivated under the conditions described in Section 3 was 

added to each test vessel, (b), (c) and (d), so that the concentration of the suspended 

solid reached 30 mg/L. 

. 000185 

-10- 
14019 

p. 86 

4.3 Instruments and conditions of cultivation 

(1) Instruments for cultivation 

Closed system oxygen consumption measuring apparatus 

(Temperature controlled bath and measuring unit : 

Ohkura Electric Co., Ltd .) 

(Data sampler : Asahi Techneion Co ., Ltd.) 

Vessel 300 mL in volume (improved type) 

Absorbent for carbon dioxide 

Soda lime No. l (for absorption of carbon dioxide, 

Wako Pure Chemical Industries, Ltd.) 

(2) Conditions of cultivation 

Cultivation temperature 25±1 °C 

Cultivation duration 28 days 

Stirring method Each test solution was stirred by a magnetic stirrer. 

(3) Room Apparatus room No . 511 

4.4 Observation and measurement of test conditions 

(1) Observation of test solution 

During the cultivation, the appearance of the test solution was observed 

periodically and conditions of the instruments were checked properly. 

(2) Measurement of biochemical oxygen demand (BOD) 

During the cultivation period, the change in BOD of the test solutions was 

measured by autorecording using a data sampler. Cultivation temperature was 

measured and recorded once a day. 
4.5 Analysis of test solution 

After the termination of the cultivation, the test item in the test solutions -vvas 

determined . 

4 .5 .1 Pretreatment of test solutions for analysis ' 

After the termination of the cultivation, the test solution (water + test item), the test 

solutions (sludge + test item) and the test solution (control blank) were pretreated for 

I -performance liquid chromatography (HPLC) analysis of the test item as follows. ~Iialh 

Test solution 300 mL 

-Sodium chloride 90 g (even balance) 

-Chloroform. 90 mL (graduated cylinder) 

" Shaking for 10 min 

Water layer Chloroform layer 

" Filtration and dehydration (I PS filter paper) 

" Filling up to 100 mL (chloroform, volumetric flask) 

" Taking out 1 mL (transfer pipet) 

" Filling up to 10 mL (chloroform, volumetric flask) 

Sample for HPLC analysis 
4.5 .2 Quantitative analysis 

Determination of test item 

The samples for HPLC analysis were analyzed under the following conditions . 

The concentration of the test item in the sample for HPLC analysis was calculated 

proportionally by comparing the peak area on the chromatogram of the sample for 

HPLC analysis with that on the chromatogram of 30.0 mg/L standard solution (see 

Table-3 and Fig. 4). 

The lowest detectable peak area of the test item was regarded as 16000 [IV ~ sec 

considering the noise level, which corresponded to the test item concentration of 

0.30 mg/L . 

(1) Analytical conditions 

Instrument 

Pump 

Detector 

Column oven 

Auto injector 

Degasser 

Column 

Column temp. 

Eluent 

Flow rate 

Measurement wavelength 

Sample size 

Detector output 

High-performance liquid chromatograph 

Shimadzu Corporation type LC-l OADvp 

Shimadzu Corporation type SPD-lOAvp 

Shimadzu Corporation type CTO-l0ACvp 

Shimadzu Corporation type SIL-lOADvp 

Shimadzu Corporation type DGU-12AM 

Shodex GPC KF-402HQ 

(SHOWA DENKO K.K.) 

25 cm x 4.6 mm I.D . 

40 °C 

Chloroform 

0 .2 mL/min 

262 nm (see Fig. 5) 

5 ~tL 

2 AU/V 

(2) Preparation of standard solution 

The standard solution to determine the concentration of the test item in the 

sample for HPLC was prepared as follows. 

100 mg of the item supplied by the sponsor was accurately weighed and 

dissolved in chloroform to obtain 1000 mg/L solution of the test item. 30.0 

mg/L standard solution was then prepared from this solution by dilution with 

chloroform . 

(3) Calibration curve 

7.50, 15 .0 and 30.0 mg/L standard solutions were prepared by the same 

method as described in (2) . These solutions were analyzed according to the 

analytical conditions described in (1) . A calibration curve was drawn based on 

the relation between the peak area on the chromatograms and the respective 

concentrations (see Fig. 2) . 

-13- 

000188 
14019 p~ 89 

4 .5 .3 Recovery test and blank test 

Each two test solutions (water + test item) and two test solutions (sludge + test 

item) for recovery test were prepared according to the methods described in Section 4.2 . 

The test solutions were pretreated in accordance with the method described in Section 

4 .5 .1, then analyzed according to the procedures and analytical conditions described in 

Section 4.5 .2 . 

A test solution for blank test was prepared according to the method described in 

Section 4.2 . The test solution for the blank test was analyzed in the same way as the 

recovery test . As for the blank test, no peaks appeared around the peak of the test 

item on the chromatogram. 

Two individual recovery rates and their averages on the analytical procedure are 

shown below. The average recovery rates were used as correction factor for the 

determination of the test item in the analytical samples (see Table-2 and Fig. 3) . 

Recovery rate of the test solutions (water + test item) 

98.1 %, 99.5% average 98 .8 % 

Recovery rate of the test solutions (sludge + test item) 

99.5%, 96.7% average 98 .1 % 
4.6 Calculation of percentage biodegradation 

The percentage biodegradation was calculated by the following equations and 

expressed in whole numbers. 

(1) Percentage biodegradation by BOD 

Percentage biodegradation 

BOD-B 

(%) = T~D x 100 

BOD 

B 

TOD"5 

*5 

Biochemical oxygen demand in the test solution 

(sludge + test item) (experimental) (mg) 

Biochemical oxygen demand in the control blank 

(experimental) (mg) 

Theoretical oxygen demand required when the test 

item was completely oxidized (theoretical) (mg) 

The purity was regarded as 100 °lo and TOD was calculated from the 

composition formula of CiosHss06 at n = 5 . 

(2) Percentage biodegradation by HPLC 

Sw - Ss 

Percentage biodegradation (%) = SW x 100 

Ss 

Sw 

Residual amount of the test item in the test solution 

(sludge + test item) (experimental) (mg) 

Residual amount of the test item in the test solution 

(water + test item) (experimental) (mg) 

4.7 Treatment of numerical values 

Values were rounded off in accordance with JIS Z 8401 :1999 rule B. 

, 

-1 I " pul, ITS 

- 15 

- 000190 
14019 p. 91 

5 . Validity of test conditions 

Percentage biodegradations of aniline calculated by the BOD values were 61 % and 

77 % after 7 and 14 days, respectively. It was concluded that these test conditions were 

valid (see Table-1 and Fig. 1) . ' 

6. Factors possibly affecting accuracy 

No adverse effects on the reliability of this test were noted. 

7. Results 

7.1 Appearances of test solutions 

Appearances of test media in cultivation vessels were as follows. 

Test solution Appearance pH 

Water + test item The test item was not dissolved . 

I 

- 

At the start 

I of cultivation 

Sludge + test item The test item was not dissolved. - 

Water + test item Insoluble compound was observed . - 

At the termination 

of cultivation Insoluble compound except the sludge 

Sludge + test item was observed. - 

Growth of the sludge was not observed . 
7~2 Analytic results of test solutions 

Analytic results of the test solution after 28 days were as follows . 

(Water + 

test item (Sludge + test item) Theoretical ' 

Table Fig amount . 

Vessel-1 Vessel-2 Vessel-3 Vessel-4 

BOD"6 mg 0 .4 0 0 0 82 .2 1 1 

Residual amount mg 29.3 29 .4 29.0 30.0 30.0 

and percentage 

-------- - residue of test item 

----------- ------------- ------------ ------------- ---------------- 3 4 

(HPLC) % 98 98 97 100 - 

*6 The value of control blank was subtracted from the values of the test solutions 

(sludge + test item). 

7.3 Percentage biodegradation 

Percentage biodegradations after 28 days were as follows. 

Method 

Percentage biodegradation (%) 

Vessel-2 Vessel-3 Vessel-4 Average 

Table 

BOD 0 0 0 0 1 

HPLC 0 1 0 0 3 

7 .4 Conclusion 

The test item was not biodegraded by microorganisms under the present test 

conditions. 

000192 

-17- 
14019 p.93 

8 . Remarks 

8 .1 Instruments used for test 

Fourier transform infrared spectrophotometer : 

Shimadzu Corporation type FTIR-8200PC 

Closed system oxygen consumption measuring apparatus : 

see page 11 

High-performance liquid chromatograph : 

see page 13 

Electronic analytical balance : Sartorius AG type BP210S 

Sartorius AG type BP301 S 

Ultraviolet and visible spectrophotometer : 

Shimadzu Corporation type UV-2200A 

Shaker : Taitec Corporation type SR-2w 

8.2 Reagents used for analysis 

Chloroform (reagent grade) : Kishida Chemical Co., Ltd. 

Sodium chloride (reagent grade) : MANAC Incorporated 

000193 

-18- 
Table 1 

F 

Tes-t 

T 

No . 14011 Cultivating Duration : 28 ctays 

7th day 14th day 21st day 28th day Vessel 

No . BOD Deg . BOD Deg . BOD Deg . BOD Deg . 

Mean 

Deg 

(mg) (%) (mg) (%) (mg) (%) (mg) (%) 

. 

% 

© 56 .8 61 72 .9 77 78 .4 78 79 .4 76 

1 .7 - 3 .3 - 8 .4 - 10 .9 - 

3 .3 2 5 .5 3 8 .7 0 8 .7 0 0 

2 .5 1 4 .4 1 7 .1 0 7 .1 0 

® 3 .0 2 5 .1 2 8 .6 0 8,9 0 

0 .0 - 0 .0 - 0 .4 - 0 .4 - 

Deg . : Percentage biodegradation 

Vess el no . © : Sludge + Aniline 

Vess el no . Control blank [B] 

Vess el no . 02 3~ ~ : Sludge + Test substance 

Vess el no . 1 : Water + Test substance 

Test substance of 30 mg was added . 

Char t of BOD : Fig . 1 

Deg . = [ BOD - B ] / [ TOD ] x 100 (~ ) 

TOD of test substance : 82 .2 (mg) 

C-Lo6H8g06 + 124 .5 02 - 106 C02 + 43 H20 

124 .5 02 / C1o6H8606 = 3983 .85 / 1455 .8 .1. = 2 .74 

TOD = 30 .0 x 2 .74 = 82 .2 (mg) 

TOD of aniline : 90 .3 (mg) 

CBH-,N + 8 .75 OZ - 6 C02 + 3 .5 H20 + N02 

8 .75 02 / CsH-,N = 279 .99 / 93 .13 = 3 .01 

TOD = 30 .0 x 3 .01 = 90 .3 (mg) 

2003 .02 .19 Name ._ )6GY~C, 

7j, iD 19 9 

Calculation table for the percentage biodegrad;ltion by BOD . 

ooo194 
Table-2 Calculation table for recovery rate by HPLC 

Sample description 

Standard solution 30.Omg/L 

Water + test item -1 

Water + test item -2 

Sludge + test item -1 

Sludge + test item -2 

Control blank 

A : 

B : 

C : 

D : 

E : 

F : 

G : 

Study No. 14019 

F 

1679639 

1648549 29.4 98.1 98.8 

1671479 29.9 99.5 

1671930 29.9 99.5 98.1 

1624782 29.0 96.7 

n.d . 

Amount of test item added : 30 (mg) 

Peak area (uV~sec) 

Final volume : 10 (mL) 

Ratio of portion used for analysis : 1/100 

Recovery amount (mg) 

D = G x (A / A(Standard)) x (B / C ) / 1000 

Recovery rate (%) 

E=D/30(mg)x100 

Average recovery rate (%) 

Concentration of standard solution :30.0 (mg/L) 

See Fig. 3 

December 12, 2002 Name /k/ - /` 
p. 96 

Table-3 Calculation table for percentage biodegradation by HPLC 

Srudv No. 14019 

Sample descriptio n A E F G H 

Standard solution 30 .0mg/1_ 1582026 

[1]Water +testitem 1528540 29 .3 98 

[2] Sludge + test item 1522509 29.4 98 0 

[3] Sludge + test item 1498059 29.0 97 1 0 

[4] Sludge + test item 1553440 30.0 100 0 

[5] Control blank n.d . 

Amount of test item added : 30 (mg) 

A : Peak area (l.LV~sec) , 

B : Final volume : 10 (mL) 

C : Ratio of portion used for analysis : 1/100 

D : Recovery rate : 98.8 (%) (Water + test item) 

98.1 (%) (Sludge + test item) 

E : Residual amount of test item (mg) 

E = I X ( A / A(Standard)) X ( B / C ) / ( D / 100 ) / 1000 

F : Percentage residue (%) 

F = E / 30 (mg) x 100 

G : Percentage biodegradation (%) 

G = {( E(Water + test item) - E(Sludge + test item)) 

/ E(Water + test item)} x 100 

H : Average percentage biodegradation (°lo) 

I : Concentration of standard solution : 30.0 (mg/L) 

See Fig. 4 

February 20, 2003 Name ~ 
Fig . l Chart of BOD 

Test No . 14019 ( Test substance 

Apparatus . . . . . . . . . . . . . . . . . . . . . . . . . . . No . CN(-31 

) 

Cultivating conditions : 

Concentration 

Test substance . . . . . . . . . . . . . . . . . 100 (mg!!?) 

Reference substance( aniline ) -- 100 (Mg/!?) 

Activated sludge . . . . . . . . . . . . . . I 30 (mg/!>) 

Temperature . . . . . . . . . . . . . . . . . . . . . . . 25 ± 1'C; 

Duration . . . . . . . . . . . . . . . . . . . . . . . . . . 28days(Jan .l-"---Feb .19,2003) 

Note : Regular condition 

V l d i ti 

B 0 la (mg) 

esse 

no : 

Sample escr p on 

7thday 14thday 21stdn.y 28thday 

M Water + Test subst ance 0 .0 0 .0 0 .4 0 .4 

Sludge + Test substance 3 .3 5 .5 8 .7 8 .7 

Sludge + Test substance 2 .5 

_ 

4 .4 7 .1 7 . .1 

® Sludge + Test substance 3 .0 

_ 

5 .1 8 .6 8 .9 

C ontro l blank [B] 1 .7 

_ 

3 .3 8 .4 10 .9 

© Sludge + Aniline 56 .8 

_ 

72 .9 78 .4- 79 .4 

100-1 

80- 

_E 

b 

C 

N 

E 

U 

Q 

C 

OJ 

x 

0 

U 

U 

U 

O 

CQ 

60- 

4 0-'~ 

20- 

0 

0 

0 

4 

f 

( 

- - - -

-- 

I -T-T-7-1 

14 21 28 

Cultivation Time ( 0-28thday) 

2003 .02 .19 Name 

? 

1-41 12 

p0019"7 
p. 98 

Study No. 14019 

Solvent blank 

Peak position 

II . d. 

I 

0, 0 5 . 0 10.0 15. 0 20.0 

Operating date : Feb. 20, 2003 

PKNO Time Area Height Conc. 

(min) ( ;LV " sec) ( ;LV) ( 

Total 0 0. 00 

Operator : Kaoru Kondo 

Standard solution 7.50 mg/L Operating date : Feb. 20, 2003 

PKNO Time Area Height Conc. 

(min) (uV " sec) (uV) M 

1 12.50 400293 3575 100.00 

Total 400293 ]Do. 00 

--, 

0. 0 5 . 0 10 .0 15. 0 20.0 Operator : Kaoru Kondo 

Standard solution 15 .0 mg/L Operating date : Feb. 20, 2003 

PKNO Time Area Height Conc. 

(min) (g, V " sec) (uV) (%) 

1 12.49 801572 7132 100.00 

Total 801572 100.00 

- , 

0. 0 5. 0 10 .0 15 .0 20.0 Operator : Kaoru Kondo 

Standard solution 30 .0 mg/L Operating date : Feb. 20, 2003 

PKNO Time Area Height Conc. 

(min) 0-,V-sec) (, .tV) (%) 

1 12 .50 1609359 14380 100.00 

Total 1609359 100.00 

0. 0 5 . 0 10. 0 15 . 0 20. 0 Operator : Kaoru Kondo 

Fig . 2 - 1 Chromatogram of HPLC analysis for calibration curve . a 

Date : Feb. 20. 2003 Name ; x , x~yZ~C-~ 

~'~~ .~ .3 
Study No. 14019 

1800000 - 

.. 

U 

U 

Cz 900000 

N~ 

cd 

N 

0-1 

/ 

/ 

o ~~ , 

0 17.5 35 

Concentration (mg/L) 

y =53593x 

r = 1.00 

Concentration 

(mg/L) 

Peak area 

(i V " sec) 

7.50 400293 

_ 15.0 801572 

30.0 1609359 

F o, ic~. 2 - 2 Calibration curve of test item. 

March 5, 2003 Name 

000199 
Study No.P .41f0D 

Standard solution 30 .0 mglL 

J 

Operating date : Dec. 12, 2002 

PKNO Time Area Height Conc. 

(min) ( ;cV~sec) ( ;tV) (%) 

1 12. 57 1679639 14718 100,00 

Total 1679639 100.00 

0 .0 5 .0 10 . 0 15.0 20.0(min) Operator : Kaoru Kondo 

Water + test item -1 Operating date : Dec. 12, 2002 

PKNO Time Area Height Conc. 

(min) (ttV " sec) (uV) M 

1 12 . 56 1648549 14395 100.00 

Total 1648549 100.00 

0.0 5.0 10. 0 15.0 20.0(min) Operator : Kaoru Kondo 

water + test item-2 Operating date : Dec. 12, 2002 

PKNO Time Area Height Conc. 

(min) (uV~sec) (uV) (/6) 

1 12.56 1671479 14725 l 00. OC 

Total 1671479 100.00 

0.0 - - 5 .0 . 10 . 0 15.0 20.O(min) Operator : Kaoru Kondo 

Fig . 3 - 1 Chromatogram of HPLC analysis for recovery test . 

Date : Dec. 12, 2002 Name 

000200