# B11-0732p. 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 AFFECTEDTHE STUDY 1) There were no unforeseeable circumstances that might have affected the reliability ofthe study. 2) Deviations fromthe 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 fromday 6 to day 2 (recovery) since soft stool was observed on day 6 of the dosing period. The above-mentioned deviation fromthe 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 fromday 6 to day 28 . Conditions ofthe Occurrence of Soft Stool Soft stool was separately or sporadically observed fromday 6 to day 28. Conditions ofthe Occurrence of Diarrhea Diarrhea was separately or sporadically observed fromday 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 ofthe Occurrence of Salivation Salivation was sporadically or almost continuously observed only immediately after dosing from day 7 to day 28. 

# Conditions ofthe Occurrence of Soft Stool Soft stool was separately or sporadically observed fromday 8 to day 28. Conditions of the Occurrence of Diarrhea 

# Diarrhea was separately or sporadically observed fromday 9 to day 24. Conditions ofthe 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. ORGANWEIGHTS (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 200mg/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 performa 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 ofthe 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 ofthe 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 andwas considered to be oflittle 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 ofthe 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 newchanges 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 200mg/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®® Q0010SN M O 07

~+ A A o tU ¢7 cC N 'O 'T7 '~ e-~ \ \ \ C 4o 60 hn O ~d -'eq .YJ U \~ \~ \ hU h0 ha m E E E U o O O -+ C' o O

N O N - 7 ~`a QJ O U Q)

- o 0 0 m o ~n v v~r r~ 

### 7 1----T 0 0 0 o ~n o n'7 N N 

### I 0 N CLj

. .E b 4' .



### I 0 0 N >a ctl -C

-o

N

` CO N

I N f0

L+ C A

a U .% O
ti1 4+ O I O
~~ N I

+> I m

i~ .

--i a~ a~

Ga cO .a . .

. a~ - 1 a> A 3 c a a~ w 3 0 E- m



### eo c=. 

# 00010(;N C~J C O

^-1 ~- ~ . 7a O ~ f0 c7 N 'D 'o 'O +-+\ \\ d 60 M bA O .~4 ?G `

.-C U \ \ \ h0 hO bA _a~ E 6 E V O O O V~ o 0 23 N O CL) -

^ QJ

0 U

0 CSi La

d

o 0 0 0 0 o ~r o .n o m N N .~ -ti b

-O

I N

~ CD N

^N F+

a
N a .~ V O L+ O N 0 I rr .D

Y [d A7 N d A r-+ E m ~, cz,

m .v . . no ~ ~ ea v+ 3 Y "' c a

a, ~o 3 o E- m

I N


# ooolo7 O t Q
t~.N O

Lti Q) ' U N

i~
.ti I1~

. _ -~ . . . 1 p O O O O C~ ~'7 N 

## ( ~ E p / I E I / g -+ T . A A O cC ~C R1 ir 'S7 'i7 'D y~~1 C b0 E+A bO O ~`G ~G ~l hD b0 t+0 

### a> E E E V O O O r+ C C O

N O d 

# ooao ? .

-m

I N
N

Y LC Fy G

Ir N Y N
-U .X O
G+ O d I I Q7

d Q G7 d Cd [q " p . . ' Y V] ,C' Ql

-~ [C 1 C " Y d O 3 0 H ~ .

N

rL 

# ooosO$ `! ~1M,
~, .' .N C~7 O
> . m 

# 00



# Q% ^-~ G-+ Ds A 

### o ~e cc m
~. wa a w~ \

\ \ . O6O hLl 60 O Sd -1q `~ U\\\ OO b0 60 a~ E 6 6 c~CD oo -~~roo ~ Np N - 

# ooao

I N
N (V N G 

# I~II U

. ~. .y y-) Cb

" ry

Q O r-1 O

I .D Y N N GL -~ N cC E A Fx. m b . . - _c a>

m .m ." ca A "-+ G 'O d O O F fs,

N N
O C p t+] N O p



## ( S E P / 7 E 1 / ~ ) A I~ N " O N A

. O

(~r 

# 000109

# IA-1 IA732

Table I Twenty-eight-day repeated-dose oral toxicity study in rats Summary ofcl 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.N M n O

A L C T y T
O y L O

'L7 EO a~ V7 ad a~ dL 0 . e0 

### y . . .. L d 3 T 

## .fl .ty I O b0 W I T r~ cd C B CJ 0 3 T F rn N T A 00 N

N

N

.b
m a c 0 y N L w N .G .i

N 

## a

Cl)

N

W O N L . . " ~ a7 A " z A C1 ~, O 'O ED X d ~ 

### x aa w e cr " n mO OQ7 Lo .i

C`7 co (- CD rd cc (o cc) c0 N c0 rl L-- .-" 1 l- N C') C7 C`7 C7 ti +i +i + "

C- O l- m 000 v) co M co N Ln c0 [~ Oc') C' N t17 r1 in .-" CO N C'7 C7 M N ti ~i +i ti

co 00 C- Ln Ln N 07 LO mN O~ cm Lo 00 a) .-1 N N ~ N - N .-1 C7 P~ C'~ C] +i ti +~i t" C~ a~ N LO C`') u7 d' CJ Ln "V co U-) L) c7 00 LC) N N N N + " +

" +

" +i a) Ln M

Lo l O co .Zv m <D a) Ln NN 

### O ~ N. "-i 0-

N N N N +i +i -ri +i

~co ~ N o~ c- O o~ Q] l~ l'- - Cc '-1 ~ N cm O

ti O~ .-+ O

ti r-I N ~ N + " +i +i -
c0 O [- l[7 CV LC! .-1 Q) i [`- C l-cc a) CD O O NO O

O I-- C`7 ti LC] I Q" d' CIO" LO O ""-1 M M

"--i N N 03 O "-4 a0 ."~ M

.-i 00 r+ M

.-~ +~ +~ ~

.~ +i +~ +~ + "

~ [l- (m N L-Co m o OC co 00 C7 -l- - 12-~ .y -,}' to- Ln r1 N N N N N C " ) 00 CZ l-- C : 73 m La O o0 00 aD M c'7 M N ti ~ cc Ll- 

## -*" +~ +~ +~

00 I-- co O tn .-" co" ca N in c OD ~ .ti '-I N N N N N N

CON HM O1 N OO h 'i' 00 ul7 ~' Ca cc CO tfl

H ti ~4 ti +i t " tl

c7 t17 N -I -,I- LO r.- 0 CD CO CO V

" l- d' llln LO In l17 ti +i ti +i
OO co in O

to m

r+ (-- C' CD c7 I- c7 L rN C7 cn C') C7 .-1 ry ' "1 .--1 tl tl t" t" N CO CO N

N "-+ Z 4°, O O O c' O O -° c N O d O

i N a~ x m c A H a) . "-i ~' l~ O I~ v' N O rn c`] co LO l- M co LO in +i +

" ti ~i cr) N CZ c0 O C'J cr C7 Q7 .+ --~ [- [- [l- Ou'1 N ti ~ N ti H ti rl +1 t" tl + "
LO z t- 00 00 t- cc V Q1 (- Q

l17 l- "d' QJ lfJ N c7 N N

H ti

~ " ti ti t"
O7 Lr7 M

~ 

### ln v4 ~Md' ti ti t" +1
N CC CG

N -- 

### - o NO -IT O i1) ~ in Ln

N

~ L O O O .c c ~ O O

N O

. .-I


## m al e Lc . 1t~ O O O Q. G . y A

- " O O L L -r" Y G C O U U U N ~+ -~ U .,~ t G7 C7 > > 9 B O O L L w w a. " C C U y L L N mww w .b
a~ C C cd 

### +I " ° c eo m " -- c ~-. rn c" ~ m * i i! iN c7 O m

C L C a

a a .~

. O v L O Ql O

~ 00 dv +~ N W Cd N 1 : d m d .~ L y 3 > . m a 1 O bo w .U

.C 9 WE3 F v~ O O

n . T L d > O U

.-1

W p N L " r Q7 N ~ 8 9 .^ 

### c z m G >~ C O CO ~0 " ~e n . \ X C=1 B C

13M r+ Q7 v'-1 OLn N C'] Co N C V~ ti ti

IIT ~ ti m -O m(- Or) ON

O CD Cp (p Q] CD m

(M t-- N OON m +i m-fi

ME- C

DO m l-- l-- Q) tn N CON +1 +i
CD CD
C) - O U L S C a~ o U O O O

N N x

m v~ m m x F (M N C) 00 l- l-- ,1' LO ~--I N N

I- (m cn cco t- m

Cl) C7 V, ~ N N +-i +1

CD OC Lo N C+) ~ N N t . +~

M N N LOCO NQ] l~ N N N +i +t

m " - ^ O U L O .-+ O L G co p

d 

### a tC O O v O. i a~ C C ^ O O L L .~ +~ G O p U U a7 m -~ ^ U U ". . .C 67 G7 > > a a O O L L w w +~ C C U d L L d N w .- a T c ca G U ". . . -~ w v~ w .. . '}I " C ECp cn m cr~ 

### dN M O
co

m G
a y T .U

. O
O m O m I 'D b0 y N m U d Y 

### n . m w J L q

. ma -c o

. .~ w L eo w y L m c e U 9 N T m b 00 N

N N .b O U d a 0 m L w

<

C'7



### -" i

W O L a~ m L 6 

### c z m G m O 'C L ea so c . ~ x o0 

### e

I 

### y x m .n °' m ~ `dFd~LO l~ mV~ M [~ N (~ rl l~ .-1 N N N l~ N N

00 UD N l-- m O') cD N l- .-1 cc .-1 N N N

V' O M

V NN l(] N C' ti u .-1 N N N Oti CO N N

N

~' C7 c'] Ol l!7 Q] C N ^7 N C7 O M O N N N N +I ~1
l,- CD CO r1 ~-i .--1 .--1 N N ~I ~I

NO N V' O

N .~ N

00 c0 co ti N O pO O -4 O~ N N tl -fl +1 N cc

v ~ O O p c N W O o V' O p H tl 00 V' C ~ O m NLo l~ ti W

ri CO .-7 co* .'a tt +~ r., -f, (- ~' O

cn ca c0 .~ O cm O [- .-i 00 .-1

O c`] Vr N t- .~ l .--~ co .--~ ca -, (- -

coN O Q7 00 N f~ O ~-i cD O cD .r

~ tl tl -rl O cc N

t- O

Ln m

~ Cc .-y CD '-1

O v . cmO cm00 CD .-a tf) - V~ O Lo .-~

ti ti ti

N cD H

U C U L - c O

m e cw . CD N

O p O O N O LI] O O O o v v n . n . m Q O L L v +~ C c O O U U 4J L t N > 9 E C O L L w W y r"~ C C d y L L Q7 N W w w w ".- . b a 

### c m " m U ~ ~ ._. . W ~n w

. . . +I '~ cn m rn F 1f iFN p 

# m

_rn L C .b V fn y

.

# 0 .4 O y L >, O ~d b m \ O cd " L7 L 1 b m y N Q7 .1! C 0 N a~ L C cd 'O I O y W L m4+ U I a >> L c F. cn 

# b

.n O

00 L U G T m > 0 U N L4'

W O L .-N . a7 cd .O 9 q - . 7 " C 2 :d G >, O "C7 L \ m m a \ x m c., s 

# -1 71 m 1-1 r- N CO --I N N +I +I

- N C

C) C- N CO N N N +I +I

t- LO 7) -4 CD .-1 CO N N N tl +I

w co

Ql -~ U L _C C C7 O ^! U O

O O

N I a~ x a~



## _.. ~

;
_

. m OD O Q7 N .y .-I



### co (M ti m 000 a)-
-1 +I

NO OLo G] N m ~ +I +I

cc cc

.-, O U L .~ J .C C d O > U O



## e l!J p O

. p O v G . y ^ O O L L +~ y c n O O U U N N 7+ l .- 17 37 N > > B 6 O O w w y C N L L d a~ w W W w . . . . " n 'II C a] " cd U " .-. w Nw 

### " c m +I m " - c ca cn v 

## * »N O
m

C 'O h

K y N --~ O .r L +~ O W C fy .r O cd Z7 iC I OJ +~ W td U G. m 07 O L Q ,~ aY cV Lt " d B I U y eo w

" w m C B F a] N

OF- 6

U H U G . ~ O a U w 5 dt'

\ O K N y rb a.
J U "O S \

S b0 U q. v

U W S

W

ba

N O K 

### z

3 J

a O K W O N L . r ® .r

o v^`d L \ ov on Y p " \ G~ 9 *

m In In t- " m . . .--I N m tl tl

in ti t` ti

~ +I c- .-+ co t, ! u~ .--1 co co

m N L~- ,-I I .y " p~ CO CV N N j N N tl +11 -~-1 +I

U7 t1] C- N CD V' -o' cq, L--*

.r -y .-I tl tl tl

Q " ~ ,-I '-I N '-I m

N +I tl y-I -1-1

Q1 .--1 .--1 C~ QO C9

" ~ O> " -r N CO Q7 .--1 rr .--I F ti ti +I +1 tl Q! N CD cc [~ N l~ N tl tl

O "-- C

u~ +I +1 O~ V~1 c7 tn 1!! p O-II co m mp ti i rl ti +U tl tl

.-+ m C" Och .-i c'n mO m

O m

O c`7 p m m m cm +I +I +1 tl
O W .r m m C- -r m 00 00 C~0 P p N N N tl +1 tl "-I O N CO u7 C'7 O N O cm m tl tl
cc In m

m cc O cD O tl +1
CD t- ll- -w V' N C- Q] i m cD ON OO N p0~ fD .~ co co cn W u7 tl +I -1-1 , +I In o~ tlfJ .--1 u7 .-1 C' C tl tl N N " -1 m

f0 ^i <D O C T tl tl
O c0 -r m N C
~ O tr~ p tn O ti H tl ~ +I tl C- CD C~ -r tl C'GO tip tl
O -~r C 1

mm

I ~+ It7 tt7 ~p ~n O

I u~ p u7 O ti ti +1 ; -~-1 ~ +1

l- c0 N t- o) O r+N O-I ~IN p-+

ti ti +I tl tl +1

N ID C

" p) l(7 C7 In . " 1 n n +1 tl u] In tI] C- ON O +I +1
ll] W Q1 c,3 : C- (D C+J In NI C " m ti i tl +11 +I
CD CL7 CO O . O O cn ~N

U

1 ~ ^ ^ D O a

O O

- . .L .+ d' O O I >, " ~ ., O i d o N p i N G7 p O ~ U r"I O ,y IU d
I d K d d F a ~r OIn In a~ .~ to : u~ m c" 7 m Nc'm N N m N N"--I I mN N "-+ N N N N ~ N N +I tl +I tn tl +I

N GQ ^-1 47 u7 u7 Q~ mV7 C"7I 1 m

m

. . "
. . . i >n O ef0 CO TOi ~ p d" O tl ~ +I ~ t~ ~ +I ; +1 +1

N. "+ +I
m .-1

1 .ti .-I m N I O

O O

" -~ ~ tl +1 +I~ I +I O u7 u] V' l~ l~ " I 47 ti Cd" N .-1 ~ ~f] W V " 1 C

" m, cN N .-1 "ti ~1 ~ N N" -I

H ti ti ~ tl +I +li +I tl
~JC'O N N Nm c) =1 p N m C'7 cn o c~ o m

o m cpI a

" p m

p m cn c~ o~ 1 m m ~I +I +1 +li +I +I

cn u] a0 u] V' l17 m lCJ ~ N Cp m d' ~O O]O O]O O)Oi m O O m ti 1 tl ~

+1 tl ~+I ; tl tl

m N ~t7 [D m O N d" i m (- a0 "--I W .r QJ " ti 07 N O rl ~ U7 " -r <O " -1 u~ m ' In cn v~ In tl +1 +1 -Fli ~1-1 -~"1 OK) CO C- c~ CMN tl] = .I CD C- CA m It] rl ~fJ .-1 U7 r1 CD ~ i Q' r1 C'J r1 V' V' C' C 'O " ~' +I -tl +I tu tl ~I

m c0 N e}' m C' met' I N lA 00 lo ~O In O ~7O Cl ; ~n p d'O

rY ri "-1 I ~i ~ +1 YI tl tlj ~ tl tl

ICJ N V' p 1L1 [.- Co N ~ N N O~ CV m

c"1 l'- ,-r c0 N i t~ -+ +I tl +I tl tl -fl

In c'7 O3 W W ~ " ~ N I 7 CD co C7 CO N ao m f~ N l o) w ti ti ~ t` +I +I +I tl

cc

G7 .r ^ D ^ L y m o cc ID p , p co 'r cc m tl
p

G1 ^ O O z ~ O O O I a." r ,~ O N O il-~ Q O

i > > U " --I ~ D ^ "1

U i 1G1 ~
N u ; o O ~V v a. G . a~ ay m ^ O O L L +-+ +~ C G D U O U ^ ~ U " r t d N > > e 8 O O L L w w y LJ ~, C QJ 67 L L G) mw w w w " r - zy
+~ O C tE - cd U p U " r .r w y W

.r
" C 00 pp . .r O " (n tC ln C7 M tt iFN O] O La

p L 

### p .n N T y O .~ vl O C .^ . L aa O 41 C

. N 9 O 0 v x I U d .- . W U 

### ".~ eo a a~ o L -- . T +O-~ w w 'D 6 I N ya a mW ._ . p .U I T C B a~ e F f/~ O

G J
\ N U U N w 0 O
p Q7 L w Cf O <a

O p .

h Z

p m 

### z W 0 rn L

.

L m no Y a ~

. )i CO G .7 6 .-IN 00 <M cD C 13m

; v>a

" 00 .I OO O O O O O O j OO O O ~-I +1 tl +II tl +I 

### .-1 aa m

<r co .-+ -W~i co -1 cm/n CD .-1 c0 .-i cD N /l] .-li N N " -IC0 Q] OJ Q7 Q) Q1 O] tl t/ tl ~i-I ; tl tl

,=-C=, 00 00 Cp Oi 00 00 O O O O OO O O I O O OO +1 tl tl tll 1-I tl

co m co c t, cc w ~ I o, c co 0 00 00 00 OOi "-10 NN +I tl tl +/! -fl tl

- T CJ cD -t- c+] =! f'1 N M- N.-"+ N .-1 P') .-1 I 47 N +I +I tl +11 O O tl

O O 00 OO cn a]i N~ " -yN OO C

DC) (=.o C=,O i O O OO I +I tl +11 -fl .tl c0 CID cD

a~ - L a) o =~- U O

C CD ~p

O O I ~ O p N O I L t p

_ I O a~ a) o '-l I Q ~ U

IN N t 

## x m .n E. x NC' 00 OO Nc7 r1 N 00 00 00 OOi 00 00 y-I tl tl tll tl +1

O) N c9 N c7 u7 /f1 [~ i V' 00 ch C' Q] <T Q] Q] I Q) Q) +I tl tl +1! tl +1
C),=, O O C )c, (=)V : CD cp CD OO OO C)= CDO; O O O O

I tl ~1 t11 1

C' <T C' lf7 C C' O~I I c7 c+] a] N O O O O O O " -~ .-11 N r+ rl .-/ +1 +~I tl . tl +1

~00 NQJ M CD C' QS i Q7 CO V^ .-1 ti O ~ OI " " -+ "CD: v~ N C~ "-1 tl t/ tl/ tl

00 ~ " +N 00 OOi c'7c~ Nc7 

### Oo 00 00 ooi o0 00 ti 1 tl tP 1 tl

cc CP to CD ! CO cD

O O O L G "O O 1 T ~ y O y O N O I L a C Q ~ U ., i al N O " 1 > > U .-r 1 o r.l jU Im ICq



### w e cL LC~ O

. o O V G . ctl p O L L +~ a~ p 0 O U U U U

. . . a 

### a a~ m > > B O O L L W W 

### +~ o p U d L. L N mw w W w " . . T +~ p p W " N U

. .~ W 

## +I "a m m .- . p . .+ Vj 

### U » ~ , . »N 

### m 0 m

L C .D N

O V1 +~ G O a] .~ L cd O c Q~ 6 N 'a c T4 'O U 'b r . U cC ++ U td " .~ d d N a] t L U 3, "C td O 'O _O 0o w
. a I T T L a~ cE C q Q7 6 F rn 0

. w L 6 C 

### a \ a -°-° C G7 y O J L " t7 G . \ I h0 F, v Q7 ~~ v~ a U \ EEU

e C7

b

\ GI1 V B E^
J O 'O L \ U GO I 8

\ Ls] ~ L U

\ C . . ~ Q v
J E- ~ t3. . .-~ V

\ f- " O V W O fn Q) <C L 6 O C Z .d d >T ~ m o \ m ~ea p . \ [~ 6 tn co 00 ~ mcCD O O

O o O rl O "-1 O "-^I O +1 +1 ti'1 r+ CD : CO N Cu 

### o - a, o +11 I +I

N O N O N O N O~ N O

-1-I +I +I~ +~ 00

NO +1

tD r1 CD ~i LI- N C' N t f7 N V' N If, O ~1] O In O I<7 O I tfi O ~n O +I +I tl +I! +I rtl

.-1 O c~) u] N LC- N V' i cD CO O] Lf] N .-1 N C N C~
- : C' "ti m .-1 +I +1 +1 +11 +t +1

m 00 V

G~ f0 07 "-1 co! C " t'7 O

C' i37 N Cp '-i 11] " -1 oo N ~ 1A .-i l!) r"1 +I +I +I tll +I -FI

O m

O] CO (~ N N CD i 40 u7 Q) lt7 lt7 <N C ^'1 47 I C "a' +1 +1 +1 +1! +1 +1

N I G'J ct' la7 N OO h " Op cD I Q) C l17 "Q " O " -I O +I tl +I _ +I +I
iF M O O+ C') l~" c'r7 O I O

OC

co C~7 lI7 C Il] .-" ~! Q - "1 ef tl +I +I +II +1 rtl

d' .-I NCA tl7 tl] Om i CI O] N CD Cl47 Lh m do co V " t~l N m .~ m C ~' "d' C C7 C7 +I tl +t +I~ +1 +t

If7 m ~' c~J C7 N .--' Nj C- ~D ~ CJ N N N C7 .--II N N +1 +1 +I +t! +1 rtl

L!J l~ ." ti tD m l- l!7 011 l- tTJ [~ l- CO ~ CIO .-+ l-- +I +1 +1 +li ~ .I tl
V V O V

0 L y t C N O > " U O V V

p O v ~ O O O iT " ^+~ O N O i y y o O

' i >?` U

. .t I O .y IU i U

x .n ~n co m E-" I~C] NO ~c0 ~NI m .-~ CD m o o o ~O "--1 O c l! .r p "-+ +I +1 ~I +II I
Q] .-.~ ON .-1 ^-I Q N ~ Q7 N 0O NO C'70 M p M

CD, NO NO I t +I! I

t+ N t, m f, N to C' I ~ m V " " ~ ~ O ~ O 1<7 O tn O I u~ O In O tl +I +1 +I~ +I tl

l~ cO c'7 GO --~ d' C- tf)i cD N O Q1 rl P] m r-I N N "-I C'] +1 ~

+1 +I +II +1 +I

l+ [.- t~ V~ N 1L7 Q7 Cpl IT m m W

. "" I N N r1 N

-" 1 +I +I J-li +I +I

Cc co O ~ C'l M ; m

O l- CV 11] .r CD [~ ^r co 'rl an -y cD -i tl +1 tl +1! +I +1

N ~ C7 IT

. . .^, t`- .~, Q i p p[~ c~J NO --10 NO NC)i NO . " +O tl tl I +tl 1

Ou'7 L- h IC7 tt] i " ~ C N N .-1 U7 47 l- W IP CG l~ I C") N C~7 CD C') --1 N N N C'J .r m +I +1 tl tll tl +I

U:, pp N "ti (-- c7 O ~i 'm cc t, lt] IA CO co Ca l!~ l" , U~ I to "--i CO d" N N N N 1 .-f +1 tl tl +1 ; +I +1

CD m 1(] C'7 L- CV CI cc ; cn~ N V~ N N.-1 N .-1 N +I tl tl tt! +I ti-I
f') l~ C

"J N Oq CP . "~ C ~ t-N N [- . "" (p W .-11 t~ .-~ L~ 'r tl +I tl +II tl +I ll"7 O O G . N V

. p O L L Y +~ O C O U U IU ~ " U "

.~ " L d tv > > B 9 O O L L W w +~ C to co cc c . CD CD ,

0 U L .r C p O C O

N m -" O ! ~ O G7 O 7 U p ta, .~,~ O p i L s c p

N a7 O ' i > > U ' " --I tU 1 d
67 

### e m C G7 07 L L. 0) a) 

### w w W W . ., T T y +~ O C cd

. W U p U "" ^ y W

. . " +! " C 00 eo " . " S w kN m 0
m

.N

. O v1 y O N C,3 L tC O C cu E9 o x 'd Q7 1 " ~} ^ti a7 cd +~ U CIS 

### a) B a a~ L U cd O 'O O y L L mw " o I T y C ER W e F ~] N J \ 

## a 8 C7

OC \

w

9 Z

J n . 6

\ m Cd v V
b [9 m 1 B
Q7 G C W\ aJ m L 8



### a \ Z m m 4r 0 N cC ~ 9 g . .. . 7 C Z cd
a T o b mm a \ iG m G7 9


### N pp Cl) "--1 O O cc N O : !D .1a Ll 7 In N In .r fO .ti It7 " -i i l~- N [- ti p b O O ~ O O +1 +1 tl 411 tl +1

Nc7 .rN Q)~ ON~ NC-'J In . :r C'O C'O C`70 Cbl O C' O

I 1 I I : 1 +i

m N C`] C' C C ~ ~' a' +l +1 +t +li tl +l

CO n co C) LD C' cc cOI aD -.zr CD u7 C~ O t~ O t~ Ot~ O i cD O CD O tl +1 +I +I! tl tl

.-+d" N N NN Q1N1 ~M m N 00 00 C OQ]CD,i M O M

O
~+l +l +I +I I +1 +1

O~ ^ti 00 ^+ m N cD N

j O'-+ Q7 N 00 O b O O CDOi Cb 00 O O O O OO O Oi OO OO tl , I 1

.-1 c') Oc'] OC' OC7 i C^7 C`"7 C N N O N C N O N CD : N O N O O O OO OOI OO I O O OO +1 1 YI~ +I +I

Ca .-1 ~r N In OO) c " ]' Y

" ti C] . "y N

" -"I N

"-I " --I .-1I c "f .-y
~+I tl +I +11 tl


### m c~ co co t` <n d' ti
~ +1


### co ca

a O C O ; Z +~ ~T O O I y ." -" .~ O LG GV O iL~c C m o 1 c~ a~ o ? U ^ I 7 7 U ' IU IN



### m N cn 07 c'J t- m U'31 U'3 C, co C:) C+ rl CD .r co rr L- r+i CJ " ~ co N O O p b ~ b O tl tl +1 +11 Y-1 +1

NC' P7 N NN C'N~ CII7 V' c7 c'CD CO V~O Cl : c' O C " O tt +I tl +l, 1

-I N m C C C~ 'r ti ti ti +I +I +1 +I i -f I +1
ll] CD C~f u7 .y CO -r C' I C'7 cO " --I d' t~ O C~ b t- O (~ O~ cc O ~D O +t tl +1 +1! +1 tl

CON ON ON 00 "1 00 N Q~ O 00 00 m OI 1170 M O +1 +I ~ +1 q +1 +I
7F N x ir I C~ - . a~-+ oc~ a~ .~ ; Nm N-, O O O O O O I O

.-1 " --1 b C . C) O C) C, CD 1:1 c::, +1 tl +I I, +I tl
c'] C7 " ti N N N " -I M . [~. N L- N N O N O N O NCD ; N O N O OO OO OO O CD! ~ O O b O +I I -fl 1 ~1
c') C O It7 ~n Q) O cn' N L~" C) N
~ .-I C .r c')' " 1 V' Co N co N

^y "'1 i +1 ~I +1 -tll -tl tl lf7 O O v v 0- O . y O O L L +-~ r~ C C O O U d U U " -+ .^, c t y at > > e B O U L L w w +~ C G OJ d L L Q7 y w w ~. . t
+ "+ C 

### ca cp c. co cc

0 L y L C mo ~ U O O O ~ ~ O

C O ~ T

" - . .+ O N C ILt c p 

## - I» o - U i G7 

### d e C td " cC U G] U " ~+ rn w " .- " 

### tl " " ° c m m " - ~ w ' "' % +tN M O C]

N m F. C T N T .% O m 4 O O L Y m N v7 a m m m 7-, T T m m y 4 Niea w 

### .m o
m C e eN F C/=~ m O Lu

~. Q7 y O C7 O O 5_ 7 U U O C L 7
m N m C O m Y I

+ + +

+ + 

## +I I

C

. O G



### n

O V
mU +

+ + 

## I

O n C G O 47


### >- N

9

4+ 0 N 

### m m 7 " C Z m

T 

### n m o m `_C n eo X g O C

O O O O O O O N .-+ G ~
tD to
O O M N c'7 ~+7 C .~
^ O O O c'7 M Q . N N C'1 a Q, o O .~ p
O O .- .

M M C7 ^r O O p
C' N M N C' CI c`7 N O

UI cD m 

### 10 <O cp

~O to
^ O M p~ O N .-+



## +~ +I +1

C

aw ^ . . p t C N O 7 U ~O tD tD

P O

O

X f F t11

O C cD

p ~D

O O LO O

O

cD (p
O p

O p
O M M O
O C N O C

M M O

u7 O O
M M c`9 M

^ M ^ M 

## +I +I

a~) O C G 

### w.. ., u o 4 v O p ~D to tD , Lp to
O O O

O O Q N O O O

O O O O .-. p to ~ 10

N C7 .~ C -» O N p c] M O N

O G O O O C

.- . _ ~. G P'1 . . N ! N .. . N c' C C C

V' M N N c'7 ~
O to OD M O c"1 

## +1 +I +1

G C


### v ^, O C t' 'eCD

N > u

m 9 L O O O O O p 10 to

a' C

.~ O O
N M V' M
O N ^ to 

## +I +1 10 CC ~ to

O .°

.~ 1. U ir O y . .y ++ p > L C p p v O U > U .-, u7 O O . .O o a 4 t' m m O Li 4 ~+ ~+ q O O U U . .N .

" + t L U W > > e B O O F. W w N ++ C C m d 4, wm dw w w , w .Q T .--i .r p7 +, T c .~ o f/] m U .-~ tl 

### c M " c " o° .° m c m ~ .mN h a~

iF Y _ mw iF ul i

# C11

0 0 bb C w D

,u C

:)

> m

0 A 6 g .^. z cC C1 T ~ cd o -o L \ 00 m tr4 N .-f Lo O .-I O

CID Go .--I l17 .--I lo C' N C . " 1 ~ rl C) C) C'7 tl +1
fT ~ 00 CD co c C7 C d' CS) U')! LO LO M N LO CO; d, O 00 tlIJ - : mC'7 OJ CV C7 C+') ~7 +I +II tl +I Cl) M Voo! Q7 cc ,1, 00; V' LO , IC!
-~I tl +1 tl
C' C7 l[7 00 f17 O7 ( . "+ co O CC O 

## 00 00 00 -fl ?I ~f c- CD fn ti +I C .- 00: d' N ~N CMO i CC) r+ C- .~ 0~ 00 00 +I : +I +I

co -It M

00 t l- l cOf O C13 -lt` cD 'm0 m

O m

0 cm 0

. 00 00 FCD ~O -O -~O ; NO NO +I +I +I +I ; Y-I +I
I I I I ~ 1 ~ l I I

LO .^1 N

m LO d' NN

; O Co Q) cc O N O

ti 00 N m

rl! m

C+7 c`) O m0 NO C\] c; NO C70 TI +I +I +li y-I +I 00 d' ON cc l-- t- cc; Cl) (7) N N l'- C] C'- N CD .-1 00 .-~ ~GON O] N N O CV O NO NOi N O NO y-I +I +i y-u ~-I +I cD d' C~ O Na~ ~n C3i m Go -1n ~d' NO c') l- 00 O ; (md' .-+ m O rl O

rl O

O O

ti~ O

.-i O +I +1 +I Y-P tl +I
CO CG CC CD IO co

G7
_. . N ~ ~ O O O O

O t c N O iL "cc O a~ O I a~ a~ O > U ' f > > U " .-I I O ry I U

Ql x cli F co O O C`7 G~ (, 00 N 01 CZ
~ to ."-I [l) T ~ t- N ~ a m 07 ~ O CV N ^~ " -1 I N N tl tl +I ~" II tl tl
vO co C7 O d' c`7 df ! u7 c7 V' Lf) lo .--f cp cc' LO * Q ; i NC'7 V' 00 CO CO r1 CO Cz I~ CG tl tl -fl +I! +1 tl
CO In O L`- -,Zr .-f Cf l-I C'Q' cc O 'C' O Lo O V O , V O u7 - 

# Oo 00 00 00! C :) C) 00 +1 -1 +I +I1 +1 +1 l!) C') QO d' OD C' 07 co: NCJ L-- C-0 l-- O ('- O t- " O t-- (0, c0 O 000 -O rl O ~ O " -I C)! - O """a O tl tl tl tl ; +I tl C+7 C7 +-t l- V' cc [- c) ; O O NO7 co V' C~ C O -~ a . cni -+ e' O tn (-- ti CO .-i co N l- I Go - an .ti
+I tl tl I, +, +f
I I I I ~ I I I I I I

CO c O00 OC' Do CID : ON coo

CO - Cc ' "1 ffJ r11 I'- " L- .-1

" -1 O -y C ~ O rl O i ~ O F O +~ +I +I -~li +I +f
V' ~D N ~ I-C'J N O i C7 Lo -0 Q] cLJ zr ~ O h c U] ; Oo C] Lo O coO co O Lo 0 ; cc C) cc O +I +i tl +I! ti . .I

cc cc cc CD cc cc

~ 0 y L .~ t c N O O C O C U ~ O

O C O N Q ' L L C O

, d d O " i 3 ~ U " IU

c In o O o v a. d 

### m

- " o O y y o C O O U " U N O7 " - . " U U a" - as `c, w ai >

_ > B O 6 O C O L L W v~ w m 3+~ G m V1 OJ L

- " L OJ " N d W w W W . . . ca O 'O W T

.~ W+~ c U O o7 - m u p . .a U . .,

. y . .-, W V7 . .r W

" ~ y C GO

. C V] " V~ ^ a! CS7 if i!N M n O
m

y m

. a v a w .^ O N L N O d m ~ .^ O d Z7 3 , N cd a~ EO G7 L G1 p a m m L > >, +-+ mm "v - v L L CO W ^ U L m c e 3 E~ F ~7
U WFm Eo 3 'O b0 O ~- m

-- " pd af o C O L "v ca 6 a

o en mo a~ o G . \

c no " - o m o L .--, m

m > . o L C o > \ Oaaa

~ om " -" +~ o N -J N \ F ~a

>, eo a~ o c o

. \

L pp Uo > O 

### ca

w O w a7 

### .o a a ce n . ~, cd 0-0 m en

. Y a\ x m [s7 9

N h N.-1 LO O r1 O NM ; Lo t!7 O) N CM c0 -1 t1) ~ m in Cn ; V4 O 00 lti' N "i' ^I 1f) O) C`') m N 

### v~ c~ m m ~ m M t, t, ~, +u ti +,

in Ln co C7 -z :' t- C' C7 rl L .- 

### v .-i d~ ^~ d~ "-a m c-) : c ~ cm,-~ -~, ti t, +,! +, +,

.-1 C') Qn N Q) N cm cq ; (n C! CO C"7 N O ~ O .--i O ^IO 00 00 00 co : 00 00 +, +, +, +,! +, +,

00 Ln N C7 CO C`7 CD -,z:, ; .-I C'7 .-I C7 m O Lo O in O Ln O ; Ln O u7 O 00 00 00 00 : 00 00 +, +, +,, +, +, 

### I I I I I I I I ! I I I I

OC~7 cm l- -'Zr u7 Nc')! V, O O cV m .~ coo 00 0 00 0i L- .-a 00 0 00 00 00 00' 00 00

.~ M (M C- OO U .-i LO : Nlf] C'7 ln oo0 L O P- O 00 0 : [- O l~0 O0 I 00 00 001 00 00

U) N O .-7 N [- Cc CT7 ; co Cp M N O

N N! l,- .-i N O cr7 p

co CD Cp 

### CO O

P70 C9 0

; NO NO +, t +,

N ^ C3 O O O -u o p LCJ =O ~ OCV O I ~ L' C Q 9 U "' , > > p . U

N 

### S cn o OC7 Q) l a0 N i C ") t~ O] co

" -1 CD ~-1 C") O) .-i t- N O] Q] Orl ri " -I OJ "ti m "ti : N M .-i N N Cq N t, t, t, + +, ti
* c0 c0 ~ CC " ~O .~ cc ; a' c' l- C7 ^I ln .-I V' m

V' C) Vi N

N cc N C`7 C'J CJ m , C7 N ~, t, +, +i, +, t,
V' N C' V' N ~' N"T ; N

C] V' V' NO NO NO NO ; NO NO 00 00 00 CD 0 : 00 00 +, +, +, -r,! +, +,
c0 c0 u'1 tf7 cn 'd' O LO; 00 ra :) O CO o CO O O) O i coo t- O 00 00 00 00~ 00 00

. , 07 .ti N

C7 " -i CD m

CM! O

N c. LlI'- t[7 O) Ln OO) [-- C i co in [- c0 m C7 V' Co . C7 C'] +i +, +, ~,i +, +,
I I I I I I I I ~ I I I I

a) c0 in m O

c') O

Ln ! cc c .-~ C' I~ O Op 0 Oo0 00 O : h0 l- 0 00 00 00 00; 00 00

V C7 d' I"- C7 .--~ m cc: V' " ~ C`7 C] O) .-~ O

- O

N O] .~~ [- N OO N NO " ^70 P70 NO ; NO cV O ti t, +, +u +i ti 00 o v y y O L +~ G C p U U " U 

### " b a~

U U " ^ GL L C7 cC d > > 

### .~ e o e o c o L L w mw w +~ 3 +~ c O N d L L U " fA d W W W a " n m _ R! +~ O U G a7 [d U G y U " .
. y .~

. W I ~' ^ C CCI " C 00 r~ pa ".-~ C C/J " c < m w * 

### ca cp ca co , co cc

.- . p t c aJ O 0 j 41~

O O U L O O ~ >, . .. y O N O ~ L t - O

~ma~o , > > U

U 

### e n~N M r O

N

U X O C - O O C y H O k '9 U U U 

## R 'a o a 0 U

. E 4r oU O 

# E u E 3 

# r U

N f: .

U N L T d0 -E 

# E o a~ o > 0 0 CL 0 0 0 0 0 N O C

O O O O O N
C

# 2.'

O U 4 . > O O U U U N U N C > o
O U O > r: y 

## CG

U ~ >
"~ C O C U u U N O U



## eo c m

m

N

A h

U U 

### u

. 0 C 

## 0 

# z 0 

# 0 0
O

0

O

O

O
0

O

O

O



# ~. O cUC O 

## o .r = U 'fl Ca 

# m cc 0

0 0
O

O

O

O

O

O

O



## c 0 s 

# 3 0
0 0

O

O

O

O
O
0

O

O



## .
, 0 0 Y 

## c

X u N 

## a.E o ~r `° o m 

# p. 22



# 000102"2 wsN fn r C 

## p

A

C .T J i H L' y V C 

## o w c `0 3 x U O U_ CD N O cc - U O a L i cA' C 

# b

. . s CO O T R C E U E ? 

# F- v~ 0 ^ U



# E U

R L o u

C O ^ U

U U U
, T A .Q ~00 

# .x E

O C C O O N O c C~ .

U .N p U ,7 UO C O U
L O U O > O O
O C O
O C N O R _U - L~` U E >

O .~ U 

### U - - o L C 

## o U d A v

C 

### w L .

.~ .



### m

0 b

L

U 

## G a

U U 

## u

.C 0 C 

## 0 

# z I,I

~ . ~D~C

.

~O!O

O

-
~O ' O

:

.
' ~C . O

+



# . O 

# U . E U 

## o o . _ o C O U 

# z !z 'a O 

# 2 z U U 

### u C E o 7 C 

## ~ c 

# =z . b

b

U y 9



# .C 

## 0 C 

# E C 

# v U U 

## u

.G C 0 C 

## 0 

# z U

U 

## a U Q

_ 

## c o U 

## U C 

## 0 U U U U U



# .C 0 C 

## 0 

# z O 

# cu z = b

L U U U N 

### F C 0 E . ~ .

~C :O :O

, ~ .

!

;
O_ O

:

. I , I 

# 10 W^ . ~O ~ C

+ +

U ~ U V O U . W U . a i ,n , c ." ' eC O' O . 7

C O 

### c' c' en C v 

## c c = 

# > z .~ . .~ ~ . 

## E K v 

# E_ O L C 

# z = ~ rn U G' U _O U y - T cC cc ~ . Vl 

## a o e r~ ~ o

= E O O ~ y' C y Sl +X 

### -C U . 

## E ou y~ 7 7 z ._ 

# -z z _ .y c L i +



# p. 23



# 000123N M r O C

y

A C .T
y C 

## x o R C `GQ ;L N b
. " 0 R Q 

## a = L 

# ° L L 4^ 00 O .T c3 

# C E U i 

# r c L N

R 

## E u

U R R 

# 71 ab x E o u o > 0 0 C 

# 0 0
O O N O C O V O v 6! C U > O U U N L O C O U
L O 0~ O > O O ^ U O O O O O N O <t N v O d

> O U p U U CU L C

L



### e~n R

R
R
R

R

R

R
.C .

V



### C .C

U O .D H U

.
c L R 

## 0 

# z T 

## c U y N
C L O 

# z c b

U u f/1 U



### . ¬ 0 C O 

# z R 

## 1.0

U u U

. ¬ O C L 

## 0 

# z 

# x C



# E X N cc 

# E O

.~ 

## E 0 

# z .v N G O y m U
N



## .C .D 

## 0 

# z h j~ cq R 

## c . .E .E .ri 

# o o E C U 

# ~zzz ¬ E E 

# p. 24



# 000124 ^ f

# pB~lr~-0732

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, 37,38,39, 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

__ 46.47.48 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 ofhair (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 60 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 1,000mg/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.N n O
m



### m c T

.~ N T
O L -+ O cd 9 y . . . N C O a7 b Z U p Y Z`

. a " - . m b L c T " ~ ca w . 'O O y ,n L +~ b0 ~

- " pp T 3 C T N Zy 3 O H m i N 6 G 

### a N T .D N

CJD N

N

O .` d a C J L y 2y d 

### r H pa0 tn CO O~ O] M M .--i .-~ c~ ~+ cDNru'JC

")~M[l- CO On NON rco C- ~OL--N 11) CD Co woo MCT]MC)-IT MC']MMMC7M
Ln Cl) O

c0 Ln -V N-i 00 M Mtcmcc) OM-~a2 co Md~o0l LO ca " v CD 00] U*n r1C'r ~vc0 MC`MMC`'1ClJ co MM MM 07C7
tn`-tNUncOd'cOM00 LO 0 cnCOOJ ~CD r ONtf)OtcnM M CO in Nm " --1 M O) "-a M Cl)C7C')NM MNM c'7NC')M
C] N N ,-1 (- [') .-1 M CO M

~-1 M a0cO CrOrp)c'7 v cn co Cd' Oo00cnNcn rcOO= Do O M N C7 NC] NNNMNNCJ
C`7r ONC'7Na~ V'C'J~ ~'r N IcM

.Cr r ~~ONO00~!' -ilr .-~ I' GO C~ LO M r L[) M

~' CO M~i' LI) NN NNN

NNN

N NN N
COCOOm

ONI l M

O C7 00 Q3 M

r C'7NC'][~ t- LO co M

OOMOON NN NNNN NNN

NNN

C'M

.y

N I 0 z cb d CL T a O ` 00 bd " dG G aC 00 c*.7 S



### x cD N C' f .] ,-t c~ V' V` CD r ~ r M .~ Ln C OO t17 v co c0 rl N LO 

## co c- r co oo r r ca co c- ca C--
t- -a N Ooao" Un .-i M rn'ZI, m Nl!)lnCOlf)1- 117Q]rCDCOIn C9 to 1t') llzf' CO LO l17 d' = Lo -:I . Lo

ry ti .-1 .-1 ri ry .y rr .a
Q)C'OC1~00] Na0 N07c0 Q1 MtC7NN(mM ~TC7l .- r-~ cr MMM[ ") d' MM Cl) ~ m

MM
.-i N Cl) VW

cD rco M

o.-+ N ~-+ -, -a

U r

~. p U L .C C a~ p > U O-N .-i ~m 00 co CD N m Q . CO CD co r . C707C7MC')M

. "~ mr OV' 07 V'cDN~O~ !r N Ln Ln LO cD C'J CJ C7 C) C') CC')

11700 rQ)M-1 L " .c'70N~tn P70 NN (7MCJCJM

C7 

### OW O'IT t, CO cD - " + C~7 N N Ora7aDa7CD C7NNN N N
Mh~cJCOC7Q~

rI NCOCONM CD coCd'V'Ln NN NNN N

C7 c0 O(m Ln N cD a) 00 O

o] in NO----

. NNNNN


## r .-+ o r .~+ m ON ^+ C) r+ La 

## co r-oowc-r

Nc0 NQ7 'IV CD

C`']r CO Lf) CD U

.3 Ln lf7 .q . .1 ry
c0 m "t'MO]00 rNcnC'7Ln~r M C`7 M C`7 M V' .-1 .-~ ti .y rv .~ M eV U) corm - .^i -

O



### cc

E pp O7 00 O

l-O) m cc Cl) C7 M

N cc carrn IT ao M(7C7MMM
C7 Ln L'r V' " O N Lo .-~ cc c- 00 llJlncD rNCO c'] C7 C`7 C7 Co M Q)Om

C'OU7 --1Q10]N ~~D NNNC'~M MC7f7C)NM

r~nrc~~ncn O~C7N00 M~D a0000L- O CV C ")C7MNC']

d' r ~ C] ~-1 O) Q]COC- CONln d' Lo 117 in ['] CD NNNNNN
7~Or~v m

ca IT U7 N lf7 l~ M .-1 . . . OM N N N N N N
d~0 rih HC`7NCC)COOt

## rrrrrca

N~ m

0NI~ NInOm

MM 

## M Ln LOU)

~ r v ONOJ ~n[~O~M

"-+ C7Mv M[`7d'
M 0~-+NM

d' " -INNNNN

O O N mom=" M=M C'7 1'CD M .^]OJlf7C

.OC'JCD d'COI- Nd' CD O U7 W

O Ln a0 00 c0 V' Q7 r r+ v MMCC'7C'7C')C')MC'1C`7 C`')

co CD- co C7- LC) CN C' V) 00 N~OCn V'NC')m1C) co N LA optnra)C'r r Ln C7 r CD O C7CMMMMC7MM M M C7 M

N<DCDMMt- MCCO w Mw

- OrrOrNm .-i0 m

d' LO NNLO NM~NCD MC']MM

C7C'JMC'7 M C") C7 N
CON r r r-y~C7MC0 r M caMrMaomraoMcomcc "m cm NasO-iM cc 0M

ca M NNM

N M M NNM

NN

.-i CO V' 07 M " a l~- CO l`- V' tn t'~ cn ~-+ t0 c') O Ln l- cm l^'] cG ca LO d~ r ca co t-- Ln d~ in Ln M NNNNNNNNNNNN
rl r M

h " V' O

N Cl) dr cfl tf) C7 in M O d' Ha) N tid'Mr 00 N N -C7 NNM N .-1N .-1 O N N N N N N N N N N N N

M N W

.-1 Ln N Q7 N P ") M ~ cD OC`]u7 .-~O C~7 NQ7 N~~CO 

### mrhcaaomaooor-rr-rLo
Cric7d'CDO7ti0pr1cpN[O N d'NOl`r NO " In r- la, . CO LO l17 CD lS) Cp Cp tp tn t(~ 1n l!7 .-1 - - rd .-1 .-1 .-1 - - r-1 'r .-1
NN~' C'7CDr1NOMlC-Mtn ~co "-+C'rd'c7 O r cP C7 N V'C7C7C

" 7Md` cT .Zr co co MC'J
u~c7rcOa~OriNC`~d'tncD NNNNCVCJM C+7 [h C7 C7 ['7

O O O ti

# a

L 

### c a .zy a > . y

.TC O

. .~ r . L .~ O td B 47 .' . O W b ma y b

. a7 > a7 'o L C 'L7 O r~ V7 L OO C m " a7 . I N _T 3 c T a~ n 3 0 Hw N N B 

### ¢ 

# a
W N

CJ N

N

0 .L N a c 0 m c. y N .G h

N .b 

## a

ac

N

N I
O Z e C G >s O m m

. ~C 

### a ~ K m w e

N 

### Lrn c,) co cc o t -,r cn m in co o .-1 Q l, l- ~-7 I- G`') m co cD NCO O~Cl OO

dl - ~ m

N~+ r+ NNNNNNNN I-1 N NN
c-Ot -IT mma~ul C'OOC~ C-mcOml- cc men C7 P~cDm mmcID rnme~00M~O.-(

ry .-1NNN~NN N
C') cD [`J c0 O cD cD 1rJ I~ CO N t17 [- CO VP "-~m COOoUJN ao(MCM'mmc7a~a~~OwQ .-i ~ N- .-i Nti .-i ~ Nri N
in 00 NLnNOOPJ tn O d'M l`- CD C7 .-1 N O v co N (m O C] C- OJ .-1 CO CO N CO CO C~ ~ 00 Q~ rl .-1 N
a~a~nininm minLn CD O cm~T Ol- O Lo (-- N LO I'v CD N Cp CD l--(nl-CO CD 00 C- CO

ln CQ700NO]d'OOtfJ rICD00 l- N -1 ~ d' t0 O O) Lo M V L`- lt7 LO l,- lf] CD [-- ln 'cf' il) CD CO

~ ti~nCa~cOt~0d' cOaD c0 CZ ~c'7Nd'OC'~c. c']iP r-1 C'") C'7U'7C7CU7 .y07 P7 C' d'~



## cmmm cn m m

.-~m.~+'Ir OO " -1 l- Co C7 '-1 CD C' C' C7 .-4 CNNC7NC'] V'rIN N C'7 C~'J C7

~cco .-,oc-~t LnrNO o7 O (-- c") c7 'J .-r On cD O N .-1 N
C`OOC)O "I, Lo cn POO C7C7C7d' V'C'C'C'C'C'v er

N O U ~. , .c c U O ~mC`7(~CD O7 U7 C') Cn d'ONN'IT O NNNNNN

m m 07 m.i l-- c0 LO V' <!' l O ClQ1NNCJ ~ N.-1 NNNN

.d Cl N LO Ln Lo NCOtnaO .-i0700NO~ N- NNN~

c0 N ~ O v cD cn N N .~ u7 .~ Q) [0 O) .-a '-1 ~

NN C7 l- O

"-1 d' CD co NOCI] CO CD t-CO 07 I- .-1

~r lf7N['- NM 47 U7 = c0'ncncol- Un

MV-, ' V' U~lODNCDNm to C'MC`J1t7CC7



## ~v t-mC-t- tC7 v C'7CoCD Co C~'J NNC7f7N


### in dV Q V M t17 Q) ~O) O m C) N
M O~NCTJ-, :p ,4'Ln Lr) L-) Lo m

Q

c



### e m wm NL- t- CON ONI- (M CD d' ONmNNr1 NN ~ N NN
.~O~C'Ol w LO LO Q] N CO Q) O) -cONNO -N-"""
Nt~Nxmw l v~Ninoo ~00000 ~C~ " -IN ~NN ~

- cnOO<PLn N-+ m

.-~ -~ O t a~ [~ a~ O

o0 ,-1 .-1 .H .ti N~

1171l- NCCDIn C7 N C7 I-- l° (`- lot--SO r-PCz 'd' m ~i' tfJ .-+ C7 Co CO N 'O' d' cD 'It' N O CD co Lo Co CT) 07 O t0 C' O O .-+ m M O c7 --i N

.-i m c'') NNN ~ NNNNN NNN

mC70)O d'Ln "TOOt1'JCOC70) Nc7 C] O L[7 t- l~ llQ' 01 Oc 00 N M m~NONr1 N ~ N N N H N N N N N N

C'7d'm N[- Q)UJC7N1l7 C'ti7 

### ca~ m:v .a .-,cCLnmvcrm

~N rINNNr-INN
.-1 CO [- C7 m

CO 'C' Q7 m

NN C7 ~L--L0 COLD ~Ioocmccocq COl- oOI- OCO0a000000

N .-1 N '-1 N .-7 N N
Ol .- c m

'v P]tOl t-- .-~mCC- c0 m

.-1 c0 d' OD d' C7 l- tn N W CD CD CD CO CD I~ CO 00 CO (~p ~p

"zf' NC' L: :V y' C, ~-s L : ~7` L : NQ' O

W c'7 O m t7 O [7 N in «7 Nc7 - .~ -cO ~' cO m ~v m -,I' co co in in in in in (-- m co LOco u') co cn 

## r+ .-r .-i r-i r, .-i .-i r. .--i .-i r, .-i
Na0V'Ot-M tDNm

C) O(M N V' N C C~ m .-+~ .ti ti .y ~ MOM-CONCDON rICON c' cc O

CC) [- un tn d' t- cc ll- C'J C'1C7-IT C7 C' C7 V' m d' m 'T -1:v 

## mmcM

coo .~O] NNNL° NNNC'3C7N ti r1 ti .-1 ~-1 ri
C`7 r+0tiNlNC700 [-c0

LOco f- c0 0~ O

U~ ln Co

Q O N 00 C. .-I -r N ~D l~ N I~ 00 N C'

LOW N V~ m l,- f`7 C7 tiNCDN NNC7Nt'JNC'J NC7NC]C7

WCDtl7 .-+NQNI- M '-1C7G7 .yd'COODm(_ CJO [-_ C " ~Nco .y r+ ~ ON

.a N Cl V' M CZ L- CO 67 O .-I N CG co co cc CO CD CO CO CD l .- I- CO O tiN C`7 O 

### w

O

cd L a

. O h0 .b

O L a7 G a L U O V U C Cl)ONco .~ln



### ONC0V.-iap M Cl) ca ao c~ cn mllrdr m~r'r -IT N1n "-I C7 rl .-1 OOC'Ct[7h lfJ N .ti Lo CCO 

# ~c v~ ~r ~ rr c~

a] m co O " ~ OoI m

00 c7 O) ~P) d'
lCO 'D N N "I CO CD 1f7 ln co .~ ~ O C] c0 .-IN NO m CrJNCD CJC'd'C7d"d'c"CC7 V " "t'C7

QO N C'7 CD U) zr m LO mco co lzr m v'ca0<Mco0 C7 C7 d, C`'7 m I'

L .- . O <d 9 p~ .' . a1 c O cd F i ce ~° a> > G . . . . O



### z >. 

### ca w hy -a o i +~ VI " C L +-~ Q b0 L ., pp y . .-" I d a 3 a y c >, O 'D U b L \ 3 o e0 m F m " .x

d . \ X [z1 B m N m (M 00 "--~ V' CO Cc C)Nco M

d' NcDQ)Nt0CO M M 07 cl) M

M h01) (M O

.ti N

0 - U L .a c C`') CO COco N c"7 M' .41 00 CD O cO Cc .ti O

cr) V'C7 Mzr 'WC')

00 N0Ot- 0 ~hMCOCO t.- 00 CC Li7 M

h .-y m C') C ") L7 C7 C'7

-NC7-1~'lC1 CO co co C') C`7 C'J C'7

O O O COOa0cOhh

~d'a0 .aco0 V'd'Ntt7 1'l[7 NNNNNN

~-iF000 l17 CTJ V' a0 N

t- COC'7 N

C7 V' v NNNNN

N

LO u')-zV h ~"v d' 'cl, ~ O

c' 00 NN .-1C7NN NNNNNN

~ h h CT7 .~ 00 LO V' co C7 t m '-+ --i (M N O ~ N N .-INNN CO CLo co hpp V " CC'C

" V V



### m-- -- o U L c O ln C`] N C') CD co

d'hcOv .-~O 

### t- co comhcc NNNNNN

co 00 00 Cc .ti op c0 c7 C co h co c0 V " tn N Lf7 ,zr NNNNNN

cm ha' .~in~ OOOm

C') l17 N -,I " .-1 ln V' NNNNNN

m V' N CD N N N CD cD co co .~ 07 O

cr) c "7 NNNNNN
hcOM

O .-iN co ca Cc h h h

0 O O

6 7 c X ~ y m c a v, ;p m g a Q TN mCO 

### w

N L c T .b a N > . T y U \_ 

## x cd o L . .-> \ m W N L - O cd 9 y .~ N C O W i
m > G
. . ~ a~ p L C
. m w ^d O .c N 

### no x
. . ~e GJ aJ I G c -o a7 O 

### ~ o F+ [+- 

### i a c ¢ N

W CV

N N b L d O . 0 L N Q CO

O Z m 6 ¢
O T7 L \ 

### ea be
. a \ x en c4 e

x m pQ~t~C7C-OCC OC-WWm

c0 Lo Cn CO (A .-i I'll m m tANC0 NN CV NNC7NNNNNN

O] I-- LO C] ef' .-1 m C' --1 00 V' 07 

### in~roNcmocom CO LOt~cr NN co G13 NCJ NNNN NN

d' O ~ d' LO a0o0N~1o00) CD U7 ~," CONC-ccNC7CW ~~'L17 NN CV NNCV NNNCV NN

cD Lo .~ c0 .~+ O] m C- c0 W

LO l17 d' NV'OW

C'] -IOCONNC7 NNN

NNNNCV NN NN

C7 .-1 V' Q7 In co N m co CD c7 CJ N H N (M LC) -y '-1 4) ('7 O O
- N N N ~NNN .-1NNNN

07N C'~h-W ~[- co 'IT CT]la~a~ O [~(N cn 0[- Nm co CIO N N

r1N C] d'LO CD l- COO7N

-~ O U L

. ., . .~ t C m o >- U CO v7 C7 ~N N co q"Cncm 03 aJ N N N N N N

C'NONC-C 

### ao-Izr cacocoti N NN N NN

.-~ 00 l- a) Cl) cc CO N C7 Vq co l(7 N NNN NN

Om c'7 m ~d"O C`'J C'7 Co d' LVLVNNNN

.-I m

C7 . Lo CO M NON .-~O N ca C14 NNNN

NO NC0,^7 W -+Cn OOOW

m N.-1 N

.-1 .-1 -

C7 d' 1flCD[~ W

O



### mcc MM [-1CJ .y [ .- co 1n co CA c NNNNNN
C') ~ ODo El

## co c~ r- cc tT cNNNCV NN

00 CO CD lzr OCc !iq l17 ln cD C7 In N NGV NNN

W N C'7 O) V' C7 Ndr C'7C'7NC' C\l NN NNN

.-ilClN r1CDG7

N m

^I :7 NNNNNN

CQ Lo CD c0 C

Lo o7WOti00 - - NNNN
O~O~NC7V~ .-INNNNN

O O N o] O G') a] d' .1 l c0 d' .-~ .-t 6)

~ cnOM

LO 0 co C` tom a) m C7NC7NNC'7NN NNNN

NO co .-iNM

--I cc d' .~OOLO r,t m

occtm

amc-m

aoco-:3, C)NNC)NNNN NNNN

--~NM

l~ NCD CD mCl) Nm co mmm

m C- l co C Ln = mm N N N N N N N N N N N N

d'cDCDCDC']Ln 00 ,Z!* cc 0 Cc LO d"d'N CO d'L1J LO C V"d'C'IN NNNNNNN N NN NN
u) u) c7 Nc0 00 'd~ it7 CO OO t~ NNO

C7 C'J N

C7 N.-i C~ C7 O NNNNNNN N NN NN

.-1 W

co d'tf70NMlf7NLl7M OW p00 .-q W Om

aO N r-1 riNNNNN r1N .~ .-~
tnCDI-W

mO ~NC+7 V'tncp NNNNN

C') C)[7 C`")mmm

O O ON G`7 O
m

N m G
7 m a a +--~ a] ^ -O " U \ a y +e m O L m m G O m 1 .2 ~ C 

### o m o m m m N r'~ a -. m -o L q m w v o +~+ m L QJ OO ~C



### - . m
" Q] al _~, .. . G T7 3 0 FL, N r7 a C .D C 

### -~a b ¢ N

.b N

N N .b O L U R C O m G y C 6 

### ca

0 Z m a .c Q R >, O \ n b~
. ~a G . \ x eo Cz7 6



### x NOC71- m -4v U7 V'U~ Nt~~c7 CO l- (MCO LO O l- 00 co 00 00 00 - .-1 .-1 .-I ~ N .-1 .-1 .-1 .-, - .-1

-C'7 =NmNL-knM -It C'7d' cn a0 l~ 00 c0 I- m

L~ tn O

t- W

C7 cD .-1 C [~ V' Q7 l~ l~ lf7 O] ~fJ Ln cc Q7 CD Ln CO l'- CO lf3 L- m 00

C'cG ln CcNV~ L- t- co-OM c0 cD C- CD C~ CO l~ l17 t(: l~ h o0

d`tr"117 C) .-1 L'J .-I NaJ -,zr NLCJ V' co cm Cn 00 l~ ~' CD cD C~ 00 00 ~~

ti ~Hti ~ ti H

ti

Q~O~N.-ic0 C7Nl~ [~07C7 Ln Ln CO Ln (h L- C'] LO CCD 47 40
l~COa)O-iNC7 V'~f7cDNG~ C'JC'~CJ V'C' V'd' V' V'~Tv I

n~ - -- a U G

. . .~ .O C a~ o U ~ ~m NN .-1 O r- c0 M

O M Nr+ .-+ .-i Nr-1

a~N~McOaoO c0 aD c0 cD O C~ .-1 .-1 r1 .-1 N .i

tnCON :~COL'] M CO f- C) GO 00 .-1 .-I r-1 ~-1 .~ ri


### comirncncoo co cDCCcocor u7cn0 t~00

~ O ~ M

m M ri .-1 .i .H .H .--1
C000[~OCO 

## caooincoa~t- ~i r--V ry .~ .-1 ~-1

00_^~N .~c' 117C- C0 W

1- 1 .0

CO NSQ r1 L- c:J Q' CD If] (- CD Ln



### P O .-i N .-i cI m

cmUn ~r cn .-~ cD cOc0 P

co c0 1 C'7 t- "t4 CD c0 l- .y .-I ti N

.-+ .-i

O G~ c0 C~ c0 .~ 

### cc<r~rrunco

o~P+iNC7V~

O V 

### m

u) v in in v 

## ', ".r - -, -

t17C~I~ COO) O 

### Lo u7 u7 min cD

O O N

C7 

### w e m ~nM6~ FcDI 0000 COO c0 t- ca t- c0 (-- ~ I- c0 c0 O O)

min .-i0 ~cDNCa C-'d'cD~ L [~ h t~- t0 t~- O C- a0 f- Q7 CO

l~ CG r+ ~ r- Q7 ~' N .~ r, r+ C CO I- GO lfJ l~ cD M CD N CO (M 00

u-3 Lo ~~,-"r+N : :070 ~ CC c0 cD co tfl co co Cp C' OD CO CIO CO

CV CO C7 N r- .-i C`7 CD lf] O 'd' tr7 Lr) N

Cc N

Ln m

Ln Go C~ N

d'~-+a~a~m~~tM~l~0irn0 

### Un U-n co v in in t- zr cc r mcn - - r, ., . ., r, r, r,

.~ NC~7 d~ ~C7 cD l~ 00 O~ O .-~ N cp cD cD CJ cO CD co cA CO C .- C~ C~

O O O riN C+] O
N

y L C T 

# b
T T a~ W 

### .--a U \ K ca O L +-~ \ L O ca B m c o cd 

### 7 T7 cV y b cb . . . o> > " 47 'C L G T .^" cd w -o 0 L d mx

-. cd y a C 'D a7 O F Cz . I`7 m e .b C 47 Q 

## <r

b O L a1 

## a m 

# A L 0 N

d'

O Z m 6
a >, a ~ O 'fl L \ pp ho p . \ x on WFa

K d d~d'Ntc7Cc cD

LOc~ oc, cm co NNC'JNNN

a~o .-+c~N~ c~co o~ <r oti N N NNm

N

a) C`') -I O

in N ~W 00 V) 00 N NNNNNN
I- 00 a] O

-4 N

W - U _L C d O U

U

cd S 00 t!~ O 07 'O' CO 

### incO cl- Napu~ NNNCVNN



## m cou-~ mcoin LO ~~L- 00 m NNNNNN

.-~ co cD .-~ [~ d~ m l- 117C0 L- N (.,a NCV N N N

- N m -,,r X0 co C7 C'J C'] c'7 C7 Cn

0 C O m

(MLO C' NO 

## rcn (I- co m

(M

o Lo Ln irn ca Ln 

## cl- CD00 cm00 00

N 07 co .-i t0 Q) L~I~07CpNm

.-I N .-1
C'1d'LncO [- m d' C' C' CCV'

a~ o U L

~ U

C7

® G . 

### ca~md~ .,~r Nll- O

CD - m N.-iN - N-

m (Mto w

(M 00 NCOml`-07m

cr .~ CD CD Cp C7

- 00 ( .- C

- O] m N .-i a r, .y .-1

t- 00 (M 0-iN 

### cc mccc-Nr

C O tiN ti O
m

i 

### c.

. 'o y
X +~ 8 a) ~ m T7 27 >
. o "o m c 

### . au n. o au L m a 0 m -a 

## n I +~ W .q U pp . ., .~ EO a~ O a w am e 

### x m F Z

B .b N a b 6 E- U

H U ¢

H N

7 U a) aP CG -- d d m o . O X

V '~7 U M S v

x aa U C1 E



### v w

.r

.b `

N 0 3
a \ 

### 0 x 0 z a7 B Q CL T o b eo ea " x CL `\ X bo G .7 9

d QJLO OJhi FMl1] NO (-- M ONCnm

N~ OcOM

.-lm M NC7 NNNNi C'7 NNC "7NC'7



### .-a .~ 00 l,- d' O tiF Iz w ~t- L- Q] CO O7 L-- LA ; ,- ", l(7 CD CO (n Ln ^I .-1 .-1 .-1 .--1 .-i! N ^I rl .-1 .-1 ~-i

COOOONLn

00 CG Q] MM LC7 : M

l- .-~ Cc V' CO E- . .-1 l(7 .i OC`7 i Q] CD N.-~ CC N ON .-1N00; titiOM NN

CO C7 d' C`7 COa0 ; .-~ O~ co [') co TJC`7 C7 ('7N Ni C7 C'] C'rJNC7N m co o) cn cmcq ~ co co com m cm

v r+~co00 OOOaJr+0 NN Nr1NN M, O r+[- ~tn (oJ Qi GO MOp .y r-1 .-y .-1 .-y r~
N d' V' O) v Co m Nd' CC) Om ~v t- [- l cc CD CO CD If] CD CO! Ln l17 LL) U7 In lf)

N CD O a] CO ~i O) M co Cc Lo V~ LID m

a0 m~ l~ LO ~- t t O cf d' d' C V' C~ V' 'V' d' C 'V' tI7
O O~ O C'7 m ~ ~ O) .ti co Ln 00 LO Lo Ln U13 LO-Izp 

### in u7 u7 u7 in co
c') co 00 l co O rl r1 i[7 L- rl N .~v 00 t- c .i C7 00 O) lh O

d' F titi

MN tn .--IOptI7i COON O)C7 N Cl) -,:v -t'Nln0 ; Cc d' - CV N m C- ll- (- Cc L- C- : Cc Na0COa0U7
c. -iNC'7d't17c0

; y lc0 m

O .-~ N

N --+ O U
U L

. r a a, o ~ :.. U ('7C~N0 LO N M " -1mN . .iC] C13 C, NC7C+7(7

M ONNCO cna0t a~Ocn .~ . .r1 C13-



### -1 ONNOc')
NLo NCOLn dD N1- LO 00C7 M ~ Nr+ 00 .-i O ~iF~ Fti

.-i .-~ 07 O cD O) C'7 CO C)C'7 NN [o C7 C] C+J co CJ
cDaOCOd'aD" OmmOMO N~-I .-i NF N
NC~Ln OOCON Na)cOFOti CO LO St') cm to CO

LP Cc 00 C' C'llf] CD N CD CD CD C'Q' C' C' C' C

-~ V' tn C-) ~a' 40 In rM Ln L17 l!7

C7 ~D C[- C- 07 .-~aiN~Om rl ti ti
C')Q7NNCoCy NN NLO = O L- N ~ ~cl- tc'»' tn m

C- 03 .ti .--1 rr --i .a ~
O

^

m r1Nd'CONCD

mON NC7NNC`7C`')


### momomV

t~ .~ L-n M tn t-

. "y .ti ~ ti .~ N

C'J~ NNv,--i
NC7COON0 V~W co vOL ~~ONC`)O

u7cn NcoM O N (+] C-) N NC`7 N N N N N N

CO V' co CO N IT MMMOMO .-1 rl .~ N r-I N
O .~ .-~ Cy si' - .-i 00 O) N00 C7 CD Lo In CD ln CD
Unt- O

m NCp ~D r- RT C' C' C' V

'Q' d'
-y M co C' Un tl17 V LA lf7 l1] V

LO .-1 cD O

co O NU70NmN

C7 mco CD l~ Ca 

### Cc co mwo O N~~N00t-

m O .-i N Mw .-INNNNN
O O N N(~ TCD lc7 C`7



## r-cocoinoco NNNNC'7N NNC+7pV'(- 07 cc .-~ c0 N Cc' N N C`7 NC7 N

I- N .~cD O7 N : C' O Cc Ou7 O Lo t-- Lo Co O O i O

Co LC7 c0 .-7 Co ,-1 ,y . -I r1 N C-4: N . " i ti .-I N ri

N"ZV COI OOd'ri00

i
M NNC'7 CO M

~ Op CO ~t) Ln .-I N i!) O co ~ .-i in : Nc0 O c0 !h COON

; ~m

M O~O
cOONNO)00 COCOC'JV7LO C7 M (n CID C7NNi NNC`7NPJ N 

### mcn cn co m

mi c~ c') mmm cn

N N CD 'V' 'A Ni Cc [-- 00 O LO CO 00m000 ; COaoQO(m m Cc NN.-1NNN!

00- v FLn ; l- N C'C`7C') LO O ~ a)

.--~ r+ '-I i CD [- CD 00 QO [- co CD L!J CO CO CO ~ LO !C) LL') Ul) LO 11]
CD Oa0v W

coi cz .-+N .-yITC .
. . . . . i . . . . . . c co CD v Cc C04 CO CD f`- LL7 CO CC) 'IT ll~'V C'f'"t i d~C' V'C'C'd'

CNcO (- Cn O] : QJOOOI-- N .-1 LO 1n LO V' LO U7 i lf7 117 ln V Cc If)

.1 l- ON[- cni CX7 C'7 ~ v t~ Cc NO.-IOm

[-- : CO m

NNOM

to cr N C7 N COi L- f0 00 N CO LOrnNCo 117 ; 1170 C') l,- co - C- t- l [- C- t~! 00 00 00 1-- 00 00
T 

### c. rD U) m l- t0 M

Oi > " rNco V' m N N N N N C7 i OC'J : J lTl C'J C7 C'') G1 O 0 ON N C- ,
m

m L c
y
.U-. y 

### " X --~ o C
. O -^ cd O ""- b > .D .b a~ a a~ w G . O N L W y

-; U

- . pd " U O i y a c .f m a F S N C B 7 .n C .b .D Q a

E-^ U v 4

F N G

a U d m

m y GL \ X

U "_O U ~0

- m U GL E

V w S

w

.zy \ '~ Oa J \ 0 X m 3


### 0 K
O Z CV Q C1 ~. a ~a ba EP Y G. \, X 00 W 9

X CO (D C'3 (- i .- N CD NL17CONC0 ti NNNN~ C~ LO C7h h47 NNhN~PO NNNNNN 

### -,I, LO NV'mc')' c+MOOcov 0

. . . . . . ; . . . . . " U) Ln LO Un rN V' ~ ~ ti F F ~

NOO7rl
COcn 00 0

cm -'d' 1* Lo Lod'

000000

m M 00 C- O

.-i OO

.-i~v' co c0 r1C7 NcD= m NNNN~ "~

~ h .-i 00 ~17IV Lo C ~C7

ONN

. " +ON 

## a c ., a~ h un cD h Lfll-- O hi co OOd'C7Do d'IcDNC')011fl V' O C`) co C`7N ~ Co NCn .ti0 .-+

N O N M

O aD; N O co O N h~ C7 Cl) C'J C7 M Mi v d' co "i' C' P7 

## c-~ co co co cn co; M

M om M cm c+)

C~J ~ l()OtflCOi rfNd'<l'riCOm o)OOn 0! cm O400m CO N r1 .-1 N r-1 C q' ti C4 -' .-1 -K r1

N .--1 OD cD NU,3; CO tdl 10 C) 00 co '-1 O~ N Q) OJ r1 i U') Q) ,}' C- 1l7 lo COSf7 m11] m to! lfJ llJ t!) Lo I1J ll)

.-I N Q' N h P7 i [~- .-I C7 h N CD u7 C') LO c0 CO co ! C) d' h C N lo

Ov) .~in .-aco~ OOON"t Q' lf~ C Lo in co Ln i 1C) tt) tD ~f) V' 1 .I)

.-1 O CO O1 C') C" : c') O C7 C7 T 

### aacoaohMM

; ca M

co = CDc~

h .-1 C7 tr N P7; ,V m 00 to CO 1n C7 C`7 h l' " NtC7 ; oo er tD 00 l27 N h h h I~" Ot-! C- C- co C" l"- (70
h 00 CJO~N C'7 C7 C'`') C' 'a' d' T L ~(~7d' 117CpC- pp oC'C'CC' "~r!' Q1 d y ^ O L .~ c c N O > U Cl) C7C"crNOD C) C7 C7 C+) Cn N 

## mM mm~cn

~"~1 C7 O co t'] N cn 00mM

0 .-1 NN.-I ri N
l-- m cn h0 CD hOm

co CO .y La CD in I17 to CD
h (- 47 O

.q t - U-) CD Co h V~V'C~V'V'C

N Ql CO "q' C7 CD InC' V'LOu71n

.r -

NhCDN0 L] m m O c7 h .-~ ti ti ti

C7 V'Nln Q) C7 C7 GO 07 t-- t-- l'- C- hhh
M O .-+ N t'~ V C Ln Ln M

u7 tn
O

N

10 B U Ca. o~hQ7-yd'O CO O NNN"r NNNNNN
Ln C7 NNNM 

### Lo d'm,r e' v

--~ .--

OC700
O v m NO7tn ID ~hM

0a0 O

OcaNm

O d' C7 C7 C7NC`7C7 

### v-) c7 cmm

co cm

.-"+ h L[7 M

~ Lo (m 00 an O

m cn ti .-i .-i N. .a rl

DO h CD t- f- N h to Op CO U7 LO L!1 CD U7 U7
h C' CIO CO C'C t_ CD -'r CO 117 "r V' ~t' <Y ~' ~

.^ d'
CIO co a) 'cM O

cc) 47 u7 V' L7 L-) V F ti - ti - -

"V O Un in o ") d' h h " V' ~00 00

N Lo V'Ln Co t- NC'J CD La 00 CD cc ao hhNtin co hc000

O O N " -i OLO ~C'1 in; Cc h Cm c " 7 L~ c0 C " ) ONrl .ti -t- l .-1 N W C'J C'J Cn NNNCV NN! NN^-INNN

N C7 lf7 d' Ln .-I ! N Ln C') N ln C']

. . . . . . ; . . . . . . ,4, Z), in ; tn V'mtn"I' cn

c+) -q N.+cO~i 0 CD C :)
hC-co OOaOm

h Co Co O

Lo C7tf)i C'[7 a70 NU) Nw C'7 C7 ; 'C' O) .-1 d' ~ N

NCOct+00[O

; h C7 LO C00C) Cn C'7 Co C7 Nc

q : C7 V' [7 C') C'7 

## m co m co m clI Cl) co m

cm

cm co lncD~r Ni NCONU-) 'i'd' m O C1 Q] G1 O

! a) a) a~ c0 0~ cm r1 N ' "1 . "i .-I N

m cc) 0Lnca=1 M tnNh O, ' "1 cO O O .-i i co h h v h lln CD V) lL] CO co! lf7 U-3 in It] In 1f7
cD CV cD CV <14 h

i C] d' "-1 CO C'7 t-- Lo m

co tD ~+! u7 C"NC'C7N tv "r "r C' t^ d' i ~' C V' 'd~ C~'

00 - C7 N CO cc) : C') N rl O CD CTJ lf) LO Ln In C' Lf! i L17 Lo V tf) '-I - - - - . "i ! '-1 .y - - - .
d' c0 NOO

-4; c" 07 Lo h h N to 0[- : hOa~haOCo

sM .-I Cc [- l17 lf] ; h c0 .-1 N 00 C7 Co 00 h CD C,- : QJ h C7 Ln C'7 hhhhhh! hhhCd[- h

a L .-iNC7C

. LoCDi> hC0070-iN CO CDCDCD co co~ocnmcohhh ~U I iFC O O O ryN O G

N m

.

### a .a m a

" x - L O -~ C7 ~ uJ 'D ° v " >_ i d y .~ . a~ w a o d c. cd a w i .-+ m t U m " ~



### -" m m o y ° c w me F 

## m e b ¢ c

S

N m m a U O 

### x m c ° y 

### 0 c m 0 w y N w c m Z

w m z 0 z a Q n . >1 c m o -ct\ e~n eo x ca ca 8 

## k m tn 00000 : tnO00Lo0 OOOOOOi 00~000

OLn 0000 ; LO 00M

in 0 C'J (- cDLIJOJ C-i co ONV'(m"r m m cn m m cm: m

cn a) m

co m

O COOO

O ; O

OO O O O O OOO

O O ! O

OO O O O

Ln m Oin00 OOmm OLO O O r1 O.-I .-i i N N .ti N N .-I

000u700

; OOinOOtn cc N c7 .-1 C14: d' OD Ln C'J 00 C7
C)00000 ; O O O OO O OOOOOO ; 00000~

cn -'I' Lo cc 

### a

c. j [~ CO °) O

.-1 N d C 0 y c'



### . .~ 2 c N O ? U 000000 000000

OOtnp00 l-- cml1) CD CO O) 

### cn m m= c cn

O O O OOO 000000

M 00000 O ~ O

LnO mO O O N C7 CC'7 - O

O O O OOO 000000

C7 V' ll7 Cp l- CO

O



## m It x OLnu70m0 O O '~ O O O

OLamtnOu7 -,t r-- -,v L-- (m 00 m on cn cn cn cn

O OO O OO 000000

m m 0000 OON~00

LnLn O

u- j in Lo U7 -y N .ti O .-A

O OO O OO O OO O O O

a) O'-+NO7 V ~ NN NNN
O O N Loa Ln O OO ; O O OOO

O O O O O OO i O O OOO

O

Ln 00Lnm0 ,T Lo = m

m co mcn a) m

0= Lo mLnOLnO

OtnC7Nl-- a)mmmmmrO OO O O O ; OO

O OO O O O O O O O! OO

O OO O

m in OOO

Un~ in u7 000Un
" -iON0

; C' ., .yQ'O17

LnLn OOOU) ; OOU'1OU70 C : d' .-r LO C' LO C^ . l17 C' Nc0 i

OOLnu7 Ln0! OOOOOU7 OOOOO

O ; O O OOO

O

m co[ aOmOO)~~nco NNNNNC7: OC7C7m C7(~~ U i 47 0 O O tiN N O
m

N L 

### c

N y N 'x O cC J C w L O U C N b O " -~ 'D i m a m ~ . . a . o d L a I y t U pp .r " " d O I ~ " + a O +~ r~ c7 cC Q7 B 3 a) F s C
B C Ql Q 

### 0

x

n . a a

m y T U O d 0 CO
.~ C .~ C L w 4 . c .O

m Z

m z p Z
e .q Q
cC O 'O L \ ~U 70 G \ Cz]

U h OO

O O O O ; O O O O tn ~n F 00000

; O o O O O O 

# Ln OOonLn ; oOOOOLO l-- l- COmo)CDi NO]O]O] . 

### mmcman mm

: m cc m ao (m m

O OO O OO I O o o O

O O

. . . . . .i . . . . . . O OO OO O : C D C) O

O O O

LO LO U~ O00i u70toOOLn O O OO O ~~ N^7 O

Vrl N

O tn tn O

LO in1 irn UM irn m O LO

. . . . . . : . . . . . . .-I N O

c q: m

l- O co L~ N

000000~ OtnOLnLc70 O OO O O O ; OO

O O O O

L [~ W Q70c'JrMlr7 Cc 1.- 00 C'JCO CJC

: UV'V'Q'C~TC' C N ._. p U L

. .y y t c U O U OOOOOo O OO o O O


## oOMOOtn a0 O [- 00 l- p) O) 00) TO]Q)

O OO O OO OO O O O O

CD OOOtn0 ~O .-r000

F O .-I .y NO

000M00 OO O OO O

M C) -I NO» V Ln U7 LO Ln Ln

d CC B QJ OOOOoO 000000 

# oLnoLnOLO cn 'n 0000300 m cn Om

m p)

000000 000000 O Ln O O O O ; OO

tn oO

O 

## Ooooool 0o00oo 

# ooLOOMO

; ooLnom

o tl7 'm l- Q7 00 co : V' V' -WN Lo Co 

### m an (m m

cn cn : an cn cn m CD an

O O O O O OI O

O o OO

O O O O O O O ; OO

O O O O
-) OOu70LnI00Lntnmtn; O to t[) OLnu7
. . . . . .I . . . . . . . . . o000-+OIC)0000 NO-yv

LnM 0000 O V O~ti~ Q Ln 0 u7 C) in ; 0 l(~ ln {IJ U] U]

N O N o tiN : d'u]p7m NN

O O OO O O 000000 OOOOOOi OOOm~nO O O O O OO ; O O OO OO

L mcDl cOM

O t17 l17 in lfJ Lo CD .tiNC7 C' M CDi~ 1- D0 M O .~N CO CO Cp cc CD co : U Cp cc Ct7 [~ (lI O O N O O O ti

# p. 39 N t~7 O
m

N W C -o h T y

" U fn O 6 y .~ L .~ O W N 'L7

. O > -p .^. ~ t7 'C C c~ .^. cd w+ N O a au ca c . +~ m a-o +-~ U ~0 9 " ~ GJ "d L 1 U T r~ 'a G O a~ o 3 -- F- m i 6 b C N Q O

C c . C7 <
c C 

### b m G d a a 

# a \ i co F al m a o v

V B F

a O 'L7 .C \ U Lb E-"


### a. -- a U \

W = L .- .



### a c . _ Q

\ E^ 

### o . U v

a O - G7 ~~ 0 z cd Q C . >, ~ aJ O "O eo ca n . \ X CO (J7 6

>< N CO N

O -,11 0 CD O~OOON .y 'r .~ r+ ,~ .~


### Go cn ooco m

o CC ONNdl (- 00 .-tNOW



### titimw

C- ~ NN NNNC`7! NNNNN N

V Ln an l(7 00 in 

### ln Ln Lo in uz m Nd' C7 . " 1 C7 CD

C7C7 .~a)ONi l~ ti' O .-iN a) NNC ")O ~M

; M Lo U~ N

C' co

~fJ O .-i V 00 co ~ moo .-1 M CD CO Ln N -,z}' CO (m lfl i In I- Ll) d' V C'

N C7 N V7 (M 00 : Q1 t G') C- m -4 Lo Co U-i In lf7 (7 Izi' l17 !}' LO Lo
O] l-- N .tiC'JtC : d'40 CO N CD I-- NN M

NNNi -y .~--INN .-1

C- OJ CV O] .-i u7 ! C7 a) C7 N ln LO C'] C7 C] 'C' C' N ! C'7 LO 4J C' C') C'J

l C7 .-1 C`7 Q7 47 i mN ll- N ln 1f) o] O 00 f- m- ; O V' O c0 [- d' V l17 C`7 d' C'] -, :V! C') C') O7 "'mC^ .

N CC l- CO .-1 4o ~ V' .ti 4'1 .-i d' O~ NNN

CV Cl "! NN C'7 NC') N

l- T .-~ [- C7 co ; L- C') V' co .y O~ 

## co~rm~~; t- t- L- CC Oo

.-1 N [7 d' lo Cc T



### c. cc On orlN 5 d r+ O U L N 

### .c c U O U C' I-. NOO--:v co-iN00 .ti .ti .-~ rr .-t ~


## a~ a~ a~ o m

m NNNCI7 NN

1- U Lo 47 CC (~ 

### u-J minmmm

O .~ co rl M LO [o NNNN .~

OG7cVCo Lf7N O ca [- CO CO '0' H

C'7 00 O

t0 v O U7 'C' M

LO C .yti CJ LO to



## 00 .-~ x c'-- co 00 `T CJ Ln l[7 S"

m C- m N00 ln v Co O

"f, 00 N C7 m

C7

Ufl CD co m

Coco C'a .--INNNN

cm ON

CD .-I m 

## ro Co r~r- t,

Cu co t,- 00

O

d OO(~(- tf) O

OOmmr+0 ^i^~00~~



### mmm

ca o co NNNNC'7 N

moomrcov 

## V) Lo Lo LO L-) M
,I- cm O

C7NN ^ico V, cn C+7 m ti ti H~ ~ ~

d' NO

jn c0 ~ h- C- C- C7 C7 in

CD c0 CC CO d' O lC) l[li Lo N 'IV C'

m C-) t,- C.- m

OJ C7 C \J' .-1 N.-i



### M cNm- ac C' kLJ V' C] C7

tC)m c'JOO0tn ti'O[- C') I- t-- lfJ lf] U7 CJ V' d'

VO m

v7 l~ c'7 NN NN NN

cc O co co M C' l,- L, . [h Co 00 CC

070-4 Nc+7 C ~ N NNNN

O O N l-- O [ .- CD Ntii cD co =,D N CD m O .-1 N

i mm

mm .-i m O O O o "O



## m ao r. o~ rn a~ titiE- tO t- CM NNNNNN; NNNNNN

C- co Ov U-) cr7 ; LOco m Cl)


# . . . . . .~ . . . . . . LO U7 Lm Lo Ln U-3 ; LO U) U] Un W) V)

CO 00 CO --i O C'7 CD Cl [-- N co co u7 NNN: co mm tf)NN
cov)c)o t-- 00 : N N NCCQ~ L[7 00 C' CO N CO V), tO C C7 .tr Co d'

r-1 i

N CJ 00 P') CO 00 ; V' N 11] .-i N Iu'] C' Ln 1n U') C'! ~' ~f' In l!7 117 ct' C]m~~Nvn .-ico NOOCD N .y .-1 .-1 N r+ i .ti .-i .-i r1 N '-I

C'T ;+)C'3Ln ;D ; CN :D O IT O V'zv CC U) co d' V' CU7 V' a' V'

V f') co a1 Lo Coi v OO - O O 00 00 00 ~CC R1C`')i CT)NM rrv N C' C' C' CJ C) UJ ; CJ C7 C7 mN C'J

C :),o C7 C' C'J N

i .-I CD 00 C~- Ln N C'lNC7NLf]Ni C ") NNNNN

I- Q1 NO- Oi 07 no 00 CDc0N 00 c0 a0 00 NC~i CD cD cD l-- Q7 l,- I 

### in ca [- a0 Im O

i > ^~ N .^7 V m cn NNNNCVC7:i O CJ C'7 Cl) C]C7C7 V
O O S

ooo i VV

# p. 40 N m 0 m

N y m L a
N T .U . tA >C W O 6 . 

### - It L .-+ O c

, O >
. v c 

### 4» W 6) O a a) Rf L + .~ b - I m +~ U s . . . m 9

. . U "d ~ I U q O 3 F m N ln
CJ 'C7 6 0

v 

## a
c El -2 m Q y G O J L 'O G \ I m F^ . .r

N J O L1 U `~ 6 U

J \ C7 6

O 'C r \ U ~m F V

n . --~ C7 \ I =

Gi7 ^ L

J \ C V

\ C . .- . C7

E- _ 

## o .- C7 0 Z

4 G. T O '4 L \ en no

~ . \ 

### x m r, e rr .-i1 .n00

OCO.tiNOO


## c,r-oocorn NNc7C7 NN

cD oO r C CD 00 u,l L17 LC, 1f) to 1S') OCrIDrN ONOamON .-r-rtiOti~



### m.-~mcamm NCJ NNNN

pp CO Co M

CO ~-1 in >n Lo 4~ LO Ln

M dl Lo .-I ca in ; clJ [I-Lt7 cO O O rl N N ; C`7 N.ti

M lt7 ln cD .-7 a) I l[7 c0 N V~ ~ CV

cD ~ O.1 d' Lo : V' LO cc 00 CO CD C' CI u] r i cc l- l17 lC) V' m

rl co Cl c0 00 to ; ( m CO O .-i lNNNN NN N

N u7 lr 'd' mN Co in r N .-1 L'7 G` C,') p ',17 ~ N ;p CM - cZ r C`~ .ti ~F .-i N V~ i M .-1 Lo C] N Co

~ d'r N r (-i r01o 'T co cm M00 " 3' in Go Ni r V' t- l- lf7 cc N .-i N C7 N N; '-I .-1 .r - .-1 .-y

CD M

.--I 00 QJ In ri N N'-1 r-1 N ll-t1J Op .i mCO N ~ N

cn 'm d

. C'7 u] cc ; c'1 cc am .-I Co M oooocorrco ; rcn'm cc cor
T l-ooO~ O

.-1N CMMC'J CV'~' L ,j C7 v l17 co t- CD

U O U_ _L -C C O > U mOcpCn d . <i' -I N m

.-4 O~



## ov~ c~ c <r r ~ .aOCDNON C`7 m NC7NCl)

t LO c " 7rnr0 lo Ul u7 Lo in G

.

moo 0c{1COCh C') ^7 VI N .-I C'M

C7 Lh cm m-~ tN N--I .~NN

cm 'IzP mv LO 0 ~O U' ln CD CD
ammin- ON

~ NN

cc a~00-cD -+ C' a) m

OM NN ~NNC`7

C`7 w 00 - tD m Nt--ToorcD - :JNNN N

mOmo=O --IN .-I

cc MLrJNCo V' 

### m t rrcD(m

mO--INC'7 d, 

## vv) v) Lo Lo Ln

d

~."

td

N m C l!] .-I N.-I .ti .-INti .~~

NNO~m

O C'MC7C7 C) NLr1 

## mo'~T mM

r Lo CD Ln v) UJ Lo

NDo mCrr .-INNN"T V'

Ln cn ~(m.-1CD NN.-~ .+ N ~

(m LO u7'O'MN cD 01 u7 C-- IIJ Imcoo~e~a C'JC'7NNNO]

Cc-~rCVrO NOC7frC7 ~ C'] C'7 C7 N N N

NmOL7NC7 to ooNQINr-I N~NNC7 :7

mooLn co co m .y .-~ ~-1 r-1 r, rl
c,4 co O

CO cc r rccococo(-

in <o r cc m

O m Ln u ; m u-) co

O N Oc10crL-i cOMcOcDco N

.-~ .~ O

C~J rr O

~ .-i cm O

r+ r+ .-~

NNM

OOt7a31 C~rrm mc co C]Nc'o NNi NCV NN NN

--1 mC

.ON NCO C'cDNln cc l17 l17 L7 m L17 ! l17 lf7 lo Lo LfJ Ln

C' N r- cm "

^7 cmi NNOcD CO d' N mN ^li'7N; C'7 N v ~ co C']

ttJ cc CJ cDI c ") O) Om Lt] CM ^iNNNi r-I .-INN MN

m V'NLncoV; "z- OD CO m -.:I . CD 

## t-r~rlnCo cc! cc) Ilzr cc co c-r

CDOmOmmN1 r 'm r1Q~ ~T N rINN~tiN .-i .--~ Nti

tn~rco ~-,%

'S --~0 "- " -+u7tn .-r c "7 v~ oo NCo: .-I cn Cm Lo -,:r O co c-) c,41

N ~ CD N m ri m

~C`MCO M

C7 Co cc CC L- cc OOi r CO C7 CC) N c .7 NC'7NNN^+, --ir-INN- r,

~D mC70 mml N .~C'7L7 cDco rICn NN NNNN'-IN



### co .-,inc-- co ooi Lo m v, inr,r r OOmcD t- co: r lrCOl La c0

T L ~NC`71, m

cc : c- Go c70 riN :o co cc ca co co : o co cc cc r r r

IcC

O G '-1

VO V y i v

# p. 41

N m n O
m \

9 U

Y J C 9

a m 6 z lf] (h CL7 -,r On O) ; t O cD m .-1 C7 CD Q) CV Lo SC) V' i C- tf) to [l- N to OOOOOi 0000--~0

cc O O] .-i LO -,r l C7 'd' a) co 'm O 07 V' CT "T cM .:1,! "!' C' PJ m d' d'

V'd'O NP')C7~ NONd~'i0) v d' d' d' d' rf' i CCC'd' ~' C`7 co CD Q) C'l O] CC`CD CL[7m in 000000

N N I-- N V' ,:I, CO v 2

. "r
-NC'C')CC) C V'CC~'C .a .-i .-a .ti .y -y an C- mO l- m tn 1n cD tn 00 C`7 000000 ".y .ti ti .ti ti

[- fD l1] cC Cc .~ MC7Cn Cn
(OC'MC'CJ lnM V' d' V' V' C

rl' N .--I l- l-- 00 co : .-y Ndo O~ CA co "I'm 'd'CD, d'i co t- co 00 C- O] 000000 ; 000000

O O7 .-~ co O

C7 i CJ .-+ 'd, Nd' V' V' C'7 V' co V

! d' d' -V u') d' V'

.-i C'] -C'7 CJ C7 Q' ~t' d' d' V' ~M .~NOwNN d' ~' c' c~ d' ~ Wlr~

L

.~
~U U] 

### x m o e c r. m o m a m t~ m . . . o > ^O d y .~. R1 W mO a d m L +~ a - i m ~-' U a GO 9

. . y a7 ~ I U a

. C O m p 3 -~ 

## s-" m m a c m 

# < a

'zy n- e

a w 9 U

m ~m F GN G

~ . .7 +~ 'U m eo L 6

Z CO CO 0 z d .q Q G >

. c m O "O 

### eo eo a ~ x m c.~ a CO CO Na] r1Cc' CmOC7c0U'~

N~ W

tco L- i cat.-cacccofL`- c] C'7 l- co UJ N .-1 CD Co Q7


### . . . . . .i . . . . . . cn m O a~00' (M 00m m a

cc m tiCO aOl-i a000 ~NO 00 tiCD 00

; O

r+ " -+ti~+ .-+

. . . . . .i . . . . . . O 0000

C :) : 00O0

O 0

CO CO O] rd ri 00 1 N m" C'J QJ CO NN .-ICV N N NN .-IN 

# 000000! oooocl o

tnd'Il- C'in0 NL7m

'IT Cl) C'] titi H~~i ti 

### o~a~co= mEN C C`7 .-1 .-~ ~ H ~ r1~r-1~1
a L .-i N c- -, :v Ln 

### o ._, ,. .., , ..,

m y ^r - O U L

. s a w o ~r U cb m [- .ti a0 m

mO -COO OO OO OO - - .-, - .y ti

t- co 00 00 O

co 0000-0 O O O O OO

-IT Nl~O0r1C0 CV CV - r1 N '-1 

# 000000

r- NO

cn er m ~' NN.-1 N.-1 ti ti ti - - H
C7 ~1' ~CO l~ CO

O V



### d V'c'7c~irnWO

ONt- cl- n00

Q' OM

a0 -It' r+ OOOcn00 .y .-i - .-i .--i

Om 0 ~Occ - O - -~ --i O O O O OOO

C- CC) NOC- CD N .-i NNti .-1 O O OO O O

07Nm

to L'7m

- - .y .-1 .-1 rl

c~t v7 C ^iN NN NN
O O N C' ["7 Co 00 LO 00 cm cD C7 cn c0



### t- r ca co t'- cc . cn m ea ro r- cm

co co CO N c] N ; O - .--~ .-1 CO \I) m = m

O m

0~ OOOOOn on ~ Fi r+~ti~

h Q] Cc CD lc] In ; Cc O N l- Cc .-1 000000

; CDF " -i00 .-+ OO0

00 0i 000000

d'Nl-- C7NCDi LO NC'm NN- N- --I ; NNNNNN 

## 000000: 0oo00 o

OLC)I-CDd' Wi C'C70 t-CON
~ Fm00 ^-~ ; CD IOCD NNm --1 ri .y .y r~1 .-I ! .y ti ' . - .-i '-1
L in tn [-w

070; ~ .-~Nmvtnco NCVNCV [V C7' 'OC7m07C7m m U i U O O O 

# 0001.41.N M O m

N L

.T .b y T y " U f/] 

### o e ~l .^ . C L - . O ~d aJ 'a y . . . O > 'a b 'b c y . . . . y 

### w .3 w o a a~ m L +~

+> U QO 9 ., y " O7 L 1 U T a~ 'b G O a~ o 3 - F m


### e a °m a ¢ ?

B U

9

` 

### ca w m a z ~-

'L7 m .c-- ®

Z7 m e am U
'[7 m ~m F N G c -~ J ra 'C m ` m m 4 8 U

Z CO m 9 m v O Z cA 8

. Q
a ~. 7 cd O 'L7 b0 bU 

### a ~. ee eo w e

x ~n .-i l 00 O

V~ N ~ CD 00 lt7 O CO CD O O O O O O F ~ ti ~ ti F CD 00 Oa0[- M

C0C~- .i00000

L" 'T d'C7-,zr C'i C7LIJ -O'NQ' V' -,t -,p C' CC'7V
. CCl) 'IV U-) ~~

.~ .y F Nc

") -4 : .-i -4 oc0 m o) d' V' -T d' C

c"i C

C' V' C'7 M

C')

OOOaocOC7; 'IVa~cD .-~mO h l~ I [P CO ll- Lq in co co ca (-

C- co 00 C- O

-i 00 LO C'- a' M t--

. . . . . .i . . . . . . m m O)cnOO! a]= (M CMODa)

T L ~CO rTV) CD I-- W 

## o<r-~r-,T v~ v c U .-~ .~ c'7 .-, ti C7 ~ O t, .-~ N c0 d' O C O OO CD! O O O O OO

G7 LC .i N cm C''J N C'7 : cO C'7 CD l- Ca ln NNNNNNi N C'J N N NN

. . . . . .~ . . . . . . O O O OO O; O O O O OO

tnMNC'QlaJ NN cD O] rl CO lntnln -IV l i m CD t-- NcDtO - .-1 .ti .-1 .-1 - ! .~ N .-1 r.l --I .H [- CO - 0--~N C7 C'7 C'') d' tY' d'
d -- o U L r c G7 O > U ~~~ONN t- CO CO <rcOL~ 000000

.-1 .~ me-1 CD CD

d' d' d' d'

C :) C) d' "T '1' ~t' V' 'It
u) ao co cc co v c0 co h I`- L- lcn a] t ONcn cnO»000

00 mO) W

O tOOOOti0 O OO OO O

O-ic'Jd'm0 NNNN- N 000000

O00Ln d' N C') CO C'7 tf] ri .-1 .-1 .-1 .y - O) O-tiNc7V , :r in to m

Un u~
O



### w

e d' [- Cp CD cD co U~ CO CO co t[J 00 000000

vCO m

CNC7 d'o7v <t'e'~'

.~c'JN~00 

## IT v -T --dl v, .-, - .r r. - ..a

O c m

d' 00 co l-- co co tm ~00 O

c0 cO 

# oOMaMm C .- Cl Lo N 00 00 ['- CO v) Co c0 O] cm O) i O7 CO N t`- CO C000000; 00.-+000

C-- Ncc to .-1 Cn-i [-- N CO O CTJ C' TIzT "tf'CC'd`~ ~'d"d'CV'~'

.r (M O m -4 .-1 

## m v co .Zr ~ra' O cn -4 OD m

m 

## <r c ; a, m m m ~" ' . .-, r, .-

J' M

Lo cm

; t- in Lo -,J'

. . . . . .i . . . . . . CO c0 l~ C- lh CO, CO Cm LO 1n cmcc



### .~r.- C-- ooc. .~ ; C() Cm Lo inm cn ommmmo~ mrnmmmm .,

in .-i OQ7 CO m loo a0 aJ O cO o) i O c7 cn N CV .~ - ^+ - O O O I O O O ~ OC :) ; -1 '-+ .-+ .-+ .~ .~ OOOOOOI000000! Co0000
V, O07cn C7 C7 Cl NN riN N 000000 Q1 O cV f~ Ncc! CD O) o) 07 to P7 .iNN NN.-If NNNNNN

. . . . . .~ . . . . . . OOOOoC ; 000000

NO[.- NL') :D CDN^iNC')LO r, .--i .y " .y .J,
LO cn[- a0 m

0 

### M LO minmca
O O N O C .7 CO l17 C' C7 CTJ m

co .~ - 'i .-4 t" O .-I lf) C .- 'c}- tl- co l- CD M

T L ~ NC7 C' LO Ca ; ~ f- CO OJ O .-1 N 

### cDcaco~~ :D~ococncnNt .- cI V 1 U IpC O O 0 4

# p. 43 N M !` O m

rn C 9 a~+ N T O a+ q 9 m W N ti O tp I 'O '9 . .~ 

### d > N {+ W O C C 'p a+ I m m U
. I T T .r .+ q~ C 

### a ~H
B a m ¢ C U m C L O 4 .
N N O L1
O D m 7 O C 7 .4 . m
y N C 07 Y

C i . O.

G

4 O

N

. > 

### 0 z c0

G T O 'C X m W e

a J W O O O O O O O O O O O O

T + +1 '

+

O lt: O u~ u: C t~ cD h CO 'D t- % l17 C ~ O 117 ti 'D !` ti t` ~

y ~^ >+ Y Y Y y Y Y Y Y

O O [~ 11] m C,3 00

T -+ N MC' 4] CD ~ Ql t~ 00 Q1 ;O ioz

N ~r U f.~ L G aU o > U O .-. N O O O O O



# +1 +1 1 1

C ~ ~% G ~n O c~ c0 tD l~ tp t`

Y >, Y Y >

. Y h VI N U~

O, ~ Mer CJ

N

O O C O O O O

t + + 'f'

~n G O O u7 O ti ti ti [~ tD t-

~n Y~ Y Y

t"M ~ m

^. ~D O N .r M

O O -~ N MV~ ^ N N N N N

O N

m co O O O O O O O O O O O O

1

T+ ~

+1 i'1 +1 +1i + '

lf7 lA O O lt) O ; O O O O O l17 n O ! " t` t6 ti ! !` !` ti n n ti

Y Y Y Y Y Y 

## VI Ln (n ul En y, >, ~ Y Y Y y U~ En

^ O t1) en O N i O O O <D . .

N N N N ; ,. .,

T ~ <O l~ 00 ~ O ~ C1 .r N Mv~ ll7 to N N N N N C'M I > f~J fM C7 M MC) i0 U ~ U

O O 

### a 0 ai T

. .T .c a m o in a~ Y 

# 000143

# p. 44

N A O
m

N 4 . G

Y N u U O

-. m .9 O Gm N N ti O W

~ . . . d > w a N d
~ O
u L 00 U

. I T > . .y C G 

### a w F- _ N 9 N 

# e C

N m C L O N \ v

m O 7 C
L O C U U O C 

### a s

y G7 C `+ N 

### x

c .0 a

[1

~. O c U

N 

### e 2 -~ e >

O Z
¢

4 a, 7 C O ' .1 3+ \ ba ho Y 4 \ x eo w B O O O O O O O O o O O O



## I I I I I li I i I I I I

I I I I I I I, I I ; I $ I

I I I 1 I I~ I I I I I I

I I I I I Ij I I I I I I

+I 1 1+1+1+1 ;! +11 1+11 1

~n o LO o ~n u~ c~t~~ct`~p~ 

### ooM LOoo r` ti ti ~ ti ti

y Y >- Y Y~ > . Y YYY Ln Ln U) 

### cnLncntn

a> ^ ~ in c~ A~ c- o o a, r co

t`- W

m O .-~ N ~ N c7 c~ tn tn C`7 C'7 C7 4' < V~ ~ > C C' <^ C IU

O t C 71 O > U A co C C' O O O O O O



## I i I I I I

I I $ I +I I

I I I I I I

I I I I I I



## +1+1+1+ 1 I

LO ooooo ~t`ticoc~~o

Y >~ Y >- V] t/7



### cc co mc c-~ a,

01 O .-N c"7 ~ Q' lA ln 47 Ln t(7

O

C

B O O O O O O



## I I I I I I

I I Jil l

I I I I I I

I I I I I +I



## I 1+11 I +

U~ ~ U~ in o Ln t0 <O tD tr A t0

Y Y Y Y Y >" h V) ti

C, N Q~ O O7 N

Ln tD A p] Ql O LA 4~ 1o 117 lt-, t0

O N O O O O O C ; : O O O O O O



## I I I I I li I I I I I i

I I +i I I I ; I I I I I I

I I i I I I~ I I I I I I

I I I I I li I i ~ I I I

1+1+11 1 lit

00m

u~ in in t Ln LO ~n u~ in U~ At~ fD tD (D t0 i A tD fD tD tD (D

>- >- Y r~ Y >- Y 

### cn v~ Ln vri Ln ~" Ln ~' h >'

CO [~ A ^ -r V' I In ~ O p~ Op

T N C") C' IA tp ' r,J tA 00 Q> O -+ N !G tD CD CD ID t0 i > :D fD ID A A t~ U !C

O O 

### a 0
T ea O v7 y ~7+ w



# 000144N L - Cl m

L

.

### a b
a rn J~-+ " U q K C
L 'p O " -+ > v1 27 O c 'a w U o td N d a~ Q7 h0 m a 3 1 cU

. .~ pp L L MO ,a7 at I +~ C O 3 -C F ¢

e v ° U .b a Q t

bi0 3 a -- -o ~a OV m

c L e ~¢ v

c a~ r, mm n .'r

c ca eu m

a L .~ Wm > B O -r

+-i b0 tN V EF

a G OD Y

L a~ r . > Ca

O z 8 .C G
n . a O'L7 L \ OQ Ca .Y d,\ x m c~ e

K OF00O NQ) ; O .z:, C) mL- C-1 .i C'7L[70N lC)Ni cc m OOJ CO C7 lfl c+7 Lt7 Q] C- L(7 ; LO Oc7 LO C) .-i C`7 c`') C7 N m M! C`J V' C C7 m

~fJ ~t' l-- CO GO L- i co CO l- .-1 C' I-

. . . . . . . . . . . . . l-- U7 O) O C) in C7 O C7 Ln d'd'V'CD ~m Ln LnCDCD l- hlc7C]l-- N

C') Co OONC'f') CD . "1 C') Q' Q

. Q . C7C'')C7NMC7

C7 c0 ooN C7 N N.-I cr) cA 1;1' V

.- Lo tr7 Ln 'C V' dCD O) L- (- 00 .~ i O CZ CIln lc7 M VMOC7 CO M 

### rnincncnoor ; r-- c- co cot mcoc~rcomco O O O O O O i OO

o O O o ; o o O

OoO

(n NNCM

U) CDi C- lfl CO CO U-)- a7 m

CD mQn cm: co O00a7o NN N.-1 N



### co c+m o v~ in V; co co M = m co OOt~C'J .-i0 : C'[.- N-iNV mC7 N c`] C+') CO ; N N C°) C7 C7 N

~CDO)Nr-i0! C'J<PM~NO CO d'ON--l(Mi to CO0'd'ON NNm

NC7N; NN C'7 NC'J m

N LO t'- lo Lo ,zr .-~ -1 O) CO cD N NN CDLIJ 00 ~ O v v O O M Ol~ N (M - N

-1N C7 C~u) CDi CDLW C70 .--~c,7 i > ^- O d un Ol Nt~~ o On oOC00 Nr1NN--1 N

co FNOO~M OO NNa0a0 C'7 C7 C] .^7NN

NC " 7t- NP

;ln L- lo 0)CD :I'Q1 N N N N N N

N ~Ov' co ~ C7 NNO0 cc "t NC) OM

a70 .~ .r
c'7 C Lo cc l~- CO CK Q U _L .c C C a~ O U O] Lo C "J ll) d' N (- ~ co C'] C7 .zM C') d' V' LC) .-i lC) M C7 C'J C) m(7

mmoo Q) rl ri ti00M

C-70 Lo -,I, Lo m V)

~m m~~co 

## cc co m NmN O OO coo

l- t .- t- O

L-n (- (Ma :000~CO .~FNN.-4 .-+

-IT C7 lfJ N .:I' .-1 C) M

~ ~ _,t F CO NN NNC''M

CV m

v co O l- -}' w

Cp lfJ CD 00 CV NN NNN
C)tf1 C7 NCOCc C7cDNl- d' C' CD CM O~ Cn 0

m O-~NC7 C ~ NNNNN

O N 00 C'cD0 ~-) 00 ; co .~ NL`-O Co

. . . . .~ . . . ;1 tf) N CD vi l-- i Ql CA 0c l'7 00 LL] Cc CO cc l- CO LO : .i Q7 [ .- N .--1 L[7 C " ) C`') C] C'7 Cl) C') ! d' C7 C'7 c'7

t,- (`-Q70 co C :) : C N OON .-IN .--1 r-1 On CO cn ln i UJ N [- .-1 CD O] ~t-- CC d'LOi d' Lo LC7C0m 'v

Och mto d` [-i c'7 V' cc co V' c'7 co c- co c- Ln cc : co co 00 co r.- in OOOOOOi 000000

m C7 O v co Oi OJ 'v N C`') cc W m 0m

wO0i OOO~+(3) m .-I N-i .-1 N N i CV N N

OO CO M

l[J : 00 N C'7 CO V' ~-7 CG M

.-1 O) C- O) i C7 C" ) ON N 's NNO3NNN! C') O) m co CJ N

.-ia0C'00 d'cc~ d'u70CCOd, I- c0 CO (M OO 00 Q1 CO co 00 Ell NNNNNC) ; NN N c'7 NN

O~u7 OLO .-i : [h c0 C ") d' l- ca OoDNv CD cc ; O c7 c']d0m 0

. . . . . .i . . . . . . cV(n N000; NOO0

a LO CO l- 07 O) O NC') CLn Co NNNNNL7i j C7 C7 C'7 C7C~J C+7 !O

O O 2N O 

### m

.~ L

.~. b N 

### e O W a> O .~. > a c -p . . . _N O
a . L d ~0 m ~T 3 " c~ a ~ cC y m .G L m O
" aJ N I +~ C O d C/3 3 .O E^ 4 N N e b 6 3

~o ea cn

n~ bo L 0 Qv

C
~ . a> bo 03 a

G 

### oa en L 

## m

G . --~ 

### m ao

+~ CO

L > on Jv

O z c0 d 3 a o m OTJ L \ b~ Y n.~. x eo W 6

U C'- C] l- C- Un O~ c0 O 07 co - 00

.-iLO '0 "Q* d1 CZ, ca 0 a2 ONIT O] d~ NO) LO '-I ! .-1 N OC] C`7 C7 N N N~ NNNN
C] tn V' tn C') N NLo OQ)U70'7 L17 M C'7 C- N N P O m

I-- -+ dl CD t~ ~- C~ C- I-

Cn d'ONNd'i 00M t-- coo0't t1] 't' u7 C' -IV Lt) d' V' U') C~ C~ d' OOOOOOj 000000

Nd'cOtnu70i a00C- .-iC7cM l Nl- N[- c0 ; C- 00 00 cc a0m 00 m

CV CO C'4 C,) LO V'OCd'ca N O] O] N ~NNN .-~

mC7 cD W

I`- m O Nco Co La "-y Op CD CD (-lnm

Ul NCC r- c) 'cf' C' d' C1f7 co 000000

lh- LO N.-i ~ C] l- l'- c0 00 00 [- 

## .-+ .-, .., - r, ., O cc -+OOt CO m V' (- N00 co Oc00-c71 ~ N.-i N

mCD CO m -i lOoOV~m0~ c0 uocp u» INcc l`h C~ c0 c0 V'C`JNlnln V' OO O O O O



### mmc-rroocntr, r. .1 - - 

## .~

Oc70NCOini ~c0C~Go c'JNItncOa0lchOd' t- .-iap =V h- lC7 r, C7 CC i C7 N CD CO .-1 Col N C'J N .-1 ~A N in I .- Il7 O 00 l[7 f~ c: O (~ l CO i C- CO c0 cc O O) I O CO l .- OJ O) coI co t0 CD m

cooa~cncoca! o) ocna~Om C~ V' L- coi to cD GU xn m [- 

### .~ " -i ^+ .--i " - -

CO NN tfJL-- r1~ CO to -Zf'C)o N .-y to O [- C')'rcD~ CO= co ONO l .: CO co t[7 LO cG ~ U'l CD LfJ Ca CD c0

C'- 00 IM OLC')-zf'u7c0l- 00 C'J M

C`~ C~ V' 'C7~ i J C 'cM V' V' ~ C'

a d -- O U L

. . . y a~ O > v tnCOe0C7v N Ocntno0m

### c N- r1 .-i .-, -

C`7mcOCp Lo C', Occ NCOChm ( - 1 .c) c0 U:D c:)
O .-i NCh d~ C, l1J l!7

O

Q1

e Gc, cc) 0 N NCON

-V t- [- co 

### .-, '-" ! . - -y - - NNd'00; ~ COI- tn O "-+ CO ri Nco ; CO Lo C' CO f- in O)090)mNO ; CN V'- IfJv .-~ .-+ .-i rrN~! N NN NN(N

CD O LO -'Zr lf) CD ; In V 'S N O l (~ CV O00 co M, CD .^~C7 N Lo CD C- lY) CD l`-i rm :O CO 1n (- CO

CJ LC) L- d'cDC-i N r- Lo ~N m ~' LfJ L' : d' -zM C7; tf] C7 cc co C OOOOOOi 000000

- 00 Lo 00 O

l-i 'd' .-i cm cn 00 Ln co t- Go CGOJI- i m co 00 (n [~ W

00 ~-i O

C- C M i Co 'IT co tD CC ~ to ONC-- C-) 00 : ONOO)C'C^ . tD [~ O] C- l~ c0 i Q) .-i 00 co O CO

C- Q' N! h ln N07 CO tc0 Lo Cc C'7 l- c0i L- tn Co vrn t'-
- .-1 r-, .-, - -! - r, r, H.r .-,

CD117cDQ)CT]OIC'= ~MNcO .-iOtf7cDCD<f' ~-iCJ N d'O" I V'- cnln (h6) : SD d' 00 cc C'J (M ln CD Lo CD P CO Lo CD U) Lc- CO U7 ~ Co co (p Lo 00 : . .
tnco~o000 in Lo 'n Lo Lo :a !D cc) co co cc cD ; yt,D cD cp C- l~ C~ ~O i
O N O O ON C'] O
cn

N J L

w7 N T rA U 8 .% ._
ca ~ L b ""- > uJ 'L7 y .r O c b .~
"O w y O cV m U r .~ G . .G N Eo d T 3 a c w ho t L GO O
" d d 1 > T " .r c m U.- . 3 a~ E "" cC 00 s c ¢ 1 L 00 a^ 'n on 0 - m

_ . pp W O C O U -y L h0 -0 ¢ e

c m a~ o a~ o n . ~ ~ m

c m af o c . _ .

en TO L O C -r > \ O em

v7 h0 " -+ O m - . \ F+ ea a~hN

O- cc 0Na0

; OV''m

. .i CO LO ONlnNi Cc CM O00UJ CO in C7 ln cn h LO ; ln O mLO Q] .~ C7 C7 m

NC'J C')! C`") d' "r C') C7 C'

C7Ll7 N O7 d'I- t- .iM 00 ti V CO C ") V' C'7 CO Ni L" C'7 N V L[7 Lo

in 00 a] m

co O ; O c] UJ 00 en f7 N" . .iN NN

: N.-I ti -.y N 000000; 000000

co hcOcD C'4 cc : c-)OCo [-OnOn ln LL u7 CD Lo LO; tl7 M -'T LO -, ;p OO0

000i 000000

hOhC'd~c0~ m a0L7mN0 cOcn h-y[OaC; cc co haD00co CD OO~OOi 000000

T Ga UO C O 

### ce eo " ~ cr] cO CO C'7 C \I : V' V' O co CD t-- Cc h0OhcOa0i t- cc h ca h rl-
. 000000

4 ho 17 O > O 

### ho
O Z

¢ O . T = Ct! ob b0 h0

. 

### r~ e

x a ; w hto M (m co h NNC7Nco m C7 O7 Otn CA - LO h M

lf7 CO m N N N N N N C13 CID C' lnCDi w t.- cc m

0.-1N

.~ p U L

. ., y .c c N O > U " - U C7 C hhU7C`]hN CJ cn CD N V C7 O ^imCC' C C')C7C7C7C7C7

"ZV It O)IzI'Q] CO d'COlnd'NC7 - .--i - - .-+ -
o00c')a0cpO) -i NNrIri'y 000000

co o "M

.,Tcn L17 CD cc lf) Lo l0 O O O O O O

I I I I I I

CLo in Nti N 00 07 Q» CO OD O O OO OO

LO OCOhOcD hCOCOhII-CO O O OO O O

m .~ .~h O C7 c') M

OCOa00 CJ N m

NNC+)
C7 cM 1[7 c0 h CO cJlnC')1nC'N h .-1 CD mm d' C7 V' C in .~ lI) C'7 C°) CJ C7 ('] C`')

N00 h Q7 00 .-i .-1 L- co m-:I . ti ti ti ti ti
m0[- OCO.-i rl N.-1 N.-1 CV O O O OOO

00 000 (-NC7 L17 LO C'] LO CD l!) 000000

I I I I I I

OCDNh00C0 07cOC0 hhcO OO O OOO

NC7 G : C'7 m

.-1 haohhcaap 000000

hm m NNLn O 00 m Cr O O) C'7NNC)C7N

m O ~N m

V ti NNN NN 00 ,r CO 0 C-) 00, c0-1N h000 C7 1n N co Lo t-- : O) OD CO M CO LI) c0 co cc l~- C) ln , '-1 07 h N .ti lfl C7 C'7 Cl) C7 C`7 Co ; Q' M Cr) 'IT CC`]

NC'00CO o» d' .-i C-) cli 1114 LO - N - .ti - .i ~ VCJ V d'00 .-1 -r u') CC'7 :7 .-i - rl r-i - -

=N mO

cD O]' O c0 c" ] co 00 tn ti N .-i N .-1 .-1~ N .-i N -I " ~-"I Coo coo

: 000000

C7 .~NN .-ICD ; O ~('70 h CD lf7 CC L'7 1f1 CD LO : Lo Lo l[7 LO d' Lo 000000; 000000

I I I I I I I I I I I I

mcc in m .~C ; O hCON h- 00 00 h CO 00 : 00 00 00 h h 00 OOOOOOi 000000

rfOO0M

Lo 00; 00 C'CO]a0h h QO h h co c0: CO h h h cc h OOOO

O O i O

O OO OO

ONOOhOh ~ cc Oco (n cDcn CTJ O) C'7 h O (n : OO co h h QO CO .^7 NC7 NP7 N

; NN

NNNCV
tnCOh00QJOi N C'7 zi'lf]CO N CV NNNC7, > C-7 (o N NN N !O U 4J CC
0 C O O N



### m m O O ON O m

y L C y

b17 T^ 'b CO GL7

- " ~ WO cd O G O N 'r L \ 

## ¢ a

C EC N O a3 o G .\ 

### cn eo

C ho a! O L "

- m

m ao L O cO --+ \ O m H
V) CO N \ H m a b 7 wJ N a r~ y

. . m U B x y m c L 'p p .. . > >. OO

67 O C O " b -y 

### ~e be

dl "- . L O~ N 'p Q7 O p C > O i -p w m y p Q7 CL t ' d 00 I Q L " Z N a 3 cE R1 " b C B 1 ~ +~ h0 "C m p 

### i > a . . . G >+ C's C cy O" b C) 3 a~ eD na F cC G\

x to G4 E N 00 E_ I c x m c~ 

# < I C-a~l L-- LO m ; c . Oo~M~oO ~Lo u7d'd'Ci x Oa~ONd' OM NM 00'-I ; .-IML')C) ~ tiN -1 ~N! NN NNNN

C- .^7 ri V' O

" -1 l!) N MV ('- Cp h- CC O tf7 Oa) ; Ln N <t C) O ~ C')N ~' co C13 C7C7C7NC7M

CO NNNinlf7~ NN [h O .+OJ NNNNNN; NNNNNrV 000000! pOO000

~~00 0 in CO .-1 N QJ CD Ql 00 ~ 0p (.- cm m

CO! CO 00 CO C- I- t,- C) OOOOOi 000000

4'J C' lf~ CD m 4, ; '~. LC) co m cc I-- C- -,T CM cpo) --4i c+: t- ti mCO rn C) C'J "ZI' C) C) M, C7 [`J CT7 N d' (7

OLnM

l-i C-C7NmN CD 

## cn t-t- r~r- ; r-tir= cot- -000000i Oo0000

co t- 0470 Lo~ m co 'm Ctpcp rn OO

C- c0 CD. c0 -i co cc CO LID :V C7C']NNCTJ : NC7 NNNN
G~ 47 m

O -i Ni ~' C] v Lo cp t+ O C7 C'iC'JC'C' -,v -7. C' C'Cv U U QJ 

### a 4J --" p U L r . c y O > U CDO]NCDNC+7 und'Od'cPCo Nm .--i r1Nm N ~ NN N.-1

CO O ['- 00 00 a' lfJ N .-1 lf) 'l' CC CT7 L`7 C'") mN N

ONC'7 NC'JN NNCV NN

C7 000000

o00C-- " a'tia0 l- m cc co CD 00 000000

co c0 ir) m

a0 O 117N V'hNN C' C' C) C7 V C7

.~ m m in lao m cc t- cc apc 

# 000o00

N00oC'JN --i Ql M

- 00 [7 C')NNcTJNOo

m Or+N^]z, "V lf7 If) L7 Lf7 U7

d m E OcP- Oor90T d' ~NOO N O a0 O~m rIN ~-1NNr1

'1' O Ncm OJ .-+ N Op L7 CO Ch CD M NcT1NC')M

N CO LO CZ Co C{J N NN N OOCOCO

~ -,t LO (- co O m OOT00OJ= 000000

Cl- OtnN[- N C N Ln 'c}' In CO C7 C7 C'7C]117 'IV

00 co t- C-)
-.V' -q 

## c-- c- C-- cooom 000000

C'oJc.^

.VNN C'- Q7 CO" m~ NN NC'7 .^7C']

Ln cz l- Cc Lm O U) lf) Lo Ln lf] co

O N -NNC'OOi .icOl- Ln0~-+

'-f r-1 co .-i N C] i aD Ln d' Ol-- Ln 07 p] OJ ~ N c] ; 'G' N V' .-I U7 d'

.-IN'-1! NNNNNN

N V' co Uf7 c0 N' O -i .-i C' O ~ ONtnOcOco co cc c70Ln MM C')c'7N V

; NNNNL'7N
[n m m co NN'-i NN C'] N'-1 NN OCO000 ; 000000

LO C'J c'] Q7 .i N ; LO O :p rl Q7 Ln a) mm

OD CO c : t- 00 t-- Q]COt

# 000000

; 000000

Ol 'ITcD " --Vi cpCO m (m I- (m LO Co ccOm u7 ; c. m N- O C'') C7 C7 V' ~" C') M i C) C' Cn C') C C`7

< < j

d' O] NN a0v"i .-f (m 00 (- N a0l ml Lm~ C-cmcnc~~ti 0000Oo, 000000

tf) Vm07 t17 CO: CD C-) O a) :D M a0 NoJCOCOi CL) CO CC tONC0 NC') NNC7C)! N N N NC'JN
.-I N C7 d' t17 L C- 07 mO -i N co C : GO C

.7 c0 ~0, j aA CD cc L- C- l~

!O Q7 

### m
C C H

# p. 49 B11-0732 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 findingsa)
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 abnormalitiesdetected 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 B11-0732 Addendum 9-2 Twenty-eight-day repeated-dose oral toxicity study in rats

Pathological fi ndings of individual animals - - - Sex Exp.group Noal 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 Macroscopic 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: glandularstomach and macroscopic lesion. ta, terminal autopsy. ++, moderate.

# p. 53 B11-0732 Addendum9-5 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 Glandularstomach

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 B11-0732 Addendum 9-6 Twenty-eight-day repeated-dose oral toxicity study in rats

Pathological findings ofindividual animals Sex Exp~group Animal Fate Macroscopic findings Histopathological findings')

(melk da ) N

o. -- -- ------ --- - ---- -- 31 ta No abnormalities detected No abnormalities detected

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

----------------------------------- .------------------------------- . . . .------------------------------ Male 1,000 33 ta No abnormalities detected Noabnormalities 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 Vehiclecontrol 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 B11-0732 Addendum 9-8 Twenty-eight-day repeated-dose oral toxicity study in rats

Pathological findings 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 -- -- Pathological 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 Notexamined

------------------------------------------------------------- . . . . . . . . .-------- . . .--------- . . .-------- 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 fi ndings 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 ofindividual animals Sex Exp~group Animal

( Fate Macroscopic findings Histopatholo mg/kg/day) No. 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 abnormali ties detected No abnormalities detected ta, terminal autopsy.

# B11-0732p. 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 ofTest Substance Homogeneity and Stability ofTest Substance Formulations MEASUREMENT DATE Stability ofTest Substance: February 5, 2003 (before dosing period) May 1, 2003 (after dosing period) Stability ofTest Substance Formulations: March 11, 2003 to March 18, 2003 Homogeneity ofTest 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 ofTest Substance Stability ofthe test substance during the dosing period was confirmed with IR spectrum before and after dosing period. The infrared absorption spectrumwas 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 confirmthe stability. 2.2 Homogeneity and Stability ofTest 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 roomtemperature. 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 ofTest Substance
(1) The test substance formulations treated as follows. Sample preparation: KBr tablet Homogeneity and Stability ofTest 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 oftest substance formulation was filled to volume of 10 mL with tetrahydrofuran. This solution was filtrated (DISMIC-13JP, Tokyo Roshi Kaisha) and served as a HPLCsample (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 (HPLCI) Interface: Pump: Auto Sampler: UV-VIS Detector: Column Oven: DataAnalyzer : (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 Systemmanager, Hitachi, Ltd. ShodexAsahipak GF-310HQ7.6 mm I .D.X300 mm 40°C Tetrahydrofuran 1 mL/min 254 rim 10 pL 

# 0-1
..f!_-0q 000164

# 3. DATA PROCESSING IN HOMOGENEITYANDSTABILITYTESTS 3.1 Detection Value Peak area of the test substance in each sample was measured as a detection value. 3.2 Generation ofCalibration 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 ofTest 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 ofTest Substance IR spectrumof the test substance provided fromthe 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 of0.999. 

# " 0001GS I'at'sf)

# B11pa U2

4.3 Stability ofTest Substance Formulations The results ofstability 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 ofTest 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 oftest substance in test substance formulations

R .S.D.(%) : Relative standard deviation

# B11-0732

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 spectrumprovided by the sponsor

70-I 

## 1,00 3 , 2 5

S



# sa-~ 2sbo 2000 1sao Wavenumber (an-1) 

# p. 67



# Fig-2 IR spectrummeasured prior to the administration period 

# OC016'7

-

# 1TI16~732

2ea3. S, /



# s
. E e C 4F

### WavenumCer (crrrt)



# Fig.3 IR spectrummeasured after the end ofthe 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 3by 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 

# Studynumber 14019
I, the undersigned, hereby declare that this report provides a correct Englishtranslation 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 STATEMENT Kurume Laboratory Chemicals Evaluation and Research Institute, Japan Sponsor 

# C
Title Biodegradation study of E ]by microorganisms 

# Studynumber 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 NewChemical 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



# QUALITYASSURANCE STATEMENT Kurunte Laboratory Chemicals Evaluation and Research Institute, Japan Sponsor Title Study number 

# C 1 Biodegradation study of E 7bymicroorganisms 

# 14019 The inspections in this study were carried out and the results were reported to the test facility management andthe StudyDirector by Quality Assurance Unit of Kurume Laboratory, Chemicals Evaluation andResearchInstitute, Japan as follows. Itemof inspection Date of inspection Date of report to Study Director Date ofreport to test

facility management Studyplan ~ January 17, 2003 January 17, 2003 January 17, 2003

January 22, 2003 January 22, 2003 January 22, 2003 t C T 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 Testfacility Objective Test method Applied GLP Dates Storage oftest item, raw data, etc. Personnel Approval offinal report SUMMARY 1 . Test item 2 . Itemsupplied by sponsor 3. Activated sludge 4 . Performance of biodegradation test 5 . Validity oftest conditions 6. Factors possibly affecting accuracy 7. Results 8 . Remarks 

# T"T'IP59

# Contents oftables and figures

Contents oftables Table-1 Calculationtable for percentage biodegradation by BOD Table-2 Calculationtable for recovery rate by HPLC Table-3 Calculationtable for percentage biodegradation by HPLC Contents offigures Fig. 1 Chart of BOD Fig. 2 Chromatograms of HPLCanalysis for calibration curve and

calibration curve Fig. 3 Chromatograms of HPLCanalysis for recovery test Fig. 4 Chromatograms ofHPLC analysis for test solution Fig. 5 UVspectrumoftest item Fig. 6-1 IRspectrumoftest itemmeasured before experimental start Fig. 6-2 IRspectrumoftest itemmeasured after experimental completion Reference IRspectrumsupplied by sponsor



# 000175

# Study No. 14019

Title Biodegradation study ofI 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; andNo.392, Basic Industries Bureau, Ministry of International Trade and Industry, Japan), and "Ready Biodegradability: Modified MITI Test (1) (Guideline 301C, Revised July 17, 1992)" inthe OECD Guideline for Testing ofChemicals.

# 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 andWelfare; 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 oftest item, raw data, etc. (1) Test item About 5 g of the itemsupplied by the sponsor is sealed in a storage vessel and stored in archives in this laboratory forten years afterthe receipt of notice that the test item comes under No.1, No.2 or No.3 in Clause 1, Article 4 of "LawConcerning Examination and Regulation of Manufacture, etc. of Chemical Substances" . Treatment of the itemsupplied 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 ofwith approval ofthe 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 rawdata and materials, etc. after the storage period is discussed with sponsor. 

# '~"~1'~~ 

# 000177 -

# 14uiy p. 78 

# Personnel Study Director Takakazu Kayashima Studypersonnel Kaoru Kondo (Operation of biodegradation test) Stafffor cultivation ofactivated sludge Yasuko Matsunobu Approval offinal report StudyDirector Date March 7, 2003 Signature Signed in original

Takakazu Kayashima

# 14019 p~79 

# SUMMARY
Title Biodegradation study of [ ]by microorganisms Conditions ofcultivation (1) Concentration oftest item 100 mg/L (2) Concentration of activated sludge 30mglL (asthe concentration ofsuspended solid) (3) Volume oftestsolution 300 ML (4) Cultivation temperature 25f1 °C (5) Cultivation duration 28days Measurementand analysis for percentage biodegradation (1) Measurement of biochemical oxygen demand (BOD) by means of a closed system oxygen consumptionmeasuring 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. Itemsupplied by sponsor

2 .1 Supplier and lot number*I (1) Supplier (2) Lot number 

# 0-6182 2.2 Purity*' (1) Test item 99.9wt% (2) Impurity Water 0 .1 wt% The test itemwas treated as 100% in purity. 2.3 Confirmation oftest item

Two infrared (IR) spectra ofthe test itemprovided by the sponsor and measured at this laboratory were confirmed to be identical (see Fig. 6 andReference) . 2.4 Physicochemical properties*l

Appearance Tawnysolid Melting point 48 °C (DSC) Solubility Water c1 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 itemwas 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 lOlocations 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 fromsewage 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 ofactivated sludge

Activated sludge was prepared as follows to maintain its uniformity. Thefiltrate (5 L) of the supernatant ofthe 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 (10L) was aerated*3 afterthe pHvalue ofthe mixturewas adjusted to 7.0±1 .0. *2 The activated sludge cultivated the mixed filtrate (10L) ofthe supernatant of sludge collected at the tenlocations. *3 Prefiltered open airwas used.
d r. _ . 71 

# 000182

# 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 ofthe 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 ofthe solution for each component. The pH ofthe solutionwas adjustedto 7.0±1 .0with sodiumhydroxide. 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 rawdata. Microflora in the activated sludge was microscopically observed and sludge with no abnormal symptoms was used for the test. 3.6 Inspection ofactivity and date ofinitiation of use ofactivated sludge (1) Inspection ofactivity Activity ofthe sludge was assessed using a reference item . (2) Date ofinitiation of use January 21, 2003

# 4

. Performance of biodegradation test 4.1 Preparations for test (1) Measurement ofconcentration ofsuspendedsolid The concentration ofsuspended 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 ofsuspended solid in the activated sludge was 3500

mg/L. (2) Preparation ofbasal culture medium 3 mL each ofsolutions A, B, Cand D, whichare prescribed in JIS K0102-1998 Section 21, was made up to 1000 mL with purified water (Takasugi Seiyaku Co., Ltd .), and then the pH ofthis solution was adjusted to 7.0. (3) Reference item Aniline (reagent grade, Showa Chemicals Inc. Lot No. SN-2331 M) was used as a reference itemto confirm that the sludge was sufficiently active. This test is effective when the percentage biodegradation calculated fromthe BODofaniline 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 ofChemicals.



# 17?~U,179 000184

# 14019 p. $5



# 4.2 Preparation oftest solutions

The following test solutions were prepared and cultured under the conditions described in Section 4

.3. (1) Addition oftest itemor aniline ' (a) Test solution (water +test item) (n=l, Vessel No. 1) In one test vessel, 30 mg ofthe itemsupplied by the sponsor was accurately weighed and added to 300 mL of purified water, so that the concentration of the test itemreached 100mg/L. (b) Test solution (sludge +test item) (n=3, Vessel No.2, 3 and 4) In each test vessel, 30 mg ofthe itemsupplied by the sponsor was accurately weighed and added to the basal culture medium(the volume was less than 300mL bythe volume (2.57 mL) ofactivated sludge inoculated), so that the concentration ofthe test itemreached 100mg/L. (c) Testsolution (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 concentrationreached 100mg/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 ofactivated 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 ofthe suspended solid reached 30mg/L.

. 

# 000185 -10-

# 14019 p. 86 

# 4 .3 Instruments and conditions ofcultivation (1) Instruments for cultivation Closed systemoxygen consumption measuring apparatus

(Temperature controlled bath and measuringunit :

Ohkura Electric Co., Ltd.) (Data sampler : Asahi Techneion Co., Ltd.) Vessel 300mL in volume (improved type) Absorbent for carbon dioxide

Soda lime No.l (for absorption ofcarbon dioxide,

Wako Pure Chemical Industries, Ltd.) (2) Conditions ofcultivation Cultivationtemperature 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 oftest conditions (1) Observation oftest solution

During the cultivation, the appearance of the test solution was observed periodically and conditions ofthe instruments were checked properly. (2) Measurement ofbiochemical 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 oftest solution

After the termination of the cultivation, the test item in the test solutions -vvas determined. 4.5.1 Pretreatment oftest solutions for analysis '

After the termination ofthe cultivation, the testsolution (water +test item), the test solutions (sludge + test item) and the test solution (control blank) were pretreated for I -performance liquid chromatography (HPLC) analysis ofthe test itemas follows. ~Iialh Test solution 300mL -Sodium

chloride 90 g (evenbalance) -Chloroform

. 90 mL (graduated cylinder) " Shaking for 10 min Water layer Chloroform layer " Filtration and dehydration (IPS filter paper) " Filling up to 100mL (chloroform, volumetric flask) " Taking out 1 mL (transferpipet) " Filling up to 10 mL (chloroform, volumetric flask) Sample for HPLC analysis

# 4

.5.2 Quantitative analysis Determination oftest item The samples for HPLC analysis were analyzed under the following conditions . The concentration ofthe test itemin the sample for HPLC analysis was calculated proportionally by comparing the peak area on the chromatogramof the sample for HPLC analysis with that on the chromatogramof 30.0 mg/L standard solution (see Table-3 andFig. 4) . The lowest detectable peak area ofthe test itemwas regarded as 16000 [IV~sec considering the noise level, which corresponded to the test item concentration of 0 .30mg/L. (1) Analytical conditions

Instrument Pump Detector Column oven Auto injector Degasser Column Columntemp. Eluent Flow rate Measurement wavelength Sample size Detector output High-performance liquid chromatograph Shimadzu Corporation type LC-lOADvp Shimadzu Corporation type SPD-lOAvp Shimadzu Corporation type CTO-l0ACvp Shimadzu Corporation type SIL-lOADvp Shimadzu Corporation type DGU-12AM Shodex GPCKF-402HQ (SHOWADENKOK

.K.) 25 cmx 4

.6 mm I .D. 40°C Chloroform 0.2 mL/min 262 nm(see Fig. 5) 5 ~tL 2AU/V (2) Preparation ofstandard solution Thestandard solution to determine the concentration ofthe test itemin the sample for HPLCwas prepared as follows. 100 mg of the itemsupplied by the sponsor was accurately weighed and dissolved in chloroformto obtain 1000 mg/L solution of the test item . 30.0 mg/L standard solution was then prepared fromthis 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) . Acalibration 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 itemon 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 ofthe test itemin the analytical samples (see Table-2and Fig. 3) . Recovery rate ofthe test solutions (water +test item) 98.1 %, 99.5% average 98.8 % Recovery rate ofthe test solutions (sludge +test item) 99.5%, 96.7% average 98.1 %

# 4.6 Calculation ofpercentage 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 thetest itemwas completely oxidized (theoretical) (mg) The purity was regarded as 100 °lo and TOD was calculated from the composition formula ofCiosHss06at n = 5. (2) Percentage biodegradation by HPLC Sw - Ss Percentage biodegradation (%) = SW x 100 Ss Sw Residual amount ofthe test itemin the test solution

(sludge +test item) (experimental) (mg) Residual amountofthetest iteminthetest solution (water + test item) (experimental) (mg) 4.7 Treatmentofnumerical values

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



# ,-1 I"

# pul, ITS

- 15 

# - 000190

# 14019 p. 91

5. Validity oftest conditions Percentage biodegradations of aniline calculated by the BODvalues 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 possiblyaffecting accuracy 

# No adverse effects on the reliability ofthis test were noted. 7. Results 7.1 Appearances oftest solutions

Appearances oftest media in cultivation vessels were as follows.

Test solution Appearance pH Water +test item The test itemwas not dissolved. I - 

# Atthe start ofcultivation I Sludge +test item The test itemwas not dissolved. -

Water +test item Insoluble compound was observed. - Atthe termination ofcultivation Insoluble compound except the sludge

Sludge +test item was observed. -

Growth ofthe sludge was not observed.

# 7~2 Analytic results oftest solutions 

# Analytic results ofthe 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 oftest item ----------- ------------- ------------ ------------- ---------------- 3 4 (HPLC) % 98 98 97 100 - *6 The value of control blank was subtracted fromthe 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 fortest

Fourier transforminfrared spectrophotometer : Shimadzu Corporation type FTIR-8200PC Closed systemoxygen consumption measuring apparatus : see page 11 High-performance liquid chromatograph : see page 13 Electronic analytical balance : Sartorius AG type BP210S Sartorius AG type BP301S Ultraviolet andvisible 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) : MANACIncorporated



# 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,iD1 99 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 itemadded : 30 (mg) Peak area (uV~sec) Final volume : 10 (mL) Ratio of portion used foranalysis : 1/100 Recovery amount (mg) D= Gx (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 Sampl e description 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 itemadded : 30 (mg) A: Peak area (l .LV~sec) , B: Final volume : 10 (mL) C: Ratio of portion usedfor 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 ti i d B 0 la (mg) esse no : 

# escr on p Sample 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 ® Sl udge + Test substance 3 .0 _ 5 .1 8 .6 8 .9 Control 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- 40-'~ 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

Operating date : Feb. 20, 2003 

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

# Standard solution 15.0 mg/L 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

Operating date : Feb . 20, 2003 

# Standard solution 30.0 mg/L 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