Sanitized Version 

",-UDYNUMBER 654240 

rudy Referel Number KSG040165 

Report Page 45 

GLP - CERTIFICATION 

The Swiss GLP Monitoring Authorllles 

Statement of GLP Compliance 


it Is hereby con!'mled \hat 

dwlng the period of November 18 - 22, 2002 

the foBow/ng Test FaclUtJee of RCC Lttl 

4452 ItIngan 

Switzerland 

were Inspected by the Federal OffIce of PublIc Hllallh. the Swiss Agency for Therapeulic 

ProcIutIII and the SwIss Agency for the Environment. fonJsls and Landscape Vtith respect 10 

the compliance with the SwIss legislation on Good Laboratory PnroIice. 

Test Facilities 	 Aleas of expertise * 

• Toxlcolony 	 TOX, ACC, MUT, 

OTH (Safety Phannaeology) 

• Environmental Chemistry and ACe, ECT, ENF. EMN. PCT, 

Pharmanalytlcs RES, OTH (Animal metabOlism) 

The. inspedlons were performed In agreemenlwtth the OECO Guidelines for Natlonal GLP 

Inspedlons and Audits. II was found that the aforementioned iesl fadlilles were opereting In 

compliance wtth the Swiss Ordinance relating la Good Labotalory Practice IRS 813.016.5) at 

the lime they _Inspected. 

Federal Offioe of Public Health 

The Director 

Bern. Mardl2003 	 Prof. Th. zeltner 

Attachment 014 - Page 45 
ATTACHMENT HEADER SHEET 


Attachment Number 015 

Attachment Name 


Attachment 15 


Associated PMN Section Number 

N/A 

Does not contain CBI 

Report Number 


EPMN100421732888414 

Sanitized Version 

RCC Study Number 851276 

Sponsor Study Number KF 030425 

I 

.. A 

7-Day Range-Finding Oral Toxicity 

(Gavage) Study in the Wistar Rat 

Report 

Author: 

Sponsor: 

Page 1 of 54 

Attachment 015 ~ Page 1 
Sanitized Version 

STUDYNUM 276

GENERAL 

In this dose range-finding toxicity study C l1was administered da~y by 

oral gavage to SPF-bred Wistar rats of oth sexes at dose levels of 10, 100 or 1000 mg/kg 

body weight for a period of seven days. A control group received a similar dose volume (10 

mllkg body weight) of the vehicle, bidistilled water. The study comprised two animals per 

group and sex which were sacrificed after seven days of treatment. Clinical signs, food 

consumption and body weights were recorded periodically during the acclimatization and 

treatment periods. At the end of the dosing period, all animals were killed, necropsied and 

examined post mort9m. The results of the study are summarized as follows: 

Mortality 

All control animals and all rats treated with 10 mglkglday and 100 mglkglday survived until 

scheduled necropsy. 

One male (no. 8) and both females (nos. 15 and 16) treated with 1000 mglkglday were found 

dead on Day 1 of treatment, and the remaining male (no. 7) treated with 1000 mglkglday was 

killed for ethical reasons on same day. 

Clinical Signs 

One hour after administration, three rats treated with 1000 mgJkglday were found dead. Male 

no. 7 had convulsive contractions and was prostrate. When observed again approximately 10 

minutes later, these signs were still present and signs of somnolence were recorded. This 

male was sacrificed for ethical reasons. 

No clinical signs were seen in rats treated with 10 mgIKglday or 1000 mgIKglday from days 1­

7 of treatment. 

Food Consumption 

The mean daily food consumption of the surviving test item-treated males and females was 

not affected during days 1-7 of treatment. 

Body Weights 

The mean body weights of the remaining test item-treated males and females compared 

favorably to those of the respective control values. 

Organ Weights 

No test item-related effects on mean absolute and relative organ weights were noted after 7 

days' treatment when comapred with the controls. 

Macroscopical Andlngs 

Bilateral renal pelvis dilation was noted in one female (no. 12) treated with 10 mglkglday. 

This is considered to be a typical background finding and is unrelated to the treatment with 

the test item. 

Dark red thymic foci were noted in one female (no. 16) which was found dead on treatment 

day 1. 

All other animals were without macroscopical changes at necropsy. 

Attachment 015 - Page 2 

2 
Sanitized Version 

ASSESSMENT 

Based on the results of this seven-day dose range-finding study and discussions with the 

sponsor, dose levels of 1, 10 or 100 mglkg bod : . ..or the subsequent 

2B-day study (RCC Study Number 851277) with 

Study Director W.H. Braun 

.. ····~·····t·· ..········..··· 

DaretS-tVIII.t""J 


Attachment 015 - Page 3 

3 
Sanitized Version 

• STUDY NUMBElii1276 

FIGURES 


Attachment 015 - Page 4 

4 
Sanitized Version 

FC-SPLT - 1 

24-NOV-03 

FOOD CONSUMPTION 

MALES 

GlANIHAlIOAY 

PRETEST TR£A1l£NT 

24 /

/ 

/ 

/ 

22 / 

/ 

20 

18 

1& 

14 

12 

- -- - / 

/ 

-1.0 -0.5 0.0 0.5 1.0 

VED<S 

----- GR(lp 1 (0 tiilKG) 

- - - - - - - - GR(XP 2 (10 HGlKG) 

- - - - GROCP 3 (100 HGlKG) 

- - - - - GRtlP 4 (1000 NGIKG) 

Attachment 015 • Page 5 

5 
Sanitized Version 

FC-SPLT - 2 

24-NOV-03 

FOOD CONSUMPTION 

FEMALES 

GIANIHAlIOAY 

24­

22­

20­

18 ­

16 ­

14 ­

12­

~1.0 0.0 O.S 1.0 

PRETtST 

-

-

-

-

-

-

-

- -

-

. . . • . -O.S 

TR(ATtENT 

- - -

• . 

\lEEKS 

----- GROlP 1 (0 Ki/KG) 


- - - - - - - - GROCP 2 (10 t1iIKG) 


- - - - GROCP 3 (100 HGlKG) 


- - - - - GRtlP 4 (1000 HG/KGJ 


Attachment 015 - Page 6 

10 

6 
Sanitized Version 

RFC-SPLT - 1 

24-NOV-03 

RELATIVE FOOD CONSUMPTION 

MALES 

GlKG BODY \/EIGHTIDAY 

140 PRETEST TREATtENT

130 

\ 

120 \ 

\ 

\ 

\ 

110 \ 

\ 

.. \ ,.,.. .. ,.,.. ,.,.. 100 .. .. / .. .. ". .. .. *" - - .. - ­

90 

-1.0 -0.5 0.0 0.5 1.0 

WEEKS 

----- GROlP 1 (0 Ki/KGJ 


- - - - - - - - GROUP 2 (10 MGlKGJ 


- - - - GROlP:3 (100 MGIKGJ 


- - - - - GR(lJ' 4 (1000 MGIKG) 


7 

Attachment 015 - Page 7 
Sanitized Version 

RFC-SPLT - 2 

24-NOV-03 

RELATIVE FOOD CONSUMPTION 

FEMALES 

GlKG BODY VEI9frIDAY 

140 PRETEST TR£ATI"£NT

130 

120 

110 

" " 

100 

,b90 

" 

-1.0 -0.5 0.0 0.5 1.0 

\lEEKS 

----- GR()(,p 1 (0 tti/KG) 

- - - - - - - - GR()(,p 2 (10 t1GIKG) 

- - - - GR()(,p 3 (100 MG/KG) 

- - - - - GR()(,p 4 (1000 r«iIKG) 

8 

Attachment 015 - Page 8 
-----

- - - - - - - -

- - - -

- - - - -

240 

Sanitized Version 

6 BW-SPLT - 1 

24-NOV-03 

BODY WEIGHTS 


MALES 

GRAM 

PRETEST 

220 

200 

180 

160 

140 

120 

TREATtENT 

"., 

"., 

"., .. 

-1.0 -0.5 

c:ROlP 1 (0 tlilKG) 

GRClP 2 (10 t1GIKG) 

GROLP 3 (100 HGIKG) 

GROlP 4 (1000 HGlKG) 

0.0 0.5 1.0 

WEEKS 

Attachment 015 - Page 9 

9 
Sanitized Version 

6 BW-SPlT - 2 

24-NOV-03 

BODY WEIGHTS 

FEMALES 

PRETEST TREATrt:NT 

240 

220 

200 

190 

160 

140 

--­- -- --­ 120 

--­

-1.0 -0.5 0.0 0.5 1.0 

WEEKS 

----- 6R(1JP 1 (0 tfilKG) 

- - - - - - - - GRfl.P 2 (10 MG/KG) 

- - - - 6R(1JP 3 (100 HGlKG) 

----- 4 (1000 116/1(6) 

Attachment 015 - Page 10 

10 
Sanitized Version 

~1276 

SUMMARY TABLES 


Attachment 015 - Page 11 

11 
Sanitized Version 

6 FC-SUM' - 1 

24-NOV-OJ 

FOOD CONSUMPTION (G/ANIMAL/DAY) SUMMARY 

MALES 

purEST GROUP 1 GROUP 2 Gaoup 3 CJl.OUP , 

o IIG/KO 10 IIG/EG 100 HO/JtO 1000 ltG/EO 

DAYS l-a KKAN 16.6 IS.4 18.' 19.7 

HUltS 1/2 ST.nEY. 

N (CAGS) 1 1 1 1 

Attachment 015 - Page 12 

12 
Sanitized Version 

FC-SUM - 2 

24-llOV-03 

FOOD CONSUMPTION (G/ANIMAL/DAY) SUMMARY 

MALES 

'rREJI.TMEHT GaOUP 30 GROtll' 2 GlI.OUP ;) GROtrP 4 

o KG/K:O 10 KG/ItG 100 KG/EG 30000 110/1:.0 

DAYS 1-3 KIUH 17.9 lB.2 19.8 WBEIt 1 IIT.DKV. 

N (CAGII:) 1 1 1 0 

DAYS 3-5 KIUH 19.8 19.8 22.0 

nu 1 ST.UKV. 

N (CAGE) 1 1 1 0 

DAYS 5-7 KIUH 20.6 21.0 24.3 WU 1 ST.UKV. 

N (CAGle) 1 1 1 0 

KIU.N OJ' If3ANS 

OVER '11IlCATMEHT U.S 11.6 22.0 

• / .0 • Dunnett·Teat baaed on pooled var1ance a1gn1f1eant at 5' (0) or l' (••) level 

Attachment 015 - Page 13 

13 
Sanitized Version 

6 FC-SUM - 3 

24-WV-03 

FOOD CONSUMPTION (G/ANIMAL/DAY) SUMMARY 

FEMALES 

PU'rBST GltOOP 1 CR.OUP :I aROUP l GltOUP .­

o KG/ICC 10 KG/r::a 100 KG/ICC 1000 JIa/ICC 

DAYS l-B KI!:AH 1:1.7 12.2 12.8 15.0 

wnltS 1/'1. ST.DEY. 

N (CACE) 1 1 1 1 

• / *. , Dunnett-Te.t ba••d on pooled var1ance .1gn1f1cant at 5~ (*) o~ 1~ (**) level 

Attachment 015 - Page 14 

14 
Sanitized Version 

dec FC-StM - 4 STUDY NUMBER 8.6 

24-NOV-03 

FOOD CONSUMPTION (G/ANIMAL/DAY) SUMMARY 

FEMALES 

TlU!.A1'KI!:tn' GllOtJP 1 

a 110/1.0 

DATS 1-3 KEAJf 

REIt 1 ST.OEV. 

K (CAGE) 

OATS 3-5 KUN 

Rite 1 Br.DIN. 

H (CAC'I) 

OATS 5-7 JIEAH 

WBIt 1 sr.OEY'. 

N (CAGB) 

MEAN Oil' MEANS 

OWR TREATKIDIT 

12.8 

1 

14.4 

1 

15.0 

1 

14.0 

GROUP 2 

10 KG/ItC 

13.0 

1 

U.3 

1 

14.2 

1. 

13.5 

GROUP 1 

100 KG/loG 

12 •• 

1 

14.3 

1 

14.1) 

1 

14.0 

CR.otI1i' 4 lOGO m/itG 

0 

II 

0 

• / •• , Dunnett-Teat baaed On pooled variance .ign1f~cant ac 5' to) or l' tOO) level 

Attachment 015 - Page 15 

15 
Sanitized Version 

S'.l'ODY NDMBER. 6 RFC-StlM - 1 

24-rov-03 

RELATIVE FOOD CONSUMPTION SUMMARY 

(G/KG BODY WEIGHT/DAY) MALES 

P:RETEST GROUP 1 o KG/XG 

GROUP 2 

10 HG/m 

aaoup 3 

100 HG/ltO 

GROUP C 

1000 KG/ICO 

DAYS 1-8 

RUS 1/7. 

KBl\]f 

ST.DEY. 

N (Cl.GIU 

112.0 

1 

103.7 

1 

122.3 

1 

136.0 

1 

Attachment 015· Page 16 

16 
Sanitized Version 

S1'DDY NUMBER RFC-SllM - 2 

24-mV-03 

RELATIVE FOOD CONSUMPTION SUMMARY 

(G/KG BODY WEIGHT/DAY) MALES 

'nBATKSJI'l' C1I.OUP l. o H.Q/~G GROUP 2 

10 KGIl;G 

GROUP , 

100 HG/~G 

GROUP 4 1000 HG/XC 

DAYS 

K£Blt 

l.-3 

l. ICBAH ST.OEY. 

N (CAGE) 

92.0 

l. 

,o.7 

l. 

'4.5 

1 0 

DAYS 

K£U: 

l-S 

1 

KZAN 

ST.OEV'. 

H (CAGE) 

U.2 

1 

U., 

1 

91.6 

l. 0 

DAYS 

K£B~ 

5-7 

1 

KUJf 

Br.DIN. 

N (CACH) 

'5.1 

1 

U.:I 

1 

l.03.:) 

1 0 

)(EA}f OF KBANS 

OVER TR.I!A'1'ICEHT '4.4 '2.' 99.1 

• I ••• Dunnett·Test b~.ed on poolsd variance 8ignificant at 5\ (.) or 1\ (0') l.eval 

17 

Attachment 015 - Page 17 
Sanitized Version 

RFC-StIM - 3 

24-:NOV-03 

RELATIVE FOOD CONSUMPTION SUMMARY 

(G/KG BODY WEIGHT/DAY) FEMALES 

PliUITBST cntOOP 1 GROUP 2 Gll.OUP 1 Gll.OOP ... o KO/XO lO KG/r.o lOO KC/F:.G 1000 IG/F:.O 

DAYS 1-8 NEAll 103.5 103.( 108.1 125.5 

KUXS 1/2 ST.DEV. 

I( (CAGE) 1 1 1 1 

Attachment 015 • Page 18 

18 
Sanitized Version 

RELATIVE FOOD CONSUMPTION SUMMARY 

(G/KG BODY WEIGHT/DAY) FEMALES 

TREA'I'KENT GROUP l. GROUP 1 GROUP 3 GROUP " 

o KG/itO 10 KG/leG 100 KG/J:O 1000 lIG/1tQ 

DAYS 

'KED: 

1-3 

1 

Kli:AK 

S'f .1lXV'. 

If (CAGE) 

89.0 

1 

94.6 

1 

19.1 

1 0 

DATS 

NED: 

3-S 

1 

KEJI.Jf 

ST.DEV'. 

If (CAGB) 

96.J 

1. 

9t.l 

1 

117.0 

1 0 

DATS 

'HEEl: 

5-7 

1 

KEJI.Jf 

ST.DEY. 

If (CAGE) 

96.0 

1. 

96." 

1 

!J5.8 

1 0 

KllAH or KEJ.JlS 

OVBR 'fltEA'l'ICDT 93.7 95.1 93.9 

Attachment 015 - Page 19 

19 
Sanitized Version 

STUDY 6 BW-SOM - 1 

24-NOV-03 

BODY WEIGHTS (GRAM) SUMMARY 

MALES 

PllE'l'KST CIilOUP 1 CIilCR1l' :I GROUP 3 GROUP t o HG/ltG 10 KG/ltG 100 HG/ltG 1000 KC/ltG 

DAY' 1 HlU.X ltl.2 148.4 154.3 11.5.1 

MEII( 1 ST.DEY'. 4.7 9.5 t.2 6.3 N 2 2 .2 :I 

Attachment 015 - Page 20 

20 
Sanitized Version 

STUDY NUMBER 6 BW-SllM - 2 

24-lIOV-03 

BODY WEIGHTS (GRAM) SUMMARY 

MALES 

TltBAtHImT GROUP 1 GROUP 2 GROUP l GJtOUP • o HG/ItG 10 HG/IC.G 100 MG/ltCil 1000 IIG/I:Q 

DAY 

WiBX 

1 

1 

IIU.N 

ft.DBV. 

U 

17'.1 

2.1 

2 

183.0 

10.3 

2 

19J.6 

5.0 

2 

U:I.4 

5.5 

2 

DAY 

WiU 

3 

1 

lI:aH 

S'1'.111r1t • 

H 

1".7 

1.6 

:2 

200.2 

11.1 

2 

209.0 

J.6 

:2 0 

DAY 

W£U. 

5 

1 

JCDH 

ST.DBV. 

H 

206.3 

•• S 

2 

210.S 

12.6 

2 

220.6 

5 •• 

:I 0 

DAY 

WEB 

'1 

1 

MKl\K 

ST.DEV. 

H 

216.5 

6.2 

2 

222.9 

14..1 

2 

23••9

..7 

2 0 

Attachment 015 - Page 21 

21 
Sanitized Version 

BW-SUN - 3 riCC STUDY NUMBER 8i!1'76 

24-NOV-03 

BODY WEIGHTS (GRAM) SUMMARY 

FEMALES 

PRETEST OROUP 1 altoUP 2 GJtOtIP 3 GJtOllP 4 

o 1eG/ItG 10 NO/XG 100 HG/XG 1000 KG/XG 

DAY 1 KlWf 122.4 117.5 ll.8.4 


WU:X 1 ST.DEV. 1.9 0.5 1.4 
 N :I 2 2 

• / ••• Dunaett-Teat ba.ed on pOOled variance significant at 5' (.) or l' (••) level 

Attachment 015 - Page 22 

22 
Sanitized Version 

BW-SUK - 4 

24-NOV-03 

BODY WEIGHTS (GRAM) SUMMARY 

FEMALES 

TRKA'1'NKNT CROUP 1 CROUP 2 GROUP 3 CROW 4 

o NO/ItO 10 NO/J:G 100 KC/ICC 1.000 M:/ItG 

DAY 

WEEIt 

1 

1 

I«liIAN 

S'r.DEV. 

If 

135.3 

1.3 

2 

127.5 

2.1 

2 

135.9 

3.3 

2 

1.40.5 

0.9 

2 

DAY 

WB:EIC 

3 

1 

I«liIAN 

ST.DEV. 

N 

1"'.2 

2.0 

2 

137.5 ,., 

2 

14t.O 

1.2 

2 

DAY 

Wl!:EIt 

5 

1. 

KIWI 

ST.DEV. 

B 

1".1 

1.1 

2 

140.6 

3.9 

2 

1t7.7 

'.5 

2 

OAY 

Wl!:EK 

7 

1 

KIWI 

ST.DEV. 

If 

155.7 

1.6 

2 

147.6 

5.5 

2 

155.6 

2.3 

2 

Attachment 015 - Page 23 

23 
RCC STUDY NUMBER 8 

ORGAN WEIGHTS 

AFTER 7 DAYS 

MALES 

BOD.,. If. 	 KIi:AN 

ST.tlEV. 

H 

HURT 	 KKAH 

ST.DIN. 

H 

LIVli:R. 	 KKI.N 

ST.DEV. 

H 

'1'sncus 	 KKAH 

ST.DIN. 

H 

ItImm.,.s 	 KKAH 

ST.DIN. 

If 

AllRENALS 	 tmAH 

ST.DIN. 

N 

Sl'LUN 	 tmAH 

ST.DIN. 

If 

TBS2'II'S 	 HlI:AH 

ST.DIN. 

If 

6 

(GRAM) SUMMARY 

GROUP 1 GR.OUl' 2 

o KG/ltG 10 KG/ltG 

21'1.94 22).05 

10.'1'1 l8.U 

2 2 

0.762 0.812 

O.OOl 0.114 

2 2 

9.fiO 10.05 

O.fiO 1.U 

:I 	 :I 

0.52 0.59 

0.12 0.05 

2 2 

l.56 1.7'1 

0.30 0.30 

2 2 

0.Ot5 0.052 

0.00'1 O.OOt 

2 2 

O.fiU 0.'167 

0.0'11 0.04.0 

:I 2 

2.fiO 2.75 

0.11 0.31 

2 2 

CUtOUP 1 

100 KG/ItG 

231.96 

'1.94 

2 

0.102 

0.004. 

2 

10.02 

o.n 

2 

0.64 

0.02 

2 

1.73 

0.0" 

:I 

0.050 

0.001 

:z 

0.76'1 

0.092 

:z 

2.1' 

0.10 

:.I 

Sanitized Version 

OW-SUK - 1 

2S-NOV-03 

GROUP I 

1000 KG/Jelf 

0 

0 

0 

0 

0 

0 

0 

0 

Attachment 015 - Page 24 

24 
Sanitized Version 

OW-SlM - 2 

2S-llOV-03 

ORGAN/BODY WEIGHT RATIOS SUMMARY 

APTER 7 DAYS 

MALES 

caoup 1. 

o NG/J:G 

GROUP 2 1.0 KG/I'(; 

aaoup 3 

100 MC/EG 

CROUP " 

1000 KG/IG 

SODY If. 

(0ItAK) 

XIi:AN 

ST.DBV. 

If 

211.94 

10.77 

2 

22l.05 

18.46 

2 

231.96 

1." 

2 0 

HKART 

(') 

KBAX 

ST.DBV. 

If 

0.350 

0.01.9 

2 

O.lU 

0.021 

2 

0.346 

0.010 

:I 0 

LIVER 

(') 

XIi:AN 

Sl'.I)BV. 

If 

4.40 

0.06 

2 

4,50 

0.2' 

:2 

~.l2 

0.06 

:I 0 

'l'llYlmS 

I,) 

JUAK 

8T.DEV. 

H 

0.24 

0.04 

2 

0.2' 

0.00 

:I 

0.2. 

0.02

, 0 

J:IDNllYS 

(\) 

JUAK 

Sl'.DBV. 

10' 

0.71 

0.10 

2 

0.79 

0.01 

2 

0.75 

0.01. 

2 0 

ADRENALS 

(t) NII:AN 

ST.DEV. 

N 

0.021 

0.002 

2 

0.023 

0.000 

:z 

0.0::11 

0.001 

2 0 

SPLEEN 

('10) 

'KEAN 

ST.DEV. 

N 

0.l07 

0.011 

:2 

O.l.... 

O.Oll 

2 

0.330 

0.029 

2 0 

TESTES 

(,) 

JUAK 

IT.DBV. 

K 

1.:10 

O.ll. 

2 

1..23 

0.05 

" 

1.18 

0.00 

2 0 

Attachment 015· Page 25 

25 
STtlDY NOHBER 

ORGAN WEIGHTS 

AFTER 7 DAYS 

FEMALES 

DOtlT 1(. 	 HU.Jf 

S'1' .DKV. N 

HQJtT 	 KDH 

ST.DKV. 

H 

LIVER 	 HEI\.K 

S'1' .DKV. H 

TImmS 	 KJU.N 

ST.tr.IV. K 

JC.tDNIfYS 	 HEI\.K 

S'f.DKV. 

H 

AIlREHALS 	 HBA.H 

ST.tlKV. 

N 

SPLEBN 	 MBAN 

ST.DZV. 

H 

(GRAM) SUMMARY 

GKOIJi' 1 (lItOUP :2 

I) KG/XG 10 HO/kO 

151.86 148.22 

1.86 1.45 

'2 2 

0.U6 0.558 

0.012 0.001 2 	 :2 

6.110 ti.13 

0.5S1 0.66 

2 2 

0.55 0.46 

0.09 0.05 

2 2 

1.23 1.24 

0.0' 0.01 :2 :2 

0.065 0.060 

O.OOti 0.004 

2 	 :2 

0.400 0.4" 

0.015 O.OU 

2 2 

aItOVP 3 

100 HO/J::G 

149." 

6.68 

'2 

0.615 

0.008 

'2 

'.n0.35 

:2 

0.46 

0.01 

:2 

1.26 

0.03 

:2 

0.061 

0.007 

'2 

0.4" 

0.13S 

:2 

Sanitized Version 

OW-SUM - 3 

2S-NOV-03 

CROUP 4 

1000 KG/r.O 

0 

0 

a 

0 

0 

a 

0 

Attachment 015 - Page 26 

26 
6 

ORGAN/BODY WEIGHT RATIOS 

AFTER 7 DAYS 

FEMALES 

GROUP 1 

o HO/r;O 

BODY If. KU.N 

(GRAHl IIT.DKV. 

N 

IIlUUtT MUll' 

(\1 8'r.DKV. 

N 

LIVER. NIWI 

(\1 ST.DKV. 

If 

THYHt7S 	 lCDH 

(\1 ST.DKV. 

N 

ltIDHEYS KU.N 

I'lil S'r.DKV. 

N 

ADUNALS 	 KU.N 

ST.DKV. '\. N 

SPLIU:N JCB.M 

(\) S'r.DKV. 

If 

15l..86 

l..8' 

:I 

o.u. 

O.Oll 

2 

4.48 

0.33 

2 

O.lIi 

0.0' 

2 

0.8l. 

0.05 

2 

O.OU 

0.001 

2 

0.264 

0.013 

2 

SUMMARY 

GROUP • 10 MG/J:G 

1U••2 

l.U 

.2 

0.3'76 

0.008 

:I 

4.27 

0.l5 

:I 

0.31. 

0.04 

:I 

0.84 

0.02 

:I 

O.OU 

0.004 

:z 

O.llS 

0.028 

2 

GROUP 1 

100 tro/J:G 

1U.U'.68 

l 

O.·UO 

O.Oll 

:I 

4.61 

0.014

• 

O.:U 

0.02 

2 

0.8. 

0.02 

:I 

0.041 

0.003 

2 

0.329 

0.105 

2 

Sanitized Version 

OW-S'\JM - 4 

2S-NOV-03 

GIilOUP 4 

1000 KGIIG 

0 

0 

0 

0 

0 

0 

0 

Attachment 015 - Page 27 

27 
Sanitized Version 

,liUDYZUMBlij1276 

INDIVIDUAL TABLES 


Attachment 015 - Page 28 

28 
Sanitized Version 

6 MORT-DID - 1 

25-:NOV-03 

MORTALITY DATA 

MALES 

GROUP 1 (O MG/KG) 

SCHEDULED SPOMTANSOl1S KILLED IN 

AtJDQL NECROPSr DKA'l'H EXTlitli:KIS 

1 24-NOV-03 1'-KOV-Ol 23-HOY-Ol 

2 24-NOV-03 1'-NOV-03 23-HOY-Ol 

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29 
Sanitized Version 

1iiiiiiiiiiiii176 MORT-rNO - 2

2S-:NOV-03 

MORTALITY DATA 


MALES 


GROUP 2 (10 MG/KG) 


SCHEDULED SPONTANEOUS ~XLLBD IN 


All'IKAL NBOI.OPSY DEATH EX'l'RSKIS 


,

3 17-NQV-03 21-HQV.Ol 

17-NOV-03 21-NOV-03 

Attachment 015 - Page 30 

30 
Sanitized Version 

6 mRT-DID - 3 

2S-lIOV-03 

MORTALITY DATA 

MALES 

GROUP 3 (100 MG/KG) 

AlfIHl\.L 

scmrourzo 

NSCIlOPS1: 

SPONTANEoas 

DEATll 

XILLEl> IN 

BXnBXIS 

TItEATKE.NT 

PROM TO 

S :H-!lOV.Q) 17-NOV-Ol 23-ROV-Ol 

6 2l-NOV-Ol 17·NOV-Ol 2l-NOV-Ol 

Attachment 015 - Page 31 

31 
Sanitized Version 

dec STCDY NUMBER. 8176 MORT-INn - 4 

25-NOV-03 

MORTALITY DATA 

MALES 

GROUP 4 (1000 MG/KG) 

ANtHAL 

SCllE.DOLED 

HBCROPSY 

Sl'OH'rANBOUS 

DBA'l1i 

II:XLLBD XN 

BXTRBMXS 

T1l.IATtODn: 

FROK TO 

7 17-NOV-03 17-NOV-03 l'-PQV-03 

8 17-NOV-03 17-NOV-03 17·PQV-Ol 

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32 
Sanitized Version 

STUDY NtlMBER 76 

MORTALITY DATA 

FEMALES 

GROUP 1 (0 KG/KG) 

SCBKDOLBI) SPONTANEOUS 

AJfnu.L NEOOl'Sr DEATH 

EILLIUI IN 

~s 

TRZATHENT 

nOM TO 

MORT-DID - 5 

2S-NOV'-03 

, 2t*IIQV·03 17-HOV-Ol 21*IIQV-03 

10 It-IIQV-03 17-HOV-Ol 21-IIQV-03 

Attachment 015 - Page 33 

33 
Sanitized Version 

STUDY NUMBER 8 

MORTALITY DATA 

FEMALES 

GROUP 2 (10 KG/KG) 

SCJBDtn.lW SPONTANEOUS ltILLED:IN 

M:IHAL NBCltoPSY DB:ATH IX'l'Iil.IK:IS 

11 17-NOV-03 2l-NOV-OJ 

12 17-NOV-03 23-NOV-Ol 

Attachment 015 - Page 34 

34 
Sanitized Version 

STOnY NUMBER 

MORTALITY DATA 

FEMALES 

6 

GROUP 3 (~OO KG/KG) 

SCHEDULED SPONTANEOUS kILLED IN 

ANIMAL NECROPSY DEATII IitXnJIKl:S 

DIATICBNT 

raOK '1'0 

MORT-DID - 7 

2S-NOV-03 

13 2ot-HOV-03 17-HOV-Ol Z3-NOV-OJ 

14 24-HOV-Ol 17-HOV-Ol 2l-HOV-OJ 

Attachment 015 - Page 35 

35 
Sanitized Version 

STUDY NOMBBR MORT-IN> - 8 

2S-N:>V-03 

MORTALITY DATA 

FEMALES 

GROUP 4 (1000 KG/KG) 

ANIMAL 

SCHED"C:lLJ:D 

NECROPSY 

SPONTANEOUS 

DEATH 

KILLED IN 

EXTREMIS 

TIlEATKBHT 

,aOM TO 

1" 17-NOV-Ol 17-NOV-Ol 17-NOV-Ol 

16 17-NOV-03 17-NOV-03 17-NOV-03 

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36 
Sanitized Version 

PC-INO - 1 

24-WV-03 

FOOD CONSUMPTION (G/ANIMAL/DAY) MALES 

PRETEST 

DAYS 1-8 1-3 l-5 5-7 

MEEU 1/2 1 1 1 

CJ.CE 

caoup 1 (0 KG/ItG) 

1 16.6 19.8 20.' 

GROIll' 2 (10 KC/ItG) 

2 15." 18.2 19.8 21.0 

CROUP 3 (100 KG/EO) 

3 18.' 19.8 22.0 2".3 

GROUP .. (1.000 KG/ItC) 

.. 19.7 

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37 
Sanitized Version 

FC-lJID - 2 

24-N'OV-Ol 

FOOD CONSUMPTION (G/ANIMAL/DAY) FEMALES 

PRB'1'UT 

DAl'S 1-8 1-3 l-5 5-7 

WE".US 1/2 1 1 1 

CAGE 

GR.OllP 1 to KG/EG) 

5 12.7 12.B H.t. 15.0 

GROUP 2 (l0 Ma/I'.G) 

(; 12.2 13.0 13.3 14.2 

GROUP J (lOO KG/EGI) 

7 12.8 12.8 14.3 

GROUP .. (1000 KG/ICG) 

8 15.0 

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38 
Sanitized Version 

RFC-DID - 1 

24-:NOV-03 

STUDY NllMBER 6 

RELATIVE FOOD CONSUMPTION 

(G/KG BODY WEIGHT/DAY)

MALES 

DAYS 1·1 1-3 3-S S-7 

nus 1/2 1 1 1 

CAGE 

GROtIP 1 (0 KG/ml 

1 112.0 92.0 96.2 95.1 

CROUP 2 (10 KO/ltG) 

2 103.7 90.7 

GROUP 3 (100 KO/ltGI 

3 122.3 94.5 99.1i 103.3 

GROUP 4 (1000 KG/ltCI 

4 136.0 

Attachment 015 - Page 39 

39 
Sanitized Version 

RFC-IND - 2 

24-NOV-03 

STUDY NUMBER. 6 

RELATIVE FOOD CONSUMPTION 

(G/KG BODY WEIGHT/DAY) FEMALES 

PUTIS'l 

'DAYS ~-8 1.-3 3-5 5·' 

WBKr;S 1/2 1 1. 1 

CAGll 

GROUP 1 (0 IIC/r;G) 

5 103.5 89.0 '6.3 '6.0 

GROUP 2 (10 KG/~G) 

Ii 103.4 94.6 '4.2 96 •• 

GROtIP 3 (l00 MO/I:C) 

7 108.1 89.1 91.0 95.8 

GROUP " (1000 KGI") 

8 1.25.5 

o 

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40 
Sanitized Version 

BW-DtC - 1 


24-NOV-03 


BODY WEIGHTS (GRAM) 

MALES 

-----.~--------------------------.-----------.-------- ---- DAYS 1 1 1 5 7 

WEIi:J::S 1 1 1 1 1 

AHI'KAL 

GROUP 1 (0 Ka/m) 

1 

:z 151.5 lU.8 

180.6 

111.6 

In.6 

195.9 

203.1 

209.5 

2U.l 

220.9 

GROUP 2 (10 KG/EC) 

3 

4 

155.2 

1U.7 

190.3 

175.7 

208.1 

192.4 

219.7 

201.9 

232.9 

213.0 

GROUP 3 (100 KG/xa) 

5 

6 

151.3 

157.3 

197.1 

lllO.l 

211.6 

206.4 

224.4 

216.8 

238.3 

231.6 

CROUP 4 (1000 MG/XG) 

7 

8 

140.7 

149.6 

188.6 

196.3 

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41 
Sanitized Version 

STUDY NIlMBER BW-IND - 2 

24-NOV-03 

BODY WEIGHTS (GRAM) FEMALES 

flAYS 

PIUi:UST ':I1I.BATKENT 

.----------.. --.------------~-.-------.- .. ~---- '1 '1 3 5 

"'''' ....­..........­

7 

nilES 1 1 1 1 1 

ANIMAL 

GROUP 1 (0 KG/ItG) 

51 123.1 136.2 145.6 10.8 156.8 

10 121.0 13..... 142.8 148.3 15... ' 

GROO'P 2 (10 HO/EC) 

11 111.2 129.0 140.9 143 ... 151.5 

12 117.9 126.0 13".0 131.9 In.1 

GROm> 3 (l00 MG/EC) 

13 119.3 138.2 144.8 150.9 151.2 

14 111." 1ll.' 143.1 1 ..... 6 15".0 

GROW .. (1000 1(0/11:.0) 

15 111." 139.8 

16 121.1 141.1 

Attachment 015 - Page 42 

42 
Sanitized Version 

MAC-DID - 1 

2S-NOV-03 

MACROSCOPICAL FINDINGS 

MALES 

GROUP 1 (0 KG/KG) 

ANIlO.L 1 (SCUSDULBD NECROPSY, 24-HOV-200J) 

NO FINDXNGS NOrBD 

AHIKAL 2 (SCHZDULSD NECROPSY, 24-NOV-2003) 

NO II'INDXNGS NOrBD 

Attachment 015 - Page 43 

43 
Sanitized Version 

MAC-INn - 2 

2S-NOV-OJ 

MACROSCOPICAL FINDINGS 

MALES 

GROUP 2 (10 MG/KG) 

(SCUOOLlCl WCaQPSY. 2(-NOV-200l) 

NO rIlltlINOS NOTEl) 

(SCHEDULBD WCROPSX. 2(-NOV-200ll 

Attachment 015 - Page 44 

44 
Sanitized Version 

RCC STtJDy MAC-J:ND - 3 

25-NOV-03 

MACROSCOPICAL FINDINGS 

MALES 

GROUP 3 (~OO MG/KG) 

ANIMAL 5 

NO PINDINGS NOTIm 

NO 1"1HDmGS NOTBD 

Attachment 015 - Page 45 

45 
Sanitized Version 

6 M7l.C-DID - 4 

2S-NOV-03 

MACROSCOPICAL FINDINGS 

MALES 

GROUP 4 (1000 MG/KG) 

ANIMAL 7 (~ILLED IN ~IS. 17-NOV-200l) 

ANIMAL 8 (SI'OHTAIIlroUS %:lEATH, 17-OOV-2003) 

Nt) I'.IKDINGS NOTED 

Attachment 015 - Page 46 

46 
Sanitized Version 

MAC-IlID - 5 

2S-NOV-03 

MACROSCOPICAL FINDINGS 

FEMALES 

GROUP 1 (0 MG/KG) 

.MIHAI. , (SCHEDULED HBCROPST. 2t-NOV-200l1 

NO FINDINGS NOTBD 

.MrKAL lO (SCHEDULED HBCROPSY. 2t-NOV-20011 

NO FINDINGS NOTBD 

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47 
Sanitized Version 

6 

MACROSCOPiCAL FINDiNGS 

FEMALES 

GROUP 2 (10 MG/KG) 

(SCKKDULID NECROPSY. l4-KCW-l003) 

NO FINDINGS NO'rBD 

(SCKBDULKD NECROPSY. l4-NCW-2003) 

ItIDtlBYS ••••••••••••• BOTH SIPES. PE~VIC DILATION. 

Attachment 015 - Page 48 

48 
Sanitized Version 

STUDY MAC-DID - 7 

2S-NOV-03 

MACROSCOPICAL FINDINGS 

FEMALES 

GROUP 3 (100 MG/KG) 

(SCHEDULED NECRO'SY. 2t-NOV-20011 

NO FllfDIJI'GlS NOTED 

Attachment 015 - Page 49 

49 
Sanitized Version 

STUDY 6 MAC-DID - 8 

25-lDV-03 

MACROSCOPICAL FINDINGS 

FEMALES 

GROUP 4 (1000 MG/KG) 

(SPONTAHEOOS D~TH. 17-HOV-200l) 

NO I':tNDXNGS NOTRD 

ANl:KAL 16 (SPONTAHEOOS DUII'D, 17-HOV-200l) 

TIflOmS............ .. FOCUS/FOCI, ISOLATED. D.1 10(, DARlC RED. 


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50 
Sanitized Version 

STODY NtlMBER OW-DID - l. 

2S-lIOV-03 

ORGAN WEIGHTS (GRAM) AFTER 7 DAYS 

MALES 


GROUP 1 (0 MG/KG) 


Alfl:MAL 1'1001' H. HUIlT LIVER THYJ(US KIDNEYS ADIUUIALS SPLB:1tK TESTES 

HUDU 

1 210.32 0.76t '.1.8 0.t3 1.35 O.OU 0.610 2.67 

2 225.55 0.75' 10.02 0.61 1.77 0.050 0.719 2.52 

GROUP 2 (10 MG/KG) 

Alfl:MAL 1'1001' If. HEART LIVER THrKUS ICIDHII:YS ADIUI:KALS SPLEItK T8:Sns 

'NtIK8U 

3 236.10 0.8n 11.10 0.63 1.98 0.055 0.795 2.98 

t 210.00 0.731 '.01 0.55 1.56 0.049 0.7n 2.51 

GROUP 3 (100 MG/KG) 

AHIKAL BODY H. UAJtT LIVER THTKUS r;,IDHII:YS ADIlEHALS SPLBBN TESTES 

HUDER 

5 2l7.57 0.80t 10.35 0.6] 1.76 0.049 0.832 2.81. 

ti 226.3<1 0.799 9.69 0.66 1.71 0.050 0.701 2.67 

GROUP 4 (1000 MG/KG) 

AHtHAL 1'1001' W. B.EAJlT LlVi:R THnrus KIDNEfS ADREKALS SPL&.BN TESTES 

HUK8KR 

7 

8 

Attachment 015· Page 51 

51 
Sanitized Version 

STUDY NUMBER e 6 OW-IN) - 2 

25~NOV-03 

ORGAN/BODY WEIGHT RATIOS (%) AFTBR 7 DAYS 

MALES 


GROUP 1 (O KG/KG) 


AlfIK&L BOOY W. KEJUtT LIVD THYKDS ICrDayS ADIl1lN'ALS SPLKD TESTBS 

NUMBER (GIWI) 

1 210.32 0.363 4.3' 0.::11 0.64 O.OU 0.2'5 1.:n 

2 225.55 0.337 4.U 0.27 0.78 0.022 0.31l1 1.12 

GROUP 2 (10 KG/KG) 

ANIMAL BODY \Of. KURT LIWR THYKDS J:IDNlrrS ADRENALS SPLED TBSTES 

NUMBSR (GJW() 

1 236.10 0.31. 4.70 0.27 0.84 0.023 0.337 1.26 4. 210.00 O.Ha (.:U 0.26 O.H 0.023 0.352 1.20 

GROUP 3 (100 KG/KG) 

ANIMAL BODY K. BJU.RT LIVllR THYKDS ICIIlNJ:YS ADJtl:KALS SPLEEN TEsms NtlMJIIR (GIWI) 

5 237.57 O.llll 4.lIi 0.26 0.7( 0.021 0.350 1.18 

Ii 225.:H 0.353 (.28 0.29 0.75 0.022 0.310 1.18 

GROUP 4 (1000 MG/KG) 

AHIHAL BODY W. HEAP.T LIVER TIlTM1JS KInRYS ADR.iINALS SPLEEN msns 

NUMBER (GJW() 

7 

a 

Attachment 015 - Page 52 

52 
Sanitized Version 

6 OW-INO - 3 

2S-NOV-03 

ORGAN WEIGHTS (GRAM) AFTER 7 DAYS 

FEMALES 


GROUP 1 (0 MG/KG) 


AlI'IKAL BOor If. IlKART 1.IW. THYMUS ICIDtorrS ADREHALS SIi'LBBH 

NmCBBR 

, 150.54 0.6l5 6.l8 0.'" 1.17 o.on 0.411 

10 153.17 0.611 7.22 0.62 1.U 0.069 O.lfO 

GROUP 2 (10 MG/KG) 

ANl:KAL BODY If. IlBAR1" LIVER 'nIYKO'S ltIDNJ:rs ADREHALS SPt.EBH 

K'DIOIBR 

11 150.66 0.558 6.80 0.42 1.Z4 0.057 0 • ...,4 

12 145.78 0.557 5.86 0.'" 1.24 0.061 0.518 

GROUP 3 (100 MG/KG) 

AXIlotAL BODY If. HDRT LIVER Ts:nroS ICIDtorrS AllIilENALS IIIi'LKBH 

NUMBSR 

13 145. ;13 0.60' 7.14 0.41 1.24 0.056 0.585 

14 154.68 0.620 6.65 0.46 l.Z8 0.061 0.3'" 

GROUP 4 (1000 MG/KG) 

AKIHAL BODY W. HSMlT LIV'&1l TIlYKUS ICIDK'BYS ADtuDU.LS SP1.liCBH 

NUMBER 

15 

16 

Attachment 015 - Page 53 

53 
Sanitized Version 

STUDY NUMBER 8 6 OW-:tND - 4 

2S-NOV-03 

ORGAN/BODY WEIGHT RATIOS (%) AFTER 7 DAYS 

FEMALES 


GROUP 1 (0 KG/KG) 


BODY W. LXVl:R TIlYIItIS ltXD.NEYS 

(0lWf) 

II 150.54 0.422 0.32 0.71 0.0'0 0.213 

10 153.17 0.403 0.40 0." 0.Of5 0.254 

GROUP 2 (10 KG/KG) 

BODY W. LIVI:R TB'nCI19 lCIDNEl'S ADREHALS SPLRSH 

(GIUUC) 

1.1 150.66 0.371 f.51 0.28 0.12 0.038 0.31.5 

1.2 US.78 0.112 4.0:1 O.H 0.85 0.043 0.355 

GROUP 3 (100 KG/KG) 

BODY W. LIVER TIlYIItIS "lONErS ADREHALS SPLEBH 

(GIUUC) 

13 U5.:U 0.419 4.92 0.32 0.85 0.039 0.'03 

1t 15f .68 0.401 4.30 0.30 0.83 O.OU 0.255 

GROUP 4 (1000 MG/KG) 

BODY K. LIVER nrnms ltIDtmYS ADUN'ALS SPLEJ:N 

(GIUUCI 

15 

16 

Attachment 015 - Page 54 

54