### Sanitized Version ",-UDYNUMBER 654240 rudy

### Referel NumberKSG040165 

## Report Page 45 

# GLP- CERTIFICATION The Swiss GLP Monitoring Authorllles


# Statement of GLP Compliance

itIs herebycon!'mled\hat 

### dwlng

### theperiod

### of November 18
- 22,2002 

### thefoBow/ngTestFaclUtJee of 

### RCC 

### Lttl 4452 

### ItIngan Switzerland

were Inspected 

### by the 

### Federal 

### OffIce of PublIc 

### Hllallh. the Swiss Agency for Therapeulic ProcIutIII andthe

### SwIss Agencyforthe 

### Environment. fonJslsand Landscape Vtith respect 10 the compliancewiththe SwIss legislation

# onGood LaboratoryPnroIice. Test Facilities Aleas

### ofexpertise

### *
•Toxlcolony TOX, ACC, MUT, OTH (SafetyPhannaeology) • EnvironmentalChemistryand ACe, ECT, ENF. EMN. PCT,

Pharmanalytlcs 

### RES, OTH 

### (Animal metabOlism) The.inspedlonswere 

### performed 

### In agreemenlwtth

### theOECO Guidelines for Natlonal 

### GLP Inspedlons andAudits. II

### was found thatthe

### aforementionediesl

### fadlilles were opereting In compliance

### wtththe Swiss Ordinance relating

### laGood 

### Labotalory Practice IRS813.016.5) at the lime

### they_Inspected. Federal

### OffioeofPublic Health 

### The

### Director


### Bern. Mardl2003 

### Prof.Th. zeltner



### Attachment

## 014
- Page

## 45

## ATTACHMENT HEADER SHEET
Attachment Number015 Attachment Name Attachment 15 

## Associated PMN Section Number N/A Does not contain CBI



## Report Number EPMN100421732888414

### SanitizedVersion



# RCC Study Number851276 SponsorStudy NumberKF030425 

# I

.. A



# 7-Day Range-Finding Oral Toxicity (Gavage) Study in the Wistar Rat Report 

# Author: Sponsor:

Page 1of

### 54

Attachment015**~** 

### Page 1

## SanitizedVersion 

## 276 STUDYNUM


## 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 postmort9m.

## The results ofthe studyaresummarized asfollows: 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. 15and 16) treated with 1000mglkgldaywere found deadon Day 1oftreatment, and the remaining male (no. 7) treated with 1000 mglkgldaywas killed for ethical reasons onsame day. Clinical Signs One hourafteradministration, three rats treated with 1000 mgJkglday werefound dead. Male no. 7 had convulsivecontractions and was prostrate.When observed again approximately 10 minutes later, these signs were still present and signs of somnolence were recorded. This malewas sacrificedfor ethical reasons. No clinical signs were seen in rats treatedwith 10 mgIKgldayor 1000 mgIKgldayfrom days 1­ 7 oftreatment. Food Consumption The mean daily food consumption of the surviving test item-treated males and femaleswas notaffected during days 1-7

## oftreatment. BodyWeights The mean body weights of the remaining test item-treated males and females compared favorablyto thoseofthe respective control values. Organ Weights No test item-related effects on mean absolute and relative organ weights were noted after 7 days'treatmentwhen comapredwith thecontrols. 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 thetest item. Dark red thymic foci were noted in one female (no. 16) which was found dead on treatment day 1. All otheranimalswere without macroscopicalchangesat necropsy.

Attachment015 - Page 2 

## 2

## Sanitized Version

ASSESSMENT 

## Based on the results of this seven-day dose range-finding study and discussions with the sponsor, dose levelsof 1, 10or 100mglkg bod :

# . .

# . orthe subsequent 2B-day

## study (RCC 

## Study Number 851277)

## with Study Director 

## W.H. Braun



# ..**····~·····t··**

# ..········..··· 

# DaretS- tVIII.t""J

Attachment015 - Page 3 

## 3

## Sanitized Version



## • STUDYNUMBElii1276



# FIGURES

Attachment015 - 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) Attachment015 • 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 Attachment015 - 

## Page 6 

## 10



## 6

## Sanitized Version 

# RFC-SPLT - 1 

# 24-NOV-03 

# RELATIVE FOOD CONSUMPTION MALES
GlKG BODY \/EIGHT IDAY TREATtENT 

## 140 PRETEST



# 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 Attachment015 - Page 7

## Sanitized Version 

# RFC-SPLT - 2 

# 24-NOV-03 

# RELATIVE FOOD CONSUMPTION FEMALES
GlKG BODY VEI9frIDAY

140 TR£ATI"£NT PRETEST



## 130



# 120

110 

# "" 100 ,b
## 90 

# "

-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 Attachment015 - Page 8

## -----



## - - - - - - - -



## - - - -

- - - - - 

## 240 SanitizedVersion 

# 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

Attachment015 - 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)
Attachment015 - Page 10 

## 10

### Sanitized Version

## ~1276



# SUMMARYTABLES

Attachment015 - Page 11 

## 11

### SanitizedVersion 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



### Attachment015 - 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 

### Attachment015 - 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 

### Attachment015 - Page 14 

## 14

### Sanitized Version FC-StM - 4 

# dec 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 

### Attachment015 - 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



### Attachment015· 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 Attachment015 - 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



## Attachment015 • Page 18 

## 18

### SanitizedVersion



# 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



### Attachment015 - 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



## Attachment015 - Page 20 

## 20

### SanitizedVersion
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



### Attachment015 - 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 

### Attachment015 - 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



### Attachment015 - 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



### Attachment015 - Page 24 

## 24

### SanitizedVersion 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



### Attachment015· 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 

# '.n 0.35 :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



### Attachment015 - 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



### Attachment015 - Page 27 

## 27

### Sanitized Version 

# ,liUDYZUMBlij1276



# INDIVIDUALTABLES

Attachment015 - Page 28 

## 28

### SanitizedVersion
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



### Attachment015 - Page 29 

## 29

### SanitizedVersion MORT-rNO - 2 

# 1iiiiiiiiiiiii176 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



### Attachment015 - Page 30 

## 30

### SanitizedVersion
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



### Attachment015 - 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



### Attachment015 - Page32 

## 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



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### 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



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### 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



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## 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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## 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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### SanitizedVersion 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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### 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



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### 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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### 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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### Page 41 

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## 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



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### 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



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### 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



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### 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



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### 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



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### 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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## 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.



## Attachment015 - Page 48 

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### 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



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### 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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### 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



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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

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### 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



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### 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



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