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### APPENDDC 13 • INDMDUAL PATHOLOGY DATA
UDIII.L 110. ., SD. r DOIII. 1000 PPI oa 1mJD'I'. '2 4QW (1& .... ) III:IIIIIDL**llleaoP~ ~DIV&l'IOJ1**  - ... ror.r.llll:llll '1'1 ..... __ IIID I ftDIU8 I 'l'DCBal , VJLlIDIIIY BL&IlIIa I V'l'.DUB I VJlQIJU. I VO.....UI:**~ ro~I15**  !'JIll ID:CI:CIIIICOPIC

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IREGULATORYIREPOR.T

- S1090 DAY INHALATIOI\ TOXICrY SWDY IN THE RATWITH RECOVERY PHASE 

### APPENDIX 13 • INDMDUAL PATHOLOGY DATA

'2

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- 515

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REGULATORY/REPORT
- 512

### 90 DAY INHAlATION TOXICfY STUDY IN THE RAT WITH RECOVERY PHASE 

### APPENDIX 13 .. INDIVIDUAL PATHOLOGY DATA

.. DIU. 110. 

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### 'REGULATORY/REPORT
- 51390 DAY INHAL\TIONTOXicrY STIIDY IN TIlE RAT\\olTI{ RECOVERY PHASE 

### APPENDIX 13• INDIVIDUAL PATHOLOGY DATA
I\It'lJIIt.L 1'0 I 

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'REGUlATORY/REPORT
- 514

### 90 DAY INHAlATlONTOXICfY STUDY 

### IN THE RAT 

### WITH RECOVERY PHASE 

### APPENDIX 13 - WDMDUAL PATHOLOGY DATA

UDAL 10, 9. DOSlh 1000 pa- c. SnD'!, 924q'a (14 lOIIa) 'l'DIII1IIJ; 

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REGULATORY/REPORT
- 516

### 90 DAY INHALI\.TIONTOXICI'Y STUDY IN THE RAT WITH RECOVERY PHASE 

## APPENDIX 13 • INDIVIDUAL PATHOLOGY DATA

UDCAL 110, t7 BD, P DOIihIl 10ao ps- _ 81'UD'1'. 12 4ap (U 1IIU, fIIIHDIIIJ.**II&CIO'~** It111M I"al.otlaua 'ID I'OLLOIfIH**~u_.**

# ..... IIaIIIIIlI'ID U'RIIII.II.L GLIIID z 1Da7,. I BLOOD I lIOIII

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### 'REGUIATORY/REPORT
- 511

### 90 DAYINHALATION TDXICTY STUDYIN THE RAT WITH RECOVERY PHASE 

### APPENDIX 13 -INDIVIDUAL PATHOLOGY DATA
AlIlJIIIlo 10 I 17 8JCl[. I' DOId. 1000 

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### REGULATORYIREPORT

- 518 

# •

### 90 DAY INHALATION TOXICfY STUDY IN THE RATWITH RECOVERY PHASE 

### APPENDIX 13 • INDIVIDUAL PATHOLOGY DATA

HIIDL IKII ,. sa, F DOSI, 1000 PPI ow ImIDY, !12 day.**(~"** 

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### IREGULATORY/REPORT
-**~19**

### 90 DAY INHALATION TOXICfY SfUDY IN 1HERATWITH RECOVERY PHASE 

### APPENDIX 13 -INDIVIDUAL PATHOLOGY DATA

DIDIo 110. II sa. I' DOD. 1000 PPI 

## 011 IIII!IIDI'. IQ <lap 

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### REGULATORYnrnPORT

- 520

# -- 90 DAY INHALATIONTOXICIY STUDY IN THE RAT

## wrrn RECOVERY PHASE



### APPENDIX 13· INDIVIDUAL PATHOLOGY DATA

...I ......(h bOU. 1000 PfIII 011 BftDJ'. t2 _. (I" BIll 'l'IIJIIln:&L 

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### 'RBGULATORY/REPORT
- 521

### 90 DAY

### INHALATION IDXlCT'y STUDY 

### IN THE 

### RAT

## wrm RECOVERY PHASE 

### APPENDIX 13· INDMDUAL PATHOLOGY 

### DATA

D'IKA.L 110. 

## .t su. r DOR. 1000 lis- mr 1mII:II. 

# .2. IliQII (140 ... , 'IIIIIIDDL .ICJIOPI.'l'JKII'.iOID: IU1IB1'**I.t.ret~** ....1ICOl.1t:b.t. • .t•• 

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### - 522

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### PHASE 

### APPENDIX. 13 • INDIVIDUAL PATHOLOGY DATA

,UfDIaI. 110, 10) au. r DOell. 1000 ppt .. II'!UDYI 9J "'"J'a (11 wIuI) 'l'DII1WA.l. IUC8iOJ'A'IIIOLOCD 'I'D I'OLI.IlII:IJICJ IIICI08COI''IC**Q8SDVA~[a.a** .... _ IIJ:IaI[f Iatn.taJlu1&r a1.OlI:Ollt:U.4l.1 •• (lI1a.t.aal.l !.lVD lIOIaoa_1<NJ:o OC' a1;n4**1a~~toJ:.y** oe.l1 :l.a1!J.1t:rat.to. • (a:la:laal. 1 .ut:i.focal.) SCUflC ...". o..y.:u:u.t:l_ • (8:l.a1aal.) 

## --------------------------.-.-.---.--------------------... OP**AkIKIL··-----·---·-~----------··--------·-·-··---····---------------- ~EGULAIORY~PORT**  

### - 52490 DAY INHALI\.TION TOXICI'Y STUDY INTHE RATWITH RECOVERY PHASE 

### APPENDIX 13 • INDMDUAL PATHOLOGY DATA

.. lDL 110, 4i 1 IIlIJ: I II ilOSIIl o so.- a. 1I'I'UIl'f. 120 &qo'II (11 1IIr_) IIiCO'VUY IIIaCJl(DHIIOI.OG'I K.1l..1.e4 bJ' lIal.ot.IaII.IM 'I'D I'OI'oI'.OIn:JI I'IIIstJa .... IJIIaIftD Al>1DAL GLaBD J AOn'A I II1:.OOD I 1lOIII HUJIOW-1JIIIIIll I 

# _-I'DUII....'I'IJ'LII .JODI!' 1 IlIAD I CUCUII I , IICIODD_ ; 

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### APPENDIX 13 • INDMDUAL PATHOLOGY DATA

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## a.IMI£---------------------------------------------------------------­**~GULATORY~ORT** • 526

### 90 DAY INHALATION TOXICfY STUDY IN THE RAT

# wrm RECOVERY PHASE 

### APPENDIX 13 -INDIVIDUAL PATHOLOGY DATA

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## JM)IIII-.........,
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## ------------------------------------------.------------..0 or 

## IBXNIL-----------------------------------·-----------_-----.---------­

IREGULA10RY/REPORT - 527

# .. 

# ..

o

### 90 DAY INHALATION TOXICfY STUDY IN lHERAT Wfl1:I RECOVERY PHASE 

### APPENDIX 13 • INDIVIDUAL PATHOLOGY DATA

Allno.L 110. 015 SU... DOeI. o lis- a. 8!'11'DJ:. 120 Gal'_ (.I'
.. ) UC09DI**NICIlOI'''~LOGII** I:U1e4 I>r 1Ialot:1Ma. 1'D l'OLUJIIlJIIil S!IIIRIIIS _ ..anm ADIIDAL ra..IIID : AOIl'I'A , &OQD , ... 1IiUUIaI-1'DUll : BOIIB·...uJl+SS!II'UI .JOIlft' I IIII&DI J CI.III:aI : c:or..mr I IIUODIiIIIIII , &IDJDnlIB , lID + D'll: .... o:n'lC ...... , IURDIIIlIAil IJ.AIID J .... , , I.... ; JUUIIIIIII I lIM1l1' I r..t.CllDIAL 4ILIIID I r.aJrI'III[ r t.IVD I :r.u.; : t.JIIII. ""'-Cl:llnCUo : LIDII 1ICXB-"'IIIIII'l'DIC I ...... Colon'!'!' J 0BIICJlIIIAA;VI , Qft" r I'UCD&II r ' ....... 'IIU.oID IiIWIIID I nmm. 'a • .rc:K/18 I I'IIAIlDIX J I'I'IVl'lDJ' IiIWIIID , I'IIOB'I&'IJI IiIWIIID I IIaC'IUII I hIonAlllf CILAD r 

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## ---------------------------------.----------.-----.----BID or**AII~-·---·--··-------·--·----·-------·----·---·--------------------**



### IlEGULATORY/REPORT
- 52990DAY INHAlATION TOXICfY STUDY INTHE RATWrm RECOVElY PHASE 

### APPENDIX 13 -INDMDUAL PATHOLOGY DATA

AIIDI&L 1101 .. IIDI II DOSI. o 

# .... a. smDY. 

### lie ... (11 

### n., DCO'nIt'f
ImCIIClPI.IIIOLOGT 1ti.lJ.414 by**fIel.o~** I'I1II: I'OLLOIIDIC '1'1II811II8 DJII su.!!'DD ADmIIIU. tLI.IID J .IIOR'I'A J II:.ooD J _ 

## lI&IUIOI-"" J**1ImIII~""'+8!'1J'UI** .I0Ill'l' ; .....0 J CUc::ml I CIOI'.a. I IIVOIIaUII J IIrIDID'lWIS I ftII +**~DIA.O"IC** JID9'II I ILUDDI.UI GL.UID I .....!' I :u.a1JIC I .Jll1UJIaI J IIIIJmIJ' I UCIIDQL 0....., J IoII.a:IIIZ J IoD'lllt J 'IDIIS I L'IIIPB IIODIH3Rnc:.&L J I.DII'II 1I011l:-lililiSBiffdlC I IIU.I.L CAYI'J'I' I 0IIII01IIA8U8 I 0It.U. CAVIn I I'.IIK:II&U J t ......'I'IIIJIOID GLI.IID J ._" .I.'I'CII/IB I'DImD: , l"'I'O'IUIt'l QL.UII) : PIlO8!'HII m.ID ; ..crull I &l.LrnJI'I' 8LUD I BCII.!'IC ...". I RICI.II.U YUICr.II I IIDlI .RImrr rr..um) S.DQL COIID ; u..... ; 8'111111l1111 WI_ __ IP.IIJIOII' I I'I'OIIIlICB I ",nIB J 'III'lIm1 I**~ID** 8LUD J I:U.ClIILl J**mt~** 8LI.IIDD I YOLUII'DJtt M08CLII 'l'1li: rOl'.r.owDIQ IIIACJlO8COPlC OBllUYllIIa.8 ..:a IIAIIIK ADUUL tLI.IID Adbad._/a • r1g1at a4!:u.a1 f
..... to 1.1...., •

....... CAnn • BtUAla. _4 ao•• _UCIIMCI al.t.aSCML11J' BOt**a~** at: --'-J'­ 110 AaOIID.LI!'ID .... IS .. !'1 .... !I'J'I.MTIIIII)


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## 1111......-------------------------·---·-·----------·--------·-.-----.---­

1.lEGULATORY /REPORT
- 530

### 90 DAY INHALATION TOXICfY SI'UDY IN TIlE RATWlTH RECOVERY PHASE 

### APPENDIX 13 ·INDIVIlUAL PATHOLOGY DATA

AIIIKIlo 110. 

### " su. II DOIJJI:o o 

# .... 011 BIUDI'. 12C1 4aJ'll (11 -.) IIIECOVDr DC:IIWI.'IBOLOII! IllU..ra bf IIal.otb•• lUI roLloOllI_ 'l'DII1IJIS .... SUalUftIID MIII8JIL eLM!) I ....A J BLOOD , BCIIII IDJIJIOI-I'IIIIIII'R J**aa.a·~+B'I'IPLK** ml]l'l' ; IIDla I : cor.o. J _ , DIDDDl:8 I 011 

### * 

## IIftDlA.orllC _ _IAII GLAD I IIUJl'I' r:umIIII .DlVInIII ; J JoACItIllUo UoI.IID uaJJIX , ,rID 

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......DIX t JlI'I'VI'I'JaJ' J I'ltOSYftII C;r.AIII) I BC'I'IIII J ULIV.lD IILAIID J IIICU'f:C JIIIIlVII I 

### a.:uru YD:rCLB , BUll cal'" n.unc) J Bl'DIAL CORD ; SPUIIIl J II'I'I:IIIIUII III'DI BOllI .... J Ir<*ACII I 'lU'l'18 J tIIDIIIII ; ft1'IIOID IIIioAIID J .......... , VIIDIAIn JIl.ADDIDl I 9OLun'Ml' IIIIBCLII



## ·-------·--·····---·----.·---------.··•••--...-.•-----.IKD .,**AII~---·---·---------·-----··-·--··----·----·----·----·-------~---- REGULAroRY~ORT**  

### - 53190DAY INHALATIONTOXICfY STUDY IN nIBRATWITH RECOVERY**P~E** 

### APPENDIX 13 -INDMDUAL PATHOLOGY DATA
.utI1AI. ItO. 41 sa. If DOell 

### o ps- <* tmJD1' I 120 4ap (18 ... ) u<:ovJIn
DCIIOI'A'IIIOLOGI' UU .. 'lit'**lIalot~**
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... ___ I ft'OIaC8 I**'III.~18** : 'I'I'IIlU8 , UIJIOn UIoIIIIl I 'I.'ItIoCIIIU. I u:a'DIAU BLIoDDBII , VOL1III'HII!' IlUIICLII 110**.....,..,.I~I** .......... D 'l'1li**~I.au:aB** UlIIJDD 

## ------------------------------------.------------------..oar**,..~-----------.---.--------------.-** 

## ...---------------..-----------­

IREGULATORY/IEPORT 

### • ,S32

### 90 DAY INHALATION TOXICTY STUDY IN 1HERAT WITH RECOVERY PHASE 

### APPENDIX 13 .. INDIVIDUAL PATHOLOGY DATA 

# ,. nz.. MDIU. 110. DOSI. o PPI 011 ftVDY. 12. 4a,'r1I (JI wilt.) DCO\IUI'**_A~** lUlle4 by hl.otb_ 'IIIIi

__IIIG 'fII8UIIB .... av.IftBD ADItIII.IL GLAJID , AOftA , ILOC:JD : _ lCUII:OIf-n:HUII , 

### -.-..-.ftrrs& .Jonrr J II1II&0 l QBCUIII J c:oLCII , DIIIOD_ , g:QUDDIS I OJ: • IIII'l'ID.OP!'IC IIIIlYIi , IIDDDIUI ILUID , aaII'I' I ILII'UX : a:;nIIIUII ,**U~** , ....CltDIAL c..a J L.IJDU J L.... J 10.,.. , It1lll'll 1IOOII-a.¥ICI.L : lillO. IICIIS,"8IIII:I'IJI.IC : IIlIIIAL CAYl'l'l' , , ORaL CAVl'ft' , I'MCIIKU I .&ItADDIOm GLIIBD , l'ImD'S**l'A~/"** , I'DaDIX I I'llfUl'l'.utI ca.AB J l'IlOS'I'AU GLiIIIII : I IlALnII:D ..... J IICIA'I'IC I .... .." W8l:a:.. J aD 

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### 'REGULATORY/REPORT
- 533

### 90 DAY INHAlAnONTOXICTY STUDY INTHE RAT WITH RECOVER.Y PHASE 

### APPENDIX 13 - INDIVIDUAL PATHOLOGV DATA

MDIlIla 1'0. .t . mIX. I DOSII; o ps- 011 aftH. laO Gap (11 lib) UCOVUT lACIIO'AftICIL()CR Ulle<ll bJ IIal.otlula. ftI:I rord.oClIIIJN 'IIBIIIlIa ... IlUlKIftID lIIIIII:III.L GLAIID I Mll:'l'A , IHDOD J lIOII: DIUIOII-..-m I 1IOIIII-..-.l+U1n.1**"o~** J BllAIII , CAIICIJM , COLQl( , : ID'XDIIIDIIII I BIll + IIIftDlA,QI'I:tc IIIII9'B , _1M GL.UID I IIIINI'I , ILIUM , I Kl'IlIIIn' ,. LIIoCIIDIIIo ...,.. , ........ , 101.,.. I .... J L ..... IIQDS-CD'IIcu, I L_ ..,.-_BiIC I DSIIL CAn!'! , CDIIOIBIAIIVII r 0ItU0 C&YD"f , I.IIIICIDM , HMD'I'IIIOm CU'.UID , IDD" I'A!'Ca:/II' _:no: I I'I'IVl'l'U'f IilLAIID I IJIOIII'l'Am Gt.IUID I I DLIV.M'r GL&IID r SC:l.I.'I:r:c .... I 8aIIIAL V1I8ICL1i , DD (U., PLIIIIl, 1 SI'DIUo CCJm) I Sl'LDa' I 111ft IIQIIII JIMIIOII I 1I!'018CB I Rlln. I 'I'IIIJIVII I IBIIlOXD IiLlollD r l'JIAaIIIA I 1IJIXDR'1' JILADIIIII; I YOI.8II'I'AIl'I IIIIJI<:Y 1'0 ABIJOIIiIU.ftDB ..... .... 111 'I'BIi 'l'I1I1IIIBS • .."....,

----- •••••••• ----.----------.------.--.--.------.--- •• -.-D 

### or ..

## DIIIo-····-····-----------·-----------··--------·---··------ .......-.

IREGUlATORY/REPORT • 53490DAYINHALATION TOXIcrV S11JDV IN THERAT WITH RECOVERYPHASE 

### APPENDIX 13 - INDIVIDUAL PATHOLOGY DATA
(II 8nzr.r. laO __ (18 ._) DlDIAL 110. 101 SUI r DOS•• o PIll HC:OYIIIl'! '-PAIBCII.ClGY IUl.l.oMI b7**lIILlo~** 'fill I'OI.LC*'IIIG '1'1 .......... _lftD ADIDI.L ar.a.D J AOIt'l'A J IILOCD J ... taItaOW-1'IIIDJt J**_-~8'flrLK** 30Dft' , 1IlU. I CQCIAI , CD't'tX , cou. • IDIIODIIIIUII : lIl!I: + D'l'IlII., OP'I'IC IIJDrYII I IIDDDDII GL.IIID , IIIlAft J ILaUII l DIUIIIIII J It:ua.! J J: 'c:!tTlDr. I r.&:I:'IU I LIVD I loaG I 1'01'II1'II 1IOIIIi-Cllll'n:C'AI. , IioIJD'll 

# JIODII-......,..,c. ; _ I .asu. CAnft : _P11aGt18 I oa.u. can'l'1' I OVUI' J P.IIICIU&U , P.AllllllllIOID GLAD I HDII'S PA'l'lCB/U I II'IIIUl'I1IX I PI'l'UI'l'AID' GIoAIID : .. J au.razr GLAIID I SCD"l'IC ...... I IIII:m ,aJlilR"l' I'LIIII) I ..DIU. com» I IIIPWIa I __ WI!II __ __ ; ftQII.CB ; _ l '!IIIJlOID c::r.uD I 'I'I.lCBILI. I VltIJIH! .....,..... I U"l'DUI I VUIID I**~** III8ICLIi 

## -------------------------------------------------------.-0 OF**~.-.--.-----.-------------.-.-----------.------.----------.----. ~GULATORY~ORT**  

### - 535

### 90DAY INHALATION TOXICI'Y STUDY IN TIlE RATWlTH RECOVERY PHASE 

### APPENDIX 13 .. INDIVIDUAL PATHOLOGY DATA 

# • _ 8ftID1:. 12. 4qa (U

# lib,

..DIAL 110. it2 

### an. r Il08l. PPI UCO'¥IIU 1&mIO.1.'I'IIIJI.OG! UUe4 1I!r alof:llue !'U J'Of.I:.OIIIIIG "I..... __ svaa'I'I'IID ADDDL GLUID , 10JtB , &GOD , ...**~,.....,.** ;**"':-J'IIIUIl+II'I'~** "'0111'1' I IIIta.IJI , CUCUM I CIaIVU , I DQODDqI I DB
­ 1:IlTIJII..CI"IIC ...... I IlUllllltJU QLIlID I ....., J ILIIIIIl r ....... r Dillin' , J.MI!'I1QL 6tAIID I LU.'UIlE ; "no J 1._ I LI1II'II IIOmH:IIWIc:.u. I ......... - ........IC I IIUIIIAIlY BLUm J JIAIIUj, CAYI'IY I oaot'D8U8 I CIIaL CAVIn , 0¥lUD' I • .111C1111&8 I ._'ftIDOI• ....., ,**~'S** , .. ',ca/ll_ , .....1l1li: I JOIruIl'U'I' GL.II.IJ) I DC'I'!III , 8AJ:.JYDY GLUD , IICU'I!tC IIDVlI I IIDlI (JlIGIn' JIl.UIJl) J ..DUo com I ID'LIID , 8'naQI U'III .. .....,. I 1'I'OIDaI I I**~D)** GIL.IID , ftIACIII& I**UIt~** JILI.1IOD I Ift'D'II8 , VMIJII. I**~** IIII'8CLII 110 JI.IIIIOaIII.LI'fIllS .... ... III ftB 'l'ISSUltS UIJlJ....



## ------------ ...----------------------------------------laP oor**~-------------------------.---.----------** ••.. ---.-------.--.----­**~OULATORYnrnpORT** 

### • 536o

### 90 DAY INHALATION TOXICfY STUDY IN 1HE RATWITII RECOVERY PHASE 

### APPENDIX 13 .. INDMDUAL PATHOLOGY DATA

_ 1mJOI. 1:110 ClaY1l III

__ , AlQIUJo ..,. 10. su. r DOlI. o w- UCOQU

..**caoP&~LOR** K.lu.... by JIa1Dtbuae 'l'1li I'OLloOWJIIG 'rJllllQ&
.... IJU8IIIWD &DRaM. 6LUID I**aoJI~&** J :n.ooo J ........ - ..... J

__**~1"** __+8.,1n. 10l1l'i'1 B8&U I c:&ac:. I CDYD I c:m.o. ; I lin • DTIJI&.oruc liliii9i: r ........t .. GLUID I IIUIl'I' I ILIIIIII I I J:n.ft I LaCaJDL IIUIID I L.QDDt I IoIVb I 101lllG I 101llQ IIODJI-CD'IIC&L ; IoDIPII 'OO'- ....... IC I GIoIIID J IIAIAL Cl.Vl:ft r 0K80111AGU11 r .... Cl.nn r 09II:Ir I r&IIC2KAII I rUlllnRJlOl1l Q.&D I 'IIU%D: I 'Ift:I'&iIY C3.UD I mIC'IUII I**UL~** CiILIIIID , BCUIrIC IIDVI I RIll (al..,. ..... ' : IP1II&Io COlD I I'nD'S •

# .a.'fCB," I I SI'IIIIInRI WIIB 1lOIII D--.oII I 8'1C*AC11 I tBJIIIJ8 I ftRaOID GLUID I I UltDAKr BUDDD I U'Ia1IW I VUDr& ,**~U1'** ImIJCLII

..,**~II'Ia** ... SDIr 

## r. 'l'1li 1'1__ IPI'AIrTWKP**-~-~-~------------------.------------------------------..o** OP**~~----.----~--------------------~----~------------.~-------------**



### IREGULATORY/REPORT

- 538

### 90 DAY INHALATION TOXICfY STUDY IN TIlE RATwrIH RECOVERY PHASE 

### APPENDIX 13 .. INDIVIDUAL PATHOLOGY DATA

AJlllIGL 110, us su., Il08l. o ppa a. B!'IID'!. 12• ...,.. IU wka) UC09lIIIr
IIII.Cllmll'l'JlOLOGr 1I:1U104 b7 JIal.otbua. nil .POLLOIrDIII 'II..... .... -..:t'l'lJll) lIIIIIBIIU. II.UID I ....-rA r BLOOD J JIaIII 

## 1DIIaOI'...... , ...-.......'1'1J'r.K JODft : ..Il0l11 , C&KW I CDYU: J cot.C* , I BIll ..**~:utI..OP"IC** ..... I BUDD!ur GLaD : IIII.U'l' I I .... I J lUllBKI' I LlaJIIII.L AUlD , LI:I'DX I LDD , L'IaI I L'lllP1 lIOIlB·canc.u. i LDIl'II .OI'IH.......IC : lIfA*AIl'I CILJIIID I ...." CAVIn I 0U0'I'II8U8 I OUL c:a.Ylft I ovurr f
........ I •**.It.I&~JIl** 8LIIIID : I'IRD'. IlI.KII/•• , :na:ua , 1'I'l'VI'AI!'I ID.Am ; UC'Jtll I DLJYUrr GI'.UD I IICIAI'XC IIDYI , .III (IllClH 1'DJIIt) I 8l'11IU. COD I ULaII , S'tlPDRIII IIXD _ .....- , .'I'OIIACI I ftIIIaII , 'IlIIJIHD GLUm , 'l'JIACIIU. I 1IlIIIIU:I' IILAIJIID , U'IDU8 I VM:utI. ,**~LDII'I'AI!'I** lGI8CI'dI 110 .J\BW'R'QLt'1'x.8 .... _ III 'I'D '1'IS8VJIS ruvnq:D



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### 'REGULATORY/REPORT
- 539

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### 90 DAY INHALATIONTOXICTY STUDY IN THE RAT WITH RECOVERY PHASE 

### APPENDIX 13 - INDIVIDUAL PATHOLOGY DATA

.. DIAL 110. 117 

### su• ., DOSI. o 

# ... _ B'l'UD1'. laO clays (11 lID) lIIlCOVBIlr JaCaOPA'I'JICILOGS til1e4 ... lIal.otlwae

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_ I**8CU.~lC** ...... J UD CIXCIft PLUI:) I 8JI.aL COllI) I uu:a , __ UIB lie.
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## ----....-...---...-....-......-....---.-.-.---.--------BRD or ..**~.---.--** •••-------.-••-----.---.--.-•• ------------.---------.---­**~GULATORY~ORT** • 541

### 90 DAY INRI1\LATION TOXJCfY STUDY INTHE RATwrrHRECOVERY PHASE 

### APPENDIX 13 • INDMDUAL PATHOLOGY DATA

IJIDIlL 110. 101 

### sa. p DOSII. o JIpa 

# '* _1'0 120 4aya (1' wk.) DCOYaI' lI.lCIO'A'I'1IOLOft JUl.l...,. bJ' lIal.otbuae 'ftIII roLr.OIfDllil 1I88UU .... SUIIIIlfftD

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### on.n , .MCUU , 'AM'fIDII011:

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## ----.---------------.----------------------------.-----.-DOP M!MIL---------------------------------------------------------------­

,REGULATORYnrnPORT

- .542 I

### 90 DAY INHALATION TOXICfY STUDY IN TIlE RAT WITH RBCOVERY PHASE 

### APPENDIX 13 -INDIVIDUAL PATHOLOGY DATA

AIIDIlIL ItO. lOt SJIl[, P uon:. o Ps- C. B'IUD1'. 12. c1&ya (11 ... ) UCO'IIIIIl 1DC'II!)JI.I.'IIIOI.OIil1' 

### uu..s bJ' JIal.at:hilule 'IllS rot.:LOIJ:DII;l**~11I8VIi8** .... IIUIIIIX'I"RD .I.DIIDIoIo .LI.EI J AOa'l'A J JIl.OOD**~** ____-I'IUIIIII I ....**-P_+8~IJ'U** JODl'l' I .....111 I CAlCUlI r CIDrt'llI: I cor.o. I IIUOIIaIIIK I as + _IJIA.OI"I'IC ...... J IIlIi_IU GUIlD I IIIWl'l' I I1._ ; a",.. I 1:u.:B'f. : I'olICIIIIlU. GUIlD I LlIIJ'D I Iol'lllll J LlIIIiI ; 101'II1'II "'-CD':VlCUo J LDRIl _-.........uaIC J ...... 1' CII.&IID I IIAoUL CAVI'!'! ; OaJOlllll.GVll I 0I.U0 CAVIft J O'IUT I PAIICIIAS I JI.t.Uftr1'IIOID &aD I PftD'S**PA~'_** I JlB.'IUt'IIIZ • JlI'l'U['IUJ' CILIIID J _ I BALIYlollr GIoIIIID I SCUflC ..... J 

### sa::ar [ala'!' nMII:) I UIIlU. 00.. I SPLDIJ I 8ftJQ1U11 lIUIl ... IIIADOII I • 'I'II.'IIm8 I 'ftID01D GLID I I tIJlD.UrJ' BLUlRJI I U'f.I.'IVS I YM:DIA , vor.lllft'DI' IIIIJIICLII 'IllS POIoIoOlfDlGl III.CIlOtICOPlC**~nc.a** 

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### REGUlATORY/REPORT - 543

# ... ... o 

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### APPENDIX 13 - INDIVIDUAL PATHOLOGY DATA
MIlIA(, 110. 51 SD... D08I:. 1000 JIIII 0.- 1mJD'I'.**12~** 4&78 UI wIla) asconn
IIACIIOPl.ftIOLOCn Ulle4 br lI&l.othue ftlI POLLOIrDIG U_II .... su.zt'DD 6LUID , .IOIlrA I Br.ooD , ... MI.QOW-J'DIDII , IIOIIB-PBIUIl+8rIl'r.II .;rOllft , 8III.DI , CI.JICDIC ; c:or,qr J D-.mr , UIDIDDIIS ; l1'l1I +**~1"'.OP~rIC** IIDVJI I IIUDIIIlIU GUIlD I ....,. , ItnII I DI1III1M I 1IIDmn' I uca:nar. u.aIID I UKDIZ I LIVD : 1_ , 10_ IIODB-CDVICAL ; tDll'B IIOOI-USU'furC I IIASAL CAVIn' I 0lIII0_ I OII&L CAy:n I PAII:IlDII , ......**~ID** 8L11111) I**~'J** pl.fl:II/a , PDIIDIlt I PI'l'Ulrur CILlIIID I PJIOIftID m.DID : Dc:ruJ( J SALIYUl'I' GLaIIII , Kl.I.rlC ...". , IIaIDI.I.I. valCLII r 8I[D lallm'! rLAa) r III'DIAL COItD ; 1II'r.a.' ; S_ 0 ___ IUDOW , ftOIQCB r DarlS r 'III1IIU& ; ftDIOlD GLAIID r DAaJU. r uaDIAm' IlLAllDD , VOLUlftAlll' ..ac:r&

., &BJIOIIIII.LlrDB .... .... I. ftII US11V118 llAMJDD 

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## a.IMI.t---------------------------------------------------------------­

REGULATORY/REPORT
- 545

### 90 DAY INHALATION TOXICfY STIIDY IN TIlE RATWITH BECOVERY PHASE 

### APPENDIX 13 ·INDMDUAL PATHOLOGY DATA

lIIIlDL 110. sa au. II DOD, 1000 ppt 011 BIVD'I. 120 cIaJ'lI UI wIuo) IUIC:IOYIIU**IIACII'.A~** Kille4 b7 Balotbaae 'ftIII: J'OLIOWDIGI 'l'IJIRJIIS .... Ba.:r:'fl'SD ADJIDIIL GLMD I AOIlft , IILOOD ; ...**~.~** I _- ....... ftIFldI JOIII'1' I DUll : CI.IICUII I COLCII ; I**lD'lDI~8** , lID

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MODI. III,. 1111 

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### -**~49**

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AIIIDJ. 110. 16 

# sa..**~.** 1000 .. iJ'I'UD'f. 110..,.. IU 

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### APPENDIX 13 -INDIVIDUAL PATHOLOGY DATA
UDAL 110. 111 

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## APPENDIX 13 .. INDMDUAL PATHOLOGY DATA

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### APPENDIX 13 -INDIVIDUAL PATHOLOGV DATA

UIIIU 110. 115 SUI J' POR. 1000 1II1II 0If l'l'8Dlh no _p ell .... ) UCOVIU
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### - SS9

### 90 DAY INlIALATION TOXICIY STUDY IN THE RAT

## wrm RECOVERY PHASE 

### APPENDIX 13 ·INDMDUAL PATHOLOGY DATA
lIJIDrU. 11). 116 111m. r DOB'I. 1000 PI- 011 BftDJ:. 120 cIa,.a 

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### fREGULATORY/REPORT

- 560

### 90 DAY INHAl.ATION TOXICfY STUDY IN THE 

### RAT WITH RECOVERY PHASE 

### APPENDIX 13 - INDMDUAL PATHOLOGY DATA
_DIAL 110. 117 

# 1mlI:.. DOSIh 1000 

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### .IIIIKaL---------------------------------------------------------------­

fREGULATORY/REPORT
- 561

### 90 DAY INHALATION TOXICfY STUDY IN TIlE RATWITH RECOVERY PHASE 

### APPENDIX 13 -INDIVIDUAL PATHOLOGY DATA

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........ 1'1'011 .... _ III 'I'I1II: 'l'IBBUa BDllJIID 

## -------------------------------------------------------IBO or ..**~--~------------------------------------------------------------ ~ULATORY~ORT**  

### - 552

### 90 DAY INHAlATION TOXIcrY Sl11DY IN mE RAT WITH RECOVERY PHASE 

### APPENDIX 13 - INDIVIDUAL PATHOLOGY DATA UDIII.I. .,. u. sa. F voe:s:. 1000 

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## ------------------------------------------.----.----.--.-D or 

### JlllDIII.I.--------------------------.----------------.-------------------­

'REGULATORY/REPORT
- 563

### 90 DAY INHALATIONTOXICI'Y STUDY IN THE RAT WITH RECOVERY PHASE 

### APPENDIX 13 ..**~DMDUAL** 

### PATHOLOGY DATA 

### lUIDI.U. 10. 12. 

### lID. r 

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......8'I'IPLI JOIft , JIIl&U , CUCUII ; ClDl'l'D: f COLOll , DtIODBII'IIII f JIU .. 1Ift11D..Oft1C IIIIIn'I , .... , .... I ILIIlIIr , ,. ...... , II:llIIIIIrI' , LaClDII.L , LA&DIlI: I LX.... , LOllI , L'IICPII IIODB-CIIII9IC&L , LDII'II ..........au:c: , IDIIIIIUI'f CILUD , asar. c.A'f'ln I OIl:8GHUAJ8 , ou.:r. &Y1U I OIVUI I l'UCIIDB J ....'fDIlOm GJ'.AIID I I!n:D'S IPIIICI./IIS J PIIlIJRD , PI'l'lJI'I'IIJtI ca..&III ; IIIIC'rIJI , au.nu:r IIIoaID I acD.UC IIDYIi , RIJI OlIGIII rwmt) I IIIDDL COD I S.LIOIB: , DIDIIIIIII nft IIOBII ___ I S'IClICACII I 'I'BDUII , '!'ImIlOr1l CLNID I 'l'llAc::au. ; UtiJIIIII'I' IILIIIDD I 1ft'IDIIIII , VUIJD. , VOUIII'I'UtY IIUBCLIi 110**~I'I'IIIS** no _ I. 'IIIIi D_S ............, 

## --------.----------------------------------------------..0 or 

### lUIIRaL---------------------------------------------------------------­

'REGULATORY/REPORT - 564

# p-**o~J -~**  

# 3r PAGE I OF 16 PACES 

## PFCE!VED

ACUTE EYE IRRITATION INTHE RABBIT

t') --.**~** . ...- ""\1 

# -**:~~ ~~~:** **:r~ -:~:"~**  

## :- . _:.(-,**"-':J~:** 

### o 

# - .. U1 N 3: -.I 

### AUTHOR:**~ .-~**  ,.I**.";~** 

# -**':,,~,** f''V ........, r-r; "". .,,,**~** _.t.:.. '--"'1

,. ,,-"-,," 

### 9 --' en w 

### STUDY SPONSOR: 

### TESTFACILITY:

111111111111

# "III 11111

# I~II11111

# "III "III11111

# ~llllfllIIII 11I1I111111 500 5 0 0 0 3 822 I SPAGE 2 

### QUALI1Y ASSURANCE REPORT 

### This study type 

### is classed as sholNenn. 

### The standard test 

### method for this 

### study type 

### ("General 

### Study PJan" 

### in aECD terminology) was 

### reviewed for compliance once only on 

## initial production. Inspection of

### the routine and repetitive procedures that constitute the study is carried out as a continuous process designed to 

### encompass the majorphases at 

### or about the time this study 

### was in progress. This 

### report has 

### been audited by 

### Quality Assurance Unit, and 

### is considered to 

### be 

### an accurate accountofthe data generated 

### and 

### ofthe procedures 

### followed. In 

### each case, 

### the outcome ofQA evaluation is reported 

### to the Study Director 

### and Management on the day 

### ofevaJuation. Audits of study 

### documentation, and 

### process inspections appropriate to the type 

### and schedule ofthis study 

### were as follows:

§ § 

### 28 March 2002 Standard Test Method Compliance Audit 05 November 2002 Test Material Preparation 18 November 2002 

## Animal Preparation 18 November 2002 Dosing 20 November 2002 Assessment ofResponse 12 December 2002 Draft 

### Report Audit Date ofQA Signature Final Report Audit § 

### EvaJuation specific to 

### this study 

## 28 FEB 2003 DATE: 

# ................ ,

# ...................................

• Authorised QA SIg..atares:_ ...PAGEl 

## GLP COMPLMNCE STATEMENT The work described 

### was perfonned in compliance with 

### UK. GLP 

### standards (Schedule I, 

### Good Laboratory Praetice ReguJations 1999 (91 1999131

# (6». These Regulations are 

### in 

### accordance with 

### GLP 

### standards published 

### as 

## OECD Principles 

### on Good Laboratory 

### Practice (revised 1997, 

## ENVIMCICHEM(98)17); and 

### are 

### in accordance 

## with. and 

### implement. the requirements of 

### Directives 87/18IEEC 

### (as amended 

## by Directive 1999/11/EC) 

### and 

## 881l20lEEC (as amended 

## by Directive 19991121EC). These international standards are acceptable to the Regulatory agencies of the following countries: Australia, Austria, Belgium, Canada, the 

### Czech 

### Republic. Denmark, 

### FinJand, France. Gennany. Greece, Hungary. Iceland. Ireland, Israel, Italy. Japan. Republic of Korea, Luxembourg. Mexico. The Netherlands, New Zealand. Norway, Poland. Portugal, Slovenia, 

### Spain, Sweden, SwitzerJand. Turkey, the United KingdoD'l; and 

### the United States ofAmerica. This report funy 

### and accmately reflects the procedures used 

### and data 

### generated.

DATE: ..........

## ?I.f.~.~ 

# ..**~~~~** 

# ................... Study 

### DirectorPAGE 4 

### CONTENTS QUALITYASSURANCE REPORT 2 GLP COMPLIANCE STATEMENT 3 CONTENTS 4**SU~Y** 

### 5 1. INTRODUCTION 6 2. TEST MATERIAL 6 

### 2.1 Description. Identification 

### and Storage Conditions 6 2.2 Preparation ofTest Material 6 

### 2.3 Measurement ofpH 7 3. METHODS 7 

### 3.1 

### Animals and Animal Husbandry 7 3.2 

### Procedure 7 3.3 Interpretation 

### ofResults 8 

## 4. ARCHIVES 9 5. RESULTS 10 6. CONCLUSION 10 TabJe 1 Individual Scores and Individual 

### Total Scores for 

### Ocular Irritation 

### 11 

### Table 2 Individual 

### Total Scores And Group Mean Scores For Ocular

### Irritation 12 Appendix 1 Initial PiUn 

### Reaction 13 Appendix 

### 2 Draize 

### Scale for Scoring OcuJar Irritation 

### 14 Appendix 

### 3 Modified 

### Kay and Calandra Interpretation

### ofEye Irritation 

### Test IS Appendix 4 Statement ofOLP Compliance 

### in Accordance 

### with Directive 

### 88/320lEEC 16PAOE'


### ACUTE EVEIRRITATION IN THE RABBIT 

## SUMMARY IntrodllCtlon. The study 

### was pcrfonned to assess the irritancy potential 

### ofthe test 

### material to 

### the eye of

### the New 

### Zealand 

### White 

### rabbit. The 

### method was 

### designed to 

### meet the 

### requirements ofthe following:
• OECD Guidelines 

### for the Testing 

### of Chemicals 

### No. 405 "Acute 

### Eye Irritation/Corrosion" 

### (adopted 24 February 1981)


### • Commission 

### Directive 921691EEC 

### Method B5 Acute Toxicity (Eye Irritation) Reslllt. 

### A 

### single application of the test material to the non-irrigated eye of three rabbits 

### produced moderate conj1Dlctival irritation. 

### Two treated eyes appeared 

### normal at 

### the 

### 24-hoUt observation and the remaining treated 

### eye appeared nonnal at

### the 

### 48·hour observation. 

## Conclusion. The test 

### material produced a maximum group mean score of

### 8.0 

## was classified as 

### a minimal irritant 

### (Class 3 

### on a 1 to 8 scale) to 

### the rabbit eye according to 

### a modified Kay and 

### Calandraclassification system. The test 

### material did 

### not meet the criteria for classification as irritant 

### according to 

### EU labelling regulations Commission Directive 2001/S91EC.

### 1.1 PAGE 6



### ACUTE EVEIRRITATION IN TIlE RABBIT 

### 1. INTRODUC110N 

### The study was 

### performed to 

### assess the irritancy 

### potential ofthe test 

### material following a single application to 

### the rabbit eye. The 

### method was 

### designed to meet 

### the requirements ofthe following:
• OECD 

### Guidelines for the 

### Testing of Chemicals 

### No. 405 "Acute Eye 

### Irritation/Corrosion" (adopted 24 

### February 1987)


### • CommissionDirective 921691EEC Method BS Acute Toxicity (Eye Irritation) 

### The albino rabbit has 

### been shown to 

### be a suitable model for this type 

### of 

### study and is recommended in the testmethod. The 

### results of

### the study are believed to be 

### ofvalue in predicting the likely eye irritancy potential ofthe test material to man. 

### The study was 

### performed between 12 November 2002 and 21 November2002. 2. TEST MATERIAL 

### Description, Identification and Storage Conditioos Sponsor's identification Description clear colourless liquid Batch nwnber 

### Date received 09 September 2002 Storage conditions room temperature in

### the dark Data relating to the identity, purity and stability 

### ofthe test 

### material are the responsibility ofthe 

### Sponsor. 

### Preparation ofTelt 

### Material For the purpose ofthe 

### study the test material was 

### used 

## as supplied. The absorption ofthe test 

### material was not determined. 

### 1.1PAGE 7 

### 1.J Me.surementof 

### pH Detennination ofthe pH was attempted by no reading could be obtained. 

### 3. METHODS 

### 3.1 Ani.als aDd 

### Animal HusblDdry Three New 

### Zealand White rabbits were supplied by



### . At the 

### stan oithe study 

### the animals were 

### in the weight range of2.0 

### to 3.5 kg and were twelve 

### to twenty 

### weeks old. After 

### an acclimatisation period 

### ofat

### least five days 

### each animal was given 

### a numberunique 

### within the study which was 

### written 

### with 

### a black indelible 

### marker-pen onthe inner 

### surface of

### the earand on the cage label. The animals were individually housed 

### in suspended metal cages. Free access to 

### mains drinking water and food 

### was allowed throughout the study. The diet 

### and drinking water

### were considered not to contain any contaminant of

### a level that 

### mighthave 

### affected the purpose or integrity ofthe 

### study. The temperature and relative humidity were set to achieve limits of 

### 11 

### to 23 c

### C and 

### 30 to 

### 700.4 respectively. Any occasional deviations from these targets were considered not 

### to have 

### affected the pwpose or integrity ofthe study. The rate ofair 

### exchange 

### was at 

### least 

### fifteen changes per hour 

### and the lighting 

### was controlled. by a time switc;h to 

### give twelve hours continuous light (06:00 

### to 

### 18:00) and 

### twelve hours darkness. The animals were provided 

### with environmental enriclunent 

### items which were considered not 

### to contain 

### any contaminant ofa level 

### that might have 

### affected the purpose orintegrity 

### ofthe 

### srudy. 3.2 

### Procedure Immediately before the start ofthe test, 

### both eyes 

### ofthe provisionally selected test rabbits were examined for evidence ofocular irritation or defect with the aid ofa light source from a standard ophthalmoscope. Only animals free ofocular damage were 

### used. Initially. a single rabbit 

### was treated. A volwne of0.1 mJ ofthe test 

### material. 

### was placed into the conjunctival sac ofthe 

### right eye, fonned by gently pulling the lower lid away from the eyeball. The upper and lowereyelids were held together for about one second immediately after 

### treatment,

. to oreVet:lt In!ilc:nf

### thp. t,.<11 mA,,.rh, L "ntl**tn,."_.,....l;o,g,~** Th... l,.A- ...."' .. .........A .1J ..+r...M ........ .-.d .........____..

### 3.3 PAGEl 

### used for 

### control purposes. Immediately after administration ofthe test 

### material, an assessment of the initial pain reaction was made according to 

### the six point scale shown inAppendix ]. After consideration of the ocular responses produced in the first treated animal, two additional animals were treated. Assessment ofocular damage/irritation was 

### made approximately I hour and 24, 48 and 72 hours following treatment, according to the numerical evaluation given in Appendix 2, (from Draize J 

### H (1977) "Dennal and 

### Eye Toxicity Tests" In: 

### Principles and 

### Procedures for Evaluating the Toxicity ofHousehold Substances, National Academy ofScienccs. Washington DC pAS to 49). Any 

### otherocular effects were 

### also noted. Examination ofthe eye was 

### facilitaled by the use ofthe light 

### source from a standard ophthalmoscope. 

### InterpretadoD ofResults The numerical values corresponding to 

### each 

## animal, 

## tissue and observation time were recorded. The 

### data relating to the conjunctivae were designated 

### by the letters A (redness), B (chemosis) and C (discharge), 

### those relating 

### to the iris designated 

### by the letter D and those relating to the cornea by the letters E (degree ofopacity) and F (area ofcomea involved). For each tissue the score was calculated as follows: Score for 

### conjunctivae = 

### (A+ B+C)x2 Score 

### for iris = 

### DxS Score 

### for cornea 

### (ExF)xS 

### Using the numerical data 

### obtained a modified version of the system described by Kay J H and Calandra J 

### C (1962), J. Soc. Cosmet. Chern. 13, 281-289 (see Appendix 3) was used to 

### classify the ocular irritancy potential ofthe test material. 

### This was achieved by adding together the scores for the cornea, 

### iris 

### and 

### conjunctivae for each 

### time point for each rabbit. The group means ofthe total 

### scores for each observation were calculated. The highest of these group means (the maximum group mean score) together with the 

### persistence ofthe reactions enabled classification ofthe eye 

### irritancy potential of

### the test material. Ifevidence ofirreversible ocular damage is noted, the test material will be classified as corrosive to the eye.PAGE 9 

## 4. ARCHIVES Unless instructed otherwise by 

### the Sponsor. all original data 

### and the final report will be 

### retained in the archives for five years, after which instructions will be sought as to 

### further retention or disposaLPAGE 10 

### 5. RESULTS Individual and 

### group mean scores for ocularirrilation are given 

### inTable 1 and Table 2. No corneal oriridial effects were noted during the study, Moderate corVunctival irritation 

### was noted 

### in all treated 

### eyes one hour after treatment with minimal conjunctival irritation 

### inone

### treated eye atthe 24-hour observation. Two 

### treated eyes appeared normal 

### at the 24-hour 

### observation 

### and the remaining treated eye appeared normal at the 48-hour 

### observation. 

### 6. CONCLUSION The test material produced a maximum group mean score of 8.0 and was cwsified as a MINIMAL IRRITANT (CLASS 3 ON A 1 TO 8 SCALE) to 

### the rabbit eye according to a modified Kay 

### and Calandraclassification system. The test 

### material did not meet the criteria for classification as irritant according to EU labelling regulations Commission Directive 2001l591EC.:ACUTE EYE IRRITATION IN TIlE RABBIT 

### Table I Individual Scores and Individual Total Scores for OeularIrritatioD lPR=2 IPR-l IPR 2 

### Rabbit Numberand Sex 

### 90 Male 61 Male 62 Male Time AfterTreatment I 24 

### 48 72 I 24 

### 41 

## n I 24 

### 48 72 Hour 

### Hours Houn Hours 

### Hour 

### Hours Hours Hours 

### Hour Hours 

### Hours Hours CORNEA E Degree ofOpacity 0 0 0 0 Q 0 0 0 0 0 0 0 F ..Area ofCornea Involved 0 0 0 0 0 0 0 0 0 0 0 0 Score (E x F) x S 0 0 0 0 0 0 0 0 0 0 0 0 IRIS 0 0 0 0 0 0 0 0 0 0 0 0 0 Score(DxS) 0 0 0 0 0 0 0 0 0 

## a 0 0 CONJUNCTIVAE AzRedness I 0 0 0 t I 0 0 I 0 0 0 8 =Chemosis 

# , 0 0 0 I 0 0 0 I 

### 0 0 0 C .. Discharge 2 0 0 0 2 0 0 0 2 0 0 0 Score (A 

### +B 

### + C) x 2 8 0 0 0 

### 8 2 0 0 B 0 0 0 Total Score 8 0 0 0 8 2 0 0 8 0 0 0



# - - - -

IPR = lnitill! IJ<1in mu;Uon PAGE IIPAGE 12 ACUI'EEYE 

### IRRITATION IN THE 

### RABBIT 

### Table 1 IndividualTotal Scores ADd Group 

### MeaD Scores ForOcular IrritaCioD

Rabbit Number Individual Total Scores At: and Sex J 

### Hour 24 Hours 41 Hours 

### 72 Hours 90 Male 8 0 0 0 61Malc 8 2 0 0 62 Male 8 0 0 0 Group Total 

### 24 2 0 0 Group Mean Score 8.0 0.7 0 0PAGE 13 :ACUfEEVE 

### IRRITATJON IN THE RABBIT 

### Appendix I 

### I'ddal raiD 

### ReadieD When the material is instiUed 

### in the eye 

### there may be 

### an initial local pain 

### reaction. The reaction vvill be graded 

### as follows: Class Reaction by 

### Animal Descriptive

### Ratlnl

0 

### No 

### response No initial pain 1 

### A few blinks only. nonnal within 

### one ortwo minutes 

### Practically no 

### initial pain 2 Rabbit bJinks and tries to open eye, but 

### reflex closes it Slight initial 

### pain 3 

### Rabbit holds eye shut and puts 

### pressure on lids, may 

### rub 

### eye with 

### paw Moderate initial

### pain 4 

### Rabbit holds eye shut vigorously. may squeal 

### Severe initial 

### pain 

### 5 

### Rabbit bolds eye shut

### vigorously, may 

### squeal. claw at 

### eye,jump and try

### to escape 

### Very 

## severe initial pain There is often no correlation between the initialpain and the subsequent eye irritation.PAOEI4 

## ACUTE EYE IRRITATION IN THE RABBIT Appendix 1 

### Dra.ize Scale for Scoring OcularIrritation 1. CONJUNCTIVAE (A) R.aetS (rr:fen to palpebrallllld ....lbarc:oqjuru:tivae cxclading cornea and iris) Vessels nonna.I 

## o Vessels dctiaitdyinjcclc:d above normal I More dlftWle. deeper crimson red, Individual vessels not euJl)' discernible 2 DlftUse beefy red 3 

### (B) ClaeDI_ NoswdUns 

### o Any swollinl above normal (includes nictibllin. mcmbranc:) I OIMousS'Wdlina with partial eversion ot'lids 1 SwclJIR. with Uds about halfdosed 3 Swellina wMb lids halfclosed to eomp!etely dosed 4 (C) 

### Dilcballe No 

### djJ(:barJe 0 Any amount different 6'om normal (does not include smaD amounts observed in inner canthus of nol'1Dlll animal,) Discharge with moiSleftIn& ofthe lids and hairsjustadjacent to lids 2 Discl1arac with moisteniDJ ofthe lids IIIId hairs.considerable area around the eye 3 THE TOTAL SCORE - (A 

### + B 

### + C) xl MAXIMUMTOTAL -10 

### 2. IRIS (D) 

### Values Normal 

## o Folds above normal. con&estion. swelling. cin:umc:omeal injection (any or all ofthese or almbinttion ofany thereof) iris still relCling to IlJht (sluggish reaction is positive) No l'CKtIon to 

### lip"haemorrhage. 11'05$ destruction (811)' orall ofthcse) 2 

### THE TOTAL SCORE - D X 

### S MAXIMUMTOTAL"'10 3. CORNEA (1:) 

### Degreeof

### Opacity (most dense area JUed) Noopeci1y 

## o Scattered or diftUse .areas, delails ofiris clearly visible I Easilydiscernible translucent 

### areas. details oriris slightly obscured 2 OpaIaccnt IRU, no detaiLt oliris visible. size ofpupil hire/)' discemible 3 Opaqw;, iriJnotdlsccmlble Ihmugh !heopaci1y 4 (F) 

### AreaofConeaIavolved One qllllftCr (or less) but not zero Great« thanone quarter but less than half 2 Orealiii' than halIbut less than three quartm 3 Greater than three quarteTs. up 10 whole lIRa 4 THE TOTAL 

### SCORE - (E:l Ii)

### x 

### 5 MAXIMUMTOTAL - 80 MAXIMUMTOTAL SCORE POSSmLE

## = 110501080**PAGEJ~** ActrrEEYE IRRITATION IN mERABBIT 

### AppeJldix3 

### Modified Kay aDd Calandra Interpretation of

### Eye Irritation Teat

MAXMJM PtsCRlPl'lON RATING

MEAN I'USIST£NCI OFSCORE (AND CLASS) SCORJ: Gt-.._ ...._atUINNB-O N_irritIm <I) 0.01D0.5 aro.,._1OIIlI _11124 """"' >0 1"II.cdca11y -.,1IritW. (2) GftIIIp _ -' _It 24 hou:s - 0 PrIaiaIIy DCJIIoirritInt (2) C.S 1D2.5 0r0up_IOIIlI.:oreIt:l4 houri >0 M'lIItma1im- (3) GrrJap _ kIIaI_lII4I houri • 0 MIIIiIDal Jni1an! (:I) ;UID IS 0nJap
_ ....._ at41 houtI > 0 Milclirriunt (4) On.p
_ -'
_ at

### n boars-O MIld irriIIm (4) IS IO:lS Gn.p_ tIIIII_ at 12 hours > 0 Mo4cnte irrItInt ($) More .........of!beiIIdIviduaI tIIIII_ M4denIIII irrillllf (5) .'-.1001'_ Oroup-tOIlII

__ 7 days Man!dian IaIfoftheindjva..! ...._ lSloSO :10

# or_ al 7 dayI > 10 hut 110 indivi4I&aJ IGII/
_ Modcnde i1Ti.1II!f (5)
., .>30 MonIIban IaIroftho individuallOllll_ at , dqJ > 10 IIId indtvidualllCOfllll , SeYeIe irmInI (6) .>30 OI'OllP _1OIIlI1CCI1I11 7day& >20 Smnirri'lallt (6) MeRthan lairofthoIncIIvidIIIIlIOllll _**~irtiI&nr** (6) ., dIyt30or lea Morethan ..Ifot tho indivWal toIIII

_ Group ml'Alllllltll score II 1days at 7 dIyt> 30buI noindivldull toral _ 

### .sc--c inilanl (6) 40or leu 1It7day1>60 M-= !!ran halfofthe mdividual total _ It 7 day. > 30 lind individllllllOCal _ II: Very sew:re irritant (7) 7 days > 60 Oroup 1IIIIIIII toCIII
_ ., days »40 Vt:r)/-=init&M (7) M_ tIM halfotllle indlvid1lallOllll
_ Vety
_ irriMM lit 7da)/l60 or leu (1) Mote IhIn halfofthe indMdMl tOIal

_ Orcup _1OIIlI_1I 1 da)'l SOlO 100 It 1 days ;> 60 MIlO Indivlcllal IeIII
_ lOorllll. V.,,_in11U1 (7) III 1 da)II > 100 M_tIM hair 

## orIhe indi\liduallOllll_ II: , days > 60 Mel indlvidllal kIIaI .:ore lit**~Iy** severe IITitInI (I) 'cIa)/l> 100 Group

__Iscoreat 1 days > 10 ExIJemeIy severe ftiIanI (II Group _1OIIlI
_ at 7days IWra 110 1001'1_ V." Je\'CI'e irriIaIII (1) Gmom

__I_at7da'\1l1>80**ExIIem~** __ irritant (1\PAGE 16 

### Appcndix4 Statement

### 01GLP Compliance in Aeeordanc:e with Directive 881310IEEC



### THE DEPARTMENTOI'IIEALTIIOFTBEGOVERNMENT 

### OF "I'BE tJNI'l'EI)

### ICINGDOM

A.aaIJIIaI

### au 'fI, 

# ....11._..11'. lawkJ.p••tIIT..., 

# ........

# ­ ....,..a..T- Tall 

## '0.,

A. 

## .-.a ........ lor -,J'- willi .... PnIldpMs 01 001IIII l..IbcIrIIor.r Pnai&:Ol

- nnW .. It die ...... Iabut_, • ,.,. of UI:

### au 

## c-,n-**~** A.t ... 111M ttl ...iMpIctiN aD _ lou.. 01 taft'Idnt
......... Ie ... die 

### walldfIJ of lIIOHHtriC'll

# .-ie. pcrlOl1lllld AI 1liiie I'lIdIkia.

### PAGEl OF 11 PAGES



## ACUTE DERMAL IRRITATION IN THE RABBIT

o U1


### AUTHOR: 

### 5 tJ'1 N



## STUDY 

## SPONSOR: TEST FACILITY:PAGE 2 

### QUALITY ASSURANCE REPORT This study type 

### is classed as short-term. The 

### standard test 

### method for this study type 

### ("General Study Plan" in DECO terminology) 

### was reviewed for compJiance once only on initial production. Inspection of 

### the routine and repetitive procedures that 

### constitute the study is carried out as a continuous process designed to encompass the majorphases at or about the 

### time this 

### study was in progress. This report 

### has been audited by Quality 

### Assurance Unit, 

### and is considered to be 

### an 

### accurate account ofthe 

### data 

### generated and ofthe procedures 

### followed. In each case, the.

### outcome of

### QA evaluation is 

### reported to the Study Director and Management on 

### the day ofevaluation. Audits ofstudy docmnentation. and process inspectionS appropriate to 

### the type 

### and schedule ofthis study 

### were as follows:



### § § 28 March 2002 Standard Test Method 

### CompJiance Audit 22 October 2002 TestMaterial Preparation 14 October 2002 Animal 

### Preparation 03 

### October 2002 Dosing 11 October 2002 Assessment ofResponse 29 November 2002 Draft Report Audit Date 

### ofQA Signature 

### Final 

### Report Audit § 

### Evaluation specific to this study



### DATE: .............

## ?.~ 

# .**..f.~.~.~~~t** 

# .........

*A.thorised QA Sialli.t11res: Head ofDepartment: Deputy Head ofDepartment: Senior Audit Staff:PAGE 3**GLPCOMPL~CESTATEMENT** 

### The worle described 

### was performed in compliance with UK. 

### GLP standards (Schedule I, 

### Good Laboratory 

### Practice Regulations 1999 (SI 1999/3106». 

### These Regulations are inaccordance with 

### GLP 

# stlndards published 

### as 

### OECD Principles on Good 

### Laboratory Practice (revised 1997, ENVIMCICHEM(98)17); 

### and are in 

### accordance**wi~** 

### and 

### implement, the requirements 

### of Directives 87/181EEC 

### (as amended by 

### Directive 1999/111EC) and 88/320lEEC 

### (as amended by 

### Directive 19991121EC). 

### These international standards are acceptable to the 

### Regulatory agencies of the 

### following 

## countries: Au.stral.ia; Austria. Belgimn, Canada, 

### the Czech Republic, 

## Denmark. Finland., France, 

### Gennany. Greece, Hungary, 

### Iceland, Ireland, 

## Israel. Italy. Japan, 

### Republic of Korea. Luxembourg, Mexico, The**Netherl~** 

### New Zealand, 

### Norway, Poland, Portugal, Slovenia. Spain, Sweden, Switzerland, Turkey, the United Kingdom, and the United States ofAmerica. This report fully 

### and accuratelyreflects the 

### procedures 

### used and data generated. 

## . 2 7 FEB 

# 2003 DATE...................................................... Study DirectorPAGE 4 

### CONTENTS QUALITYASSURANCE REPORT 

### 1**GLPCO~LLlNCESTATEMENT** 

### 3 CONTENTS 

# .. SUMMARY 

### 5 

# , 1. INTRODUCTION 

# , 2. TESTMATERIAL 

### 2.1 Description., Identification 

### and Storage Conditions 

### 6 2.2 

### Preparation ofTest

### Material 6 2.3 Measurement ofpH 

### 7 

### 3. METHODS 7 

### 3.1 Animals and

### Animal Husbandry 

### 1 3.2 Procedure 7 

### 3.3 Interpretation ofResults 

### 9 

### 4. ARCHIVES 9 

# s. RESULTS 

## 10 6. CONCLUSION 10 

### Table 1 Individual Skin Reactions 11 Appendix 1 Statement ofGLP Compliance 

### inAccordance with 

### Directive 88/320lEEC 12

/ ·-7 f**~.** !PAGES



### ACUTE DERMAL IRRITAflONIN THE RABBIT SUMMARY 

### Introduction. 

### The study 

### was perfonned to assess the irritancy 

### potential ofthe test

### material to 

### the 

### skin ofthe 

### New Zealand 

### White 

### rabbit The method 

### was designed to 

### meetthe requirements ofthe 

### followin&=
• OECD Guidelines 

### for the Testing ofCbemicals No. 404 "Acute 

### Dermal 

### InitationiCorrosion" (adopted 17 July 

### 1992) 

### • Commission Directive 921691EEC Method B4 Acute Toxicity (Sldn Irritation) Resllll&. 

### A single 

### 4-hoUl'. semi-occlud.ed. application 

### ofthe test material to the 

### intact skin ofthree 

### rabbits produced no evidence 

### ofskin irritation. COlI.cbuiDn. 

### The test 

### material produced a primary 

### irritation 

### index of0.0 and was 

### classified as non-initant to 

### rabbit skin according to the Draize classification scheme. No corrosive 

## effects were 

### noted. 

### The test material did not meet the criteria for classification as irritant or corrosive according to the 

### EU labelling regulations Commission Directive 2001l59IEC.PAGE'



### ACUTEDERMAL IIlRITATION IN THE RABBIT 

### 1. INTRODUCfION 

### The study was perfonned 

### to assess the 

### irritancy potential of

### the test 

### materia1 following a single, 

### 4-hour, semi-occluded application to 

### the intact rabbit skin. The 

### method 

## was designed to 

### meet the requirements ofthe following:
• DECO Guidelines 

### for the Testing 

### ofChemicals No. 404 

### "Acute 

### DennaI 

### Irritation/Corrosion" (adopted 

### 17July 1992) 

### • CommissionDirective 

### 921691BBC Method B4 Acute Toxicity (Skin Irritation) The albino rabbit bas 

### been shown to 

### be 

## a suitable model for this type 

### of 

### study and 

### is recommended in

### the test

### method. The

### results of the 

### study are believed 

### to be ofvalue inpredicting the likely 

### skin irritancypotential 

### ofthe test

### Inaterlal to man. The 

### study was performed between 

### OS November2002 and 08November 2002. 

### 2. TEST MATERIAL 2.1 Description, Identlfieation and Storage Conditions Sponsors

### identification Description clear colourless Jiquid 

### Batch Dumber 

### Date received 09 September 2002 Storage conditions 

### room temperature in the dark 

### Data relating to 

### the 

### identity. purity 

### and stability ofthe test 

### material are the responsibility ofthe 

### Sponsor. 

### 2.2 PreparanGIl of

### Test Material 

### Forthe pmpose ofthe study the test material was used 

### as supplied. The 

### absorption of

### the test 

### material 

### was not determined.PAOE? 

### 1.3 MeasuremeDt ofpH Detennination ofthe pH ofthe test

### ma1er:ial was

### attempted but could not be detennined. 

### 3. METHODS 

### 3.1 Animals 

### aud ADlmal 

### HUlbaadry 

### Three**N~** 

### ].ealand White rabbits were supplied 

## by At 

### the start ofthe 

### study the 

### animals were in the 

### weight range of2.0 to 

### 3.S kg 

### and were twelve to twenty weeks old. After an acclimatisation period 

### ofat

### least five days 

### each 

### animal was given a nwnber unique within the study 

### which was written 

### with 

### a black indelible marker-pen onthe inner surface ofthe 

### ear and 

### on the 

### cage label. The 

### animals were individually 

### housed 

### in suspended metal cages. Free access 

### to mains 

### drinking 

### water and 

### food was allowed throughout the study. The diet and 

### drinking water were 

### considered not 

### to 

### contain any contaminant ofa level that might 

### have affected the

### purpose or integrity ofthe study. The temperature and relative humidity were set to 

### achieve limits of 17 to 

### 23°C and 

### 30 to 70% respectively, Any 

### occasional deviations from these targets were 

### considered not to 

### have affected the 

### purpose or integrity ofthe study. The rate ofair 

### exchange was at 

### least fifteen changes per hour and 

### the lighting was controlled by a 

## time switch to 

### give twelve hours continuous light (06:00 to 18:00) IlIld 

### twelve hours darkness. 

### The animals were provided with environmental enrichment items which were considered not to contain 

### any contaminant ofa level that might have 

### affected the purpose or integrity of

### the study. 3.2 

### Proeedure On the day before the test each of a group ofthree rabbits was 

### clipped free 

### of fur from the dorsal/flank area using veterinary 

### clippers. Only 

### animals with 

### a healthy intact 

### epidermis by 

### gross observation were 

### selected for the study. On the day ofthe test 

### a suitable test site was 

### selected on the back ofeach rabbit. A quantity of 0.5 

### mJ of

### the test material 

## was introduced under a 2.5 em x 2.5 em cotton gauze patch and placed in position on the 

### shom skin. The patch was secured in position with a strip of

### SW'gical adhesivePAGES 

### tape. 

### To 

### prevent the animals in.terfcrinqwithlltlqpatclle'oilllth"J1l1Dl.k afreachllClbbi.t WII9I\\-TBppedPnlIlI 

### an elasticated corset and the animals were returned to 

### their cages for the duration ofthe 

### exposure period. 

### Four hours 

### after application the corset and 

### patches 

### were removed from each animal 

### and any residual test 

### material 

### removed by gentle swabbing with 

### cotton 

### wool soaked in distilled water. 

### Approximately one hour 

### following 

### the removal ofthe patches. and 24, 48 and 72 hours later. the test 

### sites 

### were examined for evidence ofprimary 

### irritation and 

### scored according 

### to the 

### following scale: EVALUATION OFSKIN REACI'IONS 

### Erythema and Eschar Fonnada. Value No eryt}leum..............................................................................**~**.............................................. 

# o Very slight erythema (barely perceptible) ..................................................................... t 

### Wcll-defin.ec:l erytI:lema................................................................................................................. 2 

### Moderate to 

### se:vere erytItenla......................................................... I ............**~** ...................... . 

### 3 Severeerythema (beet

### redness) 

### to slight eschar fonnation 

### (injmies in

### depth).............. 

### 4 Oedema Formation 

### No oedema ..................................................................................................................... 

# o Very slight oedema (barely perceptibJe)........................................................................ I 

### Slight oedema (edges ofarea well-defined 

### by definite raising)..................................... 2 

### Moderate oedema (raised 

### approximately 1millimetre)................................................. 3 

### Severe oedema (raised 

### more than 1mil1imetre and extending beyond the 

### area of 

### exposure)........................................................................................................................ 4 Any 

### other skin 

### reactions, ifpresent, were also recorded.

### 3.3 PAGE 9 

### IDterpretatioa ofResults Calculation ofPrimary Irritation Index 

### IIDd GradiDgofInitancy Potelltfa) 

### Ulml the Draize Sebeme 

### The scores for erythema and 

### oedema at the 

### 24 and 

### 72-hourreadings were totalled for the three test 

### rabbits (12 

### values) and 

### this total was 

### divided by six to 

### give 

### the primary 

### irritation index ofthe test material. 

### The test 

### material 

### was classified according to the following scheme devised by 

### Draize 

### JH {1959} "Dennal Toxicity" In: Appraisal ofthe 

### Safety ofChemicals in Foods, Drugs and Cosmetics. Association ofFood and 

### Dm.g Officials ofthe 

### United States, Austin, Texas, p.47: Primary 

### IrritatioD 

### IDde:s: C....ification of

### Irritaaey 

# o Non-irritant 

### >Oto2 Mild irritant >2toS 

### Moderate 

### irritant >Sto8 

### Severe initant 

### If irreversible alteration of the dennal 

### tissue is noted in any 

### rabbit, as judged by 

### the Study 

### Director, which include ulceration and clear necrosis or signs of scar 

### tissue, the test 

### material 

### is 

### classified as corrosive to 

### rabbit skin. Classification according to 

### Draize may, therefore, not be 

### applicable. 

### 4. ARCHIVES Unless instructed otherwise by 

### the Sponsor, all original data and the final report 

### will be

### retained in 

### the archives for five years, after 

### which instructions will be 

### sought as to fwther retention ordisposal.PAGE 10 

### 5. RESULTS The 

### individual scores for erythemaIescbar and oedema, BIC 

### given 

### in Table 1. Noevidence ofskin irritation 

### was noted during the study. 

### 6. CONCLUSION The test material produced 

### a primary initatiOD 

### index of 0.0 and was 

### elassified as NON-IRRITANT 

### to rabbit skin according 

### to the Draize classification seheme. No 

### corrosive effects were noted. The test 

### material did not meet the criteria 

### for classification as 

### irritant or 

### colTOsive according to

### the 

### EU labelling regulations Commission Directive 2001/59IEC.PAGE II 

### ACUTE DERMAL IRRITATION IN THE RABBIT 

### Table 1 Iadivid1lal 

### SkiD ReactiODl
SkiD 

### Reaction Obsorvatioo Time Inclividual. &coteS
­ RabbitNumber and Sox 

### 62 Male 

## as Male 86 Male Total 

### 1 Hour 0 0 

### 0 (0)**~** Formadon 

### 24 Hom!. 48 Hours 

### 0 0 

### 0 0 

### 0 0 0 (0) 

### 12 Hours 0 0 0 0

J Hour 0 0 0 (0) Oedema FOl'DUltion 

### 24Houra 

### 48 Hours 0 0 0 

### 0 0 

### 0 0 

### (0) 72 Hours 0 0 0 0 Sum of24aDd 72-bour R.eadinp (8) ; 0 Primary Irritation Index ($16) : 0/6 =0.0 

### Classifk:aDoo NON-IR.RITANT



### ( ) .. Total values not used 

### for caIctllation ofprimary 

### irritation indexPAGE 12 

### Appendix 1 

## Statement ofGLP COlDpJiuee 

### iD 

## Accordance with Directive 881l10JEEC

S'UIIMIKI'OFODIoIJUAftCE IV ACCOJIIMNCEWI'IB...-.cD\'B .....

## ac
AMlIdalQ '"

.... t .. .... 

## ..._ ....T...wc,


# ........'..,.**~T_** 

### T.......

A ......**j~** ,.**&:CIIIIIpI~** wid! die Priecipla of Good LaIIantacy Pnadce

... anild GIll
.. 1M .tIIIOw IIdIDnrDl'1 .... of UK: OLP CampIiuIcc .......... AI till: lillie of 1be ........ DO ilevilUoM .... fOdli ofJIIIIiciaI ..... 1... 10 IIrect die "alidily of -.eli ... llllltiea**perI~** at ......facilida.

## ACUTE DERMAL IRRITATION INTHE RABBIT

1 verify 

### that this is an exact 

### copy of the original 

### n:port 

## which is located in 

### the Archives of



# . 0" HAft lOUl DAm .. jO ••••••••••••• ..iII: ................ "'t...................... ..... .

## REPORT r:**~,H** V 

## O

,j i .f) j - 

### 1 

# '1.#" -, '_c I I 

### J: 

## f

## 8

Study Title 

## ACTIVATED SLUDGE RESPIRATION INHIBl1l0N TEST WITH (CONTACT TIME: 30 MINUTES)

; 

## :::'::**~** ,..-")**~- .""".~'-.**  ,'..) Study 

### completion date 

# -, 20 January 

### 2005

Test Facilitv



### L§boratorv Project Identification

• Page 1 of 14 •



## IIUI'I'1111"III "1'1IIIII"IIIUIII'"" IIIII I'll' 11'1'11'1III11'1'IIlUI 500 5 000 382 2 I S 

# -,D 

# P /O<{-I.Q3S

### 1. CONTENTS 1. CONTENTS
...................................................,.......................................................................2 2. STATEMENT OF GLP COMPLIANCE
............................................. ,. ................................... 3 3. QUALITY ASSURANCE STATEMENT
.................................................................................4 4. SUMMARy
......................................,......................................................................................5 5. INTRODUCTION
.................................................................................................................... 6 5.1. Preface
........................................................................................................................... 6 5.2. Aim of the study.............................................................................................................. 6 

### 5.S. Guidelines
.......................................................................................................................

### 6 5.4. Storage and retention of records and materials ............................................................. 

### 6 5.S. DefInitions
.......................................................................................................................7 6. MATERIALS AND METHODS
............................................................................................... 7 

### 6. 1. Test substance ............................................................................................................... 

### 7 6.1.1. Test substance ..................................................................................................... 

### 7 6.1.2. Test substance - preparation andtest concentrations ........................................ 7 

### 8.2. Reference substanoe ..................................................................................................... 

### 8 6.2.1. Reference substance ...........................................................................................8 6.2.2. Reference substance - preparation and test concentrations .............................. 

### 8 

### 6.3. Test system .................................................................................................................... 

### 8 6.4. Test procedure and conditions .......................................................................................

### 9 6.5. Interpretation ................................................................................................................ 10 6.5.1. Calculations
........................................................................................................ 10 6.5.2. Acceptability of the test ...................................................................................... 11 

### 6.S. List of 

### protocol deviations ............................................................................................. 11 7. RESULTS
............................................................................................................................. 11 

### 7.1. TOlClcity of the reference substance (3,5·dichlorophenol)
............................................ 

### 11 

### 7.2. TolCicity of
............................................................................... 12 

### 7.3. Experimental conditions ............................................................................................... 12 8. CONCLUSION
..................................................................................................................... 12 APPENDICES APPENDIX I - TABLES AN D FIGURES
..................................................................................... 13 APPENDIX 11- CERTIFICATE OF ANALYSIS
........................................................................... 14 TABLES Table 1 Controls 

### (C) and reference substance (R; 3.S-dlchlorophenol): pH. oxygen concentration, O)(VQen consumption and percentage inhibition .................................. 11 Table 2 Controls (C) and (T): pH. oxygen concentration, oxygen consumption and percentage inhibition....................................................................... 12 Table 3 Determination of the EC50-value for 3.5..tfichlorophenol
.............................................. 13 FIGURES Figure 1 Influence of 3,5-dlchlorophenol on the respiration rate of aerobic waste water (activated sludge) bacteria (values In % ofthe control)
.............................................. 13

- Page 2­2. STATEMENT OF GLP COMPLIANCE
The study described in this report has been correctly reported and was conducted in compliance with: The Organization for Economic Cooperation and Development (DECO) Good Laboratory Practice Guidelines (1997). Whioh essentially conform 

### to: The United States Food and Drug Administration Good laboratory Practice Regulations. The United States Environmental Protection Agenoy Good Laboratory Practloe Regulations. The sponsor Is responsible for Good Laboratorv Practice (GLP) compliance for all test substance information unless determined by

Date: ....•.: .

# ...Io/~J.Oo:r.: 

# ................

- Page 3 ­3. QUALITY ASSURANCE STATEMENT
This report was inspected by the Quality Assurance Unit to confirm that the methods and results accurately and completely reflect the raw data. The dates of Quality Assurance Inspections are given be/ow. During the on-site process Inspections procedures applicable to this type of study were 

### Inspected.
Type or Phase 

### I Section 

### Start End Inspection Reporting date inspections Inspection d8te(S) date(s) Protocol (Study) 30 July 2004 

### 30 July

### 2004 30July

### 2004 On-site (Process) Ecotoxlcology & 

### 26July 2004 

### 2 August 

### 2004 3 August 

### 2004 biodegradation Report (Study) 

### 20January 

### 2005 20 January 

### 2005 20January 

### 2005



### Head of Quality Assurance

- Page 4­4. SUMMARY The influence of on the respiration rate of activated sludge was investigated after a contact time of 

### 30 mi"lutes, The study procedure was based on 

### OECD Guideline No. 

### 209. adopted April 

### 4, 1984 and 

### EEC Dlrectiva 

### 67/548 amended November 

### 18. 1987 (871302), Part C, Publication No. 

### L133, adopted May 

### 30, 1988. /Vas a clear colourless liquid with a purity of 

### 99.985%. The water solubility of at 

### 20.1 ::t 

### 0,5°C was determined to be 

### 0.805 gil, using the flask method Since Nas extremely volatile. • .. no stock solution 

## ot was prepared, but the test substance was quantitatively added to the test vessels. A nominal concentration of 

### 100 mg/l was tested in duplicate. Since was known to 

### be extremely volatile 

### and the test concentration was 

### not confirmed analytically (not a reqUirement of the test guideline). the stabJlHy of the test substance 

### In the test system could not 

### be shown. However, every possible effort was made to prevent the test substance 

### from evaporating from Ihe test vessels (low airflow, narrow flasks with a minimum of headspace and drect addition 

### of the test substance). Results were based on nominal concentrations. No significant inhibition of respiration rate of the sludge was recorded at nominallQO mg per litre. The duplicate measurement confirmed the result of the first measurement. Therefore, no further testing was needed. 

### Since all criteria for acceptability 

### of the test were met, this study was considered to 

### be valid. In conclusion, under the conditions of this present test, was not toxic to waste water (activated sludge) bacteria 

### at a nominal concentration of 

### 100 mg/l.

- Page 5·

### 5. IN"rRODUCTION 

### 5.1. Preface Sponsor
Study Monitor Test Facility
Study Director Technical Coordinator Study Plan Start Completion 16 September2004 16 September 2004 

### 5.2. 

### Aim of the study The principal objective of this test method was the assessment of the effect of a test substance on micro-organisms by measuring the respiration rate under defined oondtions in the presence of different concentrations of test substance. The test method Is a rapid screening method whereby test substances which may adversely affect aerobic micrObial trea1ment plants 

### can be identified. 

### 5.3. Guidelines The study procedures described In this 

### repor1 were based 

### on the following guidelines: • Organization for Economic Co-operatlon and Development (OECD). OECD Guidelines for Testing of Chemicals, Section 

### 2: Effects on biotic systems, Guideline no. 

### 209. "Activated Sludge, Respiration InhibitionTest". adopted April 4. 1984. • European Economic Community (EEC). EEC DirectiVe 

### 67/548 amended November 18, 1987 (871302), Part C: Methods for the determination of ecoto)(icity. Publication No. L 

### 133. "Biodegradation: Activated sludge respiration inhibition test-. adopted May SO, 1988. 

### 5.4. Storage and retention 

## or records and materials Records 

### and**mate~al~_lJ:8rtalnlng** to the study including protocol, raw data and the final report are retained In the archives for 

## a period of at least 

### 10 years afterfinalization of the report. After this period, the sponsor will be contacted 

### to determine whether raw data and specimens should be retumed to them. retained or destroyed on their behalf. NOTOX will retain a test substance sample until the expIry date. but no longer than 10 years after finalization of the report. After this period the sample will be destroyed.

• Page 6·5.5. OetlnltJons Activated sludge: the accumulated biological mass produced in the treatment of waste water bythe growth of bacteria and other micro-organisms In the presence of dissolved oxygen. Suspended solids: the solids removed from activated sludge by filtration and dried 

### to a constant mass, expressed in grams per litre. Respiration rate: the oxygen consumption of aerobic activated sludge or waste water microorganIsms expressed generally as mg 

### O2 per litre per hour. EC : the concentration of the test substance at which the respiration rate 

### Is 50% of the 80 respiration rate of the controls underthe conditions of the test. 6. MATERIALS AND METHODS 

### 6.1. Test substance 

### 6.1.1. Test substance Identification Structure Molecular formula Molecular weight CAS Number Description Clear colourless liquid Batch Purity 99.985% Test substance storage In refrigerator In the dark Stability under storage conditions Stable Expiry date 07 July 2005 Specific Gravity 

### 1.47 Stability In vehicle Wa1er Not indicated 

### 6.1.2. Test substance - preparation and test concentrations was a clear coklurless liquid with a purity 

### of 99.985%. The water solubility of at 

### 20.1 =t: 

### O.soC was determined to be 0.805 gil. using the flask method Since was extremely volatile . no stock solution of was prepared, but the test substance was quantitatively added to the test vessels. A nomina' concentration of 100 mg/l was tested in duplicate. Since was known to 

### be extremely volatile and the test concentration was not confirmed analytically (not a requirement of the test guideline). the stability of the test substance In the test system could not be shown. However, every possible effort was made to prevent the test substance from evaporating from the test vessels (low air frow. narrow flasks with a minimum of headspace and direct addition of the test substance). Results were based on nominal concentrations.
- Page 7­6.2. Reference substance 

### 6.2.1. Reference substance Identification number 

## Name Description Molecular formula Molecular weight CAS number Batch number Article number Purity Expiry Date 

### Certified Storage conditions Supplier RS92 3.5-Dichlorophenol White powder (determined at NOTOX) CI2C6

### H3

### 0H 163.00 591-35-5 15809KI·392 D 7,060'() 97% 24 June200B No At room temperature in the dark Aldrich 6.2.2. Reference substance - preparation and test concentradons A solution of 0.5 g/l3,5-dichlorophenol was prepared by dissolving 249.9 mg in 5 ml 1 N NaOH. diluting 

### It to approximately 15 ml with MiKi-Q water and adding under stirring 1 N H2S04 

### to the point 

### ot incipient precipitation. Finally, the solution was diluted to 500 ml with MillI-Q water. The pH was 8.0. Aliquots of 50 ml were stored in a freezer until use. On the day of testing the reference substance solution was defrosted at room temperature. Three concentrations were tested: 3.2, 10 and 32 mg/l. 

### 6.3. Test system Test System Source
Number of mlcro-organisms Preparation of the sludge

Rationale Micro-organisms 

### in activated sludge. Municipal sewage treatment plant: 'Waterschap de Maaskant'. ·s·Hertogenbosch, the Netherlands, receiving predominantly domestic sewage. Number of micro-organisms was determined as the amount of Mixed Liquor Suspended SolidS (MLSS) per litre test medium. The sludge was coarsely slaved, washed and diluted with tap-water. A small amount of the sludge was weighed and dried at ca. 105°0to determine the amount of suspended solids (3.0 

### gil of sludge, as used for the test). The pH was 7.2 on the day of sampling and 7.9 on the day of testing. The batch of sludge was used on the day after cotrectlon. therefore 50 ml of synthetic sewage feed was added per litre of activated sludge at the end of the day. The sludge was kept aerated at test tamperatura until use. Recognized by international guidelines as the recommended test system,

·Page8­6.4. 

## reat procedure end conditions Contact time Vessels MillI-AO / Mil/J-Q water
Synthetic sewage feed

Air supply Oxygen meter Recorder Performance of the test 30 minutes, during which aeration and stirring took place. All glass, approximately 300 ml oxygen bottles and 1 I test bottles. Tap-water purified by reverse osmosis (Milli-AO) and subsequently passed over activated carbon 

### and ionexchange cartridges (MiIIi-Q) (Millipore Corp., Bedford, Mass., USA). 

### 16 g peptone 11 9 meat extract 3 9 urea 

### 0.7 g NaCI 

### 0.4 

### g CaCI 2

### .2H2

### 0 0.2 9 M9

### S04.7H

### 20 2.8g K 2HPO" Dissolved in Milli-Q water, made up to 1 I and filtered. The pH 

### was 7.1. Clean, oil-free air. WTW Inolab Oxi Level 2 supplied with a WTW CellOx 325 oxygen electrode, electrolyte type ELY/G. Flatbed recorder 

### SE 102 (Kipp 

### &Zonen). The synthetic sewage leed (16 mJ) and an adequate amount 

### of the test substance were mixed and made up to 

### 300 ml with MilJi-AO water. 

### Activated sludge (200 ml) was added to provide a final volume of 

### 500 ml. The mixture was then aerated in a 1 J bottle during the contact time, 

### using a pipette as an aeration device. Then a well mixed sample 

### at the contents was poured into a 

### 300 ml oxygen bottle, and the flask was sealed with an oxygen electrode connooted 

### to a recorder, forcing the air out of the vessel. Oxygen consumption was measured and recorded 

### torapproximately 

### 10 minutes. During measurement, the sample was not aerated 

### but continuously stirred on a magnetic stirrer. The pH and temperature were determined in the remaining part of the reaction mixture. This procedure was repeated for the duplicate concentration. Two controls without test substance were tested in each test series, one at the start and one at the 

### end. The batch of activated sludge was checked for sensitivity by testing the reference substance**3.5·dlchloroph~nol** .

• Page 9·

### The scheme below gives an overview of the contents 

### of the various flasks tested. Flask Synthetic R 

### T Made upto sewage 

### Stock sol. 

### e ..!) 300mf with teed (ml) 

### 0.5 gil**M"II~RO** water 

### Jm!) C1 

### 16 

# . · + R1 

### 16 

### 3.2**~** 

### + R2 

### 16**~"'-'** 1-' 

### 10 

# · +



### -­ R3 

### 16 

### 32 

# · + 

### C2 16 

# - I 

# · + C3 

### 16 

# - 

# - + T1 16 

# . 34 

### +

... T2 

### 16 

# - 34 + 

### C4 16 

# . I 

# - + Activated Sludge

(ml) 

### 200 200 

### 200 200 200 

### 200 200 200 200 Cane. (mgll)



### 0 

### 3.2 10 

### 32 0 

### 0 100 

## I 100 

## I 0 C: Control. R: Reference substance, 3.5-diohlorophenol. T; Test**subeta~.** quantitatively added. 34 III corrsaponds with 50 mg (Specific Gravity: 1.47) 

### 6.5. InterpretatJon 6.5.1. Calculations The respiration rate from each vessel, in mg**O~r.** 

### was calculated from the linear part of the respiration curve, which was generally between 2.5 and 6.5 mg 

## 0211. The inhibitory effect (percentage Inhibition) at a concentration was calculated as: % inhibition

# =(1- 2>I< Rt ) ... 

## 100 % Re (start test series) 

### +Re (end test series) 

### in which Rc

### and Rt

### were respiration rates of controls and test/reference substance respectively**(inmg~r).** 

### A figure of more than 10% inhibition was considered significant. No EC50 

### could be calculated because the test substance proved to be non-toxic (ECco > 

### 100 mg/l). For the 

### reference substance the percentage inhibition was plotted against the logarithm of the concentrations and the EC60

### was determined using Inear regression analysis.

- Page 10­

### 6.5.2. Acceptability of

### the 

### test 1. The mean respiration rate of control 1 and 2 was 32 mg O:lllhr. The difference between the controls was within 1S% of each other (3%). The 

### mean respiration rate of control 3 and 

### 4 was 36 mg O;lllhr. 

### The difference between the controls was 

### within 15% of each 

### other (3%). 2. The EC60 of 3,S-dlchlorophenol was in the accepted range of 5-30 mgll (14.9 mgll, regression line: Y

# = 47.0S X ·S.21 , Y

# =% inhibition and X 

### = log concentration (mgJl)). Since all critlilrla for acceptability of the test were met, this study was considered to be valid. 

### 6.6. List of protocol deviations There were no deviations from the protocol. 7. RESULTS 

### 7.1. Toxicity of 

### the reference substance (3,5-dlchlorophenol) Table 2 presents: pH; oxygen concentration at the start of the measurement; the Influence of the controls and 3,S-dlchlorophenol on the oxygen consumption of microbes In actlva1ed sludge; and the percentage inhibition of the respiration rate. Table 

### 1 Controls (C) and reference 8ubltane. 

### (R; 3,5-dichlorophenol): pH, oxygen concentnltlon, oxygen consumption and percentage Inhibition 

### Flask ConcentraUon 

### (mgll) Oxygen cone. At

### the 

### start (=ma 

### 021'0 Oxygen consumption



### ma OJ1lhr % Inhibition pH C1 0 6.2 32 

## - 8.1 C2 

### 0 

### 6.6 31 

# - 8.1 Mean 

### C 1+C2 - 32 (A**3'Y~)** R1 3.2 6.7 

### 25 21 

### 8.2 R2 

### 10 6.3 20 37 

### 8.0 R3 32 

### 6.8 10 

### 68 

### 7.9 The calculated percentages inhibition allowed 

### for a reliable determination 

### of an EC60-value (see Table 3 and Figure 1 

### of Appendix I).

- Page 11 ­7.2.. Toxicity 

### of Table 2 presents: pH; oxygen concentration at the start of tha measurement: the influence of the controls and on the oxygen consumption of microbes In activated sludge; and the percentage inhibition 

### of the respiration rate. Table 2 Controls (C} and 

### :1"): pH, oxygen concentration, oxygen consumption and percentage Inhibition Flask Concentration (mgll) Oxygen cone. 

### at the start (smQOJl) Oxygen consumption

mgOJllhr % Inhibition pH 

### C3



# - 0 

### 6.2



# -­ 35 

## . B.O 

### C4 

## a 5.5 36 

# - B.Q_ MeanC3+C4 36 (A 3%) 

### T1 

### 100 

### 5.2 35 1 

### 7.9 T2 

### 100 • 

### 6.2 34 

### 4 8.1 

### No**signif!~t** inhibition 

### of respiration rate of 

### the sludge was recorded at nominal 100 mg 

### per litre. 

### The duplicate measurement confirmed the result of 

### the first measurement. Therefore, no further testing was needed. 

### 7.3. Experimental conditions The temperature of the test medium was between 19.0 and 20.5"C. 8. CONCLUSION Under the conditions of 

### this present test, was not toxic to wasta water (activated sludge) bacteria at a nominal concentration of 100 mg/!.

- Page 12­

### APPENDIX 1- TABLES AND FIGURES Table 3 Determination ofthe ECso·value for 3.5-dichlorophenol

Parameter: % 

### inhibition

Concentration 

### X Y (mcll} 

### Loa cone. 

### (maIn Inhibition (%)

3.2 

### 0.505 21 10 1.000 

### 37 32 1.505 68 

### Slope: 47.0498 

### Intercept: -5.2114 Multiple R: 0.9845 n 

### = number of observations: 3 Prediction 

### of X values based on known Y values Known Y 10Xr&G 10 X95%­ 10)(95%+ Inhibition (%) (mall) (mall) (mgIJ) 

### 50 14.9 

### 0.2 1150.9 Regression line: Y- 47.05 X -5.21



### 100



## 80 

# - tfl. 

# - c 

## 60 0 

## E .Q 

## 40 :2 

## .E 20 0 1 

### 100 I I , 

# -- ........ 

### __ .... I 

# - , , 

# / 

# /'**A/~**

-- 10 

## Concentration (mgll) Figure 1 Innuance of 3,5-dlchlorophanol on the respJration rate of aerobic waste water (activated .'udge) bacteria 

### (values In % of the 

### control) Dashed curves represent the 95 % confidence limits.

• Page 13·

### APPENDIX 11- CERTIFICATE OF ANALYSIS

Certificate ofADalysia July 13, 2004 I 

### !:ertifY ihatloUOwlnS anaJ,ytiw relllLlta of &II far a. I COIlClu·n. are cerreet a.nd true 1. Subsia.nee identity

1) Chemical name 2) Prod1lCi II.lUJle s) CAS No•
.., LaiNo. 6) Appearance Liquid 8) Color ColorltJlIII 7) Manufacturina'date July 7,2004 July 9, 2004 B. Anal)'t::ical method



## oBquipment AGIIBNT 11890 

### cas chromatograph 2) Column J&W DB' 1301 80m a.D. 0.2511lJll, Film 1!laU a) CoJumn conditions lnitial4ot:: (10min hoW. Rata 10"C/min, FiDaJ 250"C (l4min hold) 4) IIIjectiom temp. 21W"C 6) DatactioJ:l temp. 250"C 6) Detedoor FlO '7) Sample eirte 1/4L 8) Splitratio 1150 9) Carrier pJI Helium 10) Carrier pslinear velocity 25 II4Iclmin 11) Hydrocen flow rate 90 mJhn.in 12,) Air tlow rate 400 mJlmtn 4.ADal,yticaJ relulta

1) Purity 99.985% 2.) Impurity

Please see nruct. pap fur OC chart. II. Pedlnned. WIder GLP: No 8. 'le&ti.Ilj laboratory

QualityAllauranee Dept.

- Page 14·

### P-04-635 

## REPORT
. r 1;1 tv' 

# OS l.I

### ~ V '}! 

# p'4 ,': 

# ''''' L: 

# 09

StudyIitle 

## DETERMINATION OF 

## THE AUTO·IGNITION TEMPERATURE (LIQUID) OF

StUdy completion date



### October 18, 2004 

### Test Facility

Laboratory Project Identification**~** Page 1 of 10**~** 

### -",

., 

# - .. - o



# ..

# I\I~ ,,'Ill

# Ii''''**~ll~ I~II."~**  \D 

# p.-r 04 -(03)

### 1. CONTENTS 1. CONTENTS
........................................................................................................................... 2 2. STATEMENT OF GLP COMPLIANCE
.................................................................................. 3 3. QUALITY ASSURANCE STATt::MENT .................................................................................4 

### 4. SUMMARy
............................................................................................,........................." ..... 

### 5 5. INTRODUCTION
..................................................................,................................................ 

### 6 5.1. Preface
...........................................................................................................................6 5.2. Alms of the study............................................................................................................6 

### 5.3. Guidelines
...................................................................................................................... 6 5.4. Storage and retention of records and materials............................................................. 6 

### 6. MATERIALS AND METHODS
............................................................................................... 

### 7 6.1. Test substance ...............................................................................................................7 6.2. Test system and rationale .............................................................................................. 7 6.3. Validation 

### ofthetest method.......................................................................................... 7 6.4. Perfonnance of

### the test. ................................................................................................. 7 6.4.1. Procedure of injection .......................................................................................... 7 

### 6.4.2. Main study............................................................................................................ 

### 8 6.5. Test conditions .......................................,..........................,............................................ 8 

### 6.6. 

### Interpretation .................................................................................................................. 8 

### 6.1. List of

### protocol deviafions
............................................................................................... 8 7. RESULTS
......................................................,....................................................................... 9 7.1. Preliminarytesl .............................................................................................................. 9 

### 7.2. Main study...........................................................................................................,.......... 9 8. CONCLUSION
.......................................................................................................................9
TABLES Table 1 

### Aulcrignltion temperature of
............................................. 9
FIGURES Figure 1 Correlation between auto-/gnltion temperature and test substance volume ..... 10

- Page 2­

### 2. STATEMENT OF GLP COMPLIANCE


### The study described In this report has been correctly reported and was conducted in compliance with: The 

### Organization for Economic Cooperation and Development (DECO) Good 

### Laboratory Practice Guidelines (1997). Which 

### essentiany conform to: The United States Food and Drug Administration Good Laboratory Practice Regulations. The United States EnvIronmental Protection Agency 

### Good Laboratory Practice Regulations. The sponsor Is responsible for Good Laboratory 

### Practice (GLP) compliance for all test substance information unless determined by**~ruay** 

### Ulr8Clor Section Head Analytical & 

### Physical Chemistry

-Page3­3. QUALITY ASSURANCE STATEMENT
This report was inspected 

### by the Quality Assurance Unit to confirm that the methods 

### and results accurately and completely reflect the 

### raw data. The dates ofQualityAssurance inspections are given below. 

### During the on-site process inspecrons procedures applicable 

### to this type 

### of study were Inspected.
Type of Phase 

### I Section Start 

### End Reporting date 

### Inspections Inspection Inspection date(s) 

### date(a) Protocol (Study) 03\AUG\04 03\AUG\04 03\AUG\04 On-site (Process) 

### Analytical and 

### 05\JUl\04 15\JUl\04 19\JUL\04 Physical Chemistry Report (Study) 15\oCTI04 15\OCT\04 15\OCTI04



### Head 

### ofOualltv Assurance

- Page 4 ­

### 4. SUMMARY 

### The determination ofthe auto-Ignition temperature of was performed in accordance with EEC-Diractive 92/69 EEC, A.15 "Auto-Ignition temperature (liquids and gases), 1992", DIN 51794 "Bestimmung der Zundtemperatur" (1978) and IEC standard 79-4: Method of 

### test for Ignition temperature (1975). Three tests were performed. In each test, different volumes oftest substance were injected successive times 

### Into a test vessel. The temperabJre in the

### testvesselwa8 

### lowered gradually 

### from a sufficient high 

### temperature until a temperature at which 

### it was obvious that no mora 

### ignition occurred. Ignition of the 

### test substance resulted 

### in a blue 

### shining with 

### a small orange flame. The 

### lowest measured 

### auto-Ignition temperature was 590°C at an 

### injection volume of751JL. This temperature Is reported as the 

### autlrignltion temperature of In conclusion, 

### is auto-ignitable with 

### an auto·ignltion temperature of 590°C.

-Page5­

### S. INTRODUCTION 

### 5.1, Preface Sponsor
Study Monitor Test Facility Study Director Study Plan Start Completion 

### 06 October 

### 2004 07 October 2004 

### 5.2. Alms ofthe study The purpose of the study 

### was to determine the degree of

### auto-lgnitablllty In terms of the autoIgnition temperature. 

### 5.3. Guldellnee The study procedure described in 

### this report is 

### based on the 

### following guidelines: 

### European Economic Community (EEC), EEC-Directive 92/69 EEC, Part 

### A. Methods for the determination of physlco-chemical properties, A.15 

### "Auto-Ignition temperature (liquids and gases)", 

### EEC Publication No. L383, 

### December 1Q92. 

### DIN 51794 "Bestimmung der ZDndtemperatur", January 1978. IEC standard 

### 79-4 "Electrical apparatus for explosive gas atmospheres. Part 

### 4, Method of test 

### for Ignition temperature", 1975. SA. Storage and Attention of 

### recorda and 

### materials Records and materials pertaining to the 

### study including protocol, raw data, specimenl?**L'~9.e.PJ** 

### specimens requiring refrigeration orfreezing) and the final report are retained in the archives 

### for a 

### period ofat/east 

### 10 years after finalization ofthe 

### report. After this period. the 

### sponsor

## wi" be contacted to 

### determine whether 

### raw data and specimens should be returned to them, retained 

### or destroyed on their behalf. 

### Those spedmens requiring 

### refrigeration or freezing 

### wHl be retained by for as 

### long as the quality of the specimens permits evaluation but 

### no longer than 

### three months after finalization ofthe report 

### will retain 

### a test substance sample until 

### the expiry date, 

### but no longer than 10 years after finalizatJon of the report. After this period the sample 

### will be destroyed.

-Page6­8. MATERIALS AND METHODS 

### 6.1. Test aubstance Identlflcation Structure Molecular formula Molecular weight 

### CAS Number Description Clear colourtess liquid Batch 

### Purity 99.985% 

### Test substance storage 

### In refrigerator in the dark Stability under storage conditions 

### Stable Expiry date 

### 07 July 2005 The sponsor Is 

### responsible for all test 

### substance data 

### unless detennlned 

### by 

### 8.2. Test aystem and rationale Apparatus Auto 

### Ignition Temperature 

### apparatus (Chllworth Technology, 

### Southampton, UK) 

### according to 

### OIN 51794 

### and IEC standard 

### 79-4. Rationale Recognized by 

### the international gUIdelines (EEC, DIN, IEC) 

### as recommended test system. 

### 8.3. Validation ofthe 

### test method 

### The test method as outlined in this 

### report is validated 

### periodically using n--heptane. The result did meet the criteria as outlined in DIN 51794. 

### 8A. Performance 

### ofthe 

### test 8A.1. Procedure of rnJection Test 

### substance wa$ 

### Injected into the test 

### vessel 

### by means 

### of a variable volumetric pipette 

### to assure a rapid 

### injection (!ii: 

### 2 seconds). Successive injections were performed. After each Injection, it 

### was observed visually whether Ignition ofthe 

### test substance occurs. The 

### time lag between injection and ignition was measured. After each Injection, the test vessel was flushed completely 

### with clean and 

### dry air (Air zero; 

### 02: 

### 20,9 

### ± 1%, Air Products, Brussels, Belgium). After flushing, a 

### sufficient time Interval was allowed to ensure 

### that the vessel temperature was stabilized atthe desired temperature before 

### the next test substance sample was Injected. 8.4.2. Preliminary test 

### The test vessel was 

### heated at a rate of

### apprOximately SOC/minute. Starting at200°C, 

### every 20°C, 70 

### loll test 

### substance was 

### injected into the test vessel until ignition occurred (i.e. at 620°C).

- Page 7­Going down from 635"C, the temperature ofthe test vessel was deaeased. Every 5°C, 70 IJL test substance was Injected Into the test vessel until 

### it was obvious tnat no more ignition occurred. The lowest temperature at which ignition occurred, is the estimated auto-Ignition temperature. 

### 8.4.3. MaIn study Test procedure Going down from a suitable higher temperature than 

### the estimated auto-ignition temperature, 

### every 2°C, a known volume oftest substance 

### was Injected Into the test vessel. SUccessive Injections were performed until it was obvious that 

### no more ignition OC9lrred. This was repeated with two other sample volumes. Tests 

### 1 to 

### 3 Three tests were performed. In Test 1, 50, 70 and 100 IJL test substance were injected 

### at temperature ranges of604-596, 598-58S and 601-593°C, respectively. In Test 2,50, 80 and 110 

### III 

### test substance 

### were Injected at 

### temperature ranges of606-594, 599-593 and 

### 609­ 601°C, respectively. 

### In Test 3,50, 

### 75 and 100 

### ilL test substance 

### were injected at temperature ranges of603-599,600-586 and 615-603°C, respectively. . 

### 8.5. TestcondltJons Each test was performed using a clean test vessel. The atmospheric pressure was 1015.5 hPa during the preliminary test and 1017.5 hPa during Tests 1to 3. 6.B. Interpretation The auto-ignition temperature is the lowest temperature atwhich the test substance ignites when mixed with air under the conditions defined in 

### the test method. For each ofthe 1hree tests ofthe main study, a plot was generated showing the correlation between the injected test substance volume and the measured auto-ignition temperature. Each test yielded a minimum auto-lgnltlon temperature. The maximum deviation between the three minimum auto-Ignition temperatures meets the criteria as outilned In the protocol 

### « 20"C when an auto-ignition temperature ;;> 3oo·C was determined). The auto-ignition temperature for is the lowest auto-Ignition temperature measured during the main study. 

### 8.7. Liltofprotocol devIations There were no deviations from the protocol.

-PageS­

### 7. 

### RESULTS 7.1. 

### Prellmrnary test 

### The auto-ignition temperature of was estimated to be 

### 570°C. Ignition of the test substance resulted in a blue shining with 

### a small orange flame. 7.2. Main study 

### Table 1 

### summarizes 

### the Injected test 

### substance volumes, !he measured auto-ignition temperatures and time lags. Ignition ofthe test substance resulted In a blue shining with a small orange flame. Figure 1 shows the corre/ation between the Injected test 

### substance volume and the measured auto-ignition temperature for each test. Table 1 

### Auto-ignition temperature 

### of Test 

### Injected test 

### substance

volume

[ul] 

### Auto-ignition temperature 

### [0C] Time lag 

### [s}
Test 1 

### 50 

### 70 100 

### 600 592 597 1 1 

### 1 

### Test 2 

### 50 80 110 

### 598 597 605 1 

### 1 1 

### Test 3 

### 50 75 

### 100 

### 603 590 

### 607 1 1 

### 1
The lowest measured auto-ignltlon temperature Is 

### 590°C (see Table 1). This temperature Is reported as the 

### auto-Ignition temperature of
8. CONCLUSION 

### Is auto-Ignitable with 

### an auto-ignition temperature of590a

### C.

- Page 9­FIGURES



### 608 606 604



# - 602 

## o o 

# - e 600

# ~ !. 598 E CDf

### 596 594 

### 592 590 0 

# •

. t I 

# • : :

,I

I , 

### :



# - 0 

### :/ 

# . 0 0 

# \\ . 0

### : I



### .... "

:....... A 

# '\'**~.** .. ..

# _ ... 

# . , t:

, 

# / 

# \\ 

# 7**~/** . , 

# . : 

## o 20 

### 40 

### 60 

### 60 100 120 140 

### Injected volume (",I) 

### I---Test1 -.j._. 

### Test 2 ....... 

### Test 3 

# I Figure 1 Correlation between auto-ignition temperature and test substance volume**~** Page 10**~**

### P-04-635 

## REPORT

SbJdy Title 

## DETERMINATION OF THE BOILING TEMPERATURE OF BY DIFFERENTIAL 

## SCANNING CALORIMETRY &ttb2r Study completion date

November 01! 2004 Test Facilitv



### Laboratory profect Identification

- Page 1 of 1 0 ­



# 1J

### 1. CONTENTS 1. CONTENTS
..__.......................................................................................................................

### 2 2. STATEMENT OF GlP COMPLIANCE
.................................................................................. 3 

### 3. QUAliTYASSURANCE STATEMENT
.................................................................................4 

### 4. SUMMARy
............................................................................................................................. 

### 5 4.1. Guidelines
..........................................................:........................................................... 

### 5 4.2. Experimants ................................................................................................................... 5 

### 4.3. Conclusion
......................................................................................................................

### 5 5. INTRODUCTION
...................................................................................................................

### 6 

### 5.1. Preface ........................................................................................................................... 6 5.2. Aims ofthe study............................................................................................................

### 6 5.3. Guidelines
...........................................................................................................,.......... 

### 6 5.4. Storage and retention of 

### records and materials............................................................. 

### 7 6. MA.TERIAlS AND METHODS
............................................................................................... 7 6.1. Test substance............................................................................................................... 7 6.2. Test system and rationale .............................................................................................. 7 6.3. Valldatfon ofthetast procedure ..................................................................................... 7 

### 6.4. Performance ofthe test. .................................................................................................

### 8 6.4.1. Experiments .........................................................................................................8 

### 6.4.2. Conditions
............................................................................................................

### 8 6.5. Interpretation .................................................................................................................. 8 6.S. List of protocol deviations...............................................................................................8 7. RESULTS
.............................................................................................................................. 9 7.1. Experiments ................................................................................................................... 9 

### 7.2. Conclusion
...................................................................................................................... 9
FIGURES Figure 

### 1 DSCcurveof FIrst experiment ...................................... 10 Figure 2 

### DSCcurve of Second experiment ................................ 10



### - Page 2­

# /~

### 2. STATEMENT OF GLP 

### COMPLIANCE
The study described in this report has been correctly reported and was conducted in compliance 

### with: The Organization for Economic Cooperation 

### and Development 

### (DECO) Good 

### Laboratory Practice Guidelines (1997). Which essentially conform to: The United States Food and Drug Administration Good Laboratory Practice Regulations. The United States Environmental Protection Agency 

### Good Laboratory Practice Regulations. The sponsor is responsible for Good Laboratory Practice (GLP) compliance for 

### all test substance Information unless determined by



### Study Director Section Head Analytical 

### & Physical Chemistry**~** Page 3­

### 3. QUALITY ASSURANCE STATEMENT
This 

### report was inspected 

### by the Quality Assurance Unitto confinn that 

### the methods and results accurately and completely 

### reflect the raw 

### data. The dates of Quality Assurance inspections 

### are given below. During the on-site process Inspections procedures appHcabJe to this type ofstudy were 

### inspected. 

### Type of 

### Phase 'Section Start 

### End Reporting date Inspections Inspection 

### 'ns.,.ctlon date(a) date(s) Protocol (Study) 03\AUG\04 03\AUG\04 03\AUG\04 On-site 

### (Process) DSC and vapour 23\SEP\04 23\SEP\04 2B\sEP\04 

### pressure Report (Study) 28\OCT\04 28\OCT\04 28\OCT\04

Head ofQuality Assurance



### Date: .).
..

## ::J.J.::9.~ 

## .........

- Page 4­ 

## /L-)

### 4. SUMMARY 

### 4.1. Guidelines The determination 

### ofthe boiling temperature 

### of MiS performed in aooordance 

### with the following guidelines: European Economic Community (EEC). EEC-Directive 

### 92/69 eEC, Part A, Methods for the determination of physlco-chemlcal properties, A.2 "Bolling temperature", EEC Publication No. L383, December 1992. Organization for Economic Co-operation and Development (OECD), OECD guidelines for testing of Chemicals, Guideline no. 103: "Boiling poinr, July 27,1995. 

### 4.2. Experlmenta 80th 

### the test substance and an Inert reference were heated in a differential scanning calorimeter (DSC). The difference between the heat flow to the sample and the heat

### ftow to the reference was recorded. Two Etxperlments were performed. The results of both experiments were considered for the conclusion, The atmospheric pressure during the performance of the 

### testwas**._.~** 

### . 

### 4.3. ConclUSion The boiling temperature of , was determined to 

### be 56°C (329 K).

- Page 5­



# It{

### 5. 

### INTRODUCTION 5.1. 

### Preface 

### Sponsor
study Monitor 

### Test Facility

The testwas perfonned at the

Study Director Principal 

### Scientist Study Plan 

### Start Completion 21 October 2004 21 October 2004 5.2. 

### Alms ofthe atudy The purpose of

### the studywas to evaluate the boiling temperature ofthe test substance using differential scanning 

### calorimetry (DSC). 

### This technique 

### records the difference in heat 

### flow to two crucibles, one filled 

### with 

### test substance and the ather filled 

### with an inert 

### reference material. while these crucibles are subjected to 

### a controlled temperature programme. When the test 

### substance undergoes a transition, such as evaporation, this Is Indicated by

### a deviation from the base Hne ofthe 

### heat-flow record. Because evaporation 

### is a process In 

### which heat is consumed, for this process the 

### deviation from the base line is In the 

### endothermic: direction. 

### 5.3. Guidelines The 

### study procedure described in this report Is based 

### on the following guidelines: 

### European Economic Community (EEC), EEC-Dlrecttve 

### 92169 EEC, Part A. Methods for the determination of physico-chemical properties, A2 "Boiling temperature", EEC 

### Publication No. 

### l383, December 

### 1992. Organization for 

### Economic Co..;()peration and Development (OECD), OECD 

### guidelines for testing of Chemicals, 

### Guideline no. 103: "Bolling 

### polnr, July 27, 1995.



### - Page 6­



# I (

### 5.4. Storage and retention 

### of recorda and materials Records and materials pertaining to 

### the study Including protocol, raw data, specimens (except specimens requiring refrigeratton or freezing) and 

### the final report 

### are retained 

### in the 

### archives for a period of at least 10 years afterfinalization of

### the report 

### After this period, the sponsor will be contacted 

### to determine whether raw data snd specimens should be retumed 

### to them, retained or destroyed on their behalf. Those specimens requiring refrfgeration or freezing will be 

### retained b) 

### for as long 

### as the quality of the specimens permits evaluation but no longer than three months after finalization ofthe report. 

### will retain 

### a test substance sample until the expiry date, 

### but no 

### longerthan 10 years after finalization ofthe report. After this period the sample will 

### bedestroyed. 8. MATERIALS AND METHODS 

### 6.1. Testsubetance Identification Structure Molecular formula Molecular weight 

### CAS Number Description
.**CI~r .~Iourless**  

### Uquid Batch Purity 

### 99.985% Test substance storage In 

### refrigerator in the 

### dark Stability under storage conditions Stable 

### Expiry date 07 JuJy2005 The sponsor Is responsible for all test substance data unless determined 

### by 6.2. Teat system and rationale Differential scanning calOrimeter (Seiko 

### RDC-220, Setko, Japan) Detection limit: approximately 10 fJW Sample container: aluminium, closed with 

### a lid in which a small hole was drilled Reference: sample container filled 

### with alumina The test system Is recognized 

### by the International guidelines (EEC, OECO) as recommended test system. 

### 8.3. Validation ofthe teat procedure The test procedure as outlined in this report is validated periodically, using one ofthe following metals3 Indium, tin or lead. The results are in accordance wIth the ;riteria for the validation.

• Page 7­ 

# II

# e.... Perfonnance ofthe 

### test 6....1. Experiments The first experiment was performed with 15.00 mg test substance. The sample was heated from 

### 25"C to 125°C with a rate of 20°C/minute. 

### An amount of 13.42· mg test substance 

### was used during the 

### second experiment This sample was 

### heated from 

### 25"C to 

### 12S"C with a rate 

### of 20"e/minute. 8.4.2. 

### CondJtlona All experiments were 

### performed under a flow of 

### air (about 200 mUmlnute) under atmospheric pressure. Before and after each experiment, the weight ofthe test substance sample was measured. The sample was inspected visually for changes in consistency. The atmospheric pressure during 

### the performance of the test was 

### recorded. 

### 6.5. Interpretation The standard boiling temperature Is defined as 

### the temperature atwhich the vapour pressure of a 

### liquid Is the same as the standard pressure (101.325 

### kPa). The boiling temperature of a pure substance is evaluated from a DSC-curve as the extrapolated onset temperature 

### of the endothermic evaporation peak. i.e. 

### as the cross point of

### the extrapolated base line and the linear part of

### the rising section ofthe evaporation peak. The measured boiling temperature depends on the atmospheric pressure. The actual atmospheric pressure 

### was recorded but the determination ofthe correction factor to 

### standard pressure Is beyond the scope of this srudy. No pressure correction was applied to the boiling temperarure observed. Boiling temperature Is 

### given in 

### degrees Celsius 

### C·C) and kelvin 

### (t<). Temperature In 

### kelvin 

# =Temperature in °C + 

### 273.15. 

### 6.6. Listof protocol deviations 1 Due to changes in the planning, the study was performed in week 43 instead of in the period 

### between weeks 39 and 

### 42. 2 The 

### pressure measured by KNMI 

### (Royal Dutch Meteorological Institute). De Bilt, the 

### Netherlands, was used 

### as the pressure during the performance of

### the test at the Utrecht University. The study Integrity was not adversely affected by the deviations.

• Page 8­ 

# I

### 7. RESULTS 7.1. 

### Experiments The atmospheric pressure during 

### the performance of the test 

### was 1010 hPa (source KNMI, De Bilt, the 

### Netherlands). Figure 1 shows the DSC-curve of the first experiment (25°C - 125°C). A large 

### endothermic effect between 50°C 

### and 80°C, probably caused by evaporation of the test 

### substance. was observed. The extrapolated onset temperature ofthe evaporation peak is 

### S6°e. After the experiment, the sample container seemed empty. Weighing showed a mass-loss 

### of 99%. Figure 2 shows the DSC-curve ofthe second experiment (25°C - 125°C). The curve showed a large endothermic effect between 47"C and 80"C with the extrapolated onset temperature at 56"'C. Weighing showed a mass-loss of 100%. 

### 7.2.**Con~lu.lon** The 

### boiling temperature 

### of was 

### determined to be 

### 56"C (329 K).

- Page 9­ 

# !

### FIGURES



# -**~** <l

Figure 1

Agure 2 20



## o

-60 25 50 100 125


### DSC-curve of Flrst expertment (endothennic effects plotted downwards).
10

-5



### -35

-50 25 50 75 

# rIce 100 

### DSC-curve of. Second experiment. (endothermic enecIS plOtl6U uuwllwlfrds). 125

- Page 10­

### P-04-635 

## REPORT

StudvTltle 

## DETERMINATION OF THE DENSITY (LIQUID) 

## OF

Study completion datI 

### October 13, 2004 Test Facility

Laboratory 

## Prqlect Identification



### - Page1of9­

### 1. CONTENTS 1. CONTENTS
.......................................................................................................................,... 2 2. STATEMENT OF GLP COMPLIANCE
.................................................................................. 3 

### 3. QUALITYASSURANCE STATEMENT
....................." ..........................................................

### 4 

### 4. SUMMARy
.............................................................................................................................

### 5 

### 5. INTRODUCTION
...................................................................................................................

### 6 5.1. Preface
........................................................................................................................... 6 5.2. Aims ofthe study............................................................................................................6 5.3. Guidelines
......................................................................................................................6 

### 5.4. Storage and retention of records and materials........................................................" ... 

### 6 6. MATERIALS 

### AND METHODS
............................................................................................... 

### 7 6.1. Test substance............................................................................................................... 7 

### 6.2. Test system and rationale ............................................................................................... 

### 7 6.3. Reagents ........................................................................................................................ 7 6.4. Performance ofthe test.................................................................................................. 7 

### 6.5. Interpretation .................................................................................................................. 

### 6 

### 6.6. Ust of

### protocol deviations............................................................................................... 

### 8 7. RESULTS
..............................................................................................................................8 8. CONCLUSION
....................................................................................................................... 6 APPENDICES APPENDIX 

### t Individual test data ..................... P ........................................................................ 9 TABLES Table 1 Density of at 20°0............................................................. 8

-Page2­

### 2. STATEMENT OF GLP COMPLIANCE
The study described in this report has been correctly reported 

### and was conducted in compliance with: The Organization for Economic Cooperation and Development (OECD) Good Laboratory Practice Guidelines (1997). 

### Which essentially conform 

## to: The United States Food and Drug Administration Good laboratory Practice 

### Regulations. The United States Environmental Protection Agency Good Laboratory Practice Regulations. The sponsor fs responsible for Good laboratory Practice (GLP) compliance for all test substance information unless determined by
Study Director Section 

### Head Analytical & 

### Physical Chemistry

- Page 3­ ")

)3. QUALITY ASSURANCE STATEMENT
This report was Inspected by the Quality Assurance Unit to confirm that the methods and results accurately and completely reflect the 

### raw data. The dates of Quafity Assurance inspections are given below. During the on-site process inspections procedures applicable to this type of study were 

### Inspected.
Type of Phase 

### I Section 

### start End Reporting date Inspections In8f)8Ctton InapecUon date(s) date(s) Protocol (Study) 03\AUG\04 D3\AUG\04 03\AUG\04 On-site (Process) Analytical and 

### 05\JUl\04 15\JUl\04 19\JUL\04 Physical Chemistry Report (Study) 12\OCn04 12\OCn04 12\OCn04



### Head of Quality Assurance



### Date:**J(...:.~!? .~.k**  

### ........

- Page 4 ­ 

### l/4. SUMMARY 

### The determination ofthe density (liquid) of was perfonned in accordance with the 

### EEC-OIrectIve 92/69 EEC, A.3 "Relative density" {1992) and OECD guideline no. 109 "Density of liquids and solids" (1995). 

### Aglass 

### pycnometerwith a nominal 

### volume of 10 ml 

### was used. 

### The temperature of measurement was 20.0 :t 

### O.5"C. The density ofASAHIKLlN AE-3000 Is 1.48 glcm3 (1.48x1

## d'**kg/m~.** The 

## D;o Is 1.48.



### - Page 5­5. INTRODUCTION 

### 5.1. Preface Sponsor
Study Monitor Test Facility Study Director Study Plan 

### Start Completion : 23 August 2004 : 23 August 2004 

### 5.2. Alms ofthe study The purpose ofthe study was 

### to determine the density oftne liquid test substance at 20°C by means of

### a pycnometer. 

### 5.3. Guidelines The study procedure described In this report Is based on the following guidelines: 

### European Economic Community (EEC). EEC-Oirectlve 92/69 EEC, Part A, Methods 

### for !he determination of physico-chemical 

### properties, A.3 "Relative density". 

### EEC Publication No. 

### L3S3, December 

### 1992. Organization for Economic Co-operation and Development 

### (OECD). OECD 

### guidelines for Testing ofChemicals. guideline No. 

### 109: "Density of liquids and solids", July 

### 27, 1995. 

### SA. Storage and retention 

### of records and materials Records and materials pertaining to the study including protocol, raw data, specimens (except specimens 

### requiring refrigeration or freezing) and the 

### final report are retained In 

### the archives for a period ofat least 10 years after finalization of

### the report. After this period. the sponsa' will be contacted 

### to determine whether raw data and specimens should be returned 

### to them, retained ordestroyed on their 

### behalf. Those specimens requiring refrigeration or freezing will be retained by for as long as the quality ofthe specimens permits evakJation but no longer than three months after finalization ofthe report 

### will retain a test substance 

### sample until the expiry date. but no longer 

### Ihan 10 years after 

### finalization of

### the report. After this period the sample will be destroyed.

- Page 6­ 

# J C6. MATERIALS AND METHODS 

### 6.1. Test substance Identification Structure Molecular formula Molecular weight CAS Number Description Clear colourless liquid Batch 

### Purity 99.985% Test substance storage In refrigerator in the dark Stability under storage conditions Stable Expiry date 

### 07 July 

### 2005 The sponsor is responsible for all test substance data unless determined by 6.2. 

### Testsystem and rationale Test system A pycnometer with a volume of 10 mL, with a ground-In thermometerand a capillary side-tube. Rationale Recognized by the international guidelines (EEC, DECO) as recommended test system. 

### 6.3. Reagents MiIIi-Q water Tap water purified by reversed osmosis and 

### subsequently passed over 

### actiVated carbon and ion­ 

### exchange cartridges; Mlllipore 

### Corp., Bedford, MA, USA 

### 6.4. Perfonnance ofthe 

### test The clean pycnometer was weighed dry and empty. Then It was filled wtth MIIU-Q water, thoroughly dried on the outside and weighed again. The temperature ofthe 

### MIIII-Q waterwas measured. The procedure was 

### performed In duplicate. Thereafter 

### the pycnometer 

### was filled 

### with test substance, thoroughly dried on the outside and weighed. The temperature 

### of the test substance was measured. This procedure was also performed In duplicate. All handlings were performed with 

### MIIII-Q water and test substance 

### at 20.0 :i: 

### 0.5°C and with equipment having the same temperature. The welghings 

### were performed on an analytical balance with an accuracy 

### of 0.1 mg.

- Page 7­

### 6.5. Interpretation The density of a substance is the quotient ofthe mass and the volume ofthe substance 

### at a specific temperature. SI 

### unit in kg/m3

. 

### One gram per 

### an3 

### corresponds with 1000 

### kg/m3• 

### The mass 

### of the test substance used for the experiment was calculated from the difference 

### in weight between the 

### with test substance 

### filled pycnometer 

### (C) and the empty pycnometer 

### (A; mean value). The volume of the test substance used 

### for the experiment is the same as the volume of the pycometer 

### (0; mean value). The density ofthe test substance is 

### calculated as the quotient of 

### Its mass and volume. D

### = {B- A)I E 

### (C - A ) I 0 = Density ofthe test subslance**[g/cm~** 1liiian ,.., A 

### = Weight of

### the empty pycnometer [g] 

### B 

### = Weight of the pycnometer filled 

### with MIlIi..Q water [g} 

### C 

# = Weight of !he 

### pycnometer 

### filled with test substance [g] 

### D 

### = Volume of

### the pycnometer**[cm~** 

### E 

### = Density ofwater atthe test temperature 

### (20°C]; 0.9982 g/om3 

### (eRe Handbook of Chemistry and Physics, 1981) In addition, 

### the relative denslty

### D~was reported. This is the 

### ratio between the mass ofa volume ofthe test substance, determined at 

### 20°C, and the mass ofthe 

### same volume ofwater, determined at 4°C {=1000 

### kg/m\ The relative density has no dimension. 6.6. List 

### ofprotocol deviations There were no deviations from the 

### protocol. 7. RESULTS 

### Two tests were performed. Appendix I 

### shows.tflejndMdual test data. Table 1 

### summarizes the 

### densities measured 

### for 

### Table 1 Density of Test 

### Mean**d~~Sity**

## oen~~ 

# I [a/em ra/cm 1 1.483 2 

### 1.484 1.48


### 8. CONCLUSION 

### The density of Is 1.48 

### g/cm 3 (1.48x103**k:g/m~.** 

### The 

# nio is 1.48.



### - Page 8­



### ,.

### APPENDIX I Individual 

### test data 

### Test 1 Test 2 Mean Mass empty pycnometer (A) Temperature MIlIi-Q water Mass pycnometer with Milli-Q water (8) 

### Volume pycnometer (D) Temperature test substance Mass pycnometer 

### with test substance (C) 26.3291 9 

### 2O.O°C 36.1240 9 9.8126 cm3 

### 20.0°C 40.B822g 

### 26.3281 g 

### 20.0°C 36.1187 g 9.8083 cm 3 

### 20.0°C 40.8870g 26.3286g
9.8105 cm

### a

- Page 9­

f: ) I:'

### P-04-635 

## REPORT

Study Title 

## STATEMENT ON THE EXPLOSIVE PROPER1-IES OF

$tullY completion date

October 06, 2004 Test Facilltv



### laboratory Project Identification

M 

### Page 1of8 ­

### 1. CONTENTS 1. CONTENTS
........................................................................................................................... 

### 2 2. STATEMENT OF GLP COMPLIANCE
.................................................................................. 

### 3 3. QUALITY ASSURANCE STATEMENT
.................................................................................

### 4 4. SUMMARy
............................................................................................................................. 5 

### 5. INTRODUCTION
................................................................................................................... 

### 6 5.1. Preface ........... ................................................................................................................ 6 5.2. 

### Aims 

### ofthe study............................................................................................................6 

### 5.3. Guidelines
...................................................................................................................... 6 5.4. Storage and retention 

### of records and materials............................................................. 6 

### 6. MATERIALS AND METHODS
............................................................................................... 7 

### 6.1. Test substance .. .............................................................................................................7 6.2. list of 

### protocol deviations........... ....................................................................................

### 7 7. STATEMENT
.........................................................................................................................

### 8 7.1. Molecular structure......................................................................................................... 

### 8 7.2. 

### Oxygen balance ............................................................................................................. 8 

### 8. CONCLUSION
....................................................................................................................... 8

- Page 2 ­

) 

# ;/2. STATEMENT OF GLP COMPLIANCE


### The study described in this report has been correctly reported and was conducted in compliance with: The Organization for Economic Cooperation and Development (OECD) Good Laboratory Practice Guidelines (1997). 

### Which essentially conform 

### to: The United States Food and Drug Administration Good Laboratory Practice Regulations. The United States Environmental Protection Agency Good Laboratory Practice Regulations. The sponsor Is responsible for Good Laboratory Practice (GLP) compliance for all test substance information unless determined by



### Study Director Section Head Analytical & 

### Physical Chemistry



### Date: ...

# Q~J**d9.~!1** 

# ..0..6".**~QQ(.(** ....... .

- Page 3 ­

### 3. QUALITY ASSURANCE STATEMENT
This report was inspected by the :lualityAssurance Unit 

### to confirm that the methods and results 

### accurately and completely reflect the 

### raw data. 

### The dates of Quality Assurance Inspections are given below, 

### Type of Inspections 

### Protocol (Study) 

### Report (Study) Ph..e'Sectlon 

### Start Inspection date(e) 03\AUG\04 05\OC1\04 End 

### InspecUon date(e) 03\AUG\04 

### 05\OCT\04 Reporting date
03\AUG\04 

### 05\OCT\04

Head of Quality Assurance

Date: ...

## 3:,:-:.\~::-:9.t:, 

## ....

- Page 4 ­

### 4. 

### SUMMARY The procedure for the determination of the e)(ploslve properties Is descrIbed In the 

### following guideline: 

### European Economy Community (EEC), EEC-Directive 92169 EEC, 

### Part 

### A. Methods for

### the determination of physlco-chemical properties, A.14 "Explosive properties", EEC Publication No. L383, December 1992. The 

### molecular structure 

### of does 

### not contain any chemically 

### instable or highly energetic groups that might lead to 

### an explosion. has an 

### oxygen balance of-68%. This value is within the region where there may 

### bea potential for explodability. However, 

### there are 

### no plosophores (bond 

### groupings known to confer explosive 

### properties) orauxoploses (explosive enhancing groups) present 

### In the structure. The high oxygen balance Is considered due to the presence of

### the ether 

### group in the (small) 

### molecule. 

### In conclusion, is 

### not explosive.



### -Page5­

### 5. INTRODUCnON 

### 5.1. Preface Sponsor Study Monitor Test Facility 

### Study Director Study Plan Start 

### Completion 30 September 2004 

### 30 September 2004 5.2. Alma ofthe study 

### The purpose ofthe study was 

### to evaluate the explosive properties ofthe test substance. 

### 5.3. Guidelines The 

### procedure for the determination 

### of the 

### explosive properties is described 

### in the followIng guideline: European Economy Community (EEC), EEe-Dlrective 92/69 EEC, Part A, Methods for

### the determination of physlco-chemlcal properties, A.14 

### "Explosive properties", EEC Publication No. 

### L383, 

### December 1992. 

### 5.4. Stonge and retention of records and 

## materl." Records and materials pertaining 

### to the study including 

### protocol, 

## raw data, specimens (except 

### specimens requIring refrigeration or freezing) and the final report are retained 

### In the archives for a period 

### ofat least 10 years after finalization ofthe report 

### After thIs period, the sponsor will 

### be contacted to determine whether raw data 

### and specimens should be returned to them, retained ordestroyed on their behalf. Those specimens requiring refrigeration orfreezing wit be retained by for as long 

### as the quality of the 

### specimens permits evaluation but no longer than 

### three months afterfinalization ofthe report 

### will retain a

## test substance 

### sample until the expiry date, but no longer than 1 0 

### years after finalization of

### the report. After this period the sample will be destroyed.

- Page 6 ­

### 6. 

### MATERIALS AND METHODS 

### ••1. Teet

### 8ubstance Identification 

### Structure Molecular formula Molecular weight 

### CAS Number Description Clear colourless liquid 

### Batch 

### Purity 99.985% Test substance storage In refrigerator in the dark Stability under storage conditions Stable expiry 

### date 07 JuJy2005 

### The sponsor 

### Is responsible for all 

### test substance data unless determined 

### by 

### 6.2. Llct of protocol dew.Uone There were no deviations from the protocol.

- Page 7­ 

# 3C7. STATEMENT 

### The tendency ofa compound to undergo violent or explosive decomposition is an important safety consideration. In genera', the oxygen balance and various structural parameters (bond groupings) are factors associated with explosive properties. 7.1. Molecularstructure The molecular structure of does not contain any chemically instable or highly energetic groups that might lead 

### to an explosion. 

### 7.2. Oxygen balance The oxygen balance of

### a compound is the difference between 

### the oxygen content ofthe compound and that required 

### to fully oxidize the carbon, hydrogen and other oxidisable elements to carbon dioxide, water, etc.. Nitrogen is not considered ox/disable and is usually liberated as the gaseous element during explosive decomposition. The oxygen balance is calculated for the chemical reaction: CcHhOo + 

### Ie + (h/4) - (0/2)] 0: C CO2 + (h/2) H20 (where 

### c, hand 0 

### are the numbers 

### of carbon, hydrogen and oxygen atoms respectively) using the formula: Oxygen balance (%) 

### =-1600 x 

### [2 x c + (h/2)
- 

### 0] I molecular 

### weight. 

### If there Is a deficiency of oxygen, 

### the balance 

### Is negative, while 

### an excess of oxygen 

### gives a positive balance. Compounds with a positive balance can act 

### as oxidants and 

### are often explosive in nature. However, there are known explosives with an oxygen balance of -64%. Compounds with an oxygen balance which Is more negative than -200% are not considered 

### to pose 

### an explosive 

### risk. Molecular formula for 

### Molecular weight: 

### 200.07 g/mol The calculated oxygen balance for is -68 

### %. This value Is within the region where there may be a 

### potential for explodab/llty. However, there are no plosophores (bond 

### groupings known to 

### confer explosive properties) or auxoploses (explosive enhancing groups) present In the structure. The high oxygen balance is considered due to the presence of the ether group in the (small) molecule. Overall consideration of the properties does not suggest a 

### risk of explodability,


### 8. CONCLUSION is 

### not explosive.

- Page 8­

### P-04-635 

# REPORT

Study Title 

## STATEMENT ON THE FLAMMABILITY (CONTACT WITH WATER) 

## OF

Study completion date

October

# oa, 2004 Test facjlity



### Laboratory Prolect Identification

• Page 1of 7**~**

### 1. CONTENTS 1. CONTENTS
...........................................................................................................................2 2. STATEMENT OF GlP COMPLIANCE
.................................................................................. 3 

### 3. QUALITY ASSLIRANCE STATEMENT
................................................................................. 

### 4 4. SUMMARV
.............................................................................................................................

### 5 

### 5. tNTRODUCTION
...................................................................................................................

### 6 

### 5.1. Preface ........................................................................................................................... 6 5.2. Alms of the 

### study............................................................................................................ 6 

### 5.3. Guidelnes
...................................................................................................................... 6 5.4. Storage and retention of records and materials............................................................. 6 6. MATERIALS AND METHODS
............................................................................................... 7 

### 6.1. Test substance ............................................................................................................... 7 

### 6.2. Reagents ........................................................................................................................7 6.3. 

### list of protocol deviations............................................................................................... 7 7. STATEMENT
......................................................................................................................... 7 8. CONCLUSION
.............................................................................:......................................... 7

- Page 2­

) I

### 2. STATEMENT OF GLP COMPLIANCE


### The study described In this report has been correctly reported and was conducted in compliance with: 

### The Organization for Economic Cooperation and Development (OECD) Good Laboratory Practice Guidelines (1997). 

### Which essentially conform 

### to: The United States 

### Food and Drug 

### Administration Good Laboratory Practice Regulations. The United States Environmental Protection Agency Good Laboratory Practice Regulations. The sponsor Is 

### responsible for Good Laboratory Practice (GLP) compliance for all 

### test substance information unless determined by
Study Director . Section Head Anafytical 

### & Physical Chemistry

Date: ....

# a.i9.b..**~.,** 

# ..**~.........** Date: 

# .O.c..job-..c6..

# '::~~~/ ..

- Page 3­ /3. QUALITY ASSURANCE STATEMENT
This reportwas inspected by the QualityAssurance Unit to confirm that the methods 

### and results accurately and 

### completely reflect the 

### raw data. The dates of QualityAssurance inspections 

### are given below. During the on-site process inspections procedures applicable to this type of study were inspected. Typaof Ph••e'Sectfon Inspections Protocol (Study) On-site (Process) Analytical and 

### Physical Chemistry Report (Study)

Head of Quality Assurance



# . 1- 

# -,0 -0,", • Date............................ . Start End Reporting date In.pactlon Inspection 

### date(8) date(s) 03\AUG\04 03\A.UG\o4 03\A.UG\04 05\JUL\o4 15\JUL\04 19\JUL\04 05\OC1\04 05\OCn04 05\OCn04

- Page 4­

### 4. SUMMARY 

### The procedure for the determination ofthe flammability (ccntact with water) Is described In the following 

### guideline: European 

### Economic Community (EEC). EEC directive 

### 92169 EEC, Part A, 

### Methods for the 

### determination of physico-chemical properties, A.12 "Flammability (contact 

### with water). EEC Publication No.L3B3, 

### December 1992.



### ..**eaJ.~ed** 

### on its**molecul~r** 

### structure and 

### on an experiment, 

### it was concluded that 

### s Incapable of developing a dangerous amount of 

### (flammable) gas In contactwith damp 

### air or water.



### - PageS­ 

### )

### 5. INTRODUCnON 

### 5.1. Preface Sponsor Study Monitor Test Facility
Study Director Study Plan Start Completion 30 August 2004 (experiment) 31 August 2004 (statement) 

### 5.2. AIm8 

### of

### the study The purpose ofthe study was

### to evaluate whether reaction ofthe test substance with water or damp air leads 

### to the development of dangerous amounts of gas or gases that may be highly flammable. 

### 6.3. Guldell.... The procedure for the determination 

### of the flammability (contact with water) is described in the following guideline: 

### European Economic Community (EEC). EEC directive 

### 92169 EEC, Part

## A Methods for the determination of physico-chemlcal properties, A.12 "Flammability 

### (contact with water), 

### EEC Publication No. L3B3, December 1992. 

### SA. 

### Storage and retention of

### records and materials Records and materials pertaining to the study including protocol. 

### raw data, specimens (except speelmens 

### requiring refrigeration or

### freezing) and the final report are retained In the archives for a period 

### ofat least 10years after finalization 

### ofthe report. After this period, the sponsor will be contacted to determine whether raw data and specimens should 

### be retumed 

### to them, retained 

### or destroyed on their behalf. Those specimens requiring refrigeration or freezing will 

### be retained by for as long as the quality ofthe specimens permits evaluation but no longer than three months after finallza60n ofthe report 

### Nil! retain a test substance sample until the expiry date, but no longer than 10 years after finalization of the report. After this period the semple will 

### be des1royed.

-PageS­

/

# e. MATERIALS AND METHODS 

### 6.1. Teat 

### 8ubstance Identification Structure Molecular formula Molecularweight CAS Number Description Clear colourless liquid 

### Batch Purity 99.985% Test substance storage In refrigerator in the dark Stabifity under storage conditions Stable 

### expiry date 07 July 2005 The sponsor is responsIble for all test substance data unless determined by 

### 6.2. Reagenla Double distilled water 

### 6.3. Listofprotocol deviations There were no deviations from the protocol. 7. STATEMENT 

### Substances that, in 

### contact with water or damp air, evolve 

### highly flammable gas(es) 

### in dangerous quantities at a minimum rate of 

### 1 Ukg per hour 

### are highlyflammable. The structure of 

### does not contain groups that might lead to evolution of highly flammable gases In dangerous 

### quantities when coming Into 

### contactwith damp airof water. Furthermore, 

### no metals, transition metals, boron or silicon are present In order to obtain 

### some additional information, 

### an experiment 

## was performed 

### In which double dlstifled waterwas added 

### 10 a small amount oftest substance 

### (0.5 gl50 mL): no spontaneous ignition took place and no evolution of gas occurred. 

### 8. CONCLUSION is Incapable ofdeveloping a dangerous amount of (flammable) gas(es) In contact with damp airorwater.

- Page 7­

### P-04-635 

## REPORT

Sludylitle 

## DETERMINATION OF THE FLASH..POINT OF

Study comoletlon date

November29,2004 

### Test Facilitv

Laboratory 

### P!'QJea Identification

• Page1of8­

### 1. CONTENTS 

### 1. CONTENTS
........................................................................................................................... 2 

### 2. STATEMENT 

### OF GLP COMPLIANCE
.................................................................................. 

### 3 

### 3. QUALITY ASSURANCE STATEMENT
.................................................................................

### 4 4. SUMMARy
.......................................,....................................,................................................ 

### 5 5. INTRODUCTION
.............................................................................,..................................... 

### 6 5.1. Preface
........................................................................................................................... 6 5.2. Aims ofthe study............................................................................................................ 6 

### 5.3. Guidelines
......................................................................................................................

### 6 5.4. Storage and retention of records and materiafs
............................................................. 6 6. 

### MATERIALS AND METHODS
...............................................................................................7 

### 6.1. Test substance ............................................................................................................... 7 6.2. Test system and rationale .............................................................................................. 7 S.3. 

### Validation of the test method..........................................................................................7 6.4. Perfonnance ofthe test. ................................................................................................. 7 6.4.1. Preparations before the test ................................................................................ 7 6.4.2. Test procedure......................................................................................................7 6.4.3. Preliminary 

### test .....................................................................,.............................. 7 

### 6.4.4. Main study............................................................................................................ B 6,4.5. Test conditions ..................................................................................................... B 

### 6.5. Interpretation ..................................................................................................................8 6.6. LIst of protocol deviations.. ,............................................................................................ 8 

### 7. RESULTS
.................................,............................................................................................ 

### 8 8. 

### CONCLUSION
....................................................................................................................... 8

- Page 2**~**

### 2. STATEMENT OF GLP COMPLIANCE
The study described In this report has been correctly reported and was conducted in compliance With: 

### The Organization for Economic Cooperation and Development (OECD) Good Laboratory 

### Practice Guidelines (1997). Which 

### essentially conform to: The United States Food and Drug Administration 

### Good Laboratory Practice Regulations. 

### The United States Envtronmental Protection Agency Good Laboratory Practice Regulations. The sponsor is responsIble for Good Laboratory Practice (GlP) compliance for all test 

### substance information unless determined by ... - _.__ .
Study Director Section Head Analytical & Physical 

### Chemistry



### Date: ...

# ().o.v.~1:).b.~.~

# ....'?rg.,...

# ?.Q.Q~ .. ...

- Page 3­

### ~I 

# 7

### 3. QUALITY ASSURANCE STATEMENT
This report was Inspected by the Quality Assurance Unit to confirm that the methods and results accurately and completely reflectthe raw data. 

### The dates of QualityAssurance inspections are given below. During the on-site 

### process Inspections procedures applicable 

### to this 

### type ofstudy were 

### Inspected.
Type 

### of Phase ISection Start End ReporUng date Inspections Inspection Inspection date(s) date(s) Protocol (Study) 11\NOV\04 11\NOV\04 

### 11\NOv\04 On-site (Process) Analytical and 

### 04\OCn04 12\OCn04 

### 25\OCT\04 Physical 

### Chemistry Report (Study) 

### 26\NOV\04 26\NOV\04 26\NOv\04

Head of Quality Assurance

- Page 4 ­

### 4. 

### SUMMARY The determination ofthe f1ash-point of NBS 

### performed in accordance 

### with EEC-Dlrectlve 92189 EEC, A.9"Flash-point" (1992) and 

### DIN EN 22719: "Bestlmmung des 

### Flammpunktes Verfahren naeh Pensky-Martens im geschlossenen Tlegel"; December 1993. No**flash~point** for could 

### be 

### determined using a Pensky-Martens closed 

### cup 

### flash-point apparatus. No flammable vapour/air mixture was produced in the test 

### vessel at temperatures below 

### boiling. visually observed at 55°C.

- Page 5­

### S. INTRODUCTION 5.1. Preface Sponsor Study Monitor Test F acUity 

### Study Director Study Plan Start Completion 15 

### November 2004 15 

### November 2004 

### 5.2. Alms ofthe study 

### The purpose of

### the 

### study was to determine the**f1ash~point** 

### of the test substance. S.3. Guidelines 

### The study procedure described In this report is based on the followtng guidelines: European Economic Community (EEC).**EEC~Directive** 92/69 EEC, 

### Part A, Methods 

### for 

### the determination of**physl~hemlcal** 

### properties, A.9 

### "Flash-point", EEC 

### Publication No. 

### L383. December 

### 1992. DIN EN 22719: 

### -Bestimmung des 

### Flammpunktes Verfahren nach Pensky-Martens 1m geschlossenen Tlegel"; December 

### 1993. SA. Storage and retention of 

### records and materials 

### Records and materials pertaining 

### to the**s~y** 

### including protocol, 

## raw data; specimens (eXGe.ot specimens requiring refrigeration or freezing) and the final report are retained 

### in the archives for a period ofat least 10 

### years after finalization of

### the report. Afterthis period, 

### the sponsorwill 

### be contacted 

## to determine whether nM 

### data and specimens should 

### be retumed to them, retained or destroyed on their behalf. Those specimens requiring refrigeration or freezing will be retained by 'or as long as the quality of the specimens permits evaluation but no longer than three months after finalizatlon ofthe 

### report. will retain a test substance sample until 

### the expiry date, but no longer than 10

### years after finalization ofthe 

### report. After this period the sample will be 

### destroyed.

- Page 6­

### 6, MATERIALS AND METHODS 

### 6.1. Teataubstance Identification Structure Molecular formula Molecular weight CAS Number Clear colourless liquid Description Batch Purity 99.985% Test substance storage 

### In refrigerator 

### in the dane Stability under storage conditions 

### Stable Expiry date 07 July 2005 The sponsor is responsible for aU test substance data unless determined 

### by 

### 6.2. Teat system and rationale A Pensky-Martens closed flash-point apparatus (according to Test system DIN EN 22719). Recognized by 

### the international guidelines (EEC, DIN) as Rationale recommended test system. 

### 8.3. Validation ofthe 

### test method The test procedure as outlined In this report is validated periodically, using p-xylene. The results are In accordance with the criteria for validation. 

### 8A. Performance of

### the 

### test 6.4.1. Preparations before thetest The cup of the flash-point apparatus was filled with the test substance to the level indicated by the filling mark. The lid, with a thermocouple for detection ofthe flash pOint and a resistance thermometer for measuring the sample tamperature. was placed on the cup. Thereafter, the cup was placed in the heating block. 

### 6.4.2. Testprocedure The test substance was heated In 

### the apparatus 

### with a temperature rise of approximately 5"C/mlnute. The sample was stirred during heating. The test flame was applied so that the flame was lowered into the vapour space of the cup in 0.5 seconds, left in Its lowered position for 1 second, and quickly raised to Its high position. The sample was not stirred While the test flame was applied. 

### 8.4.3. Preliminary 

### tNt Duplicate tests were performed. The test substance temperature was 17°C and 1S"C atthe start. ofTest 1 and 2. respectively. Starting at 19°C (Test 1) and 20°C (Test 2), a test flame was applIed every 2°C temperature rise.
Page 7­8.4.4. Main study 

### The results of the 

### preliminary test indicated that the main study did not have to be performed. 8.4.!, Test conditions 

### The Pensky-Martens closed flash-point apparatus was 

### placed in a fume-cupboard. The 

### window of the cupboard was left open to reduce the draft 

### to a minimum. 

### The atmospheric pressure on the 

### day ofthe 

### test was measured using a calibrated barometer to 

### be 102.78 kPa. Each 

### test was 

### performed with 

### a new sample. 

### 6.6. Interpretation The flash-point for a test substance is 

### the lowest temperature at 101.3 

### kPa. at which the 

### test liquid in 

## a closed testvessel evolves vapours, under the conditions defined in the test method, In such amount that a flammable vapour/air mixture will be 

### produced In the test vessel. 

# 6... Lilt of

### protocol deviations There were no deviations from the protocol. 7. RESULTS 

### During 

### each of the two 

### (preliminary) tests, it was 

### observed visually 

### that the 

### test substance started to boil at 55°C. 

### No flammable vapour/air mixture was produced in the test vessel at temperatures below bOiling. 

### No further testing was necessary. 8. CONCLUSION 

### No f1ash-point for could be determined using a Pensky-Martens closed 

### cup flash-point apparatus. No flammable vapour/air mixture 

### was produced 

### In the test vessel 

### at temperatures below boiling, 

### visually observed at 

### 55"0.



### - Page 8­

### P-04-635 

## REPORT

StydvTltle 

## DETERMINATION OF THE FREEZING TEMPERATURE OF

Study comPletion date October 

### 13,2004 Test Facility



### Laboratory Prolect Identffication

- Page1ofB­

/'

### 1. CONTENTS 1. CONTENTS " ........................" ............" ................................................................................. 2 

### 2. STATEMENT 

### OF GlP COMPLIANCE
.................................................................................. 

### 3 3. QUALITYASSURANCE STATEMENT
........................................................" ....................... 

### 4 

### 4. SUMMARy
.............................................................................................................................

### 5 5. INTRODUCTION
................................................................................................................... I) 5.1. Preface
...............................................................'" ......................................................... I) 5.2. Aims ofthe study............................................................................................................I) 

### 5.3. Guidelines
......................................................................................................................

### 6 5.4. Storage and retention of records and materials............................................................. 6 

### 6. MATERIALS AND METHOOS
............................................................................................... 

### 7 

### e.1. Test substance.................................................................................................,............. 

### 7 6.2. Test 

### system and rationale .............................................................................................. 7 6.3. Validation 

### of the test method.......................................................................................... 7 6.4. Performance of the test.................................................................................................. 7 6.4.1. Preliminary test .................................................................................................... 7 6.4.2. Main study............................................................................................................7 

### 6.5. Interpretation ..................................................................................................................8 6.S. list of

### protocol deviations...............................................................................................

## a 7. RESULTS
..............................................................................................................................a 7.1. Preliminarytest............................................................................................................... 8 8. CONCLUSION
....................................................................................................................... 8



### -Page2­

### 2. STATEMENT OF GLP COMPLIANCE


### The study described in this report has been correctly reported and**~s** 

### conducted in compliance with: 

### The Organization for Economic Cooperation and Development (OECD) Good Laboratory Practice Guidelines (1997). Which essentially conform to: The United States Food and Drug Administration Good Laboratory 

### Practice Regulations. 

### The United States Environmental Protection Agency Good Laboratory 

### Practice Regulations. The 

### sponsor Is 

### responsible for Good Laboratory Practice (GLP) 

### compliance for all test substance Information 

### unless determined by
Study Director 

### Section Head Analytical 

### & Physical Chemistry

Date: ...

# Q(,J

# o.b.e.r:\
....

# I.~. >" ••

# ~o.o. 

# -4.....

- Page 3­**~.**

### 3. QUALITY ASSURANCE STATEMENT
This report was inspected 

### by the Quality Assurance Unit 

## to confirm that the methods and results accurately and 

### completely reHeet the 

## raw data. The dates ofQuality Assurance inspections are given below. During the on·slte 

### process inspections procedures 

### applicable to this 

### type ofstudy

### were 

### Inspected. Type of Phase I 

### Section Start End Reportfng date 

### lnepactfons InepectJon 

### Inspectfon date(s) date{s) Protocol (Study) 

### 03\A.UG\04 03\A.UG\04 03\AUG\04 On-site (Process) Analytical and 

### 05\JUL\04 15\1UL\04 19\JUL\04 Physical 

### Chemistry Report (Study) 

### 12\OCT\04 12\OCT\04 . 12\OCn04

Head of Quality Assurance

Date: 

# J**~':'** 

# ..**l.~** ..

### -:-~.~.r 

### ....

- Page 4 ­

### 4. 

### SUMMARY The determination ofthe freezing temperature was performed in accordance with EEC-Olrective 92169 EEC, A..1 "Melting/Freezing temperature 

### (1992) and on 

### OECD Guideline no. 

### 102 "Melting PointlMelting Range" 

### (.1981). After_storage for 2 hours at temperatures of

### 4.1/5.1"C, -26.0/-24.3°C and 

### -82.6I-81.4"C, remained a 

### clear colourless liquid 

### without showing any indication 

### of a freezing process (preliminary screening test). No main 

### study was performed. 

### In conclusion, the freezing 

### temperature of Is < 

### -81°C 

## « 192 K).

- PageS­

### 5. INTRODUCTION 

### 5.1. Preface Sponsor 

### Study Monitor Test Faclnfy 

### Study Director 

### Study Plan 

### Start 24 August 

### 2004 Completion 24 August 

### 2004 

### 5.2. Alms of

### the study The 

### purpose of the study was 

### to evaluate 

### the freezing temperature of

### the test substance 

### uSing a liquid bath. 

### 5.3. Guldelin
.. The 

### study procedure described 

### In this report is 

### based on the following guidelines; Organization 

### for Economic 

### Co-operatlon and Development (DECO), OECD Guidelines 

### for Testing ofChemicals, Guideline no. 102 "Melting Point! 

### Melting Range", 

### May 12, 1981. European Economic Community (EEC), EEC·Ofrective 92169 EEC, Part

## A. Methods for the 

### determination of pllyslco-chemlcal properties. 

### A.1 "Melting/Freezlng temperature", 

### EEe Publication No. L383. December 1992. 

### SA. Storage and retention of records and materials Records 

### and materials pertaining 

### to the 

### study including protocol, 

### raw data,**speclmens(e~c.m** ._ specimens 

### requlring refrigeration or

### freezing) and the 

### final report are retained in the 

### archives for a period ofat least 10 years after finalization of the report. After this 

### period, the sponsor wfll be contacted 

### to determine whether 

### raw data and specimens should be 

### returned to them, retained or destroyed on their behalf. Those specimens requiring 

### refrigeration or freezing wfn be 

### retained by 'or as long as the quality ofthe specimens permits evaluation but no longer than three months after finalization ofthe 

### report. will retain a 

### test substance sample 

### until the expiry date, 

### but no longerthan 

### 10 years after finalization ofthe report. Afterthis period the sample will 

### be destroyed.

• PageS.

### S. MATERIALS AND METHODS 

### 6.1. Teat 8ubstanca Identification Structure 

### Molecular formula Molecular weight 

### CAS Number 

### Description Clear colourless 

### liquid Batch 

### Purity 99.985% Test substance storage 

### In refrigerator In 

### the dark Stability 

### under storage 

### conditions Stable 

### Expiry date 

## 07 July 2005 

### The sponsor 

### is responsible forall test substance data unless determined b) 

### 8.2. Testsystem and rationale Preliminarytest 

### Test substance in test tubes; 

### placed in refrigerator. 

### -20°C freezer 

### and -80"C freezer. 

### The temperature 

### in the 

### refrigeratorJfreezers 

### was measured continuously, 

### using a 

### validated compUterised system (Rees Scientific, NJ, USA). Rationale Recognized by the international gUidelines 

### (EEC, OECD) 

### as recommended 

### test system. 

### 6.3. VaUdation of

### the test method The test procedure 

### as outlined In this 

### report is validated periodically, using n-octane and water. The 

### results are 

### In accordance with the criteria 

### for the 

### validation. 6.4. Performance of

### the 

### test 6.4.1. Preliminary test 

### One of three 

### test tubes containing apprOXimately 

### 5 mL test substance was placed In 

### a refrigerator at

### 4.1 I 

### 5.1 "C. The 

### second was placed 

### in a freezer 

### at -26.0 1-24.3°C. The third 

### was placed in a freezerat-82.61-81.4"C. 

### After 1 and 

### 2 hours, the 

### contents ofthe three 

### tubes were visually

### checked for solidifICation. 8.4.2. Main study 

### Because the preliminary test 

### evaluated a freezing point <.: 

### -81 

### DC, the 

### main study was 

### not performed.**~** 

### Page 7**~**

### 6.5. Interpretation The freezing temperature is defined as the temperature at which the phase transition from liquid to 

### solid state tekes place at normal atmospheric pressure. This temperature ideally corresponds 

### to the solidification or freezing temperature. The temperature 

### of relevance 

### is given 

### in degrees Celsius CC) 

### and kelvin (K). Temperature In 

### kelvin 

### = Temperature in"C 

### + 273.15. 8.8. Llllt 

### of protocol deviations 

### There were no deviattons from the protocol. 7. RESULTS 

### 7.1. Preliminary test 

### Table 1 

### summarizes the temperatures and the visual observetions durfng the preliminary screening test. Table 

### 1. Screening 

### test for the freezing temperature of

Temperature range during storage rOC] Test substance appearance after 1 hour Test substance appearance after an additional 1-hour perfod 4.1105.1 

### Clear colourless liquid Clear colourless liquid -26.0 to -24.3 Clear colourfess liquid Clear colourless liquid 

### -82.6 to -81.4 

### Clear colourless liquid Clear colourless liquid remained a clear colourless liquid without 

### showfng any Indication of a freezing process. Therefore no main study was performed. 8. CONCLUSION The 

### freezing temperature of is < 

### -81"C 

### « 192 

### 1<).

-Page8­

### P-04-635 

## REPORT

Study Title 

## DETERMINATION OF THE tH NMR SPECrRUM OF

Study completion date October 

### 26, 2004 Test Facility

laboratory Pro;ect IdsntifiQ§tlon

- Page 1 of 14 ­1. CONTENTS 

### 1. CONTENTS
...........................................................................................................................

### 2 2. STATEMENT OF GLP COMPLIANCE
..................................................................................

### 3 3. QUALITY ASSURANCE STATEMENT
................................................................................. 

### 4 4. SUMMARy
.............................................................................................................................

### 5 5. INTROOUCTION
.................................................................................................................... 

### 6 5.1. Preface
........................................................................................................................... 6 5.2. Aims of

### the study ............................................................................................................6 

### 5.3. Guidelines
....................................................................................................................... 

### 6 5.4. Storage and retention of records and materials ............................................................. 7 

### 6. MATERIALS AND METHODS
...............................................................................................

### 7 

### 6.1. Test substance ...............................................................................................................

### 7 6.2. Reagents ........................................................................................................................

### 7 S.3. Criteria 

### and sensitivity ....................................................................................................

### 7 6.4. Performance of the test .................................................................................................. 

### 8 6.5. List of protocol deviations...... ,........................................................................................8 7. RESULTS
............................................................................................................................... 8 8. CONCLUSION
....................................................................................................................... 8 FIGURES Figure 

### 1 

### 'H NMR spectrum of
......................................................... 

### 9 Figure 

### 2 'H NMR spectrum of Including measurement conditions and integrals ..................................................................................... 

### 10 Figure 3 'H NMR spectrum of Including measurement conditions and peak picking ............................................................................... 11 Figure 

### 4 'H NMR spectrum ofdimethylsulfoxide (solvent)
.............................................. 12 APPENDICES APPENDIX I Assignment table and signature of principal scientist........................................ 13

- Page 2­

### 2. STATEMENT OF GLP COMPLIANCE
The study described in this report has been correctly reported and was conducted In compliance with: The Organization for 

### Economic Cooperation and Development 

### (OECO) Good Laboratory Practice Guidelines (1997). Which essentially conform to: The United States Food and Drug Administration Good Laboratory Practice Regulations. The United States Environmental Protection Agency Good laboratory Practlce Regulations. The sponsor is responsible for Good Laboratory Practice (GLP) compliance for all test substance information unless determined by

Study Director 

### Section Head Analytical & Physical Chemistry

Date: ....

# O.c..~.b.t~ 

# ...**'2..~.;**...

# 21>.o.H....

4 

### Page 3­3. QUALITY ASSURANCE STATEMENT


### This report was inspected by the 

### Quality Assurance Unit to confirm that the methods and 

### results accurately and 

### completely renect the raw data. The dates of Quality Assurance Inspections are given 

### below. During the 

### on-site process inspections procedures applicable to 

### this type of study were inspected.
Type

# 0' Phase I Section 

### Start 

### End Reportrng InspectIons 

### InspectIon Inspection date date(s) date(s) 

### Protocol (Study) 03\AUG\04 03\AUG\04 03\AUG\04 On-site 

### (Process) Analytical and PhysIcal 05\JUL\o4 15UUL\04 19\JUL\04 Chemistry 

### On-site (Study) Test Item weighing, 07\OCn04 07\OCnD4 11\OCn04 formulation, exposure, measurement Report 

### (Study) 25\OCn04 25\OCT\04 25\OCn04



### Head 

### of QualityAssurance

Date:

### .~j. t;?JO/.; •••.. '" .. , •

- Page 4­ 

# / / C 7' 

# .**~**

### 4. SUMMARY 

### The determination of the 'H NMR spectrum was based on the following guideline: Working Document of the 18th Meeting of competent Authorities. Conception to Harmonize Requirements for Spectral Data. to 

### be submitted eccording to Directive 19/8311EEC. 

### The NMR spectrum 

### of Is In agreement with the structure of the test 

### substance.

• Page 5­5. INTRODUCTION 

### 5.1. Preface Sponsor
Study Monitor Test 

### Facility

The test was performed by

Study Director Principal Scientist Study Plan 

### Start 

### 5 October

### 2004 Completion 

### 7 October 

### 2004 5.2. Alms of the study The purpose ofthe study was 10 record a standard tH NMR spectrum. Protons 

### can absorb 

### specific radio frequencies In a constant magnetic

### field. These frequencies are presented in Hz 

### or ppm. The fundamental NMR equation correlating electromagnetic frequency (v) with magnetic field strength 

### (Bo) is: v 

## = (1 Bo) 12n 1 

### = magnetogyrlc ratio 5.3. GuIdelines The study procedure described tn this report is based on the following guideline: Working Document ofthe 18th Meeting ofcompetent Authorities. Conception to Harmonize Requirements for Spectral Data, to be submitted according to Directive 79/831/EEC.



### - Page 6­ 

## (

### 5.4. Storage and retention of records and materials Records and materials pertaining to the study including protocol, 

## raw data, specimens (except specimens requiring refrigeration or freezing) and the 

### final report are 

### retained 

### In the archives for 

### a period of 

### at least 10 years after 

### finalization ofthe report. After this period, the sponsor will 

### be contacted to determine whether r<Ni 

### data and specimens should 

### be returned to them, retained or destroyed on their behalf. Those specimens requiring refrigeration or freezing will be 

### retained by for as 

### long as the 

### quality of the specimens 

### peon its evaluation 

### but no longer than three 

### months after finalization 

### ofthe report. NOTOX will retain a test substance sample until the 

### expiry date. but no longerthan 10 

### years after finalization ofthe report. After this period the sample will be destroyed. 6. MATERIALS AND METHODS 

### 6.1. Testsub5tance Identification Structure Molecular formula Molecular weight 

### CAS Number Description Clear colourless liquid Batch Purity 99.985% Test substance storage In refrigerator in 

### the dark Stability under storage conditions Stable Expiry date 07 July 2005 The sponsor is 

### responsible for all test substance data unless deteonined by NOTOX. 

### 6.2. Reagents Dimethylsulfoxide For spectroscopy. Merck Darmstadt, Germany Chloroform in 

### aceton-O. solution Varian Associates, Palo Alto, California, USA Ethyl benzene In chloroform-O solution Varian ASSOCiates, Palo Alto, 

### California, USA Dimethylsulfoxide-De 0-99.9%.0.05 

### vlv% TMS, Cambridge Isolope Laboratories 

### 6.3. Criteria and 

### sen8ltlvlty To ensure that the Instrument was perfonnlng satisfactory, spectra of reference solutions of chloroform in acetone-De (for resolution) and ethyl benzene in chloroform-O 

### (forsensitivity) were recorded on the day of 

### recording the spectrum ofthe test substance. The spectrometerwas capable ofrecording spectra with a resolution (line width al a half maximum) of < 

### 0.45 Hz and a sensitivity (slgna/-ta-nolse ratio) 

### of> 150. •



### - Page 7­6.4. Perfonnance of the 

### test Prelimlnaty solubility test To 0.5 ml 

### of the test substance 10 ml dimethylsulfoxide was added and observations concerning the solubility were made. 

### 6epa

### ratus A Varian Mercury Vx NMR spectrometer for 'H NMR 

### was used. Solvent Dimethylsulfoxide-De Reference TetramethylsJlane (TMS) Instrument settings Frequency Spectralwidth 400.16 MHz 6000 Hz Pulse width 7 micro seconds Relaxation delay 

### 3 seconds 

### Line width (chloroform) 

### 0.45 Hz Sensitivity (ethyl benzene) sin 

### 185**Pr~paration** of

### the samole A sample of the test substance was dissolved In dimethylsulfoxide-De (approximately 80 mg/ 0.95 g) and transferred to a 5 mm NMR tUbe. Appearance: clear colorless solution. Test procedure The glass tube with the sample was placed In the sample holder, and a standard 

### 1H NMR spectrum was recorded at ambient temperature using the internal deuterium lock. 

### 6.5. List of protocol deviations There were no deviations from the protocol. 7. RESULTS Dimethylsulfoxide appeared to be a suitable solvent for recording a 

### 1H NMR spectrum of The**~H** 

### NMR spectrum of in 

### dimethylsulfoxide-De Is 

### shown In Figure 1. Figures 2 and 3 show the 

### same spectrum InCluding measurement condHlons, Integrals and peak picking. The 

### 1H NMR spectrum of dimethylsulfoxide-De (solvent) Is shown In Figure 4. Table 1 shows possible assignments ofthe peaks. Signals In the blank measurement (solvent) were observed at 3.3 ppm, 2.5 ppm and 0 ppm. These signals may 

### be present in the spectrum ofthe compound, but do not relate to the compound Itself, but to water, dimethylsulfo)(ide and TMS. respectively. Table 1 Assignments, based on interpretation only 

### Chemical shift (ppm) Peak structure Possible asslQnment 6.6 multiplet 

### 4.6 multiplet 

### 8. CONCLUSJON The signals in the 1M NMR spectrum are In line with the structure of the test substance.

### FIGURES !


## ...



# ..

..



# ..**~** 

# .. H 

# . h 

# .. i
M 

# .. 

# . W**~** 

# .. ..**~** ; 

## j 'l A 

# • 

# [.

Figure 1 

### 1H NMR. spectrum of.



### • Page 9·

## • 

## ... ...

N



# .. }:

•



# ..... l

including measurement conditions Figure 2 'H NMR spectrum of and integrals

- Page 10­

# . . 

# .. 

# .. ..**~ --~~-~-.-** **~ !·~·~~~~~~=:E~=~~-~**  i



# ..

•



# . .. ..

.. D 

### I i 

# .. 

# ! i

:! 

## = 2 

# .. ..

including measurement 

### conditions Figure 3 'H NMR spectrum of and peak picking

- Page 11 ­

# .. 

# ...... . 

## i::i:= i

..............



# .•. "". f II ......**~**

# ....

# -"' G· .... ••



## =::=== I" ..



## ...........

...... 1 

### l:.... •**~** D .......... - 

### a



# ·



# ·**~** 

# - .. 

# I !

& 

# . · '"



## ...

....



# ..

...

ell



### • 

# ...

'H NMR spectrum of dimethylsulfoxide (solvent) Figure 4

- Page 12­APPENDIX I Assignment table and signature of principal scientIst

- Page 13­ )Determination of the IH NMR spectrum


### Int.erpretlltfon ofspectrum Signals observed in the blanc measurement include: the water peak at ca. 

### 3.3 ppm, the DMSO peak at 2.5 ppm andthe TMS peak at 0 ppm. These signals may be present in the spectrum of the compound, but do nol relate to the compound itself.
PartialLAssignment

### Table. based 

### on**jnter~etation** only Peak structure Chemical 

### shift 

## (Qpml Possible assignment 

# -_ .. "

# ..... 6.6 multiplet c 

### 4.8 multiplet Remarks: Spectrum In line with given structure.

Signature: Signature:
Date: 14-1**O~2004** Date:**14~10-2004**



### • Page 14· 

### ! -_./

### P-04-635 

## REPORT

StydyTltle 

## DETERMINATION OF THE IR ABSORPTION SPECTRUM OF

Stydv completjoo date 

### October 25, 2004 Test Facility

Laboratory Project IdentifICation

- Page 1 of 9 ­1. CONTENTS 

### 1. CONTENTS
...........................................................................................................................

### 2 2. STATEMENT OF GLP COMPLIANCE
..................................................................................

### 3 

### 3. QUALITYASSURANCE STATEMENT
.................................................................................4 

### 4. SUMMARy
.......................................................................................................................:...... 

### 5 5. INTRODUCTION
....................................................................................................................

### 6 

### 5.1. Preface
...........................................................................................................................6 5.2. Alms of the study............................................................................................................6 5.3. Guidelines
.......................................................................................................................6 5.4. Storage and retention of records and materials.............................................................7 

### 6. MATERIALS AND METHODS
...............................................................................................

### 7 6.1. Test substance ...............................................................................................................7 6.2. IR spectrometer..............................................................................................................

### 7 6.3. Data Acquisition and Processing ...................................................................................7 

### 6.4. Performance ofthe test ..................................................................................................7 6.5. List of protocol deviations............................................................................................... 

### 8 7. RESULTS
...............................................................................................................................

### 8 

### 8. CONCLUSION
........................................,.............................................................................. 

### 8 FIGURES 

### Figure 1 IR spectrum 01 ¥lth the wave numbers ofthe most significant absorption bands................................................................................9



### - Page 2­

### 2. 

### STA'rEMENT OF GLP COMPLIANCE
The study described in this report has been correctly reported and was conducted in compliance 

### with: The Organization for Economic Cooperation and Development (OECD) Good Laboratory Practice 

### GuldeHnes (1997). Which essentially 

### conform to: The United States Food and Drug Administration Good 

### Laboratory Practice Regulations. The United States Environmental Protection Agency Good Laboratory Practice Regulations. 

### The sponsor Is responsible for Good Laboratory Practice (GlP) compliance for aU 

### test substance Information unless determined by



### Study Director Section Head Analytical 

### & Phvsical 

### Chemistry

Date: ...

# DQo.~ 

# ...?J:
..,..**~.~** 

# ...... Date: .•

# f~:~ 

# ..**~.~.,.~~~** 

# .......**~** Page 3· 

# 77

### 3. QUAUTY ASSURANCE STATEMENT
This report was Inspected by the Quality Assurance Unit to oonfirm that the methods 

### and results accurately and completely reflect the 

### raw data. The dates of Quality Assurance Inspections are given below. During 

### the on-site process inspections prooedutes applicable to this type of study were Inspected. 

### TVpeof 

### Inspections Phase 'Section Start Inspeclon 

### End Inspection 

### Reporting date date(s) date(s) Protocol (Study) 03\AUG\04 03\AUG\04 03\AUG\04 

### On-site (Process) Analytical 

### & Physical 05\JUL\o4 1S\JUL\o4 19\JUL\o4 Chemistry On-site (Study) Exposure, 13\SEP\04 13\SEP\04 13\sEP\04 measurement Report (Study) 19\001"\04 19\OCT\04 19\OCT\04

Head ()f**9t..J~~!ty** Assurance

Date: •.

### l..b.~.aQ:':~ 

## .......

• Page 4­

### 4. SUMMARY The study procedure described in this repon Is based on the following guideline: Working Document of the 18th Meeting of competent Authorities. Conception to Harmonize Requirements for Spectral Data, to be submitted according to Directive 79/B31/EEC. The IR-absorption spectrum of s in agreement with the structure of the test 

### substance.

- Page**5~**

### 5. INTRODUCTION 5.1. Preface Sponsor Study Monitor Test Facility Study Director Study Plan Start 13 September 2004 Completion 13 September 2004 5.2. Alms ofthe study The purpose of

### the study was to obtain structural information of the test substance by measuring absorption wavelengths in the IR region. Band positions in infrared spectra are presented either 

### as wave numbers or wavelength$. The wave number (em'1) 

### is directly proportional to the energy of vibration. Wavelength Is reported in micrometers (pm). Wave numbers are reciprocally related to the wavelength as follows: cm-1 =_1_

### x104 JIm 

### Specific absorptions and absorption ranges are given In em ,1. 

### Band Intensities are expressed as transmittance (T). 

### which 

### is the ratio of the radiant power transmitted by 

### a sample to the radiant power incident on the sample. 5.3. Guidelines The study procedure described 

### i1 this report is based on the following guideline: Working Document of the 18th Meeting of competent Authorities. Conception to Hannonlze ReqUirements for Spectra' Data, to be submitted according to Directive 

### 79/831/EEC.

- Page 6·5.4. Storag.e and retention ofrecords and materials 

### Records and materials pertaining to the study including protocol. raw data.**speclmer.ts'~~9~.QJ _**  

### specimens requiring retrtgeratlon or freezing) and the flnal report are retained in the archives for a period of at least 10 

### years after finalization of the report. After this period, the sponsor 

### will be contacted to determine whether 

### raw data and specimens should be retumed to them, retained or destroyed on their behalf. Those specimens requiring refrigeration or freezing 

### will be retained by for as long 

### as the 

### quality of the specimens permits evaluation but no longer than three months after finalization of the report. NOTOX will retain a test substance sample until the expiry date, but no longer than 10 

### years after finalization ofthe report. After this period the sample will be 

### destroyed. 6. MATERIALS AND METHODS 

### 6.1. Test substance Identification Structure Molecular formula Molecular weight 

### CAS Number Description Clear colourless liquid Batch Purity 

### 99.985% Test substance storage In refrigerator in the dark Stability under storage conditions Stable expiry date 07 July 2005 

### The sponsor Is responsible for all test substance data unless determined 

### by 6.2. IR spectrometer 

### FTIR 8400-S spectrophotometer (Shimadzu Corporation, Kyoto, Japan) 

### 6.3. Data Acquisition and Processing Data acquisition and data processing was performed using Shimadzu IRsolution software (Shlmadzu Corporation, Kyoto, Japan) version 

### 1.10. 

### SA. Performance ofthe test 

### A 10 

### em stainless steel gas cell was used to record the IR spectrum ofthe test substance. After a successful performance check oftha FT-IR speetrometerwith a standard polystyrene sample, a background spectrum of the optical unit was reoorded. SUbsequently, a sample of the test substance was injected Into the gas cell and measured after 30 seconds. The IR-spectrum ofthe 

### test substance was recorded between 

### 4000 em" and 

### 400 em" at a resolution of 2 em,1 and at room tempereture (24°C).
.

• Page 7­ 

# ZI

### 6.5. List of protocol deviations A 10 em stainless steel gas cell was used to record the IR-spectrum of the test substance. Evaluation: the test 

### substance was 

### too volatile to be recorded using the Golden Gate Single 

### Reflection Diamond 

### ATR system. The study integrity was 

### not adversely affected by this deviation. 7. RESULTS Figure 1 shows the 

### IR spectrum of The spectral characteristics are summarized and assigned in Table 1. The spectrum was recorded at room temperature (24°C). 

### Tabla 1 AsSignments

Band maximum (cm-') Vibration Structural element 3000 C-H stretching 1400-1000 C-F stretching (multiple bands) 1436 C-H deformation 8. CONCLUSION The 

### IR-absorption spectrum 

### of is in 

### agreement with the proposed structure.



### - Page 8·

### FIGURES



# I 

# r

l

I 

## ! j

0

# ~i' Figure 1 

### IR spectrum of 

### with the wave numbers of the most significant absorption ban.....

- Page 9­

### P-04-635 

## REPORT

Study Title 

## STATEMENT ON THE OXIDIZING PROPERTIES OF

Study completion date 

### October 12.2004 Test facility

Laboratpry project Identification

• Page 1 of7 ­1. CONTENTS 

### 1. CONTENTS
................. ,.........................................................................................................2 2. STATEMENT OF GLP COMPLIANCE
.................................................................................. 

### 3 3. QUALITY ASSURANCE STATEMENT
.................................................................................

### 4 

### 4. SUMMARV
..................................................................................................,.......................... 5 

### 5. INTRODUCTION
...................................,...............................................................................

### 6 5.1. 

### Preface ............ ...............................................................................................................6 

### 5.2. Aims of 

### the study.................... ........................................................................................ 

### 6 5.3. 

### Guidelines
........................................................................................:............................. 6 5.4. 

### Storage and retention of records and materials............................................................. 6 6. MATERIALS AND METHODS....... ........................................................................................ 7 

### 8.1. 

### Test substance ............................................................................................................... 7 6.2. 

### Ust of protocol deviations.....................................................,......................................... 7 7. STATEMENT
.........................................................................................................................

### 7 

### 8. CONCLUSION
.......................................................................................................................

### 7

- Page 2 ­

### 2. STATEMENT OF GLP COMPLIANCE


### The study described in this report has been correcUy reported and was conducted In compliance 

### with: The Organization for Economic Cooperation and Development (OECD) Good Laboratory Practice Guidelines (1997).
. 

### Which essentially conform 

### to: The United States Food and Drug Administration Good Laboratory Practice Regulations. 

### The United States Environmental 

### Protection Agency 

### Good Laboratory Practice Regulations. The sponsor 

### is responsible for Good**Laborat9r'l.p!@.~~** (GLP) 

### compliance for 

### all test substance 

### information unless 

### determined by



### Study Olrector Section Head 

### Analytical 

### &Physical Chemistry

Date: ...

# Q~-J.o.b.e~ 

# ...l.1......

# 1..QQ~ ...... Date: ..

# o..cJ~.6: 

# .**.r:s.,..2:~~** 

# ...

- Page 3­ 

# c3. QUALITY 

### ASSURANCE STATEMENT
This report was Inspected 

### by the QualityAssurance Unit to confirm 

### thatthe methods 

### and results accurately and completely reflect the raw data. The dates of Quality Assurance Inspections are given below. 

### TypeD' Ph..

# e' Section Start End Reporting date 

### Inspections Inspection 

### Inspection date(s) date(s) 

### Protocol (Study) 03\AUG\04 03\AUG\04 03\AUG\04 Report 

### (Study) 11\OCT\04 11\OCn04 11\OCT\04

Head of

### QualityAssurance

Date: .

### ..l~

## .-:-.t9.**::-g~** 

### ....... .

- Page 4 ­..... SUMMARY 

### The procedure for the determination ofthe oxidiZing 

### properties is described in 

### the following guideline: 

### European Community (EC), 

### CommissIon directive 

### 2004n3/EC, 

### Part A, 

### Methods for the determination of physico-chemical properties, A.21: "Oxidizing properties (liquids)". EC Publication No. 1..152, April 2004. Examination ofthe molecular structure of 

### establishes beyond reasonable doubt that the substance Is Incapable of showing a positive result In the test described In the 

### EC 

### A.21 guideline. The substance does not 

### contain any group

### that might act as an oxidizing 

### agent. The oxygen atom that is preSent In the chemical is bonded to carbon, which Indicates 

### that the molecule is oxygen-deficient. In conclusion, has no 

### oxidizing properties.

- Page 5­6. INTRODUCllON 

### 5.1. Preface Sponsor Study Monitor Test Facility 

### Study Director 

### Study Plan 

### Start Completion 

### : October 

### 04. 2004 ; October 

### 04, 2004 5.2. Alms ofthe study 

### The purpose 

### of

### the study was 

### to evaluate 

### the oxidizing 

### properties ofthe test substance. 

### 5.3. Guidelines The procedure for the detennination of

### the oxidizing properties Is described in 

### the follOwing guideline: 

### European Community 

### (EC). Commission directive 2004fl3lEC, 

### Part 

### A, Methods forthe 

### determination ofphysico-chemical properties, 

### A21: "Oxidizing properties (liquids)", 

### EC Publication No. L152, April 2004. 

### 6.4. Storage and retention of records and materials Records and materials pertaining 

### to the study Including protocol, 

### raw data, specimens (except 

### specimens 

### requiring refrigeration orfreezing) and 

### the flnal report are 

### retaIned In the archives for 

### a period of

### at least 

### 10 years after

### finalization of

### the report 

### After this period, 

### the sponsor will be contacted 

### to determine 

### whether 

### raw data and specimens should be 

### retumed to 

### them, retained or destroyed on their behalf. Those specimens 

### requiring refrigeration 

### orfreezing will be retained 

### by 

# ror as long as 

### the quality of the 

### specimens permits evaluation 

### but no longer than three months after 

### finalization of

### the report. will 

### retain a test substance sample 

### until the expiry date, 

### but no longer than 

### 10 years 

### after ffnalization ofthe report. After this 

### period the sample will 

### bedestroyed.

- Page 6­

### 6. MATERIALS AND METHODS 

### 6.1. Teat aubstance Identification Structure Molecular formula Molecular

### weight CAS Number Description Clear colourless liquid Batch Purity 99.985% Test substance storage In refrigerator In the dark Stability under storage conditions 

### Stable 

### Expiry date 

### 07 July 2005 The sponsor 

### is responsible for 

### all test 

### substance data unless determined 

### by 6.2. Ust 

### of protocol deviations There were no deviations from the protocol. 

### 7. STATEMENT 

### According to the 

### EC A.21 guideline, a liquid substance 

### is to be 

### considered as an oxidizer when: a) a 1: 1 mixture, by mass, ofthe substance and cellulose spontaneously Ignites; or b) a 1:1 mixture, by mass, ofthe substance and cellulose exhibits a mean pressure rise time less than or equal to the mean pressure rise time ofa 1:1 mixture. by mass, of 65% (w/w) aqueous nitric acid and cellulose. examination ofthe molecular structure of establishes beyond reasonable doubt that the substance Is 

### Incapable of

### showing a positive 

### resun In the test described in the EC 

### A,21 gukfeline. The substance 

### does not contain 

### any group 

### that might act as an 

### oxidizing agent. The oxygen atom that 

### Is present 'n the chemical Is bonded to carbon, 

### which Indicates that the molecule Is oxygen-deflclent. 

### 8. CONCLUSION 

### has no oxidizing properties.

- Page 7­

### P-04-635 

## REPORT

Study Title 

## STATEMENT ON THE PYROPHORIC PROPERTIES 

## OF

Study completion date



### October06,2004 Teft Facilitv

Laboratory erqject Identification

- Page 1 of 7 ­

### 1. CONTENTS 1. 

### CONTENTS
.... ".....................................................................................................................2 

### 2. STATEMENT OF GLP 

### COMPLIANCE
.................................................................................. 3 3. QUALITYASSURANCE STATEMENT
.................................................................................

### 4 4. SUMMARy
....................................................,....,................................................................... 5 

### 5. INTRODUCTION .. ................................................................................................................. 

### 6 

### 5.1. 

### Preface
........................................................................................................................... 6 5.2. Alms ofthe 

### study... ......................................................................................................... 

### 6 5.S. Guidelines
.........................................................................................." .......................... 

### 6 5.4. 

### Storage and retention of records and materials............................................................. 6 6. MATERIALS AND 

### METHODS
............................................................................................... 7 6.1. 

### Test substance ...............................................................................................................7 

### 8.2. list of protocol deviations..........................,................ .................................................... 

### 7 

### 7. STATEMENT
.........................................................................................................................

### 7 8. CONCLUSION
.......................................................................................................................

### 7



### - Page 2­

### 2. STATEMENT OF GLP COMPLIANCE
The study descrfbed in this report has been correctly reported and was conducted in compliance with: The Organization for Economic Cooperation and Development (DECO) Good Laboratory Practice Guidelines 

### (1997). Which essentially conform 

### to: The United States Food and Drug Administration Good Laboratory Practice Regulations. The United States Environmental Protection Agency Good Laboratory Practice Regulations. The sponsor is responsible for Good Laboratory Practice (GLP) compliance for all test substance information unless detennlned by

Study Director Section Head Analytical & Physical Chemistry



### Date: ...

# Q'~Qb.~.~ 

# ..**.Q.~** •..

# ~Q4 ....... .

- Page 3­

### 3. QUALITY 

### ASSURANCE STATEMENT
This reportwas Inspected by 

### the ::lualilyAssurance Unit to confirm that the methods aoo results accurately and completely reflect the raw data. The dates ofQuality Assurance inspections are given below.


### Type of 

### Inspections Protocol (Study) Report (Study) 

### Phase I 

### Section 

### Start 

### In.paction date(s) 03\AUG\04 05\OCT\04 

### End Inspection 

### date(.) 03\AUG\04 05\OCT\04 

### Reporting date
03\AUG\04 05\OCT\04

Head ofQuality Assurance

Date: ....

## '3..::--'~.::9.h 

# ....**~** Page 4 ­

### 4. 

### SUMMARY The procedure for the determination ofthe pyrophoric properties is descrlled In the 

### following guideline: European Economic Community (EEC), EEC directive 

### 92169 EEC, Part 

### A, Methods for the determination ofphysico-chemical properties. A. 

### 13: 

### "Pyrophorlc properties ofsolids and liquids", EEC Publication No. L383. 

### December 1992. Based on 

### its molecular structure and on experience in hendling. itwas concluded that s not pyrophoric.

- Page 5­ /-. ,'/ L!

!

### S. INTRODUCTION 1.1. Preface Sponsor Study Monitor Test Facility Study Director Study Plan Start Completion 01 October 2004 01 October 2004 6.2. Alms ofthe 8tudy The purpose ofthe study was 

### to evaluate 

### the pyrophoric properties ofthe test substance. 

### 5.3. Guidelines The procedure for the determination ofthe pyrophoric properties is described in 

### the following guideline: European Economic Community (EEC). EEC directfve 92/69 EEC. Part 

### A. Methods for the determination ofphysico-dlamlcal properties. A.13: 

### "Pyrophorlc properties ofsolids and liquids", 

### EEC Publication No. L3B3, December 1992. 5A. 

### Storage and retention of

# NCO" and materials 

### Records and materials pertaining to the study including protocol, raw data. specimens (except specimens requiring refrigeration or freezing) and the final report are retained in the archives for a period ofat least 

### 10 years after

### finalization ofthe report. After this period. the sponsor 

### will be contacted 

### to determine whether 

### raw data and specimens should be 

### returned to them, retained ordestroyed on their behalf. Those 

### specimens requiring refrigeration or 

### freezing 

### will be retained by for 

### as long as the quality 

### of the specimens permits evaluation but 

### no longer than three months after finalization of the report. will 

### retain a test substance sample until the expiry date, but no longer than 10 years after 

### finalization ofthe 

### report. After this period the sample will be 

### destroyed.**~** 

### Pages**~**

### 8. MATERIALS AND METHODS 

### 8.1. Teataubstance Identification Structure Molecular formula 

### Molecular weight CAS Number 

### Description Clear colour1ess liquid Batch 

### Purity 99.985% 

### Test substance 

### storage In remgerator 

### in the dark Stability under storage conditions Stable Expiry 

### date 07 July 2005 

### The sponsor Is responsible 

### for all test 

### substance data unless determined by 

### 6.2. 

### LIat ofprotocol 

### deviations 

### There were no deviations from the protocol. 7. STATEMENT 

### The molecular structure of does not contain any chemical group that might 

### lead to 

### spontaneous Ignition a srlon time after comlno Into contact with air. Furthermore, 

### experience In handling during other shows that the 

## test substance does not ignHe 

### spontaneously after coming in contact 

### with air at room temperature (circa 2O"C). 8. CONCLUSION 

### Is not pyrophoric.

-Page7­ 

## ,I, , I

### P-04-635 

## REPORT

Study TWe 

## DETERMINATION OF THE SURFACE TENSION 

## OFAN 

## AQUEOUS SOLUTION OF

Study completion date

October 27, 2004 

### Test Facility

Laboratory Prolect Identification

• Page 1 of 12 ­

### 1. CONTENTS 1. CONTENTS
........................................................................................................................... 2 2. STATEMENT OF GLP COMPLIANCE
.................................................................................. 3 

### 3. QUALITY 

### ASSURANCE STATEMENT
.................................................................................

### 4 4. SUMMARy
............................................................................................................................. 5 5. INTROOUCTION
...................................,............................................................................... 6 5.1. Preface
... :....................................................................................................,.................. 6 5.2. Alms of the stucly.........................,.................................................................................. 6 

### 5.3. Guidelines
...................................................................................................................... 

### 6 5.4. Storage and retention of records and materials.............................................................

### 6 

### 6. MATERIALS AND METHODS
.....................................................,......................................... 

### 7 6.1. Test substance............................................................................................................... 7 

### 6.2. Test system and rationale .............................................................................................. 

### 7 6.3. Validation of 

### the test procedure .....................................................................................

### 7 

### 6.4. Perfonnance ofthe test....... ,..........................................................................................

### 7 6.4.1. Preparations 

### before the test ................................................................................ 

### 7 6.4.2. Calibration of

### the tensiometer.............................................................................. 

### 8 

### 6.4.3. Preparation ofthe test solution ............................................................................ 

### 8 6.4.4. Test procedure.....................................................................................................

### 8 6.5. Interpretation .................................................................................................................. 

### 9 6.6. List of

### protocol deviations............................................................................................... 

### 9 7. RESULTS
............................................................................................................................ 10 8. CONCLUSION
..................................................................................................................... 11 APPENDICES APPENDIX I Determination of

### the calibration factor 

### <llb.......................................................... 12 TABLES Table 1 

### Harkins and Jordan 

### correction ............................................................................. 9 Table 

### 2 Surface tension of an 

### aqueous solution of (Test 1)
........ 

### 10 Table 3 Surface tension of an aqueous solution of (Test 2)
........ 

### 10 Table 4 Surface tension ofwater 

### at 20.DoC (Test 1)
...................................................... 

### 12 Table 5 Surface tension ofwater at 

### 20.0"e (Test 

### 2) ...................................................... 12

- Page 2­2. STATEMENT OF OLP COMPLIANCE
The study described in this report has been correctly reported and was conducted in compliance with: The 

### Organization for 

### Economic Cooperation and Development (OECD) Good laboratory Practice 

### Guidelines (1997).
. Which essentially conform to: The United States Food and Drug Administration Good Laboratory Practice Regulations. The United States Environmental Protection Agency Good 

### Laboratory Practice Regulations. The sponsor is responsible for Good laboratory 

### Practice (GlP) compliance for all test substance Infonnatlon unless determined by

Study Director Section Head Analytical 

### & Physical Chemistry

- Page 3­3. QUALITY ASSURANCE STATEMENT


### This report was inspected 

### by the )uality Assurance Unit to 

### confirm that the methods and results accurately and completely reflect the 

### raw data. The dates of Quality Assurance Inspections are given below. During the on-site process Inspections procedures applicable to 

### this type of study were inspected. 

### Type of Phase 

### I Section Start End ReportIng date inspections Inspection Inspection date(s) date(s) Protocol 

### (Study) 03\AUG\04 03\AUG\04 03\AUG\04 

### On-site (Process) Analytical and 05\JUL\04 15\JUL\04 19\JUL\04 

### On-site (Study) Physical Chemistry 

### Report (Study) 

### 26\OCTI04 26\OCT\04 26\OCn04

Head of Quality Assurance

- Page"'­

### 4. SUMMARY 

### The determination ofthe surface tension of an 

### aqueous solution of ft'as performed in accordance 

### with the EEC-Directlve 92169 

### EEC, 

### A.S "Surface tension" (1992) and OECD guideline no. 

### 115: "Surface tension of aqueous solutions" 

### (1995). Two tests were performed in which the surface tension 

### of an 

### aqueous solution, prepared at a 90% saturated concentration, was determined. Especially In Test 2 utmost care 

### was taken 

### to reduce evaporation 

### ofthe 

### highly volatile 

### test substance 

### to a minimum. GC analysis showed thatthe resultant test solution contained approximately 560 mglL test 

### substance after the 

### last measurement. Surface tension 

### result of

### Test 1: 71 mN/m (at 20.0°C). 

### Surface tension result ofTest 2: 72 mN/m (at 21.0-21.5°C). 

### According 

## to the criteria as outlined in the EEC guideline, 

### is not surface active.

.Page5­ 

# I

### 5. INTRODUCnON 

### 5.1. Preface Sponsor Study Monitor 

### Test F acUity
Study Director 

### Study Plan Start Completion : : 31 August 2004

20 October 2004 

### 5.2. Alma of

### the 8tudy 

### The purpose ofthe study was to 

### evaluate the surface tens/on ofthe test substance in an 

### aqueous solution at 20.0 :t 

### 0.5°C, by 

### means of a ring 

### tensiometer. 

### 5.3. Guidelines The study procedure described in this 

### report is based on the following guidelines: European Economic Community (EEC), EEC-Directive 92/69 

### EEe, Part A, 

### Methods for 

### the determination of

### pnysico-.chemical properties, A.5 "Surface tension", EEC Publication No. L383, December 

### 1992. 

### Organization for 

### Economic Co-operation and 

### Development (OECD), OECD guidelines for 

### Testing of

### Chemicals, guideline no. 

### 115: "Surface 

### tension of aqueous 

### solutions", July 

### 27,1995. 5.4. Storage and retention of recorda and 

### materials Records and matenals pertaining to the study 

### Including protocol, 

### raw data, specimens (except specimens requiring refrigeration or

### freezing) and the 

### final report are retained';n the archives for a period ofat least 10 

### years after

### finalization of the "report After this 

### period. the 

### sponsor will be 

### contacted 10 determine whether 

### raw data and 

### speCimens should 

### be returned 

### to them, retained ordestroyed on their behalf. 

### Those specimens requiring refrigeration 

### or freezing 

### will be 

### retained by for as long as the quality 

### of the 

### specimens permits evaluation but 

### no longer than three 

### months after finalization 

### ofthe report 

### will retain a test substance sample until the expiry date, but no longer 

### than 10 years after finalization ofthe 

### report. After this period the sample 

### will be 

### destroyed. .

-Page6. 

# /6, MATERIALS AND METHODS 

### 6.1. Teshubstance Identification Structure Molecular formula Molecular weight CAS Number Description Clear colourless liquid Batch Purity 99.985% 

### Test substance storage In 

### refrigerator in the dark 

### Stability under 

### storage conditions Stable Expiry date 07 

### July 2005 

### The sponsor is 

### responsible for all 

### test substance data unless determined 

### by 

### 8.2. Testsystem 

### and ntlonale Test system Tensiometer (model 

### K6; KrOss GmbH. Hamburg, Germany). The measuring body Is 

### a platinum-Iridium ring 

### wfth a wire 

### radius of0.185 

### mm and a ring radius of 9.545 

### mm. Water Milli-Q water Tap water purffied by reversed osmosis and subsequently passed over activated carbon and ionexchange cartridges; Mlilipore Corp., Bedford, 

### MA, USA Rationale Recognized by the International guidelines (EEC, OECD) as recommended test system. 

### 6.3. 

### ValIdation ofthe 

### teat procedure The test procedure as outlined in this report is 

### validated periodically. using n-hexane. The results are in accordance with the criteria 

### of OECD Guideline No. 115 

### "Surface tension of 

### aqueous solutions", July 

### 27. 

### 1995. 8.4. Perfonnance ofthe

### teat 

### '.4.1. PreparatIons before the

### test All 

### glassware used was washed with 

### chromo-sulphuric acid. The measurement vessel was 

### washed with hot chromo-sulphuric acid and subsequently 

### with syrupy phosphoric acid. Thereafter all glassware was thoroughly rinsed in tap-water and finally washed with water. The measuring body 

### (ring) was rinsed thoroughly in 

### water, briefly immersed in chromo-sulphuric acid. washed In water and finally briefly heated above a flame.

-Page7­

/ 

# / U

### 6.4.2. Calibration ofthe tensiometer 

### The tensiometer was calibrated using water with established surface tension. The calibration factor 

### ct>b. by which all the Instrument readings are multiplied, was determined in accordance with the equation: 

### ct>b = 

## a o 

### I 

## ag eTa 

### = the surface tension ofwater at the testtemperature cited in the literature (Gebrauchsanwelsung fOr Tensiometer 8451. KrOss GmbH, Hamburg, Germany). Og 

# = measured surface tension ofthe water at the test temperature. 

### 6.4.3. Preparation ofthe test 

### solution First test: A mixture of test substance in water was prepared by stirring 

### 105.3 mg test substance with 100 mlwater for 0.5 hour1 In a 

### closed Erlenmeyer flask. A moderate stirring rate was chosen. The temperature in the test room was between 

### 19.9 and 20.3°C during the stirring. To remove all the undissolved test substance, the mixture was centrifuged for 

### 5 minutes at 3500 g and 20DC. In accordance with the guidelines. a test solution at 90% of the maximum concentration was prepared. Hereto, 2.0 mL water was brought Into 

### a 20.0 mL volumetric flask and the flask was filled 

### up to the mark with the supernatant. The resultant clear solution was used as the test solution. Second test: Because ofthe high volatility of

### the test substance it Is possible that during the different steps In 

### the first 

### test. test 

### substance had evaporated from the aqueous solution. Therefore a 

### second test was performed in which utmost care was taken to reduce evaporation oftest substance to a minimum. 

### An amount 135.7 mg test sUbstance was 

### stirred 

### with 20 mlwater 

### in a 20 mL 

### glass vessel that 

### was tightly sealed with a**septum~rtmpcap.** 

### The temperature 

### in the test room was between 19.7 and 20.SoC during the 24·hour stirring period. After the phases had separated (without centrifugation), the upper layer was taken for the preparation ofthe 90% saturated test solution (as 

### described in Test 1). 

### 6.4.4. Test procedure The clean measurement vessel was filled with the test solution. The measurement vessel was placed In a thermostated water bath (20.0 ± 

### a.5°C) on the mobile sample table. The temperature of the test 

### solution was checked prior 

### to the measurements. The table was raised until 

### the ring was immersed below the surface of the solution. SubsequenUy. the table 

### was lowered until the ring was making contact with the liquid surface. After some additional lowering ofthe table. the ring exerted a torque on the force measuring system. This torque was compensated for by bJmlng the large knob on the force measuring system cfockwise. lowering ofthe table and subsequent 

### compensatfon ofthe resulting torque were continued In small increments until the lamina broke. This is when the upward force on the ring 

### completely overcame the surface tension force and the rtng was torn 

### away from the surface. The surface tension was then recorded. Measurements were repeated until aconstant 

### surface tension value 

### was reached. 

### The time pa$$ed 

### since the solution was transferred to the measurement vessel was recorded for each measurement

A longer stlmng period of 2 hours resulted In complete evaporatlor'l Of the testsubstance (visual observation) when using an Erlenmeyer flask.



### - Page 8­

/.'l '': / ".,',/ ';Additionally. It was investigated whether the test solution ofTest 2 stili contained dJssolved test substance during the measurements. For this, a sample ofthe test solution was taken 

### Immediately after the last measurement 

### and injected**(afte.rJ:M~lna dlru~**  

### by afactor of 

### 100 with MIIII..Q water) into the 

### GC system as described ir (development 

### and validation ofan analytical method 

### for the analysis of ) In MIIII-Q water). The 

### test substance concentration 

### In the test solution was estimated from the measured 

### GC responses. 

### 8.5. Interpretation 

### The surface tension 

### is given 

### in mN/m 

### (SI sub-unit), In order to calculate the surface tenSion, the value read on the apparatus was multiplied 

### by the calibration factor 

### cf>b. This yielded a value that was onry approximate. and required additional correction. The additional correction was made using 

### a table compiled on the basis of HarkinsJordan correctIon (W.O. Harkins, H.F. Jordan, J. Amer. Chern. 

### Soc. 

### g, 1751 (1930»; see Table 1. Tab'. 

### 1 Harkins and Jordan correction Experimental Corrected Experimental Corrected value 

### value (water value value 

### (water [mN/m] calibration) [mN/m) calibration) [mN/m] (mN/mJ 

### 20 18.1 

### 50 48.6 22 20.1 52 50.7 24 22.1 

### 54 52.8 26 24.1 56 

### 54.9 28 26.1 58 57.0 30 28.1 

### 60 59.1 32 30.1 62 

### 61.3 34 32.1 64 

### 63.4 36 34.1 

### 66 

### 65.5 38 36.1 

### 68 67.7 40 38.2 70 69.9 42 40.3 72 72.0 

### 44 42.3 74 

# - 46 44.4 76 

# - 48 46.5 76 

# - According to the criteria as out.ned In the EEC Directive, substances showing 

### a surface tension lower than 

### 60 mN/m under the conditions ofthis method, should be regarded as being surface 

### active materials. 8.8. List ofprotocol devlatlona 

### The temperature of

### the test solution of Test 2 during the measurement was 21.0-21.5°C instead of In the range of 

### 20.0 :t O.5°C. Because the measurements for the test solution were started without 

### a previous equilibration period 

### (in order to reduce 

### evaporation to 

### a minimum), the temperature ofthe test solution was not

### yet In equilibrium 

### with the water bath used. Because the difference Is not slgnlficanl. the study Integritywas not adversely affected by the deviation.

-Page9­ 

# I

### 7. RESULTS Determination of the calibration factor ¢lb 

### is shown in Appendix I. Tables 2 and 3 show the individual measurements and the corrected 

### surface tensions for the test 

### solutions prepared In Test 1 and 2, respectively. Temperature ofthe 

## test solution In Test 1: 20.0°C. Temperature of the 

### test solution in Test 2: 21.Q..21.5°C. GC 

### analysis showed 

### that the lest 

### solution of

### Test 2 

### contained approximately 560 mglL test 

### substance after the last measurement. This demonstrated that unless the high volatility of the test substance, the 

### aqueous test solution sti'l contained a large amount 

### oftest substance during the measurements. Table 2 

### Surface tension ofan aqueous solution of Test 1).



### Measurement Time expired Surface tension [mN/mJ {minutes) measured 

### mean not corrected 

### mean corrected for



### calibration mean 

### corrected 

### using Harkins & 

### Jordan 1 2 

### 3 4 

### 5 48 

### 49 50 51 

### 52 70.8 70.7 

### 71.0 71.1 71.0 70.9 71.6

.. 

### 71.2

TIme passed since the test 801ullon was transfelTed to the measurement vessel. The test solution was transferred to the measumnenlvessel 2 mi'lutes after preparation. Table 3 

### Surface tension ofan aqueous solution of (Test 2).

Measurement TIme expired Surface tension ImN/ml [minutes] measured 

### mean not 

### mean mean 

### correecorrected 

### corrected 

### for ted using calibration Harkins & 

### Jordan 

### 1 1 

### 71.1 

### 2 2 71.1 

### 3 

### 3 71.0 71.1 

### 72.3 72.3 4 

### 4 71.1 

### 5 5 71.1
f Time**pas~d** since the lesttolutlon was transferred to the measurement vessel. The test SOlution was tran....rred to the measurement YeSSellmmedlalely after preparation.



### - Page 10­ 

# I

### 8, 

### CONCLUSlON Surface tension test result ofTest 

### 1: 71 mN/m (20.0°C). Surface tension test result of Test 2: 72 mN/m (21.0-21 

### .SOC). According 

## to the criteria as outlined in the EEC guideline. s not surface 

### active.

-Page11­ 

# /

### APPENDIX I Detennlnatlonofthe 

### calibratIon factor 

### CPb Table 4 Surface tension atwater at

### 20.0°C (Test 1)

Measurement Time expired 1 Surface tension [mN/mJ [minutes] measured mean Og 

### 1 30 71.9 

### 2 31 

### 71.8 

### 3 32 71.8 71.9 4 

### 33 71.8 5 34 72.0 11me pissedsince the waterwas transferred to the measurement vessel. Determination ofthe calibration factor ¢b

### crest 1) 001 

# = 72.59 mN/m (KrOss GmbH, at

### 20.0 °C) ¢lb 

### = 0 0 

### I 

### ag 

### = 

### 1.010
TableS Surface tension otwater at 20.0°C (Test 2)

Measurement 

### Time explred 1**Surfacetens~n** [mN/m 

### [minutes] measured mean 

### ag 

### 1 

### 2 3 4 

### 5 6 20 

### 21 

### 22 23 

### 24 25 70.8 71.4 71.3 71.4 71.4 

### 71.5 71.4

TIme pasted since the waterwas transferred to !he measurementveuel. 2 Several measurements _"' performed until a state ofequilibrium was readied. The mean was calculated from measurements 2 •6. 

### Determination 

### ofthe calibration factor ¢bITest 

### 2) 0 0 

# = 72.59 mN/m (KrOss GmbH. at 

### 20.0 DC)

- Page 12­

### P-04-635 

## REPORT

StuwTitle 

## DETERMINATION OF THE UV-VIS ABSORPTION SPECTRA 

## OF

Study completion date October 18, 2004 

### Test Faciljty

Laboratorv Project Identification

- Page 1 of 9 ­

### 1. CONTENTS 1. CONTENTS
....................,......................................................................................................2 2. STATEMENT OF GLP COMPLIANCE
................" .............. ,................................................. 3 3. QUALITY ASSURANCE STATEMENT
................................................................................. 4 4. 

### SUMMARy
.............................................................................................................................5 5. INTRODUCTION
.. " ..................,............................................................................................6 

### 5.1. Preface
...........................................................................................................................6 5.2. Aims of the study.............. ,.............................................................................................6 

### 5.3. Guideftnes
............................,...... ,..,.... ,.......,... , ,.............................................................

### 6 5.4. Storage and retention of records and materials ............................................................. 6 6.. MATERIALS AND METHODS
............................................................................................... 7 

### 6.1. Test substance...........................................................,................................................... 7 6.2. Reagents ........................................................................................................................7 

### 6.3. Test system ....................................................................................................................

### 7 6.4. Calibration ofthe

### test system ......................................................................................... 7 6.5. Perfonnance ofthe test...............................,.................................................................. 7 6.5.1. Preparation ofthe test solutions .......................................................................... 7 6.5.2. Test proeedure ..................................................................................................... 8 6.6. Interpretation .................................................................................................................. 8 6.7. List of

### protocol deviatJons............................................................................................... 8 7. RESULTS
.........................,.................................................................................................... 8


### FIGURES Figure 1**UV~Vis** 

### spectrum ofthe empty cuvette holder ..................................................... 9 Figure 2 UV-VIS spectrum of undiluted test substance ...................................................... 9**-Page2~** 

# II/

### 2. STATEMENT OF GLP COMPLIANCE
The study described in this report has been correctly reported and was conducted in compliance with: The Organization for E:conomlc Cooperation and Development (DECO) Good Laboratory Practice Guidelines (1997). 

### Which eBsentialy 

### conform to: The United States Food and Drug Administration Good Laboratory Practice Regulations. 

### The United States 

### Environmental Protection Agency Good Laboratory Practice Regulations. The sponsor is responsible for Good Laboratory Practice (GLP) compliance for all lest substance 

### information unless determined 

### by

Study Director 

### Section Head 

### Analytical & 

### Physical ChemIstry

Date: .....

# Q~l9..6~r.. 

# ....

# ,.a.,..**~~!1** ...... .

- Page 3­



# / I)3. QUALITY ASSURANCE STATEMENT
This report was Inspected by the :)uality Assurance Unit to confirm that the methods and results accurately and completely reflect 

### the 

### raw data. 

### Tne dates of 

### Quality Assurance inspections are given below. 

### During the on-site process Inspections procedures applicable 

### to this type 

### of study were inspected.
Type of Phase 

### I Section 

### Start End Reporting date Inspections Inepec1lon Inspection date(a) date(s) Protocol (Study) 03\AUG\o4 03\AUG\04 03\AUG\o4 On-sfte (Process) Analytical and 05\JUl'04 15\JUl\04 19\JUl\04 Physical Chemistry Report (Study) 1S\OCT\04 15\OCT\04 15\OCT\04

Head of Quality Assurance



### Date:

# .9.i'~'~"!"I"~~

• Page 4 • 

# /**/~**

### 4. SUMMARY The 

### determination ofthe UV-Vls absorption 

### spectra of NaS 

### based on OECD 

### guideline no. 101: 

### lOW-Vis absorption spectra" (1981). 

### UV-Vis absorption spectra of in methanol at different concentrations (1.45, 10.3 and 100.2 giL) 

### were recorded betv.leen 900 

### nm and 210 

### nm. None ofthe spectra showed any test substance response. An UV-Vis absorption spectrum of undiluted MIS 

### recorded between 900 

### nm and 210 nm. Some 

### response was observed 

### around 210 

### nm without showing a maximum. 

### The Intercept with the y-axis (Absorbance) was < 

### 0.5 units. Temperature 

### of measurement was 25.0 :t a.soc.

- Page 5­ 

## ' , I I C/ ,. !5. INTRODUCTION 5.1. Preface Sponsor
SbJdy Monitor Test Facility 

### Study Director SbJdy Plan Start 

### 31 August 

### 2004 Completion 

### 31 August 

### 2004 5.2. Alma 

### ofthe study The purpose ofthe study 

### was to have some Indication ofthe wavelengths, In the Ultraviolet (UV)NIsibie 

### (VIs) region. atwhich the test substance absorbs radiation. The absorption ofa 

### test substance 

### Is due to 

### its particular chemical form. 

### It is often 

### the case that different forms are present, depending on whether the medium is neutral, acidic oralkaline. Consequently, UV-V1s absorption spectra under neutral and (if possible) under acidic and alkaline conditions are recorded, using a spectrophotometer. Each absorbance maximum is characterized by the wavelength, the (molar) absorption coeffICient and 

### (if possible) the band width. 5.3. Quldellnea The sbJdy procedure described In this report is based on the 

### following guideline: Organization for Economic Co-operatlon 

### and Development 

### (OECD), OECD guideline for testing of chemicals no. 

### 101: "UV-V1s Absorption Spectra", Adopted 

### May 12, 1981 5.4. Storage and retention 

### of 

### records and materials

. Records and materials pertaIning to the study Including protocol, raw data, specimens (except

speelmens requiring refrigeration orfreezing) and the final report are retaIned In the archives for a 

### period 

### of at least 10 

### years after finalization ofthe report After this 

### period. the sponsorwi. be contacted

### to determine whether

### raw data and speCimens should be retumed to them, retained or destroyed on their behalf. Those specimens requiring refrtgeratlon or freezing will be retained by .for as long as the quality ofthe specimens permits evaluation but no longer than three months afterfinalization ofthe report. Nill retaIn a test substance sample until the expiry date, but no longerthan 10 years after finalization ofthe report. After this period the sample will 

### be destroyed.

-PageB­

### I. MATERIALS AND METHODS 

### 8.1. Testsubetance Identification Structure Molecularfonnula Molecularweight CAS Number Description Clear colourless liquid Batch 

### Purity 99.965% 

### Test substance storage In refrigerator In the dark Stability under storage conditions Stable Expiry date 07 July 2005 

### The sponsor is responsible for all 

### test substance data unless detennined by 

### NOTOX. 8.2. Reagents 

### Methanol HPLC-grade, 

### 8.3. Testsystem 

### . Asingle-beam spectrophotometer (model Varian Cary 50 probe: 

### Varian Nederland B.V.,

Houten, The Netheriands), a 1.00 an quartz cuvette and a water bath (model MP-19, Julabo 

### Labortechnik GmbH, Seelbach, Germany). SA. Calibration ofthe

### test syetem The 

### instrument Is vaHdated periodically 

### using potassium dichromate solutions (for absorbance accuracy) and a holmium perchlorate solution (forwavelength accuracy). The results are 

### in accordance with the criteria 

### of OECO guideline no. 

### 101: "UVNis 

### absorption 

### spectra" (1981) (absorbance accuracy) and the Netherlands Pharmacopoeia, ninth edition, Staatsuitgeverij. 's-Gravenhage 1983, V.6.19-2 (wavelength accuracy). 8.5. Perfonnance of

### the test 

### 8.5.1. Preparation ofthe

### test solutions The 

### solubility of in 

### weter, the preferred solvent, was < 1 giL 

### and less than In 

### methanol. Therefore methanol was 

### chosen as solvent Test substance solutions were prepared 

### by dissolving 72.7 mg., 515.0 mg. 5.010 9 of test substance In 50.0 mL methanol. Because of

### the high**volatlli~** 

### ofthe 

### test substance, each volumetric flasks was first filled with a certain amount of methanol, then 

### the weighed amount of test substance was added and finally, the flask was filled up 

### to the mark with methanol. The solutions were scanned as soon as 

### possible after preparation. Because the UVNIs spectra ofthe lest substance solutions In methanol did 

### not show any test substance response, an WNis spectrum of undiluted test substance was also recorded.

- Page 7­

### 6.5.2. Test procedure The cuvette was rinsed thoroughly and filled with the blank solution (e.g. methanol). The cuvette was placed In the cell holder. A background-correctlon scan was made from 

### 900 nm to 210 nm. After the background-correctlon scan, the blank solution was scanned. The blank scan was recorded. aftersubtraction of the background. SubsequenUy. the cuvette Was emptied. rinsed thoroughly and filled 

### with the test substance solution and the scanning was repeated. The scan of 

### the test solution was recorded, after subtraction of the background. The scan speed was 

### 300 nm/minute. The temperature of 

### the cuvette holder compartment was controlled at 25.0 ± 

### O.soC using the water bath. The temperature of

### the test solution 

## was considered to be 

### in equilibrium with the temperature ofthe water bath 

## used. For the spectrum of the undiluted test substance, an empty cuvette holder was used as backgroundlblank. 

### 6.6. 

### Interpretatron Wavelengths were expressed In nm (= 10-9 m). 

### Because the recorded UV-Yis spectra did not show an absorption maximum or signifIcant absorbanoe. no (molar) absorption coefficients or band widths were calculated for ASAHIKLlN AE-3000. 

### 6.7. 

### List of

### protocol deviations 1. The UVNls spectra of the test substance solutions In 

### methanol. at different concentrations, did not show any test substance response. Therefore, no acidic or alkaline test substance solutions were tested. Additionally an UYNIs spectrum of undiluted test substance was recorded. 

### An empty cuvette holderwas used as backgroundlblank. 2. In order to reduce the loss of test substance by evaporation, the spectra of the 'est substance (solutions) were recorded as soon as possible after preparation and were not pre-equilibrated In a water bath of 25.0 :oj: 

### a.soc. The study Integrity was not adversely affected by

### the deviations. 7. RESULTS None of the UY·Vls spectra of In methanol, recorded at different concentrations (1.45. 10.3 and 100.2 gil) showed any test substance response. -rhe UVNis spectra of undYuted and the 

### reference are shown in Figures 1 and 2. Some response 

### was observed around 210 nm without showing a maximum The Intereept with the y-axis (Absorbance) was 

### < 0.5 units. • Temperature of measurement was 25.0::t O.SOC.

- Page 8­
J 

# 11

### FIGURES



### Figura 1

Figure2 1,5 1,0 0,5**~04------------------------------------------** 

### 400 600 

### 800 Wavelength (nm)**W~VJS** 

### spectrum 

### of the empty cuvette holder Blank solution: empty cuvette holder Scanspeed: 300 

### nm/minute 

### 1,5 1,0 0,5 

### 0,0 400 800 800 Wavelength (nm) 

### W-VJs spectrum of undiluted test substance Blanlc empty cuvette holder Scanspeed: 300 nmlmlnute

• Page 9­ 

# 11Z

### P-04-635 

## REPORT

SbJdyTItie 

## DETERMINATION OF THE VAPOUR PRESSURE OF BY THE STATIC METHOD

Study completion date

November24. 2004 

### Test Facility

Laboratory prolect ldentlficat/gn

- Page 1 of11 ­



# //1'

### 1. CONTENTS 1. CONTENTS
...................................................................._ ...................................................... 2 2. STATEMENT OF GLP COMPLIANCE
............_, .................................................................... 3 

### 3. QUALITYASSURANCE STATEMENT
............,....................................................................

### 4 4. SUMMARy
.........................:...................................................................................................

### 5 5. INTRODUCTJON
...................................................................................................................6 

### 5.1. Preface................................................................................................:.......................... 6 

### 5.2. Alms 

### ofthe 

### study.... :.......................................................................................................6 5.3. Guidelines
......................................................................................................................6 5.4. Storage and retention ofrecords and materials ............................................................. 7 

# e.. MATERIALS 

### AND UETHOOS
............................. ................................................................. 

### 7 6.1. Testsubstance............................................................................................................... 

### 7 6.2. Teet**~tem** and rationale .............................................................................................. 7 6.3. Calibration of

### the test system.............................................,........................................... 7 

### 6.4. Performaoce ofthe 

### test......................;........................................................................... S 6.5. Interpretation ..................................................................................................................

### 8 6.B. Ust

### ofprotocol devtatlone........................._ .................................................................... 8 

### 7. RESULTS
...................,..........................................................................................................

### 9 8. CONCLUSION
..................................................................................................................... 

### 10 APPENDIX I Inclvldual 

### rneasurements ................................................................................... 11 TABLES 

### Table 1 Vapour pressure of Et 3 different temperatures ................ 9 FIGURES 

### Figure 1 

### Graphical repl'e$EII'ltation ofthe vapour pressure measurements....................... 9 Figure 2 Vapour pressure curve for
............................................. 10



### -Page2­

# /.**I.~**



### ct·,)

### 2. STATEMENT OF GLP COMPLIANCE
The study described 

### In this report has been correctly reported and

### was conducted In compliance 

### with: The Organization for economIc Cooperation and Development (OECD) Good Laboratory Practice Guidelines (1997). Which 

### essentially conform

### to: The United Slates Food and Drug AdministratIOn Good laboratory 

### Practice Regulations. The United States Environmental Protedfon Agency Good laboratory Practice Regulations. The sponsor Is responsible for Good**LaboratgrL~** (GLP) compliance for all test substance 'nformatlon unless determined by

Study Director SectIon Head 

### Analytical & 

### Physical Chemisby

Date: .....

# OOUe.bb..?-.4.,..**~**

- Page 3­3. QUALITY ASSURANCE STAlEMENT
This report

### was Inspected bythe 'QualityAssurance Unit

### to conffrm that the methods 

### and results accurately and completely reflect the·

### raw data. Thedates of**Qual~** Assurance Inspections are given below. 

### Dumg the 

### on-slte process inspections procedures applicable 

### to thIs type 

### of study were 

### inspected.
Type of Ph ... , Section 

### Start End 

### ReportIng date Inspections Inspec1lon 

### IMpection date{s) date(s) 

### Protocol (Study) 

### 03\AUG\04 

### 03\AUG\04 

### 03\AUG\04 On-eite (Process) DSC and vapour 23\sEP\04 23\SEP'\04 28\sEP\04 pressll'e Report (Study) 19\NOV\04 19\NOV\04 19\NOV\04

Head.of**Q~~11ty** Assurance



### Date:

## .~4.:-:H.: 

## ..9.J1"""

-Page4­ 

# IJ]

### 4. SUMMARY The determination of the vapour pressure of. 

### was performed in accordance with the fallowing guidelines: European Economic Community (EEC), EEC directiVe 92/69 EEC, Part

## A. Methods for the determInation of physlco-chemlcal properties, A.4 "Vapour pressure-, EEC Publcation No. 

### L383, December 

### 1992. Organlsatlon for 

### Economic Co-operation and Development (OECD). 

### OEOD guidelines for TesUng chemicals, Guideline No.104: 

### "Vapour pressure curve", July 27, 1995. 

### Using the 

### StatiC 

### Technique, the vapour pressure of 

### at20"C 

### Is: p (20°C) 

### = 30.8 ± 0.4 kPa 

### = 231 :t 3 

### mm Hg



### - PageS­



# / ) 3

## s. INTRODUCTION 5.1. Preface Sponsor SbJdy Monitor Test Facility
The 

### test was performed at the

Study Director Pl1ncipal Scientist Study Plan Start Completion : 23 September2004 : 24 September2004 5.2. Alma ofthe study 

### The purpose or the 

### study 

### was to evaluate 

### the vapour pressure 

### ofthetest 

### substance at 20·C. The vapour pressure Is 

### afunction of 

### the temperature and is specified 

### in 

### Pascal (Pa) 

### or In mm Hg. 

### One mm Hg 

### equals 133.322 Pa. Temperature In Kelvin 

### =Temperature in ·0 + 273.15. 

### The static 

### Technique 

## was used 

### to determine the vapoUr

### pressure at 20·C. In the static process, atthennodynamic equrUbrium. the vapour 

### pressures established In a closed system are determined atthree spec/flo temperatures. 

### The measured results (In p) are plotfBd versus the reclprocallemperature (in Kelvin) 

### and yield a rectilnear curve for

### the limited temperature range. The vapour pra.ure

### at 20·C 

### was caiculated from this curve. 

### 5.3. Guldallne. The study procedure described In this 

### report Is 

### based on the folloWing guidelines: 

### European Economic 

### Community (EEC), 

### EEC directive 92/69 EEC, 

### PartA. Methods for the determination ofphy8fco-chemical properties, A4 "Vapour pressure-, EEC PublicatJon No. L3S3, December 1992. Organisation for Economic Co-operatlon and Development (OECD), OECD guidelines fOr Testing chemicals, Guideline No.104: "Vapoor pressure curve", July 27, 1995.

-Page6­5.4. storage and retention of recorda and materials Records 

### and mBtetlals pertaining 

### to the study Inc:ludlng protocol. raw

### data, specimens (except specimens requiring refrigeration or freezing) and the final report are retained 

### in the archives for a period of

### at least 10 years afterfinafczallon 

### ofthe report. After 

### this period, 

### the sponsor

### Win be contacted 

### to determine whether RlW 

### data and specimens should 

### be retumed 

### to them, retained ordestroyed on their behalf. Those specfmens requiring refrigeration or freezing 

## wi. be 

### retained by for as long as the quality of

### the specimens 

### permits evaluatlon but no longerthan three monthe after finalization of lt1e report. wiD retain a testsubstance sample until the expiry date, but no than 10 years after finalization ofthe report. After this period 

### the sample wiD 

### bedestroyed. 8. MATERIALS AND METHODS 

### 8.1. Test substllnce



### .Identification Structure Molecularformula Molecularweight CAS Number Oescrfptfon
. glear**~1our185S** liquid 

### Batch Purity 99.985% Test substance storage In refrigerator In the dark Stability under storage conditions Stable expiry date 

### 07 July 

### 2005 The sponsor 

### 1$ responsible for sltest substance data unless determined by 8.2. Tutsystem and rationale The 

### StaticTechnique. Recognised bythe intemational guidelines (EEC, OECO) as recommended 

### teet system. 8.3. CallbraUon ofthetesls)I$lem 

### The Static Technique Is calibrated periodically 

### using the prfmary pressure standard 

### type 6-201-0001 (CEC DMsion of Bell & HoweD Company. California, USA).



### -Page7­6.4. Pelformance ofthe 

### test Statevapour pressure measurements were made 

### with a capacitance manometer fitted with a 133 kPa capacitive senSor. The reference pressure atthe right-hand side 

### ofthe diaphragm of the pressure aensorwas kept below 10'" Pa. The temperature of the sample was measured 

### with a plaCInum 

### resIsIanc:e thermometer. A clean and drY sample vassel 

### was flDed with 15.2 9 

### ofthe iest substance. 

### After attaching the vessel 

### to the measuring set-up, it

### was evacuated for 1 minute. The vessel

## was thereafter Immersed in a therm08tatIG water 

### bath at 38.92"0 and the measurements were started. After measurement 14, the temperature 

### ofthethermostatic bath 

## was lowered 

### to 30.49"0, and finally 

### after measurement 23 tl) 23.31·C. A 

### totar of31 measurements 

### were performed. 

### 6.5. Interp....tIon 

### Because the measured vapour pressures were 

### > 0.1 Pa, no correction for thermal transpiration was made. Thetest substance wasconsidered to show ideal beh8lliOur. Thus the vapour pressure curve 

### was derived by using a 

### Ie.,st squares method 

### to calculate 8 strafght line that best fils the measured data (Clapeyron). The vapour pressure 

### at 20"C was extrapolated from thevapour pressure curve. The three 

### testtemperatures, In degrees Celsius (6C), are also expressed In Kelvin (K). Temperature In Kelvin • Temperature In 

## "c +273.15. 6.6. Ustofprotocol deviations There were no deviations from the protocol.

-Page8­

### ••••••••••••••

# •••••••••

# •••••••• 7. RESULTS The mealUred vapour pressures and their natural logarithms ant summarised in Appendix I and 

### plotted In 

### Figure 1. The

# "rattwo measurements 

### ofthe

### first serfes and the 

### first measurement of the 

### third serieswere nottaken Into accountfor the calculations (see Appendix I). The results of the vapour pressure calculations are summarised in Table 

### 1.

11.0 

# l .Iii 10.5

10.0 -I-

_____ __

# --_-----_....--..J o 10 20 30 Maasuramenl n.....mer Figura 

### 1 Graphical representation ofthevapour pressure measurements.

Table 1 Vapour pressure of at

### 3 different temperatures Measurement Temperature Mean vapour pressure ± 2 x calculated error 

### [pal rOCl [1<1 p 

### Ino 3-14 15-23 25-31 36.92 30.49 23.31 310.07 303.84 296.48 58033±286 46111:1: 61 35020:1;227 10.969 ± 0.005 10.739± 0.001 10.464 ± 0.006 Figure 2 shows the plotofthe In p values from Table 1against the reciprocal temperature 

### 1000IT (with Tin Ketvln), taking into accountthe calculated error.

- Page 9­

### 11.0
ii" . 

### ) 10.5

10.0 

# ..J-----..,-------r------r----....J 3.20 3.25 3.30 

### 3.35 10001T FIguI"82 

### Vapour pressure curve for Fitting 

### these 

### data using the least squares method gives a value of30.78 kPa for the vapour pressure ofthe 

### testsubstance 

### at 20·C. The errorfor thevapour ptHSure (P) calculated from the 

### fit was 

### 0.5 %. The deviation between each 

### ofthe three data poInts and the fit

### was s 0.2 %. 

### The 

### error made In esHmating the maan vapoc.r pressure pertemperature 

### sertes was S0.3 

### %. Taking all these errors Into account, a value 

### of0.4 kPa (J.e. 1.3 %) was found to be reasonable for the uncertainty in the cafculalel;t vapour pressure at20·C. 8. CONCLUSION 

### Using the Static 

### Technique, the 

### vapour 

### pressure of at20·C Is: p (20"C) 

### = 30.8 ± 0.4 kPa 

# = 231 :t 3 

### mm Hg

- Page 10­ 

# IJ 2

### APPENDIX I individual 

### mea.urements The measured vapour pressures and 1heir naturallogarithma are summartsed belowand are 

### expressed In kPa. The values given are rounded values. 38.92·C (310.07 K) 30.49-C (303.64 K) 23.31·C (296.46 K) nr plkPa In (pIPs) 

### nr plkPa 

### In (P/PB) 

### nr plkPs In (1)IPa} 1 .. 58.86 10.98 15 46.14 10.74 24­ 35.42 10.46 2* 58.61 10.98 16 46.13 10.74 25 35.27 10.47 3 58.39 10.97 17 .46.14 10.74 26 35.13 10.47 4 58.29 10.97 18 46.08 10.74 

### 27 35.06 10.46 5 58.17 

### 10.91 19 46.10 10.74 28 

### 34.96 10.46 8 58.11 10.97 20 46.15 10.74 29 34.90 10.46 7 58.06 10.97 21 46.10 10.74 30 34,92. 10.46. 

### 8 58.03 10.97 

### 22 46.08 10.74 

### 31 34.90 10.46 

### 9 57.99 10.97 23 46.07 10.74 10 57.91 10.97 11 57.90 10.97 12 57.87 10.97 13 57.85 10.97 

### 14 57.83 10.97

• SyMem iIatabIIlly. The (1n) p value oblak1ed durlng this lTIIIIISunmentwas not uled. lOrthe ca(cul.tJons.



### -Page 11­

### P-04-635 

## REPORT

Study Title 

## DETERMINATION OF THE WATER SOLUBILITY OF

Study completion date

16 November 2004 Test Facilih!



### LaboratorY Prolect Identification

w Page 1 

### of 111. CONTENTS 1. CONTENTS
......................................................................................... _................................2 

### 2. STATEMENT 

### OF GLP COMPLIANCE
.................................................................................. 

### 3 3. QUALITY ASSURANCE STATEMENT
................................................................................. 4 4. SUMMARY
.............................................................................................................................

### 5 5. INTRODUCTION
.................................................................................................................... 

### 6 5.1. Preface
........................................................................................................................... 

### 6 5.2. Alms 

### of the study ............................................................................................................ 6 

### 5.3. Guidelines
....................................................................................................................... 

### 6 5.4. Storage and retention of records and materials .............................................................6 S. MATERIALS AND METHODS
............................................................................................... 7 6.1. Test Substance
.............................................................................,................................7 

### 6.2. Test System
.................................................................................................................... 

### 7 6.3. Performance of the test ..................................................................................................

### 7 6.3.1. Reagents .............................................................................................................. 

### 7 6.3.2. Analytical method.................................................................................................

### 7 6.3.3. Standard and calibration solutions ....................................................................... 8 6.3.4. Preliminary test .................................................................................................... 8 6.3.5. Main study (flask method)
.................................................................................... 9 

### 6.4. Interpretation .................................................................................................................. 9 6.4.1. General
................................................................................................................ 9 6.4.2. Calibration
............................................................................................................ 9 6.4.3. Samples
............................................................................................................. 10 6.5, 

### list

### ofprotocol deviations ............................................................................................. 10 7. RESULTS
............................................................................................................................. 10 1.1. Preliminarytest............................................................................................................. 10 7.2. Main study (flask method)
............................................................................................ 11 S. CONCLUSION
..................................................................................................................... 11

"Page 2" 

# I**~l**2. STATEMENT OF GLP COMPLIANCE
The study described In this report has been correctly reported and was conducted in compliance with: The Organization for Economic Cooperation and Development (OECO) Good laboratory Practice Guidelines (1997). Which essentIally conform to: The United States Food and Drug Administration Good Laboratory PractICe Regulations. The United States Environmental Protection Agency Good laboratory Practice Regulations. The sponsor Is responsible for Good Laboratory Practice (GlP) compliance for all test substance Information unless determined by

Study Director Head of Chemistry

Date: ••

# Ng.~~ 

# . .!7.:;r.,2.."':"1

. Page 3·3. QUALITY ASSURANCE STATEMENT
This report was inspected bythe :JuslityAssurance Unit to confirm that 

### the methods and results accurately and completely refleC1 the raw data. The dates of Quality Assurance Inspections are given below. During the on-site process Inspections procedures applicable to this type of study were inspected.
Type of Phase 

### I Section 

### Stan End ReportIng date Inspections Inspection Inspection dale(s) date(s) Protocol (Study) 03\AUG\04 03\AUG\D4 03\AUG\04 On-site (Process) Analytical 

### & Physical 04\OC1\04 12\OCnD4 25\OCT\04 Chemistry Report (Study) 05\N0V\04 05\NOV\04 05\N0V\04

Head of Quality .Assurance

Date:**J.~.:-:t\.:Qh** 

### ........

. Page 4­4. SUMMARY 

### The flask method was used to determine the water solubility of and was based on the following guIdelines: OECD guideline for testing of chemicals no. 

### 105: "Water SolubilitY'. Adopted July 27, 

### 1995. EEC Directive 

### 92/69 EEC. 

### Part 

### A. Methods for the determination of physlco·chemlcal properties, A.S: "Water solubility·, 

### EEC Publication no. 

### L383, December 1992. 

### The water solubility of 

### at 20.1 :t 

### 0.5"C Is 0.805 gil.

- Page 5­5. INTRODUCTION 

### 5.1. Preface Sponsor
Study Monitor Test Facility
Study Director Study Plan Start : 20 September 2004 Completion : 8 October2004 5.2. Alms ofthe study The purpose ofthe studywas to evaluate the solubility ofthe test substance In water using the flask method. 

### 5.3. Guidelines The study procedure described In this report was based on the follOWing guidelines: Organization for Economic Ccroperatlon and Development (OECD), OECO guideline for testing 

### of chemicals no. 

### 105: "Water Solubility", Adopted July 

### 27.1995. European Economic Community (EEC). EEC-Directive 

### 92169 EEC, Part 

### A. Methods for the determInation of physico-chemical properties, A.6: "Water solubility", EEC Publication no. L383. December 

### 1992. 5.4. Storage and retention of records and materials Records and materials pertaining to the study Including protocol, raw data. spec/mens (except 

### specimens requiring 

### refrigeration or freezing) and thefinal 

### report are retained In the archives for a period ofat least 10years after flnallzatlon ofthe report. After thIs perIod, the sponsor will be contacted to determinewhether 

### raw data and specimens should 

### be returned to them, retained or destroyed on their behalf.

- Page 6­Those specimens requiring refrigeration or freezing will be retained by or as long as the quality of the specimens permits evaluation but no longer than three months efter finalization of the report. NOTOX will retain a lest substance sample until the expiry data. but no longer than 10 years after finalization of the report. After this period the sample will be destroyed. 

### 6. MATERIALS AND METHODS 

### 6.1. Test Substance Identification Structure Molecular formula Molecular weight CAS Number Description Batch Purity Test substance storage Stability under storage conditions Expiry date 

### 6.2. Test System Double distilled water.**Clearc()lowl~sS** liquid 99.985% In refrigerator in the dark Stable 

### 07July

### 2005

The test method as outlined In this report is validated periodicaRy. using 4-nltrophenof and 2.4­ cflChloro phenoxy acetic acid alternately. The results were 

### in accordance with the criteria of OECD Guideline No.1 

### OS. "Water solubility· (1981). 

### 6.3. Performance

# 0' the test 

### 6.3.1. 

### Reagents Double distilled water Methanol Milli-a water Tap water purified byreversed osmosis 

### and subsequently passed over activated carbon and ionexchange cartridges; Ml/llpore Corp., Bedford. 

### MA, 

### USA 6.3.2. Analytical method Quantitative analysis was based on the largest peak 

### In the GC chromatogram of 'Development and validation of an analytical method for the analysis of 

### :n MIIII-Q water"}
.

• Page 

### 7· 

## I) () 

## , -'.f.a**Ann'ytkA/r.ond"~ns** 

### Column Stationliry phase CP Porabond 

### Q Dimensions 

### 25 

## mx 

### 0.25 mm, 

### d,= 3 I-Im Brand Varian. Mulgrave. Victoria. Australia 

### Carrier gas Helium 

### Column flow 1 mllmin Injection Splitless Temperature 250 "C Splltless time 2 minutes Injection volume 5001-11 (Headspace) Headspace conditions Incubation temperature 

### 50 ·C Incubation time 

### 30 minutes Syringe temperature 110"C Fill speed 

### 50 /Jl/s Injection speed 50l-l'/s Oetectlon FlO (250 "C; Hydrogen: 40 mllmin; Air: 450 mllmln) Temperature program Initial temperature 40 "C Initial time 1 min Rate 

### 1 20 "e/min 

### Temperature 

### 1 190 ·C Rate 2 

### 50 ·C/min FInal temperature 250 DC Hold time 

### 3.3 min 6.3.3. Standard and calibration solutions Standard solutions 

### of Nete prepared In Methanol. On·each day 

### ofanalysis. calibration solutions In Methanol Were made upfrom two standard 

### solutions. The dlfference In matrix between pretreated 

### samples and calibration solutions was tested and found to have no Influence on responses and therefore on the concentrations 

### reported. S.3.4. Preliminarytest A preliminary test was carried out as a range finding test prior to performance 

### ofthe flask method. In a securely closed GC vial, 5328 mg 

### of the test substance was added 

### to 19 ml double distilled 

### water. The GC vial 

### was pieced on a magnetic stirring device 

### in a climate room where the temperature (20.0 

## ±0.4°C) was measured continuously using a validated computerised system (Rees ScientifiC. NJ, USA). The content ofthe GC vial was stJrred for 23.5 hours.

- Page 8 ­



# / :< 7 I**~**

### After the stirring period, the sample was centrifuged two successive times for 5 minutes at 1000 9 

### and 20DC. 

### Before centrifugation 

### as well 

### as after the first and the second centrifugation step. a 100

### pi subsample was taken from the aqueous phase and diluted by a factor of 100 with 

### Milli·Q water, prior to analysis. The pH 

### of the water mixture was measured after the second centrifugation step. 6.3.5. Main study (flask method) 

### To three securely closed 

### GC vials containing 

### 22.5 ml double distilled water, an amount between 136 

### and 138 

### mg of the test substance was weighed Into each of 

### the 20 ml GC 

### vials. The 

### vials were placed on a magnetic stirring device In a climate room where the temperature (20.1 

### ± 0.5-C) was 

### measured continuously using a validated computerised system (Rees 

### Scientific, 

### NJ, USA). The content 

### of each GC 

### vial 

### was stirred for 24, 48 

### or 72 

### hours. As 

### a blank, 22.5 

### ml double distilled water was stirred for 72 

### hours in the climate room. The 

### blank solution was pretreated and analysed In the 

### same way as the test substance containing water mixtures. After the stirring period a 100

### pi subsample was taken In duplicate from each GC 

### vial and diluted by 

### a factor of 100

### with MillJ-Q 

### water. The pH of each of 

### the water mixtures (except for the blank) was determined. 6.4. Interpretation 

### 6.4.1. General Mean: 

# x:::- 1

# L .. XI 

### n i=l 

### where Xi 

# = measured

### value 

### n 

# = number of measurements Maximum deviation: [(highest - lowest)/meanJ • 100% 

### where 'mean' 

### Is the mean value 

### of the highest and the lowest value. 

### 6.4.2. Calibration Response: 

### R 

### = Peak area test substance [units]

• Page 9·The response was correlated with the concentration Calibration curve: tnst 8ubstenc9. using /lnear regression analysis (least squares method; weighting 'actor (1/concentratlon). 

### A == a.C+b R ::: response calibration solution [units] 

### C ::: concentration of test substanoe in calibration solution [mgn] 

### a ::: slope [unlts*l/mgj b = Intercept [units] On each day of analysis, a calibration curve was conslructed using at least four concentrations. For each concentration, two responses were used. The coefficient of correlation was always> 

### 0.99. 8.4.3. Samples Concentration of , In the water samples: (A-b) • d * 10.3 

### C 

# = ...-.--..--.----..-.- {gil} 

### a R 

# = response sample [units] d 

# = dilution factor 

### a 

### = slope [unlts.llmg] b ::; intercept [units] The water solubility of a test substance is specified bythe saturation mass concentration of the test substance In water at a given temperature and Is expressed in 

### gil. Because the water solubility of was < 100gil. no correction for the mass fraction of the test substance in the water mixture was made. 

### 6.5. List

## ot protocol 

### deviations There were no devlatlons from the protocol. 

### 7. RESULTS 

### 7.1. Preliminary test Test substance was stirred with double distilled water for 

### 23.5 hours at 

### 2O.0:t O.4°C (nominal concentration 

### was 280 gil). After 

### the stirring 

### period the 

### sample was centrifuged 

### two successive times 

### for 5 minutes at 1000 9 and 20°C. Before oentrlfugatlon as well 

### as afterthe first and 

### the second centrifugation step, a 100pi subsample was taken from the aqueous phase and diluted by a faclor of 

### 100 with 

### MilJl-Q water, prior to analysis. The concentration of in the aqueous phase prior to centrifugation as 

### well as afterthe first and second centrifugation step (1000 g. 5 min. and 20"C) was 816 mgll, 827 mg/l and 819 mg/l. respectively. From this It could be safely concluded 

### that the water solubility of Is**~** 10 mgll. Therefore, the flask method was chosen for the determination 

### of the water solubility of ASAHIKLlN AE·3000. The pH of the aqueous phase after three centrifugation steps 

### was 7.2.

• Page 10­

### Because no significant difference was observed between the concentration 

### analysed prior to centrifugation as well 8S 

### those after the first and second centrlfugallon steps, It 

### was concluded that 

### no undissolved test substance was present In the aqueous phase. Therefore, it 

### was 

### decided to analyse the aqueous phase without centrifugation during the main study. 7.2. Main study (fla.k method) 

### Test substance was stirred with double distilled water (In triplicate) at a nominal concentration of approximately 6089 mgll. 

### Duplicate samples were taken from each water mIxture after 24, 48 or 72 

### hours of stirring. The aqueous phases were analysed for _. ..- The temperature of the climate room was 20.1 :I:: O.soC 

### during the performance of the test. The results for the samples taken are summarised In Table 

### 1. The calculations were performed using not-rounded concentrations. Therefore, some differences might 

### be observed when recalculating the mean values 

### as mentioned In the table below. 

### No test substance was measured In 

### the pretreated samples from the blank water mIxture. Table 1 

### AesuHs of the main study - water solubility of Stirring tIme [hours] Concentrations analysed [mgll] 1 

### Mean concentration [mgm pH
24 629 845 

### 837 9.1 48 804 

### 763 783 8.5 72 794 795 794 

### 8.5 Mean: 805 

### mgll

, Taking a dilution factor 01100 Into account 

### The 24-,48- 

### and 72- 

### hour measurements are 

### in agreement (I.e. maximum deviation < 15%), 

### Therefore, the water solubility of was calculated 

### as the mean value of all measurements. 8. 

### CONCLUSION The water solubility of using the flask method. it 

### 20.1 ± 

### O.soC 

### was detennlned 

### to be 0.805 

### gil

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