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CilLAllJ) ; PIn'D'S rA".CII/IiS , PIIAII.'I'ID I nTUIfAKlr GLAIID J UC!U I SALIYAltr GLAI'D I SCIUIC _VI , RI. (KIal rLUat) I IDIDL COlD BPLKD ; B'l'DIIUK WI'IR _ow I II'J'OKACII , :nn:JIQ8 I 'l.'llnMID QUIll) ; 'l'IlACIIIA , mtnallr IlLAD!)Im • UDIlUS I VAIlI_ , VO::.UIIt'lUlY 

IIDSCLII 

110 IIJIIIOJI!UI.LI'I'l1IS .... SDII' III '!IIJI: 'I'ISSUliS u:.uaJII:D 

ICIc:JtaPA'IROLOGI 

".18l11l1I cua. 'l'OtAL nAIIIDD !lOt JtUIj IIIIUI_ IIAD 

PIICWOCOL IUlQllJIlIIDh "!I U o o .~ 

_ PIO'l'OCOL (IIIBIIIl'IZE!h 2 o :z o .. (1KlY s.K1'I'ftI)) I 0 o .. 0 • '!IIJI: roLLCIWDIG ".USVIIS IfIr&I IIAD 

i.IlIEIIIID.L GlLAllJ) : _A I &JMB DJIItOIr-PIIIIIIJI I IIOIa:-PIIIIIIJI+B'I'Ir::.s JOIIII I BDIl( ; CUC'lJl( J CllJlVIX I COLOll ; DUODIDIlIII ; In'II • 

U'l'IIIA,OP'l'IC DJIYJI ; JlAlll)UIAII GLllMD , BIIU'I' I ILInIIIII J JII.nIII'IIII I LACIlIDL GLlIID ; Li.lIIBlf. 1 L:nBII. ; IOu.; I L'IlII'J! .on.-alVlCAL I 

LDIPR IIODIIIHmmUmDt:IC ; -.r GLAIID I IIASAL CAVIn I QBBOl'IIi.GVS ; OVAlI!' I PAIIClIlIAB ; PAlIIoD'Jll:OID GL.IUII:I • (1 ~) I P'JIrIIR'S PATCII/:Ii. ; PIIAJIDX , UCTIIII J SALIvn'! GLDD , BCU'rIC IIIIII'n I 8KIII (ItIGIft 1"l..UIIt) I 8I'Iar. COlD , sPr.DW ; B'!'ImIIlII Wl'1'11 I!IOIlB ___ I B'I'OIIACB I _ , m'nIOJD GLAIID I tJtACJrU. I mtlllUY JILUIOIa I 1I'D:DS ; ~DA I VOLaI'I'AIIr IIIJSCLI: 

'1'1I:Ii I'O(.LtlIr.IR'G IIJ:CIlOSCORlC OBSDVA'lIOII8 RJII DDI: 

'REGULATORY/REPORT - 515 
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90 DAY INHAlATION TOXlcrY STUDY IN THE RAT WITH RECOVERY PHASE 

APPENDtx 13 -INDIVIDUAL PATHOLOGY DATA 

UlIII.L 110. ., sa. r D08I: I 1000 .,. c. S1'VDI. '2 4Q'II (11 ....) 'fIIIIIIDIAI. 

IIIC1lOPA'lL'IIOLOel' 

ItIl*D' lIlunt:U:J.•.1. __.a~ _u. 1a~11.t&'.tl0•• (.u....t I :!:~ I aj,.tatU'&l.) 


'hInI.I.ui' baaa.....u.. • [1WiI1.M.l. J f~ I ..t.tat.n1, 


'I'IIbIIJ._ tU..l.atat.J._ • (-a.z.ta J ~0CIal f IIIl1.latBrtll.) 


IIltrataliNl.u' a1C1a'Ol.1tuul. • (~I 

L:nD __.u.z. CIE' IL1:P4 .ldl_toq oel.l. ~llt&'.t1oa • (1I1II.t.aJ. , .al.tU-.l) 

IIIDIOID .... 

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U'UIIUB L..:1:JIa.l. tU..l.a1at1_ • :aU_t) 

-------------------------------.----------.------------..0 ., ..~.----- .. ----------------.---.---------------------------------­

REGULATORY/REPORT - 512 

90 DAY INHAlATION TOXICfY STUDY IN THE RAT WITH RECOVERY PHASE 

APPENDIX 13 .. INDIVIDUAL PATHOLOGY DATA 

..DIU. 110. " sa, I' DOSlh 100) PIlI '* S'I'UDJ:. 9Z...,. (141 wII:.» 'I'JIIIIIllI&L 

DCIiOI'I.nor.oR 

KJ,l1ed br 11&1.01..... 

lID II'CLLOIIrJ18 'II..... .nil -.&rIISD 

AIIIIIIIIliIo ca..t.mI J .IIOa'l'A ; BLOOD , IJOIIIi 1UUIIOIIIf-J'DIUR : 1IOIIII-......8't11Lll .:roDl!' J JIIII.m , CASCUIIl I CD.lnJI:: J ccu:.o. , PII~ I BD + Jlll'tDD.OP'tIC IIDYIi I 1III.IDKIInII IlLAIID 1 IIUoJl'I' I ILIUII I JIUUIIVK : Ja...-r I r.aau:ar. fiiLIIID J LUlDIZ , r.t'ID ; L.a J L'!JIIIB 

IItlIIB-CIDl9'ICIU'. J L'IIII'II IIODJI-_IC J -.y Gf.IIID J III8U. QYI'lY I 0IIS0fII.I0IRI8 I ORAL Q'II'tft I 0VMr I 1'A11C11D8 I I'I.D'IBDOJD GLAD I RJ'D'S I'&!'CII/ILS I ....1K& I l'I'I'IU'AIt1! or.um I IIBC'!UII I s.u.IYAID' cr.&IID I SClJ.'tIC .....,. I 81:0 (JUGIn' :rr.&IIIt) I II'DaL CXIaD I SJILIID' I 8'tBIIIIDI WI".. _ 1I&ItJtaf I BlIOIIlCII I 'fII'I1IIUS I ft'DIQIJ) or.UD I '.OACIrJU,. I UItlIIUY 1ILIoIID.. I UKIIDII I V'lGID I ftf.,1JIrIAilY 

IIUSC.LII: 

110 ...........11'118 .... 8DII hi 'l'1li 1'IBBUIII IItI.UIDII:tI 


mCRO'&'!'IIOr.oGIY 

'tI8S'U11: c:IIII(:K, 'J'O'l'Uo UNIIlRD 1101' DUll lQIISDIG IUD 

I'IIO'I'OCOf. JIIIQUllIIDI e <II .. • 42 
 1101' I'IIOIOCOL (...a'I'I'ID) I 2 o 2 .. 0 


(1IO!r IAIIIIIftSI!h • 41 .. o • 


lID I'OIiLIQIIfDIG flll8ml:8 .nil _ IUD 

iIJr.aIID , .IOIl'I'A J IJOIIIi ~-...... I 1IOIR-7IIIIDI .. Ift'U'... .:roUl"l' I JIIII.m I CA:ICUII J c:mI9'I:l I COI'.I* I ; U'I + JIII'tID.OP'tIC ....,. I IlUllDI.. GLIoIID I IIUII'I' I IrdUIf : I IolCilDmL GI'.IIItI J LDDX I .111& I LDIPII IIODK-CllllVIQlo I LYIIl'II 

_IHIIBmft'lDDC I IIIIIIIIID' GLIJID I IIlIiII&L CAYI\,!, I 0II8OJ'11.1a11 I 0VNlT J 1'.itoIIC:ItUII I PAM'tlIIlIOIJ) or.uD I PBIJIIt' II 1&'rC&/IS : ....DIX I 1'Ift:I1'.un' GL.I\M: • I'art! U.talJ.• .,Dl.:r ~t. I DC'IW I lIiVort'Uy GLIIIIO I SCU!I.'IC ...". I 8I:nr (BHB'r I'L&IIII:) I DIIIAl. COItP I 8....... J 1!l'IUIII1II WI"" __ IADOIf I IrlClIW:II I mDIIII I ftICDI. I UIDlAIII 8LUII:ISIl I U!I.'IIIIU8 I 1'MIIDA I 7UL1III'l'AIII IIDlIICLIr 


lID IP01.LOWUG IUCIIOIICO:fIC OII8IIIlftno.s ...... 

'REGULATORY/REPORT - 513 

90 DAY INHAL\TION TOXicrY STIIDY IN TIlE RAT \\olTI{ RECOVERY PHASE 

APPENDIX 13 • INDIVIDUAL PATHOLOGY DATA 

I\It'lJIIt.L 1'0 I ,a BIlX• ., DOSlh 1000 pv- mr 81'11J1'. fa.,.. (14 lib' RllllDI.U. 

JlICliCWJo!IB)l.06'I' 

J:1DIIIn' In_aUU..l __1__11 uf:l.l1:nt:l.OII • (~ I lIII.llatel!'lll) 


Iat:ratlllltalAr ·ai_ll1:h:1ule I (lilliS-I) 


L:nu-.-a_lear or II:I.:&M 1IIl!~tOll'J' _11 .1.llr:lltntJoll I (1dat.a1 1 .a1tlf-.l, 

ftDOlD &UID ..-. ..,.t./a • (~1atU'al.J 

.-----•••- •••----------__ • ___ • __ ._._________ ••_________.-D 0., ~.----...--.----------------.--------.-----.----------.---'-.-..­

'REGUlATORY/REPORT - 514 
90 DAY INHAlATlONTOXICfY STUDY IN THE RAT WITH RECOVERY PHASE 

APPENDIX 13 - WDMDUAL PATHOLOGY DATA 

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

K'CIOR'I.'IIOLOGT 

J:lDKIn 

tatr-.tabGl.ar alarolU:ld...ta , ,al.5."'1:) U'l'UI'I.IJI.'I GIoMID • .artl ....t.aU. oal7 pJI4I...t. Cya1:/. , para ....1:&11•• 

---------------..-----------.--------------------------.-0 or ~------------------------------------------.---------------.-.--

REGULATORY/REPORT - 516 
90 DAY INHALI\.TION TOXICI'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 ___-rIIIIDIl I JOmI-I'IIIIVI+8'I'ULK OJO~ I IOU: : CUCUIl I _1:1 I oor.a. I I:IUCIDmIW I ICft + III'I'DIII..Ol'ftC lIIIIl9II I ............ GLIIIIi I II&UI'1' J ILBUB; J KPIIII1' I Ll.CIIl1!lIL GLIIIJ I r.AIlD:II: I JdVD J L_ z LDPa 

1IOD8-CID:9IX:It.Ii J LDIP. _-a_Je I ......... GLUm ; IIAB&L ca.VI'1"I' , I O&U. C&VI'1"I' I CWD'r I .A11C1mJ8 ; .....na:ItOID GIJUID J .....'a PA'ICIl/U I I'BAIt'IIII: I PI'l'IJl:!'UJ' GLAIID I JIIIClr1nI I 8.U.l'VIZI" GLAIID ; seIA!'n: lIIIIl9II ; _ CJll:GIIft n.uIIt) I DI:JU. CGIID I 

SrL&1III I ........ WID ... IJIIJUlOW I S!'OKIoCII I !'IIDIIJS I IIfD.OID GLAIID ~ !ll.l.CB8A , UIII_ IILUlDIII I ftIIIIUS I ¥MIlIA I YOL1II'I'H!' 

III8CLII 

110 JUIIIOaIILIII8a nu: ..... III '!'!III It_a DIIIIDID 

KtClOPBllDr.oG'I' 

IJSIIUI CIIIICK, IO'D.L IIDIIIDD Jr.)'I'DH IIJ:S8DG JIll) 

nD'IOCOL IIIQU~I 015 U o 1 U 


BIO'l' I'IIOIOCOIr (IIUJiIIlI'I'ID). 2 a a o 0 


[Il0l' 8U11U'I'ID" 0 o o o 0 


'I'D I'OLLOIfIIIC US81/U .... U881J1G 

PlIlADYROID 8LAIID I U ........t., 
 'nil I'OLIioCRfDICI IIIIIIVD .... IIUIDD IDD 

AIIISIaL ..... J .MII!'A ; ... DlIIIOIf-1'IIIIIII I :eo..-rata+SIII'LII OJOJ.II'I' I JrILUlI I CU'iCUII I CBItYXX I c:oLo<* I ; ICft .. .wID..OJft:C lIIIIl9II ; ....,.,.,U GLIIIII! I aaJII I ILBUB I a_ : 1'oI-CP'IIGJ. CilLAD I LHUI: I LIVD I r.._ , L1!IInI lJODI:-CUVlCAL 

LlIO'Il .....IIIIISIIII'I'IIIC J JIIIIIloKr CiILUD ; D&ll'. ca.nn I I 0WI:II1' , .AICIIIIU I nYU'S J'A'fICII/IIS , ...ua , 'IWltUJ' Cr.HD ; JlE.I'IIII I Ul'.XYI.It:I GLa. I 81m (I.I.,. PLllllJt, , uuu. COItD I IiIII'LIIJII( I ._111111 ...: JIAIIII.OII , B'II'ClIIItoI:: I !'IIDIIJ8 I 

'REGUIATORY/REPORT - 511 

90 DAY INHALATION TDXICTY STUDY IN THE RAT WITH RECOVERY PHASE 


APPENDIX 13 -INDIVIDUAL PATHOLOGY DATA 

AlIlJIIIlo 10I 17 8JCl[. I' DOId. 1000 .... a. BftIPI'. .2 (1<1 wIRI) ftI.IIII[A.L 

IIIc:aOJI~ 

o:.'I1BUIIIUa. - "ftIa roLlol:llllI1ll 'U._ .... _ DD 

ftfIIOm fiUID , 'III.LCImA ; 1IUDDD I ftDUS UIilPlll, lOL1WJI!PAIlT MlJIIc:'LI' 

.. roLLOnIIG JllCIIOIiCO'.IC 088IaI9a,!L'1c:as .... ..,. 

1IIu.D 

Illtrat1l'ba.L8r Ial._UtIda• .1. • (,UFt) 

IICU.!L'J:C .... 

~tl_ I t~ , 'llAi.latu.l) 

--------... --.--..----.----.-----------.-.• ----..-.--.-a.D 01' ~---.--.-----.------.---.-- •• -----••-.-.-------••-.--.------.--.­

REGULATORYIREPORT - 518 

• 
90 DAY INHALATION TOXICfY STUDY IN THE RAT WITH RECOVERY PHASE 

APPENDIX 13 • INDIVIDUAL PATHOLOGY DATA 

HIIDL IKII ,. sa, F DOSI, 1000 PPI ow ImIDY, !12 day. (~" u., 'D1IIIDWo 

1UoCH'~~ 

ll.U.led Ill" IIIal.otbuae 

J'O~ ~I1B01111 .... IlUllJlIftIID 

ADIIJIDL GLAIID ; &.OHA J ILOOD J __ 1IAUOIf-1'IIJIIIIl r 1IOIIII-r-+S"rU108 301ft J 8aAlII , ca.c1III J CllllYU J c:rou. J DUODmI1lII ; I'D + IIftID.O'~Ie DIlR J ID.IIIImlIH GLMID • DAft J ILlrIIJI J D.J1IIUII J J:I...-r J r.lCllDIAL aulD J LMDIZ J IoJVD J 101llRl , IoDIIII IIODlI-CllllYIe&r. J r.DII'8 won-IIISDftItJ:C J ....u: awE) ; DIIIUo caVIn J GUO...... ; otu. caVIn, OVU'I' , .DCUU J ....ftInlOJ:D 

GLUID ; .......' S P~~/IS J .1IUnII J PXHI~UI 8LAID J DC'IUII J &l.LlVAIII' QIoUD J scnne DIIft , 8J:1II (alGBI FLIIIIt, , DDIIiL COllI) J 

SPLBa J ftJ:IIIIUIIUftI lIOII DIIJIOIf ; B~ ; H1'IIIIB , ftI1'mm GLAD I ftI.I.~ J UIIIDIIY BIoADIIIII ; V'I'D1J8 ; ¥M~ J Wlollll'l'U1' 

IIUSCLII 

110 AIIIIOIIIUILJ:'UIB .... BID D ID ~III8UU DlIIIIIIID 

MICft••,.,LOGI!' 

nSSOll CIIIICI. roru. DAIIDIID IlO'l' IDIII MISBI8G MAD 

~Io a.QUDIBD, "5 o o 4l 

IlOl' .1IOt'OCOJ. (BVBm:ftD" z " o :I • 0 

(Il0'l' ...-tftm,. 0 o o o 0 

I'OId.OIIIIIG ~lBsua .... IIADID !lAD 

ADDDL GLAIIII J &.OHA J ___-rBKUII ; BOmI-PIII1Ill+S'rULI .lOID , IIIIAIII J CAlCUlI J CDVIJ: J c:rou. , IlUODB81DI ; DB + 

IIII'fDlA.onIe III1lYS , DIIDIJIIH GL.UIJ) J DAft , ILlrIIJI ; .lIJaIUII • IoACIlIDlo GLAIID J 1oAII1'D J 1oI9111 J LUIIG J LDII'••0D8-CIII'IIe&r. ; L1'IIP. IIODII-IIIII_IC J a.Aa'I' Q:.AIID , JIA8AL caVUI' , 0Ii1lOPBHVll I· 09U1' ; .UICIIBU J .......'rIIDOID GLJJID , (1 _'Ded) , ~'S 

.It.!'CBIIB ; .IIAJlDX ; 'I'rVI'rAll1' GUIlD J IIKIUII J SA:.IVUY 8I.lt.IID , scane __ J SID (.I8Ift rLlIMI, , SPIII&L COIIID , UQIII , 

S'rDIIOJI Wlftl IMIIII ___ J ftDID8 J ftIYaOJD Gl.AIID r ftACIIIA J UIIDIU1' BLADD_ , ftmmJ J 'lMIIIlt. 

'I'IlI J'OLLOIrDIQ MICJI08COPX( OIIIID'IA'rIOMB IIIDiI _ 

IREGULATORY/REPORT - ~19 
90 DAY INHALATION TOXICfY SfUDY IN 1HE RAT WITH RECOVERY PHASE 

APPENDIX 13 -INDIVIDUAL PATHOLOGY DATA 

DIDIo 110. II sa. I' DOD. 1000 PPI 011 IIII!IIDI'. IQ <lap ,1" lib) 'fI1IIWGL 

IIJCIlGIl'A~ 

Xl...... IIlb'atah1ar 1d.~1t.U&.t..l. • (.u...t.al) 8'1'Cl1MCJ[ 

eJ.a41al.uo IlU.l.ataUoa • ' .....lall WLIIII'J'UJ' IIIIIICLII DepDerat:l_ IIJ'OPIltbJ/__'QOLeuo _11 J.Ilfl1traUDIl I ~I 

..--------------.----------..--------------------------.-p DI' D~--------------·--·----·-·-···-·----------------------------_.---

REGULATORYnrnPORT - 520 
--

90 DAY INHALATION TOXICIY STUDY IN THE RAT wrrn RECOVERY PHASE 


APPENDIX 13· INDIVIDUAL PATHOLOGY DATA 

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

IIlICIlOJIUIIOL 

IJ.lllMl IlT IIal.otluale 

'II1II J'OLLOIn:JI8 1'1_ .... aumnftID 

.IIDDIIU. Gl.lUID , Mll'l'A J BLOOD , BOD _-....... ; _-.......SlPIPLII .lODn' , IIIADI , CUCIIII , CD'IU J COLClB , __1 lID .. 

lIII'1'IID..OI''I'IC RIIVI , ..,..1... GLlIoJI) , a&Il'r J ILII:UII , I 1:u.J' ; LAClD"" GILIIID J r.t.alD r r.:nat r LIJK J LIIIPII' 

IOD'I-CIII!'t'U:AL I 101l1l1I 1fOIq-.......tui.lC I GWJI) : 1lUU. QYIn J 0&II0I'1IltGII'S J 0IU0 QYI'!'!' J ~; .AIICDU ; .Jal'l'll'l:8OIJ) 

IiL&IID : :P.DJIIt' S :rJ.Kll/B8 I l'DIIDX I 'I'lVI'l'AIIJ' GILIIII1l J JUIC'J1IIl , BALnutI ca.&D I SCLlBC IID'n , UU (IlIGIft .1iIIII:) 1 II'I'IJII.L c:oJU) I IIPL1IIIII ; I~ Uft IM)Iq IUImIOIf J 8ftIIIILCB I J ':fIII1IOD) GLAIID J I'IIACIIlD. : DIlI:u.a: llLA1X111l 1 -. r YJQUJI. J VOL1II'I'loa'I: 

IIDfICLI: 

110 ~I'I'I" n:a lUll IJI 'l'ID USSIJIIS IDMIJIIID 

BICILOftll'llOr.oe:r 

'111_ CIIICI:. lIIOIAL IIO'l I:DIl III_DIG II.I.D 

I'IIIIO'IQCOL 1IIQUlltm, «II • 41 110'1' PIIWOCIOL (~). 2 •

2 o 0 '" o 

(IIO!P lIDBII'I"l'IIDI. 0 o o o 0 

'II1II I'OI'.LO'IIIIG nllolUllS .... _ lAD 

--...r. c:t..UID , .I.OJt'IA ; ... 1AIUlOW-1'JDIII'Il I BOId-I'IIIIUa+8'I'II'LI .lOIH , IIIADI J ClUIClJIII J CID:Yllt I co.... J I ...... 

1DDIA.000000IC ...". ; IIlUIIIBlIlUl GLAID , ...... I I ..... I .HI..... I LACIIDmL QUID , r..DlIII. I lorna , 10... ' IODIN "'-CD7ICAL I 

IJIIIIB .om:-JllUlllll'l'lltC I IIIIIIIlIaJ: GLIJII) I ID&&L QYI'f] ; 0IIII0:I'III8Ul I GRIft I .UIQBU I .....ftlllDm J IUD'S l'A'lfCIlIllS I 

IIIAIl'IJIIt I IIIICIIIIII I SALIYMr tILDID I au (litGIll' 'LlUII:) I Bl'DJAr. com I II'I'LDII : 8'I'IIDlII '0'111' ... r IftIDIDaI I lPIIIIIDB : S'I:ROID Cl'.UD J 1'I.ItoCIIIQ 1 'IItDIlIIII _ : YJQIJD. I VOL~ MIBCLB 

... .oLLO'IIIIG KlCIOIIICOI'IC (JJI1IU'B'I'JOIrS .... IIloIJII 

'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•• (.u.e.-1, 

.1'l.'V1'I'Ul' GLIIIIJ) c::r-t/- • lNIZ'8 -..talJ.•• BCLIt.'I'IC IIIIII9IE 

~J.aat::I._ • (aI.II.e.-l , -.t.lat.nl., 

O'I'DUS Cla............ dJ.lauUOIl • fal.a.e.-l, 

--.----------------------------------------------------.aD or ..x.IL---------------------------------------------------------------­

KEGULATORY~ORT - 522 
..

: 
90 DAY INHALATIONTOXIC1'Y STUDY IN THE RAT WITH RECOVERY 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 - 524 
90 DAY INHALI\.TION TOXICI'Y STUDY IN THE RAT WITH RECOVERY PHASE 

APPENDIX 13 • INDMDUAL PATHOLOGY DATA 

..lDL 110, 4i1 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_ ; umomus J lID + lDt'JD.OPIIC _ • 1lUtDD1.. GLI.lID I II&U'I' I ILlnllll • H.JUIUII , JCnIIIrI , LACa:DIU. CoII8 , LU'ID , Llva I J._ , J.DIIIPI: 

JIIGDII-c:BIIVIc..u. , L'IIII'B IIODII-~e , IIli&Ar. Cl.VIft 1 ~IWiRIS J OIAL Cl.YI'I'! I PUc:.u , .......'IIEDOlD GLAIID , IPSIJIII', PAft:II/B. J 

PD.JnJIlI. ; PI'l'UII'AR1' GLlt.8 I DIOIft'AR QLItoIID : aJIC'I'IIII i 1IUorn.Jlt GLIB ; ICIUte IDIINB ; /IIIIIDtV. ~ICLli J DIll (1C0Il'I I'LUII:J I 

SlIlI.IoI. COlD ; B.LBIIII , B'l'ZUUK UK IIOIIIB __ J 1I'I'C*AaI I nlH'1B I 'III1IOIS , 'l'IRROlD GL.UIII I 'l'UaDIA J UIlmllD llioIIIIDI:I: I 

vor.UII'DII'I' IIIJI1IICLB 

• AJIIIOIIII&!.II'l:S8 WIllI: .... III ftI 'fJIISUIIII SDIIDID 

--" ---••-- - - ------------------- --.--- ---.-- --- - - ---- _·aD 01' AJIDIAL- _••- __ ._ ---••__ •••0---- ---------- ---------- ---------------.----­

REGULATORY~ORT - 525 
90 DAY INHALATION TOXIcrY SlUDY IN THE RAT WITH RECOVERY PHASE 

APPENDIX 13 • INDMDUAL PATHOLOGY DATA 

.....DII.L 110. 402 BD.. D08l11 o JiIIIII oa 8ft1J1, 120...,.. (11 ....) ac:oovJIIl'I 

1IACIIOI.I.'IrIIOLOQY 

U.U.e4 bJ' I'al.otl&ue 

!III: I'OLLCIIIJIIiI !!ISIIIIIIII .... ....x'ft'lll 

J.DRaIIL GLIJID J MIl'I'A , III'.OQI) , 80lIl DDOII-..... , IK*II-PlIIIDI+ftll'Ll JOlII'I' I IIRA!. , CAJICUH I cor.o. I I UIDIITIIII8 : 11m • D'lDII.,OftIC ...... I ........1 ..... GLIJID I ...., I I ..... I I IU...-r I JiIIatDIN GLlUID I LlIlDII: , U'tD I L_ J LDI'II 

IIODIi-CIroII9lc:&L : L!MI'II ~"_IC I IIAIIIL CAYl'l"! I I au. CAVIn' , :rAIICIIIIUI J :r.t.DftIIlOID 8LIIID , :rDllll'S :r.l.'I'CII/U I 

I'DIt'nIlt I rlTVI'I'.t.I1' ....., J .....A'I.'Il GLIJID : I au.rnn: 8LIIIJ) I 1ICI.1.1'lC ...... J 8lllDII.L "'8]CI.i: I _ Ul]"" PLIIIIIt) I 

..I..... caao I ULIIIII I n.DIGIC '11ft ... QIDOIf I 8~ I !llS1']8 I 'fII'IJI'II8 I ftIIIIIODI I 9ACIlU. I mtIDK!' IILUIIImI J 

'I'OL..-uJtlr IIUIICLII 

10 AIIJIOIIIU.LI'I'Dl8 ......... m ,.. '1'1 __lDD 


----------------------------------------.----------.---.-D or a.IMI£---------------------------------------------------------------­

~GULATORY~ORT • 526 
90 DAY INHALATION TOXICfY STUDY IN THE RAT wrm RECOVERY PHASE 

APPENDIX 13 -INDIVIDUAL PATHOLOGY DATA 

AII'IJIlI:L 110 <II StuDY. laG _. (U ....) I 13 BU.. 1IOSI. o P.. DCO'¥IiItJ 

BCIIOf'HIIIOJ:.08! 

Itlll... II!' Italot:llue 

'IBIl I'OLIoOIf1:IIG I'D8nII .... 1IUBIIZ'ftIID 

AO...... GLAIID J , 8LOOD I .... _._-..... : ...-,.....B'l1l'LI 101ft , ....1. , CUCUJ( , , , DIJIID!IUII I IrD + lIII1'IJU,.OI'1'IC IIDYIIi ; ItIJIDDID 4ILIIIID J SAIl'! , I ..... I .......... • 11:1...... I aatIlDL IILIIID , LPIII'I I Ll9D I L1mII , "DO'S 

IIODB-CUVl:caL , LDIJIII JM)IIII-.........,..tC I .UJ\£ Gnn I 0SII0I'DIim'II , OII.U. CAVD'Y J P.IIICIUIU I P....!II1IIOIO CLIIID , JIIft'D' 8 PII.!'CII/U I nau.u: I PIIVIftKJ' GLUIl I l'I.OB'I'.lft QLUD I UC7IIIf I DLlV&D' CUIIII I SCQI'lC ..". I DKUfAL 'RBICL8 I aD (1l4illl'l' FLAB) BPIIDL COIl'D I Bl"I.ImIf ; S'lIlURIII 1fl!B 8tWB ...,. I 8'fOIIIlICII J 'I'11II'I%8 J 'I'II'IMVt , 'l'IrrIIOJD CLIIID , DACIDI& I UltDlAl:l" II.l'.IIIOIa : 

90tllhUY ICUCLII 

110 lI.IIIlOIIIlU.I'I'XU .... __ D II1II 'I'X..... IIDIIlDD 

------------------------------------------.------------..0 or IBXNIL-----------------------------------·-----------_-----.---------­

IREGULA10RY/REPORT - 527 

.... 

o 
90 DAY INHALATION TOXICfY STUDY IN lHE RAT 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 sen.ftc ...". I IIDDIAL USICLII I aD ,alCllll' J'LUII() 


DID.'L CDIID J DLlIIIII : SIBBUIII .UII lIOaI: ..... I 1'l'OIG.CII J '1J18'I'IB : 'IJIIIIU8 r 7Ia:IiOrD GL.UID I 'I'llACIIU. I UJtD&II'f IILIIIIDIIII I 


".,".....UIf _eLI: 


.0 .IIIIIIO.u.I!I'IBB ........ III '18K !l'ISSUJlB nUf1'Jl!Ul 


---------------------------------.----------.-----.----BID or AII~-·---·--··-------·--·----·-------·----·---·--------------------

IlEGULATORY/REPORT - 529 
90 DAY INHAlATION TOXICfY STUDY IN THE 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) 

--------.---------------.. -.--.-------------------.--.-IMP or 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 _ J _IAII GLAD I IIUJl'I' J r:umIIII J .DlVInIII ; J JoACItIllUo UoI.IID J uaJJIX , ,rID I r:u.G J r....... IIODII-caaflc.u. ; r...... 1IODI-...aDIDIC I IIUAL QYIft' I 0I:I0I'ID0IiIVB : our. Qv:n I JI.IIIIl:IIIIU J l~ftI:8OID GLlIIID J 1'a1'D" JI.tJrCIII/I • 

......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 - 531 
90 DAY INHALATION TOXICfY STUDY IN nIB RAT WITH 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~ 

.,.. I'CII.J.IWDIG ~I"'" _ n.aftm> 

AJ)IIJIIIU, GLaD I KInA I BLOOD , 80lIl: _-.-; _-'--+B'lIrJoII .JODI'I' I IIILU. : (lUCUII I c:or.a. I IIUOiDIIIIIIIII I UIDJDIlU8 , :RIC 

+ Illl'lIU.OHlC IID'1B I ......TO .r:.um i Daft I IU. , .n.nJII1IK i IIJ:ImO' ; r.I.CIIlDL -.&lID , t.IIIl'Jllllt r LI'9D , , L1DII 

IIODII-ClDV'Ic:.tu. , [,1111'8 1IOIII-IIIiIlauaIC I IIIIIU. ann I QllIIClIPDGU'B , 0ItAL c:&YI'ft' , .AIIC:IIIlU , 'AIIII'I1:ItOID ....... I .....'B PAKB/18 , P....1I1EI I PI'llUU'UY GLAIIII I ._~.l!!ll GLAIIIl , , II&LrAIIl' GLDII I IICUl'lC ..-VIIi I valCLI I 11111. lilt.... lI'r.IIIJt) r 8l'IRL CXIItD , III'ZoI':IIII , 8,..... WIftI ... ___ 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 1HE RAT WITH RECOVERY PHASE 


APPENDIX 13 .. INDIVIDUALPATHOLOGY DATA 

MDIU. 110. ,. nz.. 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 'III..., ......) 1 BJlDI&L aJIII) I BJlLIOII ; ........ Wl:!II __ .... , , ftftll ; 'IBJanI I IIIDtOD GLIIII> J , VllDAlll IIL&IlIIU I 

9OL1JJIDft IIIIISCr.:Ii 

110 AMOIIIALI'I'IIIS .... ... III 'I'D 'l'IIIBlIBS U»CIIID 

--.----------------••••-•••••-------.-.------••--•.--.--.D or UI~··-·-·-··--·---·--·--·---·--·---····---··---···---··- ••••------­

'REGULATORY/REPORT - 533 

90 DAY INHAlAnON TOXICTY STUDY IN THE 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 • 534 
90 DAY INHALATION TOXIcrV S11JDV IN THE RAT WITH RECOVERY PHASE 

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

III8ICLIi 

IIIPWIa I __ WI!II __ __ ; ftQII.CB ; _ l '!IIIJlOID c::r.uD I 'I'I.lCBILI. I VltIJIH! .....,..... I U"l'DUI I VUIID I ~ 

-------------------------------------------------------.-0 OF ~.-.--.-----.-------------.-.-----------.------.----------.----.

~GULATORY~ORT - 535 
90 DAY INHALATION TOXICI'Y STUDY IN TIlE RATWlTH RECOVERY PHASE 

APPENDIX 13 .. INDIVIDUAL PATHOLOGY DATA 

• ..DIAL 110. it2 an. r Il08l. _ 8ftID1:. 12. 4qa (U lib, 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 

IIII'8CLII 

, 8'naQI U'III .......,. I 1'I'OIDaI I I ~D) GIL.IID , ftIACIII& I UIt~ JILI.1IOD I Ift'D'II8 , VMIJII. I ~ 

110 JI.IIIIOaIII.LI'fIllS .... ... III ftB 'l'ISSUltS UIJlJ.... 

------------...----------------------------------------laP oor ~-------------------------.---.---------- ••..---.-------.--.----­

~OULATORYnrnpORT • 536 
o 
90 DAY INHALATION TOXICfY STUDY IN 1HE RAT WITII RECOVERY PHASE 

APPENDIX 13 .. INDMDUAL PATHOLOGY DATA 

AlQIUJo _ 1mJOI. 1:110 ClaY1l III __, ..,. 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 I'nD'S • .a.'fCB," 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 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 .. INDIVIDUALPATHOLOGY 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 

--....------..----.----.-.. -.-----.......------..------BRD or ..~---.-••••••--------.--.-.-.------.-.-••-.---.-----.•----------­

'REGULATORY/REPORT - 539 

....

.. 

~ '<1 

.. 
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 

... I'Or.J:Otfl:R 'PIISUJIB ... ~ftIID 

ADIIBU. GLaIID J ~A ; ..000 J ... JUt.'RIIOIII.1'lIIII\UJI • Bc.&-I'IIIIIDl.B'PIPLI: _lift' I B1tAl. I I c::IIII'f'U ; ; DUODIIIIIm I DII + JIftnII.,OJI'l!Jc ...... I ......1.. m:.IIID : IIII.lUI'l' I , .... I D.IWQII I II:~ I r.ac:usu. .... I 'LAIIJKI I LIYD II LUMII I L1lII'II Jiaa.-CllD'JC!I.L I IoDll'll !IOW-_naIC I ......... ....., I IUUIIII. canft I CIaOP1Q11iU15 I our. Cl.nn J OVU'I' I PAIlCIIDB I PJ.aII!I(YaOID IiiIWID I I"II'JD'S PAt'CII/•• , I'IPIlIDrl J PIftI'au GLaIII I I su,1UII1' _ I 8CU.~lC ...... J UD CIXCIft PLUI:) I 8JI.aL COllI) I uu:a , __ UIB lie. _ I 8'fClIIACI I 'IB'Df.'IIII I IIIDIIClID GLIIIII I ftl.CIISt. ; VllIJIIIII1' JILAIIIIIII J 8'DB8 I VAGDa I WLaR'U'I 

IIIfSCLIl 

.0 lUIiIIJOIIIIIlII'PU:B ... __ I. I'D 'l'IIIBtIII:s JIUI"Do:D 

----....-...---...-....-......-....---.-.-.---.--------BRD or ..~.---.--•••-------.-••-----.---.--.-••------------.---------.---­

~GULATORY~ORT • 541 
90 DAY INRI1\LATION TOXJCfY STUDY IN THE RATwrrH RECOVERY 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 

............ 6LUID , ~A J Br.OOD J 8ClIIII: IIAIIIOII-I'JIND ; IIOmI-PIIIVII+8'l'11'LII .10111'1' J BDDI J C&IICIJIII J CIIIlVD: J : IKIIIDmIUII J IIS + IIII'l'DA.OP'l'IC IIIIJlYlI J HAlDlmIM ....., I BIU'l' I ILI'CIII J .JlIi;J1lll1Jll I I~ ; LM21DL GLUID J L.IIItI'D J LI¥D I LUIIIIII J L1JII'8: 

_·CZR'IIcu. J LlIIDlI IIIDII-.......IC , IIIII.aKI' ........ I KIIIIAL QUII' , J 08AL QV1'I'I' I on.n , .MCUU , 'AM'fIDII011: 

......, J I'JII'D'& 'A'l'CJ[ja J PIIAUIIlt J '1'l'III''''1' GI'..WD J UC!UII I 8LWII) I 8CJU'IC .... J aull (UGIft' I'1.1III:) I BfIDL com IIPLJIaI ; 8'I'DIIDI WIft ......... I S'tCIIIICII I ftDmI J 'IInIIOID GLAD' , 'l'RACIIIl& I DDl.U.Y 8I.lIIDD I U'hII08 , VAIII_ I YOC.IJftAIIY 

III88CIiI: 

110 u.D1!IIAI.1'l'I1S .... .... III .,. 'l'IIIII11D IIlUoIIIJID 

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

1I'I'ICInI8D.t.n:..cIo4 • _ U-tezo. 

ItO .........IrID _ D -.nIDCI rIIIII8IaI ~ 

------.--------------~----------.--------.-------------... or ~.-----------------~--------~------.---------------- ••----------­

REGUlATORY/REPORT - 543 
...

... 

o 

I 

.. 

o 
90 DAY INHALATION TOXICI'Y STUDY IN THE RAT WITH RECOVEl.Y PHASE 

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 

-------------------------------------------------------SXD or a.IMI.t---------------------------------------------------------------­

REGULATORY/REPORT - 545 
90 DAY INHALATION TOXICfY STIIDY IN TIlE RAT WITH 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 

.......1JD..opuc IIII:VII J _IlIII rH.AIIP , DAn I ILBVK , .BiIVIIUII I (~ I Ja.CltDlUo GLI.D I r.IIa1'U J LIYD , I.UIIIII I L!DII 

JIOI)••CD9'l:cu. J ~DIII'R 1I01).i-1••~aJC , aaa.u. CAVIl'( , o.8QPB'.UIIJB I 0III0L CAUl'( , PAJICIIJIU I PAUftalIIDi .... I nJ'D'S PA'!CII/IS I 

PRAR1'U I PJ'fUI'flRJ' ~LAIII) , ....,..U GLUII) ; DCIVlI , aauUU" ca.um , IICD'IlC IIIIJI¥I: I ..a..... vaICLI , SlUR (:alar 1'u.K) I 

n:m.aL COD I IIP'-IID' I WIn .... IIIlDOIf I II'rClI'lI.C:B I UB'!'IB I 1:BImII , 'IIDIlOID &AIID , 'IItaCBI. I 1lUJIAIII .r.a:I)I)lD I 

VOI.....lID' ascu 

110 AaOIIIIoLIU.......... Dr !'Ill 'fIIJIIiUU ClII."...., 


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REOULATORY/REPORT • 546 
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90 DAY INHALATION TOXIcry STUDY IN 1lIB RATwrrH RECOVERY PHASE 

APPENDIX 13 -INDIVIDUAL PATHOLOGY DATA 

MODI. III,. 1111 B1IJ:.. DOSI. 1000 ~ 1* 8'J'U01'. 120 cia,.. (II .u) UC'09'D'I 

IIACIIO.A'ftIOLOG'I' 

Itllled ~ JIIaotllAme 

f'IIII POu.oIlIIC: !PISSIIIII 1IDJII ~ftID) 

ltoDIIIIIfAL GLUID I ~A f lILOOD ; ... _-1'IIIIIIIl f ...- ......8'I'l:l'IoIi .rOm'!' J BII&D I cuc:uJI I 1 DOODIIIfIJl: f UJDJDDD:B ; OJ: • IIIl'I'Da.C)PIIC DJl'VII , ·'JIIIID!XU CILaIID : DI.a'I' , lr..m.l , .l1I.JUJRIII , lI1*In' I La.CIIJJII.Ii GLUID , liUdII'. 1 &on. 1 I~ J L~. 

IIODB-ClllNICIL : LI11i'II ..,.-_lC , IDSAL CAVlI'll' J OIIIC>l'BIGIJS , OIl.U. CA1IJ'f1' J ....CIUIAII , ,&lllt.1II'DIOID CILaIID , .IImIIt'S 'A!ICB/. I 

1'''''0]( I I'tnlUAll'J' GLJIIttI , ..a8'D.'l'JI GLaID , , &l.LIVD'I ULIIID , IICUoBC ...... , a.:au.r. YllSICLII J BKUI IUa1r n.&III'.) , 

IIJ'DIUo COItD I su..a I ITDIRIIII w:n'II ... DJtIlOW J 8'1'Cl11M:1l I 'l'JIS'l'lS I ftI'IIIIIII : 'l'IIIJI01D QLAIID J 'l'IlaClllll I ft.DI.IJIT BL.UIIII'a I vor.urrAD' IIII8CLI 

110 ~ln......... DI 'I'D 'l'XUUIIII 'VI[QI'«D 


-------------------------------------------------------SID or ~-------------------.-----.-------------------------------------

REOULATORY~PORT - ~49 
90 DAY INHALATION TOXlCfY STUDY IN THE RAT WITH RECOVERY PHASE 

APPENDIX 13 -INDMDUAL PATHOLOGY DATA 

AIIIDJ. 110. 16 sa.. ~. 1000 JIIPII .. iJ'I'UD'f. 110..,.. IU 1dr.It, 1IIICOYIII'f

IIIIC8OPlI.'IIIOI.Oft 

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'JB ~1lIC 71........ _I'I'I'IID 

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IIODlH:IIIVIc:u. I LDII'II 1fO!IJI-.....r&ItI:C I DSAL Cil.Vl'l'l' I cmllOl'IIMIU8 , ou.:r. c:t.Tl'I'I ; • .-cIIIIU I l'......num:D 8I.UIt I nID'. 'A'tCII/U I 

l'JIIUl'IIII: I .17IJI'fU'f GLIIID I I'IlOII'IlI.D GLUID : ImC'1'IlII : a&L:n:a:R'f CILIIII:I ; KIA'l'Ie ...,. ; BaDIDL ...SIa. I IIItDf (Uan' 1'L.UIJt) I ••1IIlIL eGaD : ULDII I __ WID ... IIlUIIIOIf I BIOM&CII , 'fUt':tS , 'I'IIIIIVS , UIlIOI» IiILAIID i DACIIIrA , VllDIU'I' JILADDa , 

'I'OUM'DII'f Jm8CLI 

110 ~II!I_ ... !lUll III 'lID rllllilm8 va......... 


-------------------------------------------------------SID or ~-------.---------------------------------------------------.---

,REGULATORYIREPORT - SSO 

90 DAY INHALATION TOXICI'Y STUDY IN THE RAT WITH RECOVERY PHASE 


APPENDIX 13 -INDIVIDUAL PATHOLOGY DATA 

UDAL 110. 111 sa,. DOS.. 1000 lis- 011 .'l"\1li'1. UD c1ayIt UI lilt_I JIIiCOYDl' 

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APPENDIX 13 .. INDMDUAL PATHOLOGY DATA 

DDUUi 10. ., nx.. 1lOSJ!. 1000 PI'II _ 81'1JD'r. 120 clap (11 na) ItICOVDJ

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~ULATORYmEPORT - 553 
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90 DAY INHALATION TOXlCI'Y STUDY IN THE RAT WITH IECOVERY PHASE 

APPENDIX 13 -INDIVIDUAL PATHOLOGV DATA 

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

DCJIDI'A'fIIOLOCY 

UJ.l.1I4 IIr llaJ.otba1le 

ftIIi J'OLIoOIrDIII 7:raaua __ 8UmaftII:D 

JIDIIJIII&L GLUID I ~A I BLOOD I __ ......,.J'IIIaIIt I "'-J'DIUII+II'I'IJII.K ~OIlll' I IIII.lDI I c:&BCIII( I C3JI.YU I COJ.OIf , IIVODDQB I lID +

IIII'I'ID.onIC ....,. : _xu GLIIIID I IIIUR'I' : It._ . .JlI~ • I LK:IIIDJ. ....., I IoUI:lIItIt I LnD I r.lIIQ I 1.1l17li 

_-CU9"Ic.v. ; L_ ....•..Ba'DlUC ; GLIIIID ; ID.IU. Cl.VIU I 0GI0lBUIQ8 , oau. Cl.VH"!' I 09UY I 'aIIQI:ICU , 'UI.!'Il'!:aom 6LJIIII) J I'llI'D'. J'A'rCII,a I n:IUIDI.I: I PXnlftJn: ...., J DC'rIJIC I ISIILIYUT Gr.&IID I IICD.7IC ....... I IIUII (IUGB'I' II'oo.IoIIJ:I J IPIDL CCItE) 

SJ'LIIJIII I ..,.... WID .... IIAIUIOII I S'I'OIDC.B I I mnom ..... I 'l'IIACIIII. I ualllU'f BJ.AJlIIIIII I Vl'DIJ8 I VlGDIA J WLUftAU 

I!IDlICtoII 

110 ABIIOIIIIiUoI.,UIi .... .... D '1'BI .,IB8UI:. U"IDIIII 

--------------------------------.-------.--.-.-.-------.-DOl' UI.aL-----------·-·---·--_···_···_-----------··--------·------------­

REGULATORY~ORT - 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 ua 1IIIIt, QC01ID1 

DCIlOI'llllOr.o&J: 

0.11.. II!' IIal.ot..... 

'I'D NLLOQBG I'ISIDII& .... 8UIIIIl'l'lllP 

lItIiIaAL QUD : ~A : IIr..CNlD • 1IIUIJIiOIr-"- • ~-"""+8'1'IJ'U .JODft' I IIIIADI I Q:ICVIC • CRY.II , COLOB J IIGOIIDVK J :ID + .'I'DIA,onIC IIlDlQ ; _LUI GILIIIO , .....,. , Xu. I a.JaaI , ua.u J LACIIDrU. IJIi,UD , LIoJlBI: ; LIYD , Lag , LDIJIII. 

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JmIICLB 

lit) AIIIIOIIIILI'IU8 ... BDiII U 'IIDI 1'IBS11118 vMDD 

--------------------------.----------------------------KID 01 ..~------------------.--------------------------------------------

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 .,.. 0. 8'1'11)1', 120 dQ. (11 1IIr..) ucon:u 

1IIoC3O."'J'IIOLCKIJ' 

KU1~ bJ" llaJ.othu. 

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ImICLB 

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--------------- -------------------------------------KID or .IIIIKaL---------------------------------------------------------------­

fREGULATORY/REPORT - 561 
90 DAY INHALATION TOXICfY STUDY IN TIlE RATWITH RECOVERY PHASE 

APPENDIX 13 -INDIVIDUAL PATHOLOGY DATA 

AJIIIIUo IfOI 111 IDIJ[. r DOSI. 1000 PPl ~~. 1204a1'8 (11 wu) DCOYDJ: 

_CIle'&~ 

IU.Ue4 ~ lIal.ou... 

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IIUSCLB 

IfO ........ 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 ... a. STVDJ'. U' dan (It aa, DCO'YUr 

IIACIIOI.IIII'IIOLOID 

ItUl.. IIr lIa1otbu6 

..... ro~ 'l'I18U1I11 _ IIU1111U''ISD 

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IIlI8CLI: 

M'O .u.oJIICALIUBS .... IIlID III ftIII t:lllllVl:S IDIIIJII;lt 

------------------------------------------.----.----.--.-D or JlllDIII.I.--------------------------.----------------.-------------------­

'REGULATORY/REPORT - 563 

90 DAY INHALATION TOXICI'Y STUDY IN THE RAT WITH RECOVERY PHASE 


APPENDIX 13 .. ~DMDUAL PATHOLOGY DATA 

lUIDI.U. 10. 12. lID. r DOSII. 1000 JIIIII ~ BBDr. 12G clap (U tduI) UCOYI:Irl'

1IICIOI&1BOItOft 

1U1.1.e4 bJ' lIa.lotbu. 

'IIIIi '1'1......... SUIaIJ'I'nD 


MIItDAL GLNID , AIIIn'& , BL\lIOO I 110IIII ...,...~ , 1IOmI-......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 IN THE RABBIT 

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

- :~~ ~~~:

:r~ -:~:"~ :- . _:.(-, "-':J~: 

o -.. U1 N 

3: -.I 

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

- ':,,~, 

f''V ........, r-r; 


"". .,,, 

~ _.t.:.. '--"'1 

,. ,,-"-,," 9 --' 

en 

w 

STUDY SPONSOR: TEST FACILITY: 

111111111111 "III 11111 I~II 11111 "III"III 11111 ~llllfllIIII 11I1I 111111 500 5 0 0 0 3 822 I S 
PAGE 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 major phases 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 of evaJuation. Audits of study documentation, and process inspections appropriate to the 

type and schedule of this 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 of Response 

12 December 2002 Draft Report Audit 

Date ofQA Signature Final Report Audit 

§ EvaJuation specific to this study 

DATE: 28 FEB 2003 ................,................................... 


• 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 Director 
PAGE 4 

CONTENTS 

QUALITY ASSURANCE 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 16 

PAOE' 

ACUTE EVE IRRITATION IN THE RABBIT 

SUMMARY 

IntrodllCtlon. The study was pcrfonned to assess the irritancy potential ofthe test material to the 

eye ofthe New Zealand White rabbit. The method was designed to meet the requirements of the 

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 of8.0 was classified as a 

minimal irritant (Class 3 on a 1 to 8 scale) to the rabbit eye according to a modified Kay and 

Calandra classification 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 EVE IRRITATION IN TIlE RABBIT 

1. INTRODUC110N 

The study was performed to assess the irritancy potential of the 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) 

• 	 Commission Directive 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 test method. The results ofthe study are believed to be of value in predicting 

the likely eye irritancy potential ofthe test material to man. 

The study was performed between 12 November 2002 and 21 November 2002. 

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 of the test material are the responsibility of the 

Sponsor. 

Preparation of Telt Material 

For the purpose ofthe study the test material was used as supplied. 

The absorption ofthe test material was not determined. 

1.1 
PAGE 7 

1.J Me.surement of 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 of 2.0 to 3.5 kg and 

were twelve to twenty weeks old. After an acclimatisation period of at least five days each animal 

was given a number unique within the study which was written with a black indelible marker-pen 

on the 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 11 to 23cC and 30 to 700.4 

respectively. Any occasional deviations from these targets were considered not to have affected 

the pwpose or integrity of the study. The rate of air 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 or integrity ofthe srudy. 

3.2 Procedure 

Immediately before the start of the test, both eyes of the provisionally selected test rabbits were 


examined for evidence of ocular irritation or defect with the aid of a light source from a standard 


ophthalmoscope. Only animals free ofocular damage were used. 


Initially. a single rabbit was treated. A volwne of 0.1 mJ of the test material. was placed into the 

conjunctival sac of the right eye, fonned by gently pulling the lower lid away from the eyeball. 

The upper and lower eyelids 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 in Appendix ]. 

After consideration of the ocular responses produced in the first treated animal, two additional 

animals were treated. 

Assessment of ocular 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 other ocular effects were also noted. Examination ofthe eye was facilitaled by the use ofthe 

light source from a standard ophthalmoscope. 

InterpretadoD of Results 

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 of comea 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 of the 

total scores for each observation were calculated. The highest of these group means (the 

maximum group mean score) together with the persistence of the reactions enabled classification 

ofthe eye irritancy potential ofthe test material. 

If evidence of irreversible 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 disposaL 
PAGE 10 

5. RESULTS 


Individual and group mean scores for ocular irrilation are given in Table 1 and Table 2. 


No corneal or iridial effects were noted during the study, 


Moderate corVunctival irritation was noted in all treated eyes one hour after treatment with 


minimal conjunctival irritation in one treated eye at the 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 Calandra classification 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 Oeular IrritatioD 

lPR=2 IPR-l IPR 2 

Rabbit Number and Sex 

90 Male 61 Male 62 Male 

Time After Treatment 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 II 
PAGE 12 

ACUI'EEYE 

IRRITATION IN THE RABBIT 

Table 1 Individual Total Scores ADd Group MeaD Scores For Ocular 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 0 
PAGE 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 or two 

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 initial pain and the subsequent eye irritation. 
PAOEI4 

ACUTE EYE 

IRRITATION IN THE RABBIT 

Appendix 1 Dra.ize Scale for Scoring Ocular Irritation 

1. CONJUNCTIVAE 

(A) 	 R.aetS (rr:fen to palpebrallllld .... lbarc:oqjuru:tivae cxclading cornea and iris) 

Vessels nonna.I o 

Vessels dctiaitdy injcclc: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 

OIMous S'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& of the lids and hairs just adjacent to lids 2 

Discl1arac with moisteniDJ ofthe lids IIIId hairs. considerable area around the eye 3 

THE TOTAL SCORE - (A + B + C) xl 	 MAXIMUM TOTAL -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)' or all ofthcse) 	 2 

THE TOTAL SCORE - D X S 	 MAXIMUM TOTAL "'10 

3. CORNEA 

(1:) 	 Degree ofOpacity (most dense area JUed) 


Noopeci1y 
 o 

Scattered or diftUse .areas, delails of iris clearly visible I 

Easily discernible translucent areas. details or iris slightly obscured 2 

OpaIaccnt IRU, no detaiLt oliris visible. size ofpupil hire/)' discemible 3 

Opaqw;, iriJ not dlsccmlble Ihmugh !he opaci1y 4 

(F) 	 Area of Conea Iavolved 

One qllllftCr (or less) but not zero 


Great« than one 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 MAXIMUM TOTAL - 80 

MAXIMUM TOTAL SCORE POSSmLE =110 
501080 

PAGEJ~ 

ActrrEEYE 

IRRITATION IN mE RABBIT 

AppeJldix3 Modified Kay aDd Calandra Interpretation of Eye Irritation Teat 

MAXMJM PtsCRlPl'lON RATING MEAN I'USIST£NCI OF SCORE (AND CLASS) SCORJ: 

Gt-.._.... _atUINNB-O N_irritIm <I) 0.01D0.5 aro.,._1OIIlI _11124 """"' >0 1"II.cdca11y -.,1IritW. (2) 

GftIIIp _ -'_It24 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 _ ..... _ at 41 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!be iIIdIviduaI tIIIII_ 
 M4denIIII irrillllf (5) .'-.1001'_ 

Oroup-tOIlII __7 days Man! dian IaIfofthe indjva..! .... _ 

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 7 day& >20 Smnirri'lallt (6) 

MeR than lairoftho IncIIvidIIIIlIOllll _ ~irtiI&nr (6) .,dIyt 30 or lea 

More than ..If ot tho indivWal toIIII _ Group ml'Alllllltll score II 1 days at 7 dIyt > 30 buI no indivldull toral _ 40 or .sc--c inilanl (6) leu 1It7day1>60 

M-= !!ran half of the 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 7 da)/l60 or leu (1) 

Mote IhIn halfofthe indMdMl tOIal _ Orcup _1OIIlI_1I 1da)'l SOlO 100 It 1 days ;> 60 MIlO Indivlcllal IeIII _ lOorllll. V.,,_in11U1 (7) III 1 da)II > 100 

M_tIM hairorIhe indi\liduallOllll_ II: , days > 60 Mel indlvidllal kIIaI .:ore lit ~Iy severe IITitInI (I)

'cIa)/l> 100 

Group __I score at 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 01 GLP Compliance in Aeeordanc:e with Directive 881310IEEC 

THE DEPARTMENT OI'IIEALTII OFTBE GOVERNMENT 


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 oflIIOHHtriC'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 major phases 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 of evaluation. Audits of study 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 Test Material 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 in accordance 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 of America. 

This report fully and accurately reflects the procedures used and data generated. 

DATE. 2 7 FEB 2003 ..................................................... . 


Study Director 
PAGE 4 

CONTENTS 


QUALITY ASSURANCE REPORT 1 


GLPCO~LLlNCESTATEMENT 3 


CONTENTS .. 
 SUMMARY 5 


, 1. INTRODUCTION 

, 2. TEST MATERIAL 

2.1 Description., Identification and Storage Conditions 6 

2.2 Preparation of Test 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 in Accordance with Directive 88/320lEEC 12 

/ ·-7 f ~. 

! 
PAGES 

ACUTE DERMAL IRRITAflON IN 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 meet the requirements of the 

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 of the test material to the intact skin ofthree 

rabbits produced no evidence ofskin irritation. 

COlI.cbuiDn. The test material produced a primary irritation index of 0.0 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' 

ACUTE DERMAL IIlRITATION IN THE RABBIT 

1. INTRODUCfION 

The study was perfonned to assess the irritancy potential ofthe 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 of Chemicals No. 404 "Acute DennaI Irritation/Corrosion" 

(adopted 17 July 1992) 

• 	 Commission Directive 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 ofthe study are believed to be of value in predicting 

the likely skin irritancy potential ofthe test Inaterlal to man. 

The study was performed between OS November 2002 and 08 November 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 of the test material are the responsibility of the 

Sponsor. 

2.2 PreparanGIl of Test Material 

For the pmpose of the study the test material was used as supplied. 

The absorption ofthe test material was not determined. 
PAOE? 

1.3 MeasuremeDt of pH 

Detennination of the 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 of at least five days each animal 

was given a nwnber unique within the study which was written with a black indelible marker-pen 

on the 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 of a 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 of the study. The rate of air 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 ofthe study. 

3.2 Proeedure 

On the day before the test each of a group of three 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 of the test a suitable test site was selected on the back of each 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 ofSW'gical adhesive 
PAGES 

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 of the 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 of the patches. and 24, 48 and 72 hours later. the 

test sites were examined for evidence of primary irritation and scored according to the following 

scale: 

EVALUATION OF SKIN 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 

Severe erythema (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 1 millimetre) ................................................ . 3 

Severe oedema (raised more than 1 mil1imetre and extending beyond the area of 

exposure) ....................................................................................................................... . 
 4 

Any other skin reactions, ifpresent, were also recorded. 
3.3 

PAGE 9 

IDterpretatioa of Results 

Calculation of Primary Irritation Index IIDd GradiDg ofInitancy Potelltfa) Ulml the Draize 

Sebeme 

The scores for erythema and oedema at the 24 and 72-hour readings were totalled for the three test 

rabbits (12 values) and this total was divided by six to give the primary irritation index of the test 

material. The test material was classified according to the following scheme devised by 

Draize J H {1959} "Dennal Toxicity" In: Appraisal of the Safety of Chemicals 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 or disposal. 
PAGE 10 

5. RESULTS 

The individual scores for erythemaIescbar and oedema, BIC given in Table 1. 

No evidence 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 ­ Rabbit Number and Sox 

62 Male as Male 86 Male 

Total 

1Hour 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 of24 aDd 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 index 
PAGE 12 

Appendix 1 Statement of GLP COlDpJiuee iD Accordance with Directive 881l10JEEC 

S'UIIMIKI'OFODIoIJUAftCE 

IV ACCOJIIMNCE WI'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 of JIIIIiciaI .....1... 10 IIrect 

die "alidily of -.eli...llllltiea perI~ at ...... facilida. 
ACUTE DERMAL IRRITATION IN THE RABBIT 

1 verify that this is an exact copy of the original n:port which is located in the Archives of 

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

REPORT 

Or: ~,H V

,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 500 '1111 "III"1'1 IIIII "III UIII '""IIIIII'll' 11'1' 11'1 III 11'1'II lUI 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 and test 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 AND 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 % of the control) .............................................. 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 (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 30 July 2004 

On-site (Process) Ecotoxlcology & 26 July 2004 2 August 2004 3 August 2004 

biodegradation 

Report (Study) 20 January 2005 20 January 2005 20 January 2005 

Head of Quality Assurance 

- Page 4­
4. 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 air flow, 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 September 2004 

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 Inhibition Test". 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 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. 

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 

by the 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 under the 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 7­
6.2. 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) 

CI2C6H30H 

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°0 to 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, 

·Page8­
6.4. 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 CaCI2.2H20 

0.2 9 M9S04.7H20 


2.8g K2HPO" 


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 tor approximately 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 up to 

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 of the 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 10X95%­ 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 ihat loUOwlnS 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!l aU 

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 1/4 L 

8) Split ratio 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 

OS . r l.I 1;1 ~ V tv' '}! 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~,,'IllIi''''~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 of the test 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. Preliminary tesl.............................................................................................................. 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 

-Page3­
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 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 of Oualltv Assurance 

- Page 4 ­
4. SUMMARY 

The determination of the 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 of test substance were injected 

successive times Into a test vessel. The temperabJre in the test vesselwa8 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 of 751JL. 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 of the 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 or freezing) and the final report are retained in the 

archives for a period of at /east 10 years after finalization of the 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 

of the 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. 

-Page6­
8. 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 of the 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 of the 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 of the 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 at the 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 at 200°C, every 

20°C, 70 loll test substance was injected into the test vessel until ignition occurred (i.e. at 

620°C). 

- Page 7­
Going down from 635"C, the temperature of the 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 of test 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 of 604-596, 598-58S and 601-593°C, respectively. In Test 2,50, 80 and 


110 III test substance were Injected at temperature ranges of 606-594, 599-593 and 609­

601°C, respectively. In Test 3,50, 75 and 100 ilL test substance were injected at temperature 


ranges of 603-599,600-586 and 615-603°C, respectively. . 


8.5. Test condltJons 

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 1 to 3. 


6.B. Interpretation 

The auto-ignition temperature is the lowest temperature at which the test substance ignites 


when mixed with air under the conditions defined in the test method. 


For each of the 1hree tests of the 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. Lilt of protocol 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 of the 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 of 590aC. 

- Page 9­
FIGURES 

608 

606 

604 

-602 

o 

o

-

e 600 

~ !. 598 

E 

CD 

f596 

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. QUAliTY ASSURANCE 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 of the 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 of the tast procedure ..................................................................................... 7 


6.4. Performance of the 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 Unit to 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 of study 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 of Quality Assurance 

Date: .)...::J.J.::9.~......... 


- Page 4­

/ L-) 
4. SUMMARY 

4.1. Guidelines 

The determination of the 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 test was perfonned at the 

Study Director 

Principal Scientist 

Study Plan Start 

Completion 

21 October 2004 

21 October 2004 

5.2. Alms of the atudy 

The purpose of the study was to evaluate the boiling temperature of the 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 of the 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 after finalization 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 

of the report. 

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. 

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 of the teat procedure 

The test procedure as outlined in this report is validated periodically, using one of the following 

metals3 Indium, tin or lead. The results are in accordance wIth the ;riteria for the 

validation. 

• Page 7­

II 

e.... 	 Perfonnance of the 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 of the 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 at which 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 of the evaporation peak. 

The measured boiling temperature depends on the atmospheric pressure. The actual 

atmospheric pressure was recorded but the determination of the 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. List of 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 of the 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 of the 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. QUALITY ASSURANCE STATEMENT ..................... " .......................................................... 4 


4. SUMMARy............................................................................................................................. 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 


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


6.2. Test system and rationale ............................................................................................... 7 


6.3. Reagents ........................................................................................................................ 7 


6.4. Performance of the 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 of the 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). 

A glass pycnometer with a nominal volume of 10 ml was used. The temperature of 

measurement was 20.0 :t O.5"C. 

The density of ASAHIKLlN AE-3000 Is 1.48 glcm3 (1.48x1 d' kg/m~. The D;o Is 1.48. 

- Page 5­
5. INTRODUCTION 

5.1. Preface 

Sponsor 

Study Monitor 

Test Facility 

Study Director 

Study Plan Start 

Completion 

: 23 August 2004 

: 23 August 2004 

5.2. Alms of the study 

The purpose of the study was to determine the density of tne 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 of Chemicals. 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 of at 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 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 evakJation but no longer than three months after finalization 

of the 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 C 
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. Test system and rationale 

Test system 	 A pycnometer with a volume of 10 mL, with a ground-In 

thermometer and 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 of the 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 of the MIIII-Q water was 


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 of the mass and the volume of the 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 of the test substance is calculated as the 

quotient of Its mass and volume. 

D = {B- A)I E 

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

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 of water at the 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 of a volume of the test substance, determined at 20°C, and 


the mass of the same volume of water, determined at 4°C {=1000 kg/m\ The relative density 


has no dimension. 


6.6. List of protocol 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 oen~~ Mean d~~Sity [a/em I ra/cm 

1 1.483 

2 1.484 1.48 

8. CONCLUSION 


The density of Is 1.48 g/cm3 (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 cm3 

20.0°C 

40.8870g 

26.3286g 

9.8105 cma 

- 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 1 of8 ­
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. 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~Jd9.~!1.. 0..6". ~QQ(.(........ 


- Page 3 ­
3. QUALITY ASSURANCE STATEMENT 


This report was inspected by the :luality 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, 

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) 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. 

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 of the study 

The purpose of the study was to evaluate the explosive properties of the 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 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 returned to 

them, retained or destroyed on their behalf. 

Those specimens requiring refrigeration or freezing wit 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 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

3C 

7. STATEMENT 

The tendency of a 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. Molecular structure 

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 of the 

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 1 of 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 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 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 of the 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 

contact with 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 of the study was to evaluate whether reaction of the 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 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 finallza60n 

of the 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 

Molecular weight 

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. List of protocol 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 highly flammable. 

The structure of does not contain groups that might lead to evolution of 

highly flammable gases In dangerous quantities when coming Into contact with damp air of 

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 water was added 10 a small amount of test substance (0.5 gl50 mL): no spontaneous 

ignition took place and no evolution of gas occurred. 

8. CONCLUSION 

is Incapable of developing a dangerous amount of (flammable) gas(es) In 

contact with damp air or water. 

- 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 of the 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 of the 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 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 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 of the 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 FacUity 

Study Director 

Study Plan Start 

Completion 

15 November 2004 

15 November 2004 

5.2. Alms of the 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 of at least 10 years after finalization of the report. After this period, the 

sponsor will 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 

of the report. 

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
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 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 

Test system 
 A Pensky-Martens closed flash-point apparatus (according to

DIN EN 22719). 


Rationale 
 Recognized by the international guidelines (EEC, DIN) as

recommended test system. 


8.3. Validation of the 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 the test 

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 of the 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. Test procedure 

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 at the 

start. of Test 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 7­
8.4.4. 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 of the 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 test vessel 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. QUALITY ASSURANCE STATEMENT ........................................................ " ....................... 4 


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


5. INTRODUCTION ................................................................................................................... I) 


5.1. Preface ............................................................... '" ......................................................... I) 


5.2. Aims of the 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. Preliminary test ............................................................................................................... 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 of Quality Assurance inspections are given below. 


During the on·slte process inspections procedures applicable to this type of study 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 of the 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 of Chemicals, 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 of at 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 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 of the report. After this 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 for all test substance data unless determined b) 

8.2. Test system and rationale 

Preliminary test 	 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 of the 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 of dimethylsulfoxide (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 3­
3. 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 Quality Assurance 

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 5­
5. 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 of the 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 of the 18th Meeting of competent 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 of the 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 peonits 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 of the 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 (for sensitivity) were 

recorded on the day of recording the spectrum of the test substance. The spectrometer was 

capable of recording spectra with a resolution (line width al a half maximum) of < 0.45 Hz and a 

sensitivity (slgna/-ta-nolse ratio) of> 150. 	 • 

- Page 7­
6.4. 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. 

6eparatus 


A Varian Mercury Vx NMR spectrometer for 'H NMR was used. 


Solvent Dimethylsulfoxide-De 

Reference TetramethylsJlane (TMS) 

Instrument settings Frequency 

Spectral width 

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 of the 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 of the 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 12­
APPENDIX I Assignment table and signature of principal scientIst 

- Page 13­

) 
Determination of the IH NMR spectrum 

Int.erpretlltfon of spectrum 

Signals observed in the blanc measurement include: the water peak at ca. 3.3 ppm, the DMSO 

peak at 2.5 ppm and the TMS peak at 0 ppm. These signals may be present in the spectrum of 

the compound, but do nol relate to the compound itself. 

PartialL Assignment Table. based on jnter~etation only 

Chemical shift (Qpml Peak structure Possible assignment -_ .. " ..... 6.6 multiplet 

4.8 multiplet c

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. 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 ............................................................. 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 of the 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 of the 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 of the 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 of records 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 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 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 of the test 

A 10 em stainless steel gas cell was used to record the IR spectrum of the 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 I R-spectrum 

of the 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

c 
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 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 Quality Assurance 

Date: ...l~ .-:-. t9. ::-g~ ....... . 


- Page 4 ­
..... SUMMARY 

The procedure for the determination of the 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 of the 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 5­
6. INTRODUCllON 

5.1. Preface 

Sponsor 

Study Monitor 

Test Facility 

Study Director 

Study Plan Start 

Completion 

: October 04. 2004 

; October 04, 2004 

5.2. Alms of the study 

The purpose of the study was to evaluate the oxidizing properties of the 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 for the 

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

- 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, of the substance and cellulose spontaneously Ignites; or 

b) 	 a 1:1 mixture, by mass, of the substance and cellulose exhibits a mean pressure rise 

time less than or equal to the mean pressure rise time of a 1:1 mixture. by mass, of 

65% (w/w) aqueous nitric acid and cellulose. 

examination of the 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 F acilitv 

Laboratory erqject Identification 

- Page 1 of 7 ­
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. Alms of the 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 report was Inspected by the ::lualily Assurance Unit to confirm that the methods 

aoo results accurately and completely reflect the raw data. 

The dates of Quality 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 of Quality Assurance 

Date: .... '3..::--'~.::9.h .... 

~ Page 4 ­
4. SUMMARY 

The procedure for the determination of the pyrophoric properties is descrlled In the following 

guideline: 

European Economic Community (EEC), EEC directive 92169 EEC, Part A, Methods for the 

determination of physico-chemical properties. A. 13: "Pyrophorlc properties of solids and liquids", 

EEC Publication No. L383. December 1992. 

Based on its molecular structure and on experience in hendling. it was 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 of the 8tudy 

The purpose of the study was to evaluate the pyrophoric properties of the test substance. 

5.3. Guidelines 

The procedure for the determination of the pyrophoric properties is described in the following 

guideline: 

European Economic Community (EEC). EEC directfve 92/69 EEC. Part A. Methods for the 

determination of physico-dlamlcal properties. A.13: "Pyrophorlc properties of solids 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 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 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 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 of the 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 of protocol 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 OF AN 


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 of the test ....... , .......................................................................................... 7 


6.4.1. Preparations before the test ................................................................................ 7 


6.4.2. Calibration of the tensiometer.............................................................................. 8 


6.4.3. Preparation of the 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 of water at 20.DoC (Test 1) ...................................................... 12 


Table 5 Surface tension of water at 20.0"e (Test 2) ...................................................... 12 


- Page 2­
2. 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 3­
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. 


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 of the 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 of the highly volatile test substance to a minimum. 

GC analysis showed that the 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 of Test 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 of the study was to evaluate the surface tens/on of the 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 of at 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 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 

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. . 

-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. Test system and ntlonale 

Test system 	 Tensiometer (model K6; KrOss GmbH. Hamburg, 

Germany). The measuring body Is a platinum-Iridium ring 

wfth a wire radius of 0.185 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 of the 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 of the 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 of the 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 = ao I ag 

eTa = the surface tension of water at the test temperature cited in the literature 

(Gebrauchsanwelsung fOr Tensiometer 8451. KrOss GmbH, Hamburg, Germany). 

Og = measured surface tension of the water at the test temperature. 

6.4.3. Preparation of the test solution 

First test: 

A mixture of test substance in water was prepared by stirring 105.3 mg test substance with 

100 ml water 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 of the 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 of test substance to a 

minimum. 

An amount 135.7 mg test sUbstance was stirred with 20 ml water 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 of the 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 

of the 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 

of the table and subsequent compensatfon of the 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 a constant 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 test substance (visual observation) when 

using an Erlenmeyer flask. 

- Page 8­

/.'l '': 

/ ".,',/ '; 
Additionally. It was investigated whether the test solution of Test 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 a factor of 100 with 

MIIII..Q water) into the GC system as described ir (development and 

validation of an 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 of this method, should be regarded as being surface 

active materials. 

8.8. List of protocol 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 of the test solution was not yet In equilibrium with the water bath used. Because the 

difference Is not slgnlficanl. the study Integrity was 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 of the 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 of test substance during 

the measurements. 

Table 2 Surface tension of an 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 measumnenl vessel 2 mi'lutes after preparation. 

Table 3 Surface tension of an 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 lest tolutlon 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 of Test 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 Detennlnatlon of the calibratIon factor CPb 

Table 4 Surface tension atwater at 20.0°C (Test 1) 

Measurement Time expired1 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 pissed since the water was transferred to the measurement vessel. 

Determination of the 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 explred1 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 water was transferred to !he measurement veuel. 2 Several measurements _"' performed until a state of equilibrium was readied. 

The mean was calculated from measurements 2 • 6. 

Determination of the calibration factor ¢bITest 2) 

00 =72.59 mN/m (KrOss GmbH. at 20.0 DC) 

- Page 12­
P-04-635 


REPORT 


Stuw Title 

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 of the test system ......................................................................................... 7 


6.5. Perfonnance of the test. .............................. , .................................................................. 7 


6.5.1. Preparation of the 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 of the 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 of the 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 of the 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 of the study 

The purpose of the study was to have some Indication of the wavelengths, In the Ultraviolet 

(UV)NIsibie (VIs) region. at which the test substance absorbs radiation. 

The absorption of a 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 or alkaline. 

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 or freezing) and the final report are retaIned In the 

archives for a period of at least 10 years after finalization of the report After this period. the 

sponsor wi. 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 of the specimens permits evaluation but no longer than three months after finalization 

of the report. 

Nill 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. 


-PageB­
I. MATERIALS AND METHODS 

8.1. Testsubetance 

Identification 


Structure 


Molecular fonnula 


Molecular weight 


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. Test system 

. A single-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 of the test syetem 

The instrument Is vaHdated periodically using potassium dichromate solutions (for absorbance 


accuracy) and a holmium perchlorate solution (for wavelength 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~ of the 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 of the 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. after subtraction 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 of the 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 holder was 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 

Figure 2 

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. QUALITY ASSURANCE STATEMENT ............ , .................................................................... 4 


4. SUMMARy ......................... : ................................................................................................... 5 


5. INTRODUCTJON ................................................................................................................... 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 


e.. MATERIALS AND UETHOOS ............................. ................................................................. 7 


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


6.2. Teet ~tem and rationale .............................................................................................. 7 


6.3. Calibration of the test system ............................................. , ........................................... 7 


6.4. Performaoce of the test ...................... ; ........................................................................... S 


6.5. Interpretation .................................................................................................................. 8 


6.B. Ust of protocol 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 of the vapour pressure measurements ....................... 9 


Figure 2 Vapour pressure curve for ............................................. 10 


-Page2­

/.ct·,) 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 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 3­
3. QUALITY ASSURANCE STAlEMENT 

This report was Inspected by the 'Quality Assurance Unit to conffrm that the methods 


and results accurately and completely reflect the· raw data. 


The dates 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 September 2004 

: 24 September 2004 

5.2. Alma of the study 

The purpose or the study was to evaluate the vapour pressure of the test 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, 

at thennodynamic equrUbrium. the vapour pressures established In a closed system are 

determined at three 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, Part A. Methods for the 

determination of phy8fco-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. 

-Page6­
5.4. 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 after finafczallon of the report. After this period, the 

sponsor Win be contacted to determine whether RlW data and specimens should be retumed to 

them, retained or destroyed 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 longer than three monthe after 

finalization of lt1e report. 

wiD retain a test substance sample until the expiry date, but no than 10 years 

after finalization of the report. After this period the sample wiD be destroyed. 

8. MATERIALS AND METHODS 

8.1. Test substllnce 

. Identification 

Structure 

Molecular formula 

Molecular weight 

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 sl test substance data unless determined by 

8.2. Tut system and rationale 

The Static Technique. 

Recognised by the intemational guidelines (EEC, OECO) as recommended teet system. 

8.3. CallbraUon of the tesls)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). 

-Page7­
6.4. Pelformance of the test 

State vapour pressure measurements were made with a capacitance manometer fitted with a 

133 kPa capacitive senSor. The reference pressure at the right-hand side of the 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 of the 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 of the thermostatic bath was lowered to 30.49"0, and finally 

after measurement 23 tl) 23.31·C. A totar of 31 measurements were performed. 

6.5. Interp....tIon 

Because the measured vapour pressures were > 0.1 Pa, no correction for thermal transpiration 

was made. 

The test substance was considered 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 the vapour pressure curve. 

The three test temperatures, In degrees Celsius (6C), are also expressed In Kelvin (K). 

Temperature In Kelvin • Temperature In "c + 273.15. 

6.6. Ust of protocol 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 "rat two measurements of the first serfes and the first measurement of 

the third series were not taken Into account for 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 of the vapour 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 plot of the In p values from Table 1 against the reciprocal temperature 

1000IT (with Tin Ketvln), taking into account the 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 of 30.78 kPa for the vapour 

pressure of the test substance at 20·C. The error for the vapour ptHSure (P) calculated from 

the fit was 0.5 %. The deviation between each of the three data poInts and the fit was 

s 0.2 %. The error made In esHmating the maan vapoc.r pressure per temperature sertes was 

S0.3 %. Taking all these errors Into account, a value of 0.4 kPa (J.e. 1.3 %) was found to be 

reasonable for the uncertainty in the cafculalel;t vapour pressure at 20·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 below and 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 lTIIIIISunment was not uled.lOr the 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 11 
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. 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 of protocol deviations............................................................................................. 10 


7. RESULTS............................................................................................................................. 10 


1.1. Preliminary test. ............................................................................................................ 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 by the :Juslity Assurance 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 4­
4. 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 5­
5. INTRODUCTION 

5.1. Preface 

Sponsor 

Study Monitor 

Test Facility 

Study Director 

Study Plan Start : 20 September 2004 

Completion : 8 October 2004 

5.2. Alms of the study 

The purpose ofthe study was to evaluate the solubility of the 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 the final report are retained In the 

archives for a period of at least 10 years after flnallzatlon of the report. After thIs perIod, the 

sponsor will be contacted to determine whether raw data and specimens should be returned to 

them, retained or destroyed on their behalf. 

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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 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 

07 July 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 by reversed 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 of analysis. calibration solutions In Methanol Were made up from 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. Preliminary test 

A preliminary test was carried out as a range finding test prior to performance of the 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 of the GC vial was stJrred for 23.5 hours. 

- Page 8 ­

/ :< I 7~ 
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 100pi 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 by the saturation mass concentration of the 

test substance In water at a given temperature and Is expressed in gil. 

Because the water solubility of was < 100 gil. 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 after the 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 after the 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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