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TRADE SECRET
Study Title H-25777: Inhalation Approximate Lethal Concentration (ALC) in Rats
AUTHOR: David P. Kelly, B.S.
STUDY COMPLETED ON:July 8, 2003
3
PERFORMING LABORATORY:
E.L du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050
~~
LABORATORY PROJECT ID: DuPont-12966
p-- `WORK Raauesy Novos JA
~
-
TTT
`Company Sanitized. Do note conts ain TSCA CBI
BHETTiisn pi oeLmCOmormonmtiRs
oapenas
CERTIFICATION `We, the undersigned, declare that this `report provides an accurate evaluationofdata obtained from this study.
TE `AnatomicPathology le fSECmTfRrmets for
ety Sty itr:Lindy
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E22957777:7 nbaattiioonnAAprpormoavse LoattoCCoonnennioonn ALLCO)MiRn Sass
STUDY INFORMATION
Svnonyms/Codes
a)
* H-25777
Submitters Notebook ee
Haskell Number: 25777
puf ponrirases
Phusical Chases: Pale yellow sid Stability: dTcbohsneedritvetseitdosnubostfahencesatppdeanroedevtiodbeencsetaobflemuendteratlhewas Sponsor: EL du Pot de Nemours and Company
Wilmington, Delaware 19898 USA.
Sy Iniated Completed May , 2003 se report over page)
rr p------------ -_--
L1E25T77T7::InInhhaallaatiioonnAApppprrooxxiimmaatteeLLeetthhaall CCoonnccenevnartioonn((AALLCC))iinnRRaattss_
DuDuPpoonntt1122906666.
STUDY PERSONNEL
Study Director: David P. Kelly, B.S. PrimaryTechnician: William E. Ellis, Jr.
Management: Arthur J. O'Neill, B.S.
Anatomic Pathologist:
Management:
PSetteevrenC.R.MaFnrnam,eD,.DV..VM..M,.D,iPphl.oDm.a,tDeiAp.lCo.mVa.tPe.A.C.V.P.
`Toxicology Report Preparation: Maryanne M. Wilford, B.A.
Management: Nancy S. Selzer, M.S.
Laboratory Veterinarian: Thomas W. Mayer, D.V.M., Diplomate A.C.L.AM.
--_
--_
BompanySanitized.DoesTotcontain TSCA cay
-
J5:25777: InhalatoionnAApppprrooxxiimmaatteeLLeebtheallCCoonncceenntrrattiioonn((AALLCC))iinnRRaatsts_
DuDuPpoonntt1122996665
SUMMARY
apTecwroionoddgertnoosuaHpt-si2oo5n67fa7em7roaislnoelaiCri.rn ltT:heCesDtt*eas(ttSmcDoh)saIpmGhbeSerrBe.sRTwrheatresecwgheearnmeebreeaxrtpecodosnbecydenhnteorasateti-inoognntlshyeofftoerHs-at 2ss5ui7bngs7lt7ea,nw4cee-rhetooufrorm m1-eaosru1r4e-ddagyrraevicmoevterircyaplelryi.odR.ats were weighed and observed for clinical signsoftoxicity during a
FmRoaaltslsswoemwierndegieaenxpxaoesruporedt,yoona3ratammstioscspdfehireaormmdeetstehoresf0f.oH1r-0t2hm5eg7/7a7Lereaotxsopmloesatuenrsetceowdnecwreeenrtrerea5tt.ai8ionanensdodffo6r.0a8.1u10m-,odrary1er.s8peecmcogtvi/evLre.yly.The pepeexrrpiiooosddu,;rtaehlewraeetrsemafreritonamiintneh3gde fa0o.tr1sa0wm1eg4r-/edLareygtrraoeiuncepodvweferroyearpesra1ic4or-did.faiycAretedctfohovereaernnyadptoeofrmtiihocedpi.aRtrahetossplfeorcgtoyimevvetarhleuecaot1vi.eo8rnym,.g/AlLl ta0tsH-f2r5o7m7t7hoerd1.u8rmign/gtLheerxpeocsouvreerywpeerreisoadc.ificed and discarded.Norats died following exposure
OOctfohnHcee-rn2tt5rh7aa7tni7o,snl.tihgehHrtibesotwodelyroegwiencioaglshietgxnaliomfsiiscneaasnttmiocelnionaifcrasaltsuisingernx3speooofsbd6esderrtavose0do.ni1ne0dtmhagey/eaLxfptsoehsroeewdxerdpatonssoauttrreteeoiatth1.m8eermntgto./oL. related effects.
~ g`rUenadteerrtthheacno1n.d8itmigo/nLs.oftAhcicsorsdtiundyg,ttohHeaaspkperlolxLiambaotreatleotrhyaltocxoinccietnytcrlaatsisoifni(caAtLioCn)s,fHor-2H5.7275777i7s is
6mcao8nsspsimdm.eerdeTidaartngoeabtceerdaotdMymMnoasAmtDiscSlidgiihnatmlieynthteaorlra(tiiMo(nMaeAsrtoDusd)oiloefsAtaLhrCeef0tr.eo8s.tme2d.10a1m0e.gr4/oLps)maoiltnotmhaaillslecoowrnatmcsea,nxtHrioamwtuieovmnelrwu,ansgthe
exposure. Had the toxicity could have
gbeeneenrastoemdeawehraostolgrbeaeteenr.smaller
at
this
concentration,
i
is
possible
that
th
_
`Company Sanitized. Does not containTSCACB!
-
H:2577; Inhalatinon AopproosinmatelLeothbalCCoonnceenntraaitioonn (AALCL) iOn RaRis
bDuuppoonei122996666.
INTRODUCTION tT(ehAseLteCod)bwjoehfcHitc-ih2ve5cao7fut7sh7eidsintshmteaudldeeyawtrahatossf. tooTnhdeeetoAerrLmmCionriees adeex4fp-ihonoseuedrdaisrnahttahleeailttoihowenersaotpnpartthomexosidpmahayetroeiflecextcphoaonlsoceuonrntecreaontrtiwroiantion aetxlpeeacstted14roduatyeos ffoploltoewntiinaglehxpuomsaunree.xpTohseurienhaanldatiwoansrroeuqtueoesfteexdpboysutrheeswpaosnscorh.osen based on thtehin
STUDY DESIGN `2Tw:we1ro0emgegrx/opLuopessxeopdfonso6usmrea-elowneelrryearfseotcaraaicsnhienwdgeflero,er4ae-x1hp-oodusraeypdreerticoooadvr.eorsFyoopllelraoitwomidon;sgtphheeexprroeessmourafei,nHi-3n2ga5t37sr7af7trsiownmeatrih.eerReattas roercoave1r4y-dpaeryiroed.covery period. Rats from the 1.8 mg/L exposure were reained for a 14-day ined
Rexaptosswureer.e approximately weeks old and weighed betwen 258 and 279 grams a th time of
--_ ah`enansdiecmloailbnssiectarelvresedigocnbassocehfrtdvoaexydicffiootrrymmoiormrtmtaleaildtiiyta.4ytlRtayitasmfswteedrueerxwipenogisguerahece.hdeaDxnuprdoisonubgrseteahrenverdedcofobovsreecrrlyvienpidecrafiloords,imgoanrltlaslaittey
petaontxdihocofiltboyogotynhevtrahelecudoatavieyornfy.oplelAroliwloidrnsag,tealfxlprrooasmustrfheerao1nm.d8tamhtegl/0e.La1te0xtmpwgoi/scuLermgeorworeuerpedwuseraircnergisftaihccerirfeicceodvefroyr paenraitoodsm.iocfAs the
asphyxiation and discarded.
ed by carbon dicnige
MATERIALS AND METHODS
A. Test Substance Naasseosf uthae satnucdey;,nHoagevid7e,ncwteoeafsstisnsusubtpaspbtliailneicdtebywywaatshseaossbpssouenmrsveoedrd.taosbepsatlaeblyeeltlhorwousgohlodu.t Pthuerietxywpoasurle a}
B. Test Species
IaYrnoreiu.vnaRlg,alaediulgth,,mNaolrethCrCalr:oClDina(.SDT)hIeGSratBsRwerartesawpeprreoxriemcaetiveeldy f7orormChwaerelkess oRlidveoLrnabtoheradtaoyroifes,
~ -YY
Company Sanfizec. Doonotcontain Techcpr
12E5T77T7:IInnhhaallaattiioonnAApppprrooxxiimmaatteeLLeetthhaallCCoonncceenntraattiioonn((AALLCC))iinnRRaattss__
DuDpupoonn1t212996666.
-
Rats
Crl:
have
CD(
historically
SD)IGS BR
been used in saf
rat was selected
ety
bas
evaluation studies
ed on consistently
for inhalation toxicity testing.
acceptable health status and on
Th
e
extensive experience with the strain at Haskell Laboratory.
C. Animal Husbandry I Quarantine
`Rwaetrsewweerieghqeuadraanndtionbesdaefrtveerdafrorrivcallinoicar6l sdiagnyssopfridoirsetaostees3titngi.mesD.uring the quarantine period, rats 2. Animal Selection
Prreiloerastoedcafcrhomexqpuoarsaunrtei,ne6.maTlhee rsaetlsecwteerdeasneilmeactlesdhfaodrubseeenongatihneisntguwdeyifghrtoamtthaenroartmstahlartatweearned adtetmeomnpsttrwaatsedmandoeovteorrtasnidgonsmolfydgirsoeuapsea,niamnadlsw.ere the appropriate age and body weight. No
3. Identification atEoaccehxhparonasitumrwaeal,stachsoesutiladginlbeoedfaiednaeanctnhiifaimenadilmaafnltuemrabneedxprcoawsghueircecahrawdnadwsedrruereciomnrgadrtehkdeedroenwcioatcvhearrwyadtpeaefrrf-iiioxnde.sdotloutblheepceangse.soPtrhiaotr
4. Housing
Eaxbcoevpetcdaugreibnogaredxsp.osure, rats were housed singly in stainless steel, wire-mesh cages suspended
5. Animal Room Environment tReamtpsewreatruerheooufse1d8-i2n6prCox(itamrigteytetdo ttohe22i-nh2a4laCt)ioanncdhaamrbeelartsi.veAhnuimmiadlitryooofms30w-e7r0e%m(atianrtgaeitnededtoat40al6i0g%h)t./daArnkicmycalle.roEoxmcsurwseiroensarotuitfisciidaelolyfitlhleusmeinraatnegde(sfwlueorreeosfceinntsulfifghitc)ieonntamnaganpiptruodxeimaantde/o1r2 hour duration to have adversely affected the validityofthe study.
6. Feed and Water
tEaxpcewpattedrurwienrgeeaxvpaoisluarbel,e aPdMIlibNituutmr.ition International, LLC Certified Rodent LabDiet 5002 and
7. Animal Health and Environmental Monitoring Program
--~
fAosllsopweciinfgipedroicnetdhuereHsasakreelplerLafboorrmaetdopreyrainodiimcaalllhyeatlotehnasnudreenthvaitrocnomnetnatmailnamnotniltevoerlisnagrperboeglroawm, the those that would be expected to impact the scientific integrityofthe study:
TTT
eee Company Sanftized. Does not contalnTSCA CBE
$2577: InhalatnionaAppproesimate LLetehbalCCoonnceennrmaatbioonn(AALLCC)iinnkRaats
DDuuppoonnet1122096666
~
+
Water samples are analyzed `and other contaminants.
for
total
bacterial
counts,
and
the
presence
ofcoliforms,
lead,
+ Feed samplesareanalyzed for total bacterial, spore, and fungal counts. * bSyamtphleecsagferwoamshferress.hly washed cages andcageracks areanalyzedto ensure adequate sanitation
sqCpeuerictiriffeiimeeeddnhatensaivmaynamdefnteoaeltdso,isauefsxleacdte,oexdgiunsa,tracathneltdoermeiadnaxbtiyedmtuhheymdmcraoonncucaferanbctotrnuasrt,eiroanntsdoo fomrekgeaetnysocppeohcnoistfpaihmeaidtnneausnt.rti,tTiihonencalluding `pwroeuslednncoeotbfetheesxepeccotnetdatmoiniantms btpehleaoiwntctehgeritmtayoxfitmhuemsctoundyc.entration stated by the manufacturer alrfahfbeeocratanetidomrtayhleahnveiaalmliadtlihtvayeontfedtriehnneavriisratonu.dnym.eEnvtaalluamtoinointooftrihnegsperdoagtraadmidisnaodtmiinndiisctaetreeadnbyyctohnediattitoennsditnhgat
D. Inhalation Exposure System
1 Aunosphere Generation
--_
l1C0ah0sasmCbrteoorumnaedtl-mtbootshtpihoetmreseftslsawusebksrptelaangcceeen.deriaFnitletdehrebeaydt,ianhcgirogmshao-nlptirlzeeas.tsiuorTnehoeaftirfh,leamsekstowelraiedsdtheientattsoeutdbhstetofaalnpacperoinxaiimatweiltyh a
tt`hhmeeodf0er.ls1t0Sc8mhg5a/1mLbmeearxspwsohsefulrroeew,ac2concothnrdaoemlnlbeserar,tsicowanreiraeeedruostsehodel. evTohlevevdavpaoproprastsherdoufgrhohmeathteedhegaltasessdk ttbuubbyaiinngBg,rionFgfokors
hseeactoenddtucbhianmgbienrtfhoer aexnpiomsaulreexpcohsaumrbee.rFwohretrheea1n.w8aaemsrgof/sooLrlmeewxdap.sosfTuorhreem,eatdch.reosvoalpothrepnapsascesdefdrionmtthtehe
dTiesscthaatrmgoesipnhteortehsewfeurmeeehxohoadu.sted through an MSA charcoal/HEPA filter cartridge prior to
2. Chamber Construction and Design
3T4h1e.exApobsaufrfelechinasmibdeeresacwhercehacmonbsetrrupcrtoemdootfgedlausnsif(ocrylminddirsitcrailb)utwiiotnhoaftnhoemitnesatlatinmtoesrpnhaelrveo.lume of 3. Exposure Mode
`cDvouanrsiicanatgltanecxohpseoedsputiroeect,ehsea.neixmTpaholessurrweesetrcreahiainmnedrbsievrwiedsuroaeltlihynastretershtteerdnaioinsneeodofianpepoaelcryhfmoeartnahityemldamlsetetaxhitanlceernsydslesadtteieenltfoccyelpilnadteerswhwiitchh
chamber.
the exposure
--~ -YY YY
`Company Sanftized. Does not contain TSCA CB
He25777; Inhalation Approximate Lethal Concentration (ALC) in Rats
--
E. Characterization of Chamber Atmosphere
DuPont.12966
1. Test Substance Sampling and Analysis
aahtpemporsoapxtihmmeoarstpeehwleeyrri3ec0-cdmorniacnweunnttefrraiotntmieortnvhoaelfssHadm-up2rl5ii7nng7g7epawocarhtsetdxrepotoseuurgrmhei.ane2Kd5nbmoywmgnrafvviliotmleerutcmraeicsoafnaclhysaimsbaetr p`Cr-e3-3swMeiicgrhoebdaGlaenlcmean. gTlahses aftibmeorsp(hTeype A/E) filter. The filters were weighsesdetotne tahCatacbonstaaaidned a datimfofseprheenriceesatmhpelperde.- and post-samplriincgcfoinlcteernwteriatgihotnsodfiHv-id2e5d7b7y7t`hweasvoclalucmueloaftedchfarmobmetrhe
2. Particle Size Determination
Apaestaimcplleeletsosdtehtaenrm1i,n3e, oparrt1i0cluemsidzieadmiestterri)buwtiaosnt(amkaesnsdumreidnigaenaacehroedxpyonsaumriec wdiitahmeateSriearna1d.peSrocreinnt
210 cyclonepreseparator/Cascade impactor and Sierra series 110 constant flow air sampler.)
3. Environmental Monitoring
ohCohmura.omblTelhreeaaainrirdrflfrolewocwowwradasesdsemntoianttiattlohleryeabdengcdionnwtnhiiennnugeaolvfleyrewacichthahneagxepcsoaslwiuebrrreaettemodaaBdcrheioedovukersamtoldeeasltS1903a1irEcahnaanesgebs eper
~
2hCuhdmiaigmditbiaetlyrtwrtaaecsmepatebarlraegtetuthreeedrwamtaos5m0etta+ergr1e0at%end.dartTe2hco2err+deel2dC3.tiTmhese dtuermipnegractaucrhe ewxapsosimunorgnei.etaocCrhehdae.mxcpbooenstruirrneuealllyawith
SBReiHnoScsey1ns0it0aeCtmisdoimngoiwdtaalsptsayrcgherteodmteotbereaantdlreaesctor1d9e%d.at3ivTtehiehmeuosmxidydugirteiynngwcaoensaccemhnetearxsaputoriseoundreww.aitsChmhaeanamsOboemrreeogdxaywgmeoepdneal
el 3100R oxygen analyzerandrecorded 3 times during ach exposure
F. Anatomic Pathology Evaluation
halidlsdtaoinptiaitmhaoolnlsotfghryeoalmnudtnghmsei,0ct.rr1oa0scchmoegpa,/icLnaoleslxeypo(es4xuacrmreionsuesndds.eecrtLwiueonnnstg)a,welgairrgoyhsntsxs,pawaentrhdoeploohbgaiyrayenxsamwienraetipornosaetsseaecdriffioce.
sacrificed 1-day after exposure to 0.10 mg/L.
ined for (ne 3 quis:
~ -Y
`CompanySaniizoc. Doss not contain Tsp car
125777: ntalation Approximate Lethal Concentration (ALCi)nRats ~~
DuPont12966
RESULTS AND DISCUSSION
A. (ETxapbolseu1r)e Conditions
aeAenriomddaslmsanmwiecretdhieisaxmpsetolusederydsw(teoMrHeM-Ac2o5Dn7)s7i7wdeearrteemde5t.ao5nbaecnodmnac6re.gn8itnuraamlt.liyonrsesopifrab0.l1e0 oinr a1.t8,mgu/tL.eTphseaamtemdosipahneres Smtahlelseerh,igmhorcoenrceesnptirraatbiloenasedruoseool stihzee;choonwdeevnesrat,iiotnaapepreoasSroeelvdefrtoahralmtaittnitgsemlcpaorlugselmdpedrro:e-aa:gcgcl1o0ommpperlroiadstuhecesed,
TABLE |
:
CHARACTERIZATION OF TEST ATMOSPHERES
AEROSOLMECAOSNUCRENETDRATION mg/L)"
AEROSOL SIZE
~
MEAN
0.10
SD.
0058
MMAD
00R1A8N-G0E15 8]
im)'
sg
PERCENT G2S2D|[2< 4 T | y Spm m [ <iopm
18 012 11-15 8| 43
18
8
37 13
77 86
#
ThehfxeepeoisMpuMrreAeDtpsh(oeeMmreanasent,MlosetdaenidnaArfcditdednvyianitagiouinrce.5D.i0aC)m,eataenird)nansbgewfseorroenearc1hopmenxpeaodsperr,iobaisseodon esameplressperexposure,
4 PGeerocmeenttraiecroSstoalndmaarssd.Deviation,
la during cach
6Ch8a%mbcehramtbeemrpeariartluroewrraannggeeddffrroomm2135ttoo2245LCi,mcihna,mabnedrtrhelaotxivyegheunmisdoitmyrmanegesd fwraosm2416%to
B. Mortality, Clinical Signs, and Body Weights No deaths occurred during the study. ptFoioncnilacoiltwlyiynfogrbeesqxeuperonvsteuldryeiosnb,siwenhrhavelenadttiihonencrlsauttudsdeidweescroweliortrheemdroadtvisesudcnhrarogme otfthehreesntorsanaenrsd tehyeesc.linTiocaelssisgingsnsofare were observed during the remainderofthe recoverydpeerrrieosdtraint. No elimi signsoftoxicity.
~~ -
company Sani200.n0otc0o0nt8i car
teers ee
125777: Inhalation Approximate Lethal Concentration (ALC) in Rats
DuPont12965
"~
No body after the
weight 14-day
rleocsoevserwyepeerioobds.erved
inats
exposed
10
010
mg/L
immediately
afer
exposure
or
tpThhoersreueercoeov,fe6rfryoalptlseroeiwxoedpd.obsyedntoor1m.8almgw/eLigshhtogwaeidn asltieghatpwperiogxhitmalotsesl(y<51-010grgaimdsa)y)ofnorthheedaryomfaotlulgoeweinogc
C. A(Tnaabtleosmi2.c3)Pathology Evaluation afTnridsosmeuve3arslauwasetrehedastfurbwomemirtectaescdahcfrriraftoi:mcle3udnag1ts4,dsattyrhasactahwefaet,rrenotshsaeecre(ix4fpicocrseoudosrsen.seedcTtahiyeonasffotlelrow0i.ng10fmigv/eLs eexrpeopsruoreceasnsded
), Laryms, andpharynx
TABLE 2
SUMMARY OF MICROSCOPIC FISNDUIBNSGTSAINNCREATS EXPOSED TO 0.10 mg/L TEST
~
D(NAUYMSBAETREERXEAXMPIONSEUDR)E
T 14 06
LUNG
HNeomtorrermhaargkea,blaelveolar
1 21
Infiltration, mononuclear cell, perivascular - |
TRACHEA
Not remarkable
33
NOSE
Not remarkable
33
LARYNX
INnofitltrreamtiaornk,ambolneonuclear cell
213
PHARYNX
--NNotoremtarkarbleemarkab3l333e
vTehreyremiwneirmealn,oaanpdprweecrieablliekdeliyffaegroennaclescbhaentgweesenoctchuer2rignrgouatpst.heTthiemeaolfveosalcarrihfeicmeorrhages were
~~ aieprlpeehacrooeundsgtiodh0ebreceotdnhceu0rrbersoeunoltfttcohoftnertertoayltpsmeewanentrd.espervoevriitdyede,xptehcetcehdainngethsisprsetsreanint oifnratthse,isasduensoenxeaomfitneedm
------------------
`Company Saniized. Does notcontain Ts ca)
H2577: ninAponteLethal Consnenion (ALC)inRas
Duron.12966
P
Lung weights in 3 rats sacrificed 1 day aftr exposure to H-25777 at 0.10 `mg/L did not appear to
be.different study.
from
control
ratsofsimilar
`weights
in
a
recent
Haskell
Laboratory
inhalation
TABLE 3
FINAL BODY AND LUNG WEIGHTS ONE DAY POSTEXPOSURE
ANIMAL BOFDIYNWAELIGHT LAUBNSGOWLEUITGEHT
NUMBER
8)
2)
673575
268
1.539
EE 673576
673578
om 262 271
ues 1.540
1.606
= bReolatlivte wLeuingghtWseicgahlt-leFdl BFoodlyloWwseight 100
RELATIVE LUNG WEIGHT
(%)*
ox 0.57
-
0.59
0.59
CONCLUSIONS
~~
Under the conditionsofthis study, the approximate greater than 1.8 mg/L. According to Haskell
lethal
concebiration
(ALC)
for
H-25777
is
considered to beat most `mass median aerodynam
slightly toxic
Laboratory toxicity classifications, (aerosol ALC 0.8-2.0 mg/L) in male rats.
H-25777 is However, the
e6x8pousmur.e.TaHragedttehdeMgeMnAerDiactseddiinaameirenothsaeolrla(tbiMeoneMsnAtusDdm)iaoelslfaerrtehatefttrheoissmtecdo1 ntacoeern4otsBroalmtaittoont,hailsi.tliocsownmceanxtriamtuiomn lwuansg
toxicity could have been somewhatgreater.
possible that the
RECORDS AND SAMPLE STORAGE
NSepweacrikm,enDse(liafwaaprpel,icoarblaet)I,rronawModautnzt,aainndRtehceofridnsalMraenpaorgtemwielnltb,eWrieltmaiinnegdtoatn,HaDseklealwlarLaeb.oratory,
REFERENCES
1. SCearliceusla2t1i0onAmdebsicernitbeCdaisncSaideerrIampIancsttrourmsenatnsd, CIyncc.l,oBnuelPlreetsienp7ar-a7t9o-r2s1.9IM, Instruction Manual:
---
2. DRautPso.ntUnHpausbkleilslheLadr borat o(20r 03). H) -24678: Two-Week Inhalation ToxicityStudyin Male
-
Company Sentze. Doesno contain sp a1
eee ----