Document BVee7z6mkeamL9oZXKr5YRRL
MAz6 _ 3247
429
R226 - 32%7
Duron 9603
"TRADE SECRET
Study Title
H-25134: Inhalation Approximate Lethal Concentration (ALC) in Rats
Laboratory Project ID: DuPort.9603
AUTHOR: Thomas A. Kegelman, A.A.
STUDY COMPLETED ON: May 22, 2002
~~
PERFORMING LABORATORY: E.I du Pont de Nemours and Company
Haskell Laboratory for Health and Environmental Sciences
NElekwtaornk,RoDaedl,awP.aOr.e B1o9x71540-0050
CompanySaifized:Bowsnatconoi TSCACEI
Page 1 of 1
H25134:InhalationApprLoethaxl Coincenmtraationt(AeLC)in Rats
Dupon9603
CERTIFICATION
1, the undersigned, declare that this report provides an accurate evaluationofdata obtained from
this study.
mneySyicon: <7 Los"sFro4mSaiLtoScoalnKesgooneArA
GRHay 20
Company Sanitized. Doss not contain TSCA CBI
3
35154: bin AgLeti tConsm mion ALC) as
STUDY INFORMATION
SubstanceTested:
(a) = H-25134
Smiter Noone ont (RENN Haskell Number. 25134
ns esisom (RNIN |
EE re
--
-a
Physical Characteristics: Dark brown solid
hrs `Stability: The test substance appeared to be stable under the. conditions of the study; no evidence of instability was
Sponsor: EL du Pont de Nemours and Company Wilmington, Delaware 19898
.
USA.
.
.
Study Initiated/Completed: February 12, 2002 / (see report cover page)
In-Life Initiated/Completed: February 12, 2002/ March 19, 2002
ompanySanizsdDoss ol conta TSACE!
v
H-25134: Inhalation Approximate Lethal Concentration (ALC) in Rats
DuPont9603
--~
STUDY PERSONNEL
Study Director: Thomas A. Kegelman, A.A.
Management:
Arthur J, O'Neill, B.S. Scott E. Loveless, Ph.D.
Janice L. Connell, M.S, B.A, CLH. Primary Technician: John A. Tedesco, B.S.
i
Toxicology Report Preparation: Management.
Maryanne M. Wilford, B.A. Nancy S. Selzer, M.S.
Laboratory Veterinarian: William Singleton, D.V.M., A.CLLAM.
Company Saniized. DoRotsconstin TSCACE! _------_E-- R ----_--
H25134: Inhalation Approximate Lethal Concentration (ALC) in Rats --~
DuPont9603
SUMMARY p`eTrhireoedtgoroHu-p2s5o1f364mianlaeirC. rTle:sCtDat(mSoDs)pIhGeSreBsRwerraetsgweenreeraetxepdobsyedhenaotsien-gotnhley tfeosrtasusbinsgtlaen,c4e-thooaur mtaeragseutrededtegmrpaevirmaetturriecoalfly3.04RCat.s CwoenrceenwteriagthieondsaonftdhoebsceornvdeednsfoarticolinniacearlossoilgnosoffH-to2x5i1c3i4tywdeurreing a 14-day recovery period.
3R7at7smwge/rme.exNpooseddea1t0hsatomcocsuprhreerdeisnotfheH-22559a13n4da3t3m6emagn/cmo?nceexnptorsautiroengsroofup2s5,9,ho3w3e6v,eorr, all ras in sttuhdey3i7n7dmicga/tme?d garsotuepepwedroeseforuenspdodnesaedinwirtathsinex4phoosuerdsotofatehreoseoxlpocsounrcee.ntrTahteiolnesthsalliigthytldyathaigfhoerrthis mtohratnal3i3ty6. mgT/hme',matshesremfeodrie,anit awearsodnyotnapmriacctidciaalmettocerosndfuorcttahenaeerxopsooslurteesttheadtrraensgueldtefdrionmpa3r.t4iatlo 44pm.
o`Tnhleyoonblsyerclviendicualposnigunonflotaodxiicnigttyheobrastesrvferdomdutrhienrgestthrisaisnteursdyafwtaerseoxcpuolsaurredi.scIhnaragded.itiTohni,srastisginntwahse w2e5i9ghatn)dl3o3s6semsgo/nmt?heexdpaoysfuorlelgorwoiunpgstheexheixbpiotseudrselibguhtt bbeogdaynwetoigrhegtai(nlewsseitghhatn b5y%tohfe nineixttialdabyo.dy
~ Under the conditionsofthis study, the ALC for H-25134 is 377 mg/m'. According to Haskell
Laboratory toxicity classifications, 200 and 800 mg/n?) in male rats.
H-25134
is
considered
to
be
moderately
toxic
(ALC
between
Company Saniized. Does not contain TSCA CBI --~
ee.
1.25154: Inhalation Approsimate Lethal Concentration (ALC) in Rats
Dupo 9603
--~
INTRODUCTION
`The objectiveofthis study was to determine a 4-hour inhalation approximate lethal concentration (ALC) of H-25134 in male rats. The ALC is defined as the lowest atmospheric concentration tested which caused the death of1 or more exposed rats either on the dayofexposure or within at least 14 days following exposure. The inhalation routeof exposure was chosen based on the expected routeof potential human exposure and was requested by the sponsor.
MATERIALS AND METHODS
A. TestSubstance
Tm [The test substancg, H-25te1s3t4s,ubwsatsanscueppwlaisedabsysutmheedsptoonbseorstaasblaedtahrrkobugrhoowuntstohleidexwpiotshurapeuprhiatsyeooff
the study; no evidBhce ofinstability was observed.
B. Animals
--~
`Young adult, male Crl:CD(SD)IGS BR rats were received from Charles River Laboratories,
Inc., Raleigh, North Carolina. The rats were approximately 7 weeks old on the day ofarrival.
Rats have historically been used in safety evaluation studies for inhalation toxicity testing. The eCxrtle:nCsiDv*e(SexDp)eIrGiSenBcRe wriatthwathsessetlreacitneadtbHaassekdelolnLcaobnosriasttoernyt.ly acceptable health status and on
C. Animal Husbandry I. Quarantine and Animal Selection
Rats were quarantined after arrival for 6 days priorto testing.Duringthe quarantine period, rats were weighedandobserved for clinical signsofdisease 3 times. Rats were obtained from the general populationof sockrats released from quarantine and were selected for useonthis study from those rats exhibiting a normal patternofweight gain and no overt signsof disease.
2. Housing Rats were housed either singly or in pairs in stainless steel,wire mesh cages suspended above cage boards.
`Company Saniized. DoesnotcontainTSCACBI
-
J2H5:21531344:: IInnhhaallaattiioonnAApppprrooxriimmaatteeLLeetthhaallCCoonncceenntaattoonn((AALLCC))iinnRRaattss__
~~
3. AnimalRoom Environment
DuDPuoPnotn.99660033
EAnnviimraolnmreonotmasl wceorndeimtaiionnstoafintehdeornoaomtsimwere-rceonttarorlgleetd,teod12b-ehowuirthliinghat/t1e2m-pheoruartudraerkracyncglee.of i2n3su%ff1icCieanntdmaagnreiltautdiveeahnudm/iodridtuyrartainogneotofh5a0ve+a1d0v%e.rseElxycaufrfseicotnesd othuesivdaleidtihteyseofrtahnegesstuwdey.re of
4 Mdentification
cEaarcdharfaftixweadstaostshiegnceagdea. uPnriiqoureto6-edxipgiotsuirdeen,ttihfiectaatiiloonfneuamchberratwhwiacshccoodrerdewsiptohndweadtetro-ainnsuomlubbelreed markers so that individual rats could be identified afer exposure.
5. Feedand Water
t`aEpxcweapttedrurfirnogmeUxnpiotseudreW,aPteMrIDNeultariwtairoen wInetreernaavtaiiolnaabl,leIancd. lCiebrittiufmi.ed Rodent LabDiet 5002 and 6. Health Monitoring Program
fAosllspoewciinfgipedroicnetdhuereHsasakreelpleLrafboorrmaetdorpyerainoidimcaalllhyeatlothenasnudreenthvaitrconomnetnatmailnamnotniltevoerlisngarperboeglroawm, the those that would be expected to impact the scientific integrityofthe study: ~~ + aWnadteortshaermpclonetsaamrienaanntasl.yzed for total bacterial counts, and the presenceofcoliforms, lead, + Feed samples are analyzed for total bacterial, spore, and fungal counts. + bSyamtphleecsagferwoamshferressh.ly washed cages and cage racks are analyzed to ensure adequate sanitation rCeerqtuiifrieemdeanntismaanldfneoetd tios uesxecde,edgusatraatnetdemeadxbiymtuhemmcaonnucfeancttruarteirontsoomfekeetyscpoecnitfaimeidnannuttrsi,tiionncalluding pspreecsiefniceedohfetahveysemectoanltsa,maifnlaantotxsinb,eclholwortihneamteadxhiymdruomcacrobnocnesn,traantdioonrgstaantoepdhbosypthhaetemsa.nufTahceturer would not be expected to impact the integrityofthe study. I"Tahbeoraantiomraylahneiamlatlh vaentdereinnavriiraonn.meEnvtaalluamtoinointoofritnhgesperdoagtraadmidisnaodtmiinndiisctaetreedanbyyctohnediattitoennsditnhgat affected the validity ofthe study.
D. Study Design
wTherreeeegxrpoouspesdonfos6em-oanlleyrfatosr aeascihngwlee,re4-ehxopuorspeedritooda.erosol atmospheres of H-25134 in air. Rats
_--
Company SarDeusknoti conte ainTd SCA. CHI oe
SLH-E25S134: IInohhaalaattioonnAApppprroovxiimmaatteeLLeetthhaallCCoonncceenntrraattiioonn((AALLCC))iinRRatasts_
DDuuPPoonntt99660033.
--
Rats were exposure.
approximately
8
weeks
old
and
weighed
between
233
and
278
grams
at
the
time
of
Rsiagtnssowfertoexoibcisteyrviemdmefodriamtoretlaylaitfyerdutrhienygweearcehreexmpoovseurdefarnodm otbhseerrevsetrdaifnoerrmsofrtoallliotwyinagndexcploisnuicrael. aDnudrwienrage g1e4n-edraayllpyoswteeixgphoesduraenpderoibosde,rvaleldsfuorrvicvliinnigcarlatssiwgnesroefotbosxeircvietyddeaaiclhy udnatyilfowreimogrhttalgiatiyn,s awlelrseurovbisveirnvgedr,atasnwdertehesnacwreirfeicwedeibgyhceadrabnodn doibosxeirdveedaswpeheykxliya.tiAont atnhed ednisdcaorfdtehde.recovery period,
E. Inhalation Exposure System
1. Atmosphere Generation
wCahsampbleacreadtimnoasp1h0e0re0s-mwLerreougnedn-cbraottetdombyflaaesrkotshoaltizwaatsiohnoeafttehdetote3st04su-b3s0t9anCcev.iaTaheUntiemstanstublsetance thoeaatgeirt.atAe tshteirmreilngtemdotteosrt wmaatserpiaols.itiFoinletderoevd,erhitghhe-tporepossfutrheeaifrl,amsketweirtehdatrootdheatftlaacshkebdytao tBhreomooktsor mAdoddietlio1n3a5l5fiSlhteor-eRd,atheigRho-tpormeesstuerre, aciarrmrieetdertheedcdoonwdnesntsrateiaomnfareoromstohleifnltaostkhbeyeaxpnoisduerneticcahlamber. rthoetotmeesttesru,bdsitlauntceedwtehreetecsotnattromlolsepdhberyevatorytihnegdtehseiraeidrfcloonwcernattreasttihorn.ougChhathmebfelrascko.ncTehnetrtaetmipoenrsaotfure --_ otfhethUenitmesatnstulbeshteaantceer.inside the flask wastargetedat 304C and adjusted by varying the voltage to
cThesatrcaotamols/pHhEePrAesfilwteerrecaerxtrhiadugsetperdiotrhrtooudgihscahdarryg-eicientcootlhdetfraupmfeohloloodw.ed by an MSA.
2. Chamber Construction and Design
`2T9hLe.exApobsaufrfelechinasmibdeerthweacshcaomnbsetrrupcrtoedmooftegdlausnsif(coyrlmincdhriacmabl)erwidtihstarinboumtiionnaolftihnteertneasltvolume of atmosphere.
3. Exposure Mode
cDounriicnagl enxopsoespuireec,esr.atsTwheerreesitnrdaiivniedrusawlleyrereisntsrearitneedd iinntpoearfpoorlaytmeedtshtyalimneletshsacstreyellactyelifnadceerpslawtietwhhich
wasattachedto chamber.
the
exposure
chamber
so
that
only
the
noseofcach
rat
extended
into
the
POT Send Mon souvaen nh --~
Ed
B:25134; Inhalation Approximate Lethal Concentration (ALC) in Rats
DuPont9603
-- F. Characterization of Chamber Atmosphere
I. Test Substance SamplingandAnalysis
`Tahpepraotxmiomsaptheelyri3c0-cmonicneuntteraitnitoenrvaolfsHd-u2r5i1ng34eawcahsedxeptoesurrmei.nedKnboywgnravviomleutmreicsoafnaclyhsaimsbaetr partem-owsepihgehreedwGeerlemdarnawgnlafssrfoimbetrh(eTsyapmeplAi/nEg)pofirlttetr.roTuhgehfail2te5rsmwmerefiwleer ciasgsehotetnedathCatachonntmaoidnceld a dCi3ff3erMeinccreoibnaltahencpere.-aTnhdepoasttm-ossapmhpelriincgcfoinlcteerntwreaitgihotnsodfiHv-id2e5d1b3y4twhaesvocallucmueloatfecdhfarmobmetrhe atmosphere sampled.
A sample to determine particle size distribution (mass median aerodynamic diameter and percent
particles less than 1, 3, and 10 pm diameter) was taken during each exposure with a Sierra Series 210 Cyclone Preseparator/Cascade Impactor and Sierra Series 110 Constant Flow Air Sampler."
2. Environmental Monitoring
hCohuarm.bTehreaiarifrlfolwowwwaasssemtoantittoherebdegcionnntiinnugaolfleyawcihthecxaploisburraetetdoBarcohoikesvemoatdelelas1t31525aSirhoc-hRaantgees per
CRohtaommbeetrertsemapnedrarteucroerdweadsintiatrigaelltyedanatd2w2he+n2evCe.r cThhaengteesmpweerraetumreadweasdumroinnigtcoarcehd cexopnotsiunruea.lly with
~~ `aCnhOammbeegraremloadtievle 6h5um0iTdhietrymwoacsoutparlgeetTehdeartm5o0me&te1r0%a.ndTrheecorreldaetdiv3ethiummeisddiutryiwnagseamcehaseuxrpoesdurwei.th
CanhaOmmbeegraomxoydgeeln c5o1n0c0enDtirgaittiaolnPwsaycshtraormgeetteedr taondbereatcolredasetd 139t%i.meTshdeuroixnyggeeancchoenxcpeonstruartei.on was
`measured exposure.
with
a
Biosystems
model
3100R
Oxygen
Analyzer
and
recorded
3
timesduringcach
`Company Sanitized, Dos, notcontain TscAcay ET
22H:521513344:InIhnahlaaltaitioonnAApppprrooxxiimmaatteeLeLetthhaall CCoonncceennttrraattiioonn((AALLCC))iinnRRaattss --_
RESULTS AND DISCUSSION
DuDPuoPonntt99660033
A. Exposure Conditions (Table 1)
aAtnmiomsaplhserweesregeenxeproasteedd tion Hth-i2s5s1t3ud4yawtecroencceonntsriadteiroendsotfo2b5e9r,es3p3i6r,abolre3t7o7mamrgg/imn'a.llTyhreespirable in rats, as the mass median aerodynamic diameters (MMAD) ranged from 3.4to 4.4 pm.
TABLE 1
CHARACTERIZATION OF TEST ATMOSPHERES AND ASSOCIATED ANIMAL MORTALITY
"AEROSOL CONCENTRATION (mg/m)'
AEROSOL SIZE MORTALITY
MMAD
Percent| (# deaths/
--_
Mean
259
S.D.
405
Range n|
173-295 8|
(um) GSD <10pm'|
44 17 9%
#exposed)
0/6
336 377
274 286-373 8| 43 540 290-441 8| 34
15 16
98 99
0/6 6/6
a peRerpreexspeonstusret.heVmaelaune,ssatraenrdeaprodrdteevdi0ationig(aSi.fi)c,anntdfigruarnesg.e or each exposure, based on samples TduhreinMgMcaAchDex(pMoassusreM.idian Aerodynamic Diameter) sbasedon 1 particle siz sample ahen
4 GPeerocmeenttraiecrSosuonldmaarsdsDheavviiantgioanerodynamic equivalent diameters of ess than 10 pm.
`4C7h%a,mbcehramtbeempreariartfulroewrraannggeeddffrroomm 11991t002231CL,imcihna,mabnedrtrheeloatxiyvge ehnumciodnicteyntrraantgieodn fwraosm2310%.to `Aplatrhamoeutgehrsc,htahmebseerdetveimapteiroantsuwreeraendcornesliadtievreedhunmoitdtiotyhawveereadsvleirgshetllyyoauftfseicdteedthtehetavragliedtietdy of this study.
`eAxncuardsdiiotinooncalcuerxrpeodsduurreiwngasthcisonedxupcotseudrewitthhataemxceeaendecdontcheentlreathtailoncoonfce2n5t7ramtgi/omn'o,fthhoewetveestr, an rseusbuslttasnocfet.hiBseceaxupsoseutrheeweexrceurnsoitoncoenxsciedeedreedd twhheelnetdhealtecromnicneinntgratthieoAn LfoCr tfhoirsttheisst sstuubdsyt.ance, the
CompanySex2ee.Goesnotcont Tscace ieee
SH2:251334:IIhnhaaliatoionnAApppprrooxxiimmaatteeLLeetthhaallCCoonncceennttrrautiioonn (AALLCC))iinnRRaattss --~ B. Mortality, Clinical Signs, and Body Weights
DDuubPoonntt99660033.
Deaths occatucorncerntraetiodnsof ofexposure.
377
mg/m
H-25134.
Rats
were
found
dead
within
4
hours
tFooxlilcoitwyinogbseexrpvoesdurweas,s wochuelnarthdeisrcahtasrgwee.reDruermionvgetdhefrreommatihnederreostfratihneerrs,ectohveeornylpyerciloindi,canloscilginniocfal signsoftoxicity were observed.
Sfloilglhotwiwnegigthhte elxospsoessurwee,reanodbsrearnvgeedd ifnrroamts1ftroo3mptehrec2en5t9ofainndit3i3a6l mbgo/dmy?wegirgohtu.ps Roantsthseudbasyequently
resumed normal weight the recovery period.
gains
(approximately
5-10
g/day)
and
gained
weight
for
the
remainder
of
CONCLUSIONS U37n7demrg/thme'.conAdcictoirodnisongftthoiHsasstkuedlyl,Ltahbeoarpaptroorxytiomxaitceitlyectlhaaslsciofnicceantitornast,ioHn-(2A5L13C4) ifsorcoHn-s2i5d1er3e4ditso `be moderately toxic (ALC 200-800 mg/m) in male rats.
~
RECORDS AND SAMPLE STORAGE
`NSepweacrikm,enDs(eliafwaaprplei,coarblaet)I,rronawModautnat,aainndRtehceofridnsalMraepnoargt ewmilelnb,e Wrieltmaiinnegdtoatn,HaDsekleallwaLraebo(rfaotromreyr,ly known as the EL. du Pont de Nemours and Company Records Management Center).
REFERENCES 1. CSearliceusla2t1i0onAdmebsicernibteCdaisncSaideerrIamIpnascttrourmsenatnsd, CIynccl.oBnuellPerteisncp7a-r7a9t-or2s1.9IM, Instruction Manual:
~ -
"PenSantza"d Opo, ms ng, an TSCA ogy