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Methanol (Casrn 67-56-1) _ Iris _ Us Epa

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  • 3/2/2015 Methanol(CASRN67561)|IRIS|USEPA

    http://www.epa.gov/iris/subst/0305.htm 1/20

    ListofIRISSubstances

    SearchIRISbyKeyword

    IRISSummaries/Toxicological

    ReviewsEntireIRISWebsite

    Youarehere:EPAHome Research EnvironmentalAssessment IRIS IRISSummaries

    Methanol(CASRN67561)viewQuickView

    ReferenceDoseforChronicOralExposure(RfD)

    YouwillneedAdobeReadertoviewsomeofthefilesonthispage.SeeEPA'sPDFpagetolearnmore.

    Note:ATOXICOLOGICALREVIEWisavailableforthischemical.SimilardocumentscanbefoundintheListofAvailableIRISToxicologicalReviews.Linkstospecificpagesinthetoxicologicalreviewareavailablethroughoutthissummary.Toutilizethisfeature,yourWebbrowserandAdobeprogrammustbeconfiguredproperlysothePDFdisplayswithinthebrowserwindow.IfyourbrowserandAdobeprogramneedconfiguration,pleasegotoEPA'sPDFpageforinstructions.Inaddition,therearehyperlinkstothereferencecitationsthroughoutthisdocumentthatwilltakeyoutotheHEROdatabase(HealthandEnvironmentalResearchOnline)athttp://epa.gov/hero.HEROisadatabaseofscientificliteratureusedbyU.S.EPAintheprocessofdevelopingscienceassessments.

    0305

    MethanolCASRN67561

    HumanhealthassessmentinformationonachemicalsubstanceisincludedinIRISonlyafteracomprehensivereviewoftoxicitydatabyU.S.EPAhealthscientistsfromseveralprogramoffices,regionaloffices,andtheOfficeofResearchandDevelopment.SectionsI(HealthHazardAssessmentsforNoncarcinogenicEffects)andII(CarcinogenicityAssessmentforLifetimeExposure)presentthepositionsthatwerereachedduringthereviewprocess.SupportinginformationandexplanationsofthemethodsusedtoderivethevaluesgiveninIRISareprovidedintheguidancedocumentslocatedontheIRISwebsiteatwww.epa.gov/iris/backgrd.html.

    STATUSOFDATAFORMethanol

    FileFirstOnLine09/07/1988

    IntegratedRiskInformationSystem

    http://www.epa.gov/iris/subst/0305.htmLastupdatedon11/1/2014

  • 3/2/2015 Methanol(CASRN67561)|IRIS|USEPA

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    Category(section) Status LastRevised

    CriticalEffect PointofDeparture(POD)

    ChronicOralRfDAssessment(I.A.) online 09/30/2013

    ChronicInhalationRfCAssessment(I.B.) online 09/30/2013

    CarcinogenicityAssessment(II.) message 09/30/2013

    _I.ChronicHealthHazardAssessmentsforNoncarcinogenicEffects

    _I.A.ReferenceDoseforChronicOralExposure(RfD)

    SubstanceNameMethanolCASRN67561LastRevised09/30/2013

    TheRfDisanestimate(withuncertaintyspanningperhapsanorderofmagnitude)ofadailyoralexposuretothehumanpopulation(includingsensitivesubgroups)thatislikelytobewithoutanappreciableriskofdeleteriouseffectsduringalifetime.Dietcancontributetobackgroundlevelsofmethanol,principallyfromtheordinaryingestionoffruitsandvegetables.Thus,inthecaseofmethanol,theRfDisfurtherdefinedasanexogenousexposure(exposurefromasourceoutsidethebody)thataddstobackgroundlevelsofmethanolderivedfromadietthatincludesfruitsandvegetables(seefurtherdiscussioninSectionI.A.4).TheRfDisintendedforuseinriskassessmentsforhealtheffectsknownorassumedtobeproducedthroughanonlinear(presumedthreshold)modeofaction.Itisexpressedinunitsofmg/kgday.Pleaserefertotheguidancedocumentsathttp://www.epa.gov/iris/backgrd.htmlforanelaborationoftheseconcepts.BecauseRfDvaluescanbederivedforthenoncarcinogenichealtheffectsofsubstancesthatarealsocarcinogens,itisessentialtorefertoothersourcesofinformationconcerningthecarcinogenicityofthischemicalsubstance.IftheU.S.EPAhasevaluatedthissubstanceforpotentialhumancarcinogenicity,asummaryofthatevaluationwillbecontainedinSectionIIofthisfile.

    TheRfDof2mg/kgdayreplacesthepreviousRfDof0.5mg/kgdayenteredontheIRISdatabaseon09/07/1988.ThepreviousRfDwasbasedonanoobservedadverseeffectlevel(NOAEL)of500mg/kgdayforliverenzymechangesandbrainweightreductioninasubchronicoralgavagestudyofSpragueDawleyrats(TRL,1986),andacompositeuncertaintyfactor(UF)of1,000(10forextrapolationfromratstohumans,10forhumanvariation,and10forsubchronictochronicextrapolation).

    __I.A.1.OralRfDSummary

    UF POD/UF ChronicRfDa

    Extracervicalribs

    CD1mice

    PODInternal=43.1mg/L100 0.43

    mg/L2mg/kg

    day

  • 3/2/2015 Methanol(CASRN67561)|IRIS|USEPA

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    InhalationdevelopmentaltoxicitystudyexposureduringgestationdaysGD7GD17

    Rogersetal.(1993b)

    aTheRfDistheoraldosepredictedtoyieldamethanolbloodconcentrationequaltotheRfDinternal(PODInternal/UF)of0.43mg/L,usingthehumanPBPKmodeldescribedinAppendixBoftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013)thefinalRfDisroundedtoonesignificantfigure.

    __I.A.2.PrincipalandSupportingStudies(OralRfD)

    EPAhasderivedanRfDbyusingexposureresponsedatafromcandidateprincipalinhalationstudiesofmice(Rogersetal.,1993b)andrats(NEDO,1987)androutetorouteextrapolationwiththeaidoftheEPAphysiologicallybasedpharmacokinetic(PBPK)model[seeSection3.4oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013)].Thedecisiontouseinhalationratherthanoralstudydataisduetolimitationsinthedatabaseoforalstudies,includingthelimitedreportingofnoncancerfindingsinthesubchronic(TRL,1986)andchronicoralstudies(Soffrittietal.,2002)ofrats,thedeterminationthatdevelopmentaleffectsarethemostsensitiveeffectsofmethanolexposure[seeSection5.1.1oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013)],andthehighdoselevelsusedintherodentoraldevelopmentalstudies[seeSection5.2oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013)].ThecandidateprincipalstudiesforthederivationofanRfCandRfDaresummarizedbelowandaredescribedinmoredetailinSections4.3.2and4.4.2oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013).

    Rogersetal.(1993b)evaluateddevelopmenttoxicityinpregnantfemaleCD1miceexposedtoairor1,000,2,000,5,000,7,500,10,000,or15,000ppm(0,1,310,2,620,6,552,9,894,13,104,and19,656mg/m3)methanolvapors(99.9%purity)inachamberfor7hours/dayonGD6GD15.Therewerenomethanolrelatedreductionsinmaternalbodyweightgainorovertsignsoftoxicity.DamsweresacrificedonGD17foracomparisonofdevelopmentaltoxicityinmethanoltreatedgroupsversusthechamberairexposedcontrolgroup.Fetusesinallexposuregroupswereweighed,assessedforviability,andexaminedforexternalmalformations.Fetusesinthecontrol,1,000,2,000,5,000,and15,000ppmgroupswerealsoexaminedforskeletalandvisceraldefects.Reproductiveandfetaleffectsincludedanincreaseinthenumberofresorbedlitters,areductioninthenumberoflivepups,andincreasedincidencesofexencephaly,cleftpalate,andthenumberofcervicalribs.TheincidencesoftheseeffectsarelistedinTable44oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013).Asdescribedbelow,theincreaseincervicalribs/litterreportedinthisstudywasevaluatedforpossibleuseinthederivationofRfDandRfCvalues.

    NEDO(1987)evaluatedtheeffectsofpreandpostnatalmethanol(reagentgrade)exposure(20hours/day)onreproductiveandotherorgansystemsofSpragueDawleyrats.Inatwogenerationstudy,F0generationrats(30malesand30femalesper

    exposuregroup)wereexposedto0,10,100,and1,000ppm(0,13.1,131,and1,310mg/m3)from8weeksoldtotheendofmating(males)ortotheendoflactationperiod(females).TheF1generationwasexposedtothesameconcentrationsfrombirthtotheendofmating(males)ortoweaningofF2pups21daysafterdelivery(females).MalesandfemalesoftheF2generation

  • 3/2/2015 Methanol(CASRN67561)|IRIS|USEPA

    http://www.epa.gov/iris/subst/0305.htm 4/20

    wereexposedfrombirthto21daysold(oneanimal/sex/litterwasexposedto8weeksofage).NEDO(1987)notedreducedbrain,pituitary,andthymusweights,andearlytesticulardescentintheoffspringofF0andF1ratsexposedto1,000ppmmethanol.Toconfirmthepossiblecompoundrelatedeffectofmethanolonthebrain,NEDO(1987)performedanadditionalstudyinwhichSpragueDawleyratswereexposedto0,500,1,000,and2,000ppm(0,655,1,310,and2,620mg/m3)methanolfromthefirstdayofgestationthroughtheF1generation.ThenumberofF0parentalanimalsincludedpergroupinthissupplementalexperimentwasnotreported.However,thenumberofpupsperdosegroupper"periodafterbirth"wasreportedas1114/sex/dose/postnatalperiod,anditisreasonabletoassumethat,consistentwiththestandardcullingprotocolusedforboththeF1andF2generationsofthetwogenerationstudy(NEDO,1987pages185and189),thepupsforeachgender,doseandexposuretimecombinationcamefromadifferentlitter(toavoidproblemsassociatedwithlittercorrelation).Doserelateddecreasesinbrainweightswereobservedinthemaleandfemaleoffspringat3,6,and8weeksofage.Asdescribedbelow,brainweightchangesobservedintheseNEDO(1987)studieswereevaluatedforpossibleuseinthederivationofRfDandRfCvalues.

    DevelopmentalEffectsinPrincipalStudies

    Skeletaleffectshavebeenobservedindevelopmentalstudiesofrats(Weissetal.,1996NEDO,1987Nelsonetal.,1985)andmice(Bolonetal.,1993Rogersetal.,1993b).ThefindingsofBolonetal.(1993)andRogersandMole(1997)indicatethatmethanolistoxictomouseembryosintheearlystagesoforganogenesis,onoraroundGD7.Rogersetal.(1993b)reportedaNOAELfortheincidenceofextracervicalribsat1,000ppm(1,310mg/m3,33.6%perlitter)andaLOAELof2,000ppm(2,620mg/m3,49.6%perlitter)whencomparedtocontrols(28.0%perlitter).Increasedincidenceofcervicalribswasalsoobservedintheratorganogenesisstudy(NEDO,1987)inthe5,000ppmdosegroup(65.2%perlitterversus0%inthecontrolgroup),indicatingthattheendpointissignificantacrossspecies.Thereisevidencethatincidenceofsupernumeraryribs(includingcervicalribs)isrelatedtoageneralalterationinthedevelopmentandarchitectureoftheaxialskeletonasawhole.InCD1miceexposedduringgestationtovarioustypesofstress,foodandwaterdeprivation,andtheherbicidedinoseb,supernumeraryribswereconsistentlyassociatedwithincreasesinlengthofthe13thrib(Branchetal.,1996).Thisrelationshipwaspresentinallfetalagesexaminedinthestudy.Thesefindingsareconsistentwithsupernumeraryribsbeingonemanifestationofabasicalterationinthedifferentiationofthethoracolumbarborderoftheaxialskeleton.Thebiologicalsignificanceofthisendpointisfurtherstrengthenedbytheassociationofsupernumeraryribswithadversehealtheffectsinhumans.Themostcommoneffectproducedbythepresenceofcervicalribsisthoracicoutletdisease(Nguyenetal.,1997FernandezN