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Methanol(CASRN67561)|IRIS|USEPA

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0305
MethanolCASRN67561
HumanhealthassessmentinformationonachemicalsubstanceisincludedinIRISonlyafteracomprehensivereviewoftoxicity
databyU.S.EPAhealthscientistsfromseveralprogramoffices,regionaloffices,andtheOfficeofResearchandDevelopment.
SectionsI(HealthHazardAssessmentsforNoncarcinogenicEffects)andII(CarcinogenicityAssessmentforLifetimeExposure)
presentthepositionsthatwerereachedduringthereviewprocess.Supportinginformationandexplanationsofthemethodsused
toderivethevaluesgiveninIRISareprovidedintheguidancedocumentslocatedontheIRISwebsiteat
www.epa.gov/iris/backgrd.html.
STATUSOFDATAFORMethanol
FileFirstOnLine09/07/1988
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Category(section)

Status

LastRevised

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)
SubstanceNameMethanol
CASRN67561
LastRevised09/30/2013
TheRfDisanestimate(withuncertaintyspanningperhapsanorderofmagnitude)ofadailyoralexposuretothehuman
population(includingsensitivesubgroups)thatislikelytobewithoutanappreciableriskofdeleteriouseffectsduringalifetime.
Dietcancontributetobackgroundlevelsofmethanol,principallyfromtheordinaryingestionoffruitsandvegetables.Thus,inthe
caseofmethanol,theRfDisfurtherdefinedasanexogenousexposure(exposurefromasourceoutsidethebody)thataddsto
backgroundlevelsofmethanolderivedfromadietthatincludesfruitsandvegetables(seefurtherdiscussioninSectionI.A.4).
TheRfDisintendedforuseinriskassessmentsforhealtheffectsknownorassumedtobeproducedthroughanonlinear
(presumedthreshold)modeofaction.Itisexpressedinunitsofmg/kgday.Pleaserefertotheguidancedocumentsat
http://www.epa.gov/iris/backgrd.htmlforanelaborationoftheseconcepts.BecauseRfDvaluescanbederivedforthe
noncarcinogenichealtheffectsofsubstancesthatarealsocarcinogens,itisessentialtorefertoothersourcesofinformation
concerningthecarcinogenicityofthischemicalsubstance.IftheU.S.EPAhasevaluatedthissubstanceforpotentialhuman
carcinogenicity,asummaryofthatevaluationwillbecontainedinSectionIIofthisfile.
TheRfDof2mg/kgdayreplacesthepreviousRfDof0.5mg/kgdayenteredontheIRISdatabaseon09/07/1988.Theprevious
RfDwasbasedonanoobservedadverseeffectlevel(NOAEL)of500mg/kgdayforliverenzymechangesandbrainweight
reductioninasubchronicoralgavagestudyofSpragueDawleyrats(TRL,1986),andacompositeuncertaintyfactor(UF)of
1,000(10forextrapolationfromratstohumans,10forhumanvariation,and10forsubchronictochronicextrapolation).
__I.A.1.OralRfDSummary
CriticalEffect

Extracervicalribs

PointofDeparture
(POD)
PODInternal=43.1mg/L

UF POD/UF

Chronic
RfDa

100

2mg/kg
day

0.43
mg/L

CD1mice
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Inhalationdevelopmentaltoxicitystudyexposureduringgestationdays
GD7GD17
Rogersetal.(1993b)

TheRfDistheoraldosepredictedtoyieldamethanolbloodconcentrationequaltotheRfDinternal(PODInternal/UF)of0.43mg/L,usingthehumanPBPKmodel
describedinAppendixBoftheToxicologicalReviewofMethanol(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)].Thedecisiontouse
inhalationratherthanoralstudydataisduetolimitationsinthedatabaseoforalstudies,includingthelimitedreportingof
noncancerfindingsinthesubchronic(TRL,1986)andchronicoralstudies(Soffrittietal.,2002)ofrats,thedeterminationthat
developmentaleffectsarethemostsensitiveeffectsofmethanolexposure[seeSection5.1.1oftheToxicologicalReviewof
Methanol(Noncancer)(U.S.EPA,2013)],andthehighdoselevelsusedintherodentoraldevelopmentalstudies[seeSection5.2
oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013)].Thecandidateprincipalstudiesforthederivationofan
RfCandRfDaresummarizedbelowandaredescribedinmoredetailinSections4.3.2and4.4.2oftheToxicologicalReviewof
Methanol(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)ina
chamberfor7hours/dayonGD6GD15.Therewerenomethanolrelatedreductionsinmaternalbodyweightgainorovertsigns
oftoxicity.DamsweresacrificedonGD17foracomparisonofdevelopmentaltoxicityinmethanoltreatedgroupsversusthe
chamberairexposedcontrolgroup.Fetusesinallexposuregroupswereweighed,assessedforviability,andexaminedfor
externalmalformations.Fetusesinthecontrol,1,000,2,000,5,000,and15,000ppmgroupswerealsoexaminedforskeletaland
visceraldefects.Reproductiveandfetaleffectsincludedanincreaseinthenumberofresorbedlitters,areductioninthenumber
oflivepups,andincreasedincidencesofexencephaly,cleftpalate,andthenumberofcervicalribs.Theincidencesofthese
effectsarelistedinTable44oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013).Asdescribedbelow,the
increaseincervicalribs/litterreportedinthisstudywasevaluatedforpossibleuseinthederivationofRfDandRfCvalues.
NEDO(1987)evaluatedtheeffectsofpreandpostnatalmethanol(reagentgrade)exposure(20hours/day)onreproductiveand
otherorgansystemsofSpragueDawleyrats.Inatwogenerationstudy,F0generationrats(30malesand30femalesper
exposuregroup)wereexposedto0,10,100,and1,000ppm(0,13.1,131,and1,310mg/m3)from8weeksoldtotheendof
mating(males)ortotheendoflactationperiod(females).TheF1generationwasexposedtothesameconcentrationsfrombirth
totheendofmating(males)ortoweaningofF2pups21daysafterdelivery(females).MalesandfemalesoftheF2generation
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wereexposedfrombirthto21daysold(oneanimal/sex/litterwasexposedto8weeksofage).NEDO(1987)notedreduced
brain,pituitary,andthymusweights,andearlytesticulardescentintheoffspringofF0andF1ratsexposedto1,000ppm
methanol.Toconfirmthepossiblecompoundrelatedeffectofmethanolonthebrain,NEDO(1987)performedanadditionalstudy
inwhichSpragueDawleyratswereexposedto0,500,1,000,and2,000ppm(0,655,1,310,and2,620mg/m3)methanolfrom
thefirstdayofgestationthroughtheF1generation.ThenumberofF0parentalanimalsincludedpergroupinthissupplemental
experimentwasnotreported.However,thenumberofpupsperdosegroupper"periodafterbirth"wasreportedas11
14/sex/dose/postnatalperiod,anditisreasonabletoassumethat,consistentwiththestandardcullingprotocolusedforboththe
F1andF2generationsofthetwogenerationstudy(NEDO,1987pages185and189),thepupsforeachgender,doseand
exposuretimecombinationcamefromadifferentlitter(toavoidproblemsassociatedwithlittercorrelation).Doserelated
decreasesinbrainweightswereobservedinthemaleandfemaleoffspringat3,6,and8weeksofage.Asdescribedbelow,
brainweightchangesobservedintheseNEDO(1987)studieswereevaluatedforpossibleuseinthederivationofRfDandRfC
values.
DevelopmentalEffectsinPrincipalStudies
Skeletaleffectshavebeenobservedindevelopmentalstudiesofrats(Weissetal.,1996NEDO,1987Nelsonetal.,1985)and
mice(Bolonetal.,1993Rogersetal.,1993b).ThefindingsofBolonetal.(1993)andRogersandMole(1997)indicatethat
methanolistoxictomouseembryosintheearlystagesoforganogenesis,onoraroundGD7.Rogersetal.(1993b)reporteda
NOAELfortheincidenceofextracervicalribsat1,000ppm(1,310mg/m3,33.6%perlitter)andaLOAELof2,000ppm(2,620
mg/m3,49.6%perlitter)whencomparedtocontrols(28.0%perlitter).Increasedincidenceofcervicalribswasalsoobservedin
theratorganogenesisstudy(NEDO,1987)inthe5,000ppmdosegroup(65.2%perlitterversus0%inthecontrolgroup),
indicatingthattheendpointissignificantacrossspecies.Thereisevidencethatincidenceofsupernumeraryribs(including
cervicalribs)isrelatedtoageneralalterationinthedevelopmentandarchitectureoftheaxialskeletonasawhole.InCD1mice
exposedduringgestationtovarioustypesofstress,foodandwaterdeprivation,andtheherbicidedinoseb,supernumeraryribs
wereconsistentlyassociatedwithincreasesinlengthofthe13thrib(Branchetal.,1996).Thisrelationshipwaspresentinall
fetalagesexaminedinthestudy.Thesefindingsareconsistentwithsupernumeraryribsbeingonemanifestationofabasic
alterationinthedifferentiationofthethoracolumbarborderoftheaxialskeleton.Thebiologicalsignificanceofthisendpointis
furtherstrengthenedbytheassociationofsupernumeraryribswithadversehealtheffectsinhumans.Themostcommoneffect
producedbythepresenceofcervicalribsisthoracicoutletdisease(Nguyenetal.,1997FernandezNodaetal.,1996
Henderson,1914).Thoracicoutletdiseaseischaracterizedbynumbnessand/orpainintheshoulder,arm,orhands.Vascular
effectsassociatedwiththissyndromeincludecerebralanddistalembolism(Bearnetal.,1993Connelletal.,1980Short,
1975),whileneurologicalsymptomsincludeextremepain,migraine,andsymptomssimilartoParkinson's(Evans,1999Saxton
etal.,1999FernandezNodaetal.,1996).Schumacheretal.(1992)observed242ribanomaliesin218childrenwithtumors
(21.8%)and11(5.5%)inchildrenwithoutmalignancy,astatisticallysignificant(p<0.001)differencethatindicatesastrong
associationbetweenthepresenceofcervicalribsandchildhoodcancers.
BrainweightchangesobservedintheNEDO(1987)developmentalstudiesarealsodeemedbiologicallysignificantandrelevantto
humans.Decreasesinbrainweighthavebeenassociatedwithsimultaneousdeficitsinneurobehavioralandcognitiveparameters
inanimalsexposedduringgestationtovarioussolvents,includingtolueneandethanol(Gibsonetal.,2000Colemanetal.,1999
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Hassetal.,1995).Further,achangeinabsolutebrainweightaloneisconsideredtobeabiologicallysignificanteffect(U.S.EPA,
1998a).Thisistrueregardlessofchangesinbodyweightbecausebrainweightisgenerallyprotectedduringmalnutritionor
weightloss,unlikemanyotherorgansortissues(U.S.EPA,1998a).Whilebrainweightreductionhasnotbeenreportedinother
developmentalbioassays,ithasbeenobservedinadultratsexposedtomethanol(TRL,1986),andthereareindicationsof
possibledevelopmentalneurobehavioraleffectsassociatedwithmethanolinhalationexposuretomonkeys(2004a2004b
Burbacheretal.,1999a1999b).
TheNEDO(1987)developmentalstudiesindicatethatbothgestationalandpostnatalexposuretomethanolcontributetothebrain
weightdecreasesobservedinSpragueDawleyratpups.Thisfindingisnotunexpected,giventhattheratbrainundergoes
tremendousgrowthbeginningearlyingestationandcontinuinginthepostnatalperiod.Ratsareconsideredaltricial(i.e.,bornat
relativelyunderdevelopedstages),andmanyoftheirneurogeniceventsoccurpostnatally(Clancyetal.,2007).However,brain
effectsfrompostnatalexposurearealsorelevanttohumansgiventhat,inhumans,grossmeasuresofbraingrowthincreasefor
atleast23yearsafterbirth,withthegrowthratepeakingapproximately4monthsafterbirth(RiceandBarone,2000).
SelectionofCriticalEffects
Takingintoaccounttheadvantagesandlimitationsofthestudiesavailableforquantificationpurposesandtherelative
sensitivitiesfortheeffectsobserved(seeSection5.1.1oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013)for
details),twodevelopmentaleffectendpointswerechosenascocriticaleffectsforthepurposesofthisdoseresponse
assessment,cervicalribanomaliesinfetalCD1mice(Rogersetal.,1993b)anddecreasedbrainweightinmaleSpragueDawley
ratsexposedthroughoutgestationandlactation(NEDO,1987).Theseendpointscanbereliablyquantifiedandrepresentadverse
effectsintwoseparatesensitiveorgansystemsatkeyperiodsoftheirdevelopment.RfCderivationsfortheseendpointsusing
variousderivationoptionsaresummarizedbelowandinAppendixDoftheToxicologicalReviewofMethanol(Noncancer)(U.S.
EPA,2013).AsdiscussedinSectionsI.A.3andI.A.4belowandinSections5.1.3.1and5.3.1oftheToxicologicalReviewof
Methanol(Noncancer)(U.S.EPA,2013),themonkeystudiesofBurbacheretal.(2004a2004b1999a1999b)andNEDO(1987)
arequalitativelysupportive,butareinadequateorinferiortothecandidateprincipalrodentstudiesforquantitativedoseresponse
analysis.
MethodsofAnalysis.InhalationstudiesconsideredforderivationoftheRfCareusedtosupplementtheoraldatabaseusing
routetorouteextrapolation,aspreviouslydescribed.Benchmarkdose(BMD)approacheswereappliedtotheexistinginhalation
database,andtheEPAPBPKmodelwasusedforspeciestospeciesextrapolations.FortheBMDanalysesoftheratbrainweight
endpointfollowinggestationalandlactationalexposure,PBPKmodelestimatesofAUC(mghr/L)methanolinbloodforthedams
ofeachdosegroupwereusedasthedosemetricduetoevidencethatfetalandneonatalbrainweightissusceptibletoboththe
levelanddurationofmethanolexposure.FortheBMDanalysesofthemousecervicalribendpoint,internalCmax (mg/L)
methanolbloodconcentrationsreportedbyRogersetal.(1993b)formousedamsatday6ofgestationwereusedasthemodeled
dosemetricbecausethesmallgestationalwindowofsusceptibilityforthisendpoint(RogersandMole,1997Bolonetal.,1993)
suggestthatthelevelofexposureismoreimportantthanthedurationofexposure.
AppendixDoftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013)containsadescriptionofthedevelopmental
endpointsandBMDmodelingapproachesusedtoestimateaninternaldoseBMDlowerconfidencelimit(BMDL)pointofdeparture
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(PODinternal)foreachcandidateendpoint.AppendixBoftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013)
describesPBPKmodelsusedtoestimateacandidateRfDvalueforeachPODinternal.AsdescribedinSection5.2.2ofthe
ToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013),slightlylowercandidateRfDswerederivedforextracervicalribs
inmiceexposedduringgestationdays616(Rogersetal.,1993b)thanfordecreasedmalebrainweightinratsexposed
throughoutgestationandtheF1generation(NEDO,1987).Consequently,aBMDL05forthecervicalribendpointof43mg/L
methanolinbloodservesasthePODInternalfortheRfDderivation.
Becausethesamedataset,endpoints,BMDmethodsandPBPKmodelsusedtoderivetheRfCwerealsousedtocalculatethe
candidateRfDvalues,theRfDderivationusesthesameuncertaintyfactorsasaredescribedfortheRfCderivation(Section
5.1.3.2oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013).ConsistentwiththeRfCderivation,inorderto
avoidtheuncertaintyassociatedwithapplyingthehumanPBPKmodeltoexposurelevelsthatareabovethelevelsforwhichthe
modelwascalibratedandtoaccountforpossiblenonlinearitiesintheexternalversusinternaldoserelationshipsathighdoses,
EPAappliedthetotal100foldUFtotheinternalBMDL(PODinternal)priortoHEDderivationtoobtainanRfDinternal[seeTable56
oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013)].
RfD=43.1mg/L100=0.43mg/L==>PBPK==>2mg/kgday
(roundedto1significantfigure)
__I.A.3.UncertaintyandModifyingFactors(OralRfD)
UF=100
=10(UFH)3(UFA )3(UFD ).
InterindividualvariationUFH.Anuncertaintyfactorof10wasappliedtoaccountforvariationinsensitivitywithinthehuman
population(UFH).TheUFHof10iscommonlyconsideredtobeappropriateintheabsenceofconvincingdatatothecontrary.The
datafromwhichtodeterminethepotentialextentofvariationinhowhumansrespondtochronicexposuretomethanolare
limited,giventhecomplexnatureofthedevelopmentalendpointemployedanduncertaintiessurroundingtheimportanceof
metabolismtotheobservedteratogeniceffects.Susceptibilitytomethanolislikelytoinvolveintrinsicandextrinsicfactors.Some
factorsmayincludealterationofthebodyburdenofmethanoloritsmetabolites,sensitizationofanindividualtomethanol
effects,oraugmentationofunderlyingconditionsorchangesinprocessesthatsharecommonfeatureswithmethanoleffects.
Additionally,inherentdifferencesinanindividual'sgeneticmakeup,diet,gender,age,ordiseasestatemayaffectthe
pharmacokineticsandpharmacodynamicsofmethanol,influencingsusceptibilityintrinsically.Coexposuretoapollutantthat
altersmetabolismorotherclearanceprocesses,orthataddstobackgroundlevelsofmetabolitesmayalsoaffectthe
pharmacokineticsandpharmacodynamicsofmethanol,influencingsusceptibilityextrinsically[seeSection4.9oftheToxicological
ReviewofMethanol(Noncancer)(U.S.EPA,2013)].ThedeterminationoftheUFforhumanvariationissupportedbyseveral
typesofinformation,includinginformationconcerningbackgroundlevelsofmethanolinhumans,variationinpharmacokinetics
revealedthroughhumanstudiesandfromPBPKmodeling,variationofmethanolmetabolisminhumantissues,andinformation
onphysiologicfactors(includinggenderandage),oracquiredfactors(includingdietandenvironment)thatmayaffectmethanol
exposureandtoxicity(seeSection5.1.3.2.1oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013)forfurther
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details).
AnimaltohumanextrapolationUFA.Afactorof3wasappliedtoaccountforuncertaintiesinextrapolatingfromrodentsto
humans(UFA ).ApplicationofafullUFof10woulddependontwoareasofuncertainty:toxicokineticandtoxicodynamic.The
rodenttohumantoxicodynamicuncertaintyisaddressedbyafactorof3,asisthepracticeforderivingRfCs(U.S.EPA,1994b).
Inthisassessment,thetoxicokineticcomponentofuncertaintyisaddressedbythedeterminationofaHECthroughtheuseof
PBPKmodeling.UseofPBPKestimatedmaternalbloodmethanollevelsfortheestimationofHECsallowsfortheuseofdata
derivedextrapolationsratherthanstandardmethodsforextrapolationsfromexternalexposurelevels.Althoughuncertainties
exist,thePBPKmodelingapproachemployedisconsideredtobesufficienttoallowforreductionofthetoxicokineticuncertainty
toavalueof1forbothofthecandidateprincipalstudies[seeSection5.1.3.2.2oftheToxicologicalReviewofMethanol
(Noncancer)(U.S.EPA,2013)forfurtherdetails].
DatabaseUFD.AdatabaseUFof3wasappliedtoaccountfordeficienciesinthetoxicitydatabase(UFD ).Whilethedatabasefor
methanoltoxicityisextensiveintermsofthelaboratoryspeciesandstudydesigncoverage,consistingofchronicand
developmentaltoxicitystudiesinrats,mice,andmonkeys,atwogenerationreproductivetoxicitystudyinrats,andneurotoxicity
andimmunotoxicitystudies,therestillremainsconsiderableuncertaintywithrespecttothepotency,importanceandrelevanceof
reproductive,developmentalandchroniceffectsobservedinmonkeys.AsdiscussedinSection5.1.1.1oftheToxicologicalReview
ofMethanol(Noncancer)(U.S.EPA,2013),chronicanddevelopmentalstudiesinmonkeys,thespeciesmostlikelytobest
representthepotentialfordevelopmentaleffectsinhumans,wereconsideredinadequateorinferiortothecandidateprincipal
rodentstudiesforthepurposesofRfC/Dderivation.Thelackofaquantifiablemonkeystudyisanimportantdatagapgiventhe
potentialrelevancetohumansandtheuncertaintiesraisedbyexistingmonkeystudiesregardingthisspeciessensitivityto
reproductiveeffects[e.g.,shortenedpregnanciesdiscussedinSection4.3.2oftheToxicologicalReviewofMethanol(Noncancer)
(U.S.EPA,2013)],CNSdegeneration[e.g.,stellatecellfibrosisdescribedinSection4.4.2oftheToxicologicalReviewofMethanol
(Noncancer)(U.S.EPA,2013)]anddelayedneurobehavioraldevelopment[e.g.,VDRresponsedescribedinSection4.4.2ofthe
ToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013)]frommethanolexposure.Duetothesubstantialuncertainty
associatedwiththereproductiveandchroniceffectsinmonkeys,thosedataarenotasinformativeorreliableforthepurposeof
establishingtheappropriateUFD level.However,thedevelopmentalneurotoxicitydataarecomparableacrossthetwospecies
and,oftheuncertaineffectsobservedinmonkeys,theresultsofthevisuallydirectedreaching(VDR)testarelikelytobethe
mostreliable,discernibleandrelevant.AcomparisonofthelowestmethanolbloodLOAELs(excludingbackground)observedin
rodentandmonkeydevelopmentalneurotoxicitystudiesindicatesthattherodentLOAELbloodlevelis12foldhigherthanthe
monkeyLOELbloodlevel.Someofthis12folddifferencemaybeduetodifferencesinspeciessensitivity,forwhichtheUFA of3
foldisintendedtoaccount,butsomeofthedifferencemaybeduetootherfactors,includingwhetherappropriateand
comparableendpointswereexaminedandwhetherappropriatestudydesignsandqualitycontrolmeasureswereused.Toaccount
fortheseadditionalfactors,a3foldUFD isapplied.[seeSection5.1.3.2.3oftheToxicologicalReviewofMethanol(Noncancer)
(U.S.EPA,2013)forfurtherdetails].
ExtrapolationfromsubchronictochronicUFs .AUFof1wasappliedforextrapolationfromlessthanchronicresultsbecause
developmentaltoxicity(cervicalribanddecreasedbrainweight)wasusedasthecriticaleffect.Thedevelopmentalperiodis
recognizedasasusceptiblelifestagewhereexposureduringcertaintimewindowsismorerelevanttotheinductionof
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developmentaleffectsthanlifetimeexposure(U.S.EPA,1991).
LOAELtoNOAELextrapolationUFL.AUFof1wasappliedforLOAELtoNOAEL(UFL)becausethecurrentapproachisto
addressthisextrapolationasoneoftheconsiderationsinselectingabenchmarkresponse(BMR)forBMDmodeling.Inthiscase,
theendpointandbenchmarkresponselevelemployedfortheRfD/CderivationisappropriateforuseinderivingtheRfDunder
theassumptionthatitrepresentsaminimalbiologicallysignificantchange.
__I.A.4.AdditionalStudies/Comments(OralRfD)
AsdiscussedaboveandingreaterdetailinSections5.1.1and5.2.1oftheToxicologicalReviewofMethanol(Noncancer)(U.S.
EPA,2013),developmentaleffectsobservedintwocandidateprincipalrodentstudieswereconsideredrelevantandquantifiable
forthepurposesofRfC/Dderivation.Uncertaintiesassociatedwithchoiceofstudy/endpoint,BMDmodeling,routetoroute
extrapolation,choiceofspecies/genderandtherelationshipoftheRfCandRfDtoendogenousmethanolbloodlevelsare
discussedindetailinSection5.3oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013).
WhileinsufficientforuseasaquantitativebasisfortheRfCandRfD,monkeyreproductiveandneurotoxicitydevelopmental
studies(2004a2004bBurbacheretal.,1999a1999b)andmonkeychronicstudies(NEDO,1987)provideimportantsupportive
informationfortheRfDandRfCderivation.Burbacheretal.(2004a2004b1999a1999b)exposedM.fascicularismonkeysto
airconcentrationsof0,200,600,or1,800ppm(0,262,786,and2,359mg/m3)methanol,2.5hours/day,7days/weekduring
premating/matingandthroughoutgestation(approximately168days).Theyobservedastatisticallysignificantdelayinvisually
directedreaching(VDR)inthe600mppm(786mg/m3)groupformalesandthe1,800ppm(2,359mg/m3)groupforbothsexes.
However,adoseresponsetrendforthisendpointwasonlyexhibitedforfemales.Anothertest,theFagantestofinfant
intelligence,indicatedsmallbutnotsignificantdeficitsofperformance(timespentlookingatnovelfacesversusfamiliarfaces)in
treatedmonkeys.AsdiscussedinSection4.6.1.2oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013),the
monkeydataarenotconclusive,andthereisinsufficientevidencetodetermineiftheprimatefetusismoreorlesssensitivethan
rodentstomethanolteratogenesis.Takentogether,however,theNEDO(1987)ratstudyandtheBurbacheretal.(2004a2004b
1999a1999b)monkeystudysuggestthatprenatalexposuretomethanolcanresultinadverseeffectsondevelopmental
neurologypathologyandfunction,whichcanbeexacerbatedbycontinuedpostnatalexposure.Burbacheretal.(2004a2004b
1999a1999b)alsoreportedashorterperiodofgestationinallexposuregroupsthatdidnotappeartobedoserelated.As
discussedinSection4.6.1.2oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013),thoughstatisticallysignificant,
theshortenedgestationfindingmaybeoflimitedbiologicalsignificancegivenquestionsconcerningitsrelationtothemethanol
exposure.
IntheNEDO(1987)chronicinhalationmonkeystudies,8animals(sexunspecified)wereexposedto10,100,or1,000ppm(13,
131,and1,310mg/m3)methanol,21hours/day,for7months(2animals),19months,(3animals),or29months(3animals).
TherewasnoindicationintheNEDO(1987)reportthatthischronicstudyemployedaconcurrentcontrolgroup.Asdescribedin
Section4.4.2oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013),NEDO(1987)reportedhistopathologic
changestotheperipheralandcentralnervoussystem(CNS)ofexposedmonkeysthatincreasedwithincreasingexposure.The
mostpervasiveeffectnotedacrosstheexposureconcentrationsanddurationswas"fibrosisofresponsivestellatecells,"
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characterizedas"neurologicaldisease"intheNEDO(1987)summaryreport.These"stellatecells"arelikelytobeastrocytes,
starshapedglialcellsinthebrainthatareamongthemostnumerouscellsinallregionsoftheCNS.Thelimitedinformation
availablefromtheNEDO(1987)summaryreportsuggeststhat100ppm(131mg/m3)maybeaneffectlevelfollowing
continuous,chronicexposuretomethanol.However,asnotedinSection4.2.2.1oftheToxicologicalReviewofMethanol
(Noncancer)(U.S.EPA,2013),theNEDO(1987)studiesinnonhumanprimates,havemultiplereportingdeficienciesanddata
gapsthatmakethemdifficulttointerpret.Inaddition,confidenceinthedoseresponsedatafromthisstudyisweakenedbythe
apparentlackofaconcurrentcontrolgroupandthesmallnumberofanimalsateachexposurelevelforeachserialsacrifice(23
monkeys/timepoint/exposurelevel).Ingeneral,peerreviewersofthisstudyfeltthatitprovidesdescriptive,ratherthan
quantitative,supportfortheevaluationoftheinhalationtoxicityofmethanol(ERG,2009).
AnumberofstudiesdescribedinSection4.3.2andsummarizedinSection4.6.1.2oftheToxicologicalReviewofMethanol
(Noncancer)(U.S.EPA,2013)haveexaminedthepotentialtoxicityofmethanoltothemalereproductivesystem(Leeetal.,
1991Cameronetal.,1985Cameronetal.,1984).Someoftheobservedeffects,includingatransientdecreaseintestosterone
levels,couldbetheresultofchemicallyrelatedstrainontheratsystemasitattemptstomaintainhormonehomeostasis.
However,thedataareinsufficienttodefinitivelycharacterizemethanolasatoxicanttothemalereproductivesystem.
RelationshipofRfD/Ctobackgroundmethanolbloodlevelsandmonkeybloodlevelsassociatedwitheffectsof
uncertainadversity
InSection5.3.6oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013),PBPKmodelpredictionsfortheexpected
increaseinmethanollevelsinbloodresultingfromexposuretomethanolattheleveloftheRfCorRfDarecomparedto
backgroundbloodlevelsofmethanolestimatedfrom(1)dailyendogenousproductionanddietaryexposureestimatesfromthe
U.K.report(COT,2011)and(2)asamplebackgrounddistributionderivedfromrelevantstudygroups.BoththeEPAandtheU.K.
dataareconsistentwithapproximately2.5mg/Lrepresentingahighendoftherangeofbackgroundmethanolbloodlevels
associatedwithadietthatincludesfruitsandvegetables.EPAestimatesthattheshiftinEPA'ssamplebackgroundmethanol
bloodleveldistributionthatwouldbeassociatedwithdailyexposuresoftheentirepopulationtomethanolattheRfCortheRfD
wouldincreasethenumberofindividualswithpeakmethanolbloodlevelsatorabove2.5mg/L.from~7%to~14%..EPA's
PBPKmodelpredictsthatacontinuousdailymethanolexposureattheRfDorRfCwouldraisethepeakmethanolbloodlevelofan
individualwithanbackgroundmethanolbloodlevelof2.5mg/Ltojustunder3mg/L.AsdiscussedinSection5.3.7ofthe
ToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013),this3mg/Lmethanolbloodlevelisatthelowendoftherange
ofmethanolbloodlevelsthathavebeenreportedinmonkeychronicandgestationalexposurestudiestobeassociatedwithCNS
andreproductive/developmentaleffectsofuncertain,butpotentialadversity.
FormoredetailonSusceptiblePopulations,exittothetoxicologicalreview,Section4.9(PDF).
__I.A.5.CONFIDENCEINTHECHRONICORALRFD
StudyMediumtoHigh
DatabaseMedium
RfDMediumtoHigh
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TheconfidenceintheRfDismediumtohigh.ConfidenceintheRogersetal.(1993b)studyishighandconfidenceintheNEDO
(1987)developmentalstudiesismedium.TheRogersetal.(1993b)studywaswelldesigned,includinglargesamplesizes,well
documented,peerreviewedandpublished.Whilethereareissueswiththelackofdetailregardingmethodsandresultsinthe
NEDO(1987)report,theobservedeffect(brainweightreduction)isarelevantendpointthathasbeenreproducedinanoralstudy
ofadultrats(TRL,1986),andtheexposureregimeninvolvingpreandpostnatalexposuresaddressesapotentiallysensitive
humansubpopulation.Thus,theoverallconfidenceinthetwocriticalstudiesismediumtohigh.Confidenceinthedatabaseis
medium.Despitethefactthatskeletalandbraineffectshavebeendemonstratedandcorroboratedinmultipleanimalstudiesin
rats,mice,andmonkeys,somestudyresultswerenotquantifiable,thereisuncertaintyregardingwhichisthemostrelevanttest
species,andthereislimiteddataregardingreproductiveordevelopmentaltoxicityofmethanolinhumans.Thereisalso
uncertaintyregardingthepotentialactiveagenttheparentcompound,methanol,formaldehyde,formicacidorsomeother(e.g.,
reactiveoxygen)species.Therearedeficienciesintheknowledgeofthemetabolicpathwaysofmethanolinthehumanfetus
duringearlyorganogenesis,whenthecriticaleffectscanbeinducedinanimals.Thus,themediumtohighconfidenceinthe
principalstudiesandthemediumconfidenceinthedatabasetogetherwarrantanoverallconfidencedescriptorofmediumtohigh.
ConfidenceintheRfDisslightlylowerthanfortheRfCduetothelackofadequateoralstudiesfortheRfDderivation,
necessitatingaroutetorouteextrapolation.
FormoredetailontheCharacterizationofHazardandDoseResponse,exittothetoxicologicalreviewSection4
("HazardIdentification")orSection5("DoseResponseAssessments").
__I.A.6.EPADocumentationandReviewoftheOralRfD
SourceDocumentToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013)
ThisdocumenthasbeenprovidedforreviewtoEPAscientists,interagencyreviewersfromotherfederalagenciesandthe
ExecutiveOfficeofthePresident,andthepublic,andpeerreviewedbyindependentscientistsexternaltoEPA.Asummaryand
EPA'sdispositionofthecommentsreceivedfromtheindependentexternalpeerreviewersandfromthepublicisincludedin
AppendixAoftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013).
AgencyCompletionDate09/30/2013
__I.A.7.EPAContacts(OralRfD)
PleasecontacttheIRISHotlineforallquestionsconcerningthisassessmentorIRIS,ingeneral,at(202)5661676(phone),
(202)5661749(FAX)orhotline.iris@epa.gov(internetaddress).

__I.B.REFERENCECONCENTRATION(RfC)FORCHRONICINHALATIONEXPOSURE
SubstanceNameMethanol
CASRN67561
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SectionI.B.LastRevised09/30/2013
TheRfCisanestimate(withuncertaintyspanningperhapsanorderofmagnitude)ofacontinuousinhalationexposuretothe
humanpopulation(includingsensitivesubgroups)thatislikelytobewithoutanappreciableriskofdeleteriouseffectsduringa
lifetime.Dietcancontributetobackgroundlevelsofmethanol,principallyfromtheordinaryingestionoffruitsandvegetables.
Thus,inthecaseofmethanol,theRfCisfurtherdefinedasanexogenousexposure(exposurefromasourceoutsidethebody)
thataddstobackgroundlevelsofmethanolderivedfromadietthatincludesfruitsandvegetables(seefurtherdiscussionin
SectionI.B.4).TheRfCconsiderstoxiceffectsforboththerespiratorysystem(portalofentry)andforeffectsperipheraltothe
respiratorysystem(extrarespiratoryeffects).TheinhalationRfC(generallyexpressedinunitsofmg/m3)isanalogoustotheoral
RfDandissimilarlyintendedforuseinriskassessmentsforhealtheffectsknownorassumedtobeproducedthroughanonlinear
(presumedthreshold)modeofaction.
InhalationRfCsarederivedaccordingtoMethodsforDerivationofInhalationReferenceConcentrationsandApplicationof
InhalationDosimetry(U.S.EPA,1994b).BecauseRfCscanalsobederivedforthenoncarcinogenichealtheffectsofsubstances
thatarecarcinogens,itisessentialtorefertoothersourcesofinformationconcerningthecarcinogenicityofthischemical
substance.IftheU.S.EPAhasevaluatedthissubstanceforpotentialhumancarcinogenicity,asummaryofthatevaluationwillbe
containedinSectionIIofthisfile.
AninhalationassessmentformethanolwasnotpreviouslyavailableonIRIS.
__I.B.1.CHRONICINHALATIONRfCSUMMARY
CriticalEffect
Reducedbrainweightinratpupsat6weeksofage
MaleSpragueDawleyrats
Developmentalinhalationexposurethroughgestationand3,6or8
weekspostnatal

PointofDeparture
(POD)

UF

POD/UF

Chronic
RfCa

PODInternal=858mg
hr/L

100

8.58mg
hr/L

2101
mg/m3

NEDO(1987)
a

TheRfCistheinhalationconcentrationpredictedtoyieldamethanolbloodconcentrationequaltotheRfCinternal(PODInternal/UF)of8.58mghr/L,usingthe
humanPBPKmodeldescribedinAppendixBoftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013)thefinalRfCisroundedtoonesignificant
figure.

___I.B.2.PRINCIPALANDSUPPORTINGSTUDIES(INHALATIONRfC)
EPAhasderivedanRfCbyusingresponsedatafromcandidateprincipalinhalationstudiesofmice(Rogersetal.,1993b)andrats
(NEDO,1987)[seeSection5.1oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013)].Thesecandidateprincipal
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studiesandassociateddevelopmentalskeletal(extracervicalribs)andneurological(reducedbrainweight)effectsidentifiedfor
thederivationofanRfCandRfDaresummarizedinSectionI.A.2above.
MethodsofAnalysis.AsdescribedinSectionI.A.2above,PBPKmodelestimatesofdailyAUC(mghr/L)methanolintheblood
oftheNEDO(1987)ratdamswasusedasthedosemetricfortheBMDanalysesoftheratbrainweightendpoint,andinternal
Cmax (mg/L)methanolbloodconcentrationsreportedbyRogersetal.(1993b)formousedamsatday6ofgestationwasusedas
thedosemetricfortheBMDanalysesofthemousecervicalribendpoint.AppendixDoftheToxicologicalReviewofMethanol
(Noncancer)(U.S.EPA,2013)containsadescriptionofthedevelopmentalendpointsandBMDmodelingapproachesusedto
estimateaninternaldoseBMDLpointofdeparture(PODinternal)foreachcandidateendpoint.AppendixBoftheToxicological
ReviewofMethanol(Noncancer)(U.S.EPA,2013)describesPBPKmodelsusedtoestimateacandidateRfCvalueforeach
PODinternal.AsdescribedinSection5.1.3oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013),slightlylower
candidateRfCswerederivedfordecreasedmalebrainweightinratsexposedthroughoutgestationandtheF1generation(NEDO,
1987)thanforextracervicalribsinmiceexposedduringgestationdays616(Rogersetal.,1993b).Consequently,theBMDLfor
aonestandarddeviationreductioninbrainweight(BMDL1SD )inmaleratsof858mghr/Lmethanolinbloodservesasthe
PODInternalfortheRfCderivation.
AsdescribedinSection5.1.3.2oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013),inordertoavoidthe
uncertaintyassociatedwithapplyingthehumanPBPKmodeltoexposurelevelsthatareabovethelevelsforwhichthemodelwas
calibratedandtoaccountforpossiblenonlinearitiesintheexternalversusinternaldoserelationshipsathighdoses,EPAapplied
thetotal100foldUFtotheinternalBMDL(PODinternal)toobtainanRfCinternal.TheRfCinternalisthenconvertedtoanRfCusing
thehumanPBPKmodeldescribedinAppendixB[seeTable54oftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,
2013)].
RfC=858mghr/L100=8.58mghr/L==>PBPK==>2101mg/m3
(roundedto1significantfigure)
___I.B.3.UNCERTAINTYFACTORS
UF=100
=10(UFH)3(UFA )3(UFD ).
SeeSectionI.A.3foracompletedescription.
___I.B.4.ADDITIONALSTUDIES/COMMENTS
SeeSectionI.A.4.
___I.B.5.CONFIDENCEINTHECHRONICINHALATIONRfC
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StudyMediumtoHigh
DatabaseMedium
RfCMediumtoHigh
SeeSectionI.A.5foracompletedescription.
___I.B.6.EPADOCUMENTATIONANDREVIEWOFTHECHRONICINHALATIONRfC
SourceDocumentToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013)
ThisdocumenthasbeenprovidedforreviewtoEPAscientists,interagencyreviewersfromotherfederalagenciesandthe
ExecutiveOfficeofthePresident,andthepublic,andpeerreviewedbyindependentscientistsexternaltoEPA.Asummaryand
EPA'sdispositionofthecommentsreceivedfromtheindependentexternalpeerreviewersandfromthepublicisincludedin
AppendixAoftheToxicologicalReviewofMethanol(Noncancer)(U.S.EPA,2013).
AgencyCompletionDate09/30/2013
___I.B.7.EPACONTACTS
PleasecontacttheIRISHotlineforallquestionsconcerningthisassessmentorIRIS,ingeneral,at(202)5661676(phone),(202)
5661749(fax),orhotline.iris@epa.gov(emailaddress).

_II.CARCINOGENICITYASSESSMENTFORLIFETIMEEXPOSURE
SubstanceNameMethanol
CASRN123911
MESSAGE:Acarcinogenicityassessmentisnotavailableatthistime.

_III.[reserved]
_IV.[reserved]
_V.[reserved]
_VI.Bibliography
SubstanceNameMethanol
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CASRN67561
LastRevised09/30/2013
_VI.A.OralRfDReferences
Bearn,PPatel,JO'Flynn,WR.(1993).Cervicalribs:Acauseofdistalandcerebralembolism.PostgradMedJ69:6568.
Bolon,BDorman,DCJanszen,DMorgan,KTWelsch,F.(1993).Phasespecificdevelopmentaltoxicityinmicefollowing
maternalmethanolinhalation.ToxicolSci21:508516.
Branch,SRogers,JMBrownie,CFChernoff,N.(1996).Supernumerarylumbarrib:Manifestationofbasicalterationin
embryonicdevelopmentofribs.JApplToxicol16:115119.http://dx.doi.org/10.1002/(SICI)10991263(199603)16:2<115::AID
JAT309>3.0.CO2H.
Burbacher,TMGrant,KShen,DDamian,DEllis,SLiberato,N.(1999a).Reproductiveandoffspringdevelopmentaleffects
followingmaternalinhalationexposuretomethanolinnonhumanprimatesPartII:developmentaleffectsininfantsexposed
prenatallytomethanol.Cambridge,MA:HealthEffectsInstitute.
Burbacher,TMGrant,KSShen,DDSheppard,LDamian,DEllis,SLiberato,N.(2004a).Chronicmaternalmethanol
inhalationinnonhumanprimates(Macacafascicularis):reproductiveperformanceandbirthoutcome.NeurotoxicolTeratol26:
639650.
Burbacher,TMShen,DGrant,KSheppard,LDamian,DEllis,SLiberato,N.(1999b).Reproductiveandoffspring
developmentaleffectsfollowingmaternalinhalationexposuretomethanolinnonhumanprimatesPartI:methanoldispositionand
reproductivetoxicityinadultfemales.Cambridge,MA:HealthEffectsInstitute.
Burbacher,TMShen,DDLalovic,BGrant,KSSheppard,LDamian,DEllis,SLiberato,N.(2004b).Chronicmaternal
methanolinhalationinnonhumanprimates(Macacafascicularis):exposureandtoxicokineticspriortoandduringpregnancy.
NeurotoxicolTeratol26:201221.
Cameron,AMNilsen,OGHaug,EEikNes,KB.(1984).Circulatingconcentrationsoftestosterone,luteinizinghormoneand
folliclestimulatinghormoneinmaleratsafterinhalationofmethanol.ArchToxicol7:441443.
Cameron,AMZahlsen,KHaug,ENilsen,OGEikNes,KB.(1985b).Circulatingsteroidsinmaleratsfollowinginhalationofn
alcohols.InPLChambersECholnokyCMChambers(Eds.),ArchivesofToxicologySupplement:ReceptorsandOtherTagetsfor
ToxicSubstances(pp.422424).Berlin:SpringerVerlag.
CERHR(NTPCenterfortheEvaluationofRiskstoHumanReproduction).(2003).NTPCERHRmonographonthepotentialhuman
reproductiveanddevelopmentaleffectsofmethanol.
http://www.epa.gov/iris/subst/0305.htm

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Clancy,BFinlay,BLDarlington,RBAnand,KJ.(2007).Extrapolatingbraindevelopmentfromexperimentalspeciestohumans.
Neurotoxicology28:931937.http://dx.doi.org/10.1016/j.neuro.2007.01.014.
Coleman,CNMason,THooker,EPRobinson,SE.(1999).Developmentaleffectsofintermittentprenatalexposureto1,1,1
trichloroethaneintherat.NeurotoxicolTeratol21:699708.http://dx.doi.org/10.1016/S08920362(99)000355.
Connell,JLDoyle,JCGurry,JF.(1980).Thevascularcomplicationsofcervicalribs.ANZJSurg50:125130.
http://dx.doi.org/10.1111/j.14452197.1980.tb06648.x.
COT(CommitteeonToxicity).(2011).COTStatementontheeffectsofchronicdietaryexposuretomethanol.
http://cot.food.gov.uk/cotstatements/cotstatementsyrs/cotstatements2011/cot201102.
ERG(EasternResearchGroupInc.).(2009).Externalletterpeerreviewofreportsdocumentingmethanolstudiesinmonkeys,
ratsandmiceperformedbytheNewEnergyDevelopmentOrganization(NEDO).Lexington,MA.
Evans,AL.(1999).Pseudoseizuresasacomplicationofpainfulcervicalribs.DevMedChildNeurol41:840842.
http://dx.doi.org/10.1017/S0012162299001668.
FernandezNoda,EINuezArguelles,JPerezFernandez,JCastillo,JPerezIzquierdo,MRiveraLuna,H.(1996).Neckand
braintransitoryvascularcompressioncausingneurologicalcomplications,resultsofsurgicaltreatmenton1300patients.J
CardiovascSurg(Torino)37:155166.
Gibson,MASButters,NSReynolds,JNBrien,JF.(2000).Effectsofchronicprenatalethanolexposureonlocomotoractivity,
andhippocampalweight,neurons,andnitricoxidesynthaseactivityoftheyoungpostnatalguineapig.NeurotoxicolTeratol22:
183192.
Hass,ULund,SPSimonsen,LFries,AS.(1995).Effectsofprenatalexposuretoxyleneonpostnataldevelopmentandbehavior
inrats.NeurotoxicolTeratol17:341349.http://dx.doi.org/10.1016/08920362(94)00093S.
Henderson,MS.(1914).Cervicalrib:Reportofthirtyonecases.JBoneJointSurgAm11:408430.
Lee,EBrady,ANBrabec,MJFabel,T.(1991).Effectsofmethanolvaporsontestosteroneproductionandtestismorphologyin
rats.ToxicolIndHealth7:261275.
NEDO(NewEnergyDevelopmentOrganization).(1987).Toxicologicalresearchofmethanolasafuelforpowerstation:summary
reportontestswithmonkeys,ratsandmice.Tokyo,Japan.
Nelson,BKBrightwell,WSMacKenzie,DRKhan,ABurg,JRWeigel,WWGoad,PT.(1985).Teratologicalassessmentof
methanolandethanolathighinhalationlevelsinrats.ToxicolSci5:727736.
http://www.epa.gov/iris/subst/0305.htm

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Nguyen,TBaumgartner,FNelems,B.(1997).Bilateralrudimentaryfirstribsasacauseofthoracicoutletsyndrome.JNatl
MedAssoc89:6973.
Rice,DBarone,S,Jr.(2000).Criticalperiodsofvulnerabilityforthedevelopingnervoussystem:Evidencefromhumansand
animalmodels.EnvironHealthPerspect108:511533.http://dx.doi.org/10.1289/ehp.00108s3511.
Rogers,JMMole,ML.(1997).CriticalperiodsofsensitivitytothedevelopmentaltoxicityofinhaledmethanolintheCD1mouse.
Teratology55:364372.
Rogers,JMMole,MLChernoff,NBarbee,BDTurner,CILogsdon,TRKavlock,RJ.(1993b).Thedevelopmentaltoxicityof
inhaledmethanolintheCD1mouse,withquantitativedoseresponsemodelingforestimationofbenchmarkdoses.Teratology
47:175188.
Saxton,EHMiller,TQCollins,JD.(1999).MigrainecomplicatedbybrachialplexopathyasdisplayedbyMRIandMRA:Aberrant
subclavianarteryandcervicalribs.JNatlMedAssoc91:333341.
Schumacher,RMai,AGutjahr,P.(1992).Associationofribabnomaliesandmalignancyinchildhood.EurJPediatr151:432
434.http://dx.doi.org/10.1007/BF01959357.
Short,DW.(1975).Thesubclavianarteryin16patientswithcompletecervicalribs.JCardiovascSurg(Torino)16:135141.
Soffritti,MBelpoggi,FCevolani,DGuarino,MPadovani,MMaltoni,C.(2002).Resultsoflongtermexperimentalstudieson
thecarcinogenicityofmethylalcoholandethylalcoholinrats.InMAMehlman(Ed.),Carcinogenesisbioassaysandprotecting
publichealth:commemoratingthelifeworkofCesareMaltoniandcolleaques(pp.4669).Bologna,Italy:Ann.N.Y.Acad.Sci.
TRL(ToxicityResearchLaboratories).(1986).Ratoralsubchronictoxicitystudywithmethanol.(TRLNo.032005).Muskegon,MI:
ResearchTriangleInstitute.
U.S.EPA(U.S.EnvironmentalProtectionAgency).(1991).Guidelinesfordevelopmentaltoxicityriskassessment[EPAReport].
(EPA/600/FR91/001).Washington,DC:U.S.EnvironmentalProtectionAgency,RiskAssessmentForum.
http://www.epa.gov/iris/backgrd.html.
U.S.EPA(U.S.EnvironmentalProtectionAgency).(1994b).Methodsforderivationofinhalationreferenceconcentrationsand
applicationofinhalationdosimetry.(EPA/600/890/066F).ResearchTrianglePark,NC:U.S.EnvironmentalProtectionAgency,
OfficeofResearchandDevelopment,OfficeofHealthandEnvironmentalAssessment,EnvironmentalCriteriaandAssessment
Office.http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=71993.
U.S.EPA(U.S.EnvironmentalProtectionAgency).(1998a).Guidelinesforneurotoxicityriskassessment.(EPA/630/R95/001F).
Washington,DC:U.S.EnvironmentalProtectionAgency,RiskAssessmentForum.
http://www.epa.gov/raf/publications/pdfs/NEUROTOX.PDF(89pp,182K).
http://www.epa.gov/iris/subst/0305.htm

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U.S.EPA(U.S.EnvironmentalProtectionAgency).(2013).ToxicologicalreviewofMethanol(CASRN67561)insupportof
summaryinformationontheIntegratedRiskInformationSystem(IRIS).(EPA/635/R11001).Washington,DC.
Weiss,BStern,SSoderholm,SCCox,CSharma,AInglis,GBPreston,RBalys,MReuhl,KRGelein,R.(1996).
Developmentalneurotoxicityofmethanolexposurebyinhalationinrats.(HEIResearchReportNumber73).Boston,MA:Health
EffectsInstitute.

_VI.B.InhalationRfCReferences
SeeSectionVI.A.
NEDO(NewEnergyDevelopmentOrganization).(1987).Toxicologicalresearchofmethanolasafuelforpowerstation:summary
reportontestswithmonkeys,ratsandmice.Tokyo,Japan.
Rogers,JMMole,MLChernoff,NBarbee,BDTurner,CILogsdon,TRKavlock,RJ.(1993b).Thedevelopmentaltoxicityof
inhaledmethanolintheCD1mouse,withquantitativedoseresponsemodelingforestimationofbenchmarkdoses.Teratology
47:175188.
U.S.EPA(U.S.EnvironmentalProtectionAgency).(1994b).Methodsforderivationofinhalationreferenceconcentrationsand
applicationofinhalationdosimetry.(EPA/600/890/066F).ResearchTrianglePark,NC:U.S.EnvironmentalProtectionAgency,
OfficeofResearchandDevelopment,OfficeofHealthandEnvironmentalAssessment,EnvironmentalCriteriaandAssessment
Office.http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=71993.
U.S.EPA(U.S.EnvironmentalProtectionAgency).(2000a).Benchmarkdosetechnicalguidancedocument[externalreviewdraft].
(EPA/630/R00/001).Washington,DC:U.S.EnvironmentalProtectionAgency,RiskAssessmentForum.
http://www.epa.gov/raf/publications/benchmarkdosedocdraft.htm.
U.S.EPA(U.S.EnvironmentalProtectionAgency).(2013).ToxicologicalreviewofMethanol(CASRN67561)insupportof
summaryinformationontheIntegratedRiskInformationSystem(IRIS).(EPA/635/R11001).Washington,DC.

_VI.C.CarcinogenicityAssessmentReferences
None.

_VII.RevisionHistory
http://www.epa.gov/iris/subst/0305.htm

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SubstanceNameMethanol
CASRN67561
Date

Section

Description

09/07/1988

I.A.

OralRfDsummaryonline

09/30/2013

I.,VI.,VIII.

RfDassessmentupdated.RfCadded.

_VIII.Synonyms
SubstanceNameMethanol
CASRN67561
LastRevised09/30/2013
67561
Carbinol
Methanol
methylalcohol
Methylhydroxide
Monohydroxymethane
Pyroxylicspirit
woodalcohol
Woodnaptha
woodspirit
IRISHome
ChronicHealth
HazardsforNon
CarcinogenicEffects
ReferenceDosefor
ChronicOral
Exposure(RfD)
OralRfD
Summary
Principaland
Supporting
Studies
Uncertaintyand
ModifyingFactors
Additional
Studies/Comments
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Confidenceinthe
OralRfD
EPA
Documentation
andReview
Reference
Concentrationfor
ChronicInhalation
Exposure(RfC)
InhalationRfC
Summary
Principaland
Supporting
Studies
Uncertaintyand
ModifyingFactors
Additional
Studies/Comments
Confidenceinthe
InhalationRfC
EPA
Documentation
andReview
Carcinogenicity
Assessmentfor
LifetimeExposure
EvidenceforHuman
Carcinogenicity
Weightof
Evidence
Characterization
Human
Carcinogenicity
Data
Animal
Carcinogenicity
Data
SupportingData
forCarcinogenicity
Quantitative
Estimateof
CarcinogenicRisk
fromOralExposure
SummaryofRisk
Estimates
DoseResponse
http://www.epa.gov/iris/subst/0305.htm

19/20

3/2/2015

Methanol(CASRN67561)|IRIS|USEPA

Data
Additional
Comments
Discussionof
Confidence
Quantitative
Estimateof
CarcinogenicRisk
fromInhalation
Exposure
SummaryofRisk
Estimates
DoseResponse
Data
Additional
Comments
Discussionof
Confidence
EPA
Documentation,
Reviewand,
Contacts
Bibliography
RevisionHistory
Synonyms

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

20/20