Diphenylmethane Diisocyanate (Mdi)

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DIPHENYLMETHANEDIISOCYANATE(MDI)
Thisreportcontainsthecollectiveviewsofaninternationalgroupofexpertsanddoesnotnecessarily
representthedecisionsorthestatedpolicyoftheUnitedNationsEnvironmentProgramme,the
InternationalLabourOrganization,ortheWorldHealthOrganization.
ConciseInternationalChemical
AssessmentDocument27
DIPHENYLMETHANEDIISOCYANATE
(MDI)
FirstdraftpreparedbyDrJ.Sekizawa,NationalInstituteofHealthSciences,Japan,incollaboration
withDrM.M.Greenberg,USEnvironmentalProtectionAgency
PublishedunderthejointsponsorshipoftheUnitedNationsEnvironmentProgramme,the
InternationalLabourOrganization,andtheWorldHealthOrganization,andproducedwithinthe
frameworkoftheInterOrganizationProgrammefortheSoundManagementofChemicals.
WorldHealthOrganization
Geneva,2000
TheInternationalProgrammeonChemicalSafety(IPCS),establishedin1980,isajointventureof
theUnitedNationsEnvironmentProgramme(UNEP),theInternationalLabourOrganization(ILO),
andtheWorldHealthOrganization(WHO).TheoverallobjectivesoftheIPCSaretoestablishthe
scientificbasisforassessmentoftherisktohumanhealthandtheenvironmentfromexposureto
chemicals,throughinternationalpeerreviewprocesses,asaprerequisiteforthepromotionof
chemicalsafety,andtoprovidetechnicalassistanceinstrengtheningnationalcapacitiesforthesound
managementofchemicals.
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(ParticipatingOrganizations),followingrecommendationsmadebythe1992UNConferenceon
EnvironmentandDevelopmenttostrengthencooperationandincreasecoordinationinthefieldof
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pursuedbytheParticipatingOrganizations,jointlyorseparately,toachievethesoundmanagementof
chemicalsinrelationtohumanhealthandtheenvironment.
WHOLibraryCataloguinginPublicationData
Diphenylmethanediisocyanate(MDI).
(Conciseinternationalchemicalassessmentdocument27)
1.Isocyanatestoxicity2.Riskassessment3.Environmentalexposure
4.InternationalProgrammeonChemicalSafetyII.Series
ISBN9241530278(NLMClassification:QV280)
ISSN10206167
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TABLEOFCONTENTS
FOREWORD
1.EXECUTIVESUMMARY
2.IDENTITYANDPHYSICAL/CHEMICAL
PROPERTIES
3.ANALYTICALMETHODS
4.SOURCESOFHUMANANDENVIRONMENTAL
EXPOSURE
5.ENVIRONMENTALTRANSPORT,
DISTRIBUTION,ANDTRANSFORMATION
5.1Water
5.2Soil
5.3Air
6.ENVIRONMENTALLEVELSANDHUMAN
EXPOSURE
6.1Environmentallevels
6.2Humanexposure
7.COMPARATIVEKINETICSANDMETABOLISM
INLABORATORYANIMALSANDHUMANS
8.EFFECTSONLABORATORYMAMMALSANDIN
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VITROTESTSYSTEMS
8.1Singleexposure
8.2Irritationandsensitization
8.2.1Irritation
8.2.2Sensitization
8.3Shorttermexposure
8.4Longtermexposure
8.4.1Subchronicexposure
8.4.2Chronicexposureandcarcinogenicity
8.5Genotoxicityandrelatedendpoints
8.6Reproductiveanddevelopmentaltoxicity
9.EFFECTSONHUMANS
9.1Casereports
9.2Epidemiologicalstudies
9.2.1Irritationandsensitization
9.2.2Longtermexposureandcarcinogenicity
10.EFFECTSONOTHERORGANISMSINTHE
LABORATORYANDFIELD
10.1Aquaticenvironment
10.2Terrestrialenvironment
11.EFFECTSEVALUATION
11.1Evaluationofhealtheffects
11.1.1Hazardidentificationanddoseresponse
assessment
11.1.2Criteriaforsettingtolerableintakesorguidance
valuesforMDI
11.1.3Sampleriskcharacterization
11.2Evaluationofenvironmentaleffects
12.PREVIOUSEVALUATIONSBY
INTERNATIONALBODIES
REFERENCES
APPENDIX1SOURCEDOCUMENTS
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APPENDIX2CICADPEERREVIEW
APPENDIX3CICADFINALREVIEWBOARD
INTERNATIONALCHEMICALSAFETYCARD
RSUMDORIENTATION
RESUMENDEORIENTACIN
FOREWORD
ConciseInternationalChemicalAssessmentDocuments(CICADs)arethelatestinafamilyof
publicationsfromtheInternationalProgrammeonChemicalSafety(IPCS)acooperative
programmeoftheWorldHealthOrganization(WHO),theInternationalLabourOrganization(ILO),
andtheUnitedNationsEnvironmentProgramme(UNEP).CICADsjointheEnvironmentalHealth
Criteriadocuments(EHCs)asauthoritativedocumentsontheriskassessmentofchemicals.
CICADsareconcisedocumentsthatprovidesummariesoftherelevantscientificinformation
concerningthepotentialeffectsofchemicalsuponhumanhealthand/ortheenvironment.Theyare
basedonselectednationalorregionalevaluationdocumentsoronexistingEHCs.Beforeacceptance
forpublicationasCICADsbyIPCS,thesedocumentsundergoextensivepeerreviewby
internationallyselectedexpertstoensuretheircompleteness,accuracyinthewayinwhichthe
originaldataarerepresented,andthevalidityoftheconclusionsdrawn.
TheprimaryobjectiveofCICADsischaracterizationofhazardanddoseresponsefromexposuretoa
chemical.CICADsarenotasummaryofallavailabledataonaparticularchemicalrather,they
includeonlythatinformationconsideredcriticalforcharacterizationoftheriskposedbythe
chemical.Thecriticalstudiesare,however,presentedinsufficientdetailtosupporttheconclusions
drawn.Foradditionalinformation,thereadershouldconsulttheidentifiedsourcedocumentsupon
whichtheCICADhasbeenbased.
Riskstohumanhealthandtheenvironmentwillvaryconsiderablydependinguponthetypeand
extentofexposure.Responsibleauthoritiesarestronglyencouragedtocharacterizeriskonthebasisof
locallymeasuredorpredictedexposurescenarios.Toassistthereader,examplesofexposure
estimationandriskcharacterizationareprovidedinCICADs,wheneverpossible.Theseexamples
cannotbeconsideredasrepresentingallpossibleexposuresituations,butareprovidedasguidance
only.ThereaderisreferredtoEHC1701foradviceonthederivationofhealthbasedtolerableintakes
orguidancevalues.
WhileeveryeffortismadetoensurethatCICADsrepresentthecurrentstatusofknowledge,new
informationisbeingdevelopedconstantly.Unlessotherwisestated,CICADsarebasedonasearchof
thescientificliteraturetothedateshownintheexecutivesummary.Intheeventthatareaderbecomes
awareofnewinformationthatwouldchangetheconclusionsdrawninaCICAD,thereaderis
requestedtocontactIPCStoinformitofthenewinformation.
Procedures
TheflowchartshowstheproceduresfollowedtoproduceaCICAD.Theseproceduresaredesignedto
takeadvantageoftheexpertisethatexistsaroundtheworldexpertisethatisrequiredtoproduce
thehighqualityevaluationsoftoxicological,exposure,andotherdatathatarenecessaryforassessing
riskstohumanhealthand/ortheenvironment.
Thefirstdraftisbasedonanexistingnational,regional,orinternationalreview.Authorsofthefirst
draftareusually,butnotnecessarily,fromtheinstitutionthatdevelopedtheoriginalreview.A
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standardoutlinehasbeendevelopedtoencourageconsistencyinform.Thefirstdraftundergoes
primaryreviewbyIPCStoensurethatitmeetsthespecifiedcriteriaforCICADs.
Thesecondstageinvolvesinternationalpeerreviewbyscientistsknownfortheirparticularexpertise
andbyscientistsselectedfromaninternationalrostercompiledbyIPCSthroughrecommendations
fromIPCSnationalContactPointsandfromIPCSParticipatingInstitutions.Adequatetimeisallowed
fortheselectedexpertstoundertakeathoroughreview.Authorsarerequiredtotakereviewers
commentsintoaccountandrevisetheirdraft,ifnecessary.Theresultingseconddraftissubmittedtoa
FinalReviewBoardtogetherwiththereviewerscomments.
TheCICADFinalReviewBoardhasseveralimportantfunctions:
toensurethateachCICADhasbeensubjectedtoanappropriateandthoroughpeerreview
toverifythatthepeerreviewerscommentshavebeenaddressedappropriately
toprovideguidancetothoseresponsibleforthepreparationofCICADsonhowtoresolveany
remainingissuesif,intheopinionoftheBoard,theauthorhasnotadequatelyaddressedall
commentsofthereviewersand
toapproveCICADsasinternationalassessments.
Boardmembersserveintheirpersonalcapacity,notasrepresentativesofanyorganization,
government,orindustry.Theyareselectedbecauseoftheirexpertiseinhumanandenvironmental
toxicologyorbecauseoftheirexperienceintheregulationofchemicals.Boardsarechosenaccording
totherangeofexpertiserequiredforameetingandtheneedforbalancedgeographicrepresentation.
Boardmembers,authors,reviewers,consultants,andadviserswhoparticipateinthepreparationofa
CICADarerequiredtodeclareanyrealorpotentialconflictofinterestinrelationtothesubjectsunder
discussionatanystageoftheprocess.Representativesofnongovernmentalorganizationsmaybe
invitedtoobservetheproceedingsoftheFinalReviewBoard.ObserversmayparticipateinBoard
discussionsonlyattheinvitationoftheChairperson,andtheymaynotparticipateinthefinal
decisionmakingprocess.
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1.EXECUTIVESUMMARY
ThisCICADondiphenylmethanediisocyanate(MDI)waspreparedbytheNationalInstituteof
HealthSciences,Japan,incollaborationwiththeNationalCenterforEnvironmentalAssessment,US
EnvironmentalProtectionAgency(EPA).TheCICADwasbasedprincipallyonthereviewsofthe
JapanSocietyforOccupationalHealth(JSOH,1994)andtheUSEPA(1998)forthetoxicological
evaluationandtheEuropeanUnion(EU,1999)fortheenvironmentalassessment.Itshouldbenoted
thattheEUdocumentisstillanunapproveddraftandthattheinformationpresentedinthe
environmentalsectionsisbasedmainlyonunpublishedstudies.TheliteratureuptoNovember1998
wassearchedusingMEDLINEtoidentifyanynewinformationrelevanttotheassessment.The
preparationandpeerreviewofthesourcedocumentsaredescribedinAppendix1.Informationonthe
peerreviewofthisCICADispresentedinAppendix2.ThisCICADwasapprovedasaninternational
assessmentatameetingoftheFinalReviewBoard,heldinStockholm,Sweden,on2528May1999.
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ParticipantsattheFinalReviewBoardmeetingarelistedinAppendix3.TheInternationalChemical
SafetyCard(ICSC0298)forMDI,producedbytheInternationalProgrammeonChemicalSafety
(IPCS,1993),hasalsobeenreproducedinthisdocument.
Diphenylmethanediisocyanate(MDI)isthegenericnameofaproductusedinindustrialsettings.
PolymericMDI(PMDI),theprimarytechnical/commercialformofMDI,isactuallyamixturethat
contains2580%monomeric4,4MDIaswellasoligomerscontaining36ringsandotherminor
isomers,suchasthe2,2isomer.TheexactcompositionofPMDIvarieswiththemanufacturer.
Monomeric4,4MDIisawhitetopaleyellowsolidatroomtemperature,withamolecularweightof
250.Ithasaboilingpointof>300Cat101.3kPa,ameltingpointof3943C,andavapour
pressureof<1mPaat20C.Ithasatransientexistenceinwaterthus,itswatersolubilityisonly
notional.However,monomericMDIissolubleinoctane,benzene,andkerosene.PMDIisadark
reddishbrownliquidwithanindefinitemeltingpointaround0Candavapourpressureof<1mPaat
20C.MDIishighlyreactiveintheenvironmentorwhentakenupbyorganismsandisrapidly
hydrolysedtoform4,4methylenedianiline(MDA),whichreactswithexcessMDItoyieldinsoluble
oligoureasandpolyureas.
MDIisusedforpolyurethaneelastomers(rollers,packing,rubbervibrationinsulators,synthetic
leather,etc.),spandexfibres,andrubbershoesoles.PMDIisusedtomakerigidandflexiblefoam,
foundryresinsandbinders,andheatinsulatingmaterial.ThetotalannualglobalproductionofMDI
andPMDIwasabout1.2milliontonnesin1991,1.5milliontonnesin1993,1.78milliontonnesin
1994,and1.95milliontonnesin1996.
Aftertheappropriatecollectionoftheaerosolformbyimpingers,bubbles,orfilters,high
performanceliquidchromatography(HPLC)isusedfortheanalysisofMDIandPMDI.Detection
limitsofHPLCforMDIandPMDI,whichvarydependingonthesamplingmethodology,canbe
below0.01mg/m3.FreeandacetylatedMDAareidentifiedinnearlyallstudiesafterstrongly
hydrolysingconditions.TheseconditionswillalsoformMDAfromconjugatedMDI.Anewmethod
hasrecentlybecomeavailablefordeterminingthecompositionofcomplexmixturesofairborne
isocyanatesandrelatedcompoundsformedduringthethermaldecompositionofpolyurethaneby
derivatizationofisocyanateswithdibutylamine.
Undernormalcircumstances,exposureofthegeneralpublictoMDIislikelyonlyfromreleasestothe
atmosphere.Highexposuresinambientenvironmentsarerare.Wherespillageistosoilorwater,MDI
hasatransientexistenceduetoitsreactionwiththewatertoproducepredominantlyinsoluble
polyureas.MDAconcentrationsformedintheenvironmentbythereactionofMDIwithwaterare
alwayslow.ApondstudyprovidesevidencethatMDIaccumulationthroughtheaquaticfoodchainis
extremelyunlikely,asmightbeexpectedconsideringitsverylowsolubilityandhighreactivityin
aqueoussolution.Theinformationonoccupationalexposureislimitedindifferentindustries,8h
timeweightedaverageexposuresinexcessof50g/m3havebeenreportedtooccurinfrequently.
ThereisverylimitedinformationonthetoxicokineticsofMDI.Onceabsorbed,itappearstobe
predominantlyconjugatedtoprotein.Withrespecttoinhalationexposure,onlylimitedstudiesusing
ratsareavailable.AninhalationexposurestudyusingradiolabelledMDIindicatesthatsomeformor
portionofMDIisdistributedthroughoutthebody,predominantlyinthelungs,muscle,kidneys,and
digestivetract.ThefaecalandurinaryeliminationofMDIanditsmetabolitesover4dayswas57%
and13%oftherecoveredradioactivity,respectively.Lessthan1%oftheradioactivitywasrecovered
fromthemajororgans,although23%oftheadministereddosewasrecoveredinthecarcass.Inurine,
smallamountsoffreeandacetylatedMDAwereidentified.
StudiesofworkershaveidentifiedfreeMDA,acetylatedMDA,andadductsofbothwith
haemoglobinoralbumininurineandblood.Thesestudiessuggestthatplasmaacidhydrolysable
MDAmaybeausefulbiomarkeroflongtermexposuretoMDI.Thehalflifeofacidhydrolysable
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MDAintheurineofaworkerexposedtoPMDIwas7080h,andinserum,21days.
MDIisnotacutelytoxictolaboratorymammals.Animaldataprovideclearevidenceofskinand
respiratorysensitizationduetoMDI.Humoralaswellascellularimmunitymaybeinvolvedinthe
pathogenesisofhypersensitivityduetoisocyanates.Severerespiratorydistressandasignificant
decreaseinbodyweightgainwereobservedinmaleandfemaleratsexposedtoPMDIaerosolata
concentrationof13.6mg/m3for6hperday,5daysperweek,overaperiodof2weeks,withmuch
lessseveresignsofrespiratorydistressandonlyslightlyreducedbodyweightgaininmaleratsat4.9
mg/m3.Basedonamarginalincreaseinlungtobodyweightratioathigherdoses,itwasconcluded
that2.2mg/m3,whichwasthelowestdoselevelexamined,wasanoobservedadverseeffectlevel
(NOAEL).
Ina2yearchronicinhalationtoxicity/carcinogenicitystudy,ratsthatwereexposedtoPMDIaerosol
atconcentrationsof0,0.19,0.98,or6.03mg/m3showedchangesintherespiratorytract.Pulmonary
adenocarcinomaobservedinonecasewasconsideredasinsufficienttoidentifyPMDIasananimal
carcinogenhowever,insitugenerationofMDA,whichisaknownanimalcarcinogenviadrinking
water,couldberesponsiblefortheeffect.Basalcellhyperplasiaintheolfactoryepitheliumdetected
at0.98and6.03mg/m3wasjudgedanoncarcinogeniccriticalendpoint.Thenonneoplastic
informationinthisstudysuggestsaNOAELof0.19mg/m3andalowestobservedadverseeffect
level(LOAEL)of0.98mg/m3.
BothpositiveandnegativeresultswereobtainedwhenmonomericMDIdissolvedindimethyl
sulfoxide(DMSO)wastestedinvitrowithSalmonellatyphimurium.However,becauseoftheknown
interactionofDMSOwithMDItoyieldMDAandpossiblyotherreactionproducts,thesepositive
resultsshouldnotbeconstruedasmeaningfulforhumanhealthriskassessment.
ExposureofgravidWistarratstomonomericMDIresultedinanincreasedincidenceofasymmetric
sternebraeinfetusesat9mg/m3however,astheincreasewaswithinthelimitsofbiological
variability,theNOAELfordevelopmentaltoxicityinthisstudywasestimatedtobe9mg/m3.In
anotherstudyinwhichratswereexposedtoPMDI,theNOAELformaternalandfetaltoxicitywas
estimatedtobe4mg/m3,basedonthefindingofprematuredeathsofpregnantfemalesand
statisticallysignificantdecreasesinplacentalandfetalweightsat12mg/m3.Therehavebeenno
studiesthathaveexaminedtheeffectofpolymericormonomericMDIonreproductiveparameters.
Thehealthendpointsofmostconcernareoccupationallyinducedasthma,hypersensitivity
pneumonitis,andinflammatoryupperrespiratorytractdiseasesthroughinhalationofpolymericor
monomericMDI.Althoughnotyetwellunderstood,humoralaswellascellularimmunological
reactionsappeartobeinvolvedintheallergicreactions.Casereportsaswellasepidemiological
studieshavedescribedMDIasacauseofoccupationaldermatitis,skinsensitization,andasthma.
Althoughlimitedinvariousways,acohortstudyandaretrospectivestudyshowednosignificant
associationwithcancermorbidity.Therearenodataavailablefororalexposure,butitisunlikelythat
humansareexposedtoMDIbytheoralroute.
MDIdidnotshowtoxicitiestofish,aquaticinvertebrates,algae,ormicroorganismsunderanyacute
orlongtermexposuretestingconditions.However,resultsofaquatictestsarenotmeaningfulbecause
ofMDIsvirtualinsolubilityinwater.Similarly,afewtestsonterrestrialorganismsdidnotshowany
effectsunderthetestingconditions.Availabledatashowthatthereisnoneedforconcernregarding
theeffectsofMDIonorganismsintheenvironment,althoughmoredetailedinformationregarding
theformationofMDAintheenvironmentanditseffectsonorganismsisrequiredbeforeanyfirm
conclusionscanbedrawn.
2.IDENTITYANDPHYSICAL/
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CHEMICALPROPERTIES
MDIisthegenericnameofaproductusedinindustrialsettings.PMDI,theprimary
technical/commercialformofMDI,isactuallyamixturethatcontains2580%monomeric4,4MDI
aswellasoligomerscontaining36ringsandotherminorisomers,suchasthe2,2isomer.This
compositionrendersthematerialsemisolidandsuitableforaerosolgeneration.Thecompositionof
PMDIvarieswiththemanufactureranduse.Therangeofvariationreflectsvariationsfromvarious
sourcesofinformation,i.e.,fromaGermanreview(DFG,1997),USToxicologicalReview(USEPA,
1998),andtheEUdraftdocument(EU,1999).Figure1giveschemicalstructuresof4,4MDIand
PMDI,andTable1providesChemicalAbstractsService(CAS)registrynumbersofseveralMDI
isomersandPMDI.
Table1:IsomersandpolymersofMDI.
Name
CASregistrynumber
4,4MDI
101688
2,4MDI
5873541
2,2MDI
2536052
nonisomerspecificMDI
26447405
PMDI
9016879
Monomeric4,4MDIisawhitetopaleyellowsolidatroomtemperature,withamolecularweightof
250.26.Ithasaboilingpointof>300Cat101.3kPa,ameltingpointof3943C(capillarymethod)
or40C(differentialscanningcalorimetryorDSCmethod)(Kellyetal.,1997),andavapourpressure
of<1mPaat20C(DFG,1997).Ithasatransientexistenceinwaterthus,itswatersolubilityisonly
notional.However,monomericMDIissolubleinoctane,benzene,andkerosene(ChemicalSocietyof
Japan,1989).TheconversionfactorforMDIisasfollows:1ppm=10.4mg/m3.Additional
propertiesforMDIarepresentedintheInternationalChemicalSafetyCard(ICSC0298)reproduced
inthisdocument.
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PMDIisadarkreddishbrownviscousliquidwithanindefinitemeltingpointaround0Canda
vapourpressureof<1mPaat20C(DFG,1997).
PMDIistheformproducedcommerciallyfromanilineandformaldehydeusinghydrochloricacidas
catalyst.ThiscondensationreactionproducesMDAandacomplexmixtureofpolyamines,whichare
phosgenatedtoobtainamethylenediphenyldiisocyanatemixture.4,4MDIcanbeobtainedby
purifyingthediphenylmethanediisocyanatemixture.
3.ANALYTICALMETHODS
BecausecommercialapplicationsusingPMDIgenerateaerosols(Dharmarajan,1979),traditional
techniquesthathavebeensuccessfullyusedtomeasureisocyanatevapours(e.g.,theMarcaliand
papertapecolorimetricmethods)aregenerallynotsuitableforquantitativemeasurementsofMDIin
air.Thestrengthsandlimitationsofimpingers,bubbles,andfilterswithrespecttocollectionand
detectionofbothMDIaerosolsandvapourshavebeendiscussedbyStreicheretal.(1994).When
puremonomericMDIwasheatedunderlaboratoryconditions,a0.5mporesizefilterblockedmore
than87%oftheMDIfromenteringanimpinger.
UsuallyHPLCisusedfortheanalysisofMDIandPMDI(NIOSH,1985IARC,1986Spanneetal.,
1996Tinnerbergetal.,1997).DetectionlimitsofHPLCforMDIandPMDI,whichvarydepending
onthesamplingmethodology,canbebelow0.01mg/m3.
Complexmixturesofairborneisocyanatesandrelatedcompoundsformedduringthethermal
decompositionofpolyurethanewereanalysedbyderivatizationofisocyanatesinimpingerflasks
containingdibutylaminewithformationofureaderivatives.Derivativeswereanalysedbyreverse
phaseliquidchromatographywithmassspectrometryorwithultraviolet(UV)detection.The
detectionlimitofMDIwithUVdetectionwas0.50.8g/m3fora15litreairsample,andthatwith
massspectrometry(instrumentaldetectionlimit)was4fmoloftheMDIderivative(Spanneetal.,
1996Tinnerbergetal.,1997).
4.SOURCESOFHUMANAND
ENVIRONMENTALEXPOSURE
MDIisusedforpolyurethaneelastomers(rollers,packing,rubbervibrationinsulators,synthetic
leather,etc.),spandexfibres,andrubbershoesoles.PMDIisusedtomakerigidandflexiblefoam,
foundryresinsandbinders,andheatinsulatingmaterial.ThetotalannualglobalproductionofMDI
andPMDIwasabout1.2milliontonnesin1991,1.5milliontonnesin1993,1.78milliontonnesin
1994,and1.95milliontonnesin1996(ChemicalWeek,1998).InJapan,0.200.27milliontonnes
wereproducedin19921996(ChemicalDaily,1997).
MDIisusuallypresentinworkplaceairasvapour,butsomeaerosolmayalsocoexist,dependingon
thetypeofoperation(DFG,1997).Insuchatmospheres,exposuremaybetounreactedMDIortoa
mixtureofMDIandpolyols,reactantsusedtoconvertMDItopolyurethanefoams.Therangeof
particlesizewillvarywiththeapplication,andthemethodofsamplingandanalysisshouldbesuited
totheworkplacerequirement.
TheextenttowhichMDI,ineithermonomericorpolymericform,dispersesinairbeyondthepointof
releaseandexposesgeneralpopulationsisnotknown.
5.ENVIRONMENTALTRANSPORT,
DISTRIBUTION,ANDTRANSFORMATION
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ThecomplexnatureofMDIcompositionandreactionsintheenvironmentoftenmakesinterpretation
difficult.
TheobservedorlikelyfatesofMDIinair,water,andsoilhavebeendescribedbyBrochhagen&
Keller(1983)andGilbert(1988).Morerecently,comprehensivestudiesonthebehaviourofMDIin
theaquaticenvironmenthavebeencarriedoutbyYakabeetal.(1994)andHeimbachetal.(1996).
5.1Water
WhenMDIisaddedtowater,itsNCOgroupsreactreadilywithOHgroupsofthewatertoform
mixturesofdiisocyanatesandamines,whichthenreadilyreactwithmoreMDItoproduceinert,solid,
insolublepolyurea(EU,1999).Thehydrolysisofisocyanatesinaqueoussolutionisrapidahalflife
of20shasbeenmeasuredforphenylisocyanate(Castroetal.,1985).However,thesubsequent
reactionoftheformedaminewithfurtherisocyanate,toproduceaurea,isevenfaster(Hegartyetal.,
1975).
Yakabeetal.(1994)studiedthefateofPMDIinwaterundertwoconditionsnamely,vigorous
stirringandstaticconditions,whichsimulatetwoscenariosofaccidentalspillsofPMDI.PMDIused
inexperimentsiscomplexandcomposedof56majorconstituentshaving24aromaticrings.When
MDIcomesintocontactwithwater,itdoesnotdispersereadily,butformsglobulesorsolidmasses,
whichreactattheirsurface.Undersuchheterogeneousconditions,thedisappearanceofPMDIshows
zeroorderkinetics.ProductionofwatersolubleMDAincreasesgraduallywithtime,andtheMDA
reachesanearlyconstantconcentrationafter16htheamountofMDAformedislessthan0.5%of
thenominalconcentrationofPMDIinitiallyadded,andthemajorproductsofPMDIbreakdownare
solid,insolublepolyureas.ThepolyureasformedfromMDIappeartobestabletochemicalattack,as
wouldbeexpectedfromitsinsolubilityandthestabilityofureas.
SupportforthechemicalstabilityofMDIisgiveninonestudyinwhichthepolyureaformedfromthe
reactionofPMDIwithwaterwasstirredat40Cinaqueousbuffersolutionsfor14days.Nosoluble
products(dissolvedorganiccarbonorMDA)weredetected(Yakabeetal.,1994).
AfurtherpotentialbreakdownproductofMDIinwaterisanoligourea.Anoligoureawassynthesized
from4,4MDIand4,4MDAandshowntobemainlydiurea.Itwasinsolubleinwaterandfoundto
benotinherentlybiodegradable(Yakabeetal.,1994).
InthestudybyHeimbachetal.(1996),upto10gofPMDIwasaddedperlitreofwaterintoartificial
outdoorponds,simulatingaccidentalpollutionofapond.Threepondscontainedgroundwater,above
naturallakesediment,towhichcagedrainbowtrout(Oncorhynchusmykiss)wereadded.Following
equilibration,PMDIwasaddedtopartofthesedimentoftwopondsatdosagesof1and10g/litre.
Thethirdpondservedasanuntreatedcontrol.Waterchemistry,MDIandMDAconcentrations,and
populationsanddiversityofdifferenttrophiclevelsweremonitoredover112days.The
concentrationsofMDIandMDAweremonitoredinthethreecompartments(water,fish,and
sediment)overthedurationofthestudy.NoMDIorMDAwasdetectedinthewater(detectionlimits
4and10g/litre,respectively)orinthefish(detectionlimits0.5and1.4mg/kg,respectively).The
studyprovidesevidencethatMDIaccumulationthroughtheaquaticfoodchainisextremelyunlikely,
asmightbeexpectedconsideringtheverylowsolubilityandhighreactivityofMDIinaqueous
solution.
5.2Soil
MDImaycomeintocontactwithsoilafteraccidentalspillageduringtransportationorstorage.
5.3Air
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TheatmosphericconcentrationofMDIarisingfromareleaseisnaturallylowonaccountofMDIs
verylowvolatility.ItisexpectedthatairborneMDIwillhavearathershorthalflifeasaconsequence
ofreadydegradationtoinorganiccompoundsbyhydroxylradicalspresentinthetroposphere.
ThequestionofwhetherMDIvapouroraerosolcanhydrolyseinhumidairtoyieldMDAwas
assessedinalongtermstudy(Appelmanetal.,1986)andastudyofchipboardproduction(Giersig,
1989).Inthefirststudy,lowconcentrationsofMDA(notdetectedto90g/m3)wereobservedinair
samplesfromthesubchronicinhalationstudyinratsexposedtoPMDI(Appelmanetal.,1986).
Detectedconcentrationswereindependentoftheconcentrationsofthetestatmosphere(0,0.2,1,and
5mg/m3)thus,itwasconsideredthatthedetectionofMDAwascausedbyartefacts.Inthesecond
study,noMDAwasdetected,althoughthePMDIconcentrationsrangedupto5mg/m3when
polyurethaneparticleboardwasheatedupto80C(thedetectionlimitforMDAinairwas10g/m3)
(Giersig,1989).Thisresulthasbeenaccountedforasfollows:MDAisformedonlyslowlyatneutral
pHandreactsrapidlywithexcessMDItoyieldoligoureasandpolyureasMDIaerosolscanforma
shellofpolyureaonthesurfaceofthedroplets,andthisshellpreventsfurtherreactionoftheenclosed
MDI(Mann,1987).
6.ENVIRONMENTALLEVELSAND
HUMANEXPOSURE
6.1Environmentallevels
CommercialsynthesisofMDItakesplaceinclosedsystemswherecontactofMDIwithwateris
carefullyavoidedthroughproductionandstoragestages,sincetheNCOgroupofMDIreactsreadily
withtheOHgroupofwater(EU,1999).ThereisnoinformationaboutlevelsofvariousformsofMDI
intheambientair.Wherespillageistosoilorwater,MDIhasatransientexistenceduetoitsreaction
withthewatertoproducepredominantlyinsolublepolyureas.
6.2Humanexposure
Undernormalcircumstances,exposureofthegeneralpublicislikelyonlyfromreleasestothe
atmosphere.
Occupationalexposuredatafromawiderangeofapplicationsandprocessescollectedacrossindustry,
measuredbyrecentstandardsandcapturingtotalinhalableMDI(i.e.,vapourandaerosol)overa
varietyofexposuretimes(0.258h),areavailable(ISOPA,1998).Outof1238measurements,138
(11%)wereabove0.0125mg/m3,and31(2.5%)wereabove0.05mg/m3these31measurements
weredetectedduringprocessesinrigidpolyurethanefoampreparationforroofpanelsforthermal
insulationorpreparationofcoatings,adhesives,sealants,andelastomersforsprayfloorcoating,
bridgedeckingprimer,orparticleboard.SinceaccidentalexposuretoMDIinoccupationalsettings
mayresultfromincidentssuchasspillages,splithoses,andleakingdrums,theintroductionof
EuropeanIsocyanateProductionAssociation(ISOPA)guidelinesfortransport,storage,handling,and
useofdiisocyanatehasreducedthepotentialofaccidentalexposuresoverthepast20years.
AnalysisconductedrevealedthattheenvironmentalMDIconcentrationwas0.05mg/m3orlessin
273outof319samples,andonly2samplesexceeded0.2mg/m3.Itisreported,however,thata
ventilationductwasinstalledabovethemouldingmachineseveralmonthsbeforetheanalysis,and
thatbeforethensamplesexceeding0.2mg/m3hadoccurredfrequently(Diller&Herbert,1982).
Sepaietal.(1995b)examinedbiologicalsamples(urineandblood)from20workers(aswellas2
unexposedreferenceworkers)exposedtoMDIvapourduringthemanufactureofpolyurethane
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products,togetherwiththelevelsofMDIintheairoftheworkingenvironment.Inmostcases(17out
of20),theairlevelswerebelowdetectionlimits.Thebloodandurinesampleswereanalysedforthe
presenceofadductsandmetabolitesusinggaschromatographymassspectrometrymethods.The
amountofMDAreleasedafteracidhydrolysis(inhydrochloricacidat3mol/litre,at100C,for60
min)wasonaverage6.5timeshigherthantheamountoffreeMDAandacetylatedMDApresentin
urine.
TheOntarioMinistryofLabour,Canada,assessedthecauseofmultiplerespiratorycomplaintsamong
workersataplantthatmanufacturesautomotiveinstrumentpanelsusingpolyurethane(Lissetal.,
1996).Of137samplesanalysedforMDIbetween1986and1992,129(94%)werebelowthelimitof
detection(notgiven).Oftheothereight,allbutone(withaconcentrationof60g/m3)werebelow50
g/m3.Tarloetal.(1997)reportedthat40%ofmeasuredMDIconcentrationsin19841988in20
companieswithcompensatedisocyanateasthmaclaimsexceeded50g/m3,whilethefigurewas27%
for203companieswithnocompensatedisocyanateasthmacases.
7.COMPARATIVEKINETICSAND
METABOLISMINLABORATORY
ANIMALSANDHUMANS
AnimalinhalationstudieshaveshownthatPMDIexposure(seesection8.4.2fordetailsofparticle
sizedistribution)resultsinsignificantdepositionbothinthenasalregionandinthealveolarregionof
thelungs(Reuzeletal.,1994a,b).Onceabsorbed,PMDIappearstobepredominantlyconjugatedto
protein,buttheroleofotherbiomolecules,suchasglutathione,hasnotbeeninvestigated(theroleof
glutathionehasbeenshownforotherisocyanatesbyDayetal.,1997).
Inanunpublishedpharmacokineticstudy(Istin,1977),noseonlyexposureofmaleSpragueDawley
ratstoanaerosol(particlesizeslessthan5m)ofradiolabelled(inthemethylenegroup)monomeric
MDIfor15minresultedinthedistributionofradioactivity,predominantlytothelungsandavariety
ofextrarespiratorysites(principallymuscle,liver,kidneys,andthedigestivetract),after96hwhen
theanimalsweresacrificed.Labellingofthedigestivetractwasconsideredtobearesultof
transferenceoflabelledmaterialfromthelungs.After4days,70%oftheabsorbeddosewas
eliminated(57%faecaleliminationand13%urinaryelimination).Therewasnoattempttoidentify
thenatureoftheexcretedradioactivity.Twentythreepercentoftheradioactivityadministeredwas
foundinthecarcasshowever,lessthan1%oftheradioactivitywasrecoveredfromthemajororgans.
Thefateoftheother22%isnotknown.
HaemoglobinadductswerefoundafterrepeatedexposureofratstoMDIaerosolsfor17hperday,5
daysperweek,over3or12monthsinaninhalationchamber(Sepaietal.,1995a).Inlaboratory
animalsexposedtoPMDI/MDI,MDAinurineandbloodformedbystrongacidhydrolysiswasused
asabiomarkerforexposure(Sepaietal.,1995a).
WhenpregnantWistarratswereexposedfor6hongestationday19toanaerosolof20mgMDI/m3
(particlesizedistributionnotknown),maternalblood,amnioticfluid,fetus,andplacentawere
measuredforMDIanddegradationproducts(asMDAafteracidhydrolysisdetailsofhydrolysis
conditionsnotknown)immediatelyafterexposure(Bartschetal.,1996).ThehighestlevelofMDAor
degradationproductswasdetectedinthematernalblood,followedbytheplacenta,fetus,and
amnioticfluid(at66.4%,42.4%,and13.6%ofthematernalbloodlevels,respectively).
Inhumans,MDAlevelsinurineand(afterstrongacidhydrolysis)inbloodwerereportedtobe
correlatedwithexposuretoPMDI/MDI(Schuetzeetal.,1995Sepaietal.,1995bSkarping&
Dalene,1995).ThehalflifeofMDAintheurineofaworkerexposedtoPMDIwas7080h,andin
serum,21days(Skarpingetal.,1995).OtherreportsalsosuggestthatplasmaacidhydrolysableMDA
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maybeausefulbiomarkeroflongtermexposuretoMDI(Sepaietal.,1995bDaleneetal.,1996).In
arecentstudyofworkersoccupationallyexposedtoeitherPMDI/MDIorMDA,freeMDAwas
detectedinurinepriortoacidhydrolysis(Schuetzeetal.,1995).
Sepaietal.(1995b)reportedtheformationofadductsofMDAandacetylatedMDAwith
haemoglobinoralbumininthebloodofworkersexposedtoMDI,asdescribedinsection6.2.MDA
wasdetectedasahaemoglobinadductinall20subjects,atlevelsrangingfrom70to710fmol/g
haemoglobinthisincludedonecaseofhaemoglobinadductofacetylatedMDA,whichwas
presumablyformedbytheinvivohydrolysisofMDI.PlasmaMDAlevelsrangedfrom3.9to70
fmol/mgplasmaproteinin20workers,andupto120fmol/mgwerefoundtobecovalentlyboundto
albumin.MDIintheairandMDAintheplasmawereobservedinastudyofpolyurethanepipe
welders(Skarpingetal.,1995Daleneetal.,1996Tinnerbergetal.,1997).Thehaemoglobinadduct
ofacetylatedMDIwasconsideredtobeformedbyinvivohydrolysis.
8.EFFECTSONLABORATORYMAMMALS
ANDINVITROTESTSYSTEMS
8.1Singleexposure
OralLD50sforMDI(25%incornoil)andPMDI(undiluted)administeredtoratsinsinglegavage
doseswerereportedtobe31.6g/kgbodyweightandhigherthan10g/kgbodyweight,respectively
(MobayChemical,1961Wazeter,1964a).
PMDI(liquidform0,2.5,3.9,6.0,and9.4g/kgbodyweight)wasappliedtotheabradedskinof
immobilizedalbinorabbits(2persexpergroup)whosebackswerethencoveredinrubberizedcloth
for24h(Wazeter,1964b).AfterthePMDIwaswashedoff,animalswerekeptfor14daysfor
observation.Transientlyslightatoniawasobservedinafewanimalsatthethreehighestdoselevels.
Animalswereessentiallynormal,exceptforslightoedemaobservedatthe9.4g/kgbodyweightdose.
GuineapigsexposedtomonomericMDIaerosolatconcentrationsbetween0.6and350mg/m3(no
otherdetailsavailable)for3hshowedadecreaseinrespirationrateandanincreaseintidalvolumeat
lowerconcentrations,whereasaconcentrationdependentincreaseinrespirationratewasseenabove
10.4mg/m3(Thorneetal.,1986).Incontrast,therespirationratewasdecreasedinadosedependent
mannerinmiceexposedtoMDIaerosolconcentrationsbetween10.2and58.5mg/m3(Weyel&
Schaffer,1985).
WhenratswereexposedtoPMDIaerosol(inwhichmorethan99%ofparticlesweresmallerthan5
m)for4hatconcentrationsof384,418,500,or523mg/m3,animalssatquietlywithclosedeyes
duringexposure,andtheirbreathingbecamelabouredandnostrilsdilated,especiallyinthehighest
concentrationgroup(Appelman&deJong,1982).Autopsyoftheanimalsimmediatelyafterexposure
showedhaemorrageandoedemainthelungs.TheLC50inthisstudywasestimatedtobe490mg/m3.
8.2Irritationandsensitization
8.2.1Irritation
WhenPMDI(liquidform0,2.5,3.9,6.0,or9.4g/kgbodyweight)wasappliedtotheabradedskinof
albinorabbits(2persexpergroup)for24h(Wazeter,1964b),oneanimalatthehighestdose
exhibitedslightoedemaduringthefirstandseconddays.Slighterythemaobservedinitiallyatalldose
levelsdidnotlastafter7days.Nodesquamationorfissuringwasnotedwiththecompound.
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8.2.2Sensitization
ThereisclearevidenceofskinsensitizationduetoMDI.Humoralaswellascellularimmunitymay
beinvolvedinthepathogenesisofhypersensitivityduetoisocyanates.
Inamouseearswellingtest,whichindicatestheextentofcontactsensitivity,MDIatconcentrations
rangingbetween0.6and187mg/kgbodyweightwasappliedtotheshavedanddepilatedabdomens
of45malemice(Thorneetal.,1987).After4days,themicewerechallengedontherightearwith
acetoneandontheleftearwithacetonecontainingadoseofMDIthatwasnonirritating.The
thicknessoftheearsat24hafterchallengewascomparedwiththatimmediatelybeforechallenge.
AftercalibrationoftheearswellingresponsewithMDIsensitizationdoseinlogscales,anear
thicknessincreaseofmorethan0.03mmwasjudgedtobesignificant.Thechallengewithacetonedid
notproduceanyearswelling.TheresponsetoMDIchallengeindicatedadoseresponseeffectat0.6
37mg/kgbodyweight.Crossreactivitytotoluenediisocyanate(TDI)andotherisocyanateswas
demonstrated.
Usingearthickeningasthecriterion,transferofMDIinducedcontactsensitivitywithorwithoutT
celldeletionbymonoclonalantiThy1,2antibodywasstudied(Tanakaetal.,1987).A1%solutionof
MDI(reagentgrade)inethylacetatewasappliedtoagroupof797weekoldmalemice.The
challengesolutioninducedearswellingofdelayedonset,withitspeakat24h.Passivetransferofthe
MDIinducedcontactsensitivitywasachievedbyinjectinglymphocytesfromthelymphnodesof
MDIsensitizedmiceintothecaudalveinofsyngeneicmice,andtheeffectorcellswerefoundtobe
Tcells.
8.3Shorttermexposure
Fourgroupsof10maleand10femaleWistarratswereexposed,wholebody,toPMDIaerosolfor6h
perday,5daysperweek,overaperiodof2weeks(Reuzeletal.,1994a).Theoverallmean
concentrationswere2.2,4.9,and13.6mg/m3,respectively.Ninetyfivepercentoftheparticleshada
massmedianaerodynamicdiameter(MMAD)below5m.NoMDAandnophenylisocyanatecould
bedetectedinthetestatmospheres.Severerespiratorydistressandastatisticallysignificantdecrease
(extentnotgiven)inbodyweightgainwereobservedinmaleandfemaleratsexposedto13.6mg
PMDI/m37outof10malesand1outof10femalesdied.Maleratsexposedto4.9mg/m3showed
muchlessseveresignsofrespiratorydistressandonlyslightlyreducedbodyweightgaincompared
withcontrols.Lungtobodyweightratiosweresignificantlyhigheronlyinthemidandhigh
concentrationgroupsrelativetocontrols.Grosspathologicalexaminationremainedessentially
negativenodataonhistologicalexaminationwerereported.Basedonthemarginalincreaseinlungto
bodyweightratios,itwasconcludedthat2.2mgPMDI/m3,whichwasthelowestdoselevel
examined,wasaNOAEL.TheresultsshowthatthetoxicityofMDI(whichislowafteroral
exposure)isclearlyhigherbytheinhalationroute,withlocaleffectstothelungafterrepeateddosing.
NoshorttermstudyonmonomericMDIandnodatafromoralordermalrouteswereavailable.
8.4Longtermexposure
8.4.1Subchronicexposure
InasubchronicstudybyReuzeletal.(1994a),SPFWistarrats(30persexperexposurelevel)were
exposed,wholebody,toPMDI(Desmodur44V20fromBayerAG,withmonomericMDI52%,
isocyanatecontent30%)aerosolat0,4.1,8.4,or12.3mg/m3for6hperday,5daysperweek,for13
weeks.Morethan95%oftheparticleshadanMMADoflessthan5m.Thehighestconcentration
resultedin25%mortality(15/60animals,onlyduringthefirst7weeks),growthretardation,severe
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respiratorydistress,degenerationofnasaltissues,andfocalinflammatorychangesinthelungs.Signs
oflesssevererespiratorydistresswerealsoobservedinanimalsexposedto8.4mg/m3.Bodyweights
inmalesofthehighconcentrationgroupweresignificantlydepressedthroughweek13.Somebody
weightdepressionwasobservedinmalesofthemidconcentrationgroupthroughweek10.Body
weightdepressionwasnotobservedinfemales.Therewasnotacleardoseresponsetrendin
macrophageaccumulation,althoughmacrophageswereincreasedinincidenceinalltestgroupsover
controls.Tissuesexaminedbylightmicroscopyincludednose,larynx,trachea,lungs,liver,and
kidney.Theincidenceofolfactoryatrophywasstatisticallysignificantinhighdosemales(5/10)and
highdosefemales(6/10).At4.1mg/m3,olfactoryepithelialatrophyoccurredinfrequentlyinexposed
animals.Therewasasignificantaccumulationofmacrophagesinthelungsandmediastinallymph
nodesofallexposedanimalscomparedwithcontrols.Theincreaseinmacrophageaccumulationat
thelevelofthealveolarseptawasrelatedtoexposure,andthedifferencebetweentreatmentgroups
andcontrolswasstatisticallysignificantinmalesexposedto4.1mg/m3andinfemalesat8.4mg/m3.
Sincethefirststudyfoundhighmortality,probablyduetotheuseofveryyounganimals,another13
weekstudywasconductedatactualmeanconcentrationsof0.35,1.4,and7.2mg/m3(Reuzeletal.,
1994a).Unlikethefirststudy,transientgrowthretardationandanincreasednumberofpulmonary
macrophagesweretheonlyeffectsnotedatthehighestconcentration.
Thus,thesestudiesdemonstratedclearadversepulmonaryandnasaleffectsat8.4mg/m3,andthey
arestatisticallysignificantat4.1mg/m3.
8.4.2Chronicexposureandcarcinogenicity
A2yearchronictoxicity/carcinogenicityinhalationstudywascarriedoutwithSPFWistarrats(60
persexperexposurelevel)exposedwholebodytoPMDIaerosolat0,0.19,0.98,or6.03mg/m3for6
hperday,5daysperweek(Reuzeletal.,1994b).Anadditionalsatellitegroupof10persexper
exposurelevelwassimilarlyexposedandusedforhistopathologyat1year.Ninetyfivepercentof
theparticleshadanMMADlessthan5mtheMMADandgeometricstandarddeviation(in
parentheses)correspondingtotheexposurelevelswere0,0.68m(2.93),0.70m(2.46)and0.74
m(2.31),respectively.
Effectsat24monthswereconfinedtotherespiratorytract.Compoundrelatedchangeswerefoundin
thenasalcavity(olfactorydegenerationandbasalcellhyperplasia),thelungs(fibrosisandinterstitial
pneumonitis),andthemediastinallymphnodestosomedegree,theywerealreadypresentafter1
yearofexposure,asindicatedinthesatellitegroup.Olfactoryepithelialdegenerationwaselevated
significantlyatthehighconcentrationinbothsexes.Basalcellhyperplasiaintheolfactoryepithelium
waselevatedsignificantlyinmalesonlyatthemidandhighconcentrations.
Noadverseeffectsonthedistributionandincidenceoftumourswerefoundwiththeexceptionof
tumoursinthelungs.Solitarypulmonaryadenomas,describedasrareinthisstrain,wereobservedin
males(6/60)andfemales(2/59)exposedto6.03mg/m3comparedwithcontrols(0/120).The
adenomaswereonlyafewmillimetresinsizeandwerelocatedadjacenttoareasinwhich
haemorrhage,macrophageaccumulation,andfibroblasticreactionswereobserved.Onlyone
pulmonaryadenocarcinoma(10mminsize)wasobservedinonemaleexposedtothisconcentration.
ThenasalolfactoryandlunglesionsindicateaNOAELof0.19mg/m3andaLOAELof0.98mg/m3.
Compoundassociatedyellowishparticulatematerialwasfoundinalveolarluminarmacrophagesin
bothsexesat0.98and6.03mg/m3.Localizedfibrosiswassignificantinmalesexposedto6.03mg/m3
andinfemalesat0.98and6.03mg/m3.Theamountofparticulatematerialaccumulatedatthelevelof
thealveolarductincreasedwithtimeaswellaswithlevelofexposure.Macrophageswithyellow
pigment(aformofMDIwithinthemacrophage)werealsofoundinthealveolarinterstitium,and
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accumulationofthesemacrophagesalsooccurredinthemediastinallymphnodes.Theaccumulation
ofmacrophagesandlocalizationoftissuedamageinthisareasuggestthatthethoraciceffectisdue
primarilytotoxicitytothemacrophage,withsecondarytissuedamage.
Achronicinhalationstudy(Hoymannetal.,1995,1997)hasalsobeenconductedwith99.5%pure
monomeric4,4MDI.FemaleWistarrats(80perexposuregroup)wereexposed(wholebody)to
MDIinaerosolat0.23,0.70,or2.05mg/m3(MMADabout1m)for17hperday,5daysperweek,
forupto24months.Aseparategroupof20perexposurelevelwasexaminedhistopathologicallyat
12months.Smallernumbersofanimalswereassessedatvarioustimepointsforlungfunctionandfor
examinationofbronchioalveolarlavage(BAL)fluidforcellcountsandproteinandenzyme
determinations.Statisticallysignificantconcentrationrelatedpulmonarylesionsincluded(1)an
increaseinfocal/multifocalalveolarandbronchioalveolarhyperplasia,(2)interstitialfibrosis,and(3)
anaccumulationofparticleladenandpigmentedmacrophages.Alveolarcellhyperplasia,considered
preneoplastic,exhibitedaconcentrationresponsetrend,withtheincidencereachingsignificancein
thehighexposuregroup.Theseeffectscorrelatedwithpulmonaryfunctiondeficits(FEF25[forced
expiratoryflowfrom25%oftheforcedvitalcapacity,orFVC]andcarbonmonoxidediffusion),
particularlyinthehighexposuregroup.Allgroupsexhibitedsignificantlyincreasedrelativelung
weightsatalltimeperiods(morethan60%at20months),withsignificantincreasesin
hydroxyprolineinBALfluid(morethan70%at12months).Incontrasttotheresultsreportedby
Reuzeletal.(1994b)forPMDI,therewasnoapparenteffectofmonomericMDIonnasaltissuesat
anyexposurelevel.Inonehighdoseanimal,abronchioloalveolaradenomawasobserved.Becauseof
theconcentrationrelatedlungeffects,0.23mg/m3isconsideredaLOAEL.ThereisnoNOAELin
thisstudy.
MDIreactswithwatertoproduceMDA.MDAhasalsobeenstudiedforcarcinogenicitybyoral
administration.Treatmentrelatedincreasesintheincidencesofthyroidfollicularcelladenomaand
hepatocellularneoplasmswereobservedinbothmaleandfemalemicegiven150or300mg
MDA/litreindrinkingwaterfor103weeks.InratsadministeredMDAinasimilarmanner,treatment
relatedincreasesintheincidencesofthyroidfollicularcellcarcinomasandhepaticnoduleswere
observedinmales,andthyroidfollicularcelladenomasoccurredinfemales(Weisburgeretal.,1984
NTP,1986).TheincidenceofthyroidtumourswasgreaterwhenMDA(1000mg/kgdietfor19
weeks)wasadministeredorallyafterasingleintraperitonealinjectionof2800mgNbis(2
hydroxypropyl)nitrosamine(DHPN)/kgbodyweightthanwhenDHPNwasgivenalone(Hiasaetal.,
1984).TherelevanceoftheseresultstotheevaluationofthecarcinogenicresponsetoMDIandits
potentialmetaboliteisnotcertain.
8.5Genotoxicityandrelatedendpoints
WhenthemutagenicityofisomersandhomologuesofMDI(4,4MDI,2,4MDI,amixtureof
monomericMDIisomers,andPMDI)wasdeterminedintheSalmonella/microsometestusingDMSO
andethyleneglycoldimethylether(EGDE)assolvents,positiveresultswereobtainedforDMSO
solutionsofallfourdiisocyanatesinthepresenceofS9mixcontaining30%S9fraction.Uniformly
negativeresultswerefoundwhenthediisocyanatesweredissolvedinEGDE(Andersenetal.,1980
Herbold,1980a,bWoolrich,1982Shimizuetal.,1985Zeiger,1987Herboldetal.,1998).MDIis
notstableinDMSO,therebeingmanyproductsgeneratedwithinminutes(Herbold,1990a,b
Gahlmann,1993).Thus,itseemsthatpositivetestresultsinanyinvitrotestsystemarecausedbythe
degradationproductsofMDIinDMSO,ratherthanbyMDIitself.Oneofthedegradationproductsof
MDIisMDA,whichisknowntobegenotoxicandwhoseformationwasdetectedwhenMDIwas
dissolvedinDMSO(Herboldetal.,1998).NoMDAcouldbedetectedinsolutionsofMDIinEGDE.
ItisthereforeconcludedthatthepositiveresultsobtainedwithdiisocyanatesinDMSOsolutionsare
duetotheformationofMDA.ThestabilityofMDIinamodelandarealtestenvironmentwas
studied(Seeletal.,1999).WhenMDIwasdissolvedinDMSO,morethan99%oftheMDIwas
degradedbeforethestartofincubationwithtestingredientsoftheSalmonellamutagenicityassay,and
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MDAwasdetectedat2.12.8%oftheMDIconcentrationwithin45sofincubation.Testsassessing
themutagenicpotentialofMDIinvitroandinvivoshownoconvincingevidenceofmutagenic
activity.
FemaleWistarratsweretreatedtopically(ontheback)with14CMDI(labelledinthering)inacetone
toinvestigatethepossibilityofsystemiccirculationandDNAbindingpotencyofMDI(Vock&Lutz,
1997).About10%oftheradioactivitywasretainedatthesiteofapplication.DNAradioactivityinthe
liverwasatthelimitofdetection.Inasecondexperimentusingtopicaladministration,32P
postlabellinganalysisdidnotrevealisocyanateDNAadductsintheskin(Vock&Lutz,1997).
TissuesobtainedfromfemaleWistarratsexposedtoa0.9maerosolofMDIfor17hperday,5days
perweek,for1year,atlevelsof0,0.3,0.7,or2.0mg/m3,wereanalysedforDNAadductsusinga
32Ppostlabellingmethod(Vocketal.,1996).Inthelung,neitherisocyanateadductsnorthe
arylamineadductwasdetectable.Thesamenegativeresultwasseenintheliver,bladder,kidney,
respiratoryepithelium,andperipherallymphocytes.Intheolfactoryepithelium,ontheotherhand,the
arylaminederivedDNAadductnucleotidesweredetectedatverylowlevels(510adductsper1010
nucleotides).
8.6Reproductiveanddevelopmentaltoxicity
NospecificfertilitystudiesareavailableforMDI.
Inawellconducteddevelopmentalrangefindingstudy,conductedaccordingtoOrganisationfor
EconomicCooperationandDevelopment(OECD)GuidelineNo.414,matedfemaleWistarrats(8
pergroup)wereexposedtoPMDIbyinhalation(wholebody)atexposurelevelsof0,2,8,or12
mg/m3for6hperdayfromday6uptoandincludingday15ofpregnancy(WaalkensBerendsen&
Arts,1992).Onday21ofpregnancy,thefemaleratsweresacrificedandacaesareansectionwas
performed.Noclinicalsignsormortalityrelatedtotreatmentwasobservedduringthestudy.The
meannumberofcorporalutea,implantationsites,earlyandlateresorptions,and,consequently,pre
andpostimplantationlossshowednostatisticallysignificantdifferencesamongthecontroland
treatedgroups.Fromday6today9ofpregnancy,maternalbodyweightgainofthe8and12mg/m3
groupswasslightlydecreased(notstatisticallysignificant)whencomparedwiththecontrolgroup.No
otherdifferenceswereobservedinbodyweightandbodyweightgain,carcassweight,ornetweight
gainwhencomparedwiththecontrolgroup.Fetalbodyweightswerecomparableinallgroups,and
noexternaltreatmentrelatedabnormalitieswereobservedinthefetuses.TheNOAELofPMDI
aerosolbyinhalationformaternaltoxicityis8mg/m3,basedontheincreasedlungweights(relative
weightincreasedby14%)anddecreasedfoodintakeat12mg/m3.TheNOAELofPMDIaerosolby
inhalationfordevelopmentaltoxicityinthisstudyis12mg/m3.
TheprenataltoxicityofPMDIinpregnantWistarratswasalsoinvestigatedbyaerosolinhalation
(wholebody)accordingtoOECDGuidelineNo.414byBASF(1994).Twentyfivematedfemalerats
pergroupwereexposedtoconcentrationsof1,4,or12mg/m3(MMAD<2.8m)for6hperday
fromday6today15ofgestation.Thestudywasperformedintworeplicatescomprisingabouthalfof
theanimalseach.ExposuretoPMDIaerosolsataconcentrationof12mg/m3causedprematuredeath
in2outof25animals.Inthisgroup,statisticallysignificantdecreasesinplacental(6%decrease
comparedwithcontrol)andfetalweights(10%decreasecomparedwithcontrol)occurred,and
fetuses/litterswithskeletalvariations(irregularshapedsternebra,bipartitesternebra)andretardations
(incompleteormissingossificationofskullbones,vertebralcolumn,sternebra,metatarsalbones,and
partsofthepelvicgirdle)occurredatanincreasedrate.Meanpercentagesforskeletalvariationswere
38.9,48.7,47.8,and63.2%(p0.05),andmeanpercentagesforoverallvariationswere24.6,34.7(p
0.05),33.4(p0.05),and40.0%(p0.01),at0,1,4,and12mg/m3,respectively.Notreatment
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relatedfindingsindamsandfetusesoccurredat1and4mg/m3.TheNOAELformaternalandfetal
toxicitywas4mg/m3,andtheNOAELfordevelopmentaleffectswas4mg/m3.
GravidWistarratswereexposedbywholebodyinhalationtocleanair(control)andtomonomeric
4,4MDIat1,3,or9mg/m3for6hperdayfromday6today15postconception(Buschmannetal.,
1996).TheMMADoftheaerosolwas1.1m.Ratsweresacrificedonday20.Theabsoluteand
relativelungweightsinthehighdosegroupweresignificantlyincreased(23%)comparedwiththe
shamtreatedcontrolanimalsthisendpointwasnotexaminedintheotherexposuregroups.
Treatmentdidnotinfluenceanyothermaternalorfetalparametersinvestigated,althoughaslightbut
significantincreaseinlitterswithfetusesdisplayingasymmetricsternebrawasobservedafter
treatmentwiththehighestdose.Sincethenumberoftheeffectsobservedinthe9mg/m3groupwas
withinthelimitsofbiologicalvariability,aNOAELfordevelopmentaleffectsof9mg/m3was
determinedinthisstudy.
9.EFFECTSONHUMANS
Itiswelldocumentedthatisocyanatesareacauseofoccupationalasthma(Vandenplasetal.,1993).
Humoralaswellascellularmechanismsareinvolvedinthepathogenesis.Immediateorlateallergic
reactionsorbothcanoccur.ThespecifichumoralimmuneresponsecanbeIgEaswellasIgG
mediated,butmanypatientswithsensitizationtoisocyanateshavenodemonstrativeserumantibodies
againsttheisocyanates.Severalpublicationsindicatethatcompleximmunologicalreactionsare
involvedintheprocessofsensitizationtoMDI(Pezzinietal.,1984Tseetal.,1985Lissetal.,1988
Cartieretal.,1989).
Toinvestigatetheimmunopathogenesisofdiisocyanatecausedasthma,diisocyanateexposedworkers
wereevaluatedforinvitroproductionofantigenspecificmononuclearcellderivedhistamine
releasingfactor(HRF).ThemeanHRFresponsetodiisocyanatehumanserumalbumin(HSA)
antigenswassignificantlygreater(p<0.05)inpatientswithoccupationalasthmathanin
diisocyanateexposedasymptomaticsubjects.AnalysisofHRFproductionbysubpopulationsof
peripheralbloodmononuclearcellsshowedthatlymphocytesandadherentcellsweremajorsources
ofbothspontaneousandantigenstimulatedHRF(cellularimmuneresponse)(Herd&Bernstein,
1994).
PlasmaalbuminconjugatesofMDIfoundinworkersexposedtoMDIcancausetheonsetof
respiratorydisordersinhumans(Sepaietal.,1995a).Lushniaketal.(1998)evaluatedwhetherMDI
specificIgGorIgEcouldbesensitivebiologicalmarkersofdiseaseorofMDIexposure.Thestudy
groupconsistedofnineMDIexposedworkersandninenonexposedworkers.AirsamplingforMDI
andPMDI,occupationalandmedicalhistories,respiratoryphysicalexaminations,preandpostshift
spirometry,andselfadministeredpeakexpiratoryflowrateswereperformed.SerumspecificIgEand
IgGantibodiestoanMDIHSAconjugatewereassayedbytheradioallergosorbenttest(RAST)and
theenzymelinkedimmunosorbentassay,respectively,andcomparedwithninenonexposed
laboratorycontrols.ThemeanlevelofMDIspecificIgGwassignificantlygreateramongexposed
workerscomparedwithnonexposedworkersandlaboratorycontrols(p=0.044).Thisstudy
demonstratesthatserumconcentrationsofMDIspecificIgGappeartobeamoderatelysensitive
biologicalmarkerofMDIexposure,butnotanindicatorofoccupationalasthma.WorkerswithIgG
antibodiesspecificforonediisocyanateHSAconjugateexhibitcrossreactivitytoantigensprepared
withotherdiisocyanates.
9.1Casereports
ANIOSH(1994a)reportnotedskinirritationattributedtoMDI.Mineworkerswereexposedto"rock
glue"composedofMDI(componentA)andamixtureofpolyether/polyolblendandtertiaryamine
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catalyst(componentB).Itwasmentionedthatthechemicalprotectivegloveswerenotroutinely
utilizedbyminerswhoweredescribedashavingskincontactleadingtochronicskinirritation.In
anotherNIOSH(1994b)report,nasalandeyeirritationwerethetwomostfrequentlyreported
symptomsafterMDIexposure.
Ahypersensitivitypneumonitistypeofreactionhasalsobeenreported.Vandenplasetal.(1993)
investigatedninesubjectswhocomplainedofrespiratoryandgeneralsymptomsrelatedtoworkplace
exposure.AllthesubjectshadworkedinaplantwherearesinbasedonMDIwasusedinthe
manufactureofwoodchipboards.TheyunderwentinhalationchallengesusingtheMDIresinfor
progressivelyincreasingperiodsoftimeonseparatedays.Ineightsubjects,exposuretosubirritant
amountsofMDIinducedapatternofreactionconsistentwithhypersensitivitypneumonitisi.e.,
significantdecreasesinbothforcedexpiratoryvolumein1s(FEV1:31%range2340%)andFVC
(23%range1735%)associatedwithariseinbodytemperatureandanincreaseinbloodneutrophils.
SpecificIgGandIgEantibodiestoMDIHSAconjugateswerepresentinallsubjects.Theauthors
concludedthattheMDIresincausedahypersensitivitypneumonitistypeofreactioninatleast8
(4.8%)ofthe167potentiallyexposedworkersemployedintheplant.
Inacasewhohadexperiencedrepeatedattacksofaworkrelatedpulmonaryorsystemicdisease,
associationwithexposuretoMDIwasexaminedbecauseofacuterespiratorydisorder,
rhinoconjunctivitis,andalatesystemicreactionafterexposuretopolyurethanepyrolysisproducts,
includingMDI(airlevel15g/m3)(Littorinetal.,1994).Spirometryshowedapartlyreversible
obstructivedysfunction,andaskinpricktestwaspositiveforMDIHSA.MDAwasdetectedin
hydrolysedserumandurine.Inserum,specificIgG1,IgG4,andIgEantibodiesandaveryhightotal
IgEweredetected.Thespecificantibodiesdeclinedduringthe5yearsafterexposure.Invitro,the
circulatingimmunecomplexesinserumincreasedaftertheadditionofMDIHSA.Thereactions
associatedwithMDIexposure(incombinationwithexposuretopyrolysisproducts)hadfeatures
compatiblewithimmediatehypersensitivityandwithacomplementmediatedimmunecomplex
respiratoryreaction.
EighteenemployeesofasinglewoodproductsplantusingheatedMDIinthemanufactureofa
syntheticwoodproductwithlowerrespiratorytractsymptomswerelaterconfirmedtohave
occupationalasthmaafterexaminationoftherelationshipbetweenonsetofsymptoms,smoking
behaviour,priorexperience,andfamilyhistoryofrespiratorydisorder(Woellneretal.,1997).All
casesoccurredduringa2.5yearperiodafterexposuretoanewmanufacturingprocessusingsteam
heatedMDIresininanewmanufacturingfacility.Initially,workersdevelopedsymptomsrelatedto
theprocesswithpossiblehigherMDIexposuresandprobablehigherresintemperatures.Later,most
workerswhodevelopednewsymptomsweremostlyexposedtoheatedboards.Thissuggeststhat
MDIsensitizationarisesatlowertemperaturesthanwaspreviouslyconsideredlikelyforthis
substance.ItispossiblethatthereactionproductsofsteamandpolymersofMDI,aloneorin
combinationwithMDI,maybethecausativeagents.
AfoundryworkerwhodiedatworkhadadiagnosisofoccupationalasthmainducedbyMDIassessed
5yearsearlier,buthadhadapoorprognosisforoccupationalasthmaandhadcontinuedtobeexposed
toMDI(Carinoetal.,1997).Postmortemmicroscopicexaminationofthelungshowedepithelial
desquamation,eosinophilic/neutrophilicinfiltrationofthemucosa,dilatationofbronchialvessels,
oedema,hypertrophy,anddisarrayofsmoothmuscle.
Theneuropsychologicalfunctioningoffivemensufferingallegedphysical,cognitive,and
behaviouralchangesfollowingexposuretoMDIwasinvestigated(Reidy&Bolter,1994).The
subjectshadbeenexposedtohydrocarbonsolventaswell,butnoneofthemwassymptomaticuntil
MDIwasintroducedtotheworkplace.Althoughthedurationandseverityofexposurevariedamong
patients,formalanalysisofMDIlevelswasnotcompletedduringtheexposureperiod.Atthetimeof
assessment,fourofthefivepatientsremainedsymptomaticdespitehavinghadnocontactwithMDI
forperiodsrangingfrom5to9months.Allpatientsreportedexperiencingsubjectivesymptoms
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consistingofrespiratorydistress,headaches,depression,irritability,forgetfulness,decreased
calculatingability,wordfindingproblems,reducedconcentration,andsignificantemotionaldistress
onanobjectivepersonalitymeasure.Despitethesedata,thesmallsamplesize,possibleselectionbias
forworkersinvolvedinlitigation,possibleconfoundingfactors,lackofpertinentmatchedcontrol,
lackofobjectiveexposuredata,andlackofknowledgeonmechanismprecludethecredibilityofthe
findings.
9.2Epidemiologicalstudies
9.2.1Irritationandsensitization
Bernsteinetal.(1993)reportedonlythreecasesofoccupationalasthmainacrosssectionalstudyof
243workersexposedtoPMDIinaurethanemouldplantthathadbeendesignedtominimize
exposureonecasewasattributabletoaspill.Levelswerecontinuouslymonitoredandnever
exceeded50g/m3.
Inanepidemiologicalstudyofoccupationaldermatitisinfivedifferentshoefactories,246workers
wereinterviewed,examined,andpatchtestedusingstandardandoccupationalpatchtestprocedures
oftheInternationalContactDermatitisResearchGroup(Mancusoetal.,1996).Noinformationon
occupationalexposurewasreported.Intwoworkerswithallergiccontactdermatitis,sensitizationto
MDIwasdetected.OneoftwoworkersreactedsimultaneouslytobothMDIandMDA.Theotherone
reactedonlytoMDI.
Ahealthstudyofthe78workersinanironandsteelfoundryinVancouver,Canada,wascarriedout,
andtheresultswerecomparedwiththosefoundin372railwayrepairyardworkers(Johnsonetal.,
1985).MDIconcentrationsintheworkingenvironmentwereshowntosignificantlyinfluencelung
function.ThefoundryworkerswereexposedtoPepSet,whichconsistsofMDIandphenol
formaldehydeandtheirdecompositionproducts,aswellastosilicacontainingparticulate.Compared
withthecontrols,thefoundryworkershadmorerespiratorysymptomsandasignificantlylowermean
FEV1andforcedexpiratoryflowfrom25%to75%oftheFVC(FEF2575,ormidexpiratoryflow
rateoftheFVC).Threeworkershadradiographicevidenceofpneumoconiosis,and12hadasthma,
definedasthepresenceofbronchialhyperreactivity,cough,andadditionalrespiratorysymptoms,
suchaswheeze,chesttightness,orbreathlessness.SensitizationtoMDIisprobablythecauseof
asthmaintheseworkers.
AcrosssectionalevaluationofworkersinasteelfoundryinwhichPMDIwasusedasacomponentof
abindersystemusedtomakecoresandmouldswasperformed26currentlyexposed(groupI),6
formerlyexposed(groupII),and14nonexposedworkers(groupIII)wereinvolved(Lissetal.,
1988).ThemeannumberofMDIexposureyearswas8.6,1.1,and0yearsforgroupI,groupII,and
groupIII,respectively.Symptomscompatiblewithoccupationalasthmawereelicitedfromseven
workersofgroupI,whereasnonewasfoundingroupIII.Thisstudydemonstratedthatinductionof
bothMDIspecificIgGresponsesandIgEmediatedrespiratorysensitizationoccurredinapopulation
ofworkersexposedtoMDIinasteelfoundry.OneworkerfromgroupIwithasthmaticsymptoms
exhibitedcutaneousreactivityandRASTbindingtoMDIHSA(25.5%).
Musketal.(1982)followed107polyurethanemanufacturingworkersexposedtoTDIalone(17),
MDIalone(25),orboth(6)prospectivelyfor5years.MDIwasusedatthemanufacturingplants
duringonlythelast2yearsofthestudyperiod.Spirometricmeasurements(e.g.,FEV1)weremadeon
94workersatthefifthyearovertheworkshift,onMondaymorningafteraweekendofnoexposure,
andafter2weekvacations.Therewerenostatisticallysignificantdifferencesinthetotal5year
decrementinFEV1amongexposedworkersversusFEV1valuesinunexposedworkers.Becauseof
therelativelylownumberofworkers(25)exposedtoMDI(lessthan0.04mg/m3),theshortstudy
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duration,confoundingfrompriorexposuretoTDI(0.05mg/m3)andpossiblytoaminecatalyst,and
theuncertaintyintheactualdurationofMDIexposure,thisstudyofferslimitedassurancethatMDIis
withouteffectonpulmonaryfunction.Theinvestigatorsdiscussedthepossibilitythattheremaybe
selectionbias,becausethestudygroupdidnotincludeanysubjectwithsymptomssuggesting
hypersensitivitytoisocyanatethosewhowereexperiencingadverseeffectsmayhavebeenincluded
inthesmallnumbersofsubjectswhohadleftandbeenlosttofollowup.
In1976and1981,Phametal.(1988)prospectivelystudiedagroupof318polyurethanefoamworkers
(including104women)whoweregroupedaccordingtotheirjobcategoryasfollows:unexposed,
indirectlyexposed,anddirectlyexposed.Atfollowupin1981,onlyhalfoftheinitialcohort
remained(114males,45females),althoughnoreasonsweregivenastowhytheotherhalfleft.The
5yearlongitudinalchangesinFEV1inexposedgroupswerestatednottobesignificantlydifferent
fromthecontrolpopulation.Anincreasedprevalenceofasthmawasreportedhowever,the
limitationsofthestudyprecludeanymeaningfulassociations.Thebasisforthediagnosisofasthma
wasnotstated.Whethertherewasexposuretoothersubstancesthatcouldcauseasthmaorwhether
therewaspreexistingasthmawasnotreported,andguidelinesfollowedforperformingFEV1
measurementswerenotstated.Exposurewasnotwellcharacterized.
EffectsonlungfunctionwereassessedbyDFG(1997)basedontheresultsofninestudiesnamely,
Cavelieretal.(1977),Phametal.(1978,1986,1988),Martinetal.(1982),Diller&Herbert(1982),
Musketal.(1982),Gee&Morgan(1985),andSulottoetal.(1990).Althoughthereweremany
limitations,suchasinvolvementofconfoundingfactorsinmixedexposuresandlackofknowledgeof
actualexposureconcentrations,itwasconcludedthatsignificantimpairmentoflungspirometry
valueswasobservedinthecollectiveexposedtoPMDIconcentrationsupto0.87mg/m3.Inthe
collectiveatconcentrationsbelow0.2mg/m3,nosignificantchangesinlungspirometrywerefound.
However,significantlymorefrequentrespiratorysymptomsweresometimesobservedatthese
concentrations,althoughitisnotclearwhethertheywerecausedbysimultaneousexposuretoother
compounds.SuchsymptomswerenolongersignificantlymorefrequentatPMDIconcentrationsof
0.1mg/m3.Withoneexceptioninwhichworkerswerepreviouslyexposedtoconcentrationsofupto
0.9mg/m3,allthecollectiveexposedtoconcentrationsof0.05mg/m3orlesswaswithoutsymptoms.
WorkrelatedrespiratorydiseaseswerereportedintheUnitedKingdombyalmost800chestand
occupationalphysicianswhoparticipatedvoluntarilyintheSWORDprojectfrom1989to1992
(Meredith&McDonald,1994).Outof5541newcasesreportedbetween1989and1991,28%were
occupationalasthma.Isocyanatesweresuspectedasacausalagentofasthmain336casesoutof1528
reportedfor19891991.
9.2.2Longtermexposureandcarcinogenicity
Cancerincidenceandmortalitypatternswereinvestigatedinacohortof4154workersemployedin
Swedishpolyurethanefoammanufacturingplantsforatleast1year(Hagmaretal.,1993a).TDIhad
beenusedinalltheplantsandMDIinallbutone,soitwasimpossibletoevaluatetheirindividual
effects.Airborneexposuretotheisocyanateshadbeenmeasuredon618occasionsateachplanton
724days.ThetimeweightedaveragelevelsofTDIhadnormallybeenlessthan0.1g/m3andwere
currently0.02g/m3.ThecorrespondingvaluesforMDIhadbeenlessthan0.01g/m3.However,
muchhighervaluesupto3mg/m3forTDIandupto0.35mg/m3forMDIhadbeenrepeatedly
measured.Therewasalsoilldefinedexposuretoblowingagents,mouldlubricants,amine
accelerators,andvariousorganicsolvents.Therewasnoincreasedriskofdeathcausedbybronchial
obstructivedisease.Thereducedincidence,againstcontrol,ofallmalignantneoplasmwasalmost
statisticallysignificant.The"noexposure"grouphadfewerrectalcancersthanexpected,whereasthe
"apparentexposure"grouphadmorethanexpected.Asimilar,smallerdifferencewasseenwithnon
Hodgkinslymphoma.Whenaminimumlatencyperiodof10yearswasapplied,theincreasesagainst
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controlwereevenhigher,buttherewereveryfewcases.Asthecohortwasyoungwithrelatively
shortexposuretotheisocyanates,futurestudieswouldallowamoreconclusiveevaluation.Acase
referencestudywithinthecohortwasmadetoassessmorethoroughlytheassociationbetween
exposuretoTDIandMDIandriskofcancer(Hagmaretal.,1993b).Itwasfoundthatthetentative
associations,derivedfromthepreviouscohortstudy,betweenexposuretoisocyanatesandexcessrisk
fornonHodgkinslymphomasandrectalcancerwerenotsupported.Instead,nonsignificant
associationswithprostatecancerandpossiblycoloncancerwereseen.
Aretrospectivemortalityandcancermorbiditystudywasconductedtoinvestigateassociations
betweenhealthriskandexposuresfrompolyurethanefoamproduction,particularlyexposuresto
diisocyanates(Sorahan&Pope,1993).Thestudypopulation(n=8288)wastakenfrom11factories
inEnglandandWalesinwhichTDIwastheprincipalisocyanate(MDIrepresented5%oftheamount
ofTDIused).Thehighestexposurecategorycomprisedjobsinwhicheitherthe8htimeweighted
averageexposure(toisocyanates)during19781986wasgreaterthan0.04mg/m3orexcursions
above0.1mg/m3occurredonmostdays.Theinvestigatorsdidnotfindanassociation(using
standardizedmortalityratiosorSMRs)betweenexposuretodiisocyanatesandcancer.Thecohortwas
young,andfollowupwasrelativelyshort.
10.EFFECTSONOTHERORGANISMS
INTHELABORATORYANDFIELD
10.1Aquaticenvironment
ResultsofmoststudiesavailableonthetoxiceffectsofMDIonaquaticorganismsarebasedon
nominalconcentrationsoftestsubstance.Inalltestssummarizedinthissection,MDIwasaddedto
thetestsolution,andnoconcentrationmeasurementswereperformedsubsequentlyduringexposure.
Althoughdifferentmethodswereappliedtosolubilizethetestsubstanceinthetestmedia(e.g.,
stirringforseveralhours),theresultspresentedinsection5.1indicatethatonlyminoramountsofthe
appliedMDIcouldhavebeenpresentinthetestsolution,astheMDIwouldhaverapidlyundergone
hydrolysis.Asaresult,duetothevirtualunavailabilityofMDIinwater,evenforthehighest
concentrationstested,noadverseeffectsontheexposedtestorganismswereobserved.
Inshorttermtests,nominalconcentrationsintherangeof5003000mgMDI/litrecausednolethal
effectonfreshwaterfish(RhonePoulencChimie,1977Nakata,1983Caspersetal.,1986).Aquatic
invertebratesshowednoimmobilizationaftera24hexposuretonominalconcentrationsofupto1000
mgMDI/litre(RhonePoulancChimie,1977Caspersetal.,1986).After21daysofexposuretothe
highestnominalconcentrationtested(10mg/litre),PMDIhadnoeffectonthereproductionrateof
Daphniamagna(Caspersetal.,1986).Blom&Oldersma(1994)observednoeffectsoncell
multiplicationofthefreshwateralgaScenedesmussubspicatusaftera3dayexposuretoanominal
concentrationof1640mgPMDI/litre.ConcerningtheimpactofPMDIonmicroorganisms,the
highestappliedconcentrationsofupto100mg/litrewerenotinhibitorytocellmultiplicationof
Escherichiacoli(Fujiwara,1981)ortotherespirationrateofactivatedsludge(Caspersetal.,1986).
Heimbachetal.(1996)addedPMDIatconcentrationsof0,1,and10g/litreontopofthesedimentof
threeartificialoutdoorponds,simulatingaccidentalspillageinsmallstandingfreshwaterecosystems
(seesection5.1).Thepondscontainednaturallakesedimentandgroundwater,towhichcagedfish
wereadded.ThefateofthePMDIandecotoxiceffectsontheaquaticpopulationweremonitoredfor
112days.
MDIpolymerizedtoinertpolyureaandstayedontopofthesediment,formingahardenedlayeratthe
interfaceofthecompoundandwater.NoMDIwasfoundinthewaterorinthefishafterapplication.
Neitherapplicationratecausedanydirecttoxiceffectontheaquaticcommunity,butsomesignificant
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indirecteffectsonpartsofthemacrobenthoswereobserved.Someofthemoreimmobilepopulations
(Oligochaeta,Bivalvia,Diptera)werealmostcompletelywipedoutasaresultofphysicalobstruction
bythepolyurealayer,lackofoxygen,andtoxiccarbondioxideconcentrations714daysafter
application.
Mostofthemacrobenthospopulationsregaineddensitiesequivalenttothecontrolpopulationsafter2
monthsofexposure,withtheexceptionofBivalvia(becauseoftheirlonggenerationtimes).Mobile
partsofthemacrobenthos(e.g.,Gastropoda)remainedunaffected.Theabundanceofsome
zooplanktonspecies(Cladocera)wasclearlyreducedinthehighdosedpond28weeksafter
application.Asaconsequence,therainbowtroutinthispond,whichwerefeedingonCladoceraas
theirmainnaturalfoodsource,lostweight,andthreeofsixfishinthisponddied1monthafterthe
applicationofMDI.
10.2Terrestrialenvironment
ResultsfromanearthwormtoxicitytestconductedaccordingtoOECDGuidelineNo.207anda
terrestrialplantgrowthtestconductedaccordingtoOECDGuidelineNo.208arepresentedinTable
2.Inthesestudies,thetestsubstancewasinitiallydissolvedinacetone,whichwasthenmixedwith
sand.Thesolventwasevaporatedandthecoatedsandmixedwithsoil.Thetreatedsoilwasthenused
forthestudies.NotoxiceffectofMDIontheterrestrialorganismstestedwasobserved.
Table2:ToxicityofMDItoterrestrialorganisms.a
Organisms
Endpointb
Loading(mg/kg)
Eiseniafetida
(earthworm)
14dayLC50
>1000
14dayNOEL(weight
increase)
>1000
14dayNOEL
(behaviour,appearance)
>1000
NOELemergence
>1000
NOELsurvival(14days)
>1000
NOELgrowth(14days)
>1000
NOELemergence
>1000
NOELsurvival(14days)
>1000
NOELgrowth(14days)
>1000
Avenasativa(oats)
Lactucasativa
(lettuce)
aSource:vanderHoevenetal.(1992a,b).
bLC50 =medianlethalconcentrationNOEL=noobservedeffectlevel.
11.EFFECTSEVALUATION
11.1Evaluationofhealtheffects
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11.1.1Hazardidentificationanddoseresponseassessment
Thehealthendpointofmostconcernisanassociationbetweenexposuretoairbornepolymericand/ormonomericMDIandoccupationally
inducedasthma.Thereisabundantevidencenotonlyfromepidemiologicalstudiesandcasestudies,butalsofromanimalstudies.However,
thereisinsufficienthumanevidencetodescribe(1)thenatureoftheMDIcontainingmaterial,(2)theconcentrationresponserelationship,or
(3)themechanismofisocyanateinducedasthmaandsensitization.Althoughtherearenohumanoranimalstudiesthathaveexaminedthe
oralrouteofexposure,itisunlikelythathumanswouldbeexposedbytheoralroute.Therefore,itisdifficulttoquantitativelyestimaterisk
fromhumanexposure.
Theavailablehumanevidencefromcancerincidenceandmortalitystudiesofworkersexposedtoisocyanatesisinadequatetodescribethe
carcinogenicpotentialofpolymericormonomericMDI.Noassociationsbetweenisocyanatesandcancerincidenceweredemonstrated.The
increaseintheincidenceofmostlybenignpulmonarytumoursinratsexposedtoMDIbyinhalationisnotconsideredtobeademonstration
ofcarcinogenicity.Thepublishedstudieshaveanumberoflimitations(e.g.,shortdurationofexposure,concomitantexposuretoother
substances),whichresultinlowpowertodetectcanceroccurrenceintargetorgansofinterest.ThefindingofplacentaltransferofMDIand
itsdegradationproductfrompregnantratsexposedtoaerosoltofetusesdemandsfurtherstudyonitsrelevancetohumanriskassessment.
11.1.2CriteriaforsettingtolerableintakesorguidancevaluesforMDI
AnexampleofaguidancevaluecalculationisgivenintheUSEPAsIntegratedRiskInformationSystem(IRIS)(seewww.epa.gov/irisfor
details).TheBenchmarkConcentration(BMC)analysisdescribedthereinisbasedonthefindingofanincreaseinbasalcellhyperplasiainthe
olfactoryepitheliuminthechronicinhalationstudywithmaleWistarrats(Reuzeletal.,1990,1994a).However,itshouldbenotedthatthis
guidancevaluemaynotprotectagainstoccupationalsensitization.
Thevalueconsideredmostappropriateasabasisfordevelopmentofatolerableconcentration(TC)inairisthelower95%confidencelimit
ontheBMCatthe10%risklevel(BMC10 )usingtheReuzeletal.(1990,1994a)dataset.TheBMC10 isfirstconvertedtoahumanequivalent
concentration(HEC)byapplicationoftheRegionalDoseDepositedRatio(RDDR)calculatedusingacomputerprogramprovidedinUSEPA
(1994).TheRDDRadjustsfordosimetricdifferencesbetweenlaboratoryanimalsandhumansbyapplyingnormalizingfactorstovarious
areasoftherespiratorytract.
OncetheBMC10 (0.14mg/m 3 )isderivedfromtheReuzeletal.(1990,1994a)datasetbyBMCanalysis,itismultipliedbytheRDDR
(0.453).Theresultingvalue,0.06mg/m 3 ,istheBMC10 (HEC).ThreeuncertaintyfactorsareappliedtotheBMC10 (HEC)10for
intraindividualvariation(includingthepossibilityofgeneticpredisposition),10 1/2 forthelackofreproductivedata,and10 1/2 for
interspeciesvariationtoderiveahumanTCof610 4 mg/m 3 .
11.1.3Sampleriskcharacterization
Therearenoadequatedataavailabletoserveasabasisforestimatingriskofoccupationalasthma.Theexamplegivenhereisapragmatic
approachtoreduceoccupationalexposuretotheminimumpossible,becauseathresholdforthiseffectcannotbeestablished.
IntheGermanstudyevaluatinglungdecrement,significantreversibleadverseeffectsonlungfunctionwereobservedinpersonsexposedto
MDIconcentrationsabove0.2mg/m 3 .WhenMDIconcentrationswerekeptlargelybelowthisconcentration,significantchangesinlung
spirometrywerenolongerseen,althoughtheincidenceofrespiratorysymptomswasincreasedsignificantly.Suchdisorderswerestill
observed,butnomorefrequentlythaninthegroupatconcentrationsbelow0.05mg/m 3 .Becauseoftheseobservations,0.05mg/m 3 was
establishedastheMAK(themaximumconcentrationintheGermanworkplace)valueforMDI,tobereasonablypracticableunderworkplace
conditions,andthereisacontinuingremittoreduceexposurelevelsasfarasreasonablypracticablewithtechnologythatiscurrently
available.
11.2Evaluationofenvironmentaleffects
Undernormalcircumstances,exposureislikelyonlyfromreleasestotheatmosphere.HighexposuresinvolvingMDIinambient
environmentsareexpectedtoberare.Wherespillageistosoilorwater,MDIhasatransientexistenceduetoitsreactionwiththewaterto
producepredominantlyinsolublepolyureas.MDAmaybeformedonlyasaminorreactionproductandwillthusbepresentatlow
concentrations.ThepondstudyprovidesevidencethatMDIaccumulationthroughtheaquaticfoodchainisextremelyunlikely,asmightbe
expectedconsideringtheverylowsolubilityandhighreactivityofMDIinaqueoussolution.
AvailabledatashowthatthereisnoneedforconcernregardingtheeffectsofMDIonorganismsintheenvironment,althoughmoredetailed
informationregardingtheeffectsofminuteamountsofMDAformedintheenvironmentonorganismsisrequiredbeforeanyfirm
conclusionscanbedrawn.
12.PREVIOUSEVALUATIONSBY
INTERNATIONALBODIES
IARC(1999)concludedthatthereisinadequateevidenceforthecarcinogenicityofmonomericorpolymericMDIinhumansandlimited
evidenceforthecarcinogenicityofamixturecontainingmonomericandpolymericMDIinexperimentalanimals.Itsoverallevaluationwas
thatMDI(industrialpreparation)isnotclassifiableastoitscarcinogenicitytohumans(Group3).
ForMDA,IARC(1986)concludedthattherewerenodatainhumansandsufficientevidenceforcarcinogenicityinanimals.Itsoverall
evaluationwasthatMDAwaspossiblycarcinogenictohumans(Group2B).
REFERENCES
AndersenM,BineruML,KielP,LarsenH,MaxildJ(1980)Mutagenicactionofisocyanatesusedintheproductionofpolyurethanes.
Scandinavianjournalofwork,environment&health,6:221226.
AppelmanLM,deJongAWJ(1982)AcuteinhalationtoxicitystudyofpolymericMDIinrats.Zeist,CIVOInstituteTNOToxicologyand
Nutrition(ReportNo.82).
25/34
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AppelmanLM,deJongAWJ,KellerJ(1986)AdditionalstudiesintothepresenceofMDAinsamplesoftestatmospherescontaining
polymericMDIaerosol.Zeist,CIVOInstituteTNOToxicologyandNutrition(unpublishedReportNo.V84.313/220758).
BartschW,BuschmannJ,HoymannHG,HeinrichU(1996)[ChronictoxicityandcarcinogenicitystudyonMDI.]Hannover,Fraunhofer
InstituteforToxicologyandAerosolResearch(unpublished)(inGerman).
BASF(1994)PrenataltoxicityofpolymericMDIinrats.Aerosolinhalation.PreparedbyBASF,Ludwigshafen,forUSEnvironmental
ProtectionAgency(unpublishedProjectNo.31R0354/93046,39.09.1994).
BernsteinDI,KorbeeL,StauderT,BernsteinJA,ScintoJ,HerdZL,BernsteinIL(1993)Clinicalaspectsofallergicdisease.Thelow
prevalenceofoccupationalasthmaandantibodydependentsensitizationtodiphenylmethanediisocyanateinaplantengineeredforminimal
exposuretodiisocyanates.Journalofallergyandclinicalimmunology,92(3):387396.
BlomAJM,OldersmaH(1994)EffectofDesmodur44V20PMDIonthegrowthofthegreenalgaScenedesmussubspicatus.TNO
InternationalIsocyanateInstitute(ReportNo.11156).
BrochhagenFK,KellerJ(1983)Accidentinvolvingaroadtankercarryingtolulenediisocyanate(TDI)countermeasuresandexperience.
Leverkusen,BayerAG.
BuschmannJ,KochW,FuhstR,HeinfichU(1996)Embryotoxicitystudyofmonomeric4,4methylenediphenyldiisocyanate(MDI)aerosol
afterinhalationexposureinWistarrats.Fundamentalandappliedtoxicology,32:96101.
CarinoM,AlianiM,LicitraC,SarnoN,IoliF(1997)Deathduetoasthmaatworkplaceinadiphenylmethanediisocyanatesensitizedsubject.
Respiration,64:111113.
CartierA,GrammerL,MaloJL,LagierF,GhezzoH,HarrisK,PattersonR(1989)Specificserumantibodiesagainstisocyanates:association
withoccupationalasthma.Journalofallergyandclinicalimmunology,84(4Pt1):507514.
CaspersN,HamburgerB,KanneR,KlebertW(1986)Ecotoxicityoftoluenediisocyanate(TDI),diphenylmethanediisocyanate(MDI),
toluenediamine(TDA),diphenylmethanediamine(MDA).PreparedbyInternationalIsocyanateInstituteforBayerAG,Leverkusen(Report
No.10417).
CastroEA,MoodieRB,SansomPJ(1985)Ecotoxicityofdiisocyanateswithspecialreferencetocontrolledexposureofhumans.
Internationalarchivesofoccupationalandenvironmentalhealth,61(8):495501.
CavelierC,PhamQT,MereauP,MurJM,RombachF,CicolellaA,BuiDinhLongL,ToamainJP,BaudinV,HenquelJC,PoincelotF,Malo
JP,VincentR(1977)[Isocyanatesandrespiratoryfunction.]Cahiersdenotesdocumentaires,88:315(inFrench).
ChemicalDaily(1997)13398chemicalproducts.Tokyo,ChemicalDailyCo.,Ltd.,pp.642643.
ChemicalSocietyofJapan(1989)[AntidisasterGuidelinesNo.98:4,4Diphenylmethanediisocyanate(MDI).]Chemistryandindustry,
42:14081415(inJapanese).
ChemicalWeek(1998)Market&economics/productfocusMDI.ChemicalWeek,April5,1998,p.37.
DaleneM,JakobssonK,RannugA,SkarpingG,HagmarL(1996)MDAinplasmaasabiomarkerofexposuretopyrolysedMDIbased
polyurethane:correlationswithestimatedcumulativedoseandgenotypeforNacetylation.Internationalarchivesofoccupationaland
environmentalhealth,68:165169.
DayBW,BasalygaDM,KramarikJA,KarolMH(1997)Formation,solvolysisandtranscarbamoylationreactionsofbis(Sglutathionyl)
adductsof2,4and2,6diisocyanatotoluene.Chemicalresearchintoxicology,10:424431.
DFG(1997)Occupationaltoxicants.CriticaldataevaluationforMAKvaluesandclassificationofcarcinogens.Deutsche
Forschungsgemeinschaft,VCH,8:6595.
DharmarajanV(1979)Occupationalexposurestomethylenebisphenylisocyanate(MDI):gaseousoraerosol?Journalofenvironmental
pathology,toxicologyandoncology,2:18.
DillerWF,HerbertE(1982)[LungfunctionandotherhealthparametersmeasurementbyworkinanisocyanateplantofMDImanufacturer.]
ZentralblattfrArbeitsmedizin,32:128137(inGerman).
EU(1999)Riskassessmentformethylenediphenyldiisocyanate.Brussels,EuropeanUnion(draftreport).
FujiwaraK(1981)AccumulationofTDI,NDI,TDA,MDAinfishandtheirtoxicity.Aquaticlifestudy,PhaseII2.Tsukuba,International
IsocyanateInstitute(ProjectFEE19II2).
GahlmannR(1993)AcriticalreviewfortheInternationalIsocyanateInstitute.June1993.Wuppeltal,BayerAG,InstituteforToxicology.
GeeJB,MorganWKC(1985)A10yearfollowupstudyofagroupofworkersexposedtoisocyanates.Journalofoccupationalmedicine,
27:1518.
GiersigM(1989)PolyharnstoffgebundeneSpanplatten.Lecture,UniversityofBielefeld,Bielefeld,June(unpublishedreport).
GilbertDS(1988)FateofTDIandMDIinair,soilandwater.Journalofcellularplastics,24:178192.
HagmarL,WelinderH,MikoczyZ(1993a)CancerincidenceandmortalityintheSwedishpolyurethanefoammanufacturingindustry.
Britishjournalofindustrialmedicine,50:537543.
HagmarL,StroembergU,WelinderH,MikoczyZ(1993b)Incidenceofcancerandexposuretotoluenediisocyanateandmethylene
diphenyldiisocyanate:acohortbasedcasereferentstudyinthepolyurethanefoammanufacturingindustry.Britishjournalofindustrial
medicine,50:10031007.
HegartyAF,HegartyCN,ScottFL(1975)Thereactivityofphenylisocyanateinaqueoussolution.JournaloftheChemicalSociety,Perkin
26/34
10/03/2015
Transactions,11:11661171.
HeimbachF,JaegerK,SporenbergW(1996)FateandbiologicaleffectsofpolymericMDIinsmallartificialponds.Ecotoxicologyand
environmentalsafety,33:143153.
HerboldB(1980a)[MDISalmonella/microsometestforinvestigationofpointmutationactivity.]Wuppeltal,BayerAG(unpublishedBayer
ReportNo.9130,9.5.1980)(inGerman).
HerboldB(1980b)[MDISalmonella/microsometestforinvestigationofpointmutationactivity.]Wuppeltal,BayerAG(unpublishedBayer
ReportNo.9341,1.8.1980)(inGerman).
HerboldB(1990a)Specialstudy,Salmonella/microsometestwithDesmodur44v20usingTA100.Wuppeltal,BayerAG(unpublishedBayer
ReportNo.19561,27.9.1990).
HerboldB(1990b)Specialstudy,Salmonella/microsometestwithDesmodur44M(4,4MDI)usingTA100.Wuppeltal,BayerAG
(unpublishedBayerReportNo.19570,27.9.1990).
HerboldB,HaasP,SeelK,WalberU(1998)Studiesontheeffectofthesolventsdimethylsulfoxideandethyleneglycoldimethyletheronthe
mutagenicityoffourtypesofdiisocyanatesintheSalmonella/microsometest.Mutationresearch,412:167175.
HerdZL,BernsteinDI(1994)Antigenspecificstimulationofhistaminereleasingfactorsindiisocyanateinducedoccupationalasthma.
Americanjournalofrespiratoryandcriticalcaremedicine,150:988994.
HiasaY,KitahoriY,EnokiN,KonishiN,ShimoyamaT(1984)4,4diaminodiphenylmethane:promotingeffectonthedevelopmentof
thyroidtumorsinratstreatedwithNbis(2hydroxypropyl)nitrosamine.JournaloftheNationalCancerInstitute,72:471476.
HoymannHG,BuschmannJ,HeinrichU(1995)Examinationsaboutthechronictoxicity/carcinogenicityof4,4methylenediphenyl
diisocyanate(MDI).Hannover,FraunhoferInstituteforToxicologyandAerosolResearch(ReportNo.11606084).
HoymannHG,CreutzenbergO,ErnstH,HohlfeldJ,HeinrichU(1997)Lungfunctionchangesinratsafterchronicinhalationexposureto
4,4methylenediphenyldiisocyanate(MDI).In:MohrU,ed.Relationshipsbetweenrespiratorydiseaseandexposuretoairpollution.
Washington,DC,InternationalLifeSciencesInstitutePress,pp.353356.
IARC(1986)4,4Methylenedianilineanditsdihydrochloride.Lyon,InternationalAgencyforResearchonCancer,pp.347365(IARC
MonographsontheEvaluationoftheCarcinogenicRiskofChemicalstoHumans,Vol.39).
IARC(1999)4,4Methylenediphenyldiisocyanateandpolymeric4,4methylenediphenyldiisocyanate.Lyon,InternationalAgencyfor
ResearchonCancer,pp.10491058(IARCMonographsontheEvaluationoftheCarcinogenicRiskofChemicalstoHumans,Vol.71).
IPCS(1993)InternationalChemicalSafetyCardMethylenebisphenylisocyanate(MDI).Geneva,WorldHealthOrganization,International
ProgrammeonChemicalSafety(ICSC0298).
ISOPA(1998)SubmissionforthereviewoftheacuteinhalationtoxicityofMDI.Brussels,EuropeanIsocyanateProductionAssociation
(unpublishedreport).
IstinM(1977)PharmacokineticsofMDIafterinhalationexposureofratstolabeledMDI.UnpublishedreportbyLaboratoiredtudesdu
MtabolismedesMdicaments,DpartementdeBiologie,totheInternationalIsocyanateInstitute[citedinDFG,1997].
JohnsonA,ChanYeungM,MacLeanM,AtkinsE,DybunchioA,ChengF,EnarsonD(1985)Respiratoryabnormalitiesamongworkersin
anironandsteelfoundry.Britishjournalofindustrialmedicine,42:94100.
JSOH(1994)[RecommendationandthereasoningfortheoccupationalexposurelimitsonMDI.]SangyoIgaku(Japanesejournalof
industrialhealth),35:360363(inJapanese).
KellyM,OuttersideS,PembertonD(1997)PhysicalpropertiesofMDIandTDI:areview.Manchester,InternationalIsocyanateInstitute
(unpublishedIIIReportNo.11272).
LissGM,BernsteinDI,MollerDR,GallagherJS,StephensonRL,BernsteinIL(1988)Pulmonaryandimmunologocalevaluationoffoundry
workersexposedtomethylenediisocyanate(MDI).Journalofallergyandclinicalimmunology,82(1):5561.
LissGM,TarloSM,BanksDE(1996)Evidenceforoccupationalasthmaamongcompensationclaimantsatapolyurethaneutilizingfacility.
Canadianjournalofpublichealth,87(6):401403.
LittorinM,TruedssonL,WelinderH,SkarpingG,MartenssonU,SjoeholmAG(1994)Acuterespiratorydisorder,rhinoconjunctivitisand
feverassociatedwiththepyrolysisofpolyurethanederivedfromdiphenylmethanediisocyanate.Scandinavianjournalofwork,environment
&health,20:216222.
LushniakBD,RehCM,BernsteinDI,GallagherJS(1998)Indirectassessmentof4,4diphenylmethanediisocyanate(MDI)exposureby
evaluationofspecifichumoralimmuneresponsestoMDIconjugatedtohumanserumalbumin.Americanjournalofindustrialmedicine,
33:471477.
MancusoG,ReggianiM,BerdondiniRM(1996)Occupationaldermatitisinshoemakers.Contactdermatitis,34:1722.
MannM(1987)EvidencefortheformationofhydrateofMDI[lettertotheeditor].AmericanIndustrialHygieneAssociationjournal,
48:726.
MartinFD,FichetD,ArsanianG,LeloupMC(1982)[Epidemiologicalstudyonthetoxicityofisocyanatesinworkingenvironment.]
Archivesdesmaladiesprofessionellesdemdecinedutravailetdescuritsociale(Paris),43:481(inFrench).
MeredithSK,McDonaldJC(1994)WorkrelatedrespiratorydiseaseintheUnitedKingdom,19891992:reportontheSWORDproject.
Journalofoccupationalmedicine,44:183189.
MobayChemical(1961)Toxicityandsafetyhandlingofisocyanates[citedinUSEPA,1998].
27/34
10/03/2015
MuskAW,PetersJM,DiBerardinisL,MurphyRLH(1982)AbsenceofrespiratoryeffectsinsubjectsexposedtolowconcentrationsofTDI
andMDI.Journalofoccupationalmedicine,24(10):746750.
NakataM(1983)Testreportonfishtoxicityofpolymethylenepolyphenylpolyisocyanate:internalcommunication.Amagasaki,Sumitomo
BayerUrethaneCo.(unpublishedreport).
NIOSH(1985)NIOSHmanualofanalyticalmethods,3rded.Vols.1and2with1985supplementandrevisions.Cincinnati,OH,US
DepartmentofHealthandHumanServices,PublicHealthService,CentersforDiseaseControl,NationalInstituteforOccupationalSafetyand
Health.Washington,DC,USGovernmentPrintingOffice,February1984,p.55211.
NIOSH(1994a)LetterfromNIOSHtoJimWalterResources,Inc.withastudyreport.Cincinnati,OH,USDepartmentofHealthandHuman
Services,PublicHealthService,CentersforDiseaseControl,NationalInstituteforOccupationalSafetyandHealth(ReportNo.HETA94
0027,May24).
NIOSH(1994b)LetterfromNIOSHtoDistinctiveDesignsInternationalInc.withastudyreport.Cincinnati,OH,USDepartmentofHealth
andHumanServices,PublicHealthService,CentersforDiseaseControl,NationalInstituteforOccupationalSafetyandHealth(ReportNo.
HETA9103862427,May).
NTP(1986)Toxicologyandcarcinogenesisstudiesofcommercialgrade2,4(80%)and2,6(20%)toluenediisocyanateinF344/Nratsand
B6C3F1 mice(gavagestudies).ResearchTrianglePark,NC,USDepartmentofHealthandHumanServices,PublicHealthService,National
InstitutesofHealth,NationalToxicologyProgram(TechnicalReportNo.251NIHPublicationNo.862507).
PezziniA,RivieraA,PaggiaroP,SpiazziA,GerosaF,FilieriM,TomaG,TridenteG(1984)SpecificIgEantibodiesintwentyeightworkers
withdiisocyanateinducedbronchialasthma.Clinicalallergy,14:453461.
PhamQT,CavelierC,MereauP,CicolellaA(1978)Isocyanatesandrespiratoryfunction:astudyofworkersproducingpolyurethanefoam
moulding.Annalsofoccupationalhygiene,21:121.
PhamQT,MeyerBischC,MurJM(1986)[StudyonclinicalandrespiratoryfunctionchangeofworkersexposedtolittleamountofMDIin
5years.]Archivesdesmaladiesprofessionellesdemdecinedutravailetdescuritsociale(Paris),47:311(inFrench).
PhamQT,TeculescuD,MeyerBischC,MurJM(1988)Effectsofchronicexposuretodiisocyanates.Bulletineuropendephysiopathologie
respiratoire,23:561564.
ReidyTJ,BolterJF(1994)Neuropsychologicaltoxicologyofmethylenediphenyldiisocyanate:areportoffivecases.Braininjury,8(3):285
294.
ReuzelPGJ,ArtsJHE,KuypersMHM,KuperCF(1990)Chronictoxicity/carcinogenicityinhalationstudyofpolymericmethylenediphenyl
diisocyanateaerosolinrats.PreparedbytheCIVOInstitute,Zeist,fortheInternationalIsocyanateInstitute(ReportNo.V88.122).
Reuzel,PGJ,KuperCF,FeronVJ,AppelmanL,LoserE(1994a)Acute,subacute,andsubchronicinhalationtoxicitystudiesofrespirable
polymericmethylenediphenyldiisocyanate(polymericMDI)aerosolinrats.Fundamentalandappliedtoxicology,22:186194.
ReuzelPGJ,ArtsJHE,LomaxLG,KuijpersMHM,KuperCF,GembardtC,FeronVJ,LoserE(1994b)Chronicinhalationtoxicityand
carcinogenicitystudiesofrespirablepolymericmethylenediphenyldiisocyanate(polymericMDI)aerosolinrats.Fundamentalandapplied
toxicology,22:195210.
RhonePoulencChimie(1977)BiologicalactionofTDIandMDIinwater.Paris(unpublishedreportReportNo.770906).
SakuraiH(1997)BriefintroductiontooccupationalexposurelimitsinJapan.Journalofoccupationalhealth,39:246.
SchuetzeD,SepaiO,LewalterJ,MikscheL,HenschlerD,SabbioniG(1995)Biomonitoringofworkersexposedto4,4methylenediamine
and4,4methylenediphenyldiisocyanate.Carcinogenesis,16(3):573582.
SeelK,WalberU,HerboldB,KoppR(1999)Chemicalbehaviourofsevenaromaticdiisocyanates(toluenediisocyanatesand
diphenylmethanediisocyanates)underinvitroconditionsinrelationshiptotheirresultsintheSalmonella/microsometest.Mutationresearch,
438:109123.
SepaiO,SchuetzeD,HeinrichU,HoymannHG,HenschlerD,SabbioniG(1995a)Hemoglobinadductsandurinemetabolitesof4,4
methylenediamineafter4,4methylenediphenyldiisocyanateexposureofrats.Chemicobiologicalinteractions,97:185198.
SepaiO,HenschlerD,SabbioniG(1995b)Albuminadducts,hemoglobinadductsandurinarymetabolitesinworkersexposedto4,4
methylenediphenyldiisocyanate.Carcinogenesis,16(10):25832587.
ShimizuH,SuzukiY,TakemuraN,GotoS,MatsushitaH(1985)Theresultsofmicrobialmutationtestforfortythreeindustrialchemicals.
SangyoIgaku(Japanesejournalofindustrialhealth),27:400417.
SkarpingG,DaleneM(1995)Determinationof4,4methylenediphenyldianiline(MDA)andidentificationofisomersintechnicalgrade
MDAinhydrolysedplasmaandurinefromworkersexposedtomethylenediphenyldiisocyanatebygaschromatographymassspectrometry.
JournalofchromatographyB,Biomedicalsciencesandapplications,663:209216.
SkarpingG,DaleneM,LottorinM(1995)4,4methylenedianilineinhydrolysedserumandurinefromaworkerexposedtothermal
degradationproductsofmethylenediphenyldiisocyanateelastomers.Internationalarchivesofoccupationalandenvironmentalhealth,
67:7377.
SorahanT,PopeD(1993)MortalityandcancermorbidityofproductionworkersintheUnitedKingdomflexiblepolyurethanefoam
industry.Britishjournalofindustrialmedicine,50:528536.
SpanneM,TinnerbergH,DaleneM,SkarpingG(1996)Determinationofcomplexmixturesofairborneisocyanatesandamines,Part1.
Liquidchromatographywithultravioletdetectionofmonomericandpolymericisocyanatesastheirdibutylaminederivatives.Analyst,
121:10951099.
StreicherRP,KennedyER,LorberauCD(1994)Strategiesforthesimultaneouscollectionofvaporsandaerosolswithemphasisonisocyanate
28/34
10/03/2015
sampling.Analyst,119:8997.
SulottoF,RomanoC,PiolattoG,CoggiolaM,PolizziS,CiaccoC,BerraA(1990)Shorttermrespiratorychangesinpolyurethanefoam
workersexposedtolowMDIconcentrations.Internationalarchivesofoccupationalandenvironmentalhealth,62:521.
TanakaK,TakeokaA,NishimuraF,HanadaS(1987)Contactsensitivityinducedinmicebymethylenebisphenyldiisocyanate.Contact
dermatitis,17:199204.
TarloSM,LissGM,DiasC,BanksDE(1997)Assessmentoftherelationshipbetweenisocyanateexposurelevelsandoccupationalasthma.
Americanjournalofindustrialmedicine,32:517521.
ThornePS,HillebrandJA,KarolMH(1986)Pulmonaryirritationandhypersensitivityinguineapigsexposedto4,4diphenylmethane
diisocyanate(MDI)aerosol.Toxicologist,6:15.
ThornePS,HillebrandJA,LewisDR,KarolMH(1987)Contactsensitivitybydiisocyanatespotenciesandcrossreactivities.Toxicologyand
appliedpharmacology,87:155165.
TinnerbergH,SpanneM,DaleneM,SkarpingG(1997)Determinationofcomplexmixturesofairborneisocyanatesandamines,Part3.
Methylenediphenyldiisocyanate,methylenediphenylaminoisocyanateandmethylenediphenylamineandstructuralanaloguesafterthermal
degradationofpolyurethane.Analyst,122:275278.
TseKS,JohnsonA,ChanH,ChanYeungC(1985)Astudyofserumantibodyactivityinworkerswithoccupationalexposureto
diphenylmethanediisocyanate.Allergy,40:314320.
USEPA(1994)Methodsforderivationofinhalationreferenceconcentrationsandapplicationsofinhalationdosimetry.Washington,DC,US
EnvironmentalProtectionAgency(EPA/600/890/066f).
USEPA(1998)Toxicologicalreviewofmethylenediphenyldiisocyanate(MDI).Washington,DC,USEnvironmentalProtectionAgency.
VandenplasO,MaloJL,DugasM,CartierA,DesjardinsA,LevesqueJ,ShaughnessyMA,GrammerLC(1993)Hypersensitivity
pneumonitislikereactionamongworkersexposedtodiphenylmethanediisocyanate(MDI).Americanreviewofrespiratorydisease,147:338
346.
vanderHoevenN,RozaP,HenzenL(1992a)DeterminationoftheeffectofTDI,TDA,MDI,andMDAontheemergenceandgrowthofthe
plantspeciesAvenasativaandLactucasativaaccordingtoOECDGuidelineNo.208.Zeist,InternationalIsocyanateInstitute(unpublished
IIIReportNo.11024).
vanderHoevenN,RozaP,HenzenL(1992b)DeterminationoftheLC50 (14days)ofTDI,TDA,MDI,andMDAtotheearthwormEisenia
fetidaaccordingtoOECDGuidelineNo.207.PreparedbyTNO,Zeist,forInternationalIsocyanateInstitute(unpublishedIIIReportNo.
11025).
VockEH,LutzWK(1997)DistributionandDNAadductformationofradiolabeledmethylenediphenyl4,4diisocyanate(MDI)intherat
aftertopicaltreatment.Toxicologyletters,92:93100.
VockEH,HoymannHG,HeinrichU,LutzWK(1996)32 PpostlabelingofaDNAadductderivedfrom4,4methylenedianilineinthe
olfactoryepitheliumofratsexposedbyinhalationto4,4methylenediphenyldiisocyanate.Carcinogenesis,17(5):10691073.
WaalkensBerendsenDH,ArtsJHE(1992)ReportofadevelopmentaltoxicityrangefindingstudyofinhaledpolymericMDIaerosolinrats.
Zeist,TNONutritionandFoodResearch(unpublishedTNOReportNo.V92.102).
WazeterFX(1964a)Acuteinhalationtoxicity(LC50 )inmalealbinorats12.3.64.InternationalResearchandDevelopmentCorporation
(unpublishedreport)[citedinEU,1999].
WazeterFX(1964b)Acutedermaltoxicity(LD50 )inmalealbinorats27.01.64.InternationalResearchandDevelopmentCorporation
(unpublishedreport)[citedinEU,1999].
WeisburgerEK,MurthyASK,LiljaHS,LambJC(1984)NeoplasticresponseofF344ratsandB6C3F1 micetothepolymeranddyestuff
intermediates,4,4methylenebis(N,Ndimethyl)benzenamine,4,4oxydianiline,and4,4methylenedianiline.JournaloftheNationalCancer
Institute,72:14571463.
WeyelDA,SchafferRB(1985)Pulmonaryandsensoryirritationofdiphenylmethane4,4diisocyanateanddicyclohexylmethane4,4
diisocyanate.Toxicologyandappliedpharmacology,77:427433.
WoellnerRC,HallS,GreavesI,SchoenwetterWF(1997)Epidemicofasthmainawoodproductsplantusingmethylenediphenyl
diisocyanate.Americanjournalofindustrialmedicine,31:5663.
WoolrichPF(1982)Toxicology,industrialhygieneandmedicalcontrolofTDI,MDIandPMPPI.AmericanIndustrialHygieneAssociation
journal,43:8997.
YakabeY,MoriE,TadokoroH(1994)StudyonthefateofpolymericMDIinwater.Kurume,InternationalIsocyanateInstitute(unpublished
IIIReportNo.11122).
ZeigerE(1987)Salmonellamutagenicitytest:III.Resultfromtestingof225chemicals.Environmentalmutagenesis,9(9):1110.
APPENDIX1SOURCEDOCUMENTS
JSOH(1994)
TheoriginalreviewinJapanesewastranslatedintoEnglishbytheNationalInstituteofHealthSciences(NIHS)andisavailablefromthe
DivisionofChemBioInformaticsofNIHSatthefollowingaddress:
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NationalInstituteofHealthSciences
1181Kamiyoga,Setagayaku
Tokyo,Japan
TheJapanSocietyforOccupationalHealth(JSOH,formerlytheJapanAssociationofIndustrialHealth)isanacademicorganizationconsisting
ofexpertsinoccupationalhealth,includingscientistsinuniversitiesandinstitutions,industrialphysicians,occupationalhealthnurses,
industrialhygienists,managementstafffromhealthandsafetydepartments,andgovernmentofficialsinoccupationalhealthsectors.
TheCommitteefortheRecommendationofOccupationalExposureLimitsofJSOHreviewsscientificinformationonthehealtheffectsof
chemicalsubstancesandphysicalagentswithspecialreferencetoexposureeffectandexposureresponserelationshipsandappliesits
researchtothecreationofanOccupationalExposureLimit(OEL)andtothedocumentationofthereasoningbehindtheOEL.The
CommitteesubmitstheOELasaprovisionalOELtoameetingofJSOHcouncillorsandtoanannualgeneralmeetingofJSOHfortemporary
approval,afterwhichtheprovisionalOELanddocumentationarepublishedinJSOHsofficialjournal,SangyoEiseigakuZasshi(formerly
SangyoIgaku[JapaneseJournalofIndustrialHealth].TheCommitteeacceptsopinionsbasedonscientificaspectsoftheprovisionalOEL
untilthenextannualgeneralmeeting.IfnoopinionscontrarytotheprovisionalOELarefiledwiththeCommittee,itisadoptedastheformal
OELrecommendedbyJSOH.IfopinionscontrarytotheprovisionalOELarefiledwiththeCommitteeanddeemedvalid,theCommittee
thenproceedstoreexaminetheprovisionalOELandthedocumentation(Sakurai,1997).DrSakurai,whochairstheCommittee,peer
reviewedandassistedinthepreparationofthedraftoftheCICADforMDI.
USEPA(1998)
ThereportentitledToxicologicalreviewofmethylenediphenyldiisocyanate(MDI)andsummaryinformationonIRIS(IntegratedRisk
InformationSystem)havereceivedpeerreviewbothbyEPAscientistsandbyindependentscientistsexternaltoEPA.Subsequenttoexternal
reviewandincorporationofcomments,thisassessmenthasundergoneanagencywidereviewprocesswherebytheIRISProgramManager
hasachievedaconsensusapprovalamongtheOfficeofResearchandDevelopment,OfficeofAirandRadiation,OfficeofPrevention,
Pesticides,andToxicSubstances,OfficeofSolidWasteandEmergencyResponse,OfficeofWater,OfficeofPolicyPlanningandEvaluation,
andtheRegionalOffices.Theauthorandreviewersarelistedbelow.
ChemicalManager/Author
MarkM.Greenberg
NationalCenterforEnvironmentalAssessment
OfficeofResearchandDevelopment
USEnvironmentalProtectionAgency
ResearchTrianglePark,NC
InternalEPAReviewers
JamesW.Holder,Ph.D.
Toxicologist
Washington,DC
CherylScott
Epidemiologist
Washington,DC
EricD.Clegg,Ph.D.
Toxicologist
Washington,DC
ExternalPeerReviewers
CharlesH.Hobbs,DVM
DirectorofToxicology
LovelaceBiomedicalandEnvironmentalResearchInstitute
Albuquerque,NM
ThomasLedoux,Ph.D.
DivisionofScienceandResearch
NewJerseyDepartmentofEnvironmentalProtection
Trenton,NJ
WilliamE.Brown,Ph.D.
ProfessorandHead
DepartmentofBiologicalSciences
CarnegieMellonUniversity
Pittsburgh,PA
EU(1999)
TheEURiskassessmentformethylenediphenyldiisocyanatehasnotyetbeenpeerreviewedorpublished.However,thisistheonlysourceof
environmentalinformationandextensivereviewavailableatpresenttotheFinalReviewBoard.
APPENDIX2CICADPEERREVIEW
ThedraftCICADondiphenylmethanediisocyanate(MDI)wassentforreviewtoinstitutionsandorganizationsidentifiedbyIPCSafter
contactwithIPCSnationalContactPointsandParticipatingInstitutions,aswellastoidentifiedexperts.Commentswerereceivedfrom:
A.Aitio,WHO,Switzerland
M.Baril,InstitutdeRechercheenSantetenScuritduTravailduQubec,Canada
R.Benson,USEPARegionVIII,USA
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T.Berzins,NationalChemicalsInspectorate(KEMI),Sweden
R.Cary,HealthandSafetyExecutive,UnitedKingdom
ChemicalIndustriesAssociation(CIA)IsocyanateProducersSectorGroup(IPSG),UnitedKingdom
M.Collins,GilbertInternationalLimited,UnitedKingdom
P.Edwards,DepartmentofHealth,UnitedKingdom
T.Fortoul,NationalUniversityofMexico,Mexico
R.Hertel,BundesinstitutfrGesundheitlichenVerbraucherschutzundVeterinrmedizin,Germany
J.Lesage,InstitutdeRechercheenSantetenScuritduTravailduQubec,Canada
H.Nagy,NationalInstituteforOccupationalSafetyandHealth,Cincinnati,USA
D.Willcocks,NationalIndustrialChemicalsNotificationandAssessmentScheme,Australia
P.Yao,ChineseAcademyofPreventiveMedicine,PeoplesRepublicofChina
K.ZieglerSkylakakis,GSFForschungszentrumfrUmweltundGesundheitGmbH,Germany
APPENDIX3CICADFINALREVIEWBOARD
Stockholm,Sweden,2528May1999
Members
MrH.Abadin,AgencyforToxicSubstancesandDiseaseRegistry,CentersforDiseaseControlandPrevention,Atlanta,GA,USA
DrB.kesson,DepartmentofOccupational&EnvironmentalHealth,UniversityHospital,Lund,Sweden
DrT.Berzins(Chairperson),NationalChemicalsInspectorate(KEMI),Solna,Sweden
MrR.Cary,HealthandSafetyExecutive,Bootle,Merseyside,UnitedKingdom
DrR.S.Chhabra,GeneralToxicologyGroup,NationalInstituteofEnvironmentalHealthSciences,ResearchTrianglePark,NC,USA
DrS.Dobson(Rapporteur),InstituteofTerrestrialEcology,MonksWood,AbbotsRipton,Huntingdon,Cambridgeshire,UnitedKingdom
DrH.Gibb,NationalCenterforEnvironmentalAssessment,USEnvironmentalProtectionAgency,Washington,DC,USA
DrR.F.Hertel,FederalInstituteforHealthProtectionofConsumersandVeterinaryMedicine,Berlin,Germany
DrG.Koennecker,ChemicalRiskAssessment,FraunhoferInstituteforToxicologyandAerosolResearch,Hannover,Germany
DrA.Lf,NationalInstituteofWorkingLife,Solna,Sweden
DrA.Nishikawa,NationalInstituteofHealthSciences,DivisionofPathology,Tokyo,Japan
ProfessorK.Savolainen,FinnishInstituteofOccupationalHealth,Helsinki,Finland
DrJ.Sekizawa,DivisionofChemBioInformatics,NationalInstituteofHealthSciences,Tokyo,Japan
MsD.Willcocks(ViceChairperson),ChemicalAssessmentDivision,NationalOccupationalHealthandSafetyCommission(Worksafe
Australia),Sydney,Australia
ProfessorP.Yao,InstituteofOccupationalMedicine,ChineseAcademyofPreventiveMedicine,MinistryofHealth,Beijing,Peoples
RepublicofChina
Observers
DrN.Drouot(representingECETOC),ElfAtochem,DSEPIndustrialToxicologyDepartment,Paris,France
MsS.Karlsson,NationalChemicalsInspectorate(KEMI),Solna,Sweden
DrA.Poole(representingCEFIC),DowEuropeS.A.,Horgen,Switzerland
DrK.ZieglerSkylakakis,GSFForschungszentrumfrUmweltundGesundheit,InstitutfrToxikologie,Neuherberg,Oberschleissheim,
Germany
Secretariat
DrA.Aitio,ProgrammeforthePromotionofChemicalSafety,WorldHealthOrganization,Geneva,Switzerland
MsM.Godden,HealthandSafetyExecutive,Bootle,UnitedKingdom
MsL.Regis,ProgrammeforthePromotionofChemicalSafety,WorldHealthOrganization,Geneva,Switzerland
DrP.Toft,DivisionofHealthandEnvironment,WorldHealthOrganization,RegionalOfficefortheAmericas/PanAmericanSanitary
Bureau,Washington,DC,USA
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DrM.Younes,ProgrammeforthePromotionofChemicalSafety,WorldHealthOrganization,Geneva,Switzerland
INTERNATIONALCHEMICALSAFETYCARD
METHYLENEBISPHENYLISOCYANATEICSC:0298
RSUMDORIENTATION
CeCICADsurlediisocyanatedediphnylmthane(MDI)atprparparlInstitutnationaljaponaisdessciencesdelasantencollaboration
avecleNationalCenterforEnvironmentalAssessmentdelEnvironmentalProtectionAgencydestatsUnis(EPA).Ilreposeessentiellement
surdesmisesaupointdelaSocitjaponaisedemdecinedutravail(JSOH,1994)etdelEPA(USEPA,1998)pourlvaluation
toxicologiqueetdelUnioneuropenne(EU,1999)pourleseffetssurlenvironnement.IlestnoterqueledocumentdelUnion
europennenapasencoretdfinitivementapprouvetquelesdonnesprsentesdanslesparagraphesrelatifslimpactcologiquedece
produitproviennentpourlessentieldtudesnonpublies.Ledpouillementbibliographiqueatpoursuivijusqunovembre1998laide
dusystmeMEDLINE,larecherchedetouteinformationnouvellesusceptibledtreutilelvaluation.Laprparationdessources
documentaireetleurexamenpardespairssontexposslappendice1.DesrenseignementssurlexamenpardespairsduprsentCICAD
sontparailleursdonnslappendice2.CeCICADatapprouventantquvaluationinternationalelorsdunerunionduComit
dvaluationfinalequisesttenueStockholm(Sude)du25au28mai1999.LalistedesparticipantsauComitdvaluationfinalefigure
lappendice3.Laficheinternationalesurlascuritchimique(ICSC0298)duMDI,tablieparleProgrammeinternationalsurlascurit
chimique(IPCS,1993),estgalementreproduitedansleprsentdocument.
Ondsignesouslenomgnriquedediisocyanatedediphnylmthane(MDI)unproduitutilisdanslindustrie.LeMDIpolymris
(PMDI),quiestlaformetechniqueetcommercialeprincipaledececomposestenfaitunmlangecontenant2580%de4,4MDI
monomreetdesoligomres36cyclesplusquelquesisomrescommelisomre2,2.LacompositionexacteduPMDIvarieselonles
producteurs.
Le4,4MDIseprsentesouslaformedunsolidejauneplelatempratureambiante,dontlamassemolculaireestde250.Sonpoint
dbullitionestde>300C101,3kPaetsonpointdefusion,de3943C.Satensiondevapeurestinfrieure1mPa20C.Commeilne
subsistequepeudetempsdansleau,sasolubilitdanscesolvantestpurementthorique.Ilesttoutefoissolubledansloctane,lebenzneet
lekrosne.LePMDIestunliquidebrunrougefoncdontlepointdefusion,maldfini,sesitueautourde0C.Satensiondevapeurest
infrieure1mPA20C.LeMDIesttrsractifdanslenvironnementoulorsquilestabsorbpardesorganismesvivantsetilest
rapidementhydrolysen4,4mthylnedianiline(MDA),laquelleragitsontoursurleMDIenexcspourdonnerdesoligouresetdes
polyuresinsolubles.
LeMDIestutilispourlafabricationdelastomresbasedepolyurthane(roulements,emballages,amortisseursdevibrations,cuirs
synthtiques,etc.),defibres(spandex)etdesemellesdechaussures.LePMDIsertlaconfectiondemoussesrigidesousouples,deliants
poursabledemoulageetdisolantsthermiques.LaproductionannuelletotaledeMDIetdePMDIatdenviron1,2millionsdetonnesen
1991,de1,5millionsen1993,de1,78millionsen1994etde1,95millionsdetonnesen1996.
Unefoisleproduitrecueillisousformedarosolsurunimpacteur,dansunbarboteurousurdesfiltres,onfaitappellachromatographieen
phaseliquidehauteperformance(CLHP)pourledosageduMDIouduPMDI.LalimitededtectiondelaCLHPpourcesdeuxproduits,
quivarieenfonctiondelamthodedchantillonnage,peuttreinfrieure0,01mg/m 3 .Selontouteslestudesdisponibles,ontrouvedela
MDAlibreouactyleenmilieufortementhydrolytique.Enpareilcas,ilseformegalementdelaMDAauxdpensduMDIconjugu.On
disposedepuispeudunenouvellemthodepourdterminerlacompositiondesmlangescomplexesaroportsdisocyanatesetdecomposs
apparentsquiprennentnaissanceaucoursdeladcompositionthermiquedupolyurthane.Elleconsistefaireragirlabutylaminesurles
isocyanatesetdoserlesdrivsforms.
Danslesconditionsnormales,lexpositiondelapopulationgnraleauMDIdevraitproveniruniquementdesmissionsdececomposdans
latmosphre.Ilestrarequelonsoitfortementexposdanslemilieuambiant.Rpandusurlesoloudversdansleau,leMDInesubsiste
quebrivementenraisondesaractionavecleauquiconduitprincipalementlaformationdepolyuresinsolubles.Ilseformegalement
delaMDAmaissaconcentrationesttoujoursfaible.UnetudesuruntangamontrquelaccumulationduMDIlelongdelachane
alimentaireaquatiqueestextrmementpeuprobable,commeonpeutsyattendredufaitdesatrsfaiblesolubilitetdesaforteractiviten
solutionaqueuse.Onnedisposequededonneslimitessurlexpositionprofessionnelledesvaleurssuprieures50g/m 3(enmoyenne
pondreparrapportautempssur8h)onttsignalesdetempsautre.
LesdonnestoxicocintiquesrelativesauMDIsonttrslimites.Unefoisabsorb,ilsembleseconjuguerprincipalementauxprotines.Pour
cequiestdelexpositionparlavoierespiratoire,onnedisposequedtudeslimitessurlerat.Lunedecestudes,basesurlutilisationde
MDIradiomarqu,amontrquunecertaineproportiondeMDIserpartitdanslorganismesousuneformeousousuneautre,
essentiellementdanslespoumons,lesreins,lesmusclesetlesvoiesdigestives.Lecomposestensuiteliminavecsesmtabolites,57et13%
delaradioactivittantrespectivementrcuprsdanslesmatiresfcalesetlesurinesauboutde4jours.Moinsde1%delaradioactivita
trcuprdanslesprincipauxorganes,mais23%deladoseinitialeonttretrouvsdanslacarcasse.Danslesurines,onamisenvidence
unepetitequantitdeMDAsouslesdeuxformes:libreetactyle.
Destudesportantsurdesouvriersontpermisdemettreenvidencedelamthylnedianilinesousdiversesformesdansleursangetleurs
urines:MDAlibre,MDAactyleetadduitsMDAhmoglobineetMDAalbumine.CestravauxdonnentpenserquelaMDAplasmatique
acidohydrolysablepourraitconstituerunbiomarqueurintressantduneexpositiondelonguedureauMDI.Chezunouvrierexposau
PMDI,onaconstatquelademiviedelaMDAacidohydrolysabletaitde7080hdanslurineetde21joursdanslesrum.
LeMDIneprovoquepasdintoxicationsaiguschezlanimal.Lexprimentationanimaleapportecependantdespreuvesindiscutablesdune
sensibilisationcutaneetrespiratoireprovoqueparleMDI.Ilestpossiblequelimmunitcellulaireetlimmunithumoralejouentunrle
danslapathognsedelhypersensibilitprovoqueparlesisocyanates.ChezdesratsmlesetfemellesexpossunarosoldePMDIla
concentrationde13,6mg/m 3 ,6hparjour,5joursparsemaine,pendant2semaines,onaobservuneintensedtresserespiratoireetune
rductionsensibledugaindepoids,lessignesdedtresserespiratoiretantbeaucoupmoinsmarqusetlegaindepoidsjusteunpeurduit
chezlesmleslaconcentrationde4,9mg/m 3 .Ensebasantsuruneaugmentationmarginaledurapportpoidsdupoumon/poidsducorps
auxdoseslesplusleves,onaconcluquelaconcentrationde2,2mg/m 3 laplusfaibletudiecorrespondaitladosesanseffetnocif
observable(NOAEL).
Lorsdunetudede2ansvisantvaluerlatoxicitrespiratoirechroniqueetlacancrognicitduPMDI,desratsexpossdesarosolsde
PMDIdesconcentrationsde0,0,19,0,98et6,03mg/m 3 ,ontprsentdesanomaliesauniveaudesvoiesrespiratoires.Onnapasconsidr
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quelesadnocarcinomespulmonairesobservsdansuncasconstituaientunepreuvesuffisantedelacancrognicitduPMDIpourlanimal
enrevanche,laformationinsitudeMDA,composcancrognebienconnuparlintermdiairedeleaudeboisson,pourraittrelorigine
deceteffet.Onagalementconsidrquelhyperplasiedescellulesbasalesdelpithliumolfactifconstateauxdosesde0,98et6,03
mg/m 3 constituaitunpointdaboutissementtrsimportantdelactiontoxique,maisdenaturenoncancrogne.Lesrsultatsdecettetude,
permettentderetenirendehorsdetouteffetcancrognelavaleurde0,19mg/m 3 pourladosesanseffetnocifobservable(NOAEL)etde
0,98mg/m 3 pourladoselaplusfaibleproduisantuneffetnocifobservable(LOAEL).
DuMDImonomredissousdansledimthylsulfoxyde(DMSO)etmisenprsenceinvitrodeSalmonellatyphimurium,adonndesrsultats
tanttpositifs,tanttngatifs.Toutefois,sachantqueleDMSOragitsurleMDIpourdonnerdelaMDAetpeuttredautresproduits,onne
peutpasconsidrercesrsultatscommesignificatifsenvuedunevaluationdurisquepourlHomme.
LexpositionderattesWistargravidesduMDImonomreaentranuneincidenceaccruedesternbresasymtriqueschezlesfoetusla
concentrationde9mg/m 3 toutefois,tantdonnquecetaccroissementsesituaitdansleslimitesdelavariabilitbiologique,onaestim
pouvoirprendrelavaleurde9mg/m 3 commereprsentantlaNOAELrelativeauxeffetstoxiquessurledveloppement.Dansuneautretude
surlePMDI,laNOAELrelativelatoxicitpourlesmresetlesfoetusatestime4mg/m 3 ,ensebasantsurlamortprmaturedun
certainnombrederattesgravidesetsurladiminutionstatistiquementsignificativedupoidsplacentaireetdupoidsfoetalladosede12
mg/m 3 .IlnyapaseudtudesconsacresauxeffetsduMDIouduPMDIsurlesparamtresgnsiques.
Lespointsdaboutissementtoxicologiqueslesplusproccupantssontlasthmedorigineprofessionnelle,lespneumopathiesdhypersensibilit
etlesaffectionsinflammatoiresdesvoiesrespiratoiressuprieuresconscutiveslinhalationdeMDIoudePMDI.Mmesionenvoitencore
mallemcanisme,ilsemblequedesractionsimmunitaireshumoralesetcellulairesjouentunrledanslesmanifestationsallergiques.Un
certainnombredecasonttdcritsqui,linstardediversestudespidmiologiques,mettentencauseleMDIdanscertainesdermatiteset
dansdesproblmesdesensibilisationoudasthmedorigineprofessionnelle.Unetudesurcohorteetunetudertrospective,prsentantilest
vraiuncertainnombredelimitations,ontmontrquilnyavaitaucuneassociationentreleMDIetlamorbiditcancreuse.Onnedispose
daucunedonnesurlexpositionparlavoieorale,maisilestpeuprobablequelHommesoitexposauMDIparcettevoie.
LeMDIneprsenteaucunetoxicitpourlespoissons,lesinvertbrsaquatiques,lesalguesoulesmicroorganismesdansdesconditions
dexpositionsusceptiblesdegnreruneintoxicationaiguouchronique.Toutefois,lesrsultatsdestestspratiqusdanslemilieuaquatique
nesontguresignificatifstantdonnqueleMDIestpratiquementinsolubledansleau.Demme,uncertainnombredetestspratiqussur
desorganismesterricolesnontdonnaucunrsultatpositifdanslesconditionsexprimentales.Ilnya,lalumiredesdonnesdisponibles,
aucuneproccupationavoirquantauxeffetsduMDIsurlestresvivantsdansleurmilieunaturel,encorequilfailleobtenirdavantagede
renseignementsconcernantlaformationdeMDAdanslenvironnementetseseffetssurlesorganismesvivantsavantdetirerdesconclusions
dfinitives.
RESUMENDEORIENTACIN
ElpresenteCICADsobreeldiisocianatodedifenilmetano(MDI)sepreparenelInstitutoNacionaldeCienciasdelaSalud,Japn,en
colaboracinconelCentroNacionalparalaEvaluacindelMedioAmbiente,laAgenciaparalaProteccindelMedioAmbientedelos
EstadosUnidos(EPA).SebasprincipalmenteenlosexmenesdelaSociedadJaponesadeSaludOcupacional(JSOH,1994)ydelaUSEPA
(1998)paralaevaluacintoxicolgicaydelaUninEuropea(EU,1999)paralaevaluacinambiental.Hayquesealarqueeldocumento
delaUEestodavaunborradorpendientedeaprobacinyquelainformacinquepresentaenlasseccionesrelativasalmedioambientese
basafundamentalmenteenestudiosnopublicados.Sebusclabibliografahastanoviembrede1998medianteMEDLINE,paralocalizar
cualquierinformacinnuevapertinentealaevaluacin.Lapreparacindelosdocumentosoriginalesysuexamencolegiadosedescribenen
elapndice1.LainformacinsobreelexamencolegiadodeesteCICADfiguraenelapndice2.EsteCICADseaprobenunareunindela
JuntadeEvaluacinFinalcelebradaenEstocolmo,Suecia,losdas2528demayode1999.Enelapndice3figuralalistadeparticipantes
enestareunin.LaFichainternacionaldeseguridadqumica(ICSC0298)paraelMDI,preparadaporelProgramaInternacionalde
SeguridaddelasSustanciasQumicas(IPCS,1993),tambinsereproduceenelpresentedocumento.
Eldiisocianatodedifenilmetano(MDI)eselnombregenricodeunproductoutilizadoenlaindustria.ElMDIpolimrico(PMDI),forma
tcnico/comercialprimariadelMDI,esenrealidadunamezclaquecontieneun25%80%de4,4MDImonomrico,ascomooligmeros
con36anillosyotrosismerossecundarios,comoelismero2,2.LacomposicinexactadelPMDIvaradeunfabricanteaotro.
El4,4MDImonomricoesunasustanciaslidadeuncolorentreblancoyamarilloplidoatemperaturaambiente,conunpesomolecular
de250.Tieneunpuntodeebullicin>300Ca101,3kPa,unpuntodefusinde3943Cyunapresindevapor<1mPaa20C.Su
presenciaenelaguaesfugazaspues,susolubilidadenaguaespuramenteterica.Sinembargo,elMDImonomricoessolubleenoctano,
bencenoyqueroseno.ElPMDIesunlquidodecoloroscuroentrerojizoymarrn,conunpuntodefusinindefinidoalrededorde0Cy
unapresindevapor<1mPaa20C.ElMDIesmuyreactivoenelmedioambienteocuandoloabsorbenlosorganismosysehidrolizacon
rapidez,formando4,4metilendianilina(MDA),quereaccionaconelMDIenexcesoparaproduciroligoureasypoliureasinsolubles.
ElMDIseutilizaenlafabricacindeelastmerosdepoliuretano(rodillos,embalaje,aislantesdecauchocontralasvibraciones,pielsinttica,
etc.),fibrasexpandidasysuelasdegomaparazapatos.ElPMDIseutilizaparafabricarespumargidayflexible,aglutinantesdearenay
resinadefundicinyaislantestrmicos.LaproduccinanualtotaldeMDIyPMDIentodoelmundofuedealrededorde1,2millonesde
toneladasen1991,1,5millonesdetoneladasen1993,1,78millonesdetoneladasen1994y1,95millonesdetoneladasen1996.
Unavezrecogidademaneraadecuadalaformaaerosolmedianteinterceptadores,burbujasofiltros,elMDIyelPMDIseanalizanmediante
cromatografalquidadealtorendimiento.LoslmitesdedeteccindeestatcnicaparaelMDIyelPMDI,quevaranenfuncindela
metodologademuestreo,puedenserinferioresa0,01mg/m 3 .EncasitodoslosestudiosseidentificaMDAlibreyacetiladadespusde
mantenerunascondicionesmuyhidrolizantes.EnestascondicionestambinseformaMDAapartirdelMDIconjugado.Desdehacepocose
disponedeunnuevomtodoquepermitedeterminarlacomposicindemezclascomplejasdeisocianatosycompuestosafinessuspendidosen
elaireformadosduranteladescomposicintrmicadelpoliuretanomediantelaproduccindederivadosdelosisocianatoscondibutilamina.
Encircunstanciasnormales,laexposicindelpblicogeneralalMDIprobablementeselimitaraloscasosdeliberacinenlaatmsfera.Son
raraslasexposicionesaltasenelmedioambiente.Cuandoseproduceunvertidoalsuelooalagua,elMDItieneunaexistenciafugaz,debido
aquereaccionaconelaguaparaproducirdemanerapredominantepoliureasinsolubles.LasconcentracionesdeMDAqueseformanenel
medioambienteporlareaccindelMDIconelaguasonsiemprebajas.Enunestudiodeunestanquesecomprobqueesmuypoco
probablequeseproduzcaacumulacindeMDIalolargodelacadenaalimentariaacutica,comocabraesperarconsiderandoquetieneuna
solubilidadmuybajayunaelevadareactividadensolucinacuosa.Lainformacinsobrelaexposicinocupacionaleslimitadaendiferentes
industriassehanotificadoquenosonfrecuenteslasexposicionesmediasponderadasporeltiempodeochohorassuperioresa50g/m 3 .
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HayunainformacinmuylimitadasobrelatoxicocinticadelMDI.Unavezabsorbido,pareceestarpredominantementeconjugadoa
protena.Conrespectoalaexposicinporinhalacin,solamentesedisponedeestudioslimitadosenratas.Unestudiodeexposicinpor
inhalacinconMDIradiomarcadoindicaquealgunaformaopartedelMDIsedistribuyeportodoelorganismo,sobretodoenlospulmones,
losmsculos,losrionesyelaparatodigestivo.LaeliminacinfecalyurinariadelMDIysusmetabolitosdurantecuatrodasfueel57%yel
13%delaradiactividadrecuperada,respectivamente.Serecupermenosdel1%delaradiactividaddelosrganosprincipales,aunqueel
23%deladosisadministradaserecuperenlacanal.EnlaorinaaparecieronpequeascantidadesdeMDAlibreyacetilada.
EnestudioscontrabajadoressehanidentificadoMDAlibre,MDAacetiladayaductosconhemoglobinaoalbminaenlaorinaylasangre.
EstosestudiosparecenindicarquelaMDAhidrolizablecidadelplasmapuedeserunbiomarcadortildelaexposicinprolongadaalMDI.
LasemividadelaMDAhidrolizablecidaenlaorinadeuntrabajadorexpuestoalPMDIfuede7080horas,yenelsuerode21das.
ElMDInotieneunatoxicidadagudaparalosmamferosdelaboratorio.Losdatosobtenidosenanimalesproporcionanindiciosclarosde
sensibilizacincutneayrespiratoriadebidaalMDI.Enlapatognesisdelahipersensibilidaddebidaalosisocianatospodraintervenirla
inmunidadhumoral,ascomolamediadaporclulas.Seobservarontrastornosrespiratoriosgravesyunadisminucinsignificativadel
aumentodelpesocorporalenratasmachosyhembrasexpuestasaunaerosoldePMDIconunaconcentracinde13,6mg/m 3 duranteseis
horasalda,cincodasalasemana,duranteunperododossemanas,consntomasmuchomenosgravesdetrastornosrespiratoriosyslouna
ligerareduccindelaumentodelpesocorporalenratasmachoscon4,9mg/m 3 .Tomandocomobaseunaumentomarginaldelaraznpeso
delpulmn:pesocorporalcondosismselevadas,sellegalaconclusindeque2,2mg/m 3 ,elniveldedosismsbajoexaminado,erauna
concentracinsinefectosadversosobservados(NOAEL).
Enunestudiodetoxicidad/carcinogenicidadporinhalacincrnicadedosaos,lasratasexpuestasaunaerosoldePMDIenconcentraciones
de0,0,19,0,98,y6,03mg/m 3 mostraroncambiosenelaparatorespiratorio.Seconsiderqueeladenocarcinomapulmonarobservadoenun
casonoerasuficienteparaidentificaralPMDIcomocarcingenohumanosinembargo,lacausadeeseefectopodraserlageneracininsitu
deMDA,queesuncarcingenoconocidodelosanimalesatravsdelaguadebebida.Seconsiderquelahiperplasiacelularbasalenel
epitelioolfatoriodetectadacon0,98y6,03mg/m 3 eraunefectofinalcrticonocarcinognico.Lainformacinnoneoplsicadeesteestudio
pareceindicarunaNOAELde0,19mg/m 3 yunaconcentracinmsbajaconefectosadversosobservados(LOAEL)de0,98mg/m 3 .
SeobtuvieronresultadostantopositivoscomonegativoscuandoserealizaronpruebasinvitroconMDImonomricodisueltoen
dimetilsulfxidoenSalmonellatyphimurium.Sinembargo,debidoalainteraccinconocidadeldimetilsulfxidoconelMDIparaproducir
MDAyposiblementeotrosproductosdelareaccin,estosresultadospositivosnodeberanconsiderarsevlidosenlaevaluacindelriesgo
paralasaludhumana.
LaexposicinderatasWistarpreadasaMDImonomricodiolugaraunamayorincidenciadeesternebrasasimtricasenfetoscon9mg/m 3
sinembargo,comoelaumentoquedabadentrodeloslmitesdelavariabilidadbiolgica,laNOAELparalatoxicidadeneldesarrolloenese
estudioseestimen9mg/m 3 .EnotroestudioenelcualseexpusieronratasaPMDI,laNOAELparalatoxicidadmaternayfetalseestimen
4mg/m 3 ,basadaenelresultadodelasmuertesprematurasdehembraspreadasyenlareduccinestadsticamentesignificativadelpesodela
placentaydelfetocon12mg/m 3 .NosehanrealizadoestudiosenlosquesehayaexaminadoelefectodelMDIpolimricoomonomricoen
losparmetrosreproductivos.
Losefectosfinalesenlasaludmspreocupantessonelasmadeorigenocupacional,laneumonitisporhipersensibilidadylasenfermedades
inflamatoriasdelasvasrespiratoriassuperioresmediantelainhalacindeMDIpolimricoomonomrico.Aunqueannoseconocenbien,
enlasreaccionesalrgicasparecenintervenirreaccionesinmunitariasdecarcterhumoral,ascomodelasmediadasporclulas.En
notificacionesdecasos,ascomoenestudiosepidemiolgicos,sehadescritoelMDIcomocausantededermatitisocupacional,sensibilizacin
cutneayasma.Enunestudiodecohortesyunestudioretrospectivo,aunqueeranlimitadosenvariosaspectos,sepusodemanifiestoqueno
habaunaasociacinsignificativaconlamorbilidaddelcncer.Nohaydatosdisponiblesparalaexposicinoral,peroespocoprobablela
exposicindelaspersonasalMDIporestava.
ElMDInomostrtoxicidadparalospeces,losinvertebradosacuticos,lasalgasolosmicroorganismosenningunadelascondicionesde
pruebadeexposicinagudaoprolongada.Sinembargo,losresultadosdelaspruebasacuticascarecendevalor,debidoaqueelMDIes
prcticamenteinsolubleenagua.Anlogamente,enunpequeonmerodepruebasrealizadasconorganismosterrestresnoseobservaron
efectosenlascondicionesdelaprueba.LosdatosdisponiblesindicanquenohayquepreocuparseporlosefectosdelMDIenlosorganismos
delmedioambiente,aunqueparallegaraconclusionesdefinitivassenecesitarainformacinmsdetalladasobrelaformacindeMDAenel
medioambienteysusefectosenlosorganismos.
FOOTNOTES
1InternationalProgrammeonChemicalSafety(1994)Assessinghumanhealthrisksofchemicals:derivationofguidancevaluesforhealthbasedexposurelimits.
Geneva,WorldHealthOrganization(EnvironmentalHealthCriteria170).
SeeAlso:
ToxicologicalAbbreviations
34/34

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