Upload File

diphenylmethane diisocyanate (mdi)

34
 10/03/2015 DIPHENYLMETHANE DIISOCYANATE ( MDI) http://www.inchem.or g/documents/cicads/cicads/cicad27.htm 1/34 This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organization, or the World Health Organization. Concise International Chemical Assessment Document 27 DIPHENYLMETHANE DIISOCYANATE (MDI) First draft prepared by Dr J. Sekizawa, National Institute of Health Sciences, Japan, in collaboration with Dr M.M. Greenberg, US Environmental Protection Agency Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organization, and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals. World Health Organization Geneva, 2000 The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organization (ILO), and the World Health Organization (WHO). The overall objectives of the IPCS are to establish the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals. The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO, the United Nations Industrial Development Organization, the United Nations Institute for Training and Research, and the Organisation for Economic Co-operation and Development (Participating Organizations), following recommendations made by the 1992 UN Conference on Environment and Development to strengthen cooperation and increase coordination in the field of chemical safety. The purpose of the IOMC is to promote coordination of the policies and activities  pursued by the Participating Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment. WHO Library Cataloguing-in-Publication Data Diphenylmethane diisocyanate (MDI). (Concise international chemical assessment document ; 27) 1.Isocyanates - toxicity 2.Risk assessment 3.Environmental exposure 4.International Programme on Chemical Safety II.Series ISBN 92 4 153027 8 (NLM Classification: QV 280) ISSN 1020-6167 The World Health Organization welcomes requests for permission to reproduce or translate its  publications, in part or in f ull. Applications and enquiries should be addressed to the Office of 

Upload: joaomanoelravasio

Post on 05-Oct-2015

20 views

Category:

Documents


0 download

Report

DESCRIPTION

Isocianatos fórmulas

TRANSCRIPT

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 1/34

    ThisreportcontainsthecollectiveviewsofaninternationalgroupofexpertsanddoesnotnecessarilyrepresentthedecisionsorthestatedpolicyoftheUnitedNationsEnvironmentProgramme,theInternationalLabourOrganization,ortheWorldHealthOrganization.

    ConciseInternationalChemicalAssessmentDocument27

    DIPHENYLMETHANEDIISOCYANATE(MDI)

    FirstdraftpreparedbyDrJ.Sekizawa,NationalInstituteofHealthSciences,Japan,incollaborationwithDrM.M.Greenberg,USEnvironmentalProtectionAgency

    PublishedunderthejointsponsorshipoftheUnitedNationsEnvironmentProgramme,theInternationalLabourOrganization,andtheWorldHealthOrganization,andproducedwithintheframeworkoftheInterOrganizationProgrammefortheSoundManagementofChemicals.

    WorldHealthOrganizationGeneva,2000

    TheInternationalProgrammeonChemicalSafety(IPCS),establishedin1980,isajointventureoftheUnitedNationsEnvironmentProgramme(UNEP),theInternationalLabourOrganization(ILO),andtheWorldHealthOrganization(WHO).TheoverallobjectivesoftheIPCSaretoestablishthescientificbasisforassessmentoftherisktohumanhealthandtheenvironmentfromexposuretochemicals,throughinternationalpeerreviewprocesses,asaprerequisiteforthepromotionofchemicalsafety,andtoprovidetechnicalassistanceinstrengtheningnationalcapacitiesforthesoundmanagementofchemicals.

    TheInterOrganizationProgrammefortheSoundManagementofChemicals(IOMC)wasestablishedin1995byUNEP,ILO,theFoodandAgricultureOrganizationoftheUnitedNations,WHO,theUnitedNationsIndustrialDevelopmentOrganization,theUnitedNationsInstituteforTrainingandResearch,andtheOrganisationforEconomicCooperationandDevelopment(ParticipatingOrganizations),followingrecommendationsmadebythe1992UNConferenceonEnvironmentandDevelopmenttostrengthencooperationandincreasecoordinationinthefieldofchemicalsafety.ThepurposeoftheIOMCistopromotecoordinationofthepoliciesandactivitiespursuedbytheParticipatingOrganizations,jointlyorseparately,toachievethesoundmanagementofchemicalsinrelationtohumanhealthandtheenvironment.

    WHOLibraryCataloguinginPublicationData

    Diphenylmethanediisocyanate(MDI).(Conciseinternationalchemicalassessmentdocument27)1.Isocyanatestoxicity2.Riskassessment3.Environmentalexposure4.InternationalProgrammeonChemicalSafetyII.SeriesISBN9241530278(NLMClassification:QV280)ISSN10206167

    TheWorldHealthOrganizationwelcomesrequestsforpermissiontoreproduceortranslateitspublications,inpartorinfull.ApplicationsandenquiriesshouldbeaddressedtotheOfficeof

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 2/34

    Publications,WorldHealthOrganization,Geneva,Switzerland,whichwillbegladtoprovidethelatestinformationonanychangesmadetothetext,plansforneweditions,andreprintsandtranslationsalreadyavailable.

    WorldHealthOrganization2000

    PublicationsoftheWorldHealthOrganizationenjoycopyrightprotectioninaccordancewiththeprovisionsofProtocol2oftheUniversalCopyrightConvention.Allrightsreserved.

    ThedesignationsemployedandthepresentationofthematerialinthispublicationdonotimplytheexpressionofanyopinionwhatsoeveronthepartoftheSecretariatoftheWorldHealthOrganizationconcerningthelegalstatusofanycountry,territory,city,orareaorofitsauthorities,orconcerningthedelimitationofitsfrontiersorboundaries.

    ThementionofspecificcompaniesorofcertainmanufacturersproductsdoesnotimplythattheyareendorsedorrecommendedbytheWorldHealthOrganizationinpreferencetoothersofasimilarnaturethatarenotmentioned.Errorsandomissionsexcepted,thenamesofproprietaryproductsaredistinguishedbyinitialcapitalletters.

    TheFederalMinistryfortheEnvironment,NatureConservationandNuclearSafety,Germany,providedfinancialsupportfortheprintingofthispublication.

    TABLEOFCONTENTS

    FOREWORD

    1.EXECUTIVESUMMARY

    2.IDENTITYANDPHYSICAL/CHEMICALPROPERTIES

    3.ANALYTICALMETHODS

    4.SOURCESOFHUMANANDENVIRONMENTALEXPOSURE

    5.ENVIRONMENTALTRANSPORT,DISTRIBUTION,ANDTRANSFORMATION

    5.1Water

    5.2Soil

    5.3Air

    6.ENVIRONMENTALLEVELSANDHUMANEXPOSURE

    6.1Environmentallevels

    6.2Humanexposure

    7.COMPARATIVEKINETICSANDMETABOLISMINLABORATORYANIMALSANDHUMANS

    8.EFFECTSONLABORATORYMAMMALSANDIN

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 3/34

    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.EFFECTSONOTHERORGANISMSINTHELABORATORYANDFIELD

    10.1Aquaticenvironment

    10.2Terrestrialenvironment

    11.EFFECTSEVALUATION

    11.1Evaluationofhealtheffects

    11.1.1Hazardidentificationanddoseresponseassessment

    11.1.2CriteriaforsettingtolerableintakesorguidancevaluesforMDI

    11.1.3Sampleriskcharacterization

    11.2Evaluationofenvironmentaleffects

    12.PREVIOUSEVALUATIONSBYINTERNATIONALBODIES

    REFERENCES

    APPENDIX1SOURCEDOCUMENTS

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 4/34

    APPENDIX2CICADPEERREVIEW

    APPENDIX3CICADFINALREVIEWBOARD

    INTERNATIONALCHEMICALSAFETYCARD

    RSUMDORIENTATION

    RESUMENDEORIENTACIN

    FOREWORD

    ConciseInternationalChemicalAssessmentDocuments(CICADs)arethelatestinafamilyofpublicationsfromtheInternationalProgrammeonChemicalSafety(IPCS)acooperativeprogrammeoftheWorldHealthOrganization(WHO),theInternationalLabourOrganization(ILO),andtheUnitedNationsEnvironmentProgramme(UNEP).CICADsjointheEnvironmentalHealthCriteriadocuments(EHCs)asauthoritativedocumentsontheriskassessmentofchemicals.

    CICADsareconcisedocumentsthatprovidesummariesoftherelevantscientificinformationconcerningthepotentialeffectsofchemicalsuponhumanhealthand/ortheenvironment.TheyarebasedonselectednationalorregionalevaluationdocumentsoronexistingEHCs.BeforeacceptanceforpublicationasCICADsbyIPCS,thesedocumentsundergoextensivepeerreviewbyinternationallyselectedexpertstoensuretheircompleteness,accuracyinthewayinwhichtheoriginaldataarerepresented,andthevalidityoftheconclusionsdrawn.

    TheprimaryobjectiveofCICADsischaracterizationofhazardanddoseresponsefromexposuretoachemical.CICADsarenotasummaryofallavailabledataonaparticularchemicalrather,theyincludeonlythatinformationconsideredcriticalforcharacterizationoftheriskposedbythechemical.Thecriticalstudiesare,however,presentedinsufficientdetailtosupporttheconclusionsdrawn.Foradditionalinformation,thereadershouldconsulttheidentifiedsourcedocumentsuponwhichtheCICADhasbeenbased.

    Riskstohumanhealthandtheenvironmentwillvaryconsiderablydependinguponthetypeandextentofexposure.Responsibleauthoritiesarestronglyencouragedtocharacterizeriskonthebasisoflocallymeasuredorpredictedexposurescenarios.Toassistthereader,examplesofexposureestimationandriskcharacterizationareprovidedinCICADs,wheneverpossible.Theseexamplescannotbeconsideredasrepresentingallpossibleexposuresituations,butareprovidedasguidanceonly.ThereaderisreferredtoEHC1701foradviceonthederivationofhealthbasedtolerableintakesorguidancevalues.

    WhileeveryeffortismadetoensurethatCICADsrepresentthecurrentstatusofknowledge,newinformationisbeingdevelopedconstantly.Unlessotherwisestated,CICADsarebasedonasearchofthescientificliteraturetothedateshownintheexecutivesummary.IntheeventthatareaderbecomesawareofnewinformationthatwouldchangetheconclusionsdrawninaCICAD,thereaderisrequestedtocontactIPCStoinformitofthenewinformation.

    Procedures

    TheflowchartshowstheproceduresfollowedtoproduceaCICAD.Theseproceduresaredesignedtotakeadvantageoftheexpertisethatexistsaroundtheworldexpertisethatisrequiredtoproducethehighqualityevaluationsoftoxicological,exposure,andotherdatathatarenecessaryforassessingriskstohumanhealthand/ortheenvironment.

    Thefirstdraftisbasedonanexistingnational,regional,orinternationalreview.Authorsofthefirstdraftareusually,butnotnecessarily,fromtheinstitutionthatdevelopedtheoriginalreview.A

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 5/34

    standardoutlinehasbeendevelopedtoencourageconsistencyinform.ThefirstdraftundergoesprimaryreviewbyIPCStoensurethatitmeetsthespecifiedcriteriaforCICADs.

    ThesecondstageinvolvesinternationalpeerreviewbyscientistsknownfortheirparticularexpertiseandbyscientistsselectedfromaninternationalrostercompiledbyIPCSthroughrecommendationsfromIPCSnationalContactPointsandfromIPCSParticipatingInstitutions.Adequatetimeisallowedfortheselectedexpertstoundertakeathoroughreview.Authorsarerequiredtotakereviewerscommentsintoaccountandrevisetheirdraft,ifnecessary.TheresultingseconddraftissubmittedtoaFinalReviewBoardtogetherwiththereviewerscomments.

    TheCICADFinalReviewBoardhasseveralimportantfunctions:

    toensurethateachCICADhasbeensubjectedtoanappropriateandthoroughpeerreview

    toverifythatthepeerreviewerscommentshavebeenaddressedappropriately

    toprovideguidancetothoseresponsibleforthepreparationofCICADsonhowtoresolveanyremainingissuesif,intheopinionoftheBoard,theauthorhasnotadequatelyaddressedallcommentsofthereviewersand

    toapproveCICADsasinternationalassessments.

    Boardmembersserveintheirpersonalcapacity,notasrepresentativesofanyorganization,government,orindustry.Theyareselectedbecauseoftheirexpertiseinhumanandenvironmentaltoxicologyorbecauseoftheirexperienceintheregulationofchemicals.Boardsarechosenaccordingtotherangeofexpertiserequiredforameetingandtheneedforbalancedgeographicrepresentation.

    Boardmembers,authors,reviewers,consultants,andadviserswhoparticipateinthepreparationofaCICADarerequiredtodeclareanyrealorpotentialconflictofinterestinrelationtothesubjectsunderdiscussionatanystageoftheprocess.RepresentativesofnongovernmentalorganizationsmaybeinvitedtoobservetheproceedingsoftheFinalReviewBoard.ObserversmayparticipateinBoarddiscussionsonlyattheinvitationoftheChairperson,andtheymaynotparticipateinthefinaldecisionmakingprocess.

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 6/34

    1.EXECUTIVESUMMARY

    ThisCICADondiphenylmethanediisocyanate(MDI)waspreparedbytheNationalInstituteofHealthSciences,Japan,incollaborationwiththeNationalCenterforEnvironmentalAssessment,USEnvironmentalProtectionAgency(EPA).TheCICADwasbasedprincipallyonthereviewsoftheJapanSocietyforOccupationalHealth(JSOH,1994)andtheUSEPA(1998)forthetoxicologicalevaluationandtheEuropeanUnion(EU,1999)fortheenvironmentalassessment.ItshouldbenotedthattheEUdocumentisstillanunapproveddraftandthattheinformationpresentedintheenvironmentalsectionsisbasedmainlyonunpublishedstudies.TheliteratureuptoNovember1998wassearchedusingMEDLINEtoidentifyanynewinformationrelevanttotheassessment.ThepreparationandpeerreviewofthesourcedocumentsaredescribedinAppendix1.InformationonthepeerreviewofthisCICADispresentedinAppendix2.ThisCICADwasapprovedasaninternationalassessmentatameetingoftheFinalReviewBoard,heldinStockholm,Sweden,on2528May1999.

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 7/34

    ParticipantsattheFinalReviewBoardmeetingarelistedinAppendix3.TheInternationalChemicalSafetyCard(ICSC0298)forMDI,producedbytheInternationalProgrammeonChemicalSafety(IPCS,1993),hasalsobeenreproducedinthisdocument.

    Diphenylmethanediisocyanate(MDI)isthegenericnameofaproductusedinindustrialsettings.PolymericMDI(PMDI),theprimarytechnical/commercialformofMDI,isactuallyamixturethatcontains2580%monomeric4,4MDIaswellasoligomerscontaining36ringsandotherminorisomers,suchasthe2,2isomer.TheexactcompositionofPMDIvarieswiththemanufacturer.

    Monomeric4,4MDIisawhitetopaleyellowsolidatroomtemperature,withamolecularweightof250.Ithasaboilingpointof>300Cat101.3kPa,ameltingpointof3943C,andavapourpressureof

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 8/34

    MDAintheurineofaworkerexposedtoPMDIwas7080h,andinserum,21days.

    MDIisnotacutelytoxictolaboratorymammals.AnimaldataprovideclearevidenceofskinandrespiratorysensitizationduetoMDI.Humoralaswellascellularimmunitymaybeinvolvedinthepathogenesisofhypersensitivityduetoisocyanates.SevererespiratorydistressandasignificantdecreaseinbodyweightgainwereobservedinmaleandfemaleratsexposedtoPMDIaerosolataconcentrationof13.6mg/m3for6hperday,5daysperweek,overaperiodof2weeks,withmuchlessseveresignsofrespiratorydistressandonlyslightlyreducedbodyweightgaininmaleratsat4.9mg/m3.Basedonamarginalincreaseinlungtobodyweightratioathigherdoses,itwasconcludedthat2.2mg/m3,whichwasthelowestdoselevelexamined,wasanoobservedadverseeffectlevel(NOAEL).

    Ina2yearchronicinhalationtoxicity/carcinogenicitystudy,ratsthatwereexposedtoPMDIaerosolatconcentrationsof0,0.19,0.98,or6.03mg/m3showedchangesintherespiratorytract.PulmonaryadenocarcinomaobservedinonecasewasconsideredasinsufficienttoidentifyPMDIasananimalcarcinogenhowever,insitugenerationofMDA,whichisaknownanimalcarcinogenviadrinkingwater,couldberesponsiblefortheeffect.Basalcellhyperplasiaintheolfactoryepitheliumdetectedat0.98and6.03mg/m3wasjudgedanoncarcinogeniccriticalendpoint.ThenonneoplasticinformationinthisstudysuggestsaNOAELof0.19mg/m3andalowestobservedadverseeffectlevel(LOAEL)of0.98mg/m3.

    BothpositiveandnegativeresultswereobtainedwhenmonomericMDIdissolvedindimethylsulfoxide(DMSO)wastestedinvitrowithSalmonellatyphimurium.However,becauseoftheknowninteractionofDMSOwithMDItoyieldMDAandpossiblyotherreactionproducts,thesepositiveresultsshouldnotbeconstruedasmeaningfulforhumanhealthriskassessment.

    ExposureofgravidWistarratstomonomericMDIresultedinanincreasedincidenceofasymmetricsternebraeinfetusesat9mg/m3however,astheincreasewaswithinthelimitsofbiologicalvariability,theNOAELfordevelopmentaltoxicityinthisstudywasestimatedtobe9mg/m3.InanotherstudyinwhichratswereexposedtoPMDI,theNOAELformaternalandfetaltoxicitywasestimatedtobe4mg/m3,basedonthefindingofprematuredeathsofpregnantfemalesandstatisticallysignificantdecreasesinplacentalandfetalweightsat12mg/m3.TherehavebeennostudiesthathaveexaminedtheeffectofpolymericormonomericMDIonreproductiveparameters.

    Thehealthendpointsofmostconcernareoccupationallyinducedasthma,hypersensitivitypneumonitis,andinflammatoryupperrespiratorytractdiseasesthroughinhalationofpolymericormonomericMDI.Althoughnotyetwellunderstood,humoralaswellascellularimmunologicalreactionsappeartobeinvolvedintheallergicreactions.CasereportsaswellasepidemiologicalstudieshavedescribedMDIasacauseofoccupationaldermatitis,skinsensitization,andasthma.Althoughlimitedinvariousways,acohortstudyandaretrospectivestudyshowednosignificantassociationwithcancermorbidity.Therearenodataavailablefororalexposure,butitisunlikelythathumansareexposedtoMDIbytheoralroute.

    MDIdidnotshowtoxicitiestofish,aquaticinvertebrates,algae,ormicroorganismsunderanyacuteorlongtermexposuretestingconditions.However,resultsofaquatictestsarenotmeaningfulbecauseofMDIsvirtualinsolubilityinwater.Similarly,afewtestsonterrestrialorganismsdidnotshowanyeffectsunderthetestingconditions.AvailabledatashowthatthereisnoneedforconcernregardingtheeffectsofMDIonorganismsintheenvironment,althoughmoredetailedinformationregardingtheformationofMDAintheenvironmentanditseffectsonorganismsisrequiredbeforeanyfirmconclusionscanbedrawn.

    2.IDENTITYANDPHYSICAL/

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 9/34

    CHEMICALPROPERTIES

    MDIisthegenericnameofaproductusedinindustrialsettings.PMDI,theprimarytechnical/commercialformofMDI,isactuallyamixturethatcontains2580%monomeric4,4MDIaswellasoligomerscontaining36ringsandotherminorisomers,suchasthe2,2isomer.Thiscompositionrendersthematerialsemisolidandsuitableforaerosolgeneration.ThecompositionofPMDIvarieswiththemanufactureranduse.Therangeofvariationreflectsvariationsfromvarioussourcesofinformation,i.e.,fromaGermanreview(DFG,1997),USToxicologicalReview(USEPA,1998),andtheEUdraftdocument(EU,1999).Figure1giveschemicalstructuresof4,4MDIandPMDI,andTable1providesChemicalAbstractsService(CAS)registrynumbersofseveralMDIisomersandPMDI.

    Table1:IsomersandpolymersofMDI.

    Name CASregistrynumber

    4,4MDI 101688

    2,4MDI 5873541

    2,2MDI 2536052

    nonisomerspecificMDI 26447405

    PMDI 9016879

    Monomeric4,4MDIisawhitetopaleyellowsolidatroomtemperature,withamolecularweightof250.26.Ithasaboilingpointof>300Cat101.3kPa,ameltingpointof3943C(capillarymethod)or40C(differentialscanningcalorimetryorDSCmethod)(Kellyetal.,1997),andavapourpressureof

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 10/34

    PMDIisadarkreddishbrownviscousliquidwithanindefinitemeltingpointaround0Candavapourpressureof

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 11/34

    ThecomplexnatureofMDIcompositionandreactionsintheenvironmentoftenmakesinterpretationdifficult.

    TheobservedorlikelyfatesofMDIinair,water,andsoilhavebeendescribedbyBrochhagen&Keller(1983)andGilbert(1988).Morerecently,comprehensivestudiesonthebehaviourofMDIintheaquaticenvironmenthavebeencarriedoutbyYakabeetal.(1994)andHeimbachetal.(1996).

    5.1Water

    WhenMDIisaddedtowater,itsNCOgroupsreactreadilywithOHgroupsofthewatertoformmixturesofdiisocyanatesandamines,whichthenreadilyreactwithmoreMDItoproduceinert,solid,insolublepolyurea(EU,1999).Thehydrolysisofisocyanatesinaqueoussolutionisrapidahalflifeof20shasbeenmeasuredforphenylisocyanate(Castroetal.,1985).However,thesubsequentreactionoftheformedaminewithfurtherisocyanate,toproduceaurea,isevenfaster(Hegartyetal.,1975).

    Yakabeetal.(1994)studiedthefateofPMDIinwaterundertwoconditionsnamely,vigorousstirringandstaticconditions,whichsimulatetwoscenariosofaccidentalspillsofPMDI.PMDIusedinexperimentsiscomplexandcomposedof56majorconstituentshaving24aromaticrings.WhenMDIcomesintocontactwithwater,itdoesnotdispersereadily,butformsglobulesorsolidmasses,whichreactattheirsurface.Undersuchheterogeneousconditions,thedisappearanceofPMDIshowszeroorderkinetics.ProductionofwatersolubleMDAincreasesgraduallywithtime,andtheMDAreachesanearlyconstantconcentrationafter16htheamountofMDAformedislessthan0.5%ofthenominalconcentrationofPMDIinitiallyadded,andthemajorproductsofPMDIbreakdownaresolid,insolublepolyureas.ThepolyureasformedfromMDIappeartobestabletochemicalattack,aswouldbeexpectedfromitsinsolubilityandthestabilityofureas.

    SupportforthechemicalstabilityofMDIisgiveninonestudyinwhichthepolyureaformedfromthereactionofPMDIwithwaterwasstirredat40Cinaqueousbuffersolutionsfor14days.Nosolubleproducts(dissolvedorganiccarbonorMDA)weredetected(Yakabeetal.,1994).

    AfurtherpotentialbreakdownproductofMDIinwaterisanoligourea.Anoligoureawassynthesizedfrom4,4MDIand4,4MDAandshowntobemainlydiurea.Itwasinsolubleinwaterandfoundtobenotinherentlybiodegradable(Yakabeetal.,1994).

    InthestudybyHeimbachetal.(1996),upto10gofPMDIwasaddedperlitreofwaterintoartificialoutdoorponds,simulatingaccidentalpollutionofapond.Threepondscontainedgroundwater,abovenaturallakesediment,towhichcagedrainbowtrout(Oncorhynchusmykiss)wereadded.Followingequilibration,PMDIwasaddedtopartofthesedimentoftwopondsatdosagesof1and10g/litre.Thethirdpondservedasanuntreatedcontrol.Waterchemistry,MDIandMDAconcentrations,andpopulationsanddiversityofdifferenttrophiclevelsweremonitoredover112days.TheconcentrationsofMDIandMDAweremonitoredinthethreecompartments(water,fish,andsediment)overthedurationofthestudy.NoMDIorMDAwasdetectedinthewater(detectionlimits4and10g/litre,respectively)orinthefish(detectionlimits0.5and1.4mg/kg,respectively).ThestudyprovidesevidencethatMDIaccumulationthroughtheaquaticfoodchainisextremelyunlikely,asmightbeexpectedconsideringtheverylowsolubilityandhighreactivityofMDIinaqueoussolution.

    5.2Soil

    MDImaycomeintocontactwithsoilafteraccidentalspillageduringtransportationorstorage.

    5.3Air

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 12/34

    TheatmosphericconcentrationofMDIarisingfromareleaseisnaturallylowonaccountofMDIsverylowvolatility.ItisexpectedthatairborneMDIwillhavearathershorthalflifeasaconsequenceofreadydegradationtoinorganiccompoundsbyhydroxylradicalspresentinthetroposphere.

    ThequestionofwhetherMDIvapouroraerosolcanhydrolyseinhumidairtoyieldMDAwasassessedinalongtermstudy(Appelmanetal.,1986)andastudyofchipboardproduction(Giersig,1989).Inthefirststudy,lowconcentrationsofMDA(notdetectedto90g/m3)wereobservedinairsamplesfromthesubchronicinhalationstudyinratsexposedtoPMDI(Appelmanetal.,1986).Detectedconcentrationswereindependentoftheconcentrationsofthetestatmosphere(0,0.2,1,and5mg/m3)thus,itwasconsideredthatthedetectionofMDAwascausedbyartefacts.Inthesecondstudy,noMDAwasdetected,althoughthePMDIconcentrationsrangedupto5mg/m3whenpolyurethaneparticleboardwasheatedupto80C(thedetectionlimitforMDAinairwas10g/m3)(Giersig,1989).Thisresulthasbeenaccountedforasfollows:MDAisformedonlyslowlyatneutralpHandreactsrapidlywithexcessMDItoyieldoligoureasandpolyureasMDIaerosolscanformashellofpolyureaonthesurfaceofthedroplets,andthisshellpreventsfurtherreactionoftheenclosedMDI(Mann,1987).

    6.ENVIRONMENTALLEVELSANDHUMANEXPOSURE

    6.1Environmentallevels

    CommercialsynthesisofMDItakesplaceinclosedsystemswherecontactofMDIwithwateriscarefullyavoidedthroughproductionandstoragestages,sincetheNCOgroupofMDIreactsreadilywiththeOHgroupofwater(EU,1999).ThereisnoinformationaboutlevelsofvariousformsofMDIintheambientair.Wherespillageistosoilorwater,MDIhasatransientexistenceduetoitsreactionwiththewatertoproducepredominantlyinsolublepolyureas.

    6.2Humanexposure

    Undernormalcircumstances,exposureofthegeneralpublicislikelyonlyfromreleasestotheatmosphere.

    Occupationalexposuredatafromawiderangeofapplicationsandprocessescollectedacrossindustry,measuredbyrecentstandardsandcapturingtotalinhalableMDI(i.e.,vapourandaerosol)overavarietyofexposuretimes(0.258h),areavailable(ISOPA,1998).Outof1238measurements,138(11%)wereabove0.0125mg/m3,and31(2.5%)wereabove0.05mg/m3these31measurementsweredetectedduringprocessesinrigidpolyurethanefoampreparationforroofpanelsforthermalinsulationorpreparationofcoatings,adhesives,sealants,andelastomersforsprayfloorcoating,bridgedeckingprimer,orparticleboard.SinceaccidentalexposuretoMDIinoccupationalsettingsmayresultfromincidentssuchasspillages,splithoses,andleakingdrums,theintroductionofEuropeanIsocyanateProductionAssociation(ISOPA)guidelinesfortransport,storage,handling,anduseofdiisocyanatehasreducedthepotentialofaccidentalexposuresoverthepast20years.

    AnalysisconductedrevealedthattheenvironmentalMDIconcentrationwas0.05mg/m3orlessin273outof319samples,andonly2samplesexceeded0.2mg/m3.Itisreported,however,thataventilationductwasinstalledabovethemouldingmachineseveralmonthsbeforetheanalysis,andthatbeforethensamplesexceeding0.2mg/m3hadoccurredfrequently(Diller&Herbert,1982).

    Sepaietal.(1995b)examinedbiologicalsamples(urineandblood)from20workers(aswellas2unexposedreferenceworkers)exposedtoMDIvapourduringthemanufactureofpolyurethane

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 13/34

    products,togetherwiththelevelsofMDIintheairoftheworkingenvironment.Inmostcases(17outof20),theairlevelswerebelowdetectionlimits.Thebloodandurinesampleswereanalysedforthepresenceofadductsandmetabolitesusinggaschromatographymassspectrometrymethods.TheamountofMDAreleasedafteracidhydrolysis(inhydrochloricacidat3mol/litre,at100C,for60min)wasonaverage6.5timeshigherthantheamountoffreeMDAandacetylatedMDApresentinurine.

    TheOntarioMinistryofLabour,Canada,assessedthecauseofmultiplerespiratorycomplaintsamongworkersataplantthatmanufacturesautomotiveinstrumentpanelsusingpolyurethane(Lissetal.,1996).Of137samplesanalysedforMDIbetween1986and1992,129(94%)werebelowthelimitofdetection(notgiven).Oftheothereight,allbutone(withaconcentrationof60g/m3)werebelow50g/m3.Tarloetal.(1997)reportedthat40%ofmeasuredMDIconcentrationsin19841988in20companieswithcompensatedisocyanateasthmaclaimsexceeded50g/m3,whilethefigurewas27%for203companieswithnocompensatedisocyanateasthmacases.

    7.COMPARATIVEKINETICSANDMETABOLISMINLABORATORY

    ANIMALSANDHUMANS

    AnimalinhalationstudieshaveshownthatPMDIexposure(seesection8.4.2fordetailsofparticlesizedistribution)resultsinsignificantdepositionbothinthenasalregionandinthealveolarregionofthelungs(Reuzeletal.,1994a,b).Onceabsorbed,PMDIappearstobepredominantlyconjugatedtoprotein,buttheroleofotherbiomolecules,suchasglutathione,hasnotbeeninvestigated(theroleofglutathionehasbeenshownforotherisocyanatesbyDayetal.,1997).

    Inanunpublishedpharmacokineticstudy(Istin,1977),noseonlyexposureofmaleSpragueDawleyratstoanaerosol(particlesizeslessthan5m)ofradiolabelled(inthemethylenegroup)monomericMDIfor15minresultedinthedistributionofradioactivity,predominantlytothelungsandavarietyofextrarespiratorysites(principallymuscle,liver,kidneys,andthedigestivetract),after96hwhentheanimalsweresacrificed.Labellingofthedigestivetractwasconsideredtobearesultoftransferenceoflabelledmaterialfromthelungs.After4days,70%oftheabsorbeddosewaseliminated(57%faecaleliminationand13%urinaryelimination).Therewasnoattempttoidentifythenatureoftheexcretedradioactivity.Twentythreepercentoftheradioactivityadministeredwasfoundinthecarcasshowever,lessthan1%oftheradioactivitywasrecoveredfromthemajororgans.Thefateoftheother22%isnotknown.

    HaemoglobinadductswerefoundafterrepeatedexposureofratstoMDIaerosolsfor17hperday,5daysperweek,over3or12monthsinaninhalationchamber(Sepaietal.,1995a).InlaboratoryanimalsexposedtoPMDI/MDI,MDAinurineandbloodformedbystrongacidhydrolysiswasusedasabiomarkerforexposure(Sepaietal.,1995a).

    WhenpregnantWistarratswereexposedfor6hongestationday19toanaerosolof20mgMDI/m3(particlesizedistributionnotknown),maternalblood,amnioticfluid,fetus,andplacentaweremeasuredforMDIanddegradationproducts(asMDAafteracidhydrolysisdetailsofhydrolysisconditionsnotknown)immediatelyafterexposure(Bartschetal.,1996).ThehighestlevelofMDAordegradationproductswasdetectedinthematernalblood,followedbytheplacenta,fetus,andamnioticfluid(at66.4%,42.4%,and13.6%ofthematernalbloodlevels,respectively).

    Inhumans,MDAlevelsinurineand(afterstrongacidhydrolysis)inbloodwerereportedtobecorrelatedwithexposuretoPMDI/MDI(Schuetzeetal.,1995Sepaietal.,1995bSkarping&Dalene,1995).ThehalflifeofMDAintheurineofaworkerexposedtoPMDIwas7080h,andinserum,21days(Skarpingetal.,1995).OtherreportsalsosuggestthatplasmaacidhydrolysableMDA

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 14/34

    maybeausefulbiomarkeroflongtermexposuretoMDI(Sepaietal.,1995bDaleneetal.,1996).InarecentstudyofworkersoccupationallyexposedtoeitherPMDI/MDIorMDA,freeMDAwasdetectedinurinepriortoacidhydrolysis(Schuetzeetal.,1995).

    Sepaietal.(1995b)reportedtheformationofadductsofMDAandacetylatedMDAwithhaemoglobinoralbumininthebloodofworkersexposedtoMDI,asdescribedinsection6.2.MDAwasdetectedasahaemoglobinadductinall20subjects,atlevelsrangingfrom70to710fmol/ghaemoglobinthisincludedonecaseofhaemoglobinadductofacetylatedMDA,whichwaspresumablyformedbytheinvivohydrolysisofMDI.PlasmaMDAlevelsrangedfrom3.9to70fmol/mgplasmaproteinin20workers,andupto120fmol/mgwerefoundtobecovalentlyboundtoalbumin.MDIintheairandMDAintheplasmawereobservedinastudyofpolyurethanepipewelders(Skarpingetal.,1995Daleneetal.,1996Tinnerbergetal.,1997).ThehaemoglobinadductofacetylatedMDIwasconsideredtobeformedbyinvivohydrolysis.

    8.EFFECTSONLABORATORYMAMMALSANDINVITROTESTSYSTEMS

    8.1Singleexposure

    OralLD50sforMDI(25%incornoil)andPMDI(undiluted)administeredtoratsinsinglegavagedoseswerereportedtobe31.6g/kgbodyweightandhigherthan10g/kgbodyweight,respectively(MobayChemical,1961Wazeter,1964a).

    PMDI(liquidform0,2.5,3.9,6.0,and9.4g/kgbodyweight)wasappliedtotheabradedskinofimmobilizedalbinorabbits(2persexpergroup)whosebackswerethencoveredinrubberizedclothfor24h(Wazeter,1964b).AfterthePMDIwaswashedoff,animalswerekeptfor14daysforobservation.Transientlyslightatoniawasobservedinafewanimalsatthethreehighestdoselevels.Animalswereessentiallynormal,exceptforslightoedemaobservedatthe9.4g/kgbodyweightdose.

    GuineapigsexposedtomonomericMDIaerosolatconcentrationsbetween0.6and350mg/m3(nootherdetailsavailable)for3hshowedadecreaseinrespirationrateandanincreaseintidalvolumeatlowerconcentrations,whereasaconcentrationdependentincreaseinrespirationratewasseenabove10.4mg/m3(Thorneetal.,1986).Incontrast,therespirationratewasdecreasedinadosedependentmannerinmiceexposedtoMDIaerosolconcentrationsbetween10.2and58.5mg/m3(Weyel&Schaffer,1985).

    WhenratswereexposedtoPMDIaerosol(inwhichmorethan99%ofparticlesweresmallerthan5m)for4hatconcentrationsof384,418,500,or523mg/m3,animalssatquietlywithclosedeyes

    duringexposure,andtheirbreathingbecamelabouredandnostrilsdilated,especiallyinthehighestconcentrationgroup(Appelman&deJong,1982).Autopsyoftheanimalsimmediatelyafterexposureshowedhaemorrageandoedemainthelungs.TheLC50inthisstudywasestimatedtobe490mg/m3.

    8.2Irritationandsensitization

    8.2.1Irritation

    WhenPMDI(liquidform0,2.5,3.9,6.0,or9.4g/kgbodyweight)wasappliedtotheabradedskinofalbinorabbits(2persexpergroup)for24h(Wazeter,1964b),oneanimalatthehighestdoseexhibitedslightoedemaduringthefirstandseconddays.Slighterythemaobservedinitiallyatalldoselevelsdidnotlastafter7days.Nodesquamationorfissuringwasnotedwiththecompound.

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 15/34

    8.2.2Sensitization

    ThereisclearevidenceofskinsensitizationduetoMDI.Humoralaswellascellularimmunitymaybeinvolvedinthepathogenesisofhypersensitivityduetoisocyanates.

    Inamouseearswellingtest,whichindicatestheextentofcontactsensitivity,MDIatconcentrationsrangingbetween0.6and187mg/kgbodyweightwasappliedtotheshavedanddepilatedabdomensof45malemice(Thorneetal.,1987).After4days,themicewerechallengedontherightearwithacetoneandontheleftearwithacetonecontainingadoseofMDIthatwasnonirritating.Thethicknessoftheearsat24hafterchallengewascomparedwiththatimmediatelybeforechallenge.AftercalibrationoftheearswellingresponsewithMDIsensitizationdoseinlogscales,anearthicknessincreaseofmorethan0.03mmwasjudgedtobesignificant.Thechallengewithacetonedidnotproduceanyearswelling.TheresponsetoMDIchallengeindicatedadoseresponseeffectat0.637mg/kgbodyweight.Crossreactivitytotoluenediisocyanate(TDI)andotherisocyanateswasdemonstrated.

    Usingearthickeningasthecriterion,transferofMDIinducedcontactsensitivitywithorwithoutTcelldeletionbymonoclonalantiThy1,2antibodywasstudied(Tanakaetal.,1987).A1%solutionofMDI(reagentgrade)inethylacetatewasappliedtoagroupof797weekoldmalemice.Thechallengesolutioninducedearswellingofdelayedonset,withitspeakat24h.PassivetransferoftheMDIinducedcontactsensitivitywasachievedbyinjectinglymphocytesfromthelymphnodesofMDIsensitizedmiceintothecaudalveinofsyngeneicmice,andtheeffectorcellswerefoundtobeTcells.

    8.3Shorttermexposure

    Fourgroupsof10maleand10femaleWistarratswereexposed,wholebody,toPMDIaerosolfor6hperday,5daysperweek,overaperiodof2weeks(Reuzeletal.,1994a).Theoverallmeanconcentrationswere2.2,4.9,and13.6mg/m3,respectively.Ninetyfivepercentoftheparticleshadamassmedianaerodynamicdiameter(MMAD)below5m.NoMDAandnophenylisocyanatecouldbedetectedinthetestatmospheres.Severerespiratorydistressandastatisticallysignificantdecrease(extentnotgiven)inbodyweightgainwereobservedinmaleandfemaleratsexposedto13.6mgPMDI/m37outof10malesand1outof10femalesdied.Maleratsexposedto4.9mg/m3showedmuchlessseveresignsofrespiratorydistressandonlyslightlyreducedbodyweightgaincomparedwithcontrols.Lungtobodyweightratiosweresignificantlyhigheronlyinthemidandhighconcentrationgroupsrelativetocontrols.Grosspathologicalexaminationremainedessentiallynegativenodataonhistologicalexaminationwerereported.Basedonthemarginalincreaseinlungtobodyweightratios,itwasconcludedthat2.2mgPMDI/m3,whichwasthelowestdoselevelexamined,wasaNOAEL.TheresultsshowthatthetoxicityofMDI(whichislowafteroralexposure)isclearlyhigherbytheinhalationroute,withlocaleffectstothelungafterrepeateddosing.

    NoshorttermstudyonmonomericMDIandnodatafromoralordermalrouteswereavailable.

    8.4Longtermexposure

    8.4.1Subchronicexposure

    InasubchronicstudybyReuzeletal.(1994a),SPFWistarrats(30persexperexposurelevel)wereexposed,wholebody,toPMDI(Desmodur44V20fromBayerAG,withmonomericMDI52%,isocyanatecontent30%)aerosolat0,4.1,8.4,or12.3mg/m3for6hperday,5daysperweek,for13weeks.Morethan95%oftheparticleshadanMMADoflessthan5m.Thehighestconcentrationresultedin25%mortality(15/60animals,onlyduringthefirst7weeks),growthretardation,severe

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 16/34

    respiratorydistress,degenerationofnasaltissues,andfocalinflammatorychangesinthelungs.Signsoflesssevererespiratorydistresswerealsoobservedinanimalsexposedto8.4mg/m3.Bodyweightsinmalesofthehighconcentrationgroupweresignificantlydepressedthroughweek13.Somebodyweightdepressionwasobservedinmalesofthemidconcentrationgroupthroughweek10.Bodyweightdepressionwasnotobservedinfemales.Therewasnotacleardoseresponsetrendinmacrophageaccumulation,althoughmacrophageswereincreasedinincidenceinalltestgroupsovercontrols.Tissuesexaminedbylightmicroscopyincludednose,larynx,trachea,lungs,liver,andkidney.Theincidenceofolfactoryatrophywasstatisticallysignificantinhighdosemales(5/10)andhighdosefemales(6/10).At4.1mg/m3,olfactoryepithelialatrophyoccurredinfrequentlyinexposedanimals.Therewasasignificantaccumulationofmacrophagesinthelungsandmediastinallymphnodesofallexposedanimalscomparedwithcontrols.Theincreaseinmacrophageaccumulationatthelevelofthealveolarseptawasrelatedtoexposure,andthedifferencebetweentreatmentgroupsandcontrolswasstatisticallysignificantinmalesexposedto4.1mg/m3andinfemalesat8.4mg/m3.

    Sincethefirststudyfoundhighmortality,probablyduetotheuseofveryyounganimals,another13weekstudywasconductedatactualmeanconcentrationsof0.35,1.4,and7.2mg/m3(Reuzeletal.,1994a).Unlikethefirststudy,transientgrowthretardationandanincreasednumberofpulmonarymacrophagesweretheonlyeffectsnotedatthehighestconcentration.

    Thus,thesestudiesdemonstratedclearadversepulmonaryandnasaleffectsat8.4mg/m3,andtheyarestatisticallysignificantat4.1mg/m3.

    8.4.2Chronicexposureandcarcinogenicity

    A2yearchronictoxicity/carcinogenicityinhalationstudywascarriedoutwithSPFWistarrats(60persexperexposurelevel)exposedwholebodytoPMDIaerosolat0,0.19,0.98,or6.03mg/m3for6hperday,5daysperweek(Reuzeletal.,1994b).Anadditionalsatellitegroupof10persexperexposurelevelwassimilarlyexposedandusedforhistopathologyat1year.NinetyfivepercentoftheparticleshadanMMADlessthan5mtheMMADandgeometricstandarddeviation(inparentheses)correspondingtotheexposurelevelswere0,0.68m(2.93),0.70m(2.46)and0.74m(2.31),respectively.

    Effectsat24monthswereconfinedtotherespiratorytract.Compoundrelatedchangeswerefoundinthenasalcavity(olfactorydegenerationandbasalcellhyperplasia),thelungs(fibrosisandinterstitialpneumonitis),andthemediastinallymphnodestosomedegree,theywerealreadypresentafter1yearofexposure,asindicatedinthesatellitegroup.Olfactoryepithelialdegenerationwaselevatedsignificantlyatthehighconcentrationinbothsexes.Basalcellhyperplasiaintheolfactoryepitheliumwaselevatedsignificantlyinmalesonlyatthemidandhighconcentrations.

    Noadverseeffectsonthedistributionandincidenceoftumourswerefoundwiththeexceptionoftumoursinthelungs.Solitarypulmonaryadenomas,describedasrareinthisstrain,wereobservedinmales(6/60)andfemales(2/59)exposedto6.03mg/m3comparedwithcontrols(0/120).Theadenomaswereonlyafewmillimetresinsizeandwerelocatedadjacenttoareasinwhichhaemorrhage,macrophageaccumulation,andfibroblasticreactionswereobserved.Onlyonepulmonaryadenocarcinoma(10mminsize)wasobservedinonemaleexposedtothisconcentration.

    ThenasalolfactoryandlunglesionsindicateaNOAELof0.19mg/m3andaLOAELof0.98mg/m3.Compoundassociatedyellowishparticulatematerialwasfoundinalveolarluminarmacrophagesinbothsexesat0.98and6.03mg/m3.Localizedfibrosiswassignificantinmalesexposedto6.03mg/m3

    andinfemalesat0.98and6.03mg/m3.Theamountofparticulatematerialaccumulatedatthelevelofthealveolarductincreasedwithtimeaswellaswithlevelofexposure.Macrophageswithyellowpigment(aformofMDIwithinthemacrophage)werealsofoundinthealveolarinterstitium,and

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 17/34

    accumulationofthesemacrophagesalsooccurredinthemediastinallymphnodes.Theaccumulationofmacrophagesandlocalizationoftissuedamageinthisareasuggestthatthethoraciceffectisdueprimarilytotoxicitytothemacrophage,withsecondarytissuedamage.

    Achronicinhalationstudy(Hoymannetal.,1995,1997)hasalsobeenconductedwith99.5%puremonomeric4,4MDI.FemaleWistarrats(80perexposuregroup)wereexposed(wholebody)toMDIinaerosolat0.23,0.70,or2.05mg/m3(MMADabout1m)for17hperday,5daysperweek,forupto24months.Aseparategroupof20perexposurelevelwasexaminedhistopathologicallyat12months.Smallernumbersofanimalswereassessedatvarioustimepointsforlungfunctionandforexaminationofbronchioalveolarlavage(BAL)fluidforcellcountsandproteinandenzymedeterminations.Statisticallysignificantconcentrationrelatedpulmonarylesionsincluded(1)anincreaseinfocal/multifocalalveolarandbronchioalveolarhyperplasia,(2)interstitialfibrosis,and(3)anaccumulationofparticleladenandpigmentedmacrophages.Alveolarcellhyperplasia,consideredpreneoplastic,exhibitedaconcentrationresponsetrend,withtheincidencereachingsignificanceinthehighexposuregroup.Theseeffectscorrelatedwithpulmonaryfunctiondeficits(FEF25[forcedexpiratoryflowfrom25%oftheforcedvitalcapacity,orFVC]andcarbonmonoxidediffusion),particularlyinthehighexposuregroup.Allgroupsexhibitedsignificantlyincreasedrelativelungweightsatalltimeperiods(morethan60%at20months),withsignificantincreasesinhydroxyprolineinBALfluid(morethan70%at12months).IncontrasttotheresultsreportedbyReuzeletal.(1994b)forPMDI,therewasnoapparenteffectofmonomericMDIonnasaltissuesatanyexposurelevel.Inonehighdoseanimal,abronchioloalveolaradenomawasobserved.Becauseoftheconcentrationrelatedlungeffects,0.23mg/m3isconsideredaLOAEL.ThereisnoNOAELinthisstudy.

    MDIreactswithwatertoproduceMDA.MDAhasalsobeenstudiedforcarcinogenicitybyoraladministration.Treatmentrelatedincreasesintheincidencesofthyroidfollicularcelladenomaandhepatocellularneoplasmswereobservedinbothmaleandfemalemicegiven150or300mgMDA/litreindrinkingwaterfor103weeks.InratsadministeredMDAinasimilarmanner,treatmentrelatedincreasesintheincidencesofthyroidfollicularcellcarcinomasandhepaticnoduleswereobservedinmales,andthyroidfollicularcelladenomasoccurredinfemales(Weisburgeretal.,1984NTP,1986).TheincidenceofthyroidtumourswasgreaterwhenMDA(1000mg/kgdietfor19weeks)wasadministeredorallyafterasingleintraperitonealinjectionof2800mgNbis(2hydroxypropyl)nitrosamine(DHPN)/kgbodyweightthanwhenDHPNwasgivenalone(Hiasaetal.,1984).TherelevanceoftheseresultstotheevaluationofthecarcinogenicresponsetoMDIanditspotentialmetaboliteisnotcertain.

    8.5Genotoxicityandrelatedendpoints

    WhenthemutagenicityofisomersandhomologuesofMDI(4,4MDI,2,4MDI,amixtureofmonomericMDIisomers,andPMDI)wasdeterminedintheSalmonella/microsometestusingDMSOandethyleneglycoldimethylether(EGDE)assolvents,positiveresultswereobtainedforDMSOsolutionsofallfourdiisocyanatesinthepresenceofS9mixcontaining30%S9fraction.UniformlynegativeresultswerefoundwhenthediisocyanatesweredissolvedinEGDE(Andersenetal.,1980Herbold,1980a,bWoolrich,1982Shimizuetal.,1985Zeiger,1987Herboldetal.,1998).MDIisnotstableinDMSO,therebeingmanyproductsgeneratedwithinminutes(Herbold,1990a,bGahlmann,1993).Thus,itseemsthatpositivetestresultsinanyinvitrotestsystemarecausedbythedegradationproductsofMDIinDMSO,ratherthanbyMDIitself.OneofthedegradationproductsofMDIisMDA,whichisknowntobegenotoxicandwhoseformationwasdetectedwhenMDIwasdissolvedinDMSO(Herboldetal.,1998).NoMDAcouldbedetectedinsolutionsofMDIinEGDE.ItisthereforeconcludedthatthepositiveresultsobtainedwithdiisocyanatesinDMSOsolutionsareduetotheformationofMDA.ThestabilityofMDIinamodelandarealtestenvironmentwasstudied(Seeletal.,1999).WhenMDIwasdissolvedinDMSO,morethan99%oftheMDIwasdegradedbeforethestartofincubationwithtestingredientsoftheSalmonellamutagenicityassay,and

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 18/34

    MDAwasdetectedat2.12.8%oftheMDIconcentrationwithin45sofincubation.TestsassessingthemutagenicpotentialofMDIinvitroandinvivoshownoconvincingevidenceofmutagenicactivity.

    FemaleWistarratsweretreatedtopically(ontheback)with14CMDI(labelledinthering)inacetonetoinvestigatethepossibilityofsystemiccirculationandDNAbindingpotencyofMDI(Vock&Lutz,1997).About10%oftheradioactivitywasretainedatthesiteofapplication.DNAradioactivityintheliverwasatthelimitofdetection.Inasecondexperimentusingtopicaladministration,32PpostlabellinganalysisdidnotrevealisocyanateDNAadductsintheskin(Vock&Lutz,1997).

    TissuesobtainedfromfemaleWistarratsexposedtoa0.9maerosolofMDIfor17hperday,5daysperweek,for1year,atlevelsof0,0.3,0.7,or2.0mg/m3,wereanalysedforDNAadductsusinga32Ppostlabellingmethod(Vocketal.,1996).Inthelung,neitherisocyanateadductsnorthearylamineadductwasdetectable.Thesamenegativeresultwasseenintheliver,bladder,kidney,respiratoryepithelium,andperipherallymphocytes.Intheolfactoryepithelium,ontheotherhand,thearylaminederivedDNAadductnucleotidesweredetectedatverylowlevels(510adductsper1010nucleotides).

    8.6Reproductiveanddevelopmentaltoxicity

    NospecificfertilitystudiesareavailableforMDI.

    Inawellconducteddevelopmentalrangefindingstudy,conductedaccordingtoOrganisationforEconomicCooperationandDevelopment(OECD)GuidelineNo.414,matedfemaleWistarrats(8pergroup)wereexposedtoPMDIbyinhalation(wholebody)atexposurelevelsof0,2,8,or12mg/m3for6hperdayfromday6uptoandincludingday15ofpregnancy(WaalkensBerendsen&Arts,1992).Onday21ofpregnancy,thefemaleratsweresacrificedandacaesareansectionwasperformed.Noclinicalsignsormortalityrelatedtotreatmentwasobservedduringthestudy.Themeannumberofcorporalutea,implantationsites,earlyandlateresorptions,and,consequently,preandpostimplantationlossshowednostatisticallysignificantdifferencesamongthecontrolandtreatedgroups.Fromday6today9ofpregnancy,maternalbodyweightgainofthe8and12mg/m3groupswasslightlydecreased(notstatisticallysignificant)whencomparedwiththecontrolgroup.Nootherdifferenceswereobservedinbodyweightandbodyweightgain,carcassweight,ornetweightgainwhencomparedwiththecontrolgroup.Fetalbodyweightswerecomparableinallgroups,andnoexternaltreatmentrelatedabnormalitieswereobservedinthefetuses.TheNOAELofPMDIaerosolbyinhalationformaternaltoxicityis8mg/m3,basedontheincreasedlungweights(relativeweightincreasedby14%)anddecreasedfoodintakeat12mg/m3.TheNOAELofPMDIaerosolbyinhalationfordevelopmentaltoxicityinthisstudyis12mg/m3.

    TheprenataltoxicityofPMDIinpregnantWistarratswasalsoinvestigatedbyaerosolinhalation(wholebody)accordingtoOECDGuidelineNo.414byBASF(1994).Twentyfivematedfemaleratspergroupwereexposedtoconcentrationsof1,4,or12mg/m3(MMAD

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 19/34

    relatedfindingsindamsandfetusesoccurredat1and4mg/m3.TheNOAELformaternalandfetaltoxicitywas4mg/m3,andtheNOAELfordevelopmentaleffectswas4mg/m3.

    GravidWistarratswereexposedbywholebodyinhalationtocleanair(control)andtomonomeric4,4MDIat1,3,or9mg/m3for6hperdayfromday6today15postconception(Buschmannetal.,1996).TheMMADoftheaerosolwas1.1m.Ratsweresacrificedonday20.Theabsoluteandrelativelungweightsinthehighdosegroupweresignificantlyincreased(23%)comparedwiththeshamtreatedcontrolanimalsthisendpointwasnotexaminedintheotherexposuregroups.Treatmentdidnotinfluenceanyothermaternalorfetalparametersinvestigated,althoughaslightbutsignificantincreaseinlitterswithfetusesdisplayingasymmetricsternebrawasobservedaftertreatmentwiththehighestdose.Sincethenumberoftheeffectsobservedinthe9mg/m3groupwaswithinthelimitsofbiologicalvariability,aNOAELfordevelopmentaleffectsof9mg/m3wasdeterminedinthisstudy.

    9.EFFECTSONHUMANS

    Itiswelldocumentedthatisocyanatesareacauseofoccupationalasthma(Vandenplasetal.,1993).Humoralaswellascellularmechanismsareinvolvedinthepathogenesis.Immediateorlateallergicreactionsorbothcanoccur.ThespecifichumoralimmuneresponsecanbeIgEaswellasIgGmediated,butmanypatientswithsensitizationtoisocyanateshavenodemonstrativeserumantibodiesagainsttheisocyanates.SeveralpublicationsindicatethatcompleximmunologicalreactionsareinvolvedintheprocessofsensitizationtoMDI(Pezzinietal.,1984Tseetal.,1985Lissetal.,1988Cartieretal.,1989).

    Toinvestigatetheimmunopathogenesisofdiisocyanatecausedasthma,diisocyanateexposedworkerswereevaluatedforinvitroproductionofantigenspecificmononuclearcellderivedhistaminereleasingfactor(HRF).ThemeanHRFresponsetodiisocyanatehumanserumalbumin(HSA)antigenswassignificantlygreater(p

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 20/34

    catalyst(componentB).Itwasmentionedthatthechemicalprotectivegloveswerenotroutinelyutilizedbyminerswhoweredescribedashavingskincontactleadingtochronicskinirritation.InanotherNIOSH(1994b)report,nasalandeyeirritationwerethetwomostfrequentlyreportedsymptomsafterMDIexposure.

    Ahypersensitivitypneumonitistypeofreactionhasalsobeenreported.Vandenplasetal.(1993)investigatedninesubjectswhocomplainedofrespiratoryandgeneralsymptomsrelatedtoworkplaceexposure.AllthesubjectshadworkedinaplantwherearesinbasedonMDIwasusedinthemanufactureofwoodchipboards.TheyunderwentinhalationchallengesusingtheMDIresinforprogressivelyincreasingperiodsoftimeonseparatedays.Ineightsubjects,exposuretosubirritantamountsofMDIinducedapatternofreactionconsistentwithhypersensitivitypneumonitisi.e.,significantdecreasesinbothforcedexpiratoryvolumein1s(FEV1:31%range2340%)andFVC(23%range1735%)associatedwithariseinbodytemperatureandanincreaseinbloodneutrophils.SpecificIgGandIgEantibodiestoMDIHSAconjugateswerepresentinallsubjects.TheauthorsconcludedthattheMDIresincausedahypersensitivitypneumonitistypeofreactioninatleast8(4.8%)ofthe167potentiallyexposedworkersemployedintheplant.

    Inacasewhohadexperiencedrepeatedattacksofaworkrelatedpulmonaryorsystemicdisease,associationwithexposuretoMDIwasexaminedbecauseofacuterespiratorydisorder,rhinoconjunctivitis,andalatesystemicreactionafterexposuretopolyurethanepyrolysisproducts,includingMDI(airlevel15g/m3)(Littorinetal.,1994).Spirometryshowedapartlyreversibleobstructivedysfunction,andaskinpricktestwaspositiveforMDIHSA.MDAwasdetectedinhydrolysedserumandurine.Inserum,specificIgG1,IgG4,andIgEantibodiesandaveryhightotalIgEweredetected.Thespecificantibodiesdeclinedduringthe5yearsafterexposure.Invitro,thecirculatingimmunecomplexesinserumincreasedaftertheadditionofMDIHSA.ThereactionsassociatedwithMDIexposure(incombinationwithexposuretopyrolysisproducts)hadfeaturescompatiblewithimmediatehypersensitivityandwithacomplementmediatedimmunecomplexrespiratoryreaction.

    EighteenemployeesofasinglewoodproductsplantusingheatedMDIinthemanufactureofasyntheticwoodproductwithlowerrespiratorytractsymptomswerelaterconfirmedtohaveoccupationalasthmaafterexaminationoftherelationshipbetweenonsetofsymptoms,smokingbehaviour,priorexperience,andfamilyhistoryofrespiratorydisorder(Woellneretal.,1997).Allcasesoccurredduringa2.5yearperiodafterexposuretoanewmanufacturingprocessusingsteamheatedMDIresininanewmanufacturingfacility.Initially,workersdevelopedsymptomsrelatedtotheprocesswithpossiblehigherMDIexposuresandprobablehigherresintemperatures.Later,mostworkerswhodevelopednewsymptomsweremostlyexposedtoheatedboards.ThissuggeststhatMDIsensitizationarisesatlowertemperaturesthanwaspreviouslyconsideredlikelyforthissubstance.ItispossiblethatthereactionproductsofsteamandpolymersofMDI,aloneorincombinationwithMDI,maybethecausativeagents.

    AfoundryworkerwhodiedatworkhadadiagnosisofoccupationalasthmainducedbyMDIassessed5yearsearlier,buthadhadapoorprognosisforoccupationalasthmaandhadcontinuedtobeexposedtoMDI(Carinoetal.,1997).Postmortemmicroscopicexaminationofthelungshowedepithelialdesquamation,eosinophilic/neutrophilicinfiltrationofthemucosa,dilatationofbronchialvessels,oedema,hypertrophy,anddisarrayofsmoothmuscle.

    Theneuropsychologicalfunctioningoffivemensufferingallegedphysical,cognitive,andbehaviouralchangesfollowingexposuretoMDIwasinvestigated(Reidy&Bolter,1994).Thesubjectshadbeenexposedtohydrocarbonsolventaswell,butnoneofthemwassymptomaticuntilMDIwasintroducedtotheworkplace.Althoughthedurationandseverityofexposurevariedamongpatients,formalanalysisofMDIlevelswasnotcompletedduringtheexposureperiod.Atthetimeofassessment,fourofthefivepatientsremainedsymptomaticdespitehavinghadnocontactwithMDIforperiodsrangingfrom5to9months.Allpatientsreportedexperiencingsubjectivesymptoms

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 21/34

    consistingofrespiratorydistress,headaches,depression,irritability,forgetfulness,decreasedcalculatingability,wordfindingproblems,reducedconcentration,andsignificantemotionaldistressonanobjectivepersonalitymeasure.Despitethesedata,thesmallsamplesize,possibleselectionbiasforworkersinvolvedinlitigation,possibleconfoundingfactors,lackofpertinentmatchedcontrol,lackofobjectiveexposuredata,andlackofknowledgeonmechanismprecludethecredibilityofthefindings.

    9.2Epidemiologicalstudies

    9.2.1Irritationandsensitization

    Bernsteinetal.(1993)reportedonlythreecasesofoccupationalasthmainacrosssectionalstudyof243workersexposedtoPMDIinaurethanemouldplantthathadbeendesignedtominimizeexposureonecasewasattributabletoaspill.Levelswerecontinuouslymonitoredandneverexceeded50g/m3.

    Inanepidemiologicalstudyofoccupationaldermatitisinfivedifferentshoefactories,246workerswereinterviewed,examined,andpatchtestedusingstandardandoccupationalpatchtestproceduresoftheInternationalContactDermatitisResearchGroup(Mancusoetal.,1996).Noinformationonoccupationalexposurewasreported.Intwoworkerswithallergiccontactdermatitis,sensitizationtoMDIwasdetected.OneoftwoworkersreactedsimultaneouslytobothMDIandMDA.TheotheronereactedonlytoMDI.

    Ahealthstudyofthe78workersinanironandsteelfoundryinVancouver,Canada,wascarriedout,andtheresultswerecomparedwiththosefoundin372railwayrepairyardworkers(Johnsonetal.,1985).MDIconcentrationsintheworkingenvironmentwereshowntosignificantlyinfluencelungfunction.ThefoundryworkerswereexposedtoPepSet,whichconsistsofMDIandphenolformaldehydeandtheirdecompositionproducts,aswellastosilicacontainingparticulate.Comparedwiththecontrols,thefoundryworkershadmorerespiratorysymptomsandasignificantlylowermeanFEV1andforcedexpiratoryflowfrom25%to75%oftheFVC(FEF2575,ormidexpiratoryflowrateoftheFVC).Threeworkershadradiographicevidenceofpneumoconiosis,and12hadasthma,definedasthepresenceofbronchialhyperreactivity,cough,andadditionalrespiratorysymptoms,suchaswheeze,chesttightness,orbreathlessness.SensitizationtoMDIisprobablythecauseofasthmaintheseworkers.

    AcrosssectionalevaluationofworkersinasteelfoundryinwhichPMDIwasusedasacomponentofabindersystemusedtomakecoresandmouldswasperformed26currentlyexposed(groupI),6formerlyexposed(groupII),and14nonexposedworkers(groupIII)wereinvolved(Lissetal.,1988).ThemeannumberofMDIexposureyearswas8.6,1.1,and0yearsforgroupI,groupII,andgroupIII,respectively.SymptomscompatiblewithoccupationalasthmawereelicitedfromsevenworkersofgroupI,whereasnonewasfoundingroupIII.ThisstudydemonstratedthatinductionofbothMDIspecificIgGresponsesandIgEmediatedrespiratorysensitizationoccurredinapopulationofworkersexposedtoMDIinasteelfoundry.OneworkerfromgroupIwithasthmaticsymptomsexhibitedcutaneousreactivityandRASTbindingtoMDIHSA(25.5%).

    Musketal.(1982)followed107polyurethanemanufacturingworkersexposedtoTDIalone(17),MDIalone(25),orboth(6)prospectivelyfor5years.MDIwasusedatthemanufacturingplantsduringonlythelast2yearsofthestudyperiod.Spirometricmeasurements(e.g.,FEV1)weremadeon94workersatthefifthyearovertheworkshift,onMondaymorningafteraweekendofnoexposure,andafter2weekvacations.Therewerenostatisticallysignificantdifferencesinthetotal5yeardecrementinFEV1amongexposedworkersversusFEV1valuesinunexposedworkers.Becauseoftherelativelylownumberofworkers(25)exposedtoMDI(lessthan0.04mg/m3),theshortstudy

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 22/34

    duration,confoundingfrompriorexposuretoTDI(0.05mg/m3)andpossiblytoaminecatalyst,andtheuncertaintyintheactualdurationofMDIexposure,thisstudyofferslimitedassurancethatMDIiswithouteffectonpulmonaryfunction.Theinvestigatorsdiscussedthepossibilitythattheremaybeselectionbias,becausethestudygroupdidnotincludeanysubjectwithsymptomssuggestinghypersensitivitytoisocyanatethosewhowereexperiencingadverseeffectsmayhavebeenincludedinthesmallnumbersofsubjectswhohadleftandbeenlosttofollowup.

    In1976and1981,Phametal.(1988)prospectivelystudiedagroupof318polyurethanefoamworkers(including104women)whoweregroupedaccordingtotheirjobcategoryasfollows:unexposed,indirectlyexposed,anddirectlyexposed.Atfollowupin1981,onlyhalfoftheinitialcohortremained(114males,45females),althoughnoreasonsweregivenastowhytheotherhalfleft.The5yearlongitudinalchangesinFEV1inexposedgroupswerestatednottobesignificantlydifferentfromthecontrolpopulation.Anincreasedprevalenceofasthmawasreportedhowever,thelimitationsofthestudyprecludeanymeaningfulassociations.Thebasisforthediagnosisofasthmawasnotstated.Whethertherewasexposuretoothersubstancesthatcouldcauseasthmaorwhethertherewaspreexistingasthmawasnotreported,andguidelinesfollowedforperformingFEV1measurementswerenotstated.Exposurewasnotwellcharacterized.

    EffectsonlungfunctionwereassessedbyDFG(1997)basedontheresultsofninestudiesnamely,Cavelieretal.(1977),Phametal.(1978,1986,1988),Martinetal.(1982),Diller&Herbert(1982),Musketal.(1982),Gee&Morgan(1985),andSulottoetal.(1990).Althoughthereweremanylimitations,suchasinvolvementofconfoundingfactorsinmixedexposuresandlackofknowledgeofactualexposureconcentrations,itwasconcludedthatsignificantimpairmentoflungspirometryvalueswasobservedinthecollectiveexposedtoPMDIconcentrationsupto0.87mg/m3.Inthecollectiveatconcentrationsbelow0.2mg/m3,nosignificantchangesinlungspirometrywerefound.However,significantlymorefrequentrespiratorysymptomsweresometimesobservedattheseconcentrations,althoughitisnotclearwhethertheywerecausedbysimultaneousexposuretoothercompounds.SuchsymptomswerenolongersignificantlymorefrequentatPMDIconcentrationsof0.1mg/m3.Withoneexceptioninwhichworkerswerepreviouslyexposedtoconcentrationsofupto0.9mg/m3,allthecollectiveexposedtoconcentrationsof0.05mg/m3orlesswaswithoutsymptoms.

    WorkrelatedrespiratorydiseaseswerereportedintheUnitedKingdombyalmost800chestandoccupationalphysicianswhoparticipatedvoluntarilyintheSWORDprojectfrom1989to1992(Meredith&McDonald,1994).Outof5541newcasesreportedbetween1989and1991,28%wereoccupationalasthma.Isocyanatesweresuspectedasacausalagentofasthmain336casesoutof1528reportedfor19891991.

    9.2.2Longtermexposureandcarcinogenicity

    Cancerincidenceandmortalitypatternswereinvestigatedinacohortof4154workersemployedinSwedishpolyurethanefoammanufacturingplantsforatleast1year(Hagmaretal.,1993a).TDIhadbeenusedinalltheplantsandMDIinallbutone,soitwasimpossibletoevaluatetheirindividualeffects.Airborneexposuretotheisocyanateshadbeenmeasuredon618occasionsateachplanton724days.ThetimeweightedaveragelevelsofTDIhadnormallybeenlessthan0.1g/m3andwerecurrently0.02g/m3.ThecorrespondingvaluesforMDIhadbeenlessthan0.01g/m3.However,muchhighervaluesupto3mg/m3forTDIandupto0.35mg/m3forMDIhadbeenrepeatedlymeasured.Therewasalsoilldefinedexposuretoblowingagents,mouldlubricants,amineaccelerators,andvariousorganicsolvents.Therewasnoincreasedriskofdeathcausedbybronchialobstructivedisease.Thereducedincidence,againstcontrol,ofallmalignantneoplasmwasalmoststatisticallysignificant.The"noexposure"grouphadfewerrectalcancersthanexpected,whereasthe"apparentexposure"grouphadmorethanexpected.Asimilar,smallerdifferencewasseenwithnonHodgkinslymphoma.Whenaminimumlatencyperiodof10yearswasapplied,theincreasesagainst

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 23/34

    controlwereevenhigher,buttherewereveryfewcases.Asthecohortwasyoungwithrelativelyshortexposuretotheisocyanates,futurestudieswouldallowamoreconclusiveevaluation.AcasereferencestudywithinthecohortwasmadetoassessmorethoroughlytheassociationbetweenexposuretoTDIandMDIandriskofcancer(Hagmaretal.,1993b).Itwasfoundthatthetentativeassociations,derivedfromthepreviouscohortstudy,betweenexposuretoisocyanatesandexcessriskfornonHodgkinslymphomasandrectalcancerwerenotsupported.Instead,nonsignificantassociationswithprostatecancerandpossiblycoloncancerwereseen.

    Aretrospectivemortalityandcancermorbiditystudywasconductedtoinvestigateassociationsbetweenhealthriskandexposuresfrompolyurethanefoamproduction,particularlyexposurestodiisocyanates(Sorahan&Pope,1993).Thestudypopulation(n=8288)wastakenfrom11factoriesinEnglandandWalesinwhichTDIwastheprincipalisocyanate(MDIrepresented5%oftheamountofTDIused).Thehighestexposurecategorycomprisedjobsinwhicheitherthe8htimeweightedaverageexposure(toisocyanates)during19781986wasgreaterthan0.04mg/m3orexcursionsabove0.1mg/m3occurredonmostdays.Theinvestigatorsdidnotfindanassociation(usingstandardizedmortalityratiosorSMRs)betweenexposuretodiisocyanatesandcancer.Thecohortwasyoung,andfollowupwasrelativelyshort.

    10.EFFECTSONOTHERORGANISMSINTHELABORATORYANDFIELD

    10.1Aquaticenvironment

    ResultsofmoststudiesavailableonthetoxiceffectsofMDIonaquaticorganismsarebasedonnominalconcentrationsoftestsubstance.Inalltestssummarizedinthissection,MDIwasaddedtothetestsolution,andnoconcentrationmeasurementswereperformedsubsequentlyduringexposure.Althoughdifferentmethodswereappliedtosolubilizethetestsubstanceinthetestmedia(e.g.,stirringforseveralhours),theresultspresentedinsection5.1indicatethatonlyminoramountsoftheappliedMDIcouldhavebeenpresentinthetestsolution,astheMDIwouldhaverapidlyundergonehydrolysis.Asaresult,duetothevirtualunavailabilityofMDIinwater,evenforthehighestconcentrationstested,noadverseeffectsontheexposedtestorganismswereobserved.

    Inshorttermtests,nominalconcentrationsintherangeof5003000mgMDI/litrecausednolethaleffectonfreshwaterfish(RhonePoulencChimie,1977Nakata,1983Caspersetal.,1986).Aquaticinvertebratesshowednoimmobilizationaftera24hexposuretonominalconcentrationsofupto1000mgMDI/litre(RhonePoulancChimie,1977Caspersetal.,1986).After21daysofexposuretothehighestnominalconcentrationtested(10mg/litre),PMDIhadnoeffectonthereproductionrateofDaphniamagna(Caspersetal.,1986).Blom&Oldersma(1994)observednoeffectsoncellmultiplicationofthefreshwateralgaScenedesmussubspicatusaftera3dayexposuretoanominalconcentrationof1640mgPMDI/litre.ConcerningtheimpactofPMDIonmicroorganisms,thehighestappliedconcentrationsofupto100mg/litrewerenotinhibitorytocellmultiplicationofEscherichiacoli(Fujiwara,1981)ortotherespirationrateofactivatedsludge(Caspersetal.,1986).

    Heimbachetal.(1996)addedPMDIatconcentrationsof0,1,and10g/litreontopofthesedimentofthreeartificialoutdoorponds,simulatingaccidentalspillageinsmallstandingfreshwaterecosystems(seesection5.1).Thepondscontainednaturallakesedimentandgroundwater,towhichcagedfishwereadded.ThefateofthePMDIandecotoxiceffectsontheaquaticpopulationweremonitoredfor112days.

    MDIpolymerizedtoinertpolyureaandstayedontopofthesediment,formingahardenedlayerattheinterfaceofthecompoundandwater.NoMDIwasfoundinthewaterorinthefishafterapplication.Neitherapplicationratecausedanydirecttoxiceffectontheaquaticcommunity,butsomesignificant

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 24/34

    indirecteffectsonpartsofthemacrobenthoswereobserved.Someofthemoreimmobilepopulations(Oligochaeta,Bivalvia,Diptera)werealmostcompletelywipedoutasaresultofphysicalobstructionbythepolyurealayer,lackofoxygen,andtoxiccarbondioxideconcentrations714daysafterapplication.

    Mostofthemacrobenthospopulationsregaineddensitiesequivalenttothecontrolpopulationsafter2monthsofexposure,withtheexceptionofBivalvia(becauseoftheirlonggenerationtimes).Mobilepartsofthemacrobenthos(e.g.,Gastropoda)remainedunaffected.Theabundanceofsomezooplanktonspecies(Cladocera)wasclearlyreducedinthehighdosedpond28weeksafterapplication.Asaconsequence,therainbowtroutinthispond,whichwerefeedingonCladoceraastheirmainnaturalfoodsource,lostweight,andthreeofsixfishinthisponddied1monthaftertheapplicationofMDI.

    10.2Terrestrialenvironment

    ResultsfromanearthwormtoxicitytestconductedaccordingtoOECDGuidelineNo.207andaterrestrialplantgrowthtestconductedaccordingtoOECDGuidelineNo.208arepresentedinTable2.Inthesestudies,thetestsubstancewasinitiallydissolvedinacetone,whichwasthenmixedwithsand.Thesolventwasevaporatedandthecoatedsandmixedwithsoil.Thetreatedsoilwasthenusedforthestudies.NotoxiceffectofMDIontheterrestrialorganismstestedwasobserved.

    Table2:ToxicityofMDItoterrestrialorganisms.a

    Organisms Endpointb Loading(mg/kg)

    Eiseniafetida(earthworm)

    14dayLC50 >1000

    14dayNOEL(weightincrease)

    >1000

    14dayNOEL(behaviour,appearance)

    >1000

    Avenasativa(oats) NOELemergence >1000

    NOELsurvival(14days) >1000

    NOELgrowth(14days) >1000

    Lactucasativa(lettuce)

    NOELemergence >1000

    NOELsurvival(14days) >1000

    NOELgrowth(14days) >1000

    aSource:vanderHoevenetal.(1992a,b).

    bLC50=medianlethalconcentrationNOEL=noobservedeffectlevel.

    11.EFFECTSEVALUATION

    11.1Evaluationofhealtheffects

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 25/34

    11.1.1Hazardidentificationanddoseresponseassessment

    Thehealthendpointofmostconcernisanassociationbetweenexposuretoairbornepolymericand/ormonomericMDIandoccupationallyinducedasthma.Thereisabundantevidencenotonlyfromepidemiologicalstudiesandcasestudies,butalsofromanimalstudies.However,thereisinsufficienthumanevidencetodescribe(1)thenatureoftheMDIcontainingmaterial,(2)theconcentrationresponserelationship,or(3)themechanismofisocyanateinducedasthmaandsensitization.Althoughtherearenohumanoranimalstudiesthathaveexaminedtheoralrouteofexposure,itisunlikelythathumanswouldbeexposedbytheoralroute.Therefore,itisdifficulttoquantitativelyestimateriskfromhumanexposure.

    TheavailablehumanevidencefromcancerincidenceandmortalitystudiesofworkersexposedtoisocyanatesisinadequatetodescribethecarcinogenicpotentialofpolymericormonomericMDI.Noassociationsbetweenisocyanatesandcancerincidenceweredemonstrated.TheincreaseintheincidenceofmostlybenignpulmonarytumoursinratsexposedtoMDIbyinhalationisnotconsideredtobeademonstrationofcarcinogenicity.Thepublishedstudieshaveanumberoflimitations(e.g.,shortdurationofexposure,concomitantexposuretoothersubstances),whichresultinlowpowertodetectcanceroccurrenceintargetorgansofinterest.ThefindingofplacentaltransferofMDIanditsdegradationproductfrompregnantratsexposedtoaerosoltofetusesdemandsfurtherstudyonitsrelevancetohumanriskassessment.

    11.1.2CriteriaforsettingtolerableintakesorguidancevaluesforMDI

    AnexampleofaguidancevaluecalculationisgivenintheUSEPAsIntegratedRiskInformationSystem(IRIS)(seewww.epa.gov/irisfordetails).TheBenchmarkConcentration(BMC)analysisdescribedthereinisbasedonthefindingofanincreaseinbasalcellhyperplasiaintheolfactoryepitheliuminthechronicinhalationstudywithmaleWistarrats(Reuzeletal.,1990,1994a).However,itshouldbenotedthatthisguidancevaluemaynotprotectagainstoccupationalsensitization.

    Thevalueconsideredmostappropriateasabasisfordevelopmentofatolerableconcentration(TC)inairisthelower95%confidencelimitontheBMCatthe10%risklevel(BMC10)usingtheReuzeletal.(1990,1994a)dataset.TheBMC10isfirstconvertedtoahumanequivalentconcentration(HEC)byapplicationoftheRegionalDoseDepositedRatio(RDDR)calculatedusingacomputerprogramprovidedinUSEPA(1994).TheRDDRadjustsfordosimetricdifferencesbetweenlaboratoryanimalsandhumansbyapplyingnormalizingfactorstovariousareasoftherespiratorytract.

    OncetheBMC10(0.14mg/m3)isderivedfromtheReuzeletal.(1990,1994a)datasetbyBMCanalysis,itismultipliedbytheRDDR(0.453).Theresultingvalue,0.06mg/m3,istheBMC10(HEC).ThreeuncertaintyfactorsareappliedtotheBMC10(HEC)10forintraindividualvariation(includingthepossibilityofgeneticpredisposition),101/2forthelackofreproductivedata,and101/2forinterspeciesvariationtoderiveahumanTCof6104mg/m3.

    11.1.3Sampleriskcharacterization

    Therearenoadequatedataavailabletoserveasabasisforestimatingriskofoccupationalasthma.Theexamplegivenhereisapragmaticapproachtoreduceoccupationalexposuretotheminimumpossible,becauseathresholdforthiseffectcannotbeestablished.

    IntheGermanstudyevaluatinglungdecrement,significantreversibleadverseeffectsonlungfunctionwereobservedinpersonsexposedtoMDIconcentrationsabove0.2mg/m3.WhenMDIconcentrationswerekeptlargelybelowthisconcentration,significantchangesinlungspirometrywerenolongerseen,althoughtheincidenceofrespiratorysymptomswasincreasedsignificantly.Suchdisorderswerestillobserved,butnomorefrequentlythaninthegroupatconcentrationsbelow0.05mg/m3.Becauseoftheseobservations,0.05mg/m3wasestablishedastheMAK(themaximumconcentrationintheGermanworkplace)valueforMDI,tobereasonablypracticableunderworkplaceconditions,andthereisacontinuingremittoreduceexposurelevelsasfarasreasonablypracticablewithtechnologythatiscurrentlyavailable.

    11.2Evaluationofenvironmentaleffects

    Undernormalcircumstances,exposureislikelyonlyfromreleasestotheatmosphere.HighexposuresinvolvingMDIinambientenvironmentsareexpectedtoberare.Wherespillageistosoilorwater,MDIhasatransientexistenceduetoitsreactionwiththewatertoproducepredominantlyinsolublepolyureas.MDAmaybeformedonlyasaminorreactionproductandwillthusbepresentatlowconcentrations.ThepondstudyprovidesevidencethatMDIaccumulationthroughtheaquaticfoodchainisextremelyunlikely,asmightbeexpectedconsideringtheverylowsolubilityandhighreactivityofMDIinaqueoussolution.

    AvailabledatashowthatthereisnoneedforconcernregardingtheeffectsofMDIonorganismsintheenvironment,althoughmoredetailedinformationregardingtheeffectsofminuteamountsofMDAformedintheenvironmentonorganismsisrequiredbeforeanyfirmconclusionscanbedrawn.

    12.PREVIOUSEVALUATIONSBYINTERNATIONALBODIES

    IARC(1999)concludedthatthereisinadequateevidenceforthecarcinogenicityofmonomericorpolymericMDIinhumansandlimitedevidenceforthecarcinogenicityofamixturecontainingmonomericandpolymericMDIinexperimentalanimals.ItsoverallevaluationwasthatMDI(industrialpreparation)isnotclassifiableastoitscarcinogenicitytohumans(Group3).

    ForMDA,IARC(1986)concludedthattherewerenodatainhumansandsufficientevidenceforcarcinogenicityinanimals.ItsoverallevaluationwasthatMDAwaspossiblycarcinogenictohumans(Group2B).

    REFERENCES

    AndersenM,BineruML,KielP,LarsenH,MaxildJ(1980)Mutagenicactionofisocyanatesusedintheproductionofpolyurethanes.Scandinavianjournalofwork,environment&health,6:221226.

    AppelmanLM,deJongAWJ(1982)AcuteinhalationtoxicitystudyofpolymericMDIinrats.Zeist,CIVOInstituteTNOToxicologyandNutrition(ReportNo.82).

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 26/34

    AppelmanLM,deJongAWJ,KellerJ(1986)AdditionalstudiesintothepresenceofMDAinsamplesoftestatmospherescontainingpolymericMDIaerosol.Zeist,CIVOInstituteTNOToxicologyandNutrition(unpublishedReportNo.V84.313/220758).

    BartschW,BuschmannJ,HoymannHG,HeinrichU(1996)[ChronictoxicityandcarcinogenicitystudyonMDI.]Hannover,FraunhoferInstituteforToxicologyandAerosolResearch(unpublished)(inGerman).

    BASF(1994)PrenataltoxicityofpolymericMDIinrats.Aerosolinhalation.PreparedbyBASF,Ludwigshafen,forUSEnvironmentalProtectionAgency(unpublishedProjectNo.31R0354/93046,39.09.1994).

    BernsteinDI,KorbeeL,StauderT,BernsteinJA,ScintoJ,HerdZL,BernsteinIL(1993)Clinicalaspectsofallergicdisease.Thelowprevalenceofoccupationalasthmaandantibodydependentsensitizationtodiphenylmethanediisocyanateinaplantengineeredforminimalexposuretodiisocyanates.Journalofallergyandclinicalimmunology,92(3):387396.

    BlomAJM,OldersmaH(1994)EffectofDesmodur44V20PMDIonthegrowthofthegreenalgaScenedesmussubspicatus.TNOInternationalIsocyanateInstitute(ReportNo.11156).

    BrochhagenFK,KellerJ(1983)Accidentinvolvingaroadtankercarryingtolulenediisocyanate(TDI)countermeasuresandexperience.Leverkusen,BayerAG.

    BuschmannJ,KochW,FuhstR,HeinfichU(1996)Embryotoxicitystudyofmonomeric4,4methylenediphenyldiisocyanate(MDI)aerosolafterinhalationexposureinWistarrats.Fundamentalandappliedtoxicology,32:96101.

    CarinoM,AlianiM,LicitraC,SarnoN,IoliF(1997)Deathduetoasthmaatworkplaceinadiphenylmethanediisocyanatesensitizedsubject.Respiration,64:111113.

    CartierA,GrammerL,MaloJL,LagierF,GhezzoH,HarrisK,PattersonR(1989)Specificserumantibodiesagainstisocyanates:associationwithoccupationalasthma.Journalofallergyandclinicalimmunology,84(4Pt1):507514.

    CaspersN,HamburgerB,KanneR,KlebertW(1986)Ecotoxicityoftoluenediisocyanate(TDI),diphenylmethanediisocyanate(MDI),toluenediamine(TDA),diphenylmethanediamine(MDA).PreparedbyInternationalIsocyanateInstituteforBayerAG,Leverkusen(ReportNo.10417).

    CastroEA,MoodieRB,SansomPJ(1985)Ecotoxicityofdiisocyanateswithspecialreferencetocontrolledexposureofhumans.Internationalarchivesofoccupationalandenvironmentalhealth,61(8):495501.

    CavelierC,PhamQT,MereauP,MurJM,RombachF,CicolellaA,BuiDinhLongL,ToamainJP,BaudinV,HenquelJC,PoincelotF,MaloJP,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)MDAinplasmaasabiomarkerofexposuretopyrolysedMDIbasedpolyurethane:correlationswithestimatedcumulativedoseandgenotypeforNacetylation.Internationalarchivesofoccupationalandenvironmentalhealth,68:165169.

    DayBW,BasalygaDM,KramarikJA,KarolMH(1997)Formation,solvolysisandtranscarbamoylationreactionsofbis(Sglutathionyl)adductsof2,4and2,6diisocyanatotoluene.Chemicalresearchintoxicology,10:424431.

    DFG(1997)Occupationaltoxicants.CriticaldataevaluationforMAKvaluesandclassificationofcarcinogens.DeutscheForschungsgemeinschaft,VCH,8:6595.

    DharmarajanV(1979)Occupationalexposurestomethylenebisphenylisocyanate(MDI):gaseousoraerosol?Journalofenvironmentalpathology,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,InternationalIsocyanateInstitute(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)Incidenceofcancerandexposuretotoluenediisocyanateandmethylenediphenyldiisocyanate:acohortbasedcasereferentstudyinthepolyurethanefoammanufacturingindustry.Britishjournalofindustrialmedicine,50:10031007.

    HegartyAF,HegartyCN,ScottFL(1975)Thereactivityofphenylisocyanateinaqueoussolution.JournaloftheChemicalSociety,Perkin

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 27/34

    Transactions,11:11661171.

    HeimbachF,JaegerK,SporenbergW(1996)FateandbiologicaleffectsofpolymericMDIinsmallartificialponds.Ecotoxicologyandenvironmentalsafety,33:143153.

    HerboldB(1980a)[MDISalmonella/microsometestforinvestigationofpointmutationactivity.]Wuppeltal,BayerAG(unpublishedBayerReportNo.9130,9.5.1980)(inGerman).

    HerboldB(1980b)[MDISalmonella/microsometestforinvestigationofpointmutationactivity.]Wuppeltal,BayerAG(unpublishedBayerReportNo.9341,1.8.1980)(inGerman).

    HerboldB(1990a)Specialstudy,Salmonella/microsometestwithDesmodur44v20usingTA100.Wuppeltal,BayerAG(unpublishedBayerReportNo.19561,27.9.1990).

    HerboldB(1990b)Specialstudy,Salmonella/microsometestwithDesmodur44M(4,4MDI)usingTA100.Wuppeltal,BayerAG(unpublishedBayerReportNo.19570,27.9.1990).

    HerboldB,HaasP,SeelK,WalberU(1998)StudiesontheeffectofthesolventsdimethylsulfoxideandethyleneglycoldimethyletheronthemutagenicityoffourtypesofdiisocyanatesintheSalmonella/microsometest.Mutationresearch,412:167175.

    HerdZL,BernsteinDI(1994)Antigenspecificstimulationofhistaminereleasingfactorsindiisocyanateinducedoccupationalasthma.Americanjournalofrespiratoryandcriticalcaremedicine,150:988994.

    HiasaY,KitahoriY,EnokiN,KonishiN,ShimoyamaT(1984)4,4diaminodiphenylmethane:promotingeffectonthedevelopmentofthyroidtumorsinratstreatedwithNbis(2hydroxypropyl)nitrosamine.JournaloftheNationalCancerInstitute,72:471476.

    HoymannHG,BuschmannJ,HeinrichU(1995)Examinationsaboutthechronictoxicity/carcinogenicityof4,4methylenediphenyldiisocyanate(MDI).Hannover,FraunhoferInstituteforToxicologyandAerosolResearch(ReportNo.11606084).

    HoymannHG,CreutzenbergO,ErnstH,HohlfeldJ,HeinrichU(1997)Lungfunctionchangesinratsafterchronicinhalationexposureto4,4methylenediphenyldiisocyanate(MDI).In:MohrU,ed.Relationshipsbetweenrespiratorydiseaseandexposuretoairpollution.Washington,DC,InternationalLifeSciencesInstitutePress,pp.353356.

    IARC(1986)4,4Methylenedianilineanditsdihydrochloride.Lyon,InternationalAgencyforResearchonCancer,pp.347365(IARCMonographsontheEvaluationoftheCarcinogenicRiskofChemicalstoHumans,Vol.39).

    IARC(1999)4,4Methylenediphenyldiisocyanateandpolymeric4,4methylenediphenyldiisocyanate.Lyon,InternationalAgencyforResearchonCancer,pp.10491058(IARCMonographsontheEvaluationoftheCarcinogenicRiskofChemicalstoHumans,Vol.71).

    IPCS(1993)InternationalChemicalSafetyCardMethylenebisphenylisocyanate(MDI).Geneva,WorldHealthOrganization,InternationalProgrammeonChemicalSafety(ICSC0298).

    ISOPA(1998)SubmissionforthereviewoftheacuteinhalationtoxicityofMDI.Brussels,EuropeanIsocyanateProductionAssociation(unpublishedreport).

    IstinM(1977)PharmacokineticsofMDIafterinhalationexposureofratstolabeledMDI.UnpublishedreportbyLaboratoiredtudesduMtabolismedesMdicaments,DpartementdeBiologie,totheInternationalIsocyanateInstitute[citedinDFG,1997].

    JohnsonA,ChanYeungM,MacLeanM,AtkinsE,DybunchioA,ChengF,EnarsonD(1985)Respiratoryabnormalitiesamongworkersinanironandsteelfoundry.Britishjournalofindustrialmedicine,42:94100.

    JSOH(1994)[RecommendationandthereasoningfortheoccupationalexposurelimitsonMDI.]SangyoIgaku(Japanesejournalofindustrialhealth),35:360363(inJapanese).

    KellyM,OuttersideS,PembertonD(1997)PhysicalpropertiesofMDIandTDI:areview.Manchester,InternationalIsocyanateInstitute(unpublishedIIIReportNo.11272).

    LissGM,BernsteinDI,MollerDR,GallagherJS,StephensonRL,BernsteinIL(1988)Pulmonaryandimmunologocalevaluationoffoundryworkersexposedtomethylenediisocyanate(MDI).Journalofallergyandclinicalimmunology,82(1):5561.

    LissGM,TarloSM,BanksDE(1996)Evidenceforoccupationalasthmaamongcompensationclaimantsatapolyurethaneutilizingfacility.Canadianjournalofpublichealth,87(6):401403.

    LittorinM,TruedssonL,WelinderH,SkarpingG,MartenssonU,SjoeholmAG(1994)Acuterespiratorydisorder,rhinoconjunctivitisandfeverassociatedwiththepyrolysisofpolyurethanederivedfromdiphenylmethanediisocyanate.Scandinavianjournalofwork,environment&health,20:216222.

    LushniakBD,RehCM,BernsteinDI,GallagherJS(1998)Indirectassessmentof4,4diphenylmethanediisocyanate(MDI)exposurebyevaluationofspecifichumoralimmuneresponsestoMDIconjugatedtohumanserumalbumin.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].

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 28/34

    MuskAW,PetersJM,DiBerardinisL,MurphyRLH(1982)AbsenceofrespiratoryeffectsinsubjectsexposedtolowconcentrationsofTDIandMDI.Journalofoccupationalmedicine,24(10):746750.

    NakataM(1983)Testreportonfishtoxicityofpolymethylenepolyphenylpolyisocyanate:internalcommunication.Amagasaki,SumitomoBayerUrethaneCo.(unpublishedreport).

    NIOSH(1985)NIOSHmanualofanalyticalmethods,3rded.Vols.1and2with1985supplementandrevisions.Cincinnati,OH,USDepartmentofHealthandHumanServices,PublicHealthService,CentersforDiseaseControl,NationalInstituteforOccupationalSafetyandHealth.Washington,DC,USGovernmentPrintingOffice,February1984,p.55211.

    NIOSH(1994a)LetterfromNIOSHtoJimWalterResources,Inc.withastudyreport.Cincinnati,OH,USDepartmentofHealthandHumanServices,PublicHealthService,CentersforDiseaseControl,NationalInstituteforOccupationalSafetyandHealth(ReportNo.HETA940027,May24).

    NIOSH(1994b)LetterfromNIOSHtoDistinctiveDesignsInternationalInc.withastudyreport.Cincinnati,OH,USDepartmentofHealthandHumanServices,PublicHealthService,CentersforDiseaseControl,NationalInstituteforOccupationalSafetyandHealth(ReportNo.HETA9103862427,May).

    NTP(1986)Toxicologyandcarcinogenesisstudiesofcommercialgrade2,4(80%)and2,6(20%)toluenediisocyanateinF344/NratsandB6C3F1mice(gavagestudies).ResearchTrianglePark,NC,USDepartmentofHealthandHumanServices,PublicHealthService,NationalInstitutesofHealth,NationalToxicologyProgram(TechnicalReportNo.251NIHPublicationNo.862507).

    PezziniA,RivieraA,PaggiaroP,SpiazziA,GerosaF,FilieriM,TomaG,TridenteG(1984)SpecificIgEantibodiesintwentyeightworkerswithdiisocyanateinducedbronchialasthma.Clinicalallergy,14:453461.

    PhamQT,CavelierC,MereauP,CicolellaA(1978)Isocyanatesandrespiratoryfunction:astudyofworkersproducingpolyurethanefoammoulding.Annalsofoccupationalhygiene,21:121.

    PhamQT,MeyerBischC,MurJM(1986)[StudyonclinicalandrespiratoryfunctionchangeofworkersexposedtolittleamountofMDIin5years.]Archivesdesmaladiesprofessionellesdemdecinedutravailetdescuritsociale(Paris),47:311(inFrench).

    PhamQT,TeculescuD,MeyerBischC,MurJM(1988)Effectsofchronicexposuretodiisocyanates.Bulletineuropendephysiopathologierespiratoire,23:561564.

    ReidyTJ,BolterJF(1994)Neuropsychologicaltoxicologyofmethylenediphenyldiisocyanate:areportoffivecases.Braininjury,8(3):285294.

    ReuzelPGJ,ArtsJHE,KuypersMHM,KuperCF(1990)Chronictoxicity/carcinogenicityinhalationstudyofpolymericmethylenediphenyldiisocyanateaerosolinrats.PreparedbytheCIVOInstitute,Zeist,fortheInternationalIsocyanateInstitute(ReportNo.V88.122).

    Reuzel,PGJ,KuperCF,FeronVJ,AppelmanL,LoserE(1994a)Acute,subacute,andsubchronicinhalationtoxicitystudiesofrespirablepolymericmethylenediphenyldiisocyanate(polymericMDI)aerosolinrats.Fundamentalandappliedtoxicology,22:186194.

    ReuzelPGJ,ArtsJHE,LomaxLG,KuijpersMHM,KuperCF,GembardtC,FeronVJ,LoserE(1994b)Chronicinhalationtoxicityandcarcinogenicitystudiesofrespirablepolymericmethylenediphenyldiisocyanate(polymericMDI)aerosolinrats.Fundamentalandappliedtoxicology,22:195210.

    RhonePoulencChimie(1977)BiologicalactionofTDIandMDIinwater.Paris(unpublishedreportReportNo.770906).

    SakuraiH(1997)BriefintroductiontooccupationalexposurelimitsinJapan.Journalofoccupationalhealth,39:246.

    SchuetzeD,SepaiO,LewalterJ,MikscheL,HenschlerD,SabbioniG(1995)Biomonitoringofworkersexposedto4,4methylenediamineand4,4methylenediphenyldiisocyanate.Carcinogenesis,16(3):573582.

    SeelK,WalberU,HerboldB,KoppR(1999)Chemicalbehaviourofsevenaromaticdiisocyanates(toluenediisocyanatesanddiphenylmethanediisocyanates)underinvitroconditionsinrelationshiptotheirresultsintheSalmonella/microsometest.Mutationresearch,438:109123.

    SepaiO,SchuetzeD,HeinrichU,HoymannHG,HenschlerD,SabbioniG(1995a)Hemoglobinadductsandurinemetabolitesof4,4methylenediamineafter4,4methylenediphenyldiisocyanateexposureofrats.Chemicobiologicalinteractions,97:185198.

    SepaiO,HenschlerD,SabbioniG(1995b)Albuminadducts,hemoglobinadductsandurinarymetabolitesinworkersexposedto4,4methylenediphenyldiisocyanate.Carcinogenesis,16(10):25832587.

    ShimizuH,SuzukiY,TakemuraN,GotoS,MatsushitaH(1985)Theresultsofmicrobialmutationtestforfortythreeindustrialchemicals.SangyoIgaku(Japanesejournalofindustrialhealth),27:400417.

    SkarpingG,DaleneM(1995)Determinationof4,4methylenediphenyldianiline(MDA)andidentificationofisomersintechnicalgradeMDAinhydrolysedplasmaandurinefromworkersexposedtomethylenediphenyldiisocyanatebygaschromatographymassspectrometry.JournalofchromatographyB,Biomedicalsciencesandapplications,663:209216.

    SkarpingG,DaleneM,LottorinM(1995)4,4methylenedianilineinhydrolysedserumandurinefromaworkerexposedtothermaldegradationproductsofmethylenediphenyldiisocyanateelastomers.Internationalarchivesofoccupationalandenvironmentalhealth,67:7377.

    SorahanT,PopeD(1993)MortalityandcancermorbidityofproductionworkersintheUnitedKingdomflexiblepolyurethanefoamindustry.Britishjournalofindustrialmedicine,50:528536.

    SpanneM,TinnerbergH,DaleneM,SkarpingG(1996)Determinationofcomplexmixturesofairborneisocyanatesandamines,Part1.Liquidchromatographywithultravioletdetectionofmonomericandpolymericisocyanatesastheirdibutylaminederivatives.Analyst,121:10951099.

    StreicherRP,KennedyER,LorberauCD(1994)Strategiesforthesimultaneouscollectionofvaporsandaerosolswithemphasisonisocyanate

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 29/34

    sampling.Analyst,119:8997.

    SulottoF,RomanoC,PiolattoG,CoggiolaM,PolizziS,CiaccoC,BerraA(1990)ShorttermrespiratorychangesinpolyurethanefoamworkersexposedtolowMDIconcentrations.Internationalarchivesofoccupationalandenvironmentalhealth,62:521.

    TanakaK,TakeokaA,NishimuraF,HanadaS(1987)Contactsensitivityinducedinmicebymethylenebisphenyldiisocyanate.Contactdermatitis,17:199204.

    TarloSM,LissGM,DiasC,BanksDE(1997)Assessmentoftherelationshipbetweenisocyanateexposurelevelsandoccupationalasthma.Americanjournalofindustrialmedicine,32:517521.

    ThornePS,HillebrandJA,KarolMH(1986)Pulmonaryirritationandhypersensitivityinguineapigsexposedto4,4diphenylmethanediisocyanate(MDI)aerosol.Toxicologist,6:15.

    ThornePS,HillebrandJA,LewisDR,KarolMH(1987)Contactsensitivitybydiisocyanatespotenciesandcrossreactivities.Toxicologyandappliedpharmacology,87:155165.

    TinnerbergH,SpanneM,DaleneM,SkarpingG(1997)Determinationofcomplexmixturesofairborneisocyanatesandamines,Part3.Methylenediphenyldiisocyanate,methylenediphenylaminoisocyanateandmethylenediphenylamineandstructuralanaloguesafterthermaldegradationofpolyurethane.Analyst,122:275278.

    TseKS,JohnsonA,ChanH,ChanYeungC(1985)Astudyofserumantibodyactivityinworkerswithoccupationalexposuretodiphenylmethanediisocyanate.Allergy,40:314320.

    USEPA(1994)Methodsforderivationofinhalationreferenceconcentrationsandapplicationsofinhalationdosimetry.Washington,DC,USEnvironmentalProtectionAgency(EPA/600/890/066f).

    USEPA(1998)Toxicologicalreviewofmethylenediphenyldiisocyanate(MDI).Washington,DC,USEnvironmentalProtectionAgency.

    VandenplasO,MaloJL,DugasM,CartierA,DesjardinsA,LevesqueJ,ShaughnessyMA,GrammerLC(1993)Hypersensitivitypneumonitislikereactionamongworkersexposedtodiphenylmethanediisocyanate(MDI).Americanreviewofrespiratorydisease,147:338346.

    vanderHoevenN,RozaP,HenzenL(1992a)DeterminationoftheeffectofTDI,TDA,MDI,andMDAontheemergenceandgrowthoftheplantspeciesAvenasativaandLactucasativaaccordingtoOECDGuidelineNo.208.Zeist,InternationalIsocyanateInstitute(unpublishedIIIReportNo.11024).

    vanderHoevenN,RozaP,HenzenL(1992b)DeterminationoftheLC50(14days)ofTDI,TDA,MDI,andMDAtotheearthwormEiseniafetidaaccordingtoOECDGuidelineNo.207.PreparedbyTNO,Zeist,forInternationalIsocyanateInstitute(unpublishedIIIReportNo.11025).

    VockEH,LutzWK(1997)DistributionandDNAadductformationofradiolabeledmethylenediphenyl4,4diisocyanate(MDI)intherataftertopicaltreatment.Toxicologyletters,92:93100.

    VockEH,HoymannHG,HeinrichU,LutzWK(1996)32PpostlabelingofaDNAadductderivedfrom4,4methylenedianilineintheolfactoryepitheliumofratsexposedbyinhalationto4,4methylenediphenyldiisocyanate.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)NeoplasticresponseofF344ratsandB6C3F1micetothepolymeranddyestuffintermediates,4,4methylenebis(N,Ndimethyl)benzenamine,4,4oxydianiline,and4,4methylenedianiline.JournaloftheNationalCancerInstitute,72:14571463.

    WeyelDA,SchafferRB(1985)Pulmonaryandsensoryirritationofdiphenylmethane4,4diisocyanateanddicyclohexylmethane4,4diisocyanate.Toxicologyandappliedpharmacology,77:427433.

    WoellnerRC,HallS,GreavesI,SchoenwetterWF(1997)Epidemicofasthmainawoodproductsplantusingmethylenediphenyldiisocyanate.Americanjournalofindustrialmedicine,31:5663.

    WoolrichPF(1982)Toxicology,industrialhygieneandmedicalcontrolofTDI,MDIandPMPPI.AmericanIndustrialHygieneAssociationjournal,43:8997.

    YakabeY,MoriE,TadokoroH(1994)StudyonthefateofpolymericMDIinwater.Kurume,InternationalIsocyanateInstitute(unpublishedIIIReportNo.11122).

    ZeigerE(1987)Salmonellamutagenicitytest:III.Resultfromtestingof225chemicals.Environmentalmutagenesis,9(9):1110.

    APPENDIX1SOURCEDOCUMENTS

    JSOH(1994)

    TheoriginalreviewinJapanesewastranslatedintoEnglishbytheNationalInstituteofHealthSciences(NIHS)andisavailablefromtheDivisionofChemBioInformaticsofNIHSatthefollowingaddress:

  • 10/03/2015 DIPHENYLMETHANEDIISOCYANATE(MDI)

    http://www.inchem.org/documents/cicads/cicads/cicad27.htm 30/34

    NationalInstituteofHealthSciences1181Kamiyoga,SetagayakuTokyo,Japan

    TheJapanSocietyforOccupationalHealth(JSOH,formerlytheJapanAssociationofIndustrialHealth)isanacademicorganizationconsistingofexpertsinoccupationalhealth,includingscientistsinuniversitiesandinstitutions,industrialphysicians,occupationalhealthnurses,industrialhygienists,managementstafffromhealthandsafetydepartments,andgovernmentofficialsinoccupationalhealthsectors.

    TheCommitteefortheRecommendationofOccupationalExposureLimitsofJSOHreviewsscientificinformationonthehealtheffectsofchemicalsubstancesandphysicalagentswithspecialreferencetoexposureeffectandexposureresponserelationshipsandappliesitsresearchtothecreationofanOccupationalExposureLimit(OEL)andtothedocumentationofthereasoningbehindtheOEL.TheCommitteesubmitstheOELasaprovisionalOELtoameetingofJSOHcouncillorsandtoanannualgeneralmeetingofJSOHfortemporaryapproval,afterwhichtheprovisionalOELanddocumentationarepublishedinJSOHsofficialjournal,SangyoEiseigakuZasshi(formerlySangyoIgaku[JapaneseJournalofIndustrialHealth].TheCommitteeacceptsopinionsbasedonscientificaspectsoftheprovisionalOELuntilthenextannualgeneralmeeting.IfnoopinionscontrarytotheprovisionalOELarefiledwiththeCommittee,itisadoptedastheformalOELrecommendedbyJSOH.IfopinionscontrarytotheprovisionalOELarefiledwiththeCommitteeanddeemedvalid,theCommitteethen


A Study of the Interfacial Interaction between …...The Surface Analysis Laboratory A Study of the Interfacial Interaction between Methylene Diphenyl Diisocyanate (MDI) and Metals

Toxicological Profile for Toluene Diisocyanate and … · TOLUENE DIISOCYANATE AND METHYLENEDIPHENYL DIISOCYANATE . v . FOREWORD . This toxicological profile is prepared in accordance

MDI FAQ abridged1b - Des Canadades-canada.com/includes/languages/english/gmde/mdi/MDI...MDI FAQ Version 8.1.0a Page 5 of 16 12. Can an MDI be configured for more than one interface?

Safety Assessment of Hexamethylene Diisocyanate (HDI ... · hexamethylene diisocyanate (HDI) polymers as used in cosmetics. The functions of HDI polymers include anticaking agents,

Phosgene-free Route to Toluene Diisocyanate (1)

Polyurethane Raw Materials · BASF uses carbodiimide chemistry to modify and stabilize the monomeric diphenylmethane diisocyanate. The carbodiimide-modified MDIs are liquids that

ERAPOL EMD135 PART A · 2015-09-02 · Section 3 - COMPOSITION / INFORMATION ON INGREDIENTS NAME CAS RN % polyurethane prepolymer >60 4, 4' - diphenylmethane diisocyanate (MDI) 101-68-8

Safety Assessment of Hexamethylene Diisocyanate (HDI ... · Safety Assessment of Hexamethylene Diisocyanate (HDI) Polymers as Used in Cosmetics Status: Revised Draft Final Report

Occupational Hygiene Air Monitoring for MDI and TDI · PDF fileGFF glass fibre filter HDI hexamethylene diisocyanate HPLC ... Occupational Hygiene Air Monitoring for MDI and TDI Guidance

Health and Safety Product Stewardship Workbook For of ......diisocyanate, such as toluene diisocyanate (TDI) or methylene diphenyl diisocyanate (MDI), and a blended polyol. When a

GPS Safety Summary - ISOPA · 1 GPS Safety Summary. MDI, Methylenediphenyl-diisocyanate , covers all commercially available products deriving from the pure 4,4’-MDI (CAS 101-68-8),

GPS Safety Summary - ISOPA1 GPS Safety Summary. MDI, Methylenediphenyl-diisocyanate , covers all commercially available products deriving from the pure 4,4’-MDI (CAS 101-68-8), its

Reference Exposure Levels for Toluene Diisocyanate (TDI)

HEXAMETHYLENE DIISOCYANATE 7 · HEXAMETHYLENE DIISOCYANATE 9 2. HEALTH EFFECTS 2.2.1 Inhalation Exposure Inhalation is the most common route of exposure for hexamethylene diisocyanate

Chemical/Toxins · Web viewDicyclohexylmethane 4,4’-diisocyanate (hydrogenated MDI) 5124-30-1 SeeTable Z-2 Dicyclopentadienyl iron Total Dust Respirable Fraction 102-54-5 — —

GC for Diphenylmethane

Phosgene-free Route to Toluene Diisocyanate

METHYLENE DIPHENYL DIISOCYANATE (MDI) · TOXICOLOGICAL REVIEW of METHYLENE DIPHENYL DIISOCYANATE (MDI) (CAS No. 101-68-8 and 9016-87-9) In Support of Summary Information on the Integrated

T oluene Diisocyanate (TDI) & Methylenediphenyl Diisocyanate …isopa.org/media/2609/eco-profile-mdi-tdi.pdf · 2016. 7. 27. · Intended Use and Target Audience ... profiles and

Methylene Diphenyl Diisocyanate (monomeric MDI) and ...values as measured by gravimetry were within plus or minus 10% of nominal values. Thus, nominal values will be used in the following

Polymerization of hexamethylene diisocyanate in solution

MDI Placement

Tolylene diisocyanate (TDI) - Polyurethanespolyurethanes.org/uploads/documents/eco_tdi.pdf · Eco-profiles of the European Plastics Industry Tolylene diisocyanate (TDI) A report by

Characterization of Methylene Diphenyl Diisocyanate ......Diisocyanates (dNCO) such as methylene diphenyl diisocyanate (MDI) are used primarily as cross-linking agents in the production

Toluene Diisocyanate Reference Exposure Levels - · PDF filePublic Review Review July 2014 hexamethylene diisocyanate (HDI), so direct handling of TDI containing materials by consumers

4,4-Methylene Diphenyl Diisocyanate (MDI), All Isomers · Methylene Diphenyl Diisocyanate (MDI) and 1,6-Hexamethylene Diisocyanate (HDI), All Isomers Page i DSD History Effective

4,4-Methylene Diphenyl Diisocyanate (MDI), All IsomersDec 09, 2019  · 1,6-Hexamethylene Diisocyanate (HDI), All Isomers . CAS Registry Number 822-06-0 . Prepared by . Toxicology,

EFFECTS OF TOLUENE DIISOCYANATE`S CHEMICAL …

DIPHENYLMETHANE DIISOCYANATE (MDI) · PDF fileConcise International Chemical Assessment Document 27 DIPHENYLMETHANE DIISOCYANATE (MDI) ... IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES

Blocking and Deblocking of Diisocyanate to Synthesize

Influence of Lignin and Polymeric Diphenylmethane

TOXICOLOGICAL PROFILE FOR HEXAMETHYLENE DIISOCYANATE … · HEXAMETHYLENE DIISOCYANATE 1 1. PUBLIC HEALTH STATEMENT This public health statement tells you about hexamethylene diisocyanate

Air Toxics Hot Spots Program - California Air Resources BoardMethylene Diphenyl Diisocyanate (MDI) Reference Exposure Levels Semi-volatile MDI and polymeric MDI (PMDI) used mainly

Tolylene diisocyanate (TDI) - PolyurethanesIndustrial waste 0.01

Safety Assessment of Hexamethylene Diisocyanate … · Safety Assessment of Hexamethylene Diisocyanate (HDI) Polymers as Used in Cosmetics Status: Draft Tentative Report for Panel