31804 Federal Register I Vol. 53, No. 161 I Friday, August 19, 1988 / Rules and Regulations ENVIRONP~ENTAL PROTECTION AGENCY 40 CFR Part 799 [OPTS—42054B; FRL-3431-9l Testing Consent Orders on Aniline and Seven Subatituted Anilines AGENCY: Environmental Protection Agency )EPA). ACTION: Final rule. SUMMARY: This document announces that EPA has signed enforceable testing consent orders both with manufacturers (including importers) who have agreed to perform certain health and environmental effects test5 on aniline and with manufacturers who have agreed to perform certain health and/or environmental effects tests on seven substituted anilines that they manufacture. These chemical substances were designated by the Interagency Testing Committee (ITC) for priority testing. Elsewhere in this issue of the Federal Register, the Agency announces its decision to terminate rulemaking for certain other category members for health and environmental effects and chemical fate. EFFECTIVE OATE Effective on August 19, 1988. FOR FURTHER INFORMATION CONTACT: Michael M. Stahl. Acting Director, TSCA Assistance Office (TS—799), Office of Toxic Substances, Room EB—44. 401 M Street. SW., Washington. DC., (202) 554— 1404. TIJD: (202) 554—0551. SUPPLEMENTARY INFORMAT1O4: This rule adds aniline (CAS No. 62.-53—3). 2- chloroaniline (CAS No. 95—51—2), 4- chloroaniline (C.AS No. 106—47—8), 3,4- dichloroaniline (CAS No. 95—78.-I). Z- nitroaniline (CAS No. 88—74—4), 4- nitroaniline (CAS No. 100—01—06), 2,4- dinitroaniline (CAS No. 97—02—9), and 2.6-dichloro-4--nitroaniline (CAS Ni.. 99-. 30—9) to the list of chemical substances and mixtures (“chemicals”) subject to testing consent orders in 40 CFR 799.5000. I. ITC Recommendation In its Fourth Report to EPA, published in the Federal Register of June 1. 1979 (44 FR 31866), the ITC recommended that all chemicals in the category defined as “aniline and anilines substituted in one or more positions with a chloro. bromo. or nitro group. or any combination of one or more of these substituent groups” be considered for health effects. chemical fate and environmental effects testing. The ITC recommended testing for chronic health effects with emphasis on blood and nervous system disorders, teratogenicity. carcincogenicity. mutagenic effects, and epidemiology studies. The ITC also recommended chemical fate and environmental effects testing. In response to the ITC, EPA published an Advance Notice of Proposed Rulemaking (ANPR) for the anilines category (49 FR 108. January 3, 1984). In the ANPR, EPA identified 20 individual chemicals in production in 1982. rev)ewed the available health and environmental effects information on the chemicals, indicated tentative data gaps in available health and environmental effects information, and requested public comments on a scheme to test representative category members rather than all category members. The ANPR named six subcategories (aniline. monochloroanilines, polychiorosnilines, mononitroanilines. polynitroanilines. and halo-nitroanilines) and seven representative subcategory members (aniline: 4-chloroanihine; 3,4- dichioroaniline: 4-nitroaniline: 2.4- dinitroaniline; 2-chloro-4-nitroanihine. and 2-bromo-4,8-dinitroaniline) for possible health and environmental effects testing consideration under section 4(a)(1)(A) of TSCA. In response to the ANPR, EPA received comments and new information from the Aniline Association and the Substituted Anilines Task Force (SATF). an ind~s*ry group organized as a special project of the Synthetic Organic Chemical Manufacturers Association. who~ members manufacture or import one or more of the substituted anilines (Refs. I and 2). Comments were also received from Sodyeco Inc.. Eastman Kodak, and Uplohn Company (Refs. 3 through 5). The Aniline Association and SATF provided results of surveys of processors to determine the potential for human exposure and environm~al release. The exposure and release data supplied by the SATF and some of the data supplied by the Aniline Association were submitted as Confidential Business Information [CBI) (Refs. 6 and 7). I!. Testing Consent Order Negotiations In the Federal Register of .-\uaust ii. 1986 (51 FR 23758) and in accordance with the procedures established :n 40 CFR 790.28, EPA requested that porsocs interested in participating In or monitoring testing negotiations cit aniline and seven substituted anwnes contact the Agency. EPA held pubIc meetings on August 12. 1986: October 14. 1986: January 15. 1987; and February tP, 1987 to discuss testing appropriate for these eight chemicals. On or before july 7, 1988. five manufacturers of anilna and four manufacturers of subst;euteii anilines signed eight separate ‘Pest ag Consent Orders with EPA. Under one Order, the five manufacturers of ~n:Iinu agreed to conduct or provide for the conduct of the following tests: /n v:to mouse micronucleus assay. gramrnar:d acute effects test, and daphnid chronic effects test. Under seven separate Orders, the manufacturers of the seven substituted anilines agreed to conduct or provide for the conduct of the folln’.’.:na tests for each of the substituted an:iirles they manufacture: Zn vivo cytogenet:cs (in vivo mouse micronucleus assay) for 2-chloroaniline. 4-chloroaniline. 3,4~ d.ichloroaniline. 2-nitroaniline. 4. nitroaniline, 2.4-dinitroanuline: gammarid acute effects, daphnid chronic effects, and rainbow trout acute effects (with trigger to rainbow trout early-life stage) for 2-chioroaniline: and algae acute effects. daphnid acute effects (with trigger to grammarid acute arid daphnid chronic effects), and rainbow trout early life-stage test for 2.6- dichloro-4-nitroariiline. The test standards to be followed and the testing schedule for each test are specified in each Order. Procedures for submitting study plans, modifying the Order, monitoring the testing, and other provisions were also included in each Order. The following table presents the disposition by EPA of the 20 antlines
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31804 Federal Register I Vol. 53, No. 161 I Friday, August 19, 1988 / Rules andRegulations
ENVIRONP~ENTALPROTECTIONAGENCY
40 CFR Part 799
[OPTS—42054B; FRL-3431-9l
Testing Consent Orders on Aniline andSeven Subatituted Anilines
AGENCY: EnvironmentalProtectionAgency)EPA).ACTION: Final rule.
SUMMARY: This documentannouncesthat EPA hassignedenforceabletestingconsentorders both with manufacturers(including importers)who haveagreedto performcertainhealthandenvironmentaleffects test5 on anilineandwith manufacturerswho haveagreedto performcertain healthand/orenvironmentaleffectstests on sevensubstitutedanilinesthattheymanufacture.Thesechemicalsubstancesweredesignatedby theInteragencyTestingCommittee(ITC) forpriority testing.Elsewherein this issueof the FederalRegister,the Agencyannouncesits decisionto terminaterulemakingfor certainother categorymembersfor healthandenvironmentaleffectsandchemicalfate.EFFECTIVE OATE Effective on August19,1988.FOR FURTHER INFORMATION CONTACT:Michael M. Stahl.Acting Director, TSCAAssistanceOffice (TS—799),Office ofToxic Substances,Room EB—44. 401 MStreet.SW., Washington.DC., (202) 554—1404.TIJD: (202) 554—0551.SUPPLEMENTARY INFORMAT1O4: This ruleaddsaniline (CAS No. 62.-53—3). 2-chloroaniline(CAS No. 95—51—2), 4-chloroaniline(C.AS No. 106—47—8), 3,4-dichloroaniline(CASNo. 95—78.-I). Z-nitroaniline (CASNo. 88—74—4),4-nitroaniline (CASNo. 100—01—06),2,4-dinitroaniline (CAS No. 97—02—9), and2.6-dichloro-4--nitroaniline(CAS Ni.. 99-.30—9) to thelist of chemicalsubstancesandmixtures(“chemicals”)subjecttotesting consentordersin 40 CFR799.5000.
I. ITC Recommendation
In its FourthReportto EPA, publishedin the FederalRegisterof June1. 1979 (44FR 31866),theITC recommendedthatall
chemicalsin the categorydefinedas“aniline andanilinessubstitutedin oneor morepositions with achloro. bromo.or nitro group.or anycombinationofoneor moreof thesesubstituentgroups”beconsideredfor healtheffects.chemicalfateandenvironmentaleffectstesting.TheITC recommendedtestingfor chronichealtheffectswith emphasison blood andnervoussystemdisorders,teratogenicity.carcincogenicity.mutageniceffects,andepidemiologystudies.TheITC also recommendedchemicalfateandenvironmentaleffectstesting.
In responseto theITC, EPA publishedan AdvanceNoticeof ProposedRulemaking(ANPR) for theanilinescategory(49 FR 108. January3, 1984).IntheANPR, EPA identified20 individualchemicalsin productionin 1982.rev)ewedthe availablehealthandenvironmentaleffectsinformation onthechemicals,indicatedtentativedatagapsin availablehealthandenvironmentaleffectsinformation,andrequestedpublic commentson a schemeto test representativecategorymembersratherthan all categorymembers.TheANPR namedsix subcategories(aniline.monochloroanilines,polychiorosnilines,mononitroanilines.polynitroanilines.andhalo-nitroanilines)andsevenrepresentativesubcategorymembers(aniline: 4-chloroanihine;3,4-dichioroaniline:4-nitroaniline:2.4-dinitroaniline; 2-chloro-4-nitroanihine.and2-bromo-4,8-dinitroaniline)forpossiblehealthandenvironmentaleffectstestingconsiderationundersection4(a)(1)(A) of TSCA. In responseto the ANPR, EPA receivedcommentsandnew informationfrom theAnilineAssociationandthe SubstitutedAnilines Task Force(SATF). an ind~s*rygrouporganizedasa specialprojectofthe SyntheticOrganicChemicalManufacturersAssociation.who~membersmanufactureor import oneormore of the substitutedanilines(Refs. Iand2). Commentswere also receivedfrom SodyecoInc.. EastmanKodak, andUplohn Company(Refs. 3 through5).TheAniline AssociationandSATFprovidedresultsof surveysofprocessorsto determinethe potentialforhumanexposureandenvironm~alrelease.The exposureandreleasedata
supplied by the SATF andsomeof thedatasuppliedby the AnilineAssociationweresubmittedasConfidential BusinessInformation [CBI)(Refs. 6 and7).
I!. TestingConsentOrderNegotiations
In the Federal Registerof .-\uaust ii.1986 (51 FR 23758) andin accordancewith the proceduresestablished:n 40CFR 790.28, EPA requestedthat porsocsinterestedin participatingIn ormonitoring testingnegotiationscitanilineandsevensubstitutedanwnescontactthe Agency. EPA held pubIcmeetingson August 12. 1986: October14.1986: January15. 1987; andFebruarytP,1987 to discusstesting appropriatefortheseeight chemicals.On or beforejuly7, 1988. five manufacturersof anilnaandfour manufacturersof subst;euteiianilinessignedeight separate‘Pest agConsentOrderswith EPA. Under oneOrder, the five manufacturersof ~n:Iinuagreedto conductor provide for theconductof the following tests:/n v:tomousemicronucleusassay.gramrnar:dacuteeffectstest,anddaphnidchroniceffects test. Under sevenseparateOrders,the manufacturersof the sevensubstitutedanilinesagreedto conductorprovidefor the conductof thefolln’.’.:natests for eachof the substitutedan:iirlestheymanufacture:Zn vivo cytogenet:cs(in vivo mousemicronucleusassay)for2-chloroaniline.4-chloroaniline.3,4~d.ichloroaniline.2-nitroaniline.4.nitroaniline,2.4-dinitroanuline:gammaridacuteeffects,daphnidchroniceffects,andrainbow trout acuteeffects(with triggerto rainbowtrout early-lifestage)for 2-chioroaniline:andalgaeacuteeffects.daphnidacuteeffects(with triggerto grammaridacuteariddaphnidchroniceffects),andrainbowtrout earlylife-stagetest for 2.6-dichloro-4-nitroariiline.The teststandardsto be followedand the testingschedulefor eachtestarespecifiedineachOrder.Proceduresfor submittingstudy plans,modifying the Order,monitoring the testing,andotherprovisionswere also includedin eachOrder.
Thefollowing tablepresentsthedispositionby EPA of the 20 antlines
Federal Re~istar/ Vol. 53, No. 161 I Friday, August 19, 1988 I Rules and Regulations
Aniline is producedby fivemanufacturers(DuPont,First MississippiCorp., Rubicon,Mobay ChemicalCorp.,andU.S.S.ChemicalCorp.) at fivelocationsin the UnitedStates.Productionwasabout790 millionpoundsin 1984 (Ref. 1). The productionvolumesfor substituted anilines rangefrom lessthan 1000pounds to 10 millionpounds.Themanufacturersof thesubstitutedanilineshaveprovidedEPA‘,vith exactproductionvolumesfor 1982as CBI (Ref. 8). TheTSCA section8(b)confidentialchemicalinventory updatereports that therehasnotbeenasignificantincreasein productionofthesechemicalsfrom levelsreportedin1982.
The manufacturersand processorsofaniline andsubstitutedanihinesreportthat thechemicalsare usedconsumptivelyas chemicalintermediates(Refs. 7 and9). Aniline isusedto produceisocyanates,rubberprocessingchemicals,dyes,andhvdroquinone,for drugmanufacture,andfor other uses including productionof herbicides,syntheticfibers,andphotographicchemicals.The primaryusefor most of thesubstitutedanilinesis as intermediatesin dyeandpigmentproduction.3,4-Dichloroanilineand2-chloroanilineareusedprimarily aspesticideintermediates,4-Nitro-aniline
Manufacturersof aniline report thatapproximately2.5million poundsweredisposedof by deepwell injection.2.5million poundswereincinerated.130.000poundswentto regulatedlandfills.49.500poundswere releasedto air, and14,700poundswerereleasedto water.Themanufacturersof aniline haveprovidedto EPA site-specificaquaticreleasevolumesfor 1984 as CBI (Ref.10). Total estimatedaquaticreleaseofaniline by processorswas85.155 poundsat 22 locationswith therangeoflocation-specificreleasebetween22.000pounds(3 locations)and1.000 poundsorless(14 locations)(Ref. 11). BothmanufacturersandprocessorsofsubstitutedanilineshaveprovidedEPA‘with releasevolumes for 1982as CBI.
B. HumanExposure1. Occupationalexposure—a.Aniline.
TheAniline AssociationhasprovidedEPA with informationon potentialoccupationalexposurefrom anilinemanufacturingandprocessingoperations(Refs. I and7). TheAssociationreportsthat thereis little orno occupationalexposureto anilinebecause:Few workersarepotentiallyexposedfor shortperiods:productionoccursin an enclosed,continuousprocessmostly in open-designplants(plantnot enclosedin abuilding); andrigorousworkplacecontrolsandindustrial hygienepracticesareusedtoprotectworkersfrom theknown acutetoxic effectsof aniline. Also, mostmanufacturersandprocessorsrequirethat employeeswearrubbersuits andglovesfor protectionin potentialexposuresituations suchas reactorentry, specialwork procedures,andsamplingandmaintenanceoperations,becausethe greatestpotential forexposureis throughdermalcontact(anilineis absorbedvery rapidlythroughtheskin). Air monitoring andmedical8urveillanceresultsshowcontrolpracticesareeffectivelypreventingexposuresto aniline(Ref. I).Aniline has excellentacute indicatorproperties;the olfactorydetectionlevelis 0.5 to I ppm. andacuteexposurecausescyanosis,a condition evidencedby bluish skin discolorationduetodeficientblood oxygenation.
TheAniline Associationsurveydatareportedthat487 workersinvolvedinmanufacturingarepotentiallyexposedto airborneanilineconcentrationlevelsbetween0.001 to 1.4 ppm, with 97percentof workersbelow 1 ppm.Anadditional1.524workersinvolvedininternalandoutsideprocessingofanilinearepotentiallyexposedto levelsrangingfrom 0.001 to 5 ppm with 99.9
31805
percentof total workerhoursatexposuresbelow2 ppm.TheOccupationalSafetyandHealthAdministration’s(OSHA) inspectionsummarydatatime-weightedaverages(TWA) were all below 0.25ppm andserveto supporttheAssociationsconclusions(Ref. 12). TheOSHApermissibleexposurelimit (PEL) foraniline is 5 ppm (Ref. 13). TheAmericanConferenceof GovernmentalIndustrialHygienists(ACGIH) T1vVArecommendedexposurelimit is 2 ppmfor aniline (Ref. 14).
b.Substitutedanilines.TheSATF hasprovidedEPA with confidentialinformationon potentialoccupationalexposurefrom manufacturingandprocessingoperationsof substitutedanilines(Refs.8 and8). TheSATF alsoreportsthatthereis little or nooccupationalexposureto the substitutedanilinescurrently in productionbecausevery fewemployeesarepotentiallyexposed.The SATF reports thatproductionoccursovershort timeperiodsin a closedcontinuousprocessduring which the chemicalis consumed:that workplacecontrolsandindustrialhygienepracticesareusedto protectworkers from the known or suspectedacutetoxic effectsof the substitutedartihines, and that air monitoringandmedicalsurveillanceresultsshowcontrolpracticesareeffectivelypreventingexposuresto the substitutedanilines.Somesubstitutedanilinesalsohaveexcellentacuteeffectsindicatorpropertieslike thoseof aniline.
A studyby onemanufacturer!processorto evaluatetheeffectsofpotentialairborneexposureofmanufacturingworkers to 4-chioroanilineon variousbiological(blood) parameters reported that: (1) AUthemethemoglobinlevelsmeasuredfallwithin what hasbeentraditionallyregardedasanormalrange,(2) a smallstatisticallysignificantelevationinmethemoglobinfollowing thework shiftwasobservedamongemployeesinvolvedin 4-chloroanihinemanufactureandthe matchedcomparisongroupsuggestingtheobservedincreaseinmethemoglobinamongworkersmay notbe work-related, and (3) therewasnocorrelationbetweenpost-exposuremethemoglobinand4-chioroanilineairsamplingdatawithin the narrowrangeof low level exposurestypical in thiswork setting (Ref. 15). A majormanufacturer/processorof chloro- andnitroanihinesreportsan averageof 3casesperyearor methemoglobinemia.definedas oxygensaturationbelow90percent.observedat the their main plantover the last 10 years)Ref. 16). Over the
Ing.Decision to terminate rulemak;ng found else-
where in th,~ssueof F.d,va~Registur.Consent Order: heattheffects testing.Consent Order: aquatic effects testing.
31806 Federal Regi.s~er/ Vol. 53, No. 161 / Friday, August 19, 1988 / Rules and Regulations
Therearefew monitoringdataavailablefor aniline andthesubstitutedanilinesin wastewaterof sediment.Ewing et a!. in 1977sampledsurfacewatersfrom 204sitesnearheavilyindustrializedareasacrossthe U.S.Aniline andsubstitutedanilineswerenot detectedat concentrationsaboveIppb (Ref. 17). In anotherstudywastewater,receivingwatersandsedimentsneara plant manufacturingabroadrangeof chemicalswereanalyzedfor organicpollutants(Ref. 18). One
sampleof wastewatercontained0.02ppm of aniline. Aniline wasnot detectedin river wateror sediments.Chloroaniline(isomersunspecified)wasnot detectedin wastewateror riverwaterbut wasfoundin sedimentat 1 to2 ppm. Plantandsamplinglocationswerenot reported.
GamesandHites in 1977measuredorganiccompoundsin untreatedandtreatedeffluentoriginating from a dyemanufacturingplant(Ref. 19). Resultsshowedthe presenceof six anilinecompounds.Thecompoundsincludedaniline, chioroaniline,dichloroaniline,nitroaniline. tribromoanilineandbromodinitroaniline.Theconcentrationsrangedfrom 36 to 480ppb for rawwastewaterto 7 to 96 ppb for treatedeffluent.
USEPAdatain the STORET systemincludea total of 48datapoints orobservationson environmentallevelsof
aniline in streams,and42 datapointsorobservationson levelsof 2-nitroanil nein streams(Ref. 20)The meanresiduallevel of aniline was9.47 ppb. withmaximumandminimum valuesof 13and1 ppb, respectively;the STORETdatawere collectedbetweenAugust1978andAugust 1980.The meanresidual level for 2.nitroanilinewas0.39ppb with maximumandminimum valuesof 1.7 and0.1 ppb. respectively:theSTORETdatawerecollectedbetweenJanuary1983 andMay 1985.
chloroanilineand3,4-chloroanilineandotheraromaticainineschemicallybindto organicsin soil andsediment;thereforetheseandpossiblyothercategorymembersmaybe muchlessmobile in soil andsedimentthanpredictedby the Koc (Refs.27 through31).
3.Presistence.Chemicalfate dataonaniline indicatethat it is readilybiodergradableandoxidizable insurfacewaterandsewagesludge(Refs.32 through35). The overallexperimentaldegradationhalf-life in surfacewaterislessthanI day (Refs. 36 and43).
with the organiccontentandpH of thesoil (Ref. 37). Microbial metabolismoccursslowly in soil becausethechloroanilinesbind to soil organics(Refs.38 through42). Thechloroanilineshaverelatively low log P valuesandarethereforenot likely to bioconcentrateinfatty tissueof aquaticorganisms.althoughtheir lower watersoluhilitiesandhigherlog P valuesindicate theyaremore likely to do so than aniline.
Photodegradationis likely to beaprimary routeof aquaticdegradationofthe chloroanilines(Refs.43 through41).The experimentalhalf-life of DCA indistilled water, naturalseawater,andInstantOceanis lessthan I day(Ref.43). Theratesof biodegradationofmonochloroanilinesareestimatedto beslowerthan aniline in the aquaticenvironment(Ref. 46). In aerobicenvironments4-chloroanilinebiodegradesfasterthanDCA. Inanaerobicenvironmentsthe reverseistrue (Ref. 47). Somemonochioroanilines
FederalRegisterI Vol. 53, No. 161 / Friday, August 19, 1968 I Rules and Regulations 31807
arereportedto be degradedin activatedsludge(Refs. 33 and47).
Availabledataon thechemical fate ofthenitroanilinesandhalogenatednitroanilinesarelimited. Insemicontinuousactivatedsludgetesting,4-nitroanilinehasbeendescribedasreadilydegradableand 2-nitroaniline asresistantto degradation(Ref. 48). 4-nitroanilineand2,8-dich1oro-~4-nitroaniline (DCNA) undergomicrobialdegradationin pureculture(Refs.49 and50). The relativelylow log P valuesindicatethe nitroanilinesandhalogenatednitroanilinesarenot likelyto bioconcentratein aquaticorganisms.Thenitroanilinesandhalogenatednitroanilinesmay,like otheraromaticamines,chemicallybind to organicsinsoilsandsediments,althoughtherearerio datato confirm this effect for thesechemicals.
IV. Testing Program
A. EnvironmentalEffects
In its FourthReport to the EPA,publishedin the FederalRegisterof June1. 1979 (44 FR 31866).the ITCrecommendedchemicalfatetestingbecauseof suspectedenvironmentaleffectsandalsobecausetherewereconflictingreportson the ability ofanimals,plants.andmicrobestometabolizeandtoleratethesechemica’ls~TheITC recommendedenvironmentaleffectstesting becausereportsofoccurrencesof residuesandtheirpersistencein waterandsoil suggesteda highly dispersivedischargeinto theenvironmentandavailabledataraisedaconcernthat categorymembersmayproduce adverseeffects.
UsingCBI suppliedby manufacturersandprocessorsandinformationfrom theopenliterature,EPA hascalculatedworst-caseaquaticpredictedenvironmentalconcentrations(PECs) foraniline, 2-chloroaniline.and2,6-dichloro-4-nitroaniline,which werethecategorymembersjudged to be releasedin significantamounts(Ref. 51). BecausetheAgencyhasfew dataon the fateofthe substitutedanilinesin theenvironment,calculationof their PEGswasbasedon theworst-cageassumptionthatnoneof thesubstitutedanilinesareaffectedby physicalorbiological processesotherthandilutionin the dischargeenvironment.Foraniline, PECswerecalculatedusingameasuredoveralldegradationhalf-lifeof 17.5 hours(% day) whichincludesbiodegradation.oxidation,photolysis,andhydrolysisin naturalwaters (Ref.52). In addition,theconcentrationin thedischargeenvironmentwasconservativelybasedon the lowest riverflow rate thatwould not be exceeded5
percentof the time. ThePECsfor anilineandthesubstitutedanilinesjudgedto bereleasedin significantamountsarenotdescribedherebecausetheyarederivedfrom CBI data.
The Agencyhas reviewedtheavailabledataon environmentaleffectsandthepotentialfor environmentalexposureto other anilines categorymemberscurrentlyin production(seeNoticeof Terminationof Rulemaking forCertain Anilines Category Membersappearingelsewherein this issueof theFederalRegister).The Agencyhasdeterminedthat,giventhelowanticipatedandobservedexposuretothesechemicalsandin thelight of theenvironmentaleffectsdataavailableforthis category,thesechemicalsdo notreachlevelsin theenvironmentthat‘raise a concernfor adverseeffects.
EPA has estimatedthe potential forreleasesof anilinescategorymemberstoadverselyaffect aquatic organismsbyexamining available aquatic toxicitydataandby comparingacutevertebrateand invertebrateLC5O’s to the site-specificPECs calculatedas describedinUnit IV.A.2.
EPA hasdeterminedthatconcentrationsof aniline. 2-chloroaniline,andDCNA in theaquaticenvironmentresultingfrommanufacturingand processingcouldreachlevelswhichmaybeharmful toaquaticorganisms(i.e., LC5A)’s ofsensitiveaquaticspeciesof anilIne, 2-chloroaniline,andDCNA arelikely tobe lessthanor equal to 1000 x thepredictedenvironmentalconcentrationsor lessthanor equal to 1 mg/L).Therefore,additional acutetoxicitytesting is neededto determinetheeffectsof: Aniline on daphnids,2-chloroanilineon gainmaridsandrainbowtrout, andDCNA on algaeanddaphnidswith triggerto gammarids.Testing to determinethechroniceffectsof anilineon dephanids,2-chioroanilinefrom acutetriggerto daphmd orgammaridand rainbow trout earlylifestage,andDCNA earlylife stageinrainbow trout is also neededto assessthe potentiallong-termhazardof thesechemicals to aquatic organisms.
The following is a summaryofavailableaquaticeffectsinformationtheAgencyhas consideredin its decision toissuea ConsentOrderfor aquaticeffectstestingof aniline, 2-chioroaniline,and2,8-dichloro-4-nit.roaniline.The96-hourEC5Ofor aniline in freshwateralgae(Selenastrumcapricomutom)is 19mg/L andthe48-hourEC5O for 2-chloroanilinein freshwateralgae(Scenedesmuspannonicus)is 32 mg/L(Refs.53 and54). The48-hourLCSO foraniline in Daphnia magna is 0.85mg/L
and the 48-hour EC5Ofor 2-chloroanilinein Daphniamagnais 0.48mg/L (Refs. 55and 54). The 96-hourLC5O’s for anilineand2-chloroanilinein fatheadminnowsare134 rng/L and5.8 mgJL. respectively(Ref. 58). The96-hourLC5O for aniline flrainbow trout is 8 mg/L (Ref. 57). The96-hourLC5O’s for 2,8-dichloro-4-nitroaniline in bluegill sunfish andrainbowtrout are1.08 mg/L and0.56mg/L. respectively(Refs. 58 and59).
B. HealthEffects
In its FourthReport44 FR 31866. theITC recommendedthatall chemicalsintheanulinescategorybe testedforchronichealtheffectswith emphasisonbloodandnervoussystemdisorders.teratogenicity,caricinogenicity.mutagenic effects,andepidemiologystudies.TheITC baseditsrecommendationsfor chronicheaitheffects(with emphasison blood andnervoussystemdisorders), forteratogeniceffectstesting, andforepidemiologystudieson the potent:al forsomecategorymembersto causemethemoglobinemiain humans.The ITCrecommendedmutagenic andcarcinogeniceffectstesting becausesomecategorymemberswere reportedto causemutagenicand/orcarcinogeniceffects,andtheresultsraisea tUSPtCiOfl
of theseeffectsin untestedmembers.TheAgencyin its ANPR for the anilinecategory,49 FR 108. proposedtesting forreproductiveeffectsbasedon thepotential for somecategory memberstocausemethemoglobinemiain humans.
TheAgencyhasreviewedtheavailabledataon healtheffectsandthepotential for humanexposureto thesevenanilinescategorymembersnamedin theConsentOrdersandtheotheranilinescategorymemberscurrently~nproduction (seeNotice of TerminationofRulemakingfor CertainAnilinesCategoryMembersappearingelsewherein this issueof theFederalRegister).TheAgencyhasdeterminedthat,giventhelow anticipatedandobservedexposureto thesechemicalsandin light of thehealtheffectsdataavailablefor thecategory,thesechemicalsdo not reachlevelsin the workplaceenvironmentthat raisea concernfor chronic,developmental,andreproductiveeffects.
31808 Federal Register / Vol. 53, No. 161 / Friday, August 19, 1988 I Rules and Regulations
mutagenicityfor sevencategorymembersis necessary.
This additionaltestingis necessaryaspart of a tiered testingapproachwhichinvolves a programreview to follow thedevelopmentof thein vivo cytogeneticsdataandconsidersall availablemutagenicandhealtheffectsdatatodeterminethe needfor furthermutageniceffectsor other healtheffectstesting.EPA is deferringanydecisionasto the needfor carcinogenicitytesting ofthesubstitutedanilinesuntil it hasreceivedthe resultsfrom all themutagenicitytesting to be performedundertheConsentOrders.Dataon thecarcinogenicpotentialof aniline hasbeenevaluatedandjudgedto beadequate.TheAgencywill announceitsdecisionon furthermutagenicityorcarcinogenicitytestingneedsin aseparaterulemaking.
The following is a summaryofavailablehealtheffectsinformation theAgencyhasconsideredin its decisiontoissueConsentOrdersonly for mutageniceffectstestingof sevenanilinescategorymembers.
1. Acuteeffects.The primaryacuteeffect in mammalsassociatedwithexposureto aniline andsomesubstitutedanilinesis anincreaseinmethemoglobinlevelsin blood(Ref. 60).However,a recentstudysponsoredbyAmericanHoechstshowsthat not allsubstitutedanilinesreadily causeincreasedlevelsof methemoglobininrats(Ref. 61). Thestudy wasdesignedtorate themethemoglobin-inducingpotencyof categorymembersrelativetoaniline. usinghigh dosesto maximizethe amountof methemoglobinproduced.Doseswereequimolarto 100and400mg/kg of aniline. When testcompoundsinduced the formationof methemoglobinabovevehiclecontrolsin adose-dependentmannertheywereconsideredpositive.For compoundsclassifiedaspositive, theresultsof the100 mg/kgequimolardoesat 1 hourwere thenstatisticallycomparedwith the100mgIkg aniline resultsto determineif thetestcompoundwasmorepotent,equipotent,or lesspotentthan aniline. Testcompoundsthatfailed to inducemethemoglobinemiaat eithertime point(1 hourand6 hours)or dosewereconsiderednegative.
Only 3-chloroanilineand4-chloroanilineweresignificantly morepotentmethemoglobinproducersthananiline. Fourchemicalswereequipotentto aniline: 3-nitroaniline.4-nitroaniline,2,4-dinitroaniline,and3,4-dichloroaniline:andfour werelesspotentthan aniline: 2-chloroaniline.4-chloro-3-nitroaniline,2,3-dichloroaniline,and3,5-dichloroaniline.The otherelevenchemicalswerenegative.
2. Metabolism.Studieson thedispositionandmetabolismof aniline. 4-chloroaniline,4-nitroaniline,2,4-dinitroaniline.2-bromo-4.8-dinitroaniline.2,6-dichloro-4-nitroaniline.and4-chloro-2-nitroanilinein ratsindicatethesechemicalsarerapidlymetabolizedandexcreted(Refs.63 through88). For example,the wholebody half-lifeof thesechemicalsrangesfrom ito 7 hours:andwithin 2 to 3 days,clearanceof chemical-derivedradioactivity from the body wasalmostcomplete.
Aniline andsomeof thesubstitutedmembersof the category(2-chloroaniline.3-chioroaniline,4-chloroaniline,2,3-dichlororaniline,2.4-dichloroaniline,3,4-dichloroaniline,3-nitroaniline,4-nitroaniline,and4-chloro-3-nitroaniline)arebiotransformedinratsandother mammalsintointermediateswhich initiate theformationof methemoglobinfromhemoglobin(Ref. 60). Therearetwometabolicpathwaysinvolvedin themetabolismof aniline andtheothermethemoglobin-formingmembers:(1)Thehydroxylationof thearomaticringcarbonsto produce phenolswhich arethe precursorsfor coniugatedproductsexcretedin urineor bile or (2) thehydroxylationof thenitrogenatom toform phenythydroxylamineandnitrosobenzenewhich converthemoglobinto anoxidizedform,methemoglobin.an irreversibleoxygencarrier.However, the sensitivity tomethemoglobin-forminganilinesvariesamong mammals. Cats are themostsensitiveandproducethehighestandmost sustained levelsof methemoglobin.Humans,dogs. rats, andrabbitsarelesssensitive(orderof decreasingsensitivities).Thevariationinsensitivitycould bedueto theextenttowhichthe chemicalis metabolizedtophenylhydroxylamineor to thedifferencesin the activities of enzymesthat~tutoote the reductionofmethemoglobinin the red cell backtohemoglobin.
3. Subchronicandchroniceffects.Resultsfrom prechronicor subchronicandchronic(oncogenicity)oral studiesin ratsor ratsandmice for threemethemoglobin.inducfngchemicals(aniline.4-chloroaniline.and4-nitroaniline)havebeenreported(Refs.69 through75). Somecommoneffectsthat resultfrom long term exposuretoaniline and4-chloroanilir.eat doses(10to 100mg/kg/day)that inducesignificantmethemoglobininclude:Anemia.red blood cell Heinz bodies,dose-relatedincreasein spleenweightandsize, dose-relatedcongestionofsplenicpulp, increasedred bloodcellturnoverrate,anddose-relatedincreasedpigment(hemosiderinengorgement)in spleenandin kidneyandliver at high doses(> 10 mg/kg!day).At higherdoses(30 to 100mg/kg!day), adose-dependentincreasedincidenceof primarysplenicsarcomas.principallyin male rats, wasreportedfor aniline and4-chioroaniline(Refs.69and75).
Resultsof achronicoralstudy in ratsusing 4-nitroanilineindicatetheadministrationof4-nitroanilineat levelsup to 9 mg/kg/dayfor 2 yearsdid notcauseanytreatment-relatedoncogeniceffects(Ref. 74). Thestudywasdesignedto determinewhetherchronicoroncogeniceffectsoccurfrom long-termexposureto 4-nitroanilineat dosesthatinduceincreasedlevelsofmethemoglobinin rats. Methemoglobinlevelswere increasedovercontrolsatmid (1.5 mg/kg/day)andhigh (9.0 mg/kg/day) dosagelevels. Slight anemiawasobservedmainly at the high dosagelevel. At the low (0.25 mg/kg/day)dosagelevel, the only treatment-relatedchangewasslight brownpigment insplenicreticuloendothelialcells.Theonly treatment-relatedchangeat the midandhigh dosagelevelswasaccumulationof brown pigment insinusoidalmacrophagesin the liver andin reticuloendothelialcells in the spleen.Resultsof an oral 90-daysubchronicstudy in mice using4-nitroanilinehavebeenreported.Effects in both sexesgiven30 and100mg/kg/dayinclude:Methemoglobinemia.Heinzbodies,increasedred bloodcell turn overrate,increasedspleenandliver weight.andpigmentdepositionwithin phagocyticcellsof spleen,bonemarrowandliver(Ref. 74). The NationalToxicologyProgram(NTP) is sponsoringan oralchroniceffects-oncogeriicitystudyof 4-nitroanilinein miceat doselevelsof 0. 3.30, and100mg/kg/day(Ref. 76).
Subchronicinhalation studiesusingratsandmicewith the methemoglobininducers3-chloroaniline.3.4-dichloroaniline.and4-nitroanilinereport
Federal Register / Vol. 53, No. 161 / Friday, August 19, 1988 / Rules and Regulations 31809
the sametypeof effectsthatoccuratlower dosesandover shorterexposureperiodsin oral studiesin ratsandmice(Refs. 77 through81). Subchronicoralexposureof ratsto 4-chloro-3-nitroaniline resultedin reducedtestes-weight-to-brain-weightratio at 18 mg/kg/day andtesticularatrophyalongwith other toxic effectsat 90 mg/kg/day(Ref. 82). No treatment-relatedeffectswereobservedat or below 100ppm inthe diet in two chronic/oncogenicitystudiesin ratsanddogs for 2,6-dichloro-4-nitroaniline(DCNA), which doesnotinducesignificantmethemoglobinemiain mammals(Ref. 83). An oncogenicitystudyof DCNA in mice is in progress(Ref. 84).
Becausethereis evidencefromstudieson themetabolismofmethemoglobin-producinganilinesfor anon-genotoxicmechanismfor theinductionof hemangio-andfibrosarcomasin the spleenof ratsfromdietaryexposureat high concentrations,andbecauseEPA wantsto reviewallrelevantdataon all the anilinesbeforemakinga determinationas to the needfor oncogenicitytesting. the Agencyisdeferringits decisionon the needforadditionaldataon oncogeniceffectsofsubstitutedanilinesuntil the resultsofthe in vivo mutagenicitytestsareavailable(Ref. 85). The availabledataon the oncogeniceffectsof aniline areadequatefor TSCA risk assessmentpurposes.
Also, afterreviewingtheavailablereportsandstudies on the acuteandchronichealtheffectsof theanilinescategorytheAgencyhasfound noevidenceof adversehematologicorcentralnervoussystemeffectsthatarenot likely to berelatedto the decreasedoxygen-carryingcapacityofmethemoglobicblood.Thedataprovideno basis to believethat thesechemicalsmaypresentanunreasonablerisk ofadversehematologicor centralnervoussystemeffectsat anticipated exposurelevelsas manufacturersandprocessorscontrol potentialhumanexposurebelowthe thresholdfor methemoglobinemia.Therefore,the Agencyhasconcludedthatadditional informationonhematologicor centralnervoussystemeffectsof aniline andsubstitutedanilinesis not necessaryat this time.
4. Developmentaltoxicity. Aniline, apotentmethemoglobinproducer,wasobservednot to bedevelopmentallytoxic in ratsat levels(100 mg/kg) thatproducedmaternalandfetal toxicitycommonlycausedbymethemoglobinemia(Ref. 86). Timedpregnantmice treatedwith aniline (500mg/kg/day)duringdays7 through14 ofgestationrevealedno apparenteffecton
numbersof litters produced;however,offspringviability throughthe first threepostpartumdayswassignificantly lowerthanfor the control group. Also,reductionsin birth weightandweightgainwereseenin aniline-treatedlitters(Ref. 87). No treatment-relatedmaternalor embryotoxicitywasobservedbelow125 mg/kg/day(oral administration)of4-nitroanilinein NewZealandrabbits(Ref. 88). 4-Nitroanilineadministeredbygastricintubationto pregnantratsat adoseof 25 mg/kg/dayfrom day 6 to 19of gestationwasnot maternallyordevelopmentallytoxic (Ref. 89). At 85mg/kg/daysomematernaltoxicity(increasedspleenweight) andfetotoxicity (reducedfetalweight) wereevident:however,no developmentallytoxic effectswereobserved.At 250mgikg/day,4-ni troaniline producedmaternaltoxicity. embryotoxicityandterata.No treatment-relatedmaternalordevelopmentaltoxicity wasobservedator below300mg/kg/dayof 2-nitroaniline to pregnantratsaftergavageadministrationon days6 to 15 ofgestation.Significantevidenceofmaternaltoxicity wasobservedat 2-nitroanilinedosagesof 600mg/kg with asingle malformation in one fetus eachfrom two litters at thatdosage(Ref. 90).Pregnantratsexposedto 1.1 and1.7 mgim3 of 2,4-dinitroanilinedevelopedmaternalandembryotoxicity,but nootherdevelopmentaltoxic effectswereobserved(Ref. 91). Pregnantrabbitsexposedto DCNA showedno maternaltoxicity or developmentaltoxicity at1.000ppm in diet (Ref. 92). A secondteratologystudyof DCNA in ratsis inprogress(Ref. 84).
The dataprovide no basisto believethatthesechemicalsmay presentanunreasonablerisk of adversedevelopmentaleffectsat anticipatedexposurelevels, as availabledatashowno developmentaleffectsthatoccuratexposurelevelsat whichsomecategorymemberscausemethemoglobinemiaandmanufacturersandprocessorscontrolpotential human exposurebelow thethresholdfor methemoglobinemia.Therefore,theAgencyhasconcludedthatadditional information on thedevelopmentaleffectsof aniline andthesubstitutedanilineg is not necessaryforrisk assessmentpurposesat this time.
5. Reproductiveeffects.Anilineadministeredsubcutaneouslyin femalerats(averageweight150grams)forsevendaysat 50 mg/day causedalterationsin steroidalhormonelevelsof the corporaluteum (Ref. 93). 4-Nitroaniline administeredby gastricintubationat doselevelsof 0.25, 1.5 and9.0 mg/kg/dayto the FO andFlgenerationof male andfemalerats
duringpre-matinggrowthandthroughensuingmating. gestation.andlactationintervalsshowedno significantadverseeffect on mortality ratesor body weightsin the FO andFl generations(Ref. 94). inthe FO generation,the male fertilityindexandpregnancyrate for the highdosegroupwere lower thancontroldata:however,only for the pregnancyratewas this differencefrom the controlgroupstatisticallysignificant. In the Flgeneration.mating. pregnancy.andfertility indiceswere comparablebetweencontrolandtreatedgroups.~oadverseeffectsof treatmentwereindicatedduring eithergenerationinparturitionor litter sizedata,pupweightdate,pup survival, or sexdistributiondataor deadpup observations.Likewise, grossandhistopathologicalevaluationof selectedtissuesfrom FtandF2 pups or adultsto include testes~epididyrnidesof Fo males(highdosegroup)did not revealan adverseeffect.Therecentchronicstudyusing anilinehasno mentionof long-termeffectsonreproductiveorgans(Ref. 69). Chronicstudieson 4-chloroanilineand4-riitroaniline haveno mentionof effectson reproductiveorgans(Ref. 70 and74).4-Chloro-3-nitroaniiinecausedtesticulareffectsin ratsafter subchronicoralexposureat 90 mg/kg/day.but theanimalsshowedothertoxicities as well(Ref. 82). TheNOEL wasreportedascloseto but below3.8 mg/kg/day.The3.8 mg/kg/daydoseproduceda minimaltoxic response.A spermmorphologyvaginal cytology (SMVCE) study of 4-nitroaniline reportedno effectsof thechemicalon mouseestrouscyclesbutreducedspermmotility in miceat 100mg/kg/day(Ref. 95). An SMVCE studyof 4-chloro-2-nitroanilinereportednoeffectson reproductiveparametersinmale rats: however,the chemicalappearedto interferewith the relativefrequencyof estrousstages(600 and1.200mg/kg/day)(Ref. 96). This effect islikely to becausedby alterationinhormonalactivity. A threegenerationreproductivestudyof DCNA reportednoeffectson reproductiveparametersinmaleor femaleratsat 100 ppm and10ppm in diet (Ref. 97).
Thedataprovide no basisto believethatthesechemicalsmaypresentanunreasonablerisk of adversereproductiveeffectsat anticipatedexposurelevels,as availablereproductiveeffectsdatashownoreproductiveeffectsthatoccuratexposurelevelsat which somecategorymemberscausemethemoglobinemiaandmanufacturersandprocessorscontrolpotentialhumanexposurebelowthethresholdfor methemoglobinemia.Therefore,the Agencyhas concluded
31810 Federal Register I Vol. 53, No. 161 I Friday, August 19, 1988 / Rules and Regulations
that additional informationon thereproductive effects of aniline and thesubstitutedanilines is notnecessaryforrisk assessmentpurposesat this time.
a. Aniline is reportedto havenegativeresultsin the following genemutationassays:Salmonella,E. co/i, WP2 uvr A,andAspergillus(Refs.98 through101).Aniline is positive for theL5178YTK, ±mouselymphomagenemutationassayandnegativefor theDrosophila sexlinked recessivelethal assay(SLRL)(Refs. 102 through104). Aniline isnegativefor sisterchromatidexchangein humanlymphocytes,andnegativeforchromosomalaberrations in culturedChinesehamsterovary cells(Refa. 105and106).Aniline causedan increasedfrequencyof sisterchromatidexchange(SCE) in vivo in mousebonemarrowcells andin vitro with Chinesehamsterovary cells (Refs.107and108).Anilinealsocauseda slight increaseinfrequencyof SCE’s in culturedhumanfibroblasts(Ref. 109). EPA believesthatan in vivocytogeneticstest is necessaryfor risk assessmentpurposes,andmanufacturershave agreedto performthetesting(mousemicronucleus).
b. 2-Chloroanilineis negativein theSalmonellagenemutation assay,andthere are no data oncytogeneticeffectsof 2-chloroaniline(Ref. 110). EPAbelievesthatan in vivocytogeneticstestis necessaryfor risk assessmentpurposes,andmanufacturershaveagreedto performthetesting(mousemicronucleus).
c. 4-Chloroanilineis reportedto havepositiveresultsin the following genemutation assays;Salmonella,S.coil polA, AspergillisandLSI7BY TKI±mouselymphoma(Refs.101 and111 through113). 4-Chloroanilineis positive forsister chromatid exchangeandchromosomalaberrationeffectsin vitro(Ref. 114).EPA believesthat an in vivacytogeneticstest is necessaryfor riskassessmentpurposes,andmanufacturers have agreedto performthe testing(mousemicronucleus).
d. 3,4-Dichioroaniline is reported tohavenegativeresultsin theSalmonellagenemutationassayandpositive resultsin the Aspergillusgenemutation assay(Refs. 99 and 115). There areno data onthecytogeneticeffectsof 3.4-dichloroaniline.EPA believesthat an inviva cytogeneticstestis necessaryforrisk assessmentpurposes,andmanufacturershaveagreedto performthe testing (mousemicronucleus).
e. 2-Nitroanilineis reportedto havepositive resultsin theSalmonellagene
mutation assay;thereareno dataavailable on the cytogeneticeffects of 2-nitroaniline (Ref. 118and118). EPAbelievesthatan in vivacytogeneticstestis necessaryfor risk assessmentpurposes,andmanufacturershaveagreedto performthe testing(mousemicronucleus).
f. 4-Nitroanilineis reportedto havepositiveresultsin the SalmonellaandL5178YTK±mouselymphomaassaysandnegativeresultsin theDrosophilaSLRL assay(Refs. 117, 119and122).4-Nitroaniline is weakly positive for sisterchromatidexchangeandchromosomalaberration effectsin vitro (Ref.120).EPA believesthatan in vivacytogeneticstestis necessaryfor riskassessmentpurposes.andmanufacturers haveagreedto perform~he testing (mousemicronucleus).
g. 2.4-Dinitroanilineis reportedtohave positive effectsin the Salmonellagenemutation assayandis negativeintheDrosophilaSLRL assay(Refs.116,121,and123). 2.4-Dinitroaniline is alsobeing testedfor in vitro cytogeneticseffects(Ref. 120). EPA believesthatanin viva cytogeneticstestis necessaryforrisk assessmentpurposes,andmanufacturershave agreedto performthetesting (mousemicronucleus).
V. Export Notification
Theissuanceof theseConsentOrderssubjectanypersonwho exportsorintendsto exportaniline, 2-chloroaniline, 4-chloroaniline,3,4-dichloroaniline,2-nitroaniline,4-nitroaniline,2,4-dinitroaniline.and2,8-dichloro-4-nitro-anilineto theexportnotificationrequirementsof section124b)of TSCA. Thespecificrequirementsarelistedin 40 CFR Part707.EPA addedandreservedsubpartCof 40 CFR 799.5000for a list of testingconsentordersissuedby EPA. Thislisting servesasnotificationto persons,who exportor whointendto exportchemicalsubstancesor mixtures whicharethe subjectof testingconsentorders,that 40 CFR Part 707 applies.
(3) SodyecoInc.Commentsof SodyecoInc.on the Advance Notice of ProposedRulemakingon the Needfor AdditionalTestingofAnilines Undersection4 of TSCA.Letterof March 2. 1984 from B.W. Drum toTSCA Public Information Office.
(4) EastmanKodakCompany.CommentsofEastmanKodak on theAdvanceNoticeofProposedRulemakingon the NeedforAdditional Testingof Aniline Undersection4of TSCA. LetterofMarch 2. 1984 from R.F.Brothersto TSCA Public InformationOffIce.
(5) Upjohn Company. Aniline and Chloro-,Bromo- and/or Nitroanilines: Responseto theInteragencyTestingCommitteeby UpjohnCompany. Letter of February28. 1984 fromJ.S. Mehringto TSCA Public InformationOffice.
(8) Cleary, Gottlieb, Steenand Hamilton.Commentson AdvanceNoticeof ProposedRulemakingfor Chioro-,Bromo-. and/orNitroanilines (Appendix A. ConfidentialBusinessInformation)for theSubstitutedAnilines TaskForceof the SyntheticOrganicChemicalManufacturersAssociation~(19841.
(10) SOCMA. SyntheticOrganicChemicalManufacturersAssociation.Letter from A.Rautio of SyntheticOrganicChemicalManufacturersAssociationto M. McCommas,Office of Toxic Substances.USEPA.(ConfidentialBusinessInformation). (1985).
(11) SOCMA. Letter from A. Rautio ofSyntheticOrganicChemicalManufacturersAssociationto M. McCommas.Office ofToxic Substances.USEPA. (1985).
(13) OSHA. U.S. Departmentof Labor.‘OccupationalHealthGuidelinesforAniline.” (1978).
(14) ACGIH. American ConferenceofGovernmentalIndustrialHygienists.“TLVs:Thresholdlimit valuesfor chemicalsubstancesandphysicalagentsin the workenvironmentwith intendedchanges.”HygienicGuideSeries:Aniline. (1980).
(15) Monsanto.MonsantoCompany.“Evaluationof blood methemoglobinlevelsfor workers involved in productionof parc-chloroaniline.”Unpublishedcompanydata.(3986).
(16) DuPont.Letter from T. Lewisof DuPontandCompanyto M. McCommas,Office ofToxic Substances,USEPA. (1984).
(17) Ewing.B.B. andChian.E.S.K.“Monitoring to detectpreviouslyunrecognizedpollutantsin surfacewater.”EPA ReportNo. 560/6—77—015performedbyUniversityof Illinois for Office of ToxicSubstances,USEPA.(1977).
141) Hsu.T.S. and Bartha, R. “Hydrolyzableandnonhydrolyzable3.4-dichloroanilinehumuscomplexesandtheir respectiveratesof biodegradation.’Journalof Agriculturaland FoodC’hemistry. 24:118—122.(1976).
(42) Freitag,D.. Scheunert.I.. Klein. W . ~ndKorte. F. “Long-term fate of 4-chloroaniline-14C in sodandplantsunderoutdoorconditions.A contributionto terrestrialecotoxicologyof chemicals,”JournalofAgricultural andFoodChemistry.32:203—207(3984).
(44) Miller. CC.. and Crosby,D.C.“Photooxidationof 4-chioroanilineand \.(4chloropheny~-benzenesulfonamideto ni rosaandnitro products.” Chemosphere12)9(.t217—1227. (1983).
(45) Wolff, C.J.M.. and Crossland.N 0.“Fate andeffectsuf 3.4-dichloroaniline ri helaboratoryandin ou~doorionds: I. Fate.’EnvironmentalToxicologyandChernistr;4:481-487,(1985).
(49) Zeyer, J. and Kearney.P. C. “Microbialmetabolismof 14C nitro.anilinesto ~4Ccarbondioxide.”Journalof AgriculturalandFoodChemistry31:304—308. (1983).
(50) Van Alfen, N.K. andKosuge.T.“Microbial metabolismof thefungicide 2.8-dichloro-4-nitroaniline.”JournalofAgricultural andFoodChemistry22:221—224.(1974).
(51) USEPA.“Predictedenvironmentalconcentrationsfor selectedsubstitutedanilines.” ConfidentialBusinessInformation.preparedby M. McCommas,TestRulesDevelopmentBranch, Office of ToxicSubstances.(1985).
(52) USEPA. Memo: SurfaceWaterConcentrationsof Aniline from P. Harrigan.DesignandDevelopmentBranch.Office ofToxic Substancesto M. McCommas,TestRulesDevelopmentBranch,Office of ToxicSubstances.USEPA. ConfidentialBusinessInformation. (1985).
(531 Calamari.0.. Da Casso,F.. Cslsss:.SProvini, A. and Vighi. M. “Biodegradat:unand toxicity of selectedamineaon squstorganisms.”Chemosphere9:733—752 )1Q5(~.
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(54) Canton,J.W., Sloof. W., Kook.H.).,Struys. J.’ Pouw,J.M.. Wegznan,R.C.,andPiet.C.). “Toxicity BiodegradabilityendAccumulationof a Numberof Cl/N-ContainingCompoundsfor ClassificationaridEstablishingWaterQuality Critena.”ReeulatoryToxicologyandPharmacology5.123—131.(1985).
(551 Adema, 0MM. “Daphnia magnaasatestanimal in acuteandchronic toxicitytests.” Hydrobiolagy. 59:125—134.(1978).
(64) Sipes.l.G. andCarter.D.C..“Pharmacokinetics of xenobiotics:p’~chioroaniline.” University of Arizona.Tucson,Arizona for National InstituteofEnvironmentalHealthSciences,Reaes~rchTriangle Park. NC. (1984),
(65) Matthews, H.B.. Chopade~H.M.. Smith.R.W.. and Burke. LT. “disposition of 2.4-dinitroaniline in themaleF—344 rat.”Xenobiotica16:1—10, (1986).
(66) Chopade,H.M. andMatthews. H.B.“Dispositionandmetabolismof Z’brorno-4.6-dinitroaniline in the male F—344 rat.” Journalof ToxicologyandEnvironmentalHealá17:37—50(1986).
(73) USEPA.Memo: NTP bioassay—p-chloroaniline.From LarryRosenstei.n.ChemicalInformationandAnalysisGroup.Office of Toxic Substancesto Don R. Clay,Director,Office of Toxic Substances.(1985).
(74)Monsanto.“Two-yearchronicgavagestuds’ in rats:Paro-nib’oaniline.”Conductedby BiodynamicsInc. for DepartmentofMedicineandEnvironmentalHealth.St.Louis.MO. Unpublished company data.(1985).
(78) USEPA. Memo from DorothyCanter,Assistantte theDirector,NationalToxicology Programto Dr. LawrenceRosenstein,ChemicalInformationandAnalysisGroup.Office of Toxic Substances.(1984).
(102) Amacher.D.E., Paillet. S.C..Turner,G.N., Ray, V.A.. andSalzburg.D.S. “Pointmutations at the thymidine kinase locus iraL5178Ymouselymphomacells. II. Testvalidationand interpretation.”.t!utationResearch72:447—474.(1980).
(105) Takehusa,S., andKanaya.N. “SCEinduction in humanlymphocytesbycombinedtreatmentwith anilineandnorharman.”Mutation Research101:165-172,(1982).
(108) Ishidate, M., andOdashima, S.“Chromosometestwith 134 compoundsonChinesehamsterovary cellsin vitro—aacreening for chemical carcinogens.”Mutotio~Research48:337—354.(1977).
(107) Parodie.S., Pals,M.. Ru~~o,P. at al.“DNA damagein liver, kidney, bonemarrow,and spleenof rats and mice treated withcommercialand purified aniline asdetermined by alkaline elution and SCEinduction.” CancerResearch42:2277-2233.(1982),
(118) Carner,R.C. andNutman,C.A.“Testingof someazodyes and theirreductionproductsfor mutagenicityusingSalmonellatyphimuriumTA 1538.” MutationResearch44:9—39. (1977).
(117) Thompson.C.Z.. Hill, LE,. Epp.J.K..andProbat.CS. “The induction of bacterialmutationandhepatocyteunscheduledDNAsynthesisby monosubstitutedanilines,”EnvironmentalMutagenesis5:803—811.(1983).
(liz) Valencia,R..Mason. J.M.. Woodruff,R.C.. andZimmering. S. “Chemicalmutagenesistesting in Drosophila. Ill. Resultsof 48 codedcompoundstestedtheNationalToxicology Program.” EnvironmentalMutagenesis7:325—348(1985).
(123)Woodruff,R.C.,Mason,J.M., Valencia.R.,and Zimmering. S. “Chemicalmutangenesistestingin Drosophila.V.Resultsof 53 codedcompoundstestingfor theNationalToxicologyProgram.”EnvironmentalMutrageriesis7:677—702(1985).
Confid~tialBusinessInformation,while part of the record,is not availablefor p~sblicreview.A public versionofthe record, from whichCBI has beendelete~is availablefor inspectionin theTSCA Public Docket Office, Room. NE—C004.401 M Street~SW., Washington.
31813
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