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43252 Federal RegIster / Vol. 54, No. 2ó3 I Monday, October 23, 1989 I Rules and Regulations ENVIRONMENTAL PROTECTION AGENCY 40 CFR Part. 795 and 799 [OPTS-4209Th FRL 355$~’.7l R~N 2070-ABO7 Isopropanol; Final Test Rul AGENCY: Environmental Protection Agency (EPA). ACTION: Final rule. SUMMARY: EPA is issuing a final test rule, under section 4 of the Toxic Substances Control Act (TSCA), requiring manufacturers and processors of isopropanol (CAS No. 87-83~0) to perform testing for health effects. The testing requirements include subchronic toxicity, reproductive toxicity, deveJopmental toxicity, neurotoxicity, developmental neurotoxicity, mutagenicity, oncogenicity, and pharmacokinetics. The action is in response to the Interagency Testing Committee’s (ITC) designation of isopropanol for priority testing consideration. DATES: In accordance with 40 CFR 23,5, this rule shall be promulgated for purposes of judicial review at 1 p.m. eastern [daylight or standard as appropriate) time on November 6, 1989. This rule shall become effective on December 4, 1989. FOR FURTHER ~NFORMA11OII COISTACT Michael M. Stahl, Director, Environmental Assistance Division (‘L’S.’ 799), Office of Toxic Substances, Rm. EB-44, 401 M SI, SW., Washington. DC 20460, (202) 5544404, TDD: (202) 554- 0551. SUPPLEMENTARY ~NFORMATIO5~ EPA 1. issuing a final test rule under section 4(a) of TSCA to require health effects testing of isopropanol. L Introduction A. Test Rule Development Under 7SCA The final rule is part of the overall implements tion of section 4 of TSCA (Pub. L. 94.’469, 90 Stat. 2003 et seq., 15 U.S.C. 2801 et seq.), which contains authority for EPA to reiulre the development of data relevant to assessing the risk to health and environment posed by exposure to particular chemical substances or mixtures (chemicals). Under section 4(a) of TSCA EPA must require testing of a chemical to develop data if the Administrator makes certain findings as described in TSCA under section 4(a)(1)(A) or (B). Detailed discu8sions of the statutory section 4 ‘indings are provided in the EPA’s first and second proposed test rules which were published in the Federal Register of July 18, 1980 (45 FR 48510) and June 5, 1981 (48 FR 30300). B. Regulatory History The Interagency Testing Committee (ITC) recommended isopropanol with intent to designate for health effects testing consideration In its 19th Report, published in the Federal Register of November 14, 1988 (51 FR 41417). The ITC designated isopropanol for priority testing consideration in its 20th Report (May 20, 1987, 52 FR 19020), The ITC recommended that isopropanol be tested for chronic toxicity including ancogenicity, and for genotoxicity including mutagenicity in mammalian systems and clastogenicity. Testing for developmental and reproductive effects was deferred from consideration pending the outcome of relevant studies that were being conducted In the United Kingdom by the British Industrial and Biological Research Association (BIBRA). EPA responded to the ITC’s recommendations for isopropanol by Issuing a proposed rule (March 16, 1988, 53 FR 8638), which proposed that isopropanol be tested for subchronic toxicity, reproductive toxicity. developmental toxicity, neurotoxicity, developmental neurotoxicity, mutagenicity, oncogenicity, and pharrnacokinetics. Consent order negotiations for isopropanol, attempted prior to rulemaking, were abandoned when consensus could not be reached between EPA and the Isopropanol Panel of the Chemical Manufacturers Association (CMA) on the requirements of a two.species oncogenicity bioassay. The proposed rule for Isopropanol contained the discussions on the attempted consent order, chemical profile of isopropanol, section 4(a) findings, and the proposed test standards and reporting requirements. U. Response to Public Comments EPA received written comments on the isopropanol proposed test rule from the Isopropanol PaneE of CMA (the Panel), the Procter and Gamble Company (PGC), and the Natural Resources Defense Council (NRDC) on May 18, 1988 (Refs. 1 through 3).The Panel members are: Arco Chemical Company, Exxon Chemical Corporation. Shell Oil Company, and Union Carbide Corporation. A public meeting was also requested by the Panel and was held on June 1, 1988. The Panel submitted supplemental written comments on July 21, 1988 that reiterated the issues discussed at the public meeting (Ref. 4), A summary of the conunents received on the leopropanol proposed test rule are stated in the following Units 11. A. and B. along with EPA’s responses to the comments. A. Exposure Finding The Panel stated that it does not dispute EPA’s finding that there is or may be substantial exposure to isopropanol, although it does not accept allaspects of EPA’s characterization of exposure (Ref. 1). 1. Exposure during isopropanol manufacture. The Panel expressed concern that EPA’s proposed rule may have overstated worker exposure to isopropanol during its manufacture. The Panel indicated that it had initiated a survey ofits four members, who produce all of the U.S. isopropanol at five manufacturing sites, to obtain data on potential and actual exposure during production of isopropanol (Ref. 1). The survey results, submitted to EPA as part of the Panel’s supplemental written comments, showed that there are 395 manufacturing employees in the United States who are potentially exposed to Isopropanol. The concentration of Isopropanol to which employees are exposed ranged from 0.02 parts per million (ppm)to 6.41 ppm (Ref. 1). The worker exposure level to Isopropanol of 50 mgf m~ (approximately 20 ppm) during Its manufacture, stated in the proposed rule, is the upper limit of exposure derived from EPA analysis (Ref. 5). Although worker exposure to isopropanol from manufacturing operations is generally less than this value, EPA believes that worker exposure from isopropanol manufacturing operations is only a minor source of occupational exposure to Isopropanol. Worker exposure from industrial use is a much greater source of occupational exposure to isopropanol (Ref. 5). Therefore, the data on exposure to workers at manufacturing facilities are of only limited use, since exposure to workers from processing and use of Isopropanol. which contributes a far greater proportion of the exposure upon which the substantial exposure finding Is based, was not considered by the Panel. 2. Inhalation exposure within the generalpopulation. The Panel suggested that lsopropanol may be a naturally occurring constituent of milk, therefore. the Pellizarri mother’s milk study (Ref. 6) should not be used as evidence of exposure to isopropanol in the general population. The Panel also pointed out several serious flaws with this study. EPA agrees that there are flaws in the Pellizzarl study and is not using the study to support the findings in the rule.

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Page 1: EPA/Isopropanol; Final Test Rule · isopropanol frommanufacturing operations is generally less than this value, EPA believes that worker exposure from isopropanol manufacturing operations

43252 FederalRegIster/ Vol. 54, No. 2ó3 I Monday, October23, 1989 I Rulesand Regulations

ENVIRONMENTAL PROTECTION

AGENCY

40 CFRPart.795 and799

[OPTS-4209ThFRL 355$~’.7l

R~N2070-ABO7

Isopropanol;Final TestRul

AGENCY: EnvironmentalProtectionAgency(EPA).ACTION: Final rule.

SUMMARY: EPA is issuinga final testrule, under section4 of theToxicSubstancesControlAct (TSCA),requiringmanufacturersandprocessorsof isopropanol (CAS No. 87-83~0)toperform testing for health effects.Thetesting requirements include subchronictoxicity, reproductive toxicity,deveJopmentaltoxicity, neurotoxicity,developmentalneurotoxicity,mutagenicity, oncogenicity,andpharmacokinetics.The action is inresponseto the InteragencyTestingCommittee’s (ITC) designationofisopropanol for priority testingconsideration.DATES: In accordancewith 40 CFR23,5,this rule shallbepromulgatedforpurposesof judicial review at 1 p.m.eastern[daylight or standard asappropriate) time onNovember6, 1989.This rule shall becomeeffectiveonDecember4, 1989.FOR FURTHER~NFORMA11OIICOISTACTMichael M. Stahl,Director,Environmental AssistanceDivision (‘L’S.’799), Office of Toxic Substances,Rm.EB-44, 401 M SI, SW.,Washington. DC20460,(202)5544404,TDD: (202)554-0551.SUPPLEMENTARY~NFORMATIO5~EPA1.issuinga final testruleundersection4(a) of TSCA to requirehealth effectstesting of isopropanol.L Introduction

A. TestRule Development Under7SCAThe final rule is partof theoverall

implementstion of section4 of TSCA(Pub.L. 94.’469,90 Stat.2003etseq., 15U.S.C.2801et seq.), which containsauthority for EPA to reiulre thedevelopmentof data relevanttoassessingthe risk to health andenvironment posedby exposure toparticular chemicalsubstancesormixtures (chemicals).

Under section4(a) of TSCA EPAmustrequire testing of a chemicalto developdata if theAdministrator makescertainfindings asdescribedin TSCA undersection4(a)(1)(A) or (B). Detaileddiscu8sionsof the statutory section4‘indings are provided in theEPA’s first

andsecondproposedtestruleswhichwerepublishedin theFederalRegisterof July18, 1980(45 FR 48510)andJune5,1981 (48FR 30300).

B. RegulatoryHistory

TheInteragencyTestingCommittee(ITC) recommendedisopropanolwithintentto designatefor healtheffectstestingconsiderationIn its 19thReport,publishedin theFederalRegisterofNovember14, 1988 (51 FR 41417).TheITC designatedisopropanolfor prioritytestingconsiderationin its 20thReport(May 20, 1987,52FR 19020),TheITCrecommendedthatisopropanolbe testedforchronictoxicity includingancogenicity,andforgenotoxicityincludingmutagenicityin mammaliansystemsandclastogenicity.Testingfordevelopmentalandreproductiveeffectswasdeferredfrom considerationpendingtheoutcomeof relevantstudiesthatwerebeing conductedIn theUnitedKingdomby theBritish IndustrialandBiologicalResearchAssociation(BIBRA).

EPArespondedto theITC’srecommendationsfor isopropanolbyIssuinga proposedrule (March 16, 1988,53FR 8638),which proposedthatisopropanolbetestedfor subchronictoxicity, reproductivetoxicity.developmentaltoxicity, neurotoxicity,developmentalneurotoxicity,mutagenicity,oncogenicity,andpharrnacokinetics.Consentordernegotiationsfor isopropanol,attemptedpriorto rulemaking,wereabandonedwhenconsensuscouldnotbereachedbetweenEPAandthe IsopropanolPanelof theChemicalManufacturersAssociation(CMA) on therequirementsof a two.speciesoncogenicitybioassay.

Theproposedrulefor Isopropanolcontainedthediscussionson theattemptedconsentorder,chemicalprofile of isopropanol,section4(a)findings,andtheproposedteststandardsandreportingrequirements.

U.Responseto PublicCommentsEPAreceivedwritten commentson

theisopropanolproposedtestrulefromtheIsopropanolPaneEof CMA (thePanel),theProcterandGambleCompany(PGC),andtheNaturalResourcesDefenseCouncil (NRDC) onMay 18, 1988(Refs.1 through3).ThePanelmembersare:Arco ChemicalCompany,ExxonChemicalCorporation.ShellOil Company,andUnion CarbideCorporation.A publicmeetingwasalsorequestedby thePanelandwasheldonJune1, 1988.ThePanelsubmittedsupplementalwritten commentson July21, 1988that reiteratedthe issuesdiscussedat thepublic meeting(Ref. 4),A summaryof theconunentsreceived

onthe leopropanolproposedtestruleare statedin thefollowing Units 11. A.andB. along withEPA’s responsestothecomments.

A. ExposureFinding

ThePanelstatedthat it doesnotdisputeEPA’s finding that thereis ormaybesubstantialexposuretoisopropanol,althoughit doesnot acceptallaspectsof EPA’s characterizationofexposure(Ref. 1).

1. Exposureduring isopropanolmanufacture.ThePanelexpressedconcernthat EPA’s proposedrule mayhaveoverstatedworkerexposuretoisopropanolduring its manufacture.ThePanelindicatedthat it hadinitiated asurveyofits four members,who produceall of theU.S. isopropanolat fivemanufacturingsites,to obtaindataonpotentialandactualexposureduringproductionof isopropanol(Ref. 1). Thesurveyresults,submittedto EPAaspartof the Panel’ssupplementalwrittencomments,showedthat thereare395manufacturingemployeesin theUnitedStateswhoarepotentiallyexposedtoIsopropanol. The concentration ofIsopropanolto which employeesareexposedranged from0.02parts permillion (ppm)to 6.41ppm (Ref. 1).

The worker exposurelevel toIsopropanol of 50mgfm~(approximately20 ppm) duringIts manufacture, statedin the proposedrule, is the upper limit ofexposurederivedfrom EPAanalysis(Ref. 5). Althoughworker exposuretoisopropanol frommanufacturingoperationsis generally less thanthisvalue, EPAbelievesthat workerexposure from isopropanolmanufacturingoperations is only aminorsourceof occupationalexposureto Isopropanol. Worker exposurefromindustrialuseis a much greater sourceof occupationalexposureto isopropanol(Ref. 5). Therefore, the data onexposureto workers at manufacturing facilitiesareof only limited use,since exposureto workers from processingand useofIsopropanol. whichcontributes a fargreater proportion of theexposureuponwhich the substantialexposurefindingIs based,wasnot considered by thePanel.

2. Inhalation exposurewithin thegeneralpopulation. ThePanelsuggestedthat lsopropanolmay be a naturallyoccurringconstituent of milk, therefore.the Pellizarrimother’s milk study (Ref. 6)shouldnot be usedasevidenceofexposureto isopropanol in the generalpopulation. The Panelalso pointedoutseveralseriousflaws with this study.

EPAagreesthat there areflaws in thePellizzarl study and isnot using thestudy to supportthe findingsin the rule.

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FederalRegister/ Vol. 54, No. 203 / Monday. October23, 1989 / Rulesand Regulations ~g~g

B. Health Effects TestingRequirementsThe Panelagreedwith EPAthat

additional health effectstesting forisopropanolis warranted,Therefore,thePanel’s commentsaredirectedprincipally at the scopeandsequenceofthe required testsand theselectionofappropriate methodologies(Ref. 1).

1. Routeofexposure.a. ThePanelstatedthat, since inhalation is theprincipal route of exposuretoisopropanol, Inhalation shouldbe thepreferred route of exposurefor all of themajor health effectsstudiesconducted,including reproductive toxicity,developmentaltoxicity, anddevelopmentalneurotoxicitystudies.The Panelenvisionedno technicaldifficulties In conducting therequiredstudiesby inhalation. The Panelrecommendedthat exposurebe throughdrinking water if EPAconcludesinhalation is an inappropriate route forany of the major health effects studies.ThePanelfurther statedthatgavageadministrationis particularlyinappropriate for testingIsopropanolbecauseisopropanol demonstratessaturable metabolism.

EPAconcurswith the Panelthat thereareno major technicaldifficulties withconductingdevelopmentaltoxicity testsby the inhalationroute.Thereare,however,technicaldifficulties withconductingboththe reproductivetoxicity anddevelopmentalneurotoxicitytestsby inhalation, Intheselatter teststhe animalsareexposedto isopropanol both duringpregnancy andthrough the periodofweaning.During the time from just priorto birth until the end ofweaningitwould be difficult to transferanimalsdaily to the inhalation chamberfor therequiredexposureperiods.Thisexcessivehandling of theanimals(particularly removal of themotherfromthepups)would likely resultIn adverseeffectson thepups which wasnotchemicallyrelated andwould confoundthe interpretationof theresults.Thiswouldbeparticularly~ueInassessmentsof devel~mantalneurotoxicitywhereaberrantbehaviormight be easilybe attrtb~edtohandling.In addition,If It wasdecidedto exposeboth mothersandpups in aninhalation chamber,the nestingmaterialrequired during the latter partofpregnancy andduringweaningcouldeasily absorbvaporsduringaninhalation exposure,andthe saturatedbedding couldprovidean Important, yetunquantifled. exposureto the testsubstanceto both the mothersand thepups. For thesereasons.EPA disagreesthat inhalation route should be usedfor

~ductingreproductive toxicity and

developmentalneurotoxicityteats.Further,EPAconsidersIt advisable,fortheability to comparereproductiveperformance, that thedevelopmentaltoxicity, developmentalneurotoxicity,andreproductivetoxicity testsbeconductedby similarroutes.

Administrationby gavagehassomedistinctadvantagesfor thedevelopmentalneurotoxicitytesting,The useof gavageadministrationpermits relativelypreciseestimationsofthe dosagesadministered.Bycomparison, drinking water studiesrequire estimatesof Individual waterconsumptlona.Also, somespillageofwater may occurduring drinkingandvolatile chemicalsmay be lostFurthermore, In thedevelopmentalneurotoxicity study, exposureextendsthrough the period ofweaning, andgavageadministrationensuresthatexposureof the pups only occursthroughthe mother’s milk. Since,asmentioned above, it Is desirabletoperform all the reproductiveteatsby thesameroute of administration. EPAbelievesthat gavageadministration Isthe mostappropriate route for thesestudies.

b. While the Panelsupportedthe useof inhalation exposurefor most of thehealtheffects testing, thePanelstatedthatthe Drosophila assayand the Inviva cytogeneticsassayshould not beconductedby inhalationexposure.ThePanelcontendedthat, sincethe datafrom theseassayswill not be useddirectly for humanrisk assessment,thegreaterexpenseinvolved in inhalationstudiesis not justified underTSCA, Inaddition,thePanel contendedthat vapdrphaseexposurehasprovidedInconclusiveresultsin testsof gl~colethers (ReL 7), andthat testsof a similarcompound,methanol,have beenconductedby feeding.Finally, the Panelcontendedthat theuseof a feedingstudywould allow a more readycomparisonwith otherDrosophilaassays.

EPAdoesnot agreethat feedshouldbe the route of administrationIn theDrosophilaassaybecauseof the relativedifficulty of determining thedosagesadministeredby feed.Therelsnoapparentmajor technicalobstacletoperformingthisstudywith lsopropanolusingvapor exposure.The study ofglycol ethersby McGregor (Ref. 7)doesnot indicate thatthereis anyinherentlimitationto theuseof vapor exposure,but, on thecontrary,demonstratesthatthis experimentalsystemis feasibleandhasbeenperformedin thepast.TheinconclusiveresultsreportedIn thisstudywere attributedby theauthorstothe metabolicstatusofDrosophilaand

not to the exposureconditions.Thus,EPA is requiring that lsopropsnolbeadministeredby vaporexposureorbyinjection.

ThePanelmaychooseto conduct thein vivo cytogeneticassayby a routeother than Inhalation.EPA is requiringthe other route to be either oral gavageor interperitoneal(IP).

2. Reproductivetoxicity testing.ThePanelstated that the available data onreproductivetoxicity of isopropanol areadequate.The Panelcites existingreproductive toxicity data In rats toindicatethat reproductive effectsaremoreseverein the first generation. ThePanelalso noted that a recentlycompletedBIBRA one-generationreproductivetoxicity study, currentlyunderreview in the United Kingdom,may provide the necessarydata toassessthe reproductive toxicity ofisopropanol.

The questionof one-vs. two-generation reproductive effectsstudieswas recentlyevaluatedby a panel ofexpertsin a workshop sponsoredby theEPA’sRisk AssessmentForum. ThePanelof expertsconcludedthat, byitseIf~a one-generationreproductiveeffectsstudy is Insufficientto Identifyall potential reproductive toxicantsandthat a two-generationstudy is neededfor an adequateassessment(Ref. 8).Thus, EPA considers that theone-generation studyconductedby BJBRA,evenwhen it becomesavailable in theUnited States,will not provide the dataneededfor an adequateassessmentofthis endpoint. Becausethereis nobenefit in delaying the two-generationreproductive toxicity testingforisopropanol until theBIBRA studybecomesavailable, EPAis requiringtesting for this endpoint in this rule.

3. Developmental toxicity testing.ThePanelrecommendedthat EPA Include atwo-speciesdevelopmentaltoxicitystudy in its final rule but stay therequirement to conduct testingin the ratuntil the results of a rat developmentaltoxicity study conductedby BIBRAbecomesavailable. It furtherrecommendedthat at this juncture,following a public meeting,EPAcoulddetermine whetheradditional testinginthe rat Is needed.

EPAconcurswith the Panel’scontention that the BIBRA studymayfulfill the data needsfor developmentaltoxicity testing In rats. To assurethatadequatetesting is availableIf BIBRAdataarenot submitted in a timelymanner,EPAIs requiringa two-speciesdevelopmentaltoxicity testin this rule.The testingrequirementIn the rat willbereexaminedafter the BIBRA data arereceivedby EPA.

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43~54 FederalRegister / Vol. 54, No. 203,1 Monday. October23, 1989 / Rules and Regulations

4. DevelopmentalneurotoxicitytestLng. a.ThePanelnotedthat inprevious test rules, developmentalneurotoxicitytestshave onlybeenrequired when data existsto raiseconcernabout this endpointfor the testcompound,andthat the testswererequired asa tier-il typestudy. ThePaneldisagreedwith EPA’s decision tousedata on other short chain alcohols,ethanoland t-butanol, to support thedecisionto require developmentaltoxicity testing of isopropanol. ThePanelstatedthat studiesby Nelsonandco-workers on ethanoland1-propanol(Refs. 9 and10) only reportedchangesinneurotransmitterlevels andhencecanonly be used to support similartypes oftestingrather than the more extensivetestsrequired in the proposedrule.

EPA Is concernedthat data on othershort chainalcohols have showndevelopmentalneurotoxic effects.Asstatedin the proposedrule, EPAisbasingthe developmentalneurotoxicitytesting requirement for isopropanol ontheauthorityof section4(a)(1)(B), notsection4ta)(1J(A),of TSCA. Becausethere Is a high degreeof exposuretoisopropanol, EPA hasdecidedthattesting should not be delayed.

b. The Panelalsonoteda number oftechnical issueswith regard to theconduct of the developmentalneurotoxicity testg.For Instance,statistical questionsconcerningthenumberof animalsrequiredforeachtestand neuropathology issuesregardingsuch questionsasthe typeof histologicstainsto be used.the techniquesforexaminingthe spinal cordandothernervetissues,andthe measurementofbrain tissuesneedto be resolved.

The neuropathologyissueswereraised earlier in a July 9, 1987 letterfromDr. John L O’Donoghueto the CMAGlycol EthersProgram concereingsimilar testing under a consentorder fortriethylene glycol ethers(Ref. 11).Theseissueswere subsequentlyaddressed -

(Refs.12 and 13).c.Finally, thePanelmaintainedthat

an evengreaterprobl~with regardtothe developmentalusiwotoxicity testsIsthe lack of testingI~ thatcanperform thesetestsby therequiredGood LaboratoryPrectiasStandarde(GLPS).

On the basisof infornzatlcaz availableto EPA. it appearsthat somecapabilityexistsfor conductingdevelopmentalneurotoxicity studiesat this timeandadditional capability will beavailable Inthenearfuture (Ret 14).

L Neuroto~xici~ytailing, a.The Pane!statedthat the existingstudy in humansby Mainhshet a). (Ret 15)providessufficientdata to indicatethat exposureto isopropanol doesnot resultIn any

neurologicimpairment.in this study.workers were exposedto isopropanolatan averagecencentretionof 181 ppm.with bothaaphtha(50 ppm) andhexane(39 ppm) alsopresentin theair. ThePanelnotedthat neither haxanenornaphtha ismetabolizedby alcoholdebydrogenase,nor wou.ld it beanticipated that thesecompoundswouldinducethisenzyme,andthusthemetabolism of isopropanolshouldnotbeaffectedby the co-exposure.In thisstudy, no relation wasobservedbetweensolvent exposureand10behavioralvariables.ThePanelcontendedthat the lack of observedeffectsinhumansis supportedby theanimal data by-Boughton (Ret16),whoobservedonly slight reversibledecrem.entin performancein ratsmaintainedondrinkingwatercontainingsufficientIsopropaxiolto result in weightlossin the testanimals,The Panelstatedthat this is sufficientevidencethatisopropanolhaslittle potentialto beaneurotoxic agent, andthat EPA shouldnot requirefurther testing.

EPAdisagreesthat the studiesCitedby the Panelprovide sufficientdata toevaluatethe neurotoxicity ofisopropanol. The study of Maizlishet al.has severelimitations. The entireexposedpopulationIn this studyconsistedof 240 workersin four plants:however, the subgroup referred to by thePanelwasmadeup of only 28individualsfrom one plantwhosignedconsentformsand were tested.Not onlywasthis group small,but the authors ofthe study were concernedwith biasessinceonly thosewho volunteeredweretested.Also the extentof exposurewasdeterminedthroughan analysisof air inthe breathingzonetaken only during theweek thatthebehavioraltestingwasconducted.Thereis no data to indicatethat the reportedexposurewasrepresentativeof exposurein this plant.Possiblythemostcritical limitationwaswithregardto studydesign.As theauthorsnoted,thiswasa cross-sectionalstudywhichhasmanyinherentlim1tat1ou~.Thepredominantconfoundersarethehealthyworkereffectsinceworkerswhohaveill healtharelikely to either leaveemploymentorbe transferredto otherjobs, endnotbepresentat thetimeth. studyIsconducted.in addition, sub$ectsarenotfollowed up with time, andthis doesnotpermitevaluationof deteriorationofperformanceu thesubjectsage.Also,theearlystudyby BoughtonIsInadequate.sinceonly one dosewasused,5 pu~ueitIn thinklugwater,andthe onlybehavioraltestperformedwastheactivity andmazeIsarulugtestswhichwould allowfor only a limitedability to detectneurologicaleffects.

Takentogether,thesetwo studiesareinadequate to predict thepotentialforisopropanolto produceneurologiceffects,and are insufficient to justifyeliminationof theproposedtesting.

b. The Panelstatedthat thesubchronicneurotoxicitytestshould notbe initiateduntil completion of the acutestudy. The benefitscited by thePanelinclude the ability to identifyappropriate dosesfor the subchronicstudy, and the identificationof potentialimportant endpointsin theacute studywhich maybe monitored morecloselyinthe subchronic test.

EPA agreesthat there are advantagesto conductingthesetestssequentially.There are, however,disadvantageswhich includedelays in the receiptofdata, and the Inability to conduct theacutetestsas a satelliteof thesubchronic test.Sinceit is estimated bythe Panelthat performingthe testssequentially wouldresultin anextensionof the reporting requirementsfrom 15 to 30 months, EPA hasdecidedthat this would undulydelayobtainingtheneededdataand that the scheduleasoutlined in the proposedrule shouldbemaintained.

c.The Panelstatedthat EPAmustresolvetechnicalissueswith regardtothe adult neurotoxicitytestsbefore thetestsaxerequired.Someof theseissuesare thesameasdiscussedfor thedevelopmentalneurotoxicitytestsandhave beenaddressed.(Refs. 12and 13).

In addition, the Panelnotes that foreachof the proposedmotor activitytests.“...eachtest or control group mustbe designedto contain a sufficientnumberof animalsat the completion ofthe studyto detect*40 percentchangeIn activity of the testgroupsrelative tothecontrol groupwith 90 percentpowerat the 5 percentlevel.” The Panelmaintainsthat testing laboratoriesandindustrial companylaboratorieshaveinsufficientexperiencewith thesetestprotocolsto be able to predictthenumber of animalsneeded.Data wouldnot be available from published studiessincepublishedarticlesoftenunderestimatevariation,and thesetestshave beenconductedby universitygroupswhich havea greatdeal ofexperienceIn conductingsuchtests.AlthoughthePanelexpectsthatmany oftheseissueswill beresolvedbyneurotoxlcitytestingthat is nowunderway,the Panelwantstheadultneurotoxlcltytestingto be stayedifunresolvedIssuesremainat the timeofpromulgationof the final rule onisopropanoL

As riotedIn thememorandum fromRees(Ref. 13),somejudgmentisrequiredto determiningthe parameters

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FederalRegister I Vol. 54. No. 203 I Monday, October 23, 1989 1 Rules and Regulations 43~55

to be used in the determination ofsample size.Thedetermination ofsample size to allow for confidenceinexperimental results(a not limited toneurotoxicitytesting.but is an integralpart of all test protocols.It isprofessionaljudgement which allows aninvestigator to determine thenumber ofanimals neededand dosesto be used tohave sufficient animals at theterminationof the study for validinterpretationof the results.EPAbelievesthat, with the informationgainedby ongoingtesting and the useofprofessionaljudgment.it will bepossibleto reasonablypredict thenumbersof animals neededfor the adultneurotoxicity tests,and that the smallamount of uncertainty involved withregard to the questionof number ofanimals doesnot justify a delay intesting.

6. Mutogenicitytesting.a. ThePanelagreedthat additional assessmentof thegenotoxicpotential of isopropanol iswarranted; however,It recommendedthat the first tier testsbe modified.Thestudy of Thompson(Ref.17) compared181 compoundstestedfor inductionofchromosornalaberrations in bothinvitro and in vivo assays,and reportedthat similarresultswere obtained with126compoundswhile 53were positivewhen testedin vitro andnegativeinvivo, 2 compoundswerepositive in vivoand negativeIn vitro, and 35 hadequivocalresults.The Panelstatedthatthis data indicatesthat in vitrochromosomalaberrationtestsarenotpredictive of resultsobtained in vivo,and hencethe requirement for in vitrotesting for chromosomalaberrationsshould be eliminated andan In vivomicronucleus testperformedInstead.The Panelalso statedthat the availabledata on clastogeniceffectsIn vitro.negativetestsfor meiotlcnondisjunctionin Neurosporacrassaandsisterchromatid exchange(SCE)In culturedV79 cells,IndicatethatIt I. unlikelythatisopropanolwill beactiveIn otherInvitro systems.In addition,sinceEPAconsidersthe In vf~óç~itonlosomeaberrationassayt~be eqr~lvalentto thein vivo micronucIø~test,the Panelrequestedthat therabb. modified tosubstitute the latterfor the former.Further, the micronucleustestIssubstantially lessexpensiveandhencefulfills the requirement under TSCA ofcosteffectivetesting.

EPA is not requiringthe in vitrochromosomalaberrationassayforisopropanol. Thestudyof Von der Hudeet al. (Ref.18), which evaluatedthepotential induction of SCE In vitro, hasbecomeavailable sincethe evaluationof the data for theproposedrule and

fulfills the requirement for an In vitrocytogeneticassay.This recentlypublished study reported on an assayofisopropanol at four concentration8,3.3,10.0, 33.3, and 100 mM, in the presenceand absenceof metabolic activation,and determined that isopropanol wasnegative.The highestconcentrationtestedwas reported to producecytotoxicity asindicated by a delay inthe cell cycle.

hi regards to the Panel’s argumentsforeliminationof the in vitro cytogeneticassayasa generalrule, EPAdoesnotagreewith the Panel.The study byThompsonshould not be interpreted toindicate that in vitro testing isunnecessary.In that report, the in vitrotestsidentified more compoundsaspotential genotoxicagents than did thein vivo tests.As notedby the authors,the occurrenceof activity in vitro andnot In vivo may result fromdetoxification mechanismsor barrierspresentin the whole animal.It should beconcludedfrom this studythat these“false positives” are only falsepositivesasrelatedto the In viva bonemarrowassay,while the activity observedinvitro may beexpressedat other targetsites.

b. The Panelagreedto perform Tier IIItestsif earlierresults are positive;however, the Panelnoted that there issomecontroversy overthemousevisiblespecificlocus(MVSL) test,that EPA isreexaminingthe test,andthat thereis aquestionwhether thisrelativelyexpensivetestcanactually beperformed. The Panel recommendedthatthe EPAnot requireanyTier Ill testsinthe rule, but Instead reopentherulemakingproceedingsif Tier III testsareto be requirecL

EPAI. requiringthe MVSL test in thisrule, but plansto amendall testrulesrequiring theMVSL through a separaterule. EPAhasproposedseparatelytoamendtherequirementfor the MVSL (40CFR 798.5200)for proposedand finaltestrules promulgated under section4(a)of TSCA. EPAplans to allow teatsponsorsof currenttestrules.includingthis rule for isopropanoi,to chooseeitherthe MVSL or themousebiochemicalspecificlocustest(MBSL),after it Is promulgated.to testforheritablemutationsIn mammals.EPAbelievesthat theMBSL andMVSL arecomparabletestsandareacceptablefordetectingthisendpointIn mammals.Thetestguidelinefor theMBSL wasproposedonDecember23, 1988(53FR51847)to be codifiedat 40 CFR 798.5195.EPA Is proposinga reportingrequirementof 51 monthsfor thecompletionof testingfor either theMVSL or MI3SLoncetriggered.The

provision in this final rule for publicreviewprior torequiringTier Ill testingwill permit EPAand the public toaddressmany of the concernsraised bythe Panelwith regard to Tier ill testing.Requiringthe Tier III MVSL testing inthe rule will permit a more expeditioustreatment of questionsconcerning TierIll testing than would be obtained byrequiring the reopeningof therulemaking process.

7. Oncogenicitytesting.The Panel’scommentsreiteratetheposition it tookduringthe consentordernegotiationsthat the designof the oncogenicitystudybe determinedby evaluation of data onthe pharmacokinetics,subchronic,andmutagenicitytesting of isopropanol.After evaluationof this data,adeterminationwould be made as towhether a one speciesor two speciesoncogenicitystudy would be required.

EPArequiresdata from two speciesunder its oncogenicitytesting guidelines(40 CFR 798.3300)and cancer riskassessmentguidelines(51 FR 33992).Forchemicalsof unknownactivity, suchasisopropanol, two mammalian speciesareneededto increasethe powerof thetestto detectpotential carcinogens.Also, anegativesingle-speciesbioassaywould be insufficientevidencetoexonerateisopropanol asa potentialcarcinogen(Ref. 3).

8. Phormacoltineticstesting.a. ThePaneldid not dispute thatpharmacokineticsdata were insufficient.The Panel arguedthat the reportingrequirements specifiedin theproposedrule on isopropanolwill make itnecessaryto initiate subchronic toxicitystudies prior to completion of thepharmacokineticsstudies.This wouldpreclude useof the pharotacokineticsdata for setting doselevelsfor thesubchronic studies.The Panelsuggestedthat it will be necessaryto adjust themaximumdoselevel sothat it doesnotexceedthe metabolicsaturation point,as defined from the results ofpharmacokineticsstudies.The Panelproposed that the subchronic andchronic toxicity studiesbe delayedtoallow for completionof thepharinacokInetics studies.

The proposed reporting requirementsallow15 months from the effectivedateof the final rule for completion of thepharmacokineticsstudy and the90.daysubchronic study, and 53 months forcompletion of the 2-yearchronic study.EPAbelievesthat the reportingrequirementsallow sufficient time forcompletionof the pharmacokineticsstudyand preliminary data analysisprior to initiating the subchronic andchronic toxicity studies.

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43256 FedaralRegister / VoL 54, No. 303 1 Monday, October 23, 1989 / Rulesand ReguLations

b. The Panelsuggestedthat anadditional 9 monthswill be required todevelopinhalationexposuremethodsand assayproceduresfor leopropanoland its metabolitea, andthat thesetaskswill be time-consumingbecausethemetabolismdepartmentsof many testingfacilities areunaccustomedto using theinhalation route for pharmacokineticsand metabolismstudies.

EPA conducted a study to assesstheavailability of adequatetestfacilitiesand concludedthat therewill be testfacilities andpersonnelto perform thetestingspecifiedin this rule. Copiesofthe study, “ChemicalTestingIndustry:Profile of ToxicologicalTesting,” canbeobtained through theNational TechnicalInformation Service (NTIS), 5285 PortRoyal Road, Springfield, VA 22161 (PB82- 140773).With respect to assayprocedures, the Panel’s commentsindicated that methods already exist fordetermining isopropanol and itsmetabolitesin biological materials.Therefore, EPAbelievesthat 15 monthsallowssufficienttime for completionofthe pharmacokinetics testing.

c. The Panel suggestedthatpharmacokineticsdata for the mousemay be useful for interpretingmousebloassays.ThePanelIndicatedthat It isprepared to work with EPAto initiatesuch testingvoluntarily.EPAagreesthatthis data would be extremelyuseful andencouragesthe Panel to perform thesestudies on a voluntary basis.

d. The Panel would like EPA tospecifywhether inhalationexposuresare to be conductedIn dynamicor staticexposuresystems.EPAis requiringinhalation exposuresto be conductedindynamicexposuresystems.Inhalationtoxicity studiesaregenerallyperformedunderdynamicexposureconditions;guidelinesfor subchronicInhalationtoxicity studiesspecifydynamicexposures(see40 CFR 798.24503.It Isalsothe mostconsistentwith the goalsof risk assessmentextrapolations,whichare basedon assumingcontinuousexposuresto a constantconcentrationofair-borne chemicals.Puxt,hermore, It Isthe only exposuresystemIn whichexposureto volatile mefabolitescanbeprevented.

e.The Panelexpressedconcernaboutthe requirement foruseof rsdlolsotopesin the pharmacoklnetlcsstudies.ThePanelsuggestedthatvery largequantitiesof radioactivity would berequiredfordynamicinhalationexposuresand that Incorporationofradiolabel into tissueconstituentsmayleadto confusingor misleadingdata ondistributionof thetestsubstance.

EPA believesthat useof radiolabelinconjunction with chromatographictechniquesprovides themoat reliable

and sensitivemeansfordetectingmetabolitesand forevaluatingmassbalancefor thecarbonskeletonof thetestsubstance.l’he objectiveof themetaboliteidentification requirementsspecifiedin theproposedruleis toidentify themajormetabolitesofisopropanolIn tissuesand excreta.toprovide data for evaluatingthecontribution of metabolismtodetoxification or activation ofisopropanolIn the testspecies.Ifmetabolic incorporationof theradiolabelinto tissueconstituentsisaquantitatively significantmetabolicfateof isopropanoL thenthis should bedocumentedwith data regarding theidentityof the incorporated label. Suchincorporation may representfixation ofCO1 derived from the degradationofisopropanol or may representa covalentinteractionof tissueconstituentswithreactivemetabolitesof isopropanol.Ineither case,it will be importanttodocumentthenatureof theincorporation.Indeed,only with the useof radiolabeledisopropanolis this kindof rigorousanalysispossible.

f. The Panelexpressedconcernaboutthe requirementfor collection of exhaledair, urine,and fecesexcretaduringnose-only or head-only inhalation exposures,and Indicatedthat the latteris nottechnicallyfeasible.EPAagreesthatcollectionof multiplesamplesof urineand fecesfrom suchanapparatusmaybe verydifficult andhasmodified theguidelineaccordingly.

g. ThePanel expressedconcernaboutthe definition for percent absorptionthatIs cited In the proposedrule. Thedefinitiongiven by EPA I. ...100timesthe ratio betweentotal excretionofradioactivity followingoral or Inhalationadministrationand totalexaetionofradioactivity following intravenousadministrationof testsubstance.”EPAagreesthat for compoundsadministeredby the oralroute, this calculationmayoverestimatetheactualpercentabsorptionby thatamountof chemicalthat passesthrough the gastrointestinaltractwithoutabsorption.Thus,EPAhasmodified theguidelineto reflectthischange.

h. The Panelexpressedconcernovertheselectionof anappropriatetoxicityendpoint on which to basetheselectionof thehighdoselevel to beuaedlnthepharm.cokfnetlcastudies.

The ol4ectlveof thehigh-~elevelstudyisto ex~min.theabsorption,distribution,metabolismandexoretionof the testsabatanceat thehighestdoselevelthatcanbeachievedwithoutseverelyperturbingor impairingtheabovemechanisms.Doselevelsthatproduce frank effects,e.g..convulsioou,coma,anddeath,areclearly

unacceptablesincethe dispositionmechanismsarelikely to beseverelyperturbedor impairedin severelypoisonedanimals.Ideally, thehigh doselevel should be the lowest observableeffect level.This effectwill varydependingon the chemicalanditstoxicologic characteristics,In the caseofisopropanol.for which narcosisrepresentsan Important critical effect,the doselevel at or just below thatrequired to produce mild symptomsofnarcosisseemsappropriate. Therelevant observationperiod inwhich todefine the effectwould include theexposureand samplingperiod, since itwould not beproductive to exposeananimalto a dosethat results inunconsciousnessor frank effects afterthe exposureand before the samplingwascompleted.Note that toxicity will ~define the highestdoselevel acceptablefor testing; however, this doesnotprecludetestingof several levelsbelowthe high-dose leveL althoughEPArequiresthat only onenontoxic doselevel be examined.

C. TSCA Sectionsland 12(B)RequiremenLs

PGC proposedthat EPAexcludesmallmanufacturersandimportersfrom therequirementsof section4. PGCsuggestedthis exclusionincludeproduction or importationof 25,000lb/yror less.In addition,PGCsuggestedthatEPAeliminatetherequirementfor allsection12(b) reporting for isopropanol.sincethe benefit wouldnotbecommensuratewith the burden that thisreportingrequirementwould place uponEPA.!! all section12(b) reportingis notexempted,thenPGCfurtherrecommendedthat a smallquantityexemption(shipmentof 25,000lb/yr orless)be usedto eIimin*te the burden tosmallcompanies.

Since theseissuesapply to all section4 rulesand consentordersand thecommenterhasnot distinguishedhowthis rule is anymoreburdensomethanother section4 rules,EPA rejects thesecomments.EPA iscontinuing to look atthe burdenof section4 and12(b)requirements.EPAhasproposedamendmentsto its proceduralrule thatwould alleviatetherequirementofcertain manufacturersto submit lettersof intent to testorsubmitexemptionapplications (54 FR 21237;May 17, 1989).EPAhasalsoproposedamendmentstoits section12(b)rules(54FR 29624;July12, 1989) to reducetheburdenof section12(b) notificationas it relatesto section4.

4

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Fe~sralRsg~terI Vol. $4, No. ~)3 I Mosxlay, October23, 1989 / Rules and Rsgulatios 43357

V. Swnmcr~ofNRDC’sCommentsIn general,NRDCconcurredwith the

testingprogramoutlinedby EPA In itsproposedrulefor lsopropanol.Specifically, NRDC agreed thatoncogenicftytestingmustbeconductedin two speciesand thata two-generationstudy is necessaryto adequatelyassessreproductiveeffects.NRDCrecommendedthat theBIBRA study onthe developmentaleffectsbeusedtoreplacetherequireddevelopmentaltesting in the ratonlyif it is submittedand reviewedin a timely fashion.HI. Final TestRulefor lsopropanol

A. FindingsEPA isbasingit~final health effects

testing requirementsfor loopropanolonthe authority of section4(aXl)(B) ofTSCA.

EPAfinds that isoptopanolisproducedin substantialquantitiesandthat thereis ormaybesubstantialhumanexposureto isopropanolfrom itsmanufacture,pz’ocesaing.use,anddisposal.Theavailabledataonisopropanol,discussedin Unit II. of thepreamble to the proposedrule (53 FR8638),showthat theannualproductionvolume of isopropanolhasbeeninexcessof 1 billion pounds since1956.and that it was ranked50thamongchemicalsproduced in the United Statesin 1985.There is or may be a substantialnumberof workersexposedtoisopropanolfrom activities relatedto itsmanufacturing,processing,distributionin commerce,anduse.The NationalOccupational Hazard Survey (NOHS)conductedby the National InstituteforOccupationalSafetyandHealth(NIOSH) from 1972 to 1874estimatedthat therewere 8,899,594exposuresin357,173plants,potentiallyexposing5.483,862peopleto isoprupanolin theworkplace in 1970.The NationalOccupational ExposureSurvey(NOES)estimatesthat1,857.972workers,60percent of whom were female,werepotentially exposedto leopropanolInthe workplace in 1980.

Isopropanolisusedesasolventandis a component ofnumosoindustrialproducts, consumerpsodticts,aidcomi~ercialsprays.Theaboveusesmayresultin widespreadexpameetoworkers and consumers(Ref. 5). EPAbelievesthatexposuresassociatedwiththemanufacture,processing,use,anddisposalof isopropanol and its peodizctsprovidea sufficientbasisfora findingthat there is or may be substantialhumanexposureunderTSCA section4(a)(1)fB) for isopropanoL

Under TSCA Section4(a)(1)(B)(ii)and(iii), EPAfinds that existingdata areinsufficient to reasonablydetermineor

predict the snbchronic. reproductive,developmental.naurotoxic.developmentalneurotoxic, mutagenic.and oncogeniceffects of humanexposureto isopropanolresulting fromits mamifacture.processing,use,anddisposaLEPAalsofinds that thereareinsufficientdatato reasonablypredictand compare the absorption,distribution, metabolism,andexcretionof isoprop~noiin the body asa resultoforal or Inhalationexposureduetoisoprapanol’smanufacture,processing,use,and disposal.and that an oral!inhalation comparativepharmacokineticsstudy of isopropariolis necessaryto developsuchdata. Thereasonsdata areinsufficientarefurtherdiscussedinUnit II. B. of this preamble.EPAbelievesthat the datageneratedfrom this testing Will berelevantto adeterminationas to whetherthemanufacture, processing,use, anddisposalof isopropano)doesordoesnotpresentan unreasonablerisk of injury tohuman health.B. RequiredTestingandTestSti’zndards

On thebasisof thesefindings. EPAisrequiringthatcertainhealtheffectstestingbe conductedfor isopropanolinaccordancewith scientifictestguidelinesset forth in40 CFR 795 and798.

To assessthe degreeof toxicologicalactivity of isopropanol upon varioustarget organs, EPA is requiringthatisopropanol be testedfor subchronictoxicity by inhalation(40 CFR 798.2450).

EPAIs requiring that testingforreproductive effects(40 CFR 798.4700),anddevelopmentaltoxicity (40 CFR798.4900)bedonebygevage.

To assesstheeffects of acuteneurotoxicinhalationexposurestoisopropanoLEPAii requiringanacuteaeurebehevloreltoxicity evaluationconsisting of a functional observationalbattery(40CFR 798.6860),andmeasurementof motoractivity (40 CFR798.6200).

To assessthenenrotoxiceffectsofrepeatedinhalationexposurestoisopropanol. EPA is requiringasnbchronicneurobehavioraltoxicityevaluationconsistingof aneuropatbologicevaluation of tissuesperfusedinsitu(40 CFR798.6400).afunctionalobservationalbattery(40 CFR796.8050),andmeasurementof motoractivity (40 CFR798.8200).Thisrequiredbatteryof neurotoxic evaluationmaybecombinedwith the sabthronictest(40CFR798.2450).

To assessthe developmentalneurotLudcftypotentialof iaopropanoLEPAis requiring a developmentalneurotoxicityevaluatIon(40CFR795.250).

To assessthe potentialforisopropanolto cauSegenemutations,EPA is requiringthat testingbeconductedfor genemutationsin cells inculture(40 CFR798.5300).if the resultsof the cells in culture testare positive, aDrosophila sex-linkedrecessivelethalassay(SLRL) shall beconducted(40CFR 798.5275).A positiveresultin theSLRL assayshall triggera mouse visiblespecific locus(MVSLI test(40 CFR798.5200).if the cellsin culture testisnegative,no further testingis required.Ifthe SLRL assayis negative, the MVSLtestis not required.

To assessthe potentialforisopropanol to causechromosomalaberrations, EPA is requiring that an invivo bonemarrow assay(40 CFR798.5385)be conducted.Should the invivo bonemarrowtestresults provenegative.nofurther chromosome!aberrations testing is required. if theresults of the in vivobonemarrowtestare positive, a dominant-lethalassayisrequired (40 CFR 796.5450).A positiveresult in the dominant-lethalassaywilltriggera heritablefranslocationassay(40 CFR 798.5480).

If theresultsfrom thedominant-lethalassayand/or the SLRL arepositive. EPAwill hold a.public program review priorto requiringinitiation of the heritabletranslocatlonand/ormousespecificlocus testing. Public participation in thisprogram review will be in the form ofwritten public commentsor a publicmeeting Requestfor public commentsornotificationof a publicmeeting,if one isheld, will be published in the FederalRdgister. Should EPA determine,basedonthe weightof the evidencethenavailable,that proceedingto theheritable translocationtestand/orMVSL assayIs no longerwarranted.EPAwill proposeto repealthat testrequirementand, afterpublic conunent,will issuea final amendmentto rescindthe requirement Fora more detaileddiscussionconcerning mutagenicitytiered testingand programreview, seethe final testrule for the C.aromatichydrocarbon fraction (50 FR 20662;May17, 1865).

EPAbelievesthat the oncogenicitytesting is justified withoutwaiting forthe resultsof genemutation tests.EPA isthus requiting a 2-year inhalationbioassayin two specIes(40 CFR798.3300).

To aid in ti~assessmentof thepotential toxicity of Isopropanol for riskassessmentpurposes,EPA isrequiringmetabolismandpharruacokineticstestingby theoral and Inhalationroutesof exposure.EPAbelievesthis testingofisopropanolIs necessaryto reduceuncertaintiesassociatedwith the

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4.3~5g FederalRegister / Vol. 54, N~203.I Monday, October 23, 1969 I Rules and*~a4atfeT~R

extrapolationof testdata fromhigh tolow doses,from speciesto species,andfrom one route of exposure to another.Pharmacokineticstestingin rats is beingrequired to developcomparative,dose-dependent,oral and inhalationabsorption,tissuedistribution.bioaccumulation,metabolism,andexcretion data. These data are neededfor extrapolation purposes.Thenecessaryextrapolations can be madenn the basisof metabolism andpharmacokinetics data obtained from3tudjesperformedby both routes ofisopropanol administration. Repeated‘lose studies are neededto learnwhether multiple exposuresmodify themetabolism and/or pharmacokinetics of:sopropanoL Although there are some~iurnanand rat data, thesearenotidequateto support the required‘3xtrapolations.

EPA is establishingtheTSCA healtheffectstest guidelinesas the test,tandardsfor the purposeof therequiredtestsfor isopropanol. TheI’SCA testguidelinesfor health effectstesting specifygenerally acceptedminimum conditionsfor determiningthe~iealtheffectsfor substanceslike

isopropanol to whichhumansare

expectedto be exposed.C. TestSubstance

EPA is requiringthat isopropanolof atleast99.8percent purity be usedasthetest substance.Commercial isopropanolof suchpurity is available accordingtocommentsreceivedfrom the Panel(Ref.1). EPAhasspecifieda relatively puresubstancefor testing to bestevaluatethe effects attributable to isopropanoiitself. In addition. radiolabeled14Cisopropanol is requiredfor thepharmacokinetics.

D. PersonsRequiredto TestSection4(b)(3)(B) of TSCA specifies

that the activities for which EPA makessection4(a) findings (manufacture,processing,distributionin commerce,use, and/or disposal)determine whobears the responsibility for testingachemical.BecauseEPAhas found thatthere are insufficient data andexperienceto reasonablydetermine orpredict the effectson humanhealthfrommanufacture, processing,use,anddisposalof isopropanoi, EPA is requiringthat personawho manufactureand/orprocess,or who intend to manufactureand/or process,isopropanol, other than

as an impurity, at anytimefrom theeffectivedate of the final testrule to theend of the reimbursementperiod besubject to the testingrequirementsinthis final rule. While EPAhasnotidentified anybyproductmanufacturersof isopropanol, suchpersonsarecovered by the requirements of this testrule. Thereimbursement periodwill end5 yearsafter the last final reportissubmitted to EPAor an amountof timeequal to that which was requiredtodevelopdata, whicheveris later.

E. ReportingRequirements

EPArequiresthat all data developedunderthis rule be reportedinaccordancewith its TSCA GLPS,whichappear in 40 CFRPart792.

In accordancewith 40 CFRPart 790undersingle-phaserulemakingprocedures,testsponsorsarerequired tosubmit individualstudy plans at least45daysprior to the Initiation of eachstudy.

EPA Is requiredby TSCA section4(b)(1)(C) to specify the toneperiodduringwhich personssubject to a testrulemust submit testdata. Thespecificreportingrequirementsfor eachof theteststandardsfor Isopropanolarespecifiedin the foilowthg table:

TABLE—REQUIRED TESTING, TEST STANDARDS, AND REPORTING REQUIREMENTS FOR ISOPROPANOL

Personswho exportachemicalwhichis subject to a final section4 testrulearesubject to the exportreportingrequirementsof section12(b) of TSCA.

Final rules interpretingthe requirementsof section12(b) are In 40CPRPart 707.In brief, asof the effectivedate of thefinal testrule, anexporter of

isopropanolmust report to EPAthe firstannualexport or intended exportofisopropanol to eachcountry. EPAwill

Test lest Standvd(4OCFR

(Months)’

Number011TF~~

~/eaitflEMec~Subchronic - ..-.. —.—...-- .—.-.—.-.-— ...—

2. Reprot5jctionandtwiStyeffects ... ... - - .. .___._~__..

3. Developmental ty....... - .. .. .. ........

.

4798.2450* 798.47004798,4000

152912

241

Mutagenictty . gøne,~talinjis4. Mammaliancells In cutass - .. .“-- ... ...

5. Lo aleass-lInkedrecessiv,lethal .. - .~. ._........_..........

4798.53004798.5275*798.5200

61851

—

286. Mousevisthie specificlocustaM._...... ..~. ~

Mutagenicity . Ch$flJflO5Qfl~abitTabOVI&7. In vivacytogeneticamIcronucleus. .. .. ... —-—-..—.—.— 4798.5396

4798.54501527

248. DomInantlethalassay .. ......... .. .. .. -

9. Heritabletranslocatlonassay .. .. .. ...~_. ............ .... 4798.5460 24’ 3Acute ne~1otoxIclty10. Funcnonalobeavs*ionbswy..._...._.._.. ._. *798.6050

* 798.6200

4 798.6060f 798.62004 798.6400

* 795.250

f 798.3300.

1515

18181821

53

22

2223

8

II. Motor activity .... ......

~bcfronIc ne~cl~12. Functionalobeeivationbetlisy~...__....._........ ......_....... ..._...... ..._

13. Motor activity .._........ ....._..... .-....-..-.-.-..—.. ...... —-—..-.--.....—...—

14. wopathology......,........ ~..._. - .. ...~........__.......

15. Developmentalneito~c~_- .. ...... ~.. ...

Ctworwc lo~ca~16.Oncogenlcity . . ..... ..~. ... .. ..

Phan~acolon5cs.17. Oralandk~tw.Phermacoldn46cs .__. . .............. ... 4796.231 15 2

Numberci monthsaltartheeffectivedaisci tits?aialmIs. excuet k~J,‘Figias WdcstesSw rapomIn~dest*ie,Ni months,calcutstsdfrom SW daleci noSAcedonci theWet .pcn.arby certilIed letter or FEDERAl. REGISTERnotice

that, following public progamreview of ii ci the then existing data for i.oprcpanol. the Agency Piesde~mIiedthat the reqiefud lssSngmust be performed.

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Fads,.! Rqia~e/ VoL. 54, No. ~3 /_Monday,Ooksber23, i~ /__RulesssdRegulations ~

notify the foreign onunhyconcerning theteat rule for the chemical.F. EnforcementPmvrswz,,

EPAconsidersfailure to comply withany aspectof a section4 rule to be aviolation of section13 of TSCA. Section15(1) of TSCA makesit unlawful for anypersonto fail or refuse to complywithany rule or orderissuedundersection4.Section15(3) ofTSCA makesit unlawfulfor any personto fail or refuse to: (1)Establish or maintain records, (2) submitreports. notices,or other information, or(3) permit accessto or copyingofrecordsrequiredby TSCA. Section15(4)makesit unlawful for any personto failor refuse to permit entry or inspectionasrequired by TSCA section11.Section11applies to any “...establishinent,facility,or otherpremisesin which chemicalsubstancesor mixtures aremanufactured, processed,stored, or heldbefore or after their distribution hicommerce...”EPA considersa testingfacility to be a placewherethechemicalis heldor stored and, therefore,subjectto inspection.Laboratory inspectionsand data audits will be conductedperiodically in accordancewith theauthorityandproceduresoutlined inTSCA section11 by dulydesignatedrepresentativesof EPAfor the purposeof determiningcompliancewith the finalrule for isopropanol. TheseInspectionsmay beconductedfor purposeswhichinclude verification that testinghasbegun,schedulesarebeingmet,andreportsaccuratelyreflecttheunderlyingraw data. Interpretations, andevaluations,andto determinecompliancewith TSCA GLPSandtheteststandardsestablishedin the rule.

EPA’s authority to inspecta testingfacility also derivesfrom section4(b)(1)of TSCA, which directsEPA topromulgate standards for thedevelopmentof testdata.Thesestandardsaredefinedin section3(12)(B)of TSCA to include thoserequirementsnecessaryto assurethatdatadevelopedundertestingrulesarereliableandadequate,and to Include suchotherrequirements asarenecessarytoprovide suchassurazse.EPAmaintainsthat laboratory laspecutlonsarenecessaryto providethis assurance.

Violators of TSCA are subject tocriminal and civil liability. Personswhosubmit materially misleadingor falseinformationIn connectionwith therequirementof anyprovisionof thisrulemaybesubject to penaltieswhichmaybecalculatedasif theyneversubmittedtheir data.Underthepenaltyprovisionsof section16of TSCA. anypersonwhoviolatessection15 ofTSCA couldbesubject to a civil penaltyof up to $25,000for eachviolation with eachday of

operationIn violationconstitutingaseparateviolation. This provisionwouldbeapplicableprimarily tornanufactjz’erswho fall to submit aletter ofIntent or an exemptionrequestand who continuemanufacturingafterthe deadlinesfor suchsubmissions.Thisprovi~onalsoappliesto processorsthatfail to submita letterof intentoranexemptionapplicationandcontinueprocessir~afterEPAhasontifled themof theirobligetiosito submitsuchdocuments(see40 CFP.790.28(b)).Knowing orwillful violations could leadto the imposition of criminal penaltiesofup to $25,000foreach day oiviolatioo,imprisonmentfor up to 1 year,orboth.In determiningthe amountof penalty,EPAwill takeintoaccounttheseriousnessof the violation andthedegreeof culpabilityofthe violator aswell asall the otherfactorslistedinTSCA section18. Otherremediesareavailableto EPA.undersection17 ofTSCA, suchas seekinganinjunctiontorestrainviolationsof TSCA section4.

Individualsaswell ascorporationscould be subject to enforcementactions.Sections15 and 16 of TSCA apply to“,any person”whoviolatesprovisionsofTSCA. EPA may, at its discretion,proceedagainstindividuals as well ascompaniesthemseLves.In particular,thisincludes individuals who reportfalse information or who causeit to bereported.Zn addition,the submissionoffalse,fictitious, or fraudulentstatementsis a violation under 18 U.S.C.1001.

IV. EcimosicAaaly~sof FbmI RuleTo assessthe potentialeconomic

impact of this rule, EPAhaspreparedaneconomicanalysis(Ref. 19) thatevaluatesthe potentialfor significanteconomicImpect on the Industryas aresultof the requiredtesting.Theeconomicanalysisestimatesthatcostsof conducting the required testing andevaluate,the potentialfor significantadverseeconomicImpactasa resultofthesetestscostsby examiningfourmarket characteristicsof isopropenol:(1) pricesensitivityof demand;(2)marketexpectatlons(3) Industrycostcharacteristics; and (4) Industrystructure.

Total testingcostsfor th. final rule forisopropanol are estimatedtorangefrom$2.6to $3.8million. Topredictthefinancialdecisionmakingpracticesofmanufacturingfirms, thesecostshavebeenannualized.Annualizedcostsarecomparedwithannualrevenueasanindicationof potentialImpact.Theannualizedcostsrepresentequivalentconstantcostswhich would have to berecoupedsail yearof the paybackperiodto financethetentingexpenditurein the first year.

The annualized testcosts,usinga 7percentcost of capitalovera period of15 years,rangefrom $289,000to$412,000.Basedott 1967productIonof 1.4billion pound,.theunit testcostsrangefrom $0.00(YZI to10.00029perpound.Thesecostsareequivalentto 0.09to 0.13percentof the currentprice of $0.23perpound.

EPA believes that the potentialforadverseeconomicimpact resultingfromthe costsof testing is low. Thisconclusion is basedon the followingobservations:

1.The annualized costof testingisvery low, at approximately 0.13 percentof product prices in the upper boundcase.

2~Demand for isopropanoldoesnotappear to be sensitiveto a priceincreasein this range.

Refer to the economicanalysis whichis containedIn the public record for thisrule making for a completediscussionoftestcostestimationandpotentialforeconomicImpactresultingfrom thesecosts.

V. Availability of TestFacilities andPersonnel

Section4(b)(1) of TSCA requiresEPAto consider“...the reasonablyforeseeableavailability of the facilitiesandpersonnelneededto perform thetestingrequiredunder the rule.”Therefore, EPAconducteda studytoassessthe availability of test facilitiesand personnelto handlethe additionaldemandfor testingservicescreatedbysection4 testrules.Copiesof the study,“ChemicalTestingIndustry:ProffleofToxicologicalTesting,” can be obtainedthroughthe National TechnicalInformationService(NTIS), 5285PortRoyal Read.Springfield, VA 22181(PB82.140773).On the basisof this study,EPAbelievesthat therewill beavailable testfacilities andpersonneltoperform the testing specifiedin this rule.

EPAhasreviewedthe availabilityofcontractlaboratoryfacilities to conductthe neurotoxicitytesting requirements(ReL a)) andbelievesthat facilities willbe madeavailable for conducting thesetests.The laboratory review indicatesthat few laboratories are currentlyconductingthesetestsaccordingtoTSCA testguidelinesand TSCA GLPS.However, the barriers facedby testinglaboratories to gearup for conductingthesetestsare not formidable.Laboratorieswill needto invest intesting equipmentand personneltraining, butEPAbelievesthat theseinvestmentswill be recoveredastheneurotoximtytestingprograms underTSCA sectIon4 andthe FederalInsecticide,Fungicide andRodenticide

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~3~go FederalRegister I VoL 54, No. 203 / Monday. October 23, 1989 I Rulesand Regulations

Act (FIFRA) continue. EPA’sexpectationsoflaboratoryavailabilitywereborneout under the testingrequirements of the C, aromatichydrocarbonfraction testrule (50FR20675;May 17, 1985).Pursuantto thatrule, the manufacturerswere able tocontract with a laboratory to conductthe testing according to TSCAguidelinesand TSCA GLPS.

VI. RulemakingRecord

EPAhasestablisheda record for thisrulemaking(docket numberOPTS-420978).This record includes thefollowing information:

A. SupportingDocumentation(1) FederalRegisternoticespertaining

to this ruleconsistingof:(a)Notice containingthe ITC

designationof isopropanol to thePriority List (51 FR 41417;November14,1986) andall commentson isopropanolreceived in responseto that notice.

(b) RulesrequiringTSCA section 8(a)and (d) reportingon isopropanol (51 FR4132& November14, 1986).

(c) Notice of final nile onEPA’s TSCAGood Laboratory PracticeStandards(48FR 53922 November29, 1983).

(d) Notice of Interim final rule onsingle-phasetestrule developmentandexemptionprocedures(50PR20052 May17, 1985).

(e) Notice of final rule on datareimbursementpolicy and procedures(48 FR 31788; July 11, 1983).

(f) Interim Final Rule: ProceduresGoverningTestingConsentAgreementsandTest RulesUnder the ToxicSubstancesControl Act (51 FR 2371*June30, 1988).

(2) Communicationsconsistingofi(a) Written public commentsand

letters.(b) Contact reportsof telephone

conversations.(c) Meetingsummaries.(3) Reports—publishedand

unpublished factual materl*ls includingChemical Testing Indu~tsyProflie ofToxicologicalTesting(October~1981).a References

(1)CMA’s Iaopropaen$Pr~amPaneLCommentsonEPA’s PropisedTestRulefor IsopropanolsubmittedtoPublicInformationOffice, USEPA(May16,1988).

(2) The Procter& GambleCompany.CommentsonEPA’. ProposedTest Rulefor leopropanolsubmittedto PublicInformation Offlce~USEPA(May 16,1988).

(3) NaturalResourcesDefenseCouncil. Commentson EPA’s ProposedTest Rule for Isopropanol submittedto

Public Information Office, USEPA(May16. 1988).

(4) CMA’s IsopropanolProgramPanel.Letter from GeraldineV. Cox. ChemicalManufacturersAssociation.2501 MStreetNIN, Washington, DC 20037,toRichard Troast, Test RulesDevelopmentBranch,Office of Toxic Substances,USEPA.Washington.DC (July21, 1988).

(5) USEPA. “Worker exposureassessmentfor isopropanol (WA).”

JohnD. Walker, Test RulesDevelopmentBranch. Office ofToxicSubstances,USEPA, Washington,DC(November20, 1985).

(6) Pellizzari,E.D., et al., “Purgeableorganiccompoundsin mother’s milk.”Bulletin of EnvironmentalContaminationandToxicology, 28:222-238(1982).

(7) McGregor,D.B. “Genotoxicityofglycol ethers.” E,nvirorunentolHealthPerspectives.5797-103(1984).

(8) SyracuseResearchCorporation.“Responseto public comments:Isopropanol.”ContractNo. 68-02-4209(September29, 1988).

(9) Nelson.B.K., et al., “Neurological,but not behavioral deviations In theoffspringof rats following prenatalinhalationexposureto ethanoL”NeurotoxicologyandTeratology,1015-22(1988).

(10) Nelson,B.K., etaL, “BehavioralteratologyInvestigationof 1-propanoladministeredby inhalation to rats.”Paperpresentedat Teratology SocietyMeeting(1988).

(11)EastmanKodakCompany. Letterfrom JohnL O’Dcnoghue.EastmanKodakCompany, 343 StateStreet.Rochester,NY 14650,to Carol Stack,ChemicalManufacturersAssociation,2501M StreetNW, Washington.DC20037(July 9,1967).

(12) USEPA.“Responseto industrycommentsonthe neuropathologyportion of the glycol ether testrule.”Intraagoncymemorandumfrom RobertC. MacPhail,HealthEffectsResearchLaboratory,to CarolGlasgow,TestRulesDevelopmentBranch, Office ofToxicSubstances,USEPA.Washington.DC (January8, 1988).

(13) USE.PA.“OTS-ORD commentsontheproposedprotocolforneurotoxicoloigicaltestingoftrlethylene glycol lmonomethyl ether.”Intraagencymemorandumfrom David C.Rees,Health and EnvironmentalReviewDivision, to Ralph Northrup, Test RulesDevelopmentBranch, Office ofToxicSubstances,USEPA.Washington. DC(February5,1988).

(14)Mathtech. Inc. “Developmentalneurotoxicity laboratory capability.”Intraofficememorandum from J.K Orrellto EdmundCoe,Mathtech, Inc., 5111

LeesburgPike,Falls Church, VA 22041(September19, 1988).

(15) Maizlish, N.A., et al. “Behavioralevaluation of workers exposedtomixtureof organic solvents.”BritishJournalofIndustrialMedicine,42:579-590 (1985).

(16) Boughton, LI. “The relativetoxicity of ethyl and isopropyl alcoholsas determinedby long term rat feedingand external application.” Journal ofAmericanPharmacologyAssociation,33:111-113(1944).

(17) Thompson.ED. “Comparison ofin vivaand in vitrocytogeneticassayresults.” EnvironmentalMutagenesis.8:753-767(1986).

(18) Von der Hude, W. et al.“Genotoxicity of three-carboncompoundsevaluatedin the SCEtest invitro.” EnvironmentalMutagenesis.9:401-410(1987).

(19)USEPA.Economicimpactanalysisof final testrule forisopropanol. Office of ToxicSubstances,USEPA.Washington,DC (February22,1989).

(20) Mathtech, Inc. “Evaluation ofTSCA guidelinesfor neurotoxicitytestthg~Impactof increasedtestingrequirements.” Preparedfor RegulatoryImpacts Branch, USEPA(April 14, 1987).

Confidential BusinessInformation(CBI), while part of the record, is notavailable for public review, A publicversionof the record, from which CBIhasbeendeleted,is available forinspection in theTSCA Public DocketOffIce, Rin. (3-004,NEMall, 401 M St.,SW, Washington. DC 20480.

VU.OtherRegulatoryRequirements

A. ExecutiveOrder12291

Under ExecutiveOrder12291,EPAmust judgewhether a rule is “major”and thereforesubject to the requirementof a Regulatory Impact Analysis. EPAhasdetermined that this test rule is notmalor becauseit doesnot meetany ofthe criteriasetforth in section1(b) ofthe Order~I.e., it will not have an annualeffect on the economyof at least$100million, will not causea major increaseIn prices, and wifi not have a significantadverseeffecton competition or theability of U.S. enterprises to competewith foreignenterprises.

Thisrulewassubmitted to theOfficeof Managementand Budget (0MB) forreview asrequiredby ExecutiveOrder12291.Any written commentsfrom 0MBto EPA. andany EPAresponsesto thosecomments,are Included in therulemaking record.

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FederalReglaterI VoL 54, No. 203 / Monday; October23, 1969 f Rules and Regulations 43~1

B. RegulatoryFlexibility ActUnder the RegulatoryFlexibility Act

(5 U.S.C.601 etseq.,Pub.L 96-354,September19, 1980),EPAis certifyingthat this testrule will not have asignificantimpact on a substantialnumberof small businessesbecause:(1)They are not likely to perform testingthemselves,Or to participate in theorganization of the testingeffort; (2) theywill experienceonly very minorcost, ifany, in securing exemption from testingrequirements; and (3) they areunlikelyto be affectedby reimbursementrequirements.C. PaperworkReductionAct

0MB hasapproved the Informationcollection requirements containedIn thisfmal rule under theprovisions of thePaperworkReductionAct of 1980(44U.S.C.3501 etseq.,Pub. L. 96-511,December11, 1980),andhasassignedcontrol number2070.0033.

Public reporting burden for thiscollection of Information Is estimatedtoaverage1,190hours per response.including time for reviewinginstructions, searchingexistingdatasources,gathering andmaintainingthedata needed,andcompletingandreviewingthecollection of information.

Sendcommentsregardingthe burdenestimateor any other aspectof thiscollection of information, includingsuggestionsfor reducing this burden to,Chief. Information Policy Branch (PM-223),U.S.EPA, 401 M St.,SW,Washington. DC 20460and to the Officeof Information and RegulatoryAffairs,0MB, Washington. DC 20503.List of SubjectsIn 40 CFR Parts795and799Testing,Environmentalprotection.Hazardoussubstances,Chemicals,Laboratories, Recordkeeplngandreportingrequirements.

Dated: September22. 1950V~orJ. K~ActingAssistantAdmialalrctorforPesticidesandToxicSubstances.-

Therefore,40CV*~chapterI,subchapterR. Is ~‘q”dd asfollows:

1. In part 795:a. Theauthoritycitationfor part795

continues to read asfollows:Authority: 15 U.S.C 2003.

b. By adding * 795.231to read asfollows:f 795.231 Pt~arm.caIdnstIcso~

(a)Purpose.Thepurposesof thesestudiesareto:

(1) Ascertain whether thepharmacokineticsand metabolismof the

“test substance”are similar after oraland inhalationadministration,

(2) Determine bioavailabillty of thetestsubstanceafter oral andinhalationadministration.

(3) Examinethe effectsof repeateddosingon the pharmacokineticsandmetabolismof the testsubstance.

(b) Definitions. (1) “Bioavailability”refers to the rate and relativeamountofadministeredtestsubstancewhichreachesthe systemiccirculation.

(2) “Metabolism” meansthe studyofthe sumof the processesby which aparticular substanceis handledin thebody, andincludes absorption. tissuedistribution,biotransformation, andexcretion.

(3) “Pharmacokinetics”meansthestudy of the rates of absorption. tissuedistribution, biotransformation, andexcretion.

(c) Testprocedures—(1)Animalselection—(i)Species.Therat shall beusedbecauseit hasbeenusedextensivelyfor metabolic andtoxicologicalstudies.

(ii) Testanimals. Forpharmacokineticstesting.adultmaleandfemalerats (Fischer344 or strainusedfor majortoxicity testing),7 to9weeksof age,shall be used.The annualsshould be purchasedfrom a reputabledealer and shall be identified uponarrival at the testinglaboratory. Theanimalsshall be selectedat random forthe testinggroupsandanyanimalshowing signsof ill health shall not beused.In all studies,unlessotherwisespecified,eachtestgroup shall containat leastfour animals of each sexfor atotal of at leasteight animals.

(iii) Animalcare. (A) Animal careandhousingshould be In accordancewithOHEWPublication No. fNIH)-85-23.1985,entitled“Guidelines for theCareandUseof Laboratory Animals.”

(B) The animals shouldbe housedInenvironmentallycontrolledroomswithat least10 airchangesper hour. Therooms shallbe maintained at atemperatureof 22±2C and humidity of50±20percent with a 12.hour light/darkcycle per day. Theanimalsshall be keptin a quarantinefacility for at least7days prior to useandshallbeacclimated to theexperimentalenvironmentfor a minimumof 48 hoursprior to treatment.

(C) During theacclimatizationperiod,theanimals should be housedIn suitablecages.All animalsshall be providedwith certified feedandtap water adlibitum.

(2) Administrationof testsubstance—(I) Testsubstance.The useofradioactivetestsubstanceIs requiredfor all materials balanceand metaboliteIdentification requirementsof the study.

Ideally, the purity of both radioactiveandnonradjoactive testsubstanceshould begreater than99 percent.Theradioactive andnonradioactivesubstancesshall be chromatographedseparatelyandtogether to establishpurity and identity. If the purity is lessthan 99 percent or if the chromatogramsdiffer significantly, EPAshouldbeconsulted.

(ii) Dosageandtreatznent—(A)Intravenous.The low doseof testsubstance,in an appropriatevehicle,shall be administered intravenously tofour rats of eachsex.

(B) Oral. Two dosesof testsubstanceshall be usedin the oral portion of thestudy, a low doseand a high dose.Thehigh doseshould Ideally induce someovert toxicity, such asweight loss.Thelow doselevel should correspondto ano-observedeffectlevel.The oral dosingshall be accomplishedby gavageor byadministering an encapsulatedtestsubstance.If feasible, the samehigh andlow dosesshouldbe usedfor oral anddermal studies,

(C) Inhalation. Two concentrations ofthe testsubstanceshall be usedin thisportion of the study, a low concentrationand a high concentration. Thehighconcentrationshould ideally inducesomeovert toxicity, while the lowconcentrationshould correspondto a noobservedlevel.Inhalation treatmentshould be conductedusing a “nose-cone” or “head only” apparatus toprevent ingestionof the testsubstancethrough “grooming”.

(iii) Dosingandsamplingschedule.After administration of the testsubstance.eachrat shall beplacedIn aseparatemetabolicunit to facilitatecollection of excreta.For the inhalationstudies,excreta from the rats shall alsobe collectedduring theexposureperiods. At theend of eachcollectionperiod, the metabolicunits shall becleanedto recover any~xcretathatmight adhereto the cages.All studies,exceptthe repeateddosestudy, shall beterminated at 7 days.or after at least90percent of the radioactivity hasbeenrecoveredIn the excreta. whicheveroccurs first.

(A) Intravenousstudy. Group A shallbe dosedonceIntravenouselyat the lowdoseof testsubstance.

(B) Oralstudies.(1) Group B shall bedosedonceperoswith the low doseofthe testsubstance.

(2) Group C shall bedosedonceper aswith thehighdoseof the test substance.

(C) Inhalation studies.A single6-hourexposureperiod shall be usedfor eachgroup.

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43~ FederalR~isterI Vol. ~ No. 203 / Monday. Octaber23, l9eo / R~esand R~u1atLons

(1) Group D shallbe exposedto amixture of thetestsubstancein airatthe low concentration.

(2)GroupEshallbeexposècltoamixtureof testsubstanceIn air at thehighconcentration.

(D) Repeateddosingsfuc~GroupFshallreceivea seriesof singledaily orallow dosesof nonradioactfvetestsubstanceover a periodof at least7consecutivedays.Twenty four hoursafter the lastnonradioactivedose,asingle oral low doseofradioactivetestsubstanceshall beadministered.Following dosingwith radioactivesubstance,the ratsshallbeplacedInindividual metabolicunitsasdescribedin paragraph(c)(2)~ui)of this section.Thestudyshallbe terminated7 daysafter the lastdose,orafterat least90percentof the radioactivityhasbeenrecoveredIn theexcreta,whicheveroccurs first.

(3) Typesofstudies—(i)Pharmacokineticsstudies.Groups AthroughF shall be usedto determinethekineticsof absorptionof the testsubstance.In groupsadministeredthesubstanceby intravenous or oral routes,(i.e., Groups B, C, F), theconcentrationof radioactivityIn bloodandexcreta includingexpiredair shallbe measuredfollowing administration.In groups administered the substancebythe inhalation route (i.e., GroupsD andEJ. the concentrationof radioactivityinblood shall be measuredat selectedtimeintervalsduring andfollowing theexposureperiod. In thesoupsadministeredthe substancebyinhalation (i.e., Groups D andE), theconcentrationof Padioactivityinexcreta(including eii~piredair) shallbemeasuredat selectedtime intervalsfollowing the exposureperiod.Inaddition, in the groupsadministeredthesubstanceby inhalation,theconcentrationof testsubstanceininspiredair shallbe measuredatselectedtuneinterval.sduringtheexposureperiod.

(ii) Metabolismstudies.GroupsAthrough F shall be usedto determinethemetabolismof the testsubstence.Excreta(urine, feces,~mqdred air)shall be collectedfor 1~i~lflu.stlonandquantification of teat~~bak11~endmetabolites.

(4) Measurements—(i)Pharmocokthetics.Four animal.~eachgroupshallbeu.sedfortheaepurposes,

(A) Blocvailabiiity. The levelsofradioactivity shall be determinedinwhole blood, bloodplasmaor bloodserumat 15 minutes,30 minutes,1,2,3,6,9, and18hours after dosing; and at 30minutes,3.6,6.5.7, 8,9, 12, and18 hoursafter initatlon of inhalation exposure.

(B) Extne2ofabsoip/iora.The totalquantitiesof radioactivityshallbedeterminedfur exczetacollecteddailyfor 7 days,or after at Least 90 percent ofthe radioactivityhas beenrecoveredustheexcrete.whicheveroanirsfirst.

(C) Excietioa.The quantitiesofradioactivityeliminated in the urine,feces,andexpiredair shallbedeterminedseparatelyat appropriatetime intervals.The collectionof theintact testsubstanceor its wetabolites,includingcarbondioxide,may bediscontinuedwhenless than1 percentof theadministereddoseis found to beexhaledas radioactive carbon dioxidein 24hours.

(D) Tissuedistribution. At theterminationof eachstudy, the quantItiesof radioactivityin bloodandin varioustissues.Includingbone,brain, fat,gastrointestinaltract,gonads.heart,kidney, liver, lungs,muscle,skin, spleen,and residualcarcassof eachanimalshall be determined.

(E) Changesinpharmacakinezics.Resultsof pharmacokineticsmeasurements(i.e., l~otranaformation,extent of absurptios.tissuedisthbution.and excretion)obtainedin rats receivingthe stogie low oral doseoftestsubstance(GroupB) shallbe comparedto thecorrespondingresultsobtainedinratsreceivingrepeatedoraldosesof testsubstance(GroupF).

(F) B uasjorznation.Appropriatequalitative and quantitativemethodsshall beusedto assayurine, feces,andexpiredaircollectedfrom rats.Effortsshall bemadeto identify anymetabolitewhich comprises5 percentormoreofthe doseelimingted,

(G) Chcvtgesin biotro.asforznatio.n.Appropriat,qualitativeandquantitativeassaymethodologyshall be usedtocomparethecompositionof radioactivesubstancesIn exm’etafromtheratsreceivinga singl. oral dose(Groups BandC)withthosein theexcretefromratsreceivingrepeatedoraldose.(Group F).

(li) (Reserved](d) Dataandreporting.Thefinal test

reportshallIncludethe follow4ng(1) Presentationofresults.Numerical

data shall be srnnmsr1~edIn tabularform. Pharmacokineticsdatashallalsobepresentedin graphicalform.Qualitativeobservationsshall alsobereported.

(2)Evaluationofre.suJtg. Allquantitative resultsshallbeevaluatedby anappropriate statisticalmethod.

(3) Reportingresults.In addition tothe reportingrequirementsasspecifiedin theEPAGoodLaboratoryPracticeStandards(40 CFR792.185),thefollowing specificInformationshallbereported:

(I) Speciesandstrainsof qr~7animals.

(H) (ijemical characterizationof thetestsubstance,mduding

(A) For the radioactIve testsubstance,informationon the site(s)and degree ofradiolabeling, including typeof label,specificactivity, chemicalpurity, andradiochemicalpurity.

(B) For the nonradloactivesubstance.informationon chemicalpurity.

(C) Resultsof chromatography.(ill) A full descriptionof the

sensitivity, precision,andaccuracyofall proceduresused to generatethe data.

(iv) Extent of absorption of the testsubstanceasindicatedby~percentabsorptionof theadministeredoraldose;and total body burdenafterinhal,atiaiexposure.

(v) Quantity andpercentrecoveryofradioactivity in feces,urine, expired air,and blood.

(vi) Tissuedistribution reported asquantity of radioactivityinblood andin.various tissues,including bone,brain,fat, gastrointestinaltract.~mads,heart,kidney,liver, lung. muscle,skin, spleenandin residualcarcassof eachrat.

(vu) BIotransformationpathwaysandquantitiesof thetestsubstanceandmetabolitesin excretecollectedafteradministeringsinglehighand Low dosesto rats. -

(viii) Biotransformation pathwaysandquantitiesof the testsubstanceandmetabolitesin excretecollectedafteradministeringrepeatedlow dosestorats.

(ix) Pharmaonkinetlcsmodel(s)developedfrom the experimentaldata.

2. In part799.a. The authoritycitation for part 799

continuesto read asfollows:Au*hudI~15 U.S.C.~3, ~11, ~

b. By adding * 799.2325toread asfollows: -

iaerns ~soproseoL(a) Identification of testsubstance.(1)

Isopropanol(GAS No.8743-0)shallbetestedin accordancewith this section.

(2) Isopropanolof at least99.8percentpurityshall be~stedas the testsubstance.

(b) Parsonsreqithudto submitstudyplans,conducttesV~,andsubmitdata.All personswho manufacture(includingimport or byproductmanufacture)orIntend to manufacture or processisopropanol,from the effectivedate ofthis rule to the endof the reimbursementperiod, shall submit letters of Intent toconduct testing,submitstudy plans,conducttests,andsubmit date or submitexemptionapplicationsasspecified inthis section,subpartA of this part, and

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FederalRegister / Vol. 54, No. 203 j Monday, October23, 1989 / Rules and Regulations 43263

parts 790and 792 of this chapterforsingle-phaserulemaking.

(c) Health effectstestin.g—{1)Subchronicinhalationtoxicity—(i)Requiredtesting.A subchronicinhalationtoxicity testshallbeconductedwith isopropanolinaccordancewith * 798.2450of thischapter.

(ii) Reportingrequirements.(A) Thesubchronic inhalation toxicity test shallbe completedand the final reportsubmitted to EPA within 15 months ofthe date specifiedin paragraph (d) ofthis section.

(U) Progressreports shall be submittedto EPA for the subchronic inhalationtoxicity testat 8-month intervalsbeginning8 months after the datespecified in paragraph (d)(1) of thissection until submissionof the finalreport.

(2) Reproductionandfertilityeffects—{i)Requiredtesting.Areproductionand fertility effectstestshall be conductedby gavagewithIsopropanol In accordancewith* 798.4700of this chapter.

(ii) Reportingrequirements.(A) Thereproductionandfertility effectstestshall be completedandthe final reportsubmitted to EPAwithin 29 monthsofthedate specifiedin paragraph (d)(1) ofthis section.

(B) Progressreportsshallbe submittedat 8-monthintervalsbeginning8 mouthsafter the date specifiedIn paragraph(d)(1) of this sectionuntil submissionofthe final report.

(3) Developmentaltoxicity—(i)Requiredtesting.A developmentaltoxicity testshall beconductedIn twomammalian speciesby gavagewithisopropanol in accordancewith* 798.4900of this chapter.

(ii) Reportingrequirements.(A) Thedevelopmentaltoxicity testshallbecompletedand the final reportsubmittedto EPAwIthin 12 months of the datespecified In paragraph (d)(1) of thissection.

(B) A progressreport shall besubmitted 6 months after thedatespecified in paragraph (dXl) of thissection.

(4) Mutagenicej~bct—.n.mutations—(i)Requiz.d~tb7g. (A) Agenemutation testIn ma~sllancellsshall beconductedwith isopropenolinaccordancewith * 798,5300of thischapter.

(B)(l) A sex-linkedrecessivelethaltestIn Drosophilamelanogastershallbeconductedwith Isopropanol Inaccordancewith ~798.5275of thischapter, except for theprovisIonsInparagraphs (d)(5)(ii) and(iii) of* 798.5275,unlessthe resultsof themammaliancells In the culture gene

mutation testconductedpursuanttoparagraph(c)(5)(i)(A) of this sectionarenegative.

(2) For the purposeof this section.thefollowing provisionsalsoapply’~

(1)Routeofadministration.Therouteof administration shall be by exposureto isopropanol vaporsor by injection ofisopropanoL

(ii) [Reserved)(C)(1) The mousevisible specific locus

(MVSL) testshall be conductedwithisopropanol by inhalation in accordancewith * 798.5200,exceptfor theprovisions In paragraphs (d)(5)(ii) and(iii) of * 798.5200,if theresultsof thesex-linkedrecessivelethal testconductedpursuant to paragraph(c)(4)(i)(B) of this sectionare positiveand if, alter a public programreview,EPA issuesa FederalRegisternoticeorsendsa certified letter to the testsponsorspecifyingthat the testingshallbe initiated.

(2) For thepurposeof this section.thefollowing provisionsalsoapply:

(1)Doselevelsanddurationofexposure.A minimum of 2 doselevelsshall betested.The duration ofexposureshallbe for 6 hoursper day.Duration of exposureshallbe dependentupon accumulatedtotal dosedesiredforeachgroup. -

(ii) Routeofadministration.Animalsshall beexposedto isopropanol byinhalation.

(ii) Reporth~grequirements.(A) Thegenemutation testsshallbecompletedand final reportsubmitted to EPAasfollows:

(1) The genemutation In mammaliancells assaywithin 8 monthsof the datespecifiedin paragraph (dXl) of thissection.

(2) Thesex-linked recessive-lethaltestIn DrosophilamelanogosterwIthin 18monthsof thedate specifiedinparagraph fd)(1) of this section.

(3) Themousevisible specific-locustestwIthin 51 months of thedate ofEPA’snotification of the testsponsorbycertifiedletter or FederalRegisternoticeunder paragraph (c)(4)(I)(C) of thissectionthat testingshall be Initiated.

(B) Progressreportsshallbesubmittedto EPAfor theDrosophilasex-linkedrecessivelethal testat 8-month IntervalsbeginnIng 8 month.after thedatespecifiedIn paragraph (d)(1) of thissectionuntil the submissionof the finalreport

(C) Progressreportsshall besubmitted to EPAfor the mousevisiblespecificlocus testat 8-month IntervalsbeginnIng6 monthsafter the date ofEPA’s notificationof the testsponsorthat testing shall be Initiateduntilsubmissionof the final report.

(5) Mutageniceffects—chrvmosomalaberrritions—(i) Requiredtesting.(A)(i)The micronucleustestshall beconductedwith isopropanol inaccordancewith * 798.5395of thischapter.

(2) For the purposeof this section,thefollowing provisionsalso apply:

(i) Routeof administration. Animalsshall be exposedto isopropanol byeither inhalation or oral gavageorinperitoneally (IP).

(ii) Durationof exposure.Forinhalation, the duration of exposureshall be for 6 hoursper day for 5consecutivedayswith one sacrifice timeor for 8 hours for 1 daywith threesacrifice times.

(B)(1) A dominant lethal assayshallbeconductedwith isopropanol inaccordancewith § 798.5450of thischapter. exceptfor theprovisions inparagraphs (d)(5)(ii) and (iii) of* 798.5450,unlessthe micronucleus testconductedpursuant to paragraphs(c)(5)(i)(A) of this sectionis negative.

(2) For thepurposeof this section,thefollowing provisionsalsoapply:

(1)Routeofadministration.Animalsshall be exposedto isopropanol byinhalation.

(ii) Duration of exposure.Theduration of exposureshall be for 6 hoursper day for 5 consecutivedays.

(C)(1) A heritable translocation testshall be conductedwith isopropanol Inaccordancewith * 798.5480ofthischapter. exceptfor theprovisions inparagraphs (d)(5)(iI) and (iii) of*798.5460, if the results of thedominantlethal assayconductedpursuant toparagraph (c)(5)(1)(B)of thissectionarepositiveandIf. after a public programreview,EPAissuesa FederalRegisternotice or sendsa certified letter to thetestsponsorspecifyingthat the testingshall be Initiated.

(2) For the purposeof thissection.thefollowing provisionsalso apply:

(i) Routeof administration. Animalsshall be exposedto Isopropanolbyinhalation.

(ii) [Reserved)(ii) Reportingrequirements.(A) The

chromosomalaberration testsshall becompletedandthe final reportssubmittedto EPAasfollows:

(1) The micronucleustestwIthin 15monthsof the date specifiedinparagraph (d)(1) of this section.

(2) The dominant lethalassaywithin27 months of the date specifiedinparagraph (d)(1) of this section.

(3) The heritable translocation testwithin 24 monthsof thedate of EPA’snotification of the testsponsorbycertified letter or FederalRegisternotice

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43264 FederalRegister / Vol. 54, No.203 / Monday, October 23. 1989 / Rulesand Regulations

under paragraph (cJ{SXi)(C) of thi..sectionthat testingshall beinitiated.

(B) Progressreportsshall besubmittedto EPA for the the mAcroa~aleusand thedominantlethal assaysat8-monthintervalsbeginning6 months after thedate specified in paragraph (dXl) of thissection until submissionof the finalreport.

(C) Progressreports shall besubmitted to EPA fur the heritabletranslocation assayat 6..rnonth intervalsbeginning 6 months after the date ofEPA’s notificationof the testsponsorthat testingshall be initiated untilsubmissionof the final report

(0) Neur-otoxicity—-{i)Requiredtesting. (AJ(1) A functionalobservationbattery shall be conductedwithisopropanolinaccordancewith§ 798.6050of thischapterexceptfor theprovisionsin paragraphs(d)(5) and(6)of § 798.6050.

(2) For the purposeof this section,thefollowing provisionsalso apply:

(I) Duration andfrequencyofexposure.For subchronicstudy,animalsshall be dosedforO hoursperday, 5daysper weekfor 90 days. For acutestudy, animalsshallbe dosedfor 4 to 6hours once.

(hi Routeofe.xposw’e.Anim~alsshallbe exposedto isopropanolby inhalation.

(B)(1) A motoractivity testshallbeconductedwith isopropanolinaccordancewith * 798.8200of thischapter exceptfor the provisionsinparagraphs (d)(5) and(8) of * 796.6200.

(2) For the purposeofthis section.thefollowing provisionsalso apply:

(I) Durationofexposure.Forsubchronicstudy, animalsshallbedosedfor 8 hours per day,5 daysperweekfor 90 days.For acutestudy,

animals shall be dosedfor 4 to 6 hoursonce.

(ii) Routeof exposure.Animalsshallbeexposedto iaopropa.nolby inhalation.

(C)(1)A neuropathologytest shallbeconductedwith isopropanol inaccordancewi-th § 798.8400of thischapter exceptfor the provisions inparagraphs (d)(5) and (6) of § 798.8400.

(2) For thepurposeof this section,thefollowing provisions alsoapply:

(1) Duration ofexposure.Animalsshall be dosedfor 8 hoursper day, 5daysper weekfor 90 days.

(iij Routeofexposure.Animals shallbe exposedto isopropanol by inhalation.

(D) A developmentalneurotoxicitytest shall be conductedwith isopropanolin accordancewith * 795.250of thischapter.

(ii) Reportingrequirements.(A) Theacutefunctionalobservationbatteryandmotor activity testsshall be completedand the final report submittedto EPAwithin 15 months of the date specifiedinparagraph(dill) of this section.Thesubchronic functionalobservationbattery, motor activity, andneuropathologytestsshall be completedand the final reports submittedto EPAwithin 18 monthsof the date specifiedinparagraph(d)(1) of this section.Thedevelopmentalneurotoxicftytestshallbe completedand the final reportsubmittedto EPAwithIn 21 monthsofthe datespecifiedIn paragraph(dXl) ofthis section.

(B) Progressreportsshell besubmittedto EPA for the functionalobservationbattery,motoractivity, neuropathology.and developmentalneurotoxicity testsat 8-monthIntervalsbeginning8 monthsafter the datespecified in paragraph(d)(l) of this sectionuntIl submissionofthe applicable final report.

(7) Phormacoktheticsstudies—(i)Requiredtesting.An oral andinhalatinapharmacokineticstest shall beconductedwith ieopropanol inaccordancewith * 795.231of thischapter.

(ii) Reportingrequirements.(A) Thepharmacokinetictestshall be completedand the final report submitted to EPAwithin 15 months of the date specifiedinparagraph(d)(1) of this section.

(B) Progressreportsshall be submittedto EPA for the pharmacokinetics testat6-month intervals beginning 6 monthsafter thedatespecifiedin paragraph(d)(1) of this sectionuntil submissionofthe final report.

(8) Oncogenicity—(i)Requiredtesting.An oncogenicitytestshall be conductedby inhalation with isopropanolinaccordancewith § 798.3300of thischapter.

(ii) Reportingrequirements.(A) Theoncogenicitytestshall be completedandthe final reportsubmitted to EPAwithin53 months of the date specifiedinparagraph (dill) of this section.

(B) Progressreportsshall besubmittedat 8-month intervalsbeginning8 monthsafter the datespecifiedin paragraph(d)(1) of this sectionuntil submission ofthe final report.

(d) Effectivedates.(1) This test ruleshall be effectiveon December4. 1989.

(2) The guidelinesand other testmethodscited in this sectionarereferencedasthey exist on the effectivedate of the final rule.(Information collection requirementshave been approvedby the Office ofManagementand Budgetundercontrolnumber 2070-7030).

[FR Doc. 8V-24877Filed 10.20-~:8~45am)~WNO~OOE~

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F.ds1 Ra~M.e/ VoL 54,

15 million pounds(RaL 8). No i~~rt~ofcrotonaldahydeInto theUnited Statesarecurrently repartedthowever,in 1985.930.953pound.of crotonaldahyda~zeimportedinto the United StataifromMexico (Ref~7).

Kodak reportsthat is convertsapproximatelyone—thirdof thecrotonaldehydethat it producesintocrotonicacid, usinganenclosedprocess.Kodakbelievesthat all of thecrotonaldehydethat it sells is usedas achemicalintermediate,andnoneis usedto formulateproducts(Ref. 8).

Kodak estirn.atesthat up to 20manufacturingworkersmight beexposedto crotonaldehyde.Workerexposurelevels.determinedbyindustrialmonitoring,aregenerallylessthan 0.01 ppm(8—h Time—WeightedAverage(TWA)); Kodakreportedasinglemaximumexposurelevel of 1.13ppm, which occurredunderan upsetcondition (Ref. 8.).

Envirorijuentalexposure,tocrotonaldehydecanoccur during it~transportation.use,processing,andmanufacture.EPAhasestimatedexposuresto crotanaldehydeatKingsport.TN. the siteof Kodak’seffluent dischargeto theHolstoriRiver,tobe 85 ppb during meanriver flowconditionsand350 ppb during sthctlynatural7Q’lQ low flow conditions(i.e..the lowest 7-dayaverageriverflowexpectedto occuronceevery10 years).Monthly averageconcentration.areexpectedto rangefrom 45 ppb to87 ppb(Ref. 4). However, it shouldbe notedinthis contextthat the HolstonRiver’sflow is notas variableasit would be ifit were a “wild’~river, as its flow iscontrolledby contracturalarrangementswith the TennesseeValley Authority(TVA) throughseveraldamsandholdi~pondslocatedon the River.EPA isexaminingwhateffectsthesecontractualarrangementswith TVAhaveon mitigat:ng theHolston’snaturalflow variabiity and,hence.on thep”edictedconcentrationsofcrotonaldehydein theRiver.

Crotonaidehydealso occursnaturally,having beenfoundin strawberries.al~zae—containingsedimentarydeposits,andhumans,apparentlybeingproducedas a metaboliteof othersubstances(Refs.5. 9. and 10). Crotonaldehyde isalso a commoncombustionproductofwood andhydrocarbon—basedfuel.(gasoline,jet fuel, etc.).Concentrationsof crotonaldehydein the exhaust/smokefrom thesesourceshavebeenmeasured.and rangefrom 8 ppb to 118 ppm. withthehighestvaluesfoundin woodsmoke(Ref,.5 and11 through13).

IV. Ta~ngPro~aa~mlod FateesdEnvironmentalE~

TheITC recommendedcrotonaldehydefor chemicalfatsandenvironmentaleffectstesting.The1TCdid not recommendhealtheffectstesting,statingthat crotanaldehydehasbeenextensivelystudiedfor healtheffects.EPAconcuriwith the l’Tt’srecommendation,.

Specifically, the ITC recommendedaquaticbiodegradationandvolatilitytestingandacuteaquatictoxicitytesting.

A. ChemicalFate TestrngVolatilization of crotonaldehydecan

be estimatedusing thecalculatedHenry’.Law constantTheestimatethusobtainedindicatesthat crotonaldehydehasa moderatevolatilizationhall—life of80 to 70 hoursat 20 C (Ref. 14). In air,crotonaldebydephotolyzesrelativelyquickly, with a half—4ife of only a fewhours (Ref. 14). Informationoncrotonaldehyde’sremovalby acclimatedsludgeshows37 percentremovalofmaximumtheoreticaloxygendemand.(ThOD) (Ref. 11). EPAestimatesthat.during wastewatertreatment.40 percentof crotonaldehydewill beremoved.mostly by biodegradation(Ref. 4).

In view of this information,andinformationon crotonaldehyde’sreleaseto the environment,the ITCrecommendedadditionalstudie.onvolatilizationfrom waterendaerobicbiodegradation.Specifictestingon thesekey removalprocesseswould enableEPA to better predictcrotonaldehyde’sfate in the environment.

EPA intendsthat the chemicalfeteandenvironmentaleffect. testingneededfor crotonaldehydebeconductedunderthe sponsorshipofKOdak underthis ConsentOrder.

AlthoughtheITC recommendedbothvolatility andaerobicaquaticbiodegradationtesting, thechemicalfatetestingis Limited In this ConsentOrderto the biodegradationtestingfortechnicalreasons.At the presenttime.EPAconsidersreliabletestsfordeterminingvolatility to be availableonly for high. or low.volatilitychemicals,but not for medium-volatilitysubstances,suchascrotona.ldehyda.Therefore,EPA will continueto dependuponestimatesof orotonaldehyde~svolatility, asgiven in Unit Ill of thisdocument.An indication of volatilitywill alsobeobtainedduring thealgalbioassay,whereinthe ConsentOrderrequire.thatlosses0f testsubstancedue to volatility be roughlyestimatedbymeasuringconcentrationsofcrotoneldehydein the testchambersandcomparingtheseto the nominal,

e~.ctedconcentrations.Theresult.ofthis volatility “measurement”are alsorelevantto the type of aerobicaquaticbiodegradationtestto beperformed.ifvolatility, asobservedin the algalsmay.is greaterthan 15 percentover96 hours.thena closed-bottletest(40 CFR796.3200)shall be used.if volatility islessthan or equalto 15 percenLthen themodifiedOrganizationfor EconomicCooperationandDevelopment(OE~D)test(40 CFR 796.3240)shallbe used.Protocolsanddecisioncriteria astowhich testwill be usedarespecifiedintheConsentOrder,andtestingwill be riaccordancewith theschedulesand testprotocolsspecifiedin theOrder.

B. EnvironmentalEffectsT~s.tzng

Crotonaldehydehasbeentestedusinga numberof differentaquaticorganisms.The mostrelevanttestshave beenstatic96—hourbioassay.with bluegilis.Lepomis macrochirus(96-hourLC~.,of3.5 mg/L). fatheadminnows,Pimephaiespromelas(90—hourLC~0of 2.8 mg/L~.anda saltwaterfish, the tidewatersilversides.Menidia berv1l~na~96—hourL~.of 1.3 mg/LI (Ref.. 15 and icy.

Theseacutetoxicity valuesdemonstrate that crotonaldehydemayhave significant acutetoxic1~yto marineand freshwaterfish. Sincethedatawereo~lainedusingoftenless reliablestatIcbioassaysystems. the ITCrecommendedadditior.alac’~tetox..c’.tytestingin flow-through or static-renewaltests. The ITC also recommendedthatadditionalenvironmentalspeciesbetested.to include algae.

Kodakhasagreedto conductorsponsorthe conductof acutetoxicitytestson five species:—The algal species.Selanastrurncapricorriutum:twofreshwaterinvertebratespecies,thedaphnid. Daphnia magna. and thagammarid,Gammarusfasciatus~andtwo freshwater’flshspec~es.the ~3t,~ieadminnow,Pimephalespromelas.and therainbow trout, Oncorhynchusm~ciss(formerly Salmogairdneri).All of thesetestswill be performedin accordancewith the schedulesand testprotocc~sspecifiedin the Order.

The Consent Order also requiresdaphnidchronictoxicity testingand fishearlylife stage (ELS) toxicity tesongonthemore sensitivefish (rainbowtroutorfatheadminnow).This aquaucchronictoxicity testingis requiredbecauseEPAhascalculatedthat the ratio of acutetoxicity (43-howor 96-hour EC~or LC~value)to the predicted environmentalconcentration(PEC) of crotonaldehydeIn the HolstonRiver is less thanor equalto 100. If the fish acutetoxicity dataareequivocalregardingrelativespeciessensitivity.EPA andKodak will, if

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4~4 FederalRe~ster/ Vol. 54. No. 216 / Thursday,November9, 1909 I Rules and Regulations

requestedby Kodak, meettodiscusstheinterpretationof theacutetoxicity dataas to which fish specieswill be requiredto undergoearlylife stage(ELS) testing.If KodakandEPA cannotcometoagreement.EPAhas the final authorityIn selectingthe testspecies.EPA willprovideKodak in writing with ~tsreasoningfor requiringone testsp~ciesoveranother.

Kodakbe1~evesEP~~’sP~Cfor theHoistonRiver is too ~i;h.andhasvolunteeredto measureeffluentcrotonaldehydecrncen:rationsfromtheir facility in Kin~cport.Ter.r.’~see,that releaseswastewa:erto the H~’lstonRiver. Indeper.dentof the resultsoftheseeffluentmeasurements.EPA ~1usetwo alternatecriteria t3 require thechronicaquatictoxicity testing: (1) Ifany~ or L~valuefrom conductingthefive acutetestslisted aboveis lessthan,or equal to. 1.0 mg,’L or (2) if anyfish or aquatic invertebrate toxicity EC~aor L~,value is less than,or equalto.100 mg/L and there is also an indicationof potentialcumulativetoxicity (theratio of 24—hourto 48—hour or 24—hour to96—hour toxicity valueais greaterthan,or equalto, 2).

Daphnid chronic toxicity testing andfish ELS testing will not be requiredifall of the following conditionsare met:

1. All five acute toxicity testvaluesaregreaterthan1.0 mg/L

2. All fish andaquaticinvertebratetoxicity testvaluesareless thanorequalto 100 mg/L and thereis nopotentialcumulativetoxicity asdefinedin the ConsentOrder,or all fish andaquaticinvertebratetoxicity testvaluesaregreaterthan 100 mg/L

3. Aquatic concentrationmodellingbyEPAusing Kodak’s measuredeffluentcrotonaldehydeconcentrationsandbestavailableflow datafor the HoletonRiverdenonstratethat the ratio of thelowest acutetoxicity value to thePEC(usingthe 7Q10asthe referencevalue)is greaterthan 100.

~either the ITC nor EPAbelievesthatbioconcentrationwill poseany

environmentalhazards.the low Log P ofcrotonaldehyde.estimatedto be0.55,stronglysuggeststhat thereIs nosignificantpotential forbioconcentratjon(Ref. 5).

C. MonitoringStudy

EPA andKodakhavealso includedanoptionalmonitoring study in theConsentOrder.Wastewatereffluentfrom Kodak’, Kingaportplant. whichultimatelyemptiesinto theHoistonRiver,maybe monitoredforcro~onaldehydeconcentrations.Kodakmaymonitorits own wastewatereffluent ratherthan theHolstonRiver,itself for reasonsof ease(a lesscorr.plicaredexperimentaldesign)andexpense(fewer samplesneededfor accmparsbiyaccw’atemeasureofstatisticalvariability).Thereis a trade-off, however,in that EPAwill needtouse the effluentmonitoringdataearlierin its environmentalmodelcalculationsthan would be thecasewith riversamplingdata.Nonetheless,themeasuredconcentrationsfrom theeffluentshouldgive moreaccurateestimatesof crotonaldehydeconcentrationsin the river thandopresentestimates,which arebasedmainlyon theoreticalconsiderations.The effluentmonitoring studywill alsoaddressthe question of the efficiencyofremoval of crotonaldehyde by Kodak’swastewatertreatmentsystem.whichEPAhasestimatedto be40 percent.

EPA’s basicinterestin this study liesin whetherornot it will refuteor verifytheneedfor chronictoxicity testingofcrotonaldehydeon aquaticspeciesbasedon presentPECandacutetoxicitydata.Therefore,this study is notrequired,andKodakhasdiscretionas towhetherornot it is conducted.If Kodakchoosesnot to conduct the monitoringstudy,EPAwill rely on the currentlyexistingexposureestimates,alongwiththe resultsof theacutetoxicity teststodeterminewhether chronictoxicity testsshallbeconducted. Obviously, If theacutetestingrequiredundertheConsent

Orderindicatesa needfor chronictesting(by anECeeor L~evalue lessthan,or equalto, 1.0m.g/L or potentialcumulativetoxicity), asdescribedinUnit IV.B of this notice,then Kodakwould foregothemonitoring study,becauseits resultswill haveno effect onthechronictoxicity testingrequirement.Kodak mayalso decide,for otherreasons,toproceedwith thechronictestingregardlessof the acutetoxicitytestingresultsandwithout performingthe monitoring study.

If Kodakdecidest6 perform themonitoringstudy, then thestudydus:g’iandschedulethat mustbe followed a~e

thosespecifiedin the ConsentOrdnr IfKodak decidesnot to perform themonitoring study, thenit mustnotifyEPAof its decisionandproceedwii.hchronictestingon the daphntdand themostsensitivefish species.as is alsospecifiedin theConsentOrder.

D. TestStandardsand Schedu’~s

The tests,their standards.andschedulesare thosespecificaflycontainedin theConsentOrderf.~rcrotonaldehyde.Thebasicteststandardsare as follows:

Startciard

Effluent rnonttorng

TeIIIflg pfOtOColdI’~e4OPm.r1by ~ ~ca~ ~v.”~w~’iend s~iv~o’~edby EPA, and s~ecrfie~i~i :neCcrw~

All of the above teststandards ha’. eundergonecertainminoririodi ficaI:~r

thesemodified standardshavebeenappendedto the ConsentOrder.

Testingwill be in accordancei~ ~‘

following schedule:

FraeiiweiavalgaeacuteDWtirsdScutaGammandacute ..

R~rOowtrout acuteFstheedmmnow acute...~Eff~iantmc~tonngLI~R~J ‘,4W~Jt

Felt ~ tee stage~Felt wiy We stage

Re~ortngrequ~arn.re Fret reportoa’e

12 movitta._.... No’,’embr ~, i gqoDo.

.. Do.Do.

¶2 mc he....~.. Do.Do.

MayS.199i21 mola~‘.,.,. . —. August 9, 7;5~21 autea ‘............... Do.2lmcmS’a ~... Fetnay~O.‘09227mctata~..__... Do.

Freest waistelgatacuie0epltrta~acuteGanimandacuteP~nb~trout acuteFstt’aetj me’,now acute.Oa~d~romcFelt estly We stag. ..

Astobcb~degra0eDon.

7;—

‘~6?~J

TPse ecftet~ieagøe. C Ste sMuentmoiClctlvtg e*tdy ~ nel ~wfuwted, C aaae easenedaen~Sve*e~5clty~ta rdcatea need tor flrc~+c:~-~maseltetSie~eaeC mesfs,terCmcndoi’mg‘sm aperiotmedendsa~oetaetatae$iS~dca*eaneed~ ~‘wuic teerig.

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Fed~ R~qiMa,I Vol. .54,

EPA hasspeci~da longertime thennormalfor the toxicity s.daerohicbiodegradationtests,becauseofvolatility questionsanda needtodevelopsomepracticalvolatility datarelevantto theconductof theseteats(i.e., useof openor closedsystems.appropriateflow ratefactors).Thus.EPA is allowing 12 monthsfrom theeffect:vedateto the final reportduedatefor thesetests for crotonaldehyde.

The final report for eachtestshallbesubmittedto EPA as soonas it becomesavailable but no laterthan thedatespec~fted.For all exceptthe five acutestudiesandthe biodegradationstudy.interimprogressreportsshall alsobesubmittedevery8 months,beginning8monthsafter the effectivedateof thisfinal rule.

V. Export Notification

The issuanceof the ConsentOrdersubjectsanypersonwho exportsorintendsto exportcrotonaldehyde,to theexport notificationrequirementsofsection12(b)of TSCA. The specificrequrementsarelistedin 40 CFRpart707. In the Interim Ruleof June30, 1966[51 FR 23706),establishingtheTestingConsentOrder process,EPA addedsubpartC of part 799 for listing ofchemicalsubstancesor mixtures sub~ectto testingconsentordersissuedby EPA.This list:ng servesasnotification topersonswho exportor intendto exportchemicalsubstancesor mixtures whichare the sublectof testingConsentOrdersthat 40CFR part707 applies.VI. RulemakingRecord

EPA hasestablisheda recordfor thisruleandthe ConsentOrder(docketnumberOPTS-4Z1081.This recordcontainsthe basicinformationconsideredby EPA in developingthisrule and the testingConsentOr~.

This recordincludesthe foliow~information:

4 SupportingDocumentation(1) TestingConsentOrderbetween

Kodak andEPA.(2) FederalRe~sternoticespertaining

to this noticeconsistingof:(a) Notice containingthe ITC’s

recommendationof crotonaldehydetothePriority List (53 FR 18198 May 20,1988).

(b) Notice containingtheITC’sdesignationof crotonaidaltydeto thePriority List (53 FR 48Z82~Novemher18,1988).

(c) Noticeof the interimfinal ruleanproceduresfor developingenforceableconsentagreements(51 FR 23706;Jun.30. 1986).

(3) Communicationsconsistingofi(a) Written letters.

(b)Conta~reportsof telbphooeconversations.

(c) Meetingsummaries.(4) Reports—puthahedend

unpublishedfactualmaterials.

B. References(1) Kirk.Othmer. Xii*-Othnw

EncyclopediaalCheat?ccITechnology.NewYork. N.Y. JohnWiley & Sons.Inc. VoL. 7. pp.207-21& (1979).

(2) Sax,N.L awl Lewis. R4.. Sr. Hawley’sCondensedChe.rrucalDictionary. 11th rev.ad.New York. Van NostrandRetriiold Co. p.323. (1987).

(3) Mert±.The .14erc* index. 10th edItion.Wjndholz.M.. ed. Rahway.N.J. Merck & Cop. 372. (1983).

(4) Nold, A. Mernorandwnoncrotonaidehydeaquaticecolo~tcslueessmeotAnnensNold to John Walker.U.S. EnvironmentalProte~~Agency.(April5. 1988).

(5) NRC. Na6ooalResearr.hCo~L“Formalde4iydeend otheraldebydea”.Washington.DC. Nauona)AcademyPress.(1981).

(6) TeoneaseeEastmanCo~perrv.Kingspori. TN 37862. Letter to ~. RobertH.Brink. InteragencyTestingCommittee.(June19, 1987).

(71 L’SDOC. U S. Departmentof Commerce.~ imports for CcnsumptionandGeneralinports.” Waahtr.gtort.DC. U.S. Bureauof theCensus.PubhcanonNo. FT246. p. 1—580.(1985).

(8) EastmanKodakCompany.lcmgeport.TN 37882. Letter to Mr. John Schaeffer.Officeof Peeticidesend Toxic Soheaancee.EPA.(August ii. 1~).

(9) G.edeLF., andBnicbe4,A. ‘A~~icationof pyrolo~a~gaethnet~~by..asaspecwom,,tryto the ~rec*enzationof hamiceube*an~erwlsiagfrom decayof aipsaticplants in eedi~aatasad~tse.” WcH~rResearch21:1195...1208,(1987).

(10) Krotoezynakl,BJC.. andO’Neill. H.).“Involuntary biostxe~aladeeofenviroaaieatalpoLletLsntsin asaemekAngheterng.neoushamanpcçalelicaai.”Journalof EnviroarnontalScie~nc~andHealth.A17155-163~(1982~.

(ii) Verechueran.X. HandbookofEnvirnnmeiw.alDataon OzyanicC27emIcals.2nd ed.New York, N.Y. Van NostrandReinhold Co. pp. 410-431.(1963).

(12)Miyamoto.. V. “Eye andrespiratoryirritantsin let engineexhsust.~’Aviation.Spac.and£nvi’rommer*il Medicine.57:1104..1106. (Ieee).

(13) Upart.F.. Dsah.J.M.. andSeru~e.W.F.‘~Ald.hyd,e~aioasfrom wood.beraat~fireplaces.”Envzrvmw,eetal~Technology.1~5).3a-33e.11164).

(14) DynamacCarporatios. Paá,t~s.~20852.Crv*n’w~Jdth,*~-887. ~* ~eec1No. 68-02-4231(Jiam13, Ie88~.

(15) D.ween.G.W.. ~ A.!,..Drasdowald.0.. and ~, & “the aces.toxieltyof 47 ináie~lshesalcalsel freshandae1t~lorfla~.”Jaesmei~J~rw~eeMoAsrioJa. 1.302.416.(1W?).

(16) Union Carbide.Daithury, CT 08817.Letter to U.S. EnvironmentatProtectionAgency.(May 2.3985). 813-4375238448.

ConfidentialBusinessInformation(~Z3,whilepartof the record,is notavailablefor public re,iew. A publicversionof therecorrj from which CBIhasbeendeleted,is availableforinspectionin theTSCAPublic DocketOffice. Rm.NE-C004,401 M St., SW.,Washington,DC from 8 a.m.to 4 p.m.,Monday through Friday. except legalholidays.

Vii. OtherRegulatoryRequirements

TheOffice of Mar.a~ementandBud.g’et(0MB) hasapprovedthe inforrnatoncollection requirementscontainedui tneConsentOrderunderthe pro’. 5:005 ofthe PaperworkReductionAct of 1~80.44U.S.C.3501 etseq..and hasass:gr’.cd0MB control number2070—0033.

Public reportingburdenfor th:tcollection of information is es::rr.a~d~j

a’. erage1.431 hoursper responseincluding time for review nginstructions,searchinge’~:si.ng..l .tasources.gather:ngand~na:n:a~n:’.adataneedt~d.and compenn~andreviewingthe collectionof

~nd commentsre~~~ain~ ‘hs bu~ce~es~r.ateor anyother c’~c~)f th.scoi:ectionof taformai.c’n. ,:suggestionsfor redi.ic:nc ‘h.s bor~e~‘oChief. tnfc.rm.ationPo~ U~o..:P\L.223,U.S. F,~’.virorunenta~PtAgency.401 M St.. SW. Wa~hin~:on.DC2046O~andto the Otficeof ~fana~.ie~entandBudgeL PaperworkReduooonProject (0MB Control No. 2070—0U3~t.Washington.DC 20503.

List of Subjectsin 40CFR Part759

Testingprocedures,Errvironrnentalprotection. Hazardoussubstances.Chermcala.Chemicalexport.Recordkeepingandreportingrequirements.

Dated.October2. 1988.

Linda J. Fisher,Assistant.4thrnnjstrctorfrror Pesnc’~sardToxicSubsrancros.

Therefore.40 CFRpart 799 is amendedasfollows:

PAR’T 79S—(A~ENOEDJ

1. Theauthority citationcontinuesInreadasfollows:

Authm4ty’ 15 U.S.C.2803. 2811.2825.

2. Section796..5000is amendedbyaddingcrotonaldehydeto theTableinGASNumberOrder to readas follows:

~740.1660 Te~~ceeeorstorders.

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47O~6 !.d~aI Re~star/ VoL 54, No. 216 / Thursday,November9. 1989 / Rulesand Regulations

Croton.3- Ertvtron~del’ycie. menta3

etfec’,s.Ct’empcal

tate

9. t989.

~ov~mber9. t989.

CAS numberstance

~mixturename

Teatinç~~

FW~ac.RmOS1’mC’itaaon

4170.30.3

[FR Doc. 89—26445Filed 11-8—89:8:45 am)B$WNG 0005 Ue0-S0


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