37138 Federal Register/ Vu!. 52. No. 192 / Monday, October 5. 1987 I Rules and Regulations

SUPPLEMENTARY INFORMATION: Thisdocumentpromulgatesa final s~ngie-phasetest requirementforpharmacokinetictesting of DCP, andafinal PhaseII rulespecifyingthe teststandardsandreportingrequirementsfor the testing requiredin theSeptember9, 1986 (51 FR32079) final PhaseI testrule.

I. Background

ENVIRONMENTAL PROTECTION

AGENCY

40 CFR Parts 795 and 799

IOPTS—42043C; FRL-3273-3

Testing Requirement; Final TestStandards and ReportingRequirements; 1,2-Dichioropropane

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

SUMMARY: EPA is issuinga final ruleundersection4(a)of theToxicSubstancesControl Act (TSCA)thatrequiresmanufacturersandprocessorsof 1.2-dichioropropane(DCP: CASNumber78—87—5) to: (1) Conductpharmacokinetic(absorption.distribution,metabolism,andexcretion)testingwith this chemicalsubstance,[2)utilize certainTSCA test guidelinesasthe test standardsfor previouslyandcurrentlyrequiredstudiesfor DCP, and(3) submittest datawithin specifiedtimeframes.DArES: In accordancewith 40 CFR 23.5.this rule shall be promulgatedforpurposesof judicial review at 1 p.m.eastern[“daylight” or“standard”asappropriate)time on October19, 1987.

This ruleshall becomeeffectiveonNovember18, 1987.FOR FURTHER INFORMATiON CONTACT:EdwardA. Klein, Director, TSCAAssistanceOffice (TS.-799),Office ofToxic Substances,Room E—543,401 MStreetSW., Washington.DC 20460.(202—554—1404).

On September9. 1986 (51 FR 32079),EPA issueda final PhaseI ruleunderTSCA section4 that establishedtestingrequirementsfor manufacturersandprocessorsof DCP.This PhaseI rulespecifiedthe following testingrequirementsfor DCP: (1) Neurotoxicit~.(2) mutagenicity(chromosomalaberrations),(3) reproductiveeffects, (4)developmentaltoxicity. (5) acutetoxicity to marineandfreshwateralgalandmysid shrimp,and(6) chronictoxicity to mysid shrimpandDcphniornayna.

Also on September9, 1986 [51 FR32107),EPAproposedapplicableTSCAguidelinesas teststandards.SinceTSCA testguidelineswereavailableforall the testingrequirementsincludedinthe final PhaseI rule, theywereproposedas the teststandards.A 45-daycommentperiodwasprovidedto allowthe public, including the manufacturersandprocessorssubjectto thePhaseIrule, to commenton theuseof theTSCAguidelines.

As discussedin theSeptember9. 1986proposal,underthe two-phaseprocess.personssubjectto a final PhaseI rulearenormally requiredto submitproposedstudy plansafterthe effectivedateof the PhaseI rule. However.becauseEPA proposedapplicableTSCAtestguidelinesastheteststandardsforthe studiesrequiredby the final DCPPhaseI rule, personssubjectto therule.i.e.. manufacturersandprocessorsofDCP. wereexemptedfrom thisrequirementPersonssubjectto therule.however,werestill requiredto submitnoticesof intent to testor exemptionapplicationsin accordancewith 40 CFR790.45.For theDCPPhaseI rule, DowChemicalCompanynotifiedEPA of itsintent to sponsorall therequiredtesting(Ref. 6). Theresponsibilitiesofmanufacturersandprocessorsof DCPfor testing or requestingexemptionfromtestingresponsibilitieswerediscussedin theDCPPhaseI final rule (51 FR32079).

After review of thepublic comments.EPA is nowpromulgatinga final Phase11 rulerequiringthemanufacturersandprocessorsof DCPto conductthehealthandenvironmentaleffectsstudiescontainedin thefinal PhaseI test rule in

Federal Register/ Vol. 52. No. 10 / Monday. October 5. 1987 / Rules and Regulations 37139

accordancewith the test standardsforDCP proposedin 51 FR 32107. Personswho notifiedEPA of their intent to testmust now submitstudy plans(whichadhereto the promulgatedteststandards)no later than45 daysbeforethe initiation of eachrequiredtest.

Also proposedin Si FR 32107 wasasir.gle-phasetestrule forpharmacokinetic(absorption.distribution,metabolism,andexcretion)testingwith DCP, including teststandardsandreportingrequirements.After reviewof public comments,EPA isnow promulgatinga final single-phaserule requiringthe manufacturersandprocessorsof DCP to conductthepharmacokinetictesting.As statedinUnit IV.D. of this preamble.manufacturersandprocessorsof DCParenow requiredto submit noticesofuitent to conductpharmacokinetictestingor exemptionapplicationsinaccordancewith 40 CFR 790.45.

LI. ProposedRule

A. ProposedPharmacoAineticTesting

In theSeptember9. 1986proposedrule, EPA proposedoral-inhalationcomparativepharmacokinetictesting forDCP basedon theauthority of section4(a)(1)(B)of TSCA. EPA found that DCPis producedandreleasedto theenvironmentin substantialquantities.and that its manufacture,processing,and usemay result in substantialhumanexposureto this substance.The detailedbasisfor this finding is found in UnitIV.A, of the final PhaseI test rule forDCP (51 FR 32079).

EPA also found that thereareinsufficientdatato reasonablypredictandcomparethe distributionandmetabolismof DCP in thebody asaresultof oralor inhalation exposuredueto DCP’s manufacture.processing.anduse,andthatan oral-inhalationcomparativepharrnacokineticstudyofDCP is necessaryto developsuchdata.

B. ProposedTestStandards

In the final PhaseI test rulefor DCP.the requiredtestingincludedneurotoxicity.mutageniceffects(chrornosomalaberrations).developmentaleffects,reproductiveeffects,mysid shrimpacutetoxicity,algal acutetoxicity. anddaphriidandmysid chronictoxicity.

In theSeptember9. 1986proposedrule, EPA proposedthat: (1) Thetests forneurotoxicity. i.e., neuropathology,motor activity, andfunctionalobservationalbattery,be conductedaccordingto 40 CFR 798.6400.798.6200.and798.6050,respectively:(2) thedominantlethalassaybe conductedaccordingto 40 CFR 798.5450;(3) the

developmentaltoxicity studybeconductedaccordingto 40 CFR 798.4900:(4) the reproductiveeffectstest beconductedaccordingto 40CFR 798.4700:and(~the oral-inhalationcomparativepharrca:c.kinetictest(absorption.distribution,metabolism.andexcretion)beconductedaccordingto theguidelineproposedin theFederalRegisterofNovember6. 1985 (50 FR 46104) as§ 798.74~5(codified as § 795.230in thisfinal rule(.

With regardto environmentaleffectstesting.EPA proposedthat: (1) The algalacutetestswith marineandfreshwateralgaebe.~onductedaccordingto 40 CFR797.1050usingsystemsthat control forDCPevaporation;(2) theacutetoxicitytest with mysid shrimp beconductedaccordingto 40 CFR 797.1930using flow.throughsystemsandmeasuredconcentrations;and(3) the chronictoxicity testswith Daphniamagnaandmysid shr;mpbeconductedaccordingto40CFR 797.1330and797.1950,respectively,using flow-through systemsandmeasuredconcentrations.

C. ProposedReportingRequirements

TheA~u-rcyproposedthe followingspecificreportingrequirements:

1. The ~narmacokinetic,neurotoxicity.dominant ethalassay.andallenvironmcntaleffectstestswould becomplete~andthe final reportssubmittedto theAgencywithin 1 yearofthe effective dateof thefinal PhaseIItestrule. A progressreporton eachstudy would beprovided6 monthsafterthe effective dateof the final single-phasetestruleor final PhaseII test rule,whicheveris applicable.

2. Thedevelopmentaltoxicity testwould becompletedandthe final reportsubmittedto theAgencywithin 18monthsof the effectivedateof thefinalPhaseII testrule. Interim progressreportswouldbe providedeveryBmonths.

3. Thetwo-generationreproductiveeffectstest would becompletedandthefinal reportsubmittedto theAgencywithin 29 monthsof theeffective dateofthe final PhaseII test rule. Interimprogressreportswould be providedevery6 months.

HI. Responseto Public Comments

In the September9. 1986proposedrule, EPA invited commentson thefollowing topics:

1. Theproposedtestingrequirementfor an oral-inhalationcomparativepharmacokineticstudywith DCP.

2. Requiringtheoral, ratherthaninhalation,routeof administrationinconductinghealtheffectstestswithDCP.

3. Theproposeduseof theTSCA testguidelinesas the teststandardsfor therequiredtestingof DCP.

4. The proposedschedulefor therequiredtesting.

TheAgencyreceivedwrittencomments(Ref. 1) from Dow ChemicalCompany(alsoreferredto in thisdocumentas “Dow”). A publ;c meetingwasnot requested.Dow Incorporatedbyappendixtheir previouscommentson allof theguidelinesproposedas standardsfor the DCPrequiredtesting: (1)Commentssubmittedon October12.19”9. andMarch11. 1981. whentheguidelineswere first proposed.arid (2)commentssubmittedon March20. 1986,in responseto revisionsof someof theguidelinesproposedin the FederalRegisterof January14. 1986 (51 FR 1522).The revisionshavebeenmodifiedandfinalized (52 FR 19056;May 20, 1987)aftercarefulconsiderationof allindustrycomments.including thoseofDow. TheAgencybelievesthatall of therevisions to the teststandardsrequiredin this documentareappropriateas teststandardsfor DCP.TheremainderofDow’s commentsarediscussedbelow.

A. PharmacoidneticTesting

1. Generalcomments.Dow agreesthatpharmacokineticstudiescan beuseful inhazardevaluation,but only when thesestudiesaredesignedto answerspecificquestionsposedby datageneratedfromtoxicity tests.Dow maintainsthatpharmacokineticdatathatcannotberelatedto specificaspectsof toxicity aredifficult to interpretandhavelittlevalue.Sincepharmacokineticdatashould answerspecificquestionsrelatedto toxicity. Dow believesthatthesestudiesarenot suitedfor standardprotocolsandshouldbe custom-designedfor eachchemicalsubstance.Dow furthercommentedthat if theAgencymandatesthe useof standardprotocols.theseprotocolsshouldbehighly flexible. This flexibility is neededto allow the useof newapproachesandto makeappropriatechemical-specificadaptationswherenecessary.

EPA doesnot agreewith Dow thatpharmacokineticdatahavelittle valueunlessthey arerelatedto a specifictoxicity question.Someaspectsof the”pharmacokinetictest,suchasabsorptionkinetics,producedatathatwill help the regulatorytoxicologistperformroute-to-routeextrapolations.Other aspects.suchastissuedistribution,may indicatetheneedforfurther toxicity testingasa resultof thesequesteringof thechemicalsubstanceor the detectionof high levelsin non-targettissues.TheAgencyagreeswithDow that,at times, thesedatawill be

‘7140 FederalRegister / Vol. 52. No. 192 / Monday. October 5. 1987 / Rules and Regulations

difficult to interpret, asin thehypotheticalcaseproposedby Dow inv. h;ch sex-relateddifferencesinmetabolismareobservedbut no sex-relateddifferencesin toxicity aredetected.TheAgencydoesnot believethat the potential for generatingdatathat is difficult to interpret is a soundrationalefor determiningthat a giventest should not beconducted.In theabo~eexample,the resultsof thepharmacokineticstudy would haveraisedconcernaboutthe adequacyofthe availabledatato supportanevaluationof potentialhumanrisk fromexposure.

EPA alsobelievesthatstandardprotocolsareadvantageousfrom aregulatorystandpoint.Theuseofstandardprotocolsprovidesa consistentbody of datafrom which regulatorydecisionscanbe made.Becausethisdatasetis consistent,comparisonsbetweenchemicalsubstancescanbemademoreeasilyandthe historicalresultsof regulatorydecisionsonsubstancesthathavebeendeterminedto be similar canbeusedto provideconfidencein presentandfuturedecisionmakingprocesses.

Moreover.the Agencyconsidersthestandardprotocolsas usedby theAgencyto behighly flexible. As hasoccurredwith manytestrules, thestandardprotocolmay bemodifiedas aresultof thechemical-specificneedsoftesting.This ability to modify a standardprotocolprovidesthe flexibility neededto addressthe specialcharacteristicsofa substance,or in the absenceof suchcharacteristics,allowstheAgencytoinvokethestandardprotocol.

2. Specific comments.Dow submittedspecificwritten commentson severalaspectsof the proposedpharmacokinetictestprocedure:Animalselection(requiredspecies,weightranges.animalcare,andtesting of bothsexes);administrationof testsubstance(determinationsof high dosageandmannerof dosing);determinationofbioavailability (time intervalsforcollectionof excreta,measuringtheconcentrationof test substanceinexpiredair, andmeaningof theterm‘~saturability”);andobservationofanimals(time intervalsfor collectionofblood).Commentswerealso submittedon proposeddataanalysisandreportingrequirements,evaluationof results(useof statisticsvs. a kinetic model),andthetest report(tissuedistributionandbiotransformationpathways).

TheAgencydisagreeswith someofthepointsraisedby Dow, anda detailedexplanationof theAgency’spositionmaybefound in the supportdocument(Ref. 2) preparedfor EPA by SyracuseResearchCorporation(SRC)anda

rremarandumwritten by EPA’s HealthandEnvironmentalReviewDivision ofthe Office of Toxic Substances(Ref. 3).OtherDow commentshaveresultedinguidelinemodificationsandaredescribedbelow.

a. Dow objectedto the designationofspec:ficweight rangesfor the Fischer344 ratsto beusedin the proposedpharamacokinetictest.In the proposedtest guideline,a rangeof 125 to 175gramswasspecifiedfor maleswhile arangeof 110 to 150gramswasspecifiedfor females.Dow contendsthattheserangesareneedlesslyrestrictiveandwill result in the pointlesssacrificeofotherwiseusefulanimals.Dow furthern’.aintainsthat the weightrangesaretoolow, andthatthe useof suchsmallanimalswill hinderblood collectionfrom both a technicalconsiderationinobtaining samplesandasa resultof therelatively smallbloodvolume. Dowrecommendsthatthereferencetospecificanimalweightseitherbeeliminatedfrom theproposedrule or theacceptableweightrangesbe increasedto 180 to 250gramsfor malesand130 to160gramsfor females.

The Agencyobjectivein specifyinganimal weightswasto obtaindataonyoun~tadult maleandfemaleanimals.Theaaesof animalsin eachgroupshould be closeandthe rangeshould becomparablefrom groupto group, evenwher. sexdiffers.Otherwise,agedifferencesmay complicatetheinterpretationof experimentaldata(Refs.4 and5). Consequently.thespecifiedweightrangeshavebeendeletedfrom 40 CFR795.230(c)(1)(ii),andinsteadit is specifiedthatallanimalsusedin thetestmust be7 to 9weeksold.This requirementwill ensurethat agedifferencesdo not affect testresults.

b. Dow contendedthatthe specificenvironmentalconditionsproposedforanimalmaintenacearetoo restrictiveandarenot consistentwith theguidelinesin theGuidefor the Care andUseof LaboratoryAnimals(PublicationNo. (NIH)—7—23, 1978).Theguiderecommendstheuseof roomtemperaturesbetween18 and28. C andhumidity of 40 to 70 percent.In theproposedtestguideline,thetemperatureandhumidity are8pecifiedas 25 ±2 Cand50 ±10 percent,respectively.

EPA believe.therangeoftemperaturesandhumidity suggestedbyDow for animalcareis too greatbecausebroaderrangesof temperatureandhumidity createmorevariablesinthestudyandthegreaterrangescouldstressthe animals.The Nil-f guideis ageneralguidefor careof laboratoryanimals,andnot necessarilyastandardfor changingthe temperature

requirementof 25 ±2’ C asproposedin§798.7475(c)(1)(iii)(November8. 1985; 50FR 46104) to 24 ±2’ C in§795.230(c)(1)(iii)of this final rule toavoidthe useof 27°C atemperatureabovethe rangerecommendedin theguide.The Agencybelievesthatahumidity requirementof 50 ± 10 percentis not unduly restrictiveandisunchangedin the final testguideline.

c. Dow maintainedthatmethodsarenot availableto distinguishbetweenconcentrationsof testsubstancein theinspiredandexpiredair, andstatedthattheterm “saturability” as usedin theproposedtestguidelineis unclear.

TheAgencyagreeswith this commentandhasmodified § 795.230(c)(2)(iii)(D)to eliminatethe measurementof theconcentrationof testsubstanceinexpiredair. Theconcentrationof testsubstancein inspiredairdoesnot needto be “measured,”sinceit is equalto theadministereddoselevel (concentrationin the test chamber).Thecalculationofpercentagetest substanceretention,body burden,and“saturability” hasalsobeendeleted,alongwith the test reportrequirementfor thesevalues.

d. Dow objectedto the proposedrequirementthatall resultsbesubjectedto statisticalanalysis.Dow maintainsthat statisticalanalysisrequiresthegenerationof hypothesesandthattheproposedtestruledoesnot provideguidanceas to whathypothesesshouldbe tested.Dow contendsthatthereislittle valuein identifying statisticallysignificantdifferences,sincethesedifferencesareusuallymeaninglessforpharmacokineticstudies.Dowrecommendsthat insteadof statisticalanalysis,thedatabe describedusingappropriatekinetic models.In addition,the proposedtestguidelinerequiresthatall results,both quantitativeandincidental,shall beanalyzed.andDowis unclearas to whatis meantby“incidental results.”

TheAgencydoesnot agreethatstatisticalanalysisis not usefulforpharmacokirieticdata.Dataarestatisticallyanalyzednot only to testhypotheses,but alsoto provideameasureof theamountof variabilityassociatedwith reportedpharmacokineticparameters.Theseparameters.suchasKm or Vrnax, areusually reportedalongwith a standarderior or standarddeviationthat iscalculatedusingthe resultsfrom anumberof experimentaldeterminationsThis statisticalanalysisis neededtoensurethatthestudyhas beenconductedin a c~petentmannerandthatresultspresentedarenotmeaninglessrandomvalues.For thisreason,the Agencybelievesthat

Federal Register / Vol. 52, No. 192 I Monday, October5. 1987 / Rules and Regulations 37141

;tatisticalanalysisof pharmacokineticJatadoesprovide usefulandnecessarynformation.TheAgencydoesagree,however,

.s’Ith Dow thatpharmacokineticandnetabolismdatashouldbe describedbyin appropriatekinetic model.Theseiiodels providedescriptionsof)harmacokineticprocessesandassistinhepredictionof suchvaluesas body)urdenandelimination half-life, whichire useful in assessingthehazardissociatedwith exposureto a chemical,ubstance.Pharmacokineticmodels,iowever. shouldbe employediniddition to, andnot in placeof, the.tatisticalanalysesof the data.[‘herefore, the test report sectionof thepharmacokineticguidelinein§ 795.230(d)(3)is modified to askfor anypharmacokineticmodel(s)developed~romtheexperimentaldata.

With regardto Dow’s commenton theTieaningof the term “incidental” in§ 795.230(d)(2),the phrase“quantitativeJr incidental”hasbeendeletedtoeduceanypossibleconfusion.Theectionnow reads,“All observedresultshall beevaluatedby anappropriatetatistical method.”e. Thelanguageof proposed795.230(c)(2)(iii)(C).(3)(i)(B), (ii), and

iii) havebeenmodifiedslightly in thisma)rule for the purposeof clarification.ollection of excretafrom 0 to 24 hours

md thenfrom 24 to 48 hoursis moreiccuratethan“at 24 and48 hours.” EPAielievesthat terminatingcollectionvhen 90 percentof thedosehasbeen‘xcreted will yield adequatenformation,andeliminatethe possible.ituation of collecting for additionallays only to accountfor I to 2 percentnoreof theadministereddose.

1. EnvironmentalEffectsTestingDow raisedissuesconcerningthe

vailability of facilities to performtheroposedtestingof DCPwith mysidhrimp andalgaeduringthe proposedime frames.

With regardto algal toxicity testing.)ow believesthat stopperingthe testessel,as recommendedwhentestingolatile chemical substancessuchas)CP, will resultin invalid resultsecausedecreasedCO2 levelswill limitlgal growth. Dow recommendsthatPA withdrawthe proposedtestequirementuntil suitablemethodology

developed.TheAgency agreesthat.lgal growth will be limited by thelecreasedCO2 level in the test vessel;mowever,the growthwill be limited inoth control andtreatmenttestvessels,Ilowing acomparisonto be made.Due

o this limitation effect, EPA isvithdrawingthe proposedrequirement

* 797.lO5O(C)(4)(jv) that algal growth

in controlsreachthelogarithmicgrowthphaseby 96hours.

Dow also raisedconcernabouttheavailability of suitableculturesto useinconductingtheproposedacuteandchronicmysid shrimp toxicity tests.Laboratoriesthathavebeenconductingmysid testing haveexperiencedupsetsin the rearingof mysidsor havehaddifficulty in obtainingsuitableculturesfor testing,e.g.. culturesmaysufferexcessive(greaterthan10 percent)mortality. Theupsetsmay bedie topoorviability of theyoungorganismsandmay berelatedto nutrientbalance.

While EPA acknowledgesthatsomelaboratorieshavehadthis problem,theAgencybelievesthat it is notinsurmountablewith regardto the mysidshrimp testingrequirementsfor DCP.The Agencybelievesthatadequatemysid cultureswill be availabletoconductthe acuteandchronictoxicitytesting within thetime alloted by thistest rule(1 year).

lv. Final Test Rule

A. Pharmacokinetics1. Findings

EPA is basingits oral-inhalationcomparativepharmacokinetictestingrequirementon the authorityof section4(a)(1)(B)of TSCA. EPA finds thatDCPis producedandreleasedto theenvironmentin substantialquantities.andthat its manufacture,processing.andusemay result in substantialhumanexposureto this chemicalsubstance.Thedetailedbasisfor this finding isfound in Unit IV.A. of thefinal PhaseItest rule for DCP (51 FR 32079;September9, 1988).

EPA also finds that there areinsufficientdatato reasonablypredictandcomparetheabsorption,distribution,metabolism,andexcretionof DCP in thebody as a result of oral orinhalationexposuredueto DCP’smanufacture,processing,anduse,andthat anoral-inhalationcomparativepharmacokineticstudy of DCPisnecessaryto developsuchdata.EPAbelievesthatthedataresultingfrom thistesting will berelevantto adeterminationas to whetherthemanufacture,processing,anduseofDCPdoesor doesnot presentanunreasonablerisk of injury to health.

2. RequiredTestingEPA is requiringthatan oral~

inhalationpharmacokineticstudybeconductedwith DCP.

3. OtherProvisions

Test substancespecification. personsrequiredto test(as amendedin UnitIV.D. of this document), and

enforcementprovisionspresentedin thefinal Phase.1 rulefor DCP (51 FR 32079)areapplicableto the pharmacokinetictestingof DCP.

B. Final TestStandards

TheTSCA testguidelines(40 CFRParts797 and798) specifiedin Unit ll.B.for neurotoxicity.mutagenicity(chromosomalaberrations).reproductiveeffects,developmentaltoxicity. acutetoxicity to marineandfreshwateralgaeandmysid shrimp,chronictoxicity to mysid shrimpandDaphniamagna,andoralandinhalationpharmacokinetics.as modified in thisrule. shall be the test standardsfor thetesting of DCPrequiredunder40 CFR799.1550.TheAgencybelievesthat theconductof therequiredstudiesinaccordancewith thesetest standardsisnecessaryto ensurethat theresultsarereliableandadequate.

C. Final ReportingRequirements

EPA requiresthatall datadevelopedunderthis rule bereportedinaccordancewith the TSCA GoodLaboratoryPractice(GLP)Standards,whichappearin 40CFR Part792.

Testsponsorsarerequiredto submitindividual studyplansat least45 daysprior to theinitiation of eachstudyinaccordancewith 40 CFR 790.50.

TheAgencyis requiredby TSCAsection4(b)(1)(C) to specifythetimeperiodduringwhich personssubjectto atestrulemustsubmit testdata.On thebasisof its experiencewith healthandenvironmentaleffect8testing,EPA isadoptingthe proposedschedulefor thesubmissionof final test resultsas thefinal schedule(seeUnit ll.C.).

TSCA section 14(b)governsAgencydisclosure of all test datasubmittedpursuant to section 4 of TSCA. Uponreceiptof datarequiredby this rule, theAgencywill publisha noticeof receiptin the Federal Registeras required bysection4(d).

D. PersonsRequiredTo Test

EPA doesnot intendfor anypersonswho manufactureor processDCPsolelyasan impurity to besubjectto theDCPPhaseI test ruleor this rule forpharmacokinetictestingof DCP.Thephrase“other thanas an impurity” wasinadvertentlyomittedfrom§ 799.1550(b)(1)in thefinal PhaseI rule(51 FR 32079)and from ~79~.1550(b)(5)in the proposedrule for pharmacokinetictesting(51 FR 32107).Therefore,thoseparagraphsarerevisedin this final ruleto reflect theAgency’sintention.

37142 Federal Register / Vol. 52,No. 192 / Monday, October 5, 1987 / Rules and Regulations

E. ConditionalExemptionsGranted

Thetest rule developmentandexemptionprocedures(40 CFR 790.87)indicate that, whencertainconditionsaremet,exemptionapplicantswill benotified by certifiedmail or in the finalPhaseII test rulefor a givensubstancethat theyhavereceivedconditionalexemptionsfrom test rulerequirements.Theexemptionsgrantedareconditionalbecausetheywill begivenbasedon theassumptionthatthe test sponsorswillcompletethe requiredtesting accordingto the test standardsandreportingrequirementsestablishedin thefinalPhaseII test rulefor the givensubstance.TSCA section4(c)(4)(B)providesthat if an exemptionis grantedprospectively(that is. on thebasisthatoneor morepersonsaredevelopingtestdata,ratherthanon the basisof priortestdatasubmissions),theAgencymustterminatetheexemptionif thetestinghasnotbeenconductedin accordancewith the testrule.

Sinceasponsorhas indicatedto EPAby letterof intent (Ref. 8) its agreementto sponsorall of thetestsrequiredforDCP in thefinal PhaseI testrulefor thissubstance(51 FR 33)79;September9,1986)andEPA hasadoptedteststandardsandreportingrequirementsinthis final PhaseII testrule for DCP, theAgencyis herebygrantingconditionalexemptionsto all exemptionapplicantsfor all of the testingrequiredfor DCPin40 CFR 799.1550by the final PhaseI testrule. However,manufacturersandprocessorswho aresubjectto the testingrequirementsof this rulemustcomplywith thetestruleandexemptionproceduresin 40 CFR Part 790withregardto pharmacokinetictesting.Manufacturers(includingImporters)subjectto thisrule arerequiredtosubmiteitheraletterof intent toperformthe pharmacokinetictestingoran exemptionapplicationon at before30daysafterthe effectivedateof thisfinal testrule. Therequiredproceduresfor submittingsuchlettersandapplicationsaredescribedin 40 ~FRPart790.A detaileddiscussionofpersonsrequiredto testandproceduresto be followedarepresentedin UnitIV.D. of thefinal PhaseI rule for DC?(51 FR 32079).

F. Judicial Review

Thepromulgationdatefor theDCPfinal PhaseI rulewasestablishedas Ip.m. easternstandardtime onSeptember23, 1966.To EPA’sknowledge,no petitions for judicialreviewof thetfinal P~iaeeI rulewerefiled. Any petitionfor judicial reviewofthis final rulewill be limited to a reviewof the test stasdardaandreporting

requirement8for the PhaseII nile andtothe pharmacokinetictestrequirement.standards,andreportingrequirementsestablishedin this rule.

V. EconomicAnalysisof Final Rule

To assessthe economicimpactof thisfinal rule. EPA haspreparedaneconomicevaluation(Ref. 7) thatexaminesthe coal of therequiredtesting.both for pharmacokinetictestingaloneandin conjunctionwith testingrequiredin theDC? final rule, andanalyzesfour marketcharacteristicsofDCP: (1) Demandsensitivity.(2) costcharacteristics,(3) industrystructure,and(4) marketexpectations.Theeconomicevaluationfor the DCPfinaltestrule. whichestimatesatestingcostof $144,610to $191,680forpharmacokinetictesting.andatotaltestingcostof $470,230to $608,350forboth the testsrequiredin thefinal PhaseI ruleandthepharmacokinetictesting.indicatesthatthepotential for adverseeconomiceffectsdueto theestimatedcost of testing is low. Theannualizedtotal testcosts for DCPrangefrom$121,855to $157,648.This conclusionisbasedon the following observations(Ref. 7):

1. Propyleneoxide(P0), themainproductin DCPproduction,is usedmainly as acaptiveintermediateandhasa relativelyinelasticdemand.

2. Themarketexpectationsfor P0andmanyof its derivativesarefavorable.

3. Dow manufacturersDC?andP0 attwo highly integratedplantswhereminor costincreasescan bedispersedovernumerousendproducts.

4. Theestimatedtotal unit test coats(i.e., the testcosts for DCPandP0) arenegligible, or lea.than0.02centperpoundor0.04percentof P0pricein theupper-boundcase.

Referto theeconomicanalysis(Ref. 7)for acompletediscussionof testcostestimationandthe potentialforeconoai~cimpactresultingfrom thesecosts.

VI. Availability of TestFacilitiesandPersonnel

Section4(b)(1)of TSCA requiresEPAto consider“the reasonablyforeseeableavailability of thefacilities andpersonnelneededto performthe testingrequiredunderthe rule.” Therefore.EPAconductedastudy to assesstheavailability of test facilities andpersonnelto handlethe additionaldemandfor testingservicesa~eetedbysection4 test rulesandtestprogramsnegotiatedwith industry in placeofrulemaking.Copiesof thestudy,“ChemicalT~ung[ndustlT Pr’o~1leofToxicologicalTesting”October,1981,can beobtainedthroaghtheNational

TechnicalInformationService,5285 PortRoyal Road,Springfield.Va.. 22181.underpublicationnumberPB 82—140773.On thebasisof this study,the Agencybelievesthat therewill be availabletestfacilities andpersonnelto performthetestingrequiredin this final rule.

VIL RulemakingRecord

EPA hasestablisheda recordfor thisrulemaking,(docketnumberOPTS—42043C].This recordincludesbasicinformationconsideredby theAgency indevelopingthis final rule, andappropriateFederal Register notices.This recordincludesthe followinginformation:

A. SupportingDocumentation

Thesupportingdocumentsfor thisrulemakingconsistof theFederalRegisterdocumentscontainingtheproposedandfinal PhaseI andproposedPhaseII andsingle-phasetestrules onDC?.8. References

(I) Dow, The Dow ChemicalCompany.Commentson 1.2-dichioropropaneproposedtestrule andproposedteststandards.51 FR32107.Submittedto TSCA Public InformationOffice (TS.—793).Office of PesticidesandToxic Sub&tances,USEPA. Washington.DC.DocumentControlNumberOPTS-42043.lOctober24, 1986)

(2) SyracuseResearchCorporation.Responseto generalcommentson theoralandinhalationphsrmacokineticstests.Preparedfor TestRulesDevelopmentBranch,ExistingChemicalAssessmentDivision.Office of Toxic Substances,USEPA.(Janeary22. 1987)

(3) USEPA.U.S. EnvironmentalProtectionAgency.Responseto TRDB requesten reviewof SRCresponseto onmmentsonpharmacokineticguidelines.Intraagencymemorandumto GaryE. Timrn, ExistingChemicalAssessmentDivision, from theHealthandEnvironmentalReviewDivision.(April 10, 1987)

(4) Calabrese, E.j ‘Toxic SusceptibilitrMale/FemaleDifferences. “New Yor4c: JohnWiley & Sons.(1985)

15) Calabrese,£/. “Age andSusceptibilityto ToxicSubstances.“New York: JohnWiley& Sons.(1988)

(6) Dow. The Dow ChemicalCompany.Letter of intent to conduct testingwith 1.2.dmchloropropane.Submittedto TSCA PublicInformationOffice(TS—793).Office ofPesticidesandToxicSubstances.USEPA.Washington.DC. Control NumberOPTS42043.(November14, 1986)

(7) EPA.Economicimpact Analysisof PlnalTestRule for 12-Dichloropropane.U.S.EnvironmentalProtectionAgency,Washington.DC. (1986)

Confidential BusinessInformation(CBI), while pail o~therecord,is notavailablefor public review.A publicversionof therecord,from whichCBIhasbeendeleted.is availablefor

(ç

Federal RegisterI Vol. 52, No. 192 I Monday. October 5. 1987 I Rules and Regulations 37143

Inspectionfrom 8 a.m. to 4 p.m..MondaythroughFriday.exceptlegalholidays,inRoom NE-G004.403 M StreetSW.,Washington.DC.

VIII. Other Regulator~Requirements

.4. ExecutiveOrder 72291UnderExecutiveOrder12291,EPA

must judgewhethera rule is “major”and thereforesubjectto therequirementsof aRegulatoryImpactAnalysis.This test rule is not majorbecauseit doesnot meetanyof thecriteriasetforth in section1(b) of theOrder.The economicanalysisof thetesting of DCP is discussedin Unit V ofthis notice.

This rulewassubmittedto theOfficeof ManagementandBudget(0MB) forreview as requiredby ExecutiveOrder12291.Any written commentsfrom 0MBto EPA, andanyEPA responseto thosecomments,areincludedin therulemakingrecord.

B. RegulatoryFlexibility Act

UndertheRegulatoryFlexibility Act.(5 U.S.C.601 etseq..Pub.L. 96—354.September19. 1980). EPA is certifyingthat this rulewill not haveasignificantimpact on asubstantialnumberof smallbusinessesfor the following reasons:

(1) Thereareno smallmanufacturersof 1.2-dichloropropane.

(2) Small processorsarenot expectedto performtestingthemselves,or toparticipatein theorganizationof thetesting efforts.

(3) Small processorswill experienceonly very minor costs.if any, in securingexemptionfrom testingrequirements.

(4) Small processorsareunlikely to beaffectedby reimbursementrequirements,andanytestingcostspassedon to small processorsthroughprice increaseswill besmall.

C. PaperworkReductionAct0MB has approved the information

collectionrequirementscontainedin thisfinal ruleunderthe provisionsof thePaperworkReduction Act of 1980 (44U.S.C.3501 et seq.,Pub. L. 96-511.December11, 1980), and has assigned0MB control number2O70—0033.

List of Subjects in 40CFR Parts 795and799

Chemicals.Environmentalprotection.Hazardoussubstances,Testing.Laboratories.Recordkeepingandreportingrequirements.

Dated:September25. 1987.J.A. Moors,Assistant Administratorfor PesticidesandToxicSubstances.

Therefore.40CFR Chapter 1. isamendedasfollows:

PART 795—{AMENDEDJ

1. In Part795:a. The authority citation for Part 795 is

revisedto readas follows:Authority: 15 U.S.C.2603.

b. Section795.230is added,to readasfollows:§ 795.230 Oraland InhalatIonpharmacoklnetlc test.

(a) Purpose,Thepurposeof thesestudiesis to determine:

(1) Bioavailability of test substanceafter oralandinhalationexposure.

(2) Whetheror not thebiotransformationof thetest substanceis qualitativelyandquantitativelythesameafter oral and inhalation exposure.

(3) Whether or not thebiotransformationof thetest subalanceis changedqualitativelyorquantitativelyby repeateddosing.

(b) Definitions. Bloavailability refersto the rate andextentto whichanadministeredchemicalsubstancecompoundis absorbed,i.e., reachesthesystemiccirculation,

(c) Testprocedm”es—(1)Animaiselection—(i)Species.The preferredspeciesis therat for which extensivedataon the toxicity andcarcinogenicityof numerous chemicalsubstancesareavailable.

(ii) Animals.Adult maleandfemaleFischer344 ratsshall beused.Theratsshall be7 to 9 weeksold. Prior totesting. the animalsareselectedatrandomfor eachgroup.Animalsshowingsignsof ill health8hall not beused.

(iii) Animal care.Animalsshall behousedin environmentallycontrolledroomswith 10 to 15 air changesperhour. Theroomsabet!be maintainedata temperatureof 24 ±2C andhumidity50 ±10percentwith a12-hourlight!dark cycleperday.The ratsshall beisolatedfor at least7 daysprior to use,andtheirhealthstatusshall thenbeevaluated.Theanimalsshall beacclimatedto theexperimentalenvironmentfor aminimum of 48hourspriorto treatment.Certifiedfeed andwatershall beprovidedadlibitum.

(iv) Numbers.—{A)At least8 animals(4 malesand4 females)shall beusedateachdoselevel.

(B) Femalesshall beQulliparousandnonpregnant.

(2) Administrationof thetestsubstance—{i)Testsubstance.The testsubstanceshall be at least99 percentpure.Thestudiesrequire the useof bothnonradioactiveand14C-labeledtestsubstance.Both preparationsareneededto investigatetheprovisionsofparagraph(a)(2)of this sectien.Theuseof ‘4C-testsubstanceis recommended

for the provisionsin paragraphs(aj(1),(a)(2). and(afl3) of this sectionin orderto facilitate the work. improvethereliability of quantitativedeterminations,andincreasetheprobability of observingpreviouslyunidentifiedmetabolites.

(ii) Dosageandtreatment—(A)Oralstudy.At leasttwo dosesshall be usedin thestudy.a “low” and“high” dose.Whenadministeredorally. the “high”doseshould inducesomeovert toxicitysuchas weight loss.The “low” doseshall not induceobservableeffectsattributableto the test substance.Oraldosing shall be performedby gavageusing an appropriatevehicle.

(B) inhalation study.Threeconcentrationsshall be usedin thestudy.Upon exposure.the two highercosicentrationsshould ideally inducesomeovertsymptomsof toxicity,althoughtheintermediateconcentrationmay be excludedfrom this condition.Thelowestconcentrationshall notinduceobservableeffectsattributabletotl~teatsubstance.

(iii) Determinationofbioavailability—(A) Oral studies. (1)GroupA (a minimum of 8 animals,4malesand4 females)shall bedosedonceperas with the low doseof 14C-labeledtest substance.

(2) GroupB (aminimum of 8 animals,4 malesand4females)shall bedosedonceperas with the high doseof ‘IC-labeledtest substance.

(B) inhalation studies.(1) GroupC (aminimum of 8 animals,4 malesand4females)shall be exposed(8 hours)to amixtureof non-radioactivetestsubstancein air at theprescribedlowtestsubstanceconcentration.

(2) GroupD (a minimum of 8 animals,4 malesand4 females)shall beexposed(6 hours)to a mixtureof non-radioactivetestsubstancein air at theprescribedintermediatetest substancecoflcef,tratio~.

(3) GroupE (a minimum of 8 animals,4 malesand4 females)shall beexposed(6 hours)to a mixtureof non-radioactivetest substancein airat theprescribedhigh concentration.

(4) GroupF (axrnnina~ef8 animals,4 malesand4 females)shall beexposed(6 hours)to a mixtureof tsClabeledtestsubstancein air at theprescribedlowtestsubstanceconcentration.

(5) GroupC (aminimum of 8 animals,4 malesand4 females)shall beexposed(6 hours)to amixtureof 14C—labeledtestsubstancein air at theprescribedintermediatetestsiibstsmceconcentration.

(6) GroupH (aminimum of 8 animals,4 malesand4 females)shall be exposed(6 hours)to amixtureof ‘4C-labeledtest

37144 Federal Register/ Vol. 52. No. 192 I Monday, October5. 1987 I Rules and Regulations

substancein airat theprescribedhightest substanceconcentration.

(C) Collectionof excreta.After oraladministration(GroupsA andB) andinhalation exposure(GroupsF throughH) the ratsshall be placedin individualmetaboliccagesandexcreta(urine,fecesandexpiredair) shall becollectedfrom 0 to 24 hoursandthenfrom 24 to 48hourspost~treatment,or until 90 percentof thedosehasbeenexcreted.whicheveroccursfirst.

(D) Kineticstudies.GroupsC throughE shall beusedto determinetheconcentrationof thetest substanceinblood at 0. 5, 10. 15, and30 minutes.andat 1. 2. 4, 8. 16. 24, and48hoursafterinitiation of inhalation exposure.

(E) Repeateddosingstudy.Rats [aminimum of 8 animals,4 malesand4females)shall receiveaseriesof singledaily oraldosesof non-radioactivetestsubstanceovera periodof at least7days.followedat 24 hoursafterthe lastdoseby asingle oraldoseof 14C-labeledtestsubstance.Eachdoseshallbeat the low-doselevel.Urine shall becollectedfrom 0 to 24 hoursandthen 24to 48 hoursafteradministeringthe 14 C-labeledtestsubstance.

(3) Observationof animols—(i)Bioavailability—(A)Bloodlevels.Thelevelsof total I ~C-label shall bedeterminedin wholeblood,bloodplasma.or blood serumof eachrat at 0.4. 8, 16. 24. and48hoursafterdosingratsin GroupsA-B andF—H.

(B) Expiredair. urinary andfecolexcretion.Thequantitiesof total 14C-label eliminatedin expiredair, urine,andfecesby eachrat in GroupsA andBandF throughH shall be determinedincollectionsmadefrom 0 to 24 hoursandthen24 to 48 hoursafterdosing and. ifnecessary.daily thereafteruntil at least90 percentof thedosehasbeenexcretedor until 7 daysafterdosing.whicheveroccursfirst.

(C) Tissuedistribution.Theconcentrationandquantityof 14C-labelin tissueandorgansshallbe determinedat the time of sacrificefor eachrat inGroupsA andB, F throughH. andtherepeated-dosinggroup.

(ii) Biotransformationafteroral andinhalationexposure.Appropriatequalitativeandquantitativemethodsshall beusedto assayurine specimenscollectedfrom eachrat in groupsA andB andF throughH. Suitableenzymaticstepsshould be usedto distinguish.characterize,andquantifyconjugatedandunconjugatedmetabolitesof the testsubstance.

(iii) Change(s)in biotransformation.Appropriatequalitativeandquantitativeassaymethodologiesshall be usedtocomparethecompositionof 14C-labeiedcomponentsof urinecollectedfrom 0 to

24 andthen from24 to 48hoursafterdosing rat GroupA with thosecomponentsin the urinecollectedoverthe sameintervalsafteradministeringthe radioactivedosein the repeateddosingstudy.

(d) Data andreporting—(1)Treatmentof results.Datashould besummarizedin tabularform.

(2) Evaluationof results.All observedresultsshall be evaluatedby anappropriatestatisticalmethod.

(3) Testreport. In addition to thereportingrequirementsasspecifiedinthe EPA GoodLaboratoryPracticeStindards(Subpart),Part792 of thischapter)the following specificinformation shouldbe reported:

(i) Labelingsite of the test substance.(ii) A full descriptionof thesensitivity

andprecisionof all proceduresusedtoproducethe data.

(iii) Quantityof isotope.togetherwithpercentrecoveryof the administereddosein feces,urine, expiredair, andblood for both routesof administration.

(iv) Quantity anddistribution of 14C-test substancein bone.brain, fat,gonads.heart,kidney, liver, lung.muscle,spleen.tissuewhichdisplayedparnology,andresidualcarcass.

(v) Biotransformationpathwaysandqudntitiesof test substanceanditsmE’tabolitesin urine. feces.andexpiredair collectedafteroraladministration(single low andhigh doses)andinhalation exposure(low, intermediate,andhigh concentrations).

(vi) Biotransformationpathwaysandquantitiesof the testsubstanceanditsmetabolitesin urine collectedafterrepeatedadministrationof testsubstanceto rats.

(vii) Pharmacokineticmodel(s),if any.developedfrom theexperimentaldata.

(4) Countingefficiency.Datashouldbemadeavailableto the Agencyuponrequest.

PART 799—EAMENDED)

2. In Part799:a. Theauthoritycitation for Part799

continuesto readas follows:Authority: 15 U.S.C.2603. 2611.2625.

b. Section799.1550is amendedbyrevisingparagraph(b)(1)andaddingparagraphs(b)(5). (c)(1)(ii) and(iii),(2)(ii) and(iii), (3)(ii) and(iii), (4)(ii) and(iii) and(5), and(d)(1)(ii) and(iii). (2)(ii)and(iii), (3)(ii) and(iii), and(4)(ii) and(iii). and(e) to readas follows:

§ 799.1550 1,2-Otchloropropane.

(b) * * *

(1) All personswho manufactureorprocess1.2-dichioropropane.otherthanasan impurity, from October23. 1986 to

the endof the reimbursementperiod.shall submit lettersof intentto conducttestingor exemptionapplications.conducttests.andsubmitdataasspecifiedin paragraphs(c)(1), (c)(2),(cl(3). and(c)(4). and(d) of this section.SubpartA of this Part.andParts790 and792of this chapterfor two-phaserulemaking.

(5) All personswho manufactureorprocess1,2-dichloropropane.otherthanas an impurity, from November18. 1987to theendof thereimbursementperiod.shall submitlettersof intent to conducttestingor submitexemptionapplications,conducttests.andsubmitdataas specifiedin paragraph(c)(5) ofthis section.SubpartA of this part, andParts790 and792 of this chapterforsingle-phaserulemaking.

(c) * *

(1) S *

(ii) Teststandards.Theneurotoxicitytesting with 1,2-dichloropropane,consistingof a neuropathologytest.amotoractivity test,anda functionalobservationalbattery,shall beconductedin accordancewith§ § 798.6400,798.6200.and798.6050ofthis chapter.respectively,usingtheoralrouteof exposure.Theanimalsshall bedosedwith DCPfor aminimum of 5daysperweek,overa periodof at least90 days.

(iii) Reportingrequirements.(A) Theneurotoxicitytestsshall becompletedandthe final reportssubmittedto EPAwithin 1 yearof theeffectivedateof thefinal PhaseII rule.

(B) An interim progressreportshall besubmittedto EPA 6 monthsaftertheeffective dateof thefinal PhaseII rule.

(2) *

(ii) Teststandards.Thedominantlethal assaywith 1,2-dichloropropaneshall be conductedin accordancewith§ 798.5450of this chapter

(iii) Reportingrequirements.(A) Thedominantlethalassayshall becompletedandthefinal reportsubmittedto EPA within 1 yearof theeffectivedateof thefinal PhaseII rule.

(B) An interim progressreport shall besubmittedto EPA 6monthsaftertheeffectivedateof the final PhaseII rule.

(3)* * *

(ii) Teststandard.Thedevelopmentaltoxicity testwith i.2-dichloropropaneshallbe conductedin accordancewith§ 798.4900of this chapter,using the oralrouteof exposure.

(iii) Reportingrequirements.(A) Thedevelopmentaltoxicity test8hall becompletedandthefinal reportsubmittedto EPA within 18 monthsof the effectivedateof thefinal Phase11 rule.

Federal Register I Vol. 52. No. 192 I Monday, October5, 1987 I Rules and Regulations 37145

(BI Interim progressreportsshall besubmittedto EPA at 6-monthintervals,beginning8 monthsafter the effectivedateof thefinal PhaseII ruleandendingwith the submissionof theFinal TestReport.

(4) * *

(ii) Teststandard.The two-generationreproductiveeffectstesting with 1,2-dichioropropaneshall beconductedinaccordancewith § 798.4700of thischapter.usingtheoralroute ofexposure.

(iii) Reportingrequirement(A) Thetwo-generationreproductiveeffectstestshall becompletedandthe final reportsubmittedto EPA within 29 monthsoftheeffective dateof the final PhaseIIrule.

(B) Interim progressreportsshall besubmittedto EPA at 6-month intervals,beginning6 monthsafterthe effectivedateof the final PhaseII rule andendingwith the submissionof theFinal TestReport.

(5) Pharmacakineticstudies—{i)Requiredtesting.An oralandinhalationpharmacokinetictest shall beconductedwith 1.2-dichloropropane.

(ii) Teststandard.Theoralandinhalation pharmacokinetictestingwith1.2-dichloropropaneshall beconductedin accordancewith * 795.230of thischapter.

(iii) Reportingrequirements.(A) Thepharmacokinetictest shall becompletedandthefinal report submittedto EPAwithin 1 yearof the effectivedateof thefinal single-phasepharmacokineticsrule.

(B) An interim progressreportshall besubmittedto EPA 6 monthsafter theeffectivedateof the final single-phaserule.

(d) *

(1) * *

(ii) Teststandard.The myaid shrimpacutetoxicity test with 1.2-dichloropropaneshall beconductedasaflow-through testwith measuredconcentrationsusingMysidopsisbahiain accordancewith ~797.1930of thischapter.

(iii) Reportingrequirements.(A) Themysid acutetoxicity testshall becompletedandthefinal reportsubmittedto EPA within 1 yearof theeffectivedateof the final PhaseII rule.

(B) An interim progressreportshall besubmittedto EPA 6 monthsafter theeffective dateof thefinal PhaseII rule.

(2) *

(ii) Teststandard.(A) The algal acutetoxicity testswith 1.2-dichloropropaneshall beconductedwith marineandfreshwateralgaeusingsystemsthatcontrol for L2-dichloropropaneevaporationin accordancewith

§ 797.1050of this chapter.exceptfor theprovisionsin § 797.1050(c)(4)(iv).

(B) For the purposeof this section,thefollowing provisionsalsoapply to thealgal acutetoxicity tests:

(1) Definitive test.The testbeginswhen algaefrom 7 to 10-day-oldstockculturesareplacedin thetestchamberscontainingtest solutionshaving theappropriateconcentrationsof thetestsubstance.At the endof 96 hoursthealgal growth response(numberorweightof algal cells/mi) in all testcontainersandcontrolsshouldbedeterminedby an indirect(spectrophotometry,electroniccellcounters.dry weight.etc.) or adirect(actualmicroscopiccell count)method.Indirect methodsshould becalibratedby a directmicroscopiccount. Thepercentageinhibition orstimulationofgrowth for eachconcentration,EC10,EC50, EG~,andtheconcentration-responsecurvesaredeterminedfromthesecounts.

(2) (Reserved](iii) Reportingrequirements.(A) The

algal acutetoxicity testsshall becompletedandthe final reportsubmittedto EPA within 1 yearof theeffectivedateof the final PhaseII rule.

(B) An interim progressreportshall besubmittedto EPA 6 monthsafter theeffective dateof thefinal PhaseII rule.

(3) * * *

(ii) Teststandard.Thedaphnidchronictoxicity testwith 1.2-dichloropropaneshall be conductedasaflowthroughtestusingDaphniamagnain accordancewith ~ 797.1330of thischapter.

(iii) Reportingrequirements.(A) Thedaphnidchronictoxicity test shall becompletedandthe final reportsubmittedto EPA within 1 yearof the effectivedateof the final PhaseII rule.

(B) An interim progressreportshall besubmittedto EPA 6monthsaftertheeffectivedateof thefinal PhaseII rule.

(4) • *

(ii) Teststandard.Themysid shrimpchronictoxicity testwith 1,2-dichloropropaneshall be conductedasaflowthrough testusingMysidopsisbahiain accordancewith § 797.1950of thischapter.

(iii) Reportingrequirements.(A) Themysid chronictoxicity testshall becompletedandthe final reportsubmittedto EPA within 1 year of the effectivedateof the final PhaseII rule.

(B) An interim progressreport shall besubmittedto EPA 6monthsaftertheeffectivedateof thefinal PhaseII rule.

(e)Effectivedate.The effectivedateof the final PhaseII rule and the finalsingle-phasepharmacokineticsrulefor

1.2-dichloropropaneis November18.1987.

(FR Doc. 87—22914Filed 10—2—87; 8:45amjBIWNG CODE 555O-.5O-M