48762 FederalRegister I Vol. 50, No. 229 / Wednesday,November 27, 1985 / Rules and Regulations

40 CFR Part799

(OpTS-42O2ea~FRL-2931-2)

PropyleneOxide; TestingRequirements

AGENCY~Environmental ProtectionAgency(EPA).ACT1O* Final rule.

1u~suARv:This final rule promulgatedunder section4(a) of the ToxicSubstancesControl Act (TSCA) requires.manufacturersandprocessors.ofpropylene oxide-(GAS No. 75—58—9) to.test this chemicalfor developmental-~toxicity. Test standardsand reportingdeadlinesare beingproposed-elsewhere~in this issueof. theFederalRegister.

oaiu In accordancewith 40 CFR 23.S,this rule shall be promulgatedforpurposesof judicial reviewat 1 p.m.eastern(“daylight” or “standard” asappropriate) time on December11, 1985kThis rule shall becomeeffective onJanuary 10. 1988.

FOR FURTHER INFORMATiON CONTACTEdward A. Klein, Director. TSCAAssistanceOffice (TS—799);Office-ofToxic Substances,Room E-~543,401 MStreet SW., Washington.DC 20460.TollFree:(800-424—9065).In Washington.DC~(554—1404). Outside the USA(Operator202—554—1404).-

SUPPLEMENTARY INFORMATiON: In theFederalRegister.of January 4. 1984 (49’FR 430), EPAissueda proposed-ruleunder section4(a) of TSCA to require-~testingof propyleneoxideforteratogeniceffects.TheAgencyis nowpromulgatinga final rule requiringtesting of propyleneoxide forteratogeruceffectsor, moreappropriately, developmentaltoxicity.

Llnfroduction

This noticeis part of theoverallimplementation of section 4 of theToxicSubstancesControl Act (TSCA. Pub. L.94—469, 90Stat. 2003 et seq., 15 U.S.C.2801 et seq.), which containsauthority

for EPA to require developmentof datarelevant to assessingthe risks to healthand the environmentposedby exposureto particular chemicalsubstancesormixtures.

Under section4(a)(1) of TSCA. EPAmust require testing of a chemicalsubstanceto develophealth orenvironmentaldata if the Administratorfinds that:

(A) (1) the manufacture, distribution incommerce,processing,use,or disposalof achemicalsubstanceor mixture,or that anycombination of such-activities.maypresentsn-unreasonableri~kof injury to health or theenvironment.

(Ii) thereareinsufficientdata and-expeneoceuponwhichtheeffectsof suchmanufacture,.disthbution in commerce. -

processing,use,or disposalof such substanceor mixtureor of any combination of suchactivities on health or the environmentcanreasonably be determinedorpredicted. and

(iii) testingof such substanceor mixturewith respectto such.effectsis necessarytodevelopsuchdata;or

(B) (i) a chemicalsubstanceormixture is orwill be produced-In substantial quantities,and (I) it entersor may reasonably beanticipatedto enter the environment insubstantial quantities or (11) there is or may.besignificant or substantial human exposureto suchsubstanceor mixture.

(Ii) thereareinsufficientdata andexperienceupon which the effectsof themanufacture.disthbutionin commerce,processing,use.ordisposalof suchsubstanceormixture or of any combination of suchactivitiesonhealth or the environmentcanreasonablybedeterminedor predicted,and

(iii) testing of suchsubstance-ormixturewith respecttoe4lcheffectsis-necessarytodevelopsuch-dat...

For a more completeunderstandingofthe statutorysection4 findings, thereader is-directed-tothe Agency’sfirstproposedtestlngrulepackage(chloromethaneandchlorinatedbenzene&published-in-theFederalRegisterof July lB. -1980;45 FR 48510)and to the secondpackage(dichloromethane~—nitrobenzene,and1.1.1-trichioroethane.published in theFederalRegister-ofJune5, 1981: 48 FR

30300) for in-depth discussionsof thegeneralissuesapplicable to this action.

II. Background

A. Profile

Propyleneoxide (GAS No. 75-58-9) isa volatile colorlessliquid that hasanether-like odor and is extremelyflammable.It hasa boiling point of 34.23‘C (Ref. 1) and a density of 0.859grampermilliliter (g/ml)-at 0 ‘C (Ref.1). Itssolubility in water is 405,000parts-permillion (ppm) at 20’C (Ref. 1)

In 1980.domesticproduction ofpropylene oxidetotaled 1.77billion -

pounds.Propyleneoxide-isproducedbytwo flrms.-Dow-anciARCO ChemicalCompanies.at four sitee-in the-United-States. Dowusesthe chlorohydrin -

processat its propyleneoxide plants;ARGO usesthe peroxidation process.Each processaccountsfor about50percent of total U.S. capacity. Propyleneoxide’s majoreiseis as a chemicalintermediate.It isalsousedas-astabilizerin dichioromethane.In 1977,therewere 32 processorsof proplyeneoxide (Ref. 2). Estimatesindicate that inexcessof 40,000peoplemay be exposedto propyleneoxide during itsmanufacturing, processing,and use(Ref.2). For amoredetailed discussionof theproduction, uses,and exposureofpropyleneoxide; seethe propyleneoxide support-document (Ref. 2), whichis partof this rulemaking record,andwhich is-available from the TSCA --

AssistanceOffice.

B. ITCRecommendations

In the First Report of the InteragencyTesting Committee (ITC), published intheFederalRegisterof October12, 1977(42 FR 55028),the ITC designatedthecategoryof alkyl epoxidesfor-priorityconsiderationfor epidemiologicalstudiesand testing for carcinogenicity~mutagenicity, teratogenicity. otherchronic effects,and environmental fate.Propyleneoxide is onememberof thealkyl expoxidescategory.

C ProposedRule - -

EPA issuedw proposedrule publishedin theFederalRegisteron January4,1984 (49FR 430), requiringthat testingofpropyleneoxide be performedfor terato-genicity. In theproposal,theEPA basedits testing requirementson the authorityof section4(a)(1)(A) and(B) of TSCA.

EPA’s testingdecisionon propyleneoxideas-discussedin that proposedrule(Ref. 3) andthepropyleneoxidesupportdocument(Ref. 2)areoutlinedbelow.

~ inhalation teratologystudy,sponsoredby theNationalInstituteforOccupationalSafetyanc,Health(NIOSH),conductedat a singleconcentrationof 500ppm in ratsandrabbits-was~reportedto producenoeffectsin rabbitsbutsomematernaland

- developmentaltoxicity i~irats(Ref. 4).EPA concludedin theproposedrule thatbecausea no-effectlevel hadnot beendeterminedfor developmentaltoxicityin the rat andit could not determinewhetherthedevelopmentaltoxicityobservedwasaresultof thematernaltoxicity. additional teratogenicitytestingin the rat waswarranted.Thesedata,togetherwith knownsubstantialworkerexposureand-substantialproduction.formedthe basisfor EPA’s proposedtestruleunderTSCA sections4(a)(l) (A)and(B) (Ref. 3).

EPA’s rationale,asdiscussedin theproposedrule (Ref. 3) andthe propyleneoxidesupportdocument(Ref. 2), for notproposingothertestingfor propyleneoxidewasasfollows: Tl~eAgencyconcludedthat existingdataweresufficientto reasonablypredict theenvironmentalfataof propyleneoxideandthatdatafrom completedandongoing.testing-should,besufficienttoreasonably-determine-the-reproductiveandnaurotoxiceffectsand -

carcinogenicityof propyleneoxide.EPApostponedits decision.on additionalmutagenicity.testingof propyleceoxideuntil theresultsof anumberoLmutagencitytestsin progresson theclosely relatedchemical,ethyleneoxide.wereanalyzedby the Agency.EPA alsopostponedproposingan epidemiologicalstudyfor propyleneoxideuntil aftertheAgencyevaluated-theresultsof threecarcinogenicitystudiescn propyleneoxide.

III. Public Comments

The AgencyreceivedcommentsfromIwo sources:A combinedindustrysubn)issionby Dow ChemicalCompanyand~RCO ChemicalCompany(Ref. 5)andNIOSH (Ref. 6). Thecommentsaddressedteratogenicityandmutagenicitytesting of propyluneoxide.EPA. in the propoosedn.tle (Ref. 3), alsohadaskedfor commentson whetherthe

control of propyleneoxide for itsestablishedoncogenicitywould besufficientto provide adequateprotectionagainstotherhealtheffectsof concern.However,commentswerenotreceivedon this issue.No commentswerereceivedon EPA’s exposureassessmentof propyleneoxide(Ref. 2) of EPA’seconomicimpactanalysisof the NPRMfor propyleneoxide (Ref. 7)

Comments-on teratogenicitytestingweremadeby Dow, ARCO, andNIOSH.Dow andARCO commentedthatsomesignificancehadbeenassignedby EPAreviewersto theratio of resorptionstoimplantationsites-in theNIOSHteratologystudy(Ref. 3). The-twocompaniesstatedthat-acareful -

examinationof thesepercentagesandthestandarddeviation(controls—5.96±8.27,Group2—7.88±8.54)makeitapparentthat thereis avery largevariationaroundthemeanfor both thecontrol andthe exposedgroup(thedeviationsbeinglargerthan the means).Dow andARGO concludedthat suchalargevariationin responseamongbothcontrolandtreatedanimalsdoesnotallow the conclusionthat thereis anybiological or statisticaldifferencebetweenthetwo groups.-TheAgencyinreviewingthestudynotedthisobservation,butlound theseresults tobe statisticallysignificant. In addition,otheradversedevelopmentaleffectswereobserved.

Dow andARGO commentedthat intheNIOSH teratologystudy(Ref. 4)“there is ampleevidenceof maternaltoxicity with only minormusculoskeletalandsternebralanomaliesevidentinfetuses.”EPA does-not con5idersignificantincreasesin rib -

dysmorphology,reductionin skeletalossification,or decreasesin fetalbodyweightandcrown-rumplength “minor”if observedin theabsenceof maternal.toxicity. EPA doesnot believethat thepresentstudyallows anevaluationof’whethersucheffectsoccurin the -

absenceof maternal-toxicity. Dow andARGO alsocommentedthat all of theseeffectshavebeenrelatedto maternaltoxicity causedby variouschemicals.While this is true, they mayalsobeelicited in theabsenceof maternaltoxicity (Ref. 8). In addition,maternaltoxicity doesnot alwaysleadtodevelopmentaltoxicity asevidencedbythefact thattherearenumerouscompoundsthat elicit theformer but notthe latter(Refs.9 through12).

The Dow andARCO commentsidentified threepublishedreports(Refs.13 through15) in which delayedskeletalossificationanddysmorphicribs aredescribedaschangesoften occurringwith maternaltoxicity, andnotindicative of significantdevelopment

toxicity whenobservedat maternallytoxic doses.EPA doesnot disagreewiththis interpretation;however,whatthecommentsfailed to reportis that thestudy by Murrayeta!. (Ref. 13) basedconclusionon actualdatafrom athre-~-dose level teratologystudy.For thatcompund,developmenttoxicity wasonly observedin thepresenceofmaternaltoxicity. At exposurelevelswhichcausedlittle or nomaternaltoxicity, therewereno effectsonembryonalor fetaldevelopment.Forpropyleneoxide.EPA doesnot havetheadvantageof a studyin whichmaternallytoxic andnontoxic dosesweretested:therefore,EPA cannotcometo thesameconclusionasreachedin theMurrayat a!. (Ref. 13) study.TheMurrayet a!. study(Ref. 13) is alsoagood exampleof how maternaltoxicitydoesnot alwaysoccurconcurrentlywiththesamesyndromeof adversedevelopmentaleffects.That is, whileeffectsof skeletalalterationwereobserved,therewasno effect on fetalbody weight or crown-rumplength.

Dow andARCO commentedthatresultsof the two-generationreproductionstudysponsoredby DowandARCO (Ref. 18) will providesufficient informationto adequatelyassessthe developmentaltoxicitypotentialof propyleneoxide. EPA doesnot agreefor severalreasons:(1) Theendpointsexaminedin a reproductionstudyaredifferentfrom thosein adevelopmentaltoxicity study; (2) thehighestexposurelevel in theongoingreproductionstudy(300ppm) is 200 ppmbelowthatusedin theNIOSH -

teratologystudy (Ref. 4) andmay be toolow for thepurposesof a developmentaltoxicity study,that is. in adevelopmentaltoxicity study,exposureoccursat a significantlevel overalimited periodof gestation(10days)inorderto maximizedetectionof anypotentialeffect, whereasin areproductionstudy,animalsareexposedfor a muchlongerperiod, prior to,during, andaftermating,at a lower levelof exposure:and(3) resultsof theNIOSH teratologystudy(Ref. 4) suggestthat prolongedexposureresultedinsomedegreeof acclimationin the ratsbecausethe fetusesexhibitingthegreatestdegreeof adverseeffectswerethosein which exposurebeganon day 7asopposedto thosewhich beganon dayI andthosewhosemothersbegantreatment3 weeksprior to mating.

NIOSH commentedthat, althoughit isnot clearwhetherthe rib dysmorphologyandreducedskeletalossificationobservedin theNIOSH study(Ref. 4)weredueto maternaltoxicity or weremanifestationsof developmentaleffects,

theyconcludedtheribdefectsto be - EPA.Dow andARCObelievedthatany oxide, food consumptiondecreased.“suggestiveof embryotoxicresponse furtherexzensivemutagenicitytestingof body weightswerelower,andchangesundermaternallytoxic conditionsof the ~cpylene oxideshouldawait the in tissueweightswere obaerved..Theexposure.”EPA is not convincedof this resolutionof thesebasicscientific numberof corporalutesandconclusionsincethereareno data issues,TheAgencyhasrecently implantationsitesperdamandliveshowingthat propyleneoxidedoesnot publishedits position on these fetusesperlitter decreasedin ratsthaLcausedevelopmentaleffectsin the mutagenicityissuesin its final testrule receivedpropyleneoxideprior toabsenceof maternaltOxicity. Only for the C9~aromatichydrocarbons(50FR mating.The percentageof resorbedfurther testingwouldresolvethis-issue. 20662;May 17, 1985). However.EPA has implantationsites washighestin rats

NIOSH commentedthat if EPA. after decidednot to proposeadditional exposedto propyleneoxidefrom 7consideringtheresultsof the NIOSH mutagenicitytesting of propyleneoxide through16 dg. Fetalsize wasreduced.terajologystudy(Ref.4) andother for thereasonsoutlined in Unit IV.C andtheincidenceof rib dysmorphologyfactorsrelating to propyleneoxide, below. , increasedin all propylene-oxide-concludesthatadditional teratogenicity iv. Testhigfleczaioiis exposedlitters.studiesareneeded.NIOSH woaid In a developmentaltoxicity study,anysuggestspeciesotherthan the rat or EPA hasdecidedto ~ircmulga1eafi~ observedadverseeffectsonrabbit.N1OSHco4Tunai~ed~ rule for developmentaltoxicity testingof dev arewerthyof furtheraddtional-teratogencitystudies-were propylene-oxide(seeUnit V below). considu~ion.Accordingto-WilsonHowevee,theAgencyhasdeCided-not~ (Rein.17 and18). therearefourdonein therat, arat straifiotherthanSprague-Dawleyshould beusedsince proposecarcinogerncrtyormutagenicity mainfestationsof developmentalthis speciesandstrainwasonly testingor epidemiological5tUd1~S°n toxicity~(1) In uterodeath (2) growthmarginallysensitiveundermaternally propyleneoxide-undersection4(a)of retardation;(3) structuralmalformationTSCA at this time. EPA’s rationalefortoxic conditionsof exposure.EPA thesedecisionsis discussedbelow, and(4) functionaldeficits. On the basisbelievesthat this recommendationof of theadverseeffectson developmentselectinganotherstrainappears A. DevelopmentalToxicity observedin the N1OSHteratologystudyappropriate.However, it is notpoea~b1e The resultsof ateratogenicitystudy in ratsdescribedabove.EPAconcludesto identify a “more sensitive”strata sponsoredby NIOSH havebeen that additionaldevelopmentaltoxicitybeforeconductingastudy.Although reported(Ref.4). Maternaltoxicity, testing in therat is necessarybecausetEPA maynot beableto identify a more reproductiveperformance,and - (1) A no-observed-effectlevel forsensitivestrainat thepresenttime, a developmentaltoxicology were developmentaltoxicity wasnotwell-conductedstudyUSUIg at least evaluatedin Sprague-Dawleyratsand determinedin therat,and(2) onecannotthreeexposureLevels, thehighest~ New Zealandrabbitsfislowing 7 hr/day determineit thedevelopmentaltoxicitywhich shouldproducematernaltoxicity, inhalation exposuresto 500 ppm observedin therat canbe attributedshouldanswertheconcernasto propyleneoxide.Rabbitswere entirely to maternaltoxicity.whetheror not developmentaltoxicity is artificially inseminatedandplacedon B. Carcinogenicityelicitedonly at maternallytoxic ~ oneof the following exposureregimens:If thealternatestrainfails to elicity any (1) Filteredair (control); (2) chemical EPA hasreviewedthe resultsof threedevelopmentaltoxicity evenat exposurefromdays7 through10 of carcinogenicitystudiesconductedby thematernallytoxic levels, this still would gestation(dg3 or(3) chemicalexposure Europeanproducersof propyleneoxideprovidetheanswerto theconcernasto from I through19 dg. Rat-exposure (Ref. 19). theNationalToxicologywhethertheembryo/fetusis more regimenswere asfollows: (1) Filt~’ed~ Pro~rant(NTP) (Ref. 20) andNIOSHvulnerabletoxic effectsthantheadniL (control); (2) chemicalexposurefrom7 (Ref. 21). andhasconcludedthat theA searchof theEnvironmental through18 d~(3) chemical~ datafront thesestudiesaresufficienttoTeratogenInformationCenterdatabase frn~I through18 dg or (4) chemical reasonablypredictordeterminethewhichcontainsaver33,000files exposurefor 5 days/weekf~3 ~ carcinogenicityof propyleneoxide.Theindicatedthat themoatcommonlyused prior to matinganddaily from I through resultsof thesestudiesare-summ~izedstrainsof rats to asse,steratogenicity05’ 16dg. Unexposedmale ratsand below.developmentaltoxicity include Sprague- unexposedmalerabbitswereusedin TheEuropeanchronicinhalationDawley, Wistar. Long-.Evans.Charles - mating andartificial insemination study(Ref. 19) demonstratedthatRiverCD, andFisher344.Selectionof procedures,respectively.Necropsies propyleneoxidewasoncogenicin theoneof thesestrains,otherthanSprague- wereperformedon ratsat 21 dg andon rataspartially manifestedby aDawley, to testpropyleneoxidewould rabbitsat 31) dg. Pregnantanimalswere statistically significant[p<0.0I)be appropriate.The structurallyrelated examinedfor toxic changes.including increasein mammarytumors in femalecompounds,ethyleneoxide and histopathology.Reproductivemeasures ratsat 300ppm of propyleneoxideandahutyleneoxide, havebeentestedin the includedthedeterminationof numberof statisticallysignificantincreaseFisher344andWistar strains, corporalutea,implantationsites, (p<0.005)in themeannumberofrespectively. resorptions,deadfetuses,andlive mammaryfibroadenomaspermammary~.Comment3onmutagenicitytesting fetuses.Live fetuse.s.wereweighed. fibroaderiorna-bearingfemalerat at allwere madeby Dow andARCO. The measured,andsubjectedto external dosagelevels(~0foo, and~CO~pmproducersstatedtheirbelief that there visceralandskeletalexaminationto propyleneoxide).areamplemutagenici-tvdataon detectmorphologicanomalies. The resultsof the NTP 2-yearpr~pyieneoxide. Dow andARCO also No evidenceof maternaltoxicity, carcinogenesisstudieson propylenestatedthat therearea numberof embryotoxicity.or teratogenicitywas oxide in ratsandmice as reportedin theunresolvedscientificissueson the detectedin rabbitsexposedto 500ppm NTPTechnicalreport (Ref. 20) areasinterpretation.extr~ipo1ation,and of propyleneoxide. However,maternal follows: Groupsof 50 F344/Nratsand30applicationof mutagenicitydatato anddevelopmerit.altoxicity were seenin B6C3F~miceof eachsexwereexposed.assesshumanrisk. Sitice theseissues theSprague-Daweyrat. In all groupsof to air containingpropyleneoxideatwerebeingaddressedseparatelyby ratsexposedto 500-ppmpropylene - concentrationsof 0 (chambercontrol),

- - reaerai xegister/ vot. ~u.iNo. - ZiW / Wednesday,November 27, 1985 / Rules and Regulations 48763

2oo;or400ppm for 8 hoursper.day.5daysperweek,for 103 weeks. -

Thesurvival of ratsexposedtopropyleneoxidewascomparablewiththatof the controls: terminalbodyweightswerelower than thoseof thecontrolsfor high dosemales(8 percentweight reduction)andhigh dosefemales(6 percentweight reduction).Survival ofexposedmale and femalemice decreasedrelative to that of thecontrols(male:con,troI. 42/5th low dose.34/50:highdosb,29/5th female:38/50; 29/50: 10/50),-but~thedifferencewass!gn:ficantonlyfor animalsin thehigh dosegroups.High-dosefemalemicehada mean.terminalbody weight 10 percentbelowthatof thecontrols;high dosemale-micehada terminal body weight 22percentbelowthat of thecontrols.

Therespiratoryepitheliumof thenasalturbinateswasone of theprimarytissuesaffectedin maleandfemalerats:exposure—relatedincreasesoccurredinthe incidencesof suppurativeinflammation,epithelial hyperplasia.andsquamousmetaplasia.Papillaryadenomas.involving the respiratoryepitheliumandunderlyingsubmucosalgiandsof thenasalturbinates,wereobservedin threefemaleratsandin twomaleratsexposedto propyleneoxideat400 ppm.The incidenceof adenomasinfemaleswassignificantby the trendtests. -

- -The proportionsof high-dosefemaleratswith C-cell adenomasandwith C.cell carcinomasof the thyroid glandwere increased,but only the combinedincidenceof thesetumorswas

- significant(2/45; 2/35;7/37).Thesetumorswerenotconsideredto berelatedto exposureto propyleneoxidebecausetherewas rio otherevidenceforC-cellsbeinga targettissueandbecausetherewasno increasein C-cellhyperplasia.

The combinedincidencesof female-

ratswith endometrialstromalpolyps-andendometrialstromalsarcomasoftheuterusweresignificantly increasedin thedosedgroups(3/49; 12/50;10/47).However, theoccurrenceof theselesionsin thedosedgroupswassimilarto theaverage(306/1,502.20 percent)seenin untreatedcontrolsin NTPcarcinogenesisstudies,andhencethisincreasewasnot regardedasbeingi~eIdtédtoexposuretc propyleneoxide.

Therespiratoryepitheliumof thenasal turbinateswasalsooneof theprimary tissuesaffectedin maleandfethle mice: exposure-relatedincreasesoccurredin the incidencesof -

inflammation,andsquamousmetaplasiawasobservedin onelow-dosemaleandtwo high-dosefemalemice.Onesquamouscell carcinomaandonepapilloma occurredin thenasalcavityof differenthigh dosemale mice, and

two high-dosefemalemice hadadenocarcinomasof thenasalcavity.The endothelial-cellsof the submucosalvascularplexusin thenasalturbinatesalsoappearedto be amajorsite affectedin high dosemale mice.Therehigh dosemaleandthreehigh-dosefemalemicehada sacculardilation (classifiedasangiectasis)of submucosalturbinatevessels.Further.hemangiomaswereseenin thenasalcavityof 5/50 high.dosemalemice and-3/50high-dosefemalemice,andhemangio-sarcomaswere foundin thenasalcavity of 5/50high-dosemale-miceand2/50high-dosefemalemice.The increasedincidencesof hemangiomasin males-andfemales-.andof hemangiosarcomasin maleswerestattsticallysignificant. Vasculartumorswerenot presentin thenasalturbinatesof anylow-doseor controlmice.

Underthe conditionsof thesestudies,NTP concludedthat therewas“someevidenceof carcinogenicity’for F344/Nrats, as indicatedby increasedincidencesof papillaryadenomnasof thenasalturbinatesin maleandfemaleratsexposedto propyleneoxideat 400ppm.NTP alsoconcludedthat for maleandfemaleB6C3F1mice, therewas ‘clearevidenceof carcinogenicity’.asindicatedby increasedincidencesofhemaniomasor hemangiosarcomasofthenasalturbinatesat 400 ppm. In therespiratoryepitheliurnof thenasal,turbinates.propyleneoxidealsocausedsuppurativeinflamation, hyperplasia,andsquamousmetaplasiain ratsandinflammationin mice.

In the NIOSH study (Ref. 21), thechronic inhalationtoxicity and -

carcinogenicityof propyleneoxidewereevaluatedin a 2-yearinhalationbioassay.Threegroupsof male -

weanlingFischer344 rats.80 per group,wereexposedat: (1) 0ppm (control;filtered air); (2) 100-ppmpropylene -

oxide;and(3) 300-ppmpropyleneoxide(7 hoursperday, 5 daysperweek)for104weeks.Body weights fromratsexposedto propyleneoxideat bothexposureconcentrationsweresignificantly reducedcomparedtocontrols.A statistically significantincreasein mortality wasobservedin allgroupsof exposedratscomparedtocontrols.Skeletalmuscleatrophy in theabsenceof anysciaticnerve

~1ienropatholo~ywasfotnidini~ätsexposedat 300-ppmpropyleneoxide.Among ratsexposedto propyleneoxidetherewasa dose-dependentincreaseinthe incidenceof complexepithelialhyperplasiain thenasalpassages.andtwo adenomaswere detectedin thenasalpassagesof ratsexposedat 300p~mpropyleneoxide. Theonlycompound-relatedoncogeniceffectwasa markedincreasein the incidenceofadrenalpheochrornocytomasin treated

animals:25/78at 100ppm and22/80at300 ppm vs. 8/78 at 0-ppmpropyleneoxide (controls).All rat groupswereaffectedby anoutbreakof Mycoplasmapulmonisinfectionwhich occurredabout16 monthsinto thestudy.According to NIOSH (Ref. 21), thisinfectionaloneandin combinationwiththeepoxideexposuresaffectedthesurvival of ratsin this studyandinfluencedthe developmentof theproliferative lesionsin thenasalmucosaof the propyleneoxide-exposedrats. Notreatment-relatedchangesin any-clinical chemistryor urinalysis indicesweredetected, - -

C. Mutagenicity

Thepropyleneoxideproposedtestrule (Ref. 3) statedthat EPA’s decisionconcerningtheneedfor additionalmutagenicitytestingon propyleneoxidewould be postponeduntil theresultsof anumberof mutagenicitytestsin progresson ethyleneoxide, including the mousespecific-locustest,wereanalyzedby theAgency. Ethyleneoxide is a closelyrelatedmemberof the alkyl epoxidescategory.For a reviewof themutagenicitydataon propyleneoxide,seethe propyleneoxidesupportdocument(Ref. 2). The proposedrule(Ref. 3) alsostatedthat in making itsanalysisEPA would takeinto accountavailabledataon othereffectsthatmayprovide sufficient basisfor regulations.

EPA hasconcludedthatadditionalmutagenicitytesting of propyleneoxideis not necessarybecause:(1) Ethyleneoxide,which is closelyrelatedtopropyleneoxide,wasnegativein themousespecific-locustest’, and (2)carcinogenicityandmutagenicityareprobablymechanisticallyrelatedfor thisalkylating agent,andexposurecontrolon the basisof carcinogenicityshouldprovide substantialprotectionagainstmutageniceffects.

D. Epidemiology -

The propyleneoxideproposedtestrule states,“When the Agencyhasevaluatedthe resultsof all theoncogenicitystudieson propyleneoxide.it will determinewhetheranepidemiologicalstudy is necessary

-~(Ref.-3)-EPA- hareoncludedthptanepidemiologicalstudyis not feasibleforpropyleneoxide at this time (Ref. 22).Therearetwo groupsof workerswithpotentialexposureto propyleneoxidewho maybe consideredforepidemiologicalstudy.Onegroup,approximaely2.000workers, is exposedin either theproduction(2 companies)orprocessing(32 companies)of propyleneoxide(Refa.23 and24). In a1978submissionto EPA. Dow (oneof the

48766 Fetleral Kegaster / VOL ~‘J, INO. ~ vvecinesuay,iNovemoer ‘.1, .L~OZJ / £~LLLt~ dUU £\e~u~uuuo

producers)statedthatit hadapproximately100workerswho -

routinely workedin propyleneoxideproductionareas(ReL 25). EPAestimatesthat asimilar numberofworkersare exposedin theotherproducersfacilities. The secondgroup,approximately40,000workers, isoccupationallyexposedin theurethanefoam industry wherepropyleneoxide isusedasa stabilizerindichlorometh.ane(Ráf. 23).

Fora retrospectiveepidemiologicalstudyto be feasible,severalcond.itionsmust tie metFirst,a sufficientnumberof workersmustbe exposed.Second..asufficient level of exposuremustexist,andtheexposuremustbeunique.Le,notaccompaniedby exposuresto otherchemicalsthatcouldaffectoutcome.Third. theexposuremusthaveoccurredin thepast to allow for diseasedevelopment.Last, recordsmustexistwhich allow following theprospectivestudypopulationfor a lengthof time. Aprospectiveepidemiologicalstudyrequiresthat the first two conditionsbemet.

OnJuly 9. 1985. Dow ChemicalCompanysubmit-tedits final reporteütitled“PropyleneOxide: Two-GenerationReproductionStudyinFischer344Rats’ unders-ecti-on8~d)ofTSCA (Ref. 28). EPA is evaluatingtheresults.The sabmitterconcludedthatinhalationexposureof maleandfemaleFischer344ratsto 30, 100. or ~oppm of

propyleneoxide for two generationsdidnot adverselyaffectreproductionevenat anexposureconcentrationthatcausedasignificant reductionin bodyweight in both sexes.

V. Final Test Rule for PropyleneOxide

,4. Findings

EPA finds that-thereareinsufficient-datafrom theNIOSH teratologystudy(Ref. 4) from whichto reasonablydetermineorpredict thedevelopmen;altoxicity from exposureto propyleri~oxide,andthat additional testing oxpropyleneoxide for developmentaltoxicity is necessaryto developsuchdata.

Onthebasisof thesefindings, theAgencyis requiringfor propyleneoxidea developmentaltoxicity testin rats.

B. RequiredTesting

TheAgencybelievesthatdevelopmentaltoxicity testingshould beperformedvia inhalationin therat andthatsomesignof maternaltoxicityshouldbedemonstratedat the highestdose.

EPA is requiringthat a developmentaltoxicity study on propyleneoxide beconductedby the inhalation route.Theagencybelievesthat the TSCA testguidelinewhichappearsat 40 CFR798.4350(publishedin theFederalRegisterof September27, 1985; 50 FR39252) is appropriatefor determiningthedevelopmentalhazardof propyleneoxide. A copy of this TSCA Guideline isin thepublic recordfor this rulemakingdocketnumber[OPTS-42020B).

EPA intendsto proposeshortly in aseparateFederalRegisternotice, certainrevisionsto thehealthandenvironmentaleffectsandchemicalfateTSCATestGuidelinesto provide moreexplicit guidanceon thenecessaryminimum elementsfor eachstudy.Inaddition, theserevisionswill avoidrepetitivechemical-by-chemicalchangesto thegnidelinesin their adoptionas teststandardsfor chemical-specifictestrules.EPA is proposingthat thesemodificationsbeadoptedin theteststandardsfor propyleneoxide.

All datamustbedevelopedandreportedin accordancewith theTSCAGoodLaboratoryPracticeStandardsin40 CFR Part792. -‘

C. TestSubstance -

EPA is requiringthat propyleneoxideof at least99.0percentpurity be usedasthe testsubstance.Sucha gradeisreadily availablecommercially.

D. PersonsRequiredTo Test

Section4(b)(3)(B) specifiesthat theactivities for which the Agencymakessectwn4(a) findings (manufacturing,processing,distribution, useand/ordisposal)determinewho bearstheresponsibilityfor testing.Manufacturersarerequiredto testit the findings arebasedon manufacturing(“manufacture”is definedin section3(7)of TSCA toinciade ‘import’~).Processorsare

EPA is basingthe final testingrequirementsfor propyleneoxide on theauthorityof section4(a)(1)(A) and(B) ofTSCA.

The4(a)(1)(A) findingsfor-developmentaltoxicity areas follows:

EPA finds that themanufacture,processing,anduseof propyleneoxidemay presentanunreasonablerisk ofinjury to humanhealthdueto -

developmentaltoxicity because(1)availableanimalstudiessuggestthatpropyleneoxidehasa developmentaltoxicity potential.and(2) in excessof40,000individuals arepotentiallyexposedto propyleneoxideas a resultof its manufacture,processing,anduse.

EPA also finds that thereareinsufficientanimalandhumandatato

At leasttwo of the aboveconditions reasonablydetermineorpredict thearelacking for propyleneoxide-exposed developmentaltoxicity of propyleneworkers,The answerto- the first oxide.Thefinding of “may presentancondition is twofold. Although unreasonablerisk” of developmentalproductionworkersare thepreferred toxicity is basedon a NIOSH inhalationgroup for study sinceexposuretoother teratologystudy(Ref. 4). Ratsandconfoundingchemicalsis, usually, less rabbitswere exposedto a singlethan thatfor processingworkers,not concentrationof 500-ppmpropyleneenoughworkersexist in productionof oxide.Neitherdevelopmentaltoxicitypropyleneoxide todo an normaternaltoxicity wasobservedinepidemiologicalstudy.Therefore.~7 rabbitsexposedto 500-ppm.However,cohortstudyof th~eworkersW0Ul~i developmentalandmaternaltoxicityhavein5uf&iant-po%~(adetect~ wereobservedamongfemaleratsandincreaseste~c ~er-oatcomeL. Onthe’ thelrpupsexposed-to 500-ppmotherhZflhi~& cohortStudy ‘~ propyleneoxide.A no-effectlevelforurethanefoam industryWOuld. IBOSt developmentaltoxicity in therat couldlikely, havethe necessarypower. notbe determined,andonecannotHowei’er, in theurethanefoam industry. determinewhetherthe developmental-.if anyepidemie!ogicalstudy,it wo~Adhe toxicity observedin the studycan beimpossibleto separateexposuretO attributedentirely to maternaltoxicity.propyleneoxide from that to - EPA ~ds that additionaldichloromethaneand/orotherchemicals developmentaltoxicity -testingofthat are knownor suspected propyleneoxide is necessaryto developcarcinogens.Therefore,condition tWo additional datato reasonablyevaluatehasnotbeenmet; a uniqueexposure thedevelopmentalrisks posedbydoesnotoccur. exposureto propyleneoxide.

In light of theunsatisfactoryanswers The4(a)(1)(B) findingsforto conditionsone andtwo, EPAconcludesthat anepidemiologicalstudy developmentaltoxicity areas follows;

Thereare substantialamountsofis not feasiblefor propyleneoxide, propyleneoxideproducedin or -

& ReproducLiveEffect.s importedinto theUnited Stateseachyear.The annualU.S. productionvolumeof propyleneoxide is estimatedto be approximately1.8 billion pounds,with another90 million poundsimportedinto theUnited Stateseachyear.

Estimatesindicatethatover40.000peoplemaybeexposedto-propyleneoxideeachyearvia manufacturing,processing,anduseactivities.

— -——~——— ~~~0~~’•”’ ~ ‘‘-‘j’ ~#~-~3 ‘‘‘~~ ‘ I ~ — , 0~

requiredto testif thefindingsarebasedon processing.(Section3t10) of TSCA,defines‘~process”as the preparationofa chemicalsubstanceormixture,after-its- manufacture,for distribution incommerce.)Both manufacturersandprocessorsarerequiredto test if theexposuresgiv!ng rise to thepotentialrisk occurduringuse,distribution,ordisposal.BecauseEPA hasfound thatthemanufacture.processing,anduseofthepropyleneoxidemaygive risetosub~tantialexposureandmay presentanunreasonablerisk of injury tohealth.personswho manufactureor process,orwho intend to manufactureor process,propyleneoxideat any time from theeffectivedateof this testrule to theendof the reimbursementperiodaresubject-to this rule. The endof thereimbursementperiodwill be5 yearsafter the submissionof thefinal reportrequiredunderthetestrule. Asdiscussedin theAgency’s Test RuleDevelopmentandExemptionProcedures(40CFR Part790), EPA expectsthatmanufacturerswill conducttesting andthat processorswill orthnarily beexemptedfrom testing.

BecauseTSCA containsprovisionstoavoidduplicativetesting,not everypersonsubject to this ruie.mustindividually conducttesting.Section4(b1(3)(A) oiTSCA providesthat EPAmay permit two or more manufacturersor processorswho aresubject to the ruleto designateonesuchperson or aqualified third personto conduct thetestsand submit dataon their behalf.Section4(c) provides that any personarequired to test may apply to EPA for anexemptionfrom that requirementTheAgencyexpectsthat the currentmanufacturers of propylene oxide willform the reimbursementpooLandsponsor the testing required.Manufacturersand processorswho aresubject to the testing requirements ofthis rulemustcomply with the testrulesandexemptionprocedures in 40 CFRPart 790.

E. TestRuleDevelopmentandExemptions

Elsewherein this issueof the FederalRegister,the Agencyis proposingthat aTSCA testguidelinebe utilized as thetest standardfor thedevelopmentof-dataunderthis rule for propyleneoxide.As discussedin that document and inprevious documents(50 FR 20652;May17, 1985),EPA has reviewed the methodfor the developmentof test rulesandhas decided that for mostsection4rulemakings, theAgency will utilizesingle-phaserulemaking. In light of thisdecision,EPA has-reevaluatedtheprocessfor developingteststandards forsection4 rulemakings initiated undera-

two-phaseprocessandhasdetermined to processorsthroughthepricing of-that for certainof thesetwo-phaserules, products-containingpropyleneoxide.TSCA testguidelinesareavailablefor EPA’s final regulationsfor thepromulgation as relevant test standards. issuanceof exemptionsfrom testingEPA has decidedthat where TSCA or requirements are in 40 CFR Part 790.other appropriate test guidelines are accordancewith thoseregulations.an~available, the Agency, in most caseswill manufacturer or processorsubject toproposethe relevant guidelines as the this PhaseI test rule may submit antest standards for thoserules. application to EPA for an exemption

EPA believes-that,in line with its from conducting any or all of the testscommitment to expeditethe section4 required under this rule; Ifrulemaking process.it is appropriate to manufacturersperformall the requiredproposethe applicable TSCA test testing, processorswill be grantedguidelinesas test standards at the same exemptionsautomatically withouttime as a Phase1 final test rule is issued. having to file applications.With regard to the rulemaking for In the accompanyingFederalRegisterpropyleneoxide, a TSCA testguideline notice, EPA is proposingdeadlinesforis available for the testing requirement the submissionof testdataSuchincluded in this PhaseI final rule. Thus, deadlinesarerequired undersectionin the accompanyingdocument, the 4(b)(1)(C) of TSCA. Theseproposed dataAgencyis proposing this TSCA test submissiondeadlinesareopenforguideline as a test standard. public commentand may be modified.

The public, including the whereappropriate, when the final Phasemanufacturersandprocessorssubject to II test rule is promulgated.the PhaseI rule, will have an The Agency is proposing that theopportunity to comment on the useof abovereferencedTSCA Health Effectsthe TSCA test guidelines.The Agency Test Guideline be considered the testwill review the submitted commentsand standardfor the purposesof thewill modify the TSCA guidelines,where proposed test for propyleneoxide.Theappropriate, when the test standards are TSCA guideline for developmentalpromulgated. toxicity testing specifiesgenerally

During the developmentof a test rule acceptedminimal conditions forunderthe two-phaseprocess,persons determining developmentaltoxicity forsubject to the PhaseI final ruleare substanceslike propylene oxide.Thenormally required to submitproposed Agency’s review of the guidelir.as.study plans (see40 CFR 790.30(a)(2);50 which occursyearly as described in theFR 20ej52,20658(May 17. 1985)). Federal Register of September22. 1982However, becauseEPA is proposing an (47 FR 41857),has found no reason toapplicable TSCA testguidelineas the conclude that this protocol needsto beteststandard for the study required by modified significantly.this PhaseI final rule, personssubject to p J?e ortin uirement.sthe rule, i.e., manufacturersand fJ gprocessorsof propylene oxide,arenot EPA is requiringthat all datarequired to submit proposedstudy plans developedunderthis rulebereportedinfor the requiredtesting.Personssubject accordance with the EPA Goodto this rule, however,arestill requiredto LaboratoryPractice(GLP)standardssubmitnoticesof intent to testor pursuantto 40 CFR Part 792. publishedexemptionapplicationsin accordance in theFederalRegisterof November2.9.with 40 CFR 790.25;50 FR 20852.20657 1983 (48 FR 53922).(May 17. 1985).Moreover,oncethetest EPA is requiredby TSCA sectionstandard is promulgated, personswho 4(b)(1)(C) to specify the time period -

have notified EPA of their intent to test duringwhich personssubject to a testmust submit study plans (which adhere rule must submit test data. The Agencyto the promulgated test standards) no is proposingthesedeadlines elsewhere

- later than 30 daysbefore the initiation of in the issueof the Federal‘Register.each requiredtest. (see40 CFR TSCA section 12(b)requires that790.39(a)(1J;50 FR 20652.20658 (May 17. personswho export or intend to export19851).,- -- - ~ to-a foreign country any substance

Processorsof propyleneoxidesubject subjectto testing requirementsunderto this rule, unlesstheyarealso TSCA section4 notify EPA of suchmanufacturers,will not be requiredto -exportationor intent to export.Whilesubmit lettersof intent,exemption the resultsof requiredtestingmay notapplications,or studyplans(before be availablefor sometime, a noticetotestingis initiated)unlessmanufacturers the foreign government about the exportfail to sponsorthe requiredtests.The of suchsubstancessubject to test rulesbasisfor this decisionis that servesto alert them to theAgency’smanufacturersareexpectedto passan concernaboutthesubstances.It givesappropriateportion of the testcostson thesegoverthnentstheopportunity to

48768 FederalRegister I Vol. 50, No. 229 / Wednesday,November27, 1985 I Rules and Regulations

request~ulchdatathat the Agencymaycurrently possessplus whateveraatamaybecomeavailableas a resultoftestingactivities.Thus,upontheeffective dateof this rule; personswhoexportor intendto exportpropyleneoxide mustsubmitnoticesto theAgencypursuantto TSCA section12(b)(1)and40 CFR Part 707. For additionalinformation,seetheFederalRegisterofDece,jnber18. 1980(45FR 82844).

TSCA section14(b)governsAgencydisclosureof all testdatasubmittedpursuantto section4 of TSCA. Uponreceiptof datarequiredby this rule,.theAgencywill announcethereceiptwithin-15 daysin theFederalRegisterasrequiredby section4(d). Testdatareceivedpursuantto this rule will bemade-availablefor public inspectionbyanypersonexceptin thosecaseswheretheAgencydeterminesthat confidentialtreatmentmust be accordedpursuanttosection14(b) of TSCA.

C. EnforcementProvisions

The Agencyconsidersfailure tocomply with anyaspectof a section4rule to be aviolation of section15 ofTSCA. Section15(1)of TSCA makesitunlawful for anypersonto fail or refuseto comply-withany rule or orderissuedundersection4. Section15(3) of TSCAmakesit unlawful for anypersonto failor refuseto: (1) Establishormaintainrecordsor (2) submit reports,notices,orotherrecordsrequiredby the Act or anyregulationsissuedunderTSCA.

Additionally, TSCAsection15(4)makesit unlawful for any.personto:failorrefuseto permitentryor inspectionasrequiredby section11. Section11appliesto any “establishment,facility,or otherpremisesin whichchemicalsubstancesor mixtures are-manufactured,processed,stored,or heldbeforeor after their-distributionincommerce.. .“ TheAgencyconsidersatestingfacility to be aplacewherethe -

chemicalis heldor storedand.therefore.sub~ectto inspection.Laboratoryauditsand/orinspectionswill be conducted-periodicallyinaccordancewith the proceduresoutlinedin TSCA section11 by designatedrepresentativesof theEPA for the

- purposeof determiningcompliancewiththe final rule for propyleneoxide. Theseinspectionsmaybe conductedforpurposeswhich includeverification thattesting hasbegun. that schedulesarebeingmet, that reportsaccuratelyreflectthe underlyingraw dataand -

interpretationsandevaluationsthereof.andthat the studiesarebeingconductedaccordingto EPA GLP standardsandthetest standardsestablishedin thesecondphaseof this rulemaking.

EPA’s authority to inspecta testingfaciiity alsoderivesfrom~c~ion 4(b)(1)of TSCA, whichdirectsEPA topromulgatestandardsfor thedevelopmentof testdata.Thesestandardsaredefinedin section312)(B)of TSCA to include thoserequirementsnecessaryto assurethat datadevelopedundertesting rulesarereliableandadequate.andsuchotherrequirementsasarenecessaryto provide suchassurance.The Agencymaintainsthatlaboratoryinspectionsarenecessarytoprovide this assurance.

Violatorsof ‘I’SCA.are subjecttocriminalandcivil liability. Personswho -

submitmaterially misleadingor falseinformationin connectionwith therequirementof anyprovisionof this rulemay be subjectto penaltiescalculatedas if theyhadneversubmittedtheirdata.Underthepenaltyprovisionsofsection16 of TSCA. anypersonwhoviolatessection15 couldbe subjectto acivil penaltyof up to $25,000per dayforeachviolation. Intentionalviolationscould leadto theimposition of criminalpenaltiesup to $25,000for eachdayofviolation andimprisonmentfor up to Iyear. OtherremediesareavailabletoEPA undersections7 and17 of TSCA.suchas seekingan injunctionto restrainviolations of TSCA section4.

Individuals aswell ascorporationscould be subjectto enforcementactions.Sections15 and16 of TSCA apply to“any person”who violatesvariousprovisionsof TSCA. EPA may.at itsdiscretion,proceedagainstindividualsaswell ascompaniesthemselves.Inparticular,this includesindividuals whoreport falseinformationorwho causeitto be reported.In addition, thesubmissionof false, fictitious, orfraudulentstatementsis aviolationunder18 U.S.C.1001.

VI. EconomicAnalysis of Final Test Rule

potential for a significant adverseeconomicimpact is low. Furth~~,ore,the additional productcostsimposedbythe requiredtestswould be between0,0004and0.0012centperpound.orbetween0.008and0.003 percentof thecurrentpriceperpound(47.5 cents).Thissuggeststhat the economicimpactwould be minimal.

For a morecompleteandthoroughdiscussionof themethodologyusedtoconducttheeconomicanalysisof thistest ruleseeEconomicImpactAnalysisfor Final TestRulefor PropyleneOxide(Ref. 27). A copyof this documentisavailablein thepublic recordfor thisrulema’king, docketnumber(OP’rS-.4202.8B). -

VU. Availability of Test FacilitiesandPersonnel

Section4(b)(1) of TSCA requiresEPAto consider“the reasonablyforeseeableavailability of the facilitiesandpersonnelneededto performthe testingrequiredunderthe rule.” Therefore.EPAconductedastudy to assesstheavailability of testsfacilitiesandpersonnelto handlethe additionaldemandfor testing programsnegotiatedwith industry in placeof rulemaking.Copiesof the study,“ChemicalTestingIndustry:Profile of ToxicologicalTesting,” October1981, can beobtainedthroughtheNTIS underpublicationnumberPB 82—140773.

On the basisof this study.the Agencybelievesthat therewill beavailabletestfacilitiesandpersonnelto performthetesting requiredin this test rule.

VIII. Rulemaking Record

EPA hasestablisheda public recordfor this rulemaking(docketnumberOPTS—42028B).This recordincludesthebasicinformationtheAgencyconsideredin developingthis proposal.andappropriateFederalRegisternotices.The Agencywill supplementtherecord with additionalinformation as itis received. - -

This recordincludesthefollowinginformation:

.4. SupportingDocumentation

EPAhaspreparedaneconomicevaluationthat examinesthecost of therequiredtestingandthepotentialeconomicimpactsof thosecostson themanufacturersandprocessorsofpropyleneoxidesubjectto this rule. Theanalysisconsideredfour marketcharacteristicsof propyleneoxide: (1) (1) FederalRegisternoticespertainingThe prtcesensitivityof demandfor to this actionconsistingof:propyleneoxide, (2) producercost (a) Noticecontainingthe First ITCcharacteristics.(3) industry structure, Reportdesignatingalkyl epoxidesto theond (4) marketexpectations.Costsof Priority List (42 FR 55026: October12.conductingthehealtheffectstest 1977)andcommentsreceivedinrequiredin this rule areestimatedto responsethereto,rangefrom $30,728to S92,185,with (b) Notice of theproposedtestrule onannualizedtest costsrangingfrom propyleneoxideandcommentsreceived$7,963to S23.891.From thesetest costs in response(48 FR 430: January4, 1984).andananalysisof themarket (c) Notice announcingthe final

- characteristicsof propyleneoxide, the decisionto requiretestingof propyleneeconomicevaluation indicates that the oxide.

retie~.cu i ~1~LCI / ‘~01. ,)0. .‘lU. 4,,~, ~ -

(d) Notice addingprdpyleneoxidetotheJist afchemicalssuh~ectto thepreliminaryassessment-informationrule. (47 FR 26992~June22, 1982).

{e) Noticeof final rule on EPA’s TSCAGood LaboratoryPracticeStandards(48FR 33922).

(1) Noticeof final rule on test ruledevelopmentandexemptionprocedures(49 FR 39774; October10, 1984).

(g) Noticeof final rule concerningdatareirrrbursement(48 FR 41786).

(Ii’) Notice of interim final rule on testruledevelopmentandexemption~procedures(50 FR 2D652~May17, 1985).

(2) Supportdocumentsconsistingof:~(a)Propyleneoxideteclmicalsupport

documentfor proposedrule.(b) Economicimpactanalysisof

NPRM for propyleneoxide.(c) Economicimpactanalystsof final

testrule for propyleneoxide.(3) Communicationsconsistingof:(a)Written public andintra-agencyor

interagency memoranda and comments.(b) Summariesof telephone

conversations.(c) Summariesof meetings.(4) Reports—publishedand

unpublishedfactual materials,includingcontractors’reports.

B. References

(1) Winnoltz. M. editor.TheMatte Index.9thEd. Rathway,N). MerckandCa.p. 1017.1978.

(2) USEPA.PropyleneOxide:SupportDocument.(No date).

(3) USEPA.PropyleneOxide:ProposedTestRule. 48 FR-430 Janaary4.1984:

(4) HackettP.L, M.G. Brown. R.L.Buschbom.Mi,. Clark. R.A. Miller, ILL.Musie., atal. “TeratogenicStudyof Ethylene -

andPropyleneOxide andN.Butyl Acetate.”Preparedfor theNationalInstitute forOccupationalSafetyandHealth.Cincinnati,Ohio, mde ontract2SfllO4277(NIOSHContractNo. 210—60-0013).1982.

(5) DowChemicalCompany,Midland,MichiganandArco ChemicalCompany,NewtownSquare,Pennsylvania.CommentsonProposedPropyleneOxideTestRule.Submittedto: Office of PesticidesandToxicSubstances,U.s.EnvironmentalProtectionAgency,Washington.D.C. March 2. 1984.

(8) NIOSH. Commentsby N1OSHonProposedPropyleneOxide TestRote.Submittedto: Office of PesticidesandToxicSubstances.U.S. EnvironmentalProtectionAger,cy. Washington.D.C. March3. 1984.

(7) USEPA.EconomicimpactAnalysis ofNPRM for PropyleneOxide.No dat,~.

(8) Palmer.A. K. Incidenceof sporadicmalformations,anomalies,andvariationsinrantiombredlaboratoryanimals.In: Methodsin prenataltoxicology.Evaluationofembrvotoxiceffects in experimentalanimals.NeubertD.Merker H—), KwasigrohTE., ads.Stuttgart:GeorgeThiemePublishers.pp. 52—71. 1977.

(9) Khera.K. 5. “MaternalToxicity: APossibleEtiological FactorIn Embryo-Fetal

Deathsarid iiUMaIf~iriathin of Rodent-rabbitSpecies.”Teratology31:129—153.1985-.

(10) Ghemoii~,,K~-e0~ck,IL-J.~~‘Aii ‘ri VIVC)TeratologyScreenUtilizing PregnantMice.”Journalof ToxicologyandEnvironmentalHealth 10:541—550.1982.

(11) Kavlock, R. J., Chernoff,N.. Hanish,R.C.. Gray. J.. Rogers.F.., arid Gray, L.Z.PrenatalToxicity of Endrinin Rodents.11.

FetotoxicElmecisof PrenatalExposurein Ratsand Mice.” Toxicology21:141—150.1981.

(12) Kavlock. IL J.,Chernoff. N.. andRogers,E. H. “TheEffectsof AcuteMaternalToxicity anFetal Developmentin theMouse.”TeratogenGarcinogenMutagen53—13. 1985.

(13) Murray F. J., K. 13. Nitschke,L W.RainpyandA~B. Schwetz.“EmbryotoxicityandFetotoxicity ofInhaledor IngestedVinylideneChloride in RatsandRabbits.”ToxicologyandAppliedPharmacology49:189—202.1979.

(14) Kiminel. S. A. and1. C. Wilson.“SkeletalDeviationsin Rats:Malformationsor Variations?”Teratology8:309—316.1973.

(15) Palmer,AJC 1n HandbookofTeratology,Wilson j.G. andF. C. Fraser.eds.,Vol. 4.New York, Plenum,pp. 215—253.1978.

(18) Dow ChemicalCo.,Midland.Michigan.Letterto StevenNewburg.Rinn.AssessmentDivision, Office of PesticidesandToxicSubstances,U.S. EnvironmentalProtectionAgency,Washington.D.C. 20460. May 24.1983.

(17) Wilson, J.G.Envsronme:~tandBirthDefects,NewYork~AcademicPress.pp.28-30. 1970. -

(18) Wilson, J.G. CurrentStatusofTeratology.GeneralPrinciplesandMechanismsDerivedfrom Animal StudiesLn:Handbookof Teratology,Vol. 1. Wilson, J.G.andFraserF. C.. ads.New York: Plenum,pp.57—59. 1977.

(19) USEPA.TSCAsection8(e)submission8EHQ.-0683-0439.followup response.Submittedto EPA by Dow ChemicalCompany.CAS referencenumber-D—979.ReuzalP. C. andC. F. Kuper. authors.“Chronic(25-month)inhalationToxicity/CarcinogenicityStudy ofPropyleneOxide inRats.”NetherlandsOrganizationfor AppliedScientificResearch,Division for NutritionandFoodResearchTNO. Netherlands.Submittedto: Office of Pesticidesand ToxicSubstance,.U.S. EnvironmentalProtectionAgency,Washington.D.C. June3. 1983.

(20) NTP. ‘Toxicology andCarcinogenesisStudiesof PropyleneOxide(CAS No. 75—56—9) in F344/NRatsand88C3F

1Mice

(InhalationStudies).”G. Boorman(ChemicalManager).NTP TR 267. NIH PublicationNo.85—2527.NTP—83—020.NotionalToxicologyProgram,ResearchTriangle Park.NorthCarolina.March1985.

(21) Lynch,D.W.. Lewis.T.R., Moorman,W.).. Burg, JR.. andGrath,D.H. et al.“CarcinogenicandToxicologic EffectsofInhaledEthyleneOxideand PropyleneOxidein F344Rats.” Toxicologyaria AppliedPharmacology76:69. 1984.

(22) USEPA.Memorandum:“Feasibility ofan EpidemiologicStudyof PropyleneOxideWorker,.” Preparedby C. Scott.Office ofPesticidesandToxic Substances.U.S.EnvironmentalProtectionAgency,Washington.D.C. July 13,1984.

(23) Dow ChemicalCo., Midland. Michigan.Propyleneoxide: reviewof healtheffectsandpropos~1lot voluntary tesflneLesterto SteveNewburg-Rinn.AssessmentDivision, U.S.EnvironmentalProtectionAgency.Washington,D.C. June15. 1982.

(24) SRI International.A studyof indus’dataon candidatechem:calsfor testing.Preparedfor Office of Toxic Substances.U.S.EnvironmentalProtectionAgency.Washington.D.C. EPA ContractNo. 68—01—4109 (PB 274-164).1977.

(23) DowChemicalCo.. Midland. Michigan.Responseto therecommendedtoxicologicaltestingfor alkyl epoxidesby the InteragencyTestingCommittee.Submittedto: Office ofToxic Substance,,U.S. EnvironmentalProtectionAgency,Washington,D.C. March10, 1978.

(28) Dow ChemicalCompany,Midland,Michrgae.“PropyleneOxide:Two-GenerationReproductionStudy in Fischer344 Rats.”TSCA 8(d) submission878216062.Office ofPesticidesandToxicSubstances.U.S.EnvironmentalProtectionAgency,Washington.D.C. July 9. 1985.

(27) USEPA.EconomicImpact .Analvsis forFinal Test Rule for PropyleneOxide.No date.

ConfidentialBusinessInformation(CB.l), while part of the record.is notavailable for public review. .A publicversionof the record, fr-am which GB!hasbeendeleted,is availableforinspectionfrom 8 a.ni. to 4 p.m.,MondaythroughFriday,exceptlegal holidays,inRm. E—107,401 M StreetSW.,Washington,D.C.

IX. OtherRegulatoryRequirements

A. Ciassificalion of Rule

UnderExecutiveOrder12291,EPAmust judgewhethera regulationis“major” and, therefore,subjectto therequirementofa RegulatoryImpactAnalysis.Theregulationfor this.chemicalsubstanceis not majorbecauseit doesnot meetany of the criteria setforthin section1(b) of the Order. First,the actualannualcostof all the testingproposedfor propyleneoxide is $7,963—23,891,or lessthan $92,185overthetesting andreimbursementperiod.Second,becausethe costof the requiredtesting will be distributed over a largeproductionvolume, the rule will haveonly very minor effects on users’ prices(lessthan 0.008percent) for thischemical,even if all test costswerepassedon. Finally, taking into accountthe natureof themarket for thissubstance,the low )evelof costsinvolved, and the expectednatureof themechanismsfor sharingthe costs of therequiredtesting,EPA concludesthattherewill be no significantadverseeconomiceffects cf any type as a resultof this rule.

This regulationwassubmittedto the’Office of Managementand Budget(0MB) for reviewas requiredby

48770 Federal Register / Vol. 50, No. 229 / Wednesday.November 27, 1985 I Rules and Regulations

ExecutiveOrder12291.Any. commentsfrom 0MB to EPA, andanyEPAresponseto thosecomments,areincludedin the public record.

B. RegulatoryFlexibility Act

Underthe RegulatoryFlexibility Act(15 U.S.C.601 etseq..Pub.L. 96—354.September19, 1980), EPA certifiesthatthis testrule will not havea significantimpact on a substantialnumberof smallbus~iesses’for the following reasons:

1.~Thereareno smallmanufacturersofpropyleneoxide-

2. Small processorsarenot likely to.performtesting themselves,or toparticipatein the organizationof the~testing effort - -

3~Small processorswill experienceonly minorcosts in securingexemptionfrom testing requirements.

4. Small processorsare unlikely to beaffectedby reimbursementrequirements.

C. PaperworkReduction-ActThe information collection

requirementscontainedin this rule havebeenapprovedby theOffice of -

ManagementandBudget (0MB) underthe provisionsof thePaperworkReductionAct of 1980,44 U.S.C. 3501etseq.andhavebeenassigned0MBcontrolnumber2070—0033.

List of Subjectsin 40 CFRPart 799

Testing. EnvironmentalProtectionAgency. EnvironmentalProtection,Hazardoussubstances,Chemicals.

Dated:November21. 1985. -

John A. Moore,Assistant.Administratorfor PesticidesandToxicSubstances.

PART 799—(AMENDEDI

Therefore.Part799 is amendedasfollows:

1. Theauthoritycitation for Part799--continuesto readasfollows:

Authority: 15 U_S.C. 2603. 2811, 2625.

2. New §799.3450is addedto readasfollows:

~799.3450 Propylene oxIde.(a) Identificationof testsubstance.(1)

Propyleneoxide(CAS No. 75—56—9)shallbe testedin accordancewith thissection.

(2) Propyleneoxide of at least99.0-percentpurity shall be usedas the testsu4ostancein all tests.

(b) Personrequiredto submitstudyplans,conducttests. andsubmitdata.(1) All personswho manufactureorprocesspropyleneoxide, otherthan asan inpurity, from January10. 1986.to theendof thereimbursementperiodshallsubmit lettersof intent to conduct

testing orexemptionapplications.8tudyplans,andshall conducttests,andsubmitdataasspecifiedin this section,SubpartA of this Part,andPart790 ofthis chapter.

(2) Personssubjectto this sectionarenot subjectto therequirements§ 790.30(a)(2), (5), and(6) and(b) and§ 790.87(a)(1)(ii)of this chapter.

(3) Personswho notify EPA of theirintent to conducttestsin compliancewith the requirementsof this sectionmust submitplans for thosetestsnolaterthan30 daysbeforethe initiation ofeachof thosetests.

(4) In additionto the requirementsof§ 790.87(a)(2) and(3) of this chapter,EPA will conditionally approveexemptionapplicationsfor this rule.ifEPA hasreceivedaletterof intent toconductthe testing from whichexemptionis soughtandEPA hasadoptedtest standardsandschedulesina final PhaseH test rule.

(c) Health effectstesting—{1)Developmentaltoxicity—{i) Requiredtesting.An inhalation developmentaltoxicity test in the rat shall beconductedwith.propyleneoxide.

(ii) [Reservedi.(Informationcollectionrequirementsapprovedby theOffice of ManagementandBudgetundercontrolnumber2070—0033)

[FR Doc.85—28300Filed 11—28-85;8:45 am)BIWNG CODE 65~O-5O-M