P. 1 

# OAR Box 1846 Prepped byOllie Stewart



### Document

Number: 

# 51 ) ll-F- 5 Docket Number: 

# A-90-0 7

Printed 11/18/20087:30:16

AM Sheet 51 of 93P. 2 

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### MAR 

### 2 3 1992

NOT E FROM : TO : RE : Jud

yGray TroyHil l 

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Transmitta l o f Additiona l NPRMChange s fo r th e Fuels/Additive s Program Page s o f th e NPRMcontaining th e additiona l change s w e discusse d ove r th e phon e thi s morning ar e attached . T o facilitat e you r review , th e change d materia l i s indicate d b yarrow s i nth e lef t margin , an

d th e pag e number s i n relatio nt o previou s draft s ar e show

ni n bracket s i nth e lowe r righ t corne r o f th e ne wpage . Pleas e giv e m e a cal l (374-8231 ) a s soo na s yo u complet e you r review . Thank you .P. 3

exposure s t o emission s o f th e bas e fue l alone . EP Aask s fo r commen t onth e mixing rule s tha t shoul d b e adopte d an d onth e validit yo f doping th e bas e fue l wit hth e fue l additiv e o r

— > activ e ingredient . Commen t i s als o requeste d o nappropriat e

— > additiv e concentratio nlevels , i f a doping procedur e wer e t o

— » b e adopte d fo r th e Fina l Rule .

VI . Evaluationo f Healthan dWelfar e Effect s Th e scop e and genera l structur e o f propose d provision s fo r evaluating th e potentia l healt hand welfar e effect s o f fuel s and fue l additive s wer e discusse d abov e i n Section s 1 1 I. E an

d F . Th e programfocuse s o nth e contributio n o f fuel s an d additive s t o harmfu l ai r pollution , an d include s requirement s t o determin e th e compositio nan d potentia l effect s o f fuel/additiv e emission s generate d b ybot h combustio nan

d evaporativ e processes . Healt heffect s testing provision s ar e specificall yfocuse d o nth e effect s o f inhalatio nexposur e t o fuel/additiv e emission s i nregar d t o th e following selecte d endpoints : carcinogenicity , mutagenicity , developmenta l effects , reproductiv e effects , pulmonarytoxicity , an d neurotoxicity . Th e impact s o f fue l an d additiv e emission s o nth e publi c welfar e an d th e environmen t ar e addresse d b ydat a researc hmethodologies .

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fue l familie s (e.g. , methan e o r propane ) shoul d b e exempte d fro mparticula r Tie r 2 testing requirements . Th e propose d healt heffect s testing guideline s ar e include d i nth e regulatorytex t fo r thi s proposal , availabl e i nth e publi c docke t o r b yreques t t o EPA(se e th e sectio no f thi s Notic e entitled , "Fo r Furthe r Information") . Mos t o f thes e testing guideline s ar e modifie d version s o f guideline s previousl ypublishe d unde r TSCA(4 0 CF RPar t 798) . Method s fo r performing anima l inhalatio nexposure s t o fuel/additiv e emission s ar e als o include d i nth e propose d regulatorytext .

— > Comment s an

d suggestion s ar e solicite d o nth e adequac yo f

- » thes e propose d guideline s and methodologie s fo r promotin g —i*vali d stud

ydesignand adequat e technica l performance . EP A

— > believe s tha t thes e guideline s (perhap s amende d fo r th e Fina l

— > Rul e a s a resul t o f submitte d commentary) , togethe r wit h

— » publishe d laboratorypractic e standard s (reference d below) ,

— > ar e sufficien t t o ensur e tha t Tie r 2 testing don e i n

— > conformanc e wit hthes e guideline s wil l b e acceptabl e upo n

— > subsequen t evaluatio nb yEPA . However , comment s ar e requeste d

- » onwhethe r a revie wmechanis mshoul d nevertheles s b e

— » established , enabling manufacturer s t o submi t detaile d

— > protocol s t o EP Afo r approva l prio r t o beginning th e Tie r 2

— > testing . Suc ha mechanis mwoul d provid e additiona l

— » reassuranc e t o manufacturers , bu t i n vie wo f th e larg e numbe r

- » o f individua l protocol s whic hwoul d probabl yb e submitte d fo r

— > review , woul d inevitabl yresul t i nsignifican t testin g delays . 17 5 

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-> Thus , respondent s wh o believ e tha t a revie wmechanis mi s

— » necessaryar e als o aske d fo r suggestion s onho wt o mak e th e

— » proces s feasible , give nth e statutorytim e constraint s fo r

- » programcompliance .

Simila r requirement s among th e variou s tes t guideline s i n regar d t o anima l subjects , exposur e scenarios , an d genera l technica l principle s provid e opportunitie s fo r concurren t tes t performanc e a t considerabl e cos t savings . Thes e share d stud y parameter s includ e th e following : Laboratorypractices . T o ensur e th e qualit yan d integrit yo f tes t results , th e performanc e o f al l studie s wil l b e require d t o conformwit hth e Goo d LaboratoryPractic e Standard s (GLPS ) publishe d i n4 0 CF RPar t 792 , o r wit h comparabl e standard s whic hmayb e develope d specificall yfo r thi s program . Thes e GLP S includ e facility , equipment , organization , qualit yassurance , an d personne l requirements , a s wel l a s specification s fo r prope r car e o f laboratory animals , handling o f reagent s an d tes t substances , an d conduc t o f studies . I naddition , th e provision s o f Subpar t J o f Par t 79 2 ar e t o b e followe d fo r recor d keeping an d reporting o f results . Anima l models . Wit hth e exceptio no f th e Ame s Salmonell a assay , th e propose d tes t requirement s entai l th e exposur e o f liv e laboratoryanimal s t o fuel/additiv e emissions . Mammalia n 17 6 

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require d t o furthe r explicat e th e result s o f th e screening batterie s performe d unde r Tie r 2 , bu t migh t als o addres s othe r area s o f concer nhighlighte d b yth e Tie r 1 literatur e searc h o r emissio ncharacterizatio nprocedures . Th e nee d fo r Tie r 3 testing woul d depend o nwhethe r sufficien t toxicit yan d exposur e informatio nwer e availabl e t o determin e whethe r us e o f a fue l o r fue l additiv e present s anunacceptabl e healt h risk . Th e criteri a fo r thi s determinatio nar e discusse d below . Whe na determinatio nha s bee nmad e tha t Tie r 3 testing wil l b e required , EP Awil l infor mth e responsibl e producer(s ) b ycertifie d mai l o f th e purpos e an d natur e o f th e testing t o b e performed . Subsequently , relevan t stud yguideline s an

d a timetabl e fo r completio no f al l requirement s wil l b e specified . Th e producer(s ) wil l b e expecte d t o submi t detaile d protocol s fo r revie wan d approva l b

yEP Aprio r t o

— » beginnin g th e tests . Tie r 3 testing performe d i nful l

— » conformit ywit ha protoco l pre-approve d b yEPAfo r th e give n

— > product(s ) an

d tes t objectiv e wil l b e deeme d satisfactory

- » complianc e wit hth e Tie r 3 testing requirement . 

### 1. Need for DiscretionaryTier

3 Determinations Give n th e variet yo f evaluatio nmethodologie s an d subject s include d i nTier s 1 an d 2 an d th e wid e rang e o f possibl e interrelate d outcome s whic hcoul d b e obtained , EPA believe s tha t i t i s neithe r practica l no r necessaril y 18 9 

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enabl e manufacturer s t o predic t an d pla nfo r thei r maximu m registratio nresponsibilitie s an d woul d simplif yEPA' s dat a evaluatio n tasks . EP Arequest s commen t onth e relativ e merit s o f th e discretionaryvs . automati c approache s fo r determining Tie r 3 applicability . Respondent s wh o prefe r th e automati c approac har e als o aske d fo r suggestion s a s t o th e specifi c "triggers " an

d follow-u

p test s whic hshoul d b e established .

— > Whil e EP Apropose s t o retai ndiscretio ni nth e decisio n

— » t o requir e Tie r 3 testing , i t i s possibl e t o predic t some set s

— > o f circumstance s whic hwoul d indicat e tha t Tie r 3 wil l no t b e

— » required . Thes e factor s ar e discusse d i nth e section s whic h

— > follow . EP Arequest s comment s o nthes e circumstances , an d

— » ask s fo r suggestion s o nothe r combination s o f criteri a whic h

— » shoul d b e establishe d fo r determining whe na fue l o r additiv e

— » shoul d no t b e considere d fo r possibl e elevatio nt o Tie r 3 . 

### 2. Criteriafor

Escalationto Tier

3 Thi s sectio n present s some o f th e guideline s an d consideration s whic hEP Awoul d us e i ndetermining th e necessit yfo r additiona l testing unde r a discretionaryTie r 3 testin g approach . Consisten t wit hth e propose d discretionary decision-making proces s fo r Tie r 3 , thi s discussio ni s no t intende d t o provid e anexhaustiv e o r definitiv e listing o f relevan t criteria . Rather , th e majo r purpos e o f thi s discussio n i s t o hel p furnis ha basi s fo r meaningfu l publi c comment s an

d suggestion s o nth e propose d Tie r 3 provisions .

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o f th e observe d effect s (e.g. , whethe r th e effect s woul d b e likel yt o lea d t o incapacitatin g o r irreversibl e conditions) , 5 ) th e numbe r o f specie s involve d i nth e reporte d tests , an d 6 ) th e consistenc yan d clarit yo f apparen t mechanisms , targe t organs , an d outcomes . Additiona l parameter s whic hwoul d influenc e th e decisio n o nwhethe r t o requir e Tie r 3 woul d includ e 1 ) finding s o f environmenta l persistenc e o f th e emission s and/o r th e abilit yo f th e emission s t o accumulat e i n livin g organisms , 2 ) th e natur e an d amoun t o f know ntoxi c agent s i nth e emission s stream , an d 3 ) th e observatio n o f lesion s whic hspecificall yimplicat e inhalatio na s a n importan t exposur e rout e fo r inducin g advers e healt heffects . Thes e criteri a woul d b e evaluate d i n conjunctio nwit hth e result s o f th e exposur e assessmen t t o determin e whethe r o r no t highe r leve l testin g wa s needed . I nthi s decision , bot hth e biologica l an d statistica l significanc e o f th e result s o f Tier s 1 an d 2 woul d b e take n int o account . Generally , escalatio nt o Tie r 3 woul d b e considere d whe nremainin g uncertaintie s abou t th e significanc e o f observe d outcome s and/o r exposure s interfere d wit hEPA' s abilit yt o mak e reasonabl e estimate s o f th e attendan t publi c healt hrisks . O n th e othe r hand , i f n o statisticall ysignifican t effect s wer e obtaine d a t anyexposur e leve l i n a scientificall ysoun d Tie r

— > 2 study(o r existin g tes t submitte d i nlie u o f Tie r 2 testin g

— » an d no t contradicte d b yothe r publishe d reports ) , an d i f othe r

— » m a jo r source s o f concer ndi d no t aris e (e.g. , toxi c effect s o f 19 9P. 9

— > structurall yrelate d compounds ) , the nTie r 3 testing woul d no t

— > b e require d fo r th e endpoin t i nquestion . Thi s assume s tha t relevant , high-qualit ystatistica l analysi s ha d bee ndon e t o permi t th e negativ e tes t result s t o b e properl yevaluate d an d interpreted . Th e statistica l analyse s recommende d fo r Tie r 2 i nan earlie r discussion , including determinatio no f Typ e I an d I I error , shoul d enabl e reasonabl e conclusion s t o b e draw n a s t o th e significanc e o f negativ e findings . Factor s t o b e take n int o accoun t includ e th e toxicologica l natur e o f th e finding s an

d th e exposur e level s use d i nth e test . Fo r example , i f th e statistica l analyse s wer e applie d t o a "severe " endpoin t (e.g. , majo r feta l abnormalities , majo r lung pathology , etc. ) an d th e exposur e i nquestio nwa s moderate , the n0. 1 woul d b e anappropriat e Typ e I I erro r level . I n contrast , i f a highconcentratio nlimi t tes t cause d a relativel ymino r effec t (e.g. , a smal l chang e i nlung lavag e protein) , a highe r Typ e I I erro r woul d b e allowe d (e.g. , 0.2) , effectivel yincreasing th e chanc e o f fals e negativ e conclusions .

Evaluatio no f Tie r 2 Results . Th e specifi c outcome s whic hwoul d b e considere d positiv e an d negativ e result s fo r eac hpropose d Tie r 2 tes t ar e mentione d briefl yi nth e previou s description s o f Tie r 2 requirement s and ar e define d an d interprete d mor e precisel yi nth e propose d regulatory text . Fo r example , thre e primarystudie s ar e include d i n Tie r 20 0P.1 0

2 whic hrelat e t o carcinogenicit yan d mutagenicity : th e Ames , SCE , an d micronucleu s assays . A s compare d wit happropriat e controls , a statisticall ysignifican t dose-relate d positiv e respons e i nan

yon e o f thes e assay s coul d b e caus e fo r concern , a s woul d positiv e outcome s fo r a t leas t on e concentratio ni n tw o o r mor e o f thes e tests . Suc houtcome s woul d b e indicativ e o f mutageni c risk ; however , depending on th e interna l and historica l consistenc yo f thes e result s an d thei r relationshi p t o projecte d exposures , furthe r testing migh t b e require d t o determin e th e significanc e o f thi s mutageni c activit yi nhuma npopulation s expose d b yinhalation . Thes e outcome s woul d als o indicat e tha t th e emission s coul d initiat e some o f th e mechanism s involve d i ncarcinogenesis . However , th e productio no f malignanc yi s a multi-ste p process , an d thes e result s woul d generall yno t i nthemselve s b e sufficien t t o determin e whethe r th e emission s wer e i n fac t carcinogenic . Thus , additiona l testing migh t b e require d unde r Tie r 3 t o bette r evaluat e th e associate d cance r risks . I ncontrast , i f n o statisticall ysignifican t result s wer e obtaine d i nth e thre e assay s an d n o conflicting result s foun d

- * i nth e literatur e o r i nothe r Tie r 2 tests , the nTie r 3

- » follow-u

p fo r carcinogenicity/mutagenicit ywoul d no t b e

- > required .

T o tak e anothe r example , determinatio no f th e nee d t o furthe r investigat e teratogeni c risk s woul d tak e int o accoun t th e result s o f bot hth e inhalatio ndevelopmenta l toxicit y 

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stud yan d th e reproductio nan d fertilit yassessmen t o f Tie r 2 .

— > I f negativ e result s wer e obtaine d i nbot ho f thes e test s

— > (according t o statisticall ysoun d principles ) , an

d i f thes e

— > result s wer e no t refute d b yth e existing literature , the n

— > additiona l testing woul d no t b e require d a t th e Tie r 3 leve l

— » fo r developmenta l o r reproductiv e effects . Positiv e result s woul d includ e a decreas e i nneonata l viabilit yrelativ e t o tha t i n contro l studies , a significan t chang e i nth e proportio n o f viabl e mal e vs . femal e fetuse s o r offspring , th e presenc e o f sof t tissu e o r skeleta l abnormalities , an d an increase d rat e o f embryoni c o r feta l resorption . Othe r positiv e outcome s o f th e reproductio nan d fertilit y assessment , suc ha s abnorma l change s i nsper m structur e o r function , vagina l cytology , o r reproductiv e organ histopathology , woul d b e indicativ e o f hazard s t o th e adul t reproductiv e systems . Th e nee d fo r additiona l evaluatio n unde r Tie r 3 woul d depend o nth e numbe r o f specie s fo r whic h positiv e result s wer e obtained , th e specificity , severity , an d consistenc yo f results , th e presenc e o r absenc e o f a concentration-effec t relationship , and th e significanc e o f thes e outcome s i n vie wo f projecte d exposur e scenarios . The greate r th e remaining uncertaint yregarding th e ris k o f teratogeni c o r reproductiv e effect s afte r analysi s o f suc h factors , th e highe r woul d b e th e likelihoo d tha t Tie r 3 woul d b e required .

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- > Similarly , consisten t an d statisticall ysignifican t

— » negativ e result s obtaine d i nothe r Tie r 2 tests , i nth e

— » absenc e o f significan t relate d concern s raise d i n th e

— » literature , woul d mak e Tie r 3 unnecessary . Onth e othe r hand , i f advers e effect s ar e foun d a t Tie r 2 and/o r reporte d i nth e literature , EP Awoul d determin e i f Tie r 3 follow-u p i s require d b

yattempting t o evaluat e th e nature , severity , an d significanc e o f th e finding s i nligh t o f th e likel yexposures . I f EP Adetermine s tha t Tie r 3 testing i s require d t o resolv e th e remaining uncertainties , th e Tie r 3 requirement s woul d reflec t bot hpositiv e an d negativ e results . Fo r example , i f th e result s o f Tie r 2 wer e positiv e fo r pulmonaryeffect s bu t negativ e fo r neurotoxicit y(according t o criteri a discusse d earlier) , an

d i f thes e result s wer e consisten t wit hth e literature , onl ypulmonarytoxicit ywoul d b e a likel y candidat e fo r Tie r 3 follow-u p testing .
Acut e Healt hAssessment . Unde r th e assumptio ntha t emission s exposure s wil l generall yb e lowand thu s mor e likel y t o caus e longer-term effects , thi s propose d rulemaking doe s no t focu s o n acut e effects . However , th e purpos e o f CA A sectio n21 1 i s t o protec t th e publi c health , whateve r th e exposur e duration , an d potentia l acut e effect s coul d als o b e a consideratio ni nth e Tie r 3 decision .
EP Ai s currentl ydeveloping a standardize d metho d o f assessing acut e noncance r healt heffects , an d thi s metho d 

## 20 3f!L/» 1 (ah) lP.1 3

individua l manufacturers , a hypothetica l exampl e mayhel p t o clarif yth e propose d scope , time frame , an d cost s o f th e program . Base d o nth e analysi s provide d i nth e regulatory suppor t document , a possibl e testing scenari o an d th e associate d complianc e cost s fo r a hypothetica l grou p o f product s i s discusse d belo wan d summarize d i nFigur e 6 . Thes e cost s woul d pertai nt o th e evaluatio nan d testing o f a fue l selecte d t o represen t th e hypothetica l group . Th e tota l cost s woul d subsequentl yb e share d b yal l o f th e manufacturer s wit h product s enrolle d i nth e group . Th e requirement s and cost s assume tha t th e grou p consist s o f 4 0 fuel s an d additive s whic h contai nn o "atypical " elements , tha t th e grou p doe s no t qualif yfo r exemptio nfromevaporativ e emissio ntesting , an d tha t adequat e existing studie s ar e no t availabl e t o fulfil l an yo f th e speciatio no r biologica l tes t requirements . Therefore , unde r thi s hypothetica l situation , al l o f th e potentia l requirement s o f Tier s 1 an d 2 mus t b e conducted . Combustio nemissio ngeneratio nprocedure s ar e assume d t o b e performe d usin g on e light-dut yvehicle , fo r bot hemissio n characterizatio nan d biologica l testing purposes .

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Th e approac hwhic hEPAplan s t o us e i ndetermining th e potentia l nee d fo r greate r precisio nan d accurac yi n th e exposur e informatio ni s t o conside r th e slop e o f th e toxi c response . I f th e slop e i s steep withi nth e rang e o f potentia l huma nexposures , the na smal l chang e i nexposur e i s likel yt o hav e a majo r impac t onth e eventua l ris k assessment . Greate r precisio nwoul d thu s b e require d i nth e exposur e calculation . I f advers e healt heffect s appea r likel ywithi nth e projecte d rang e o f exposures , improve d estimate s migh t als o b e neede d t o determin e th e condition s and location s unde r whic hthes e exposure s migh t occu r a s wel l a s th e siz e o f th e potentiall y affecte d populations . Onth e othe r hand , i f onl ymino r healt h effect s occu r a t level s wel l abov e ambien t concentration s an d onl ya relativel ysmal l numbe r o f peopl e ar e likel yt o b e exposed , the nadditiona l refinement s o f th e exposur e calculation s woul d no t b e warranted .

- > Tie r 3 exposur e assessmen t coul d includ e physica l

— » monitorin g studie s o r th e applicatio no f mor e sophisticate d

— > modelin g techniques , some o f whic har e describe d i nSectio n

— > VI.B.2 . However , th e precis e natur e o f thes e studie s woul d b e —»strongl yinfluence d b yinteri madvance s tha t ar e expecte d i n —»th e growing scienc e o f exposur e assessment . Th e genera l topi c

— » o f gasolin e exposur e i s receiving increase d attentio nb yth e scientifi c communit ya s a topi c fo r research , i nrecognitio n o f th e limite d knowledg e bas e currentl yavailabl e fo r determining th e risk s frommobil e sourc e emission s and from 

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ove r th e three-yea r complianc e period , th e Tie r 3 testing cos t pe r produc t i nthi s grou p woul d b e i nth e rang e o f $17-21,00 0 annuall yfo r thre e years .
I nsum , EP Aestimate s tha t th e tota l cost s t o thi s hypothetica l grou

p woul d rang e fromapproximatel y3 t o 3. 5 millio ndollars , incurre d ove r a seve no r eigh t yea r time period . Th e tota l cos t fo r eac hproduc t woul d rang e fro m abou t $75,00 0 t o $87,500 , averaging abou t $10-12,00 0 pe r year .

— > EP Aseek s comment s o nthes e estimates , give nsuc ha scenario .

— > Th e abov e discussio nillustrate s th e complianc e cost s

— > whic hth e propose d programmigh t entai l fo r a grou p o f

— » fuel/additiv e producers . However , th e propose d programcoul d

— > hav e some indirec t cos t implications , a s well . Fo r example ,

— > i f th e cost s o f complianc e represente d a significan t entry

— » barrie r int o th e fuel/additiv e marketplace , a neconomi c cos t

— > coul d b e incurre d a s a resul t o f delaye d o r deterre d —»innovation . Thes e potentia l economi c cost s hav e no t a s ye t —»bee n quantified , and EP Arequest s comment , along wit h —»supportin g data , o nho wt o evaluat e an d quantif yth e possibl e

— > indirec t economi c impact s o f th e program .



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