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SEN T B Y COURIE R Apri l 22 , 201 0 Jan e Smit h Documen t Processin g Des k (PRD-EDSP ) Offic e o f Pesticid e Program s (OPP) , Mai l Cod e 7508 P U.S . Environmenta l Protectio n Agenc y On e Potoma cYar d (Sout h Bldg ) 277 7 S . Crysta l Driv e Arlington , VA22202-450 1 Dea rJane , Enclose d i s th e 90-da yrespons e for m fo rth e EDS P Tes t Orde rfo rMGK-264 , P C Cod e 05700 1 CA S No . 113-48-4 . Als o attache d ar e thre e copie s o f ou rOthe rScientificall yRelevan t Informatio n (OSRI) , 6 pages) . I f yo u hav e an yquestions , pleas e fee l fre e t o contac t m e a t 763-593-3410 , o rvi a emai l a t ian.sharp@mgk.com . Than k you . Bes t Regards ,

Janic e K . Sharp , Ph.D . RegulatoryDepartmen t Manage r CC : Regulator

yFil e Enclosure s • • • • • • •

•• *



### Qualit y Product s Sinc e 19O 2

### McLaughli n Gormle y Kin g Co . Submissio n o f

Othe r Scientifi c Relevan t

Informatio n I n Respons e t o EDS P Testin g Orde r #EDSP-05700 1 Fo r MGK-26 4 (P C Cod e 057001 ) Submitte dApri l 22 , 201 0 I nrespons e t o th e above-cite dEDS PTestin g order , McLaughli n Gormle y Kin g Co . (MGK ) submit s th e followin g "Othe r Scientifi c Relevan t

Information " (OSRI ) t o satisf

y part o f th e testin g order . Specifically , MG K cite s a s OSRI tw o studies : 1 ) A recentl y conducte dtwo-generatio n ra t stud y tha t

examine dth e entir e reproductio n proces s i n Wista r rat s (th e "2-ge n study") . Th e 2-ge n study , whic hi s discusse di n detai l i n th e attachmen t t o thi s submissio nan di s appende dt o thi s submission , i s awell-conducte d GL Pstud y tha t

utilize dcurren t

EP A protocols . 2 ) A Combine dChroni c Toxicity/Carcinogenicit y Stud y i n Rat s (MRI D No.43005301) . Thi s wa s acomprehensiv e guidelin e stud y tha t examine dal l lexicologicall y relevan t orga n system s includin g th e thyroid-liver-pituitar y axis . Th e 2-ge n Stud y Th e 2-ge n stud y adequatel y inform s th e determinatio n a s t o whethe r MGK-26 4 "may hav e a n effec t tha t i s simila r

t o a n effec t

produce db y asubstanc e tha t interact s wit hth e [estroge n an dandrogen ] hormona l systems. " Orde r #EDSP-05700 1 a

t 5 ; 7 4 Fed.Reg . 17560 , 17566 . Specifically , th e 2-ge n study provide s "informatio n o n apotentia l consequenc e o r effec t tha t coul db e du e t o effect s o n th e [estroge n an dandrogen ] systems. " Id . Th e stud y demonstrate s tha t MGK-26 4 produce s mil deffect s o n endocrine-relate dparameter s onl y at 640 0 pp m(th e highes t

dos e tested) , fa r

above th e NOAE Lfo r

parenta l systemi c ••• • toxicit y o f 40 0 ppm . J " * J * J *** *



### . • • • • . Becaus e th e 2-ge n stud y provide s adequat e informatio n a s t o th » potentia l •*•,* • consequence s o f

MGK-26 4 o r

effect s o n th e estroge n an dandroge n system^. * . . . MG K i s submittin g th e 2-ge n stud y t o satisf y th e requiremen t

t o submit«date»fo r

t *•• * th e followin g screenin g assays : Androge n Recepto r

Bindin g ••••• • Aromatas e Estroge n Recepto r

Bindin g Estroge n Recepto r

Transcriptiona l Activatio n Hershberge r

### • Femal e Puberta l • Mal e Puberta l • Steroidogenesi s • Uterotropi c MG K believe s tha t

conductin g th e above-liste dscreenin g assay s fo r MGK-26 4 whe nawel l conducted , recent , relevan t an dapical 2-ge n stud y i s alread y available , i s unnecessar y an dunlikel y t o generat e additiona l informatio n tha t wil l assis t

EP A i nmakin g regulator y determinations . MG K als o believe s tha t t o th e exten t

EP A require s unnecessar y screening , th e Agenc y exceed s th e authorit y grante dEP A b y th e Foo dQualit y Ac t (FQPA) . Th e purpos e o f

FQP A i s clear : "t o determin e whethe r certai nsubstance s ma y hav e a neffec t i nhuman s tha t i s simila r t o a neffec t

produce db y anaturall y occurrin g estrogen , o r suc hothe r effect s a s [EPA ] ma y designate. " 2 1 U.S.C . 346a(p)(l) . Thi s languag e mus t b e rea di nligh t

o f th e FQP A directiv e tha t

th e Agenc y shal l tak e action s (e.g. , regulate ) t o ensur e th e protectio no f publi c health . 2 1 U.S.C . 346a(p)(6) . Ther e i s n o evidenc e Congres s intende dtha t EP A requir e generatio no f unnecessar y dat a o r dat ath e Agenc y couldn' t

us e t o protec t

huma nhealth . Indeed , Congres s directe dEP A t o minimiz e duplicativ e testing . Th e Combine dChroni c Toxicitv/Carcinogenicit y Stud y Th e Combine dChroni c Toxicity/Carcinogenicit y Stud y i nRat s i n combinatio nwit hth e 2-ge nstud y adequatel y inform s th e determinatio na s t o whethe r MGK-26 4 "ma y hav e a neffec t that i s simila r t o a neffec t

produce db y a substanc e tha t

interact s wit hth e [thyroid ] hormona l system. " Orde r #EDSP

05700 1 at 5 ; 7 4 Fed.Reg . 17560 , 17566 . Specifically , togethe r th e Combine d Chroni c Toxicity/Carcinogenicit y Stud y i nRat s an dth e 2-ge nstud y provid e "informatio no napotentia l consequenc e o r effec t tha t coul db e du e t o effect s o n th e [thyroid ] system. " I nth e Combine dChroni c Toxicity/Carcinogenicit y Stud y i nRats , MGK-26 4 wa s show nt o caus e dose-dependen t increase s i nbenig n thyroi dfollicula r

tumor s i nmal e rats . I nth e 2-ge nstudy , follicula r cel l hypertroph y and/o r

colloida l alteratio nwer e increase di nmale s beginnin g partl y a t 160 0 pp mi nbot hF O an dFl , an di nF O an dF l female s a t 640 0 ppm . Wit hrespec t

t o th e thyroid , EP A state s i nit s recen t Reregistratiew. . Eligibilit y Decisio n(RED ) fo r MGK-264 : • ' "I t i s noted , however , tha t

th e ra t carcinogenicit y stud y J demonstrate dincrease dthyroi dtumor s tha t ma y hav e been.relate d t o perturbatio no f

th e thyroid/liver/pituitar y axi s t o alte r thjroit l , hormon e metabolism . EP A believe s th e endpoint s an drisfc" * * J...J . scenario s evaluate dar e protectiv e o f thi s potentia l endocrin e • 

# effect. " .;;:; . Clearly , th e existin g databas e provide s sufficien t informatio nt o asses s potentia l thyroi deffec t

an dEP A ha s alread y mad e th e require dassessmen t wit h

### respec t t o MGK-264 . Th e propose dAmphibia nMetamorphosi s Assa y wil l provid e n o additiona l informatio no nwhic ht o bas e regulator y decisions . Th e Combine dChroni c Toxicity/Carcinogenicity Stud y i n Rat s an dth e 2-ge n study togethe r provid e adequat e informatio na s t o th e potentia l consequence s o f MGK

26 4 o r effect s o nth e thyroi dsystem , Fo r tha t reason , MG K

cite s th e Combine d Chroni c Toxicity/Carcinogenicit y Stud y i nRat s alon g wit hth e 2-ge nstud y t o satisf y th e requiremen t

t o submi t dat afo r th e Amphibia nMetamorphosi s Assay . Discussio n Tie r 1 data , b y itself , wil l no t

determin e whethe r

asubstanc e wil l hav e a n endocrin e effec t

i nhumans . A s EP A admits , th e Tie r 1 screen s wil l no t

determin e whethe r asubstanc e cause s advers e huma nhealt heffect s and , i f i t does , a t wha t leve l o f exposure . That

informatio n(hazar dan ddose-response ) i s determine d usin g mor e apica l testing , suc ha s EDS PTie r 2 tests , an dform s th e base s fo r science-base dregulation . Tie r 1 screenin g ca nb e useful , nonetheless , fo r determinin g whe nadditional , mor e apica l testin g i s warranted . Becaus e recent , relevan t an dwell-conducte dapica l test s hav e alread y bee nconducte dfo r MGK

264 , screenin g assay s ar e no t necessary t o determin e whethe r apica l testin g i s warrante dfo r

th e substance . Indeed , EP A shoul dhav e adequat e informatio nfro m th e availabl e apical testin g t o determin e whethe r an y regulatory action s concernin g MG K

26 4 ar e necessary t o protec t publi c health . Simpl y put , th e Tie r

1 screen s wil l no t

determin e whethe r

MGK-26 4 wil l hav e a nestrogenic , androgeni c o r thyroi deffec t

i nhumans . Significantly , thos e screen s wil l no t

determin e whethe r

MGK-26 4 cause s advers e huma nhealt h effect s a t typica l level s o f

exposure . Conversely , th e apica l studie s MG K cite s a s OSR I ca ninfor mhazar dan ddose-respons e determination s an dca nfor mth e basi s fo r Agenc y regulation . Therefore , i nth e cas e o f MGK-264 , th e Tie r

1 screen s liste dabov e ar e no t

necessar y t o determin e i f

mor e apica l test s ar e warrante d- thos e test s hav e alread y bee nconducted . While , thos e screen s ma y produc e ne w data , thos e dat acanno t

for mth e basi s o f

regulatio nand , i n an y event , ar e no t necessar y fo r

makin g regulator y decision s fo r MGK-264 . I nsum , MG K

believe s tha t

requirin g screenin g dat awhe nrelevan t apica l dat aar e availabl e wil l resul t i n "duplicativ e testing, " whic hCongres s e^xj^ljcijly . directe dth e Agenc y t o minimize . See , 2 1 U.S. C 346a(p)(5)(b) . MGKImaJntain s tha t whe nrelevan t

apica l dat aar e available , screenin g leve l dat abecome $ 

### ^ * j unnecessar y o r

duplicativ e fo r

purpose s o f

servin g th e goal s o f

FQPA : tojgerlerat e dat atha t determin e whethe r

substance s hav e a n advers e hormona l effec t in " human s an dt o infor mregulator y decisions . Whil e screenin g dat ama y b £• interestin g the y d o no t

directl y serv e th e ultimat e goal s o f th e EDSP . AVSfriatter . o f policy , EP A shoul dno t

requir e screenin g that

waste s limite dresource s an d lead s t o th e unnecessar y us e o f laborator y animal s whe ntha t screenin g wil l no t directl y benefi t

publi c health . •* •Attachmen t # 1 - Summar y o f

Combine dChroni c Toxicity/Carcinogenicity Stud y i n Rat s (MRI D No. : 43005301 ) Fiv e group s o f

60/se x Charle s Rive r

CDs . strai n rat s wer e dose di n th e die t fo r 2 4 month s a s 0 , 50 , 15 0 o r 45 0 mg/k g bw/da y o f

MGK-264 . Th e 5 0 mg/k g bw/da y dos e grou p male s ha dmarginall y increase d(14 % p < 0.05 ) termina l live r weights . Highe r

dos e level s ha dhighe r

increase s (maximu m45 % fo r th e 45 0 mg/k g bw/day hig hdos e mal e an d59 % fo r th e femal e groups) . A t

dos e level s o f 15 0 mg/k g bw/da y an dabov e pathologica l change s i n th e live r (hepatocyt e hypertroph y i n bothsexe s an dporta l bil e duc t proliferatio n an dbil e stasis , spongiosi s hepatiti s an dcyst s i n females ) an dkidne y (brow n pigmen t i n females ) wer e noted . Additiona l live r patholog y (bil e duc t

proliferation , cyst s an daltere d eosinophili c foc i i nmale s an dspongiosi s hepatiti s i nmales ) an dkidne y (brow n pigmen t an dcyst s i n males ) wer e als o note da t 45 0 mg/k g a s wel l a s increase s i n kidney , heart , an dbrai n weights . Dose-depende dincrease s i nth e incidenc e o f thyroi dfollicula r

tumor s occurre donl y i n males : adenoma s - 3/10 5 (3%) , 4/5 6 (7%) , 5/5 3 (9% ) an d6/5 5 (11% ) an dcarcinoma s - 2/7 8 (3%) , 2/3 8 (5%) , 1/3 6 (3% ) an d3/4 5 (7%) ; combine d- 5/10 5 (5%) , 6/5 6 (11%) , 6/5 3 (11% ) an d9/5 5 (16% ) fo r th e tw o combine dcontro l groups , th e 50 , 15 0 an d45 0 mg/kg/day dos e groups , respectively . Th e thyroi dchange s ar e mos t likel y an inductio n o f

oxidativ e enzyme s i n th e live r resultin g i ndecrease dseru mlevel s o f triiodothyronin e (T3 ) an d thyroxin e (T4 ) an dacompensator y increas e i nseru mlevel s o f thyroi dstimulatin g hormon e (TSH) . Th e chroni c stimulatio n o f th e thyroi dglan db y TS H i s know n t o resul t i nfollicula r

cel l tumor s i nrodents . Becaus e o f th e know n specie s difference s betwee n rodent s an dhuman s i nth e effect s o f inducer s o f

hepati c xenobioti c metabolis mo nth e thyroi dgland , thes e effect s ar e considere drat specific an dhav e n o relevanc e fo r th e protectio n o f

huma n health .

* »

•Attachmen t # 2 - Two-generatio n Reproductio n Stud y o n MGK-26 4 [MG K i s submittin g thi s stud y alon g wit hthi s OSRI submission. ] MG K recentl y complete daTwo-generatio n Reproductio n Stud y o n MG K 264 . Conducte da t

th e Baye r

Scherin g Pharm aA Glaborator y i n Wuppertal , Germany , th e stud y followe dth e OPPT S Serie s 87 0 HealthEffect s Tes t Guideline s (1998) . Dose s teste dincluded : 0 , 400 , 1600 , 640 0 pp m(th e highes t dos e teste d- HDT) . Th e followin g endocrine-relate dparameter s wer e evaluate dan dar e wort hnoting : 1 . Spermanalysi s - showe dn o substance-relate deffect s a t an y dos e includin g th e HD T (F O an dFl) . 2 . Thyroi d- Follicula r

cel l hypertroph y and/o r

colloida l alteratio n increase di n male s beginnin g partl y a t 160 0 pp mi n bothF O an dFl , an di n F O an dF l female s a t

640 0 ppm . A s wa s th e cas e fo r th e thyroi dchange s observe di n th e ra t

carcinogenicit y stud y an devaluate di n th e RED , thes e change s ar e mos t

likel y a n inductio n o f

oxidativ e enzyme s i n th e live r resultin g i n adecreas e decrease dseru mlevel s o f triiodothyronin e (T3 ) an d thyroxin e (T4 ) an dacompensator y increas e i n seru mlevel s o f thyroi d stimulatin g hormon e (TSH) . Th e chroni c stimulatio n o f th e thyroi dglan d b y TS H i s know n t o resul t i n follicula r

cel l tumor s i n rodents . Becaus e o f th e know n specie s difference s betwee n rodent s an dhuman s i nth e effect s o f inducer s o f

hepati c xenobioti c metabolis mo n th e thyroi dgland , thes e effect s ar e considere drat-specifi c an dhav e n o relevanc e fo r th e protectio n o f publi c health . 3 . Ovaries/oviduct s - Th e absolut e an drelativ e weight s o f ovaries/oviduct s wer e decrease di n th e F O female s a t 640 0 pp m(th e HDT) . 4 . Ovarian functio n - Altere dluteinizatio n o f th e corpor alute a(F O an dF l females ) and/o r

a n increase dincidenc e o f F l female s benig n met-/diestru s cycl e wer e observe donl y a t 640 0 pp m(th e HDT) . 5 . Semina l vesicles/coagulatio n gland s - Th e absolut e an drelativ«*vsigh t • o f th e semina l vesicles/coagulatio n gland s wer e increase dan d($400 pp m (th e HDT) . N o accompanyin g morphologica l change s wer e noted*t» » • 6 . Reproductiv e Performanc e - N o change s i n insemination , fertili^ , | gestation , o r

rearin g indice s a s wel l a t gestatio n lengt han dnumbe) " o £ litter s born wer e note da t

an y dos e includin g th e HDT . • • • • • (

< 7 . Litte r dat a- N o change s i n live r birt hindex , prenata l loss , numbe r o f ( pup s born , o r

se x rati o wer e note da t

an y dos e includin g th e HDT . A n additiona l observatio n wa s tha t o f areductio n i n th e mea n litte r siz e o f F l pup s a t th e HDT , resultin g fro msmal l reductio n i n th e numbe r

### implantatio nsites . Th e caus e o f thi s effec t i s unknown , bu t

on e possibilit y i s altere dovaria nfunction . 8 . Viabilit y an dlactatio nindice s -N o change s wer e note du p 640 0 pp m 

### (th e HOT) . 9 . Pu p weight s - A decreas e i n F 2 pu p weight s a t 160 0 pp mbeginnin g a t da y 1 4 post-partu mwa s noted , coincidin g withan onset o f ingestio no f

a soli ddie t containin g th e tes t

article . A consisten t

depressio ni npu p weigh t wa s note di nmos t

generation s wa s 640 0 pp m(th e HDT) . 10 . Vagina l openin g - A dela y wa s note da t 640 0 pp m(th e HDT ) likel y secondar y t o th e observe dbod y weigh t depressio na t

thi s hig hdose . 11 . Ano-genita l distanc e - N o effect s a t an y dos e includin g th e HDT . 12 . Uterin e weight s i n offsprin g - Absolut e weight s decrease di n F l weanling s a

t 6400 pp m(th e HDT ) an di n F2 aweanling s a t 1660 an d6400 pp m(no t dose-dependent) . Uterin e weight s relativ e t o bod y weight s wer e no t changed , reflectin g th e likelihoo dtha t th e depresse dbod y weight s wer e responsibl e fo r

th e observatio no f

lowe r absolut e uterin e weights . I nsummary , th e parenta l systemi c NOAE Lfro mthi s stud y wa s 40 0 ppm , base d o nth e onset

o f live r an dkidne y effect s at

th e nex t highes t dos e (160 0 ppm) . Th e NOAE Lfo r

reproductiv e parameter s wa s 1600 ppm . Potentiall y endocrin e relate deffect s wer e onl y note da s indicate dabov e an donl y a t th e highes t

dos e teste dfa r greate r (16X ) tha nth e NOAE Lfo r systemi c toxicity .

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