# Baye r

CropScienc e Report NO . Pag e 

# 11 1 1 72 , , Tes t Order/DC I # EDSP-109801-17 4

Title : 150-DA Y RESPONS E T O EPA' S TES T ORDE R FO R ENDOCRIN E SCREENIN G O N IPRODION E 

### Volum e 1 o f 2

Guideline : OPPT S 89 0 Guidelin e Serie s

Authors : Josep h M . Breier , Ph.D .

Date : Jun e 16 , 201 0 Repor t ID : US005 9 Baye rCropScienc e 

### P.O . Bo x

### 1201 4 Researc h Triangl e Park , N C 2770 9 • * •



### Pag e 1 o f 4 7

## Baye rCropScienc e Report NO . usoos s Pag e 2

_ STATEMEN T O F DATA CONFIDENTIALIT Y CLAIM S N o clai m o f confidentialit y i s mad e fo ran y informatio n containe d i n thi s documen t o n th e basi s o f it s fallin g withi n th e scop e o f FIFRA , Sectio n 10(d)(l)(A)(B) , o r(C) . Thi s statemen t supersede s an y othe rconfidentialit y claim s appearin g o n titl e page s o f stud y report s i n Appendi x1 .



### Roby n Kneen , Registratio n Manage r Compan yAgent : Roby n Knee n Baye rCropScienc e RegulatoryManage r Signature/Date : __Jun e 16,201 0

## Haye rCropScienc e Repor t NO . usoos g Pag e 3 GOO D LABORATOR Y PRACTIC E COMPLIANC E STATEMEN T Thi s repor

t i s no t subjec

t t o th e principle s o f 4 0 CF R 160 , Goo d Laborator

y Practice s Standard s (FIFRA) , a s promulgate d i n Federa l Register , fina l rule , Augus t 17,1989 .

Jun e 16 , 201 0 Josep h M . Breier , Ph.D . Dat e Toxicologis t Baye rCropScienc e



### Jun e 16 , 201 0 Roby n Knee n Dat e 

### Sponso r / Submitte r Baye r CropScienc e

## Baye rCropScienc e Report NO . usoos s Pag e 4 150-DA Y RESPONS E T O ERA' S TES T ORDE R FO R ENDOCRIN E SCREENIN G O N IPRODION E O n Januar y7 , 2010 , EP A issue d a Tes t Orde rfo rendocrin e screenin g o n iprodione . I n thi s Order , EP A provide s th e optio n t o cit e o rsubmi t existin g dat a t o satisf ypart o ral l o f th e testing . Specifically , EP A states , ".. . suc h hazard-relate d dat a woul d b e o f hig h qualit y an d achieve s th e objectiv e o f Tie r1 assay s t o provid e reasonabl e assuranc e tha t a chemica l doe s o rdoe s no t hav e th e potentia l t o interac t wit h th e estrogen , androgen , o rthyroi d systems. " I n respons e t o th e Order , Baye rCropScienc e (BCS ) believe s tha t existin g dat a o n iprodion e ar e adequat e t o asses s th e potentia l fo rthi s compoun d t o interac t wit h estrogen , androge n an d thyroi d systems . Muc h o f thi s existin g dat a come s fro m hig h qualit y regulatory studie s whic h hav e bee n reviewe d b y EP A an d ar e classifie d a s acceptable . Th e whol e organis m apica l endpoint s i n thes e studies , suc h a s reproductio n parameters , orga n weights , histopathology , an d sexua l development , reflect th e culminatio n o f an y effect s o n th e biologica l endpoint s bein g assesse d i n EPA' s Tie r1 endocrin e screenin g battery . Endocrine-relate d apica l endpoints , whic h hav e bee n assesse d i n th e Guidelin e studie s o n iprodion e tha t ar e functionall y equivalen t t o endpoint s assesse d i n EPA' s Tie r1 endocrin e screenin g battery , ar e summarize d i n Table s l a an d Ib . Functionall y equivalent , i n thi s context , refer s t o dat a o f a suitabl e natur e an d qualit y t o provid e th e sam e essentia l predictiv e informatio n o n a chemical , eve n i f differen t method s an d procedure s wer e used . I n additio n t o considerin g dat a provide d b y hig h qualit y Guidelin e studies , BC S ha s evaluate d informatio n reporte d i n th e literatur e whe n available . I n general , th e approac h o f Klimisc h e t al . (1997 ) ha s bee n utilize d t o evaluat e systematicall y th e qualit y o f wor k reporte d i n th e literature . Thi s approac h i s recognize d an d use d b y regulator y authoritie s includin g it s us e i n Europ e i n developin g th e Internationa l Unifor m Chemica l Informatio n Databas e (IUCLID) . Th e dat a reliabilit y criteri a presente d b y Klimisc h etal . ar e simila rt o th e criteri a recommende d b y EP A i n th e Hig h Productio n Volum e Progra m unde rTSCA . Assay s reporte d i n th e literatur e hav e als o bee n compare d t o th e relevan t assa ydescribe d i n th e OPPT S 89 0 Guidelin e Serie s t o identif y majo r difference s betwee n th e specifi c assa yinclude d i n EPA' s validatio n progra m fo rTie r1 screenin g an d th e on e reporte d i n th e literature . Estroge n Syste m Severa l assay s (estroge n recepto r(ER ) binding , ERtranscriptiona l activation , uterotrophic , puberta l female , an d fis h short-ter m reproduction ) hav e bee n include d i n th e EDS P Tie r1 battery t o asses s th e potentia l o f a chemica l t o affec t th e estroge n signalin g pathway . Whil e th e assay s describe d i n EPA's OPPT S 89 0 Guidelin e Serie s hav e no t bee n conducte d wit h iprodione , adequat e informatio n exist s t o asses s it s potentia l t o interfer e wit h th e estroge n system . A s summarize d i n Table s l a an d Ib , relevan t an d sufficien t dat a ar e availabl e fro m man y guidelin e toxicolog y studies , includin g multi-generatio n ra t reproduction , developmenta l toxicit y (ra t an d rabbit) , an d developmenta l neurotoxicit y studies , a s wel l a s subchroni c an d chroni c feedin g studie s i n th e rat , mouse , an d dog . Thes e studie s wer e conducte d i n accordanc e wit h U S EP A Guidelines , unde rGL P conditions , an d hav e bee n reviewe d an d classifie d a s acceptabl e b y th e EPA .

## Baye rCropScienc e Report NO . usoos s Pag e 5 Othe rScientifically-Relevan t Informatio n - i n vivo studies : Endpoint s fro m guidelin e studie s tha t ar e relevan t t o asses s a compound' s potentia l fo restrogeni c o ranti-estrogeni c activit y ar e liste d i n Table s l a an d Ib . Thi s include s th e result s fro m a multi generatio n reproductio n stud y i n rat s (Henwood , 1991) , a se xdifferentiatio n stud y i n rat s (Repetto Larsay , 1997) , developmenta l toxicit y studie s i n rat s (Tes h e t al. , 1986) an d rabbit s (Rodwell , 1985) , subchroni c toxicit y studie s i n mic e (Frye re t al. , 1990a ) an d rat s (Frye re t al. , 1990b) , an d chroni c toxicit y studie s i n mic e (Chamber s e t al. , 1993) , rat s (Chamber s e t al. , 1992) , an d dog s (Broadmeadow , 1984 ; Kangas , 1991) . Ke y desig n element s an d result s fro m thes e studie s ar e describe d below . I n a two-generatio n ra t reproductio n stud y (Henwood , 1991 ) conducte d accordin g t o EP A Guidelin e 83-4 , tw o litter s pe rgeneratio n wer e produced , allowin g extensiv e evaluatio n o f th e tes t substanc e o n reproductio n an d offsprin g development . I n thi s study , F O adult s wer e expose d t o iprodion e i n th e die t fo r1 0 week s prio rt o matin g an d the n throughou t mating , gestation , an d lactatio n periods . Indirec t exposur e o f th e F l offsprin g cover s th e i n uter o an d lactatio n periods , wit h direc t consumptio n o f th e treate d die t b y th e pup s startin g aroun d PN D 12 , continuin g afte rweanin g o n PN D 2 1 fo r1 0 week s befor e mating , an d throughou t mating , gestation , an d lactatio n fo rpup s selecte d t o becom e F l parents . Sinc e th e exposur e duratio n fo rth e F l generatio n exceede d tha t require d b yth e puberta l assay , thi s stud y provide s a mor e rigorou s assessmen t o f a compound' s potentia l t o affec t endocrine-relate d endpoints . Th e highes t dos e leve l teste d i n thi s reproductio n stud y wa s 300 0 pp m iprodion e i n th e diet , bu t du e t o th e leve l o f toxicit y observed , th e leve l wa s decrease d t o 200 0 pp m a t pairin g o f th e F l adult s fo rth e F 2 litters . Therefore , F l adult s receive d 200 0 pp m iprodion e i n th e die t throughou t mating , gestation , an d lactatio n fo rth e F 2 litters . Th e hig h dos e o f iprodion e administere d corresponde d t o 157. 7 mg/kg/da y fo rF O males , 212. 6 mg/kg/da y fo rF O females , 151. 9 mg/kg/da y fo rF l males , an d 189. 7 mg/kg/da y fo rF l females . Treatmen t wit h iprodion e di d no t affec t mating , o rmal e o rfemal e fertilit y i n an y generation . However , effect s o n offsprin g viabilit y an d growt h wer e see n a t 3000/200 0 pp m i n bot h th e F O an d F l generations . Althoug h n o treatment-relate d clinica l observation s wer e see n i n adul t animal s o f eithe rgeneration , offsprin g fro m th e high-dos e group s exhibite d smallnes s o f size , reduce d mobility , unkemp t appearance , hunching , o rtremors . Parenta l toxicit y wa s eviden t b y significantl y lowe r bod y weight s an d bod y weigh t change s fo rmale s and/o rfemale s fro m th e 1000- , 3000 - (FO ) an d 2,000/3,000-pp m (Fla ) groups . Al l effect s i n offsprin g wer e observe d onl y a t th e parentall y toxi c dose s o f 2000/300 0 ppm . A t 300 0 ppm , th e numbe ro f liv e pup s pe rlitte rwa s decrease d o n Da y 0 amon g Fl a litters , an d o n Day s 0 an d 4 amon g Fi b litters . Th e viabilit y indexwa s decrease d i n Fl a litters , whil e th e viabilit y an d lactatio n indice s wer e bot h decrease d amon g Fi b litters . Pu p bod y weight s wer e als o decrease d throughou t lactatio n acros s al l F l litter s a t 300 0 ppm . Fo rFl a dam s a t 200 0 ppm , th e duratio n o f th e firs t gestatio n wa s significantl y shorte rcompare d t o th e contro l group . Th e numbe ro f liv e pup s pe rlitte rwa s als o decrease d o n Da y 0 amon g F2 a litter s an d o n Day s 0 an d 4 amon g F2 b litter s a t 200 0 ppm . Th e tota l numbe ro f pup s delivere d pe rlitte r wa s decrease d amon g al l F 2 litter s i n thi s dos e group . I n general , pu p bod y weight s wer e als o decrease d throughou t lactatio n acros s al l F l litter s a t 200 0 ppm . Th e numbe ro f implantatio n site s

## Baye rCropScienc e Report NO . usoos s Pag e 6 pe rdam , post-implantatio n los s pe rlitter , an d pu p se xratio s wer e simila racros s al l treatmen t group s fo rbot h litter s withi n eac h generation . N o anomalie s o f externa l genitali a wer e note d fo rF l o rF 2 pups . Ther e wer e n o gros s o rhistopathologica l change s observe d i n an y reproductiv e organ s examine d (cervix , coagulating gland , prostate , epididymides , semina l vesicles , testes , uterus , o r vagina) , pituitary , o rlive rfo radul t animal s o f eithe rse xo rgeneration . I n additio n t o th e multigeneratio n study , a stud y wa s conducte d t o asses s th e potentia l effec t o f iprodion e o n se xdifferentiatio n (Repetto-Larsay , 1997) . Whe n administere d dail y fro m gestatio n da y6 t o 1 9 a t dose s o f 0,20,120 , o r25 0 mg/kg/day , iprodion e produce d sever e materna l toxicit y a t 25 0 mg/kg/da y includin g mortality . Furthe revidenc e o f materna l toxicit y a t 12 0 an d 25 0 mg/kg/da y consiste d o f statisticall y significan t reduction s i n bod y weigh t gai n an d correcte d bod y weigh t change , a s wel l a s macroscopicall yenlarge d adrenal s i n 7/2 5 an d 20/2 5 dams , respectively . Cesarea n section s performe d o n gestatio n da y 2 0 showe d tha t iprodion e ha d n o effec t o n grou p mean s an d litte raverage s fo rcorpor a lutea , implantations , litte rsize , liv e fetuses , an d earl y an d lat e resorption s a t an y dos e leve l tested . Mea n feta l weight s wer e statisticall y lowe ra t 25 0 mg/kg/da y fo rbot h sexes . N o morphologicall y abnorma l differentiatio n i n externa l an d interna l genitali a wa s foun d i n an y iprodione-expose d fetus . Th e externa l se xo f fetuse s wa s identica l t o th e se x determine d a t interna l examination , an d th e se xrati o wa s withi n norma l value s fo ral l treate d groups . I n femal e fetuses , a sligh t increas e i n th e anogenita l inde x(i.e . anogenita l distance/feta l bod y weight ) onl y wa s observe d a t 25 0 mg/kg/day , a dos e o f iprodion e whic h resulte d i n significan t materna l toxicity . Result s fo rmal e fetuse s ar e discusse d unde rth e sectio n o n th e androge n syste m below . Developmenta l toxicit y studie s i n rat s (Tes h e t al. , 1986 ) an d rabbit s (Rodwell , 1985 ) wer e conducte d accordin g t o guideline s 83-3(a ) an d 83-3(b ) wit h dail y dosin g o f dams/doe s fro m gestatio n da y 6 t o 1 6 an d fro m gestatio n da y 6 t o 18 , respectively . I n rats , treatmen t wit h iprodion e u p t o 20 0 mg/kg/da y di d no t affec t th e numbe ro f implantations , liv e young , resorptions , pre - an d post-implantatio n losses , an d mea n placenta l weights . A t 20 0 mg/kg/da y i n rats , ther e wa s a n increase d incidenc e o f spac e betwee n th e bod y wal l an d organs , indicatin g sligh t feta l immaturity , bu t feta l evaluation s showe d n o evidenc e o f an y advers e morphogeni c chang e i n respons e t o treatmen t wit h iprodione . I n th e rabbi t developmenta l study , th e numbe ro f viabl e fetuse s wa s slightl y decreased , whil e post-implantatio n los s wa s slightl y increase d a t th e hig h dos e o f 20 0 mg/kg/day ; thes e effect s wer e du e t o tw o female s tha t ha d tota l litte rresorption . Th e hig h dos e o f 20 0 mg/kg/da y als o resulte d i n significan t mea n materna l bod y weigh t los s throughou t th e entir e treatmen t perio d an d a n increase d rat e o f abortions , indicatin g tha t th e decreas e i n th e numbe ro f viabl e fetuse s an d th e sligh t increas e i n post-implantatio n los s wer e du e t o significan t materna l toxicit y a t thi s dose . Th e mea n numbe ro f implantatio n sites , corpor a lutea , feta l bod y weight , an d feta l se xratio s wer e no t affecte d a t an y dos e o f iprodione . Furthermore , n o treatment-relate d externa l anomalie s o rmalformation s wer e observe d i n fetuses . Subchroni c toxicit y studie s wer e conducte d i n mic e (Frye re t al. , 1990a ) an d rat s (Frye re t al. , 1990b ) accordin g t o guidelin e 82-1 . Effect s o n ovarie s an d uteru s wer e observe d i n bot h studie s bu t onl y a t level s tha t eithe rexceede d th e limi t dos e o f 100 0 mg/kg/da y (mice ) o rexceede d a maximu m tolerate d dos e (rats) . I n mice , decrease d mea n absolut e uterin e weight s an d uterin e atroph y wer e

## Baye rCropScienc e Report NO . usoos 9 Pag e 7

_ observe d a t 600 0 pp m (approximatel y 1303 mg/k g bod y weight/day ) an d 12000 pp m (approximatel y 260 8 mg/k g bod y weight/day) . Ovaria n weight s wer e als o decrease d a t 12000 pp m an d a n increase d incidenc e o f absenc e o f corpor a lute a wa s observe d a t 600 0 an d 12000 ppm . Thes e finding s wer e see n onl y a t dose s exceedin g th e limi t dos e o f 100 0 mg/kg/da y an d wer e no t see n a t eithe r1500 o r300 0 ppm . Increase d mea n adrena l weight s wer e see n a t 150 0 pp m an d higher , bu t wer e withou t a clea rdose-respons e relationship . I n rats , administratio n o f iprodion e vi a th e die t fo r1 3 week s resulte d i n reduce d mea n absolut e ovaria n weight s a t 200 0 an d 300 0 pp m an d uterin e weigh t a t 300 0 ppm . Macroscopically , pal e adrenal s an d uterin e thinnes s wer e note d i n al l female s at 300 0 pp m an d i n severa l animal s at 200 0 ppm . Microscopically , enlargemen t o f th e cell s o f th e zon a glomerulos a i n th e adrenals , uterin e atrophy , an d a reduce d numbe ro f corpor a lute a wer e see n a t 200 0 an d 300 0 ppm . Al l o f thes e effects , however , occurre d i n conjunctio n wit h significan t decrease s i n overal l bodyweigh t gai n see n i n female s throughou t th e cours e o f th e stud y (overal l gai n 30 % lowe ra t 200 0 pp m an d 60 % lowe ra t 300 0 ppm) , indicatin g tha t thes e change s ma yb e secondar yt o systemi c toxicit y a t dose s whic h exceede d th e maximu m tolerate d dose . Chroni c toxicit y studie s wer e conducte d i n dog s (Broadmeadow , 1984 ; Kangas , 1991 ) accordin g t o guidelin e 83-l(b) . Afte r5 2 week s o f treatmen t a t 360 0 ppm , a n increas e i n absolut e an d relativ e adrena l weight s an d fa t vacuolatio n i n th e zon a fasciculat a an d palli d zon a fasciculat a an d zon a glomerulos a wer e observed . Thes e finding s i n th e adrenal s wer e no t observe d a t 60 0 pp m an d lower . Pituitary , ovary , an d uteru s weight s wer e unaffecte d b y treatment . Further , n o treatment relate d microscopi c change s wer e see n i n th e pituitary , ovaries , uterus , o rmammary gland . I n mice , female s administere d 400 0 pp m (approximatel y 79 3 mg/k g bod y weight/day ) fo r9 9 week s exhibite d lowe rabsolut e an d relativ e uterin e an d ovaria n weights , bu t thes e change s wer e correlate d t o significantl y lowe rtermina l bod y weigh t (Chamber s e t al. , 1993) . Th e hig h dos e o f 400 0 pp m iprodion e resulte d i n lowe rmea n bod y weigh t gain s amon g female s durin g week s 18-4 5 o f treatment . Adrena l weigh t wa s no t affecte d b y treatment , bu t hypertroph y o f th e cell s o f th e zon a fasciculat a wa s see n i n female s a t 400 0 pp m a t interi m sacrific e only . A t th e termina l sacrifice , a n increase d incidenc e o f ovaria n luteoma s an d leutinizatio n an d absenc e o f corpor a lute a wer e mor e frequentl y see n a t 400 0 ppm . N o lexicologicall y significan t finding s wer e observe d microscopicall y i n th e uteru s (includin g cervix) , vagina , pituitary , an d mammar y gland . I n a two-yea r feedin g stud y i n rats , n o treatment-relate d effect s wer e observe d o n endocrine-relate d tissue s (ovary , uterus , cervix , vagina , adrenals , mammar y gland , an d pituitary ) i n female s receivin g dietar y level s u p t o 160

0 pp m (Chamber s eta/. , 1992) . Othe rScientifically-Relevan t Informatio n - i n vitr o studies : A stud y b y Anderse n e t al . (2002 ) report s dat a fro m experiment s usin g MCF- 7 cell s t o asses s potentia l effect s o f pesticide s o n th e estroge n system . Althoug h iprodion e wa s liste d a s bein g teste d i n thes e assays , onl y th e cytotoxicit y result s wer e reported . Du e t o th e lac k o f experimenta l details , dose-respons e assessment , an d lac k o f informatio n o n th e result s fo riprodione , thi s stud y doe s no t mee t th e criteri a a s describe d b y Klimisc h e t al . (1997 ) an d shoul d b e considere d a s unreliable .

## Baye rCropScienc e Repor t NO . usoos s Pag e 8 I n conclusion , ovaries , uterus , an d adrenal s hav e bee n identifie d a s targe t organ s followin g exposur e t o iprodione . I n subchroni c studies , effect s o n ovarie s an d uteru s wer e observe d onl y a t dose s whic h eithe rexceede d a limi t dos e o f 100 0 mg/kg/da y o rexceede d a maximu m tolerate d dose . I n a long-ter m stud y i n mice , effect s i n th e ovaries , includin g a n increas e i n luteomas , wer e observe d a t th e highes t leve l tested . Effect s i n adrenal s wer e als o observe d a t hig h dos e level s i n rats , mic e an d dogs . Mechanisti c studie s i n mal e rat s indicat e tha t iprodion e interfere s wit h th e biosynthesi s o f steroi d hormones , whic h coul d als o accoun t fo rman y o f th e change s observe d i n females . Androge n Syste m Assay s (androge n recepto r(AR ) binding , Hershberger , puberta l male , an d fis h short-ter m reproduction ) hav e bee n include d i n th e EDS P Tie r1 batter y t o asses s th e potentia l o f a chemica l t o affec t th e androge n signalin g pathway . Endpoint s fro m guidelin e studie s tha t ar e relevan t t o asses s a compound' s potentia l fo randrogeni c o ranti-androgeni c activit y ar e liste d i n Table s l a an d Ib . A s iprodion e induce d Leydi g cel l tumor s i n mal e rat s afte rlifetim e exposure , severa l studie s hav e bee n conducte d t o examin e underlyin g mechanism s relate d t o endocrin e systems . Further , AR , Hershberge ran d mal e puberta l assay s wit h iprodion e hav e bee n publishe d i n th e literature . Th e informatio n availabl e fro m bot h unpublishe d studie s an d th e literatur e i s discusse d belo w an d i s sufficien t fo rEP A t o asses s th e potentia l effect s o f iprodion e o n th e androge n system . A R Bindin g Assay : Th e A R bindin g assa yi s intende d t o determin e th e abilit y o f a chemica l t o compet e wit h [ 3 H ] ligan d fo rbindin g i n ra t ventra l prostat e tissu e homogenate . Th e stud y desig n o f th e A R bindin g assa y conducte d b y Fai l e t al . (1994 ) utilize d ventra l prostat e fro m intac t C D Spragu e Dawle y rat s rathe r tha n castrate d rat s a s recommende d i n OPPT S Guidelin e 890.1150 . A s positiv e control s gav e th e expecte d results , thi s deviatio n di d no t affec t th e integrit y o f th e stud y o rth e abilit y t o evaluat e th e potentia l fo riprodion e t o bin d t o th e AR . Th e relativ e bindin g assa ywa s performe d b y addin g increasin g concentration s o f competitor , eithe rth e syntheti c androge n R188 1 (positiv e control) , dihydrotestosteron e (DHT) , testosterone , flutamide , hydroxyflutamide , iprodione , o rseve n iprodion e metabolites , t o a fixe d concentratio n o f 3 H-R188 1 (2. 5 n M instea d o f 1 n M recommende d b yth e tes t guideline) . Th e assa yevaluate d seve n concentration s o f iprodione , rangin g fro m 1 u, M t o 1 m M teste d i n duplicate , an d demonstrate d tha t iprodion e cause d little , i f any , displacemen t o f 3 H R1881 . Scatchar d plo t analysi s indicate d tha t iprodion e exhibite d extremel y lo w noncompetitiv e binding . Th e principa l androgen s testosteron e an d DHT , th e activ e metabolit e o f testosterone , boun d wit h relativ e bindin g affinitie s o f 35 % an d 100% , respectively , an d demonstrat e th e lab' s abilit y t o detec t positiv e compounds . I n addition , potentia l A R bindin g wit h iprodion e wa s evaluate d i n CO S cell s expressin g th e huma n A R (hAR ) i n a competitiv e whol e cell-bindin g assa y(Blyston e e t al. , 2009) . I n thi s study , iprodion e wa s assesse d acros s te n concentration s ( 1 - 20 0 u, M i n triplicate ) fo rit s abilit y t o displac e 3 H-R1881 . Simila rt o result s see n b y Fai l etal . (1994) , iprodion e exhibite d lo w potenc y i n displacin g 3 H-R1881 , bindin g t o th e A R wit h a n IC 5 0 = 86. 0 u.M .

## Baye rCropScienc e Report NO . usoos s Pag e 9 Th e abilit y o f iprodion e t o bin d th e hA R wa s furthe revaluate d i n competitio n experiment s usin g a constan t amoun t o f 3 H-R1881 , DH T an d testosteron e a s ligand s fo rth e AR , an d eigh t tes t compound s tha t include d iprodion e an d seve n metabolite s (d e Groene , 1999) . I n thi s study , androge n receptor s wer e isolate d fro m th e huma n cel l lin e T47 D fo rus e i n th e competitiv e bindin g assay . Seve n concentration s o f iprodione , th e metabolite s RP3249 0 an d RP36115 , an d DH T teste d i n th e bindin g assa ycovere d si xorder s o f magnitude , rangin g fro m 10" 1 1 -10" 5 mol/l . Fo ral l othe r tes t an d referenc e compounds , concentration s teste d range d fro m 10" 1 1 -10" 4 mol/l . Result s indicate d tha t unlabelle d R188 1 boun d wit h a n IC 5 0 o f 1. 7 nmol/l , whic h wa s i n th e expecte d range . DH T an d testosteron e displace d 3 H-R188 1 wit h IC 5 0 value s o f 18 7 nmol/ l an d 69 4 nmol/l , respectively . On e metabolite , RP25040 , showe d wea k displacemen t o f 3 H-R1881 , bu t i t wa s no t possibl e t o calculat e a n IC 5 0 valu e becaus e onl y th e highes t concentration s o f 10" 4 an d 10'

5 mol/ l cause d som e displacement . Al l othe rtes t compounds , includin g iprodione , wer e no t abl e t o compet e wit h 3 H-R188 1 fo rth e A R (d e Groene , 1999) . Thes e competitiv e bindin g studie s provid e sufficien t dat a t o evaluat e th e abilit y o f iprodion e t o bin d th e A R an d fulfil l th e requiremen t fo ra competitiv e A R bindin g stud y a s par t o f th e tes t order . Displacemen t bindin g i n thre e differen t tes t system s fro m thre e differen t laboratorie s indicate s tha t iprodion e bind s wit h ver y lo w affinit y t o th e AR . I n addition , iprodion e wa s assesse d fo ragonis t an d antagonis t activit y i n a n AR-mediate d transcriptiona l activatio n assa yi n th e stabl y transfecte d MMTV luciferas e reporte rMDA-kb 2 cel l lin e (teste d fro m 10 0 p M t o 1 0 u, M b y Blyston e e t at. , 2007 ; teste d fro m 1 t o 30 0 u M b y Blyston e e t al , 2009) . A t 30 0 u,M , iprodion e cause d cytotoxicit y a s measure d b y th e MT T assa yan d appeare d t o crystalliz e i n th e media . Whe n teste d alone , iprodion e di d no t exhibi t agonis t activit y a s n o increas e i n luminescenc e wa s observed . Althoug h th e author s sugges t tha t iprodion e ma y ac t a s a n A R antagonis t base d o n a n IC 5 0 o f 245. 9 u. M fo rth e decreas e i n DT H induction , thi s valu e i s clos e t o th e cytotoxi c concentratio n o f 30 0 u,M . Thes e result s suppor t tha t iprodion e ha s a ver y lo w affinit y fo r A R binding . Hershberge rassay : A s par t o f a serie s o f experiment s t o asses s th e effec t o f iprodion e o n th e androge n system , a Hershberge rassa ywa s conducte d t o evaluat e th e effec t o f iprodion e o n androgen-sensitiv e tissu e weight s i n castrate d mal e rat s (Blyston e e t al. , 2009) . Onl y th e anti-androgeni c part o f th e Hershberge rassa yha s bee n conducte d wit h iprodion e i n thi s study . However , th e OPPT S 890.140 0 Guidelin e states , "Experienc e indicate s tha t xenobioti c androgen s ar e rare rtha n xenobioti c anti androgens, " an d ther e i s n o literatur e evidenc e suggestin g androgeni c activit y o f iprodione . I n thi s study , mal e Sprague-Dawle y rat s wer e castrate d o n PN D 42 . Beginnin g o n PN D 49 , animal s receive d iprodion e (0 , 50,100 , o r20 0 mg/k g bod y weight/day ) b y gavag e an d 10 0 u g testosteron e propionat e (TP ) sc . Afte r10-1 1 day s o f treatment , animal s wer e necropsie d fo rth e followin g orga n weights : glan s penis , ventra l prostate , semina l vesicle , Cowper' s gland , levato ran i + bulbocavernosu s muscl e (LABC) , liver , adrenals , an d kidneys . Iprodion e significantl y decrease d ventra l prostat e weigh t a t 20 0 mg/kg/da y an d LAB C a t al l doses ; adrena l an d live rweight s wer e significantl y increase d a t 20 0 mg/kg/da y an d 10 0 an d 20 0 mg/kg/day , respectively . Thi s stud y als o evaluate d seru m testosteron e an d leutinizin g hormon e (LH ) concentration s a t th e en d o f th e

## Baye rCropScienc e Report NO . usoos g Pag e 1 0 treatmen t period . Iprodion e di d no t affec t seru m level s o f eithe rhormon e a t an y dos e level . Th e castratio n protocol , treatmen t parameters , an d endpoin t analysi s use d i n thi s stud y ar e i n agreemen t wit h OPPT S 890.140 0 tes t guidelines . However , a concurren t positiv e contro l (flutamide ) an d a vehicl e onl y contro l wer e no t include d i n th e stud y a s recommende d b y th e OPPT S guideline . Althoug h th e lac k

o f thes e control s decrease s th e leve l o f confidenc e i n th e result s fo riprodione , th e observe d finding s ar e consisten t wit h th e overal l toxicolog y profil e fo rthi s compound . Base d o n thi s an d th e absenc e o f an y evidenc e o f androgeni c activit y i n th e iprodion e database , th e requiremen t fo rth e androgeni c portio n an d th e testin g requiremen t fo ra Hershberge rassa yshoul d b e waived . Puberta l assay : Th e puberta l assa yi s designe d t o detec t effect s o n puberta l developmen t an d thyroi d function . A mal e puberta l assa ywa s conducte d i n whic h Sprague-Dawle y weanlin g rat s wer e dose d b y gavag e wit h 0 , 50,100 , o r20 0 mg/k g bod y weight/da y iprodion e fro m post-nata l da y 2 3 - 51/5 2 (Blyston e e t a/. , 2007) , th e sam e duratio n perio d a s suggeste d i n th e OPPT S 890.150 0 tes t guidelines . I n thi s study , bloo d sample s wer e take n fo rhormon e measurement s (testosterone , androstenedione , 17ahydroxyprogesterone , progesterone , aldosterone , corticosterone , an d LH ) an d orga n weight s (liver , paire d kidney , paire d adrenals , glan s penis , ventra l prostate , semina l vesicle , LABC , paire d Cowper' s gland , paire d testes , an d paire d epididymides ) wer e evaluated . Iprodion e significantl y delaye d preputia l separatio n (PPS ) b y 2 an d 2. 8 day s a t 10 0 an d 20 0 mg/kg/day , respectively . At 20 0 mg/k g bod y weight/day , semina l vesicl e an d epididymide s weight s wer e decreased , whil e adrena l weight s wer e increased . Seru m testosteron e (al l dos e levels) , androstenedion e (100 an d 20 0 mg/kg bod y weight/day) , an d 17a-hydroxyprogesteron e (100 an d 20 0 mg/k g bod y weight/day ) wer e decreased , wherea s L H wa s unaffected . I n general , th e result s o f thi s stud y ar e consisten t wit h othe rstudie s suggestin g tha t iprodion e affect s steroidogenesi s (se e sectio n o n steroidogenesi s below) . Thi s stud y i s i n clos e agreemen t wit h OPPT S 890.150 0 tes t guidelines , an d therefor e suffice s t o provid e th e require d informatio n o n th e potentia l fo riprodion e t o interfer e wit h mal e puberta l development . Althoug h th e thyroi d wa s no t investigate d i n thi s study , result s fro m adul t animal s indicat e tha t th e thyroi d i s no t a targe t orga n fo riprodion e (se e sectio n belo w o n th e thyroi d system) . Othe rScientificall y Relevan t Information : Endpoint s fro m guidelin e studie s tha t ar e relevan t t o th e i n vitr o an d i n viv

o assay s i n EPA' s Tie r1 screenin g battery ar e show n i n Tabl e l a an d b . Al l relevan t reproductiv e effect s i n th e two-generatio n reproductio n stud y i n rat s (Henwood , 1991 ) wer e discusse d above ; a t concentration s u p t o 300 0 pp m administere d vi a th e diet , ther e wer e n o histopathologica l effect s specifi c t o an y mal e tissues , includin g epididymides , coagulatin g gland , prostate , semina l vesicles , o rtestes . Relevan t reproductiv e endpoint s fro m developmenta l toxicit y studie s i n rat s (Tes h era/. , 1986 ) an d rabbit s (Rodwell , 1985 ) wer e als o describe d above . I n a se x differentiatio n stud y i n rats , a t Cesarea n sectionin g o n gestatio n da y 20 , anogenita l distanc e wa s decrease d i n mal e fetuse s a t th e mid - (12 0 mg/kg/day ) an d high-dos e (25 0 mg/kg/day ) group s compare d t o vehicl e control s (Repetto-Larsay , 1996 ; MRI D 44365001) . However , thes e effect s occurre d a t dos e level s tha t induce d materna l toxicit y durin g a critica l perio d o f developmen t (gestatio n day s 16-20) . Further , n o difference s i n th e anogenita l inde xwer e observe d a t an y dos e

# Baye r

CropScienc e Repor t NO . usoos g Pag e 1 1 level . Wol f e t al . (1999 ) reporte d tha t iprodion e administere d a t 10 0 mg/k g bod y weight/da y fro m gestatio n da y 1 4 t o lactatio n da y 3 di d no t demasculiniz e o rfeminiz e mal e ra t pups , furthe r supportin g th e lac k

o f a n anti-androgeni c effec t mediate d b yth e A R o n sexua l differentiation . I n a subchroni c mous e stud y a t 600 0 an d 1200 0 pp m (equivalen t t o 106 6 an d 213 0 mg/kg/day) , a n increas e i n absolut e adrena l weigh t wa s observe d i n males . Histopathologica l change s i n adrenal s wer e note d onl y a t 1200 0 pp m an d consiste d o f enlarge d cell s an d vacuolatio n o f cell s i n th e zon a glomerulos a an d fasciculat a (Frye re t al. , 1990a) . I n a subchroni c ra t stud y (Frye re t al. , 1990b) , th e tw o highest level s teste d o f 200 0 an d 300 0 pp m cause d a significan t reductio n i n weigh t gai n i n male s ove rth e duratio n o f th e stud y (approximatel y 40 % lowe ra t 200 0 pp m an d 75 % lowe ra t 300 0 ppm) . Treatment-relate d microscopi c change s wer e see n i n th e testes , prostate , an d semina l vesicle s a t 300 0 pp m an d consiste d o f increase d incidence s o f interstitia l cel l hyperplasia , atrophy , an d reduce d secretion , respectively . I n th e adrenal , fin e vacuolatio n i n th e zon a fasciculat a an d enlarge d cell s i n th e zon a glomerulos a wer e observe d i n male s a t 200 0 an d 300 0 pp m an d coul d b e secondar yt o overt toxicit y o rrelate d t o effect s o n steroidogenesi s note d below . I n a chroni c stud y i n mice , absolut e adrena l weigh t wa s increase d i n male s afte r5 2 week s o f treatmen t a t 400 0 pp m bu t n o effec t wa s observe d a t stud y terminatio n afte r9 9 week s an d n o microscopi c change s wer e note d a t eithe rth e interi m o rfina l sacrific e (Chamber s eta/. , 1993) . Pituitar y an d teste s (wit h epididymides ) weight s wer e unaffecte d b y treatment . I n th e testes , generalize d vacuolatio n an d hypertroph y o f interstitia l cell s wa s eviden t a t 400 0 pp m a t th e interi m sacrific e an d a t 80 0 an d 400 0 pp m a t th e fina l sacrifice . I n a chroni c ra t study , administratio n o f iprodion e vi a th e die t u p t o 160 0 pp m (equivalen t t o 6 9 mg/kg/da y i n males ) ha d n o effec t o n pituitary o radrena l weight s a t interi m o rfina l sacrific e interval s (Chamber s e t al . 1992) . Absolut e an d relativ e teste s weigh t (wit h epididymides ) wa s increase d a t fina l sacrific e a t 160 0 pp m an d corresponde d t o a n increase d incidenc e o f testicula rtumors . Histopathologica l examinatio n o f mal e reproductiv e organ s reveale d interstitia l cel l hyperplasia , reduce d number s o f spermatozo a i n th e epididymides , an d a n increase d incidenc e o f decrease d colloida l secretio n i n th e semina l vesicle s a t 30 0 an d 160

0 ppm . Atroph y o f seminiferou s tubules , absence o f spermatozo a i n som e cases , an d increase d incidenc e o f prostat e atroph y wer e als o observe d a t 1600 ppm . I n addition , a t 160 0 ppm , interstitia l cel l (Leydi g cell ) tumor s wer e observed . Microscopi c change s i n adrenal s fro m male s include d increase d incidence s o f enlarge d cell s i n zon a glomerulos a an d vacuolatio n i n th e zon a fasciculat a a t 160

0 pp m (interi m an d fina l sacrifices ) an d vacuolatio n o f th e zon a reticulari s a t 30 0 (fina l sacrific e only) an d 160 0 pp m (interi m an d fina l sacrifices) . I n dog s administere d iprodion e vi a th e die t fo r5 2 weeks , a n increas e i n absolut e an d relativ e adrena l weight s wa s observe d i n male s a t 360 0 ppm , th e highes t leve l teste d (Broadmeado w e t al , 1984) . Microscopicall y a t 360 0 pp m i n males , bot h th e zon a glomerulos a an d th e zon a fasciculat a ha d a n increase d dept h an d th e cell s wer e large , wit h a pal e cytoplasm . Significan t decrease s wer e note d i n absolut e prostat e weight s a t 60 0 pp m an d absolut e an d relativ e prostat e weight s a t 360 0 pp m bu t n o microscopi c chang e wa s observed . Pituitary an d teste s weight s wer e comparabl e t o control , an d n o treatment-relate d microscopi c change s wer e observe d i n testes , epididymides , semina l vesicles , o rpituitary . I n a late rchroni c (52-week ) stud y conducte d u p t o 60 0 ppm , n o effec t wa s detecte d o n prostat e weigh t (Kangas , 1991) .

## Baye rCropScienc e Report NO . usoos s Pag e 1 2 Studie s conducte d i n rat s t o investigat e th e mechanis m fo rth e inductio n o f Leydi g cel l tumor s als o showe d variou s effect s o n mal e reproductiv e organs . Hormon e measurement s mad e i n thes e studie s ar e discusse d belo w i n th e sectio n o n steroidogenesis . Significan t increase s i n absolut e an d relativ e (t o bod y weight ) adrena l weights , increase s i n relativ e teste s weights , decrease s i n absolut e an d relativ e tota l accessor yse xorga n (TASO ; include s prostat e an d semina l vesicles ) weigh t an d lowe rabsolut e tota l epididymide s weight s wer e eviden t afte rtreatmen t a t 300 0 pp m (175 mg/kg bod y weight/day ) vi a th e die t fo r2 , 7 , o r1 4 day s (Fai l e t al. , 1996a ; 1996b) . A n earlie rstud y als o demonstrate d tha t a hig h dos e o f iprodion e (60 0 mg/kg bod y weight/day ) administere d b y gavag e resulte d i n decrease d siz e o f th e prostate , semina l vesicles , an d TAS O afte r1 5 o r3 0 days o f treatmen t an d decrease d epididymide s weight s an d increase d adrena l weight s afte r3 0 days . BrD U labelin g reveale d a significan t dose-relate d increas e i n Leydi g cel l proliferatio n afte r1 4 day s o f iprodion e treatmen t b y gavag e a t 70 , o r30 0 mg/kg/da y (Kennel , 2002a) . Th e toxicolog y databas e indicate s tha t th e adrenal s an d mal e reproductiv e organ s hav e bee n identifie d a s targe t organ s i n th e androge n syste m followin g exposur e t o iprodione . I n subchroni c studies , effect s o n th e adrenals , testes , prostate , an d semina l vesicle s wer e observe d onl y a t dose s whic h eithe rexceede d a limi t dos e o f 100 0 mg/kg/da y (mouse ) o rwer e secondar y t o sever e decrease s i n bod y weigh t gai n (rat) . Long-ter m studie s i n mic e an d rat s indicat e effect s i n th e adrenal s an d testes , includin g a n increas e i n Leydi g cell tumor s i n rat s observe d a t th e highes t leve l tested . Effect s i n adrenal s wer e als o observe d a t hig h dos e level s i n dogs . Mechanisti c studie s i n mal e rat s describe d belo w indicat e tha t iprodion e interfere s wit h th e biosynthesi s o f steroi d hormones . Thyroi d Syste m Assay s (ra t pubertal s an d amphibia n metamorphosis ) hav e bee n include d i n th e EDS P Tie r1 screenin g battery t o asses s th e potentia l o f a chemica l t o interfer e wit h thyroi d function . Althoug h thes e assay s a s specificall y describe d i n EPA' s OPPT S 89 0 Guidelin e Serie s hav e no t bee n conducte d wit h iprodione , adequat e informatio n exist s t o asses s iprodione' s potentia l t o interfer e wit h th e hypothalamic-pituitary-thyroida l (HPT ) axis . A s describe d below , informatio n o n thyroi d weigh t an d histolog y ar e availabl e fro m guidelin e studie s includin g lifetim e feedin g studie s i n rat s an d mice , an d a chroni c do g study . Othe rScientificall y Relevan t Information : N o effec t o n thyroi d weigh t wa s see n i n subchronic toxicit y studie s i n mic e (Frye re t al. , 1990a ) o r rat s (Frye re t al. , 1990b) . A 52-wee k stud y i n dog s als o showe d n o effec t o n thyroi d weigh t o r histopatholog y (Broadmeadow , 1984) . I n long-ter m studie s i n mic e an d rats , absolut e an d relativ e thyroi d weight s fo rbot h sexe s wer e unaffecte d b y treatmen t (Chamber s eta/. , 1993 ; 1992) . However , analysi s o f absolut e thyroi d weigh t usin g bod y weigh t a s a covariat e showe d a sligh t increas e a t th e highes t level s teste d i n mal e mic e an d mal e rat s a t stud y termination . I n th e absenc e o f histopathologica l findings , th e sligh t increase s i n thyroi d weigh t whe n adjuste d fo rbod y weigh t ar e no t considere d toxicologicall y significant . Th e significantl y lowe rabsolut e thyroi d weight s observe d i n femal e mic e a t th e 53-wee k interi m sacrific e wer e attribute d t o a n unusuall y hig h

## Baye rCropScienc e Report NO . usoos s Pag e 13

_ contro l valu e an d wer e no t considere d t o b e treatment-related . Althoug h thyroi d hormon e dat a ar e no t available , th e absenc e o f histopathologica l changes i n th e thyroi d followin g subchroni c an d chroni c exposur e a t maximall y tolerate d level s indicate s tha t iprodion e i s no t likel y t o affec t thyroi d hormon e levels . Therefore , th e existin g dat a ar e adequat e t o asses s an y potentia l impac t o f iprodion e o n th e thyroi d system . Amphibia n Metamorphosi s (Frog) : Th e Amphibia n Metamorphosi s Assa y(AMA ) involve s th e us e o f tadpole s t o determin e i f chemical s affec t th e hypothalamic-pituitary-thyroi d (HPT ) axi s durin g metamorphosi s an d consequentl y result s i n developmenta l effect s (USEPA , 2010) . Th e AM A represent s a generalize d vertebrat e mode l t o th e exten t tha t i t i s base d o n th e conserve d structur e an d functio n o f th e HP T axi s (USEPA , 2009) . A revie w o f existin g thyroi d assay s wa s reporte d b yOEC D i n a detaile d revie w pape r(OECD , 2006) . Thi s report point s ou t th e conserve d natur e o f th e HP T axis . Potentia l effect s o n th e thyroi d hav e alread ybee n assesse d i n subchroni c an d chroni c guidelin e studie s wit h conserve d model s s o a n additiona l evaluatio n wit h a n additiona l conserve d specie s i s unnecessaryt o evaluat e th e thyroi d activit y potentia l i n vertebrates . Th e existin g dat a fro m studie s i n thre e specie s (rats , mice , an d dogs ) shoul d b e deeme d adequat e fo ra screenin g leve l thyroi d evaluation . Therefore , th e conduc t o f a n AM A i s unnecessary , woul d resul t i n th e expenditur e o f resource s an d unnecessar ysacrific e o f animals , an d a waive rshoul d b e granted . Steroi d Synthesi s Chroni c exposur e o f iprodion e t o rat s resulte d i n th e formatio n o f Leydi g cel l tumors . I n th e interes t o f identifyin g a mod e o f actio n t o accoun t fo rthi s tumorigeni c response , severa l i n viv o an d i n vitr

o mechanisti c studie s wer e conducte d wit h iprodione . Althoug h th e specifi c aromatas e an d steroidogenesi s assay s require d i n th e EDS P Tie r1 screen s wer e no t performe d (OPPT S 890.120 0 an d OPPT S 890.1550 , respectively) , th e result s fro m th e mechanisti c studie s provid e pertinen t informatio n an d ar e adequat e t o asses s potentia l effect s o f iprodion e o n steroi d hormon e synthesis . I n addition , th e endpoint s discusse d abov e fo rth e estroge n an d androge n system s ar e als o relevan t forassessmen t of a compound' s potentia l to interfer e wit h steroidogenesis . Thes e endpoint s are show n i n Tabl e l a an d thos e considere d a s functionall y equivalen t t o addres s th e purpos e o f th e aromatas e an d steroidogenesi s assay s ar e indicated . I n viv o Mechanisti c Studies : Iprodion e ha s bee n show n t o caus e a dose-dependen t decreas e i n mea n plasm a testosteron e level s i n rat s administere d a singl e dos e o f 7 0 o r30 0 mg/k g bod y weigh t fro m 0. 5 - 6 hour s pos t dosin g (Chuzel , 1998 ; Chuzel , 2001) . Th e decrease s i n plasma testosteron e returne d t o baselin e concentration s b y 2 4 hour s pos t dosing , presumabl y a s a consequenc e o f th e compensator y increas e i n plasm a LH , whic h wa s significantl y increase d 2- 4 hour s afte rdosing . Th e dose s o f iprodion e teste d i n thes e studie s wer e analagou s t o thos e a t whic h benig n Leydi g cel l tumor s wer e induce d i n th e ra t 2-yea rcarcinogenicit y stud y bioassa y(7 0 mg/kg ) (Chamber s e t at. , 1992 ) an d

## (* A



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## yBaye rCropScienc e Report NO . usoos s Pag e 1 4 thos e producin g Leydi g cel l hyperplasi a i n a 90-da y ra t stud y (30 0 mg/kg ) (Frye re t al , 1990b ; Gopinat h an d Ames , 1993) . Moreover , th e transient decreas e i n testosteron e plasm a level s i s consisten t wit h change s i n th e concentratio n o f iprodion e achieve d i n th e plasm a an d teste s whic h peake d 2-1 0 hour s afte ra singl e dos e o f 7 0 mg/kg (Fisher , 1998) . Followin g repeate d ora l administratio n o f iprodion e fo r1 4 day s a t 6 , 70 , o r30 0 mg/kg bod y weight/day , significan t decrease s i n plasm a testosteron e wer e see n a t 7 0 mg/kg bod y weight/da y (pea k effec t tim e 2 hours ) an d 30 0 mg/kg bod y weight/da y (pea k effec t tim e 4 hours ) (Kennel , 2002b) . Concurren t increase s i n L H wer e see n at al l dos e levels , wit h pea k effect time s o f 1 , 2 , an d 4 hour s pos t dosin g o f 6 , 70 , an d 30 0 mg/k g bod y weight/day , respectively . Othe rrepeate d dos e studie s i n th e ra t showe d increase s i n L H an d follicula rstimulatin g hormon e (FSH ) level s followin g 14/1 5 day s o f iprodion e treatmen t an d alteration s i n th e secretio n patter n o f L H an d testosteron e followin g 30-day s o f treatmen t (Fai l eta/. , 1994 ; Fai l eta/. , 1996b) . I n vitr o Mechanisti c Studies : A s mentione d above , n o clea revidenc e o f competitiv e bindin g t o th e A R wa s foun d fo riprodion e o r it s majo rmetabolite s (R P 32490 , R P 36114 , R P 3611 8 an d R P 36119 ) (Fai l eta/. , 1994) . Iprodion e an d certai n metabolite s (RP3611 2 an d RP36115 ) hav e bee n show n t o rapidl y an d reversibl y inhibi t testosteron e secretio n fro m culture s o f porcin e Leydi g cells . Inhibitio n wa s foun d t o occu ra t medi a concentration s o f 1-1 0 ug/m l (Benhamed , 1995) . Iprodion e ha s als o bee n show n t o inhibi t testosteron e secretio n fro m ra t testicula rsection s i n vitr o a t simila rmedi a concentration s (1-10 0 ug/mL) , an d thi s inhibitio n wa s no t dependen t o n huma n chorioni c gonadotropi n stimulatio n (Fai l e t al. , 1996a) . Thes e finding s ar e supporte d b y i n vivo metabolis m dat a demonstratin g tha t a singl e 7 0 mg/kg dos e result s i n concentration s o f iprodion e i n th e teste s o f 5. 6 - 6. 8 ug/ g afte r2 hours , whic h i s withi n th e rang e o f concentration s show n t o inhibi t testosteron e secretio n i n vitr o (Benhamed , 1995) . Th e biochemical step s involve d i n iprodione-induce d change s i n steroidogenesi s hav e als o bee n investigated . Porcin e Leydi g cel l culture s wer e use d t o demonstrat e tha t iprodion e appear s t o interfer e wit h steroi d synthesi s b y disruptin g th e activ e transpor t o f cholestero l substrat e int o mitochondri a (Benhamed , 1996) . Thus , iprodione-induce d inhibitio n o f testosteron e secretio n likel y result s fro m a n indirec t inhibitio n o f steroi d synthesis . Result s o f a n aromatas e assa yhav e bee n reporte d i n th e peer-reviewe d literatur e (Anderse n e t al. , 2002) . Incubatio n o f huma n placenta ! microsome s wit h iprodion e a t a singl e concentratio n o f 5 0 u. M resulte d i n a significan t stimulatio n o f aromatas e activity , suggestin g tha t iprodion e stimulate s th e conversio n o f androge n t o estroge n i n vitro . Althoug h th e stud y incorporate d 4-androsten-4-ol 3,17-dion e ( 1 u.M ) a s a positiv e aromatas e inhibitor , a positiv e contro l fo rstimulatio n o f aromatas e activit y wa s no t include d an d th e detectio n o f compound s whic h stimulat e aromatas e wa s no t par t o f EPA' s validatio n progra m fo rthi s assay . Further , testin g onl y on e concentration , instea d o f th e eigh t concentration s require d b y th e OPPT S 890.120 0 Guideline , make s interpretatio n o f th e result s difficul t an d provide s n o confidenc e i n concludin g tha t iprodion e ma y stimulat e activity . I n addition , th e numbe ro f replicate s teste d wa s no t specifie d an d apparentl y onl y on e ru n wa s performed , instea d o f th e thre e independen t run s require d b y th e OPPT S Guideline . Base d o n thes e limitations , th e aromatas e assa yreporte d b y Anderse n eta/. , (2002 ) shoul d b e considere d unreliable .

# ® Baye rCropScienc e Report NO . usoos s j n Pag e 1 5 Th e abov e i n vivo an d i n vitr o mechanisti c studie s provid e evidenc e tha t iprodion e interfere s wit h testosteron e biosynthesi s a t concentration s tha t resul t i n Leydi g cel l tumor s i n rat s afte rchroni c exposure . Further , result s o f regulator y subchronic an d chroni c studie s i n rodent s an d dog s sho w histopathologica l changes (discusse d i n th e estroge n an d androge n section s above ) i n adrenals , testes , an d ovaries , tissue s whic h secret e steroi d hormones . Th e effect s observe d a t hig h dose s i n th e mous e ovarie s (luteinizatio n o f interstitia l cells ) an d i n th e adrenal s o f roden t an d dog s (hypertroph y and/o rvacuolatio n o f cell s i n th e zon a glomerulos a and/o rzon a fasiciculata ) ar e als o likel y t o b e relate d t o a n interferenc e i n steroidogenesis . Therefore , base d o n th e existin g information , th e requiremen t fo rspecifi c aromatas e an d steroidogenesi s assay s fo riprodion e shoul d b e waived . Conclusio n BC S believe s tha t existin g dat a o n iprodion e ar e adequat e t o asses s th e potentia l fo rthi s compoun d t o interac t wit h estrogen , androge n an d thyroi d system s an d tha t furthe rtestin g i s no t warranted . BCS' s existin g database , combine d wit h severa l peer-reviewed publications , provide s substantia l coverag e o f th e relevan t endocrin e endpoint s note d i n th e toxicit y testin g guideline s o f th e OPPT S 89 0 Guidelin e Series . Moreover , extensiv e mechanisti c testing , bot h i n vivo an d i n vitro , ha s bee n complete d t o investigat e hormona l dysregulatio n an d formatio n o f Leydi g cel l tumor s i n mal e rat s afte riprodion e exposure . Currently , endocrine-relate d endpoint s ar e th e point s o f departur e fo r bot h acut e (decrease d anogenita l distanc e i n mal e ra t fetuses ) an d (non-cancer ) chroni c (histopathologica l lesion s i n th e mal e ra t reproductiv e syste m an d effect s o n th e adrena l gland s i n bot h sexes ) ris k

assessments . Base d o n th e extensiv e endocrin e testin g alread y performed , BC S believe s tha t furthe rendocrin e testin g wit h th e Tie r1 assay s i s no t warranted .

## Baye rCropScienc e Report NO . usoos 9 Pag e 1 6 Reference s Th e followin g stud y ha s no t bee n submitte d previousl y t o EP A an d ar e include d wit h thi s response : Fryer , S.E. , Duckworth , J. , Gibson , W.A. , Gopinath , C , an d Suttie , A . (1990a) . Iprodione : Sub-acut e toxicit y t o mic e b y dietary administratio n fo r1 3 weeks . Huntingdo n Researc h Centr e Ltd. , Huntingdon , Cambridgeshire , England . C022886 , Novembe r23,1990 . Unpublished . Th e followin g studie s hav e bee n submitte d previousl y t o EP A an d ar e cite d b y MRI D number : MRI D 00144391 . Broadmeadow , A . (1984) . Iprodione : 52-wee k toxicit y stud y i n dietar y administratio n t o Beagl e dogs . Lif e Scienc e Researc h Ltd. , Eye , Suffolk , England . C021579 , Septembe r28,1984 . Unpublished . EP A classificatio n acceptable/guideline . MRI D 00162983 . Henwood , S.M . (1991) . Two-generatio n reproduction stud y wit h iprodion e technica l i n rats . Hazleto n Laboratorie s America , Inc. , Madison , Wl . HL A Identificatio n No . HL A 6224-154 . Apri l 29,1991 . Unpublished . EP A classificatio n o f acceptable/guideline . MRI D 00162984 . Tesh , J.M. , McAnulty , P.A. , Deans , C.F. , Wilby , O.K. , an d Tesh , S.A . (1986) . Iprodion e (technica l grade) : Teratolog y stud y i n th e rat . Rhone-Poulen c Agrochimie , Lyon , France . C023030 , Ma y 28,1986 . Unpublished . MRI D 42211101 . Kangas , L . (1991) . A 52-wee k dietary toxicit y stud y o f iprodion e i n th e Beagl e dog . Bio-Researc h Laboratorie s Ltd. , Senneville , Quebec , Canada . Laborator y projec t identificatio n no . 84296 , C021573 , Decembe r20,1991 . Unpublished . EP A classificatio n o f acceptable/non-guideline . MRI D 42637801 . Chambers , P.R. , Crook , D. , Gibson , W.A. , Gopinath , C , an d Ames , S.A . (1992) . Iprodione : Potentia l tumorigeni c an d toxi c effect s i n prolonge d dietar y administratio n t o rats . Rhone-Poulen c Agrochimie , Lyon , France . R014586 , Decembe r15,1992 . Unpublished . EP A classificatio n o f acceptable/guideline . MRI D 42825002 . Chambers , P.R. , Crook , D. , Gibson , W.A. , Read , R.M. , an d Gopinath , C . (1993) . Iprodione : Potentia l tumorigeni c effect s i n prolonge d dietar y administratio n t o mice . Rhone Poulen c Agrochimie , Lyon , France . C021564 , Ma y 10,1993 . Unpublished . EP A classificatio n o f acceptable/guideline . MRI D 42960701 . Fryer , S.E. , Duckworth , J. , Gibson , W.A. , Gopinath , C , an d Suttie , A . (1990b) . Iprodione : Subacut e toxicit y t o rat s b y dietary administratio n fo r1 3 weeks . Huntingdo n Researc h Centre , Huntingdon , Cambridgeshire , England . Stud yno . RN P 322/90767 , C022531 , Novembe r21 , 1990 . Unpublished . EP A classificatio n o f acceptable/guideline .

## Baye rCropScienc e Report NO . usoos s Pag e 17

_ MRI D 42960701 . Gopinath , C , an d Ames , S.A . (1993) . Iprodione : Retrospectiv e subacut e toxicit y t o rat s b y dietar y administratio n fo r1 3 weeks . Huntingdo n Researc h Centr e Ltd. , Huntingdon , Cambridgeshire , England . Stud y no . RN P 322/93132 0 (Supplemen t t o RN P 322/90767) , C022532 , Septembers , 1993 . Unpublished . EP A classificatio n o f acceptable/non-guideline . MRI D 43535002 . Fail , P.A. , Anderson , S.A. , an d Pearce , S.W . (1994) . Toxicit y testin g o f a fungicide , iprodion e i n adul t mal e C D Spragu e Dawle y rats . Laborator y o f Reproductiv e Endocrinology , Cente r fo rLif e Science s an d Toxicology , Researc h Triangl e Institute , Researc h Triangl e Park , NC . RT I Identificatio n No . 65C-5703 , C024395 . Octobe r24,1994 . Unpublished . EP A classificatio n o f acceptable/non-guideline . MRI D 43830601 . Benhamed , M . (1995) . Effect s o f iprodion e an d it s metabolite s o n testosteron e secretio n i n culture d Leydi g cells . INSER M U 407 , Sophi a Antipoli s Cedex , France . INSERM/ U 407/95001 , R014672 . Jul y 13,1995 . Unpublished . EP A classificatio n o f acceptable/non-guideline . MRI D 44171901 . Benhamed , M . (1996) . Effect s o f iprodion e an d it s metabolite s R P 3611 2 an d R P 3611 5 o n testosteron e secretio n i n culture d Leydi g cells : Site s o f action . INSER M U 407 , Sophi a Antipoli s Cedex , France . INSERM/ U 407/96001 , C024294 . Octobe r21,1996 . Unpublished . MRI D 44171903 . Fail , P.A. , Anderson , S.A. , an d Pearce , S.W . (1996a) . Toxicit y testin g o f a fungicide , iprodione : Endocrin e toxicolog y studie s o f teste s fro m adul t mal e C D Sprague-Dawle y rat s expose d t o iprodion e i n vitro . Laborator y o f Reproductiv e an d Endocrin e Toxicology , Researc h Triangl e Institute , Researc h Triangl e Park , NC . RT I Identificatio n No . 65C-6169 ; Rt95-IPDA ; RTI-532 , C024292 , Novembe r26,1996 . Unpublished . EP A classificatio n o f acceptable/non-guideline . MRI D 44171904 . Fail , P.A. , Anderson , S.A. , an d Pearce , S.W . (1996b) . Toxicit y testin g o f a fungicide , iprodione : Endocrin e toxicolog y studie s o f teste s fro m adul t mal e C D Sprague-Dawle y rat s expose d t o iprodion e i n vivo . Laborator y o f Reproductiv e an d Endocrin e Toxicology , Researc h Triangl e Institute , Researc h Triangl e Park , NC . RT I Identificatio n No . 65C-6169 ; Rt95-IPDA ; RTI-527 , C024293 , Novembe r26,1996 . Unpublished . EP A classificatio n o f acceptable/non-guideline . MRI D 44365001 . Repetto-Larsay , M . (1997) . Iprodione : Toxicolog y stud y i n pregnan t ra t b y gavag e t o examin e se xdifferentiation . Rhone-Poulen c Agr o CRSA , Cedex , France . Stud y no . SA96448 , C022658 , Jun e 9,1997 . Unpublished . EP A classificatio n o f acceptable/non-guideline . MRI D 44729201 . Chuzel , F . (1998) . Iprodione : Hormona l measurement s i n adul t mal e Spragu e Dawle yrat s followin g administratio n o f iprodion e b y gavage . Rhone-Poulen c Agr o CRSA , Cedex , France . Stud y no . SA98283 , B003656 , Octobe r14,1998 . Unpublished . EP A classificatio n o f acceptable/non-guideline .

## Baye rCropScienc e Report NO . usoos s Pag e 18

_ MRI D 44750701 . Fisher , P . (1998) . Quantificatio n o f iprodion e an d metabolite s i n th e plasm a an d teste s o f th e ra t followin g a singl e ora l administratio n o f [ 14 C]-iprodione . Rhone-Poulen c Agr o CRSA , Cedex , France . Stud y no . SA98326 , B003653 , Novembe r30,1998 . Unpublished . EP A classificatio n o f acceptable/non-guideline . MRI D 45859601 . Chuzel , F . (2001) . Iprodione : Hormona l measurement s i n adul t mal e Sprague Dawle y rat s followin g a singl e administratio n o f iprodion e b y gavage . Aventi s CropScience , Sophi a Antipoli s Cedex , France . Stud y no . SA01016 , C019327 , Jul y 26 , 2001 . Unpublished . EP A classificatio n o f acceptable/non-guideline . MRI D 45859602 . Kennel , P . (2002a) . Measuremen t o f Leydi g cell proliferatio n followin g a 14-da y treatmen t perio d wit h iprodion e b y gavag e i n th e rat . Baye rCropScience , Sophi a Antipoli s Cedex , France . Stud y no . SA01315 , C025273 , Augus t 7 , 2002 . Unpublished . EP A classificatio n o f acceptable/non-guideline . MRI D 45859603 . Kennel , P . (2002b) . Iprodione : Hormona l measurement s followin g a 14-da y treatmen t perio d wit h iprodion e b y gavag e i n th e rat . Baye rCropScience , Sophi a Antipoli s Cedex , France . Stud y no . SA01287 , C024675 , Jul y 12 , 2002 . Unpublished . EP A classificatio n o f acceptable/non-guideline . Othe rpublishe d literature : Andersen , H.R. , Vinggaard , A.M. , Rasmussen , T.H. , Gjermandsen , I.M. , an d Bonefeld-Jorgensen , E.C . (2002) . Effect s o f currentl y use d pesticide s i n assay s fo restrogenicity , androgenicity , an d aromatas e activit y i n vitro . Toxico l an d Ap p Pharmaco l 179:1-12 . Blair , R.M. , Fang , H. , Branham , W.S. , Hass , B.S. , Dial , S.L. , Moland , C.L , Tong , W. , Shi , L , Perkins , R. , an d Sheehan , D.M . (2000) . Th e estroge n recepto rrelativ e bindin g affinitie s o f 18 8 natura l an d xenochemicals : structura l diversit y o f ligands . Toxicol . Sci . 54:138-153 . Blystone , C.R. , Lambright , C.S. , Cardon , M.C. , Furr , J. , Rider , C.V. , Hartig , P.C. , Wilson , V.S. , an d Gray , Jr. , I.E . (2009) . Cumulativ e an d antagonisti c effect s o f a mixtur e o f th e antiandrogen s vinclozoli n an d iprodion e i n th e puberta l mal e rat . Toxicol . Sci . Ill : 179-188 . Blystone , C.R. , Lambright , C.S. , Furr , J. , Wilson , V.S. , an d Gra yJr. , I.E . (2007) . Iprodion e delay s mal e ra t puberta l development , reduce s seru m testosteron e levels , an d decrease s e xviv o testicula r testosteron e production . Toxicol . Lett . 174 : 74-81 . Klimisch , H.-J. , Andreae , M an d Tillman , U . (1997 ) A Systemati c Approac h fo rEvaluatin g th e Qualit y o f Experimental Toxicologica l an d Ecotoxicologica l Data . Regulator y Tox . an d Pharm .

## Baye rCropScienc e Report NO . usoos s Pag e 1 9 

### 25:1-5 . Wolf , C , Lambright , C. , Mann , P. , Price , M. , Cooper , R.L , Ostby , J. , an d Gra yJr. , LE . (1999) . Administratio n o f potentiall y antiandrogeni c pesticide s (procymidone , linuron , iprodione , chlozolinate , p,p'-DDE , an d ketoconazole ) an d toxi c substance s (dibutyl - an d diethylhexy l phthalate , PC 6 169 , an d ethan e dimethan e sulphonate ) durin g sexua l differentiatio n produce s divers e profile s of reproductiv e malformation s i n th e mal e rat . Toxicol . Ind . Healt h 15 : 94-118 . Th e followin g ar e als o use d fo rreference : d e Groene , E.M . (1999) . Huma n androge n recepto rbindin g assa ywit h th e fungicid e iprodion e an d 7 mammalia n metabolites . TN O Voeding , TN O Nutritio n an d Foo d Researc h Institute , Analytica l Science s Division , Zeist , Th e Netherlands . TN O repor t V99.616 , Projec t no . 50436 . Jun e 23,1999 . OEC D (2006) ; Draf t Detaile d Revie w Pape ro n Thyroi d Disruptio n Assays ; OEC D Environment , Healt h an d Safet y Publicatio n Serie s o n Testin g an d Assessmen t (Numbe rno t assigned) , Paris , Franc e USEP A(2010) ; Tes t Order/DCI# : EDSP-109801-174 fo rIprodione ; Issue d Ja n 7 , 2010 . USEP A (2009) ; Offic e o f Prevention , Pesticide s an d Toxi c Substances ; Tes t Guideline , 890.1100 : Amphibia n Metamorphosi s (Frog) . EP A 740-C-09-002 ; U.S . Environmenta l Protectio n Agency , Washington , D.C .

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# Bayer

CropScienc e Repor t No . Pag e US005 9 2 7 Tabl e 2 : Functiona l Equivalenc e Matri x - Apica l Endpoint s i n Existin g Studie s Relevan t t o Amphibia n Metamorphosi s Guidelin e (83-4) : Two-Generatio n Ra t Reproductio n (MRI D 00162983 ) • F l an d F 2 pu p surviva l an d growt h Guidelin e 83-3(a) : Developmenta l Toxicit y i n Rat s (MRI D 00162984 ) • Feta l surviva l an d weigh t Guidelin e 82-1 : Subchroni c Feedin g - Rat (MRI D 42960701 ) • Orga n wt s an d histopathology : adrenal , pituitary , thyroi d Guidelin e 82-1 : Subchroni c Feedin g - Mous e (Submitte d wit h Response ) • Orga n wt s an d histopathology : adrenal , pituitary , thyroi d Guidelin e 83-l(b) : Chroni c Toxicit y i n Dog s (MRI D 00144391 , 42211101 ) • Orga n wt s an d histopathology : adrenal , pituitary , thyroi d Guidelin e 83.4 : Mous e carcinogenicit y (MRI D 00070963 , 42825002 ) • Orga n wt s an d histopathology : adrenal , pituitary , thyroi d Guidelin e 83-5 : Ra t combine d toxicity/carcinogenicit y (MRI D 42637801 ) • Orga n wt s an d histopathology : adrenal , pituitary , thyroi d Amphibia n Metamorphosi s S S


## s
s
s
s

s

## Baye rCropScienc e Report NO . usoos g Pag e 2 8

APPENDI X A TITL E PAGE S WIT H MRI D NUMBER S O F REPORT S SUBMITTE D PREVIOUSL Y T O EP A

# H M Baye r

CropScienc e Report No . Pag e US005 9 2 9 MRI D 0014439 1 EP A classificatio n o f acceptable/guidelin e

CONFIDENTIA L 84/RHOOZZ/17 9 

## C0 2 

## 1 57 9

IPRODIONE : 52-WEE K TOXICIT Y STUD Y I NDIETAR Y ADMINISTRATIO NT O BEAGL E DOG S

FINA L REPOR T

To : Rhone-Foulen c Agrochlmle , Bolt e Postal e 9163 . 6926 3 Lyo n Cede x09 . France . From : Lif e Scienc e Researc h Ltd . Eye , Suffol k IP2 3 7PX England . Draft : 1 0 Jul y198 4 Final : 2 8 Septembe r 198 4

# Baye r

CropScienc e Report No . Pag e US005 9 3 0 MRI D 0016298 3 EP A classificatio n o f acceptable/guidelin e 

## HAZLETOI M WISCONSI N 730 1 KfffSVA N BOu; . fVAB D "OS. ' Gcf.c t BO M 754 6 V»2'SO»: . WISCONSI N S370 7 Sponsor : Rh8ne-Poulen c Ag Compan y Researc h Triangl e Park , Nort h Carolin a 

# C 02157 2

FINA L REPORT Stud yTitle : Two-GeneralIo n Reproductio n Stud ywit h Iprodion e Technica l i n Rat s

Dat a Requirement : Guidelin e 83- 4 Author : Susa n M . Henwood , M S Stud yCompletio n Dale : Apri l 29 , 199 1 Performin g Laboratojrv : Hazleto n Laboratorie s America , Inc . 330 1 Kinsma n Boulevar d Madison , Wisconsi n 5370 4 LaboratoryProjec t Identification :

HL A6224-15 4 Pag e 1 o f 166 8 VOLUM E 1 O F V

Fa n COe-241-722 7 T e , o » 7 O 3 9 S 6 HAZRA L

# Baye r

CropScienc e Repor t No . Pag e US005 9 

### 3 1 MRI D 0016298 4 EP A classificatio n o f acceptable/guidelin e

CONFIDENTIAL 85/RHA064/76 5 

# 02303 0

IPRODION E (TECHNICA L GRADE ) : TERATOLOGY STUD Y I NTH E RA

T

To : Rhone-Pau l en c Agroch1m1 e Bolt e Postal e 9163 F-6926 3 Lyo n Cede x0 9 Franc e From : J.M . Tes h P.A . McAnulty C.F . Dean s O.K . W1lb y S.A . Tes h Lif e Scienc e Researc h 

### Eye 

### Suffol k IP2 3 7P

X Englan d 

### 2 8 

### Ha y

### 198 6

# Baye r

CropScienc e Report No . Pag e US005 9 

### 3 2 MRI D 4221110 1 EP A classificatio n o f acceptable/non-guidelin e 

## C 02157 3 BIO-RESEARC H LABORATORIE S LTD .



### STUD Y TITL

E A 3 2 Wee

k Dietar y Toxicit

y Study o f Iprodione in the Beagle Do g

Volum e I SPONSO R Rhdne-Poulen c Canad aInc . 200 0 Argenti aRoa

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### LS N 1V 9 DAT A REQUIREMEN T N o Applicable Guidelin e AUTHO R L . Kanga s B.A.Sc . Stud y Directo

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Y PROJEC T I D 8429 6 PAG E 1 O P 44 8 PAGE S

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# Baye r

CropScienc e Repor t No . Pag e US005 9 3 3 MRI D 4263780 1 EP Aclassificatio n o f acceptable/guidelin e 

# R01458 6 CONFIDENTIA

L RN P 346/920808

IPRODION

E POTENTIA

L TUMORIGENI C AN D TOXI C EFFECTS I

N PROLONGE

D DIETAR

Y ADMINISTRATION T O RAT S VOLUM E I O F X Study completed : Dat arequirements : 1 5 Decembe r 199 2 EP A P1PRA , Subdivisio n F paragrap h 83- 2
Addressee : Rhdn e Poulen c Agrochimie , Departement

d e Toxicologie , 14-2 0 ru e Pierr e Baizet , BP9I63 , 6926 3 Lyo n Cedex 09 , FRANCE . g i Dietar

y Analysi s by : Rhdn e Poulen c Agrochimie , Departemen t

d'Analys e de s R&idus , 14-20 ru e Pierr e Baizet , BP9I63 . 6926 3 Lyo n Cede x 09 . FRANCE . ADM E Bioanalyses , Pare haut e Technologic , Sophi aAntipolis , 69 4 Avenu e du Docteu r M Donat , 0625 0 Mougins , FRANCE . Report issued : 1 5 December

1992 Authors : Pau l R . Chambers , Davi dCrook , Willia mA . Gibson , Chinikandath Gopinath , Suzann e A . Ames . Departmen t

o f Roden t Toxicology . Huntingdo n Research Centr e Ltd. , P.O . Bo x 2 , Huntingdon , Cambridgeshire . PE186ES . ENGLAND .

Pag e 1 o f

204 3

# Baye r

CropScienc e Report No . Pag e US005 9 3 4 MRI D 4282500 2 EP A classificatio n o f acceptable/guidelin e 

# C 02156 4 RN P 359/92124

0 IPRODION

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L TUMORIGBNI C HPFUCI S I N PROLONGE

D DIETAR

Y ADMINISTRATION T O MICE VOLUME I Stud y completed : Datarequirement : 1 0 Ma y 199 3 EP A FIFRA , Subdivisio

n F parsgnpb

dene Agrocbimie , t d e Toxicologie , >Pierr e Baizet , i Cede * 09 , 'analysi s by : e'Poulenc Agrochimie , t d ' Analys e de s Residus , >:Ru e Pierr

e Baizet , B3 , j:lyo n Cede

x 09 . Authors : Pau l R . Chambers . Davi dCrook , WilliamA . Gibson , Rosemar y M . Read , Chirukandat

h Gopinath . Departmen

t o f Roden t Toxicology , Huntingdo n Researc

h Centr e Ltd. , P.O . Bo x 2 , Huntingdon , Cambridgeshire , PE1 8 6ES , ENGLAND .

r _a ! Bioanalyses , i s Jtaute technologie , lAntlpolls , Ivemi e du-Docteu r

M . Dooat , f Mougins , *CE . Wr t issued : 1 0 Ma

y 1993 . Pag e 1 o f 191 8

# Baye r

CropScienc e Repor t No . Pag e US005 9 3 5 MRI D 4296070 1 EP A classificatio n o f acceptable/guidelin e

CONFIDENTIA

L RN P 322/9076 7 

# C 02253 1

IPRODION E SUB-ACUT E TOXICIT

Y TO RAT S B Y DIETAR

Y ADMINISTRATIO

N FO R 1 3 WEEK S

Stud ycompleted ! 7 Decembe r 198 9 Regulation* : Preliminar yStud yfo r EP

AFIFR A82- 1 JHAF P 5 9 NohSan No . 420 0

Addressee : Rhone Poulenc Agrochinie , Departmen t d e Toxicologie , 14-2 0 ru

e Pierr e Baizet , BP-9163 . 6926 3 Lyo

n Cede x 09 , PRANCE .

Repor t issue

d 2 1 Novembe r 1990 . Authors : Sara h E . Fryer . Juli a Duckworth , Willie * A . Gibson . Chirukandat h Gopinath , Andre w Suttie . Huntingdo n Researc h Centr e Ltd. , P.O . Bo

x 2 , Huntingdon . Cambridgeshire , PE1 B 6ES , ENGLAND . Pag e 1 o f 19 4

# £ A 

# t

E 

# 5 Baye r CropScienc e Report No . Pag e US005 9 3 6 MRI D 4296070 1 EP A classificatio n o f acceptable/guidelin e
CONFIDENTIA

L RN P 322/93132

0 Supplemen

t t o RN P 322/9076

7 

# C 02253 2

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E RNP/32 2 RETROSPECTIV E SUBACUT

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r T O RAT S B Y DIETAR

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de Toxicologle . 1 4 - 2 0 ru e Pierr

e Balzet , BP-9163 , 6926 3 Lyo n Cede

x 09 , FRANCE . Testin g facility : Huntingdo n Researc

h Centr e Ltd . P.O . Box 2 , Huntingdon , Cambridgeshire . PE186ES , ENGLAND . Repor t issued3 Septembe

r 199 3 Pag e 1 of 1 6

# Baye r

CropScienc e Report No . Pag e US005 9 3 7 MRI D 4353500 2 EP A classificatio n o f acceptable/non-guidelin e 

# C02439 5

RESEARC H TRIANGL E INSTITUT E 

# 5C4 I FINA L REPOR

T
TITLE : Protoco l 4/4 t

Protoco l 486 :
AUTHORS : PERFORMIN G LABORATORY :

SPONSOR : SPONSO RREPRESENTATIVE : STUD Y INITIATIO N DATE : EXPERIMENTAL DATES : FINA L REPOR

T DATE : RT I IDENTIFICATIO N NO. : Toxitit y Testin g o f

aFungicide , Iprodione , i n Adul t Mal e CD*Spragu

e Dawle y Rat s Toxldt y Testing o f

aFungicide , Iprodion e (Par t I) : Chemistr y Bindin g an d Dose-Rang e Findin g i n Adul t Male CD * Spragu e Dawley Rat s Expose dt o Ora l Iprodione Toxidt y Testing o f

aFungicide , [prodlone (Par t llf c 30
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Mat e CD * Spragu e Dawle

y Rat s Exposedt

o Ora l Iprodione PatridaA.FaiLPh.D . Stephani e A . Anderson , BS . Susa n W . Pearce , B.S . Laborator

y o f Reproductiv e Endocrinolog y Cente r for Lif e Science s an dToxicolog y • Chemistr y andLif

e Science s Researc h Triangl e Institute P.O . Bo x 1219 4 Research Triangl e Park . NC 27709-219 4 Rh&ne-Poulenc A g Company 2T.W . Alexande

r Driv e Research Triangl e Park , N C 2770 9 RemiG . Bare , Ph.D . Rh6ne-Poulen c A g Compan y Octobe r 11.199 3 (Protocol 474 ) Novembe

r 12,1993 (Protoco l 486

) Protoco l 474 : 10/13/9 3 - 03/3 1 /9 4 Protoco l 486 : 11/15/93-03/31/9 4 Octobe r 24,199 4 6SC-570 3 ftopwr

y o f Rhfine-Pbutan o Apochir-. i Strictly confidential : tht adocumen

t an d it s content

arc . or RStantio apurpose * only . An y othe r us e f i prohibite d withou t writte n emuen

t o f RhOne-Poulenc Agrochimi e 304 0 Ccrnwalli s Roa d . Pos t Offic e Box 1219

4 . Researc h Triangl e Park . Nort h CaroSn a 27709-219 4 US A •/: . Pag e 1 of 38 1

# Baye r

CropScienc e Report No . Pag e US005 9 3 8 

### MRI D 4383060 1 EP Aclassificatio n o f acceptable/non-guidelin e

INSTTTO

T NATIONA

L D E L A S ANTE ET D E L

A RECHERCH

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E & 0 O -f-j £ 

### INSHR M Unit 6 40 7 Unit e de Recherche s su

r le s Communication s Cellulaire s en Biologi c de l aReproductio n Directeu r : D r Mohame d BEN AHME D D Q14.6 7 2


### EFFECT S O F IPRODION E AND IT S METABOLITE S O N TESTOSTERON

E SECRETIO N IN CULTURE D LEYDI G

CELL S Author : Dr . M . Benahme d Performin g laboratory : INSER M U . 4O7 ; Communicatio n Cellulaire en Biologic de l aReproduction . Laboratoir e de Biochimie , Bat . 3 B , Centre Hospitalier Lyon-Sud , 69495 , Pierr

e Benite , France . 

### Tel : (33 ) 7 8 8 6 1 6 07 ; 

### Fax : (33 ) 7 8 8 6 3 3 44

I ? 

# i i i Sponsor : Rhone-Poulen c Secteu r Agro , 14-20 , ru e Pierr

e Baizet , Lyon , 6926 3 France . Experimental dates : 2 4 may 1994-2 3 Januar y 199 5

Fina l Repor t Date : JUL Y 13 , 199 5 Report Identificatio n N* : INSERM/U407/9500 1

Laboratoire d e Biochimi e - Bailmen t 3 B CENTR E HOSPITALIE

RLYON-SUD 6949 5 PIERRE-BENIT E Cede x (FRANCE ) Tel : (33 ) 7 8 8 6 1 6 07
- Fax : (33 ) 7 8 8 6 5 9 2 2

# H H Baye r

CropScienc e Report No . Pag e US005 9 

### 3 9 MRI D 4417190 1 EP A classificatio n o f acceptable/non-guidelin e 

# C02429 4

EFFECT S OF IPRODIONE AN D IT S METABOLITE S R P 3611 2 AN D RP 3611 5 O N TESTOSTERON E SECRETIO N I N CULTURE D LEYDI G CELLS : SITES O F ACTION .

Repor t identificatio n N° : INSERM/ U 407/9600 1 STUDY DIRECTOR : Dr . M . BENAHMED

Propert y o f Rhone-Ponlen

c Agrochuni e Strictly confidential ! thi s documen t

Badit aconten

t ar e lor registratio n purpose s only . Any oiticr us e i s prohibite d withou t writte n consent

o f RhOno-Poulcn c Aerochimi c

Experimental date : Jul y 29 . 199 4 t o Jul y 18 . 199

6 Fina l Repor t Date : Octobe

r 21 . 199 6 Performin g laborator y INSER M U 407 . Communicatio n Cellulaire e n Biologi e d e l a Reproduction . BS t

3B , Centr

e Hospitalier

Lyon-Sud . 6 9 49 S Pierre-Benit e cedex . France . Tel : (33 ) 7 8 8 6 1 6 O7 - Fax : (33 ) 7 8 8 6 5 9 22 Sponsor : Rhone-Poulen c Agrochimie
- Centr e d e Recherche
- 355 , ru e DostoVcvski
- B P 153
- F
O6903 SOPHI

A ANTIPOLJ S Cede

x

pag e 1/5 3

# Baye r

CropScienc e Report No . Pag e US005 9 4 0 MRI D 4417190 3 EP A classificatio n o f acceptable/non-guidelin e

FINA L REPOR

T 

# ^02429 2 Sponsor ; RhOne-Poulen c A g Compan y 2 T.W . Alexande

r Driv e P.O . Bo x 12014 Researc h Triangl e Park , NC 2770 9 Stud y Title ; Toxicit y Testing o f

aFungicide , Iprodione : Endocrine Toxicolog y Studie s o f

Teste s Fro mAdult

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y o f Reproductiv e an dEndocrine Toxicolog y Cente r for Lif e Science s an dToxicolog y Chemistr y an dLif e Science s Research Triangl e Institute P.O . Bo x 1219 4 Researc h Triangl e Park , N C 27709-219 4 RT I Identificatio n No. ; 65C-6169 ; Rt95-IPDB ; RTI-53 2

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## B00365 6 IPRODION

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## REPORT OFSTUD Y S A 0131 5 STUD Y DIRECTOR : P . KENNE L PERFORMiNf i Baye r CropScienc e 355 , rue DostoTevsk

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## STUD Y COMPLETE D ON : AUGUS T 07,200 2 PAG E1 O F20 1

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## STUDY COMPLETE

D ON : JUL Y 12,200

2 PAG El OF13 7