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# Baye r CropScienc e [BAYER ] R

Baye r CropScienc e 

### EP A Correspondenc e No . 10-02 E \o^'TS T D 

### " V e Februar y 12 , 201 0 Researc h Triangl e Park , N C 2770 9 Tel : 91 9 549-200 0 

### Documen t Processin g Des k

(PRD-EDSP ) Offic e o f Pesticid e Program s (7504P ) U.S . Environmenta l Protectio n Agenc y On e Potomac Yar d (South Bldg. ) 277 7 Sout h Crysta l Driv e Arlington , Virgini a22202-450 1
Re : 90-Day Respons e t o Endocrin e Disrupto r Screenin g Progra mfo r

Ethopro p Order/DCI# : EDSP-041101-4 2 Chemica l Commo n Name : Ethopro p Chemica l # : P C Code : 041101CAS# : 13194-48- 4 Dea r Si r o r Madam : W e ar e submittin g th e 90-da y respons e fo r ethopro p a s require d b y th e Endocrin e Disrupto r Screenin g Program/Dat aCall-I n tha t wa s receive d b y Baye r

CropScienc e o n Novembe r 9 , 2009 . W e hav e enclose d acomplete d Initia l Respons e For mfo r Individua l Orde r

Recipient s (EP A For mNo . 6300-05) . Th e documentatio n require d t o suppor t ou r respons e (Optio n 2.I B and/o r 2.2 ) i s include d i n th e repor t cite d below : MRI D Number ; K . Rupprech t

an d M . Kern . (2010) . 90-Day Respons e t o EPA' s Tes t Orde r fo r Endocrin e Screenin g o n Ethoprop . Baye r CropScience , Researc h Triangl e Park , NC . Order/DC I # : EDSP-041101-42 . Baye r

Repor t No . G202148 . Februar y 12 , 2010 . 3 2 pages . Pleas e phon e m e a t

(919 ) 549-287 0 o r

emai l m e a t

larry.hodges@bayercropscience.co mi f yo u hav e an y question s regardin g thi s submission . Sincerely ,

— ^ 

### Larr y R . Hodges , Ph.D . Registratio n Manager , Insecticide s

< JB A 

# Baye r CropScienc e Repor t No . G20214 8
Title : 90-DA Y RESPONS E T O ERA' S TES T ORDE R FO R ENDOCRIN E SCREENIN G O N ETHOPRO P

Order/DC I # : EDSP-041101-4 2 Guideline : OPPT S 89 0 Guidelin e Serie s

Authors : Ken t Rupprech t Matt Ker n Date : Februar y 12 , 201 0 Repor t No : G20214 8 Baye rCropScienc e P.O . Box1201 4 . . . 2 T.W . Alexande rDriv e * * * Researc h Triangl e Park , N C 2770 9 ••••• • • • • 

### • • • • • • • • • 

### • • ••••• • ••••• <

Pag e 1 o f 3 2

## (»fa

y Baye rCropScienc e " Repor t No . G20214 8
STATEMEN T O F DAT A 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)(1)(A)(B) , o r(C) .

Compan y Agent : Larr

y Hodge s Baye rCropScienc e Regulator

y Manage r Signature/Date : Februar y 12 , 201 0

Pag e 2 o f 3 2

## Kuyv rCropScienc e Repor t No . G20214 8
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 . 

# fi b 

# J 2 'Ken t Rupprech t Toxicologis t Baye rCropScienc e Dat e

Matt Ker n Ecotoxicologis t Baye rCropScience Dat e



# 0 Februar y 12 , 201 0 Larr y R . Hodge s Registratio n Manage r Sponsor/Submitte r Dat e

Pag e 3 o f 3 2

## Baye rCropScienc e Repor t No . G20214 8 90-DA Y RESPONS E T O ERA' S TES T ORDE R FO R ENDOCRIN E SCREENIN G O N ETHOPRO P O n Novembe r5 , 2009 , EP A issue d a Tes t Orde rfo rendocrin e screenin g o n ethoprop . 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 y par t o f al 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 interact 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 ethopro p 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 quality regulator y studie s conducte d accordin g t o OPPT S Guideline s an d Goo d Laborator y Practic e (GLP ) Standards . Th e whol e organis m apica l endpoint s i n thes e studies , suc h a s reproductio n parameters , orga n weight s an d histopathology , an d sexua l developmen t reflec t 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 ethopro p tha t ar e functionall y equivalen t t o endpoint s assesse d i n EPA' s Tie r1 endocrin e screenin g batter y ar e summarize d i n Table s 1 a an d 1b . Functionall y equivalent , i n thi s context , refers t o dat a o f a suitabl e natur e an d quality t o provid e th e sam e essentia l predictiv e informatio n o n a chemica l eve n i f differen t method s an d procedure s ma y b e use d fo robtainin g th e data . Estroge n Syste m Assay s (estroge n recepto r(ER ) binding , E R transcriptiona 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 batter y t o asses s th e potentia l o f a chemica l t o affec t th e estroge n signalin g pathway . A fis h ful l lif e cycl e stud y o n ethopro p wit h supportin g result s fro m tw o earl y lif e stag e studie s i n fis h i s bein g cite d t o addres s th e requiremen t fo ra fis h short-ter m reproductio n screen . Th e othe rassay 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 ethoprop . However , adequat e informatio n exist s t o asses s ethoprop' s potentia l t o interfer e wit h th e estroge n system . A s show n i n Table s 1 a an d 1b , relevan t data , whic h ar e functionall y equivalen t t o addres s th e purpos e o f EPA' s Tie r1 screenin g battery , 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 , chroni c do g studies , developmenta l toxicit y studies , an d a two-generatio n ra t reproductio n study . Al l o f thes e latte r studie s wer e conducte d unde rGL P hav e bee n reviewe d b y EPA , an d ar e classifie d a s acceptable . Fish Ful l Lif e Cycl e Study : Th e fis h short-ter m reproductio n assa y screen s fo rdisturbance s i n th e hypothalamic-pituitary gonada l (HPG ) axi s includin g (anti- ) estrogenic , (anti-)androgenic , aromatas e inhibition , steroi d modulatio n effects . Th e assa y examine s abnormalitie s associate d wit h survival , reproductiv e behavior , secondar y se x characteristics , histopathology , an d fecundit y (i.e. , numbe ro f spawns , numbe ro f eggs/spawn , fertility , an d developmen t o f offspring ) o f fis h expose d t o tes t chemical s (USEPA , 2009a) . Th e stud y begin s wit h reproductivel y matur e fathea d minnow s observe d t o b e successfu l spawner s ove ra t leas t a 1 4 da y period . Thes e "prove n breeders " ar e the n expose d t o th e tes t chemica l fo ra perio d o f 2 1 days . Th e principl e o f th e fis h short-ter m reproductio n scree n i s t o measur e th e reproductiv e performanc e o f a grou p o f fathea d minnow s a s th e primar y indicato rfo rendocrin e disruptio n (USEPA , 2009b) . Existin g dat a fo rthi s "primar y Pag e 4 o f 3 2

## Baye rCropScienc e Repor t No . G20214 8 indicator " fo rendocrin e disruptio n i s elaborate d o n below . Additiona l measuremen t o f morphological , histopathological , an d biochemica l endpoint s ar e include d t o identif y potentia l toxicologica l an d endocrin e mechanism s fo rth e tes t chemica l (USEPA , 2009b) . Th e purpos e o f th e Tie rI batter y i s t o mak e decision s i f Tie r2 test s ar e necessary base d o n availabl e data . A s state d fro m th e guidelin e above , reproductio n performanc e i s th e primar y indicato rt o scree n fo rpossibl e endocrin e activity . Fo rethoprop , a significan t databas e alread y exist s regardin g it s toxicit y t o fis h wel l beyon d a screenin g leve l evaluation . Specifically , earl y lif e stag e (ELS ) test s fo rfathea d minno w an d sheepshea d minno w hav e bee n complete d wit h ethopro p (Surprenant , 198 7 an d Sousa , 1997) . Thes e EL S studie s ra n 33-3 5 day s wit h effec t o n egg s an d larva l fis h evaluated . Further , a very comprehensiv e fis h lif e cycl e tes t wit h sheepshea d minno w ha s bee n complete d wit h ethopro p whic h include d a 11 2 da y exposur e encompassin g multipl e fis h lif e stage s (Dionne , 2004) . Thi s exposur e perio d exceed s th e 2 1 da y exposur e t o adult s i n th e propose d reproductiv e scree n guidelin e (USEPA , 2009b ) an d provide s a mor e extrem e assessmen t o f potentia l effect s i n fish . A numbe ro f endpoint s include d i n th e existin g ethopro p databas e fo rfis h ar e liste d below . A compariso n o f endpoint s require d i n th e fis h screenin g assa y an d thos e existin g fo rethopro p ar e als o presente d i n Tabl e 

### 2 . • Surviva l o f fis h t o exposure s o f ethopro p t o multipl e fis h lif e stag e i n thre e separat e studie s wit h fathea d minno w an d sheepshea d minnow . • Growt h (weigh t an d length ) fro m exposure s t o multipl e fis h lif e state s i n thre e separat e studie s wit h fathea d minno w an d sheepshea d minnow . • Impact s o n earl y lif e stag e developmen t an d reproductio n fro m earl y lif e stag e an d ful l lif e cycl e studie s wit h fathea d minno w an d sheepshea d minnow . Th e 11 2 da y fis h lif e cycl e stud y wit h sheepshea d minno w wa s carrie d ou t startin g wit h egg s grow n t o sexuall y matur e fish . Th e stud y continue d wit h th e exposur e o f F I egg s whic h develope d i n t o larva e ove ra n additiona l 4 wee k period . • Severa l biomarke rendpoint s ar e include d i n th e fis h short-ter m reproductio n scree n (Tabl e 2) . Whe n significan t reproductiv e effect s ar e noted , the y ma y infor m a s t o a lin e o f inquir y regardin g a potentia l mod e o f action . Fundamentally , th e biomarke rendpoint s i n th e scree n ar e capture d i n thes e "highe rtiered " exposure s a s translate d i n measurement s o f survival , growt h an d reproduction . Result s fro m existin g chroni c exposure s o f ethopro p showe d n o indicatio n o f reproductiv e effects . Fo rth e fathea d minno w earl y lif e stag e study , n o effect s o n embryo s u p t o th e highes t tes t concentratio n teste d (42 0 ppb ) occurre d (Surprenant , 1987) . Lengt h an d weigh t effect s occurre d a

t 5 4 pp b an d survivorshi p effect s wer e observe d a t 9 6 ppb . I n th e sheepshea d minno w earl y lif e stag e study , n o effec t o n an y endpoin t wa s observe d u p t o highes t tes t concentratio n o f 4 6 pp b (Sousa , 1997) . Fo rth e sheepshea d minno w fis h ful l lif e cycl e study , n o reproductiv e effect s occurre d a t an y tes t concentratio n (hig h leve l 1 5 ppb ) wit h th e onl y sligh t effec t occurrin g o n F

^ weight s a t 3. 7 pp b (Dionne , 2004) . Fo rethoprop , severa l fis h studie s encompassin g sensitiv e lif e stage s wer e conducte d an d n o effect s o n fis h reproductio n wer e detected . Thes e studie s wer e conducte d unde rGL P an d wer e accepte d b y th e USEP A fo rth e registratio n o f ethopro p unde restablishe d guideline s (USEPA , Pag e 5 o f 3 2

## Baye rCropScienc e Repor t No . G20214 8 1985 , 1986 , 1996a , 1996b) . At a minimum , thi s "othe rscientificall y relevan t information " (OSRI ) shoul d b e considere d adequat e t o mee t th e need s o f dat a reques t fo ra fis h short-ter m reproductiv e scree n an d therefor e th e nee d t o conduc t thi s assa y shoul d b e waived . No t full y utilizin g th e existin g fis h reproductiv e dat a fo rethopro p an d requirin g a mor e rudimentar y tie r1 scree n woul d caus e undu e expenditure s o f time , mone y an d animals . Othe rScientificall y Relevan t Information : Endpoint s fro m guidelin e studie s tha t ar e relevan t t o th e assay s i n EPA' s Tie r1 screenin g batter y ar e show n i n Table s 1 a an d 1b . I n a two-generatio n ra t stud y (Neeper-Bradley , 1991 ) conducte d accordin g t o th e 83- 4 Guideline , F O adult s wer e expose d t o ethopro p i n th e die t fo r 1 0 weeks prio rt o matin g an d the n throughou t mating , gestatio n an d lactatio n periods . At weaning , o n Lactatio n Da y 21 , twenty-eigh t (28 ) F1 A weanlings/sex/grou p wer e selecte d a s parent s o f th e F 2 generation . Durin g th e firs t post-weanin g week , significan t mortality wa s observe d i n F1 A pup s at th e hig h dos e (30 0 ppm ) an d sufficien t number s o f F1 A pup s at thi s dos e wer e no t expecte d t o b e availabl e fo rmatin g t o produc e th e F 2 generation . Sinc e th e hig h dos e exceede d th e maximu m tolerate d dos e fo rpups , th e leve l fo rF O parenta l animal s wa s decrease d b y on e hal f (15 0 ppm ) 3 week s prio rt o th e secon d matin g period . Hig h dos e F O parenta l animal s wer e maintaine d o n th e 15 0 pp m tes t diet s throug h termina l sacrifice . Approximatel y fou r(4 ) week s afte rth e weanin g o f th e las t F1 A litters , th e F O parent s wer e paire d agai n fo rthre e (3 ) week s t o produc e th e F1 B generation . Tes t die t administratio n wa s continue d throug h mating , gestation , parturitio n an d lactatio n o f th e secon d litters . Indirec t exposur e fo rth e F1 A an d F1 B offsprin g cover s th e i n uter o an d lactatio n period s wit h direct exposur e startin g aroun d postnata l day (PND ) 1 1 o r1 2 whe n pup s begi n t o consum e treate d diet . Fo rth e F1 B pup s selecte d t o produc e th e next generation , exposur e continue s fro m PN D 2 1 fo r1 0 week s prematin g throughou t mating , gestation , an d lactation . Thus , th e exposur e duratio n fo rth e F 1 generatio n exceed s tha t require d b y th e puberta l assa y an d therefor e provide s a mor e sever e assessmen t o f a compound' s potentia l t o affec t endocrine-relate d endpoints . Whe n teste d u p t o 150/30 0 pp m i n th e die t i n a two-generatio n ra t study , ethopro p ha d n o effec t o n mating , fertility , pregnancy , o rgestationa l indice s o f F O o rF 1 females . Gestationa l lengt h i n days , wer e simila racros s al l groups . Matin g indice s fo rF O an d F 1 male s wer e als o simila r acros s al l groups . A t necropsy , absolut e an d relativ e thyroi d weight s wer e unaffecte d fo rF O an d F 1 animals . N o histopathologica l change s wer e observe d i n an y reproductiv e organ s (vagina , uterus , ovaries , semina l vesicles , epididymides , prostate , testes, ) examine d fro m F O an d F 1 animals . Mea n numbe ro f liv e pup s pe rlitte ro n PN D 0 , an d se x ratio s wer e statisticall y simila racros s al l treatmen t group s fo rF 1 an d F 2 litters . I n a developmenta l neurotoxicit y ra t stud y (Sheets , 2004 ) ethopro p wa s administere d vi a th e die t fro m gestatio n da y (GD ) 6 throug h lactatio n da y (LD ) 2 1 t o mate d femal e Wista rrat s a t nomina l concentration s o f 0 , 3.0 , 3 0 an d 18 0 ppm . Ethopro p ha d n o effec t o n fertility , viabilit y o r lactatio n indice s o f females . Gestationa l lengt h i n days , wer e simila racros s al l groups . Mea n numbe ro f liv e pup s pe rlitte ro n PN D 0 , an d se x ratio s wer e statisticall y simila racros s al l treatmen t groups . Additionally , vagina l patency an d preputia l separatio n i n offsprin g wer e no t affecte d b y treatmen t a t an y dietar y level . I n a chroni c mous e stud y (Inoue , 1984) , n o change s i n th e ovaries , teste s an d adrenal s weight s o rtreatmen t relate d histopathologica l finding s i n th e ovaries , uteru s (corpu s an d cervix) , Pag e 6 o f 3 2

## Baye r CropScienc e Repor t No . G20214 8 mammar y gland , prostate , testes , epididymes , adrenal , pituitar y an d thyroi d wit h parathyroi d wer e noted . I n a chroni c ra t stud y (Williams , 1992) , animal s administere d 40 0 pp m o f th e tes t materia l i n th e die t (hig h dose ) tende d t o hav e lowe rtermina l bod y weights , compare d wit h thos e o f controls . Thi s differenc e wa s no t larg e enoug h t o b e statisticall y significant , excep t fo r male s sacrifice d afte r5 6 week s (recover y sacrifice) . However , thes e lowe rbod y weight s wer e sufficien t t o caus e lowe rabsolut e orga n weights , organ-to-bod y weigh t percentages , an d organ to-brai n weigh t ratio s fo rsom e organ s a t interim , recovery an d termina l sacrifices . Thes e difference s wer e mos t noticeabl e i n kidne y weights , bu t als o include d righ t adrena l weight s i n males . N o change s i n ovary , testes , an d thyroi d wit h parathyroi d weight s wer e noted . Al l weigh t change s no t associate d wit h lowe rbod y weight s wer e attribute d t o norma l biologica l variation . Macroscopically , ther e wer e n o observation s directl y relate d t o th e tes t material , regardles s o f th e animal' s fate . Microscopically , th e non-neoplasti c an d neoplasti c change s observe d durin g th e stud y ar e commo n t o th e strai n o f ra t a t th e age s examined . Female s give n 40 0 pp m an d sacrifice d a t th e en d o f th e stud y ha d a highe rincidenc e o f endometria l stroma l polyps , bu t thi s differenc e wa s no t statisticall y significant . I n th e chroni c do g stud y (Brown , 1986) , n o change s i n orga n weight s o rhistopathologica l finding s wer e noted . I n a developmenta l toxicit y stud y (Rodwell , 1989a) , ora l administratio n o f ethopro p t o pregnan t rat s induce d dose-dependen t materna l toxicit y a t level s o f 9 an d 1 8 mg/kg/day . Materna l surviva l wa s no t affecte d b y th e administratio n o f th e tes t article . Toxicit y wa s expresse d b y clinica l sign s an d reduce d bod y weigh t gai n an d foo d intake . Cesarea n sectio n wa s performe d a t GD2 0 an d th e resultin g gravi d uterin e weigh t an d feta l parameters , includin g th e numbe ro f corpor a lutea , implantatio n sites , pre-implantatio n sites , viabl e fetuses , earl y o rlat e resorptions , feta l bod y weight , an d se x ratio , wer e comparabl e betwee n th e contro l an d ethopro p group s wit h th e exceptio n o f th e mea n numbe ro f earl y resorption s whic h wa s significantl y decrease d i n th e mi d dos e grou p ( 9 mg/kg/day ) relativ e t o th e contro l o rothe rtreate d groups . A s a simila r findin g wa s no t observe d a t th e hig h dose , thi s decreas e wa s considere d t o b e o f rando m occurrence . I n a developmenta l toxicit y stud y (Rodwell , 1989b ) ora l administratio n o f ethopro p t o pregnan t rabbit s di d no t affec t materna l survival . Ther e wer e n o treatment-relate d clinica l sign s observe d i n th e ethopro p groups . Materna l bod y weigh t gai n an d foo d intak e wer e simila ri n th e contro l an d treate d groups . Cesarea n sectio n wa s performe d a t GD2 9 an d th e resultin g gravi d uterin e weigh t an d feta l parameters , includin g th e numbe ro f corpor a lutea , implantatio n sites , pre implantatio n sites , viabl e fetuses , earl y o rlat e resorptions , feta l bod y weight , an d se x ratio , wer e comparabl e betwee n th e contro l an d ethopro p group s wit h th e exceptio n o f th e mea n numbe ro f viabl e fetuses , whic h wa s significantl y decrease d i n th e mi d dos e grou p (1.2 5 mg/kg/day ) relativ e t o th e contro l o rothe rtreate d groups . A s a simila rfindin g wa s no t observe d a t th e hig h dose , thi s decreas e wa s considere d t o b e o f rando m occurrence . Result s o f estroge n recepto ractivit y i n i n vitr o reporte rgen e assay s wit h ethopro p (Kojima , .2004) , teste d fro m 10" 8 

### t o 10" 5 

### M di d no t identify ethopro p a s havin g estrogeni c no ranti estrogeni c activit y usin g transfecte d Chines e Hamste rOvary-K 1 cells . Du e t o th e lac k o f detail s reporte d b y Kojim a e t a/. , i n particula rth e lac k o f informatio n o n cytotoxicit y a s wel l a s a lac k o f actua l dat a reporte d fo rethoprop , thi s publicatio n doe s no t substantiall y mee t th e Klimisc h criteri a (Klimisch , 1997 ) an d shoul d b e considere d a s unreliable . Pag e 7 o f 3 2

## Baye rCropScienc e Repor t No . G20214 8 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 . A fis h ful l lif e cycl e stud y o n ethopro p wit h supportin g result s fro m tw o earl y lif e stag e studie s i n fis h i s bein g cite d t o addres s th e requiremen t fo ra fis h short-ter m reproductio n study . Thes e studie s versu s th e fis h short-ter m reproductio n scree n ar e discusse d abov e unde rth e estroge n system . Th e othe rassay 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 ethoprop . However , adequat e informatio n exist s t o asses s ethoprop' s potentia l t o interfer e wit h th e androge n system . A s show n i n Table s 1 a an d 1b , relevan t data , whic h ar e functionall y equivalen t t o addres s th e purpos e o f EPA' s Tie r1 screenin g battery , 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 , chroni c do g studies , developmenta l toxicit y studies , an d a two-generatio n ra t reproductio n study . Al l o f thes e latte r studie s wer e conducted , unde rGLP , hav e bee n reviewe d b y EPA , an d ar e classifie d a s acceptable . Othe rScientificall y Relevan t Information : Endpoints fro m guidelin e studie s tha t are relevan t i n th e assessmen t o f a compound' s potentia l t o caus e androgeni c o ranti-androgeni c activit y ar e show n i n Table s 1 a an d 1b . Th e relevan t endpoint s show n i n Table s 1 a an d 1 b fro m a two-generatio n ra t stud y (Neeper-Bradley , 1991) , developmenta l neurotoxicit y ra t stud y (Sheets , 2004) , chroni c mous e stud y (Inoue , 1984) , chroni c ra t stud y (Williams , 1992) , chroni c do g stud y (Brown , 1986) , ra t teratolog y stud y (Rodwell , 1989a ) an d rabbi t teratolog y stud y (Rodwell , 1989a ) ar e presente d i n th e "Othe r Scientificall y Relevan t Information " o f Vn e Estroge n Syste m section . I n th e two-generatio n ra t stud y thes e endpoint s includ e reproductiv e indice s i n F O an d F 1 parent , litte rparameter s (F 1 an d F2) , pu p se x rati o an d histopatholog y o f semina l vesicles , epididymides , prostate , teste s (F O an d F 1 parenta l <$)
. Th e pu p se x rati o an d preputia l separatio n ar e discusse d i n th e developmenta l neurotoxicit y ra t study . I n th e chroni c dog , ra t an d mous e studies , teste s weight s an d histopatholog y o f mal e se x organ s ar e presented . Th e feta l se x ratio s i n th e ra t an d rabbi t teratolog y studie s ar e discussed . Result s o f androge n recepto ractivit y i n i n vitr o reporte rgen e assay s wit h ethopro p (Kojima , 2004) , teste d fro m 10~ 8 t o 10~ 5 M di d no t identify ethopro p a s havin g androgeni c no ranti androgeni c activit y usin g transfecte d Chines e Hamste rOvary-K 1 cells . Du e t o th e lac k o f detail s reporte d b y Kojim a e t a/. , i n particula rth e lac k o f informatio n o n cytotoxicit y a s wel l a s a lac k o f actua l dat a reporte d fo rethoprop , thi s publicatio n doe s no t substantiall y mee t th e Klimisc h criteri a (Klimisch , 1997) an d shoul d b e considere d a s unreliable . 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 batter

y 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 ethoprop , adequat e informatio n exist s t o asses s ethoprop 1 potentia l t o interfer e wit h th e hypothalamic-pituitary-thyroida l (HPT ) axis . A s show n i n Table s 1 a an d 1b , Pag e 8 o f 3 2

## Baye r CropScienc e Repor t No . G20214 8 relevan t data , whic h ar e functionall y equivalen t t o th e purpos e o f EPA' s Tie r1 screenin g battery , 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 , chroni c do g studies , a two-generatio n ra t reproductio n study , a developmenta l neurotoxicit y (DNT ) study , an d developmenta l toxicit y studies . Al l o f thes e studie s wer e conducte d unde r GLP , hav e bee n reviewe d b y EPA , an d ar e classifie d a s acceptable . Finding s relevan t fo ra n assessmen t o f potentia l effect s o n th e thyroi d syste m ar e describe d below . Whe n teste d u p t o 150/30 0 pp m i n th e die t i n a two-generatio n ra t stud y (Neeper-Bradley , 1991) , ethopro p ha d n o effec t o n absolut e an d relativ e thyroi d weight s fo rF O an d F 1 parenta l animals . Further , n o histopathologica l change s wer e observe d i n th e thyroi d o rpituitar y examine d fro m F O an d F 1 animals . Mea n numbe ro f liv e pup s pe rlitte ro n PN D 0 wa s statisticall y simila racros s al l treatmen t group s fo rF 1 an d F 2 litters . Durin g th e firs t post weanin g week , significan t mortality wa s observe d i n F1 A pup s a t th e hig h dos e (30 0 ppm ) an d sufficien t numbers o f F1 A pup s a t thi s dos e wer e no t expecte d t o b e availabl e fo rmatin g t o produc e th e F 2 generation . Sinc e th e hig h dos e exceede d th e maximu m tolerate d dos e fo r pups , th e leve l fo rF O parenta l animal s wa s decrease d b y on e hal f (15 0 ppm ) 3 week s prio rt o th e secon d matin g period . Hig h dos e F O parenta l animal s wer e maintaine d o n th e 15 0 pp m tes t diet s throug h termina l sacrifice . Approximatel y fou r(4 ) week s afte rth e weanin g o f th e las t F1 A litters , th e F O parent s wer e paire d agai n fo rthre e (3 ) week s t o produc e th e F1 B generation . Mea n F1 B pu p bod y weight s pe rlitte r(total , mal e an d female ) were equivalen t acros s dos e group s t o L D 14 . Afte rwhic h bod y weight s wer e decrease d i n femal e an d mal e F1 B pup s a t 15 0 ppm . F1 B pu p surviva l indice s wer e unaffecte d b y treatment . F 2 pu p bod y weight s wer e equivalen t acros s dos e group s fro m birt h throug h L D 4 . Pu p bod y weigh t gain s pe rlitte rwer e significantl y reduce d a t 15 0 pp m fro m L D 4-28 . A reductio n i n F 2 pu p weigh t gai n wa s als o observe d a t 3 0 pp m fo rL D 4-7 . Increase d weigh t gai n fo rL D 14-2 1 a t 3 0 pp m mos t likel y represente d a compensator y increas e followin g a previou s weigh t los s o rstabilizatio n o f litte r weight s a s th e pup s bega n t o sel f feed . Fro m L D 7 t o 14 , a numbe r(3% ) o f pup s fro m th e 15 0 pp m dos e grou p died . Consequently , th e 14-da y F 2 pu p surviva l inde x an d th e lactationa l index wer e reduced . Pu p surviva l indice s fo rL D 0 , 4 , 7 , 2 1 an d 2 8 wer e equivalen t acros s groups . Effect s o n pu p growt h an d surviva l ar e du e t o genera l systemi c toxicit y o f ethoprop . I n a chroni c mous e stud y (Inoue , 1984) , n o treatmen t relate d histopathologica l finding s i n th e liver , pituitar

y an d thyroi d wit h parathyroi d wer e noted . I n th e chroni c do g stud y (Brown , 1986) , n o change s i n orga n weight s o rhistopathologica l finding s wer e note d i n th e pituitar y an d thyroid . Histopatholog y o f th e live rdi d indicat e treatment-relate d hepatotoxicit y a t th e hig h dose . I t i s probabl e tha t th e inconsisten t elevatio n o f GP T an d alkalin e phosphatase , reduction s i n tota l plasm a cholesterol , protei n an d albumi n level s reflecte d persistent , moderat e live rinjury , onc e thes e constituent s ar e synthesize d i n th e liver . Thes e change s ar e therefor e considere d t o b e secondar

y t o th e primar

y hepati c injury . Thre e long-ter m ra t dietar y studie s wit h ethopro p wer e performed . I n a n acceptabl e guidelin e chroni c ra t stud y (Williams , 1992) , Crl:CD®(SD)B R VAF/plus ® rat s wer e fe d wit h die t containin g ethopro p a t 0 , 1. 0 ppm , 6 0 ppm , 40 0 (reduce d fro m 60 0 pp m durin g wee k

3 ) fo r10 4 weeks . Eac h grou p containe d 7 0 animals/se x fo rth e carcinogenicit y phas e (sacrific e schedule d a t wee k 104 ) an d 1 0 animal s fo rth e chroni c phas e (sacrific e schedule d a t wee k

52) . Th e contro l an d top-dos e grou p containe d 1 0 extr a animal s fo ra reversibl y phase , pu t unde rnorma l die t fo r1 mont h afte rwee k 5 2 (sacrific e a t wee k

57) . Pag e 9 o f 3 2

## Baye rCropScienc e Repor t No . G20214 8 Statistica l analysi s demonstrate d tha t ther e wa s n o differenc e fo rthyroi d tumo rincidence s betwee n treate d an d contro l groups . Th e apparen t highe rrat e o f thyroi d tumor s i n mal e rat s treate d wit h 40 0 pp m wa s du e t o th e highe rsurviva l o f thi s group . Additionally , historica l contro l dat a demonstrat e tha t thyroi d tumo rincidence s observe d i n thi s stud y ar e no t unexpecte d an d withi n a norma l rang e o f values . Thi s support s strongl y th e absenc e o f treatment-relate d effec t fo rthi s observation . I n tw o chroni c ra t studie s (Barnett , 1983 ; Spicer , 1987) , considere d b y EP A a s supplemental , ethopro p wa s administere d t o Fishe r34 4 rat s fo rtw o years . Ther e wa s a margina l increas e o f thyroi d tumor s i n thes e tw o studie s a t th e highes t leve l tested , howeve rther e wa s n o observe d dos e response . Th e William s stud y conducte d wit h a hig h dos e tw o t o fou rtime s th e hig h dos e use d i n thes e tw o studie s demonstrate d n o increas e i n thyroi d tumor s whe n adjuste d fo r survival . Therefore , th e thyroi d tumo rincidenc e observe d i n th e ethopro p studie s shoul d no t b e considere d a s treatmen t related . 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 , 2009a) . 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 (USEP A 2009c) . A revie w o f existin g thyroi d assay s wa s reporte d b y OEC D i n a detaile d revie w pape r(OEC D 2006) . Thi s repor t point s ou t th e conserve d natur e o f th e HP T axis . A s outline d above , a numbe ro f studie s hav e bee n conducte d t o investigat e th e potentia l effect s o f ethopro p o n thyroi d system s o f vertebrates . Thes e studie s wer e als o don e 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 unnecessar

y t o evaluatio n th e thyroi d activit y potentia l i n vertebrates . Th e substantia l existin g dat a fro m studie s i n thre e species , rats , mice , an d dogs , includin g a two-generatio n ra t reproductio n stud y wit h thyroi d weight s an d histopathology , shoul d b e deeme d adequat e fo ra screenin g leve l thyroi d evaluation . Therefore , th e conduct o f a n AM A i s unnecessar y an d woul d resul t i n th e expenditur e o f resource s an d unnecessar y sacrific e o f animals . CONCLUSION S Ther e i s n o publishe d scientifi c literatur e tha t indicate s tha t ethopro p ha s an y endocrin e activity . Th e whol e organis m apica l endpoints , suc h a s reproductio n parameters , orga n weight s an d histopatholog y an d feta l an d offsprin g parameter s reflec t 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 . Baye r CropScienc e (BCS ) believe s tha t existin g dat a o n ethopro p 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 furthe rtestin g i s no t warranted . I n addition , th e toxicit y endpoint s use d fo rethopro p i n huma n healt h ris k assessment s ar e al l base d o n cholinesteras e inhibitio n whic h i s protectiv e o f al l othe rsystemi c toxicities .

Pag e 1 0 o f 3 2

## H H Baye rCropScienc e

^ Repor t No . G20214 8 REFERENCE S Th e followin g studie s hav e bee n submitte d previousl y t o EP A an d are cite d b y MRI D number : MRI D No . 00138636 . Barnett , J. ; Jenkins , L ; Parent , R. ; e t al . (1983 ) Evaluatio n o f th e Chroni c Toxicit y ari d Oncogeni c Potentia l o f Ethopro p i n Fische r34 4 Rats : GSR I Project No . 413-858 - 41 . Fina l rept . /(Unpublishe d stud y receive d Fe b 8 , 198 4 unde r359-694 ; prepare d b y Gul f Sout h Researc h Institute , submitte d b y Rhone-Poulenc , Inc. , Monmout h Junction , NJ ; CDL252358-A ; 252359) . 198 6 p . EP A classificatio n o f supplemental . MRI D No . 00160179 . Brown , D . (1986 ) Ethoprophos : 5 2 Wee k Ora l (Capsul e Administration ) Toxicit y Stud y i n th e Beagle : Rept . No . 4923-198/16 . Unpublishe d stud y prepare d b y Hazleto n Laboratorie s Europ e Ltd . 24 8 p . EP A classificatio n o f acceptable/guideline . MRI D No . 40291801 . Spicer , E . (1987 ) Lifetim e Dietar y Toxicit y an d Oncogenicit y Stud y i n Rats : IRD C Stud y No . 347-029 . Unpublishe d stud y prepare d b y Internationa l Researc h & Developmen t Corp . 258 9 p . EP A classificatio n o f supplemental . MRI D No . 40356301 . Inoue , H . (1984 ) Chroni c Feedin g an d Oncogenicit y Studie s i n Mic e wit h Ethoprop : Rept . No . 497 . Unpublishe d stud y prepare d b y Biosafet y Researc h Cente r(AN-PY O Center) . 249 0 p . EP A classificatio n o f acceptable/guideline . MRI D No . 406501-02 . Surprenant , D . C . (1987 ) Th e Toxicit y o f Ethopro p Technica l t o Fathea d Minno w (Pimephale

s promelas ) Embryo s an d Larvae . Springbor n Smither s Laboratories , Wareham , MA , USA . Laborator y Repor t Numbe rBW-87-6-2408 , Decembe r3 , 1987 . Unpublished . EP A classificatio n o f acceptable/guideline . MRI D No . 41304402 . Rodwell , D . (1989a ) Teratolog y Stud y i n Rat s wit h Ethoprop : Fina l Report : La b Project Number : 3147.39 . Unpublishe d stud y prepare d b y Springbor n Lif e Sciences , Inc . 24 1 p . EP A classificatio n o f acceptable/guideline . MRI D No . 41304403 . Rodwell , D . (1989b ) Teratolog y Stud y i n Rabbit s wit h Ethoprop : Fina l Report : La b Project Number : 3147.41 . Unpublishe d stud y prepare d b y Springbor n Lif e Sciences , Inc . 25 0 p . EP A classificatio n o f acceptable/guideline . MRI D N o 41921201 . Neeper-Bradley , T . (1991 ) Two-Generatio n Reproductio n Stud y o f Ethopro p Technica l Administere d i n th e Die t t o C D (Sprague-Dawley ) Rats : La b Project Number : 53-598 . Unpublishe d stud y prepare d b y Bush y Ru n Researc h Cente r(Unio n Carbide) . 91 3 p . EP A classificatio n o f acceptable/guideline . MRI D No . 42530201 . Williams , K . (1992 ) 104-Wee k Combine d Chroni c Toxicit y an d Carcinogenicity Stud y wit h Ethopro p i n Rats : La b Projec t Number : HLA 6224-151 . Unpublishe d stud y prepare d b y Hazleto n Lab s America , Inc . 372 0 p . EP A classificatio n o f acceptable/guideline . MRI D N o 43326001 . Rhone-Poulen c A g C o (1994 ) Chroni c Feedin g an d Oncogenicity Studie s i n Mic e wit h Ethoprop : Supplement : La b Projec t Number : 497 : 0094/025/002 . Unpublishe d study . 171 2 p . EP A classificatio n o f acceptable/guideline . Pag e 1 1 of 3 2B A 

## Baye rCropScienc e Repor t No . G20214 8 MRI D No . 444721-01 . Sousa , J . V . (1997) Ethopro p Technica l - Earl y Life-Stag e Toxicit y Tes t wit h Sheepshea d Minno w (Cyprinodo n variegatus) . Springbor n Smither s Laboratories , Wareham , MA , USA . Laborator y Repor t Numbe r97-10-7127 , Decembe r12 , 1997 . Unpublished . EP A classificatio n o f acceptable/guideline . MRI D No . 46315401 . Dionne , E . (2004 ) Ethopro p - Chroni c Toxicit y t o th e Sheepshea d Minno w (Cyprinodo n variegatus ) Durin g a Ful l Life-Cycl e Exposure . Springbor n Smither s Laboratories , Wareham , MA , USA . Laborator y Repor t Numbe r13798.6154 , Jun e 29 , 2004 . Unpublished . EP A classificatio n o f acceptable/guideline . MRI D N o 46364801 . Sheets , L ; Fickbohm , B . (2004 ) A Developmenta l Neurotoxicit y Screenin g Stud y wit h Technica l Ethopropho s i n Wista rRats . Project Number : B004723 , 201113 , 03/D72/PQ . Unpublishe d stud y prepare d b y Baye rCorp . 110 3 p . EP A classificatio n o f acceptable/guideline . Th e followin g guideline s an d revie w pape rwer e use d fo rreference : OECD , 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 Assessment . No . no t assigned . Paris , France . USEPA , 1985 . Offic e o f Pesticid e Programs . Standar d Evaluatio n Procedur e fo rFis h Earl y Lif e Stag e Toxicit y Tests . EPA-540/9-86-138 . U.S . Environmenta l Protectio n Agency , Washingto n D.C . 

### USEPA , 1986 . Offic e o f Pesticid e Programs . Standar d Evaluatio n Procedur e fo rFis h Life Cycl e Toxicit y Tests . EPA-540/9-86-137 . U.S . Environmenta l Protectio n Agency , Washingto n D.C . 

### USEPA , 1996a . Offic e o f Prevention , Pesticide s an d Toxi c Substances . Tes t Guideline , 850.1400 : Fis h Early-Lif e Stag e Toxicit y Test . "Publi c Draft" . EP A 712-C-96-121 . Apri l 1996 . U.S . Environmenta l Protectio n Agency . Washington , D.C . USEPA , 1996b . Offic e o f Prevention , Pesticide s an d Toxi c Substances . Tes t Guideline , 850.1500 : Fis h Lif e Cycl e Toxicity . "Publi c Partia l Draft" . EP A 712-C-96-122 . Apri l 1996 . U.S . Environmenta l Protectio n Agency . Washington , D.C . USEPA , 2009a . Tes t Order/DC I # : EDSP-041101-4 2 fo rEthoprop . Dat e Issued : 11/05/2009 . USEPA , 2009b . Offic e o f Prevention , Pesticide s an d Toxi c Substances . Tes t Guideline , 890.1350 : Fis h Short-Ter m Reproductio n Assay . EP A 740-C-09-007 . Octobe r2009 . U.S . Environmenta l Protectio n Agency . Washington , D.C . USEPA , 2009c . 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 . Octobe r2009 . U.S . Environmenta l Protectio n Agency . Washington , D.C . Publishe d literature : Pag e 1 2 o f 3 2

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## OopScienc e Repor t No . G20214 8 Klimisch , H.-J. , Andreae , M an d Tillman , U . (1997 ) A Systemati c Approac h fo rEvaluatin g th e Quality o f Experimenta l Toxicologica l an d Ecotoxicologica l Data . Regulator y Tox . an d Pharm . 25:1- 5 Kojima , H. , Katsura , E. , Takeuchi , S. , Niiyama , K. , an d Kobayashi , K . (2004) . Screenin g fo r estroge n an d androge n recepto ractivitie s i n 20 0 pesticide s b y i n vitr o reporte rgen e assay s usin g Chines e Hamste rOvary cells . Environ . Healt h Perspect . 112 : 524-531 .

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## Baye r CropScienc e Repor t No . G20214 8 Tabl e 2 Fis h Short-Ter m Reproductio n Assa y En d point s Compare d t o Existin g

Endpoint s Collecte d fo rEthopro p fro m Fis h Chroni c Exposures . Fis h Short-ter m Reproductio n Assa y Stud y Duration : 2 1 Day s Lif e Stage : Matur e Adult s Endpoint s Require d Reproductiv e Behavio ran d SC O appearanc e Surviva l

Growt h Adul t lengt h Adul t weigh t

Fertilizatio n succes s Fecundit y Biomarkers 3 SS C measurement s Vitellogeni n Gonada l Somati c Inde x Gonada l histopatholog y Plasm a se x steroid s (optional ) Ethopro p Fis h Earl y Lif e Stag e Assa y (2 ) MRI D No . 40650 1 -0 2 an d 444721-0 1 Stud y Duration : 33-3 5 Day s Lif e Stage ; eg g t o larva e Endpoint s Include d Genera l Behavio r Surviva l

Growt h larva e lengt h larva e we t weigh t and/o r larva e dr y weigh t

Viability an d hatchin g succes s Ethopro p Fis h Ful l Lif e Cycl e Assa y MRI D No . 4631540 1 Stud y Duration : 11 2 Day s Lif e Stage : Al l (eg g t o reproductiv e adul t t o egg s develope d fo r4 weeks ) Endpoint s Include d Genera l Behavior , F 0 reproductiv e behavio ran d SC C appearanc e F 0 28-da y surviva l F 0 55-da y surviva l F 0 112-da

y surviva l F- i 28-da y surviva l Growt h F o 28-da y lengt h F 0 28-da y we t weigh t F 0 55-da y mal e lengt h F o 55-da y femal e lengt h F o 1 12-day mal e lengt h F o 1 12-da y femal e lengt h F 0 1 12-da

y mal e we t weigh t F 0 1 12-da

y femal e we t weigh t F t 28-da y lengt h F I 28-da y we t weigh t F 0 Hatchin g succes s F ! Hatchin g succes s F 0 Fecundity F T Time-to-hatc h

a

### Biomarker s ar e use d t o sugges t apossibl e mod e o f

action . Sinc e reproductiv e endpoint s wer e no t affecte d i n lif e cycl e testin g thi s informatio n i s no t needed .

Pag e 1 8 o f 3 2

## Baye rCropScienc e Repor t No . G20214 8

Appendi x 1 Titl e Page s fo rPreviousl y Submitte d Studie s Reference d Withi n Thi s Documen t

Pag e 1 9 o f 3 2

# Baye r

OopSd'enc e Repor t No . G20214 8 MRI D No . 0013863 6 

# R00934 4

GUL F SOUT H RESEARC H INSTITUT E ATCHAFALAY A BASI N LABORATORIE S Aa m Cod > 31 8 3SS-MI I AM I Of/it * Bo * lif t Nt

w Ittrtt . Lov/tlv u fOSS O Januar y20 , 198 3

Volume I 6SR I Projec t No . 413-858-4 1 EVALUATIO

NO F TH E CHRONI C TOXICIT

Y AN D ONCOGENI C POTENTIA

L O F ETHOPRO P I NFISCHER 34 4 RAT S FIHA l REPOR T

Prepare d tor : Rhone-Poulenc , lac . Agrocheaica l Divisio n P.O . Bo x 12 5 Monnout h Junction , Ne

w Jerse y0885 2 Prepare d by : Gul f Sout

h Researc

h Institut e P.O . Bo x 117 7 Ne w Iberia , louisian

a 7056 0 

# w &*-*#-

2 > s Willia mBarnett , Jr. , Phfl ^ Toxicologist-Fina l Repor t
Lawrenc e J . Je d Manager , Departmen t o f Toxicolog y Richar d A . Parent , Ph .

Director , Lif e Scienc e Divisio n

^~ , j , , _^ h.D. , D.A.B.T .



### Pag e 2 0 o f 3 2

## Baye r CropScienc e Repor t No . G20214 8 MRI D No . 0016017 9 

# HAZLEtOf M LABORATORIE S EUROP E LT D 

### CONFIDENTIA L R00897 5

ETHOPROPHOS : 5 2 WEE KORA L (CAPSUL E ADMINISTRATION ) TOXICIT Y STUD Y I N TH E BEAGL E

Repor t for : Rtione-Poulen c Agrochlmle , 14-2 0 Ru e Pierr e Baizet , 6900 9 Lyon , FRANCE .
Prepare d by : 0 . Brown , B.Sc. , D.Phil. , Principa l Toxicologis t

Repor t No : Date : Hazleto n Laboratorie s Europ e Ltd. ,

OtleyRoad , Harrogate , Nort h Yorkshire , ENGLAND , HG 3 1PY . 4923-198/1 6 Apri l 198 6

Pag e 2 1 o f 3 2

## Baye r CropScienc e Repor t No . G20214 8 MRI D No . 4029180 1 

## C O 1 1 1 9 0 • 

## Internationa l Researc h an d Developmen

t Corporatio n MATTAWAN . MICHIGAN , U.5> . «W I TUEPHON t 16)6 1 MB- ] 1) 6

Amendman e t o Ch e Fina l Repor t (Dat a Submitted : Apri l 30 , 1985 )

Sponsor : Rhone-Foillea c Agrochiai e Tes t Article : Cthoprop Technica l Subject : Lifetim e Dietar y Toxi c it ; an

d Oncogenicit y Stud y i n Rat i
Dat e o f Submission : Jun e 5 , 198 5

347-02 9

"credence throug h research "

Pag e 2 2 o f 3 2

## Baye r CropScienc e Repor t No . G20214 8 MRI D No . 4035630 1

AN-PY O CEKTEJ t BEPOK T He . 49 7 (1984 ) 

# R00921 6

Chroni c Feedin

g an d Oneogenieit yStudie t i n Mic e vit h Ethoprp

p

(Expctiaea

t Ho . 94 )

Decesibe r 29 , 198 4

Blotafer ySeicarc

h Center , Foedc , Drug s an

d Pecticide c {AK-PT O Center ) 582-2 , A»h«nA , Ebiechlndeo , Fvikude-cho , lv«te-gun , Sbiiuokc-ken , J«pan .



### Pag e 2 3 o f 3 2B A 

## Baye r CropScienc e Repor t No . G20214 8 MRI D No . 406501-0 2 Pag e 1 o f 9 1
ETHOPRO P TECHNICA L - EARL Y LIFE-STAG E TOXICIT Y TES T WIT H SHEEPSHEA D MINNO W (Cyprinodo n varlegatus)

Guidelin e Referenc e Number : 72- 4

Submitte d to : Rhdne-Poulen c A g Compan y 2 T.W . Alexande rDrive Researc h Triangl e Park , N C 2770 9

SL I Repor

t #97-10-712 7 SL I Stud y #10566.0497.6419.52 0 Stud y Director : Josep h V . Sous a Springbo m Laboratories , Inc . 79 0 Mai n Stree t Wareham , Massachusett s 02571-1075

1 2 Decembe r199 7 FINA L REPOR T

Pag e 2 4 o f 3 2

## (B*» e



## j Baye r CropScienc e ^ ^ Repor t No . G20214 8 MRI D No . 4130440 2 Springbo m Laboratories . Inc. M*miMllM i Toxicology DMcto n S5 3 Nort h Broadwa y • SpencavBte . Ohi o 4568

7 • (419 ) 647-419 6 • Wa

x 443604 1 • Facsimile 419-647-656 0

TERATOLOG

Y STUD Y I N RAT S WIT

H ETHOPROP R 0 0 9 2 2 7 FINA L REPOR T

EP ADat a Requiremen t Guidelin e 83- 3 Autho r Dea n E . Ro d veil , M.S . Stud yComplete d o n Novembe r 13 , 198 9
Performing Laborator

y Springbo mLif e Sciences , Inc . (SLS ) Toxicolog

yan d Huma n Safet yDivisio n 55 3 Nort h Broadva

y Spencerville , O

H 4588 7

SL S Stud yMo . 3147.3 9
Submitte d to : Rhone-Poulen c A

g Compan y P . 0 . Bo x 1201 4 Researc h Triangl e Park , N

C 2770 9 Page 1 o f 24 1



### Pag e 2 5 o f 3 2

# N Baye r

CropScienc e Repor t No . G20214 8 MRI D No . 4130440 3 

# R00922 8 TERATOLOG

Y STUD Y I NRABBIT S VIT

H ETHOPRO P FINA L REPOR

T

EP ADat a Requiremen t Guidelin e 83- 3 Autho r Dea n E . Rodvell , H.S . Stud yComplete d o n Novembe r 15 , 198 9
Performin g Laborator

y Springbor

n Lif e Sciences , Inc . (SLS ) Toxicolog

yan d Huma n Safet yDivisio n 55 3 Nort h Broadwa

y Spencerville , O

H 4588 7 SL S StudyNo . 3147.4 1 Submitte d to : Rhone-Poulen c A

g Compan y P . 0 . Bo x 1201 4 Researc h Triangl e Park , N

C 2770 9 Page 1 o f 25 0



### Pag e 2 6 o f 3 2

## Baye r CropScienc e Repor t No . G20214 8 MRIDN o 4192120 1 VeluiMlof 2 t- - O f '7-^ - DocutMnt2of 2 

## BUSH Y RU NRESEARC H CENTE R 670 2 Ntoto n Bead , EKJKJII . Pwm»»h«nl a 16832*90

2 lataphor w (412 ) 73U2O O Thleoopl*r(412)73»48 M Spon«o r 

# p n n Q* » 

# O Q Jan Blacker , Ph.D. , DAB I | \U U 3 t U » 7 Shone-Poulea

c A g Conpui y 2 T . H . Alexander

Driv e Bfloearc h Triangl e Park , H C 2770 9 Stn^ v Tvo-Ccnexatio n Reproductio n Study o f Bthopro p Technica l Administere d i n th e Die t t o C M (8pra»ue-Dawley ) Bat *
Guidelin e 63-4 Substanc e Bthopro p Autho r Terec a L . Keeper-Bradley , Ph.D . Stud yCompletio

n Dat e Jun e 6 . 199 1 Performin

g laborator

y Bush yRu n Researc h Cente r 670 2 Mello n Boa

d Export , P

A15632-890 2 Laborator

yPrelec t I D 53-59 8 Pag e 1 o f 91 3 Unio n Carbid e Chemlral i an d PlMtic s Compan y Inc

. Exallenc s Throutf i Qualit

y

Pag e 2 7 o f 3 2

## Baye rCropScienc e Repor t No . G20214 8 MRI D No . 4253020 1

WISCONSI N rOS T OF'IC f BO X JJ4 I UADICOM . Wl f COM1I N t]7 » 7S« t 

# R00981 2 Sponsor : Rh&ne-Poulen c A g Compan

y Researc h Triangl e Park , Nort h Carolin a

FINA L REPOR T Stud yTitle : 104-Wee k Combine d Chroni c Toxlclt yand Carcinogenic1t y

Stud ywit h Ethopro p i n Rat s

Dat a Requirement : Guidelin e 83- 5 Author : Kevi n 0 . Williams , Ph D Stud yCompletio n Date : Septembe r 10 , 199 2 Performing Laboratory : Hazleto n Laboratorie s America , Inc . 330 1 Kinsma n Boulevar d Madison , Wisconsi n 5370 4 laborator yProjec t Identification :

HL A6224-15 1 Volum e I o f X Pag e 1 o f 372 0



### Pag e 2 8 o f 3 2

## Baye r CropScienc e Repor t No . G20214 8 MRI D N o 4332600 1 

# R0098 U

AN-PY O CENTE

R REPOR T No . 49 7 (1984 ) Chroni c Feedin g an d Oncogenicit y Studie s i n Mic e wit

h Ethopro o SUPPLEMENTAR

Y SUBMISSIO

N TO EP A ACCESSIO

N No . 4035630 1 Supplementar

y Submission Date : 2 9 Jul y 199 4 (Experimen t

No . 94 ) Decembe r 29,1984

Biosafet y Researc h Center , Foods , Drug s and Pesticide s (AN-PY O Center

) 582-2 , Arahama , Shioshinde n Fukude-cho , Iwata-gun , Shizuoka-ken , Japan .
Pag e 1 o f 171 2

Pag e 2 9 o f 3 2

## Baye rCropScienc e Repor t No . G20214 8 MRI D No . 444721-0 1 

## B00445 2 #BW-87-6-240 8 

### Pag e 1 o f

4 1

TH E TOXICIT

Y O P ETHOPRO

P TECHNICA

L T O FATHEA

D MINNO W (Pimephale s proroelas ) EMBRYO S AN D LARVAE

Guidelin

e Referenc e Number : 72- 4

RHON E POULENC , A

G COMPAN

Y T.W . ALEXANDE R DRIV E P . O . BO

X 1201 4 RESEARC

H TRIANGL E PARR , NORT H CAROLIN

A2770 9

SL S REPOR

T i : BW-87-6-240 8 SL S STUD Y | : 10566.0986.6105.12 0 STUD Y DIRECTOR : Donald C . Surprenan t

Springbor

n Lif e Sciences , Inc . 79 0 Mai n Stree t Wareham , Massachusett s 0257 1 Revise d Fina l Repor t Decembe r 3 , 198 7



### Pag e 3 0 o f 3 2B A 

## Baye r CropScienc e Repor t No . G20214 8 MRI D No . 4631540 1 

### Baye rCropScience EBERX01 1 B00467 4 STUD Y TITL E Ethopro p - Chroni c Toxicit y t o th e Sheepshea d Minno w (Cyprinodo n variegatus

) Durin g a Ful l Life-Cycl e Exposur e DATA REQUIREMEN T FIFR A Guidelin e Numbe r72- 5 AUTHO R Emil y Dionn e STUD Y COMPLETIO N DAT E 2 9 Jun e 200 4 PERFORMIN G LABORATORY Springbo m Smither

s Laboratorie s 79 0 Mai n Street Wareham , Massachusett s 02571-1075

SPONSO R Baye rCropScience 17745 S . Metcal f Avenu e Stilwell , Kansa s 6608 5 LABORATORY PROJEC T I D Springbo m Smither

s Study No . 13798.615

4 Sponso rProtocol/Projec t No . YM85280 1 Baye rStud y No . EBERX01 1 Pag e 1 of 11 4

Pag e 3 1 o f 3 2

# p4 4 Baye r

CropScienc e Va X 

## Repor t No . G20214 8 MRI D N o 4636480 1 Repor t Number 20111 3 B004723 

## A Developmenta

l Neurotoxlett

y Screening Stud

y wit h Teehnlea l Grade Ethopropho aIn Wteta r Rate Dat a Requiremen

t U.S. EPA , OPPT

S 870.630

) 

### HaaB h Canad aPMR

A DAC O No . 4.5.1 2
Author * Lany P . Sheets , PlUXan dBarr

y Rckbohm , DVM , Ph.D . Stud y Completio n Dat

e Septembe r 10,200 4 Ter t Facilit y Baye rCropSdeno

e I P 1774 5 Sout h Metoal f Avenu e SMtweH . Kansa s 68085410

4 Stud y Number 03-D72-P Q


### Pag e 1 o f 110 3

Pag e 3 2 o f 3 2