# Baye r

CropScienc e Repor t No
. G20215 5

Title : 90-DA Y RESPONS E T O ERA' S TES T ORDE R FO R ENDOCRIN E SCREENIN G O N CYFLUTHRI N (Orde rDCI # EDSP-128831-74 )

Guideline : OPPT S 89 0 Guidelin e Serie s

Authors : Dan a E
. Sargent , M S Michae l Dobbs , Ph D
Date : Februar y 26 , 201 0
Submitter : Baye rCro p Scienc e P.O
. Box1201 4 Researc h Triangl e Park , N C 2770 9

Repor t ID : G20215 5

Pag e 1 o f 3 8

## Baye rCropScienc e Repor t No
. G20215 5 STATEMEN T O F N O 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)(1)(A)(B) , o r(C)
. Thes e dat a ar e th e propert y o f Baye rCropScience , an d a s such , ar e considere d t o b e confidentia l fo ral l purpose s othe rtha n complianc e wit h FIFRA § 10
. Submissio n o f thes e dat a i n complianc e wit h FIFR A doe s no t constitut e a waive ro f an y righ t t o confidentialit y whic h ma y exis t unde ran y othe rstatut e o ri n an y othe rcountry . Th e abov e statemen t supersede s al l othe rstatement s o f confidentiality tha t ma y occu relsewher e i n thi s report . Compan y Agent : Sherr

y Movassagh i Baye rCropScienc e Regulator

y Manage r Signature/Date : 2/26/20

_

Pag e 2 o f 3 8

## Baye rCropScienc e Repor t No
. G20215 5 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
.

Dan a E
. Sargent , M S Toxicologis t Baye rCropScienc e 2 5 Februar y 201 0 Dat e

Michae l Dobbs , Ph D Ecotoxicologis t Baye rCropScienc e Dat e

Pag e 3 o f 3 8

## Baye rCropScienc e Repor t No
. G20215 5 90-DAY RESPONS E T O ERA' S TES T ORDE R FO R ENDOCRIN E SCREENIN G O N CYFLUTHRI N O n Novembe r19 , 2009 , EP A issue d a Tes t Orde rfo rendocrin e screenin g o n cyfluthri n (Orde rDCI # EDSP-128831-74)
. 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 have 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 cyfluthri n ar e adequat e t o asses s th e potentia l fo rthi s compoun d t o interact 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 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 weights , histopathology , an d sexua l developmen t 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 have bee n assesse d i n th e Guidelin e studie s o n cyfluthrin , 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 Tabl e 1 a & b
. 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 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
. I n additio n t o considerin g dat a provide d b y hig h quality 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 at . (1997 ) ha s bee n utilize d t o evaluat e th e quality 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 i n man y countrie s includin g EP A i n th e Hig h Productio n Volum e Progra m unde r TSCA
. Further , wor k

i n th e literatur e ha s bee n compare d t o th e relevan t assa y describe d i n th e OPPT S 89 0 Guidelin e Serie s t o identify majo rdifference s betwee n th e assa y include 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 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 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
. A fis h ful l lif e cycl e stud yo n cyfluthri n 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 cyfluthrin
. However , adequat e informatio n exist s t o asses s cyfluthrin' s potentia l t o interac t wit h th e estroge n system . A s show n i n Tabl e 1 a & b , relevan t dat a 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 , subchroni c an d chroni c do g studies , developmenta l toxicit y studies , a developmenta l neurotoxicit y stud y i n ra t 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 accordin g t o OPPT S Guidelines , unde rGLP , hav e bee n reviewe d b y EPA , an d ar e classifie d a s acceptable
. Fish Ful l Life Cycl e Study : A fis h short-ter m reproductio n assa y i s include d i n th e EDS P Tie r1 battery
. Thi s assa yscreen s fo r disturbance 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 xcharacteristics , histopathology , an d fecundit y (i.e. , numbe ro f spawns , numbe ro f eggs/spawn , fertility , an d developmen t o f offspring ) offis h expose d t o tes t chemical s (USEP A Order/DC I #EDSP-128831-74)
. 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
Pag e 4 o f 3 8

## Baye rCropScienc e Repor t No
. G20215 5 short-ter m reproductio n scree n i s t o measure th e reproductiv e performanc e o f a grou p o f fathea d minnow s a s th e primar

yindicato rfo rendocrin e disruptio n (EP A 200 9 890.1350)
. I n th e cas e o f cyfluthrin , potentia l effect s o n fis h reproductio n hav e alread ybee n extensivel ystudied
. A ful l lif e cycl e stud ywa s conducte d o n th e fathea d minno w (Pimephale s promelas) startin g wit h recentl y fertilize d egg s ( < 2 4 hr s old) , an d continuin g fo r30 1 day s pos t hatc h unti l th e F t fis h wer e 6 0 day s ol d (Rodes , e t a/ , 1990 ; MRI D 41450401)
. Thi s stud ywa s classifie d a s 'core' , meetin g th e guidelin e requiremen t 72-4(a ) fo ra freshwate rfis h lif e cycl e study
. A compariso n o f th e endpoint s measure d i n thi s stud yan d th e en d point s measure d i n th e Tie r1 fis h short ter m reproductio n assa yi s give n i n Tabl e 2
. Surviva l wa s th e mos t sensitiv e paramete ri n thi s study , wit h th e parenta l generatio n showin g a marke d reductio n o f surviva l durin g th e firs t hal f o f th e stud ya t th e highes t leve l teste d (0.2 9 ppb)
. Surviva l an d hatchability o f th e F 1 generatio n wer e als o reduce d a t th e highes t tes t concentration
. Hatchabilit yo f th e F O generatio n wa s no t significantl yimpacte d a t an ytreatmen t level
. N o impac t o n growt h o f th e F O o rF 1 generation s wa s observe d a t level s belo w whic h surviva l effect s wer e significant
. Wit h respect t o reproductiv e performanc e fiv e parameters wer e examined : numbe ro f spawns , numbe ro f eggs , eggs/spawn , reproductiv e days , an d eggs/pair/reproductiv e day , alon g wit h hatchability
. N o treatmen t relate d reproductiv e effect s wer e see n a t dose s whic h di d no t als o caus e significan t impairmen t o f survival
. A s previousl ynote d t o th e agency(BC S lette ro f Fe b 200 8 i n respons e t o F R notic e draft lis t o f candidate s fo rscreening ; se e Appendi x2) , ther e i s littl e evidenc e tha t cyfluthri n directl yinfluence s estrogen , androge n an d thyroi d systems . I n ecotoxicologica l test s surviva l o rgrowt h effect s wer e typicall y a s sensitive , o rmor e so , tha n reproductiv e endpoint s base d o n th e fathea d reproductio n stud y discusse d above , a s wel l a s daphni d an d mysi d reproductio n studies
. At a minimum , thi s "othe r scientificall yrelevan t information " (OSRI ) shoul d b e considere d adequat e t o mee t th e need s o f th e dat a reques t fo ra fis h short-ter m reproductiv e screen , an d therefore , th e nee d t o conduct thi s assa yshoul d b e waived
. No t full yutilizin g th e existin g fis h reproductiv e dat a fo rcyfluthri n an d requirin g a more rudimentar

ytie r1 scree n woul d caus e undu e expenditure s o f time , mone yan d animals
. Othe rScientificall y Relevan t Information : Endpoint s fro m guidelin e studie s tha t ar e relevan t i n th e assessmen t o f a compound' s potentia l t o caus e estrogeni c o ranti-estrogeni c activit yar e show n i n Table s 1 a & b
. I n a two-generatio n ra t stud y (Eigenberg , 1996 ; MRI D 4437101 ) conducte d accordin g t o OP P 83- 4 Guideline , P adult s wer e expose d t o Cyfluthri n 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 fo rth e F 1 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 post-nata l (PND ) 1 1 o r1 2 whe n pup s begi n t o consum e treate d die t an d fro m PN D 21 , continue s fo r1 0 week s prematin g throughou t mating , gestation , an d lactatio n period s fo rpup s selecte d t o becom e F 1 parents . Thus , th e exposur e duratio n fo rth e F 1 generatio n exceed s tha t require d b yth e puberta l assa yan d therefor e provide s a more 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 40 0 pp m i n th e die t i n th e two-generatio n ra t study , cyfluthri n ha d n o effec t o n mating , fertility , pregnancy , o rgestationa l indice s o f P O o rF 1 females
. Estrou s cycl e length , gestationa l lengt h i n days , an d stag e o f estru s a t necrops ywer e simila racros s al l groups . Precoita l interva l wa s equivalen t acros s al l groups . Matin g indice s fo rP an d F 1 male s wer e als o simila racros s al l groups . Ther e wa s a statisticall y significan t decreas e i n absolut e ovaria n weigh t i n th e high-dos e grou p P females , an d statisticall y significan t decreas e i n absolut e testicula rweigh t i n th e high-dos e grou p F 1 males
. Neithe r effec t wa s though t t o b e compound-relate d a s ther e wer e n o correspondin g decrease s i n th e relativ e weights , th e change s wer e no t see n acros s generations , an d n o histopathologica l change s wer e observe d i n an y reproductiv e organ s examine d (testes , ovaries , cervix , epididymis , pituitary , prostate , semina l vesicles/coagulatin g gland , uterus , an d vagina ) fro m P an d F 1 animals
. Pag e 5 o f 3 8

## Baye rCropScienc e Repor t No
. G20215 5 I n addition , th e numbe ro f implantatio n site s pe rdam , post-implantatio n los s pe rlitter , mea n numbe ro f live pup s pe rlitte ro n PNDO , an d se xratio s wer e simila racros s al l treatmen t group s fo rF 1 an d F 2 litters
. N o anomalie s o f externa l genitali a wer e note d fo rF 1 o rF 2 pups . I n a developmenta l neurotoxicit ystud y wit h beta-cyfluthri n (Sheets , 2003 ; MRI D 46054101) , acquisitio n o f vagina l patencyan d preputia l separatio n i n F 1 offsprin g wa s unaffecte d u p t o 20 0 ppm , eve n i n th e presenc e o f u p t o 10 % decrease s i n bod yweigh t an d bod yweigh t gain
. I n a ra t developmenta l toxicit ystud y(Astroff , 1996 ; MRI D 44116501 ) wit h beta-cyfluthri n ther e wer e n o effect s o n th e numbe ro f corpor a lutea , implantatio n sites , litte rsize , liv e fetuses , resorptions , pre implantatio n los s o rse xratio
. Ther e wa s sligh t increas e i n percen t post-implantatio n loss , a s wel l a s a decreas e i n feta l weight s an d a sligh t increas e i n skeleta l variant s indicativ e o f growt h retardatio n a t th e highes t dos e o f 4 0 mg/kg/day
. Thes e effect s wer e associate d wit h significan t materna l toxicity , whic h resulte d i n mortalit yfo r3 dam s i n thi s dos e group . I n a rabbi t developmenta l toxicit ystud y(Becker , 1992 ; MRI D 42675401 ) wit h cyfluthri n ther e wer e n o treatment-relate d effect s o n th e numbe ro f liv e litters , feta l weights , implantations , external , viscera l o rskeleta l malformation s an d variations
. Post-implantatio n los s (expresse d a s a percentag e o f th e numbe ro f implantatio n sites ) wa s significantl yincrease d a t 6 0 an d 18 0 mg/kg/day
. However , bot h th e stud y autho ran d th e EP A revie w conclude d tha t thi s wa s a biologica l respons e tha t occurs i n doe s wit h hig h number s o f implantatio n sites
. (EPA , HED , Toxicolog yChapte rfo r Cyfluthrin/Beta-Cyfluthrin ; date d Jul y18 , 2002 ; TXR # 005081 ; D P Barcaod e D283924 ) Ther e i s a numbe ro f developmenta l toxicit ystudie s conducte d i n ra t vi a th e inhalatio n rout e o f exposur e (Renhof , 1988 ; MRI D 40780401 ; Holzum , 1994 ; MRI D 43393401)
. Whil e ther e wer e indication s o f delaye d feta l developmen t a t th e highes t doses , mechanisti c studie s showe d thes e effect s t o b e secondar yt o impairmen t o f materna l ventilatio n (bradypne a an d hypothermia ) resultin g i n hypoxi a an d respirator y acidosis
. Ther e wa s n o significan t decreas e i n numbe ro f implantatio n sites , numbe ro f female s wit h viabl e fetuses , o rnumbe ro f resorptions
. Ther e wa s a sligh t decreas e i n corp a lute a an d numbe ro f fetuses , bu t onl ya t th e highes t dose , whic h wa s agai n considere d secondaryt o significan t materna l toxicity
. Therefore , base d o n th e dat a available , ther e ar e n o endocrine-relate d endpoint s o f concer n identifie d i n th e developmenta l toxicit ystudies
. I n a chroni c mous e stud y(Wahle , 1998 ; MRI D 44589701) , whe n CD- I mic e wer e administere d cyfluthri n technica l i n th e die t fo r1 8 months , absolut e an d relativ e ovaryweigh t wa s decrease d a t th e highes t dos e teste d (HOT) o f 160 0 pp m (equivalen t t o 309. 7 mg/kg/da yi n females ) a t th e termina l sacrifice
. However , thes e effect s wer e note d i n th e presenc e o f significan t bod yweigh t (-19% ) an d bod yweigh t gai n decreases , an d withou t a tren d i n dos e respons e o rcorrespondin g change s i n histopathology
. Therefore , th e effec t o n ovar

yweigh t wa s considere d secondar yt o bod yweigh t effects
. I n a n earlie rchroni c mous e stud y(Suberg , 1983 ; MRI D 00137304) , cyfluthri n (49.7 - 51.0 % puritya s a premi xconcentrat e i n Wessalo n S ) wa s administere d i n th e die t fo r2 3 month s t o SP F mice
. N o treatment-relate d orga n weigh t o rhistopathologica l effect s wer e note d i n thi s stud yu p t o an d includin g dose s o f 194.5/259. 9 mg/kg/da y fo rmale s an d females , respectively
. I n a chroni c ra t stud y(Wahle , 1997 ; MRI D 44459301) , ther e wa s a n increas e i n tumo rincidenc e o f mammar yglan d adenocarcinoma s a t termina l sacrific e i n th e hig h dos e female s (45 0 ppm ) whe n compare d t o control s (1/5 0 (2%) , 0/5 0 (0%) , 0/5 0 (0%) , 4/5 0 (8%))
. Th e EP A Cance rAssessmen t an d Revie w Committe e (CARC ) determin e th e following " "Dosin g wa s considere d adequat e base d o n decreas e i n body weight , compare d t o controls , as a critica l endpoin t i n thi s study
. Th e increas e i n incidenc e o f mammar

y glan d adenocarcinomas i s no t considere d t

o b e toxicologically significan t becaus e non e o f th e increase s i n mammar y tumor s were statisticall y significan t and , wit h th e exceptio n o

f on e fibroadenom a observe d o n da y 66 8 whe n th e anima l died , al l th e hyperplasi a an d mammar y tumor s were observe d a

t termina l sacrifice
. Neithe rth e incidence s o f hyperplasi a no r fibroadenomas appeare d to b e dose-related
. Historica l contro l dat a ar e as follows : 1/5

0 adenomas an d 1/5 0 adenocarcinomas i n on e stud y an d 0/5 0 fo rbot h i n a secon d stud y fro m th e sam e laboratory ; 3.8 % (mean ) an d 2-15 % (range) fo rcarcinoma s i n th e Hazleto n laboratories ; 1.5 % (mean ) an d 0 - 4.3 % (range) fo rcarcinomas i n th e Charle s Rive r(1990) laboratorie s an d 1.5% (mean ) an d 0-4 % (range) fo rth e Nationa l Toxicology Progra m (1985)
. A 1983 study (MRI D 00137303 ) o n cyfluthri n usin g Wistarrat s was negativ

e a t dose s u p t

o 25. 5 mglkglda

y an d cyfluthri n i s no

t mutageni c i n multipl e assays . Pag e 6 o f 3 8

## Baye rCropScienc e Repor t No
. G20215 5 Therefore , base d o n th e review s o f thes e studies , ther e wer e n o endocrine-relate d effect s a s a resul t o f chroni c exposur e t o cyfluthrin
. I n subchroni c an d chroni c do g studie s (vo n Kuetz , 1986 ; MRI D 4124410 9 an d Jones , 1997 ; MRI D 44435401 , respectively) , n o change s i n orga n weight s o rhistopathologica l finding s wer e noted
. I n addition , T 3 an d T 4 level s wer e evaluate d i n th e chroni c dog , showin g n o effect s o n thyroi d hormon e levels , orga n weigh t o rhistopatholog yu p t o an d includin g th e hig h dos e o f 1 5 mg/kg/day
. Result s o f a n E R transactivationa l assa ywit h cyfluthri n hav e bee n reporte d i n th e literature
. Kojim a e t al
. (2004 ) investigate d th e potentia l fo r20 0 pesticides , includin g cyfluthrin , t o bin d t o th e alph a an d bet a E R usin g transfecte d Chines e Hamste rOvary-K 1 cells
. Cyfluthri n wa s teste d a t concentration s rangin g fro m 10" 8 t o 10~ 5 M , an d th e REC 2 o (concentratio n o f chemica l tha t result s i n 20 % o f th e agonis t activit yo f 10 " 10 M E 2 ) valu e an d relativ e estrogeni c activit ya t 10" 5 M concentratio n (RLA ) wer e measured
. Accordin g t o th e result s o f thi s study , cyfluthri n showe d wea k positiv e estrogeni c activitywit h a REC 2 o a t 5.9x10" 6 M an d a RL A o f 45%
. Th e author s teste d fewe rtha n th e eigh t concentration s (onl ytw o o rthre e concentration s tested ) require d b yth e OPPT S 890.125 0 Guidelin e an d curv e fittin g doe s no t appea rt o hav e bee n performed
. Thus , thes e result s canno t b e interprete d usin g th e dat a interpretatio n criteri a provide d i n th e OPPT S 890.125 0 Guideline
. I n addition , du e t o th e lac k o f detail s reporte d fo rth e assay s performe d b y Kojim a e t al. , i n particula rth e lac k o f informatio n o n cytotoxicit yan d solubility , thes e publication s d o no t substantiall ymee t th e Klimisc h criteri a an d shoul d b e considere d a s unreliable
. Scientifi c informatio n indicate s tha n a n estrogeni c o ranti-estrogeni c compoun d woul d produc e disturbance s i n mating , estrou s cyclicit yan d alteration s i n th e weigh t an d histopatholog yo f specifi c reproductiv e organ s (e.g
. uterus , ovaries , testes , epididymes)
. Base d o n th e cyfluthri n dat a presente d above , whil e th e i n vitr

o result s fro m a singl e assa ysugges t limite d potential , th e mor e definitiv e i n viv o dat a fo rcyfluthri n show s n o clea revidenc e o f estrogeni c o ranti-estrogeni c activity
. Therefore , requiremen t o f th e estrogen-base d assay s shoul d b e waived
. 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 yt o asses s th e potentia l o f a chemica l t o affect th e androge n signalin g pathway
. A fis h ful l lif e cycl e stud yo n cyfluthri n 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 fis h ful l lif e cycl e stud yversu s th e short-ter m reproductio n scree n i s 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 cyfluthrin
. However , adequat e informatio n exist s t o asses s cyfluthrin' s potentia l t o interfer e wit h th e androge n system . A s show n i n Table s 1a&b , relevan t dat a are availabl e fro m guidelin e studie s includin g lifetim e feedin g studie s i n rat s an d mice , subchroni c an d chroni c do g studies , developmenta l toxicit ystudies , a developmenta l neurotoxicit ystud yi n rat s 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 accordin g t o regulator ytes t guidelines , unde rGLP , hav e bee n reviewe d b yEPA , an d ar e classifie d a s acceptable
. Othe rScientificall y Relevan t Information : A compoun d tha t interfere s wit h th e androge n syste m woul d b e expecte d t o resul t i n change s i n sexua l development , estrou s cyclicity , fertilit yan d othe rreproductiv e endpoints , a s wel l a s weigh t an d histopathologica l change s t o reproductiv e an d sexua l accessor yorgans . Endpoint s fro m guidelin e studie s tha t ar e 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 yare show n i n Table s 1 a & b
. A s discusse d i n th e estroge n system s sectio n above , a two-generatio n ra t stud y(Eigenberg , 1996 ; MRI D 4437101 ) wa s conducte d accordin g t o OP P 83- 4 Guidelin e fo rcyfluthrin
. Th e exposur e duratio n fo rth e Pag e 7 o f 3 8

## Baye rCropScienc e Repor t No
. G20215 5 F 1 generatio n exceed s tha t require d b y th e puberta l assa yan d therefor e provide s a more 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 40 0 pp m i n th e diet , Cyfluthri n ha d n o effec t o n mating , fertility , pregnancy , o rgestationa l indice s o f P O o rF 1 females
. Estrou s cycl e length , gestationa l lengt h i n days , an d stag e o f estru s a t necrops ywer e simila r acros s al l groups . Precoita l interva l wa s equivalen t acros s al l groups . Matin g indice s fo rP an d F 1 male s wer e als o simila racros s al l groups . Ther e wa s a statisticall ysignifican t decreas e i n absolut e ovaria n weigh t i n th e high-dos e grou p P females , an d statisticall ysignifican t decreas e i n absolut e testicula r weigh t i n th e high-dos e grou p F 1 males
. Neithe rwa s though t t o b e compound-relate d a s ther e wer e n o correspondin g decrease s i n th e relativ e weights , no rwer e ther e simila rchange s i n bot h generations
. N o histopathologica l change s wer e observe d i n an y reproductiv e organ s examine d (testes , ovaries , cervix , epididymis , pituitary , prostate , semina l vesicles/coagulatin g gland , uterus , an d vagina ) fro m P an d F 1 animals
. I n addition , th e numbe ro f implantatio n site s pe rdam , post-implantatio n los s pe rlitter , mea n numbe ro f live pup s pe rlitte ro n PNDO , an d se xratio s wer e simila racros s al l treatmen t group s fo rF 1 an d F 2 litters
. N o anomalie s o f externa l genitali a wer e note d fo rF 1 o rF 2 pups . I n a developmenta l neurotoxicit ystud ywit h beta-cyfluthri n (Sheets , 2003 ; MRI D 46054101) , acquisitio n o f vagina l patenc y an d preputia l separatio n i n F 1 offsprin g wa s unaffecte d u p t o 20 0 ppm , eve n i n th e presenc e o f u p t o 10 % decrease s i n bod yweigh t an d bod yweigh t gain
. I n a ra t developmenta l toxicit ystud y(Astroff , 1996 ; MRI D 44116501 ) wit h beta-cyfluthri n ther e wer e n o effect s o n th e numbe ro f corpor a lutea , implantatio n sites , litte rsize , liv e fetuses , resorptions , pre implantatio n los s o rse xratio
. Ther e wa s sligh t increas e i n percen t post-implantatio n loss , a s wel l a s a decreas e i n feta l weight s an d a sligh t increas e i n skeleta l variant s indicativ e o f growt h retardatio n a t th e highes t dos e o f 4 0 mg/kg/day
. Thes e effect s wer e associate d wit h significan t materna l toxicity , base d o n mortality fo r3 dam s i n thi s dos e group . I n a rabbi t developmenta l toxicit ystud y(Becker , 1992 ; MRI D 42675401 ) wit h cyfluthri n ther e wer e n o treatment-relate d effect s o n th e numbe ro f liv e litters , feta l weights , implantations , external , viscera l o rskeleta l malformation s an d variations
. Post-implantatio n los s (expresse d a s a percentag e o f th e numbe ro f implantatio n sites ) wa s significantl yincrease d a t 6 0 an d 18 0 mg/kg/day
. However , bot h th e stud yautho ran d th e EP A revie w conclude d tha t thi s wa s a biologica l respons e tha t occur s i n doe s wit h hig h numbers o f implantatio n site s (se e detaile d explanatio n i n estroge n sectio n above ; (EPA , HED , Toxicolog yChapte rfo rCyfluthrin/Beta-Cyfluthrin , date d Jul y18 , 2002 ; TXR # 005081 ; D P Barcaod e D283924))
. Ther e i s a numbe ro f developmenta l toxicit ystudie s conducte d i n ra t vi a th e inhalatio n rout e o f exposur e (Renhof , 1988 ; MRI D 40780401 ; Holzum , 1994 ; MRI D 43393401)
. Whil e ther e wer e indication s o f delaye d feta l developmen t a t th e highes t doses , mechanisti c studie s showe d thes e effect s t o b e secondar yt o impairmen t o f materna l ventilatio n (bradypne a an d hypothermia ) resultin g i n hypoxi a an d respirator yacidosis
. Ther e wa s n o significan t decreas e i n numbe ro f implantatio n sites , numbe ro f female s wit h viabl e fetuses , o rnumbe ro f resorptions
. Ther e wa s a sligh t decreas e i n corp a lute a an d numbe ro f fetuses , bu t onl ya t th e highes t dose , whic h wa s considere d secondar yt o significan t materna l toxicity
. Therefore , base d o n th e dat a available , ther e ar e n o androgen/antiandrogen-relate d endpoint s o f concer n identifie d i n th e developmenta l toxicit ystudies
. I n multipl e chroni c mous e an d rat studie s (Wahle , 1998 ; MRI D 44589701 ; Suberg , 1983 ; MRI D 00137304 ; Wahle , 1997 ; MRI D 44459301 ; Suberg , 1983 : MRI D 00137303) , eac h usin g differen t strain s o f animals , n o treatment-relate d orga n weigh t o rhistopathologica l effect s wer e noted , whic h woul d b e associate d wit h androge n o ranti-androge n disruption
. I n subchroni c an d chroni c do g studie s (vo n Kuetz , 1986 ; MRI D 4124410 9 an d Jones , 1997 ; MRI D 44435401 , respectively) , n o change s i n orga n weight s o r histopathologica l finding s wer e noted
. Result s o f A R transactivationa l assa yan d Hershberge rassa ywit h cyfluthri n an d beta-cyfluthri n hav e bee n reporte d i n th e literatur e (Zhan g e t a/.,2008)
. I n th e transactivatio n assay , usin g MDA-kb 2 cells , Zan g e f a/ , conclude d tha t cyfluthri n an d beta-cyfluthrin , teste d fro m 10~ 8 t o 10~ 5 M , demonstrate d anti androgeni c activit yb yblockin g DHT-induce d transcriptiona l activit yi n a dose-dependen t manne ra t concentration s o f 1.0x10" 7 t o 1.0x10" 5 M
. However , n o summar yo f th e actua l measure d result s wa s provide d i n th e paper . I n th e sam e paper , Zan g e f a/ , conducte d a Hershberge rassa ywit h cyfluthri n an d Pag e 8 o f 3 8

## Baye rCropScienc e Repor t No
. G20215 5 beta-cyfluthrin
. Onl yth e antiandrogeni c par t o f th e Hershberge rassa ywa s conducted
. A s describe d i n th e paper , 4 wee k

ol d mal e Sprague-Dawle yrat s wer e castrate d an d allowe d t o recove rfo rtw o weeks
. Nin e group s (n=6 ) wer e assigne d a s follows : grou p 1 wa s sham-operate d (thi s grou p wa s no t describe d furthe ri n th e paper : grou p 2 wa s vehicl e contro l ( 5 mL/kg peanu t oil) ; group s 3- 5 receive d ora l dose s o f 6 , 18 , o r5 4 mg/kg/da ycyfluthrin , respectively ; an d group s 6- 8 receive d ora l dose s o f 4 , 1 2 o r3 6 mg/kg/da y o f beta-cyfluthrin , respectively ; grou p 9 wa s th e positiv e contro l an d receive d 5 0 mg/kg/da yflutamide
. Al l group s excep t th e sham-operate d receive d testosteron e proprionat e (TP ) subcutaneousl y(0. 5 mg/kg ) befor e tes t chemica l wa s administered
. Al l group s wer e dose d b y ora l gavag e fo rseve n days
. Rat s wer e weighe d befor e eac h dosing
. Al l animal s wer e sacrifice d followin g th e las t dos e administratio n (tim e o f sacrific e no t provided)
. I n thi s study , th e positiv e contro l fo randrogeni c activity , testosteron e propionat e (0. 5 mg/kg/da ysc.) , produce d n o significan t chang e i n mea n bod yweigh t gains , termina l bod yweight , genera l orga n weigh t (liver , spleen , kidne yo radrenals ) o rse xaccessor ytissu e weight s (semina l vesicles , ventra l prostate , dorsolatera l prostate , LABC , cowper' s gland s an d glan s penis ) whe n compare d t o th e sham-operate d contro l animals
. Th e positiv e contro l fo ranti-androgeni c activity , flutamide , administere d a t 5 0 mg/kg/da yproduce d n o significan t decreas e i n overal l mea n bod yweigh t o ri n liver , kidney , adrenal s o rsplee n weights
. Flutamid e di d caus e a significan t decreas e i n se xaccessor ytissu e weight s compare d t o th e sham-operate d an d positiv e contro l fo randrogeni c activity
. Mea n se xaccessor

ytissu e weight s wer e significantl ydecrease d b ycyfluthri n a t th e mi d an d hig h dose s (1 8 an d 5 4 mg/kg/day , respectively ) an d b ybeta-cyfluthri n a t th e hig h dos e o f 3 6 mg/kg/day , compare d t o animal s receivin g testosteron e propionat e + vehicle
. Therefore , Zhan g e t al. , conclude d tha t bot h cyfluthri n an d beta-cyfluthri n showe d evidenc e o f anti-androgeni c activity
. Thi s stud ywa s no t conducte d i n accordanc e wit h th e curren t EP A OPPT S 890.140 0 Guideline , an d th e deviation s ar e note d below
. o Androgeni c activit yno t assesse d o T P - 0. 5 mg/kg/

d versu s 0. 2 o r0. 4 mg/kg/ d o Flutamid e - 5 0 mg/kg/d versu s 3 mg/kg/d o Dos e administratio n fo r7 day s versu s 1 0 day s o Animal s castrate d earlie rtha n recommende d ( 4 week s versu s 6 weeks ) o Tim e o f sacrific e no t specifie d o Sha m operate d - rol e o f thi s grou p no t define d i n th e stud y I n addition , weight s o f th e se xaccessoryorgan s wer e no t increase d i n animal s receivin g testosteron e propionat e whic h support s tha t animal s wer e castrate d to o young . Th e failure s o f th e androgeni c positiv e contro l t o produc e a n effect , alon g wit h castratio n o f animal s to o earl yi n development , constitut e significan t deficiencie s an d thus , th e result s o f th e stud yshoul d b e considere d a s unreliable
. I n addition , result s o f a hA R transactivationa l assa ywit h cyfluthri n hav e bee n reporte d i n th e literature
. Kojim a e t al
. (2004) , investigate d th e potentia l fo r20 0 pesticides , includin g cyfluthrin , t o bin d t o th e A R usin g transfecte d Chines e Hamste rOvary-K 1 cells
. T o tes t fo rantagonisti c activit y10" 10 M DH T wa s adde d t o th e cel l culture s alon g wit h cyfluthri n a t concentration s rangin g fro m 10~ 8 t o 10~ 5 M , an d th e RIC 2 o (concentratio n o f chemica l tha t show s 20 % inhibitio n o f th e androgeni c activit yo f 10~ 10 M DHT) valu e an d RLA (relativ e luciferas e activit yat 10" 5 M compare d t o 100 % o f activit yat 1 0 DHT) wer e measured
. Accordin g t o th e result s o f thi s study , cyfluthri n showe d wea k antiandrogeni c activit ywit h a REC 2 o a t 8.4x10" 6 M an d a RL A o f 74%
. Deficiencie s note d i n thi s pape rinclud e testin g fewe rtha n th e eigh t concentration s (onl ytw o o rthre e concentration s tested ) require d b yth e OPPT S 890.125 0 Guidelin e an d curv e fittin g doe s no t appea rt o hav e bee n performed
. Thus , thes e result s canno t b e interprete d usin g th e dat a interpretatio n criteri a provide d i n th e OPPT S 890.125 0 Guideline
. I n addition , du e t o th e lac k o f detail s reporte d fo rth e assay s performe d b yKojim a e f al. , i n particula rth e lac k o f informatio n o n cytotoxicit yan d solubility , thes e publication s d o no t substantiall ymee t th e Klimisc h criteri a an d shoul d b e considere d a s unreliable
. Scientifi c informatio n indicate s tha n a n androgeni c o ranti-androgeni c compoun d woul d produc e disturbance s i n mating , estrou s cyclicity , reproductiv e indices , sexua l maturatio n an d alteration s i n th e Pag e 9 o f 3 8

## Baye rCropScienc e Repor t No
. G20215 5 weigh t an d histopatholog yo f specifi c reproductiv e an d se xaccessoryorgan s (e.g
. uterus , ovaries , testes , epididymes , semina l vesicles , an d prostate)
. Base d o n th e cyfluthri n dat a presente d above , whil e th e i n vitr o result s may sugges t som e potentia l fo ranti-androgeni c effects , th e more definitiv e i n viv o dat a fo r cyfluthri n show s n o clea revidenc e o f androgeni c o ranti-androgeni c activity
. However , i n orde rt o provid e a mor e robus t weigh t o f evidence , an d t o addres s th e significan t deficiencie s note d i n th e Zhan g e t al. , Baye rwil l conduc t a guidelin e Hershberge rassa ywit h cyfluthrin
. Base d o n th e strengt h o f th e availabl e dat a fo rcyfluthrin , al l othe rrequirement s o f th e androgen-base d assay s shoul d b e waived
. Steroi d Synthesi s 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 fo rassessmen t o f a compound' s potentia l t o interfer e wit h steroidogenesi s o rinhibi t aromatase . Thes e endpoint s ar e show n i n Table s l a & b , an d thos e considere d a s functionall yequivalen t t o addres s th e purpos e o f th e aromatas e an d steroidogenesi s assay s ar e indicated
. Functionall yequivalent , i n thi s context , refer s t o dat a o f a suitabl e natur e an d qualit yt 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 yb e use d fo robtainin g th e data
. I n additio n t o effect s o n sexua l maturation , fertility , reproduction , an d reproductiv e orga n weight s an d histopathology , compound s tha t interfer e wit h steroi d synthesi s hav e als o bee n show n t o affec t th e adrena l glands , reduc e th e incidenc e o f mammar

ytumor s an d alte rcholestero l levels
. A s describe d i n detai l i n th e previou s sections , developmental , reproductive , an d developmenta l neurotoxicit ystudie s wit h cyfluthri n o rbeta cyfluthri n hav e no t show n an yindicatio n o f effect s o n sexua l maturation , fertility , reproductiv e indices , no r treatment-relate d orga n weigh t o rhistopathologica l change s i n reproductiv e an d se xaccessoryorgans . I n subchroni c an d chroni c studie s wit h beta-cyfluthri n and/o rcyfluthri n ther e wer e n o treatment-relate d histopathologica l change s i n reproductiv e organs , adrena l gland s o ri n cholestero l level s tha t woul d b e associate d wit h interferenc e wit h steroidogenesi s o raromatase . Base d o n th e availabl e data , Baye r request s tha t th e steroidogenesi s an d aromatas e assay s b e waive d fo rcyfluthrin
. 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 cyfluthrin , adequat e informatio n exist s t o asses s cyfluthrin' s 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 & b , relevan t dat a 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 , subchroni c an d 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 ystudies
. Al l o f thes e studie s wer e conducte d accordin g t o regulator ytes t guideline s unde rGLP , hav e bee n reviewe d b yEPA , 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
. Othe rScientifically Relevan t Information : Ther e wer e n o thyroi d orga n weight s o rhistopathologica l effect s note d i n an ysubchroni c o rchroni c roden t studie s (Suber g 1988 , MRI D 41244108 ; Pauluh n 1989 , MRI D 417830001 ; Pauluh n an d Renho f 1983 ; MRI D 40239301 , 40082901 , 00157793) , no ri n a subchroni c do g stud y(vo n Kuetz , 1986 ; MRI D 41244109)
. I n a on e yea rfeedin g stud yi n dogs , mil d degeneratio n an d c-cel l hyperplasi a wa s note d i n male s an d female s a t th e highes t dose
. However , th e incidenc e an d severit ywer e withi n concurren t an d historica l contro l rang e an d wer e no t considere d treatment-relate d (Jones , 1997 ; MRI D 44435401)
. I n addition , n o effect s o n thyroi d hormone s measure d i n th e chroni c do g stud y(tota l triiodothyronin e (T 3 ) ; tota l thyroxin e (T 4 ) ; an d T 3 Uptake (indirect TBG) ) wer e note d a t an yinterva l (sample s wer e analyze d a t 3 , 6 , 9 an d 1 2 months)
.
Pag e 1 0 of 3 8

## Baye rCropScienc e Repor t No
. G20215 5 Othe rdownstrea m effect s whic h migh t b e indicativ e o f interferenc e o f th e thyroi d syste m includ e change s i n endpoint s suc h a s acousti c startle , passiv e avoidanc e an d wate rmaz e measurement s (learnin g an d memory) , moto ractivit yan d brai n morphometric s i n th e DN T stud y(Sheets , 2003 ; MRI D 46054101)
. I n thi s study , dam s wer e treate d wit h beta-cyfluthri n b yth e dietar yrout e fro m gestatio n da y0 throug h lactatio n da y2 1 a t dose s o f 2.4,11. 0 an d 17. 8 mg/kg/day
. Bod yweight s an d bod yweigh t gai n wa s decrease d i n pup s a t th e hig h dos e startin g a t lactatio n da y4 throug h post-weaning
. Absolut e brai n weigh t fo rfemal e pup s a t termina l sacrific e wa s decrease d 6% , bu t ther e wa s n o effec t o n relativ e weight , n o effect s i n mal e pup s an d n o morphologica l change s wer e see n i n eithe rsex . Mal e pup s showe d a 30 % decreas e i n mea n pea k amplitud e i n th e acousti c startl e o n PN D 22
. However , thi s effec t wa s no t see n a t an yothe rtim e poin t no ri n female s a t an ytim e point , therefore , i t wa s no t considere d lexicologicall ysignificant
. I n addition , n o effect s wer e note d i n th e functiona l observatio n batter yo ran yo f th e learnin g an d memor yo rsexua l developmen t endpoints
. Base d o n th e informatio n provided , ther e i s n o evidenc e t o sugges t tha t cyfluthrin/beta-cyfluthri n interfere s wit h th e hypothalamic-pituitary-thyroida l axis
. Therefore , Baye rrequest s tha t th e ra t pubertal s an d amphibia n metamorphosi s assay s b e waived
. 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 yresult s i n developmenta l effects
. 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 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(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 cyfluthri n 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

yt o evaluatio n th e thyroi d activit ypotentia l i n vertebrates
. Th e substantia l existin g dat a fro m studie s wit h 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 ystudie s 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 yan d woul d resul t i n th e expenditur e o f resource s an d unnecessar ysacrific e o f animals
. Conclusio n Baye rCropScienc e (BCS ) believe s tha t existin g dat a o n cyfluthri n ar e adequat e t o asses s th e potentia l fo rthi s compoun d t o interact wit h estrogen , androge n an d thyroi d system s and , wit h exceptio n o f a guidelin e qualit

yHershberge rAssay , furthe rtestin g i s no t warranted
. Althoug h som e result s i n th e literature sugges t wea k

E R an d A R bindin g an d wea k anti-androgeni c activity , thes e finding s ar e no t supporte d b y th e i n viv

o Guidelin e studies
. Th e most sensitiv e toxicit yendpoin t fo rCyfluthri n i s neurotoxicity
. Curren t huma n healt h ris k assessment s ar e base d o n thi s endpoin t an d ar e protectiv e o f othe rsystemi c effects
.

Pag e 1 1 o f 3 8

## Baye rCropScienc e Repor t No
. G20215 5 REFERENCE S 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 0013730 3 Suberg , H. ; Loeser , E. ; Blass ; e t al
. (1983 ) FC R 127 2 (Cyfluthrin , th e Activ e Ingredien t o f Baythroid ) Chroni c Toxicit y Stud y o n Rat s (2-Yea rFeedin g Experiment) : 11949 ; 86032
. (Unpublishe d stud y receive d Fe b 13 , 198 4 unde r3125-351 ; prepare d b y Baye rAG , W
. Ger. , submitte d b y Mobay Chemica l Corp. , Kansa s City , MO ; CDL072365-C ) MRI D 0013730 4 Suberg , H. ; Loeser , E. ; Blass ; e t al
. (1983 ) FC R 127 2 (Commo n Name : Cyfluthrin) - Chroni c Toxicologica l Stud y o n Mic e (Feedin g Stud y ove r2 3 Months) : Repor t No
. 12035 ; 86107
. (Unpublishe d stud y receive d Fe b 13 , 198 4 unde r3125-351 ; prepare d b y Baye rAG , W
. Ger , submitte d b yMoba y Chemica l Corp. , Kansa s City , MO ; CDL : 072366-A ) MRI D 0015779 3 Pauluhn , J
. (1984 ) Stud y fo rSubchroni c Inhalatio n Toxicit y t o th e Ra t fo r1 3 Weeks : FC R 1272 (Cyfluthrin) : Rept
. No
. 12436
. Unpublishe d Mobay stud y no . 8644 3 prepare d b y Baye rA G Institut e o f Toxicolog y an d Hanove rMedica l University
. 17 0 p . MRI D 4008290 1 Pauluhn , J
. (1987 ) Stud y o f th e Subchroni c Inhalatio n Toxicit y i n Accordanc e wit h OEC D Guidlin e No
. 413 : FC R 1272 : Cyfluthrin : Addendu m t o Baye rRepor t No
. 12436 , Date d Feb
. 1 , 1984 : Stud yNo
. T9015085
. Unpublishe d Mobay Repor t No
. 8644 3 prepare d b y Baye rAG
. 15 7 p . MRI D 4023930 1 Pauluhn , J
. (1983 ) Stud y o f th e Subchroni c Inhalatio n Toxicit y i n Accordanc e wit h OEC D Guidelin e No
. 413 : Baythroid : Supplementa l Submission : Secon d Addendu m t o Baye rNo
. 12436
. Unpublishe d stud y prepare d b y Baye rAG
. 2 4 p . MRI D 4078040 1 Renhof , M. ; Pauluhn , J
. (1988 ) FC R 1272 : Commo n Nam e Cyfluthrin : Stud y fo r Embryotoxi c Effect s o n Rat s afte rInhalation : Repor t No
. 16391 : Repor

t No
. 97403
. Unpublishe d stud y prepare d b y Baye rAg
. 16 9 p . MRI D 4096850 1 Pauluhn , J
. (1988 ) Addendu m t o FC R 1272 : Cyfluthrin : Stud y fo rEmbryotoxi c Effect s o n Rat s afte rInhalation : Repor t No
. 97403 ; 16391-A
. Unpublishe d stud y prepare d b y Baye rAg
. 1 2 p . MRI D 4145040 1 Rhodes , J.E. ; McAllister , W.A. ; Leak , T. ; Stuerman , L
. (1990 ) Ful l Life-Cycl e Toxicity o f 14 C-Cyfluthri n (Baythroid ; t o th e Fathea d Minno w (Pimephale s promelas ) underflow-throug h conditions
. Repor t No
. 100097 ; 33821
. Unpublishe d stud y prepare d b y AB C Labs
. 90 5 p . MRI D 4233200 1 Renhof , M. ; Pauluhn , J
. (1988 ) FC R 127 2 (Commo n Nam e Cyfluthrin) : Stud y fo r Embryotoxi c Effect s o n Rat s afte rInhalatio n (Supp
. t o MRI D 40780401) : La b Project Number : 97403 : 16391
. Unpublishe d stud y prepare d b y Baye rAg , Wuppertal
. 5 p . MRI D 4267540 1 Becker , H. ; Biedermann , K
. (1992 ) Embryotoxicit y Stud y (Includin g Teratogenicity ) wit h FC R 127 2 (Baythroid ) i n th e Rabbit : La b Projec t Number : 309914 : 103980
. Unpublishe d stud y prepare d b yRCC , Researc h & Consultin g Co. , Ltd
. 30 3 p . MRI D 4339340 1 Holzum , B. ; Schmidt , U. ; Pauluhn , J. ; e t al
. (1994 ) FC R 1275 : Explanatory Report o n Result s an d Mechanisti c Studie s fo rEmbryotoxi c Effect s i n Rat s afte rInhalation : La b Project Number : 06369:23219:22581
. Unpublishe d stud y prepare d b y Baye rAg
. 137 4 p . MRI D 4437140 1 Eigenberg , D. ; Elcock , L
. (1996 ) A Two-Generatio n Reproductio n Stud y i n Rat s Usin g Technica l Grad e Cyfluthri n Administere d Vi a th e Diet : La b Project Number : 93-672-UZ : 107408 : 93-672 - UZ1
. Unpublishe d stud y prepare d b y Baye rCorp
. 97 3 p .
Pag e 1 2 of 3 8

## Baye rCropScienc e Repor t No
. G20215 5 MRI D 4437140 2 Eigenberg , D
. (1997 ) A Supplementar yTwo-Generatio n Dietar yReproductio n Stud yi n Rat s Usin g Technica l Grad e Cyfluthrin : La b Project Number : 94-672-CK : 107474 : 94-672-CK1
. Unpublishe d stud yprepare d b yBaye rCorp
. 77 1 p . MRI D 4445930 1 Wahle , B. ; Christenson , W
. (1997 ) Technica l Grad e Cyfluthrin : A Combine d Chroni c Toxicity/Oncogenicit yTestin g Stud yi n th e Rat : La b Project Number : 107769 : 8384 : 94-272-BK
. Unpublishe d stud yprepare d b yBaye rCorp
. 418 7 p . Relate s t o L0000267
. MRI D 4458970 1 Wahle , B. ; Christenson , W
. (1998 ) Technica l Grad e Cyfluthrin : A n Oncogenicit yTestin g Stud yi n th e Mouse : La b Projec t Number : 108041 : 95-271-DR
. Unpublishe d stud yprepare d b yBaye r Corporation
. 214 1 p . MRI D 4518920 1 Jones , R. ; Hastings , T
. (2000 ) Technica l Grad e Cyfluthri n (FC R 1272) : A Chroni c Toxicit y Feedin g Stud yi n th e Beagl e Dog : La b Project Number : 94-276-ZR : 8365 : 108007
. Unpublishe d stud yprepare d b yBaye rCorporation
. 1 4 p . MRI D 4522810 1 Wahle , B. ; Christenson , W
. (2000 ) Technica l Grad e Cyfluthrin : A n Oncogenicit yTestin g Stud yi n th e Mouse : Supplementa l Submissio n t o Baye rRepor t No
. 108041 : MRI D No
. 44589701 : La b Projec t Number : 95-271-DR : 108041-1 : 8492
. Unpublishe d stud yprepare d b yBaye rCorp
. 2 9 p . Publishe d literature : Kojima , H. , Katsura , E. , Takeuchi , S. , Niiyama , K. , an d Kobayashi , K
. (2004)
. Screenin g fo restroge 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 r Ovar ycells
. Environ
. Healt h Perspect
. 112 : 524-531
. Klimisc h HJ , Andrea e E an d Tillman n U (1997)
. A systemati c approac h fo revaluatin g th e qualityo f experimenta l an d ecotoxicologica l data
. Reg.Tox
. an d Pharm
. 25:1- 5 OECD , 2006
. Draf t Detaile d Revie w Pape ro n Thyroi d Disruptio n Assays
. OEC D Environment , Healt h an d Safet yPublicatio n Serie s o n Testin g an d Assessment
. No
. no t assigned
. Paris , France
. USEPA , 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
. Octobe r2009
. U.S
. Environmenta l Protectio n Agency
. Washington , D.C
. Zhan g J. , Zh u W. , Zhen g Y. , Yan g J. , an d Zh u X
. (2008)
. Th e antiandrogeni c activit yo f pyrethroi d pesticide s Cyfluthri n an d beta-cyfluthrin
. Reproductiv e Toxicology
. 25 : 491-496
.

Pag e 1 3 of 3 8U )

O Q V 

# o : 0

) T J 0 ^ o e n c

~ 3 i n < U 0 1 i n • 8 i t LU 7 J 7 3 f * U

_ 

## •s c 0 1 7 5 LU S (0 0 ) 0 ) U) .9 ? 3 

### 55 D ) C "55 ' x LU C U) " c ' o Q
. • Q ^ LU 7 5>le1a:FunctionalEquivalenceMatrix-ApicActionAssessedintheInVitroAssays

C D •, ! 1 - 0 i n 'i n 0 ) c 0 ) O ) o T3 2 

### 55

1 0 

### 3 03 E 2

o >

. E c l a 

### a :

T 3 — C ( 0 ro c c oj. 2 o II I

• ° C m 

### a : 2 u u * •

c Q

• ^PTS870.3100Two-GenerationRatReprodu<RID45448101)

Q

_S ^ 

## o ^ 

## s

s

s

s

I 2 ra a . LL f
— n i o u

_

" o o 1 i n | LU S

S



## s

s

^^ . ro a . LL T3 C D o LL

_ i n 

### 8 T >
1
Q
. S



## s

s

sLitterparameters(F1andF2) S

S



## s

s

g 1 3 a n X 0 ) a D
. s

S

1

S

0 ) 

# I re O ! CO S

V



# s

1PreputialSeparation(F1) 

## s



# s

s

^

( b o "t o 

### b 3 c <1 ) 

# ? s

S



# s

NExternalgenitaliaanomalies(F1andF2) s

S

1

N 

## 6 J 2 c T 3 Q ) ( 0 j! ? Q
. 

# i ^ • a T 3 ' > c o « oOrganwtsandhistopathology:uterus(withcervix),ovaries,vagina(histopathonly)(FO ;

| i 

## s k t ! I j

, 1 [ ; 1 

# ^ S [ 

### i 

### i i | 

## s
1 • 

### i ! i [ j 

## •i • j! 1 i 

## \' $ ; c £ > ' Q
. ' 5 •— • ^-< - m - £ 1 ~ o

—c "" ! £ o E f - < 0Organwtsandhistopathology:seminalvesicoagulatingglandsandtheirfluids),epididycontents),prostate,testes(FOandF1parerOrganwtsandhistopathology:pituitary(FO

i I s

S

•

^

O Tj j fi (0 o LL T3 t o o 

# 1 § 7 3 ( U "(O (A % H I S

S

•

S



## S 7 5 " c re Q , ^ —Ovarianprimordialfolliclecounts(FOandF' S

S



# s



# •

T J C C o
T3 2 Q
.

.

• ^Andrologicalparameters(spermcount,motanomalies-FOandF1parentalC?) i i i 

## i s 1 ! ! I

, I [ 1 1 

## i s i i j
• 

## i s
: ; i [ [ 

## i s [ !

^- J o ! co l co ; 

## 5 ' Q : OL \ 2 !PPTS870.6200DevelopmentalneurotoxicityPupSexRatio

O ; • S

S



# •

s

O ) o > Q
. O 7 5 '5 ) (0 S

S



# s

1

o 

# ' 2 CO QJ < u w QJ U) 

### o l S

S

S

SExternalgenitaliaanomalies

APTS870.41OObChronictoxicityindogsRID40166701L42022801)

0 - ^ O S S

S



# •

s

T3 ro ( U % 3

- o > oOrganwtsandhistopathology:uterus(withcervix),ovaries,vagina(histopathonly) CO

CO

O ) 0 1 ( D 

### a .

## to

u > r - M O C M O 

# t : o o j 

# s .

O ) U 

## 3 " o C/ D 

## a o U u >

0 > c 0 ) o > o T J 2 55
C D (A CO 1 6 E 2

O ) ^ c

TO | C cn. 2 o '•5 '& ^ c o ~ 

### o : 1 r o 

### i n «- 

## s

\

V

,

£1vesicles(withididymides(whology:seminaltheirfluids),eptes 

# p s I«« "

. c c J S

- D J O w c o > 2 t O 0 ) Q

j w c - "S'roS 1 Sg, | O ) C O C 

### 6 8 8 \ ^

S

•

,

7 3 2 

### 3 ' 5 'a
.hology:adrenal

1 3 Q
. j ^ C co
CO 0 ; | i | S ; j! 1 • 1 > ;

•

; 

## i s i 

## i i p i mIRID4278690withoviducts)rcinogenicity(Mhology:uterus((histopathonly] 

## S;i S 0) : o D ) 

### Si S 

### 5 o ! - C 

# 1| | c ^ ' w ^ "^ 1 " § ° 1 —J O o Cl i 

### ° i " Ny

V



## s

,

£vesicles(will-ididymides(whology:seminaltheirfluids),epstes 

## .1- 8 

## I

. c c r o " ° —S c TO 2 t o D > a . (/ ) C - 

## Is 1 3 3 s ral)l O ) C O C A o o O o o Ny

\

•

,

7 3 2 c ~
"5
.hology:adrenal

1

. 1

. c T3 CO (O " g co O ) Ocinogenicityinedtoxicity/car

_ Q 1 1 3 

### o : o p ° o ^ ! o o O jr - h - C3> 00 C N Q
. ^ 

### oe , \

^



## s

1

x ^

cowithoviducts)hology:uterus((histopathonly]

1 3 TM CL. E o o > 

### « 5
^ « | ^ i o 

## i f TO £ 

## o S \

y

\



### -

I

: £1vesicles(witfididymides(whology:seminaltheirfluids),epstes "5 5 w< 2 ! E c to •n CO CO 1:0) 2 tO O , Q

J 

# f c -

* 2 r- • = C r a 0)5 J S'S S O o o s

^



## s



# •

,

T3

^ £ CO .*; .*; Q
.hology:adrenal

1 3 Q
. O I n ! c T3 CO C/ ) " g CO 

# 6 C O C O
0 ) D ) co Q
.

## in

u > rs i 

### o C M O
O 

## a 

# 8 .

a> u
C O 

### D - 

# 2 u CO

C D CO t o o

. ^ ^ c C D

•4- f C o > CO co CO CO CO ^ 2 ? S i CO 2 (0 Q
. 0 "c
. co CO C D Dd t o CO
" O ^ e n c 'lo ' x LU t o c ' o • oTable1b:FunctionalEquivalenceMatrix-ApicalEn CO c ' m f » Q
. I E o F E c ( u ^ < D ^ > 0 ) E > 0 )

. Q
CO I
O 'f - Q
.
, 2 2 0 ) 

### 5
CO t o ^ > C D • c 0 > 3 Q
. ( Q D "t - To < D c J 3 t • ^ Q J D
. " -

c gOldGuideline(83-4)Two-GenerationRatReproduct(MRID41921201) i

,

\

S•Growth(bodyweight) i ! 1 i | i ; [ i ! ; i ! 1 ; i 1 I 1 i ! 

### \ i s ! [ I ! i I « 

### \ i s i i i i i 

### si s [ 1 1

, 1 I
"to" 1 '*- ' I C O ' O J
c | o : LL J CO ' 

# 1 .>;r o 3 1 X -a , a ) Q j Q j 0) ; 3 S

,

S

\

• ^•Organwtsandhistopathology:thyroid(FOandFHistopathologyonpituitary i

S

•

V•Histopathology(FOandF1parental$),vagina,uterus,ovaries i

,

S

••Histopathology:seminalvesicles,epididymides,prostate,testes(FOandF1parental<?) oOPPTS870.6300Developmentalneurotoxicity(MRI46364801) 1

S

S

\

o 1 3 

### a : X CO V ) a i

\ ^

•

S•VaginalOpening i

,



### s

•1•PreputialSeparationOldGuideline83-1(b)(1986)1-yearChronictoxicityindogs(MRID00160179) 1

\ y

1

S•Organwtsandhistopathology:ovaries,histopathologyuterus(corpusandcervix) i

,

S

•

O )

_ g•Organwtsandhistopathology:testes,histopathcepididymides,prostate S

,

S

V•Organwtsandhistopathology:adrenal,pituitary,thyroidwithparathyroidifidentifiedOldGuideline83.4(1983)mousecarcinogenicity(MRID40356301and43326001) i

Ny

1

\•Organwtsandhistopathology:ovaries,histopathologyonly:uterus(corpusandcervix),mammarygland i

,

S

••Organwtsandhistopathology:testes,histopathologyonly:epididymides.prostate S

1

S

S

T3 ' o Z
. >*
.•Organwtsandhistopathology:adrenal,histopathologyonly:pituitary,thyroidwithparath; o o

0 0 CO 

### ro a .U)

1 0 

### o 0 1



## o Q \ 0 ) 0 1



## c QJ 

## ' u C/ 3 D - 8 

### U 

# .s i

_ Q Q
~ 1
. . c o E ro < ii 5

< D 0 ) J D

. c E ( U X
o

. c C L O * i 2 0 ) 

### 5 ( U (0 TO 0 )

. Q C L

I f • § 0 ) C L U Guideline83-5(1992)Ratcombined:ity/carcinogenicityJD42530201)

" ° X 05^ , •

(

\

,

\Organwtsandhistopathology:ovaries,histopathologyonly:vagina,uterus,cervix,mammaryglands 1

V *

1

s

1

D ) " 5 - r - C OOrganwtsandhistopathology:testes,histop;only:testeswithepididymides,seminalvesicprostate \

V*

\


## V

\

£ > T3Organwtsandhistopathology:adrenal,thyrcparathyroid,histopathologyonly:pituitary Q C L 2 > , 

### 8 1 

### 1 E t o L t o o O5 CO CO OO 0 )

_ g

~ " **"*

• Q) C ^ T 3 0 3 S T 3 C O 0 5 1

i

\

,



### s

• o ra C LNumberofcorporalutea,implantationsites,,postimplantationloss,resorptions,fetuses 1

V *

^

N,
.

%

O 

# 1 X ( U i n "53 LL QGuideline83-3(1989)RabbitTeratology(MRI04403)

- 0 C O 

### 6 5 1

!

\

,

V

T3 m C LNumberofcorporalutea,implantationsites,,postimplantationloss,resorptions,fetuses 1

V '

S



### s

s

o 2 QJ CO "S ) LL 0 0 C O
0 ) 

## S 1 Q
.

# Baye r

CropScienc e Repor t No
. G20215 5 Tabl e 2 : Fis h Short-ter m reproductio n assa yendpoint s compare d t o existin g endpoint s collecte d fo rcyfluthri n fro m fis h chroni c exposure . Fis h Short-ter m Reproductio n Assa y Stud yDuration : 2 1 Days Lif e Stage : Matur e Adult s Endpoint s Include d Reproductiv e Behavio ran d SC C appearanc e Surviva l
Growt h Adul t lengt h Adul t weigh t

Fertilizatio n succes s Fecundity Biomarkers 3 SS C measurement s Vitellogeni n Gonada l Somati c Inde x Gonada l histopatholog y Plasm a se xsteroid s (optional ) Cyfluthri n Fis h Ful l Lif e Cycl e Assa y Stud yDuration : 301 + Day s Lif e Stage : Al l (eg g t o reproductiv e adul t t o egg s t o 6 0 da y ol d juvenile s Endpoint s Include d F o reproductiv e behavio r F 0 6 1 da y surviva l F 0 12 0 da y surviva l F 0 15 3 da ysurviva l F 0 30 1 da y survivalF , 60-da ysurviva l Growt h F 0 30-da ylengt h F 0 61-da ylengt h F 0 90-da ylengt h F 0 120-daylengt h F 0 90-da ywe t weigh t F 0 120-daywe t weigh t F ! 60-da ylengt h F ! 60-da ywe t weigh t F 0 Hatchin g succes s F ! Hatchin g succes s F o Fecundity

a 

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

action . Sinc e reproductiv e endpoint s wer e no t mor e sensitiv e the n surviva l i n lif e cycl e testin g thi s informatio n i s no t needed .

Pag e 1 8 o f 3 8

## Baye rCropScienc e Repor t No
. G20215 5

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

Pag e 1 9 of 3 8

# Baye r CropScienc e Repor t No
. G20215 5
MRI D 4124410 8 BAYE R A G FACHBEREICH TOXIKOLOGI E Friedrich-Ebert-Str . 217-33 3 Baye r Repor t Mo. : 1680 7 Jun e 21 . 198 8 560 0 Wupperta l 1 |B|iuep|j u Federa l Republi c o f German y

FC R 454 5 SUBCHRONI C TOXICOLOGICA L STUD Y O NRAT S (ADMINISTRATIO

NWIT H FEE D FO

R 1 3 WEEKS )
b y Dr . H . Suber g Histopathology : C . H . Woo d (Histologica l Service s Ltd. , England )

Stud yNo. : T 802308 5
En d o f Study : Novembe r 198 6

A s lon g a s the result s containe d i n thi s repor t have no t bee n published , the y ma ybe use d onl

ywit h the consent o f BAYE R AG . Thi s repor t o r an ypar t thereo f na yno t b e reproduce d b yan ymeans . I



### Pag e 2 0 o f 3 8

# Baye r

CropScienc e Repor t No
. G20215 5 MRID4126780 1 BAYE R A G FACHBEREIC

H TOXIKOLOGI E Baye r Repor t No. : 1618 0 Novembe r t , Wupperta l Federa l Republi c o f German y

FC H 454 5 STOO T OF SPBCHROMI C ORA

L TOUCH

Y T O DOC S (13-Wee k Feedin g Study ) b y Dr . E . von Keut z Institut e o f Toxicology/Pharmaceutical s Friedrich-Ebert-Straes e 217-33 3 D-560 0 Wupperta l 1 Federa l Republi c o f German y Hiatopatholog

yRepor t b

yA . J . Newman Histologica l Service s Ltd . Bromyard Roa

d Ledbur y Herefordshir e HR 8 1L G Englan d

Stud yNo. : T 8 02 2 12 1
As lon g a s the result s containe d I n thi s repor t hav e no t bee n published , theyma ybe use d onl

ywit h the consen t o f BAYE R AG . Thi s repor t o r an y par t thereo f ma

yno t b e reproduced b yan ymeans .



## Pag e 2 1 o f 3 8

# Baye r CropScienc e Repor t No . G20215 5 MRI D 41783000 1 BAYE R A

G Repor t No. : 1814 6 Departmen t o f Toxicolog yDat e report : 28.6.198 9 Friedrich-Ebert-Str . 217-33 3 D-560 0 Wupperta l 1

FC R 454 5 (c.n. : Betacyfluthrin , proposed ) SUBACUT E INHALATIO NTOXICIT

Y STUD Y I NTH E RA

T ACCORDIN

G T O OEC D GUIDELINE NO . 41 2 b y Dr . J . Pauluhn

Stud yno : T302744 6 Tota l pages : 94 6

Unti l theyar e published , th e finding s containe d i n thi s repor t ma

yonl yb e use d wit h th e approva l o f BAYE R AG . Furthe r reproductio n o f al l o r par t o f thi s repor t i s no t permissible .

1814 6 /M O -0 1 -01449 7

Pag e 2 2 o f 3 8

# Baye r

CropScienc e Repor t No
. G20215 5 MRI D 0015779 3 (1984) ; 4008290 1 (1987) ; 4023930 1 (1983 ) BAYE R A G Jul y30 , 198 7 

### Fachbereic h Toxikologi e Wuppertal-Elberfel d Federa l Republi c o f German y Baye r Repor t No. : 1546 9 A

FC R 127 2 

### (Canno n Name : Cyfluthrin , th e Activ e Ingredien t o f R

### BAYTHROID ) STUD Y O F TH E SUBCHRONI C INHALATIONTOXIC1TY I NACCORDANC E WIT H OEC D GUIDELIN E NO : 41 3
Addendu mt o Baye r Repor t No . 12436 , date d Februar y1 , 198 4 

### b y 

### Dr . J . Pauluh n Stud yCompletio n Dat e Jul y8 , 198 3 Stud yNo. : T901508 5

A s lon g a s th e result s o f th e researc h containe d i n thi s repor t hav e no t bee n published , the yma yb e use d onl ywit h th e consen t o f BAYE R AG . Thi s repor t o r an ypar t thereo f mayno t b e reproduce d b yan ymeans .
pag e 1 o f 18 2



### Pag e 2 3 o f 3 8

## Baye rCropScienc e Repor t No
. G20215 5

MRI D 0013730 3

BAYE R A G Jul y19 , 198 3 INSTITU T FUE R TOXIKOLOGI E Wupperta l Federa l Republi c o f German y Baye r Repor t No. : 1194 9



## pea1

(CYFLUTHRIN , TH E ACTIVE INGREDIEN T O F BAY7HROIDTM ) CHRONI C TOXICIT

Y STUD Y OM RAT S (2-Yea r Feedin g Experiment )

b y Dr . H . Suber g an d Or . E . Loose r

Appended : Histopatholog yRepor t

b y Or . G . Papprit z Experimenta l PathologyService s A G

A s lon g a s th e result s o f th e researc h containe d i n thi s repor t hav e no t bee n published , theymayb e use d onl ywit h th e consen t o f BAYE R AG . Thi s repor t o r an

ypar t thereo f ma yno t b e reproduce d b yan ymeans .

11949/MO-01-00314 1



### Pag e 2 4 o f 3 8B (BAYER ) JL
. 

# Baye r CropScienc e Repor t No
. G20215 5 MRI D 4445930 1

Toxfcoloay Slud y liy& u •M272-B K Stud y Titl e Technica l Grad e Cyfluthrin : A Combine dClironi c Toxicily/Oncogenicit y Testin g Stud y i n th e Ra i

Dat aRequiremen t FIFR A Guidelin e No . 83- 5 Combine dChroni c Toxicity/Oncogcnicit y Studie s OEC D Guidelin e No . 45 3 Combine dChroni c Toxicity/Oncogeiiicit y Studie s TSC A Guidelin e No . 798.332 0 Combine dChroni c Toxicily/Oncogenicil y Studie s MAF FGuidelin e 5 9 NohSa n No . 420 0 Combine dChroni c Toxicity/Oncogeiiicit y Studie s IJiijrei I'oiiHiriuiiJ n Apicultur e Divisio n Repor t Numbe r 

## 10776 9 1 FILE | 838 4



### MRI D 0013730 4 Author s U.S . Wahl e an d W.R . Christenso n Stud y Completio n Dat e Decembe r 12 , 199 7 Sponso r Baye r Corporatio n Agricultur e Divisio n Bo x 4913 , Hawthor n Roa d Kansa s City , M O 64120-(X ) 1 3 Performin g Laborator y Baye r Corporatio n Agricultur e Divisio n Toxicolog y 1774 5 Sout h Metcal f Stilwell , K S 66085-910

4 Laboratory Projec t

Stud y I D 94-272-B K Pag e 1 of418 7 MOB83B 4 J MO-00-01112 2

Pag e 2 5 o f 3 8

# Baye r

CropScienc e Repor t No
. G20215 5

BATB R A G

### Wuppertal-Blberfeld , de n 24.8.8 3 IHSTITOT

E O FTOXICOLOG

Y Repor

t no . : I2o3 5

FO R 127 2 

### (eono n nam e eyfluthrin ) Chroni c toxieologica l stud yo n ale e (Feedin g stud yove r 2 J aontns )

Dr . E . Suber

g an d 

### Dr . E . Losa

r HistopatholoK ? repor t b yBxparimanta l Patholog y Servlee s A

G (Pathologis t Dr . H . Vesten ) i n th e appendi x

Unti l the

yar e published , th e finding s contained , i n thi s repor t «a

yonl yb e use d with th

e approva l o f BAXE R AG . Further reproductio n o f al l or par t o f thi s repor t i s no t permissible .



### Pag e 2 6 o f 3 8

# Baye r

CropScienc e Repor t No . G20215 5

MRI D 4458970 1 (1998) ; 4522810 1 (2000 , suppl ) TotJcoloc

y ScudyI D NJ I 95-J7I.D R Stud y Titl e Technica l Grad e Cyfluthrin : A n Oncogcnicity Testin g Stud y i n th e Mous e DataRequirement F1FR A Guidelin e No . 83- 2 Oncogenicil y Stud y OEC D Guidelin e No . 45 1 Carcinogenicit y Stud y EEC/Directiv e 87/302/EEC : Carcinogenicit y Tes t MAF F Guideline : Oncogenicity Tes t Baye r Corporatio n Agricultur e Clivjiio a Report Numbe r 

## 10804 1 

## RL E 849 2

Author s B.S . Wahle , M.S . Phone : 913-433-524 9 E-mail : brad.wahle.b@bayer.co m W.R . Christenson , Ph.D . Phone : 913-433-522 5 E-mail : russ.christenson.b@bayer.co m Stud y Completio n Date Ma y 28 . 199 8 Sponsor Bayer Corporatio n Agricultur e Divisio n Bo x 4913 , Hawthorn Road Kansa s City , M O 64120-001 3 Performin g Laboratory Baye r Corporatio n Agricultur e Divisio n Toxicolog y 1774 5 Sout

h Metcal f Slilwcll , K S 66085-910

4 BC8432/MO-00-01E83 7 Laboratory Projec t

Stud y I D 95-271-D R Pag e 1 of214 1

Pag e 2 7 o f 3 8

# Baye r

CropScienc e Repor t No
. G20215 5 MRI D 4443540 1 (1997) ; 4518920 1 (2000 , suppl )

Technica l Grade Cyfluthri n (FC R1272) : A Chroni c Toxicity Feedin g Stud y i n th e Beagl e Do g 

## RL E 836 5

Dat aRequiremen t 4 0 CF RPart 15 8 US-EPA-FIFRA , Section 158.340 . Guidelin e 83- 1

Repor t Author s R . D . Jone s andT . F . Hasting s
Study Completio n Dat

e Novembe r 10,199 7
Test Facility Baye r (Corporatio n (formerl y Mile s Inc. ) Agricultur e Divisio n Toxicology 1774 5 Sout

h Metcalf Stilwell, Kansa s 66085-910 4 Stud y Numbe r Study Numbe r

94-276-Z R

pag e 1 o f 115 1

MOB8365/MO-00-01111 9
Pag e 2 8 o f 3 8

# Baye r

CropScienc e Repor t No
. G20215 5 MRID44H650 1

A Developmenta l Toxldt y Stud y wit h FO R 4545 Technica l I n th e Wlsta rRa t

Dat a Requiremen

t 4 0 CF R Par

t 158 US-EPA-FIFRA , Sectio n 158.135 , Guidelin e B3-3

Autho r A
. Barr y Astroff
Stud y Completio n Dat

a Septembe r4,199 6
Tes t Facilit y Baye rCorporatio n Agricultur

e Divisio n Toxicology 1774 5 Sout h Metea H Stilwen , Kansa

s 66085-910

4

Stud y Numbe r 95-612-E W
"BC79£§/'MO-01-01101 S Agricultur e DMsto n Repor t Number 

# 10745 3 RL E 798 9

10(41 1

Pag e 2 9 o f 3 8

# Baye r

CropScienc e Repor t No
. G20215 5 MRI D 4267540 1 Berich t Nr. : R 577 0 

### RC C RESEARC H & CONSULTIN G COMPAN Y LT D



## PROJEC T 30991 4

EMBRYOTOXICITY STUD Y (INCLUDIN

G TERAT06EKICITY ) WIT H FC R 127 2 I N TH E RABBI T
REPORT : PAR T I

UTHOR S ERFORHE D B Y

EPOR T COMPLETE D O

N H . Becke r , K . Blederman n

1 ) RCC , Researc h an

d Consultin g Conpan

yLt d P.O . Box , C H 445 2 Itlnge n / Switzerland 2 ) RC C UMWELTCHEMI E AC , P.O . Box , C H 445 2 Itlnge n / Switzerland DECEMBE R 3 , 199 2

- Pag e l o f 30 2 -
P.O . Bo x C H 445 2 Itlnge n / Switzerlan d Phone 06 1 / 97 5 1 1 1 1 Tele x 96 6 13 6 RC C C H Telefa x 06 1 97 1 5 2 8 4



### Pag e 3 0 o f 3 8

# Baye r CropScienc e Repor t No . G20215 5 MRID : 40780401 ; 40968501 ; 4233200 1 BAYE R A G FACHBEREIC H TOXIKOLOGI E (TOXICOLOG

Y DIVISION ) Wuppertal , 1.2.198 8 Repor t no . 1639 1

FC R 127 2 Commo n nam e cyfluthri n Stud yfo r embryotoxi c effect s o n rat s afte r inhalatio n
b y
Dr . M . Renho f
and Dr . J . Pauluh n

Studynumber : T0020125/T302168 6 Tota l pages : 16 3

Unti l the yar e published , th e finding s containe d i n thi s repor t mayonl yb e use d wit h th e approva l o f BAYE R AG . Furthe r repro ductio n o f al l o r par t o f thi s repor t i s no t permissible .

16391/MO-01-00376 9

Pag e 3 1 o f 3 8

# Baye r CropScienc e Repor t No . G20215 5
MRI D 4339340 1

STUD Y TITLE S FC R 127 2 Explanator

yRepor t o n Result s an d Mechanisti c Studie s fo r Embryotoxi c Effect s i n Rat s afte r Inhalatio n Firs t Amendmen t t o Repor t No . 2321 9 o f Augus t 12 , 199 4 Authors : B . Holzum , U . Schmidt , J . Pauluhn , W . Bomann DAT AREQUIREMEN

T U S EPA-FIFR

AGUIDELIN

E 83- 3 AUTHO R B . Holzu

m STUD Y COMPLETIO

NDAT E Firs t Amendment : Marc h 28 , 199 6 PERFORMIN

G LABORATORY BAYE R AG Institut e o f Toxicology , Friedrich-Ebert-Strass e 217-33 3 D-4209 6 Wupperta l LABORATOR

Y PROJEC T I D Firs t Amendment : Repor t No . 2321 9 A

Pag e 1 o f 9

23213A/MO-0 1 -00381 2

Pag e 3 2 o f 3 8