Do w AgroScience s LL C Repor t ID : 10156 3 Pag e 1 o f 3 1 STUD Y TITL

E Chlorpyrifos : Scientifi c Rational e fo r Citatio n o f

Other Scientificall y Relevan t

Informatio n (OSRI ) i n Fulfillmen t

o f OPPT S 890.145 0 and OPPT S 890.150 0 EDS P Tie

r I Assay s ORDE RNUMBERS : EDSP-059101-30 , EDSP-059101-31 , EDSP-059101-33 , EDSP-059101-3 4 DAT A REQUIREMEN T OPPT S 890.145 0 and OPPT S 890.150 0 EDS P Tie

r I Assay s AUTHO R Dalan d R . Juber g STUD Y COMPLETE

D O N Apri l 12,201 0 PERFORMIN G LABORATOR Y Do w AgroScience s LL C 933 0 Zionsvill e Road Indianapolis , I

N 4626 8 REPOR T ID 101563

• • o t •
, C 0 w • « • - J < - • - * J

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## . : fDo w AgroScience s LL C Report ID : 10156 3 Pag e 2 o f 3 1 STATEMEN

T O F N O DAT A CONFIDENTIALITY CLAIM S Compound : Chlorpyrifo s Title : Chlorpyrifos : Scientifi c Rational e fo r Citatio n o f

Othe r Scientificall y Relevan t Informatio n (OSRI ) i n Fulfillmen t o f OPPT S 890.145 0 an d OPPT S 890.150 0 EDS P Tie

r I Assay s N o clai mo f

confidentiality , o n an y basi s whatsoever , i s mad e fo r an y informatio n containe d i n thi s document . I acknowledg e tha t informatio n no t

designate d a s withi n th e scope o f FIFR A Section 1 0 (d)(l)(A)(B ) or (C) , an d whic h pertain s to aregistere d or previousl y registere d pesticide i s no t

entitle d to confidential treatmen t an d ma y b e release d to th e public , subjec t to th e provision s regardin g disclosur e to multinationa

l entitie s under

FIFR A Sectio n 10(g) . Company : Do w AgroScience s LL C Compan y Agent : Kennet h D . Rack e Title : Regulatory Manager Signature : Date : Apri l 12 . 2 0 1 0 / ^ A " & ^ O I O THI S DATA MA Y B E CONSIDERE D CONFIDENTIA

L OUTSID E THE UNITED STATES .Do w AgroScience s LL C Repor t ID : 10156

3 Pag e 3 o f 3 1 STATEMEN

T O F COMPLIANC E WITH GOO D LABORATOR Y PRACTIC E

STANDARD S Title : Chlorpyrifos : Scientifi c Rational e fo r Citatio n o f

Other Scientificall y Relevan t Informatio n (OSRI ) i n Fulfillmen t o f OPPT S 890.145 0 an d OPPT S 890.150 0 EDS P Tie

r I Assay s Compound : Chlorpyrifo s Thi s repor t doe s no t mee t th e definitio n o f

aGLP stud y a s i t

appear s in : Unite d State s Environmenta l Protectio n Agenc y Titl e 4 0 Cod

e o f Federa l Regulation s Par

t 16 0 Federa l Register , 1 7 Augus t

198 9 Organizatio n fo r

Economi c Cooperatio n an d Development ENV/LMC/CHEM(98)17 , Pari s - January 26,199 8 

# NON-GL P STUD Y

Kennet h D . Racke , Ph.D . Sponso r Do w AgroScience s LL C

Kennet h D . Racke , Submitter Do w AgroScience s LLC

Dalan d R . Juberg , mD . Stud y Director/Autho r Do w AgroScience s LLC Apri l 12,201 0

/ Apri l 12 , 201 0



### 2

- Apri l 12 , 201 0Do w AgroScience s LL C Report ID : 10156 3 Pag e 4 o f 3 1 QUALIT Y ASSURANC E STATEMEN T Compound : Chlorpyrifo s Title : Chlorpyrifos : Scientifi c Rational e fo r Citatio n o f

Other Scientificall y Relevan t Informatio n (OSRI ) i n Fulfillmen t o f OPPT S 890.145 0 an d OPPT S 890.150 0 EDS P Tie

r I Assay s Repor t Completio n Date : Apri l 12,201 0 NON-GLP STUD YDo w AgroScience s LL C Repor t ID : 10156 3 Pag e 5 o f 3 1 1. 1 Summar

y Thi s document

i s bein g submitte d t o addres s th e requirement s unde r th e Tie r I Endocrin e Disruptio n Screenin g Progra m(EDSP ) fo r

chlorpyrifos . Studie s conducte d o n chlorpyrifo s a s wel l a s studie s publishe d i n th e open literature were reviewe d to determin e whether sufficien t functionall y equivalent

informatio n comparabl e t o that develope d i n EPA' s proposed Tier I batter y i s availabl e fo r

th e purpos e o f

assessing th e endocrine-modulatin g potentia l o f chlorpyrifos . Othe

r Scientificall y Relevan t

Informatio n (OSRI ) i s cite d here i n addressin g tw o o f thes e requirement s becaus e the critica l endpoint s (a s define d i n the OPPTS 890.145 0 an d OPPT S 890.150

0 guidelines ) an d the associated endocrin e modes-of-actio n hav e eithe r bee n previousl y evaluate d o r

ar e i n th e proces s o f

bein g evaluate d i n on e o r

mor e o f thre e ways : a) th e endpoint

ha s been directl y assesse d i n existin g regulator y mammalia

n toxicit y studies ; b ) i n rare cases , surrogate o r

relevant endpoint s hav e been evaluate d i n regulator y toxicit y studies ; o r c ) th e relevant

endocrine mode-of-actio n wil l b e assessed i n othe r Tie r I EDS P assay s (Se e Table s 8 an d 9) . Th e state d purpos e o f

th e Endocrine Disrupter

Screenin g Progra

mi s ". . .to determin e whether certai n substance s ma

y hav e a n effec t i n human s that

i s simila r to a n effec t produce d b y a naturall y occurrin g estrogen , or such othe r endocrine effec t

a s th e Administrato r

ma y designate. " Th e state d purpos e o f Tie r I testin g ".. . i s to identif

y substance s that

hav e th e potentia l to interac t

wit h th e estrogen , androgen , o r thyroi d hormon e system s usin g abatter y of assays. " Do w AgroScience s believe s tha t conductin g th e followin g test s fro mth e Tie r I batter y wil l provid e complementar

y dat aan d sufficien t

scientifi c redundanc y to assur e tha t any potentia

l endocrine-relate d effect s o f chlorpyrifo s woul d b e clearl y identified :

• Estrogen receptor

bindin g • Estroge n receptor

transcriptiona

l activatio n • Androgen recepto

r bindin g • Steroidogenesi s • Aromatas e • Uterotrophi c • Hershberge

r • Amphibian metamorphosi s • Fis h short-ter

mreproductio n However , mal e an d femal e pubertal assay s ar e no t require d to mak

e thes e determination s sinc e existin g dat afro mmammalia n regulator

y toxicit y studie s cite d a s OSRI i n combinatio n with th e dat afro mother

Tie r I studie s mak

e thes e assay s redundan t

an d unjustifie d fro mth eDo w AgroScience s LL C Repor t ID : 10156 3 Pag e 6 o f 3 1 standpoin t o f animal use . Consequently , consistent with EPA' s mandat e t o avoi d duplicativ e testing , thes e studie s shoul d no t b e conducted . W e respectfull y as k

tha t EP A carefull y examin e th e OSR I cite d i n thi s rational e an d reques t that , base d o n it s evaluatio n o f th e OSR I an d th e other

EDS P assay s to b e conducted , th e Agenc y conside

r th e requiremen t

fo r chlorpyrifo s fo r

conductin g th e femal e an d mal e pubertal assay s (OPPT S 890.1450 , OPPT S 890.1500 ) t o hav e bee

n met . 1.2 Backgroun d Th e EPA document

entitled : "EPA' s Approac h fo r Considering Other

Scientificall

y Relevant Informatio n (OSRI) unde r

th e Endocrin e Disrupto r

Screening Program " (EPA , Marc h 2009 ) provide s guidanc e to registrant s o n ho w existin g dat ao r "...othe r scientifically relevant information " (OSRI ) i s to b e considere d i n ful l o r partial fulfilmen t

o f Tie r I EDS P dat a requirements . OSRI i s define d as". . .informatio n that inform s th e determinatio n a s t o whethe r th e substanc e ma

y hav e a n effec t that i s simila r t o a n effec t produce d b y asubstanc e that interact s wit

h th e estrogen , androgen , and/o r thyroi d hormonal systems. " Accordin g to th e EPA' s OSR I guidanc e document , th e followin g type s o f informatio n ma

y b e usefu l a s OSRI : studie s that correspond to th e assay s i n Tie r 1 or Tie r 2 , metabolis mstudies , an d other vertebrate o r

invertebrate toxicit

y studies , including , but

no t limite d to , developmenta

l toxicit y tests , carcinogenicit

y tests , toxicogenomi c data , an d reproductiv e toxicit y tests . Revie w o f

Pee r Reviewe d Literatur e In additio n t

o the 4 0 CF

RPar t 15 8 registratio n studie s evaluated , aliterature search wa s als o performe d fo r

th e purpos e o f

identifyin g an y publishe d chlorpyrifo s studie s o r dat atha t coul d potentiall y serv e a s OSRI i n fulfilmen t o f EDS P Tie

r I dat arequirements . Th e search wa s performe d i n abroad-base d manner an d yielde d anumbe r

o f potentiall y relevant

studies ; however , upo n close

r examinatio n th e majority wer e determine d to no t

b e directly relevan t

to th e EDS P Tie

r I dat arequirements . O f

th e origina

l search , asub-set

o f seven studie s wa s identifie d an d determine d to b e mor e directly german e to severa l o f th e Tie r I screening assay s o r individual end-point s withi n thes e assays . Thes e include : on e stud y tha t evaluate d thyroi d hormon e level s i n mice , severa l studie s examinin g estrogen or androgen receptor

bindin g and/o r activatio n b y variou s methods , an d tw o aromatas e assays . Followin g identificatio n o f th e seven publications , adat aqualit y evaluatio n wa s performe d o n each . T o ensur

e that thi s ste p adhere d to astandar

d an d well-documente d process , apublicly

availabl e dat aqualit

y evaluatio n too l wa s utilized . Thi s too l i s calle d th e "ToxRTool " (Toxicologica

l dat aReliabilit

y Assessmen

t Tool ) an d i s availabl e to th e publi c o n th e ECVA M (Europea

n Centr e fo r th e Validatio n o f

Alternativ e Methods ) web-sit eDo w AgroScience s LLC Repor t ID : 10156 3 Pag e 7 o f 3 1 (http://ecvam.jvc.ec.europa.eu/index.htm) . Th e purpos e o f th e too l i s to provid e atransparent an d harmonize d metho d fo r evaluatio n o f

dat aqualit y fo r

i n viv o an d i n vitr o toxicolog y studies . Th e too l provide s dat aquality criteri aan d guidanc e an d i n th e en d assign s aKlimisc h categor y o f 1 (reliabl e withou t

restrictions) , 2 (reliabl e with restrictions) , o r 3 (no t reliable ) t o a give n study (Klimisch , 1996) . A s show n i n Tabl e 1 , evaluatio n o f the seve n chlorpyrifo s literatur e studie s di d no t

yiel d an y reliabl e ( 1 o r

2 ) results . Th e primary reaso n that amore favorabl e reliability scor

e coul d no t

b e assigne d wa s du e to th e lac k o f dose-respons e dat a wher e i n multipl e studie s onl y on e dose-leve l o f chlorpyrifo s wa s teste d i n th e relevan t assay . Sinc e non e o f

th e chlorpyrifo s literature studie s identifie d wa s determine d to b e reliable , the y wil l no t b e utilize d a s OSRI i n fulfilmen t o f an y dat arequirement s an d ne w dat awil l b e generate d fo r

thes e endpoints . Thes e publication s ma y b e usefu l i n futur e weight o f evidenc e determination s followin g completio n o f Tie r I screening . Tabl e 1 ; Dat aqualit y an d reliability o f chlorpyrifo s literatur e citation s 

### '•"•StndhK ^

1

2

3 Simona , D.A. , et

al . Developmenta

l Exposure to Chlorpyrifo s Induce s Alteration s i n Thyroi d an d Thyroi d Hormon e Level s Withou t

Othe r Toxicit y Sign s i n Cd l Mice . (2009 ) Toxicologica

l Science s 108:311-319 . Lemaire , G . e

t al . Activatio n o f

alph aan d bet aestrogen receptor s b y persistent pesticide s i n reporte r cel l lines . (2006) . Lif

e Science s 79 : 1160-1169 . Grunfeld , H.T . et a/.Effec t o f i n vitr o estrogeni c pesticide s o n huma n oestroge

n recepto r alph aan d betamRN A levels . (2004) . Toxicolog y Letter s 151 : 467480 . Thyroi d hormon e an d thyroi d morphologica

l alteration s i n dam s an d F l GD I mic e Chlorpyrifo s di d no t caus e astatisticall y significan t chang e i n transactivatio n activity o f ER-alph aor

ER-beta compare d to control .

A smal l increas e i n E R mRN A level s observe d wit h chlopyrifo s treatmen t m^'A^^^^^K^^ ^

3

3

3 Stud y utilize d a subcutaneou s rout e o f exposur e for post-nata l exposure ; no t

a relevan t route fo r huma n exposure . Numbe r o f animal s per grou p wa s insufficient . Insufficien t

dose

level s teste d o r presente d i n th e paper

Measur e o f mRN A leve l i s no t considere d specifi c no r relevan t t o EDS PDo w AgroScience s LL C Repor t ID : 10156 3 Pag e 8 o f 3 1

' • » >*• • • f ^''^IwJvrarff

i 

### iNumDerKv '

4

5

6

7 Vinggaard , A.M. , e f al . Screenin g o f

Selecte d Pesticide s fo r

Inhibitio n ofCYP19Aromatas e Activit y I n Vitro . (2000) . Toxicolog y i n Vitr o 14 : 227-234 . Andersen , H.R. , e t a/.Effect s o f

Currentl y Use d Pesticide s i n Assay s fo r Estrogenicity , Androgenicity , an d Aromatas e Activit y i n Vitro . (2002) . Toxicolog y an d Applie d Pharmacology . 179 : 1-12 . Kojima , H . e t al . Screenin g fo r

Estroge n an d Androge n Recepto r Activitie s i n 20 0 Pesticide s b y I n Vitr o Reporter Gen e Assay s Usin g Chines e Hamste

r Ovar y Cells . (2004) . EHP 112:524-531 . Vinggaard , A.M. , et al . Screenin g o f

Selecte d Pesticide s fo r

oestrogen recepto r activatio n i n vitro . (1999) . Foo d Additive s an d Contaminant s 16 : 533

- 542 . N o statisticall y significan t effec t o f chlorpyrifo s treatmen t compare d t o contro l Chlorpyrifo s induce d a wea k respons e i n estrogenicit

y assay(s) ; N o effec t relativ e t o contro l i n aromatas e assa y

Chlorpyrifo s induce d a ver y wea k respons e i n E Ralph atransactivatio n assa y

N o statisticall y significan t effec t o f chlorpyrifo s treatmen t compare d t o contro l ;-KUinlscl0

3

3

3

3 Insufficien t

dose

level s teste d o r presente d i n th e pape r

Insufficien t

dose

level s teste d o r presente d i n th e paper ; MCF- 7 tes t syste mi s o f

limite d relevanc e t o EDS P

Insufficien t

dose

level s teste d o r presente d i n th e pape r Insufficien t

dose

- • level s teste d o r presente d i n th e paper ; Yeas t

an d MCF- 7 tes t

system s i s o f limite d relevanc e t

o EDSP ; significan t toxicit y issue s observe d I n additio n to th e type s o f dat anote d previousl y a s relevan t OSR I information , th e OSRI guidanc e documen

t give s specifi c mentio n to toxicit y studie s conducte d i n fulfilmen t o f th e dat arequirement s for

pesticide registratio n (4 0 CF R Par t 158) . Evaluatio n o f

thes e dat ai n addressin g Tie

r I dat arequirement s i s asignificant priorit y sinc e thes e dat adelineat e abroad rang e o f robus t toxicit y studie s that

mus t b e complete d an d critically assesse d b y th e EPA prio r to registratio n o f

apesticide activ e ingredient i n th e Unite d States . Amon g th e require d data-set ar e multipl e repeat-dos e toxicit y studie s o f

variou s duration , fro m4-1 3 week s to exposure s encompassin g th e majority o f thes e organism' s lifespan .Do w AgroScience s UL C Repor t ID : 10156 3 Pag e 9 o f 3 1 I n addition , studie s ar

e conducte d unde r

4 0 CFRPar

t 15 8 to determin e any potentia l fo r treatment-relate d effect s o n reproductio n a s wel l a s pre - an d post-nata l development . Th e dose s use d i n al l o f

thes e studie s appropriatel y challeng e th e tes t organism s an d th e dose s employe d are muc h higher tha n anticipate d huma n exposur e levels . Examinatio n o f

thi s complet

e data-set , whic h i s already availabl e fo r al l pesticid e activ e ingredients , allow s fo r

determinatio n o f

target orga n toxicity an d an y other

advers e effect s that ma y b e elicite d b y exposure . Thes e existin g studie s are capabl e o f detectin g advers e biological effect s o f

treatment tha t coul d b e elicite d b y on e o r mor e modes-of-action , includin g th e endocrine modes-of-actio n bein g addresse d b y th e EDSP . Potentia l advers e effect s resultin g fro mmodulatio n o f th e endocrin e syste mhav e alread y bee n intrinsicall y evaluate d i n th e exitin g registratio n toxicity studies . Based o n th e no-effec t level s determine d b y thes e studies , applicatio n o f th e principle s o f

ris k assessmen

t allow s fo r

appropriat

e margin s o f

exposur e i n the us e o f

thes e activ e ingredients . Bot h i n term s o f

goo d scientifi c principle s an d particularl y i n ligh t o f th e scientifi c community' s responsibilit

y fo r judiciou s us e o f

animal resources , i t

i s appropriate to conside

r existin g dat ai n th e contex t o f th e EDS P requirements , an d EPA shoul d grant exemption s fro mscreening where existin g dat aalready provide adequate information . I n fact , accordin g t o Federa l Food , Dru g an d Cosmeti c Ac t (FFDC A sectio n 408(p)(5)(B)) , EP A i s oblige d t

o ''. . ..minimiz e duplicativ e testin g o f th e scon e substanc e fo r

th e scon e endocrine effect. " Thi s polic y i s echoed b y th e Offic e o f Management

an d Budget' s respons e to EPA' s EDS P Informatio n Collectio n Respons e (ICR ) whic h direct s th e Agenc y t o ". . .promot

e an d encourag e tes t

order recipient s to submi t

Other Scientificall

y Relevant

Informatio n (OSRI) i n lie u o f performin g all or

som e o f the Tie r I assays , an d EP

A shoul d accep

t OSR I a s sufficien t to satisf y th e tes t order s to th e greates t

extent possible. " I n summary , fo r

pesticid e activ e ingredient s ther

e i s awealt

h o f existin g informatio n availabl e that ca n reduc e o r

eliminat e th e nee d fo r

Tie r I screening . I n particular , th e multi-generatio n reproductio n study alread

y availabl e fo r

pesticid e activ e ingredient s i s ahigher-tiere d assessmen t o f potentia l endocrine-mediate d toxicity , an d EPA i s i n fac t plannin g to us e i t

a s th e mammalia

n Tie r n testin g requirement . Logi c therefore dictate s tha t havin g th e higher

tiere d stud y complete d lessen s o r eliminate s th e need fo r

supplyin g lower-tiere d screening assay s o f ales s robus t

nature . Wit

h higher-tie

r dat aavailable , th e practica l utilit y o f performin g screening studie s i s highl y questionable . In addition , EPA ha s alread y evaluate d thes e existin g studie s fo r

pesticide activ e ingredients , includin g any potentia l advers e effect s resultin g fro mmodulatio n o f th e endocrine system , an d th e Agenc y ha s alread y mad e a determinatio n that

thes e activ e ingredient s ca n b e used withou t

undu e ris k

to huma n health . 1. 3 Chlorpyrifos : Overview o f Existin g Database Firs t registere d b y th e USEP

A i n 1965 , chlorpyrifo s i s apes t contro l produc t

no w registere d an d use d for

agricultura

l application s i n mor

e than 10 0 nations . N o pes t contro l produc t

ha sDo w AgroScience s LLC Repor t ID : 10156 3 Pag e 1 0 of

3 1 bee n studie d mor

e extensivel y an d presen t

application s res t

o n 4 decade s o f

use , healt h surveillanc e o f

manufacturin g worker s an d applicators , an d ascientifi c databas e o f mor e tha n 360 0 studie s o n healt

h an d th e environment . Th e toxicological databas e fo r chlorpyrifo s i s on e o f

th e mor e extensiv e fo r

an y regulate d chemical , includin g aful l se t o f reproductiv e an d developmental studie s require d fo r registratio n whic h provide s in-dept h assessment

o f numerou s potentia

l toxicologica

l endpoint s o f interest , includin g endocrine function . Specifi c studie s tha t mee t o r excee d USEP

A guideline s an d whic h are mos t relevan t fo r evaluatio n o f

potentia l interactio n wit h th e endocrin e systemar

e note d i n Tabl e 2 an d includ e subchroni c an d chroni c studie s hi severa l species , 4 developmenta

l toxicit y studie s i n thre e species , 2 multigeneratio n reproductio n studies , an d adevelopmenta l neurotoxicit

y study . Thes e studie s wer e conducte d hi accordanc e with internationall y accepte d tes t guideline s i n plac e a

t th e time , an d th e mor

e recent studie s adher

e to GLP standards . Man y o f th e studie s utiliz e rat s and , therefore , ar e considere d th e mos t

relevant to th e mammalian Tier

IEDS P dat arequirements . Taken together , thi s suite o f

studie s involvin g numerou s endpoint s o f interest , an d with th e additiona l strengt h afforde d throug h direc t

analysi s o f

effect s o n potential endocrine target organ s an d inclusio n o f

clinica l chemistr y an d histopathology , provide s th e basi s fo r arobus t determinatio n o f

any potentia

l effec t o n genera

l toxicity , development

an d maturation , a s wel l a s other endpoint s tha t

coul d signif

y a n interactio n o r

effec t o n th e endocrine system . Chlorpyrifos , alon g with othe r organophosphorou s insecticides , exer t their toxicit y to target organism s throug h inhibitio n o f th e enzyme cholinesterase . Thi s i s th e well-characterize d an d accepted mod

e o f actio n b y regulator

y authoritie s worldwide . The multigeneratio n reproductio n an d developmenta l studie s fo r

chlorpyrifo s demonstrat

e that even a t dose s thousand s o f

time s greate

r than estimate d huma n exposure level s (Bar r et al. , 2005) , chlorpyrifo s ha s n o effec t

o n mal e o r

femal e fertility , litte

r siz e o r viability , o r

number o f embryo s implante d i n th e uterus . Collectively , th e studie s reporte d i n Tabl e 2 hav e assesse d a wid e rang e o f

biologica l effect s relate d to endocrine functio n a s part o f th e FIFR A require d testin g fo r registere d pesticides , an d n o endocrine effect s hav e bee n foun d i n experimenta l animal s that

hav e bee n expose d fro mconceptio n throug h adulthoo d to ol d age , a t level s thousand s o f

time s higher

than potentia

l human exposure . Regulator y agencie s worldwide hav e evaluate d thes e studie s an d hav e no t identifie d endocrine effect s a s atoxicologica l endpoint or mode o f actio n o f concern . The EP

A ha s als o evaluate d chlorpyrifo s under FQP A an d ha s no t

identifie d i t

a s a n endocrine concern . Mor

e recently (December , 2008) , th e Californi aOffic e o f

Environmenta

l Healt h Hazar d Assessment' s (OEHHA ) Developmenta l an d Reproductiv e Toxicant Identificatio n Committe e (DART ) decline d to lis t Chlorpyrifo s a s areproductiv e (mal e o r

female ) o r

developmenta

l toxicant under Californi aPropositio n 65 . Th e DAR T conclude d that

evidenc e doe s no t

exis t fo r chlorpyrifo s whic h i s necessar y to mee t th e standard that

achemica l mus t b e clearl y show n to caus e reproductiv e and/o r developmenta

l toxicit y i n orde r fo r it s listin g under

Propositio n 65 . Finally , ther e ar e n o know n o r reporte d endocrine effect s i n human s exposed occupationally .Do w AgroScience s LL C Repor t ID : 10156

3 Pag e 1 1 of

3 1 

### Tabl e 2 : Existin g studie s (OSRI ) cited i n fulfilmen t o f Tier I dat arequirement s Citatio n Cod

e 

### A

B

C

D

E Stud y Citatio n

Rubi n etal. , 1987 . Pyrinex : Teratogenicit

y stud y i n th e rabbit . Makhteshim-Agan (America) , Inc . Lif

e Scienc e Researc h Israel Ltd . Nes s Ziona , Israel Rubi n et al. , 1987 . Pyrinex : Teratogenicit

y stud y i n th e rat . Makhteshim-Aga

n (America) , Inc . Lif

e Scienc e Researc h Israel Ltd . Nes s Ziona , Israel Deaco n etal . 1979 . Th e effect s o f orally administere d Chlorpyrifo s o n embryonal an d feta l development

i n mice . Do w Chemical . Midland , Michiga

n Ouellett e e t al . 1983 . Chlorpyrifos : Ora

l teratolog y study i n Fische r 344 rats . Do w Chemical . Midland , Michiga n Warner etal . 1980 . Result s o f atwo-yea r toxicit y an d oncogenicit

y study o f Chlorpyrifo s administere d to CD- I i n th e diet . Th e Do w Chemica l Company . Indianapolis , Indian a GL P Stud y 

### Ye s

Ye s

N o

N o

N o iVIRID Numbe r

4043640 8

4043640 7

0009526 8

0013040 0

0005435 2 & 00142902

### Do w AgroScience s LL C Report ID : 10156 3 Pag e 1 2 of 3 1 Citatio n Cod

e Stud y Citatio n GL P Stud y VIRI D Numbe r Youn g an dGrandjean , 1988 . Chlorpyrifos : 2

- yea r dietar y chroni c toxicity-oncogenicit

y stud y i n Fische

r 34 4 rats . Th e Do w Chemica

l Company , Freeport , TX Ye s 

### 40952802

Thompson , e

t al . 1971 . Thre e generatio n reproductio n an d teratolog y study i n th e ra t followin g prolonge d dietar y exposure t o Dursban : 0,0-diethy l 0

- 3 , 5,6-trichloro-2

- pyridy l phosphorothioate . The Do w Chemica

l Company , Zionsville , I N N o 

### 0002906 4 & 0006493 4

H 

### Crow n e

t al . 1985 . Pyrine x Technical : Toxicit y i n dietar y administratio n to rat s fo r 1 3 weeks . Makhteshim

Agan (America) , Inc . Nes s Ziona , Israe

l Ye s 

### 4043640 6

Gur . 1992 . Pyrine x Technical . Oncogenicit

y study i n th e mouse . Makhteshim-Agi n o f Nort h America . Nes s Ziona , Israel Ye s 

### 4253420 1

Breslinetal . 1991 . Chlorpyrifos : Two

generatio n dietar

y reproductio n study i n Sprague-Dawley rats . The Do w Chemica

l Company . Midland , M I Ye s 

### 4193030 1Do w AgroScience s LL C Repor t ID : 10156 3 Pag e 1 3 of 3 1 Citatio n Code 

### K

M

N Stud y Citatio n

Szab o et al . 1988 . Chlorpyrifos : 13-wee

k dietar y toxicity stud y i n Fischer-34 4 rats . Th e Do w Chemica

l Company . Freeport , TX . Corleyetal . 1986 . Chlorpyrifos : 13-wee

k nose-onl y vapo r inhalatio n exposur

e stud y i n Fische

r 34 4 rats . Th e Do w Chemica

l Company . Midland , M I McColliste

r e t al. , 1971 . Result s o f two-yea r dietar y feedin g studie s o n DOWC O 17 9 in rats . The Do w Chemica

l Company . Midland , M I Hoberman . 1998 . Developmenta

l neurotoxicit

y study o f Chlorpyrifo s administere d orall y vi a gavag e to Crl:CD®B R VAF/Plus ® presume d pregnant rats . Argu s Researc h Laboratories . Horsham , PA GL P Stud y 

### Ye s

N o

N o



### Ye s MRID Numbe r

4095280 1

4001390 1 & 4016650 1

0009517 8

4455690 1Do w AgroScience s LL C Repor t ID : 10156 3 Pag e 1 4 o f 3 1 1. 4 Chlorpyrifos : Scientifi c Rational e fo rSufficienc y o f OS/77 i n Fulfilmen

t o f OPPT S 890.145

0 an d OPPT

S 890.150

0 I n preparin g thi s scientifi c rationale , th e followin g proces s wa s followed : 1 . Evaluat e appropriate existin g chlorpyrifo s dat a(OSRI) , includin g primaril y guidelin e toxicity studie s an d othe

r publishe d studies . 2 . Examin e existin g dat afo r endpoint s relevant

to EDS P Tier

I . 3 . Determin e whic h Tie

r I endpoint s ar

e adequatel y addressed b y OSRI . 4 . Determin e i f

any EDS P Tie

r I assay s an d endpoint s ar

e sufficientl y addresse d b y OSRI . Fo r registere d activ e ingredient s lik e chlorpyrifos , there i s a

n abundanc e o f

availabl e informatio n tha t

i s relevan t

to determinin g i f

any endocrine-mediate d effect s occu r with treatment . Studie s submitte d a s OSR I i n fulfilmen t o f Tie r I requirement s shoul d b e carefull y considere d an d no t

dismisse d i f

onl y on e o r

afe w specifi c endpoint s requeste d b y th e Tie r I screenin g studie s wer

e no t evaluated . For

example , TS H an d T4 measurement s ar e require d endpoint s unde r

OPPT S 890.145 0 and OPPT S 890.150 0 assays , but

thes e measurement s provid e onl y on e insigh

t (an d on e base d o n asnapsho t i n time ) o n potentia

l thyroi d toxicity . It i s well-establishe d that

assessmen

t o f orga n weigh t an d histopathologica

l revie w o f

th e thyroi d glan d are mor

e deterministi c an d informativ e relativ e to thi s orga n bein g atarget

an d potentia

l implicato r o f endocrine-relate d toxicity . In thi s specifi c case , thes e type s o f dat aar e superior to discret e measurement s o n thyroi d hormones . Further to thi s point , i t

shoul d b e note d tha

t i n th e cas e o f

th e pubertal assays , man y o f th e endpoint s ar

e no t specifi c t o th e endocrine system an d ca n b e altere d a s aresul t

o f genera l systemi c toxicit

y (Stoker , 2000) . For

example , endpoint s evaluate d i n th e puberta l assay s ca n b e altere d secondar

y t o effect s o n bod

y weigh t (Carney , 2004) . Thi s i s significant a s th e guideline s for

pubertal assay s defin e reduce d bod y weigh t a s evidenc e fo r

havin g achieve d a

n appropriate hig h dose-level fo r testing . Give n th e lac k o f specificit y for man y o f th e apica l pubertal endpoints , i t

i s appropriate to conside

r surrogate endpoint s i n plac e o f thes e less-specifi c endpoint s whic h ma y no t hav e been examine d i n th e existin g databas e fo r agiven chemical . Thi s approac h wil l allo w fo r arobus t weigh t o f evidenc e determinatio n based upo n th e totalit y o f th e availabl e data . Whil e al l o f thes e endpoint s ma

y no t b e o f equa l sensitivity , consisten

t result s foun d acros s multipl e studie s an d end-point s wil l ofte n provid e ahig h degree o f confidenc e i n th e conclusion withou t th e nee d fo r

conductin g additiona

l testing . Table s 3- 5 belo w provid e example s o f end-point s commonly assesse d in 4 0 CF

R15 8 guidelin e studie s that

ca n serv e a s surrogate s fo r

other endpoint s that

asses s estrogenicity , anti

estrogenicity , an d anti-androgenicit y (androgenicit

y no t include d a s xenobioti c androgen agonist s ar

e rare) . Thes e table s present aclea r an d predictabl e patter

n o f advers e biologica

l outcome s followin g exposur e to chemical s actin g throug h estrogenic , anti-estrogeni c o r anti

androgeni c modes-of-action . I f apattern consisten

t with th e effect s presente d i n thes e table s i s no t observed , the n ates t

chemica l ca n b e considered negativ e fo r advers e effect s elicite d

### Do w AgroScience s LLC Report ID : 101563 Pag e 1 5 of 3 1 throug h variou s endocrine mode(s)-of-action . Therefore , individua l endpoint s that are lackin g o r eve n isolate d statisticall y significan t finding s are o f

limite d importanc e i n determinin g a chemical' s potential t o interac t wit h th e endocrine syste msinc e i t i s th e array o r

pattern o f effect s that

i s mos t usefu l i n makin g thi s determination . Tabl e 3 ; Advers e effect s elicite d b y estrogeni c substance s Endpoin t Estrou s cyclicit

y Tim e t o matin g Uterin e weigh t Vaginal patenc y 

### PPS Ovaria n follicl e count Fertilit y Matin g index Corpor alute a Implantation s Gestationa l lengt h Litte r siz e Anogenita l distanc e Epidydimi s sper

mcoun t Testi s Histopatholog y Epidydimi s histopatholog y Prostat e histopatholog y Ovar y weigh t Ovar y histopatholog y Mammar y histopatholog y Expecte d Chang e

Decreas e frequency ; anestrou s Increas e Increas e Accelerate d Delaye d Decreas e Decreas e Decreas e Decreas e Increas e increas e Decreas e Decreas e Decreas e Atrophy Lesions , decreased sper

m conten t Involutio n o f

ventra l prostat e epithelium ; stroma

l proliferatio n Decreas e Stroma l hyperplasia ; follicular cyst s Increased Reference s Terry , 2004 ; Abbott , 2006 ; Deli aSeta , 2008 ; Sawaki , 200 3

### Do w AgroScience s LL C Repor t ID : 10156 3 Pag e 1 6 of 3 1 Tabl e 4 ; Advers e effect s elicite d b y anti-estrogeni c substance s Endpoin t Estrou s cyclicit

y Tim e to matin g Testi s weigh t Vaginal patenc y Corpor alute a Litter siz e Testi s Histopatholog y Epidydimi s histopatholog y Prostat e histopatholog y Semina l Vesicl e histopatholog y Ovar y histopatholog y Expecte d Chang e Decreas e frequency ; anestrou s Increas e Decreas e Delaye d Decreas e or

absent Decreas e Leydi g cel l atroph y Degenerativ e change s Degenerativ e change s Degenerativ e change s Decreas e primordia

l follicles ; hemorrhagi c follicles ; interstitial/stromal hyperplasi a Reference s Vanage , 1997 ; Abbott , 2006 ;

### Do w AgroScience s LL C Report ID : 10156 3 Pag e 1 7 o f 3 1 Tabl e 5 ; Advers e effect s elicite d b y anti-androgeni c substance s 

### Endpoin t Preputial separatio n Sper mcount , motility Testi s Weigh t Vaginal patenc y Epididymi s weigh t Prostat e weight Semina l Vesicle s Weight Testi s histopatholog y Epididymi s histopatholog y Prostat e histopatholog y Semina l Vesicl e histopatholog y Anogenita l distanc e Uterin e histopatholog y Mammary glan d Estrou s cyclicit

y Tim e t o matin g Fertilit y Ovary histopatholog y Uterin e histopatholog y Expecte d Chang e Delaye d Decreas e Generall y Decreas e Delaye d Decreas e Decreas e Decreas e Carcinoma ; leydi g cell hypertrophy/hyperplasia ; germina l degeneratio n Agenesis ; spermati c depletio n Fibrosis , cellula

r infiltration ; epithelial hyperplasia ; agenesi s Fibrosis , cellula

r infiltration ; epithelial hyperplasi a Decreas e Cysti c endometria

l hyperplasi a Decreas e adenomas , adenocarcinoma s Persisten t estru s Increas e decreas e Hypertrophy Cysti c endometria

l hyperplasi a Reference s Gray , 2001 ; Shin , 2002 ; Lund , 2004 ; Va

n De r School , 1992 ; York , 2006 ; Bowman , 2005 ; Horsley , 2005 ; Rider , 2008 ; O'Connor , 2002 ;

Specifi c endpoint s define dandrequire dunder OPPTS 890.145 0 andOPPT S 890.150 0 guideline s ar

e summarize di n Table s 6 an d7 , respectively . For endpoint s wher

e th e requeste d dat aar e no t available , other

functionall y equivalent

o r surrogat e endpoint s generate di n other studie s that hav e bee n conducte dfo r

chlorpyrifo s ar

e liste d(citatio n code s refe r

to studie s liste di n Tabl e 2) . I n addition , other OPPTS EDS P Tie

r I assay s ma

y b e performe dto provid e th e missin g data-point s sinc e there i s significan t overla p i n th e Tier

I testin g progra

mfo r th e variou s endocrine-mediate dmodes-of-action . Th e conclusio n fro mthi s process , afte r carefu l consideratio n o f

th e weigh t o f th e evidenc e provide db y existin g toxicit

y studie s an dendpoint s availabl e fo r chlorpyrifo s (i.e. , OSRI) ,Do w AgroScience s LL C Repor t ID : 10156 3 Pag e 1 8 of 3 1 combine d wit h th e EDS P studie s tha t wil l b e conducted , i s tha t

th e femal e an d mal e puberta l assay s are redundan t

o f existin g relevant

information , an d are , therefore no t justifie d fro ma

n animal us e o r

scientifi c need s perspective . I n grantin g a n exemptio n fro mperformin g thes e studies . EPA wil l preven t

th e unnecessar

y us e o f a t leas t 9 0 animals .i n ti_ ,

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# 03Do w AgroScience s LL C Repor t ID : 10156

3 Pag e 2 6 o f

3 1 7. 7 Summar

y an d Conclusion s Potential effect s o f

treatmen t o n growt h an d developmen t

are evaluate d i n multi-generatio n reproductio n studies . A s thi s i s essentiall y th e purpos e o f th e EDS P pubertal assays , i t i s logica l to conclud e tha t

dat afro mmulti-generatio n studie s shoul d b e carefull y evaluate d prio r t o conductin g th e pubertal assays . I n additio n t o th e multi-generatio n stud y fo r chlorpyrifos , ther e i s arobus t an d divers e set o f toxicologica

l studie s coverin g numerou s other endpoint s an d endocrine-sensitiv e tissue s i n multipl e specie s an d includin g avertica l array o f biological assessment s (i.e. , orga n weight , growth , fertility , histopathology , clinica l chemistry) . Fo r

chlorpyrifos , there i s n o empirica l evidenc e tha t

i s suggestiv e o f

endocrin e toxicit

y no r ha s amode-of-actio n involvin g endocrine-mediate d effect s bee n postulated , investigate d o r confirmed . Whe n multi-generatio n stud y result s fo r chlorpyrifo s are combine d with other

existin g dat aan d perhap s supplemente d wit h EDS P Tie

r I screenin g dat a(t o b e generated) , i t

ma y b e conclude d tha t

th e puberta l assay s woul d b e redundan t and , therefore , no t necessar y t o mak e arobus t

determinatio n o f

potential effect s o n th e endocrin e system . A summarizatio n o f

th e collectiv e dat aavailabl e fo r chlorpyrifo s pertainin g to femal e an d mal e reproductiv e toxicit

y follows : Femal e Reproductiv e Toxicitv Ther e i s n o evidenc e fro mth e multigeneratio n reproductio n stud y i n rat s o r fro mothe r toxicologica l studie s i n whic h femal e reproductiv e organs/tissue s wer e evaluate d tha t chlorpyrifo s i s associate d wit h femal e reproductiv e toxicity . There i s n o evidenc e tha t chlorpyrifo s i s associate d wit h effect s o n femal e reproductiv e structur e o r functio n includin g geneti c damag e t o th e ovum , alteration s i n ovulatio n o r menstruation , impaire d o r altere d endocrin e functio n o r

complication s durin g pregnancy . Similarly , ther e i s n o evidenc e tha t chlorpyrifo s affect s femal e reproductiv e performanc e a s evaluate d i n th e studie s fo r whic h suc h effect s woul d nominall y b e determined , primaril y th e multigeneratio n reproductio n stud y i n th e rat . Additionally , a n evaluatio n o f bot h long-termstudie s i n rat s an d mic e fo r evidenc e o f treatment-relate d effect s t o th e reproductiv e organs/tissu e o f female s reveale d n o advers e effects . Ther e wer e n o observe d treatment-relate d effect s o n reproductiv e organ weight s no r wer e ther e an y non-neoplasti c o r

neoplasti c treatment-relate d finding s i n femal e reproductiv e organs/tissue s a t eithe r th e interi msacrific e o r

termina l sacrific e periods . Mal e Reproductiv e Toxicit y There i s n o evidenc e fro mth e multigeneratio n reproductio n stud y i n rat s o r fro mothe r toxicologica l studie s i n whic h mal e reproductiv e organs/tissue s wer e evaluate d tha t chlorpyrifo s i s associate d wit h mal e reproductiv e toxicity . Ther e i s n o evidenc e tha t chlorpyrifo s i s associate d wit h effect s o n mal e reproductiv e structur e o r functio n includin g geneti c damag e t o th e spermatozoo n o r

it s precursor , impaire d sper mo r semina l flui d production , impaire d o r altere d endocrin e function , o r

impaire d reproductiv e performance . A n evaluatio n o f long-ter mstudie s i n both rat s an d mic e fo r

evidenc e o f

treatment-relate d effect s t o th e reproductiv e organs/tissu e o fDo w AgroScience s LL C Repor t ID : 10156 3 Pag e 2 7 o f

3 1 male s reveale d n o advers e effects . Ther e wer e n o observe d treatment-relate d effect s o n reproductiv e orga

n weight s no r

were there an y non-neoplasti c o r neoplasti c treatment-relate d finding s i n mal e reproductiv e organs/tissue s a t eithe r th e interi msacrific e o r

termina l sacrific e periods . For chlorpyrifos , al l o f

the critica l endpoint s define d i n the OPPT S 890.145 0 an d OPPT S 890.150 0 guideline s an d th e associate d endocrin e mode(s)-of-actio n hav e bee n evaluate d i n on e o r mor e o f thre e ways : a ) th e endpoint

ha s bee n directl y assesse d i n existin g regulator y mammalian toxicity studies ; b ) i n some cases , surrogate o r relevant endpoint s hav e bee n evaluate d i n regulator y toxicity studies ; o r

c ) th e relevan t

endocrin e mode-of-actio n wil l b e assessed i n other Tie r IEDS P assay s (Se e Table s 8 an d 9) . I t i s clea r fro mthes e table s tha t

n o additiona

l o r critica l informatio n informin g o n endocrine-relate d effect s wil l b e generate d throug h th e conduc t o f th e mal e an d femal e puberta l assays . Tabl e 8 ; Summar y o f

OSR I fo r femal e puberta l assa

y OPPTS 890.1450 Endpoin t Growt h Ag e a t Vaginal Openin g Uterin e Weight Ovarian Weigh t Thyroi d Weigh t Live r Weigh t Kidne y Weigh

t Pituitary Weight Adrena l Weight Uterin e Histopatholog y Ovarian Histopatholog y Thyroi d Histopatholog y Kidne y Histopatholog y TSHandT 4 Estrou s cyclicit

y Clinica l Chemistry Endpoin t assesse d i n existin g studie s 

### X X X X X X X X * X X X X X

X Surrogate endpoint s

assesse d i n existin g studie s 

### X

X Mode-of

- Actio n to b e assesse

d i n othe r Tie r I EDS P assay s 

### X X X

X

X

X X
* histopatholog y dat aavailabl e whic h i s asurrogat e indicato r o f targe t orga n toxicit yDo w AgroScience s LL C Repor t ID : 10156 3 Pag e 2 8 o f

3 1 Tabl e 9 : Summar y o f

OSR I fo r mal e puberta l assa

y OPPT S 890.150

0 Endpoin t Growt h Ag e a t preputia l separatio n S V Weight V P Weigh t DLP Weight Levator ani

- weight Epididymide s Weight Teste s weigh t Thyroi d weight Liver Weight Kidne y Weigh t Pituitary Weigh t Adrenal Weight Epididymi s Histopatholog y Teste s Histopatholog y Thyroi d Histopatholog y Kidne y Histopatholog y TSHandT 4 Testosteron e Clinical Chemistr

y Endpoin t

assesse d i n existin g studie s 

### X X

X X X X X * X X X X X

X Surrogate endpoint s

assesse d i n existin g studie s 

### X Mode-of

- Actio n to b e assesse

d i n other Tie r I EDS P assay s 

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X (optional ) 

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* histopatholog y dat aavailabl e whic h i s asurrogat e indicato r o f targe t orga n toxicit y Th e confidenc e i n th e existin g studie s cite d i n thi s rational e an d abilit y to us e the mi n lie u o f performin g ne w studie s i s increase d b y examinin g th e totalit y o f availabl e informatio n an d performin g aweigh t o f evidenc e evaluation . Th e existin g databas e fo r chlorpyrifos , generate d ove r 40 + years , doe s no t demonstrate any pattern o f effect s consisten

t with advers e endocrine-mediate d effect s o n reproductiv e organ s o r

processes . Th e state d purpos e o f

th e Endocrin e Disrupte r

Screenin g Progra

mi s "to determin e whethe r certai n substance s may hav e an effec t i n human s that

i s simila r t o an effec t

produce d b y anaturall y occurrin g estrogen , o r

such other

endocrin e effec t

a s th e Administrato r

ma y designate. " Th e purpos e o f Tie r I screenin g "i s t o identif

y substance s that

hav e th e potential t o interac t wit h th e estrogen , androgen , o r thyroi d hormon e system s usin g abattery o f assays. " Base d o n th e informatio n presente d above , i t i sDo w AgroScience s LL C Repor t ID : 10156 3 Pag e 2 9 o f

3 1 clea r tha t th e mal e an d femal e pubertal assay s are no t require d t o make thi s determination . Adequat e informatio n i s availabl e base d o n existin g dat aan d throug h other Tie r I studie s tha t

wil l b e conducte d fo r chlorpyrifos . Th e puberta l assay s are , therefore , redundant , no t justifie d fro man animal us e position , an d shoul d no t

b e conducte d per

EPA' s mandat e t o avoi d duplicativ e testing . W e encourag e EP A t o carefull y examin e th e OSR I cite d i n thi s rational e an d reques t tha t th e requirement

fo r conductin g th e femal e an d mal e puberta l assay s (OPPT S 890.1450 , OPPT S 890.1500) b e considere d complete fo r

chlorpyrifos .Do w AgroScience s LL C Report ID : 101563 Pag e 3 0 o f

3 1 References : Abbott , DH , V Padmanabhan , an d D A Dumesic . (2006) . Contribution s o f androge n an d estrogen to feta l programmin g o f

ovaria n dysfunction . Repro d Bio l Endocrino l 4:17 . Barr , D . B. , et

al . 2005 . Concentration s o f selectiv e metabolite s o f

organophosphorou s pesticide s i n th e Unite d State s population . Environ . Res . 99(3) : 829-833 . » Bowman , CJ . (2005) . Validatio n o f th e Pubertal Mal e Assa

y i n Rat s (WA 4-15) . WIL-431005 . Fina l report . 1 3 Decembe

r 2005 . Carney , E.W. , C . L . Zablotny , M . S . Marty , J . W . Crissman , P . Anderson , M . Woolhiser , an d M . Holsappl e Th e Effect s o f

Fee d Restrictio n durin g i n Uter o an d Postnata l Development

i n Rat s Toxicol . Sci. , No v 2004 ; 82 : 23 7 - 249 . Deli aSeta , D , F Farabollini , F Dessi-Fulgheri , an d L Fusani . (2008) . Environmental-like exposur e t o lo w level s o f

estrogen affect s sexual behavio r an d physiolog y o f

femal e rats . Endocrinolog y 149(11):5592-5598 . EPA , 2009 . EPA' s Approac h fo r Considerin g Othe

r Scientificall y Relevan t

Informatio n (OSRI ) unde r th e Endocrin e Disrupte r

Screenin g Program . Gray , Jr , LE , J Ostby , J Furr , C J Wolf , C Lambright , L Parks , D N Veeramachaneni , V Wilson , M Price , A Hotchkiss , E Orlando , an d L Guillette . (2001) . Effect s o f environmental antiandrogen s o n reproductiv e developmen t i n experimental animals . Hu mRepro d Update 7(3):248-264 .

« Horsley , EMT . (2005) . Assessmen t o f Pubertal Development

an d Thyroi d Functio n i n Juvenil e Mal e Rats . Study No . 04-4276 . Fina l report . 2 2 Decembe

r 2005 . Klimisch , H.J. , Andreae , M. , Tillmann , U . A Systemati c Approac h fo r Evaluatin g th e Qualit

y o f Experimental Toxicologica l an d Ecotoxicologica

l Data . (1996) . Regulator

y Toxicolog y an d Pharmacolog y 25 : 1-5 . Lund , TD , D J Munson , M E Haldy , KD RSetchell , E D Lephart , an d R J Handa . (2004) . Equo l i s a nove l anti-androge n that

inhibit s prostate growt

h an d hormon e feedback . Bio l Repro d 70:1188-1195 . O'Connor , JC , S RFrame , an d G S Ladies . (2002) . Evaluatio n o f a15-da y screening assa

y usin g intac t mal e rat s fo r

identifyin g antiandrogens . Toxicol Sc i 69:92-108 . Ride:' , CV , J Furr , V S Wilson , an d LE Gray , Jr . (2008) . A mixtur e o f seve n antiandrogen s induce s reproductiv e malformation s i n rats . Int J Andro l 31:249-262 .Do w AgroScience s LL C Repor t ID : 101563 Pag e 3 1 o f

3 1 Sawaki , M , S Noda , T Muroi , H Mitoma , S Takakura , S Sakamoto , an d K Yamasaki . (2003) . I n uter o throug h lactationa

l exposur e t o ethiny l estradio l induce s clef t phallu s an d delaye d ovarian dysfunctio n i n the offspring . Toxicol Sc i 75:402-411 . Shin , JH , H S Kim , H J Moon , I H Kang , T S Kim , J H Seok , I Y Kim , K L Park , S Y Han , an d S Y Nam . (2002) . Effect s o f

flutamid e o n puberty i n mal e rats : A n evaluatio n o f th e protoco l fo r

th e assessmen

t o f puberta l development

an d thyroi d function . J Toxicol Enviro n Health , Pt A 65(5-6):433-445 . Stoker , T.E. , Louis e G . Parks , L . Ear l Gray , Ralp h L . Coope

r (2000) . Endocrine-Disruptin g Chemicals : Prepubertal Exposure s an d Effect s o n Sexua l Maturatio n an d Thyroi d Functio n i n th e Mal e Rat . A Focu s o n th e EDSTA C Recommendations . Critica l Review s i n Toxicology , Ja n 2000 , Vol . 30 , No . 2 , Page s 197-252 . Terry , KK , G D Cappon , M E Hurtt , M S Tassinari , an d U Gupta . (2004) . Reproductiv e toxicity assessmen

t o f lasofoxifene , aselectiv e estrogen recepto r modulato r

(SERM) , i n femal e rats . Birt h Defect s Re s B De v Repro d Toxico l 71(3) : 150-60 . Vanag e GR , B Dao , X- J Li , C W Bardi n an d S S Koide . (1997) . Effect s o f Anordiol , a

n Antiestrogen , o n th e Reproductiv e Organ s o f th e Mal e Rat . System s Biology i n Reproductiv e Medicine Vol . 38 , No . 1 , Page s 13-2 1 Va n der School , P . (1992) . Disturbe d testicula r descen t i n th e ra t afte r prenatal exposure t o th e antiandroge n flutamide . J Repro d Per t 96:483-496 . *York , RG . (2006) . Interlaborator y Validatio n o f

th e Pubertal Mal e Assay . Fina l Report . 3 Januar y 2006 .



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