Do w AgroScience s LL C 933 0 Zionsvill e Roa d Indianapolis , I N 46268-105 4

308/2 E Februar y 5,201 0 

# Do w AgroScience s
Documen t Processin g Des k

(PRD-EDSP ) Offic e o f Pesticid e Program s (7504P ) U
. S
. Environmenta l Protectio n Agenc y On e Potoma c Yar d 277 7 S
. Crysta l Driv e Arlington , V A 2220 2 Attn : Jan e Smit h (7508P ) AI : BENFLURALI N CHEMICA L CODE : 08430 1 CA S NUMBER : 1861-40- 1 - ORDER/DCINO. : EDSP-084301-1 5 RESPONS E T O ENDOCRIN E DISRUPTO RSCREENIN G PROGRA M (EDSP ) I n respons e t o th e Endocrin e Disrupte r Screenin g Program(EDSP) , enclose di s Do w AgroScience s EDS P respons e for m an dsupportin g scientificall y relevan t informatio n (include di n th e enclose dstudy) fo r th e activ e ingredien t

benfluralin
. Content s o f

Submissio n Volum e Content s Volum e 1 • Transmitta l documen t (thi s letter ) (Administrative ) • EDS P Respons e For mdate dFebruary 4 , 201 0 ( 1 page ) Volum e MRI D NO
. Contents/Stud y Guidelin e Volum e # 2 Benfluralin : Scientifi c Rational e fo r Citatio n o f

Othe r Scientificall y Relevan t

Informatio n i n Fulfillmen t o f OPPT S 890.145 0 an dOPPT S 890.150 0 EDS P Tie r I Assay s OPPT S Author : Sean Gehe n Repor t Date : Februar y 4 , 890.145 0 201 0 890.150 0 Stud y ID : AKH02051 0 Pages : 1-2 5 ( 3 copies ) I f yo u requir e additiona l information , pleas e contac t Cath y Galvin , Registratio n Assistan t fo r thi s product , a t 317-337-482 8 (clgalvin@dow.com)
. Sincerely ,

A F T J

- •••••••*». * Am y Hudso n • *
. Regulator y Leade r

- Regulator y Affair s • • 317-337-396 7
..... . .T
. 317-337-464 9 (FAX ) J^ 5 * akhudson@dow.co m•••• , * * • * • • *
. Enclosure s . . • • •

..... 0 AKH/cl g '
_Do w AgroScience s LL C Repor t ID : AKH02051 0 Pag e 1 o f 2 5 STUD Y TITL

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

Othe r Scientificall y Relevan t

Informatio n 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 ORDERNUMBER : EDSP-084301-1 5 DAT A REQUIREMEN T OPPT S 890.145 0 an d OPPT S 890.150 0 EDS P Tie

r I Assay s AUTHO R Sea n Gehe n
STUD Y COMPLETE

D O N Februar y 4,201 0 PERFORMIN G LABORATOR Y Do w AgroScience s LL C 933 0 Zionsvill e Roa d Indianapolis , I

N 4626 8 " '
REPORT ID AKH02051 0 •

- • •

### Do w AgroScience s LL C Repor t ID : AKH02051 0 Pag e 2 o f 2 5 STATEMENT O F N O DATA CONFIDENTIALIT Y CLAIM S Compound : Benflurali n Title : Benfluralin : Scientifi c Rational e fo r Citatio n o f

Othe r Scientificall y Relevan t Informatio n i n Fulfillmen t

o f OPPT S 890.145 0 an dOPPT S 890.150 0 EDSPTie 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 that informatio n no t

designate d a s withi n th e scop e o f FIFR A Section 1 0 (d)(l)(A)(B ) or (C) , an d whic h pertain s t

o aregistere d or

previousl y registere d pesticide i s no t

entitle d t o confidentia l treatmen t an dmay b e release d t o th e public , subjec t t o th e provision s regardin g disclosure to multinationa l entitie s unde r FIFR A Sectio n 10(g)
. Company : Do w AgroScience s LL C Compan y Agent : Amv Hudso n

Title : Regulatory Manager Signature :
Date : Februar

y 4.201 0
THI S DATA MA Y B E CONSIDERED CONFIDENTIA L OUTSID E THE UNITED STATES
.

### Do w AgroScience s LL C Repor t ID : AKH02051 0 Pag e 3 o f 2 5 STATEMEN T O F COMPLIANC E WIT H GOO D LABORATOR Y PRACTIC E STANDARD S Title : Benfluralin : Scientifi c Rational e fo r Citatio n o f

Othe r Scientificall y Relevan t Informatio n i n Fulfillmen t

o f OPPT S 890.145 0 an dOPPT S 890.150 0 EDS P Tier

I Assay s Compound : Benflurali n Thi s report

doe s no t meet th e definitio n o f

aGL P stud y a s i t

appear s in :
Unite dState s Environmental 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 dDevelopment ENV/LMC/CHEM(98)17 , Pari s - Januar y 26,199 8 

# NON-GL P STUD Y

Am y Hudso n Sponso r Do w Agroscience s LLC Februar y 4,201 0

Am y Hudso n Submitter Do w Agroscience s LLC Februar y 4,201 0

Sea n Gehe n Study Director/Autho r Do w AgroScience s LL C Februar y 4,201 0Do w AgroScience s LL C Report ID : AKH02051 0 Pag e 4 o f 2 5 QUALIT Y ASSURANC E STATEMEN T Compound : Benflurali n Title : Benfluralin : Scientifi c Rational e fo r Citatio n o f

Other Scientificall y Relevan t Informatio n 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 : February 4,201 0
NON-GL P STUD YDo w AgroScience s LL C Report ID : AKH02051 0 Pag e 5 o f 2 5
1. 1 Summar

y Th e basi s fo r

thi s scientifi c rational e i s tha t al l o f th e critica l endpoint s define di n th e OPPT S 890.145 0 an d OPPT S 890.1500 guideline s an d th e associate d endocrin e modes-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 endpoin t ha s been directl y assesse d i n existin g studies ; b ) i n rar e cases , surrogate endpoint s hav e been evaluated ; 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 (See table s 7 an d 8)
. Th e state d purpos e o f

th e Endocrin e Disrupte r

Screenin g Progra

mi s "t o determin e whethe r certai n substance s may hav e a n effec t i n human s tha t

i s simila r t o a n effec t

produce d b y a naturall y occurrin g estrogen , o r suc h other

endocrin e effec t a s th e Administrato r

ma y designate. " Tie

r I "i s t o identif

y substance s tha t hav e th e potentia l t o interac t wit h th e estrogen , androgen , o r thyroi d hormon e system s usin g abatter

y o f assays. " Base d o n th e informatio n that wil l b e presente d i n thi s rationale , i t i s clea r that th e mal e an d femal e puberta l 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 th e other Tier I studie s that

wil l b e conducted
. Th e puberta l assay s are , therefore , redundant , no t justifie dfro man anima l 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
. We , therefore , encourag e EP A t o carefull y examin e th e OSR I cite d i n thi s rational e and , respectfully , reques t

that th e requiremen t

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 complet e base d o n the submissio n o f OSRI an d th e fac t

that othe r EDS P assay s wil l b e conducte d t o als o ai d i n evaluatin g th e specifi c endpoint s relevan t fo r thes e screenin g assays . 1. 2 Backgroun d Th e EPA document

entitled : "EPA' s Approac h fo r Considerin g Othe

r Scientificall y Relevan t Informatio n (OSRI ) under th e Endocrine Disrupter

Screenin g Program " (EPA , Marc h 2009 ) provide s guidanc e to registrant s o n ho w existin g dat ao r 'other scientificall y relevant information ' (OSRI ) i s to b e considere d i n ful l o r partia l fulfillmen 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 hormona

l systems. " Accordin g to th e EPA 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 o r Tie r 2 ; metabolis mstudies ; o r other vertebrate o r

invertebrate toxicit

y studies , including , bu t

no t limite d to , developmenta

l toxicit y tests , carcinogenicit

y tests , toxicogenomi c data , an d reproductiv e toxicity tests . I n additio n to th e type s o f

dat adefine d above , th e document give s specifi c mentio n to toxicit y studie s conducte d i n fulfillmen t o f th e 4 0 CF RPar t 15 8 dat arequirement s for pesticide

### Do w AgroScience s LL C Repor t ID : AKH02051 0 Pag e 6 o f 2 5 registration
. Allowin g fo r

th e review an dconsideratio n o f 4 0 CF R15 8 dat ai n fulfillmen t o f tie r I dat arequirement s i s significant
. Thes e dat arequirement s delineat e abroa d rang e o f robus t toxicit y studie s that

mus t b e complete d an dcriticall y assesse d b y th e EP A prio r t o approva l an dregistratio n o f apesticid e activ e ingredien t i n th e Unite d States
. Amon g th e require ddata-se t

are multipl e repeat-dos e toxicit y studie s o f variou s duratio n fro m4-1 3 week s t o thos e wher e exposur e encompasse s th e majorit y o f th e lifespa n o f

th e tes t organism
. I n addition , studie s ar e conducte d t o determin e an y potentia l fo r treatment-relate d effect s o n reproductio n a s wel l a s pre - an dpost-natal development
. I n al l o f thes e studies , animal s receiv e dose-level s that

appropriatel y challeng e th e tes t organism s an dwhic h ar e muc h highe r tha n anticipate d huma n exposure levels
. Examinatio n o f thi s complete data-set , whic h i s already availabl e fo r

al l activ e ingredients , allow s fo r determinatio n o f

targe t orga n toxicit y an dan y othe r

advers e effect s that

may b e elicite d b y exposure . Thes e existin g studie s are capabl e o f detectin g advers e biologica l effect s o f

treatmen t that coul d b e elicite d b y on e o r mor e modes-of-actio n inclusiv e o f th e endocrin e modes-of-actio n bein g addresse d b y th e EDSP
. I t i s therefor e astatement

o f fac t that wit h rare exceptions , an y potential advers e effect s resultin g fro mmodulatio n o f th e endocrine syste mhav e already bee n detecte d i n th e exitin g registratio n toxicity studie s fo r agive n activ e ingredient
. Th e applicatio n o f th e principle s o f

ris k assessmen

t based o n th e no-effec t

level s fro mthes e studie s allow s fo r appropriat e margin s o f

exposur e i n the us e o f

thes e activ e ingredients
. O n th e basi s o f

good scientifi c principle s an d particularl y relativ e to th e Scientifi c Community' s responsibl y fo r judiciou s us e o f

anima l resources , i t

i s appropriat

e to conside

r existin g dat ai n th e contex t o f th e EDS P requirement s an d EPA shoul d grant exemption s fro m screenin g wher e existin g dat aalread y provid e adequate information
. I n fact , accordin g to FFDC A sectio n 408(p)(5)(B ) EPA ha s amandate to "..
. .minimiz e duplicativ e testin g o f th e same substanc e fo r

th e sam e endocrine effect. " Thi s polic y i s echoed b y th e OM B respons e to EPA' s EDS P Informatio n Collectio n Respons e (ICR ) whic h direct s EPA to "promot e an d encourag e tes t

orde r recipient s to submi t

Othe r Scientificall y Relevan t

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

som e o f th e Tie r I assays , an d EPA shoul d accept OSRI a s sufficien t to satisf y th e tes t order s to th e greates t

extent possible. " Failure to appropriatel y conside r an d accep t existin g datawil l result

i n duplicativ e testin g an dthi s scenari o i s no t justifie d fro ma

n anima l us e perspective
. I n summary , fo r

th e pesticide activ e ingredient s o n th e Tie r I lis t fo r screening , ther

e i s a wealt h o f existin g informatio n availabl e tha t ca n reduc e or

eliminat e th e need for

Tie r I screening
. I n particular , th e multi-generatio n reproductio n study whic h i s alread y availabl e fo r pesticide activ e ingredient s i s ahigher-tiere d assessmen t fo r potentia l endocrine-mediate d toxicity , an d EPA i s i n fac t plannin g to utiliz e i t

a s th e mammalia

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

tiere d stud y complet

e lessen s o r

eliminate s th e nee d fo r supplyin g lower-tiere d screening assay s o f ales s robus t

nature . Wit

h higher-tie

r dat a available , th e practica

l utility o f performin g screening studie s i s questionable
. I n addition , EPA ha s alread

y evaluate d thes e existin g studie s fo r pesticide activ e ingredients , includin g anyDo w AgroScience s LL C Report ID : AKH02051 0 Pag e 7 o f 2 5 potentia l advers e effect s resultin g fro mmodulation o f th e endocrin e system , an d mad e a determinatio n tha t

thes e activ e ingredient s ca n b e use d withou t undu e ris k

t o huma n health
. 1. 3 Benfluralin : Overview o f Existin g Data Se

t A s wit h othe r

pesticid e activ e ingredients , th e 4 0 CF RPar t 15 8 require d studie s hav e been conducte d fo r

benfluralin
. Whil e th e entire dat ase t i s muc h larger , th e studie s considere d mos t relevan t fo r assessin g an y potentia l fo r interactio n with th e endocrin e syste mar e foun di n Tabl e 1 an d includ e 2 multi-generatio n reproductio n studies , 2 sub-chroni c toxicit y studies , 2 chroni c toxicity/oncogenicit y studies , an d 1 teratology/developmental toxicity study
. Thes e studie s wer e conducte d i n accordanc e wit h internationall y accepted tes t guideline s i n plac e a

t th e time , an d th e more recent studie s adhere d t o GL P standards
. Th e studie s utilize d rat s and , therefore , are considere d th e mos t relevan t t o th e mammalian Tie r

I dat arequirements
. Where appropriate , dat ai n other

specie s ma

y als o b e cite d whe n considere d relevant
. Th e multi

generatio n reproductio n studie s i n particula r provid e th e foundationa l data-set fo r benflurali n relativ e t o th e Tie

r IEDS P assays . Additiona l end-point s no t specificall y assesse

d i n thes e tw o studie s bu t

requeste d b y th e OPPT S guidelin e hav e been assessed i n other repeat-dos e studie s that make u p th e cor

e registratio n data-packag e fo r benfluralin
. Taken together , thes e studie s provid e arobus t

determinatio n o f

an y potentia

l effect s o n genera

l toxicity , development

an d maturation , a s wel l a s othe r end-point s that

coul d b e impacte d throug h a n effec t o n th e endocrin e system . Examinatio n o f

th e existin g benflurali n data-set di d no t reveal an y potential fo r

specifi c modulatio n o f

th e estrogen o r

androgen system s i n th e tes t organisms
. Consistent

wit h other dinitroanilin e herbicides , benflurali n target s th e liver , kidney s an d thyroi d gland
. A s wil l b e show n i n th e table s below , th e effect s o f benflurali n o n th e thyroi d hav e been wel l characterize d i n existin g studie s where thyroi d weigh t an d histopatholog y hav e bee n examined
. A mode-of-actio n (MOA ) study i s currentl y bein g conducte d with benflurali n t o furthe r elucidate th e high-dos e thyroi d effects ; result s s o fa r appea r consistent

wit h a n expecte d MO A involvin g inductio n o f

UDP-GT , increase d clearanc e o f thyroi d hormone s (T 3 an d T4) , increased productio n o f

TSH , chroni c stimulatio n o f follicula r cell s an d increase d neoplasi a (Fischer , 1991,1993 ; Saghir , 2005)
. Th e ke y event s responsibl e fo r thyroi d toxicit

y i n rat s d o no t occu r i n human s du e to th e presenc e o f high-affinity thyroxin e bindin g protei n (TBG ) i n human s an d alac k

o f i t i n rat s (Hil l et

al. , 1989,1998)
. Du e to th e lack o f TB G i n rats , fre e T4 i s muc h large

r i n rat s than i n human s an d i s muc h mor e susceptibl e to remova

l fro mth e blood , whic h trigger s th e cycl e o f TS H stimulatio n an d follicula r cell stimulation
.

### Do w AgroScience s LL C Report ID : AKH02051 0 Pag e 8 o f 2 5 Tabl e 1

- Existin g Studie s (OSRI ) Cite d i n fulfillmen t o f Tie r I dat arequirement s Citatio n Code Stud y Citatio n GL P Stud y MRI D Numbe r A 

### Trutter,J. ( 1995 ) Two

Generatio n Reproductio n Stud y i n Rat s wit h Benefin : Final Report : La

b Projec t Number : HWA 174

- 136
. Unpublishe dstud y prepare d b y Hazleto n Washington , 

### Inc
. 

### Ye s 4362870 1

B 

### Adams , E
. R
. e t al
. (1973 ) A Multi

Generatio n Rat Reproductio n Study with Benefin , R0305 , R0795 , R0057 , R0657 , R0316
. Unpublishe d stud y prepare d b y Lill y Researc h Labs
. Stud y Conducte d Prior to GLP Regulation s 0003767 6

Adams , E. ; Jordan , W
. (1996 ) Subchroni c Toxicit y Studie s o f Benefi n (Compoun d 054521 ) Administere d Orall y i n th e Die t

to Fische r 34 4 Rat s fo r

3 Months : La

b Projec t Number : R33989 : R44089 : R29990
. Unpublishe d stud y prepare d b y Lill y Research Labs
. 

### Ye s 4405000 1Do w AgroScience s LL C Repor t ID : AKH02051 0 Pag e 9 o f 2 5 Citatio n Code Stud y Citatio n GL P Study MRID Numbe r 

### D Moore , M. ( 1996)

Benefin : Two-Yea

r Dietar y Chroni c Toxicity/Oncogenicit

y Stud y i n Fische r 34 4 Rats : Final Report : La

b Projec t Number : CH V 174-133 : DR-0097

- 3397-005
. Unpublishe d stud y prepare d b y Cornin g Hazleto n Inc
. 

### Ye s 44050002

Worth , H
. M. , e t

al
. (1966)Subacut e Toxicity o f

Benefi n t o Rats
. Unpublishe d stud y prepare d b y Lill y Researc h Labs
. Stud y Conducte d Prior to GLP Regulation s 0002465 1

Gibson , W
. R
. e t

al
. (1973 ) A Stud y o f

th e Effect s o n Rat s fro mth e Ingestio n o f

Benefi n fo r Tw o Years
. Unpublishe d stud y prepare d b y Lill y Researc h Labs
. Stud y Conducte d Prio r to GLP Regulation s 0003767 5

Dalgard , D
. (1993 ) Benefin : 13-Wee

k Ora l Toxicit y Stud y i n Beagl e Dogs : La b Projec t Number : HWA 174-135 : DR-0097

- 3397-003
. Unpublishe d study prepare d b y Hazleto n Washington , Inc
. 

### Ye s 4307230 1

### Do w AgroScience s LL C Report ID : AKH02051 0 Pag e 1 0 o f 2 5 GL P Stud y MRID Numbe r 

### Ye s 4362870 2



### Ye s 0014753 5 Citatio n Code 

### H Stud y Citatio n

Walker , M. ( 1995 ) Benefin : One-Yea

r Oral Chroni c Toxicit

y Stud y i n Beagl e Dogs : Fina l Report : La

b Projec t Number : CH V 174-143 : DR-0097

- 3397-004
. Unpublishe d stud y prepare d b y Cornin g Hazleto n Inc
. 38 1 p . 

### MacKenzie,K.(l985 ) Rat Teratolog y Stud y wit h Benefin : Stud y No
. 6180-101
. Unpublishe dstud y prepare d b y Hazleto n Laboratorie s America , 

### Inc
.Do w AgroScience s LL C Report ID : AKH02051 0 Pag e 1 1 o f

2 5
1. 4 Benfluralin : Scientifi c Rational e fo rSufficienc y o f OSR I i n Fulfillmen

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 adhere d to : 1
. Collec t

appropriat e existin g benflurali n dat a(OSRI) , includin g primaril y guidelin e toxicit y studie s 2
. Examin e existin g dat afo r endpoint s relevan t

t o EDS P Tie r

I 3
. Determin e whic h Tier I endpoint s ar e adequatel y addresse d b y OSR I 4
. Determin e whic h i f

any EDS P Tie

r I assay s are sufficientl y addressed b y OSR I therefor e makin g the mredundan t 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 d b y th e individua l toxicity studie s availabl e fo r benflurali n combine d wit h th e EDS P studie s that

wil l b e conducted , i s tha t

th e femal e an d mal e puberta l assay s ar e essentiall y redundan t an d are , therefore , no t

justifie dfro man anima l us e perspective
. I n grantin g an exemptio n fro mperformin g thes e studies
. EP A wil l preven t th e unnecessar

y us e o f a t leas t 9 0 animals
. Th e dat aavailabl e fo r

th e specifi c endpoint s define d i n th e OPPT S 890.145 0 an d OPPT S 890.150 0 guideline s are summarize d i n Table s 5 an d 6 respectively
. Fo r any endpoint s wher e th e requeste d dataare no t

available , other

OPPT S EDS P Tie

r I assay s ma

y b e performe d to provid e th e missin g data-point s sinc e there i s significant overla p i n th e Tie

r I testin g progra

m fo r th e variou s endocrine-mediate d modes-of-action
. I n addition , Othe r Scientificall y Relevan t Informatio n (OSRI ) ma

y b e availabl e to hel p determin e th e relativ e significanc e o f th e missin g endpoint s (i.e
. i f apreponderanc e o f

othe r endpoint s ar

e availabl e whic h essentiall y addres s th e sam e endrocrine M O A)
. Fo r

registere d activ e ingredients , there i s a n abundanc e o f

availabl e informatio n that 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 OSRI i n fulfillmen 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 screening studie s wer e no t evaluated
. Further

to this , i t shoul d b e note d that 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 to th e endocrine syste man d ca

n als o b e altere d b y a s th e resul t o f genera l systemi c toxicit

y (Stoker , 2000)
. For example , endpoint s evaluate d i n th e pubertal assay s ca n b e altere d secondar

y to effect s o n bod y weigh t (Carney , 2004)
. Thi s i s significant a s th e guideline s fo r

pubertal assay s defin e reduce d bod y weight

a s evidenc e fo r

havin g achieve d a

n appropriat

e hig h dose-level fo r testing
. Give n th e lac k

o f specificit y fo r man y o f th e apica l pubertal endpoints , i t

i s appropriate t

o 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 agive n chemical
. Thi s approac h wil l allo w fo r

arobus t weight o f evidenc e determinatio n base d 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 dacros s multipl e studie s an d end-point s wil l ofte n provid e ahig h degre e o f confidenc e i n th e conclusio n withou t

th e nee d fo r

conductin g additiona

l testing
. Table s 2- 4 belo w provid eDo w AgroScience s LL C Report ID : AKH02051 0 Pag e 1 2 o f

2 5 example s o f

end-point s commonl y assessed i n 4 0 CFR15 8 guidelin e studie s that ca n serv e a s surrogate s fo r

other endpoint s tha t

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)
. I f a patter n consisten t

wit h th e effect s presente d i n thes e table s i s no t observed , the n ates t chemica l can b e considere d negativ e fo r advers e effect s elicite d throug h th e endocrin e modes

of-action
. Th e conduc t

o f special endocrin e mode-of-actio n studie s (i. e E Rbinding , A R binding , steroidogenesis , aromatose ) may no t b e necessary , bu t

can furthe r

suppor t th e weigh t o f evidenc e conclusions
. Tabl e 2

- Advers e Effect s Elicite d b y Estrogeni c Substance s Endpoin t Estrou s cyclicity Tim e t o matin g Uterin e weigh t Vagina l patenc y 

### PP S Ovarian follicl e coun t Fertility Matin g inde x Corpor alute a Implantation s Gestationa

l lengt h Litter siz e Anogenita l distanc e Epidydimi s sper

mcount Testi s Histopatholog y Epidydimi s histopatholog y Prostat e histopatholog y
Ovar y weight Ovary histopatholog y Mammary 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 Atroph y Lesions , decreased sper

m conten t Involutio n o f

ventra l prostat e epithelium ; stroma

l proliferatio n Decreas e Stroma l hyperplasia ; follicula r cyst s Increased Reference s Terry , 2004 ; Abbott , 2006 ; Deli aSeta , 2008 ; Sawaki , 200 3Do w AgroScience s LL C Repor t ID : AKH02051 0 Pag e 1 3 o f

2 5 Tabl e 3

- Advers e Effect s Elicite d b y Anti-Estrogeni c Substance s Endpoin t Estrou s cyclicity Tim e t o matin g Testi s weigh t Vagina l patenc y Corpor alute a Litte r siz e Testi s Histopatholog y Epidydimi s histopatholog y Prostate histopatholog y Seminal Vesicl e histopatholog y Ovary histopatholog y Expecte d Chang e Decreas e frequency ; unestrou s Increas e Decreas e Delaye d Decreas e o

r absen t 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/stroma l hyperplasi a Reference s Vanage , 1997 ; Abbott , 2006 ;Do w AgroScience s LL C Report ID : AKH02051 0 Pag e 1 4 o f

2 5
Tabl e 4

- Advers e Effect s Elicite d b y Anti-Androgeni c Substance s Endpoin t Preputia l separatio n Sper mcount , motilit y Testi s Weigh t Vagina l patenc y Epididymi s weigh t Prostat e weigh t Semina l Vesicle s Weigh t Testi s histopatholog y Epididymi s histopatholog y Prostate histopatholog y
Semina l Vesicl e histopatholog y Anogenital distanc e Uterin e histopatholog y Mammary glan d Estrou s cyclicit

y Time t o matin g Fertility.
. 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 cel l hypertrophy/hyperplasia ; germina l degeneratio n Agenesis ; spermati c depletio n Fibrosis , cellular

infiltration ; epithelial hyperplasia ; agenesi s Fibrosis , cellula

r infiltration ; epithelia l hyperplasi a Decreas e Cysti c endometria

l hyperplasi a Decreas e adenomas , adenocarcinoma s Persistent estru s Increas e decreas e Hypertroph y 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 ;G

S i ' o C/ 5 

# I

2 O H 

# I

5 P
.

P 1= 1
' o 'o p



### ^ w " 8 u o £



### 8 O 

# I S

a2 6 S o o 

### S a g ^• y 

### P
II I S W U o o o f 2

S



# s PQ

O ffl 

### •' > 

## f B.&1SI J

. O

— 1 03 

### I

## ^ ^

. a fc< o < C/ 5 

# i s < ( N 

# I a t s 

## I 02 £

< u 

# i ^ ^ C?J " O 

## •a a o

* ^ '• 3 

### <

5 P Q ) 8 ) ' 3 

# lll l H : g 3 a S H a - a g £ ? or ? S " O ^ 3 S *

^ O t
i ^ g ' o n o 

# s ~ ^ S S -&4 L
. '.;*: • t l W 3 

## a ' 3 

## 3> o •j ^ C/ J

^ 

# Hal t
" 8 ° 3 S • - o 

## J w " " "OPPTS890.1450Endpoint 

# q

u > , Q



### . Q 

### I r5 * • * O 

### & i ^ 1 l-itf f &
. gU " J B 2 g ^' | 

### S s -s s 

### > 2 2 - 3 ^ *^ g f 3 3 ^ S 2 4 ? r< u o > f i > H o o u

1 § 2 < U D

..- .

U H u f|UterineWeight| -• •

u . 

### w Q U|OvarianWeight| M ' ^ - S " ? ^ S C ca i S 

### • S J - o " ^ - O ^ U M C 3 l p 1 - S |
• ^ "p 3 G 

### '|^( | 

### ^ a ^ 1 " f 2 < 2
. 3 1 " i - ^ 1 3 ^ '•S 3 S .i 2 " § —c > • C u c a C M •<t l c a . 2 t/

i

O

• G § "o , 3 £ D 

### < 2 S

* N- » UH * 

### q uThyroidWeight [i ,

u f Q U
^|LiverWeight [i f Q U

• <|KidneyWeight r ^

1 ' 3 'S

.

^ «

_ 3
C ^ 0 >



### . a "^ 3 2 a o _> i Q o

ffi OPituitaryWeight P U o f Q U|AdrenalWeight ^

^ 

# L I f i c ° ° 

### e . 2 ' 5 s ^ 5 S. I

tL , Q 

### o " co " <UterineHistopathology Q

U 

### CQ " <OvarianHistopathology .5 2 < u ^ \ *^ 3 2 u g 11 1 

### ? a 1 

# sl' l s ^" 1 " 9 2 2 M J a W ^ > «1 S " ^ fl j • S 5 ^ "S

. y < S

. 3 o c/ 3 ^ J *^ 3 ^ 3 S

. 2 

# til t < > u 3 c « A ty j

t u ttf Q ( J 

### CQ " 

### <

" o I t 

### P S P U 

## [i f Q U CQ " <(Kidney|Histopathology t o '£ , J 

# 1
4 ^ J H M 9 3 1 T3 2 >- , •5 

### " S
C/ 5 ^ 3 a

# H- l|TSHandT4~~|

# §

J J ' 3 o o 

## <N, r 2 ^ £ 

### a < u 

# 1 

# i a

- a 1 3 a 

### o 

# 1

< MOPPTSEDPSStudiestobeconductedthataddressendpoin

1



### . 9 | a a » - —s 

# l l & S " « . 2 a* 2 

## a3 « " 3 

# 1 1 i 1 ^
^
T f

• fl

° 2 * " 0 H j S 

## S ° i >

• S 3 *

u . c d

- 2 •"" * ' § > 

# S i 1 £ o rt 3 —fl j S ^ 'Q
. 

### ^ 1 I U "7 3 

## S I - a 

## l-S f > v 3 C 3 J J t oSteroidogenesis,Aromatase,

u P Q

** 3 ^ ^ 

## Ill s 5 * ] u " o 

## u " 3 1 

## t 3 u . 

## w Q U

^ W5 ' B

- C O o 

# : § u 2 a o c j 

### 1

i/ ) I J S " 3

## S
o n ^ 

# l a < u 

# a » a-

< u

" 3

o o 

# 1 O < u

8 > , 

### C L $ 0 § 3 1 J J i £ ^ Q ) 1 

# i i ^vantareintets 

# * l 5 f « o S O 0 0 f* ^ • 9 

### a S

' 2Growth(dailybodyweAgeandbodyweightatOrganweights(sealcomplex,epididymHistology(epidiymHormones(testosteClinicalchem



### o o o o o o 

## w



# S

*•• * 

# S j j 

# 3Additionaldata/.co 

# §

a w 

# l l S i
3 s S 

### «•§• § 8 

### "

§ §


## I I C Q


### g i l l s > i 8 " 8 

## o O Q 

# •

C/

3o s

• n < N
_ < U O 2 c - ri i )

. a ^ Sf l o < • « J C/i O N 4 2



### a V
o 

# 1
• 3 Sr f 

# ! '• 5 

### ^ < 3 

# Sill

g 3 5 2
. | 

### Illl l H Jf l •*• » 3 ^ X ^ 3 C J iZ r

t 

## S 5 = ^ 

## S 5 5 m~ a

i O ^ G C 8

< i



### . 9 

# 1 1 

# ? 

# l !

• B
. 2 

### a- 3 U 3 G J * 3 • S v ? M

>. ^ § 

## = 3 

## = ' ^ S « i 

### ao 

# Jla J 

# ll fOPPTS890.1500Endpoint Q Q fa



### u u Q j

- > , r

j 

# t Q



# - ° I" ' 

# I""/

- 1 * 2 § 5 e» , , - S
. > , • § J 2 §» w u , 2 8 S
. " 3 - § c i- - 1 • § o- S S w W 5 2



## . « g , 

## ao j , 

## « • § h H S " Qi I ^ O Q
. K 

### 2 o « 

### yi- ao M .5 2 « ob'! ) U tn • ^ I^ N - 3 .I

—> >• > .- G g K f D > " *
. 3

Qi 4 S ^ ( O b * i ) * ^ 

### g q£ > H £ w D t- i



# a>

u 2 3

<t> 1 'e 3 cS 1SeminalVesicleWeight U i

(L > 

### S ? 1 

# " i u B

I I 0) 

# S J f T , P J 

# i ^ i .2 ? ^ 1 k> 2> 1 1 2 S



# i u 

# s J Pn p qDorsolateralProstateWeight i

_ § > !2 

# a

<uNotavailabllevatorani/bulbocavemosusmusclecomplexweight U i 

# & 

# 1 £ u B

<uNotavailablEpididymidesweight tu w Q U

M 1 « 5 E^ 3 

## c - a

## a o . s j y ' 3 '< ^ U Q , 

# ^ s " 3 i (+ LJ 3 2 ° O rt C ^ J 

### S 3 j g • - i

- S • § • ao , . ^ • 5 «*

- . S « 2 ^s j -7 3 - S ^• 9 3 c 

## I'i'S l U > q j > 

# .• § 

# s-e ^ i^«s l Q.' S S ' 3 

## < ^
_ 3 ^ t/ ) " O C «

^ ^ fc" ttJ Q UThyroidWeight P

u 

## u" Q U <|LiverWeight fc 

### w Q U <|KidneyWeight| 

### B 

## a|PituitaryWeight]O « n

— < < N O J 

## I O 

# | e ^ t i 

# a > po | 0 y
s j 

## • a =

. 2 

### *-* ^ 

### = 9 3 1 « g 1 1 I I 

# g 1 3 1 1 

# Hil l

o

1



### . 3 i •o a V /

- s 

# ^ 8 t/ j p^ 4 

# i l -§ 1
a j - 5 

## SD hi 3



### a
= " " S " 3 

### 1
. 2 3 ^ '• 3 • - ^ * 2 

# HI 1

- 

# £| | U H

[i f Q O

" I1AdrenalWei Q U

MEpididymisHistopatholo 

### tu u f Q U 

### CQ "


### > ,TestesHistopatholo 

### 5 3 

### c 1 i 

### a • 2 - a

### ~ | l 

### 1 1

" ^ !=-'> > 

### g S -" g " 3

" ° t S c ^ 

# '§S1 « ^• ^ 3 c Jil l

• C ef l i q j

~ .- < Q - O Q." 9 3 ^ j i g e d >

tC 

### u f
*• Q U 

### PQ " § 3ThyroidHistopatholo U * 

### u f Q U C Q

MKidneyHistopatholo 13 

# e " 1 i J 1> ' 3 ^ i n Q
. 3 V — 

### g S ^ " 3 T 3 J 3 e " 

# '§2l i 

# tl| | I'l l I J

—Ct f j D fl l « T L
. i •j ^ •«• " O * Q o " O ^ "1 3 *«4 - 5 4

J v 3 

# < 3 - as

# 

# s 

# 1 1

5eroidogenesis,romatase,ershberber(optioisessment)


### ft < S %

_ u 3 c 3 

## 1 1SerumTestosterone tu

u f Q " UClinicalChemistry <y ; >

r

. 0
4

—•

^ * O
1

^ > 

# • s 1 1 3ibenfluralin;an



### 5 3 3 S 

# • a

" 3



### ~ 3 Q U
!/ )
• S 

### • 3
U

. ^ o 

# € U (U


# . s 1

c j

J

1 

# s '- a a 1 J * •£ 3 

# i
c 8 w

. Scurrentlybe

### Do w AgroScience s LL C Report ID : AKH02051 0 Pag e 2 1
1. 7 Summar

y and Conclusions Potentia l effect s o f

treatmen t o n growt h an ddevelopmen t

are evaluate d i n multi-generatio n reproductio n studies
. A s thi s i s als o essentiall y th e purpos e o f th e EDS P puberta l 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 puberta l assays . Whe n th e multi-generatio n stud y result s ar e combine d wit h other existin g dat aan d perhap s supplemente d wit h EDS P Tier I screenin g data , i t

may b e conclude d that

th e pubertal assay s woul db e redundan t

and , therefore , no t

necessar y t o make arobus t

determinatio n o f

an y potential effect s o n th e endocrin e system . Thi s i s i n fac t

th e cas e fo r

benflurli n wher e al l o f

th e critica l endpoint s define d i n th e OPPT S 890.145 0 an d OPPT S 890.150 0 guideline s an d th e associate d endocrin e modes-of-actio n hav e bee n evaluate d i n on e or

more o f thre e ways : a) th e endpoin t ha s been directly assesse

d i n existin g studies ; b ) i n rar e cases , surrogate endpoint s hav e bee n evaluated ; c ) th e relevan t endocrin e mode-of-actio n wil l b e assessed i n other

Tier I EDS P assay s (Se

e table s 7 an d 8)
. It

i s clea r fro mthes e table s that

n o critica l informatio n wil l b e gaine d b y conductin g th e pubertal assays . Tabl e 7

- Summar y o f

OSR I fo r Femal e Puberta l OPPTS 890.145

0 Endpoin t Growt h Ag e a t Vagina l Openin g Uterin e Weight Ovaria n Weight Thyroi d Weight Liver Weigh t Kidne y Weight Pituitary Weight Adrena l Weight Uterin e Histopatholog y Ovaria n Histopatholog y Thyroi d Histopatholog y Kidne y Histopatholog y TSHandT 4 Estrou s cyclicit

y Clinica l Chemistr

y Endpoint

assesse d i n existin g studie s 

### X
X X X X X X X X X X X X * X Surrogat

e endpoint s assesse d in existin g studie s 

### X

X Mode-of-Actio n t o b e assesse d i n othe r Tier I EDS P assay s 

### X X X

X

X

X X *current dat afo r trifluralin ; benflurali n dat abein g develope dDo w AgroScience s LL C Report ID : AKH02051 0

Pag e 2 2 Tabl e 8

- Summar y o f

OSR I fo r

Mal e Puberta l OPPT S 890.150

0 Endpoin t Growth Ag e a t preputia l separatio n S V Weight V P Weight DL P Weigh t Levato r ani

- weigh t Epididymide s Weigh t Teste s weigh t Thyroi d weigh t Live r Weight Kidne y Weight Pituitary Weigh t Adrena l Weight Epididymi s Histopatholog y Teste s Histopatholog y Thyroi d Histopatholog y Kidne y Histopatholog y TSHandT 4 Testosterone 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 X * X Surrogat e endpoint s

assesse d in existin g studie s 

### X

X Mode-of-Actio n t o

b e assesse

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

### X X X X X X
X X (optional ) X (optional ) X (optional )



### X

X (optional ) 

### X *current datafo r trifluralin ; benflurali n dat abein g develope d
Th e confidenc e that

on e ha s 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 lei u o f performin g ne w studie s i s increased b y examinin g th e totalit y o f availabl e informatio n an d performin g aweight

o f evidenc e evaluation
. Th e existin g databas e fo r benflurali n doe s no t demonstrat

e any patter

n 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 thyroi d i s atarget fo r benflurali n an d furthe r

studie s are bein g conducte d to furthe r understan d ho w benflurali n affect s th e thyroid
. Th e state d purpos e o f

th e Endocrine Disrupter

Screenin g Progra

mi s "t o determin e whether

certai n substance s ma

y 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 , or

suc h other

endocrine effec tDo w AgroScience s LL C Report ID : AKH02051 0

Pag e 2 3
a s th e Administrato r

may designate. " Tie r

I "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 a battery o f assays. " Base d o n th e informatio n presente d above , i t i s clea r that th e mal e an d femal e puberta l assay s ar e no t

require d t o mak e thi s determination
. Adequat e informatio n i s availabl e base d o n existin g dat aan d th e other Tie r I studie s tha t

wil l b e conducted
. Th e puberta l assay s are , therefore , redundant , no t

justifie dfro man anima l us e position , an d shoul d no t b e conducte d pe r

EPA' s mandat e t o avoi d duplicativ e testing
. We , therefore , encourag e EP A t o carefull y examin e th e OSRI that wa s cite d i n thi s rational e and , respectfully , reques t

that th e requiremen t

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 complet e base d o n th e submissio n o f OSR I an d th e fac t tha t other Tie r IEDS P sceenin g assay s wil l b e conducte d t o als o ai d i n evaluatin g th e specifi c endpoint s an d relevan t

fo r thes e assays .Do w AgroScience s LL C Repor t ID : AKH02051 0

Pag e 2 4

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

ovarian dysfunction
. ReprodBio l Endocrino l 4:17
. Bowman , CJ
. (2005)
. Validatio n o f th e Puberta l Mal e Assay i n Rat s (W A 4-15)
. WIL-431005
. Fina l report . 1 3 December

2005
. E
. W
. Carney , 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 Utero an d Postnata l Developmen t

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

estroge n affect s sexual behavio r

an d physiolog y o f

femal e rats . Endocrinolog y 149(11):5592-5598
. 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 , Marc h 2009
. Fischer , J
. (1991 ) 92-Da

y Thyroi d Functio n Study i n Albin o Rat s wit h A C 92,553 : La

b Projec t Number : T-0270
. Unpublishe d stud y prepare d b y America n Cyanami d Co
. 17 1 p . Reference d in : U.S
. EPA , 1997
. Reregistratio n Eligiblit y Decisio n (RED ) Pendimethalin
. Jun e 1997
. MRD D 4205460 1 Fischer , J
. (1993 ) 56-Da

y Thyroi d Functio n Stud y i n Albin o Rat s with A C 92,553 : Pendimethalin : La b Projec t Number : AX93/1 : L/2366
. Unpublishe d stud y prepare d b y America n Cyanami d Co
. 23 5 p . MRI D 43135001
. Reference din : U.S
. EPA , 1997
. Reregistratio n Eligiblit y Decisio n (RED ) Pendimethalin
. Jun e 1997
. 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 environmenta

l antiandrogen s o n reproductiv e developmen

t i n experimenta

l animals
. HumRepro d Update 7(3):248-264
. Hill , R.N. , Crisp , T.M. , Hurley , P.M. , Rosenthal , S.L. , Singh , D.V. , 1998
. Ris k assessmento f

thyroi d follicula r cell tumors . Environ
. Healt h Perspect
. 106,447-457
. Hill , R.N. , Erdreich , L.S. , Paynter , O.E. , Roberts , P.A. , Rosenthal , S.L. , Wilkinson , C.F. , 1989
. Thyroi d follicula

r cel l carcinogenesis
. Fundam
. Appl
. Toxicol
. 12,629

- 697
. Horsley , EMT
. (2005)
. Assessment o f Puberta l Developmen

t 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
.

### Do w AgroScience s LL C Report ID : AKH02051 0 Pag e 2 5 Lund , TD , D J Munson , M E Haldy , KD RSetchell , E D Lephart , an dRJ Handa
. (2004)
. Equo l i s a nove l anti-androge n tha t

inhibit s prostate growt

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

y usin g intac t mal e rat s fo r

identifyin g antiandrogens
. Toxicol Sc i 69:92-108
. Rider , CV , J Furr , V S Wilson , an dL E 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
. Saghir , Shaki l A
. (correspondence) ; Charles , Grantle y D. ; Battels , Michae l J. ; Kan , Lyn n H.L. ; Dryzga , Mar

k D. ; Brzak , Kath y A. ; Clark , Am y J
. Mechanis mo f

trifluralin-induce d thyroi d tumor s i n rats . Toxicolog y Letters , (3 0 Ju l 2008 ) Vol
. 180 , No
. 1 , pp . 38-45
. Sawaki , M , S Noda , T Muroi , H Mitoma , S Takakura , S Sakamoto , an d K Yamasaki
. (2003)
. I n uter o throug h lactational exposure t o ethiny l estradio l induce s clef t phallu s an ddelaye d ovarian dysfunctio n i n th e 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 dS Y Nam
. (2002)
. Effect s o f

flutamid e o n pubert y 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 developmen t

an d thyroi d function
. /

Toxico l Enviro n Health , Pt

A 65(5-6):433-445
. Tamm y E
. Stoker , Louis e G
. Parks , L
. Ear l Gray , Ralp h L
. Coope

r (2000)
. Endocrine-Disruptin g Chemicals : Prepubertal Exposure s an dEffect s o n Sexual Maturatio n an dThyroi d Functio n i n th e Mal e Rat
. A Focu s o n th e EDSTAC Recommendations
. Critica l Review s i n Toxicology , Ja n 2000 , Vol
. 30 , No
. 2 , Page s 197-252
. Terry , KK , GD Cappon , M E Hurtt , M S Tassinari , an d U Gupta
. (2004)
. Reproductiv e toxicit y assessmen t o f lasofoxifene , aselectiv e estrogen receptor modulato r

(SERM) , i n femal e rats . Birt h Defect s Re s B Dev 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 the Reproductiv e Organ s o f the Mal e Rat
. Systems 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 to th e antiandroge n flutamide
. J Repro d Per t 96:483-496
. York , RG
. (2006)
. Interlaborator y Validatio n o f

th e Puberta

l Mal e Assay
. Fina

l Report
. 3 January 2006
.