### STUD Y TITL E Other Scientifi c Relevan t

Informatio n (ORSI) : EPI C EDS P Tes t

Order

DAT A REQUIREMEN T Tes t Order/DC I # : EDSP-041401-6 4

AUTHO R Gai l T
. Arce , PhD Arc e Consultin g
COMPLETIO N DAT E 

### Febl9,201 0

SPONSO R Gowa n Compan y P.O
. Bo x 556 9 Yuma,A Z 8536 6

PERFORMIN G LABORATOR Y

No t applicabl e

PROJEC T IDENTIFICATIO N ' • ' • .. . 

## ••:•• : MEC2010- 2 ••;-. . • • •



### Pag e 1 o f 6 4

### STATEMEN T O F N O DAT A CONFIDENTIALIT Y CLAIM S

N o clai mo f

confidentiality i s mad e fo r an y informatio n containe di n thi s repor t o n th e basi s o f it s fallin g withi n th e scop e o f FIFR A Sectio n 1 0 (d ) (1 ) (A) , (B) , o r (C)
.
Company : G o wa n Compan y
Company Agent : Elizabet h Codre a Directo r o f Regulatory Scienc e

Date : ' * """ " ^- ol b



### Pag e 2 of6 4 • • • •

• •• • • •

### GOO D LABORATOR Y PRACTIC E STATEMEN T

Thi s submissio n i s no t

a"study " withi n th e meanin g o f 4 0 CF RPar

t 158 , thu s th e Goo d Laboratory Practice s standard s are no t applicable
. Submitter : Gowa n Compan y
Compan y Agent : Elizabet h Codre a Director o f Regulatory Scienc e



### Date :

• • • • • • ••••• • • * * • • • . • • • •


## . . 

## . ••••• • • • • 

### • • • • •



# , .
Pag e 3 o f 6 4

### ORGANIZATIO N O F SUBMISSIO N

I
. Executiv e Summar y II
. Introductio n III
. Endocrine-Mediate d Effect s o f th e HP G Axi s IV
. Endocrin e Mediate d Effect s o f th e HG T Axi s V
. EDS P Tie r

I Battery vs . EPT C Databas e VI
. Summar y an d Conclusion s VII
. Reference s VIII
. EPT C Studie s - Supplementa l Detai l A
. Reproductio n Studie s

a . 2-Generatio n Reproductio n 198 5 b
. 2-Generatio n Reproductio n 198 2 B
. Developmental Studie s

a . Rabbi t

Developmental 198 7 b
. Rabbi t

Developmenta

l 198 5 c . Ra t Developmental 198 3 d
. Ra t Developmental 198 5 e . Ra t Developmental Neurotoxicity C
. Intermediate-Ter

mStudie s a . 90-Da y Ra t Ora l Toxicity b
. 90-Da y Ra t Inhalatio n Toxicit

y c . 90-Da y Ra t Neurotoxicity d
. 90-Da y Do g Toxicit

y D
. Long-termStudie s

a . 1-Yea r Do g 198 6 b
. 1-Yea r Do g 198 7 c . 1-Yea r Ra t d
. 2-Yea r Ra t Chronic/Oncogenicity 198 3 e . 2-Yea r Ra t Chronic/Oncogenicit

y 198 7 f
. 24-Mont

h Mous e Oncogenicit

y 197 8 g . 18-Mont

h Mous e Oncogenicit

y 198 6 E
. Wildlif

e Studie s a . MallardDuc k

Reproductio n Study b
. Bobwhite Quai l Reproductio n Stud y IX
. OSR

I Titl e Page s Pag e 4 o f 6 4I
. EXECUTIV E SUMMAR Y

Thi s submissio n discusse s th e Other Significan t

Relevan t Informatio n (OSRI ) that

shoul d b e considere d i n conjunctio n with Gowa n Company' s respons e t o th e Novembe r 12 , 200 9 Endocrin e Disrupte r Screenin g Program(EDSP ) Dat aCall-I n Notic e fo r th e activ e ingredien t

carbamothioi c acid , dipropyl- , S-ethy l ester (EPTC)
. Th e purpos e o f

th e EDS P Tie

r 1 battery i s t o provid e apreliminary assessment o f endpoint s that

may b e indicativ e o f

estrogen , androge n o r

thyroi d activity i n aserie s o f i n vitr o o r short-ter mi n viv o tests . Th e assay s i n th e Tier 1 battery includ e intentional redundanc y wit

h respec t t o monitore d endpoints
. A s ascreen , th e Tier 1 test s ar e no t definitive
. Th e definitiv e test s for endocrine disruptio n ar

e th e longer-ter

min-lif e studie s that evaluate endocrin e toxicity directly
. I f hormonal level s o r

endocrin e organ s are disrupted , significan t

biologicall y advers e impact s o n healt h statu s wil l b e apparen t

i n th e longer-ter mstudies
. Th e regulatory i n viv o studie s allo w fo r dose-respons e assessment an dsubsequen

t human ris k

assessmen

t no t possibl e wit

h th e Tie r 1 test s an d thus , represen t ahigher tie r i n th e EDS P testin g program . Th e EDS P Tier

1 i n viv o studie s primaril y evaluat e effect s suc h a s weigh t change s and/o r histopatholog y finding s i n sexua l organ s an d tissues , o r

change s i n developmenta l milestone s a s indicator s o f possibl e endocrin e disruption
. EPT C ha s bee n evaluate d i n 'numerou s acceptabl e regulator y studie s that

directl y addres s mos t

o f suc h endpoint s include dth e i n viv o Tier

1 screenin g battery
. Th e fe w endpoint s no t directl y evaluate d ar e associate d wit

h multipl e advers e effects ; thes e othe r effect s woul d hav e bee n evident i n th e regulator

y studie s fro mth e othe r

monitore d parameters . Th e relevan t

regulatory studie s includ e reproductio n studie s i n rat s an dbirds , multipl e developmental studie s hi rat s an d rabbits , an d long-ter mstudie s i n rats , mic e an d dogs
. Th e diversit

y o f test s an dteste d specie s reflect s th e redundanc y sought i n th e EDS P assays . Altogether , thousand s o f animal s i n multipl e specie s hav e bee n evaluate d fo r effect s o n relevan t

organ weights , gros s patholog y an dhistopathology
. N o effect s wer e observe d i n either

se x to sexua

l organ s o r

to an y endocrin e glan d (adrenal , pituitary , thyroid)
. N o effect s wer e foun dthat woul d indicat e endocrine-mediate d impairmen t o f reproductio n functio n o r

alteratio n i n developmental progress . Th e absenc e o f an y effec t o n seru mcholestero l i n th e whole-animal regulator y studie s confirm s that

EPT C doe s no t caus e perturbatio n o f

steroidogenesis
. Th e Agenc y develope d th e ToxCas t TM programt o predic t

endocrin e activ e agent s an d profile dove

r 30 0 chemical s includin g EPTC
. ToxCas t result s indicate d EPT C ha s avery lo w potential fo r

endocrin e disruption
. EPT C show s n o endocrine-relate d toxicity , either clinica l o r biochemica

l a t maximall y tolerate d dose s o f

EPTC
. Histopathologica l effect s i n nerv e an d muscle , primaril y heart , define s th e critical regulator y NOAEL s at

level s significantl y lowe r than an y other advers e effects
. Gowa

n Compan y believe s that

collectivel y th e availabl e dat afulfil l th e Pag e 5 o f 6 4requirement s o f th e Endocrin e Disrupto r

Screenin g ProgramDat aCall-I n an dthat th e overwhelmin g weight-of-the-evidenc e show s that EPT C i s no t

anticipate dt o produc e an y effec t i n human s simila

r t o an effec t

produce db y anaturall y occurrin g estrogen . Therefore , EPT C meet s th e standar dfo r an exemptio n unde r

FFDC A sectio n 408(p)(4)
.

Pag e 6 o f 6 4II
. INTRODUCTIO N

I n thi s document , th e EPT C databas e i s discusse di n relationshi p t o anticipate d endocrine-relate dtoxi c effect s o n th e hypothalamus-pituitary-gonada l (HPG ) axi s an d hypothalamus-pituitary-thyroi d(HPT ) axis
. Th e EPT C studie s wil l the n b e assesse d agains t specifi c Tier

1 test s fo r

functiona l equivalenc y o f data
. More detaile dindividua l study informatio n pertainin g t o th e HP G o r HP T axi s ha s bee n provide da s supplemental detai l a t th e en do f

th e document
. III
. ENDOCRINE-MEDIATE D EFFECT S O F TH E HP G AXI S Multiplicity o f

Estroge n an d Androge n Mediate d Effect s o f th e HP G Axi s Endocrin e activ e chemical s disrup t awid e rang e o f

biological endpoint s measure di n th e reproductiv e process . Fo r example , estroge n deficienc y wil l b e manifeste db y altere d ovarian developmen t

an dfunctio n suc h a s chroni c anovulation , cysti c an dhemorrhagi c follicles , absen t

corpor alutea , interstitial/stromal hyperplasi a(Abbott et . al. , 2006)
. Octylphenol , aknow n estroge n antagonist , induce dearl y vagina l openin g an d persisten t estru s afte r

maturatio n bu t

als o produce dincrease dproliferatio n i n th e endometrial epitheliu mi n animal s dose dfro mpostnatal da y (PND ) 1 to 1 5 an d increase duterin e weigh t an dincrease dproliferatio n o f th e endometrial epitheliu mi n adul t female s dose d fo r 2 8 day s (Hasegaw aet . al. , 2000)
. Androge n deficienc y (induce db y anaboli c steroids ) that altere dtestosteron e level s displaye dhistopathological finding s suc h a s arres t o f advance dspermatids , sever e depletio n o f

Leydi g cell s with altere dweight s o f no t jus t th e teste s bu t prostate gland s an d semina l vesicle s (Groket

t et . al. , 1992)
. Th e effect s are intertwine da s antiandrogeni c chemical s ca n als o b e estrogeni c (Moore et . al
. 1991 ; Gray et . al
. 1988)
. Multipl e effect s i n male s an dfemale s fo r estrogenicit

y hav e bee n show n (Hasegaw aet . al. , 2000 ; Atanassov e et . al. , 2000 : Hes s et . al. , 2000 ; Abbott et . al. , 2006 ; Sawak

i et . al. , 2003 ; Olivier aet . al. , 2003 ; Terr y et . al. , 2004 ; Garcia-Flore z et . al. , 2005)
. Antiestrogeni c activit y als o display s multipl e effect s (Vanag e et . al. , 1997 ; Ch o et . al. , 2003 ; Abbott

et . al. , 2006 ) a s d o androgeni c an dantiandrogeni c chemical s (Gray et . al
. 2001 ; Groket t et . al. , 1992 ; an dAbbott

et . al. , 2006)
. Th e mechanis mo f

actio n o f endocrin e disruptor s i s varied , a s are th e biologica l effect s the y produce
. Some bin dto receptor s som e d o not . Som

e bloc k o r disrup t metaboli c pathway s neede dfo r

synthesi s o f

th e hormones
. Some sho w dual mode s o f action
. Regardles s o f

th e mechanis mo r

mod e o f action , al l manifes t

biological effect s i n th e reproductiv e system s i n bot h male s an dfemales
. Biochemical parameter s relevan t t o estroge n an dandroge n biosynthesi s an drecepto r bindin g are sentine l events , no t necessaril y advers e events , o f HP G disruption
. Th e mos t direc t an dbiologicall y relevan t measur e o f HP G axi s functio n i s reproductiv e performanc e h i whol e animal studies
. Orga n weight s an dhistopatholog y o f bot h reproductiv e an dendocrin e organ s are criticall y importan t i n assessin g damag e an dare inextricabl y linke dt o chemical s resultin g i n endocrin e disruption
. Pag e 7 o f 6 4

### I n al l th e literatur e reviewed , n o short-ter mindicato r

o f endocrin e disruptio n wa s observe dwithou t

significan t

histopatholog y o r

reproductiv e repercussion
. Th e response s ar e multipl e an dconcomitant
. Th e assessment o f thes e multipl e effect s for mth e basi s o f aweight-of-the-evidenc e approac h th e Agenc y use dt o establis h an dprioritiz e th e conduc t o f th e Tie r 2 tests . Lac k o f EPT C Estroge n an d Androge n Mediate d Effect s o f th e HP G Axi s Ke y indicator s collate dfro mth e literatur e an dth e Endocrin e Disrupto r Screenin g Program : Statement

o f Policy : Notic e (F RDecembe r 28,199 8 p p 7154 2 - 71568 ) can b e use dt o asses s th e endocrin e disruptin g potential o f EPTC
. Th e EPT C studie s collectivel y evaluate nearl y al l relevan t biological endpoint s o f

estroge n o r

androgen-mediatio n o f

th e HP G axis
. Multipl e studie s addres s mos t o f th e endpoint s o f

concern . Th e fe w endpoint s no t directl y evaluate dar e associate dwit h multipl e advers e effects ; thes e other effect s woul dhav e bee n eviden t

i n th e regulatory studie s fro mth e other monitore dparameters . N o indicatio n o f

EPT C induce dendocrine-relate deffect s wa s observe di n an y study
. Potential hormonal effect s can b e detecte dthroug h behaviora l changes , mating , fertilit y an dgestational indices , duratio n o f gestation , sign s o f

difficul t o r prolonge dparturition , implantatio n site s (corpor alutea ) an dimplantatio n loss , numbe r o f pups , feta l developmen t

an dgrowth , stillbirths , litter sizes , pu p survival , se x rati o o f th e offspring , postnatal growth , feminizatio n o r masculinizatio n o f

offspring , gros s patholog y o f pup s an dF I adults , organ weight s (ovaries , uterus , testes , epididymides , semina l vesicles , prostate ) an dhistopatholog y o f th e reproductiv e organ s (ovaries , uterus , vagina , testes , epididymides , semina

l vesicles , prostate ) o f

matin g adults
. Thes e endpoint s are evaluate di n th e traditional regulatory developmental an d reproductio n studies
. Th e Agenc y ha s conclude dthat n o developmental o r

reproductiv e effect s are foun da

t dose s lowe

r than maternall y toxi c treatmen t level s (U S EPA , 1990 ) an dn o FQP A safety facto r wa s applie dbase do n thes e results
. Endocrine-relate dorga n weight an ddetaile dhistopathological examinatio n o f long-ter mstudie s reveale dn o evidenc e o f

endocrin e disruption
. Histopathological finding s o f myocardial degeneratio n wer e use dt o establis h th e chroni c regulatory NOE L o f 2. 5 mg/k g fro mth e 2-generatio n reproductio n study (reproductiv e NOE L wa s 4 0 mg/kg)
. Reproductiv e and Developmenta l Parameter s Reproductiv e performanc e i s an indicatio n o f th e functionality o f

th e mal e an dfemal e endocrin e system . Result s o f th e 2-generatio n ra

t reproductio n studie s demonstrate n o effec t o n mating , fertility , gestational indices , parturitio n o r matin g behavio r

at 4 0 mg/k g (MacKenzie , 1985 ) o r

5 0 mg/k g (Mino r

et . al
. 1982)
. Sever

e maternal toxicity wa s manifes t a s bod y weigh t

decrement s i n P O an dF I male s an dfemale s i n th e hig h dos e group s o f bot h reproductio n studie s an dmortality i n th e rabbi t developmental study (Neme c 1983)
. Other

indicator s o f

reproductiv e functio n suc h a s th e numbe r o f corpor a lutea , post-implantatio n loss , resorptio n o f fetuses , a s measure di n developmental studie s were unaffecte da s determine di n tw o ra t developmental studie s (Nemec , 1983 , Jame s Pag e 8 o f 6 41985 ) an dtw o rabbi t (James , 1985 , Gilles , 1987 ) an di n adevelopmental neurotoxicit y study (Lees , 2004)
. . Offsprin g were unaffecte dat dose s les s than maternall y toxi c dose s i n th e developmenta l an dreproductio n studies
. Evaluate dparameter s include dlitte r size , liv e births , pu p survival , pup se x ratio s an ddevelopmental marker s suc h a s pre - o r pos t implantatio n loss , feta l los s o r

resorptions
. Ther

e wer e n o external , visceral o r skeleta l anomalie s presen t

i n th e absenc e o f

maternal toxicity
. I n th e developmental neurotoxicity study , F I female s were examine ddail y fro mday 2 9 t o determin e th e day o f

ag e o f vaginal opening
. F I male s wer e examine dfro mday 4 1 t o determin e th e ag e o f

preputial separation
. Mal e an dfemale s i n th e F I generatio n were evaluate dfo r

ana l genita l distanc e (AGD)
. AGD , vagina l openin g an dpreputia l separatio n wer e normal a t al l treatment

levels
. Orga n Weigh t

an d Patholog y Whether estrogeni c o r

androgenic , an dagonis t

o r antagonist , organ weigh t an d histopatholog y o f

endocrine-relate dorgan s wil l b e affected
. Estrogeni c an dandrogeni c activ e chemical s resul t i n acascade an dintertwine dse t o f effect s describe di n Sectio n III
. Endocrin e Mediate d Effect s o f th e HP G Axis
. Fo r

- example , decrease dtesticula r weight s associate dwit

h estrogeni c o r

androgeni c activity sho w concomitan t

decrease s i n sper

mcoun t an dabnormal histopatholog y o f th e Le y di g cell , epididymal , an d prostate . Estrogeni c compound s that leadt o teste s weigh t

decrease s als o resul t

i n increase duterin e weight an d decrease dovaria

n weight
. Uterin e histopatholog y wil l b e presen t a s cysti c an dendometrial hyperplasi aan dth e ovarie s wil l b e polycysti c o r

hyperplastic
. Estrogeni c chemical s wil l als o demonstrate reproductiv e an ddevelopmental effect s wit h decrease s h i th e numbe r o f corpor alutea
. Similarly , antiandrogeni c chemical s wil l als o leadt o endometrial hyperplasi ao f th e ovary an d uterus . Non e o f thes e indicator s o f

endocrin e disruptio n wer e evident followin g either

shor t o r lon g ter mexposure t o EPTC
. There were n o polycysti c o r hyperplasti c ovaries , cysti c uteruse s o r

endometrial hyperplasia , n o effec t o n mammary carcinoma , an dn o adenom a o f th e vagina
. I n th e males , n o degenerativ e o r hyperplasi c event s were note di n th e prostate , epididymides , Leydi g cells , o r degeneratio n i n th e semina l vesicles
. Organ s weigh t an d histopathological evaluation s i n th e tw o ra t 2-generatio n reproductio n studie s (MacKenzie , 1985 ; Mino r et . al. , 1982) , rabbi t

developmenta

l study (Gilles , 1987) , 90

- da y oral an dinhalatio n ra

t toxicity studie s (Tisde l 1983 ; Scott , 1985 , 90-da y do g toxicity study (Dal y 1985) , tw o one-yea r do g chroni c studie s (Dicki e 1986 ; Spragu e an dTaylor , 1987) , one-yea

r ra t chroni c stud y (Trutter , 1978 ) tw o 2-yea r ra t chroni c oncogenicit

y studie s (Warne r

1983 , Dicki e 1987) , a

n 18-mont

h mous e oncogenicit

y study (Tisdel , 1986 ) an dtwo-yea

r mous e oncogenicit

y stud y (Goldenthal 1978) , collectivel y wer e al l normal
.
Pag e 9 o f 6 4Th e dat arepresen t aver y larg e numbe r

o f observation s fo r

al l organ s o f

interes t i n awid e rang e o f studies
. Th e organ weigh t finding s are summarize d an d collate d i n Tabl e 1 an d histopathological finding s are presente d i n Tabl e 2
.

- Tabl e 1
. Bod y an d Orga n Weight s Stud y
2-Ge n Repr o 198

2 Rabbi t De v 198 7 9 0 Day Rat

Ora l 9 0 Day Rat

Inha l 9 0 Da y Do g 198

5 1 yr Do g 198 6 1 y r Do g 198 7 1 y r Ra t 197 8 2-y r Ra t 198 3 2-y r Ra t 198 7 2 y r Mous e 197 8 Bod y

weigh t 100(4 * 

### V
. 18/3mg4

- V 

### V V V 20mg4 ' 25mg4 ' 9mg i 

### V Live r



### V V

. V 

## V V 

## V 6 0 mg ta r 

### V V V 

## V Kidne y 

### V V 

## V V V V V V V V Pituitar y

ISOO^ar (f ) 

### V V


## v. Adrena l



### V V

- V V V

. V Thyroi d

V 

### V V V V Teste s

Ovar y V(i ) V V V V 18004>ar(m )



### . V V V V V Prostat e

Uteru s


### V

(1 ) Teste s onl y V = Norma l - I - decreas e t = increas e a (m ) = mal e (f

) = femal e = absolut e r = relativ e #= Dos e i n pp munles s wher e indicate d Finding s i n liver , pituitary an d teste s wer e onl y see

n i n on e do g study i n on e se x bu t were no t confirme d b y th e second do g stud y o r foun di n an y other

study
. Thes e finding s are discusse d below
. Liver : Alteratio n i n live

r weight wa s observe d i n onl y on e do g study an donl y i n females
. Weight s wer

e increase d fo r

female s a

t th e highes t

dos e (6 0 mg/kg ) i n th e one year do g chroni c study (Spragu e an dTaylor , 1987)
. I n th e 6 0 mg/k g males , absolute live r weight s were normal bu t relativ e liver

weight s were increased
. There were n o concomitant

change s i n live r

relate d clinica

l chemistry
. Whil e apparentl y treatment
related , i t wa s arelativel y mil d effect
. Al l other orga n weight s were comparabl e t o contro l animals
. Live r

weight s were unaffecte da t 54. 7 mg/k g i n th e other

one-yea r do g chroni c study (Dickie , 1986)
. Histopathological examinatio n o f th e live r reveale d n o abnormalitie s i n an y o f

th e studie s Pituitary : Pituitary weight s wer e lower i n onl y on e do g study an donl y i n females
. Female s treate d wit

h 180 0 pp m(54. 7 mg/k g equivalent ) showe d lower absolut e an d relativ e pituitary weight s whe n compare d t o contro l animals
. I n th e absenc e o f microscopi c change s an d withou t additional supportiv e evidenc e t o substantiate adirec t Pag e 1 0 o f

64relatio n t o treatment , thes e weigh t change s wer e considere d biologicall y unimportant
. N o effec t wa s seen i n th e other

one-yea r do g study evaluate d at

dose s u p t o 6 0 mg/kg
. (Dickie , 1986)
. Histopathological finding s i n th e pituitar y wer e norma l i n al l studie s (se e Tabl e 2 fo r

lis t o f studie s where teste s histopatholog y wa s evaluated)
. Testes : I n on e do g study (Dickie , 1986) , absolute teste s weight s i n th e 180 0 pp m(48. 5 mg/k g equivalent ) grou p male s wer e lower tha n controls
. I n th e absenc e o f microscopi c change s an d withou t

additiona l supportiv e evidenc e to substantiate adirec t relatio n to treatment , thes e weigh t

change s were considere d biologicall y unimportant
. Teste s weight s were normal i n th e Spragu e an dTaylo r (1987 ) stud

y that evaluate d EPT C up t o 6 0 mg/k g an di n al l other studie s i n rat s o r

mice
. Histopathologica l finding s i n th e teste s were normal i n al l studie s (se e Tabl e 2 fo r lis t o f studie s where teste s histopatholog y wa s evaluated)
. Ovary : N o change s i n ovary weight s were observe d i n an y study
. Thes e include d th e rat reproductio n studies , 9 0 day ra t an ddo g studies , an dth e lon g termrat , mous e an ddo g studies
. Likewise , al l ovarie s examine d had normal histomorphology
. Se x Accessory : Al l uterin e an d prostate weight s were norma l i n al l studie s i n whic h the y wer e evaluated
. Histopatholog y wa s norma l i n th e prostate, , epididymides , semina l vesicles , spermati c cords , ovary , cervix , uterus , vagin aan d mammar y gland s i n al l studie s where evaluated
. Endocrin e organs : N o organ weight effect s were observe d i n th e thyroi d o r adrenal glands
. Histopatholog y wa s norma l i n th e thyroid , parathyroid , pituitary , an dadrenal gland s i n al l studie s evaluated
.

Pag e 1 1 of 64Tabl e 2
. Mammalia n Orga n Histopatholog y Evaluatio n
Histopatholog y Organ s evaluate d
Live r Kidne y Thyroi d Parathyroi d Pituitary Adrena l Teste s Prostate Bulbo-urethra l glan d Coagg l glan d Epididymide s Seminal vesicle s Spermati c cord s Urethr a Ovary Oviduc t Cervi x Uteru s Vagin a Mammary glan d STUD Y 2-Generatio n Reproductio n 

### FO/F , 198 2 

### V V



## ^ V 

## V V V ' V V V

. V L

_^ 

### V 

## T J V 

## V F , 198 5 

### V V -

V V
V V 

### V V 9 0 Da

y Ra t Ora l 

### V V V V V V 

## V V 

## V V V V 

## V V V 9 0 Day Do g



### " V V V V V V 

## V V 

## V

V V 

## V V 

## V lY r Do g 1986 

### V V V V 

## V V 

## V V

V V V V 

## V lY r Do g 198 7 

### V V • V
. V V V 

## V V V
V V V V V 1 Y r Ra t 197 8 

### V V
. V V V V 

## V V V V V 

## V V V 2Y r Ra t 1983 

### V V 

### V V 

### V V 

## •V V V V V V • 

## V V V 2Y r Ra t 198 7 V V V V V V V V 

### V V 

### V V 

## V V V 2Y r Mous e 197 8 V V V V V V 

## V V 

## V V V 

### V 

## V V 

## V• 1 8 M

o Mous e 1986 V 

## V V V V V V V 

### V V 

## v . V V 

### V 

## v .
= Evaluate dwit h norma l patholog y 

### Biochemical Seru mcholestero l i s o f

particula r importanc e a s cholestero l i s amolecula r precurso r o f al l steroi dhormone s i n humans , includin g estrogen s an dandrogens
. Earl y disruptio n o f steroidogenesi s ca

n leadto altere dlevel s o f

cholestero l an ddisruption s i n cholestero l synthesi s ca

n affec t steroidogenesis
. Cholestero l level s were unaffecte di n al l studie s i n whic h i t wa s measure dincludin g bot h mal e an dfemal e rat s (9 0 da y oral an dinhalatio n studie s an dtw o yea r studies) , an ddog s (9 0 da y an done-yea

r studies)
. ToxCast TM PrioritizationofEPT C Th e Agenc y ha s bee n developin g th e ToxCas t progra mdesigne dt o tes t

th e hypothesi s that multi-dimensiona

l evaluatio n o f

chemica l propertie s an deffect s acros s abroa d spectru mo f

informatio n domain s (e.g. , molecular , cellular , an dorgan responses ) wil l provid e dat athat

wil l b e predictiv e o f

toxicity
. ToxCas t

profile dth e response s o f

ove r 30 0 chemical s (mainl y pesticide s an dother select chemicals) , chosen becaus e o f th e lexicological understandin g fro mexistin g traditional anima l tes t dat aan dthei r

intende d Pag e 1 2 o f

64activitie s a s biologica l agents .

I n apresentatio n b y Rei f

(2009 ) th e result s o f

th e prioritizatio n o f

thes e chemical s wa s provide da s i t

relate dt o th e EDSP
. EPI C wa s on e o f th e chemical s modele dfo r endocrin e activity
. Th e mode l incorporate dmulti-assay profile s i n combinatio n with informatio n o f

relevan t chemica l properties , toxicity pathways , an di n viv o study results
. Ranking s wer e the n develope dfo r th e chemicals
. EPI C ha d ascor

e o f 0.1 3 (Tropsha , 2009 ) whic h place s EPI C i n th e lo w prioritity rang e a s depicte db y Rei f

(2009)
. HP G Endpoint s vs . EPT C Databas e There wa s n o evidenc e o f an y HP G endocrine-disruptin g effec t i n th e rat reproduction " studies , th e rat

o r rabbi t developmental studies , th e rat o r do g subchroni c studies , an dth e long-termchroni c o r

oncogenicit

y studie s i n th e rat , mous e o r dog
. N o relevan t

change s i n orga n weight s o r

histopatholog y were identifie di n an y o f thes e studies
. Likewise , cholestero l level s were no t affecte db y treatmen t

with EPTC
. Th e rang e o f

availabl e mammalian studie s an dth e indicator s fo r HP G endocrin e disruptio n ar e presente di n Tabl e 3 (female ) an d Tabl e 4 (male)
. Th e selecte dendpoint s were collate dfro mth e literatur e an dfro mth e Agency' s Statement o f Polic y fro mth e 199 8 Federal Registe r

(U S EP A 1998c)
. Th e EPT C study result s are provide dadjacen t t o th e endpoin t

o f interest , togethe r

wit h th e stud y reference
.

Pag e 1 3 o f

64Tabl e 3
. Femal e Endpoint s Relevan t t o Endocrin e Disruptio n - HP G
Estrou s cyclicir

y Vagina l Openin g Ovarian follicl e coun t Fertility Inde x Matin g inde x Corpor alute a
Implantation ; pre an dpos t implantatio n los s Resorption s

Parturitio n
Gestationa l length
Litte r siz e o f pup s (liv e births )

Se x ratio s o f

pup s

Survival o f

pup s
Uterin e weigh t Stud y Typ e 2- G Repro 2- G Repr o DNT : No t evaluate d 2- G Repr o 2- G Repr o 2- G Repr o 2- G Repr o RatDe v RatDe v Rabbi t De v Rabbi t De v RatDe v Rat De v Rabbi t De v Rabbi t De v RatDe v RatDe v Rabbi t De v Rabbi t De v 2- G Repr o 2- G Repr o Ra t DN T 2- G Repr o 2- G Repr o DN T 2- G Repr o 2- G Repr o Rat Dev : Rat Dev : Rabbi t De v Rabbi t De v Ra t DN T 2- G Repr o 3- G Repro Rat De v Rat Dev : Rabbi t De v Rabbi t De v Ra t DN T 2- G Repr o 2- G Repr o Rat DN T Rat De v Rabbi t De v Observatio n

Norma l Norma l Norma l Norma l Normal Norma l Norma l Norma l Norma l Norma l Norma l Normal * Norma l Norma l Norma l Normal * Normal * Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Normal * Normal * Normal * Norma l Norma l Normal * Norma l Norma l Norma l Norma l Norma l Norma l Norma l Normal * Norma l Normal * Norma l Norma l Stud y Referenc e

MacKenzi e 198 5 Mino r 198 2 Lee s 200 4 MacKenzi e 198 5 Minorl98 2 MacKenzi e 198 5 Mino r 198 2 Neme c 198 3 Jame s 198 5 Gille s 198 7 Jame s 198 5 Neme c 198 3 Jame s 198 5 Gille s 198 7 Jame s 198 5 Neme c 198 3 Jame s 198 5 Gille s 198 7 Jame s 198 5 MacKenzi e 198 5 Mino r 198 2 Lee s 2004 MacKenzi e 198 5 Mino r etal
. 198 2 Lee s 200 4 MacKenzi e 198 5 Mino r 198 2 Neme c 198 3 Jame s 198 5 • Gille s 198 7 Jame s 198 5 Lee s 200 4 MacKenzi e 198 5 Mino r 198 2
. Neme c 198 3 Jame s 198 5 Gille s 198 7 Jame s 198 5 Lee s 200 4 MacKenzi e 198 5 Mino r 198 2 Lee s 2004 Neme c 198 3 Gille s 198 7 Normal * = Norma l i n th e absenc e o f materna l toxicity o r

systemic'toxicity

Pag e 1 4 o f

64Tabl e 3 (co n t. ) Endpoint s Relevan t t o Endocrin e Disruptio n - HP G FEMALE S Ovar y weigh t

Adrena l weigh t

Uterin e histopatholog y

Ovar y histopatholog y

Adrena l histopatholog y Stud y Typ e Rabbi t De v Ra t 9 0 Da y Ora l Ra t 9 0 Da y Inh Do g 9 0 Da

y Dog l y r Do g lyr : Ratly r Rat2y r Rat2y r Mous e 2 y r Ra t 9 0 Da y Inh Do g 9 0 Da

y Do g 1 y r Do g lyr : Rat2y r Mous e 2 y r 2- G Repr o 2- G Repr o Ra t 9 0 Da y Oral Do g 9 0 Da

y Do g 1 y r Do g lyr : Rat 1 y r Rat2y r Rat2y r Mous e 1 8 M o Mous e 2 y r 2- G Repr o 2- G Repr o Ra t 9 0 Da y Oral Do g 9 0 Da

y Do g 1 y r Do g lyr : Rat 1 y r Rat2y r Rat2y r Mous e 1 8 M o Mous e 2 y r Ra t 9 0 Da y Oral Do g 9 0 Da

y Do g 1 y r Do g lyr : Rat 1 y r Rat 2 y r Rat2y r Mous e 1 8 M o Mous e 2 y r Observatio n

Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Normal Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Normal Norma l Norma l Norma l Norma l Norma l Norma l Study Referenc e

Gille s 198 7 Tisde l 198 4 Scot t 198 5 Dal y 198 5 Dicki e 198 6 Spragu e 198 7 Trutte r 197 8 Warne r 198 3 Dicki e 198 7 Goldentha l 197 8 Scot t 198 5 Dal y 198 5 Dicki e 198 6 Spragu e 198 7 Dicki e 198 7 Goldentha l 197 8 MacKenzi e 198 5 Minor 198 2 Tisdel 1984 Dal y 198 5 Dicki e 198 6 Spragu e 198 7 Trutte r 197 8 Warne r 198 3 Dicki e 198 7 Tisde l 198 6 Goldentha l 197 8 MacKenzi e 198 5 Mino r etal
. 198 2 Tisde l 1984 Dal y 198 5 Dicki e 198 6 Spragu e 198 7 Trutte r 197 8 Warne r 198 3 Dicki e 198 7 Tisde l 198 6 Goldentha l 197 8 Tisde l 198 4 Dal y 198 5 Dicki e 198 6 Spragu e 198 7 Trutter 197 8 Warne r 198 3 Dicki e 198 7 Tisde l 198 6 Goldenthal 197 8

Pag e 1 5 o f

64Tabl e 3 (cont. ) Endpoint s Relevan t t o Endocrin e Disruptio n - HP G FEMALE S Vaginal histopatholog y

Mammary histopatholog y

Seru mcholestero l

A Rbindin g E Rbindin g Stud y Typ e 2- G Repr o 2-GRepr o Ra t 9 0 Da y Ora l Do g 9 0 Da

y Do g 1 y r Do g lyr : Rat l y r Rat2y r Rat2y r Mous e 1 8 M o Mous e 2 y r 2- G Repro Ra t 9 0 Da y Ora l Do g 9 0 Da

y Do g 1 y r Do g lyr : Ra t ly r Rat2y r Rat2y r Mous e 1 8 M o Mous e 2 y r Ra t 9 0 Da y Oral Do g 9 0 Da

y Do g 1 y r Do g lyr : Rat l y r Rat2y r Rat2y r No t evaluate d No t evaluate d Observatio n

Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Normal Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Normal Norma l Norma l Norma l Norma l Norma l Norma l Norma l Study Referenc e

MacKenzi e 198 5 Mino r 198 2 Tisde l 1984 Dal y 198 5 Dicki e 198 6 Spragu e 198 7 Trutter 197 8 Warne r 198 3 Dicki e 198 7 Tisdel 198 6 Goldentha l 197 8 Mino r 198 2 Tisde l 1984 Dal y 198 5 Dicki e 198 6 Spragu e 198 7 Trutter 197 8 Warner 198 3 Dicki e 198 7 Tisde l 198 6 Goldenthal 197 8 Tisde l 1984 Dal y 198 5 Dicki e 198 6 Spragu e 198 7 Trutter 197 8 Warne r 198 3 Dicki e 198 7

Pag e 1 6 o f

64Tabl e 4
. Mal e Endpoint s Relevan t t o Endocrin e Disruptio n - HG P
Sexual behavio r Epididymal sper

mcoun t Fertility Inde x Matin g index Se x ratio s o f

pup s

Anogenital distance , AG O Balano-preputial separatio n Teste s weigh t

Epididymi s weigh t
Prostate weight Semina l vesicl e weigh t Adrena l weigh t

Teste s histopatholog y Stud y Typ e 2- G Repr o 2-GRepr o Observatio n

Norma l Norma l No t evaluate d 2- G Repr o 2- G Repr o 2- G Repr o 2- G Repro 2- G Repr o 3- G Repr o Ra t De v Rat Dev : Rabbi t De v Rabbi t De v Ra t DN T DN T DN T 2-GRepr o Rabbi t De v Ra t 9 0 Da y Ora l Ra t 9 0 Da y Inh Do g 9 0 Da

y Dog l y r Do g lyr : Ra t ly r Rat2y r Rat2y r Mous e 2 y r 2- G Repr o Do g 9 0 Da

y Ra t ly r No t evaluate d No t evaluate d Ra t 9 0 Da y Inh Do g 9 0 Da

y Do g ly r Do g 1 y r Rat2y r Mous e 2 y r 2- G Repr o 2- G Repro : Ra t 9 0 Da y Ora l Do g 9 0 Da

y Do g 1 Y r Do g 1 Y r Rat 1 Y r Rat2Y r Rat2Y r Mous e 1 8 M o Mous e 2 Y r Norma l

Norma l Normal Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l
. Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l
Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Stud y Referenc e

MacKenzi e 198 5 Mino r 198 2 MacKenzi e 198 5 Mino r etal
. 198 2 MacKenzi e 198 5 Minor
. 198 2 MacKenzi e 198 5 Mino r 198 2 Neme c 198 3 Jame s 198 5 Gillesl987
. Jame s 198 5 Lee s 200 4 Lee s 200 4 Lee s 200 4 Mino r 198 2 Gille s 198 7 Tisde l 1984 Scot t 198 5 Dal y 198 5 Dicki e 198 6 Spragu e 198 7 Trutter 197 8 Warne r 198 3 Dicki e 198 7 Goldentha l 197 8 Mino r 198 2 Dal y 198 5 Trutte r 197 8
Scot t 198 5 Dal y 198 5 Dicki e 198 6 Spragu e 198 7 Dicki e 198 7 Goldenthal 197 8 MacKenzi e 198 5 Mino r 198 2 Tisde l 198

4 Dal y 198 5 Dicki e 198 5 Spragu e 198 7 Trutte r 197 8 Warner 198 3 Dicki e 198 7 Tisde l 198 5 Goldentha l 197 8 

### Pag e 1 7 o f

64Tabl e 4 (cont. ) Mal e Endpoint s Relevan t t o Endocrin e Disruptio n - HP G MALE S Epididyma l histopatholog y

Prostate histopatholog y

Seminal vesicl e

Adrena l histopatholog y

Seru mcholestero l

A Rbindin g E Rbindin g Stud y Typ e 2- G Repr o Ra t 9 0 Da y Ora l Do g 9 0 Da

y Do g 1 Y r Ra t 1 Y r Rat 2 Y r Rat2Y r Mous e 1 8 M o Mous e 2 Y r 2- G Repro 2- G Repr o Ra t 9 0 Da y Oral Do g 9 0 Da

y Do g 1 Y r Do g 1 Y r Rat 1 Y r Rat 2 Y r Rat 2 Y r Mous e 1 8 M o Mous e 2 Y r 2- G Repr o 2- G Repr o Ra t 9 0 Da y Oral Do g 1 Y r Rat 1 Y r Rat2Y r Rat 2 Y r Mous e 1 8 M o Mouse d Y r Ra t 9 0 Da y Ora l Do g 9 0 Da

y Do g 1 Y r Do g 1 Y r Rat 1 Y r Rat 2 Y r Rat 2 Y r Mous e 1 8 M o Mous e 2 Y r Ra t 9 0 Da y Ora l Ra t 9 0 Da y In n Do g 9 0 Da

y Do g 1 Y r Do g 1 Y r Rat2Y r Rat2Y r Observatio n

Norma l Norma l Norma l Norma l Norma l Norma l Normal Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l Norma l No t evaluate d No t Evaluate d Stud y Referenc e Mino r 198 2 Tisde l 1984 Dal y 198 5 Spragu e 198 7 Trutte r 197 8 Warne r 198 3 Dicki e 198 7 Tisde l 198 6 Goldenthal 197 8 MacKenzi e 198 5 Mino r 198 2 Tisde l 1984 Dal y 198 5 Dicki e 198 5 Spragu e 198 7 Trutte r 197 8 Warne r 198 3 Dicki e 198 7 Tisde l 198 5 Goldentha l 197 8 MacKenzi e 198 5 Mino r 198 2 Tisde l 198 4 Spragu e 198 7 Trutte r 197 8 Warne r 198 3 Dicki e 198 7 Tisde l 198 6 Goldentha l 197 8 Tisde l 1984 Dal y 198 5 Dicki e 198 5 Spragu e 198 7 Trutte r 197 8 Warne r 198 3 Dicki e 198 7 Tisde l 198 5 Goldenthal 197 8 Tisde l 1984 Dal y 198 5 Dicki e 198 6 Spragu e 198 7 Trutte r 197 8 Warne r 198 3 Dicki e 198 7 '



### Pag e 1 8 o f

64

### IV
. ENDOCRINE-MEDIATE D EFFECT S O F TH E HG T AXI S

Thyroi d Mediate d Effect s Thyroi dhormone , T 3 an dT4 , synthesi s an dsecretio n i n th e thyroi dglan di s regulate db y asensitiv e feedbac k

mechanis mthat

respond s t o th e change s i n th e circulatin g level s o f th e thyroi dhormones
. Thyroi dStimulatin g Hormon e (TSH ) i s secrete db y th e anterio r pituitar y glan dan dcause s th e thyroi dt o initiat e ne w thyroi dhormon e synthesis
. Increase s i n iodin e uptake , th e iodinatio n o f thyroglobulin , an dendocytosi s an d proteolysi s o f

colloi dare al l observe di n respons e to TS H stimulation
. I f TS H i s secrete d an dthyroi dfunctio n i s increased , thi s wil l b e eviden t i n th e thyroi dhistopathology
. Sinc e thyroi dhormone s are cleare db y th e liver , increase s i n live r weight an daltere d histopatholog y ca

n sometime s b e observe d(Hil l et . al , 1998)
. Long-ter mdisturbance s i n thyroid-pituitary hormona l feedbac k resultin g i n elevate dTS H lead s t o follicula r

thyroi dhyperplasia , an dsubsequen t thyroi dfollicular

cel l tumor s (adenomas , carcinomas)
. Accordin g to EPA (Hil l et . al , 1998) , "treatment s o f rodent s tha t caus e thyroid-pituitar

y disruptio n resul t

i n chroni c reductio n i n circulatin g thyroi d hormon e levels , increas e i n TS H level s an dth e developmen t o f increase dcel l division , increase dsiz e an dnumber s o f thyroi dcells , increase dthyroi dglan dweigh t and , finally , tumor s o f th e thyroid
. I n some cases , ther e i s als o an increas e i n tumor s o f th e pituitary cell s that produc e TSH. " Thi s ha s als o bee n recognize db y OEC D (2005 , documen t prepare dunde r

contrac t fo r EPA)
. I t reads , 'Thyroi dweigh t

provide s arelativ e measure o f it s stimulatio n b y TSH ; thus , thyroi dhormon e level s ar e altere dsubtly , thyroi dweigh t may reflec t

achange
. Thyroi dhistopatholog y may provid e amore sensitiv e indicato r o f thi s process. " Rat s are particularl y sensitiv e t o thi s proces s (Hil l et . al. , 1998 , OECD , 2005)
. OEC D (2005 ) implie s that i f th e biologica l chang e doe s no t tak e place , th e alteratio n o f T3 , T 4 o r TS H ha s littl e biological relevance
. A s note dabove , T 3 an dT 4 level s are delicatel y regulate dan dth e smal l persisten t change s that

resul t i n disruptio n o f

thyroi d hormon e homeostasi s lead s t o alteration s i n colloi dare aan dfollicular cel l height
. Thes e wil l b e readil y eviden t

i n an y histopathological analysis
. Th e classi c thyroi dinhibitors , ETU , PT U an dchlorate , hav e bee n extensivel y studied
. Th e effect s o n thyroi dmorpholog y ar e immediat e an deffect s resultin g fro mperinata l an dadul t exposure are similar
. I n th e cas e o f

sodiu mchlorate (NT P 2005) , expose danimal s showe dincidence s o f minimal t o mil dthyroi dfollicular

cel l hypertroph y i n a s fe w a s thre e weeks
. Thyroi dglan dfollicula r cel l carcinom ai n mal e rat s an dthyroi dglan dfollicular cel l adenom ao r

carcinom a (combined ) wa s observe di n male s an dfemale s afte r tw o years . Evaluatio n h i th e puberta l development

assa y als o implie s that

thyroi dweight

an dadvers e histopatholog y wil l b e measurabl e afte r

2 0 day s o f

exposure .

Pag e 1 9 o f

64I t

i s unlikel y that

pup s woul db e sensitiv e bu t adult s refractory t o thyroi ddisruption
. Whe n PT U i s give n t o dam s o f tw o rat strain s fro mgestatio n day (GD ) 6 throug h postnatal da

y (PD ) 10 , aclea

r dos e respons e relationshi p fo r thyroi dhormone s wit

h decrease dT 3 an dT 4 an dincrease dTS H level s fo r dam s (G D 20 , P D 21) , fetuse s (G D 20 ) an d pup s (P D 4 & 21 ) i s observe d(Schneide r et . al. , 2009)
. A t

thes e tim e points , dams , fetuse s ari dpup s o f bot h ra t strain s demonstrate dcomparabl e T 3 an dT 4 inhibitio n an dTS H stimulatio n a s wel l a s comparabl e sign s o f diffus e hypertroph y an dhyperplasi a o f th e thyroi dglan dfollicular cell s o f dose-dependent

severity
. Thi s comparability i s als o born e ou t i n longer-ter

mstudies
. NT P (1992 ) evaluate dth e rol e o f perinata l ET U exposure b y comparin g th e effect s o f thre e differen t

dosag e regimens : perinatal only , combine dperinatal an dadult , an dadul t onl y i n long-term studie s i n rat s an dmice
. I t i s clea r fro mth e dat athat

ther e i s n o increase dsensitivit y t o thyroi dhormon e disruptio n o f youn g rat s o r

mic e t o earl y ET U exposure . Again , thyroi d disruptio n i n th e pup s i s als o manifes t i n th e adults
. Thus , histopathological change s a s th e resul t o f pituitary-thyroi dhomeostasi s disruptio n appea r earl y an d progres s i n severit y wit h long-ter mhormon e disruption
. Becaus e o f th e hig h degre e o f

conservatio n o f

th e thyroi dsyste mboth acros s vertebrate s an dag e o f organism s (OEC D 2005) , i t i s unlikel y that

acarefu l evaluatio n o f

th e adul t animal s fo r either gros s patholog y (includin g weights ) o r histopatholog y wil l mis s an y potential thyroi dinhibito r

i n eithe r adult , juvenil e o r

neonatal animal s (mammals , birds , fis h o r amphibians)
. Lac k o f EPT C Thyroi d Mediate d Effect s A s discusse dabove , mino r alteration s i n thyroi dfunctio n ar e sensitivel y manifeste di n histopatholog y o f

th e thyroi dfollicular

cells
. Thi s effec t

wa s no t observe di n an y EPT C study
. Likewise , n o change s h i thyroi dweight s were present i n th e rat , do g o r mous e studie s o f

an y duration
. Th e studie s evaluatin g thyroi dweigh t an d histopatholog y were show n i n Tabl e 1 an d Tabl e 2
. I n som e case s concomitant increase s i n live r

weight s are induce db y chemical s tha t alter thyroi dfunction
. EPT C treatmen t di dno t affec t live r weight s i n an y o f

th e studie s performed
. Histopathological evaluatio n o f th e live r tissue s reveale dn o histopathological effect
. Similarly , th e pituitary , par t o f th e HP T axis , i s no t

affecte d b y EPT C exposure . Sinc e th e thyroi dcontrol s bod y temperature regulation , bod y temperatur e measure s are relevant
. Temperature measurement s (recorde da t pre-test , 3 , 6 , 9 an d1 2 months) x i n th e 1-yea r do g study als o reveale dn o change s followin g EPT C exposure s t o up t o 6 0 mg/k g (Spragu e an d Taylor , 1987)
.

Pag e 2 0 o f 6 4

### Th e lac k o f thyroi dweigh t

changes , histopathology , live r weight s o r

body temperatur e in
. th e ra t an ddo g intermediate

- an dlong-ter mstudie s i s aclea

r indicatio n that

EPT C doe s no t interac t wit h th e thyroid
. V
. EDS P TIE RI BATTERY V S EPT C DATABAS E Tabl e 5 delineate s th e Guidelin e studie s require di n th e Tier 1 testin g battery alon g with th e majo r endocrin e endpoint s that

are measured
. Fo r

eac h o f th e Guidelin e test s i n th e Tier 1 battery , th e direc t

o r functiona l equivalenc y o f th e EPT C dat aexist s t o infor mth e Agenc y o n th e endpoint s bein g evaluated
.

Pag e 2 1 o f

6 4Tabl e 5
. Compariso n o f Availabl e Dat at o EDS P Tier I Endpoint s Guidelin e

890.110 0

890.135 0

890.115 0

890.120 0

890.155 0

890.125 0

890.130 0 Stud y

Amphibia n Metamorphosi s (Frog )

Fis h Short-Ter

m Reproductio n

Androge n Recepto r Bindin g (Ra

t Prostate Cytosol )

Aromatas e (Human Recombinant )
Steroidogenesi s (Huma n Cel l Lin e - H295R )

Estroge n Recepto r Bindin g

Estrogen Receptor Transcriptional Activatio n (Huma

n Cel l Lin e HeLa-9903 ) Rout e
i n viv o

i n viv o

i n vitr o

i n vitr o

i n vitr o

i n vitr o

i n vitr o Majo r

endocrin e endpoint s
Hin dlim b length , snout-ven t

length , developmental stage , thyroi dhistolog y

Gonadal-somati c index , gonadal histo , mal e secondar

y se x characteristics , plasm aVTG , plasm ase x steroid s

Potentia l t o compet e with 3 H ligan dfo r bindin g ra t ventral prostate tissu e homogenat e

Conversio n o f

androge n t o estroge n i n microsome s
Compare s abilit

y to elici t productio n o f testosteron e o r

estradio l to positiv e control s (forskoli n an dprochloraz )

Ability t o bin dwit

h estroge n receptor s isolate dfro mrat

uteru s

Abilit y to induc e reporte

r gen e produc t followin g bindin g t o aspecifi c recepto r an dsubsequen t

transcriptiona l activatio n Availabl e EPT C dat a informin g endpoin t N o thyroi dweigh t

effect s N o thyroi dhistopatholog y effect s N o other thyroi drelate deffect s N o developmenta l effect s
N o reproductiv e effect s i n bird , ra t o r rabbi t studie s N o effec t o n se x orga

n weigh t o r histopatholog y No thyroi deffect s
N o effec t o n se x orga

n weigh t o r histopatholog y N o developmenta l effect s N o reproductiv e effect s N o effec t o n AG D o r

PP S
N o change s i n cholesterol , N o imbalanc e o f

estroge n o r androge n pe r

orga n weigh t o r histopatholog y
N o effec t o n cholestero l N o imbalanc e o f

estroge n o r androge n per

orga n weight/histopatholog y
N o effec t o n reproductiv e organ s N o effec t o n se x organ weigh t

o r histopatholog y N o effec t o n AGD , VO , PP S o r estrou s cyclicit

y
N o effec t o n se x orga

n weigh t o r histopatholog y N o developmental effect s N o reproductiv e effect s N o effec t o n AGD , VO , PP S o r estrou s cyclicit

y

Pag e 2 2 o f

6 4Tabl e 5 cont . Compariso n o f Availabl e Dat at o EDS P Tie r I Endpoint s Guidelin e

890.140 0

890.145 0

890.150 0

890.160 0 Stud y

Hershberger

(Rat)

Femal e Puberta l (Rat )

Mal e Puberta l (Rat )

Uterotrophi c Rout e

i n viv o

i n viv o

i n viv o

i n viv o Majo r

endocrin e endpoint s Weigh t change s i n 5 androgen

dependen t tissue s i n castrate
peripubertal male : ventral prostate , semina l -vesicle , LAB C muscle , Cowper' s glan dan dglan s peni s

Growth , age/w t

at vagina l opening , orga n wts , histology , seru mthyroxin e an dTSH , estroge n cyclicity , standard bloo dpane l

Growth , age/w t

a t preputia l separation , organ wts , histology , seru mthyroxine , TS H an dtestosterone , standar dbloo d pane l

Uterin e weigh t

i n ovarectomize drat s an dmic e Availabl e EPT C dat a informin g endpoin t N o effec t o n se x organ weigh t

o r histopatholog y N o developmental effect s N o reproductiv e effect s N o effec t i n F ] male s N o AG O o r

PP S effec t
N o effec t o n se x organ weight

o r histopatholog y N o reproductiv e effect s N o effec t i n F , female s N o developmenta l effect s N o effec t o n thyroi d N o AG O o r

V O effec t N o estrou s cyclicit

y effec t
N o effec t o n se x orga

n weigh t o r histopatholog y N o reproductiv e effect s N o effec t i n F I male s N o developmental effect s N o effec t o n thyroi d N o AG O o r

PP S effec t
N o effec t o n se x orga

n weigh t o r histopatholog y N o developmental effect s N o reproductiv e effect s N o effec t i n F I female s N o AG D o r

V O effec t N o estrou s cyclicity effec t

EPT C clearl y ha s n o endocrin e disruptin g potential a s evidence db y th e reproduction , developmental , intermediate-ter man dlong-ter

mstudies
. Th e mos t

powerfu l indicatio n o f endocrin e disruptio n i s th e histopatholog y o f endocrine-relate dorgan s an dEPT C i s withou t effect
. Screenin g Endpoint s No t Availabl e i n EPT C Databas e Amphibian studie s hav e no t bee n performed
. Sinc e n o thyroi dhistopathological effect s wer e observed , an dsinc e thi s i s avery sensitiv e indicato r o f T3 , T 4 o r

TS H disruption , i t i s no t necessar y t o measure thyroi dhormon e level s o r fro g malformation s cause db y Pag e 2 3 o f

6 4

### hormon e alteration
. Fis h studie s t o predic t reproductiv e outcome s i n mammals , whe n th e mammalia n reproductiv e studie s hav e bee n performed , ar e no t necessary . Biochemical measure s o f

estroge n an dandroge n bindin g hav e no t bee n directl y performed
. Again , i n th e absenc e o f an y biological indicatio n o f estroge n o r

androge n disruption , th e measure o f thes e biochemical endpoint s wil l b e o f littl e value
. Th e definitiv e i n viv o studie s hav e bee n performed
. I n anove l study , Fo x (2004 ) evaluate da numbe r o f pesticides , includin g EPTC , i n an assa y usin g nodulatio n D (NodD ) protei n receptor s fro mRhizobium
. Recent dat ahav e show n that

man y o f th e same syntheti c an d natural environmental chemical s that disrup t endocrin e signalin g i n vertebrate s als o disrup t phytoestroge n Nod D recepto r signalin g i n soi l bacteria
. EPT C showe dn o activity o n no dexpression
. Th e Hershberger , uterotropic , pubertal s hav e no t bee n performe dusin g EPTC
. However , fo r thes e i n viv o studies , clea r functiona l equivalenc y exists
. Th e dat afro mth e longer exposure studies , i.e. , 2-generatio n reproductio n studies , provide s amuc h riche r databas e than th e short-ter

mTier 1 studies
. Evaluatio n o f

F I male s an dfemale s dose dimmediatel y pos t weanin g i n th e regulatory reproductio n studie s matche s th e dosin g regime n o f th e Hershberger , uterotropic , mal e an dfemal e pubertals
. Sinc e thes e animal s ar e dose dfo r a longer perio d(u p t o 23 0 day s i n on e 2-generatio n reproductio n study) , an y effect s wil l b e magnified
. Th e histopatholog y o f th e se x organ s an dse x accessor y organs , a s wel l ha s other endocrine-relate dorgans , showe dnorma l histomorphology
. Thi s measure o f endocrin e damag e i s superio r t o that o f se x organ weight s afte r

onl y afe w week s o f exposure an dpu p growth
. Measure s o f AGD , VO , PP S an destrou s cyclin g showe dn o alteration s i n F I animal s (Lees , 2004)
. Gowa n Compan y believe s tha

t functiona l equivalenc y exist s fo r al l th e assay s i n th e Tier 1 battery
. VI
. SUMMAR Y AN D CONCLUSION S Th e EPT C databas e represent s aful l assessment o f an y potential endocrin e advers e effec t that migh t b e identifie di n th e EDS P Tie r I battery
. Thes e studie s allo w fo r dose-respons e assessment

an dsubsequen t

huma n ris k

assessment

no t possibl e wit

h th e Tie r I scree n an d thus , represen t

ahighe r tie r i n th e EDS P testin g program . ' Th e relevan t

regulatory studie s includ e reproductio n studie s i n rat s an dbirds , multipl e developmenta

l studie s i n rats , rabbit s an dlong-termstudie s i n rats , mic e an ddogs
. Th e diversit y o f test s an dteste d specie s reflect s th e redundanc y sought i n th e EDS P assays . Altogether , thousand s o f

animal s i n multipl e specie s hav e bee n evaluate dfo r effect s o n relevan t orga n weights , gros s patholog y an dhistopathology
. N o effect s were observe di n either se x t o sexua

l organ s o r

t o an y endocrin e glan d(adrenal , pituitary , thyroid)
. N o effect s wer

e foun dtha

t woul dindicate endocrine-mediate dimpairmen t o f reproductio n functio n o r

alteratio n i n developmental progress . Th e absenc e o f an y effec t o n seru m cholestero l i n th e whole-animal regulatory studie s confirm s that EPT C doe s no t

caus e perturbatio n o f

steroidogenesis
. Pag e 2 4 o f 6 4N o evidenc e exist s t o sho w EPT C ha s an y hypothalamic-pituitary-gonadal (HPG ) an d

hypothalamic-pituitary-thyroi d(HPT ) activity
. Th e EPT C databas e i s comprehensiv e an d sufficien t fo r ris k assessment

purposes . Histopathological effect s i n nerv e an dmuscle , primaril y heart , define s th e critical regulatory NOAEL s at

level s significantl y lowe r than an y other

advers e effects
. N o biologicall y relevan t

effect s relate dt o endocrin e disruptio n hav e bee n identifie d followin g maximall y tolerate d dose s o f EPTC
. Additional screenin g fo r potential endocrin e disruptio n woul dno t resul t i n either lower NOEL s o r

adifferen t

ris k assessment

analysis
. Therefore , additional testin g fo r potentia l endocrin e effect s wil l hav e n o impac t

o n th e ris k

assessmen

t analysi s fo r

EPTC
. G o wan Company believe s tha t collectively , th e availabl e dat afulfil l th e requirement s o f th e Endocrin e Disrupto r

Screening ProgramDat aCall-i n an d that th e overwhelmin g weight-of-the-evidenc e show s tha t EPT C i s no t

anticipate dt o produc e an y effec t i n human s simila

r t o an effec t

produce db y anaturall y occurrin g estroge n o r androgen
. Therefore , EPT C meet s th e standar dfo r an exemptio n unde r

FFDC A sectio n 408(p)(4)
.

Pag e 2 5 o f

6 4

### VII
. REFERENCE S

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Pag e 2 9 o f 6 4

### VIII
. EPT C STUDIE S - SUPPLEMENTA L STUD Y DETAI L

Th e EPT C registratio n studie s consis t o f tw o studie s fo r

mos t registratio n requirement s sinc e ther e wer e tw o registrants , Stauffe r an dPPG , a

t th e tim e o f

initia l data development
. Al l relevan t studie s t o endocrin e disruptio n are discussed
. Thi s i s no t intende dt o b e aful l stud y revie w bu t onl y thos e facet s o f

th e stud y that

impac t an assessmen t o f EPT C o n th e endocrin e system . REPRODUCTIO N AN D DEVELOPMENTA L STUDIE S Tw o rat reproductio n studie s an dfou r developmental (ra

t an drabbit ) studie s hav e bee n performe dwit

h EPT C that

hav e direc t

relevanc e o n th e i n viv o effec t o f endocrin e disruptio n i n mammal s an drepresent ahighe r tie r tes t than th e EDS P Tie

r I screenin g tests . Two-generatio n Reproductio n Stud y - Mackenzi e 198 5 - MRI D 0016159

7 EPT C wa s administere dt o 3 0 mal e an dfemal e immature rat s a t dietary concentration s o f 0 , 50 , 20 0 o r

80 0 ppm . F I animal s were administere dEPT C fo r 1 0 week s pos t

weaning
. A t week 11 , selecte dF I animal s (5/sex/group ) were sacrifice dan dnecropsie di n additio n to thos e sacrifice da

t th e terminatio n o f

th e study
. Th e breedin g programwa s repeate d

, o n th e remainin g animal s (25/sex/group ) t o produc e an Fa alitter
. Systemi c Toxicity : Fo r

P O an dF I adul t

male s an dP O an dF I adul t females , bod y weight s wer e significantl y reduce dat

80 0 pp man di n F O male s an dP O female s an di n F I male s at 200ppm
. • ' Body weight

wa s decrease dapproximatel y 10 % (17 % bod y weigh t gain ) i n th e P O male s a t 80 0 pp man d9 % bod y weight gai n decrement s a

t 20 0 ppm . Mean weight s were reduce d12 % fo r

th e 80 0 pp mP O female s wit h significan t

body weigh t

gai n los s a

t 200ppm
. Similarly , th e F ; male s an dfemale s displaye dmea n bod y weigh t

los s a t 80 0 pp mdurin g th e growt

h phas e an di n th e reproductiv e phas e (females)
. F I male s showe d significan t weigh t gai n decrement s at

20 0 ppm . Reproductiv e parameter s Matin g indices : Matin g indice s were unaffecte dfo r either male s o r female s i n th e P O fo r F I generation
. Estrou s cvclicity : Th e stag e o f estrou s wa s determine d fo r al l dam s i n th e P O a

n FI generations
. Time t o matin g i n al l group s fo r al l mating s were comparabl e t o contro l matin g pairs
. Fertility indices : Fertility indice s wer e unaffecte dfo r either male s o r female s i n th e P O fo r F I generatio n i n eithe

r th e firs t o r secondmating
. Gestatio n indices : Unaffecte di n an y dam
. Pag e 3 Oo f

6 4

### Gestationa l length : Comparabl e i n al l group s fo r al l pregnan t

dams
. Parturition : N o observation s o f difficul t deliverie s o r

abnormal behavio r

were noted
. Behavioral : N o behaviora l abnormalitie s were note di n an y group . Offsprin g Litte r size : Mea

n litter siz e wa s no t

significantl y affecte db y ETP C ingestion
. Pu p Weights : Mea

n pu p weight

significantl y reduce dat

80 0 ppm . Liv e birth : N o effec t

o n numbe r

o f pup s born alive
. Numbe r o f pup s foun ddead , thoug h no t statisticall y significant , were 2-fol dhighe r than control s at

80 0 pp mi n th e F I litter
. Viability Index : N o effec t Survival index : N o effect : (weanin g index ) Se x ratio : N o effect s Parent s Organ Weight : N o orga

n weight s were taken
. Macroscopic : Al l macroscopi c observation s fo r th e FO , Fj aweanling s an dFj aadult s were simila

r t o controls
. Histopatholog y F I adults : Histopatholog y evaluate dth e heart , liver an dkidne y an dse x organ s o f bot h male s an dfemale s consistin g o f testes , semina

l vesicle , prostate , ovaries , uterus , an dvagina
. Histopatholog y wa s no t performe do n th e P O animals
. Th e onl y histopathological findin g wa s degenerativ e cardiomyopath y observe di n bot h male s an dfemale s a

t 80 0 ppm . NOEL : Parental 5 0 pp m(2. 5 mg/kg ) NOEL : Reproductiv e 80 0 pp m(4 0 mg/kg ) NOEL : Developmenta

l 20 0 pp m(1 0 mg/kg ) 2-Generatio n Reproductio n - Minor , Down s an d Zwicker 198 2 - MRI D 00121284 , supplemen t

4042040 8 EPT C wa s administered , to Spragu e Dawle y 1 5 mal e an d3 0 femal e rat s a t concentration s o f 0 , 40 , 20 0 o r

100 0 pp mfro m4 0 day s o f ag e with mating s occurrin g a t da y 13 0 an d

Pag e 3 1 o f

6 4

### agai n a t da y 186 , Thi s study i s atw o litte r per generatio n desig n (evaluate s tw o litter s fro mth e P O parent s an dtw o litter s fro mth e Fi b parents)
. Pup s fro mth e secon dlitte r (Fib ) were administere dEPT C fro mweanin g an dcontinue d throug h terminatio n a

t 23 0 day s wit

h mating s a

t 10 0 an d15 5 day s o f

age . Systemi c toxicitv : Fo r

P O an dF I adul t

male s an dP O an dF I adul t females , bod y weight s were significantl y reduce da t 1000 ppm . Bod

y weigh t wa s decrease d approximatel y 10 % i n th e P O male s an dbetwee n 1 4 - 17 % i n th e F I males
. Mean weight s fo r th e 100 0 pp m female s at tim e o f firs t matin g wer e reduce d13 % fo r bot h P O an dF I females
. N o effect s o n any grou p were note da t dose s o f 4 0 o r 20 0 ppm . Reproductiv e parameter s Matin g indices : Matin g indice s were unaffecte dfo r eithe r male s o r female s i n th e P O fo r F I generatio n i n eithe r

th e firs t o r secon dmating
. Estrou s cyclicity : Th e stag e o f estrou s wa s determine dfo r al l dams
. Tim e t o matin g i n al l group s fo r

al l mating s wer e comparabl e t o contro l matin g pairs
. Fertilit y indices : Fertility indice s wer e unaffecte dfo r eithe r male s o r female s i n th e P O fo r F I generatio n i n eithe r

th e firs t o r secon dmating
. Gestatio n indices : Unaffecte di n an y dam
. Gestational length : Comparabl e i n al l group s fo r al l pregnan t

dams
. Parturition : Th e mean delivery lengt h wa s comparabl e betwee n al l groups . N o observation s o f

difficul t deliverie s o r

abnorma l behavio r

were noted
. Retrieval time : Mean retrieval time s o f th e dam s followin g delivery were normal
. Offsprin g Litte r size : Mean litter

siz e wa s no t

significantl y affecte db y ETP C ingestion
. A t 100 0 pp mth e litter

size s were consistently , bu t no t significantly , lowe r

than control
. Thi s effec t wa s secondar

y t o th e reduce dbod y weight s o f th e dam s at

th e hig h dose
. Litter weights : Mean litte r

weight s were affecte dat

th e hig h dos e bu t

wer e th e resul t

o f materna l toxicity
. Liv e birth : N o effect s were observe di n an y litter
. Viability Index : N o effec t Lactatio n index : N o effec t
Pag e 3 2 o f 6 4

### Survival index : N o effect :

Se x ratio : N o effect s Developmental landmarks : Mil k i n stomach , detache dpinna , insciso r eruptio n an dey e openin g were unaffecte di n an y litter
. Parent s Orga n Weight : Liver , kidney , heart , brai n an dteste s wit h epididymide s were weighe di n th e P O an dF l adults
. There were decrease s i n absolut e weigh t o f th e liver , kidney , heart o r brai n (mal e only ) i n on e o r bot h generation s i n bot

h male s an dfemale s however , relativ e weight s wer

e norma l indicatin g th e finding s wer e eithe r incidenta l o r consequential t o th e reductio n i n bod y weight s at thi s dose
. Teste s weight s were no t affecte di n eithe r

generation
. Femal e gonad s wer e no t weighed
. Histopathology : Histopatholog y evaluate dth e heart , liver an dkidne y an dnearl y al l se x organ s o f bot h male s an dfemales
. Thes e consiste do f th e testes , epididymides , spermati c cord , semina

l vesicle , coagulatin g gland , prostate , urethra , bulbo-urethra l gland , ovarie s an doviduct , uterin e horns , cervix , an dvagina
. Al l reproductiv e organ s wer e norma l i n bot

h PO , an dF I male s an dfemales
. Th e onl y histopathological findin g wa s increase dseverit y o f myocardia l degeneratio n i n al l dos e groups . Althoug h th e protoco l an dmethod s indicate dthat teste s wit h epididymide s an dovarie s fro mweanling s were examine dhistopathologically , w e coul dfin dn o dat ai n th e report o r addendum
. Gros s Necropsy : N o growth-relate dmorphologica l change s were observe di n an y o f th e weanling s fro man y litter
. Th e DER , however , cite s an increas e i n anomalou s pup s at 1000 pp mafte r

arecalculatio n o f

pup s wit h multipl e anomalie s wa s correcte dfro mth e report . NOEL : Parental systemi c effect s wa s <4 0 pp m( 2 mg/kg ) - cardiomyopath y NOEL : Reproductiv e effect s wa s >100 0 pp m(5 0 mg/kg)
. NOEL : Developmental 20 0 pp m(1 0 mg/kg ) - pu p weight PND14-2 1 decreas e Rabbi t Developmenta l —Gille s 198 7 - MRI D 4049230 2 Gravi dfemal e rabbit s were gavag e administere d0 , 5 , 4 0 an d30 0 mg/kg/day i n cor n oil
. Animal s were treate dfo r

1 3 consecutiv e day s fro mgravi dda y 7 to 1 9 (Gille s 1987)
. Systemi c Toxicitv : Maternal toxicit y wa s observe da

t 30 0 mg/k g consistin g o f

bod y weight loss , reduce dfoo dconsumptio n an dsign s o f cholinesteras e inhibitio n (RB C inhibite d-70%)
. Pag e 3 3 o f 6 4

### Fertility o f th e dam s wa s unaffected
. Total corpor alute aan dcorpor alutea/damwere unaffecte da s were tota

l implantation s an dimplantations/dam
. There were n o effect s o n either earl y mi do r

lat e intrauterin e resorptions
. Pre an dpost-implantatio n los s were simila r level s i n al l groups . Th e numbe r o f liv e fetuse s wa s simila

r i n al l groups . Ther

e wa s n o effec t

o n se x ratio
. Embryofetal toxicit

y secondar

y t o maternal toxicity occurre da t 30 0 mg/k g an dconsiste d o f reduce dmean fetal bod y weigh t bu t wa s no t biologicall y o r

statisticall y significant
. Fetuse s showe dn o external , soft-tissu e o r skeletal anomalie s a

t an y treatmen t

level
. Th e se x rati o wa s unaffected
. Orga n Weight : Liver , ovaries , placentas , reproductiv e tract , uteru s were no t affecte d NOELs : Maternal cholinesteras e NOE L < 5 mg/k g (decrease dseru mcholinesterase ) Maternal Systemi c NOE L 4 0 mg/k g Developmental NOE L > 3 0 0 mg/k g Rabbi t Developmenta l - James , Smith , Masters , an d Offe r 198 5 - MRI D 0016159 9 EPT C wa s administere db y gavag e t o rabbit s a t dail y dose s o f

0 , 30,100 , an d30 0 mg/k g fro mda y 6 g o 1 8 o f

gestatio n (Jame s et

.al
. 1985)
. Systemi c Toxicity : Ther

e wa s a n increas e i n transitor

y non-specifi c sign s o f

toxicity
. Body weight

gai n wa s increase di n dam s give n 30 0 mg/k g EPT C alon g with increase d foo dconsumption
. Reproduction/Litte

r Parameters : EPT C ha s n o effec t o n pregnanc y rate eithe

r i n th e rangefinde r

(hig h dos e 360 ) o r

th e definitiv e a

t 30 0 mg/kg
. There were n o effect s o f litte r size , pre - o r

post-implantatio n los s o r resorptions
. Th e mean numbe r o f corpor alute a wa s simila

r i n al l dos e groups . Offspring : Mean litter

an dfetal weigh t

showe dn o difference s betwee n treatmen t groups . Se x ratio s were unaffected
. Ther e wa s n o incidenc e o f

either viscera l anomalie s o r

skeleta l variations
. Ra t Developmenta l ~ Neme c 198 3 - MRI D 0013891 9 Gravi dC D rat s were gavage dadministere d0 , 30 , 100 , an d30 0 mg/kg/day fro mgestatio n day s 6 throug h 1 5 (Nemec , 1983)
. Systemi c Toxicity : Mortality (60% ) wa s observe da t th e hig h dos e o f

30 0 mg/kg
. Mean bod y weight s losse s an ddecrease dbod y weigh t gain s occurre dthroughou t th e gestatio n perio di n th e 30 0 mg/k g dosag e grou p only
. Gravi duterin e weight s a t 10 0 an d3 0 mg/k g were comparabl e t o controls
. Pag e 3 4 o f 6 4Reproductio n Parameters : Fertility o f th e dam s wa s unaffecte dat an y dose
. Total corpor a lute aan dcorpor alutea/damwere unaffecte da s were implantations/dama t 3 0 o r 10 0 mg/kg
. Post-implantatio n los s wa s increase di n th e 30 0 mg/k g group bu t wa s unaffecte d at 10 0 mg/k g o r

3 0 mg/k g EPTC
. A s aresul t th e mean numbe r

o f viabl e fetuse s wa s decreased
. Feta

l se x ratio s wer e simila

r i n al l groups . Offspring : Embryotoxicity wa s presen t at 30 0 mg/k g a s evidence db y increas e i n earl y litte r resorptio n an dadecreas e i n th e numbe r o f viabl e fetuses
. Mean feta l bod y weight wa s als o reduced
. Feta

l evaluation s o f

th e hig h dos e grou p were unsuitabl e fo r evaluatio n o f teratogenicity
. Fetuse s showe dn o external , soft-tissu e o r skeleta l anomalie s a

t an y treatmen t level
. Th e se x rati o wa s unaffected
. NOELs : Th e NOEL fo r

systemi c toxicit

y wa s 10 0 mg/kg
. Th e NOE L fo r embryotoxicity wa s 10 0 mg/kg
. Ra t Developmenta l - James , Smith , an d Joh n 198 5 - MRID s 0016159 8 Gravi dC D rat s were gavage dadministere d0 , 30 , 100 , an d30 0 mg/kg/day fro mgestatio n day s 6 throug h 1 5 (Jame s et . al 1985)
. A preliminary study wa s als o reporte da t dosag e level s o f 0 , 160 , 240 , an d36 0 mg/kg/day
. Systemi c Toxicitv : I n th e preliminary study , aretardatio n o f weigh t gai n wa s observe d throughou t

th e treatmen t

period
. I n th e definitiv e study , bod y weigh t gai n wa s decrease d a t 30 0 mg/kg/day
. Reproductiv e parameters : Th e numbe r o f corpor alute awere determine db y dissectio n a s wel l a s bot

h placenta l an dembryoni c remnant s visibl e a t termination
. N o effect s were observe di n eithe

r th e preliminary study o r

i n th e definitiv e i n pregnanc y rate s o r pre implantatio n loss
. I n th e preliminary study , mean value s fo r litter size , mean litte r

an dfetal weigh t

wer e simila r i n al l groups . I n th e definitive , mean embryoni c deat h wa s marginall y highe r

a t 36 0 mg/kg
. Result s were simila r i n th e definitiv e study , litter siz e wa s marginall y reduce da t 30 0 mg/kg
. Mean fetal weigh t wa s reduce da

t 10 0 an d30 0 mg/kg/day bu t wa s no t statistically significant
. Se x ratio s were unaffecte db y treatment . There wa s n o incidenc e o f eithe r viscera l anomalie s o r

skeleta l variation s a

t dose s belo w 30 0 mg/kg
. Ra t Developmenta l Neurotoxicit y -Lees2004-

- MRID s 46319101 , EPT C wa s evaluate di n pregnan t Wista r rat s a t 0,100 , 30 0 o r

100 0 pp mi n th e die t

fro m day 7 o f gestatio n throug h lactatio n day 2 3 postpartum . Pup s wer e weane do n day 2 9 an d allowe dt o gro w t o adulthood
. Neurotoxicity evaluation s were performed
.
Pag e 3 5 o f

6 4Systemi c toxicity : A t 100 0 pp mEPT C ther e were lower bodyweight s a

t day s 1 4 an d2 2 o f gestatio n an dlove r

foo dconsumptio n throughou t gestatio n dosin g an dpos t partum . Pu p bod y weight

wa s lower

i n male s an dfemale s at

day 1 postpartu mat

1000 pp mwit

h n o effect s a

t lowe r dos e levels
. Reproductio n Parameters : There were n o treatment-relate d effect s o n gestatio n length
. Th e proportio n o f

liv e bor n pup s wa s lowe r a t 1000 pp mEPT C compare d t o contro l du e t o tw o litter s that

suffere dlitter

losses
. Th e proportio n o f pup s bor n liv e at

100 0 pp mwa s 96.6 % bu t

wa s unaffecte dwhe n th e 2 late litte r losse s were exclude d fro mth e assessment . There were n o treatment-relate d effect s i n animal s i n th e 10 0 o r 30 0 pp m treatmen t groups . N o effect s wer e observe d fo r gestatio n lengt

h o r parturition
. Litte r size s were no t

affecte da

t birth bu t wer e reduce d a

t 100 0 pp mfro mDa

y 1 1 t o 5
. Pu p survival wa s als o no t affecte dat

birth bu t wa s decrease s fro mDay 1 to'5
. Pu p bod y weigh t wa s decrease d a

t 1000 bu t total litter

weight wa s no t affected
. Se x ratio s were unaffected
. Developmenta

l Landmarks : F l female s were examine d dail y fro mday 2 9 t o determin e th e da y o f ag e o f vaginal opening
. F 2 male s were examine d fro mda y 4 1 to determin e th e ag e o f preputia l separation
. Bot h vaginal openin g an d preputia l separatio n wer e normal
. Organ Weights : Onl y th e brai n weight s wer e measured
. Histopathology : Th e focus'o f thi s stud y wa s o n brai n an dneura l tissues
. N o othe r organ s were evaluated
. INTERMEDIATE-TER M STUDIE S 90-Da y Oral Ra

t ~ Tisdel , M. , 198

3 - MRI D 0014465 1 Dos e level s o f

0 , 18 , 36 , 72 , an d12 0 mg/k g phosmet wer e administere d i n th e die t to C D rat s fo r th e firs t 6 week s o f

th e stud y an dth e mi dan dlo w dose s were reduce d t o 3 an d1 5 mg/k g fo r th e remaine d o f

th e study
. Clinical : There wa s adose-relate d decreas e i n bod y weight s and/o r weight gain s i n al l treatmen t group s bu t

were muc h les s a

t th e 18/ 3 mg/k g dos e (no t

statisticall y significant)
. Mean bod y weight

wa s 52 5 g i n contro l male s compare d t o 42 8 g i n th e hig h dos e group ) Cholesterol : Cholestero l wa s measure d pre-stud y an dat termination
. N o effect s wer e observe d tha

t wer e relate d t o treatment . Organ weights : Endocrin e relevan t orga n weight s fo r

liver , kidney , teste s (right an dleft ) an dovar y (right an dleft ) wer

e taken
. Absolut e weight s o f al l organs , wit

h th e exceptio n Pag e 3 6 o f

6 4o f

th e heart , were al l simila r t o contro l animals
. An y increase s i n th e relativ e weight s were no t considere dt o b e biologicall y significan t du e t o th e larg e bod y weigh t losses
. Th e U S EP A DE Rfoun donl y relativ e hear t weight t o b e biologicall y significant
. Histopathology : Adrena l pituitary thyroid , parathyroid , prostate , seminal vesicle , testes , epididymides , ovary , uterus , vagina , cervix , an d mammar y glan dwere al l examin e macroscopicall y an dmicroscopically
. Al l tissue s were normal
. Th e findin g o f

cardiomyopath y (myocardia l degeneration ) i n bot h sexe s wa s observe di n al l dos e group s bu t

showe ddose-relate dseverity
. NOEL : Th e NOE L wa s 3 mg/k g base do n bod y weigh t los s an dfinding s o f cardiomyopathy a

t 32/1 5 mg/kg
. 9 0 Da y Inhalatio n - Scott , 1985 - MRI D 0015478 4 I n thi s 9 0 da

y inhalatio n study , rat s wer e expose dt o 0 , 8.3 , 5 8 an d29 0 mg/m 3 EPT C fo r 1 3 weeks
. There were n o change s i n bod y weight
. Systemi c Toxicity : Body weight s wer e unaffecte dbu t foo dconsumptio n wa s reduce di n th e 5 8 an d 29 0 mg/

m 3 exposure groups . Som e clinical chemistr

y parameter s wer

e als o affecte da t 5 8 mg/ m 3 Brai n cholinesteras e wa s significantl y inhibite da t 29 0 mg/m 3 wit

h mino r reduction s a

t th e 8. 3 mg/m 3 dos e level
. Cholesterol : Total cholestero l wa s measure dan dfoun dt o b e withi n norma l range s fo r al l groups . Organ Weights : O f

interest , organ s weighe dwere liver , kidney , adrenal s an dgonad s (testes , ovary)
. N o weight s were affected
. Histopathologv : Examinatio n wa s limite dt o nasal passages , liver , kidne y an d targe t tissue
. Th e majo r

findin g wa s myocardia l degeneratio n at 29 0 mg/m 3

. NOEL : Th e NOE L wa s 8. 3 mg / m 3 define dclinical sign s an ddecrease dfoo d consumption
. 9 0 Da y Neurotoxicit y - Tinsto n 199 5 - MRID s 4292190 1 (supplement s 43964401 , 4398301 ) Ra t wer e fe ddiet s containin g 0 , 100 , 50 0 o r 250 0 pp mEPT C fo r

1 3 week s an devaluate d fo r neurotoxicity
. (Tinsto n 1995 ) Systemi c Toxiciry : Reduction s i n bod y weight gai n were see n i n male s an dfemale s fe d 50 0 o r 250 0 pp mEPTC
. Pag e 3 7 o f 6 4Organ weight : Organ weigh t measure s were take n fo r th e brai n only
. Reduction s i n brai n weigh t

wer e see n i n male s an dfemale s fe d250 0 pp man di n female s fe d50 0 pp m EPTC
. I n female s reduction s i n brai n weigh t were accompanie db y reduction s i n brai n lengt h an dwidth
. Histopathology : Histopathological examination s were mad e i n th e brai n an dnerve s only
. Minimal neurona l cel l necrosi s i n th e dentat e gyru s and/o r pyrifor mcorte x wa s seen i n on e femal e fe d250 0 ppm . N o functiona l impairmen t a s th e resul t

o f morphologica l change s were observed
. NOEL
. Th e NOE L fo r

thi s stud y wa s 10 0 pp mEPT C base do n bodyweigh t change s an d brai n weigh t

i n th e 50 0 pp mfemales
. 9 0 Da y do g - - Daly , 1985 - MRI D 00150327 EPT C wa s administere di n th e die t at 0,200 , 60 0 an d180 0 pp mo f Beagl e dog s fo r

a perio do f thre e months
. Systemi c Toxicity : Th e mean bod y weight s o f th e 180 0 pp mmal e grou p wer e lower than contro l animal s throughou t th e study
. Bodyweight s fo r th e female s wer e comparabl e i n al l dos e groups . Cholinesteras e (plasma ) wa s slightl y reduce di n hig h dos e male s a t week 7 an dtermination
. Cholesterol : Tota

l cholestero l wa s measure dpre-test , a t week 7 an da t termination
. Level s i n bot

h male s an d female s o f

al l treate d group s wer

e normal
. Organ Weights : O n endocrin e interest , liver , kidney , adrenals , thyroi dan dparathyroids , teste s with epididymide s an dovarie s were weighed
. Histopathology : Liver , kidney , thyroi dan dparathyroids , pituitary , adrenals , teste s with epididymides , prostate , ovary,'uteru s an dcervix , an dmammar y glands
. NOEL : 60 0 pp m(1 5 mg/kg ) base do n reduce dplasm acholinesteras e a t 18 0 pp m(4 5 mg/kg ) LONG-TERM STUDIE S 1 Year Do g -Dicki e 1986

- MRI D 0016159 5 EPT C wa s administere di n th e die t t o si x beagl e dog s per

grou p a t dos e level s o f

0 , 200 , 600 , an d180 0 pp mfo r

on e year . Systemi c Toxicirv : Body weight s an dbod y weigh t gain s wer e significantl y lowe r i n male s i n th e 60 0 pp mgroup . N o effect s wer e observe di n male s fe d20 0 o r 180 0 pp m EPTC
. N o effect s o n bod y weigh t were observe dh i female s i n an y treate dgroup . Pag e 3 8 o f

6 4Cholesterol : N o treatment-relate dchange s wer e observe di n tota l cholestero l levels
.

Orga n Weights : Endocrin e relate dorga n weight s were take n fo r liver , kidney , pituitary , adrenals , thyroid s (wit

h parathyroid) , teste s an dovaries
. Absolut e teste s weight s i n th e 180 0 pp mmale s were lowe r than controls
. I n th e absenc e o f microscopi c change s an d withou t additiona l supportiv e evidenc e to substantiat e a direc t relatio n t o treatment , thes e weigh t change s were considere dbiologicall y unimportant
. Female s treate dwit

h 180 0 pp mshowe dlower absolut e an drelativ e pituitary weight s whe n compare dt o contro l animals
. I n th e absenc e o f microscopi c change s an dwithou t additional supportiv e evidenc e t o substantiat e adirec t relatio n t o treatment , thes e weigh t change s were considere dbiologicall y unimportant
. Al l othe r weight s wer

e comparabl e to contro l animals
. Histopathology : Endocrin e relate dorgan s evaluate dwer e liver , kidney , thyroid, parathyroid , pituitary , adrenal , testes , prostate , ovary , uterus , cervix , vagin aan d mammar y glands
. There were n o microscopi c finding s relate dt o treatmen t i n an y group . 1 Year Do g - Spragu e an d Taylor , 198 7 - - MRI D 4044230 1 EPT C wa s administere dt o beagl e dog s b y capsul e at dos e level s o f

0,1 , 8 , an d6 0 mg/k g fo r on e year . Systemi c Toxicity : On e hig h dos e mal e do g showe dprogressiv e weigh t los s an dwa s terminate do n da

y 8 4 becaus e o f

sever e toxicity
. Reduce dbod y weigh t gai n i n th e 6 0 mg/k g male s wa s observe dbu t n o effec t wa s note di n th e lower

dosag e group s o r

i n an y o f th e femal e dos e groups . Cholinesteras e inhibitio n o f plasm awa s observe da

t 6 0 mg/k g i n male s an dfemales
. Cholesterol : Tota

l cholestero l wa s measure da t pretest , 3 , 6 , an d1 2 months
. Althoug h th e femal e leve l wa s elevate di n th e 1 2 month sampling , i t wa s no t statisticall y significant
. N o change s i n cholestero l were observe di n an y other treate dgroups . Orga n weights : O f

endocrin e interest , liver , kidney , adrenals , pituitary thyroid s (includin g parathyroids) , teste s (withou t epididymides ) an d ovaries
. Live r weight s wer e increase dfo r female s a

t th e highes t

dos e (6 0 mg/kg)
. I n th e 6 0 mg/k g males , absolute live r weight s were normal bu t relativ e live r

weight s wer

e increased
. Ther

e wer e n o concomitan

t change s i n live

r relate d clinica

l chemistry
. Whil e apparentl y treatment-related , thi s effec t wa s relativel y mild
. Al l other organ weight s were comparabl e t o contro l animals
.
Pag e 3 9 o f 6 4

### Histopatholgy : O f endocrin e interest , liver , kidney , thyroid , parathyroid , pituitary , adrenal , testes , epididymides , prostate , ovary , uteru s (horn s an dbody) , cervix , vagin aan d mammary glands
. N o treatment-relate deffect s were observe di n microscopi c analysi s o f thes e organs . Th e primary findin g wa s i n th e nerve s an dmuscle
. NOEL : Th e NOE L fo r

thi s stud y wa s 1 mg/kg/da y base do n muscl e degeneratio n secondar y t o nerv e degeneratio n at 8 mg/kg/day
. 1 Yea r Rat - Trutter , 197 8 - MRI D 0002210 1 Epta mwa s evaluate d fo r

toxicologica

l effect s i n albin o rat s (60/sex/group ) followin g dietar y administratio n o f

0 , 5,20 , an d8 0 mg/k g (adjuste dweekl y base do n bod y weights ) fo r 5 4 weeks
. Th e dietar

y level s ofte n rat s o f

eac h se x wa s increase dfro m8 0 to 16 0 mg/k g beginnin g a

t week 16
. Systemi c Toxiciry : Sligh t t o moderat e growt

h retardatio n wa s observe di n th e low-dos e ( 5 mg/kg ) male s an dmid-dos e (2 0 mg/kg ) male s an dfemales
. Clinical chemistr y assay s showe dmean SGO T (seru mglutami c oxaloaceti c transaminase ) to b e higher than contro l i n th e 8 0 an d16 0 mg/k g groups , indicativ e o f hear t tissu e damage
. Orga n Weight : Heart , liver , brain , spleen , kidne y an dteste s wit h epididymide s an d ovarie s were weighed
. There were n o finding s attributabl e t o treatment . A s a consequenc e o f

reduce dterminal bod y weights , som e relativ e organ weight s appeare d highe r bu t were no t considere dbiologicall y relevant
. Histopathology : O f

endocrin e interest , liver , kidney , thyroid , parathyroid , pituitary , adrenal , testes , epididymides , seminal vesicles , prostate , ovary , uterus , vagin aan d mammary glands
. Th e majo r findin g i n thi s study wa s an increase dincidenc e o f chroni c myocarditi s i n th e 8 0 an d16 0 mg/k g dos e group s o f both sexes . 2 Year Ra t - Warne r

1983 - MRID 00146311 , addendu m0014631 1 (1985 ) I n atwo-yea

r chroni c an doncogenicit

y study , level s o f

5,25 , o r 12 5 mg/k g (adjuste dfo r body weight ) were fe dt o 6 0 mal e an dfemal e C D rats . Systemi c Toxicity : Mortality wa s highe r fo r th e mal e rat s treate dwit

h 12 5 mg/k g EPTC
. Bod y weight

depression s wer

e note da t 2 5 an d12 5 mg/k g i n th e male s an dfemales
. Cholesterol : N o change s i n tota l cholestero l wer e observe d i n an y treatmen t group .

Pag e 4 0 o f

6 4Organ Weight : O n endocrin e relevance , liver , kidney , pituitary , adrenals , thyroi d

(includin g parathyroids) , testes , an dovarie s were weighe da t 1 2 month s (interi msacrific e o f 1 0 animals/sex/group ) an da t 2 4 months
. N o organ weigh t change s were observed
. Histopathology : O f

endocrin e relevance , histopathologica l examinatio n wa s mad e o n liver , kidney , thyroid , parathyroid , pituitary , adrenal , testes , wit h epididymides , semina

l vesicles , prostate , ovary , uterus , cervix , vagina , bon e an dmammary glands
. N o macroscopi c lesion s were note di n either th e interi mo r

termina l sacrifice
. N o tes t articl e relate dmicroscopi c change s were presen t i n th e 1 2 month interi msacrifice
. N o finding s i n endocrine-relate dorgan s wer e observe di n th e termina l sacrifice
. Finding s o f nerv e an dmuscl e degeneratio n were foun di n th e 2 5 an d12 5 mg/k g treatmen t group s i n male s an dfemales
. NOEL : 5 mg/k g 2 Year Ra t - Dicki e 198

7 - MRI D 00145004/4021500 1 I n thi s chroni c an doncogenicity stud y i n C D rats , EPT C wa s administere di n .th e fee da t 0 , 9,18 , 3 6 o r

7 2 mg/k g (adjuste dfo r

bod y weight ) fo r

tw o years . I n thi s stud y 9 0 rats/sex/grou p wer

e teste dwith interi msacrifice s a t 6 , 12 , an d1 8 months
. Systemi c Toxicity : Earl y decrease s i n body weigh t wer e evident i n al l treatmen t

group s bu t b y wee k 104 , th e bod y weight s o f male s i n th e 9 an d1 8 mg/k g treatmen t group s an d i n female s i n th e 9 mg/k g group were comparabl e t o contro l animals
. Cholesterol : Blood s were evaluate dpre-test , an da t 6 , 12,1 8 an d2 4 months
. N o change s i n total cholestero l were observe di n an y treatmen t group . Organ weight : O f

endocrin e relevance , liver , kidney , teste s an dovarie s were weighe da t 6,12,1 8 an d 2 4 months
. N o change s i n orga n weight s wer e observed
. Histopathology : O f

endocrin e relevance , histopathological examinatio n wa s mad e o n liver , kidney , thyroid , parathyroid , pituitary , adrenal , testes , wit h epididymides , semina l vesicles , prostate , ovary , uterus , cervix , vagina , bon e and'mammary glands
. Macroscopi c finding s wer

e limite dt o th e muscl e an dheart
. N o finding s i n endocrin e relate dorgan s wa s eviden t

i n an y treatmen t

groups . Finding s o f

sciati c nerv e demyelinization , muscl e degeneratio n an dcardiomyopath y were presen t dow n t o an dincludin g 9 mg/kg/day EPTC
. NOEL : <9mg/k g 2 Year Mous e - Goldentha l 197 8 - MRI D 0002210 0 ETP C wa s administere di n th e die t t o CD- I mic e at

dosag e level s o f

5,20 , an d8 0 mg/k g (adjuste dfo r

bodyweight ) fo r

2 4 months
.
Pag e 4 1 o f

6 4Systemi c Toxicity : N o sign s o f systemi c toxicit

y were observed
. Organ weights : O f

endocrin e relevance , liver , kidney , pituitary , adrenals , thyroid , teste s an dovar y were weighe dafte r

5 2 week s an da

t terminatio n a

t 10 4 weeks
. Althoug h there wer e numerou s weight

variation s observe da

t both 1 2 an d2 4 months , the y were sporadi c an dnon-dos e responsive
. I n th e absenc e o f compound-relate dmorphologi c changes , the y were considere dt o b e o f undetermine dbiologica l significance
. Histopathology : O f

endocrin e relevance , histopathological examinatio n wa s mad e o n liver , kidney , thyroid , parathyroid , pituitary , adrenal , testes , wit h epididymides , seminal vesicles , prostate , ovary , uterus , cervix , vagina , bon e an dmammary glands
. Th e histopatholog y o f

treate danimal s wa s simila r t o contro l animals
. 1 8 Month Mous e - Tisde l 1986 - MRI D 0016159 6 ETP C wa s administere di n th e diet to CD- I mic e a

t dosag e level s o f

Q , 200 , 60 0 o r

180 0 pp mfo r 1 8 months
. Systemi c Toxicity : Bod y weigh t reductio n wa s eviden t

i n female s dose d60 0 pp m (slight ) an di n male s an dfemale s receivin g 180 0 ppm . Orga n Weights : N o organ weight s were measured
. Histopathologv : O f

endocrin e relevance , histopathological examinatio n wa s mad e o n liver , kidney , thyroid , parathyroid , pituitary , adrenal , teste s wit h epididymides , semina

l vesicles , prostate , ovary , uterus , cervix , vagina , bon e an d mammary glands
. Th e histopatholog y o f

treate danimal s wa s simila r to contro l animals
. Al l tissue s showe d norma l histopathology
. NOE C 60 0 pp m(9 0 mg/kg ) NOE C Onco : > 180 0 pp m(27 0 mg/kg ) WILDLIF

E Mallar d Reproductio n ~ Temple , Martin , Beavers , an d Jabe r 200 5 —MRI D 4655430 1 A toxicit y an d reproductio n study wa s conducte dwit h group s o f

mallar dduck s (male s an dfemales ) fe dt o EPT C at 240,600 , an d150 0 pp mi n th e die t fo r 2 0 week s beginnin g 1 0 week s prio r

to eg g laying
. There wer

e n o effect s o n mortality o r over t sign s o f toxicity a t 24 0 o r 60 0 ppm . There wer e n o effect s o n reproductiv e parameter s a t 24 0 o r 60 0 ppm . A t

th e 150 0 tes t concentratio n ther

e were mino r

clinical sign s o f

toxicity , transien t

effect s upo n adul t bod y weight

an dfee dconsumptio n an dtreatment-relate deffect s upo n multipl e reproductiv e parameters , includin g eg g productio n an dth e percentag e o f viabl e embryo s Pag e 4 2 o f

6 4(a s apercentag e o f egg s set)
. There were n o effect s o n eg g shel l thickness
. Offsprin g bod y weight s wer

e no t affected
. Quai l Reproductio n ~ Temple , Martin , Beavers , an d Jabe r 200 5 —MRI D 4655430 2 A toxicity an dreproductio n study wa s conducte dwith group s o f quai l (male s an d females ) fe dt o EPI C a

t 240 , 600 , an d150 0 pp mi n th e die t fo r 2 6 week s beginnin g 1 3 week s prio r

t o eg g laying
. Th e author s conclude dthat there wer e n o treatment-relate dmortalities , over t sign s o f toxicity o r

biologicall y meaningfu l treatment-relate deffect s upo n bod y weight o r fee d consumptio n at

an y o f th e concentration s tested
. Additionally , there wer e n o treatmen t - relate deffect s upo n an y o f th e reproductio n parameter s measure dat th e 240 , 60 0 o r

150 0 pp ma.i
. tes t

concentrations
.

Pag e 4 3 o f 6 4

### IX
. Titl e page s fo r OSRIEPT C submissio n

Pag e 4 4 o f 6 4Stud y Title : Two-Generatio n Reproductio n Stud y wit h EPT C i n Rat s Tes t Substance : Phosme t

technical , 98.4 % PP G Dat aRequirement : U S EP A Guidelin e 83. 4 Authors : Kare n MacKenzi e Completio n Date : Marc h 1,198 5 Laboratory : Hazelto n Laboratorie s America , In c

330 1 Kinsman Boulevar d Madison , WI5370 4 Laborator y Repor t No. : 6100-10 8 MRID : 0016159 7 Classification : Acceptabl e

Pag e 4 5 o f 6 4Study Title : A Two-Generatio n Ra t Reproductio n Stud

y wit h Epta mTechnica

l Tes t Substance : Phosme t

technical , 98.6 % (Lo t

#EHC-0048-01 ) Dat aRequirement : U S EP A Guidelin e Authors : J
. R
. Minor Completio n Date : Octobe r 8,198 2 Laboratory : Stauffe r

Chemica l Company Environmenta

l Healt h Cente r Farmington , C T 0603 2 Laborator y Repor t No. : T-1012 3 MRID : 00121284 , (patholog y supplement 40420408 ) Classification : Acceptabl e



# * .Pag e 4 6 o f 6 4Stud y Title : Teratolog y Stud y i n Rabbit s with Epta mTechnica

l Tes t Substance : EPT C technical , Dat aRequirement : U S EP A Guidelin e 83-3 B Authors : P.A
. Gille s Completio n Date : Augus t 12,198 7 Laboratory : Stauffe r

Chemica l Compan y Environmental Healt

h Cente r Farmington , C T 0603 2
Laboratory Repor

t No. : T-1298 2 MRID : 4044230 2 Classification : Acceptabl e

Pag e 4 7 o f 64Stud y Title : Effec t o f EPT C o n Pregnanc y o f

th e Rat Tes t Substance : EPT C technical , (Batc h No
. 51899 6 PPG ) Dat aRequirement : U S EP A Guidelin e 83-3 A Authors : P
. James , J
. Smith , an dD Joh n Completio n Date : Novembe r 6 , 198 5 Laboratory : Huntingdo n Researc h Centre , Ltd. ,

Huntingdon , Cambridgeshire PE1 8 6E S Laboratory Report

No. : PP G 19/85100 2 MRID : 0016159 8
Classification : Acceptabl e

Pag e 4 8 o f 6 4Stud y Title : A Teratolog y Stud y i n Rat s wit h EPTA M Tes t Substance : EPT C technical , (Lo t #CH K 0601 ) Dat aRequirement : U S EP A Guidelin e 83-3 A Authors : M.Neme c Completio n Date : Novembers , 198 3 Laboratory : Wi l Researc h Laboratories , In c

1407 Montgomer

y Townshi p Roa d Ashland , O H 44805-928 1 Laborator y Report No. : WIL-2701 3 MRID : 0013891 9 Classification : Acceptabl e

Pag e 4 9 o f 6 4Stud y Title : Effec t o f EPI C o n Pregnanc y o f

th e Rabbi t Tes t Substance : EPT C technical , (Batc h No
. 51899 6 PPG ) Dat aRequirement : U S EP A Guidelin e 83-3 B Authors : P
. James , J
. Smith , R
. Masters , an dJ Offe r Completio n Date : October 10 , 198 5 Laboratory : Huntingdo n Researc h Centre , Ltd. ,

Huntingdon , Cambridgeshir e PE1 8 6E S Laboratory Report

No. : PP G 1 4 & 18/8560 1 MRID : 0016159 9 Classification : Acceptabl e

Pag e 5 0 o f 6 4Study Title : EPTC : Developmental Neurotoxicity Study i n Rat s

Tes t Substance : EPT C technical , (Lo t #CH K 0601 ) Dat aRequirement : U S EP A Guidelin e OPPT S 870.630 0 Authors : D
. Lee s Completio n Date : Jul y 2,200 4 Laboratory : Centra

l Toxicolog y Laborator

y Alderle y Park , Macclesfiel d Cheshire , U K

SKI 04T J Laboratory Repor

t No. : CTL/RR0926/Regulatory/Report MRID : 46319101,4303970 1 an d4396440 1 Classification : Acceptabl e

Pag e 5 1 o f 6 4Stud y Title : Thirteen-Wee k Subchroni c Study i n Rat s wit h EPT C Tes t Substance : EPT C technical , (PP G Lo t No
. B R83-64 ) Dat aRequirement : U S EPA Guidelin e 82-1 A Authors : M
. Tisde l Completio n Date : September 14 , 198 4 Laboratory : Hazelto n Laboratorie s America , Inc
.

220 1 Kinsma

n Blv d Madison , WI5370 7 Laborator y Repor t No. : 6100-10 5 MRID : 0014465 1 Classification : Acceptabl e

Pag e 5 2 o f 64Study Title : Subchroni c Inhalatio n Toxicity o f Eptami n Rat s Tes t Substance : EPT C technical , Dat aRequirement : U S EP A Guidelin e Authors : J.B
. Scot

t Completio n Date : Marc h 5 , 198 2 Laboratory : Stauffe r

Chemical Compan y Environmental Healt

h Cente r 40 0 Farmingto n Avenu e Farmington , C T 0603 2 Laboratory Report

No. : T-1042 2 MRID : 0015478 4 Classification : Acceptabl e

Pag e 5 3 o f 6 4Study Title : Firs t Revisio n t o EPTC : Subchroni c Neurotoxicit y Stud y i n Rat s Tes t Substance : EPT C technical , 98.4 % (P4/D7534/10 ) Dat aRequirement : U S EP A Guidelin e 82- 7 Authors : D
. J
. Tinsto n Completio n Date : Novembe r 20,199 5 Laboratory : Zenec aCentra l Toxicolog y Laborator y Alderle y Park , Macclesfield , Cheshire , U K Laboratory Repor

t No. : PRO92 9 MRID : 43233090 1 (supplement s 43964401 , 4398301 ) Classification : Acceptabl e

Pag e 5 4 o f 6 4Study Title : A Thre e Mont h Subchroni c Ora

l Dietary Toxicity Study o f EPT C i n Beagl e Dog s Tes t Substance : EPT C technical , 98.4 % B R84- 1 1-9-8 4 Dat aRequirement : U S EP A Guidelin e 82-I B Authors : I
. Dal y Completio n Date : February 15,198 5 Laboratory : Bio/Dynamic s

P O Bo x 4 3 Eas t Millstone , N J 0887 3 Laboratory Report

No. : 83-278 1 MRID : 0015032 7 Classification : Acceptabl e

Pag e 5 5 o f 6 4Stud y Title : One-Yea r Ora l Feedin g Stud y o f

th e Chroni c Toxicity o f

EPT C i n Dog s Tes t Substance : EPT C technical , 98.4 % (Lo t No : 518-996 ) Dat aRequirement : U S EP A Guidelin e 83-I B Authors : B.C.Dicki e Completio n Date : Jun e 10 , 198 6 Laboratory : Hazleto n Laboratorie s America , In c

330 1 Kinsma

n Blv d Madiso n WI , 5370 7 Laborator y Repor t No. : 6100-10 9 MRID : 0016159 5 Classification : Unacceptable , n o NOEL
. I s supplemental fo r assessment

o f other effect s

Pag e 5 6 o f

6 4Study Title : One-Yea r Ora l Toxicit y Study wit

h Epta mTechnica

l i n Dogs
. Tes t Substance : EPT C technical , 97.6 % (WC RNo : 492 1 -4-25 ) Dat aRequirement : U S EP A Guidelin e 83-1 B Authors : G.L
. Spragu e an dD.O.N
. Taylo r Completio n Date : September 8 , 198 7 Laboratory : Stauffe r

Chemica l Company 40 0 Farmingto n Avenu e Farmington , C T 0603 2 Laborator y Repor t No. : T-1272 3 MRID : 4044230 1 Classification : Acceptabl e

Pag e 5 7 o f 6 4Stud

y Title : 54-Week

Feedin g Stud

y i n Rats : EptamTechnical Tes t Substance : EPT C technical , 98.0 % (Lo t No : 3905-3 5 Stauffer ) Dat aRequirement : U S EP A Guidelin e 83-1 A Authors : J
. Trutte r Completio n Date : September 18,197 8 Laboratory : Hazleto n Laboratorie s America , In c

330 1 Kinsman Blv d Madiso n WI , 5370 7 Laborator y Report No. : 132-13 1 MRID : 0002210 1 Classification : Unknow n

Pag e 5 8 o f 6 4Study Title : Tw o Yea r Oral Toxicity/Oncogenicity Study i n Rat s Tes t Substance : EPT C technical , i Dat aRequirement : U S EP A Guidelin e 83-1 A Authors : M
. Warne r (mai n report ) E
. Goldenthal (addendum ) Completio n Date : September 30 , 198 3 mai n report , Ma y 198 5 addendu m Laboratory : International Researc h an dDevelopmen t Corporatio n (IRDC ) Mattawan , M I 4907 1 Laborator y Report No. : 153-10 0 MRID : 00145004,0014631 1 addendu m Classification : Acceptabl e wit h histopatholog y addendu m(T-1001 ) Apri l 23,198 5

Pag e 5 9 o f

6 4

### Study Title : Two-Yea r Oral Feedin g Stud y o f

th e Oncogenicit

y an dChroni c Toxicit y o f EPT C i n Rat s Tes t Substance : EPT C technical , 98.4 % (Lo t No
. 518-99 6 PPG ) Dat aRequirement : U S EP A Guidelin e 83-1 A Authors : B.C.Dicki e Completio n Date : Marc h 20,198 7 Laboratory : Hazelto n Laboratorie s America , In c

330 1 Kinsman Blv d Madison , W I 5370 7 Laboratory Repor

t No. : HLA6100-10 6 MRID : 4021500 1 Classification : Acceptabl e fo r oncogenicity
. Fo r

th e chroni c portio n o f

th e study , n o NOE L wa s establishe dan dwa s upgrade dt o acceptabl e wit h anothe r toxicity study that establishe daNOEL
.

Pag e 6 0 o f 6 4Study Title : Lifetim e Ora l Study i n Mic e Tes t Substance : EPT C technical , (Lo t No
. 3905-3 5 Stauffer ) Dat aRequirement : U S EP A Guideline : Pr

e 198 2 (83-2B ) Authors : E
. Goldenthal Completio n Date : December 22 , 197 8 Laboratory : International Researc h an d Developmen t Corporatio n (IRDC ) Mattawan , M I 4907 1 Laborator y Repor t No. : 153-01 1 MRID : 0002210 0 Classification : Unknow n

Pag e 6 1 o f 64Stud y Title : Oncogenicit y Study i n Mic e with EPT C Tes t Substance : EPT C "technical , 98.4 % (Lo t No
. 518-99 6 PPG ) Dat aRequirement : U S EP A Guidelin e 83-2 B Authors : M
. Tisde l Completio n Date : Ma

y 15 , 198 6 Laboratory : Hazelto n Laboratorie s America , In c

330 1 Kinsma

n Blv d Madison , WI5370 7 Laborator y Report No. : 6100-10 4 MRID : 0016159 6 Classification : Acceptabl e

Pag e 6 2 o f 6 4

### Stud y Title : EPIC : A Reproductio n Stud y wit h th e Mallard Tes t Substance : EPT C technical , 98.1 % (Batc h FL-02131 7 Gowan ) Dat aRequirement : U S EP A Guidelin e OPPT S 850.230 0 Authors : Temple , D. ; Martin , K. ; Beavers , J , Jaber , M
. Completio n Date : Ma

y 19 , 200 5 Laboratory : Wildlif

e International , Ltd
. 859 8 Commerc e Driv e Easton,MD2160 1 Laboratory Repor

t No. : Projec t

Number : 334/11 2 MRID : 4655430 1 Classification : Acceptabl e

Pag e 6 3 o f 6 4Stud y Title : EPIC : A Reproductio n Stud y wit h th e Northern Bobwhit e Tes t Substance : EPT C technical , 98.1 % (Batc h FL-02131 7 Gowan ) Dat aRequirement : U S EP A Guidelin e OPPT S 850.230 0 Authors : Temple , D. , Martin , K. , Beavers , J
. an dJaber , M
. Completio n Date : Ma

y 19 , 200 5 Laboratory : Wildlif

e International , Ltd
. 859 8 Commerc e Driv e Easton,MD2160 1 Laborator y Repor t No. : Projec t

Number : 334/11 1 MRID : 4655430 2 Classification : Acceptabl e

Pag e 6 4 o f 6 4