p. 1 CBI C Contro l Numbe r 

# 35742 1
P.O . Bo x331 , Millwood , V A 2264 6 (540 ) 837-160 2

Decembe r 17,201 3 B Y HAN D Documen t Contro l Offic e Offic e o f Pollutio n Preventio

n an dToxic s Roo m6428 U.S . Environmenta

l Protection Agenc

y 120 0 PennsylvaniaAve. , N.W . Washington , D C 2046

0 Re : Testin

g Consen t Orde r fo r Ethylen e Dichloride : Reques t fo r Modificatio n o f

Enforceabl

e Consen t Agreemen t an dAmendmen

t t o Stud y Pla n (Docke t No . OPPT

2003-0010

) Dea r Sirs : Th e HA P Tas k Forc e request s amodificatio n o f

th e Enforceabl

e Consen t Agreemen

t fo r Ethylen e Dichloride ("EDC") , 68 Fed . Reg . 3312 5 (Jun e 3 , 2003) , a

s amended

, 7 4 Fed . Reg . 3619 6 (Jul

y 22 , 2009) , a

s furthe r amende db y Addendu

mModificatio n providedb y lette r date dNovembe

r 23 , 201 1 fro mMari aJ . Doa, an da s furthe r amende db y Addendu

m Modificatio n providedb

y lette r date dJul y 22 , 201 3 fro mMari aJ . Doa(th e "ECA") . Si

x copies o f thi s submissio

n ar e enclosed . Pursuan t t o th e ECA an dth e Stud y Pla n fo r a n extende done-generatio

n drinkin g wate r reproductive toxicit

y stud y o f ethylen e dichlorid

e i n rats , submitte

dJul y 2 , 2012 , an

d amende dJul y 16 , 2012 , Augus

t 7 , 2012 , Ma

y 24 , 2013 , an

dJul y 24 , 2013 , th

e experimenta

l star t dat e wa s Septembe

r 1 , 2013 , an

dth e fina l report, unles s asecon dgeneratio

n stud y wa s triggered , wa

s du e Septembe

r 15 , 2014 . Th e stud y bega n o n schedule, bu

t wa s terminate

do n Novembe

r 14 , 201 3 afte

r th e Tas k Forc e wa s notifie dtha

t th e numbe r o f litter s fro mth

e F 0generatio

n \ * i s lowe r tha n expecte di n control s a

s wel l a s i n th e thre e treate dgroups . Althoughth

e e l ec t wa s not dose
related , th e numbe r o f litter s wa s insufficient

t o continu e th e study . WIL1 . i s agree

dt o conduc t astud y t o determin

e th e caus e o f th e lo w litter

survivability , a

s describe di n th e 

# Tas k Forc e 7 201 3 C D C o 

## § o a* . o



## DE C 

## 1 1 201 3p . 2

Documen t Contro l Offic e Decembe r 17,201 3 Pag e 2 enclose dsummary . Th

e variables WI Lwil l b

e investigating are : (1 ) Harla n Tekla d2016C M vs . PM I LabDie

t 5002 : t o asses s th e effec t o f th e Harla n low-phytoestroge

n die t o n pu p viability . (2 ) Harla n Tekla d2016C M (Meal) vs . Harla

n Tekla d2016C M (Pellets) : t

o asses s whethe r th e particle siz

e o f Harla n low-phytoestroge

n die t ha s a n effec t o n pu p viability . (3 ) Harla n Tekla d2016C M vs . PM I Casei

n LabDie t 5k96 : t o asses s anothe r low
phytoestroge

n die t a s apossibl e candidat e fo r us e o n reproductiv

e toxicit y studies tha

t requir e low-phytoestroge

n die t pe r guideline . (4 ) Aspe n Beddin g vs . Standar

dCor n Co b beddin g (Be dO'Cobs) : t

o asses s th e effect , i f any , o f th e us e o f Aspe n beddin g fo r reproductiv

e toxicit y studies wher

e th e guideline s discourag

e us e o f corn-co b beddin g du e t o its endocrin

e disruption potential . (5 ) Glass bottle s (Teflo n capped ) vs . Automatic Wate

r Syste m(Lixits) : t

o asses s th e effect , i f any, of th e us e of wate r bottles . Th e schedul e i s a s follows : Anima l Receipt : 0 7 Januar y 201 4 Firs t AnticipatedG

D 0 : 2 1 Januar

y 201 4 Firs t AnticipatedL D 0 : 1 1 Februar y 201 4 Firs t AnticipatedLD10 : 2 1 Februar y 201 4 WI Lanticipate s tha

t i t wil l b e abl e t o provid e complet e dat afro mthi s stud

y b y Februar y 28 , 2014 . I nlight o f thi s unfortunat

e an dunforeseeabl

e development

, th e Tas k Forc e seek s EP A approva l o f amodificatio n o f

th e EC A an damendmen

t t o th e Stud y Pla n t o provid e fo r a n experimenta

l star t dat e fo r th e extende done-generatio

n drinkin g wate

r reproductiv

e toxicit y stud y o f Marc h31 , 201 4 an

dafina l repor

t deadlin e (unles s asecon

dgeneratio

n stud y i s triggered ) o f Apri l 14 , 2015 . Th

e Tas k Forc e also seek

s modificatio n o f

th e ECA t o provid e ane w deadlin e o f Jul y 14 , 201 5 fo r

route-to-rout

e extrapolatio

n o f th e dose-respons

e dat a fro mthi s an

dextan t studies .Documen t Contro l Offic e Decembe r 17 , 201 3 Pag e 3 W e loo k forwar d t o hearin g fro m EPA . Sincerely

,
Pete rE . Voytek

, Ph.D . Manage r Enclosur e cc : Joh

n E . Schaeffe

r W . Caffe y Norman

, Esq .

4819-6034-2036.1 .

### ||WIL RESEARC H P- 4 Page : 1 o f 1 A n Investigativ e Stud y t o Determin e Possibl e Cause s fo r Lo wNeonata l Surviva l o n WIL-41700 5 Compliance : non-GL P Grou p Diet Variable s Beddin g Wate r No . o f Female s 1 Harla n 2016C M (Meal ) Aspe n Be d Glas s Bottle s 1 0 2 Harla n 2016CM(Meal ) Be d O'Cob s Glas s Bottle s 1 0 3 Harla n 2016C M (Pellet ) Aspe n Be d Glas s Bottle s 1 0 4 PM I LabDie t 500 2 (Meal ) Aspe n Be d Glas s Bottle s 1 0 5 PM I LabDie t 500 2 (Meal ) Be d O'Cob s Glas s Bottle s 1 0 6 PM I Casei n Diet 5k9 6 (Meal ) Aspe n Be d Glas s Bottle s 1 0 7 Harla n 2016C M (Meal ) Aspe n Be d Lixit s 1 0 Objective : Animals : Groups : Viabilit yObservations : Clinica l Observations ; Body Weights: Food Consumption: Wate rConsumption : F 0Assessments : F 1 Assessments : Qualit yAssurance : Reports : T o determin e possibl e cause s fo rlo wneonata l surviva l o n WIL-417005 . Sexuall yMatur e Adul t Spragu e Dawle yFemal e Rat s 7 0 female s o n study , 8 0 female s ordered . Untreate d sexuall ymatur e male s o f th e sam e strai n an d sourc e wil l b e use d t o induc e pregnancies . 1 contro l grou p (mimi cWIL-417005 ) an d 6 Variable-Controlle d groups . Twic e dail yobservation s fo rmoribundit yan d mortality . Onc e dail yan d al l female s observe d 3- 4 time s dail ydurin g th e perio d o f anticipate d parturitio n an d durin g th e firs t 1 0 day s o f neonata l life . Twic e weekl yfro m receip t throug h LD10 . Twic e weekl yfro m receip t throug h LD10 . Stoc k mal e rat s wil l receiv e th e diet s specifie d fo rth e on-stud yfemale s durin g th e matin g period . Twic e weekl yfro m receip t throug h LD10 . Gestatio n lengths , liv e litte rsize ; offsprin g se xratio . Evaluatio n o f physica l abnormalities ; postnata l survival ; bod yweight s throug h PN D 10 . Th e stud ywil l b e no t b e monitore d b yth e Qualit yAssuranc e Unit . Asummar yrepor t wil l b e generate d an d archive d accordin g t o WI L Research' s SOP s fo rin-hous e studies . Variable s Assessed : (1 ) Harla n Tekla d 2016C/W vs . PM I LabDie t 5002 : t o asses s th e effec t o f th e Harla n low-phytoestroge n die t o n pu p viability . (2) Harlan Teklad 2016CM

(Meal) vs. Harlan

Teklad 2016CM

(Pellets):

to assess whether

the particle size of Harlan low-phytoestrogen

diet has an effect on pup viability. (3 ) Harla n Tekla d 2016CMvs . PM I Casei n LabDie t 5k96 : t o asses s anothe rlow-phytoestroge n die t a s a possibl e candidat e fo rus e o n reproductio n studie s tha t requir e low-phytoestroge n die t pe rguideline . (4 ) Aspe n Beddin g vs . Standar d Cor n Co b beddin g (Be d O'Cobs) : t o asses s th e effect , i f any , o f th e us e o f Aspe n beddin g fo rreproductio n studie s wher e th e guideline s discourag e us e o f corn-co b beddin g du e t o it s endocrin e disruptiv e potential . (5 ) Glas s bottle s (Teflo n capped ) vs . Automati cWate rSyste m (Lixits) : t o asses s th e effec t i f an yo f th e us e o f wate rbottle s o n thi s study . Grou p 1 woul d b e treate d exactl yth e sam e a s al l group s o n WIL-417005 . Th e remainin g 6 group s includ e on e (o rtwo ) variable s t o hel p identif ya possibl e caus e fo rlo wpu p viability , i f i t wa s relate d t o thes e variables . CONFIDENTIA L W e hav e listenin g dow n t o a science .