DAT A TRANSMITTA L DOCUMEN T Oxamy l Nam e ari dAddres s o f

Submitter : E.I . DuPon t

d e Nemour s an dCompan y 109 0 Elkto n Roa d P.O . Bo x 3 0 Newark ; D E 1971 4 Phon e (302) 366-527 4 Regulator y Actio n i n Suppor t o f Whic h thi s Packag e i s Submitted : Informatio n Submitte di n Support o f continue dregistratio n o f Oxamy l Produc t Name : DuPont TM Oxamyl ® Technica l 4 2 Insecticide/Nematicid e EP A Registratio n No : 352-40 0 Transmitta l Date : Februar y 19 , 200 9 Lis t o f Submitte dStudies : 

# o l

Dat a Requiremen t N A. ' Do c Numbe r

DuPont-2982 7 Stud y Titl e

Oxamyl : Othe r

Scientificall y Relevan t Informatio n Pertainin g T o EP A Tes t Order EDSP

- 10 3 8 0 1-6 3 MRI D

Submitter : 

## WUUM . Patrici ap . Devin e U.S . Produc t

Registratio n Manage r Compan y Name : E.I . d u Pon t d e Nemour s an dCompan y Compan y Contact : Patrici aG . Devin e Date :

• • L •«••• -DuPont-2982 7



### TRAD E SECRE T Position Pape

r Title 

### OXAMYL : OTHE R SCIENTIFICALLYRELEVAN TINFORMATIO N PERTAININ G T O EP ATES TORDE R EDSP- 1 0380 1 -6 3 Author s Kari n S . Bentley , Ph.D . Kristi n E . Brugger , Ph.D . Test Guidelin e No t Applicabl e Dat e Complete d February 18 , 201 0 Applicant/Sponso r E . I . du Pon t

d e Nemour s an dCompan y Wilmington , Delawar e 1989 8 U.S.A . Author s Locatio n DuPon t Cro p Protectio n Stin e Haskel l Researc hCente r 1 09 0 Elkto n Roa d Newark , D E 1971 1 DuPon t Projec t Identificatio n . DuPont-2982 7 - ' • • .

.Pag e 1 o f

3 9DuPont-2982 7 

## STATEMENT S O F CONFIDENTIALITY Th e Followin g Statemen t Applie s T o Countrie s Othe r Tha n Th e Unite dState s o f America : Thi s repor t i s th e property o f

E . I . du Pon t

d e Nemour s an dCompan y an dcontain s confidential an dtrad e secret information . Excep t

a s require db y law , thi s report shoul dno t b e partiall y o r

full y (i ) photocopie do r

release di n an y for mt o an outsid e party withou t

th e prior writte n consen

t o f E . I , d u Pont d e Nemour s an dCompany o r it s affiliates , o r

(ii ) use db y aregistratio n authority t o support th e registratio n o f

an y other product withou t th e prio r writte n consent

o f E . I . du Pon t

d e Nemour s an d Compan y o r

it s affiliates .
Th e Followin g Statemen t Applie s T o Th e Unite dState s o f America : 

## STATEMEN TO F N o DAT

ACONFIDENTIALIT

Y N o clai mo f

confidentiality i s mad e fo r an y informatio n containe di n thi s stud y o n th e basi s o f it s fallin g withi n th e scop e o f FIFRA Sectio n 10(d)(l)(A) , (B) , o r (C) . Company E . I . du Pon t

d e Nemour s an dCompan y Company Agent : U.S . Produc t

Registratio n Manager



### • • • • Date ' ' ••••••» • •! • W e hav e submitte dthi s materia l t o th e Unite dState s Environmental I*t»^e«tion * * * * Agenc y specificall y under th e provision s containe di n FIFR A a s amefidS dand , . . hereby , consen t

t o us e an ddisclosure o f

thi s material b y EP A accordin g t o FIFR&.*** 0 Notwithstandin g th e wordin g o f ou r markin g TRAD E SECRET , thi s marking , bj*«»» , itself , convey s n o supplemental claim s o f confidentiality unde r

FIFRA Section s VQ$ ) o r 10(b) . I n submittin g thi s material t o EP A accordin g t o metho dan dforma t requirement s containe di n P RNotic e 86-5 , w e d o no t waiv e an y protectio n o r

righ t involvin g thi s materia l tha t woul dhav e bee n claime db y th e Compan y i f thi s materia l ha dno t bee n submitte dt o th e EPA , no r d o w e waiv e an y protectio n o r righ t provide d unde r FIFR A Sectio n 10(g) .DuPont-2982 7



### GOO D LABORATOR YPRACTIC E COMPLIANC E STATEMEN T U.S . EP A Goo dLaboratory Practic e Standard s (4 0 CF RPart 160 ) d o no t

appl y t o th e curren t document . Applicant/Sponso

r E . I . du Pon t

d e Nemour s an dCompan y Wilmington , Delaware 1989 8 U.S.A . Autho r Kari n S . Bentley , Ph.D . Senior Regulatory Toxicologis t Dat e Applicant/Sponsor DuPon t Representativ e DateDuPont-2982 7



### SIGNATUR E OXAMYL : OTHE R SCIENTIFICALLYRELEVAN TINFORMATIO N PERTAININ G T O EP ATES TORDE R EDSP-10380 1 -6 3 Position Paper

by : KarmS . Bentley , Ph.D . f f . Date (/ Senior Regulatory Toxicologis t

Kristi n E . Brugger , Ph . Senior Regulatory-Ecotoxicologis t Date Completed : February 18,201 0 Applicant/Sponsor : E . I . d u Pon t de Nemour s an dCompany Wilmington , Delawar e 1989 8 U.S.A .

### DuPont-2982 7



### TABL E O F CONTENT S Titl e Pag e ....* . 1 Statement s o f

Confidentialit y 2 Goo dLaboratory Practic e Complianc e Statemen t 3 Signatur e ' . .. 4 Tabl e o f Content s 5 1. 0 Summary ' . 6 2. 0 Introductio n an dBackgroun d6 2. 1 Othe r Scientificall y Relevan t

Informatio n (OSPJ ) 8 2. 2 Toxicologica

l Profil e o f

Oxamy l 9 3. 0 Summar y o f

Relevan t Mammalia n Toxicolog y Studie s 1 1 3. 1 Discussio n o f

studie s supporting " registratio n 1 1 3. 2 Discussio n o f

availabl e informatio n i n th e ope n literatur e 2 5 3.2. 1 Summary o f

th e Potentia l t o Modulat e Estroge n o r Androge n Recepto r Functio n ..2 5 3.2. 2 Summary o f

th e Potentia l o f

Methomy l Modulat e Placenta l Aromatas e Activit y In vitr o ' . '.....2 1 3. 3 Availabl e Informatio n fro mth e EP A ToxCast TM Projec t ..2 7 4. 0 Summar y o f

Relevan t Ecotoxicolog y Studie s 2 8 4. 1 Discussio n o f

studie s supportin g registratio n !..2 8 4. 2 Discussio n o f

availabl e informatio n i n th e ope n literatur e : .3 2 5. 0 DuPon t

Positio n an dConclusion s 3 2 5. 1 Potentia l fo r

Oxamy l t o Interac t

wit hth e Endocrin e Syste m3 2 5. 2 Functionall y Equivalen t Informatio n Fulfillin g th e EDS P Tie r IBatter y 3 3 5. 3 Overal l Conclusio n 3 5 6. 0 Reference s 3 6 

### TABLE S Tabl e 1 Cite dOxamy l Toxicit y Studie s Supportin g Registratio n 3 8 Tabl e 2 Endocrin e Tissue s Evaluate di n Mammalia n Toxicolog y Studie s

Conducte dwit hOxamy l ..3 9

### DuPont-2982 7



### OXAMYL : OTHE R SCIENTIFICALLYRELEVAN TINFORMATIO N PERTAININ G T O EP ATES TORDE R EDSP-10380 1 -6 3 1. 0 SUMMAR Y

Thi s documen t

i s i n respons e t o EP A Tes t Orde r EDSP-103801-6 3 requirin g DuPon t t o tes t th e pesticid e activ e ingredien t Oxamy l (CAS #23135-22-0 ) i n th e Tie r 1 screenin g batter y o f

th e Endocrin e Disruptio n Screenin g Progra m(EDSP) . DuPon t i s supplyin g scientificall y relevan t informatio n whic hfulfill s th e purpos e o f th e Tie r 1 EDS P battery - t o asses s th e potentia l t o interac t wit hestrogen , androge n an dthyroi d hormon e processes . Oxamy l ha s bee n evaluate di n alarg e numbe r o f mammalia n toxicolog y an decotoxicolog y studie s supportin g th e registratio n o f thi s produc t

whic h hav e assesse dpotentia l subchronic , chronic , reproductiv e o r developmenta l toxicity i n rats , mice , dogs , rabbits , fish , o r birds . Severa l studie s fro mth e ope n literatur e hav e reporte dresult s fo r

th e testin g o f

oxamy l i n estroge n an dandroge n transactivatio n assays , an doxamy l ha s bee n include dfo r testin g i n th e man y endocrine-relate di n vitr o test s i n th e EP A ToxCast TM project . Th e result s overwhelmingl y demonstrat e th e lac k o f interactio n b y oxamy l wit hestrogen , androgen , o r

thyroid . Therefore , furthe r assessmen t

o f oxamy l i n th e Tie r

1 EDS P

.. . screenin g assay s i s no t warranted . 

## 2. 0 INTRODUCTIONAN

D BACKGROUN D I n Augus t 1996 , Congres s passe dth e Foo dQuality Protectio n Ac t tha t require dth e U S Environmenta l Protectio n Agenc y (EPA ) "t o develo p ascreenin g progra musin g appropriat e validate dtes t

system s an dothe r

scientificall y relevan t

informatio n t o determin e whethe r

certai n substance s ma y hav e a n effec t i n human s tha t

i s similar t o a n effec t produce db y anaturall y occurrin g estrogen , o r suc hothe r

effect s a s [EPA ] ma y designate" . EP A subsequently initiate dit s Endocrin e Disrupte r Screenin g Programi n 199 8 base do n th e recommendation s o f th e Agency' s Endocrin e Disruptio n Screenin g an dTestin g Advisor y Committe e (EDSTAC) , whic hwa s compose do f

stakeholder s representin g industry , governmenta l agencies , researc h scientists , an denvironmenta l an dpubli c healthgroups . A two-tiere dapproac htha t addresse s potentia l huma n an decological effect s an dexamine deffect s o n estrogen- , androgen- , an dthyroi dhormone-relate dprocesse s wa s recommended . Th e purpos e . o f Tie r 1 "screening " i s t o identif y substance s tha t

hav e th e "potential " t o interac t wit hestrogen , androgen , o r thyroi dhormon e system s usin g abattery o f assays . Th e purpos e o f

Tie r 2 "tests " i s t o identif

y an destablis h"dose-respons e relationships " fo r an y advers e effect s tha t

migh t resul t fro mth e interaction s identifie di n th e Tie r 1 assays . Ove r

th e nex t year s th e Agenc y move dforwar dt o develo p an dvalidat e a numbe r o f Tie r I assays . I n Octobe r

2009 , EP A announce dth e availabilit y o f th e fina l Tie r 1 screenin g battery an dth e relate dtes t guidelines . Th e fina l Tie r I endocrin e screenin g batter y i s compose do f th e followin g assays :DuPont-2982 7 In vitr o assays : • estroge n recepto r

bindin g - an in vitr o mode l whic hassesse s the abilit y of a substanc e t o interac t

withth e estroge n receptor s i n rat uterin e cytoso l • androge n recepto r

bindin g - a n i n vitr o mode l whic hassesse s th e ability o f a substanc e t o interac t

wit hth e androge n receptor s i n ra t prostat e cytoso l • estroge n transcriptiona l activatio n (HeLa990 3 cells ) - a n assay tha t assesse s th e bindin g o f

achemica l t o th e estroge n recepto r an dth e subsequen t

downstrea m transcriptio n o f

areporte r gen e produc t • aromatas e - a n i n vitr o mode l t o identif y substance s tha t

ma y inhibi t

th e catalyti c activit y o f th e enzym e (CYP19 ) responsibl e fo r th e conversio n o f

androgen s t o estrogen s • steroidogenesi s (H295 Rcells ) - a n i n vitr o mode l intende dt o identif y substance s tha t interfer e wit hsteroi dhormon e synthesi s resultin g in.testosteron e an d

. estradiol/estron e productio n I n viv o mammalia n assays : • ~ rat uterotrophi c - a n i n viv o model t o asses s th e ability o f asubstanc e t o elici t uterin e weigh t

change s consisten t

wit hagonist s o r

antagonist s o f

natura l estrogen . • ra t Hershberge r

- a n i n viv o mode l t o asses s th e abilit y o f asubstanc e t o elici t mal e reproductiv e organ weigh t change s consisten t

wit handroge n agonist s an d antagonist s an d5a-reductas e inhibitor s • femal e ra t

puberta l - a n assa y t o identif y substance s that

interac t wit hth e endocrin e syste mb y assessin g endpoint s associate dwit hpuberta l developmen t an dthyroi dfunctio n i n femal e animal s • mal e ra t

puberta l - a n assay t o identif y substance s tha t

interac t withth e endocrin e syste mb y assessin g endpoint s associate dwithpuberta l developmen t an dthyroi d functio n i n mal e animal s In viv o wildlif

e assays : • Amphibia n metamorphosi s - ageneralize dvertebrat e mode l t o identif y substance s whic hinterfer e wit hth e norma l functio n o f th e hypothalamic

pituitary-thyroi d(HPT ) axi s • Fis hshort-termreproductio n i n fathea dminno w - ashort-termassay measurin g reproductiv e fitnes s an dbiochemica l endpoint s tha t reflec t effect s associate dwith th e disturbanc e o f

th e hypothalamus-pituitary-gonada l (HPG ) axi s I n Apri l 2009 , EP A publishe dafina l lis t o f substance s t o b e initiall y teste di n th e Tie r 1 screenin g batter y (Federa l Registe r 74 ; 17579) . Beginnin g Octobe r 20.09 , EP A ha s issue dtes t

order s t o registrant s o f

th e listed , substance s whic hmandat e testin g unde r th e EDSP . A tes t

orde r fo r Oxamy l ha s bee n receive db y DuPont , Order/DC I # EDSP-103801-63 , issue do n November12 , 2009 . .DuPont-2982 7

2. 1 Othe r

Scientifically Relevan t

Informatio n (OSRI

) EP A ha s provide dregistrant s a n opportunit y t o eithe r submi t o r cit e existin g dat atha t ma y fulfil l i n part

o r completel y th e requirement s o f th e Tie r 1 EDS P screenin g batter y (EPA' s Approac hfo r Considerin g OSRI unde r

th e EDSP , Marc h26 , 2009) . EP A ha s provide dth e followin g understandin g o f wha t constitute s OSRI : "Other scientificall y relevan t

informatio n " i s informatio n tha t inform s th e determinatio n a s t o whethe r th e substanc e may hav e an effec t tha t i s similar t o an effec t produce db y asubstanc e tha t interact s wit hth e estrogen , androgen , and/o r thyroi dhormona l system s (e.g. , informatio n tha t identifie s substance s a s havin g th e potentia l t o interac t wit hestrogen , androgen , and/o r thyroi d system(s) ; informatio n demonstratin g whethe r substance s hav e a n effec t o n th e functionin g o f

th e endocrin e system) . OSR I may eithe r

b e functionall y equivalen t t o informatio n obtaine dfro mth e Tie r 1 assay s - tha t

is , dat afro massay s tha t perfor mth e sam e functio n a s EDS P Tie r 1 assay s —o r

may includ e dat atha t provid e informatio n o n apotentia l consequenc e o r effec t tha t coul db e du e t o effect s o n th e estrogen , androgen , o r thyroi dsystems . EP A furthe r

state s tha t

th e followin g type s o f

studie s ma y contai n informatio n tha t th e Agenc y woul dlikel y regar da s scientificall y relevan t information : studie s tha t correspon dt o assay s i n Tie r 1 an d2 ; metabolis mstudies ; o r othe r vertebrat e o r invertebrat e toxicit y studies , including , bu t no t limite dto , developmenta l toxicit y

- tests , carcinogenicit y tests , toxicogenomi c data , an dreproductiv e toxicit y tests . EP A goe s o n t o indicat e tha t othe r type s o f studie s may als o b e considere d scientificall y relevant . Fo r instance , testin g conducte dunde r 4 0 CF RPart

15 8 data ' requirement s t o support

pesticid e registratio n ma y b e considered . Judgment s b y EP A abou t whethe r th e OSRI satisfie s al l o r

part o f th e Tie r 1 Tes t Orde r wil l base do n th e "weight o f th e evidence " fro mal l relevan t informatio n availabl e takin g int o accoun t : th e datase t

a s awhol e fo r

th e subjec t

chemical . O n Octobe r

2' , 200 9 th e Whit e Hous e Offic e o f Managemen t

an dBudge t

(OMB ) approve dth e pendin g Informatio n Collectio n Reques t (ICR ) require dfo r

th e implementatio n o f

th e initia l Tie r

1 screenin g unde r

th e EDSP . I n approvin g th e initiatio n o f

thi s program , OM B urge dEP A t o "promote an dencourage " tes t orde r recipient s t o submi t

"functionall y equivalent " dat ai n lie u o f "performin g al l o r

som e o f th e Tie r 1 assays " an dt o accep t

existin g FIFRA tes t

guidelin e dat a"t o th e greates t exten t possible" . A s part o f th e 4 0 CF RPart

15 8 dat arequirement s fo r registratio n unde r

FIFR A Sectio n 3 , pesticid e activ e ingredient s ar e require dt o b e evaluate di n abroa drang e o f mammalia n toxicolog y studie s includin g test s fo r acute , subchronic , an dchroni c toxicity , mutagenicity , acut e an dsubchroni c neurotoxicity , reproductiv e an d developmenta l toxicity , an dcarcinogenicity an di n avariet y o f wildlif e studie s includin g test s fo r

toxicii y i n fis han deffect s o n avia n reproduction . Man y o f thes e studie s provid e amean s fo r assessin g th e potentia l o f asubstanc e t o alte r

endocrin e

### DuPont-2982 7 functio n (Steven s e t

al , 1997 ; ECETOC , 1996) . O f particula r valu e i n th e assessmen t

o f advers e endocrine-mediate deffect s i n th e intac t organis mar e th e followin g type s o f

regulatory studies : .

• Subchroni c toxicity studie s i n rats , mice , an ddos s - Thes e studie s ar e capabl e o f detectin g hormonall y mediate dmacroscopi c andmicroscopi c change s in morpholog y and/o r siz e o f th e pituitary , thyroid , adrenals , uterus , ovary , mammar y gland , testes , epididymis , an dothe r

se x accessory organ s a s aresul t o f repeate dtreatment . Both DBS

- an dDDT-induce dincrease s i n uterin e weigh t wer e observe di n thi s typ e o f stud y (Buri n e t

al , 1993) . • Prenata l developmenta l toxicity studie s i n rat s an drabbit s - Thes e studie s examin e hormonall y induce deffect s suc ha s abortion , resorption , o r prematur e delivery , abnormalitie s i n reproductiv e development , an dmasculinizatio n o r feminizatio n o f

femal e an dmal e fetuses , respectively . Substance s suc ha s th e phytoestroge n coumestero l an dth e anti-androge n cyproteron e acetat e wer e detecte d i n thi s typ e o f

stud y (va n Ravenzwaay , 1992) . • Multiseneratio n reproductio n stud y i n rat s - Th e multigeneratio n reproductio n stud y is recommende dby EDSTA C (1998 ) as the definitiv e Tie r 2 stud y for

the assessmen t

o f advers e effect s o f

hormonall y activ e substance s i n th e intac t animal . Therefore , thi s stud y play s apivota l rol e i n th e determinatio n o f advers e endocrin e effect s relativ e t o reproduction , growth , an ddevelopment . Thes e studie s ar e capabl e o f detectin g hormonall y induce deffect s coverin g every phas e o f developmen t

an d reproductio n includin g behavior , maintenanc e o f pregnancy , gestatio n length , difficul t o r prolonge dparturition , fertility , se x rati o o f offspring , feminizatio n o r masculinizatio n o f

offspring , numbe r

o f pups , stil l births , an dgros s an dmicroscopi c patholog y o f

th e vagina , uterus , ovaries , testes , epididymis , semina l vesicles , prostate , etc . Procyrnidone-induce dhypospadia s an dvinclozolin-induce dfeminizatio n o f mal e pup s wer e identifie di n astud y o f thi s typ e (van Ravenzwaay , 1992) . • Combine dlifetim e chroni c toxicity/oncosenicity studie s i n rat s an dmic e an d chroni c toxicity studie s i n dog s —Thes e studie s includ e extensiv e histopatholog y o f primar y endocrin e tissue s an dsecondary accessory organ s includin g pituitary , thyroid , adrenals , ovary , uterus , vagina , mammar y gland , testes , epididymis , prostate , an dsemina l vesicles . Weak hormonall y mediate deffect s whic hresul t i n tumor s o f endocrin e tissues , suc ha s testicular tumor s (Hseu he t

al. , 1977 ) o r

mammar y glan d tumor s (Grugg s e t

al. , 1983) , ar e ofte n detecte di n thes e studies . 2. 2 Toxicologica

l Profil e of

Oxamy l Th e mammalia n toxicit y o f oxamy l i s wel l characterize dbase do n th e result s o f a n extensiv e batter y o f

toxicolog y studie s conducte di n rats , mice , dogs , rabbit s an d Guine apig s an dwel l a s th e result s o f anumbe r o f i n vitr o assays . Th e primary toxicologica l effec t

o f thi s substanc e i n mammalia n specie s i s th e inhibitio n o f acetylcholinesters e i n th e nervou s system , whic hi s rapidl y reversible . A s aresul t oxamy l demonstrate s hig hacut e toxicity b y th e oral , ocular , an dinhalatio n routes . Th e primar y symptom s ar e thos e associate dwit hcholinesteras e inhibition . N o cumulativ e effect s o n th e nervou s syste moccu r wit hrepeate dexposure .

### DuPont-2982 7 Oxamy l doe s no t

induc e tumor s i n rat s o r

mic e an di s classifie db y EP A a s Grou p E (no t likel y t o b e carcinogeni c t o humans) . Oxamy l i s no t mutageni c an dha s produce dnegativ e result s i n abatter y genotoxicit y studies . Increase dsensitivity o f offsprin g was not

observe din multigeneratio n reproductio n anddevelopmenta l toxicit y studie s a s offsprin g NOAEL s ar e equivalen t t o o r greate r tha n thos e fo r parenta l animals . Th e principl e effect s i n thes e studie s wer e clinica l sign s o f cholinesteras e inhibition , body weight reductions , an dreduce dpup weight . Oxamy l i s considere dneithe r

areproductiv e no r

developmenta l toxicant . Throughou t th e mammalia n toxicolog y database , ther e i s n o evidenc e suggestiv e o f a n advers e effec t o n an y componen t

o f th e endocrin e system . Th e ecotoxicity o f

oxamy l i s similarl y wel l characterize dbase do n th e result s o f extensiv e acut e an dchroni c testin g withbirds , fish , aquati c an dterrestria l invertebrate s a s wel l a s aquati c an dterrestria l plants . Th e primar y toxicologica l effec t o f oxamy l i n vertebrat e an dinvertebrat e anima l specie s i s th e inhibitio n o f acetylcholinesters e i n th e nervou s system , whic hi s rapidl y reversible . A s aresul t oxamy l demonstrate s hig hacut e toxieit y b y th e ora l an daquati c route s o f exposure . Th e principl e effect s i n chroni c exposur e studie s i n fis hwer e reduce dembry o hatchin g an dlarva l swim-up , an di n bird s wer e reduce dnumber s o f egg s laid , tota l eg g mass , an dnumbe r

o f fertil e egg s produced , al l relate dt o fran k toxicit y o f

th e carbamate . Throughou t

th e ecotoxicolog y database , ther e i s n o evidenc e suggestiv e o f a n advers e effec t

o n an y componen t

o f th e endocrin e system . Summarie s o f

relevan t existin g 4 0 CF RPar t

15 8 toxicolog y an decotoxicolog y studie s tha t

support th e curren t

FIFR A Sectio n 3 registratio n o f oxamy l an dprovid e .informatio n o n th e potentia l o f thi s produc t

t o interac t

wit hth e endocrin e syste mar e provide di n Section s 3 an d4 o f thi s document . Thes e studie s includ e subchroni c an d chroni c toxicit y studie s i n rats , mice , an ddog s an dreproductio n an ddevelopmenta l studie s i n rat s an drabbits . Als o provide dar e summarie s o f studie s whic hhav e bee n conducte dt o evaluat e an y potentia l developmen t an dreproductiv e effect s o f oxamy l i n bird s an dfis hspecies . Tabl e 1 list s fo r eac hstud y th e MRI D numbers , repor t numbers , titles , whethe r

th e stud y wa s reviewe db y EPA , an dth e Agency' s classificatio n a s to acceptability . I n addition , a s requeste db y EPA , har dcopie s o f th e fron t pag e o f eac hreport

whic hha s bee n previousl y submitte dt o EP A ar e bein g supplie dunde r

separat e cover . Finally , informatio n availabl e fro mth e ope n literatur e tha t i s relevan t

t o th e potentia l interactio n o f oxamy l wit hth e endocrin e syste mi s als o summarized . Har dcopie s o f thes e paper s ar e bein g provide dunde r separat e cover

a s a courtes y t o EP A fo r

th e Agency' s interna l us e wit hunderstandin g tha t DuPon t doe s not hav e authorit y to gran t

EPA permissio n to distribut e or pos t thes e thir dparty studie s o n th e EP A website .

1 0DuPont-2982 7



### 3. 0 SUMMAR YO F RELEVAN TMAMMALIA N TOXICOLOG YSTUDIE S 3. 1 Discussion of

studie s supportin g registratio n Snee , D.A . (1969) ; Ninety-day feedin g stud y i n rat s wit hl-(Dimethylcarbamoyl)-N

- (Methylcarbamoyloxy)thioformimidi c acid , methy l ester (IND-1410) . DuPon t Repor t No . HL R308-69 , MRID 00066911 , doe s no t satisf y guidelin e bu t acceptabl e chroni c stud y i s available . Material s an dMethods ; Group s o f 1 6 mal e an d1 6 femal e weanlin g albin o rat s (Charle s River-C D strain ) wer e orall y administere doxamy l (100 % purity ) i n pulverise dbasa l die t (containin g 1 % cor n oil ) at concentration s o f

0 , 50 , 10 0 an d50 0 pp mfo r 91-9 5 days . Becaus e o f sever e toxicit y a t

th e 50 0 pp mdos e leve l durin g th e firs t fou r days o f th e study , th e animal s i n th e 50 0 pp mdos e grou p wer e fe dacontro l die t fo r thre e day s an dthe n place do n adie t

containin g 15 0 pp mo f

th e tes t substance . Al l animal s wer e observe dfo r clinica l sign s o f

toxicity , an dmortality . Bod y weight s andfoo dconsumptio n wer e recorde dthroughou t the study . Haematology , clinica l chemistry (alkalin e phosphatase ) an durinalysi s evaluation s wer e performe do n 1 0 mal e an d1 0 femal e rat s fro mth e control , mid- , an dhigh-dos e group s at month s 1,2 , an d3 . Glutamic-pyruvi c transaminas e (GPT ) wa s measure di n th e contro l an d high-dos e group s monthly . All but 6 mal e and6 femal e rat s in eac hgrou p wer e sacrifice dafte r

91-9 5 days . Histopatholog y wa s conducte do n sacrifice danimal s fro mth e contro l an dth e high-dos e group s (includin g adrenals , pituitary , testes , prostate , ovary , uterus , an dthyroid) ; absolut e an drelativ e organ weight s (includin g adrenals , pituitary , an dtestes ) wer e determine dfo r al l animal s a t

termination . A reproductiv e toxicit y assessmen t wa s conducte do n th e remainin g 6/sex/grou p o f th e tes t animal s followin g 91-9 5 day s o n study . Eac hfemal e wa s co-house dwit h thre e male s fro mth e sam e grou p ( 5 day s wit heac hmale) . A t th e en do f

th e 15-day matin g period , female s wer e separate dan dexamine ddail y fo r parturition . Fou r

day s afte r parturition , th e numbe r

o f F) apups'wa s reduce dt o amaximu mo f 1 0 pe r litter . Weanin g o f

th e F] apup s wa s don e o n da y 2 1 o f lactation . Th e sam e procedur e wa s followe dt o produc e a n Fi b litter . Matin g behaviour , numbe r o f pregnancies , numbe r o f youn g i n eac hlitte r

at birthan dat

4 , 12 , an d2 1 day s o f

age , an dbod y weight s o f th e youn g a t

weanin g wer e recorded . Findings : Genera l Observations : On e 50 0 pp mmal e wa s foun ddea do n Day 5 . On e 10 0 pp m : mal e wa s foun ddea do n da y 30 . Male s i n th e 50 0 pp mgrou p starte dt o fasciculat e afte r 2 days ; afte r

4 days , al l male s an dfemale s exhibite dfasciculations , ruffle dfur , mil ddiarrhoea , bulgin g eyes , lacrimation , excessiv e foo dspillage , an dweigh t loss . Whe n animal s wer e place do n contro l diet , th e sign s disappeare do r lessene di n severity . N o treatment-relate dclinica l sign s o f toxicit y wer e note dat

50 , 100 , o r 15 0 ppm . Foo dconsumptio n wa s significantl y lowe r i n 15 0 pp mmales. ; Foo d consumptio n wa s significantl y increase di n 5 0 pp mmales . Ther e wer e h o treatment 

### 1 1DuPont-2982 7 relate deffect s o n foo defficiency . Significantl y depresse dbod y weigh t gai n i n 15 0 pp mmale s an di n 10 0 pp mmale s an dfemale s wa s noted . Haematology , clinica l chemistry , urinalysis : N o treatment-relate dabnormalitie s i n haematolog y parameter s wer e detected . N o treatment-relate dabnormalitie s wer e detecte di n alkalin e phosphatas e an dglutamic-pyruvi c transaminas e activities . A n increase dincidenc e o f

protei n an dbloo di n urin e wa s note di n 15 0 pp mmale s an d females . Reproductiv e effects : N o significan t difference s betwee n contro l an dtes t group s wit hrespec t

t o reproductio n an dlactatio n performanc e wer e noted . Bod y weight s o f weanling s a t

al l dietar y level s i n bot hFl aan dFi b generation s wer e reduced . Gros s pathology , orga n weights , histopathology : N o significan t treatment-relate d gros s lesion s wer e detected . Statisticall y significan t decrease s i n absolut e kidney , heart , thymus , an dsplee n weight s i n 10 0 an d15 0 pp mmale s wer e noted . Statisticall y significan t

decrease s i n absolut e live r weigh t i n 15 0 pp mmale s an d female s an dincrease s i n stomac hweigh t i n 15 0 pp mfemale s wer e noted . Statisticall y significan t

decrease s i n absolut e kidney , liver , an dlun g weight s i n lO Q pp mfemale s wer e noted . N o change s i n relativ e orga n weigh t t o bod y weigh t ratio s wer e evident . N o significan t treatment-relate dmicroscopi c lesions wer e detected . Ther e wer e n o tes t substanc e relate deffect s suggestiv e o f a n advers e effec t o n th e endocrin e system . Conclusion : No-observed-effe.c t

leve l fo r adul t animals : 5 0 pp m(equivalen t t o 3. 9 mg/k g bw/da y fo r male s an d4. 3 mg/k g bw/da y fo r females ) - base do n depresse dbod y weigh t gai n an dorgan weigh t

effect s at 10 0 ppm . Ther e wa s n o evidenc e o f adirec t advers e effec t o n th e endocrin e syste mi n thi s study . Noising , G.C . (1969) ; 1 3 week oral administratio n - dog s - insecticid e 1410 . DuPon t Repor t No . HL O 328-69 , MRID 00113398 , doe s no t satisf y guidelin e bu t acceptabl e chroni c stud y available . Material s an dMethods : Group s o f 4 mal e an d4 femal e Beagl e dog s eac hreceive doxamyl , 100 % purity " (assumed) , i n pulverise dbasa l die t at concentration s o f

0 , 50 , 100 , an d15 0 pp mfo r 1 3 weeks . Al l animal s wer e observe ddail y fo r clinica l sign s o f

toxicit y an dmortality ; bod y weight s an dfoo dconsumptio n wer e recorde dweekly . Haematology , bloo d chemistry , an durinalysi s evaluation s wer e performe dprio r t o initiatio n an da t

week s 4 an d1 3 o n al l animals . Gros s necrops y wa s performe dan dorga n weight s (includin g adrenals , teste s wit hepididymis , an dthyroid ) wer e recorde dfo r al l animal s a t termination . Histopatholog y wa s performe do n selectiv e tissue s (includin g adrenals , testes , ovary , uterus , an dthyroid ) o f th e control an d15 0 pp manimals . Histopatholog y wa s performe do n th e liver , kidneys , an dunusua l lesion s o f th e SOppman dlOOpp manimals : . 

### 1 2DuPont-2982 7 Findings : Genera l Observations : Tes t substance-relate dmortality di dno t occu r durin g th e cours e o f thi s study . N o tes t

substance-relate dclinica l sign s o f toxicit y wer e noted . N o tes t substance-relate deffect s o n foo dconsumptio n o r bod y weight s wer e noted . Haematology , clinica l chemistry , urinalysis : N o treatment-relate dhaematology , clinica l chemistr y o r

urinalysi s effect s wer e noted . Gros s pathology , orga n weights , histopathology : N o tes t substance-relate dgros s lesion s wer e observe dat

necropsy . N o tes t

substance-relate dchange s i n mea n orga n weight s wer e apparen t

a t an y dietar y concentration . I t wa s note db y th e stud y pathologis t

tha t th e leve l o f

activit y i n th e testes , ovaries , an dthyroi dwer e withi n norma l limit s an dcomparabl e betwee n th e contro l an dtreate danimals . Ther e wer e n o tes t substanc e relate deffect s suggestiv e o f a n advers e effec t

o n th e endocrin e system . Conclusion : No-observed-effec t

level: >15 0 pp m(5. 0 mg/k g bw/da y fo r male s an d4. 2 mg/k g bw/da y fo r

females ) - highes t

dos e tested . There wa s n o evidenc e o f adirec t advers e effec t o n th e endocrin e syste mi n thi s study . Mebus , C.A . (1990) ; Chroni c toxicity stud y wit hoxamy l (IN D1410-196) one-yea r feedin g stud y i n dogs . DuPon t Report No . HLR381-90 , MRID 41697901 , satisfie s Guidelin e 83-1b . ' Material s an dMethods : Fou r group s o f

5 mal e an d5 femal e Beagl e dog s eac hreceive doxamyl , purit y 97.1% , i n th e die t at concentration s o f

0 , 50 , 150 , an d25 0 pp mfo r 1 2 months . Bod y weight s an dfoo dconsumptio n wer e recorde dweekly . Clinica l sign s o f chroni c toxicity wer e recorde dweekly ; clinica l sign s o f acut e toxicit y wer e recorde ddaily , thre e hour s afte r th e dog s wer e fed , fo r

th e firs t thre e month s o f

th e study . Haematology , clinica l chemistry , andurinalysi s evaluation s wer e conducte dfor all animal s at

pretes t andat month s 3 , 6 , 9 , an d12 . O n Day s 7 , 34 , 88 , 187 , 270 , an d363 , bloo dwa s draw n fo r analysi s o f

cholinesteras e (ChE ) levels . A n ophthalmoscopi c examinatio n wa s conducte dat

pretes t an do n Day 358. Gros s necropsy , organ weigh t (includin g teste s an dthyroid ) an dhistopatholog y (includin g adrenals , pituitary , testes , prostate , epididymis , ovary , uterus , vagina , mammary , an dthyroid ) evaluation s wer e performe dat

study terminatio n o n al l survivin g dogs . Cholinesteras e activit y wa s determine di n section s o f

brain s take n fro mth e caudat e nucleus , cerebellum/medulla , an dcerebrum ! Findings : Genera l Observations : On e 25 0 pp mfemal e wa s foun ddea do n da y 348 . Th e .caus e o f deathcoul dno t

b e determine dfro mth e gros s an dhistologica l examinations , an dther e wer e n o apparen t compound-relate dlesions . A statisticall y significan t increas e i n th e incidenc e o f tremor s an dvomitin g i n 15 0 an d25 0 pp mmale s and/o r 

### 1 3DuPont-2982 7 female s was noted . Increase dincidenc e of diarrhoea , vomiting , andmucoida l stoo l in 15 0 an d25 0 pp mmale s and/o r female s wa s no t

statisticall y significan t

bu t wa s consisten t wit hsymptom s o f

Ch E inhibitio n and , therefore , wa s considere d biologicall y significant . Ther e wa s n o statisticall y significan t differenc e betwee n contro l an dtreatmen t

group s wit hregar dt o clinica l observation s o f chroni c toxicity . Ther e wa s ahighe r

incidenc e o f

vomitin g i n male s at

15 0 an d25 0 pp man di n female s at 25 0 ppm , whic hrepresent s acontinuatio n o f th e acut e toxicit y beyon d thre e hours . Statisticall y significan t decrease s i n foo dconsumptio n an dfoo d efficienc y wer e note di n 25 0 pp mmale s throughou t th e study ; statistiqall y significan t decrease s i n foo defficienc y wer e note di n 15 0 an d25 0 pp mfemale s durin g th e firs t wee k o f th e study . Statisticall y significan t reduction s i n mea n bod y weight s an d mea n bod y weigh t

gain s wer e note di n 25 0 pp mmales . Decrease dmea n bod y weigh t an dbod y weigh t

gai n wer e note di n 15 0 an d25 0 pp mfemale s (no t statisticall y significant ) bu t

wer e correlate dwit hdecrease dplasm aCh E activit y and , therefore , considere dbiologicall y significant . A sligh t dose-relate ddecreas e in mean bod y weigh t an dbod y weigh t

gai n wer e note di n 5 0 an d15 0 pp mmale s (no t statisticall y significant)-bu t

wer e als o considere dbiologicall y significan t becaus e th e decrease s wer e correlate dwit hdecrease s i n plasm aCh E activity . Ther e wer e n o tes t substance-relate dophthalmoscopicall y visibl e change s i n th e eye s o f eithe r mal e o r femal e dog s a t

an y dietar y concentration . Haematology , clinica l chemistry , urinalysis : N o treatment-relate dhaematolog y o r urinalysi s effect s wer e noted . Significantl y decrease dplasm aan dbrai n (caudat e nucleus ) cholinesteras e activit y occurre di n mal e dog s administere d5 0 pp man d above . Plasm acholinesteras e activity wa s als o significantl y lowe r i n female s fe d15 0 o r 25 0 pp mdiets . Biologicall y significan t decrease s i n cholinesteras e activit y wer e observe di n th e caudat e nucleu s section s o f th e brai n fo r

female s i n th e 15 0 an d 25 0 pp mgroups . Gros s pathology , orga n weights , histopathology : N o treatment-relate dgros s patholog y effect s wer e noted . Statisticall y significan t increase s i n mea n relativ e brai n an dkidne y weight s wer e note di n 25 0 pp mmale s an dwer e attribute dt o th e decrease d mea n fina l bod y weigh t

i n thes e animals . Minima l t o mil drena l tubular epithelia l alteration s wer e note di n thre e 25 0 pp mmales , whic hwer e judge dt o b e regenerativ e an ddi dno t

correlat e wit han y clinicall y observabl e o r clinica l patholog y findings . Termina l aspiratio n o f

ingest awa s atreatment-associate deffec t see n i n al l mal e treatmen t group s an dwa s attribute dt o th e emeti c propertie s o f oxamyl . Ther e wer e n o othe r compound-relate dmicroscopi c finding s observe di n treate danimal s a t sacrifice . Ther e wer e n o tes t substanc e relate deffect s suggestiv e o f a n advers e effec t o n th e endocrin e system . Conclusion : No-observed-effec t

level : <5 0 pp m(<1.5 6 mg/k g bw/day ) i n male s an d5 0 pp m (1.4 6 mg/k g bw/day ) i n female s base do n decrease s i n plasm aan dbrai n cholinesteras e activit y a t

>5 0 pp mi n male s an d>15 0 pp mi n females , accompanie d b y decrease dbod y weigh t an dclinica l sign s indicativ e o f cholinesteras e inhibitio n a t 15 0 an d25 0 ppm . Ther e wa s n o evidenc e o f adirec t advers e effec t

o n th e endocrin e syste mi n thi s study . 

### 1 4DuPont-2982 7

Dickrell , L . (1991) ; 52-wee k dietary toxicity stud y withIND-141 0 (oxamyl ) i n mal e dogs . DuPon t

Repor t No . HL O 555-90 , MRID 4205 2 701 , i n combinatio n wit hth e abov e 1-yea

r stud y in dogs , satisfie s Guidelin e 83- 1 b . Material s an dMethods ; Fiv e group s o f

5 mal e Beagl e dog s eac hreceive doxamyl , purit y 97.1% , i n th e die t at concentration s o f

0 , 12.5 , 20 , 35 , an d5 0 pp mfo r 5 2 weeks . Thi s stud y wa s conducte dt o establis haNOE Lfo r cholinesteras e inhibitio n i n males . Animal s wer e observe dfo r

clinica l sign s o f

toxicity . Bod y weight s an dfoo dconsumptio n wer e recorde dthroughou t

th e study . A n ophthalmi c examinatio n wa s performe da t pretes t an dat week s 26 , 39 , an d52 . Haematolog y an dclinica l chemistr y evaluation s wer e performe dat

pretes t an dat week s 13 , 26 , 39 , an d53 . A t stud y termination , th e animal s wer e necropsie dan dexamine dmacroscopically , selecte dorgan s wer e weighe d(includin g teste s an dthyroid) , an dselecte dtissue s wer e preserved . Tissue s wer e no t examine dmicroscopicall y a s th e primar y purpos e o f thi s stud y wa s t o defin e aNOAE Lfo r

cholinesteras e inhibitio n i n mal e dogs . Findings ; Genera l Observations : Tes t substance-relate dmortalit y di dno t occu r durin g th e cours e o f thi s study . N o clinica l sign s o f toxicit y wer e observed . Ther e wer e n o tes t substance-relate deffect s on bod y weights , bod y weigh t gains , or foo dconsumption . Ther e wer e n o tes t

substance-relate dophthalmoscopicall y visibl e change s i n th e eye s at an y dietar y concentration . Haematology , clinica l chemistry : N o treatment-relate dhaematolog y effect s wer e noted . N o treatment-relate deffect s o n plasma , RBC , an dbrai n Ch E activit y wer e noted . • , Gros s patholog y an dorga n weights : N o treatment-relate dgros s lesions wer e observe dat

necropsy . N o tes t

substance-relate dchange s i n mea n organ weight s wer e apparen t at an y dietar y concentration . Ther e wer e n o tes t substance-relate d macroscopi c finding s observe di n treate danimal s a t sacrifice . Base do n th e endpoint s evaluated , ther e wa s n o tes t substanc e relate dfinding s suggestiv e o f a n advers e effec t o n th e endocrin e system . Conclusion : No-observed-effec t

level : 5 0 pp m(1.3 6 mg/k g bw/da y i n males ) - highes t dos e tested . Ther e wa s n o evidenc e o f adirec t advers e effec t

o n th e endocrin e syste mi n thi s study .



### 1 5DuPont-2982 7 Malley , LA . (1991) ; Combine dchroni c toxicity/oncogenicity stud y wit hoxamy l (IN-D1410-196 ) long-termfeedin g stud y i n rat s ( 4 volumes) . DuPon t Report No . HLR278-91 , MRID 41963201 , satisfie s Guidelin e 83- 5 Material s an dMethods : Fiv e group s o f

6 2 mal e an d6 2 femal e Spragu e Dawle y rat s wer e fe ddiet s containin g 0 , 25 , 50 , 100 , an d15 0 pp moxamyl , purit y 97.1% , fo r approximatel y 2 years . Clinica l sign s o f

toxicity , bod y weights , an dfoo dconsumptio n wer e recorde d throughou t

th e study . Haematology , clinica l chemistry , an durinalysi s evaluation s wer e performe do n al l rat s at approximatel y 3 , 6 , 12 , 18 , an d2 4 months . Plasm aan d RB C cholinesteras e activit y wa s determine dat on e monthan dat

al l othe r clinica l chemistr y samplin g times . Ophthalmoscopi c examination s wer e performe do n al l rat s prio r t o initiatio n an dat

1 2 an d2 4 months . A t

1 2 months , 1 0 rat s pe r

se x pe r grou p wer e sacrifice dfo r

organ weigh t

determinatio n an dhistopathologica l evaluation . A t 2 4 months , al l survivin g rat s wer e sacrifice dfo r orga n weigh t

(includin g testes ) determinatio n an dhistopathologica l (includin g adrenals , pituitary , testes , epididymis , prostate , semina l vesicles , ovary , uterus , vagina , mammary , an dthyroid ) evaluation . Brain s wer e collecte da t

th e interi man dfina l sacrific e an dassesse dfo r brai n cholinesteras e activity . Findings : Genera l Observations : Ther e wa s n o tes t substance-relate deffec t

o n mortality . A tes t substance-relate dtren dfo r greate r surviva l i n 10 0 an d15 0 pp mmale s an di n 50 , 100 , an d15 0 pp mfemale s wa s noted , whic hcorrelate dwit hlowe r bod y weigh t observe di n 10 0 an d15 0 pp mmale s and ; females . Hyperreactivir y an dswolle n legs/paw s wer e note di n 10 0 an d15 0 pp mmale s an dfemale s (swolle n legs/paw s i n female s at 15 0 pp monly) . Ski n lesions includin g sore s an dalopeci awer e note di n 10 0 an d15 0 pp mfemales . Decrease dbod y weigh t an dbod y weigh t

gai n wer e note d i n 10 0 an d15 0 pp mmale s an dfemale s (a s muc ha s 22 % an d30% , respectively) . N o treatment-relate deffect s wer e note do n foo dconsumption ; however , foo d efficienc y wa s decrease di n male s an dfemale s at 10 0 t o 15 0 ppm . A highe r incidenc e o f

retina l photorecepto r

cel l atroph y occurre di n 15 0 pp mfemale s at th e 2-year sacrific e onl y andwas considere dto be asecondary effec t of nutritiona l statu s an dageing . A dose-relate dincreas e i n th e incidenc e o f pal e ocular

fund i wa s note di n 15 0 pp mmales . Microscopi c evaluatio n o f th e ocular

tissue s i n male s di dno t

revea l compound-relate deffects . Th e highe r incidence s o f

pale , ocular

fund i i n 15 0 pp m male s may b e du e t o anaemia , thinnin g o f th e retina , o r

th e lowe r numbe r o f animal s whic hsurvive dunti l th e ophthalmi c exa mi n th e 0 an d2 5 pp mgroup s compare dwit h th e 10 0 an d15 0 pp mgroups . Haematology , clinica l chemistry , urinalysis : N o treatment-relate dchange s i n haematolog y o r

urinalysi s wer e noted . Decrease dplasm aCh E activit y wa s note di n 10 0 an d15 0 pp m.male s at severa l samplin g interval s an di n 10 0 an d15 0 pp m female s a t th e one-monthsamplin g interva l only . N o effect s o n RB C an dbrai n Ch E wer e observed .



### 1 6DuPont-2982 7 Gros s pathology , orga n weights , histopathology : A t th e one-year

sacrifice , absolut e live r

weights wer e decrease dan dmea n relativ e heart an dbrai n weights wer e increase di n 15 0 pp mmales . Female s i n th e 15 0 pp mgrou p ha dincrease drelativ e kidne y weights , an dfemale s i n th e 10 0 o r 15 0 pp mgroup s ha dincrease drelativ e hear t an dbrai n weights . Th e change s i n orga n weigh t wer e secondar y effect s du e t o th e lowe r bod y weights . A t

th e one-year

sacrifice,

- n o tes t

substance-relate deffect s wer e note do n tissu e morphology . A t th e two-year

sacrifice , absolut e brai n weigh t wa s significantl y highe r

i n 15 0 pp mmale s an di n 10 0 an d1'50 pp mfemales . I n addition , 15 0 pp mmale s ha ddecrease dabsolut e kidne y weights . Female s i n th e 10 0 an d15 0 pp mgroup s ha dincrease drelativ e kidney , liver , an dbrai n weights . Female s i n th e 15 0 pp mgrou p als o ha dincrease drelativ e hear t weights . Ther e wer e n o histopathologi c change s i n thes e organs ; and , therefore , thes e change s wer e considere dt o b e secondar y t o th e lowe r bod y weigh t

and/o r greate r survival . A t

th e two-year sacrifice , dose-relate dincrease s i n th e incidenc e o f ulcer/erosion s o n th e limbs , nodule s o n th e tail , tai l deformity , periocula r chromodacryorrhea , stomac h ulce r o r erosion , larg e aorta , brai n compression , an ddiscoloratio n o f th e kidney s wer e noted . Th e observation s at th e two-year

sacrific e ar e commo n i n geriatri c o r stresse d animals , an dth e apparen t

dos e respons e i s considere drelate dt o th e increase d surviva l an ddecrease dbod y weigh t i n 10 0 an d15 0 pp mrats . Ther e wer e n o tes t substanc e relate dfinding s suggestiv e o f a n advers e effec t

o n th e endocrin e system . Conclusion : No-observed-effec t level : 5 0 pp m(1.9 7 mg/k g bw/da y i n male s an d 2.6 9 mg/k g bw/da y i n females ) - base do n lowe r bod y weigh t

an dbod y weigh t

gai n an dplasm acholinesteras e inhibitio n at 10 0 an d15 0 ppm . Oxamy l wa s no t oncogeni c i n thi s study . Ther e wa s n o evidenc e o f adirec t advers e effec t

o n th e endocrin e syste mi n thi s study . Adamik , E.R . (1981) ; Lon g termfeedin g stud y i n mic e wit hoxamyl . DuPon t Repor t No . HL O 252-81 , MRID 00076813 , satisfie s Guidelin e 83-2 : Material s an dMethods : Fou r group s o f 8 0 mal e an d8 0 femal e weanlin g CD- I mic e wer e fe ddiet s containin g 0 , 25 , 50 , an d10 0 pp moxamyl , purit y 97.1% , fo r approximatel y 2 years . Becaus e o f unexpecte dhig hmortalit y rate s at th e 5 0 an d10 0 pp mdos e level s durin g th e firs t fe w weeks , th e 10 0 pp mgrou p wa s decrease dt o 7 5 pp mat wee k 6. , Bod y weights , foo dconsumption , an dclinica l observation s wer e recorde dfo r al l animal s throughou t

th e study . Al l mic e wer e palpate donc e weekl y fo r masses . Haematologica l evaluation s wer e performe do n 1 0 male s an d1 0 female s fro meac h grou p afte r

1 , 3 , 6 , 12 , an d1 8 month s o f dosin g an dprio r

t o terminatio n o f

th e study . Gros s an drelativ e orga n weight s (includin g testes) wer e determine dfo r al l animal s a t termination . Gros s necropsie s wer e performe do n al l survivin g animal s at stud y termination . Histopathologica l evaluation s wer e performe d(includin g adrenals , testes , epididymis , prostate , semina l vesicles , ovary , uterus , cervix , mammary , an d thyroid) .


### 1 7DuPont-2982 7 Findings : Genera l observations : Earl y death s (throug hWee k 4 : 2 males , 9 female s at

5 0 ppm ; 1 4 male s an d1 1 female s at 10 0 ppm ) wer e likel y du e t o an acut e exposur e t o th e tes t compound ; n o long-ter mtreatment-relate dincrease s i n mortalit y wer e noted . N o treatment-relate dclinica l sign s o f toxicit y wer e noted . Decrease dbod y weight s wer e note di n male s u p t o Wee k 8 1 (5 0 ppm ) o r

u p t o Wee k

4 2 (100/7 5 ppm ) an di n female s u p t o wee k

21 . Statisticall y significant 1 decrease s i n foo dconsumptio n wer e note dfo r 100/7 5 pp mmale s fro mWee k 1 1 throug hWee k

84 . Haematology : Sporadi c statisticall y significan t increase s an ddecrease s i n haematolog y parameter s wer e observe da t 100/7 5 pp mwer e suggestiv e o f a n effec t o n RB C mass , particularl y at Wee k 4 . Thi s effec t

appeare dsporadicall y durin g week s 4-52 ; however , i t

wa s no t note dafte r

Wee k 52 . Gros s pathology , orga n weights , histopathology : N o tes t substance-relate dgros s lesion s wer e observe dat

necropsy. : N o tes t

substance-relate dchange s i n mea n organ weight s wer e apparen t

at an y dietar y concentration . N o treatment-relate dincreas e i n microscopi c finding s wa s noted . Ther e wer e n o tes t substanc e relate dfinding s suggestiv e o f

a n advers e effec t

o n th e endocrin e system . Conclusion : No-observed-effec t

level : 2 5 pp m(equivalen t t o 4. 2 mg/k g bw/da y fo r

male s an d 5. 2 mg/k g bw/da y fo r

females ) - base do n haematolog y effect s a t 100/7 5 pp man d mortalit y an ddecrease dbod y weight s a t >5 0 ppm . Oxamy l wa s no t oncogeni c i n thi s study . Ther e wa s n o evidenc e o f adirec t advers e effec t

o n th e endocrin e syste mi n thi s study . Sherman , H . (1972) ; Long-termfeedin g stud y i n rat s an ddog s wit h1

- (dimethylcarbamoyl)-N-(methylcarbamoyloxy)-thioformimidi c acid , methy l ester (IND-1410) . DuPon t

Repor t No . HLR37-72 , MRID 00083352 . Material s an dMethods : Group s o f 3 6 mal e an d3 6 femal e Sprague-Dawle y rat s receive doxamyl , purit y 95.0% , i n th e die t

at concentration s o f

0 (tw o groups) , 50 , 100 , an d15 0 pp mfo r 2 years . Th e animal s wer e evaluate dfo r clinica l sign s o f

toxicity , bod y weights , an d foo dconsumption , whic hwer e recorde dthroughou t th e study . Clinica l chemistr y (alkalin e phosphatas e an dglutamic-pyruvi c transaminase ) an dhaematolog y (RBC , haemoglobin , hematocrit , an dleukocyt e count) , an durinalysi s wer e conducte do n 1 0 rats/sex/grou p at

10 0 an d15 0 pp man do n 5 rats/se x i n th e contro l grou p at Month s 1 , 3 , 6 , 9 , 12 , 18 , an d24 . (Th e sam e animal s wer e use dfo r haematolog y an d urinalysi s evaluations ; differen t animal s wer e use dfo r

clinica l chemistry evaluations. ) Bloo dcholinesteras e evaluation s wer e conducte do n 10/sex/grou p fro mth e contro l an dhigh-dos e group s o n Day s 4 an d8 an dat Month s 1,6 , 12 , an d2 4 (additiona l cholinesteras e evaluation s wer e conducte do n th e 10 0 pp mgrou p at month s 1 an d6) . Aliesteras e activit y wa s measure do n bloo dfro mthes e rat s a t Month s 1 > 12 , an d24 . Gros s patholog y an dhistopatholog y (includin g adrenal , pituitary , testis , epididymis , 

### 1 8DuPont-2982 7 prostate , ovary , uterus , mammary , an dthyroid ) evaluation s wer e conducted , an d organ weight s (includin g adrenal , pituitary , an dtestes) wer e recorde dfo r interim

sacrific e animal s a t

1 2 month s an dfo r

al l survivin g animal s a t

2 4 months . Thi s stud y als o containe dareproductiv e assessmen t i n rats . Afte r approximatel y 1 2 week s o f oxamy l administratio n i n th e die t a t concentration s o f 0 , 50 , 100 , an d15 0 ppm , 1 6 female s rats/grou p wer e house dseparatel y an dmate d (fo r approximatel y 1 5 days , 5 day s eac hwit h3 separat e males) . Animal s wer e observe ddurin g gestatio n fo r th e birt ho f

young . Th e numbe r

o f pup s (Fi a ) i n eac h litte r wa s determine dat

birt han dat

4 , 12 , an d2 1 day s o f

age . Pu p bod y weight s wer e recorde da t

weanin g (2 1 days) . Litter s wer e culle da t da y 4 postpartum. ' Th e F] alitter s wer e sacrificed . Th e parenta l animal s wer e mate dasecon dtim e t o produc e Fi b litters . Th e Fi b animal s wer e fe dthei r respectiv e diets . Whe n th e Fi b generatio n wa s 11 0 day s o f

age , the y wer e mate dt o produc e th e p2 aan dF2 b litters . Thi s proces s wa s repeate dt o produc e F3 aan dFab litters . A t weaning , tw o male s an dtw o female s fro meac ho f

fiv e Fs b litter s fro mth e contro l an dhigh-dos e grou p wer e evaluate d histopathologicall y (includin g adrenal , testis , epididymis , ovary , an dthyroid) . Becaus e o f

decrease dbod y weight s observe dconsistentl y i n th e weanlin g rat s at 10 0 A and150 ppm , astud y was conducte dto ascertai n whethe r thes e lowe r

bod y weight s . reflecte dtoxi c o r

.nutritiona l effects . Twenty mal e an d2 0 femal e pup s o f th e Fab litte r wer e selecte dat

weanin g fro m5 o r

mor e mother s i n th e contro l an d15 0 pp mgroup s an ddivide dint o subgroup s o f 1 0 male s an d1 0 female s each . On e subgrou p fro mth e control s an don e subgrou p fro mth e 15 0 pp mgrou p wer e maintaine do n thei r respectiv e diets ; th e othe r subgrou p fro mth e control s wa s transferre dt o th e 15 0 pp m grou p whil e tha t

fro mth e 15 0 pp mgrou p wa s transferre dt o th e contro l group . Th e animal s wer e maintaine do n thei r diet s fo r eigh t weeks . Group s o f 4:mal e an d4 femal e Beagl e dog s eac hreceive ddie t at concentration s o f 0 , 50 , 100 , an d15 0 pp mfo r 2 years . Bod y weight s an dfoo dconsumptio n wer e recorde dweekly . Clinica l sign s o f toxicit y wer e recorde ddaily. Haematology , bloo d biochemistry , an durinalysi s evaluation s wer e conducte dfo r al l animal s a t

pretes t an d a t Month s 1 , 2 , 3 , 6 , 9 , 12 , 15 , 18 , 21 , an d24 . Cholinesteras e an daliesteras e activit y wer e measure dat

pretes t an dat 1 , 6 , 12 , an d2 4 months . Gros s necrops y an d histopatholog y (includin g adrenal , pituitary , testis , epididymis , prostate , ovary , uterus , fallopia n tubes , mammary , an dthyroid ) evaluation s wer e performe dfo r on e mal e an don e femal e do g eac hfro mth e contro l an d15 0 pp mgrou p at on e year . A t stud y termination , al l survivin g dog s wer e give n agros s necropsy . Complet e histopatholog y evaluation s wer e performe do n al l dog s i n th e control an d15 0 pp m dos e groups . Onl y liver , kidne y an dtesti s wer e examine dmicroscopicall y fro mth e low

- an dmid-dos e groups . Orga n weight s wer e recorde dfo r a} l animal s at termination . Findings : Genera l observations : N o treatment-relate deffect s o n mortalit y wer e noted . N o treatment-relate dclinica l sign s o f toxicit y wer e observed . Decrease dbod y weigh t i n 10 0 an d15 0 pp mrat s wa s observe dthroughou t th e study . N o treatment-relate d bod y weigh t

effect s i n dog s wer e noted . Slightl y decrease dfoo dconsumptio n wa s 

### 1 9DuPont-2982 7 note di n 15 0 pp mmal e an dfemal e rats . N o treatment-relate deffect s o n foo d efficienc y wer e note di n mal e o r femal e rats . N o treatment-relate dfoo dconsumptio n effect s i n dog s wer e noted . Haematology , clinica l chemistry , urinalysis : N o treatment-relate dhaematolog y effect s wer e note di n rat s o r dogs . Bloo dCh E activit y wa s decrease di n 15 0 pp m femal e rat s at

da y 4 an di n mal e rat s at

Da y 8 . Increase dalkalin e phosphatas e an d .cholestero l level s wer e note di n 15 0 pp mmal e an dfemal e dogs . N o treatment-relate d urinalysi s effect s wer e note di n rat s o r dogs . Gros s pathology , orga n weights , histopathology : N o tes t substance-relate dgros s lesion s wer e observe dat

necrops y i n rat s o r

dogs . N o tes t

substance-relate dchange s i n mean organ weight s wer e apparen t at an y dietar y concentratio n i n rat s o r dogs . N o treatment-relate dmicroscopi c finding s wer e note di n rat s o r dogs . Reproductiv e effects : Litte r siz e an dviabilit y an dlactatio n indice s wer e slightl y decrease di n th e 10 0 an d15 0 pp mgroups . Ther e wer e n o treatment-relate deffect s o n reproductiv e o r

lactatio n parameters . Effect s o n pups : Slightl y decrease dweanlin g bod y weight s wer e note di n th e 10 0 an d15 0 pp mgroups . Thes e bod y weigh t effect s appear

t o reflec t a n advers e nutritiona l effec t

rathe r tha n atoxi c one ; th e reversibilit y o f thi s effec t wa s see n b y a greate r rat e o f bod y weigh t

gai n whe n pup s wer e transferre dfro mth e tes t die t t o th e contro l diet . N o treatment-relate dhistopathologica l effect s wer e note dat 15 0 pp mi n th e Fs b weanlin g pups . Conclusion : No-observed-effec t

leve l i n adul t

rat s wa s 5 0 pp m(equivalen t t o 2. 3 mg/k g bw/da y i n male s an d2. 8 mg/k g bw/da y i n females ) - base do n decrease dbod y weigh t a t > 10 0 

### ppm . No-observed-effec t

leve l fo r reproductio n wa s >15 0 pp m(>7. 5 mg/k g bw/day 1 ) - highes t dos e tested . (Calculate dbase do n standar dconversio n metho do f pp mx 0.0 5 mg/k g bw/day) . Th e NOE Li n pup s wa s 5 0 pp m(2. 5 mg/k g bw/day 1 )-base d o n sligh t pu p bod y weigh t

effect s a t >10 0 ppm . No-observed-effec t

leve l i n dog s wa s 10 0 pp m(equivalen t t o 2. 8 mg/k g bw/da y i n male s an d3. 0 mg/k g bw/da y i n females ) - base do n increase dalkalin e phosphatas e an dcholestero l level s at

15 0 ppm . There wa s n o evidenc e o f adirec t advers e effec t

o n th e endocrin e syste mo f eithe r rat s o r dog s i n thi s study .

2 0DuPont-2982 7 Hurtt , M . E . (1990) ; Reproductiv e an dfertilit y effect s withoxamy l (IN D1410 ) ' multi-generatio n reproductio n stud y i n rats . DuPon t Repor t No . HL R423-90 , MRID 41660801 , satisfie s Guidelin e 83-4 . Material s an dMethods : Group s o f 3 0 mal e an d3 0 femal e Spragu e Dawle y rat s eac hreceive doxamyl , purit y 97.1% , i n th e die t

at concentration s o f

0 , 25 , 75 , an d15 0 pp mfof e approximatel y 7 0 day s pre-matin g an ddurin g mating , gestation , an dlactation . F j weanling s (30/sex/group ; 1 rat/sex/eac hlitte r wher e possible ) wer e randoml y selecte dan d continue do n thei r

respectiv e diets . Th e F I animal s wer e bre dt o produc e ¥ 2 offsprin g whe n al l ha dbee n o n tes t

at leas t 10 5 days . O n Da y 0 postpartum , liv e an ddea dpup s i n eac hlitte r wer e counted ; liv e pup s wer e weighe dcollectivel y b y sex . O n Da y 4 postparrum , pu p count s an dweight s wer e determined , an dth e litter s wer e culle drandoml y t o 8 (4/sex ) wher e possible . Litte r count s an dweight s wer e als o determine dafte r cullin g o n Day 4 an do n Day s 7 an d1 4 postparrum . O n Da y 2 1 (weaning) , individua l pu p weight s wer e taken . O n Day s 0 , 4 , 7 , 14 , an d21 , offsprin g wer e individuall y examine dfo r abnorma l behaviou r

an d appearance . Clinica l sign s o f

toxicit y wer e evaluate di n al l P I an dF I rat s weekly . Al l P I an dF I . rat s wer e weighe dweekl y durin g premating . Durin g gestatio n an dlactation , female s wer e weighe do n Day s 0 , 7 , 14 , an d2 1 o f eac hperiod ; male s wer e weighe dweekly . Foo dconsumptio n wa s determine dweekl y throughou t prematin g fo r

P I an dF I rats ; foo dconsumptio n o f

pregnan t rat s wa s als o recorde do n Day s 0 , 7 , an d1 4 o f gestation . Al l parenta l rat s (P i an dFI ) wer e evaluate dfo r gros s lesions . Orga n weights of

selecte dtissue s (includin g testes ) wer e recorded . Tissue s fro mparenta l rat s fro mth e contro l an d15 0 pp mdos e group s i n bot hgeneration s wer e examine d histologicall y (includin g pituitary , testes , epididymis , prostate , semina l vesicles , coagulatin g gland , ovary , uterus , an dvagina) . Twenty F I (fro mthos e no t continuin g t o th e nex t

generation ) an d¥ 2 weanling s pe r se x pe r grou p wer e als o necropsie dan d give n agros s exam . Reproductiv e functio n indice s wer e calculate dfo r P I an dF I parenta l rats . Findings : Genera l observations : I n th e 15 0 pp mgroup , thre e F I male s an don e P I femal e wer e foun ddea ddurin g th e stud y (no t considere dt o b e treatmen t related) . Treatment

relate ddecrease s wer e observe di n mea n bod y weigh t an dbod y weigh t

gai n i n 7 5 an d 15 0 pp mP I an dF I parenta l rat s durin g prematin g an dgestation . Durin g lactation , decrease dbod y weigh t

an dincrease dbod y weigh t gai n wer e observe di n 7 5 an d 15 0 pp mP I an dF I females . I n 7 5 pp m(males ) an d15 0 pp m(male s an dfemales ) significan t reduction s i n foo dconsumptio n an dfoo defficienc y wer e note di n P I an d F I rat s durin g premating . Foo defficienc y wa s significantl y decrease di n 15 0 pp m P I an dF I female s durin g gestation . Significan t upwar dtren di n th e incidenc e o f hyperreactivit y i n F I male s an dfemale s (premating ) wa s observe d(statisticall y significan t i n male s a t

15 0 ppm) . Durin g th e prematin g and/o r gestatio n periods , 7 5 an d15 0 pp mF I female s showe dastatisticall y significan t dose-relate dincreas e i n alopecia . 

### 2 1DuPont-2982 7 Gros s pathology , orga n weights , histopathology : N o tes t substance-relate dgros s lesion s wer e observe dat

necrops y i n parenta l rats , weanlings , o r pups . N o tes t substance-relate dchange s i n mea n organ weight s wer e apparen t at an y dietary concentration . Mea n relativ e teste s weigh t wa s significantl y highe r

i n 7 5 an d15 0 pp mP I an dF I male s du e t o lowe r bod y weight . N o treatment-relate dmicroscopi c finding s wer e note di n P I o r F I adul t male s an dfemales . Reproductiv e parameters : Ther e wer e n o treatment-relate deffect s o n mating , fertility , an dgestatio n lengthi n th e P I an dF I rats . Litte r size , pu p survival , an dpu p weight : I n th e 15 0 pp mgroup , statisticall y significan t decrease s i n mea n numbe r o f pup s (male s an dfemale s combined ) bor n pe r litter , bor n aliv e pe r

litter , an dth e numbe r

o f pup s aliv e o n da y 4 precullin g i n th e F I and'F 2 generation s wer e noted . A significan t increas e i n th e numbe r

o f pup s observe d wit hn o mil k

spo t wa s note di n th e F 2 offsprin g (attribute dt o lo w pu p weight) . I n th e 7 5 an d15 0 pp mdos e groups , astatisticall y significan t decreas e i n pu p bod y weigh t wa s observe di n F I an dF 2 male s an dfemale s throughou t mos t o f th e lactatio n period . Ther e wa s n o impac t

o f treatmen t o n th e se x rati o o f

th e F I an dF 2 pup s at

an y dos e level . Conclusion : Parenta l NOEL : 2 5 pp m(equivalen t t o 1.4 3 mg/k g bw/day ) - base do n bod y weigh t effect s i n male s an dfemale s at >7 5 ppm . Pu p NOEL : 2 5 pp m-.base do n bod y weigh t effect s a t >7 5 pp man ddecrease dpu p surviva l at

15 0 ppm . Reproductiv e NOEL : >15 0 pp m(equivalen t t o 12. 2 mg/k g bw/day ) - highes t dos e tested . Ther e wa s n o evidenc e o f adirec t advers e effec t

o n th e endocrin e syste mi n thi s study . Richard , I.E . (1988) . Teratogenicity stud y o f IN D1410-19 6 i n th e rat . DuPon t Report No . HLR473-8 8 an daccompanyin g pape r DuPont-1954 , MRID s 4085920 1 and44737501 , satisfie s Guidelin e 83-3 . Material s an dMethods : Group s o f 2 5 femal e Sprague-Dawle y rat s each receive doxamyl , purity 97.2% , i n distille dwate r

at concentration s o f

0 , 0.2 , 0.5 , 0.8 , an d1. 5 mg/k g bw/da y orall y b y gavag e dail y fro mDay s 7 t o 1 6 o f gestation ; th e dosin g volum e wa s 1 0 mL/k g bw . Th e da y copulatio n wa s confirme d(b y th e presenc e o f avagina l plug ) wa s designate d a s Da y 1 o f

gestation . Th e animal s wer e observe dfo r clinica l sign s oftoxicit y i n th e mornin g o n Day s 1-2 2 o f

gestatio n an dat

approximatel y 2 hours.postdosin g o n Day s 7-1 6 o f

gestation . Bod y weights wer e recorde do n Day s 1,7-17 , an d2 2 o f gestation . Foo dconsumptio n wa s recorde do n Day s 1 , 3 , 5 , 7 , 9 , 11 , 13 , 15 , 17 , 19 , an d2 2 o f gestation . Female s wer e sacrifice do n Da y 2 2 o f gestatio n an dwer e examine dfo r

gros s lesions . Th e live r

an dgravi dan dnon-gravi duter i wer e weighed . 2 2DuPont-2982 7 Th e dam s wer e examine dfo r reproductiv e effects . Foetuse s wer e weighed , sexed , an dexamine dexternally , viscerally , an dskeletally . Se x wa s confirme dupo n viscera l exam . Findings : Materna l effect s General observations : Tes t substance-relate dmortality di dno t occur durin g th e cours e o f thi s study . Tremors , salivation , diarrhoea , ey e discharge , an dwe t area s o f th e bod y wer e observe ddurin g th e dosin g perio di n 1. 5 mg/k g bw/da y rats . Tremor s wer e observe di n 0. 8 mg/k g b w rat s durin g dosin g period . Significan t dose-relate d decrease s i n bod y weigh t

change s wer e note dat

0. 8 an d1. 5 mg/k g b w durin g th e dosin g perio d(reduce db y -21 % an d30% , respectively , compare dwit hcontrols) . A sligh t bu t no t statisticall y significan t

decreas e i n bod y weigh t

gai n wa s note di n 0. 5 mg/k g b w rat s durin g th e dosin g perio d(reduce db y ~9 % compare dt o controls) . Significan t

dose-relate deffect s o n foo dconsumptio n wer e note di n 0. 8 an d1. 5 mg/k g b w rat s durin g th e dosin g period . , Reproductiv e outcomes : N o treatment-relate deffect s o n reproductiv e parameter s , (se x ratio , pregnanc y rate , incidenc e o f tota l resorptions , incidenc e o f earl y deliveries , corpor alutea , o r

th e numbe r

o f stunte dfoetuses ) wer e observed . Ther e wa s n o apparen t tes t substanc e relate deffect s o n endocrin e functio n pertainin g t o maintenanc e o f

pregnanc y o r

foeta l development . Gros s pathology , orga n weights : N o tes t substance-relate dgros s lesion s wer e , observe da t

necropsy . A n upwar dtren di n increase drelativ e live r weight s wa s observe d(n o statistica l significanc e wa s note di n an y group) . Foetal effect s Significan t

reduction s i n mea n foeta l bod y weight s wer e note dat 0. 8 an d1. 5 mg/k g bw/day . A minima l (reduce db y <4 % compare dt o controls) , ye t statisticall y significan t decreas e i n mea n foetarbod y weigh t wa s note da t

0. 5 mg/k g bw/day ; however , subsequen t

analysi s o f

th e dat a(DuPont-1954 ) indicate s tha t th e mea n foeta l weigh t

o f thi s dos e group i s wel l withi n th e laboratory historica l contro l range . Therefore , i t

i s no t considere dadverse . Moreover , i t occurre di n th e presenc e o f a similar sligh t depressio n i n materna l bod y weigh t gai n durin g th e dosin g period . N o treatment-relate dstructura l malformation s wer e noted . Conclusion : No-observed-effec t

leve l (materna l toxicity) : 0. 5 mg/k g bw/da y - base do n decrease d bod y weigh t

an dfoo dconsumptio n an dtremor s a t >0. 8 mg/k g bw/day . No-observed-effec t

leve l (foeta l toxicity) : 0. 5 mg/k g bw/da y - base do n adversel y decrease dfoeta l weight s a t >0. 8 mg/k g bw/day . No-observed-effec t

leve l (developmenta l toxicity) : >1. 5 mg/k g bw/da y - highes t dos e tested . Ther e wa s n o evidenc e o f adirec t advers e effec t

o n th e endocrin e syste mi n thi s study . 2 3DuPont-2982 7

Hoberman , A.M . (1980) ; Teratolog y stud y i n rabbit s - oxamyl . DuPon t Repor t No . HL O 0801-80 , MRID 00063009 , satisfie s Guidelin e 83-3b : Material s an dMethods ; Group s o f 1 7 femal e pregnan t

Ne w Zealan dWhit e rabbit s eac hreceive doxamyl , purit y 97.1% , i n distille dwate r at concentration s o f

0 , 1 , 2 , an d4 nig/kg bw/da y orall y b y gavag e dail y fro mDay s 6 t o 1 9 o f gestation ; th e dosin g volum e wa s 1 mL/k g bw/day . Female s wer e artificiall y inseminated ; th e da y afte r artificia l inseminatio n wa s designate da s Da y 0 o f

gestation . Animal s wer e observe dfo r clinica l sign s o f

toxicit y daily . Individua l bod y weight s wer e recorde do n Day s 6 , 11 , 15 , 19 , an d2 9 o f gestation ; individua l foo dconsumptio n wa s recorde do n Day s 7 throug h2 9 o f gestation . O n Da y 2 9 o f

gestation , femal e rabbit s wer e sacrificed , th e foetuse s wer e take n by^caesarea n section , an dth e doe s wer e examine dfo r viscera l gros s pathology . The ovarie s anduteru s (withandwithou t foetuses ) of

eac hrabbi t

wer e weighe dand th e numbe r

o f corpor alute aan dimplantation s determined . Eac h foetu s wa s examine dexternally, weigh t an dcrown-rum p distanc e determined , an daviscera l examinatio n conducted . Th e head s o f one-thir do f

th e foetuse s wer e remove dan d sectione db y Wilson' s techniqu e fo r examination . Al l foetuse s were , evaluate dfo r skeleta l anomalie s followin g fixatio n an dstaining . Eac hpu p wa s sexe db y interna l exam . Findings : Materna l effect s Genera l Observations : N o treatment-relate dmortalit y wa s observed ; on e lo w dos e pregnan t rabbi t an don e hig hdos e nonpregnan t rabbi t die ddurin g th e stud y (death s likel y du e t o intubatio n error) . N o treatment-relate dclinica l sign s o f toxicit y wer e noted . Sporadi c incidence s o f ey e discharg e an dre dstain s i n th e tra y unde r th e cag e wer e note di n th e contro l an dmid-dos e groups . Statisticall y significan t decrease s i n bod y weigh t

gai n wa s note di n th e 2 an d4 mg/k g bw/da y group s durin g th e treatmen t period . N o treatment-relate deffect s i n foo dconsumptio n wer e noted . Gros s pathology , orga n weight : N o tes t substance-relate dgros s lesion s wer e observe da t

necropsy . Slightl y decrease dovaria n an duterin e weight s withan d withou t foetuse s wer e note d(no t statisticall y significant ) in the 2 and4 mg/k g bw/da y group s presumabl y du e t o th e effect s o f treatmen t o n bod y weight . Reproductiv e outcomes : N o treatment-relate deffect s wer e note do n pregnanc y rate , number s o f

corpor alute aan dimplantations , implantatio n efficiencies , o r se x ratio . N o treatment-relate deffect s wer e note do n foeta l bod y weight s an dlengths . I n th e 2 an d4 mg/k g bw/da y groups , slightl y increase dincidenc e o f resorptio n wa s note d(no t statisticall y significant : 2 high-dos e doe s ha d100 % resorption ; 1 dea dfoetu s i n th e mid-dos e group) . Foeta l viabilit y wa s slightl y lowe r a t 4 mg/k g bw/da y bu t

wa s no t statisticall y significant . Ther e wa s n o apparen t tes t substanc e relate deffect s o n endocrin e functio n pertainin g t o maintenanc e o f pregnanc y o r

foeta l development . 2 4DuPont-2982 7 Foetal effect s N o tes t substance-relate deffect s wer e noted . Conclusion : No-observed-effec t

leve l (materna l toxicity) : 1 mg/k g bw/da y - base do n statisticall y significan t decrease dbod y weigh t

gai n a t 2 an d4 mg/k g bw/day . No-observed-effec t

leve l (foeta l toxicity) : 2 mg/k g bw/da y - base do n increase d percen t resorption s at

4 mg/k g bw/day . No-observed-effec t

leve l (developmenta l toxicity) : > 4 mg/k g bw/da y - highes t dos e tested . Ther e wa s n o evidenc e o f adirec t advers e effec t

o n th e endocrin e syste mi n thi s study . 3. 2 Discussio n o f

availabl e informatio n i n th e open literature 3.2. 1 Summar y o f

th e Potentia l t o Modulat e Estroge n o r Androge n Recepto r

Functio n I n aserie s o f

publications , researcher s use di n vitr o assay s t o evaluat e th e ability o f oxamyl , an dit s clos e structura l analogu e methomyl , t o modulat e activit y o f th e estroge n (ER) , androge n (AR) , o r progesteron e (PR ) receptors . I n th e report

b y Klotz , Arnold , an dMcLachla n (1997) , oxamy l an dmethomy l wer e evaluate dfo r

thei r abilit y t o modulat e E Ran dP Ractivity usin g transactivatio n assay s (MCF- 7 huma n breas t

cance r cells , Ishikaw ahuma n endometria l cancer cells , an d T47 D huma n breas t

cancer cells ) an dwhole-cel l competitiv e bindin g assays . I n th e transactivatio n assays , oxamy l an dmethomy l wer e teste dat aconcentratio n o f 10 0 n M an dth e response s compare dt o 17p-estradio l (50 0 p M i n MCF- 7 cells ; 1 n M i n Ishikaw acells ) o r

progesteron e ( 1 n M i n T47 D cells) . I n th e whole-cel l competitiv e bindin g assays , oxamy l an dmethomy l wer e teste dat concentration s o f 10 0 nM , IjaM , an d1 0 u M an dth e abilit y t o inhibi t bindin g o f

17p-estradio l (50 0 p M i n MCF- 7 cell s fo r

E Rbindin g assay ) o r

th e P Ragonis t

R502 0 ( 1 n M i n T47 D cell s fo r P Rbindin g assay ) wa s measured . The y report tha t bothoxamy l an dmethomy l weakly activate dER

- an dPR-responsiv e reporter gene s an ddecrease destradiol

- o r progesterone-induce dreporte r gen e activit y i n breas t

an dendometria l cance r

cells . Th e author s als o report

tha t a s aclass , th e carbamate s teste ddemonstrate dlimite d capacity t o displac e E Ro r P Rrecepto r

ligand s fro mth e E Ro r

P Ri n whol e cel l assays . The y sugges t

tha t th e carbamate s evaluate dac t a s partia l steroi dhormon e recepto r agonists/antagonist s i n bindin g assay s throug hamechanis mseparat e fro m ligan dbinding . Nishihar aan dcoworker s (2000 ) evaluate dmor e tha n 50 0 chemicals , includin g methomyl , i n ayeas t

two-hybri dtransactivatio n assay syste mwit hth e estroge n recepto r ER aan dth e coactivato r

TIF2 . Methomy l wa s teste du p t o amaximu m concentratio n o f

2x10" 4 M , an dth e respons e wa s compare dt o th e activit y o f 17p-estradiol . Methomy l showe dn o activit y unde r th e condition s o f

th e study . I n th e report

b y Anderse n an dcoworker s (2002) , methomy l wa s evaluate dfo r it s abilit y t o modulat e E Ran dP Rrecepto r activit y usin g transactivatio n assay s

_DuPont-2982 7 [MCF- 7 cells , an dChines e Hamste r Ovary (CHO ) Cells] , an dit s abilit y t o induc e cel l proliferatio n i n MCF- 7 huma n breas t cance r cells , amarke r

o f estrogeni c activity . I n - th e transactivatio n assays , methomy l wa s teste dove r aconcentratio n rang e o f

10" 8 t o 5xlO~ 5 M an dth e response s wer e compare dt o th e activit y o f 17p-estradio l (1 0 n M i n MCF- 7 cells ) o r

th e P Ragonis t

R l 88 1 (0. 1 n M i n CH O cells) . I n th e cel l proliferatio n assays , methomy l wa s teste dove r aconcentratio n rang e o f

10" 8 t o 5x10" 5 M i n MCF- 7 cell s an dth e response s wer e compare dt o th e activit y o f 17p-estradio l (concentratio n rang e o f

10~ 1 2t o 12~ 8 M) . Fo r

th e transactivatio n assay s an dth e cel l proliferatio n assay , methomy l wa s als o teste dafte r co-administratio n wit h 17p-estradio l (0.0 1 n M i n th e cel l proliferatio n assa y i n MCF- 7 cells ; 1 0 n M fo r th e E Rtransactivatio n assay i n MCF- 7 cells ) o r R188 1 (0. 1 n M fo r

th e transactivation . assa y i n CH O cells) . Unde r th e condition s o f

th e study , methomy l showe dn o : significan t

activit y i n an y o f

th e E Ro r

A Rtransactivatio n assay s o r th e cel l proliferatio n assay . I n th e report

b y Kojim aan dcoworker s (2004) , oxamy l an dmethomy l wer e evaluate d fo r their abilit y t o modulat e recepto r activit y usin g transactivatio n assay s fo r huma n ERa , huma n ERp , o r

huma n A Ri n CH O cells . I n al l o f th e assays , oxamy l an d methomy l wer e teste dove r aconcentratio n rang e u p t o 10" 5 M an dth e response s wer e compare dto-th e activit y o f 17p-estradio l o r

dihydrotestosteron e (DHT ) fo r th e E Ro r A Rassays , respectively . Relativ e luciferas e activit y wa s calculate drelativ e t o th e positiv e control s (17p-estradio l fo r ER aan dERp ; DH T fo r

AR) . I n addition , fo r measuremen t

o f antagonis t

activity , assay s wer e evaluate dwit hth e tes t materia l co-administere dwit h17p-estradio l (10' " M fo r ERa ; 10' 1 0 M fo r

ERP ) o r DH T (10' 1 0 M ) fo r th e E Ran dA Rtrasactivatio n assays , respectively . Unde r th e condition s o f

th e study , oxamy l an dmethomy l showe dn o significan t activit y i n an y o f

E Ro r A R transactivatio n assays . I n th e repor t

b y Nendz aan dWenze l (2006) , oxamy l an dmethomy l wer e evaluate d fo r thei r abilit y t o modulat e E Ractivit y usin g aYeas t Estroge n Scree n (YES) . I n th e assay , oxamy l an dmethomy l wer e teste dove r aconcentratio n rang e o f

10 0 mg/ 1 t o 5 0 ug/ml , an dth e response s wer e compare dt o th e activit y o f 17p-estradio l (concentratio n 3,00 0 ng/m l t o 1. 5 ng/ml) . Unde r th e condition s o f

th e study , oxamy l an dmethomy l showedn o significan t activit y i n th e YE S assay . I n th e report

b y Jia o an dcoworker s (2008) , atransgeni c yeas t screenin g syste musin g fis hE Rwa s establishe dan duse dt o evaluat e anumbe r o f xenobiotic s includin g methomyl . Methomy l wa s teste dat concentration s o f

10" 9 , 10" 7 , an d10" 5 M an dth e response s wer e compare dt o th e activit y o f 17p-estradio l o r

dihydrotestosteron e (DHT ) fo r

th e E Ro r

A Rassays , respectively . I n addition , fo r measuremen t

o f antagonis t activity , assay s wer e evaluate dwit hth e tes t materia l co-administere dwit h 17p-estradio l (concentratio n no t stated) . Unde r

th e condition s o f

th e study , methomy l showe dn o activity t o th e fis hE Ri n an y o f th e transactivatio n assay s that wer e performed . I Together , th e dat afro mthes e fiv e report s sugges t tha t oxamy l an dit s clos e structura l analogu e methomy l d o no t interac t wit hth e E Ro r

AR . Th e dat afro mfiv e o f th e si x report s wer e al l negative . I n th e repor t b y Klot z an dcoworkers , oxamy l an d methomy l activate dth e E Ran dPR . However , the y als o repor t tha t al l o f th e 

### 2 6DuPont-2982 7 carbamate s teste dweakl y activate dER

- o r PR-responsiv e reporte r

gene s an d decrease destradiol

- o r

progesterone-induce dreporte r gen e activit y i n breas t

an d endometria l cance r

cells . Th e author s als o report tha t th e carbamate s teste d demonstrate dlimite dcapacit y t o displac e E Ro r P Rreceptor , ligand s fro mth e E Ro r P Ri n whol e cel l assays . The y sugges t tha t th e carbamate s ac t

a s partia l steroi d hormon e recepto r

agonists/antagonist s i n bindin g assay s throug hamechanis m separat e fro mligan dbinding . However , severa l factor s i n thes e studie s sugges t tha t th e observe deffect s wer e non-specifi c an dunrelate dt o tru e receptor-mediate d effects . Thes e response s di dno t occu r i n adose-dependen t

manner , aserin e proteas e inhibito r (phenylmethy l sulfony l fluoride ) demonstrate dvery simila r activity , an d finally , th e compound s appeare dt o affec t bothth e E Ran dP Rsystem s t o a n equa l extent . Thes e ar e important point s i n tha t

whil e ther e i s "cross-talk " betwee n recepto r system s i t i s rar e tha t

acompound , endogenou s o r exogenous , wil l equall y affec t mor e tha n on e recepto r

system . I n fact , man y compound s evaluate di n thi s stud y ha d similar potencies , suggestin g tha t ther e ar e non-specifi c factor s involved . Thi s study provide s n o soli devidenc e tha t oxamy l o r

methomy l ar e steroi dhormon e recepto r agonists/antagonists , an dth e author s themselve s stat e tha t th e reporte dactivit y wa s no t recepto r mediated . Th e weigh t

o f evidenc e suggest s tha t

neithe r oxamy l no r methomy l interac t

wit hth e E Ro r

AR . 3.2. 2 Summary o f

th e Potentia l o f

Methomy l Modulat e Placenta l Aromatas e Activit y I n vitr o I n th e report

b y Anderse n an dcoworkers , th e clos e structura l analogu e o f oxamyl , methomyl , wa s evaluate dfo r it s abilit y t o modulat e CYP1 9 aromatas e activit y i n huma n placenta l microsome s usin g th e classi c tritiate dwate r releas e method . Methomy l wa s teste dat

asingl e concentratio n (5 0 |^M) an dth e respons e wa s compare dt o th e activit y o f 4-androsten-4-ol-3,17-dion e ( 1 uM) . Whe n teste da t a singl e concentratio n (5 0 |im ) unde r th e condition s o f

th e assay , methomy l induce d aromatas e activity t o approximatel y 120 % o f control . Whil e thes e dat asugges t tha t methomy l ma y hav e th e potentia l t o modulat e aromatas e activity , th e significanc e o f th e findin g i s unclea r

give n th e result s wer e no t repeate di n thi s study , onl y asingl e tes t concentratio n o f

methomy l wa s evaluated , an dn o finding s suggestiv e o f a n advers e effec t

o n aromatas e ha s bee n observe di n th e man y anima l studie s conducte d wit hoxamy l an dmethomyl . 3. 3 Availabl e Informatio n fro mth e EPA ToxCast TM Projec t EP A ha s initiate daprogra mt o scree n alarg e numbe r o f environmenta l chemical s i n a batter y o f i n vitro , high-throughpu t

screens . I n th e firs t

phas e o f thi s project , 30 9 substance s hav e bee n selecte dfo r testing , mos t

o f whic har e food-us e pesticide s fo r whic hextensiv e anima l toxicolog y testin g result s ar e availabl e (Judso n e t al , 2009) . Thes e substance s ar e bein g evaluate dwithnin e i n vitr o assay s technologie s coverin g 46 7 cell-fre e o r

cel l base dassays . Th e tota l numbe r o f endpoint s measure d fo r eac hchemica l i s 624 . ToxCas t ha s profile dman y o f

th e EDS P chemical s selecte d fo r initia l testin g i n th e Tier

I endocrin e battery , includin g oxamyl , usin g assay s whic hcharacteriz e recepto r binding , activation , inhibition , an dtarge t gen e regulatio n that ar e relevan t

t o estrogen , androgen , an dthyroi dan dothe r endocrine-relate d
2 7DuPont-29827 , processes . Include dar e si x assay s relate dt o estrogen , fou r assay s relate dt o androgen , fou r assay s relate dt o thyroid , an d1 assay relate dt o aromatas e a s wel l a s 7 0 othe r nuclea r receptor s an dxenobioti c metabolizin g enzyme s tha t hav e potentia l fo r endocrin e signalin g (Kavloc k e t al , 2009) . Th e result s fo r th e 30 9 chemical s i n Phas e I hav e bee n presente db y Rei f e t al. , (2009) ; base do n th e pictoria l presentatio n o f th e results , oxamy l appear s t o hav e produce dn o "hits " fo r an y o f th e endocrine

relate di n vitr o endpoints . 

### 4. 0 SUMMAR YO F RELEVAN TECOTOXICOLOG YSTUDIE S 4. 1 Discussio n o f

studie s supportin g registratio n Roberts , N.L. , Phillips , C.N.K. , Chanter , D.O. , McAllister , A . (1982b) ; Th e effect s o f dietar y inclusio n o f

oxamy l o n reproductio n i n th e bobwhit e quail . DuPori t Repor t No. : HL O 453-82 , MRID-00116610 , USEP A guidelin e 163.71-4 (1978) . Material s an dMethods : Group s o f youn g adul t

bobwhit e quai l (Colinu s virginianus) , wer e offere ddie t containin g technica l oxamy l (purity 97.1% ) at concentration s o f

0 , 1 0 o r 50-m g a.s./k g die t

fo r 2 8 week s (sixtee n week s prio r t o th e star

t o f eg g productio n an dtwelv e week s durin g eg g production) . Eac htreatmen t grou p comprise d 1 4 replicate s o f

on e mal e an dtw o females . Individua l adul t bod y weight s wer e recorde do n Day s 0 , 14 , 28 , 42 , 56 , 70 , 84 , an d196 ; foo dconsumptio n i n eac h replicat e wa s measure dweekl y throughou t th e pre-treatmen t

an dtreatmen t

period s o f th e adul t phase . Individua l chic k

bod y weight s wer e recorde dwithi n 2 4 hour s o f hatchin g an do n Da y 1 4 afte r hatching ; eg g shel l thicknes s wa s measure do n th e firs t tw o day s o f

Week s 1 , 3 , 5 , 7 , 9 , an d1 1 o f th e eg g productio n period . Adul t bird s an d chick s wer e observe ddail y fo r mortalit y an dclinica l signs ; al l adul t bird s wer e subjecte dt o pos t

morte mexamination . Findings : Fou r bird s die do r

wer e sacrifice d(tw o i n th e contro l an dtw o i n th e 50-m g a.s./k g die t

treatmen t group ) durin g th e pre-eg g productio n period ; al l wer e replace dwit hspar e birds . Ther e wa s n o treatment-relate deffec t o n adul t mortality ; clinica l observation s an dpos t morte mchange s wer e consisten t wit hlong-term housin g o f

bird s i n cages , an dwer e no t treatment-related . Adul t

bod y weigh t

change s ove r th e treatmen t

perio dwer e simila r

i n al l group s an dther e wa s n o evidenc e o f an y statisticall y significan t

treatment-relate deffect . Adul t foo dconsumptio n wa s significantl y lowe r

i n th e tw o oxamy l treate dgroup s compare dt o th e contro l durin g bothpre-eg g productio n an deg g productio n periods . Initia l chic k

bod y weight s wer e similar overal l i n al l treatmen t

groups ; chick s tha t die dafte r hatchin g durin g th e 14-day observatio n perio dwer e examine dan dn o abnormalitie s wer e detected . O f th e reproductiv e parameter s measured , fe w difference s wer e detecte dbetwee n th e contro l an doxamy l treatments , withtw o exceptions : th e proportio n o f damage degg s wa s lowe r i n th e 10-rn g a.s./k g die t
28 'DuPont-2982 7 treate dgrou p compare dt o th e control , an dth e proportio n o f chick s survivin g t o 1 4 day s wa s significantl y highe r i n th e 10-m g a.s./k g die t

treatmen t compare dt o th e contro l (William s test , PO.05) . Conclusion : Th e reproductiv e NOE C fo r bobwhit e quai l expose dt o oxamy l i n th e die t fo r 2 8 week s wa s 50-m g a.s./kg diet , base do n th e absenc e o f reproductiv e effect s at

th e highes t dos e leve l teste d(50-m g a.s./k g diet) . Roberts , N.L. , Phillips , C.N.K. , Chanter , D.O. , McAllister , A . (1982a) ; Th e effect s o f dietar y inclusio n o f

oxamy l o n reproductio n i n th e mallar dduck . DuPon t Report No. : HL O 337-82 , MRID-00116609 , USEP A guidelin e 163.71- 4 (1978) . Material s an dMethods : Group s o f youn g adul t

mallar dduck s (Ana s platyrhynchos) , wer e offere ddie t containin g technica l oxamy l (purit y 97.1% ) at concentration s o f

0 , 10 , o r 50-m g a.s./k g die t

fo r 2 2 week s (te n week s prio r t o th e start

o f eg g productio n an d durin g twelv e week s o f

eg g production) . Eac htreatmen t grou p comprise dsi x replicate s of

two mal e andfive females . Individua l adul t bod y weight s wer e recorde d o n Day s 0 , 14 , 28 , 42 , 56 , an d154 ; foo dconsumptio n i n eac hreplicat e wa s measure d weekl y throughou t

th e pre-treatmen t

an dtreatmen t

period s o f

th e adul t phase . Individua l chic k

bod y weight s wer e recorde dwithi n 2 4 hour s o f hatchin g an do n Day 1 4 afte r

hatching ; eg g shel l thicknes s wa s measure do n th e firs t tw o day s o f Week s 1 , 3 , 5 , 7 , 9 , an d1 1 o f th e eg g productio n period . Adul t bird s an dchick s wer e observe ddail y fo r

mortalit y an dclinical signs ; al l adul t bird s wer e subjecte dt o pos t morte mexamination . ' Findings : Seve n bird s die do r

wer e sacrifice ddurin g th e pre-eg g productio n perio dmainl y a s a resul t o f bullyin g (tw o i n th e 10-mg a.s./k g die t treatmen t an dfiv e i n th e 50-mg a.s./kg die t

treatment) , al l o f

whic h were replace dwit

hspare birds . Durin g the . eg g productio n period , si x bird s die di n th e control , tw o bird s die di n th e 10-mg a.s./k g die t

treatmen t an dnin e bird s die di n th e 50-m g a.s./k g die t treatment , o f whic hon e wa s sacrificed . Ther e wer e n o treatment-relate deffect s o n adul t mortality , foo dconsumptio n o r

bod y weight . Initia l ducklin g bod y weight s wer e simila r i n al l treatmen t groups . Duckling s tha t

die ddurin g th e 14-day observatio n perio dafte r hatchin g wer e examine dan dn o abnormalitie s wer e detected . Ther e wer e n o statisticall y significan t effect s o f treatmen t o n th e proportio n o f

eggs * cracked , mean eg g weight , embryoni c deaths , hatchabilit y o f fertil e eggs , o r

surviva l o f duckling s t o 1 4 days. I n th e 50-m g a.s./k g die t treatmen t group , statisticall y significan t reduction s compare dt o th e contro l wer e recorde do n th e number s o f egg s laid , tota l eg g mass , an dnumber s o f fertil e egg s produced .



### 2 9DuPont-2982 7 Conclusion ; Th e NOE C fo r

mallar dduck s expose dt o oxamy l i n th e die t fo r 2 2 week s wa s 10-mg a.s./k g diet , base do n eg g productio n an deg g viabilit y effect s observe dat th e highes t dos e leve l teste d(50-m g a.s./k g diet) . Hutton , D.G . (1988) ; Earl y lif e stag e toxicity ofIND1410-19 6 (oxamyl ) to rainbo w trout . DuPon t

Report No. : HLR468-88 . MRID 40901101 . (MRI D 4147230 1 fo r HLR468-88 , Supplemen t

1 , supplementa l dat afor

statistica l analysis) , USEP A guidelin e 72- 4 (1988) . Material s an dMethods : Rainbo w trou t

(Salmo gairdnerii , equivalen t t o Oncorhynchu s mykiss ) embryo s an d larva e wer e continuousl y expose dt o oxamy l (purity : 97.2% ) i n aflow-throug htes t syste mat measure dconcentration s o f 0.06 , 0.10 , 0.23 , 0.40 , 0.77 , an d1.5-mg a.s./ L fo r 6 1 days . Observation s wer e mad e o n embry o hatchin g an dlarva l surviva l an d growth . Th e tes t vessel s (aquari amad e o f

stainles s steel ) wer e fille dwit h7 litre s o f filtere d wel l wate r

(wate r depth : 1 7 cm) , maintaine dat th e tes t temperatur e (11.8-13.9°C) , wit hadissolve doxyge n concentratio n o f 9. 4 t o 10. 0 mg/L . Eac haquariu mwa s partitione di n th e middl e t o giv e tw o replicates . Fo r th e embry o phase , tw o 20 0 m L scree n bottome dglas s cup s wer e suspende di n eac haquariu mreplicat e (wate r depth : 2 t o 5 cm) , an dtwenty embryo s wer e adde dt o eac hcu p (8 0 embryo s pe r concentration) . Th e firs t

larva e hatche do n Da y 2 0 an dhatchin g wa s considere d complet e b y Da y 29 . A s th e larva e hatched , the y wer e transferre dfro mth e embry o cu p t o th e appropriat e aquarium , wit hu p t o 1 5 larva e pe r replicate ; exces s larva e wer e counte dan dthe n discarded . Surviva l o f th e remainin g larva e wa s assesse dfo r 3 2 days , an dat

th e en do f

th e stud y al l survivin g larva e wer e weighe dan dmeasured . Findings : Th e mea n measure dconcentration s o f oxamy l i n th e tes t

vessel s range dfro m75 % t o 100 % o f th e nomina l values. ' N o statisticall y significan t effect s o n embry o hatching , larva l survival , firs t

day o f larva l swim-up , o r

larva l growthwer e observe dat i

. measure dtes t

concentration s o f

0.0 6 t o 0.77-m g a.s./L . A t 1.5-m g a.s./

L(th e highes t concentratio n tested) , statisticall y significan t effect s o n embry o hatchin g an dadelay i n th e firs t da y o f larva l swim-u p wer e observe dcompare dt o th e control . Conclusion : Th e NOE C fo r

rainbo w trou t

expose dt o oxamy l wa s 0.77-m g a.s./L , base do n statisticall y significan t

effect s o n embry o hatchin g an dlarva l swim-u p a t 1.5-mg a.s./

L (mean measure dconcentrations) .

3 0DuPont-2982 7 Driscoll , R.R . (1982) ; Earl y lif e stag e toxicity ofoxamy l t o fathea dminnow . DuPon t Report No . HL R877-81 , MRID s 00094663 , 00116607 , 00126510 , and 00248463 , guidelin e "Standar dPractic e fo r

Conductin g Toxicit

y Tests wit hEarl y Lif e Stage s o f

Fishes " Committe e E-4 7 o f America n Societ

y fo r Testin g an dMaterial s (DraftNo . I.Februar y 1981) . Material s an dMethods : Duplicat e group s o f

5 0 fathea dminno w (Pimephale s promelas ) egg s (fertilise d embryos , les s tha n twent y fou r hour s ol da t

stud y initiation ) wer e expose dt o oxamy l (purity 97. 1 % ) at

nomina l concentration s o f 0 (control) , 0.25 , 0.5 , 1.0 , 2.0 , an d 4.0-m g a.s./

L i n aflo w throug hsystem . Eg g viabilit y wa s assesse ddail y unti l hatchin g wa s complete ; an y dea dembryo s o r embryo s covere di n fung i wer e removed . T o initiat e th e 28-da y larva l exposur e study , 2 0 newl y hatche dfathea dminnow s wer e randoml y selecte dfro meac hembry o replicat e an dtransferre dt o th e respectiv e tes t aquarium , wit htw o replicate s pe r concentration ; th e exces s larva e wer e counte dan d the n discarded . Th e tes t

larva e wer e fe da t

leas t onc e dail y o n liv e brin e shrimp .naupli i (Anemi asalind) . Th e tes t condition s wer e 1 6 hour s light , 8 hour s dark ; a temperatur e o f

25°C ; p H 7. 5 t o 7.7 ; an ddissolve doxyge n 7.7-7. 8 mg/L . Dail y •observation s wer e mad e o n larva l mortality , behaviou r an dappearance . Th e numbe r o f liv e fry i n eac haquariu mwa s recorde dweekly . A t tes t termination , survivin g larva e wer e measure d(mea n standar dlength ) an dindividuall y weighed . Findings : > Analytica l determination s ofoxamy l concentration s wer e withi n 25 % o f nomina l levels . Percen t

embry o hatc hwa s reduce di n on e o r bothreplicate s a t

nomina l tes t concentration s o f

0.25 , 2.0 , an d4.0-m g a.s./L ; howeve r thes e reductions , whic hwer e no t statisticall y significant , wer e considere dt o b e aresul t o f funga l growthrathe r

tha n atreatmen t

relate deffect . Significan t reduction s i n larva l surviva l wer e detecte da t nomina l tes t

concentration s o f

1.0-m g a.s./

Lan dabove . Howeve r

significan t

effect s o n larva l growth(mea n standar dlength ) occurre donl y at th e highes t

concentratio n teste d(4.0-m g a.s./L) . N o treatment-relate deffect s o n eg g viability , larva l surviva l o r growthwer e detecte dat

nomina l concentration s o f 0.5-m g a.s./Lo r

below . Conclusion : Th e NOE C ofoxamy l t o th e earl y life-stage s o f fathea dminno w wa s 0.5-m g a.s./L , base do n th e reduce dsurviva l o f fathea dminno w larva e expose dfo r 2 8 days . Th e LOE C wa s 1.0-m g a.s./L .



### 3 1. DuPont-2982 7

4. 2 Discussio n o f

availabl e informatio n i n th e ope n literatur e Additiona l informatio n wa s sough t i n th e publishe dliteratur e b y searchin g th e ECOTO X dat abas e an dTOXCENTER . Th e searc hi s summarize dbelow : TOXCENTERwa s searche db y CA S #(16752-77- 5 OR23135-22-0 ) an dke y terms :
• hormone ? o r

endocrine ? o r

endocrin e disruptio n o r

?androgen ? o r ?estrogen ? o r

testosterone ? o r

recepto r bindin g o r

reprod ? o r

develop ? o r tox ?

• i n utero ? o r

terat ? o r steroid ? o r

aromatase ? o r

thyroid ? o r

hershberger ? o r pubert ? o r utero ? o r ovar y o r ovarie s o r

teste ? o r sex ? Th e abov e searc hwa s narrowe ddow n t o thos e papers/report s relevan t t o
• amphibia n metamorph ? o r fis ho r amphibian ? o r

frog ? o r bird ? N o additiona l relevan t

ecotoxicolog y dat awa s identifie db y thes e searches . 

### 5. 0 DuPoN TPOSITIO N AN D CONCLUSION S 5. 1 Potential fo r

Oxamy l to Interac t

wit hth e Endocrin e Syste

m Oxamy l ha s no t

bee n specificall y evaluate di n th e 1 1 assay s comprisin g th e Tie r 1 EDS P battery . However , existin g toxicolog y studie s supportin g the registratio n of thi s produc t

indicat e tha t

exposur e t o mammal s o r

wildlife specie s result s i n n o effect s suggestiv e o f

interferenc e wit hestrogen , androgen , o r thyroi dhormon e function . A fairl y comprehensiv e evaluatio n o f th e structur e an dfunctio n o f endocrine-relate dtissue s ha s bee n don e i n acombinatio n o f subchroni c an dchroni c studie s i n rats , mice , an ddog s an di n multigeneratio n reproductio n an d developmenta l toxicit y studie s i n rat s an drabbit s (Tabl e 2) . Thi s ha s include d adrenals , pituitary , thyroid , testis , epididymis , prostate , coagulatin g gland , seminal vesicles , ovary , fallopia n tubes , uterus , vagina , cervix , an dmammar y gland . I n non e o f thes e studie s wer e ther e treatment-relate deffect s o n eithe r organ weigh t

o r microscopi c patholog y tha t suggeste dendocrin e syste mdysfunction. ! In long-ter m chronic/oncogenicity studies , no tumor s of any kind , includin g no tumor s of the endocrin e tissues , wer e induce db y oxamyl . Oxamy l ha s bee n evaluate dfo r effect s o n prenata l developmen t o r reproductio n i n thre e studies . I n th e prenata l developmenta l toxicit y studies , n o effect s wer e observe d o n th e maintenanc e o f

pregnancy , numbe r

o f pups/litter , feta l size , o r

feminizatio n o r masculinizatio n o f

pup s (se x ratio) . Th e onl y effect s note di n offsprin g wer e decrease s i n bod y weigh t

th e hig hdos e level s o f

0. 8 an d1. 5 mg/k g bw/day , whic h occurre din the presenc e of simila r reduction s in materna l weigh t andclinica l sign s of

. cholinesteras e inhibition . I n th e rabbi t study , th e observe deffect s a t th e hig hdose s ( 2 an d4 mg/k g bw/da y b y gavage ) wer e areductio n i n bod y weigh t gai n i n th e dam s an dasligh t

increas e i n resorption s an dreduce dviabilit y i n th e pups . Th e outcom e o f

amultigeneratio n reproductio n stud y i n rat s als o demonstrate dalac k o f an advers e effec t

b y oxamy l o n th e hormonal contro l o f sexual development , 3 2DuPont-2982 7

, growth , an dreproduction . Oxamy l produce dn o advers e effect s tha t suggeste dth e endocrin e system s associatio n wit hreproductio n an ddevelopmen t wer e negativel y impacted . Ther e wer e n o effect s o n reproductiv e parameter s suc ha s mating , fertility , an dgestatio n length . Ther e wer e als o n o dat ai n thes e studie s t o indicat e tha t sexua l differentiatio n (se x ratio) , puberta l development , productio n o f germcells , an d accessory se x organ s ha dbee n adversel y affected . Th e primar y effect s note dwer e bod y weigh t

decrease s an dreduce dfoo dconsumptio n i n parenta l animal s a t th e tw o hig hdose s o f

7 5 an d15 0 pp mi n diet . I n addition , areductio n number s o f pups , pu p survival, an dpu p weigh t

a t thes e sam e dose s occurre dan dwer e consisten t withth e bod y weigh t

effect s observe di n th e parenta l animals . I n athree-generatio n reproductio n stud y conducte di n conjunctio n wit halong-ter mchroni c study , litte r siz e an dpu p viabilit y wer e slightl y decrease da t th e sam e dos e level s a t

whic h consisten t depression s i n parenta l bod y weigh t wer e observed . N o treatment-relate d : effect s occurre do n reproductiv e parameters . Ther e wer e n o histopathologica l finding s du e t o treatmen t

withoxamy l i n anumbe r reproductiv e tissue s examine d fro m2 mal e an d2 femal e Fs b pups/litte r a t weaning . Histopatholog y o f

th e ovary , testes , an daccompanyin g accessory reproductiv e tissue s hav e bee n evaluate din anumbe r of studie s in rats , mice , anddog s followin g subchroni c an dchroni c exposure s t o oxamyl . Gonada l activit y wa s eviden t b y th e presenc e o f

follicle s an dcorpor alute ai n th e ovary an dth e presenc e o f spermi n th e teste s an depididymides . I n al l o f thes e studies , ther e ha s bee n n o indicatio n tha t oxamy l adversel y affect s estroge n o r androge n dependen t

processe s i n thre e species . Therefore , th e overwhelmin g evidenc e fro msubchronic/chroni c toxicity , multigeneratio n reproduction , an ddevelopmenta l toxicit y studie s conducte di n rats , mice , dogs , o r

rabbit s indicat e tha t

oxamy l produce s n o advers e effect s o n th e endocrin e syste mo f

mammals . Exposur e t o bobwhit e quai l resulte di n n o reproductiv e effect s a t th e highes t

dos e tested . I n contrast , reduction s i n number s o f egg s laid , tota l eg g mass , an dnumber s o f fertil e egg s produce dwer e note di n th e hig hdos e grou p o f areproductio n stud y i n mallar dduck . Chroni c exposur e t o fis hresulte di n reduction s o f embry o hatchin g an d larval swim-up . I n th e absenc e o f an y evidenc e o f

advers e effect s suggestiv e o f interferenc e o f

icstrogen , androgen , o r

thyroi dhormon e proces s i n mammalia n toxicit y studies , however , th e change s i n thes e apica l endpoint s ar e attribute dt o a direc t toxi c effec t

o f th e carbamat e rathe r

tha n endocrin e syste mdysfunctio n i n thes e species . 5. 2 Functionall y Equivalen t Informatio n Fulfillin g the EDS P Tie r IBatter y EP A outline di n it s Marc h26 , 200 9 approac hfo r considerin g OSRI unde r

th e EDS P that i t wil l mak e decision s a s t o whethe r existin g informatio n satisfie s al l o r par t o f th e Tie r 1 Tes t Orde r base do n th e weigh t

o f th e evidence . Base do n th e availabl e informatio n fro mmammalia n toxicolog y an decotoxicolog y studie s supportin g th e registratio n o f

oxamy l a s wel l a s informatio n fro mth e ope n literatur e an dToxCastTM , DuPon t propose s tha t

th e primar y purpos e o f

th e Tie r 1 EDS P screenin g battery , t o
3 3

### DuPont-2982 7

asses s th e potentia l t o interac t withestroge n androgen , o r thyroi dhormon e systems, , ha s bee n fulfilled . Th e EPA' s Tie r

1 estroge n an dandroge n recepto r bindin g assay s an destroge n transcriptio n activatio n assay ar e designe dt o identif y substance s tha t

eithe r bin dt o th e estrogen an dandroge n recepto r o r bin dto th e estroge n recepto r an dactiv e th e subsequen t

downstrea mtranscriptio n of areporte r gen e product . As note din Sectio n 3.2. 1 above, oxamyl , a s wel l a s it s structura l analogu e methomyl , ha s bee n teste di n anumbe r

o f estroge n o r

androge n transactivatio n assay s i n whic hth e majorit y o f

th e result s sugges t

alac k o f agonis t an dantagonis t

activity . EP A ToxCast TM programals o include s anumbe r o f estroge n an dandrogen.bindin g assessment s i n whic hth e reporte dresult s sugges t alack-o f activit y (Reif, 2009 ) o f bothproducts . Further , th e i n viv o mammalia n toxicolog y databas e fo r oxamy l provide s considerabl e evidenc e tha t estroge n andandroge n dependen t proces s in rats , mice , dogs , an drabbit s ar e no t adversel y affected . Therefore , i t i s DuPont' s positio n tha t i t i s unnecessary t o conduc t

furthe r estroge n o r

androge n bindin g studie s wit h oxamyl . Th e purpos e o f

th e Tie r 1 steroidogenesi s an daromatas e assay s ar e t o identif y substance s tha t

eithe r interfer e wit hsteroi dhormon e synthesi s resultin g i n testosteron e an destradio l o r whic hinhibi t

th e catalyti c activit y o f

th e enzym e responsibl e fo r

th e conversio n o f

androgen s t o estrogens . I n th e absenc e o f an y advers e effect s i n th e i n viv o mammalia n toxicolog y studie s conducte dt o dat e wit h oxamy l tha t

woul dsugges t

interferenc e of

steroi dhormon e productio n (e.g. , adrena l an dreproductiv e organ weigh t o r histopathology , fertility , gestation , se x ratio) , i t i s DuPont' s positio n tha t

n o furthe r testin g o f oxamy l i n th e steroidogenesi s an d aromatas e assay s i s necessary . Th e uterotrophi c an dHershberge r assay s ar e intende dt o determin e th e potentia l o f substance s t o induc e uterin e o r mal e reproductiv e orga

n weigh t change s consistent wit hagonist s o r

antagonist s o f

natura l estroge n o r

androgen/5a-reductas e inhibitors , respectively . Uterin e weigh t (withan dwithou t

th e product s o f

conception ) ha s bee n assesse di n developmenta l toxicit y studie s i n rat s an drabbit s conducte dwit hoxamyl . Histopatholog y o f

anumbe r o f femal e reproductiv e tissue s ha s bee n evaluate di n one . o r more o f th e studie s summarize dabove (ovary , fallopia n tubes , uterus , vagina , an d mammar y gland) . Teste s weight s wer e measure di n th e majorit y o f thes e studie s a s well . On e stud y als o include depididymi s weights . Histopatholog y o f th e testes , epididymis , an dprostat e wer e include di n mos t o f th e subchroni c an dchroni c studie s a s wel l a s th e multigeneratio n reproductio n study . Semina l vesicle s an dcoagulatin g gland s wr e als o examine di n severa l studies . I n th e absenc e o f an y advers e findings , th e weigh t o f th e evidenc e suggest s tha t oxamy l doe s no t

produc e an y effect s consisten t wit hestroge n o r

androge n agonist s o r

antagonists . Therefore , i t i s DuPont' s positio n tha t

ther e i s n o nee dt o conduc t eithe r th e uterotrophi c o r Hershberge r

assay withoxamyl . Th e inten t o f th e mal e an dfemal e puberta l assay s i s t o identif y substance s tha t interac t wit hth e endocrin e syste mb y assessin g endpoint s associate dwit hpuberta l developmen t

an dthyroi dfunctio n i n mal e an dfemal e animals . A s note di n th e abov e discussio n regardin g th e uterotrophi c an dHershberge r assays , orga n weight s and/o r 3 4DuPont-2982 7 histopatholog y o f

afairl y larg e numbe r

o f reproductiv e tissue s hav e bee n assesse di n man y o f th e existin g mammalia n toxicolog y studie s conducte dt o date . Adrena l weight s an dpituitar y weight s an dmicroscopi c patholog y hav e bee n include di n th e majorit y o f

thes e studie s a s well . Th e multigeneratio n an ddevelopmenta l toxicit y studie s hav e reveale dno concern s for an advers e effec t

on puberta l development . Thes e studie s hav e assesse dsuc hendpoint s a s matin g behavior , fertility , maintenanc e o f pregnancy , gestatio n length , offsprin g se x ratio . I n addition , athree-generatio n reproductio n stud y wa s conducte di n whic hther e wer e n o effect s o n reproductiv e performanc e ove r

thre e generations ; th e stud y als o include dhistopathologica l evaluatio n of

anumbe r of reproductiv e tissue s in F^ weanlings . Therefore , unde r thes e circumstances , i t

i s DuPont' s positio n tha t

th e evaluatio n o f

oxamy l i n th e femal e an dmal e puberta l assay s i s no t necessary . Th e amphibia n metamorphosi s assay (AMA ) i s designe dt o empiricall y identif y substance s whic hma y interfer e wit hth e norma l functio n o f th e HP T axis . Thyroi d hormone , throug hth e HP T axis , regulate s man y processe s i n a n organis mincludin g somati c growth , development , metabolism , an dreproduction . I t i s DuPont' s positio n that'th e existin g mammalia n toxicolog y studie s sufficientl y demonstrat e tha t oxamy l doe s no t interac t wit hth e HP T axis . N o treatment-relate deffect s wer e observe do n th e thyroi dglan di n th e studie s supportin g registratio n o f oxamy l an dsummarize d above , whic hinclude da n evaluatio n o f orga n weigh t

and/o r histopatholog y i n rats , mic e an ddogs . Man y o f

th e importan t

feature s o f

th e thyroi dsyste man dth e HP T axi s ar e conserve dacros s al l tax a(OECD , Detaile dRevie w Pape r o n Thyroi d Hormon e Disruptio n Assays , Apri l 2006) . Therefore , give n th e degre e t o whic hth e thyroi dha s bee n evaluate di n thre e mammalia n species , ther e i s n o nee dfo r furthe r testin g o f oxamy l i n th e Tie r

1 AM A screen . Th e fis hshort-ter mreproductio n assa y i s designe dt o measur e th e reproductiv e performanc e o f

fathea dminnow s a s aprimary indicato r o f potentia l interactio n o f xenobiotic s wit hth e endocrin e system . Th e endpoint s examine di n thi s assay includ e survival , fecundity , fertilizatio n success , change s i n morphology , an dbiochemica l endpoint s whic hmigh t

b e indicativ e o f

disturbance s i n estroge n an dandroge n dependen t processes . DuPon t

i s o f th e positio n tha t

afis hshort-termreproductio n assay shoul dno t

b e require dfo r

oxamyl . Sufficien t

informatio n i s availabl e fro mth e mammalia n toxicolog y dat abas e an dth e chroni c ecotoxicolog y studie s wit hbird s an dfis ht o demonstrat e th e lac k o f interferenc e wit hestroge n an dandrogeri " dependen t processe s an dtha t

an y effec t o n th e norma l functio n o f th e reproductio n syste mo f vertebrate s i s du e t o fran k toxicit y o f

th e carbamate , no t

t o interferenc e wit hth e reproductiv e endocrin e system . 5. 3 Overal l Conclusio n

Oxamy l i s acarbamat e insecticid e whic hexert s it s biologica l activit y b y inhibitin g acetylcholinesteras e i n th e nervou s syste mo f insects , mammals , an dothe r vertebrat e species . Oxamy l ha s hig hacut e toxicit y b y th e oral , inhalatio n an docular route s o f exposure . Th e primary toxicologica l effect s observe di n toxicolog y studie s ar e thos e associate dwit hcholinesteras e inhibition . Thi s substanc e i s no t acarcinoge n o r genotoxin , no r

i s i t areproductiv e o r

developmenta l toxicant . A s summarize dabove, ther e i s n o evidenc e i n th e availabl e mammalia n an decologica l toxicolog y studie s t o

_

### DuPont-2982 7 sugges t tha t oxamy l directl y interact s wit hth e functio n o f estrogen , androgen , o r thyroi dhormon e processe s t o caus e endocrin e dysfunction . . A similar toxicolog y databas e exist s fo r

methomyl , anothe r

DuPon t carbamat e insecticid e whic hshare s clos e structura l analog y t o oxamy l an dwhic hals o demonstrate s lo w potentia l t o interac t wit hth e endocrin e syste m(se e DuPon t respons e t o Tes t

Orde r EDSP-090301-62 , DuPon t -29838) . Oxamy l i s currently bein g regulate db y EP A usin g a n extremel y conservativ e mammalia n toxicolog y oral endpoin t base do n subtl e change s i n bloo dan dbrai n acetylcholin e esteras e activit y at very lo w dos e levels , substantiall y lowe r

tha n thos e evaluate di n th e registratio n studie s cite dabove . Likewise , th e aquati c ris k

assessmen t

fo r oxamy l i s base do n toxicit y observe di n aquati c invertebrate s (Daphni amagna) , bein g th e mos t sensitiv e species . Therefore , DuPon t consider s tha t

intent.o f th e Tie r 1 EDS P screenin g battery ha s bee n fulfille d fo r oxamy l base do n th e availabilit y o f alarg e databas e whic hindicate s alac k o f a direc t advers e effec t

o n th e endocrin e syste mo f mammal s an dwildlife species . 

### 6. 0 REFERENCE S

Andersen , H . R. , A . Vinggaard , T . Rasmussen , I . Gjermandsen , E . Bonefeld

Jorgense n (2002) . Effect s o f Currentl y Use dPesticide s i n Assay s fo r Estrogenicity , Androgenicity , an dAromatas e Activit y I n Vitro . Toxicol . Appl . Pharmacol . 179:1-12 . Burin , G. , L . Chitlik , S.L . Makris , an dJ.N . Rowe , (1993) . Reproductiv e toxicit y studies . Standar devaluatio n procedure . HealthEffect s Division : Draf t Offic e o f Pesticid e Programs . U S Environmenta l Protectio n Agency , Washington , D.C. , Octobe r 1993 . Europea n Centr e fo r

Ecotoxicolog y an dToxicolog y o f Chemical s (ECETOC ) (1996) . 'Environmenta l Oestrogens ' A compendiu mo f tes t methods . Documen t

No . 33 , Jul y 1996 . Brussels , Belgium . Gruggs , C.J. , J.C . Perkham , an dK.D . Cat o (1983) . Mammar y carcinogenesi s i n rat s i n relatio n t o th e ag e a t

tim e o f N-nitroso-N-methylure aadministration . J . Natl . Cance r Institute . 70:209-212 . Hseuh , A.J.W. , M.L . Dufau , an dK.J . Catt (1977) . Gonadotrophi n induce dhormon e receptor s an ddesensitizatio n o f testicula r 3',5'-cycli c AM P an dtestosteron e responses . Proc . Natl . Acad . Sci . US A 74:592-595 . Jiao , B . e t al , (2008) . Establishmen t o f aTransgeni c Yeas t

Screenin g Syste mfo r Estrogenicit y an dIdentificatio n o f th e Anti-Estrogeni c Activit y o f Malachit e Green . J . Cell . Biochem . 105:1399-1409 . Judson , R. , e t

al , (2009) . I n vitr o screenin g o f environmenta l chemical s fo r targete d testin g prioritizatio n - Th e ToxCas t Project . Environ . HealthPerspect . Online , Decembe r 14 , 2009 . Availabl e at

http://dx/doi/org . Kavlock , R. , e t

al. , (2009) . Biologica l profilin g o f endocrin e relate deffect s o f chemical s i n ToxCastTM . Poste r presentatio n availabl e at ' http://www.epa.gov/NCCT/toxcast/files/summit/40P%20Kavlock%20TDAS.pdf . 3 6

### DuPont-2982 7 Klotz , D . M . S.F . Arnold , an dJ.A . McLachlan . (1997) . Inhibitio n o f 1 7 Beta

Estradio l an dProgesteron e Activity i n Huma n Breas t Cance r an dEndometria l Cance r Cell s b y Carbamat e Insecticides . Lif e Sci . 60:1467-1475 . Kojima , H . e t

al , (2004) . Screenin g fo r Estroge n an dAndroge n Recepto r Activitie s i n 20 0 Pesticide s b y I n Vitr o Reporte r Gen e Assay s Usin g Chines e Hamste r Ovar y Cells . Environ . Health . Perspec . 112:524-531 . ' Nationa l Researc hCounci l (1999) . Hormonall y Activ e Agent s i n th e Environment . Nationa l Academ y Press . Washingto n DC . 43 0 pages . http://www.nap.edi^ooks/0309064198/html / Nishihara , T . e t

al. , (2000) . Estrogeni c activitie s o f 51 7 chemical s b y yeas t

two hybri dassay . J . o f

HealthSci . 46 : 282-29 8 Nendza , M . an dWenzel , A . (2006) . Discriminatin g Toxican t Classe s b y Mod e o f Action , 1 ) (Eco)toxicity Profiles) . Environ . Sci . & Pollut . Res . 13:192-203 . Reif , D. , e t

al. , (2009) . Endocrin e profilin g an dprioritizatio n usin g ToxCas t Assays . Poste r presentatio n availabl e at http://cfpub.epa.gov/si/si_public_record_report.cfm?dirEntryId=218187&fed_or g _id=1267&SIType=PR&TIMSType=Presentation&showCriteria=0&address=cor n ptox&view=citation&orderByl=FY%20desc&orderBy2=ID . Stevens , J.T. , A . Tobia , J.C . Lamb , C . Tellone , an dF . O'Nei l (1997) . FIFRA Subdivisio n Ftestin g guidelines : Ar e thes e test s adequat e t o detec t potentia l hormona l activit y fo r

cro p protectio n chemicals ? J . Toxicol . Environ . Health 50:415-431 . va n Ravenzwaay , B . (1992) . Discussio n o f prenata l an dreproductio n toxicity stud y o f Reg . No . 83-25 8 (Vinclozolin) . Dat asubmissio n t o U S EP A fro mAS F Corporation , 425813-02 .

3 7

### DuPont-2982 7



### TABL E 1 CITE D OXAMY L TOXICITYSTUDIE S SUPPORTIN G REGISTRATIO N

MRI D No . 0006691 1

0011339 8

4196320 1 0007681 3 4169790 1 4205270 1 0008335 2

4166080 1 4085920 1 4473750 1 0006300 9 0011661 0 0011660 9 4090110 1 4147230 1 0009466 3 0011660 7 0012651 0 0024846 3 REPOR TN o

HL R 308-6 9

HL O 328-6 9

HL R 278-9 1 HL O 252-8 1 HL R 381-9 0 HL O 555-9 0 HL R 37-7 2

HL R 423-9 0 HL R 473-8 8 DuPont-195 4 HL O 0801-8 0 HL O 453-8 2 HL O 337-8 2 HL R 468-8 8 HL R 877-8 1 TITL E

Ninety-da yfeedin g stud yi n rat s wit h 1 - (Dimethylcarbamoyl)-N - (Methylcarbamoyloxy)thioformimidi c acid , methy l este r(IND-1410 ) 1 3 wee k ora l administratio n - dog s - insecticid e 141 0 Combine d chroni c toxicity/oncogenicit ystud y wit h oxamy l (IN-D1410-196 ) long-ter m feedin g

stud yi n rat s Lon g ter m feedin g stud yi n mic e wit h oxamy l Chroni c toxicit ystud ywit h oxamy l (I N D1410 - 196 ) one-yea rfeedin g stud yi n dog s 52-wee k dietarytoxicit ystud ywit h IND-141 0 (oxamyl ) i n mal e dog s Long-ter m feedin g stud yi n rat s an d dog s wit h

1 -(dimethylcarbamoyl)-N - (methylcarbamoyloxy)-thioformimidi c acid ,

methy l este r(IND-1410 ) Reproductiv e an d fertilit yeffect s wit h oxamy l (I N D1410 ) multi-generatio n reproductio n

stud yi n rat s Teratogenicit ystud yo f I N D1410-19 6 i n th e .

ra t DuPont' s positio n o n foeta l weigh t change s i n rat s followin g developmenta l toxicit ytestin g

wit h oxamy l Teratolog ystud yi n rabbit s - oxamy l Th e effect s o f dietaryinclusio n o f oxamy l o n reproductio n i n th e bobwhit e quai l Th e effect s o f dietaryinclusio n o f oxamy l o n reproductio n i n th e mallar d duc k Earl ylif e stag e toxicit yo f I N D1410-19 6 (oxamyl ) t o rainbo w trou t Earl ylif e stag e toxicit yo f oxamy l t o

fathea d minno w REVIEWE D B YEP A (Y O R N ) Y

Y

Y Y Y Y Unknow n

Y Y Y Y Y Y Y Y EP A

CLASSIFICATIO N Unacceptabl e (waive d du e t o acceptabl e chroni c study ) Unacceptabl e (waive d du e t o acceptabl e 1 yea r studies ) Acceptabl e Acceptabl e Acceptabl e Acceptabl e Unknow n Acceptabl e Acceptabl e Acceptabl e Acceptabl e Supplementa l Acceptabl e Acceptabl e Acceptabl e i

3 8

### DuPont-2982 7



### TABL E 2 ENDOCRIN E TISSUE S EVALUATE D I N MAMMALIA N TOXICOLOG Y

STUDIE S CONDUCTE D WIT H OXAMY L . TISSU E Adrena l Pituitar y Thyroi d Teste s Epididymi s Prostrat e Semina l vesicle s Coagulatin g glan d Ovar y Follopia n tub e Uteru s Vagin a Mammar y glan d 90- D

RA T W , H W , H H W , H H

H

H 90- D DO G W , H W , H W , H W

H H 1-Y R DO G H H W , H W , H H H

H

H H 1-Y R DO G

w W 2-Y R RA T H H H W , H H H H

H -
H H H 2-Y R RA T W , H W , H H W , H H H

H

H H 2-Y R MOUS E H H W , H H H H

H

H H 2-Y R DO G W , H W , H W , H W , H H H

H H H H . 2-GE N REPR O H W , H H H H H H

H H 3-GE N REPRO * H H H H

H RAT DE V

G
G , W RABBI T DE V

,

G
G , W

W= orga n weight ; H = histopathology ; G. = gros s patholog y onl y * F3 b pup s

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