EPA REG I ST R A T I ON D I VISION C O M PA NY NOT IC E OF F I L I NG F O R

P E STICIDE P ETI T IONS PU B L ISH E D IN T H E F EDERAL R E GI S TER

EP A R e gi st r at i o n Di v i s io n c o nt a c t : [ Jessica Rogala 703

- 347

- 0263 ]

T E MP LA T E:

[Bayer C r opScience]

[ 2F8101 ]

EPA h a s re c e i v ed a pesticide pet i t ion ([ 2F8101 ]) f r o m [Bayer C r o pSc i ence], [2

T.W. A l ex a nder D ri v e, Rese a rch T r i a n g le P a r k

, NC 2 770 9 ] p r o p os i ng

, p u rs u a n t t o

s e cti on 4 0 8 ( d ) o f th e F e d e r al F o od

, D r ug

, and C os me ti c A c t (FFD C A)

, 21 U

. S.C

. 34 6 a ( d)

, t o a m e nd 40 CF R p a r t 1 80 by e s t a bli s h i ng a t ol e r a nc e f

o r to t al residues of

[flupyrad i f

u r o ne, 2(5H )

- f

u r a none,4

- [[ ( 6

- chlo r o

- 3

- pyri d inyl ) methyl ]( 2

, 2

-

d ifl u o r oet h y l )ami n o ] in or on t h e r a w a gr i c u l t u ral c o mm o d i ti e s [ A sp i r a t e d G ra i n s

Fr a c ti o ns] at [ 4 0 ] p p m

, [ R o ot V e ge t a bl es Exc e p t S u g ar B eets ( C r op Sub g roup 1 B )] at

[ 1

. 5 ] pp m

, [ T ube r o u s a n d Co r m V e g e t ab l e

, (C r op S u b

- G r o u p 1C) ] at [ 0

. 5 ] p p m

, [ O n i on

, b u l b

, s u bgr o u p

, ( C rop sub g roup 3

- 07A] at [ 0

. 3 ] p p m

, [ O n i o n

, g r e e n, subgrou p

, (Crop

su b gro u p 3

- 07 B )] at [3 ] pp m

, [Le a f y Ve g eta b l e s, E x cept B r assi c a V e g e t a bl es ( C r op

G r oup 4 )] at [ 40 ] pp m

, [T a ro L e a v es] at [40] pp m

, [He a d and Stem Brassica (Cr o p

Sub g r o up 5A)] at [ 6 ] p p m

, [ L e a f y Br a s si ca G r ee n s (C r op S u bg r o u p 5B)] at [40] pp m

, [ T urn i p Gr ee n s ] at [4 0 ] p p m

, [ E di b l e

- P od d e d L e gu m e V e g e t ab l es ( C r op Sub g roup 6A)]

at [ 5 ] pp m

, [S uc cu l e n t, S h e l led P e a and B e a n ( C rop Sub g roup 6 B )] at [4] p p m

, [ Drie d,

She l l e d P ea a nd B e a n ( E xc e pt S oy b e a n ) (C r op S u bg r ou p s 6C) ] at [6 ] p pm, [ F oli age o f

L e gu m e v ege t a

b l e s

, i n clu d i n g s oy bea n s (C r op G ro u p 7)

, F o r age

, G r e e n V i n e s ] at [40]

pp m

, [ F o l i a g e o f L e gu m e v e g e t a bl es, in c l u d i ng s o yb e a n s ( C r o p Gr oup 7), H a y ] at [5 0 ]

p p m

, [So y bea n

, se e d ] at [ 4 ] p p m

, [ F ru i t ing Ve g e t a b les, E x ce p t C u c u r b i t s (C r o p G r oup 8

- 10), Fru i t ] at [ 3 ] p p m

, [ T o m a to

, p aste ] at [4 ] pp m

, [ C u c u r bit V e ge t a bl e s (C r o p G r oup 9)

, Fr uit ] at [ 2 ] pp m

, [Cit r u s F rui t s (C r op G r o up 1 0

- 1 0), F r u i t ] at [ 3 ] p p m

, [C i tr u s, pulp,

d rie d ] at [15] pp m

, [ P o m e Fru i ts (Crop G r oup 11

- 1 0), F r u i t] at [ 1

. 5 ] pp m

, [B u s hb e r r y

Sub g roup (Crop Sub g roup 1 3

- 07B)] at [ 4 ] p p m

, [ S m a l l Frui t V i n e C l i m bing Sub g rou p

, E x cept F u z z y Kiwifr u i t (Crop Subgroup 1 3

- 0 7 F )] a t [ 3 ] pp m

, [G r a p e s, raisin]2

at [6 ] pp m

, [L o w Growing Berry Sub g roup (Crop Sub g roup 1 3

- 07G ) ] at [ 1

. 5 ] p p m

, [ T r ee

N ut s (C r op G r o u p 14)

, N u t m e at ] at [ 0 .1 5 ] p p m

, [Pis t ac h i o ] at [ 0 .1 5 ] p p m

, [Tree N u ts

(Cr o p Group 1 4 ), H u lls] at [1 5 ] pp m

, [ G ra i n

, c e re a l, ( C ro p G r ou p 15 )

, e x c e p t r i ce ; g r a i n ]

at [4 ] pp m

, [Swe et Co r n

, k e rn e l s p l u s c ob s wi t h hu s k s r e m o ved ( K + C WH R) ] at [ 0

. 4 ]

p p m

, [ Whe at, br a n ] at [5 ] p p m

, [ R i ce, g r ai n ( r o t a t i on a l c r o p) ] at [ 4 ] p p m

, [Grai n

, cereal,

f or a ge

, f o d der and s t r a w

, G r o up 1 6

, f or a ge ] at [2 0 ] pp m

, [ G ra i n

, cereal, f o r a ge, f o dder

a n d s tr a w

, G ro u p 16

, hay] at [ 40 ] p p m

, [ Grain

, c er eal, f o r a g e, f od der and str a w

, Gr o up

1 6

, s t raw] at [ 3 0 ] p p m

, [Grai n

, cere a l

, f or a ge, f o d d er and straw, Group 1 6

, sto v er] at [ 15]

p p m

, [ C o tto n

, un d elin t e d se e d

, (Cr o p S u b g r o up 20C ) ] at [ 0

. 9 ] p p m

, [ Co t t on

, gi n b y

p r o d uc t s] at [ 4 0 ] p p m

, [ N o n g r a s s an i m a l f e e d s, f o ra ge

, ( C r o p G rou p 1 8 )] at [ 20 ] pp m

, [ N on g r a s s a n i m al f

e e d s

, h a y

, ( Cr op G r o up 1 8) ] at [4 0 ] p p m

, [ C o ffe e

, b e an

, g r ee n ] at [2]

p p m

, [ C o ff

e e

, b e a n

, r o as t e d ; i n s t a n t ] at [ 3 ] pp m

, [ H ops ] at [ 2 0 ] pp m

, [ P eanut

, h a y ] at [ 30]

p p m

, [ Peanut, nut m eat] a t [0

. 15 ] pp m

, [ P rick l y p e a r c act us

, fr uit; ] at [ 0

. 5 ] pp m

, [ Pi t a y a,

fruit] at [ 0 .5] pp m

, [ P rick l y pea r ca c tus

, p a ds ] at [ 0

. 9 ] p p m

, [Cattle, Goat, Hog, Horse,

She e p fat] at [ 0

. 5 ] p p m

, [ C att l e, G o a t

, Ho g

, Hors e

, S he e p me a t ] at [ 1 ] p p m

, [Cattle, Goat,

Ho g

, Horse, S h ee p

, m e at by pr o du c ts] at [2 ] pp m

, [M i l k ] at [ 0

. 3 ] p p m

, [ Poult r y

, e ggs] at

[ 0

. 3 ] p p m

, [ P ou l t r y

, m e a t ] at [0. 5 ] p pm, [P oul tr y

, m eat b y prod u c t s] at [ 0

. 5 ] p p m

. EPA

ha s d et e r m i n e d t h at th e p e t i ti on contai n s d a t a o r i n f or m a t i o n r e g a r d i ng t he ele m ent s s e t

f o rth i n section 408 (d) ( 2) of F D D C A; how e v er, E PA has n o t f u l l y e v a lu a ted t he

s u ff i c i e n c y o f t h e su b m i t ted d ata at t h is t i m e or w h et h er the d a t a supp o rts gra n ting o f t he

petit i on. Add i t i onal d a t a ma y be n eeded b e f o re EPA r u les on t he pe t i t ion.

A

. R e s id u e C

he m i st ry

1. Pla n t met a b o lism. [Prim a r y c r o p m e t a b o l i s m s t u d i es h ave been perf o r m ed

o n a ppl e , to m a t o , p o t a t o , co t t o n, an d ric e (rep r es e nting fi v e div e rse cr o ps) using

fo l i a r , s o il, o r se e d t r eatment appl i c at i o n with [ 1 4 C]f l upyradifurone.

The f l u p yradifurone plant meta b o lism stud i e s h av e s h o w n a rea s ona b l y c onsi s t e n t

meta b o lic p r ofile acr o ss b o th foliar and soil appl i c a t i o n

. T h e m a jor m e t a b o l ic

p a thwa y s inv o l v ed c l e a va g e of the di f luoroethylamine a n d p y r i di n ylmet h y lam i n e

bonds l e a ding to the formati o n of d i fl u o r o a c etic a c i d (D F A ) and difluoro e t hylami n o

fur a n o ne and its c o rr e spond i n g c ounterpa r t flupy r a difurone

- C H M P, wh i ch was

e i ther c o njug a t e d with c ar b o h y dr a t e s o r o x i d i z ed to 6

- c hlor o n i c o t inic a cid ( 6

- CNA).

H y d r oxyl a t i o n of the fura n o ne moiety followed by conj u gation or co m p l e t e

de g r a d a ti on of the fur a n o ne m oi e ty a n d i n corporat i o n of c a r b on a t oms into the

natural compound poo l

, e

. g. into g l u c o s e/carbo h ydrates were also observed.

F l upyradifurone p a rent co mp ound and di f l u o roacetic acid (DFA) were consistently

observed at significant levels a cr o s s all pr i ma r y c r o p matrices. Thus, the re s idue

defini t ion f

o r e nf o rcement of fl u pyradifu r one residues i n prima r y cr o ps i s proposed

as p a re n t flupyrad i fu r o ne and di fl uroacet i c acid (D F A ).

The upt a k e and m e tabol i sm of f l u p y r adifurone w a s i n ve s t i ga t ed in the rotat i o n al

c ro ps wh e a t

, Swiss cha r d a nd tu r n ips f r o m thr e e c o nse c uti v e r o t a tions i n t w o

sep a rate exp e r i m e n t s with [fura n o ne

- 4

- 1 4 C]flupyrad i fu r o ne or [pyrid i nyl m e t h yl

-3

14 C]f l u p yradifurone. Add i tio n ally, a ll cr o p m a tric e s were a n al y z e d for

dif l u o roac e t i c acid (DFA) res i dues using LC/MS/MS. O v erall the m e t a bo l ism w a s

ve r y similar t o prima r y c r o ps and there f ore th e r esi du e d e f

i niti o n f o r e nf or cem e nt i s

th e s am e a s p rima ry c r ops

. ]

2

. A na l yti c a l metho d

. [ T o l e r ances a r e bei n g p r o p o sed in p ri m ary crops and

r o t a tio n al cr o p s and a n imal tis s ues and m i lk f o r flup y r a d i fur o ne a nd the m e t a b o lite

difl u o roac e tic acid (D F A ). The an a l y t i c a l m e t h o d i n vo l v e s , s o lve n t e x t r ac ti on,

pur i fication thro u g h a C

- 18 solid

- phase e x t r action c olu m n, a nd addit i o n of a m i xture

of st a b le, i s otop i c a lly label l ed inter n al stan d a rds. Qu a nt it a ti o n i s b y hi g h

performance l iquid ch r o mato g r a p h y

- e l ectr o spr a y i o n i z at i o n / t a ndem m a ss

spe c t r o m e t ry ( H PLC/MS /M S).]

3

. Ma g nitude of resid u es. [A f u ll program of magnitude of the res i d ue trials

was c o nducted in the va r ious req u ired regi o ns a cross the U n i ted States and Cana d a

in ac c o r d ance w i th guidance f or cr o p fi e l d tria l s from the US EPA a n d PMRA t o

sup p o rt the requested tole r a nces. Additio n a l ly, cof f e e t r ials c o n d ucted i n S o u t h

and Ce n tral America and b l ueberry tria l s co n duc t ed in North a n d S outh America,

Europe, A u s t r a li a , and New Z e al a nd were a l so subm i tt e d. T hr e e m o des of

appli c a t i o n , fo l i ar (a l l c r ops), soil drench (citr u s, fruit i n g and cucurbit vegetables,

grapes, a nd coffee )

, a n d seed tr e a t ment ( c ereal g r ains, c o t ton, and s o y b e a n) and

adj u v a nts ( m et h y la t ed seed o i l, n on

- i o nic surfactants, a n d crop oil c o ncent r a tes)

were employed i n the res i due studies.

P ro cess i n g stud i es were a l so c o ndu c ted o n a p pl e , c o ff ee , c o rn, cott o n, g r a pes,

ora n ge, p e an u t

, po t ato, so y b e a n, toma t o , and whe a t.]

B. T o xi c o lo g ic a l Prof

i l e

1

. Acu t e t o x i c i t

y

. [ T e c h n ical fl u py r a d ifurone (T o x i c i ty C a t eg o ry I I t o I V )

sho w s low a c u t e t o xic it y via the oral, d e r m al and i nhal a ti o n routes of exposure.

Techn i c al flupyradi f

u r o ne is a slight eye i r r i t a n t, bu t i s no t i r r i ta t i n g t o the sk in

( T o x i c it y C a t e gories I I I and IV, r e spectiv e ly). T he technical material is not a s k in

sensit i z er. Acute n e uroto x i city of f l up y r a dif

u rone was a s sessed in t h e rat.

Com p o un d

- re l ated eff

e cts followi n g a single oral dose of t he test s ub s t a n ce were

observed in b o th se x e s at the low d o se tested of 50 m g /kg bo d y weig h t, but were

l i m i ted to clin i c a l signs (i.e. dilated pup i ls, p i loerection) i n the i nitial acute

neurotoxicity stu d y. A fo l l ow

- up study s h owed no i n cidences of these cl i n ical si g ns

at the high e st tolerated d o se of 35 m g /kg b o dy wei g ht, w h ic h was e stabl i s hed as a

c l e a r NOAEL for a cute neurotoxicity in the rat.]

2

. G e no t o x i c t

y. [ G e n o t o x ic i ty p ot e n t i a l w a s eva lu a te d i n a s e ri es of t e s ts

includ i n g i n v i t

r o and i n v ivo t e s t s. T he r e w a s no indication o f g ene muta t i o n eith e r

in the p r esence o r a bs e n c e of metab o l i c a ctiv a ti o n i n b ot h the b a c t e r i a l r e v erse

mut a t i on and mam m al i a n g ene mutation t e sts. The i n vitro chr o m o s o m e a b e r r a t i o n

test and the i n v ivo m o us e mic r o n u c l e u s t e s t w e r e al s o b o th n e gat i ve. These st udies4

de mo nst r a t e that f

l upyradifurone h a s n o ge no t o x i c p o t e nt i al.]

3

. Imm u no t o x i c ity

. [ T h e immu n o t o x ic it y poten t ial of f l upyradifurone w a s

assessed i n a 2 8

- d ay immunot o x icity study i n the female adult rat, using t h e Sheep

Red Blood Cell E n z y me

- L i n k ed Im m uno s o r bent As s ay (SR B C EL I SA).

F l upyradifurone de m onstrated n o effect on a n ti

- S RBC IgM concentra t ions in

pla s ma or on spleen a n d thymus o r gan wei g hts. Th e ref o re, the N O AEL f

o r

immu n o t o x ic i ty is t h e highe s t d o s e tes t ed ( 230 mg a

. i

. /kg bo d y w e ig h t in fe m a le s ).

F l upyradifurone is t h er e f or e not c o nsider e d to be i m mun o t o xi c

. ]

4

. Re p r o du c t i v e a n d d evelo

p ment a l t o x i cit

y

. [In both the r e productive and

prena t al d eve l o pmental t ox i ci t y s t udies in r a ts and/or rabbits, no n

- mater n al toxicity

was identified at equivalent or h igher dos e s t h an m a ter n al t o x i ci t y in b o th spe c i e s.

In the rat tw o

- generat i o n reprod u c t i on s t u d y, decreases in body w e ight and b o dy

weight gain were obs e rved in fe m a les (P and F 1 ), and decreased bo d y weight ( F 1 ),

in c re a s e d l i ve r w e i g ht ( a b s o l u te a n d r el a t i v e t o b o d y w e i g h t) a s s o c i a t e d wi th m i nimal

h e p a tocellul a r hyp e rtrophy, a nd i n c r eased absolute t h yroid weights in ma l es.

D e c r e a ses in c y c le numbe r , l it t er s i z e , a nd the numb e r o f impl a nts were o bserv e d i n

t he F 1 - generati o n only at the HDT. Decr e a s es i n pup weight and pup weight ga i n

were due t o m ater n al eff e cts lead i ng t o s e c o n d a ri l y

- media t ed cha n ges, and o r gan

we i g ht changes (b r a in, thy m u s , spl e en) w e re c o nsider e d s eco nd a r y to decreases in

pup we i ght. The findin g s obse r v ed in r at fetuses at t h e h i gh e st d ose tes t ed (sli g ht

de c re a se in f

e t a l w e i g ht a nd i ncre a s e d i nc i den c e of s k el e t a l v a ri a t i o ns

– incomp l e t e

sk u ll bone oss i fication) were m i n o r a nd se c o n d a r y to m a t e rnal toxicity. There w a s no

indi c a t i on of a te r a togen i c e f f e c t of f l upy r a difurone in either the rat or the r a bbit.

In the devel o p m e n tal n eurot o xicity stud y , tr e a t ment

- re l a t ed fi n di n gs in offspring

were l i m i ted to de c r e a sed bo d y w e ight and b o dy weight ga i n during lact a tion,

in c re a s e d st a rt l e amp l itude in femal e s ( P ND 6 0 ), a nd incre a sed m o t o r a nd

l oc omo t or ac t i v i t y i n m a l e s o n P N D 13 o b se r v ed onl y a t th e highe s t d ie t a r y l e v e l

tes t ed of 1,200 ppm. Decr e a sed b o dy w e ight a n d b o dy weight gain we r e also

obs erv e d i n m a te r n a l an imal s at t h e s a m e di e t a ry l e v e l.]

The repro d uction and devel o pme n tal t o x icity stud i es with f l upy r a difurone d o n ot

indi c at e a n y p re

- o r p o stna t a l sus c eptibi l i t y of o f fspri n g.

5

. Su b c h r on i c tox i city. [The c o mmon t a r g et o rg a n in rats, m i c e, a nd do g s w a s

the l i v e r. Liv e r f

i ndings se e n i n th e se spe c i e s w er e in c reas e d l i v er wei g hts in b o th

sexes as s o c iated with centr i l o b ular hepat o c e l lu l a r h y pe r t r o ph y (rat )

, hep a tocellular

v ac u o l at i o n (mous e )

, a n d b r ow n p i gme n t s i n Kupffer c e l l s ( d og). In addi t ion t o the

liver, the t h yroid, kidne y , and s k e l e t al mu s cle were al s o t arg e t org a n s in rats, mice,

a nd d o gs, resp e ctiv e l y

. In the m a le r a t, i ncre a sed r e l a ti v e th y r o id weights were

assoc i ated with d a rk co l o r a t i on and follic ul ar ce l l hyp e rtrophy, but these effects

were obse r v ed on l y at the h ighest dieta r y l e vel te s ted and sho w n to be re v e r s ibl e

. In

the m a le m o use, decre a sed a bso l ute a nd br a i n wei g ht

- r e l ative k i dney w e i g hts we r e

as s o c i a t e d wit h a l os s o f c o r t i c o e p ith el ia l v a cuo l a t i o n at the highest die t ary level5

tes t ed. My o f

i ber a t roph y /de ge n e r ati o n w a s o bs e r v ed in s k e l et a l musc l e o f bo t h

sexes i n the subchronic dog stu d y

. The dog was the m o st s e nsitive spec i es, f o llow e d

by the r a t, with t h e m ouse being t h e l e a st sens i tive.

In the subchr o n i c neu r oto x ic i t y study, th e re wer e n o t re a t m en t

- r e l a te d e ff e cts

observed i n ei t h er sex up to and includ i ng th e high est d i e t a ry l e v el t e ste d o f 2

, 5 00

ppm.

In a 2 8

- d ay derm a l to x ic i ty study in r a t s, dec r ea s e d ab s olute and r e lative liver

weigh t s w e re obse r v ed i n males at 500 mg / k g / d ay, the hi g hest d o se t e s t ed.]

6

. C h r o n ic to xi c i t

y. [C h ronic t o xic i ty and c a r c i nogeni c i t y of flu p y r adifurone

was e v a l u ated in the r a t a nd mouse, and ch r o nic t o x i city in the dog. In the r a t,

tre a t m en t

- r e l a ted e f

f e cts s e en i n the l i v e r were hi g h e r mean li ve r to b o dy wei g ht

r a ti o s a ss o cia t ed with cent r il o bul a r h y pertr o ph y , c entrilobu la r h e p a t oc e l lul a r

ma c rov ac u o lati o n, l o wer i nc i dences of pe r ip o rt a l hep a toc e l l ul a r v a cu o l a ti o n, a n d

e o s i n o phi l i c, m ix e d, a n d ti g r o id fo c i o f al t ered hep a t o cyt e s. In a dditi o n, hi g her

incidences of brown pigments in Kupffer c e l l s, interst i tial m o n o nuc l e a r cell

inf i ltrate a n d per i portal hepa t o c e l l ular macrov a c u olation were obse r v ed in females.

Higher inc i dences of foll i c u l ar cell h y p er t r o p h y a nd of f o l l ic u lar ce l l p igment in b o t h

sex e s a t the fin a l s a c r i f

i c e a nd inc r ea sed in c id e nc e s o f co l l oi d alter a ti o n a t the

inte r i m ( b o t h sexes) a n d final sacr i f ice ( m a l es only) w e re obse r v ed in the t h yroi d

. There w a s no e v iden c e o f a treat m ent

- r e la t ed inc r e a sed i ncidence o f tu m o rs of a n y

t y pe i n a ny o r g a n. In the mo use, e ff e cts n ot ed in the liv e r we r e i nc r e a s e d li v e r

weigh t s as s o c iated wi t h higher i n c i d e nce and severity of dif f u se h e p a t o c e l l u l a r

v a c u o l at i o n (mainly centrilobu l a r ) in m a les, while a d ec r eased incidence of diffuse

hepato c e l l ular macrovac u olati o n ( m a i n ly perip o rtal) was noted i n fema le s. In the

k idney, lower w e ight, d e cr e a sed inciden c e a nd s e v e r i t y o f bi l a t e r a l b a sophilic

tubules, focal cortical m ine r ali z at io n, and c o r t i c o e p i theli a l vacuol a ti o n were n o ted

in m a les. N o t r e a t men t

- related neopl a s tic cha n ges we r e obser v ed at any d o se l ev e l

tes t ed in e i ther s e x. In the chr o n i c dog stud y , t re atm e nt

- r e l at e d f i ndin g s w e re

l i m i ted to m i nimal to slight myofiber atrophy and/or degener a t i o n in ske l e t al m u scle

(gastrocn e m ius, b i ce p s fem o r i s) o b served in both se x e s. ]

7

. A n im al metabolism. [ M e t a b o l i s m studi es c o n d u cte d i n t h e rat s h o w t h at

a l t h oug h > 9 0 % o f th e o r al l y a d mi n ist er e d d o s e w a s a b s or be d fo l l ow in g sing l e o r al

ad m i nis t r a t i on of [ p yr i din y l met h yl

1 4 C ]

- or [f u ra n o ne

- 4

- 1 4 C ]

- flu p y r a d i fu r o ne,

e x c r eti o n o f r a dioa c ti v i t y w a s v ery f ast a nd ne a rly c o mp l e te a t 48 h o urs after

ad m i nis t r a t i on.

The main r o ute of ex c ret i o n w as renal, r a n ging f rom 75% to 9 0 % of the

a dm i nist e red d o se. F e m ale r a t s h a d sli g htly h ig her r e nal e xc r eti o n r ate th a n m a le

r ats

. Onl y 0

. 0 2 % t o 2% o f th e a d mini s t e r e d d o se w a s reco v e red in t he expired air.

The pare n t comp o und f l upy r a difurone was f

o u nd as a sig n if

i cant, if n o t the

dom i na n t c o nstituent of t he residue i n m i l k

, e ggs, and edible t issues of both tested

species i n the l i v est o c k meta b o lism stud i es. Other metabol i tes det e rm i ned in6

comparable conce n t r ations were the na t u r a l co m pound lactose i n goat's m i lk af t er

adm i nistrat i on of [fu r a none

- 4

- 1 4 C] f lupyradi f

u rone, f l u p y r a d i furone

- a c e t yl

- A M C P

in e g gs a nd tis s ues of layi n g hens a f ter admi n i s t r a t i on of [ pyri d inylmethyl

14 C]f l u p yradifurone, and flupyra d i fu r o ne

- OH i n eggs.

D F A ( d if l u o r o a c e t ic a c i d) w a s de t erm i ned in s e le c t e d l i v e s to c k s a m ples b y hi g h

resolution LC

- MS subsequent to the m et a b o lism studies, since rat studies conducted

with [et h yl

- 1

- 1 4 C ] flupyradifu r o ne showed m a jor amounts of this metabolite in

o rg an s an d tissu es. E x t r a p o l a t i o n o f r a t d a t a s u gge s t ed h i g h DF A l e v e l s i n l i ve st o ck

tissues as we l l, which was co n firmed by t h e n on

- r a di o a c t ive L C /MS ana l y s es. B ased

on these f

i n dings, it was concluded t hat di f lu or oa c e t i c ac i d i s a ma j o r liv e s to c k

meta b o lite and s h ou l d be a const i tuent of t h e res i due defini t i on for d a ta c o l l ectio n

.

Based o n t h ese find i n g s, f l upy r a dif u rone, DFA, flupy r a d i fur o ne

- OH, and

flupy r a d i f

u r o n e

- a cety l

- AMCP, ex p r essed as flupy r a difurone e q uivalen t s , w e re

included i n the residue defin i ti o n f o r d a t a c o lle c t i o n.

B ase d o n t h e re s ul t s f

r om th e l i ve s t o c k f

e ed i n g studi es, B C S pro p ose s that

compliance with the to l e r a n c e l e vels in m i lk, m e at and m e a t b y

- p r o d u cts, a nd eggs

should be d etermined by m e asuring o n l y f l u p y r adifurone and i t s me t a b o lite,

difl u o roac e tic acid (D F A ).]

8

. M e t a bo l i t e t ox ic o lo gy

. [The to x i c o log i cal p r o perties o f t w o plant meta b o li t es

of flu p y r adifur o ne found at low l e vels in ur i n e i n the rat metabol i s m stud y , difl u o roac e tic acid (D F A ) and flu p yra di furone

- difl u o roe t h y l

- a m ino

- f u ra n o ne (

flupy r a d i f

u r o n e

- DFEAF), a nd two a d d i tio n al pl a nt metabolites c o m m on t o other

pest i c i des, flupyradi f

u r o ne

- CHMP (6

- chl o r o p y r i din

- 3

- yl m et h a n o l) and

flupy r a d i f

u r o n e

- 6

- CNA (6

- chlo r on i co t inic a c i d), were in ve stigated. Study res u lts on

the me t a b o l i tes indi c a te that all meta b oli t e s a r e le s s t oxic t h a n parent and t h at the

parent flu p y r adifurone endpo i nts are s u fficient to c o v er the residues of the

meta b o lites in r i s k assess m ent.]

9

. E n d o crine disru

p ti o n

. [ T here is n o e vidence t o s u ggest t h at flu p y r adifurone

has a n y p r i m ary endocr i ne disruptive potenti a l. T h yroid cha n ges ob s e r v ed in m a le

r a ts w e re observed at high di e ta r y l e vels of flupy r a difurone and w e re r e v ersible in

the subchron i c r a t study. Delays in s e xual develop m ent in rat pups in the t w o

generation reproduct i on study w ere obse r v ed on l y in t h e F 1 gen e r a tion and the

HDT. Reproductive a n d develo p mental find i ngs prov i ded no e v ide n ce of an

enhanced se n s i tivity of the you n g.]

C

. A ggreg at e E

x po s ure

1

. Die t a r y e x po s ure. [The to x i c o logical and exp o s u r e da t a b a se f o r

flupy r a d i f

u r o ne is c o n s i dered comp l ete. The r e w a s n o i n dic a t i on of an inc r e a sed7

sensitiv i t y of the y o ung i n a n y s t u d ies includ i n g the repro d uctive a n d dev e lopme n tal

studies in r a t s and ra b bits. Th e r e f ore, the s p ecial F Q P A safe t y f a c t or can be reduced

to 1 X a nd an uncertainty f actor of 1 0 0 i s a de qua t e t o a c count for inter

- and intra

sp e c i e s variability. Acute a n d c h ronic Populat i o n Adjusted Doses (aPAD and cPAD)

ar e, t he r ef

o r e , the sa m e a s the r ef

e r e n c e d o ses f

o r t h e p o pulati o ns a nd

subp o pulati o ns o f int e r e st. Acute di e t a ry e xp o su r e w a s e x pr e ss e d a s a p e rcent a ge of

the a P AD of 0

. 35 m g /kg bw/day fr o m a NOAEL of 35 m g /kg bw / d ay b a sed o n the

acute neurot o x icity sc r e en i ng batt e r y , w it h a n unc e r t a int y f a ct o r o f 10 0

. C h r o n i c

di e t a ry exp o su r e w a s e x pr e ssed a s a p e rcentage of the chr o nic P o pulati o n Ad j u sted

D o se ( c PA D) o f 0

. 078 mg/kg b w / d ay b a sed on a NOA E L of 7

. 8 m g /kg b w / d ay based

on tw o c o

- c ri t i c a l s tud i es, the tw o gene r a t i on repr o du c tion s t u d y i n rats and a

ch ro ni c t o xic i t y s t ud y i n do g s, w i t h a n un c e r t ai nt y f a ct o r o f 1 0 0

. ]

i

. Foo d

. [T i e r 3 ac u te a n d chron i c di etary r isk assessmen t s were conducted to

evalua t e t h e d i et a r y e x posure of t h e U.S. pop u la t i on and se l ec t ed subpopul a t ions to

flupy r a d i f

u r o ne r e sid u es. T his assessme n t includes a l l p r o p osed p o tential primary

c r op r e sid u es and i n a d v erte n t or r o t atio n al c r op residues a nd se c o n d a r y residues i n

an i mal t i s s ues and milk. The ass e ssments c o n s ervatively ass u med t h e p e rcent of a l l

crops treated was equal to the ma x imum ma r ket lead e r val u e f o r t h at crop f

r om the

last three ye a r s. The Tier 3 acute a nd chronic assessments were c o nducted usi n g

CARES V e rsion 3.0 software. Consumption d a ta used in this p r o g r a m were ta ke n

f r o m US DA ’s CSFII

, 1 9 9 4

- 1 9 9 6

, 1 99 8

. W i th t hese c o n s e r va t ive ass u mpt i ons, a c ute

e x p o sure ( 99

. 9 th p e rcenti l e ) f o r fo o d util i z e s 8.6% o f t he a PAD for the US

P o pulation and 25. 8 % for All Infan t s (< 1 yr. ol d ), the m o s t high l y e x posed

sub p o pulation. Chro ni c exposure for food o n ly ut i l i z e s 3

. 2% o f the cPAD for t h e

US Populati o n a n d 1 0

. 2% of the cPAD for C h i ldren 1

- 2 yrs. o l d, the m ost highly

exposed s u b p o pulation.]

i i. Drink i ng water. [Estimated Dri n ki n g Wa t e r Concentrations (EDWCs) from

grou n d water a nd sur f

ace w ater s o ur c e s were c a lcula t ed for the residues of

flupy r a d i f

u r o ne and t h e m a

jor environ m ent a l d ifl u o r oa c et i c a c i d (D F A)

. This

exposure a s sessme n t w a s conducted us i ng t h e m o d e l i n g approach a p proved b y the

O f fi c e of P e st i c i de P r o g ra m s o f US E P A ( E PA). T he st a nd ar d c r o p scen a ri o s

de v e l o ped by the EPA we r e used f o r surf ac e w a t e r ass e ss m ent. T he en v i r o nmental

fate p a r a m e ters used f

o r the surface wa t e r m o del P R Z M /E X A MS and the gro u nd

w a ter m o d e l SCI

- G R OW were es ti mated in accor d a nce t o the EPA i n put p a r a m e ter

gui d a nce d o cument. The h i ghe s t ground water con c ent r ati o n of f l upyradifurone

plus dif l u r o a cetic ac i d (DFA) was 0.9 μ g /L ( a cute a nd c hron i c) from a ll p ro p o s ed

uses (410 g a.i./ h a ) e x c e pt the h o p use (154 g a. i ./ h a). T he 9 0 th p e r c en t i l e ti m e

dependent Est i mated Dr i n k i n g W a ter Co n c entra t ions (EDWCs) f r om sur f a c e wat e r

s o urce were c a l culat e d f o r the prop o sed r epr e s e nt a tive flup y r a difur o ne c r o p uses.

A P C A f a c t or of 0

. 91 w a s c o n s ide r ed to a d just modeled E D WCs. Ove r a l l, the

highe s t p o t e n t i a l a c ut e E DW C v a l u e s we re es t i mate d f r o m t h e F l o r i da cu cum b er

scenario w i th an acu t e conce n tra ti o n o f 35

. 0 μg/L and the hi g h est chronic EDWC

v al u e s w e r e e s t i m a ted f r om the Nebr a s ka c o rn s c en a rio w i th a c o ncentr a ti o n of 8

. 0

μg/L8

D r i n k i n g w a t e r d i d n o t s i g ni f i c a n tl y i n c r e a se d i eta r y exposure. The i ncor p oration

o f the EDWC o f 3 5 .0 μ g /L i n to a n a cute exp o s u r e a s s e ssment r esul t ed in the U.S.

adult p o pula t ion ut i l i z ing 9 .1 % of the a P AD ( v s. 8

. 6% f or food o nl y ) a n d A l l

Infa n ts, the most highly ex p o sed sub p o pu l ation, util i z i ng 26. 2 % of the aPAD (vs.

2 5 .8% f o r fo o d o nl y ). The a ddition o f the chr o n i c EDWC o f 8

. 0 μ g /L r e sult e d in t h e

U.S. adult p o pulation ut i l i z i ng 3.4% of the c P AD ( v s

. 3

. 2% f or food on l y ) a nd

Chi l dren 1

- 2, the most highly exposed su b po pulation, util i z i ng 1 0 .5% ( v s. 1 0 .2% f o r

food only). In conclus i o n, the res u l ts of the v e ry c o n s ervative acu t e a n d chr o nic

die t a ry ex p o s u r e a n a l ys e s ( in c l uding fo o d and drin k i n g water) demons t r a t es t h at

flupy r a d i f

u r o ne d r i nking water e x posure c o nsu m es a v ery sm al l p e rc e nta g e of the

r i sk cup f

o r all s c enarios and p o p u la tion sub g r o ups ex a m ined. Th e refo re , th e r e is a

r ea s ona b l e c e r t ain t y t h a t n o h a r m wi l l r e s u l t f r o m ex p o s u r e t o p ot e n t ia l r e si d u e s o f

flupy r a d i f

u r o ne in food and wate r .]

2

. No n

- d i e tary exp o s u r e

. [Based on the use pat t e r ns non

- di e t a r y ex p o s u re to

flupy r a d i f

u r o ne is n o t ant i c i p a ted.]

D. C u m u l a tive Eff

e cts

[At this t i m e , there is no avai l ab l e in fo r mation t o i ndicate that

flupy r a d i f

u r o ne or i ts m eta b o l i tes ha v e a c ommon m ec h anism of h u m a n t o xicity

with other substanc e s. F l up y r a difur o ne is a m e m ber o f t he buten o lide cl a ss o f

chem i s t r y

. For t h is c lass of chemistry, E P A has not yet conduc t ed a d e tailed review

o f c o mm o n m e c h a nisms to d e termine wh e th e r i t is app r o p riate, or how to include

these che mi c als in a c u mu l a t i ve ri s k ass e ss m e n t

. F l u p y r a d i furone does not appear

to p r o d uce a toxic meta b o l i te produced by o t her substances. For t h e purposes of

this a ss e ss m ent, t her e f

o r e , no c o mm o n m ech a nism o f t o xi c ity h a s b e en c o nside re d .]

E

. S a fe t y D e t e r m in a t i o n

1

. U

. S

. po p ul a tio n

. [ R isk a s s e ssments f o r flup y r a difurone are based on a

c o mpl e te a nd r e l i a b l e t o xicity d a ta p a c ka g e and c o ns e r va t i v e a ssumpti o ns. Ch r o n i c

ag g regate d i eta r y exposure ( f o o d a n d water) u ti l i z es 3

. 4% of the c PA D f o r the U S

P o pul a t i o n. A c u t e ag g r e gate di e t a r y e xp o sure (f oo d a nd w at er) f

o r the U.S. a du l t

popul a t ion ut i l i z es 9.1% of t he aPAD. N o n

- d ietary exposure of the U.S. p o pulation

to flu p y r adifurone is n ot a n ti c i pated. The r efore, there is a r e a s ona bl e c e r t ain t y t h a t

no h a rm will o ccur to the US Pop u la t i on from ag g regate e xp o sure (food and

dr i n k i n g water) to residues of flu p yradifu r o n e .]

2

. I n f a nt s a n d ch i l d r e n

. [The t ox i c o l og i c a l a nd exp o sure d a t a b a se f o r

flupy r a d i f

u r o ne is c o n s i dered comp l ete. The r e w a s n o i n dic a t i on of an inc r e a sed

sensitiv i t y of the y o ung i n a n y s t u d ies includ i n g the repro d uctive a n d dev e lopme n tal

studies in r a t s and ra b bits. Th e r e f ore, the s p ecial F Q P A c a n be re d uced to 1 X and

an u n cer t a i nty f

a c t or of 100 is adequate. Ba s ed on c o n s e r vative a s sumpt i ons,9

chronic aggregate dietary ex p o sure (fo o d and water) utili z es 1 0

. 5 % of the cPAD for

Chi l dren 1

- 2 yrs. old, the most highly ex p o sed subpopulation. Acute aggrega t e

die t ary ex p o s ure ( f

ood and w a ter) utili z es 26

. 2% of the a P AD f o r A ll Inf

a n ts, the

most highly exposed s u bpopul a tion. N o n

- dietary ex p o sure of infants a nd chi l d r en

to flu p y r adifur o ne is n ot a n ti c i pated. T he r efore, there is a r e a s ona bl e c e r t ain t y t h a t

no h a rm will o ccur to in fa nts a nd chi l dren from a ggr e g a t e exposu r e (food and

dr i n k i n g water) to residues of flu p yradifu r o n e .]

F. In t erna t i o n a l To l er a nces

[No tole r a n ces have b e en estab l ished f o r flu p yradifu r o ne. Flupyradifurone is

b e in g r e vi e we d a s a n OE C D J o in t R evi e w am o n g t h e U. S.

, Ca n a d a, Aust ra lia

, B r a z il

and Mexi c o. Harm o n i z ed to l eran c es are b e i n g pro p osed t o minimi z e trade barriers

betw ee n the p a rt i c i pating regi o ns.]

August 13, 2012