Interregional Research Project #4 ( IR

- 4 )

Petition #4E8302

EPA h a s re c e i v ed a pesticide pet i t ion ( 4E8302 ) f r o m IR

- 4

, IR

- 4 P r o

ject

He a dquarters, Rut g ers, The State Uni v ers i ty o f N J

, 500 C ol l e g e Ro a d E a st, Su i te 201

W, Pr i nce t o n, N J 08540 p r o po si ng

, p u r s ua n t t o s e ct i on 4 08 ( d) o f the Fe d e ral Foo d

, Dru g

, a n d C o s m e t ic Act (FFDCA )

, 21 U.S. C

. 34 6 a ( d ), to a m e n d 4 0 C F R p art 180 by

estab l ishing a t o ler a n ce f o r resid u es of p y rimet h a n i l (4,6

- di m et h y l

- N

- pheny l

- 2

-

p y r i m i dina m i ne) in or on t he raw agric u ltur a l c o mm odi t i es c u cumber at 1.5 pp m

, O r a n g e s ub g roup 10

- 1 0 A a t 10 pp m

, L emon subgroup 1 0

- 10B at 1 1 p p m, G rap ef ruit

subgro u p 1 0

- 10C at 1 0 p p m

, F r u it, pome, gr o u p 1 1

- 10 a t 14 p p m

, F r ui t

, stone, g r o u p

1 2

- 1 2 a t 10 pp m, a nd T omato su b g r o u p 8

- 1 0 A a t 0

. 5 p p m

. The petitioner also

requests that upon approval of the above tolerances, that the tolerances for fruit,

citrus, group 10 except lemon, postharvest; lemon, preharvest and postharvest;

fruit, pome, group 11 (pre

- harvest and post

- harvest); fruit, stone, group 12; and

tomato be removed as unnecessary and also requests that the existing tolerance

for “ Onion, bulb, subgroup 3

- 07A” be changed from 2.0 ppm to 0.20 ppm.

. E PA ha s

d e ter m i n e d t h a t th e p e t i ti on con t ains d a t a or in f or m a t i o n r e ga r d i ng t h e e l e m ent s s et

fo r th i n s e cti on 408 ( d) ( 2 ) o f th e F D D C A ; howe ve r, EPA h as n o t f u lly e v al u at e d t h e

s u ff i cie n c y o f the su b m i t t e d d ata a t this t i me or whe t her t he d a t a supports grant i ng o f

t he p e tit i on. Add i t ional data m ay be ne e d e d before EP A r ul es o n the pe t i t i o n

.

A

. R e s id u e Che m i st ry

1. Pla n t met a b o lism. Th e m e t a b o li c pr o f i l e o f p yr i m e th a n i l h a s be e n

in v esti g at e d f

o llowing app l ic a ti o n to fi v e different cr o ps (appl e , c a r r o ts, g r a p e s,

lettuce and to m a t o es) a n d is well u ndersto o d. In p l ants, pyri m e th a n il i s the o nly

s i gni f icant residue ra n g i n g f

r o m e ssent ia l l y a l l of t he To t a l R a d i o a c t i ve

R e s idues ( T R R ) i n ca r r o ts a n d to m a t oe s t o 4 4 % i n l e t t u c e

. Li mi t e d m e t a b o l i s m

of p yr i m e th a n i l oc curs with m in o r am o unts (less th a n 10 % ) o f t he ph e n y l a nd

p y rim i dyl h y dr o x y l ated met a b o lites ( A E C614 2 7 6

, AE C 6 142 77

, AE C6 1 427 8

, and A E C621312) bei n g released aft e r a c i d h y d r ol y s is. Anal y s i s o f t h e f o lia g e

f r o m apples a nd car r ots confirmed t h at the m e t a b o l ism o f p y r im e t h a nil i n

pl a n ts pr o ceed e d p r im a r i l y v ia h y dr o x yl a t i o n o f the a rom a tic r i ng st r uctur e s as

w e l l a s the met h yl groups

.

2

. A na l yti c a l metho d

. The p l ant meta b o l ism stud i es demonst r a ted

t h at a n alysis for t h e pa r e nt co m pound, pyri m e t h a n il i s suff i ci e nt to e n able

the a ssessm e nt o f the r e l e v a nt r e s i du e s in cr o p c o mm o dit i es. P y ri m e th a n il

was e x t r a ct e d fr o m cucmb e rs by hom o gen i z a ti o n w i th ac et o ne. After

c le a n

- up, an a l i qu o t o f the ext r a c t was di l u t ed with a m i xture of

acet o nitri l e and water wi t h subsequent residue det er m in a t i o n b y H P L C

M S / M S. The method allows the detection and measure m ent of r e s idues in

or on ag r icultur a l c o mmod i ties at or a b o v e the p roposed to l er a nce le v el.

3

. Ma g nitude of resid u es. Magn i tu d e of residue t rials w e re conduc t ed

for pyrimet h a n i l on cucumbers g r o w n i n the gree n h o use. T rials were

conduc t ed in var i o u s r e gions across the United S t ates an d C a n a d a i n

a c co r d anc e w it h E P A gui d a nce for crop fie l d t r ials under OPPTS 86 0

. 1 500.

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

. Py ri m e tha n i l s h o w s l ow t o x i ci t y b y th e o ral ( t o x i c i t y

c a t e go r y I II ), inha l a ti on ( t o xicity c a t eg o ry II I ), and der m al ( t o x ici t y c a t e go r y IV )r o utes. It is sli g htly i rritat i ng to t h e e y es a nd n o n

- i r rit a ting to the skin in r a bbit

studies. P y r i met h anil is not a de r mal sensit i z er. Acute ne u r ot o xicity of

p y r i met h an i l in the r a t w a s a ss e ssed, t he NOAEL was 100 mg/kg due to reduced

b o d y te m perature i n m a l e s, a nd t ransient behavioral ef f ec t s obser v ed at t h e high

d o se tes t ed (HDT)

.

2

. G e no t o x i c t

y. P y r i m e t h ani l i s n o t mu t a g e ni c o r ge n o t o x i c i n a n y a ss ay

in e i ther the pr e sen c e o r absen c e of m e t a bo l i c a ctiv a ti o n

.

3

. 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

. Pyri m e t h a n i l is not a

de v e lopme n tal or r e p r o d uctive toxicant. An o r a l dev e l o pm e n t a l t o xi c i t y s t ud y i n

the Spra g ue Daw l e y rat did not r eveal a n y eviden c e of t e ratogen i c potenti a l. T he

m a t e r n a l a n d d e v e lo p m en t a l N O A E L w as 85 m g / k g/ d a y

. A n or a l dev e lopme n t al

to x i c i ty st u dy in New Z e a l and rabb i ts d i d not r e v e al a ny ev i dence o f te r a togenic

pote n t i a l a n d t h e N O A E L w a s 45 mg/kg/ d ay. The m a t er n al and d e ve l o pme nt a l

LOAEL was 300 mg/kg/day due to reduced body weights, re d uced fe c a l

p r oduction, and food c o nsu m pti o n in the d a ms and d e c r e a sed me a n b o dy w e ight,

bo d y wei g h t ga i n, fo o d consumpti o n , and an increased i n cidence of fe t uses w i th

13 t h oracic ve r teb r a e and r i b s

. A t w o

- generation rep r o d u cti o n stu d y in the

Sprague

- Daw l e y rats d i d n o t i ndicate a n y d i sruption o f rep r oducti v e fun c tion.

The NOA E L for ma t er n al and de v elo p mental t o xicity w a s 2 0

. 9 mg/kg / d ay due to

reduced bo d y weights at h igher dose le v e l s , and the r e pr o d u cti v e N O A EL w a s

2 6 6

. 7 mg / k g / d a y , the HDT.

4

. Su b c h r on i c tox i city. A 28

– day di etary toxicity stu d y was conducted i n CD

1 m i ce estab l ished a NOAEL of 202 mg/k g / d a y

. A 9 0

- day diet a ry tox i city study

in Spra g ue

- D awley r ats s h o w ed a N OA E L of 54

. 5 a n d 6 6

. 7

, in m a les a n d

females, respecti v ely. A 90

- d ay dietary to x ic i ty study w a s conduct e d in CD

- 1

m i ce a nd demon s t r a t ed a NOA E L of 139 a n d 203 mg/kg/ d ay in males and

fe m a l e s, r e spe c ti v ely, b a sed on cha n ges fo u nd i n t h e k i dne y , liver, thy r oid, a nd

urinary bladde r at high er d o s e l e ve l s. A 90

- d ay o ral t o x i c i t y st ud y i n d og s

s h o we d a N O A E L o f 80 m g / k g/ d ay du e t o d e cr e ase d b o dy wei g ht and f ood

co n sump t ion and ch a n g es in c l ini c a l chemi s t r y en d p o in t s at 800 mg / kg/ d ay. A

subchron i c neurotoxicity stu d y in Sprague

- Dawley r a ts i n dicated n o treatment

r e l ated f i ndings in behav i oral a s ses s ments, neuro p at h o logy o r br a in

mor p hometrics. The NOAEL w a s 4 4 .3 m g /kg/d a y i n f em a les b a s e d up o n

de c r eased mean b o dy weight, bo d y weight ga i n a nd food consu m pti o n a t 42 9

. 9

m g /kg / da y

. The r e wer e n o t r e a tm e nt r e l a t ed e f f e ct s i n m a l es a t a n y d os e l e ve l u p

t o 39 1

. 9 m g / k g/ d a y

. A 28

- day i m mu n o t o x icity stu d y conduc t ed in fem a le

Spra g ue

- Dawley r a t s r e vea l ed no e v idence of immu n e su ppression at d o s e levels

u p to and i ncluding 652 m g/kg/ d ay, the HDT.

5

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

y A 1 2

- m o nth ch ro ni c t o x i ci ty st ud y i n th e dog

demon s t r a t ed a NOA E L of 30 mg / kg/ d ay due to a d e cr e a s e in m e a n b o d y w e i g ht

g ai n a nd mean c o nsumpti o n of food and w at er a t h i ghe r d os e l e v e ls

. Tw o

oncogenicity studies w e re c o nd u cted us i ng CD

- 1 mice conti n u a lly exposed to

p yr i m e th a n i l by a dm i nistr a ti o n i n the di e t. These lif e t i m e f e ed i ng stud i es

de mo nst r a t ed no e v idence of o n c o g enic pote n tial at dose levels up t o , and

including 984 m g / k g/d ay ( m ale s ) an d 1 217 mg / k g/ d ay ( f e m al es )

, th e H D T

. A 2

-

y e a r c o mb i n ed chronic to x ic i ty/oncogenicity study c o nd u c t ed in t h e Spra g ue

D awley rat s h owed a N O A E L o f 1 7 m g / k g/ da y (m a l e s) a nd 2 2 m g / k g / da y

(fe m a l e s) due to d ec re a sed b o dy weight ga i n a nd food consumptio n , a nd e f fec t s

on the liver and t h yro i d at 221 mg/k g/ day (ma l es) a nd 291 mg/k g / day (f e m a les).

The resu l ts o f m ech a nist i c studi e s, demonst r a t e that the t hy r o id e f f e cts a reli ke ly se c o ndary due to in d uction o f en z ym es in the liver i n v o l ved in meta b o l ism

of thyro i d horm o n e s, a well ch a r acte r i z e d, thres h old

- med i ated mec h anism.

6

. A n im al metabolism. Meta b o l i s m a nd pharm a c o ki n e tic studies in t h e rat

show rap i d a b s o rption and el i m i n ati o n w i thin 2 4

- h o urs of p y ri m eth a n i l

a dm i nistr a t io n. The maj o r r o utes of eli m ina t ion w e re the ur i ne ( a ppr o xim a tely

7 2 % o f the a d m i n i s t e r ed dose )

, a nd the f e c e s ( 17

- 1 8 % of the a d m in i s t e r ed d o s e )

. The ma i n p a thwa y s of metab o lism i nvo l ved ox i d ation to phe n o l s i n ei t h er or b o th

a ro m at i c r i n g s

. Th e mino r p a t hw ay o f me t a b o lis m i n v olv e d oxi d a t i o n o f th e

m e t h yl group to t h e corres p o n d i ng a l coho l

.

7

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

. N ot applicable. The p ri m ary r e s i due o f c o nce r n

in both crop and a nimal c o mm o dit i es is pyrimet h anil.

8

. E n do crine disru

p ti o n

. T he r e is no e v i den c e to sug ge s t th a t p y rimeth a nil

has a n y p o tenti a l p r i m ary endocrine d i sruption. Ch r o n i c, l i fe span, and mu l ti

generatio n al b i oas s ays i n mam m als a nd a c ute a n d subchron i c studies on aqua t ic

organis m s and w i ldl i fe d i d not r e veal a ny p o t e n t i a l e nd o cr i ne ef f ects. Ch a n g es in

the thyroid are secondary to inducti o n of m et a b olic e n z ym e s in the liver, and not

due t o a direct effect o n endo c r ine me d iated functio n s

.

C

. A ggreg at e E

x po s ure

1

. Die t a r y e x po s ur e

. F o r die t a ry a n a l ysis

, a n a c ut e r e f e r e n ce do s e ( a R fD ) of

0

. 45 m g/kg/day w as deriv e d for f emales 13

- 50 f

rom an N O AEL of 45 m g / kg/ d ay

in the rabbit d e v e lopmental stu d y , based on an i n creased incidence of f e tuses with

13 th o rac i c vertebr a e a nd ribs, a nd an uncert a inty f a ctor o f 10 0

. F o r the ge n e r a l

popul a t ion includ i n g i n fa n t s and c h i ldren, the acu t e refe r ence do s e is 1

m g/kg/ d ay from on an NOAEL of 100 m g / kg/day in the a c ute r a t ne u r o t oxici t y

st udy, based on transient behavioral e f fects, and an uncert a inty f a ct o r of 10 0

. A

c h r o n i c r ef

e rence dose (c R f

D ) of 0

. 17 m g /kg/ d ay f

or a l l p o pulations w a s der i ved

from t he chr o nic to x i c i t y st u dy in the rat, based on decr e ased b o d y wei g ht gain

and food c o nsu m p tion, increased l i ver weights and histop a t h o logical cha n ges, and

an uncert a inty f

a ct o r of 10 0

. E P A has e v alu at ed the pot e ntial f o r inc r e a sed

susce p t ibility of infan t s and ch i ldr e n f r om e x p o sure to p y r i meth a n il a nd has

det er m in e d the r e was no qu a ntit a ti v e o r qu a lit a t i v e e v iden c e of i n c re a s e d

su s ce p tibil i ty f

ollowi n g pre n a t al e x pos u re (in rats a nd ra b b i t s )

, o r p o stn a t a l

e x p o sure (in r a ts )

. There were no effe c ts o n fertil i ty or r e p ro du c ti o n i n the tw o

generation reproduction study in r a ts. The special FQ P A SF has been reduced to

1 X based on tox i c o logical conside r ations, t h e n a t ure of the assumpt i ons u s ed

in the d i eta r y e x p o su r e r isk a ssess m ents, t h e c om p l e t e n e ss o f the residue

c he m ist r y and e n v i r o nmental fate dat a b a ses, and the la c k of the potential f o r

resident i al e x p o sures. A c ute a nd chr o n i c P o pul a ti o n Adjust e d D o ses (a P AD a nd

cPAD) ar e, there f

ore, t h e same a s the refere n c e do se s f o r the populati o ns and

s u bpopula t ions of interest.

i

. Foo d

. Di e t a ry ex p o s ure t o p y rim e t h ani l w a s est i mated from p o tential

residues on fo o d using CAR E S Version 3

. 0 s o ft w a r e f o r d i et a r y a n a l yses

. Th e

a c ute T i e r One a s sess m en t s used 100% c ro p tre a ted a nd t o le r a nce l e v e l residue

v al ues. The ch r o n ic Tier 2 as s essment is b a sed on toler a nces, ave r age re s i due

values f o r key c ro ps a nd p e r c ent c r o p t r e a ted values f o r key c r o ps f

r o m the 2 0 04

EPA a s s e ssmen t

. All r e g i ste r ed uses, pend i ng uses; and t he pro p o s ed u s e on

cucumbe r s were inclu d ed i n th e asse s s m e nt

. Ac u te e x p osur e utili z es 22

. 7% o f th e

a P A D fo r F e ma l e s 13

- 49 and 44. 7 % and 90. 7 % o f t h e aPAD f o r the USP o pulation and Children 1

- 2 r e spe c ti v ely. Ch r o nic exp o su r e util i z es 12. 5 % f or

the US P o pulation and 65. 4 % for Children 1

- 2, the m o st highly e x pos e d

sub p o pulation. T h ese are conserva t ive esti m at es and a ct u a l e x p o sures are l i ke l y

t o b e m u ch less.

i i. Drink i ng W

ater. E P A dri n ki n g water values ( 2 004) were used in t h e

as s ess m ent. EDWCs were c a lc u la t ed for u s e on st r a wber r i es (the s c en a rio

re s u l ting in the high e st dr i n k i n g wa t er exposure), and i nc l uded pyrimet h an i l a n d

its major meta b o lite (2

- a m i n o

- 4,6

- di m e t hyl p yrimid i ne )

. The sur f ace w a ter

es t imated dri n ki n g w a t e r c o ncentr a ti o ns ( E DWCs) we r e d e t e r mined using

P R Z M /E X A MS (Pesticide Root Z o ne Mod e l / E x p o sure A n al y s i s M o deling

S y st e m ). G r ound water EDWCs, calculated us i ng S C I

- GROW (Screeni n g

Concentration in Ground Water), model were lo w er than the sur f a ce w a t e r

E DW C s. F or s ur f

ace w a ter, the maximum estima t ed p eak acute concentration o f

the c o mbined re s idues is 37

. 8 g/L

. The maxi m um e st i mated a n nual mean non

cancer c h r o ni c e x p o sur e c o n c en t r a t i o n for the comb i n ed residues ( a d jus t ed for

r e g i o n a l p ercent c ropped ar e a ) i s 5

. 1 g/L. These estimates are w e ll below the

Dri n ki n g Wa t e r L evels of C o m p a r i s o n (DW L OC) for all subpopulations. The

aDWLOC is 2260 8

, 31413 and 6851 g/L for Fe m ales 13

- 49, the US Population

and C h i l dren 1

- 2 ( the m ost high l y ex p o sed sub p o pulation), r e specti v el y

. The

cDWLOC is 5 8 99 a nd 1 624 g/L f o r the US P o pulation and Children 1

- 2 ( the

most highly exposed s u bpopulatio n ), respe c t ivel y

.

The s e c o nser v ative est i mates indi c a t e the r e is no c o ncern for die t ary exposur e s

f r om pote n ti a l residues of p yri m e th a n il in food a nd drin k i n g w a ter.

2

. No n

- d i e tary exp o s u r e

. Pyrimet h anil is n o t r e giste r ed f o r use on a n y sites

that w o u l d r esu l t i n re s i denti a l e xp o su r e. T heref o r e , the ag gr e g ate risk is the sum

o f the ri s k f

r om f ood and w a ter

.

D. C u m u l a tive Eff

e cts

Section 40 8 ( b ) ( 2)( D ) ( v) requir e s t h a t, when c o nsider i n g w h ether t o

e s tablis h

, mo d i f

y , or revoke a t o l eran c e, the A g ency c o n sider “avai l a ble

in f o r m a t io n ” c o ncern i n g t he cu m ul a t i ve e f f e c t s of a p a rti c ul a r pest i c i d e ’s

r esidu e s a nd “ o ther subs ta n c es t h at have a common mechani s m o f t o x i c i t y

. ” E P A

h a s no t m a de a c o m m o n me c h a n i sm o f t o x icity f i n d i n g a s to pyri m e th a n il and any

other substances and p y r i methanil d o es not appear to pr o duce a t o x ic meta b o lite

produced by other subs ta n c es

.

E

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

1

. U

. S

. po p ul a tio n

. R i s k a s s e ss m en t s f o r p y r i metha n il are based on a

c o mplete a nd re l i a b l e t o xicity d a ta p a c ka g e and hi g hly c o nse r v a ti v e

a ssumptions. Ch r o n i c d i e t a r y (f oo d ) exp o su r e will util i z e 1 2 .5% o f the cPAD

f o r the US P o pul a t i o n. T he chr o nic EDWC is m ore th a n 1000 f o ld lower th a n

the cDW L O C

. EPA g ene r a lly h a s no c o ncern f o r exp o sur e s be l ow 100% of the

cPAD bec a use the cPAD r e presents the l e vel at or b e low which dai l y aggregate

e x p o su r e ov e r a l i fe t i me will not p o se a p p r eciab l e risk to h u man health. Ac u t e

dietary (food) e x p o sure for f e ma l es 1 3

- 49

, r ep r es e nting the most sens i t ive

sub p o p u l ation of the o v e r all U.S. adult p o p u lation, u t i l i z es o nl y 5

. 42% of the

a P AD u s ing h ighly c o nserv a tive a s sump t i ons a nd t he aEDWC i s m o r e th a n 500

f o ld low e r th a n the aD W L OC

. The r efor e , th e re is a r e a s o n a b l e cert a inty th a t

no h ar m w i ll o cc u r to the US Popula t ion from aggr e gate ex p o sure ( f o o d,dr i nk i n g water and non

- dietary) to residues of pyri m e t h a n i l

.2

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

. EPA h a s d e t er m ined t h at the t o x icology d a t a b a se

f o r pyrimet h a n i l regardi n g po t e n ti a l p r e

- and post

- nat a l e f f e cts i n chi l d r en is

c om plete a nd d o es not ind i c a te any p ar t i c ul a r d e v el o pm e nt a l o r r e pr o du c ti v e

c o ncerns. T he special FQPA SF h a s been r e duced to 1 X

. U sing the c o n se r v a t i ve

a s sumptions descr i bed in the exposure secti o n a b ove, chronic d i eta r y exposure to

residues o f pyr i met h a n il in f o o d f o r Child r en 1

- 2 (the most highly e x posed sub

gr o up) i s 65

. 4% o f the c P AD. The c h r on i c ED W C i s m or e than 300 f o ld low e r

th a n the c D WLOC. Acute d i e t ary ex p o sure to resi d ues o f p y r i met h an i l in f ood

for Childr e n 1

- 2 (the most highly exposed s u b g r oup) is 3 3

. 7 % o f t h e a P AD

. T h e

ch ro n ic ED W C i s m o re than 180 f old lower than the c DW L O C

. There are no

n on

- die t a r y c o ncer n s f

o r inf a nts and c h i ldren. Therefore, t h ere is a reaso n a b l e

c ertai n ty t h at n o h a rm will occur t o in f a nts and c h ildren f

r o m aggr e g a te

exposure to residues of pyri m e t h a n i l

.

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

EU a nd C o d e x MR L s h av e n o t b ee n est a blished f or pyri m et h a n i l

in cucumbers

.