Document ID: EPA-HQ-OPP-2012-0876-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-12-19T05:00Z

May 25, 2012

EPA REGISTRATION DIVISION COMPANY NOTICE OF F1LING FOR PESTICIDE 
PETITIONS PUBLISHED IN THE FEDERAL REGISTER (7/1/2007)

EPA Registration Division contact:[insert name and telephone nu mber
with area code]

INSTRUCTIONS: Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert "NA-Remove" and maintain the outline. Please do not change the
margins, font, or format in your pesticide petition.Simply  replace the
instructions that appear in green, i.e.,"[insert company name!," with
tbe information  specific to your action.

TEMPLATE:

[Bayer CropScienceI

!Insert  petition number'!

LP.C !Ja-.,  l1.T1.'liL'd .1 pe:-.uude  pct Hion ([insert petition
number])  lron1 I.Bayer CropSciencej, [P.O. Box 12014,2 T.W. Alexander
Drive, Research Triangle Park, NC 27709] prnr,l.., Jil. [HI "''ant  to
'c-ctHHl•nk e11" .  Icrop subgroup 13-078] .11  [2.01 p;trh JWr
million 1ppn1J. [Iow growing berry crop subgroup 13-07H (except
strawberry)] at LO.lSl part JKI  nu!ilnllt ppml. und [cucurbit
vegetables crop group 9] .,, [0.3] p.ut-- pet lll i lliun !ppn 1    IJ
'lll!llll' ,cnl!,l!!•-. ldl.t  ,,, II t  I :.,u;,.l l'l .'tdlll g the
l'kliiL'Iih -- 1  h'IIil Ill 'L' llnll .!(ll-) td  )( 2l

nl I;11 tin' IllIl'l nt  v, ht'i)IL'I ll1c d,H,: 'uppu1 h gran t mg. ol
the p .lll'l.'dl.'d h,:iotC' I    P 

                   

1   1-'lu!ll   ll'c'tol.,oft ''"- l ln plants. Lhe metabolism of
prothioconazole is adequately understood for purposes of establishing
these proposed tolerances.  Prothioconazole was extensively metabolized
in plants with the major residue found in all crops (wheat, peanuts and
sugar beets) being JAU6476-desthio with smaller amounts of various

iomers of JAU6476- hydroxy-desthio. and their conjugates also being
found. Triazolylalanine. triazolylhydroxypropionic acid. and
triazolylacetic acid, metabolites

                                                  

1 11111111111111 111111111111111111111

M-431155-01-1

                                        

com!l'IB)J1 LO the tri azole-derivative clas:-. of fungicides. were
also found.  Based on the abovl! data the residues of concern in planh
are prothioconai.'ole and its metabolite JtCU6476-desrhio. The risk
a'sessment for the common metabolites ari<.;ing from  the

triazolc-dcriCativc fungicideibeing addre......,ed hC  t-he US
Triazole Task Force.  [n large anirnal..... the nature of re idue-; is
abo adequately under....tood for purposes of establishing

the pruposcd tolerances.  The residueof concem in edible tissues and
milk arc prothioconazolc. irs metabolites JAU647o-desthio,
JAU6476-4-hydroxy. and their conjuga tes that can be converted to these
three compounds by acid hydrol ysis.)

t,, melon. and -.qua'>h. The validated  LOQ'> were 0.01 ppm for IH-1
,2.4-triazole and the triazole

conjugatefor blueberry fruit. cranbeJTy fruit. cucumber. melon. and
'>quash. The analytical method for ana[y..;is of large animalti!-.'>Ues
indude-. extraction of the residues of concern, followed hy addition of
an internal standard to the extract.  The extract is then hydrolyzed to
release conjugates. partitioned and analyzed by LC/MS/MS as
prothioconazole, JAU6476-desthio  and J AU6476-4- hydroxy.  rhe method
for analysis of milk eliminated the initial extract ion Ctep in the
tissue method.I

lu"11111dj   "' n 'idrr( ' IResidue trials were conducted in the various
required regions across the United States and Canada in accordance with
the EPA and PMRA guidances for crop  field trials (OPPTS 860.1500: DACO
7.4.1: DACO 7.4.2) to supp011 tl1e tolerances requested nhove including
the following:

BushbenCranberry: A total of 6 field trials were conducted in the USA
and Canada on

cranberry a'->  a repre cntative of the Low Growing BetTy Subgroup
except

Strawheny (Crop Subgroup  13-07H).

C'ucurbit Vegetables: A total of 24 fidd trials (8 trial each on cucumb
r. muskmelon.

and squash) were conducLed  in the USA and Canada.

                   

, •   't	o •   •  , •	IProthiocona.wle exhibits Cmg/kg/day
while the dermal LD50 was >2000 mg/kg/day and the four-hour rat
inhalat.ion LC50 >4990 mglm3 •  Prothioconazole was not iJTitating to
the eye or skin of rabbits and did nol t:ause skin sensitization in
guinea pigs.)

_    (;( 1111    ' >llt'    (Prothioconazole  is not mutagenic. Slightly
positive and

                                    		

equivocal  re:-11on"c een  in in vitro CC.10tc-..t!-. . j

/11  1/11-..ubchronic lt>xicity study in rats. Determination of cell
countin  the spleen and perfomwnce 1)f the plaque-forming as..;ay
'>hov:,ed no eCimmu notO.CtCity at do!->eup to 500 mg/kg.lday (the
highest do"e tested) for 31 days.  The rc... uil'i of thl'..;tudy. in
addition to additional '>tudic-.. conducted u..;ing mice and dogs.
suppon that prothiocona7.ole is not considered to he immunotoxic.l

,	• •,..	•     ' I<    , •• ,, '', ' •  ,	IProthioconaJ.olc
is not considered a primary rcprodudive toxicant in a two-Generation rat
reproduction ..;tudy. The NOAEL ror parental tox i(.;ity as well as rhe
NOAEL for reproductive and neonatal effects is 95.6 m kg bw/da y  In the
rat oral developmental toxi :ity .-,tudy the fetal NOAEL was 500

mgfkg ln.vid.t) and the maternal NOAEL V>a:-. 80 mg/kg hvdday. A doe 
leCCI or 1000

mg/kg hVIJday aJmini-..tered to the rut by the dermal route doenot 
elicit developmental

toxicity. In the rabbit, prothioconazole doe" not produce developmental
toxicity at dose levels exceeding the maximum tolerated dose. Thu:-..
prothioconazole is not tcratogeni<.: in l'ithcr the rat or rabhil.]

.;,     '	•:-ho"

" (	n  . ,	IProthioconazole is not ca rcinogenic in either the rat or
the mouse even at dose levels in the rat exceeding the maximum tolerated
dose. The liver ami kidney arc target organs or prothio<.:onazole for
non - neoplasti<.: toxicity in the rat, mouse

and do-g. The  lov.cst NOAEL established on the ba"is of Jon!!-term
toxicit v- 'tudies is 5

mg!kg hw/day in the rat chronic toxicity/carcinogent<:ity stud y and the
dog 52- week

toxicity study. I

-..:       '1  , ,; .•I     ,. ' 	•  , )..,	[The major metaholi te
of prothioconazole in the rat. plants and large animal' i-. JAU6-t76-de
thio. Therefore. a comprehensive evaluation of the mammalian toxicity of
J AU6476-desthio has been performed.

The acute oral. dermal. and inhalation toxicity of JAU6476-de..;thio in
the rat is low

( LD50 valw.:': 2806/1506mg/kg 1 male/female!. >5000mg!kg. 4-hour LC50:

>5077mg/m '. rc pectivcly). It is non-ineyes and has no cutaneous
sensitizing. potential by topical application.

The short and long-tenn ornl toxicity of J AU6476-de thio has been
investigated by

dietary admini tration  in the rat. mouse and dog. The common  target
organ  in all 3

-.pecies is the livcr. Secondarv. effects on the th.vroid  m the rat a
nd do!.:.!.

were as:-.ociated

                                    

'Nith increased hepatic enz yme induction.  In the long term studies, 51
weeks in the rat and 30 wech in the dog. the NOAEL for the rat and the
dog- were  I. I   and  I 0.1  mVk2... bw/day, respective!y. J A
U6476-desthio is not carcinogenic in either  the ra t  or the mouse.

The  NOAEL selected for human risk a;.;sessment is 1 .1  mg/kg bw/clay
established in the combined  chronic  toxicity and carcinogenicity stud
y in the rat.

JAU6-+76-deslhi<) was negati ve for mutagenicity and genotoxicity in all
in ritro and in

rim studies  both '-"'ith and"ithout metabolic  activation.

In a two-generation reproduction study the maternal  NOAEL  was 2.7
mg/kg bw/day  and the NOAEL for reproductive and neonatal effects I 0.0
mg/kg bw/day. The main targets

at  the highest dose  were dystocia (probably ->econdary to hepatic tox
i ci ty ), decreased  pup viabi lity. growth retard at ion and low
incidence of cleft palates.

In the developmental  toxicit y 'tudies deft  palateC  were :-.een in
the rat and rabbit at the highest doe  leveb and Cupemumerary rihin the
rat a t  lower dose lcC'els. The oral NOAEL i-.  l mg/kg  bw/day in the
rat and 2 mglkg/day in the rabbit.

A developmental ncmotoxicity "tudy tDNT)  in rats wa:-. conducted  with

JAU6476-desthio athe anticipated  dietary exposu re is mainl y to
JAU6476-desthio and not the parent. No evidence  of neurotoxicity was
seen in this study. i ncluding  no compound-related effects  involving 
neurobehavioral tests and neuropathology.

Compou nd-related  effects "ere limited  to overt toxicity and
developmental effects which were con"istent  with effcch seen  in other
developmentaltoxicitstudies. The overall NOAEL  was 3.6 mg./kg bw/day.j

u ''''"•t  ,, ,  ,I• 	.,,	'

                   

i i>t c   un       , ,L    (An aggregate risk assc),sment was conducted 
for all existing registered  u:-.e-. on  barley: dried beans and peas
(Crop Group 6C): canola;  peanuts; wheat: triticale: soybeans: 'ugar
beets: cereal grain crop group  15 and 16 (except  sorghum)

sweet corn: rice: al fall'a: potato a nd this proposed  petition 
requesting  toleranceon

cucu rbits (Crop (]roup ). blueberry (Crop Group  1 3B). and cranberry 
(Crop  Group

13H).  A previous Tier 2 dietary risk assessment wa:-. conducted by EPA
(PC Code

11396 I) on December h_  20 I 0. Residues  for the additional  crop
groups  were based on highest average  l'ield trial (HAFT) for acute
assessment and the average  re-.idue for chronic assessment.

The acute toxicity endpoin t  U!-.ed  in the acute assessment was the
NOAEL of 2.0

mg/kg/day from the prothioconazole-desthio rabbit developmentaltoxi<:ity
study as

dc crihed in the Agency"HED  risk assessment memorandum on
prothioconai'.ole dated

Januar y 5. 2009. No acute endpoint 'A-as identified for the general
U.S. population: Female!-.. 13-9 years of age. C'vas the only
population '-Ubgroup to be included in the aLresults l'rom applying a I
OOx unce1ta im y factor to the NOAEL of 1.1 mg/kg/day from the rat
chronicConcogenicity  prothioconal'olc-desthio toxicity 'iludy.

The acute and chronic dietary assessment<> for combined food and water
exposure show

25<-r  utili?ation of the aRID by female!-. 13-49 years and
63<'utilization of the cRfD by the most sensitive subgroup. all infants.
 Rc!-.ults from the dietary exposure assessments

<.kmPilStra tc a reasonable certainty that no hann to the overall U.S.
population or any populat iun '->Ubgroup will result from the U!-.C or
prothioc011 110l e 011 the above crops.D

'"'' (An acute. Tier 2 dietary (rood only) ri-;k as<.;essmcnt  was
conducted. For the population subgroup  females 13-49 years old. the
acute a nalysis indicates an e-xposure of 3.75% of the aRID at the 951h
percenti le. Results  from a ch ronic, Tier 2 dietary (food

on l y) risk assessment show that the most highl y exposed popul ation
'iubgroup i!-.  children I to 2 years with an exposure equal to 9.7c/c
of the cRtD followed by aJI infants at 3.9Clc. Chronic exposure to the
overall U.S. population i-. 3.2"k  of the cRtD.]

                                    

' 	fJ  ,,. ,,,,  l'i •''  !No monitoring data are available for
residues of prothioconazole in drinking water. and EPA has established 
no health adv isory levels or maximum contami nant leveb for res iducof
prot.hioconazole in drinking water. In order to addres-; drinking water.
water was included in the dietary analvsis for food. DEEM

anal ysc" v.-ere performed using the upper hound estimates for the
cranberry crop scenario: the EDWC for the acute and chronic a <.,e!-.
ment is 94 pph. For the population subgroup females 13-49 year-. old.
the acute analysiresults in an exposure of 21 ( fl  of the aRID.

Re:--.ults from a chronic. Tier 2 dietary risk u:-,:--.essrnent indicate
that the most highly

exposed population subgroup was all infants with an exposure equal  to
59% of the cRfD. Chronic exposure to lhe overall U.S. population i!-.  
18% of the cRfD.D

C  ,	,   '"! ,	[Prothioconazole j..,  not regi...tered for residential
uses nor arc any registrations pending for 'uch  use. I

                   

[Prmhiocouazole ia member of the conazole family of fungicides. The
cumulative effect!-. of the primary common metabolite!-. are being
addressed by the US Triaznlc Task Force. I

                   

l  C  ,,'i'  tf, .,,,, (In the Agency'.., HED risk a..;sc<..smcnt
memorandum on

prothioconaLOie dated October  13. 2006. it is stated that
quantification of acute risk to the general population including
infant.;; and children inot required. Based  on the conservative
exposure a sumptiont'i described above and on the completeness of the
toxicity data, it can  be concluded that total  food and drinking water 
exposure to prothioconazolc irom  all proposed uses will utilize  25% 
of the acute  RfD  for females 13-

41.)  years old ami 21.2% of the chronic RtDs for the overall U.S.
population. EPA generall y has no concerns for exposures below  100%. of
r.he RtD. because the RID represents the level  at or helow which  daily
 aggregate exposure over  a lifetime will not pose appreciable risb to
human health.j

2 . /nftlllh  tlltl, ,,, tJ'•  '' [In the Agency"s HED  risk
assessment memorandum on prothioconazole d;.tled January 5. 2009,  it is
stated: in rats. The effects seen  in these  studies suggest that
offspring are more susceptible:

'-''-'	'-

ot'f pring  effectwere seen  at leCgeneral. were of comparable or
greater severity compared to the effects observed in adults.  However.
the point of departure for the most sensitive of these stud ies (the 
rabbit developmental toxi ity)  is lower  than that of the other 
studies (2 mglkg/day), and  is based on effects observed in the fetus. 
not the parent. Therefore, the offspring are considered to be protected
and there  is no need  to retain  the  IOX FQPA  factor. and  it is
reduced to I X."

EPA also stated    assessment.

In addition to the adequacy of  the toxicity database, there  are also 
no uncertainties with respect  lo the exposure database. Both  the
dietary food and  water  exposure assessments are conservative in
nature.  Additionally, there  is no potential for residential exposure.

In Bayer"s  dmmic exposure assessment. the most highly exposed
population subgroup. all infants. uti lizecl63 Cfr   or the chronic RfD.
 EPA  generally has no concerns for

exposures helnw  I OOC1'

of the RfD. hecause the RfD  represents the level  at or below

which  daily  aggregate exposure over  a lifetime C),.'ill  not  pose
appreciable risks  to human health.!

hlf< n;,,•rr•Jt/1: I oft r(l/, t  

[lntemational tolerances/MRLs for prothioconazole have  been established
for various  crops. Hov,:ever. none  have  been established for
bushbetTies. low growing berries or cucurbit vegctahles.J