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 number 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.\ !Ja-., l1.T1.'liL'd .1 pe:-.uude pctHion ([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· W {(!J ol'thc h.:d1.'1al l·oud.Dru. a11d · 

(_',,..,nh'l ll.. \vt•f-lD(\1 _'ll S.C.3-+6aldl.toamend-4(J(l·RparliXIlh)l'"l.thli...,hiH a

•nk e11" . I· t r ..., 'd''"'"' IJ>rotbioconazole,2-[2-(1-chlorocyclopropyl)-3-(2-

chlorophenyl-2-hydroxypropyl]-1,2-dihydro-3H-1.2,4-triazole-3-thione and it 

desthio metabolitel n t I)J t1tl till.' r< '>\ o1 ptocc:-.:-.cd agJ JLUitund l<'ll!!JliJJlt) [bushberry

crop 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 llli lliun !ppn 1 I·P \ Jta, d\:t ·,mined ih.ll til'l

J'lll!llll' ,cnl!,l!!•-. ldl.t ,,, II t I:.,u;,.l l'l .'tdlllg the l'kliiL'Iih -- 1 h'IIil Ill 'L'llnll.!(ll-) td )( 2l

nl I·J)!)( \. !a•'<\ L q :.l.f' \ h.J'- IJ,,r i1dl, I.'\ <tlUc.Jll'd tlh' lll!'1, IL"llL') ll !Itt· "libsnillcd data

;11 tin' IllIl'l nt v, ht'i)IL'I ll1c d,H,: 'uppu1hgrant mg. ol the p .·tHJUn . \ddi tiomd dat a ma) lK·

lll'l.'dl.'d h,:iot\' I P·\ tllk'• 11) lilt' pt>tllinll

1 1-'lu!ll ll'c'tol.,oft ''"- lln 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
2

com!l'I{)J1 LO the triazole-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\U6476-desrhio. The risk a'sessment for the common metabolites ari<.;ing from the

triazolc-dcri\ativc fungicideibeing addre......,ed h\ 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 

conjugates that can be converted to these three compounds by acid hydrol ysis.)

t,, ·, "•' 1u 1 ,, (The analy1ical method for determining residues of concem 

in planb xtracb re-,idue'-> of prothioconazole and JAt i6476-de-;thio and com erb the 

prothioconazole to JAU6476-desthio and JAU6476-sulfonic acid. Following the addition 

of internal standards, the sample extracts are analyzed by LC/MS/MS. Radiovalidation and

independent laboratory validation have shown that the method adequately quantifies 

prothioconazole re idues in treated commodities. The validated LOQ for total 

prothioconazole-derived rc<>idues was 0.02 ppm in blueben-y fruit, cranbeJTy fruit. cucumber.

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 extraction \tep 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:

Bushben·y (Crop Subgroup l3-07B): A total of II field trials were conducted on 

blueberry as a representative of Bushherry (Crop Subgroup 13-07B) in the USA 

and Canada.

Cranberry: 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 \·ery low acute oral. dermal and 

inhalation toxicity. The acute oral LD50 ror prothioconazolc in rats was >6200

mg/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
3

J '- .,

equivocal re:-11on"c een in in vitro C\.10£encti(.: and UDS assavs were neuativc in in 1·ivo

tc-..t!-. . j

/11 1/11·11• •" 1 ,,\ llmmunotoxidty potential was evaluated i.ls part of a

-..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\·idencc of treatment-related

immunotO.\tCity 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\CI 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.]

.;, ' •· , j{}O-day feeding studte:-. condu tcd in rat:-. mice. and dog-;

:-ho"·cd the li\Lr and/or kidney to he the target organ-.. In the:-,e ...ubchronic studies 

NOAEb were established at I 00 mg/kglday for the rat and 25 mg/kg/day for the mou:-.c 

and dog. I

" ( n . , IProthioconazole is not carcinogenic 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 study and the dog 52- week

toxicity study.I

· \ u.,.,.,I '· 'il',ul, , n: [Metahol ism and pharmacokineti<.: studiein the rat 

demonstrah.' that prothioconazole is rapidly ahsorheu. metaboli7cd and eliminated. The 

primary tm:taholit" induued JAU6476-desthio. a-. \.'-'CII us S- and 0-glucurnnideof 

pnlthiocona;ok.•J

-..: '1 ,,;.•I ,. ' • , ).., [The major metaholite of prothioconazole in the rat. 

plants and large animal' i-. JAU6-t76-de thio. Therefore. a comprehensive evaluation of 

the mammalian toxicity of JAU6476-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-in·itating to kin and only very -.lightl y irritating. t0

eyes 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
4

-

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 and do!.:

.!. were as:-.ociated

'Nith increased hepatic enzyme induction. In the long term studies, 51 weeks in the rat and

30 wech in the dog. the NOAEL for the rat and the dogwere I. I and I 0.1 mVk2

... 

bw/day,

respective!y. J A U6476-desthio is not carcinogenic in either the rat 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 city), decreased pup 

viability. growth retard at ion and low incidence of cleft palates.

In the developmental toxicit y 'tudies deft palate\ were :-.een in the rat and rabbit at the 

highest doe leveb and \upemumerary rihin the rat at lower dose lc\'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. including 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• .,, '·' [The toxicology database for prothioconazole is current 

and complete. Studie-., in thi" databa:-e include evaluation of the potential effects on 

carcinogenic, reproJuct ion and de,·elopment effects including an evaluation of the 

pathology of the endocrine Grgans following short- or long-term exposure. 

Prothioconazolc i!-1 considered not to have primary cndo<.:rine cffect'i. l

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: alfall'a: potato and 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.
5

.

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. \'vas the only population '-Ubgroup to be included in the 

aL·ute <1'-'!--.Cssment. Application of a J()Ox uncertainty factor re-..ults in an acute reference 

close (aRID) of0.02 mg/kg/day. The chronic reference dose (cRfD) ofO.OJl mglkg/day

results l'rom applying a I OOx unce1taimy factor to the NOAEL of 1.1 mg/kg/day from the 

rat chronic\oncogenicity 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

<.kmPilStratc 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.}

'"'' (An acute. Tier 2 dietary (rood only) ri-;k as<.;essmcnt was conducted. For 

the population subgroup females 13-49 years old. the acute analysis indicates an e-xposure 

of 3.75% of the aRID at the 951h percentile. Results from a chronic, 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 advisory levels or 

maximum contami nant leveb for residucof prot.hioconazole in drinking water. In order 

to addres-; drinking water. water was included in the dietary analvsis for food. DEEM

analysc" 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.}

\ , , '"!, [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 \ ,,'i' tf, .,,,, (In the Agency'.., HED risk a..;sc<..smcnt memorandum on
6

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 memorandumon 

prothioconazole d;.tled January 5. 2009, it is stated: ·'There are adequate data in the 

prothioconazole (incluuing metahoiites) database to characterize the potential for prenatal or post-natal risb. to infants and child ren: two-generation reproduction studies in 

rats; developmental qudies in rats and rabbits; and a developmental neurotoxicity study

in rats. The effects seen in these studies suggest that offspring are more susceptible:

'-''-' '-

ot'f pring effectwere seen at le\·els below the LOAELs for matemal toxicity and. in

general. 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 

developmentaltoxi 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 IX."

EPA also stated ·'No acute endpoint was idenrificcl for the general U.S. population. 

Females. 13-49 years or age. wathe onIy population subgroup included in the acute

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. utilizecl63 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 \),.'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