PEST

EPA REGISTRAT

ICIDE PET

ION DIVISION COMPANY NOTICE OF FILING FOR 

ITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Reg istra tion Division contact: Heather A. Garvie, (703) 308-0034 

~ INSTRUCTIONS: P lease utilize this outline in prepar·ing th e p esticide petition. In 

case

ma

s wher·e th e outline c lement d oes not apply, please insert "NA-Removc" and 

p es

inta in the outline. Please do not ch a nge th e margins, font, or format in your 

ticide pe tition. S imply r e place th e instructions that appear 

company name!," w

in green, i.e., "I insert 

ith the info rmatio n specific to your action . 

TEMPLA TE: 

ISK Bioscicnces Corponttion 

llnsc r·t petition numherl 

1·1' \ ha .... rL·cci\L'd a pvaicitk pL'Itlton (!insert p etition numbCI"I) 

Biosc

fr()m IS K 

tm>J1""in~. 

iences 

pm"ill.llll 

Cor·poration, 74 70 A uburn Road, S uite A, Concord, O hio, 44077, 

l(l .... cl..liPn -10!\(d) ot' the h:dcral l·ooJ. Drug. and Cosmetit; t\ct 

(I I I)(· \ ). 1 l l 1 S.( · ~·~<l.t( d). to <llm:nd -10 ('I· R part l Xtl h~ C'\l<lhlishing a toli:rancc I'm 

tL idllL'" 111 the h e rbicide Tolpy ralate, 1-ll l -Ethyl-4-13-(2-mcthoxyethoxy)-2-me thy l-

.t

in

-(

cludin~ 

ml'lhyls

its 

ulfo

metabo

ny l)hen

lit

zoy

e MT

ll- 11-1-pyntzol-5-yll oxy l(•thyl methyl c~l rhona te (CAS), 

-2153, 111 ut 1111 tiH: I'll\\ ,\gncullmal rnmmoditic~ Corn 

"hiLh tncludc". 11rld 1.111'11. ·,\\L'l'l \.'lllll and f'\lpcorn. at 0.0 1 parts pL'r millton (ppml. IY.\ 

h:t..; dl'IL'I'Iilllk'd th<tl thL· pctiti,H1 -:uJ't·uns data lit' inlilf'lll<llion n.:ttanJing the dements st:t 

lunll in ..;ccli(ltl ~OX !d\1.2) ,,, ll)f)l',\: hll\\'l'\l'l. U'·\ has not l'ully e\·,llunt~d the: 

pditintl. 

<;ltJ'IiciLill.:y 

.\ddititlnal 

ol' tile "llhmith.:d 

dat:1 

d~1!.1 .11 thi-; time lll' \\ ilL'Lher tltl' d~tl<l supports granting of the 

nl,l) hl' !1L'c~kd bc!'urL' 1-.P:\ ruks on tile pc:lititlll. 

f>l<1111 

r esidue

lltdcthu/1.\111 

s in com 

The me tabolism of tolpy ntlatc a s \Yell as the nature of t h e 

tolerance. A metaboli

(maize) is adequately understood fo r the p urposes of this 

metabolite of tolpy

sm st udy was conducted with ma ize. T he main 

har·vcsts and up 

ra latc was MT-2153 comprising up to 8'Yt) in immature 

metabolites and 

to .t'Yt, in mature harvests a nd a number of minor 

bound residues. lien ee, par·cnt 

metabolite MT-2153 

tolpy ralate and th e 

define th e n.'siduc of conccm . 

2

. 111ult 

153 

nnrl 

using 

111< 

Liquid 

I!Jtld. A 

C

pn1ctical a nalytica l method for p~Ta atc and MTh roma togr aphy-MS/MS is available for analysis of a ll 

APR 1 4 2015 
2 

plant matrices. This method has been confirmed through independent 

laboratory va lidation and is available for enforcement purposes. 

, /u~nitude 1~/ n.:.,id!f(:s. Corn trials were conducted at 28 sites in the USA and 

Canada on field corn (20), sweet corn (S) a nd popcorn (3). One application 

at the target rate of 0.089 lb a. i./A (100 g ai/ha) was made to the treated plots. 

The total a pplication rate ranged from 0.070 to 0.093 lb a.i./A (78-104 g 

a.i./ha). 

No residues above the LOQ were found in samples with PH l 's of 20 days or 

longer. Processing samples tr·catcd at a 5X rate had no detected residues 

either in the cor·n gnlin or the processed fractions. 

/J 7 nxiw/op,icul l'n~ji/e 

I. .·/cute toxicitv. Results from a battery of acute toxic ity studies place techn ical 

Tolpyralate in Toxicity Categot·y III for ora l LOsu and dermal LD:-o, and 

Category IV for inhalation LCso, derma l irritation, and eye irritation. 

Technical Tolpyra late was not a dermal sensitizer. 

In an acute ne urotoxicity study, Tolpyralate was administered orally to 

groups of rats at oral doses up to 2000 mg/kg, with no evidence of 

neurotoxicity or· neur·ohistopathological change. Consequently, 2000 mgll<g 

was considered to be the NOEL. 

2. ( ;cnotoxicity. The genotoxic potential of Tolpyndate has been assessed as 

negative by several in vitro and in vivo mutagenicity studies. Tolpyralate did 

not elicit a gcnotoxic response in any of the studies conducted. 

:1. l<eproduuin· and dcn:loJmJel?lal toxicil)'. Resu lts from a two-generation study 

indicate that Tolpyn1latc is not a reproductive toxicant. T he NOEL for 

r eproductive performance was > I 000 ppm, the highest dose tested 

(equivalent to >54.9 and >8 1.8 mg/kg/day, respectively for P males and 

females and >63.3 a nd >90.2 mg/kg/day for Fl ma les and females). The noobserved-adverse-effect leve l (NOAEL) for systemic effects in par·ental r·ats is 

S ppm (0.270/0.4 1 0 mg/l<g bw/day male/female). 

Results from developmental studies in rats and rabbits provided no 

indication of teratogenic effects for fetuses of either species and no evidence 

of developmental effects in the absence of rnatcmal toxicity. For the rat 

teratology study, doses up to 500 mg/l<g bwt/day were administered between 

Days 6 and 19 of gestation. The NOEL for maternal toxicity and 

developmenta l toxicity was 10 mg/l\.g bwt/day for maternal rats and their 

fe tuses. Tolpyr alate techn ical was not teratogenic to ntts. For the rabbit 

teratology study, doses up to 500 mg/lig hwt/day were administered between 

lhys 6 and 27 of gestation. T he NOEL fo r matem a l toxicity and 

developmental toxicity was 5 mg lq~ bwt/day and that of 500 rng/kg/day is the 

effect level fo r· both of maternal rabbits and their fetuses. Tolpyralate 
3 

technical was not tcrato~c ni c to rahbits. 

4 .\uh<·hmn~<· tuxlcil.t Subchr·onic (90-day) feed ing studies wer·e conducted 

rats, mice 

in 

were 0

and dogs. Doses eva lua ted in the rat (r epeated dose, oral) study 

(equiva

, 5, 20, 2000 and 20000 ppm. T he NOAEL was 5 ppm in ma les 

1.58 mg

lent to 0.323 g/Jq~ bwt/day) and 20 ppm fo r· fema les (equivalent to 

sexes

/kg bwt/day). Effects on the liver and eye were obscr'Vcd for both 

2000 

. D

and 

oses eva luated in mice (repea ted dose, oral) study were 0, 50, 500, 

mg

7000 ppm. The NOAF.L was 500 ppm in m1lles (equivalent to 70.8 

C'entr·il

/kg/d<t

o hular 

y) and 2000 ppm for femal es (equivalent to 33 1 mg/l<g/day). 

hepatocellular hy pertrophy was H treatment-related 

for 

change 

evaluated 

the 2000 ppm group for ma les and 7000 ppm g roup for· females. Doses 

was 2000 

in the dog study were 0, 200, 2000 and 20000 ppm. T he NOAEL 

(65.33 mg/k

ppm 

g 

for males (64.61 mgll<g bw/day) a nd 2000 ppm fo r fema les 

bw/day). 

). ( '/zmnit· wridL.t An 1 8-month oncogenicity study wa s conducted 

dietary 

in mice with 

ca r c

com·entrations of 0, 70, 700 and 7000 ppm. T here Wil S no evidence of 

inogeni city. 

conccntn1tion

A 1-ycar chronic toxicity study was conducted in rats w ith d ietary 

To

s of 0, 5, 20, 2000, and I 0000 (M) o r 20000 (F) ppm techn ical 

0.925 

lpyra

mg

latc. T he systemic NOAEL was considered to be 20 ppm (males, 

/l<g bw/day; females, .J.18 mg/lq?, bw/day). 

A 2-ycar chronic toxicity/carcinogenicity study was conducted 

dietary co

in rats with 

The no-ob

nccntn1tio ns of 0, 5, 20,2000 and 10000 ppm technica l Tolpynllate. 

to be 20 ppm 

se r-ved-adverse-effect level (NOAEL) for toxicity was deter mined 

mg/

fo r· males (0.765 mg/l<glday) and 20 ppm for fema les (1.01 

l<g bw/day). T here was no evidence of carcinogenicity. 

A 52-wed< chroni c toxicity study was conducted 

conccntt·ation

in dogs with dietary 

(male

s of 0, 100, 1000 and 10,000 ppm. T he NOAEL was 1000 ppm 

s, 28.1 3 mg/l<g bw/day; fema les, 28A6 mgl l<g bw/day). 

(, .·lmmfll 

hens arc 

llil'tctl•oliwl The metabolism of Tolpyra late in rats, goats and laying 

the feces. 

a

The 

dequat

m

ely undcr·stood. Tolpyrah1tc is rapidly excreted ma inly via 

scv(•

ajority of excr eted material was uncha nged Tolpynllate, with 

no s

t·al minor metabolites present in feces, bile, urine and tissues. T her·e 1u·e 

pathwa

ign ifica nt q ualitative differences hctw(.·en rat and n rminant metabolic 

ys. 

7. 

in 

\!duho/itc 

plant or 

~rn·icoloi..!,J. No toxicologically significant metabolites were detected 

a nima l metabolism studies. The residue of concern for tolerance 

se

MT-2

tting 

15

purpo

3. Con

ses is the parent compound nnd the major pla nt metabolite, 

metabolite

sequently, there is no additiona l conccr·n for toxicity of 

s. 
4 

X. l.ndocrine di,ru;1titm. The submitted studies include evaluation of the 

potentia l effects on reproduction a nd development and an evalua tion of the 

pathology of the endoc rine orga ns following short or long-term expos ure. 

T he data demonstrate no trea tm ent-related effects on the endocrine system. 

() fmnullwloxicity. Four-wee k immunotoxicity studies were conducted in fema le 

mice. There was no effect on the immune system at any dose tested. T he 

NOEL was gt·eater- than 5,500 ppm (~ I ,002 mg/kg hwt a~ ). 

I. J>ietar.l (''(fJ/1\'/Jrc. Ex posun.' assl·ssmcnts were conducted to evaluate the 

potential risl< due to dietary exposure of the U.S. population to residues of 

Tolpyralate. 

For acute dietary exposure, an Ac ut e Refet·cnce Dose (aRf"D) is not identified 

for Tolpyralate since there was no evidence of initia l acute effects in the acute 

oral or short-temt toxicity studies, ot· the developmental toxicity studi es in 

rats and rabbits. There were no effects seen in the acute neurotoxicity study 

at the limit dose level of 2000 mg/l<g/day. No initial acute effects we re seen in 

the 90-day neut·otoxicity study. 

For d11·onic di etary exposure, the chroni c reference dose (cJHD) is 0.00270 

mg/kg bwt/day, based on the NOAEL from the ra t 2-ye:n reproductiH 

toxicity study (0.270 mg/kg bwt/day) a nd dividing by a n uncertainty fac tor of 

100. T he chronic population adjusted dose (cPA D) is also 0.00270 mg/kg 

bwt/cl:.t~ ' since the FQPA afe~· fa ctor is a nticipated to be I for Tolpy ralate. 

i. l-oud T ier· 1 ch ronic dietary exposure a na lyses wue cond ucted fo r 

Tolpyralatc in/on corn (field, sweet a nd popcorn) to det·cnnine the exposure 

contribution of this commodity to the diet a nd to asce rtain the chronic risl<. 

potential. The ex posure estimates were based on the pt·oposed tolerance level 

residues, average processing fa ctors and a ma r ket sh:u·e of 100°/., crop 

tt·catcd as a conservative assumption. The consumption data were from the 

USDA's Nationa l Health and Nutrition Examination Survey/W hat We Ea t in 

America NII ANES/WWEIA dieta ry survey conducted in 2005-20 10 (2 d<~ y 

food consumption data) using the Dietary Exposut·e Evf-tluation Modul e 

(DEEM-FCI D) software, version 4.02/10.00. 

Using all of the worst case exposure scenarios listed above, the T ier 1 chron ic 

di eta r·y exposure estimates resulted in an estimated exposure for the genera l 

U.S. population of 0.000152 mg/l<g bwt/day. This exposure corresponds to 

5.6'Yo of the cPAD. The highest ex posure estimate calcula ted was for the 

subgr·oup All Infants. This cxposut·c was determined to be 0.000551 mg/lig 

bwt/day (20.-t'Yo of the cPAD). The chronic dietat·y exposut·c analysis is 

s umma rized in the table below. 
s 

Population Expos u re Estimate % ofcPAO 

Subg roup (mg/l<g body wi/day) 

U.S. Population 0.000152 5.6 

A ll Infants(< I yea r old) 0.000551 20.4 

C hildren (1-2 years old) 0.00022 1 8.2 

C hildr·en (3-5 yea rs old) 0.000187 6.9 

Children (6-12 years old) 0.000 139 5. 1 

Yo uth (13- 1 9 years old) 0.000114 4.2 

Females ( 13-49 years old) 0.000 149 5.5 

Adults (20-49 years old) 0.000141 5.2 

Adu lts (50+ rears old ) 0.000146 5.4 

It can be concluded that lo ng-tcrn1 dietary exposure to Tolpyralate through 

r esidues on a ll commod ities s hould not be of ca use fo r concern. 

-, 

it I 1ri11~in'..! ,, 11/t'l' Using P'l RST, SCI GROW and PRZM-GW models, 

estimates of Toltw ralate r esidues in s urfa ce and oround water were • 1:> 

calcula ted. T he highest EEC value of 0.0068-J mg/L was used as input into 

the Dli:EM/FCID mod e l for drinking water (direct and indirect sou r ces). 

\r•n-.lict,o:\· c.\fi0\1/IT. Based on t he proposed uses for Tolpyralatc on the crops 

noted above, non-occupational exposure of Tolpyralate would not be 

exp ected to the g<.·nc1·al p opulation. The only anticipa ted ex posure ro u te for 

the US po p u lation is via the diet (food and wa ter only). Therefore, residenti a l 

l'is k assessments for the incid enta l oral, d ermal, and inhalat ion ex posure 

rout cs arc not 1·eq u i J'cd. 

Occupationa l post-applica tion ex posure is possible. For derma l s ho•·t-tenn 

ex p osure, n o toxicity w~• s fou nd at 1000 mg/l<g in a 28-day rat d e rmal toxicity 

study. T hc:r cfo r c, in th e :ths<.· nce of any hazard identified for dermal 

exp osure, a d ennal post-applica ti on r isl< assessment was n ot conducted . 

Poten tial inhalation cxpos u1·e was not co nsidered since it is negligible when 

assessing 1·c-cntry ris ks. 

O ccupational ex posure for mixing/loading and applying To p~Talate was 

considered. Potential exposure was considered negligible since MOEs we1·e 

g r cate1· than 1,000 fo r a ll calcu.latio ns. 

I 1 1 tlillll!tllil'c' F!!<'t'J\ 

E PA ha s not made a common mechanism of toxicit_y findin g as to Tolpy ralatc and 

any othc1· suhst<n1ces, and Tolpyralatc docs not appear to produce a toxic metabo lite 
6 

[H·odu

EPA ha

ccd 

s not 

by other s ubstances. For the purposes of this tolera nce ac tion, therefore, 

other subs

assum ed tha t Tolpyra la te has a common mecha nism of toxicity with 

tanCl'S. 

I. I·.\ I)()PIIIatiuJI 

and 

llascd on the completeness and rcliahilit)· of the toxic ity d a ta 

that 

th

no 

e conserva tive exposure assessments, there is a reasona ble cel'ta inty 

T o

ha rm will result from the aggregate exposure of r esidues of 

lpyr a la tc. 

2. lnlunl.\ 

da

and children. Based on the completeness and relia bility of the toxicity 

ce

ta a nd the consu vativc exposure assessments, there is a r·ea sona ble 

ex

r

p

ta

o

inty that no harm will r·csult to infants and children fro m the aggr ega te 

sure of residues ofTolpyralatc. 

F lntanutiuno/ Ji,fert/1/(,' 

Presently, thet·c ar·c no Codex maximum residue levels (M RLs) established for 

resid ues of Tolpyn1latc on a ny crop.