UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

Office of Chemical Safety and Pollution Prevention 

MEMORANDUM 

Date: May 22,2014. 

SUBJECT: Pyroxasulfone. Application for Amended Section 3 Registration for Use on Com. 

Summary of Analytical Chemistry and Residue Data. 

PC Code: 090099 

Decision No.: 482174 

DP Barcode: D414667 

Registration No.: 63588-91, 63588-92 and 63588-

93 

Petition No.: 3F8196 Regulatory Action: Amended Section 3 

Registration 

Risk Assessment Type: NA Case No.: NA 

TXR No.: NA CAS No.: 447399-55-5 

MRID No.: None 40 CFR: 180.:5~ /1 .~ / r4--

Ver.Apr.os ~ / ~· ;,/v[/'{ 

FROM: Thurston G. Morton, Chemist ~~f/"" Risk Assessment Branch IV /Health Effects Division 

(RABIV /HED; 7509P) 

THROUGH: Elissa Reaves, PhD, Chief 

Risk Assessment Branch 4 

Health Effects Division (7509P) 

TO: Bethany Benbow 

Herbicide Branch/RD (7505P) 

The registrant is currently requesting to amend the com use pattern to include the addition of 

adjuvants to the products. The additional com field trials conducted with the addition of 

adjuvants resulted in a need for increased tolerances from those established. 

Page 1 of27 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667 

Executive Summary 

Pyroxasulfone is an herbicide belonging to the pyrazole class of selective herbicides. It provides 

contact and residual control of a broad spectrum of broad leaf weeds and grasses, including 

glyphosate-resistant varieties. Pyroxasulfone acts as a potential inhibitor of very-long-chain fatty 

acid (VLCFA) biosynthesis, similar in mode to the K3 group of herbicides (Group 15). 

Under PP#3F8196, K-1 Chemical, U.S.A. Inc. is proposing tolerances are established for 

residues of the herbicide pyroxasulfone, including its metabolites and degradates, in or on 

the commodities in the table below. Compliance with the tolerance levels specified 

below is to be determined by measuring only the sum ofpyroxasulfone [3-([[5-

( difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1 H-pyrazol-4-yl]methyl]sulfonyl]-4,5-

dihydro-5,5-dimethylisoxazole] and its metabolites [5-(difluoromethoxy)-1-methyl-3-

(trifluoromethyl)-1 H -pyrazol-4-yl]methanesulfonic acid (M -1 ), 5-( di fluoromethoxy )-1-

methyl-3-(trifluoromethyl)-lH-pyrazol-4-carboxylic acid (M-3), and [5-

(difluoromethoxy)-3-(trifluoromethyl)-1H-pyrazol-4-yl]methanesulfonic acid (M-25), 

calculated as the stoichiometric equivalent of pyroxasulfone, in or on the commodity. 

Com, field, forage .................................................... : .. 0.09 ppm 

Tolerances are established for residues of the herbicide pyroxasulfone, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance 

with the tolerance levels specified below is to be determined by measuring only the sum 

of pyroxasulfone [3-[[[5-( difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1 H-pyrazol-4-

yl)methyl]sulfonyl]-4,5-dihydro-5,5-dimethylisoxazole] and its metabolite [5-

( difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1 H-pyrazol-4-carboxylic acid (M-3) 

calculated as the stoichiometric equivalent of pyroxasulfone, in or on the commodity. 

Corn, field, grain ................................................ ......... 0.02 ppm 

The nature of the residue in plants is tentatively adequately understood based on metabolism 

studies with field com and soybeans. The nature of the residue in rotational crops is adequately 

understood based on confined rotational crop studies with rotated soybean, radish, and wheat. 

The metabolic pathway of pyroxasulfone is similar in primary and rotational crops, and mainly 

involves cleavage of the methyl sulfone bridge of the parent compound, oxidation and/or 

demethylation of the pyrazole cleavage product to yield metabolites M-1 and M-25, and reaction 

of the isoxazoline cleavage product with cysteine and/or glutathione; further demethylation, 

deamination, and/or conjugation ofthese metabolites occurs, yield additional metabolites 

including M-3. The residues of concern in wheat hay, forage, and straw for tolerance 

enforc.ement in the U.S. are pyroxasulfone and its metabolites M-1, M-3, and M-25. The RABIV 

Risk Assessment team has determined the residues of concern in wheat grain for tolerance 

enforcement are pyroxasulfone and its metabolite M-3. These residues of concern are similar to 

the residues of concern for com raw agricultural commodities (RACs). 

The nature of the residue in livestock is adequately understood based on metabolism studies with 

goats and hens. Metabolism of pyroxasulfone in livestock occurs primarily via cleavage between 

the rings, to form metabolites M-1, M-8, M-10, and/or M-15, followed by oxidation, to yield 

metabolite M-3, and/or demethylation, to yield metabolites M-12 and M-9. The parent 

compound may also undergo demethylation, hydroxylation followed by oxidation, or oxidation 

Page 2 of27 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667

Page 3 of 27

followed by ring cleavage. HED has determined that the residues of concern in livestock 

commodities for tolerance enforcement in the U.S. are pyroxasulfone and its metabolites M-1, 

and M-3. Residues of concern in livestock commodities for risk assessment in the U.S. are 

pyroxasulfone and its metabolites M-1, M-3, M-25, and M-28. However, at this time no 

livestock tolerances are required except for milk. 

The petitioner has proposed high performance liquid chromatography/triple quadrupole mass 

spectrometry (LC/MS/MS) methods for the enforcement of tolerances for pyroxasulfone residues 

in/on crop commodities. The methods are adequate to determine residues of pyroxasulfone and 

metabolites M-1, M-3, M-25, and M-28 in corn, soybean, and wheat commodities. For the 

methods to be considered adequate for enforcement purposes, the methods must be amended to 

define confirmatory analysis procedures. The validated limit of quantitation (LOQ) is 0.005 ppm 

for each analyte in corn and soybean commodities, with the exception of M-3 in corn meal and 

M-1 in corn oil, soybean seed, and soybean meal, for which the LOQ is 0.01 ppm. The proposed 

enforcement methods for crop commodities have been previously deemed acceptable by the 

Analytical Chemistry Branch of the Biological and Economic Analysis Division (ACB). 

Enforcement methods for livestock commodities are not needed at this time but may be required 

in the future. Adequate LC/MS/MS methods were used for data collection for crop and livestock 

commodities. The FDA multiresidue methods of PAM Vol. I. are suitable for the determination 

of pyroxasulfone (using Sections 303 and 304.

Storage stability of KIH-485, M-1, M-3, and M-25 was assessed over periods fully 

encompassing the total storage time for each analyte in corn commodities. 

An adequate cattle feeding study has been previously submitted. The data indicate that 

tolerances for livestock commodities (except for milk) are not needed to support the proposed 

pyroxasulfone wheat and cotton use. A poultry feeding study is not needed at this time.

The data indicate that the proposed amended tolerances for corn, field, grain and corn, field, 

forage are adequate. 

There are no corn processed commodity tolerances and none are needed with this amended use.

The field rotational crop study submitted (D402247, T. Morton, 1/10/13) is adequate and 

supports a plantback interval (PBI) of 120 days.
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667

Page 4 of 27

Regulatory Recommendations and Residue Chemistry Deficiencies

HED has examined the residue chemistry database for pyroxasulfone. Pending submission of a 

revised Section B (see requirements under Directions for Use) and analytical reference standards 

(see requirements under Submittal of Analytical Reference Standards), there are no residue 

chemistry issues that would preclude granting this amended Section 3 registration for the 

requested use of pyroxasulfone, or establishment of tolerances for residues of pyroxasulfone as 

follow:

Tolerances are established for residues of the herbicide pyroxasulfone, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance 

with the tolerance levels specified below is to be determined by measuring only the sum 

of pyroxasulfone [3-[[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-

yl]methyl]sulfonyl]-4,5-dihydro-5,5-dimethylisoxazole] and its metabolites [5-

(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methanesulfonic acid 

(M-1), 5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-carboxylic acid 

(M-3), and [5-(difluoromethoxy)-3-(trifluoromethyl)-1H-pyrazol-4-yl]methanesulfonic 

acid (M-25), calculated as the stoichiometric equivalent of pyroxasulfone, in or on the 

commodity.

Corn, field, forage .......................................................0.09 ppm

Tolerances are established for residues of the herbicide pyroxasulfone, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance 

with the tolerance levels specified below is to be determined by measuring only the sum 

of pyroxasulfone [3-[[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-

yl]methyl]sulfonyl]-4,5-dihydro-5,5-dimethylisoxazole] and its metabolite [5-

(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-carboxylic acid (M-3) 

calculated as the stoichiometric equivalent of pyroxasulfone, in or on the commodity.

Corn, field, grain.........................................................0.02 ppm

A human health risk assessment is forthcoming.

860.1200 Directions for Use

 The field rotational crop study submitted (D402247, T. Morton, 1/10/13) is adequate and 

supports a plantback interval (PBI) of 120 days.

860.1550 Proposed Tolerances

 The proposed tolerances are adequate. 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667

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860.1650 Submittal of Analytical Reference Standards

 Analytical standards for metabolite M-28 are not currently available in the EPA National 

Pesticide Standards Repository. Analytical reference standards of pyroxasulfone and 

metabolites M-1, M-3, M-25, and M-28 must be supplied and supplies replenished as 

requested by the Repository. 

860.1360 Multiresidue Methods

 The petitioner should test pyroxasulfone under Protocol D using a matrix of higher 

moisture content than soybean hay, such as sweet corn K+CWHR. 

Background

Pyroxasulfone is a new herbicide in the pyrazole class of selective herbicides. It provides 

contact and residual control of a broad spectrum of broadleaf weeds and grasses, including 

glyphosate-resistant varieties. Pyroxasulfone acts as a potential inhibitor of VLCFA biosynthesis 

similar in mode to the K3 group of herbicides (Group 15). Pyroxasulfone has little effect on 

germination, yet potentially inhibits shoot elongation of the germinating seed. Pyroxasulfone is 

translocated in plants through xylem and is apoplastic. K-I Chemical is proposing pyroxasulfone 

for use on soybean in the U.S. The chemical structure and nomenclature of pyroxasulfone and 

its metabolites proposed for regulation are presented in Table 1, and the physicochemical 

properties of the technical grade of pyroxasulfone are presented in Table 2. This petition 

represents the first food/feed uses of pyroxasulfone proposed in the U.S.

The chemical names and structures of pyroxasulfone metabolites are presented in Appendix 1.
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667

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Table 1. Pyroxasulfone Nomenclature.

Chemical structure

Common name Pyroxasulfone

Company experimental name KIH-485; AE 2196191

IUPAC name 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethylsulfonyl]-

4,5-dihydro-5,5-dimethyl-1,2-oxazole

CAS name 3-[[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-

yl]methyl]sulfonyl]-4,5-dihydro-5,5-dimethylisoxazole

CAS registry number 447399-55-5

End-use product (EP) Pyroxasulfone 85 WG Herbicide (85% WG; EPA File Symbol 63588-OE)

V-10233 Herbicide (42.5% WG; EPA File Symbol 63588-OG)

Chemical structure of M-1

metabolite

[5-(difluoromethoxy)-l-methyl-3-(trifluoromethyl)-lH-pyrazol-4-

yl)]methanesulfonic acid

Chemical structure of M-3

metabolite

5-(difluoromethoxy)-l-methyl-3-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid

Chemical structure of M-25

metabolite

[5-(difluoromethoxy)-3-(trifluoromethyl)-1H-pyrazol-4-yl)]methanesulfonic acid

F

F

O

N

N

CF3

CH3

S

O

O

N

O

CH3

H3C

F

F

O

N

N

CF3

S

O

O

HO

CH3

F

F

O

N

N

CF3

CH3

HO

O

F

F

O

N

H

N

CF3

S

O

O

HO
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667

Page 7 of 27

Table 1. Pyroxasulfone Nomenclature.

Chemical structure of M-28

metabolite

3-[1-Carboxy-2-(5,5-dimethyl-4,5-dihydroisoxazol-3-ylthio)ethylamino]-3-

oxopropanoic acid

Chemical structure of 

Metabolite C

None provided (malonyl dehydrogenated cysteine derivative of isoxazoline 

group)

Table 2. Physicochemical Properties of Pyroxasulfone.

Parameter Value Reference1

Melting point 130.7 oC MRID 47701615

pH 5.03 at 22 oC MRID 47701613

Density 1.60 g/cM-3 MRID 47701616

Water solubility 3.49 x 10-3 g/L at 20.0 ± 0.5 oC MRID 47701619

Solvent solubility g/L at 20 oC 

Methanol: 11.4

Acetone: > 250

Ethyl acetate: 97.0

n-Hexane: 0.0721

Toluene: 11.3

Dichloromethane: 151

MRID 47701620

Vapor pressure 2.4 x 10-6 Pa at 25 oC MRID 47701621

Dissociation constant, pKa Not applicable (pyroxasulfone Ncontaining rings are not expected to be 

protonated in a practical pH range)

MRID 47701617

Octanol/water partition coefficient, 

Log(POW)

log POW = 2.39 at 25 oC, pH 8.7 MRID 47701618

UV/visible absorption spectrum at pH 1.13:

λmax = 225.5 nm; ε = 7291 Lmol-1cm-1

at pH 7.23:

λmax = 225.0 nm; ε = 7340 Lmol-1cm-1

at pH 10.91:

λmax = 225.5 nm; ε = 7334 Lmol-1cm-1

MRID 47701614

1

 As reported in “Pyroxasulfone Annex IIA, Section 1, Points 1, 2, 3 and 9” (Tier II - Document M-II). 

860.1200 Directions for Use

A summary of the proposed amended use pattern on corn is presented in Table 3.
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667

Page 8 of 27

Table 3. Summary of Directions for Use of Pyroxasulfone.1

Applic. Timing, 

Type, and Equip.

Formulation

[EPA File 

Symbol]

Applic. Rate 

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Corn (Field, Pop, Sweet, and Seed)

Fall application

Broadcast

Ground

85% WG

[63588-OE]

C: NA

M: 0.11-0.15

MF: 0.15-0.19

F: 0.19-0.21

NS

0.267 37 (sweet 

corn ears)

Application may be 

made in the fall to 

minimum or no tillage 

fields to be planted to 

corn the following 

spring. 

Preplant

Broadcast 

surface or 

incorporated

Ground

85% WG

[63588-OE]

C: 0.08-0.11

M: 0.11-0.15

MF: 0.15-0.19

F: 0.19-0.21

NS

Surface application 

may be made up to 45 

days prior to planting, 

and soil incorporated 

application may be 

made up to 14 days 

prior to planting.

Preemergence

Broadcast

Ground

85% WG

[63588-OE]

C: 0.08-0.11

M: 0.11-0.15

MF: 0.15-0.19

F: 0.19-0.21

NS

Early 

postemergence

Broadcast

Ground

85% WG

[63588-OE]

C: 0.08-0.11

M: 0.11-0.15

MF: 0.15-0.19

F: 0.19-0.21

NS

Application may be 

made up to V4 stage 

(visible 4th leaf collar). 

A 7-day pregrazing 

interval (PGI) is 

proposed for corn or 

corn forage.

Corn (Field)

Fall application

Broadcast

Ground or aerial

42.5% WG

[63588-OG] 0.08-0.12 NS

NS NS

Application may be 

made in the fall to 

minimum or no tillage 

fields to be planted to 

corn the following 

spring. 

Preplant

Broadcast 

Ground or aerial

42.5% WG

[63588-OG] 0.08-0.12 NS

Corn must be planted 

within 7-30 days after 

application.

1

 C = Coarse soil texture; M = Medium soil texture; MF = Medium-fine soil texture; F = Fine soil texture. NA = 

Not applicable. NS = Not specified.

Conclusions. The use directions are adequate to allow evaluation of the residue data relative to 

the proposed use in the U.S. The proposed maximum seasonal rates are supported by the 

submitted field trial data. 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667

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860.1300 Nature of the Residue - Plants

(MRIDs 47701649 and 47701650)

The petitioner submitted studies pertaining to the metabolism of pyroxasulfone in corn and 

soybean. Two different radiolabels were used in the plant studies; the label positions are 

presented below:

[pyrazole-5-

14C]pyroxasulfone [isoxazoline-3-

14C]pyroxasulfone

A number of metabolites were identified in these studies. The chemical structures and report 

names for these metabolites are provided in Appendix I. 

A summary of the nature of the pyroxasulfone residues in/on corn and soybean (first study) are 

summarized in the following memorandum (T. Morton, D365229, 12/15/2011). 

Soybean (MRID 48390903) Second Study: 

The metabolism of KIH-485 was investigated in soybean following a single application of 

[14C]-KIH-485 (pyrazole or isoxazoline labeled) diluted with a formulation blank and water at a 

rate of ca 300 g ai/ha (0.268 lb ai/A) pre-emergence or ca 209 g ai/ha (0.186 lb ai/A) postemergence, in an application volume of 500 or 700 L/ha, respectively.

Total radioactive residues (TRR) following pre-emergence applications with [pyrazole-5-

14C]KIH-485 were 0.369 mg/kg in soybean forage (growth stage R1 to R2), 0.280 mg/kg in hay 

(mid-full bloom), and 0.157 mg/kg in seed (maturity BBCH 99). Following pre-emergence 

application with [isoxazoline-3-14C]KIH-485, TRR were 0.427, 0.172, and 0.219 mg/kg in 

soybean forage, hay, and seed, respectively.

Following post-emergence applications with [pyrazole-5-14C]KIH-485, TRR were 0.431 mg/kg 

in soybean forage (growth stage R1 to R2), 0.354 mg/kg in hay (mid-full bloom), and 0.042 

mg/kg in seed (maturity BBCH 99). Following post-emergence application with [isoxazoline-3-

14C]KIH-485, TRR were 0.462, 0.185, and 0.080 mg/kg in soybean forage, hay, and seed, 

respectively.

Surface washes removed up to 3.1% TRR from forage and up to 1.7% from hay; no radioactivity 

was removed from seed with the surface rinse. The majority of the remaining TRR was removed 

with the acetone:water and water extractions, with levels of recovered radioactivity ranging from 

78.0-82.6% TRR (0.302-0.363 mg/kg) in forage, 75.6-91.4% TRR (0.130-0.323 mg/kg) in hay, 

and 59.7-89.4% TRR (0.035-0.169 mg/kg) in seed. Further sequential extractions of forage, hay, 

and seed samples with 0.1M hydrochloric acid and/or sodium hydroxide, 2M hydrochloric acid 

and/or sodium hydroxide, and acetone individually released up to 16.3% TRR. No radioactivity 

was extracted with 2M hydrochloric acid and sodium hydroxide from post-emergence seed 

S

O

O

N

N O N

CF3

CH3

H3C

CH3

O

F2HC

*

S

O

O

N

N O N

CF3

CH3

H3C

CH3

O

F2HC

*
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667

Page 10 of 27

samples (pyrazole label) and with acetone from pre-emergence and post-emergence seed samples 

(pyrazole label) and post-emergence forage samples (isoxazoline label). Levels of unextracted 

residue ranged from 6.6 to 11.7% TRR (0.029 to 0.052 mg/kg) in forage, 4.7 to 14.2% TRR 

(0.017 to 0.026 mg/kg) in hay, and 5.8 to 8.2% TRR (0.003 to 0.017 mg/kg) in the seed. The 

highest unextracted residue levels (14.2% TRR) were in hay, with the lower levels being in 

forage and seed. 

In general, there were no significant differences in the radioactivity extracted between the two 

radiolabelled forms or between the pre- and post-emergence applications. For the acetone:water 

extractions, the radioactivity recovered was similar, though slightly higher for the pyrazole-label 

as compared to the isoxazoline-label; radioactivity recovered was also similar, though slightly 

higher for post-emergence applications as compared to pre-emergence applications, except for 

seed. Unextracted residues were generally higher in the isoxazoline-labeled samples as 

compared to the corresponding pyrazole-labeled samples, especially for hay. Similar unextracted 

residue levels were found in the pre- and post-emergence applications.

The nonextractable residues from the isoxazoline-labeled forage and hay samples following preemergence application underwent bound residue fractionation. Soxhlet extraction with 

acetonitrile released only 0.8% TRR in forage and no radioactivity in hay. Incorporation into 

pectin accounted for 4.3-5.8% in forage and hay and incorporation into lignin accounted for 1.5-

2.2% TRR in forage and hay. Remaining residues in forage and hay were characterized as 

hemicellulose, accounting for 1.5-1.7% TRR, or as cellulose, accounting for 0.4-0.6% TRR. 

Nonextractable residues remaining following these procedures were 2.6% TRR for forage and 

2.3% TRR for hay.

Samples of soybean forage, hay, and seed were analyzed for metabolite 

characterization/identification. Metabolites were identified and quantitated by HPLC.

The parent, KIH-485, was not identified in forage, hay, and seed following either pre-emergence 

or post-emergence application of [pyrazole-5-14C]-KIH-485 and [isoxazoline-3-14C]-KIH-485. 

Following pre-emergence or post-emergence application of [pyrazole-5-14C]-KIH-485, KIH-485 

was extensively metabolized to M-1 and M-25 and the unknown metabolites @ 24 minutes and 

29 minutes (tentatively characterized as a conjugate of M-9). Following pre-emergence and 

post-emergence application of [isoxazoline-3-14C]-KIH-485, KIH-485 was extensively 

metabolized to M-28 and M-29 and a number of unknown metabolites characterized as being 

more polar than KIH-485.

Specifically, in forage and hay following pre-emergence or post-emergence application of 

[pyrazole-5-14C]-KIH-485, M1 was the major metabolite identified, accounting for 18.2-22.6% 

TRR (0.079-0.084 mg/kg) in forage and 26.6-39.5% TRR (0.075-0.140 mg/kg) in hay. M-25 

accounted for 7.2-8.6% TRR (0.031-0.032 mg/kg) in forage and 12.5-18.6% TRR (0.035-0.066 

mg/kg) in hay. Minor metabolites identified were M-3, M-8, and M-9. M-3 accounted for 2.1-

3.7% TRR (0.008-0.016 mg/kg) in forage and 2.5-2.6% TRR (0.007-0.009 mg/kg) in hay. M-8 

and M-9 accounted for 1.3-2.5% TRR (0.006-0.009 mg/kg) and 3.7-5.2% TRR (0.013-0.022 

mg/kg), respectively, in forage. In hay, M-8 and M-9 were 2.6% TRR (0.007 mg/kg) and 3.2% 

TRR (0.009 mg/kg), respectively, following pre-emergence application and were not detected 

following post-emergence application. A number of unknown metabolites were also detected in 

these samples. They included unknowns @ 13, 24 and 29 minutes, present at levels equivalent 

to 1.0-3.1, 4.1-10.5, and 10.2-22.1% TRR, respectively, in forage and 1.9-2.3, 2.9-3.2, and 11.5-
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667

Page 11 of 27

12.9% TRR, respectively, in hay. Unknown metabolite @ 13 minutes was tentatively identified 

as N-glycoside of M-9 and unknown metabolite @ 29 minutes was tentatively characterized as a 

conjugate of M-9. The remaining radioactivity was characterized as unresolved background or 

other unknown metabolites; other unknown metabolites accounted for 14.6-20.1% TRR (0.063-

0.074 mg/kg) in forage and 12.6-21.1% TRR (0.044-0.060 mg/kg) in hay.

In seed following pre-emergence or post-emergence application of [pyrazole-5-14C]-KIH-485, 

M-3 and M-25 were the only metabolites identified, accounting for 2.6-3.5% TRR (0.001-0.005 

mg/kg) and 4.6-11.1% TRR (0.005-0.007 mg/kg), respectively. A number of unknown 

metabolites were also detected in the seed samples, including unknowns @ 13, 24 and 29 

minutes, present at levels equivalent to 1.7-4.7, 2.8-6.7, and 7.1-10.1% TRR, respectively. The 

remaining radioactivity was characterized as unresolved background or other unknown 

metabolites; other unknown metabolites accounted for 22.4-49.2% TRR (0.009-0.078 mg/kg).

Following pre-emergence or post-emergence application of [isoxazoline-3-14C]-KIH-485, M-28 

and M-29 were the only metabolites identified in forage, hay, and seed. M-28 accounted for 

12.6-15.7% TRR (0.058-0.067 mg/kg) in forage, 12.7-13.3% TRR (0.023-0.024 mg/kg) in hay, 

and 7.5-9.8% TRR (0.008-0.017 mg/kg) in seed. M-29 accounted for 12.8-16.1% TRR (0.059-

0.069 mg/kg) in forage, 10.6-13.4% TRR (0.020-0.023 mg/kg) in hay, and 2.6% TRR (0.006 

mg/kg) in seed (pre-emergence only); M-29 was not detected in seed following post-emergence 

application.

Conclusions. The submitted data are partially adequate to satisfy data requirements for the use 

of pyroxasulfone on soybeans

. 

HED has concluded that, for the purposes of this petition, the residues of concern for risk 

assessment and tolerance enforcement in soybean forage and hay consist of pyroxasulfone and 

its metabolites M-1, M-3, and M-25. Residues of concern for risk assessment and tolerance 

enforcement in soybean seed consist of pyroxasulfone and its metabolites M-3, M-25, and M-28. 

860.1300 Nature of the Residue - Livestock

There are several livestock feedstuffs associated with the proposed use of pyroxasulfone. The 

petitioner provided livestock metabolism studies with lactating goats and laying hens, which are 

summarized in the following memorandum (T. Morton, D365229, 12/15/2011). 

860.1340 Residue Analytical Methods

A summary of the analytical methods associated with pyroxasulfone and the method validations 

are summarized in the following memorandum (T. Morton, D365229, 12/15/2011). 

860.1360 Multiresidue Methods

A summary of the analytical methods associated with pyroxasulfone are summarized in the 

following memorandum (T. Morton, D365229, 12/15/2011). 

860.1380 Storage Stability

The previously submitted corn magnitude of the residue studies are supported by adequate 

storage stability data. This data was reviewed previously.
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Table 4. Summary of Storage Conditions and Durations of Samples from Crop Field Trial and 

Processing Studies. 

Matrix Storage 

Temperature

(°C)

Maximum Storage 

Duration

Interval of Demonstrated Storage 

Stability

Pyroxasulfone, M-1, and M-3 determination

Corn forage Frozen 332 days (10.9 months) 13 months

Corn grain and K+CWHR Frozen 391 days (12.8 months) 13 months (grain)

Corn grain for processing Frozen 337 days (11.1 months) 13 months (grain)

Corn stover Frozen 357 days (11.7 months) 12 months

Corn processed 

commodities

Frozen 196 days (6.4 months) 6 months (oil)

7 months (starch, flour, and meal)

Soybean forage Frozen 466 days (15.3 months) 17 months

Soybean hay Frozen 452 days (14.9 months) 17 months

Soybean seed Frozen 359 days (11.8 months) 19 months

Soybean seed for 

processing

Frozen 364 days (12.0 months) 19 months

Soybean meal and hulls Frozen 231 days (7.6 months) 10 months

Soybean oil Frozen 220 days (7.2 months) 7 months

Wheat forage Frozen 58 weeks (13.3 months) 13 months (corn forage)

Wheat grain and straw Frozen 36 weeks (8.3 months) 13 months (corn grain)

12 months (corn stover)

M-25 determination

Corn forage Frozen 710 days (23.3 months) 24 months

Corn grain and K+CWHR Frozen 777 days (25.5 months) 26 months (grain)

Corn grain for processing Frozen 689 days (22.6 months) 26 months (grain)

Corn stover Frozen 747 days (24.5 months) 25 months

Corn starch Frozen 479 days (15.7 months) 16 months

Corn grits, flour, and meal Frozen 520 days (17.1 months) 18 months (meal)

23 months (flour)

Corn oil Frozen 575 days (18.9 months) 17 months (33% degradation)

Soybean forage Frozen 799 days (26.3 months) 12 months

Soybean hay Frozen 727 days (23.9 months) 12 months

Soybean seed Frozen 891 days (29.3 months) 12 months

Soybean seed for 

processing

Frozen 720 days (23.7 months) 12 months

Soybean hulls Frozen 519 days (17.1 months) 14 months

Soybean meal Frozen 567 days (18.6 months) 14 months

Soybean oil Frozen 497 days (16.3 months) 13 months

Wheat forage Frozen 58 weeks (13.3 months) 12 months (corn forage)

Wheat grain and straw Frozen 36 weeks (8.3 months) 12 months (corn grain and stover)

860.1400 Water, Fish, and Irrigated Crops

There are no proposed uses that are relevant to this guideline topic.
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860.1460 Food Handling

There are no proposed uses that are relevant to this guideline topic.

860.1480 Meat, Milk, Poultry, and Eggs

(MRID 47701659)

The dietary burdens of pyroxasulfone to livestock were calculated using the procedures of the 

most recent guidance developed by HED (June 2008); see Table 5. The estimated dietary 

burdens are 0.036 ppm for beef cattle, 3.05 ppm for dairy cattle, 0.018 ppm for poultry, and 

0.016 ppm for swine. K-I Chemical previously submitted a feeding study with cattle, which is 

summarized below, and requested a waiver of the requirement for a poultry feeding study.

Table 5. Calculation of Dietary Burdens of Pyroxasulfone Residues to Livestock.

Feedstuff Type1 % Dry 

Matter2 % Diet2 Residue (ppm)HR or STMR4

Dietary Contribution 

(ppm)3

Beef Cattle

Corn, field, stover R 83 5 0.139 HR 0.0084

Corn, field, forage R 40 10 0.054 HR 0.014

Corn, field, grain CC 88 40 0.025 STMR 0.0060

Corn, field, milled 

byproducts

CC 85 40 0.05 STMR 0.0061

Soybean, meal PC 92 5 0.032 STMR 0.0017

TOTAL BURDEN -- -- 100 -- 0.036

Dairy Cattle

Corn, field, stover R 83 5 0.139 HR 0.008

Wheat, forage R 25 20 3.2 HR 2.56

Soybean, forage/silage R 35 20 0.781HR 0.446

Corn, field, milled 

byproducts

CC 85 25 0.025 STMR 0.0074

Corn, sweet, cannery waste CC 30 10 0.063 STMR 0.021

Soybean, seed CC 89 10 0.032 STMR 0.0036

Soybean, meal PC 92 10 0.032 STMR 0.0035

TOTAL BURDEN -- -- 100 -- 3.05

Poultry

Corn, field, grain CC 88 75 0.013 STMR 0.0098

Soybean, meal PC 92 25 0.032 STMR 0.008

TOTAL BURDEN -- -- 100 -- 0.018
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Table 5. Calculation of Dietary Burdens of Pyroxasulfone Residues to Livestock.

Feedstuff Type1 % Dry 

Matter2 % Diet2 Residue (ppm)HR or STMR4

Dietary Contribution 

(ppm)3

Swine

Corn, field, grain CC 88 35 0.013 STMR 0.0046

Corn, field, milled 

byproducts

CC 85 50 0.013 STMR 0.0065

Soybean, meal PC 92 15 0.032 STMR 0.0048

TOTAL BURDEN -- -- 100 -- 0.016

1

 R: Roughage; CC: Carbohydrate concentrate; PC: Protein concentrate.

2

 OPPTS 860.1000 Table 1 Feedstuffs (June 2008). 

3

 Contribution = ([tolerance /% DM] X % diet) for beef and dairy cattle; contribution = ([tolerance] X % diet) for 

poultry and swine.

4

 HR: Highest Residue; STMR: Trial Median Residue.

Cattle: The magnitude of the residue of pyroxasulfone and metabolites M-1 and M-3 in dairy 

cow tissues and milk was determined in a feeding study. For 28 consecutive days, lactating dairy 

cows were administered pyroxasulfone at a target dose level of 1.8 ppm (estimated by the 

petitioner to be 1x, designated “group 2”) and at exaggerated target dose levels of 5.4 ppm

(designated “group 3”) and 18 ppm (designated “group 4”). A control group (designated “group 

1”) was not dosed. A total of 14 cows were included in the study, two in group 1, three each in 

groups 2 and 3, and six in group 4. The average daily dose of pyroxasulfone was 36.3 

mg/cow/day for group 2, 109.3 mg/cow/day for group 3 and 364.2 mg/cow/day for group 4. The 

dose levels of 1.8, 5.4, and 18 ppm represent 50x, 150x, and 500x, respectively, the maximum 

estimated dietary burden to beef cattle and 0.6x, 1.8x, and 5.9x, respectively, the maximum 

estimated dietary burden to dairy cattle.

Animals were observed twice daily for any clinical signs of toxicity or ill health. Body weights 

were determined at weekly intervals, and feed consumption was monitored daily. Milk yields 

were recorded twice daily.

Milk samples from each animal were collected twice daily and combined as one pooled sample. 

On days 13 and 28, milk samples from all cows, except those cows designated for the depuration 

phase and cows from the mid dose group, were separated into cream and skim milk for separate 

analysis. Animals were sacrificed within 24 hours after the final dosing, and tissue samples were 

taken, except for three cows of the high dose group which were sacrificed 4, 8, and 15 days after 

the final dose to determine residue levels post dosing. All samples were stored frozen prior to 

analysis. Samples were analyzed for residues of pyroxasulfone, M-1, and M-3 using the 

LC/MS/MS data collection method for cattle commodities (described under 860.1340). The 

LOQ was 0.001 ppm for each analyte in milk matrices and 0.01 ppm for each analyte in tissues.

The longest storage interval from sampling until analysis for any matrix was 186 days for cream 

samples, 87 days for tissue samples and 154 days for milk samples. Storage stability analyses 

showed that all analytes were stable in milk for up to 6 months frozen storage and tissues for up 

to at least 3 months of frozen storage, except for pyroxasulfone in liver which showed only a 

40% recovery after 120 days of storage; recovery was 94% after 15 days of storage.

Samples of milk from day 7 were the only milk samples analyzed for the low and mid dose 

groups. For the control and high dose groups, milk samples from study days 1, 2, 3, 4, 5, 6, 7, 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667

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10, 13, 16, 19, 22, 25, and 28 were analyzed. There were no residues of pyroxasulfone or its 

metabolites M-1 or M-3 in milk greater than the LOQ (0.001 ppm) at any dose level (including 

the control) except for three milk samples from cows at the high dosing level where 

pyroxasulfone was found at 0.002-0.004 ppm on study day 7. Skim milk and cream samples 

from study days 13 and 28 for the control, low, and high dose groups were analyzed. No 

residues of pyroxasulfone or its metabolites M-1 or M-3 were found above LOQ (0.001 ppm) in 

any samples. 

No residues of pyroxasulfone or its metabolites M-1 or M-3 were found greater than the LOQ 

(0.01 ppm) in any tissue samples (liver, kidney, subcutaneous fat, abdominal fat, perinephric fat, 

loin muscle, and round muscle) from cattle in the control and high dose groups. No tissue 

samples from the low and mid dose group were analyzed.

No residues of pyroxasulfone or its metabolites M-1 or M-3 were found greater than the LOQ in 

any of the samples taken from cows sacrificed during the depuration period (including samples 

from the control group). Milk samples were collected 3, 7, and 14 days following the end of 

dosing.

The results for maximum residues of pyroxasulfone and its metabolites detected at the high dose 

level (18 ppm) are summarized in Table 6 below. 

Table 6. Maximum Residues in Samples from Cows Dosed at 18 ppm (5.9x).

Samples

Residues (ppm)

Pyroxasulfone M-1 M-3

Whole milk <0.0041 <0.001 <0.001

Skim milk <0.001 <0.001 <0.001

Cream <0.001 <0.001 <0.001

Round Muscle <0.01 <0.01 <0.01

Loin muscle <0.01 <0.01 <0.01

Liver <0.01 <0.01 <0.01

Kidney <0.01 <0.01 <0.01

Subcutaneous fat <0.01 <0.01 <0.01

Abdominal fat <0.01 <0.01 <0.01

Perinephric fat <0.01 <0.01 <0.01

1

 Day 7 samples only; residues in samples from all other sampling days were <0.001 ppm.

If the nonquantifiable residues of pyroxasulfone in liver from the high-dose cattle are adjusted 

for potential decline during storage of 45% (estimated decline after 3 months of storage), 

residues would be <0.02 ppm. 

Conclusions. The submitted cattle feeding study is adequate to satisfy data requirements. 

Radiovalidation data for the analytical method were not submitted, however, the extraction 

procedures for the analytical method is similar to the method used in the nature of the residue 

study in livestock.

The submitted data indicate that no tolerances are needed for livestock tissues. Residues of each 

analyte were <0.01 ppm at a dosing level corresponding to 5.9x the estimated dietary burden to 

dairy cattle. HED concludes that the proposed uses of pyroxasulfone fall under category 3 of 40 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667

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CFR 180.6(a) for ruminant tissues; there is no reasonable expectation of finite residues in cattle, 

goat, hog, horse, and sheep tissue commodities. However, a tolerance is required for milk.

Poultry: The petitioner concluded that residues of pyroxasulfone and its major metabolites are 

not expected to accumulate above the LOQ in poultry matrices destined for human consumption. 

In the corn, soybean, and wheat field trials, residues of pyroxasulfone, M-1, M-3, and M-25 were 

below the LOQ in/on all samples of grain and seed, except one soybean trial in which residues of 

M-3 in seed were approximately twice the LOQ and two other trials where M-25 residues in seed 

were just above the LOQ. Of the processed matrices consumed by poultry, soybean meal and 

hulls had residues of M-3 just above the LOQ. No quantifiable residues were found in corn 

processed commodities; a wheat processing study has not yet been conducted. Based on these 

results and the results of the poultry metabolism studies, the petitioner concluded that a poultry 

feeding study is unnecessary.

In the poultry metabolism studies, the maximum residues observed for an individual identified 

metabolite were 0.039 ppm of M-1 in liver. Assuming a feeding level of ~820x (based on the 

14.8-ppm dosing level and a dietary burden of 0.018 ppm), expected residues of M-1 at a 10x 

feeding level would be <0.002 ppm. Therefore, HED concludes that a poultry feeding study is 

not needed at this time. The proposed uses of pyroxasulfone fall under category 3 of 40 CFR 

180.6(a) for poultry; there is no reasonable expectation of finite residues in poultry commodities. 

The petitioner should note that a poultry feeding study may be needed in the future if additional 

uses with poultry feedstuffs are proposed.

860.1500 Crop Field Trials

K-I Chemical previously submitted field trial data from corn field trials conducted in the U.S. 

The purpose of this study was to obtain Raw Agricultural Commodity (RAC) residue data for 

pyroxasulfone (KIH-485) and its metabolites M-1, M-3, and M-25 on corn commodities 

following the addition of adjuvants to the registered products. The results from these field trials 

along are discussed previously (D402247, T. Morton, 1/10/13). A summary is provided in Table 

7.

HED converted residues of metabolites to parent equivalents for calculation of total residues; 

molecular weight conversion factors of 1.262 for M-1, 1.504 for M-3, 1.321 for M-25, and 1.286 

for M-28 were used. The full LOQ value was used for residues <LOQ for calculating total 

residues. 
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Table 7. Summary of Residue Data from Corn Crop Field Trials with Pyroxasulfone 85 WG.

Crop matrix Target Applic. 

Rate

(lb ai/A)

PHI 

(days)

Total Residues of Pyroxasulfone and Metabolites M-1, M-3, and 

M-25 (ppm)1

n Min. Max. HAFT2 Median Mean Std. 

Dev.3

Corn forage 0.147-0.270 59-68 36 <0.025 0.099 0.086 0.036 0.043 0.019

Corn stover 105-113 36 0.025 0.051 0.047 0.025 0.030 0.007

Corn grain 105-113 36 <0.025 <0.028 <0.026 0.025 0.025 0.001

1

 For the purposes of calculating total residues, HAFT, median, mean, and standard deviation, the LOQ was used 

for residues reported as <LOQ. Metabolite residues were converted to parent equivalents. 2 HAFT = Highest 

average field trial result.

Conclusions. The submitted corn field trial data are adequate to satisfy crop field trial data 

requirements. The number and locations of the field trials are in accordance with OPPTS 

Guideline 860.1500 for corn. Field trials were generally conducted at ~1x the proposed 

maximum single application rate and the application timing represents the latest proposed 

timing. 

860.1520 Processed Food and Feed

K-I Chemical previously submitted processing study data for corn. A summary of the average 

processing factors found for the processed commodities of corn is presented in Table 8. 

Table 8. Summary of Processing Factors for Pyroxasulfone.

RAC Processed Commodity Processing Factor

Pyroxasulfone M-1 M-3 M-25 Total

Field corn Grits NC1 NC NC NC --

Meal NC NC NC NC --

Flour NC NC NC NC --

Starch NC NC NC NC --

Dry-milled Oil NC NC NC NC --

Wet-milled Oil NC NC NC NC --

1

 NC = Not calculated; residues of this analyte were below the LOQ in both the RAC and the processed commodity.

Conclusions. The corn processing study is adequate to satisfy data requirements. The available 

processing data indicate that no tolerances are needed for pyroxasulfone residues in the 

processed commodities of corn. 
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860.1650 Submittal of Analytical Reference Standards

Analytical standards for pyroxasulfone metabolite M-28 is not currently available in the EPA 

National Pesticide Standards Repository (personal communication with Theresa Cole, ACB, 

6/27/13). This analytical standard must be submitted to the address below.

The Repository has the following from Kumiai Company:

pyroxasulfone, expiration date 7/21/2015

pyroxasulfone metabolite M-1, expiration date 11/19/2015

pyroxasulfone metabolite M-25, expiration date 11/19/2015

pyroxasulfone metabolite M-3, expiration date 4/9/2014

Analytical reference standards of pyroxasulfone and metabolites M-1, M-3, M-25, and M-28

must be supplied and supplies replenished as requested by the Repository. The reference 

standards should be sent to the Analytical Chemistry Lab, which is located at Fort Meade, to the 

attention of Theresa Cole at the following address:

USEPA

National Pesticide Standards Repository/Analytical Chemistry Branch/OPP

701 Mapes Road

Fort George G. Meade, MD 20755-5350

(Note that the mail will be returned if the extended zip code is not used.)

860.1850 Confined Accumulation in Rotational Crops

The results of the previously submitted study indicate that the metabolism of pyroxasulfone in 

rotated crops is similar to that for primary crops. However, several conjugates and cysteine 

derivatives of the isoxazoline group (metabolites A, B, C, D, and P1) were found in rotated crops 

that were not found in primary crops. 

860.1900 Field Accumulation in Rotational Crops

The field rotational crop study submitted (D402247, T. Morton, 1/10/13) is adequate and 

supports a plantback interval (PBI) of 120 days.
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860.1550 Proposed Tolerances

K-I Chemical has proposed that tolerances for pyroxasulfone residues of concern in crop 

commodities be expressed in terms of combined residues of pyroxasulfone and its major 

metabolites M-1, M-3, and M-25, calculated as pyroxasulfone. HED has concluded that the 

proposed tolerance expression is appropriate. The tolerance expression should be stated as 

follows:

Tolerances are established for residues of the herbicide pyroxasulfone, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance 

with the tolerance levels specified below is to be determined by measuring only the sum 

of pyroxasulfone [3-[[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-

yl]methyl]sulfonyl]-4,5-dihydro-5,5-dimethylisoxazole] and its metabolites [5-

(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methanesulfonic acid 

(M-1), 5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-carboxylic acid 

(M-3), and [5-(difluoromethoxy)-3-(trifluoromethyl)-1H-pyrazol-4-yl]methanesulfonic 

acid (M-25), calculated as the stoichiometric equivalent of pyroxasulfone, in or on the 

commodity.

Corn, field, forage .......................................................0.09 ppm

Tolerances are established for residues of the herbicide pyroxasulfone, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance 

with the tolerance levels specified below is to be determined by measuring only the sum 

of pyroxasulfone [3-[[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-

yl]methyl]sulfonyl]-4,5-dihydro-5,5-dimethylisoxazole] and its metabolite [5-

(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-carboxylic acid (M-3) 

calculated as the stoichiometric equivalent of pyroxasulfone, in or on the commodity.

Corn, field, grain.........................................................0.02 ppm

There are no Codex MRLs established for residues of pyroxasulfone in any commodities.

The tolerances proposed by K-I Chemical are listed in Table 9, along with the tolerance levels 

recommended by HED. The Agency’s Guidance for Setting Pesticide Tolerances Based on 

Field Trial Data was utilized for determining appropriate tolerance levels for raw agricultural 

crop commodities; see Appendix II for tolerance calculations. 

The data indicate that the proposed tolerances for corn, field, grain and corn, field, forage are 

adequate. 

Table 9. Tolerance Summary for Pyroxasulfone.

Commodity Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Corn, field, forage 0.09 0.09

Corn, field, grain 0.02 0.02
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667

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Attachments: 

Appendix I - Chemical Name and Structure Table

Appendix II - Tolerance Assessment Calculations

Template Version September 2005
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APPENDIX I. Chemical Names and Structures of Pyroxasulfone and Metabolites. 

Code IUPAC Name Common Name Chemical Structure

KIH-485

3-[[[5-(difluoromethoxy)-1-methyl-3-

(trifluoromethyl)-1H-pyrazol-4-

yl]methyl]sulfonyl]-4,5-dihydro-5,5-

dimethylisoxazole

Pyroxasulfone

M-1

[5-(Difluoromethoxy)-1-methyl-3-

(trifluoromethyl)-1H-pyrazol-4-

yl]methanesulfonic acid 

N/A

M-3

5-(Difluoromethoxy)-1-methyl-3-

(trifluoromethyl)-1H-pyrazol-4-carboxylic acid N/A

M-5

3-(5-Difluoromethoxy-3-trifluoromethyl-1Hpyrazol4-ylmethanesulfonyl)-4,5-dihydro-5,5-

dimethylisoxazole

N/A

M-6

3-(5-Difluoromethoxy-1-methyl-3-

trifluoromethyl-1H-pyrazol-4-

ylmethanesulfonyl)-4,5-dihydro-5,5-

dimethylisoxazol-4-ol

N/A

M-8

(5-Difluoromethoxy-1-methyl-3-trifluoromethyl1H-pyrazol-4-yl)methanol N/A

M-9

5-Difluoromethoxy-3-trifluoromethyl-1Hpyrazole-4-carboxylic acid N/A

M-9 malonyl 

glucoside 

(RT26)1

None provided NA

F

F

O

N

N

CF3

CH3

S

O

O

N

O

CH3

H3C

F

F

O

N

N

CF3

S

O

O

HO

CH3

F

F

O

N

N

CF3

CH3

HO

O

H

H

H

O

HO

H

O

HO

OH

O

O

H

OH

O

N

H

N

CF3

F2HCO

O
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APPENDIX I. Chemical Names and Structures of Pyroxasulfone and Metabolites. 

Code IUPAC Name Common Name Chemical Structure

N-glycoside 

of M-9 

(Unknown @ 

13 mins.)1

None provided NA

M-10 5-Difluoromethoxy-1-methyl-3-trifluoromethyl1H-pyrazole-4-carbaldehyde N/A

M-11

[3-(5-Difluoromethoxy-1-methyl-3-

trifluoromethyl-1H-pyrazol-4-

ylmethanesulfonyl)-4,5-dihydro-5-

methylisoxazol-5-yl] methanol

N/A

M-12 (5-Difluoromethoxy-3-trifluoromethyl-1Hpyrazol-4-yl) methanol N/A

M-13

3-(5-Difluoromethoxy-1-methyl-3-

trifluoromethyl-1H-pyrazol-4-

ylmethanesulfonyl)-4,5-dihydro-5-

methylisoxazole-5-carboxylic acid

N/A

M-15

2-Amino-5-[1-(carboxymethylamino)-3-(5,5-

dimethyl-4,5-dihydroisoxazol-3-ylthio)-1-

oxopropan-2-ylamino]-5-oxopentanoic acid

N/A

M-16 2-Acetylamino-3-(5,5-dimethyl-4,5-

dihydroisoxazol-3-ylthio)propanoic acid N/A

M-22 5,5-Dimethyl-4,5-dihydroisoxazole N/A

M-25 [5-(Difluoromethoxy)-3-(trifluoromethyl)-1Hpyrazol-4-yl]methanesulfonic acid N/A

N

N

O

F

F F

F F

H

C184

O

HO

O

OH

OH

OH

OH

F

F

O

N

H

N

CF3

S

O

O

HO
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APPENDIX I. Chemical Names and Structures of Pyroxasulfone and Metabolites. 

Code IUPAC Name Common Name Chemical Structure

M-28

3-[1-Carboxy-2-(5,5-dimethyl-4,5-

dihydroisoxazol-3-ylthio)ethylamino]-3-

oxopropanoic acid

N/A

M-29 3-(5,5-Dimethyl-4,5-dihydroisoxazol-3-ylthio)-2-

hydroxypropanoic acid N/A

M-302 3-cyano-2-hydroxy-2-methylpropanoic acid N/A

Metabolite A1 None provided (cysteine glucose conjugate of 

isoxazoline-ring metabolite) N/A

Metabolite B1 None provided (dimethylpropyl cysteine 

sulfoxide derivative) N/A

Metabolite C1 None provided (malonyl dehydrogenated cysteine 

derivative of isoxazoline group) N/A

Metabolite D1 None provided (cysteine conjugate of dimethyl 

acrylic acid) N/A

P11

None provided (malonyl cysteine conjugate of 

isoxazoline-ring products following reaction of 

KIH-485 or metabolites with glutathione)

N/A

1

 Proposed structure.

2

 Tentatively identified.

HO

H C3 COOH

CN

S

O

H3C

CH3

NH2

O

O-Glucose

S

NH2

O

OH

O

H3C

CH3

S

NH2

O

H3C OH

O

HO

S

O N

H3C N

H

HO O

OH

O O

OH
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Appendix II. Tolerance Assessment Calculations.

International Residue Limits 

Pyroxasulfone (090099; 3/13/2013)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex

40 CFR 180.659

General (1) Plant: determined by measuring only the sum of 

pyroxasulfone [3-[[[5-(difluoromethoxy)-1-methyl-3-

(trifluoromethyl)-1H-pyrazol-4-yl]methyl]sulfonyl]-4,5-dihydro-5,5-

dimethylisoxazole] and its metabolite [5-(difluoromethoxy)-1-

methyl-3-(trifluoromethyl)-1H-pyrazol-4-carboxylic acid (M-3) 

calculated as the stoichiometric equivalent of pyroxasulfone

None None

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Corn, field, grain 0.02

40 CFR 180.659

(2) Plant: determined by measuring only the sum of 

pyroxasulfone [3-[[[5-(difluoromethoxy)-1-methyl-3-

(trifluoromethyl)-1H-pyrazol-4-yl]methyl]sulfonyl]-4,5-dihydro-5,5-

dimethylisoxazole] and its metabolites [5-(difluoromethoxy)-1-

methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methanesulfonic acid 

(M-1), 5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1Hpyrazol-4-carboxylic acid (M-3), and [5-(difluoromethoxy)-3-

(trifluoromethyl)-1H-pyrazol-4-yl]methanesulfonic acid (M-25), 

calculated as the stoichiometric equivalent of pyroxasulfone

None None

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Corn, forage 0.09

US Canada Mexico2 Codex

40 CFR 180.659

Livestock: determined by measuring only the sum of pyroxasulfone

[3-[[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol4-yl]methyl]sulfonyl]-4,5-dihydro-5,5-dimethylisoxazole] and its 

metabolites [5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1Hpyrazol-4-yl]methanesulfonic acid (M-1) and 5-(difluoromethoxy)-

1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-carboxylic acid (M-3), 

calculated as the stoichiometric equivalent of pyroxasulfone

None None

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Completed: M. Negussie; 03/13/13

1

Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and 

not those proposed by the applicant.

2 Mexico adopts U.S. tolerances and/or Codex MRLs for its export purposes.
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667

Page 25 of 27

Pyroxasulfone

Field Corn Forage

US Parent, M1, M3, M25

with Adjuvant

Total number of data (n) 31

Percentage of censored data 48%

Number of non-censored data 16

Lowest residue 0.025

Highest residue 0.086

Median residue 0.026

Mean 0.033

Standard deviation (SD) 0.014

Correction factor for censoring (CF) 0.677

Proposed MRL estimate

- Highest residue 0.086

- Mean + 4 SD 0.087

- CF x 3 Mean 0.066

Unrounded MRL 0.087

Rounded MRL 0.09

Residues (mg/kg) n

< 0.025 15

0.026 1

0.027 1

0.028 2

0.029 2

0.03 1

0.033 1

0.034 1

0.037 1

0.038 1

0.045 1

0.053 1

0.054 1

0.059 1

0.086 1
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667

Page 26 of 27

Pyroxasulfone

Field Corn Stover

US Parent, M1, M3, M25

with Adjuvant

Total number of data (n) 31

Percentage of censored data 58%

Number of non-censored data 13

Lowest residue 0.025

Highest residue 0.131

Median residue 0.025

Mean 0.031

Standard deviation (SD) 0.019

Correction factor for censoring (CF) 0.613

Proposed MRL estimate

- Highest residue 0.131

- Mean + 4 SD 0.108

- CF x 3 Mean 0.057

Unrounded MRL 0.131

Rounded MRL 0.15

High uncertainty of MRL estimate.

[High level of censoring]

Residues (mg/kg) n

< 0.025 18

0.026 2

0.027 3

0.028 1

0.029 1

0.03 1

0.034 1

0.037 1

0.038 1

0.047 1

0.131 1

Pyroxasulfone
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667

Page 27 of 27

Field Corn Grain

US Parent, M3

with Adjuvant

Total number of data (n) 31

Percentage of censored data 97%

Number of non-censored data 1

Lowest residue 0.013

Highest residue 0.016

Median residue 0.013

Mean 0.013

Standard deviation (SD) 0.001

Correction factor for censoring (CF) 0.355

Proposed MRL estimate

- Highest residue 0.016

- Mean + 4 SD 0.015

- CF x 3 Mean 0.014

Unrounded MRL 0.016

Rounded MRL 0.02

High uncertainty of MRL estimate.

[High level of censoring]

Residues (mg/kg) n

< 0.013 30

0.016 1