Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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Executive Summary

Pyroxasulfone is a new herbicide belonging to 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 very-longchain fatty acid (VLCFA) biosynthesis, similar in mode to the K3 group of herbicides (Group 

15). 

Under PP#9F7560, K-I Chemical, U.S.A. Inc. is proposing tolerances for combined residues of 

the herbicide, pyroxasulfone [3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl 

methylsulfonyl]-4,5-dihydro-5,5-dimethyl-1,2-oxazole], and its major metabolites, M-1, M-3, 

and M-25 calculated as pyroxasulfone equivalents in/on the following commodities:

Field Corn Kernel........................................................................... 0.01 ppm

Field Corn Forage .......................................................................... 0.15 ppm

Field Corn Stover........................................................................... 0.15 ppm

Sweet Corn Ears............................................................................. 0.02 ppm

Sweet Corn Forage......................................................................... 0.15 ppm

Sweet Corn Stover.......................................................................... 0.15 ppm

Field Corn Grits ............................................................................. 0.01 ppm

Field Corn Meal ............................................................................. 0.01 ppm

Field Corn Flour............................................................................. 0.01 ppm

Field Corn Starch ........................................................................... 0.01 ppm

Field Corn Oil (wet and dry milled)............................................... 0.01 ppm

Wheat Grain .................................................................................. 0.02 ppm

Wheat Forage ................................................................................. 0.20 ppm

Wheat Straw................................................................................... 0.20 ppm

Soybean Seed ................................................................................. 0.05 ppm

Soybean Forage................................................................................ 1.0 ppm

Soybean Hay .................................................................................... 2.0 ppm

Soybean Meal................................................................................. 0.05 ppm

Soybean Hulls................................................................................ 0.02 ppm

Soybean Refined oil ....................................................................... 0.01 ppm

Review of the submitted petition is being conducted as a tri-lateral review work-share effort 

which will be carried out in part with Canada (PMRA) and Australia (APVMA). 

In conjunction with this petition, K-I Chemical is requesting registration of two new products 

containing pyroxasulfone, Pyroxasulfone 85 WG Herbicide, an 85% water-dispersible granule 

(WG) formulation (EPA File Symbol 63588-OE), and V-10233 Herbicide, a 42.5% WG 

formulation (EPA File Symbol 63588-OG). The products are proposed for use on field corn, 

sweet corn, pop corn, soybean, and wheat. Applications to field corn, sweet corn, pop corn, and 

soybean are to be made preplant, preemergence, or early postemergence at 0.08-0.21 lb ai/A 

(depending on soil texture) with a maximum seasonal rate of 0.267 lb ai/A; pre-harvest intervals 

(PHIs) and/or pre-grazing intervals (PGIs) of 7-37 days have been proposed. Application to 

wheat is to be made as a single preplant or preemergence application at 0.05-0.11 lb ai/A 

(depending on soil texture) with a 42-day PGI. 

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

studies with field corn and soybeans; additional data pertaining to immature soybean crop 

commodities along with additional storage stability related data are needed. The nature of the 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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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 of these metabolites occurs, 

yield additional metabolites including M-3. HED Residues of Concern Knowledge-Base

Subcommittee (ROCKS) has determined that the residues of concern in crop commodities for 

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

M-3, and M-25 in corn and wheat. RABIV has concluded the residues of concern for corn grain 

are parent and M-3. Thus, the residue definition for corn grain will be harmonized with Canada

as well as the tolerance value. The residues of concern in soybean for risk assessment in the U.S. 

are pyroxasulfone and its metabolites M-1, M-3, M-25, and M-28. The residues of concern in 

soybean for tolerance enforcement in the U.S. are pyroxasulfone and its metabolites M-1, M-3, 

M-25. M-28 may need to be included pending reanalysis of the soybean seed samples for M-28.

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 

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. 

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, and M-25 in corn, soybean, and wheat commodities. The methods have

been modified to include the recommendations of the independent laboratory which were 1) 

include instructions for reporting metabolite residues in parent equivalents, 2) include a warning 

that emulsions may form, and 3) include the procedures for analysis of wheat commodities. 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 deemed acceptable by the Analytical Chemistry Branch of the Biological 

and Economic Analysis Division (ACB) by HED using ACB SOP 19. Since no tolerances are 

needed for meat, milk, poultry and eggs due to the corn use, no enforcement method for livestock 

commodities is needed. However, in the future a livestock enforcement method may be required. 

Adequate LC/MS/MS methods were used for data collection for crop and livestock commodities. 

The data indicate that the PAM Vol. I multiresidue methods, including Protocol D (report IIA 

4.3/14) and Protocols E and F (report IIA 4.3/11) may be applicable for determination of 

pyroxasulfone per se; however, the FDA multiresidue methods are not suitable for determination 

of the metabolites M-1, M-3, and M-25.

Pyroxasulfone (KIH-485) and metabolites M-1 and M-3 were found to be stable in corn stover 

through 12 months of frozen storage and in corn grain and forage through 13 months of frozen 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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storage. Pyroxasulfone, M-1, and M-3 were found to be stable in corn processed commodities 

during 6 months (oil) or 7 months (starch, flour, and meal) of frozen storage. M-25 residues were 

stable in forage for 24 months, grain for 26 months, stover for 25 months, starch for 16 months, flour 

for 23 months, and meal for 18 months. M-25 residues in com oil were moderately stabile at 67% 

remaining after 17 months of frozen storage. 

Pyroxasulfone was found to be stable in soybean forage and hay through as much as 17 months 

of storage, where no significant degradation of the residue was observed. Pyroxasulfone was 

found to be stable for up to 19 months frozen storage in seed, up to 7 months in refined oil, and 

up to 10 months storage in meal and hulls. M-1 was found to be stable in forage and hay for up 

to 17 months, up to 6 months in seed, up to 7 months in oil, and up to 10 months in meal and 

hulls. M-1 declined by approximately 40% in soybean seed at 19 months of frozen storage. M-3 

was found to be stable in forage and hay up to a 17-month period of storage up to a 19-month 

storage interval in seed, and up to 10 months in oil, meal, and hulls. Some decline in M-1 and 

M-3 was detected within 7 months and 10 of frozen storage, respectively, in refined oil, while 

both analytes were found to be stable in meal and hulls for up to 10 months of frozen storage. 

M-25 was found to be stable in forage hay, and seed after 12 months of frozen storage, in oil 

after 13 months of frozen storage, and in hulls and meal after 14 months of frozen storage. 

For M-25, the longest storage interval samples of soybean processed commodities (24-26 

months) remained to be analyzed at the time this report was finalized. The petitioner stated that 

this will be reported in a future report amendment.

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

livestock commodities are not needed to support the proposed pyroxasulfone uses. A poultry 

feeding study is not needed at this time.

Pending amendment of the proposed labels, adequate field trial data have been submitted for 

field corn and sweet corn. Soybean seed samples are required to be reanalyzed for M-28. The 

submitted field trial data for wheat reflect studies conducted in Australia and do not include 

residue data for wheat hay. HED has concluded that the Australian wheat data may be used to 

partially fulfill field trial data requirements for wheat; additional data from field trials conducted 

in the U.S., which include data for wheat hay, must be submitted. Adequate field trial data are 

available to support the proposed tolerances for: corn, field, grain; corn, field, forage; corn, field, 

stover; corn, sweet, kernel plus cob with husks removed (K+CWHR); corn, sweet forage; corn, 

sweet, stover. The data indicate that the proposed tolerance for field corn grain is too low; 

tolerance of 0.015 ppm would be appropriate. The data indicate that the proposed tolerances for 

field corn forage and sweet corn forage are too high; tolerances of 0.06 ppm and 0.10 ppm, 

respectively, would be appropriate. The available processing data indicate that no tolerances are 

needed for pyroxasulfone residues in field corn processed commodities. 

No residue data were submitted to support the proposed uses on popcorn. The submitted data for 

field corn may be translated to popcorn because the proposed uses on all types of corn (field, pop,

and sweet) are identical. Tolerances are needed for popcorn commodities, at 0.015 ppm for 

popcorn grain and 0.15 ppm for popcorn stover.

Pending submission of additional storage stability data for processed commodities of soybean, 

adequate processing studies have been submitted for field corn and soybean. No processing 
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study was submitted for wheat; a processing study is required. The adequacy of proposed 

tolerances for soybean raw agricultural commodities (RACs) and soybean processed 

commodities will be evaluated pending submission of the final reports of the storage stability 

studies and additional residue data. In addition, soybean processing data on the metabolite M-28 

may be needed if it is determined to be a residue of concern.

The petitioner has proposed an 18-month plantback interval (PBI) for all crops not on the label, 

based on the results of the confined rotational crop study, which indicated the potential for 

quantifiable residues of concern in/on rotated radish, soybean, and wheat commodities from 30-

and 120-day PBIs; and in rotated soybean and wheat commodities from a 365-day PBI. The 

results of the confined rotational crop study indicate that no quantifiable pyroxasulfone residues 

of concern would be expected in root crops planted 12 months following treatment at 1x; 

however, no data are available demonstrating that residues of concern will be below the LOQ 

in/on other rotated crop commodities at a PBI of 18 months. A limited field rotational crop study 

must be submitted. The study must be conducted in the U.S. and should reflect application at the 

maximum proposed seasonal rate (0.267 lb ai/A) and planting of rotated crops at plantback 

intervals of 1, 6, and 12 months. If quantifiable residues are found at the 12-month, then, 

extensive field trials will be required to set rotational crop tolerances. Until the required 

rotational crop data have been submitted, the petitioner must modify the labels for both products 

to specify that only root crops and crops on the label may be planted after pyroxasulfone 

application; crops on the label may be planted any time after application, and root crops may be 

planted 12 months after application.

One of the two products associated with this petition is a multiple active ingredient (MAI) 

product; the 42.5% WG formulation contains flumioxazin in addition to pyroxasulfone. The 

subject review only addresses the adequacy of the available data to support the proposed uses of 

pyroxasulfone. The adequacy of available or concurrently submitted data to support the 

proposed uses of flumioxazin is not addressed herein.

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), a revised Section F (see 

requirements under Proposed Tolerances), and analytical reference standards (see requirements 

under Submittal of Analytical Reference Standards), there are no residue chemistry issues that 

would preclude granting conditional Section 3 registration for the requested uses 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 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 .......................................................................... 0.015 ppm

Corn, sweet, kernel plus cob with husks removed........................ 0.015 ppm
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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Corn, pop, grain ........................................................................... 0.015 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 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 .......................................................................... 0.06 ppm

Corn, field, stover........................................................................... 0.15 ppm

Corn, sweet, forage ........................................................................ 0.10 ppm

Corn, sweet, stover......................................................................... 0.15 ppm

Corn, pop, stover............................................................................ 0.15 ppm

A human health risk assessment is forthcoming.

860.1200 Directions for Use

The product labels for the 85% WG and 42.5% WG formulations should be amended to 

remove any mention of soybean and wheat, since these uses are not being recommended 

for registration.

The petitioner must amend the product label for the 85% WG formulation to specify the 

following maximum seasonal application rates: (1) 0.268 lb ai/A for field and sweet corn 

grown in fine-, medium-fine-, and medium-textured soils; (2) 0.148 lb ai/A for field and 

sweet corn grown in coarse-textured soils.

The product label for the 42.5% WG formulation must be amended to specify a 

maximum seasonal rate for field corn. Because application rates on this product are not 

dependent on soil type, the proposed maximum seasonal must be ≤0.148 lb ai/A.

The petitioner must amend the product label for the 85% WG formulation to specify that 

no more than one application may be made in the spring to corn. 

A label statement prohibiting the use of an adjuvant for post-emergent application to corn 

must be added to the label for the 42.5% WG formulation, since no residue data was 

submitted to support the use of an adjuvant.

The 42.5% WG formulation, which is only proposed for application to field corn, 

includes a restriction against the grazing of treated fields or feeding of treated forage or 

hay to livestock. HED does not believe that a restriction against the grazing or feeding of 

treated field corn forage or stover is practical; therefore, the restriction must be removed. 
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The proposed rotational crop restrictions for the 85% WG and 42.5% WG formulations 

are not supported by the available rotational crop data. Until the required rotational crop 

data have been submitted, the petitioner must modify the labels for both products to 

specify that only crops on the label may be planted after pyroxasulfone application; crops 

on the label may be planted any time after application and root crops after 12 months.

860.1550 Proposed Tolerances

Proposed tolerances for the following commodities are too low; increased tolerances must 

be proposed: 

o field corn grain (0.015 ppm)

Proposed tolerances for the following commodities are too high; reduced tolerances must 

be proposed: 

o field corn forage (0.06 ppm)

o sweet corn forage (0.10 ppm)

Proposed tolerances for field corn processed commodities (grits, meal, flour, starch, dry 

milled oil, and wet milled oil) are not needed and should be removed from the list of 

proposed tolerances. 

The following tolerances must be proposed to support the requested uses on popcorn: 

o popcorn grain (0.015 ppm)

o popcorn stover (0.15 ppm) 

Proposed tolerances should be revised to reflect the correct commodity definitions as 

specified in Table 10.

860.1650 Submittal of Analytical Reference Standards

Analytical standards for pyroxasulfone and its metabolites M-1, M-3, and M-25 are not 

currently available in the EPA National Pesticide Standards Repository. Analytical 

reference standards of pyroxasulfone and metabolites M-1, M-3, and M-25 must be 

supplied and supplies replenished as requested by the Repository. 

Once revised Sections B and F are submitted and analytical standards for residues 

contained in the tolerance expression, HED can recommend for an unconditional 

registration for the requested use on corn. HED cannot at this time recommend for 

registration for the requested uses on soybean and wheat due to outstanding residue 

chemistry data.

860.1300 Nature of the Residue - Plants

For the soybean study, residues in the immature commodities soybean forage (foliage 

collected at first flower) and hay (foliage collected at mid-fruit) were not sufficiently 
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characterized/identified. Nonextractable residues in these commodities were 13-26% 

TRR (0.092-0.811 ppm). Additional attempts should be made to release radioactivity, 

such that nonextractable residues are <10% TRR or <0.05 ppm. 

The petitioner must provide additional information pertaining to storage stability for the 

soybean metabolism study. The dates of sample extraction and analysis should be 

provided for all samples, including the samples that were re-extracted for storage stability 

confirmation. These data will allow HED to determine whether the data are sufficient to 

determine that the identity of residues did not change during the period between 

collection and final analysis. In addition, supporting storage stability data will be needed 

for the required additional analyses for immature foliage matrices.

860.1340 Residue Analytical Methods

Livestock commodities

Radiovalidation data must be submitted for the method for livestock. 

860.1380 Storage Stability

Crop commodities

Final reports of the ongoing storage stability studies must be submitted. The final reports 

should include data for M-25 in soybean processed commodities reflecting intervals of up 

to 16 months for oil, 17 months for hulls, and 19 months for meal. 

With submission of the final reports, the petitioner should include additional 

information/data pertaining to the procedures used for the storage stability studies, 

including identification of the fortification levels for each analyte in each matrix, a correct

listing of the fortification dates (and storage intervals) for each of the spiked samples, and 

a discussion of any problems encountered during completion of the studies. An 

explanation should be provided for not using the data from the 3-month storage interval 

for M-1 in soybean forage. All residue data spreadsheets for storage stability analyses 

should be provided.

860.1500 Crop Field Trials

Soybean

Soybean seed samples need to be reanalyzed for metabolite M-28.

Wheat

The petitioner must submit 16 additional field trials on wheat, conducted in Zones 2 (1 

trial), 5 (5 trials), 7 (5 trials), 8 (4 trials), and 11 (1 trial). In these trials, the petitioner 

should collect and analyze samples of wheat forage, hay, grain, and straw; samples should 

be collected at normal harvest times, and the crop growth stage at harvest should be 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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reported for each sample. The texture of the soil should be reported for each of the field 

trial sites. If these residue data show that residue levels in forage, grain, and straw are 

similar to those found in the Australian field trials, HED will not require additional field 

trial data for wheat hay (i.e., the 16 field trials conducted in the U.S. for wheat hay will be 

considered sufficient to support a tolerance). 

The study submissions for wheat included no raw data for the analytical portion of the 

study. Raw data from the sample analyses must be submitted; these data should include 

sample extraction and analysis dates to allow HED to verify sample storage intervals.

860.1520 Processed Food and Feed

A processing study must be submitted for wheat.

860.1900 Field Accumulation in Rotational Crops

The petitioner must submit a limited field rotational crop study with pyroxasulfone. The 

study must be conducted in the U.S. and should reflect application at the maximum 

proposed seasonal rate (0.267 lb ai/A) and planting of rotated crops at plantback intervals 

of 1, 6, and 12 months. If quantifiable residues are found at the 12-month, then, 

extensive field trials will be required to set rotational crop tolerances. Pyroxasulfone, M1, M-3, M-25, M-28, and Metabolite C must be determined in these studies. Based on the 

results of the confined rotational crop study, the limited field rotational crop study does 

not need to include a root crop. 

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 glyphosateresistant 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 field 

corn, sweet corn, pop corn, soybean, and wheat 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.
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Table 1. Pyroxasulfone Nomenclature.

Chemical structure of 

Pyroxasulfone

F

F

O

N

N

CF3

CH3

S

O

O

N

O

CH3

H3C

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

F

F

O

N

N

CF3

S

O

O

HO

CH3

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

yl)]methanesulfonic acid

Chemical structure of M-3

metabolite

F

F

O

N

N

CF3

CH3

HO

O

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

Chemical structure of M-25

metabolite

F

F

O

N

H

N

CF3

S

O

O

HO

[5-(difluoromethoxy)-3-(trifluoromethyl)-1H-pyrazol-4-yl)]methanesulfonic acid
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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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 10-3g/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 10-6Pa 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

The petitioner has submitted undated draft specimen labels for the 85% WG (Pyroxasulfone 85 

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

Symbol 63588-OG) formulations of pyroxasulfone. The 42.5% WG formulation is an MAI 

product that also contains flumioxazin at 33.5%. 

A summary of the proposed use patterns on corn, soybean, and wheat are presented in Table 3.
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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.
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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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

Soybeans

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 15 (seed)

Application may be 

made in the fall to 

minimum or no tillage 

fields to be planted to 

soybean 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

M: 0.08-0.11

MF: 0.11-0.15

F: 0.15-0.19

NS

Application may be 

made from the first- to 

third-trifoliate leaf 

stage. A 7-day PGI is 

proposed for soybean 

or soybean forage, hay, 

or straw.

Fall application

Broadcast

Ground or aerial

42.5% WG

[63588-OG] 0.08-0.12 NS

0.12 NS

Application may be 

made in the fall to 

fields to be planted to 

soybean the following 

spring. 

Preplant or 

preemergence

Broadcast or 

banded

Ground or aerial

42.5% WG

[63588-OG] 0.08-0.12 NS

Preemergence 

application is to be 

made within 3 days of 

planting. May be 

applied to soils 

containing up to 5% 

organic matter.

Wheat (fall or winter-seeded wheat)

Preplant or 

preemergence

Broadcast

Ground

85% WG

[63588-OE]

C, M: 0.05-0.08

MF, F: 0.08-0.11 1 0.267 NS

Preplant application 

may not be made more 

than 14 days prior to 

planting. Application 

to durum wheat is 

prohibited. A 42-day 

PGI is proposed for 

wheat or wheat forage, 

hay, or straw.

1

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

Not applicable. NS = Not specified.
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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For the 85% WG formulation, the proposed label specifies that the product may only be applied 

using ground equipment. Application through any type of irrigation system is prohibited. 

Applications are to be made in a minimum of 10 gal/A. Application of the 85% WG formulation 

to peat or muck soils or soils with ≥10% organic matter is prohibited. The 85% WG formulation 

may be impregnated or coated onto dry bulk granular fertilizer for fall and preplant surface and 

preplant incorporated applications. 

The label for the 42.5% WG formulation specifies that the grazing of treated fields or feeding of 

treated forage or hay to livestock is prohibited. The label states that activity on emerged weeds 

requires the addition of an adjuvant (crop oil concentrate, methylated seed oil, or nonionic 

surfactant). Applications are to be made in a minimum of 10 gal/A for ground equipment or a 

minimum of 5 gal/A for aerial equipment.

The label indicates that the 85% WG formulation may be applied in a tank mix with one or more 

other herbicides. The most restrictive label for all products is to be followed. The following 

tank mix partners are identified: for corn, atrazine, Balance Pro® (isoxaflutole), Callisto®

(mesotrione), Guardsman Max® (dimethenamid-P and atrazine), glyphosate, Outlook®

(dimethenamid-P), and Python® (flumetsulam); and for soybean, Extreme® (imazethapyr and 

glyphosate), Gangster FR® (cloransulam-methyl), Gangster V® (flumioxazin), glyphosate, 

Lorox® (linuron), Outlook® (dimethenamid-P), Prowl® (pendimethalin), Pursuit® 

(imazethapyr), Python® (flumetsulam), Scepter® (imazaquin), Valor SX® (flumioxazin), and 

Valor XLT® (flumioxazin and chlorimuron ethyl). For wheat, the label for the 85% WG 

formulation specifies that the product may be tank mixed with herbicides registered for use on 

fall and winter wheat. 

The label for the 42.5% WG formulation specifies that the product may be tank mixed with the 

following herbicides for application to soybean: 2,4-D, Command® (clomazone), Extreme® 

(imazethapyr and glyphosate), Firstrate® (cloransulaM-methyl), glyphosate, Lorox® (linuron), 

metribuzin, paraquat, pendimethalin, Pursuit Plus® (imazethapyr and pendimethalin), Python® 

(flumetsulam), Scepter® (imazaquin), Select® Max (clethodim), and Weedmaster® (dicamba 

and 2,4-D). The product may be tank mixed with glyphosate and/or dicamba for application to 

field corn.

A 12-hour restricted entry interval is specified.

The 42.5% WG formulation includes use directions for applications to fallow land and non-crop 

areas of farms, orchards, and vineyards, at 0.16-0.27 lb ai/A.

The following rotational crop restrictions have been proposed for the 85% WG formulation: a 0-

day PBI for any crop on the label, with a prohibition against a second application of 

pyroxasulfone; and an 18-month PBI for crops other than corn, soybean, and wheat. 

For the 42.5% WG formulation, the proposed rotational crop restrictions are dependent on 

application rates. For applications at up to 0.12 lb ai/A, a 0-day PBI is proposed for soybeans; a 

14-day PBI is proposed for minimum or no-till field corn; a 30-day PBI is proposed for 

conventionally tilled field corn; and an 18-month PBI is proposed for all other crops. For 

applications at up to 0.16 lb ai/A, a 4-month PBI is proposed for soybeans and field corn and an 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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18-month PBI is proposed for all other crops. For applications at up to 0.27 lb ai/A, a 6-month 

PBI is proposed for soybeans and field corn and an 18-month PBI is proposed for all other crops. 

We note that applications at 0.16 or 0.27 lb ai/A may only be made to fallow land or non-crop 

areas.

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 generally supported by 

the submitted field trial data. HED has determined that the proposed PHIs and PGIs for corn and 

soybean commodities are not necessary. Label amendments are required to remove the proposed 

PHIs and PGIs and to modify the proposed maximum seasonal rates for some soil types.

The proposed uses on field corn, sweet corn, and soybean are all restricted to crop growth stages: 

for field and sweet corn, application is to be made up to the V4 growth stage; for soybean, 

application is to be made up the third trifoliate leaf growth stage; and for wheat, application is to 

be made preemergence. Because applications are based on defined growth stages, and crop 

commodities were harvested at appropriate crop growth stages in the field trials submitted with 

this petition, no PHIs or PGIs need to be specified for any field corn, sweet corn, or soybean

commodity. Therefore, the product label for the 85% WG formulation should be amended to 

remove the following: the 37-day PHI for sweet corn ears; the 7-day PGI for corn and corn 

forage; the 15-day PHI for soybeans; and the 7-day PGI for soybean and soybean forage, hay, and 

straw.

For wheat, the proposed use is also restricted to crop growth stage (preemergence). However, in 

the crop field trials submitted with this petition, wheat forage was harvested at various intervals, 

at unspecified crop growth stages. The tolerance calculation for wheat forage was based on 

residue data reflecting PHIs of ≥40 days; therefore, the proposed PGI of 42 days is appropriate. 

When the required additional crop field trial data for wheat have been submitted, HED may 

determine that a PGI is no longer needed for wheat.

The available field trial data for field and sweet corn reflect a single postemergence application at 

0.268 lb ai/A for fine- and medium-textured soils or at 0.148 lb ai/A for coarse-textured soils. 

The petitioner must amend the product label for the 85% WG formulation to specify a maximum 

seasonal rate of 0.268 lb ai/A for field and sweet corn grown in fine-, medium-fine-, and 

medium-textured soils, and a maximum seasonal rate of 0.148 lb ai/A for field and sweet corn 

grown in coarse-textured soils.

The product label for the 42.5% WG formulation must be amended to specify a maximum 

seasonal rate for field corn. Because application rates on this product are not dependent on soil 

type, the proposed maximum seasonal rate must be ≤0.148 lb ai/A.

The available field trial data for soybean reflect a single postemergence application at 0.186 lb 

ai/A for fine- and medium-textured soils or at 0.112 lb ai/A for coarse-textured soils. Insufficient 

field trial data were submitted to support single application rates greater than 0.186 lb ai/A. The 

petitioner must amend the product label for the 85% WG formulation to specify a maximum 

single and seasonal application rate of 0.186 lb ai/A for soybean grown in fine-, medium-fine-, 

and medium-textured soils, and a maximum seasonal rate of 0.112 lb ai/A for soybean grown in 

coarse-textured soils.
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Based on the use pattern information included with the OECD dossier submission for the 85% 

WG formulation, the petitioner intends that only one application be made in the spring to corn, 

soybean, and wheat. For corn and soybean, for which two applications may be made, the 

petitioner intends that the split application be made as one application in the fall before planting 

and one application in the spring. The petitioner must amend the product label to specify that no 

more than one application may be made in the spring. 

The product label for the 85% WG formulation must be amended to specify a maximum seasonal 

application rate to wheat of 0.11 lb ai/A. 

The label for the 42.5% WG formulation states that activity on emerged weeds requires the 

addition of an adjuvant. No residue data have been submitted to support the use of an adjuvant 

with application of the product. The statement about adjuvant use must be removed from the 

product label.

For the 42.5% WG formulation, the petitioner must remove Weedmaster® from the list of tank 

mix partners for application to soybean, as this product (EPA Reg. No. 7969-133) is not 

registered for use on soybeans. The petitioner should also amend the label to specify that when 

the product is to be applied in a tank mix, the most restrictive label of all products used must be 

followed. 

The 42.5% WG formulation, which is only proposed for application to field corn and soybeans,

includes a restriction against the grazing of treated fields or feeding of treated forage or hay to 

livestock. HED does not believe that a restriction against the grazing or feeding of treated field 

corn forage or stover is practical; therefore, the restriction must be amended to state that the 

restriction only applies to soybeans. 

The proposed rotational crop restrictions for the 85% WG and 42.5% WG formulations are not 

supported by the available rotational crop data (see 860.1850 and 860.1900); additional data are 

required to determine whether rotational crop tolerances are needed to support the proposed 18-

month PBI for crops not on the label. Until the required rotational crop data have been 

submitted, the petitioner must modify the labels for both products to specify that only root crops

and crops on the label may be planted after pyroxasulfone application; crops on the label may be 

planted any time after application, and root crops may be planted 12 months after application.

860.1300 Nature of the Residue - Plants

Monograph for Pyroxasulfone, Sections B.7.1.1 and B.7.1.2 (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:
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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[pyrazole-5-

14C]pyroxasulfone

S

O

O

N

N O N

CF3

CH3

H3C

CH3

O

F2HC

*

[isoxazoline-3-

14C]pyroxasulfone

S

O

O

N

N O N

CF3

CH3

H3C

CH3

O

F2HC

*

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

names for these metabolites are provided in Appendix I. 

Field corn (MRID 47701649): The metabolism of pyroxasulfone was investigated in field corn 

following a single application of [14C]pyroxasulfone (pyrazole or isoxazoline labeled), 

formulated as a WG formulation in water, at a rate of approximately 1500 g ai/ha (1.34 lb ai/A; 

~5x the proposed maximum seasonal rate). Application was made preemergence or early 

postemergence (growth stage V4) in an application volume of 500 or 822 L/ha (53 or 88 gal/A), 

respectively. 

Total radioactive residues (TRR) were 2.717, 1.132, 3.485, and 2.474 ppm in corn foliage 

harvested at BBCH 34 (forage stage), 53 (tassel emergence stage), 79 (mid-fruit development 

stage), and 99 (maturity), respectively; and 0.073 and 0.132 ppm in corn grain (kernels)

harvested at BBCH 79 and 99, respectively, following preemergence application of [pyrazole-5-

14C]pyroxasulfone. TRR were 2.213, 1.444, 1.771, and 3.250 ppm in corn foliage harvested at 

BBCH 34, 53, 79, and 99, respectively; and 0.034 and 0.101 ppm in corn grain harvested at 

BBCH 79 and 99, respectively, following preemergence application of [isoxazoline-3-

14C]pyroxasulfone.

Following postemergence applications with [pyrazole-5-

14C]pyroxasulfone, TRR were 1.905, 

5.118, and 3.315 ppm in corn foliage harvested at BBCH 53, 79, and 99, respectively; and 0.007 

and 0.024 ppm in corn grain harvested at BBCH 79 and 99, respectively. TRR were 4.861, 

4.121, and 2.894 ppm in corn foliage harvested at BBCH 53, 79, and 99, respectively; and 0.026 

and 0.048 ppm in corn grain harvested at BBCH 79 and 99, respectively, following 

postemergence application of [isoxazoline-3-

14C]pyroxasulfone.

TRR levels in the foliage treated postemergence were higher than those observed in the samples 

from preemergence treatment for both labels. TRR in grain were lower in samples treated 

postemergence than in samples treated preemergence. 

Surface wash with acetonitrile (ACN) removed a greater proportion of the foliage residues from 

the samples treated postemergence (up to 40% TRR) than from the foliage samples treated 

preemergence (up to 7%); <1% of the TRR was removed from grain with the surface rinse. The 

majority of the remaining TRR was removed with acetone/water extractions, with levels of 

recovered radioactivity ranging 52-94% TRR in foliage and 58-70% TRR in grain (preemergence

treatment only); no radioactivity was extracted from grain treated postemergence. Further 

extraction of foliage samples with water, 0.1 M hydrochloric acid and sodium hydroxide, 2 M 

hydrochloric acid and sodium hydroxide, and acetone individually recovered further levels of 

TRR up to 6% TRR. Only 2 M acid/base hydrolysis released additional radioactivity (3-11% 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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TRR) from mature grain treated preemergence. Levels of unextracted residue ranged 0.5-24% 

TRR (0.014-0.973 ppm) in the foliage and 29-100% TRR (0.007-0.048 ppm) in the grain; 

unextracted residues were <10% TRR or <0.05 ppm in all matrices, with the exception of foliage 

harvested at BBCH 79. 

Only the mature samples were analyzed for metabolite characterization/identification. 

Metabolites were identified by high performance liquid chromatography (HPLC) and thin layer 

chromatography (TLC) co-chromatography. HPLC isolation followed by LC/MS analysis was 

used in an attempt to elucidate the potential structures of the unknowns that formed the major 

part of the residue.

No pyroxasulfone was found in mature foliage (stover) following preemergence application; the 

metabolites M-1 (37% TRR; 0.91 ppm), M-25 (27% TRR; 0.68 ppm), and M-29 (16% TRR; 

0.50 ppm) were major contributors to the residue. The majority of the residue in stover was in 

the form of parent pyroxasulfone (23-33% TRR; 0.77-0.95 ppm) and its metabolites M-1 (23% 

TRR; 0.77 ppm) and M-25 (24% TRR; 0.79 ppm) following postemergence application. The 

metabolites M-3, M-6, M-8, M-9, and M-10 were identified as minor residues in stover following

preemergence treatment, each at <4% TRR (<0.08 ppm); and metabolites M-1, M-6, M-9, and 

M-29 were identified as minor residues in stover treated postemergence, each at <10% TRR 

(<0.30 ppm). Approximately 73-76% TRR was identified in stover treated with [pyrazole-5-

14C]pyroxasulfone and 16-43% TRR was identified in stover treated with [isoxazoline-3-

14C]pyroxasulfone.

Pyroxasulfone was not detected in grain following preemergence application. Because 

radioactivity could not be extracted from postemergence application grain, the nature of the 

residues could not be characterized. The metabolites M-1, M-3, M-25, and M-29 were 

components of the grain residues; however, their levels in grain (each ≤5% TRR, ≤0.006 ppm) 

were much lower than in stover. Approximately 30% TRR was identified in grain treated with 

[pyrazole-5-

14C]pyroxasulfone and 1.1% TRR was identified in grain treated with [isoxazoline-3-

14C]pyroxasulfone.

Unidentified minor metabolites in stover and grain were not considered to be significant (each 

≤9.5% TRR, with the exception of one unknown in stover, which was found at 13.7% TRR, 

0.446 ppm). One unknown found in stover at 4-5% TRR (0.11-0.13 ppm) and in grain at 19% 

TRR (0.025 ppm) was tentatively identified as the N-glycoside of M-9. Another unknown found 

in stover at 3-4% TRR (0.08-0.13 ppm) was characterized as a conjugate of M-9.

The petitioner proposed that pyroxasulfone is metabolized in corn via cleavage of the methyl 

sulfone bridge of the parent, forming an intermediate metabolite (M-7, which was not found in 

corn matrices) which undergoes oxidation to form the sulfonic acid metabolite M-1. Metabolite 

M-25 is formed following demethylation of M-1. For the other pyrazole-ring metabolites, the 

carboxylic acid metabolite M-3 likely forms from metabolites M-8 and M-10, with subsequent 

demethylation to form M-9, which may be further conjugated. In the case of the isoxazoline-ring

metabolites, an intermediate cysteine conjugate (M-26, which was not found) may form from 

pyroxasulfone; subsequent deamination of M-26 would result in the formation of the conjugate 

M-29.
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HED notes that the petitioner additionally characterized/identified radioactivity in samples of 

corn root; these data are not discussed here. No unique metabolites were found in roots.

The initial analyses of the treated acetone/water, acid and base extracts and the unretained 

material were completed within six months of harvest. Analysis of the confirmatory extracts by 

HPLC was not completed within six months of harvest but the profiles confirmed the results 

from the initial analysis.

Postulated pathways of formation of metabolites identified in field corn following preemergence and post-emergence treatment with KIH-485
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Soybean (MRID 47701650): The metabolism of pyroxasulfone was investigated in soybean 

following a single application of [14C]pyroxasulfone (pyrazole or isoxazoline labeled),

formulated as a WG formulation, in water at a rate of 0.535 lb ai/A (~600 g ai/ha) preemergence

(2.5x the proposed maximum preemergence application rate of 0.21 lb ai/A) or 0.373 lb ai/A 

(~418 g ai/ha) postemergence (2x the proposed maximum postemergence application rate of 0.19 

lb ai/A), in an application volume of 500 or 700 L/ha (53 or 75 gal/A), respectively. 

TRR were 1.339, 2.175, 0.496, and 3.796 ppm in soybean foliage harvested at BBCH 49 (forage 

stage), 61 (first-flower opening stage), 75 (mid-fruit/seed development stage), and 99 (maturity), 

respectively; and 0.015 and 0.312 ppm in soybean seed harvested at BBCH 75 and 99, 

respectively, following preemergence application of [pyrazole-5-

14C]pyroxasulfone. TRR were 

3.700, 1.142, 0.498, and 3.347 ppm in soybean foliage harvested at BBCH 49, 61, 75, and 99, 

respectively; and 0.014 and 1.137 ppm in soybean seed harvested at BBCH 75 and 99, 

respectively, following preemergence application of [isoxazoline-3-

14C]pyroxasulfone.

Following postemergence application of [pyrazole-5-

14C]pyroxasulfone, TRR were 4.445, 1.517, 

and 5.671 ppm in soybean foliage harvested at BBCH 61, 75, and 99, respectively; and 0.011 and 

1.267 ppm in soybean seed harvested at BBCH 75 and 99, respectively. TRR were 3.410, 1.468, 

and 6.945 ppm in soybean foliage harvested at BBCH 61, 75, and 99, respectively; and 0.016 and 

1.362 ppm in soybean seed harvested at BBCH 75 and 99, respectively, following postemergence
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application of [isoxazoline-3-

14C]pyroxasulfone. During the subsequent characterization and 

identification of the residues, it became evident that there had been a mix-up during the sampling 

procedures. In general, the composite samples from the postemergence treatment plots contained 

a mixture of plant material that had been treated with [pyrazole-5-

14C]pyroxasulfone and 

[isoxazoline-3-

14C]pyroxasulfone. However, for samples harvested at BBCH 75, the foliage and 

seed samples from both plots consisted solely of material that had been treated with [pyrazole-5-

14C]pyroxasulfone.

After preemergence treatment with the [pyrazole-5-

14C]-label or the [isoxazoline-3-14C]-label, 

the TRR levels in the foliage and roots were a similar order of magnitude at each harvest, and 

showed little difference between the two radiolabelled forms of pyroxasulfone. Levels were low 

in the seeds at the mid-fruit/seed development harvest, but had increased considerably by the 

time maturity had been reached. The lowest TRR values in all matrices were obtained at the 

mid-fruit/seed harvest. This may be attributed to the poor health of the plants at this stage. Some 

evidence of phytotoxic effects was observed during the growth of the plants and, in order to 

ensure sufficient sample was available for the mature harvest, a decision was made to harvest the 

plants in the poorest state of health at the mid-fruit/seed harvest. The healthiest plants were 

sampled at maturity since these were used for profiling.

As a result of the sampling error, it was not possible to compare the distribution of radioactive 

residues between the two radiolabelled forms of pyroxasulfone in the postemergence crop 

fractions. Nevertheless, the TRR levels observed at each harvest interval, following application 

to postemergence plants, were of a similar order of magnitude to those following preemergence

application.

Surface washes with ACN removed up to 15% TRR from foliage; no radioactivity was removed 

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

acetone/water and water extractions, with levels of recovered radioactivity ranging 66-84% TRR 

in foliage, and 85-91% TRR in mature seed; no radioactivity was extracted from seed collected at 

the mid-fruit/seed development stage (BBCH 75). Further extraction of the mature samples with 

0.1 M hydrochloric acid and sodium hydroxide, 2 M hydrochloric acid and sodium hydroxide,

and acetone individually recovered further levels of TRR up to 13% TRR. Levels of unextracted 

residue ranged 13-26% TRR (0.092-0.811 ppm) in immature foliage, 9-14% TRR (0.325-1.000 

ppm) in mature foliage, and 3-7% TRR (0.021-0.049 ppm) in mature seeds. In the 

postemergence foliage samples, there appeared to be a decrease in the %TRR extracted with 

acetone/water as the samples matured. This differs from the preemergence foliage samples 

where a decrease in extractability with acetone/water was not clearly evident. Mature seed 

samples had the highest extractability.

Metabolites were identified by HPLC and TLC co-chromatography. HPLC isolation followed by 

LC/MS was used in an attempt to elucidate the accurate masses and potential structures of the 

unknowns that formed the major part of the residue.

Foliage collected at the first flower harvest (BBCH 61) is considered to be representative of 

soybean forage, and although foliage collected at the mid-fruit harvest (BBCH 75) was not dried, 

it was collected when soybean hay is typically harvested. No pyroxasulfone was identified in 

first-flower harvest foliage, and only small amounts (≤1% TRR) of pyroxasulfone were identified 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 23 of 87

in mid-fruit harvest foliage. The major residues identified in both first-flower and mid-fruit 

harvest foliage were M-1, M-25, and M-28 following pre- and postemergence application. 

Metabolites M-1, M-25, and M-28 accounted for 5.7-14% (0.20-0.30 ppm), 5.1-13% (0.17-0.27 

ppm), and 38-55% TRR (0.63-2.46 ppm), respectively, in first flower harvest foliage, and 13-

16% (0.07-0.20 ppm), 6.8-12% (0.055-0.17 ppm), and 35% TRR (0.17 ppm), respectively, in 

mid-fruit harvest foliage. An unknown tentatively characterized as a possible conjugate of M-9 

was the major residue detected in first flower harvest foliage following preemergence application 

accounting for 34% TRR (0.75 ppm) and in mid-fruit harvest foliage accounting for 20-31% 

TRR (0.15-0.30 ppm); this metabolite was a minor residue (~8% TRR, 0.26 ppm) in first flower 

harvest foliage following postemergence application. Approximately 35-61% TRR was 

identified in BBCH 61 and 75 foliage. HED notes that because samples harvested at BBCH 75 

from both plots consisted solely of material that had been treated with [pyrazole-5-

14C]

pyroxasulfone, there was no sample available of mid-fruit harvest foliage treated with 

[isoxazoline-3-

14C]pyroxasulfone.

Limited amounts of pyroxasulfone (≤1.6% TRR, ≤0.11 ppm) were present in mature foliage and 

seeds following pre- and postemergence application. In the mature foliage, M-1 was the main 

metabolite accounting for up to 32% TRR (up to 1.2 ppm) while M-25 was a minor metabolite 

(<7% TRR, ≤0.26 ppm). M-1 and M-25 were not detected in the seeds. The conjugate M-28 

was a major metabolite in mature foliage (≤33.2% TRR, ≤1.49 ppm) and mature seeds (≤52.0% 

TRR, ≤0.65 ppm), following pre- and postemergence application. The conjugate M-29 (coeluting with M-1) was also considered a major metabolite, accounting for up to 13.5% TRR (0.94 

ppm) in mature foliage. Other metabolites were formed but comprised only a small proportion of 

the residue; those metabolites which were unable to be identified were each present at ≤7.8% 

TRR. Approximately 34-64% TRR was identified in mature foliage and 43-52% TRR was 

identified in seed, except seed treated preemergence with [pyrazole-5-

14C]pyroxasulfone, in 

which only 5.5% TRR was identified. 

The petitioner proposed that pyroxasulfone is metabolized in soybean via cleavage of the methyl 

sulfone bridge of the parent, forming an intermediate metabolite (M-7, which was not found in 

soybean matrices) which undergoes oxidation to form the sulfonic acid metabolite M-1. 

Metabolite M-25 is formed following demethylation of M-1. For the other pyrazole-ring

metabolites, the carboxylic acid metabolite M-3 likely forms from metabolites M-8 and M-10, 

with subsequent demethylation to form M-9, which may be further conjugated. In the case of the 

isoxazoline-ring metabolites, an intermediate cysteine conjugate (M-26, which was not found) 

may form from pyroxasulfone; subsequent deamination of M-26 would result in the formation of 

the conjugate M-29. Malonylation of M-26 results in the formation of malonyl-cysteine 

conjugate M-28.

HED notes that the petitioner additionally characterized/identified radioactivity in samples of 

soybean root; these data are not discussed here. Two metabolites were identified in roots that 

were not identified in foliage or seeds, M-8 and M-10 (each at <2% TRR). 

Samples were stored frozen prior to analysis but no dates of extraction and/or analysis were 

provided for any sample. Based on the sample harvest dates and the reported date of completion 

of metabolite identification, samples may have been stored for up to 23 months prior to 

completion of analysis. The petitioner stated that because initial analyses of the treated samples 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 24 of 87

were not completed within three months of harvest, sub-samples of the mature foliage (pre-and 

postemergence) were re-extracted and analyzed; comparison of the HPLC profiles to the original 

data reportedly confirmed the stability of the samples during frozen storage. No data were 

provided to support these statements, including any indication of the length of time between the 

initial analyses and the repeat analyses. 

Conclusions. The submitted data are partially adequate to satisfy data requirements. Although 

the petitioner harvested and extracted immature corn samples, the petitioner did not 

identify/characterize radioactivity in corn forage, a major raw agricultural commodity (RAC) of 

corn. Normally data on corn forage would be required. However, the petitioner did identify a 

high percentage of radioactivity in corn stover. Therefore, metabolism data on corn forage will 

not be required.

For the soybean study, residues in the immature commodities soybean forage (foliage collected at 

first flower) and hay (foliage collected at mid-fruit) were not sufficiently characterized/identified. 

Nonextractable residues in these commodities were 13-26% TRR (0.092-0.811 ppm). Additional 

attempts should be made to release radioactivity, such that nonextractable residues are <10% 

TRR or <0.05 ppm. In addition, the petitioner must provide additional information pertaining to 

storage stability. The dates of sample extraction and analysis should be provided for all samples, 

including the samples that were re-extracted for storage stability confirmation. These data will 

allow HED to determine whether the data are sufficient to demonstrate that the identity of 

residues did not change during the period between collection and final analysis. In addition, 

supporting storage stability data will be needed for the required additional analyses for immature 

foliage matrices.

Due to a sampling mix-up, no samples were available of soybean hay from plots treated with 

[isoxazoline-3-

14C] pyroxasulfone. Based on the sample used in the radiovalidation study 

(MRID 47701665), the petitioner appears to have initiated another soybean metabolism study. 

When the required additional data described above and/or the new soybean metabolism study 

have been submitted and evaluated, HED will determine whether any additional data for soybean 

hay treated with [isoxazoline-3-

14C] pyroxasulfone are needed.

Postulated pathways of formation of metabolites identified in soybean following preemergence and post-emergence treatment with KIH-485
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 25 of 87

Pending submission of the additional crop metabolism data, HED (G. Kramer, 7/30/2010, 

D379930) has concluded that, for the purposes of this petition, the residues of concern for risk 

assessment and tolerance enforcement in cereal grains consist of pyroxasulfone and its 

metabolites M-1, M-3, and M-25. Residues of concern for tolerance enforcement in soybeans 

consist of pyroxasulfone and its metabolites M-1, M-3, and M-25. However, residues of concern 

for risk assessment in soybeans consist of pyroxasulfone and its metabolites M-1, M-3, M-25, 

and M-28. After reanalysis of soybean seed samples for M-28, this metabolite may need to be 

added as a residue of concern in tolerance enforcement for soybean.

860.1300 Nature of the Residue - Livestock

Monograph for Pyroxasulfone, Sections B.7.2.1 and B.7.2.2 (MRIDs 47701651-47701655)

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

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

summarized below. 

Hen

N

N

O N

H C S

3

H3C

CF3

CH3

F2HCO

O O

KIH-485 N

N

O N

H C S

3

H3C

CF3

CH3

F2HCO

O O

KIH-485N

S N

CF3

CH3

HO O

F2HCO

M-7 N

S N

CF3

CH3

HO O

F2HCO

M-7 N

S N

CF3

CH3

F2HCO

O O

HO

M-1 N

S N

CF3

CH3

F2HCO

O O

HO

M-1 N

H

S N

CF3

F2HCO

O O

HO

M-25

N

H

S N

CF3

F2HCO

O O

HO

M-25 N

N

CF3

CH3

F2HCO

H

O

M-10N

N

CF3

CH3

F2HCO

H

O

M-10 N

N

CF3

CH3

F2HCO

O

HO

M-3 N

N

CF3

CH3

F2HCO

O

HO

M-3 N

N

CF3

F2HCO H

HO

O

M-9 N

N

CF3

F2HCO H

HO

O

M-9

M-9 conjugate

N

N

CF3

CH3

F2HCO

HO

M-8N

N

CF3

CH3

F2HCO

HO

M-8

[ ] = Not detected

M-26

O S N

H3C

CH3

NH2

O OH

M-29

O

O S N

H3C

CH3

OH

OH

M-28

O N

S

H3C

HO O

N

H

O O

OH

H3C

M-28

O N

S

H3C

HO O

N

H

O O

OH

H3C
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 26 of 87

MRID 47701651: The absorption, distribution and excretion of [14C] pyroxasulfone were 

investigated following repeated oral administration to the laying hen. [Pyrazole14C]Pyroxasulfone was orally administered daily to five laying hens at a nominal dose level of 10 

ppm in the diet for 10 consecutive days. Excreta were collected daily and eggs collected twice 

daily. Approximately 23 hours following the final dose administration, the hens were sacrificed,

and liver, skin, muscle and fat were either excised or sampled as appropriate. Radioactivity was 

determined in all samples by direct liquid scintillation counting (LSC) or LSC following 

solubilization. 

The actual mean dose was 2.129 mg/animal/day, equivalent to 14.8 ppm in the diet, which is 

~780x the estimated dietary burden to poultry (see Table 6). The mean recovery of radioactivity 

was 88% of the administered dose; 86% of the administered dose was excreted. 

Radioactivity was detected in egg yolks, at 0.0494-0.1281 ppm, and egg whites, at 0.0250-0.0798 

ppm, at all time points. Steady-state conditions were achieved within 3 days of the first dose in

egg white and within 10 days in egg yolk. Radioactivity was detected in all tissues; 

concentrations were 0.4973 ppm in liver, 0.1054 ppm in muscle, 0.0492 ppm in skin and 0.0216 

ppm in fat. Concentrations of radioactivity were 0.1113 ppm in blood and 0.0578 ppm in 

plasma.

Residues in egg white and egg yolk were relatively extractable with organic solvents [hexane, 

ethyl acetate (EtOAc), ACN, acidified ACN, and methanol], at 90% and 57% TRR, respectively; 

protease digestion and 6 M acid hydrolysis released an additional 15% and 18% TRR from egg 

yolk. Residues in the tissues were not easily extractable with either organic (hexane, EtOAc, 

ACN, acidified ACN, and methanol) or more polar solvents (water, 1 M HCl, and 1M NH3), 

which extracted 32-40% TRR in total from each matrix. The residues were mostly released 

following protease digestion (32-51% TRR) or vigorous acidic hydrolysis (19-27% TRR). The 

petitioner concluded that the more aggressive extraction methods may have converted the 

residues to different components which may or may not have been present in the original sample. 

Nonextractable residues after exhaustive extraction were <10% TRR or <0.05 ppm in all 

matrices.

Extracts were analyzed by HPLC, and proposed identities were assigned to the putative residues 

based solely on the chromatographic retention times. 

Approximately 3-28% TRR was identified in egg and tissues. There were two identifiable 

metabolites which exceeded a concentration of 0.01 ppm in any matrix which were M-1, at 0.039 

ppm (7.8% TRR) in liver, and M-12, at 0.0130 ppm (2.6% TRR) in liver and 0.0114 ppm (9.5% 

TRR) in egg yolk. There was only one identifiable metabolite which exceeded 10% of the total 

radioactive residue for any matrix, M-12 at 11% TRR (0.0030 ppm) in egg white. 

A peak with similar chromatographic properties to pyroxasulfone was found only in egg yolk, fat 

and skin, at less than 0.002 ppm (0.8-3.3% TRR). Many of the residues showed similar 

chromatographic properties to supplied metabolite standards, namely M-1, M-3, M-5, M-6, M-8, 

M-9, M-10, M-11, M-12 and M-13. The metabolites identified in egg white were M-12, M-5, 

and M-6, each at <12% TRR (<0.004 ppm), and the metabolites identified in egg yolk were M-1, 

M-12, M-5, M-6, M-8, M-9, M-10, and pyroxasulfone, each at <10% TRR (<0.012 ppm). 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 27 of 87

Metabolites identified in muscle were M-1, M-10 and M-3 (0.1-3.0% TRR, each <0.004 ppm); in 

fat were M-12 and pyroxasulfone (each <4% TRR, ≤0.0008 ppm); and in skin were M-3, M-12, 

M-11, M-13, M-5 and pyroxasulfone (0.4-4.9% TRR, each <0.005 ppm). Analysis of liver 

showed M-1, M-8, M-3, and M-9 and/or M-12 (a residue tentatively identified as M-12 could be 

either M-9 or M-12), each at <8% TRR (<0.04 ppm). 

The remaining residues in analyzed extracts consisted of unidentified peaks, none of which 

accounted for greater than 0.037 ppm in an individual matrix. 

Samples were stored frozen prior to analysis but no dates of extraction and/or analysis were 

provided for any sample. Based on the reported dates of first dosing and completion of the 

experimental phase, final sample analysis may have been completed within 5.5 months of sample 

collection. 

Based on the observed metabolites, the petitioner proposed that pyroxasulfone is metabolized in 

hens via cleavage between the rings to form metabolites M-1, M-8, and M-10. Oxidation of 

M-10 would yield metabolite M-3, and metabolites M-12 and M-9 could be formed via 

demethylation of M-8 and M-3, respectively. Hydroxylation of pyroxasulfone would yield 

metabolites M-6 and M-11, and further oxidation of M-11 would yield M-13. Metabolite M-5 

could be formed via demethylation of pyroxasulfone.

MRID 47701652: The absorption, distribution and excretion of [isoxazoline-3-

14C]

pyroxasulfone were investigated following repeated oral administration to the laying hen. The 

test substance was orally administered daily to five laying hens at a nominal dose level of 10 ppm 

in the diet for 3 consecutive days. Excreta were collected daily and eggs collected twice daily. 

Approximately 23 hours following the final dose administration, the hens were sacrificed, and 

liver, skin, muscle and fat were either excised or sampled as appropriate. Radioactivity was 

determined in all samples by direct LSC or LSC following solubilization. 

The actual mean dose was 11.66 ppm in the diet, equivalent to ~610x the estimated dietary 

burden to poultry (see Table 6). The mean recovery of radioactivity was 103%; >99% of the 

administered dose was excreted. 

Radioactivity was detected in egg yolks, at 0.0097-0.0976 ppm, and egg whites, at 0.0263-0.1080 

ppm, at all time points. Radioactivity in egg whites may have reached a steady state by the end 

of the study; however, radioactivity in egg yolks appeared to be increasing at the end of the study. 

Radioactivity was detected in all tissues; concentrations were 0.1152 ppm in liver, 0.04081 ppm

in muscle, 0.03265 ppm in skin and 0.008731 ppm in fat. Concentrations of radioactivity were 

0.1918 ppm in blood and 0.0355 ppm in plasma. Due to low radioactivity levels, fat was not 

subjected to residue characterization.

Residues in egg white and egg yolk were relatively extractable with organic solvents (hexane, 

EtOAc, ACN, acidified ACN, and methanol), at 80% and 81% TRR, respectively. Residues in 

the tissues were not easily extractable with organic (EtOAc, ACN, acidified ACN, and methanol) 

or more polar solvents (water, 1 M HCl, and 1M NH3), which extracted 18-46% TRR and 5-11% 

TRR, respectively. The residues were released only following protease digestion (18-28% TRR) 

or vigorous acidic or basic hydrolysis (9-26% TRR). The petitioner concluded that the more 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 28 of 87

aggressive extraction methods may have converted the residues to different components which 

may or may not have been present in the original sample. Nonextractable residues were <10% 

TRR or <0.05 ppm in all hen matrices following solvent and/or exhaustive extraction.

Extracts were analyzed by HPLC, and tentative identities of residues were assigned based solely 

on their chromatographic properties.

Very few of the residues showed similar chromatographic properties to supplied metabolite 

standards; only pyroxasulfone, M-5, M-11 and M-13 were tentatively identified. Pyroxasulfone

was tentatively identified in liver (1.4% TRR, 0.0016 ppm), M-5 was tentatively identified in egg 

yolk (5.9% TRR, 0.0058 ppm), M-11 was tentatively identified in egg white and yolk (<1.5% 

TRR, <0.0015 ppm), and M-13 was tentatively identified in egg white, egg yolk, and skin (1.2-

19.5% TRR, 0.0004-0.019 ppm). Only one identifiable metabolite exceeded a concentration of 

0.01 ppm or a TRR of 10% in any matrix, which was M-13, at 19.5% TRR (0.0190 ppm) in egg 

yolk. Approximately 27% TRR was identified in egg yolk and <10% TRR was identified in egg 

white, liver, and skin; no metabolites were identified in muscle.

The remaining residues in analyzed extracts consisted of unidentified peaks, none of which 

accounted for greater than 0.031 ppm. 

Samples were stored frozen prior to analysis but no dates of sample collection, extraction, or 

analysis were provided. The petitioner stated that the organic extracts from all samples were 

subjected to HPLC re-analysis following all metabolite profiling and that comparison of the data 

with the original analyses indicated stability of the residues during sample storage for the 

duration of the study. No data to support this statement were included in the submission. Based 

on the reported dates of first dosing and completion of the experimental phase, samples may have 

stored for up to 12 months prior to completion of analysis. 

Based on the observed metabolites, the petitioner proposed that pyroxasulfone is metabolized in 

hens via demethylation to form metabolite M-5 or hydroxylation to form metabolite M-11;

further oxidation of M-11 would yield M-13. 

Conclusions. The submitted hen metabolism studies are adequate to satisfy data requirements for 

nature of the residue in poultry. 

Proposed metabolite pathway of KIH-485 in laying hens following at a daily dose level of 2.129 mg/ 

animal/day [pyrazole14C]-KIH-485 (equivalent to 15 ppm in the diet) over 10 days
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 29 of 87

O N

S

N

N

O O

F F F

O

F

F

KIH-485

N

N

O

O

HO

F

F F

F

F

M-3

N

N

O

F

F

F

F F

S

O

O

HO

M-1

N

N

S

O N

O

F

F

O O

F F

F

O

HO

N

N

O

F

F

S

O

O

HO O N

F

F

F

M-11

M-13

N

N

O

F

F

S

O

O

O N

F

F F

OH

M-6

N

N

O H

F

F

S

O

O

O N

F

F F

M-5

N

N

O

HO

F

F F

F

F

M-8

N

N

O H

O

HO

F

F F

F

F

M-9

N

N

O H

HO

F

F F

F

F

M-12

N

N

O

O

F

F F

F

F

M-10

Goat

MRID 47701653: The absorption, distribution, metabolism and excretion of [14C] pyroxasulfone

were investigated following repeated oral administration to the lactating goat. [Pyrazole14C]Pyroxasulfone was orally administered daily to a lactating goat at a nominal dose level of 10 

ppm in the diet for 5 consecutive days. Excreta were collected daily and milk collected twice 

daily. Approximately 23 hours following the final dose administration, the goat was sacrificed 

and liver, kidneys, muscle, and fat were either excised or sampled as appropriate. Radioactivity 

was determined in all samples by direct LSC or LSC following solubilization. 

The actual dose was 11.89 ppm in the diet, equivalent to ~250x and 160x the estimated dietary 

burden to beef and dairy cattle, respectively (see Table 6). The recovery of radioactivity was 

91.9% of the administered dose; the majority of radioactivity (84%) was excreted in the urine,

with minimal amounts being recovered in the feces (4%).

Radioactivity was detected in milk at all time points: 0.0026-0.0042 ppm in morning samples 

and 0.0239-0.0297 ppm in afternoon samples. Steady-state conditions were achieved within two 

days of the first dose administration. Radioactivity levels in tissues were 0.2181 ppm in liver, 

0.0171 ppm in kidneys, 0.0034 ppm in muscle, and 0.0015 ppm in omental fat. Radioactivity 

was below the limit of quantification in renal fat. Concentrations of radioactivity were 0.0052 

ppm in blood and 0.0046 ppm in plasma.

Residues in milk (Day 5 pm sample), liver, and kidney were not readily extractable with organic 

solvents (hexane, EtOAc, ACN, acidified ACN, and/or methanol) or more polar solvents (water, 

1 M HCl, and 1 M NH3); 4-48% TRR was organosoluble and 5-7% TRR was aqueous soluble. 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 30 of 87

A large proportion of the residue was bound to endogenous materials and required more 

aggressive methods of extraction. The residues were mostly released following protease 

digestion (21-80% TRR), subsequent ACN extraction (2.5-12% TRR), or vigorous acidic 

hydrolysis (16-25% TRR). Nonextractable residues in milk, liver, and kidney after solvent 

extraction, protease digestion, and acid and base hydrolysis were <5% TRR. Due to low 

radioactivity levels, residues in muscle and fat were not subjected to residue characterization.

Extracts were analyzed by HPLC, and residues were tentatively identified based solely on their 

chromatographic properties. 

Approximately 47%, 12%, and 23% TRR were identified in milk, liver, and kidney, respectively. 

Only one identifiable metabolite exceeded a concentration of 0.01 ppm in any matrix, M-12 at 

0.0135 ppm (6.2% TRR) in liver. There was only one identifiable metabolite which exceeded 

10% of the TRR for any matrix, M-13 at 25.2% TRR (0.0067 ppm) in milk. 

In addition to M-13, the metabolites identified in milk were M-1, M-3, M-8, M-9, M-11, and 

M-12 (0.8-7.2% TRR, each <0.002 ppm). In addition to M-12, the metabolites identified in liver 

were M-1, M-3, M-5 and/or M-6, M-8, M-9, and M-11 (0.2-2.4% TRR, each <0.006 ppm). The 

metabolites identified in kidney were M-1, M-5 and/or M-6, M-8, and M-9 and/or M-12 (2.3-

8.2% TRR, each <0.002 ppm). None of the residues released showed similar chromatographic 

properties to pyroxasulfone. The remaining residues in analyzed extracts consisted of 

unidentified peaks, none of which accounted for greater than 0.028 ppm.

Based on the observed metabolites, the petitioner proposed that pyroxasulfone is metabolized in 

goats via cleavage between the rings to form metabolites M-1 and M-8. Oxidation of M-8 would 

yield metabolite M-3, and metabolites M-12 and M-9 could be formed via demethylation of M-8 

and M-3, respectively. Hydroxylation of pyroxasulfone would yield metabolites M-6 and M-11, 

and further oxidation of M-11 would yield M-13. Metabolite M-5 could be formed via 

demethylation of pyroxasulfone.
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 31 of 87

Proposed metabolite pathway in a lactating goat (n= 1) following oral administration of [14C]-KIH-485 at a 

daily dose level of 19 mg/ animal/day (equivalent to 12 ppm in the diet) over 5 days

O N

S

N

N

CH3

O O

F F F

O

F

F

KIH-485

N

N

O

O

HO

F

F F

F

F

M-3

N

N

O

F

F

F

F F

S

O

O

HO

M-1

N

N

S

O N

O

F

F

O O

F F

F

O

HO

N

N

O

F

F

S

O

O

HO O N

F

F

F

M-11

M-13

N

N

O

F

F

S

O

O

O N

F

F F

OH

M-6

N

N

O H

F

F

S

O

O

O N

F

F F

M-5

N

N

O

HO

F

F F

F

F

M-8

N

N

O H

O

HO

F

F F

F

F

M-9

N

N

O H

HO

F

F F

F

F

M-12

MRID 47701654: Because M-25 was identified as a major metabolite in the corn metabolism 

study, the petitioner examined goat urine, from the above metabolism study with [pyrazole14C]

pyroxasulfone, for the presence of M-25 and other metabolites of pyroxasulfone. 

Day-5 goat urine, and urine fortified with pyroxasulfone and reference standards, were analyzed 

by HPLC. There were up to 13 regions of interest in the profile of day-5 goat urine. Seven of the 

regions had similar chromatographic properties to the reference standards. The metabolites 

tentatively identified included M-25, accounting for 0.3%; M-1, accounting for 5.9%; M-12, 

accounting for 0.4%; M-7, accounting for 3.4%; M-8, accounting for 0.3%; M-3, accounting for 

0.4%; and M-13, accounting for 3.2% of the administered dose.

MRID 47701655: The absorption, distribution, metabolism and excretion of [isoxazoline-3-

14C]

pyroxasulfone were investigated following repeated oral administration to the lactating goat. The 

test substance was orally administered daily to a lactating goat at a nominal dose level of 10 ppm 

in the diet for 3 consecutive days. Excreta were collected daily and milk collected twice daily. 

Approximately 23.8 hours following the final dose administration, the goat was sacrificed and 

liver, kidneys, muscle, and fat were either excised or sampled as appropriate. Radioactivity was 

determined in all samples by direct LSC or LSC following solubilization. 

The actual dose was 10.15 ppm in the diet, equivalent to ~210x and 140x the estimated dietary 

burden to beef and dairy cattle, respectively. The recovery of radioactivity was 82% of the 

administered dose. The majority of radioactivity was excreted in the urine (61%), with moderate 

amounts being recovered in the feces (11%).
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 32 of 87

Radioactivity was detected in milk at all time points: 0.0256-0.0335 ppm in morning samples 

and 0.0665-0.0912 ppm in afternoon samples. Steady-state conditions were not achieved during 

the study; the highest residues observed in milk were obtained on the last sampling day. 

Radioactivity was detected in all tissues; concentrations were 0.899 ppm in liver, 0.290 ppm in 

kidneys, 0.066 ppm in muscle, 0.040 ppm in renal fat and 0.039 ppm in omental fat. 

Concentrations of radioactivity were 0.291 ppm in blood and 0.362 ppm in plasma.

Residues in milk (Day 3 pm samples) and tissues were not readily extractable with organic 

solvents (hexane, EtOAc, ACN, acidified ACN, and/or methanol) or more polar solvents (water, 

1 M HCl, and 1 M NH3); 6-29% TRR was organosoluble and 5-7% TRR was aqueous soluble. 

The residues were mostly released following protease digestion (42-65% TRR), subsequent ACN

extraction (4-23% TRR), or vigorous acidic hydrolysis (9-26% TRR). Nonextractable residues in

milk and tissues after solvent extraction, protease digestion, and acid and base hydrolysis were 

<10% TRR or <0.05 ppm. 

Extracts were analyzed by HPLC and residues were tentatively identified based solely on their 

chromatographic properties and co-chromatography with supplied metabolite standards. Further 

investigation of residues that were not retained on HPLC analysis and an unknown in the 

protease extract of liver was attempted using TLC and/or LC/MS; neither technique yielded 

additional metabolite identifications.

Many of the residues showed similar chromatographic properties to supplied metabolite 

standards, namely M-5, M-6, M-13, M-15, M-16, M-22 and pyroxasulfone, but each accounted 

for less than 0.014 ppm. Approximately 11% TRR was identified in milk and 1.3-3.1% TRR 

identified in liver, kidney, and muscle; no metabolites were identified in fat. No identified 

metabolite exceeded 10% of TRR in any matrix measured, and only one identified metabolite 

exceeded a concentration of 0.01 ppm, M-22 in liver at 0.0135 ppm (1.5% TRR). In addition to 

M-22, metabolites M-5, M-13, and M-16 were identified in liver (each <1% TRR, <0.007 ppm). 

Identified metabolites in milk were M-13, M-16, and M-22 (0.9-6.7% TRR, each <0.007 ppm); 

identified metabolites in kidney were M-6, M-15, M-22, and pyroxasulfone (each <1% TRR, 

<0.003 ppm); and only M-22 was identified in muscle (2.7% TRR, 0.0018 ppm). 

Only residues which were not retained on the HPLC column individually accounted for greater 

than 0.050 ppm. TLC analysis of these un-retained residues did not yield any metabolite 

identifications. The petitioner stated that comparison of these results with results from a rat 

metabolism study (MRID 47701728; Covance Study Number 0535/138) indicated that the unretained residues were multi-component and probably included metabolite M-30 and 5 methyl-5-

isoxazoline carboxylic acid; however, limited data/discussion to support this statement were 

provided.

Based on the observed metabolites, the petitioner proposed that pyroxasulfone is metabolized in 

goats via oxidation, to form metabolite M-13, or hydroxylation, to form metabolite M-6. 

Cleavage of M-13 between the rings would yield 5-methyl-isoxazoline carboxylic acid, which 

may be further metabolized to M-30. Metabolite M-5 could be formed via demethylation of 

pyroxasulfone. Metabolite M-15 is formed via cleavage of pyroxasulfone, and further 

metabolism would yield metabolite M-16 and then M-22. 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 33 of 87

Proposed metabolite pathway in a lactating goat (n= 1) following oral administration of [14C]-KIH-485 at a 

daily dose level of 13.6 mg/ animal/day (equivalent to 10 ppm in the diet) over 3 days

O N

S

N

N

O

O

F

F F

O

F

F

KIH-485

N

N

S

O N

O

F

F

O O

F F

F

O

HO

M-13

N

N

O

F

F

S

O

O

O N

F

F F

OH

M-6 M-15

SG

O N

S

O N N

H

O

OH

O

M-16

O N

O

HO

5-methyl-5-isoxazoline carboxylic acid

HO

CO2H

CN

M-30

N

N

O

F

F

S

O

O

O N

F

F F

M-5

O N

M-22

Samples were stored frozen prior to analysis but no dates of extraction and/or analysis were 

provided for any sample. The petitioner stated that the first organic extracts from all samples 

were re-subjected to HPLC analysis after all metabolite profiles had been determined and that 

comparison of the data indicated stability of the residues during sample storage for the duration 

of the study. No data to support this statement were included in the submission. Based on the 

reported dates of first dosing and completion of the experimental phase, samples may have stored 

for up to 12 months prior to completion of analysis. 

Conclusions. The submitted goat metabolism studies are adequate to satisfy data requirements 

for nature of the residue in ruminants. Initially, for the study conducted with [isoxazoline-3-

14C]

pyroxasulfone, the petitioner was required to provide additional discussion and supporting data 

for their statements that un-retained radioactivity accounting for >0.05 ppm was likely 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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multicomponent and contained M-30 and 5-methyl-5-isoxazoline carboxylic acid. The petitioner 

was required to explain why a reference standard for potential metabolite M-30 was not used in 

this study (an M-30 reference standard was used in the analogous hen metabolism study). The 

petitioner was also required to provide further explanation (and supporting data if available) of 

the attempts to identify residues by LC/MS. 

No dates of sample collection, extraction, or analysis were provided. The petitioner was required 

to submit dates of collection, extraction, and analysis for each sample from all of the submitted 

studies. For the hen and goat studies reflecting pyrazole labeling (MRIDs 47701651 and 

47701653), if the required data indicated that final sample analysis was not completed within 6 

months of sample collection, evidence should be provided that the identity of residues did not 

change during the period between collection and final analysis. For the hen and goat studies 

reflecting isoxazoline labeling (MRIDs 47701652 and 47701655), the petitioner was required to

provide the comparative chromatographic data that were cited in the studies. 

The petitioner has submitted theses outstanding data and these data were found to be acceptable 

(T. Morton, D395720, 11/17/11).

Based on the results of the goat and hen metabolism studies, HED has concluded that the 

residues of concern for tolerance enforcement in livestock commodities consist of pyroxasulfone 

and its metabolites M-1 and M-3. Residues of concern for risk assessment in livestock 

commodities consist of pyroxasulfone and its metabolites M-1, M-3, M-25, and M-28.

860.1340 Residue Analytical Methods

A summary of the analytical methods associated with this petition is presented in Table 4. 
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Table 4. Summary of Residue Analytical Methods.

Matrix Analytes Method Limit of quantitation (ppm)

Crop commodity enforcement method + independent laboratory validation

Corn forage, grain, stover, 

grits, starch, meal, flour, 

oil

Pyroxasulfone

M-1

M-3

M-25

LC/MS/MS 0.01 for M-3 in corn meal 

and M-1 in corn oil

0.005 for all other analytes 

in corn matrices

Soybean forage, seed, hay, 

meal, hulls, oil

Pyroxasulfone

M-1

M-3

M-25

LC/MS/MS 0.01 for M-1 in soybean 

seed and oil

0.005 for all other analytes 

in soybean matrices

Crop commodity data generation method (Australia)

Wheat forage, grain, straw Pyroxasulfone

M-1

M-3

M-25

LC/MS/MS

(Method No. ATM-0031-02)

0.01

Livestock commodity enforcement method + independent laboratory validation

Milk, muscle, liver, 

kidney, fat

Pyroxasulfone

M-1

M-3

LC/MS/MS 0.001 for pyroxasulfone, 

M-1, M-3 in milk; 

0.010 for pyroxasulfone, 

M-1, M-3 in muscle, 

liver, kidney, and fat

Poultry egg Pyroxasulfone

M-1

M-3

LC/MS/MS 0.01

Crop commodities

Monograph for Pyroxasulfone, Sections B.5.2.1 and B.5.2.3 (MRIDs 47701656-47701658, 47701661, 47701662, 

47701665)

Enforcement methods: K-I Chemical has proposed LC/MS/MS enforcement methods for the 

determination of residues of pyroxasulfone and its metabolites M-1, M-3, and M-25 in/on crop

commodities. The methods were developed in conjunction with the corn and soybean field trial 

studies.

Corn commodities: The method for corn commodities is entitled: KIH-485/M-3, M-l and M-25 

Analytical Method in Corn as Described in “Magnitude of the Residue of KIH-485 WG 85 

Herbicide in Corn (field corn and sweet corn) Raw Agricultural Commodities.” The method 

includes individual instructions for the extraction and analysis of samples of corn grain, forage, 

stover, grits, flour, starch, meal, and oil. 

In general, samples are extracted with ACN:water (3:1, v:v) [grain, oil] or methanol:water (3:1, 

v:v) [forage, stover, grits, flour] via shaking and sonication (after allowing to soak overnight for 

grain and stover). The extract is partitioned with hexane, and the hexane phase is discarded. The 

aqueous layer is diluted to volume with extraction solvent and divided into two aliquots, one for 

the determination of pyroxasulfone and M-3 and the other for the determination of M-1 and 

M-25. The pyroxasulfone/M-3 aliquot is concentrated to remove the ACN or methanol, mixed 

with 0.5 M NaHCO3 and, for grain and oil, saturated NaCl solution, and partitioned twice with 

hexane. The combined hexane layers, containing pyroxasulfone, are concentrated to near dryness 
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and reconstituted in ACN. The aqueous phase, containing M-3, is acidified (using 0.5 M citric 

acid) and partitioned twice with hexane:EtOAc (3:7, v:v); the organic phases are combined, 

evaporated to dryness, and redissolved in ACN. The pyroxasulfone and M-3 extracts are cleaned 

up on Envi-Carb solid-phase extraction (SPE) cartridges; the eluates are combined, evaporated to 

dryness, and redissolved in ACN:water (1:1 or 2:1, v:v) for analysis. 

For determination of M-1 and M-25, the ACN/water aliquot is concentrated, mixed with pH 5 

acetate buffer [grain, oil] or water [forage, stover, grits, flour], and partitioned with EtOAc. The 

aqueous phase is either: (1) mixed with saturated NaCl solution and partitioned twice with ACN;

the ACN phases are combined, evaporated to dryness, and redissolved in ACN:water (1:9, v:v) 

for analysis [M-1 in grain and M-1 and M-25 in oil]; (2) diluted with water for analysis [M-25 in 

grain, stover, grits, flour]; or (3) cleaned up on an NH2 SPE cartridge and diluted to volume with 

water for analysis [M-1 in forage, stover, grits, flour, and M-25 in forage]. 

For corn starch, samples were extracted with ACN:water (3:1, v:v), via shaking and sonication, 

and the extract was evaporated to dryness and reconstituted in ACN. The extract was cleaned up 

on an Envi-Carb SPE cartridge; the eluate was evaporated to dryness and redissolved in 

ACN:water (2:8, v:v) for analysis (pyroxasulfone and M-3 in one aliquot, M-1 in a second 

aliquot, and M-25 in a third aliquot). For corn meal, samples were extracted with ACN:water 

(3:1, v:v), via shaking and sonication, and the extract was concentrated, mixed with NaCl and 

water, and partitioned with ACN. The ACN layer was evaporated to dryness, reconstituted in 

ACN, and cleaned up on an Envi-Carb SPE cartridge. The eluate was diluted with ACN and 

divided into two aliquots; one aliquot was used for the determination pyroxasulfone and the other 

for the determination of M-1, M-3, and M-25. The pyroxasulfone aliquot was evaporated to 

dryness and redissolved in ACN for analysis. The M-1/M-3/M-25 aliquot was evaporated to 

dryness and redissolved in ACN:water (1:1, v:v) containing 0.5% acetic acid. The extract was 

cleaned up on a C-18 SPE cartridge and the eluate was evaporated to dryness and redissolved in 

ACN:water (2:8, v:v) for analysis (separate aliquot for each of the three analytes). 

The petitioner reported that several LC/MS/MS analysis methods were necessary to achieve 

acceptable recovery; many matrices required more than one method due to varying enhancement 

from matrix co-extractives. All methods used a C-18 column; methods varied in the solvent 

system and gradient used. For pyroxasulfone and M-3 in grain, M-3 in stover, grits, and meal, 

and M-1 and M-25 in all commodities, a gradient of water and ACN, each containing 0.05% 

formic acid was used. For pyroxasulfone and M-3 in grain, forage, starch, oil, and flour and 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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pyroxasulfone in stover, grits, and meal, a gradient of water and methanol, each containing 

0.05% formic acid, was used. Residues were quantified using a calibration curve of external 

standards. The method did not include any information about converting residues of metabolites 

to parent equivalents.

The ion transitions used for quantitation of the pyroxasulfone analyte were the sum of 392 m/z →229 m/z and 392 m/z →179 m/z.

The ion transitions used for quantitation of the M-1 analyte were the sum of 309 m/z →259 m/z and 309 m/z →195 m/z..

The ion transitions used for quantitation of the M-3 analyte were the sum of 259 m/z →215 m/z and 259 m/z →165 m/z.

The ion transitions used for quantitation of the M-25 analyte were were the sum of 295 m/z →181 m/z and 295 m/z →163 m/z..

The LOQ for each analyte in each commodity was 0.005 ppm, except for M-3 in corn meal and 

M-1 in corn oil, for which the LOQ was found to be 0.01 ppm. The petitioner stated that due to 

the difficulties encountered in the determination of pyroxasulfone, M-1, M-3 and M-25, some of 

the analyses were conducted with solvent-based calibrants while others were based on calibrants 

prepared in control matrix final extract; the matrix-based calibrants were necessary when mass 

spectral ionization demonstrated significant matrix enhancement or matrix suppression of the 

signal.

The petitioner stated that matrix blanks (controls) were analyzed concurrently to evaluate 

potential analytical interferences and that there were no known interferences from corn 

components or from reagents, solvents and glassware used; results for controls analyzed during 

method validation were not reported. However, apparent residues of each analyte were below the 

LOQ in/on all untreated samples from the corn field trials, except that apparent residues of M-3 

were found in/on one sample of untreated field corn grain, at 0.006 ppm. 

The method was validated in corn forage, grain, stover, grits, starch, meal, flour, and oil by 

fortification with each analyte at 0.005, 0.01, and 0.10 ppm for pyroxasulfone, M-1, and M-3, 

and at 0.005 and 0.05 ppm for M-25; corn forage was additionally fortified with pyroxasulfone at 

50 ppm. Average recoveries were within acceptable limits (70-120%) for all analytes in all 

matrices with the following exceptions: pyroxasulfone in corn grits at the 0.005-ppm 

fortification level (average recovery 65%); M-1 in corn forage and stover at the 0.01- and 0.10-

ppm fortification levels (average recoveries 132-156%); and M-25 in corn stover and oil at the 

0.05-ppm fortification level (average recoveries of 69% and 57%, respectively). The overall 

relative standard deviations (RSDs) were <20% for all analytes in all matrices with the following 

exceptions: pyroxasulfone in corn meal (21%); and M-1 in corn forage and stover (26% each). 

Recoveries from all matrices ranged 60-120% for pyroxasulfone (average of 88%; four 

recoveries <70%), 52-157% for M-1 (average of 99%; three recoveries <70% and 12 recoveries 

>120%), 55-116% for M-3 (average of 88%; four recoveries <70%), and 54-120% for M-25 

(average of 86%; five recoveries <70%). 

The method was subjected to independent laboratory validation (ILV) using samples of corn 

grain, forage, stover, grits, starch, meal, flour and oil fortified with pyroxasulfone, M-1, M-3, and 

M-25 at 0.005 ppm and 0.05 ppm each. The average recoveries were within acceptable limits 

(70-120%) for all analytes in all matrices with the exception of M-1 in meal (both fortification 

levels; 142% and 123% average recovery) and M-3 in stover (both fortification levels; 121% and 

124% average recovery). The RSDs were <20% for all analytes in all matrices with the 

exception of M-3 in grits (lower fortification level; 27.2% RSD) and M-25 in stover (lower 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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fortification level; 28.5% RSD). The ILV laboratory stated that for M-3 in stover, the absence of 

blank matrix contributions, precision of the replicate values for M-3, and comparable recoveries 

for both fortification concentrations was considered adequate to validate the method. For M-1 in 

meal, the ILV laboratory concluded that enhancement of the response was evident at the levels 

tested. 

The ILV laboratory reported that one set of pyroxasulfone, M-1, M-3, and M-25 samples (total of 

12 samples) required approximately four days to complete, including LC/MS/MS instrument 

time for quantitation, and required three full analyst’s days for extraction and preparation for 

analysis. The laboratory recommended that a warning be issued as part of each method that it is 

not known if the partitions will lead to emulsions, and suggested that for flour, the elution 

volume for pyroxasulfone for the Envi-Carb SPE extraction cartridge be increased and the 

volume used for reconstituting the dried eluate be increased; these minor modifications increased 

the recovery of pyroxasulfone greater than 10%. The registrant has submitted MRID 48430001 

which contains the suggestion of the ILV laboratory for a warning regarding emulsions forming 

along with the corn flour extraction revisions.

Adequate concurrent method recovery data for pyroxasulfone, M-1, M-3, and M-25 in field corn 

forage, stover, grain, grits, meal, flour, starch, dry or wet milled oil, and sweet corn forage, 

K+CWHR, and fodder were submitted with the crop field trial and processing study submitted 

with this petition; samples were fortified at 0.01 and 0.10 ppm for pyroxasulfone, M-1, and M-3 

in each matrix, and at 0.005 and 0.05 ppm for M-25 in each matrix. For all analytes, average 

concurrent recoveries were generally within the acceptable range of 70-120%. Recoveries <70% 

were observed from corn oil fortified with M-25 at 0.005 and 0.05 ppm (52% and 57%).

Soybean commodities: The method for soybean commodities is entitled: KIH-485/M-3, M-l and 

M-25 Analytical Method in Soybean as Described in “Magnitude of the Residue of KIH-485 WG 

85 Herbicide in Soybean Raw Agricultural Commodities.” The method includes individual 

instructions for the extraction and analysis of samples of soybean seed, forage, hay, hulls, meal, 

and oil. 

In general, samples are extracted with ACN:water (3:1, v:v) [seed, hay, hulls, meal, oil] or 

methanol:water (3:1, v:v) [forage] via shaking and sonication. The extract is partitioned with 

hexane, and the hexane phase is discarded. The aqueous layer is diluted to volume with 

extraction solvent and divided into two aliquots, one for the determination of pyroxasulfone and 

M-3 and the other for the determination of M-1 and M-25. The pyroxasulfone/M-3 aliquot is 

concentrated to remove the ACN or methanol, mixed with 0.5 M NaHCO3 and saturated NaCl 

solution [seed, hay, hulls, meal, oil] or with 0.5 M NaHCO3 only [forage], and partitioned twice 

with hexane. The combined hexane layers, containing pyroxasulfone, are concentrated to near 

dryness and reconstituted in ACN. The aqueous phase, containing M-3, is acidified (using 0.5 M 

citric acid) and partitioned twice with hexane:EtOAc (3:7, v:v); the organic phases are combined, 

evaporated to dryness, and redissolved in ACN. The pyroxasulfone and M-3 extracts are cleaned 

up on Envi-Carb SPE cartridges; the eluates are combined, evaporated to dryness, and 

redissolved in ACN:water (2:1, v:v) for analysis. 

For determination of M-1 and M-25, the ACN/water aliquot is concentrated, mixed with pH 5 

acetate buffer [M-1 in seed; M-1 and M-25 in hay, hulls, meal, oil] or water [M-25 in seed; M-1 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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and M-25 in forage], and partitioned with EtOAc. The aqueous phase is either: (1) mixed with 

saturated NaCl solution and partitioned twice with ACN; the ACN phases are combined, 

evaporated to dryness, and redissolved in ACN:water (1:9, v:v) for analysis [M-1 in seed, hay, 

meal; M-1 and M-25 in hulls, oil] or redissolved in water for analysis [M-25 in hay]; or (2) 

cleaned up on an NH2 SPE cartridge and diluted to volume with water for analysis [M-25 in seed, 

meal; M-1 and M-25 in forage]. 

LC/MS/MS analyses were conducted using a C-18 column and a gradient mobile phase of water 

and ACN, each containing 0.05% formic acid [for pyroxasulfone and M-3 in seed, hay, and hulls; 

and M-1 in forage, seed, and hay] or a gradient mobile phase of water and methanol, each 

containing 0.05% formic acid [for pyroxasulfone and M-3 in forage, seed, hay, meal, and oil; and 

M-1 and M-25 in all commodities]. Residues were quantified using a calibration curve of 

external standards. The method did not include any information about converting residues of 

metabolites to parent equivalents.

The ion transitions used for quantitation of the KIH-485 analyte were the sum of 392 m/z →229 m/z and 392 m/z →179 m/z.

The ion transitions used for quantitation of the M-1 analyte were the sum of 309 m/z →259 m/z and 309 m/z →195 m/z..

The ion transitions used for quantitation of the M-3 analyte were the sum of 259 m/z →215 m/z and 259 m/z →165 m/z.

The ion transitions used for quantitation of the M-25 analyte were were the sum of 295 m/z →181 m/z and 295 m/z →163 m/z..

The LOQ for each analyte in each commodity was 0.005 ppm, except for M-1 in soybean seed 

and meal, for which the LOQ was found to be 0.01 ppm. The petitioner stated that due to the 

difficulties encountered in the determination of pyroxasulfone, M-1, M-3, and M-25, some of the 

analyses were conducted with solvent-based calibrants while others were based on calibrants 

prepared in control matrix final extract; the matrix-based calibrants were necessary when mass 

spectral ionization demonstrated significant matrix enhancement or matrix suppression of the 

signal.

The petitioner stated that matrix blanks (controls) were analyzed concurrently to evaluate 

potential analytical interferences; results for controls analyzed during method validation were not 

reported. However, in the soybean field trials, apparent residues of each analyte were below the 

LOQ in/on untreated samples, with the following exceptions: (1) apparent residues of M-1 were 

found in/on five samples of untreated soybean forage, at 0.007-0.027 ppm; (2) apparent residues 

of M-25 were found in/on one sample of untreated forage at 0.011 ppm and one sample of 

untreated soybean hay, at 0.017 ppm; and (3) apparent residues of pyroxasulfone were found 

in/on one sample of untreated soybean seed, at 0.020 ppm (residues in/on treated samples from 

this site were <0.005 ppm). The petitioner believes that the untreated hay sample bearing 

quantifiable residues of M-25 may have been switched with a treated sample at the same site, as 

one treated sample bore residues <0.005 ppm and the other bore residues very similar to those 

found in the untreated sample (0.018 ppm). No other discussion of apparent residues found in 

untreated samples was provided.

The method was validated in soybean forage, seed, hay, meal, hulls, and oil by fortification with 

each analyte at 0.005, 0.01, and 0.10 ppm for pyroxasulfone, M-1, and M-3 (0.01 and 0.10 ppm 

only for M-1 in seed and meal), and at 0.005 and 0.05 ppm for M-25; soybean forage was

additionally fortified with pyroxasulfone at 25 ppm, with M-1 at 0.50 ppm, and with M-25 at 

0.20 ppm. Average recoveries were within acceptable limits (70-120%) for all analytes in all 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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matrices with the following exceptions: M-3 in soybean oil at the 0.005-ppm fortification level 

(average recovery 65%); M-25 in soybean oil at the 0.005-ppm fortification level (average 

recovery 65%); and M-25 in soybean meal, hulls, and oil at the 0.05-ppm fortification level 

(average recoveries 62-67%). The RSDs were <20% at for all analytes in all matrices at all 

fortification levels. Recoveries from all matrices ranged 63-108% for pyroxasulfone (average of 

83%; one recovery <70%), 66-120% for M-1 (average of 94%; one recovery <70%), 63-116% 

for M-3 (average of 84%; four recoveries <70%), and 58-112% for M-25 (average of 81%; seven

recoveries <70%). 

The method was subjected to ILV using samples of soybean seed, forage, hay, hulls, meal, and

oil fortified with pyroxasulfone, M-1, M-3, and M-25 at 0.005 ppm and 0.05 ppm each. The 

average recoveries were within acceptable limits (70-120%) for all analytes in all matrices with 

the exception of M-1 in forage (both fortification levels; 66.7 and 69.0% average recovery), M-3 

in hay (lower fortification level; 68.0% average recovery), and pyroxasulfone, M-1, and M-25 in 

hulls (higher fortification level; 67.7-69.9% average recovery). The RSDs were <20% for all 

analytes in all matrices. For all instances where the mean recovery did not meet the desired, the 

petitioner concluded that the RSDs were sufficiently small to demonstrate good reproducibility.

The ILV laboratory reported that one set of pyroxasulfone, M-1 and M-3 samples (total of 12 

samples) required approximately four days to complete, including LC/MS/MS instrument time 

for quantitation, and required three full analyst’s days for extraction and preparation for analysis. 

The laboratory recommended that a warning be issued as part of each method that it is not known 

if the partitions will lead to emulsions, and that for all commodities, the method include the 

addition of saturated NaCl solution at the step where the aqueous phase is basified with 0.5 M 

NaHCO3. The registrant has submitted MRID 48430001 which contains the recommendation of 

the ILV laboratory pertaining to a warning regarding emulsions forming. 

Adequate radiovalidation data for this method were submitted using a sample of soybean hay 

from soybean plants treated postemergence with pyrazole-label [14C]pyroxasulfone (from a 

soybean metabolism study which does not appear to have been submitted to EPA). The sample 

bore quantifiable residues of metabolites M-1, M-3, and M-25 but no quantifiable residues of 

pyroxasulfone. The data indicated that the method adequately recovered incurred residues of 

M-1, M-3, and M-25 from soybean hay; no quantifiable residues of pyroxasulfone were found in 

the sample when analyzed using the residue method.

Adequate concurrent method recovery data for pyroxasulfone, M-1, M-3, and M-25 in soybean 

forage, hay, seed, meal, hulls, and refined oil were submitted with the crop field trial and 

processing study submitted with this petition; samples were fortified at 0.01 and 0.10 ppm for 

pyroxasulfone, M-1, and M-3 in each matrix, and at 0.005 and 0.05 ppm for M-25 in each matrix 

(M-25 was additionally validated at 0.5 ppm in soybean hay). For all analytes, average 

concurrent recoveries were generally between 70% and 120%. Average recoveries <70% were 

observed from M-25 in soybean hay and meal at the 0.05-ppm fortification level (67% each) and 

in soybean oil at both fortification levels (62% and 65%). In addition, soybean seed from the 

processing study fortified with M-25 at 0.05 ppm yielded a recovery of 64%, soybean hull 

fortified with M-25 at 0.005 and 0.5 ppm yielded recoveries of 36% and 59%, respectively, and 

soybean oil fortified with M-1 at 0.10 ppm yielded a recovery of 69%.
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Data collection method: An LC/MS/MS method similar to the enforcement methods was used 

for the determination of residues of pyroxasulfone and its metabolites M-1, M-3, and M-25 in 

wheat commodities in the wheat field trial studies and in the field pea and wheat commodities in 

the field rotational crop studies submitted with this petition. The method, ATM-0031, is entitled: 

Determination of KIH-485 and the metabolites M-1, M-3 and M-25 in or on plant material by 

LC MS/MS. The method includes instructions for the analysis of samples of grain, straw, and 

forage.

Briefly, water is added to the sample, and the mixture is sonicated and then shaken. ACN is 

added, to bring the ACN:water ratio to 3:1, and the mixture is sonicated and shaken. The extract 

is filtered prior to being partitioned with n-hexane. The n-hexane phase is discarded, and an 

aliquot of the ACN/water phase is analyzed for pyroxasulfone, M-1 and M-3 by LC/MS/MS. For 

the determination of the M-25 analyte, an aliquot of the ACN/water layer is reduced to dryness

and reconstituted in water for LC/MS/MS analysis. Residue levels are quantitated using a 

calibration curve of matrix-matched standard solutions containing pyroxasulfone, M-1, M-3 and 

M-25. A single ion transition is monitored for each analyte. The method includes molecular 

weight conversion factors to allow conversion of metabolite residues to parent equivalents, but 

does not specify that metabolite results be reported in parent equivalents.

The LOQ, expressed as analyte equivalents, is 0.01 ppm for each analyte in all crop matrices. 

Apparent residues in the control samples tested were ≤30% of the LOQ.

The method was validated in cereal forage, grain, and straw; the petitioner did not identify the 

crop used for method validation studies. Samples were fortified with each analyte at the LOQ 

and 10xLOQ. Average recoveries were within acceptable limits (70-120%) and RSDs were 

<20% at both the 0.01- and 0.1-ppm fortification levels for pyroxasulfone and the M-1, M-3 and 

M-25 metabolites. Recoveries from all three matrices ranged 73-112% for pyroxasulfone 

(average of 91%), 70-109% for M-1 (average of 92%), 76-110% for M-3 (average of 91%), and 

70-104% for M-25 (average of 85%). 

Adequate concurrent method recovery data for pyroxasulfone, M-1, M-3, and M-25 in wheat 

forage, grain, and straw were submitted with the crop field trial studies submitted with this 

petition; samples were fortified with each analyte at 0.01 and 0.10 ppm. For all analytes, average 

concurrent recoveries were between 70% and 120%. 

Conclusions. The submitted residue analytical method data are adequate to satisfy data 

requirements. The methods are adequate to determine pyroxasulfone residues of concern in corn, 

soybean, and wheat commodities. For the corn and soybean commodity methods to be 

considered adequate for enforcement purposes, the methods were required to be modified to 

include the recommendations of the independent laboratory and to include instructions for 

reporting metabolite residues in parent equivalents. Finally, the methods were required to be 

amended to include instructions for the analysis of wheat commodities. The petioner submitted 

these data which were acceptable (T. Morton, D389651, 5/25/11). 

HED consulted Charles Stafford (personal communication via email July 20, 2010) who stated 

the crop enforcement method would not need to be forwarded to ACB for validation.
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Livestock commodities

Monograph for Pyroxasulfone, Section B.5.2.2 (MRIDs 47701659, 47701660, 47701663, 47701664)

Data collection methods: An LC/MS/MS method was used for the determination of residues of 

pyroxasulfone and its metabolites M-1 and M-3 in cattle commodities in the cattle feeding study 

submitted with this petition. In addition, the petitioner submitted an LC/MS/MS method for the 

determination of residues of pyroxasulfone, M-1, and M-3 in poultry eggs. 

Cattle commodities: The method for cattle commodities is entitled: KIH-485, M-3 and M-l 

Analytical Methods as Described in “Magnitude of KIH-485 Residues in Bovine Tissues and 

Milk from a 28-Day Feeding Study.” The method includes individual instructions for the 

extraction and analysis of samples of milk, muscle, liver, kidney, and fat.

For determination of pyroxasulfone and M-3, samples of milk, cream, and skim milk are 

extracted twice with ACN:water (3:1, v:v), and the combined extracts are partitioned with 

hexane, with the hexane phase discarded. The aqueous ACN extracts are diluted to volume with 

ACN:water (3:1, v:v), and an aliquot is concentrated, basified (using 0.5 M NaHCO3), mixed 

with saturated NaCl solution, and partitioned with hexane to extract pyroxasulfone. The hexane 

phase is concentrated to dryness and reconstituted in ACN for further Envi-Carb SPE cleanup 

and subsequent LC/MS/MS analysis for pyroxasulfone. The aqueous portion is acidified (to ~pH 

4 using 0.5 M citric acid) then partitioned with hexane:EtOAc (3:7, v:v) to extract M-3. The 

organic phase is cleaned up on an Envi-Carb SPE cartridge for LC/MS/MS analysis. 

Milk samples are analyzed separately for residues of M-1. The proteins are precipitated with 

acetone and the supernatant is concentrated to remove the acetone. The aqueous extract is 

partitioned twice with hexane and the aqueous phase is mixed with saturated NaCl solution and 

partitioned with ACN. The ACN phase is concentrated to dryness and redissolved in ACN:water 

(1:9, v:v) for LC/MS/MS analysis.

Samples of tissues are homogenized with water and extracted twice with ACN. The combined 

extracts are partitioned with hexane, and the hexane phase is back partitioned with ACN, after 

which the hexane phase is discarded. The ACN:water extracts are combined, brought to volume 

(using an unspecified solvent), and divided into two aliquots, one for determination of 

pyroxasulfone and M-3, and the other for determination of M-1. The pyroxasulfone and M-3 

aliquot is basified (using 0.5 M NaHCO3), mixed with saturated NaCl solution, and partitioned 

with hexane to extract pyroxasulfone. The hexane phase is concentrated to dryness and 

reconstituted in ACN for further Envi-Carb SPE cleanup; the extract is evaporated to dryness and 

reconstituted in ACN:water (2:8, v:v, containing 0.5% acetic acid) for LC/MS/MS analysis for 

pyroxasulfone. The aqueous portion is acidified (using 0.5 M citric acid) then partitioned with 

hexane:EtOAc (3:7, v:v) to extract M-3. The extract is evaporated to dryness and reconstituted 

in ACN:water (2:8, v:v, containing 0.5% acetic acid) for LC/MS/MS analysis for M-3. The 

aliquot for M-l determination was concentrated, diluted to volume with water (muscle, kidney, 

liver) or acidified to pH 5 (using 0.2 M acetic buffer; fat), and partitioned twice with EtOAc.

The aqueous phase is mixed with NaCl, and residues of M-l are partitioned into ACN. The ACN 

extract is evaporated to dryness and reconstituted in ACN:water (2:8, v:v, containing 0.5% acetic 

acid) for analysis by LC/MS/MS.
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LC/MS/MS analyses were conducted using a C-18 column with a gradient mobile phase of ACN 

and water, each containing 0.05% formic acid (for determination of pyroxasulfone and M-3), or 

water and methanol, each containing 0.05% formic acid (for determination of M-1). Residues 

were quantified using a calibration curve of external standards. The method did not include any 

information about converting residues of metabolites to parent equivalents.

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

petitioner stated that matrix blanks (controls) were analyzed concurrently to evaluate potential 

analytical interferences, and in all cases where there was enhanced residue recovery (>120%), 

there were no residues detected for pyroxasulfone, M-1 or M-3. Results for controls analyzed 

during method validation were not reported. In the cattle feeding study, apparent residues of 

each analyte were below the LOQ in/on all samples of milk, skim milk, cream, muscle, fat, liver, 

and kidney from the undosed cattle.

The method was validated in milk by fortification with pyroxasulfone, M-1, and M-3 at 0.001 

and 0.010 ppm each and was validated in muscle, liver, kidney and fat by fortification with each 

analyte at 0.01 and 0.10 ppm each. Average recoveries were within acceptable limits (70-120%) 

for all analytes in all matrices. The RSDs were <20% for all analytes in all matrices at all 

fortification levels, with the following exceptions: pyroxasulfone in muscle at the 0.01-ppm 

fortification level (23%) and M-1 in liver at the 0.10-ppm fortification level (21%). Recoveries 

from all matrices ranged 83-130% for pyroxasulfone (average of 94%; one recovery >120%), 66-

136% for M-1 (average of 95%; one recovery <70% and two recoveries >120%); and 86-118% 

for M-3 (average of 102%). 

The method was subjected to ILV using samples of cattle milk, muscle, liver, kidney, and fat

fortified with pyroxasulfone, M-1, and M-3, at 0.001 ppm and 0.01 ppm each for milk and 0.01 

and 0.10 ppm each for tissues. The average recoveries were within acceptable limits (70-120%) 

for all analytes in all matrices with the exception of M-1 in liver (0.10-ppm fortification level; 

122% average recovery), M-3 in liver (0.01-ppm fortification level; 68.1% average recovery),

and M-3 in kidney (0.01-ppm fortification level; 121% average recovery). The RSDs were <20% 

for all analytes in all matrices. The average recoveries outside the 70-120% range were accepted 

by the petitioner as adequate validation based on the high precision of the replicate analyses

(≤4.7% RSD). The ILV laboratory stated that one set of samples (total of 12 samples) required 

approximately four days for completion, including LC/MS/MS instrument time for quantitation, 

and required three full analyst’s days for extraction and preparation for analysis. 

No radiovalidation data were submitted for the method. 

Poultry eggs: An LC/MS/MS method was submitted for the determination of residues of 

pyroxasulfone and its metabolites M-1 and M-3 in poultry eggs. 

Samples of egg are homogenized with water and extracted twice with ACN. The combined 

extracts are partitioned with hexane, and the hexane phase is back partitioned with ACN, after 

which the hexane phase is discarded. The ACN/water extracts are combined, brought to volume 

using ACN:water (9:1, v:v), and divided into two aliquots, one for the determination of 

pyroxasulfone and M-3 and the other for the determination of M-1. The pyroxasulfone and M-3 

aliquot is concentrated, basified (using 0.5 M NaHCO3), mixed with saturated NaCl solution, and 
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partitioned three times with hexane. The combined hexane extract is concentrated to dryness and 

reconstituted in ACN for further purification by Envi-Carb SPE; the extract is evaporated to 

dryness and reconstituted in ACN:water (2:8, v:v, containing 0.5% acetic acid) for LC/MS/MS 

analysis for pyroxasulfone. The aqueous portion remaining after the hexane partition is acidified 

(using 0.5 M citric acid), and M-3 is partitioned into hexane:EtOAc (3:7, v:v). The organic 

phase is evaporated to dryness and reconstituted in ACN:water (2:8, v:v, containing 0.5% acetic 

acid) for analysis by LC/MS/MS. The M-1 aliquot of the original extract is concentrated, 

acidified to pH 5 (using 0.2 M acetate buffer), and partitioned with EtOAc. The remaining 

aqueous phase is purified by NH2 SPE for LC/MS/MS analysis. 

LC/MS/MS analyses were conducted using a C-18 column with a gradient mobile phase of ACN 

and water, each containing 0.05% formic acid (for determination of pyroxasulfone and M-3), or 

water and methanol, each containing 0.05% formic acid (for determination of M-1). Residues 

were quantified using a calibration curve of external standards. The method did not include any 

information about converting residues of metabolites to parent equivalents. 

The LOQ was 0.01 ppm for each analyte in poultry egg. The petitioner stated that matrix blanks 

(controls) were analyzed concurrently to evaluate potential analytical interferences; no analytical 

interferences were detected in matrix blanks (the limit of detection was 0.0005 ppm for 

pyroxasulfone and M-3 and 0.0025 ppm for M-1). 

The method was validated in poultry egg by fortification with pyroxasulfone, M-1, and M-3 at 

0.01 and 0.10 ppm each. Average recoveries were within acceptable limits (70-120%) and the 

RSDs were <20% for all analytes. Recoveries ranged 81-124% for pyroxasulfone (average of 

100%; one recovery >120%), 65-95% for M-1 (average of 83%; one recovery <70%); and 91-

111% for M-3 (average of 102%). 

The method was subjected to ILV using samples of poultry egg fortified with pyroxasulfone, 

M-1, and M-3 at 0.01 and 0.10 ppm each. The average recoveries were within acceptable limits 

(70-120%) for all analytes with the exception of M-3 at the 0.01-ppm fortification level (131% 

average recovery). The RSDs were <20% for all analytes at both fortification levels. The high 

average recovery for M-3 at the LOQ was accepted by the petitioner as adequate validation based 

on the high precision of the replicate analyses (3.1% RSD) and the absence of any integrated 

response for M-3 matrix blanks. The ILV laboratory stated that one set of samples (total of 12 

samples) required approximately four days to complete, including LC/MS/MS instrument time 

for quantitation, and required three full analyst’s days for extraction and preparation for analysis. 

No radiovalidation data were submitted for the method.

Conclusions. The submitted residue analytical methods data are partially adequate to satisfy data 

requirements. Radiovalidation data must be submitted for the method for cattle commodities. 

HED notes that for the method for poultry egg to be considered adequate for data collection 

purposes, radiovalidation data would be required. However, these data are not required at this 

time because no poultry feeding study data are required to support this petition.
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The petitioner is not proposing tolerances for livestock commodities in the U.S. HED notes that 

for the above method(s) to be considered adequate for enforcement purposes, the method(s) 

would need to be modified to include the recommendations of the independent laboratory and to 

include instructions for reporting metabolite residues in parent equivalents. In addition, radiovalidation data are required. 

860.1360 Multiresidue Methods

Monograph for Pyroxasulfone, Section B.5.2.4 (MRID 47701673)

K-I Chemical submitted data on the testing of pyroxasulfone, and its three principle metabolites, 

M-1, M-3, and M-25, through a select portion of the FDA PAM multiresidue methods. 

None of the test substances are N-methyl carbamates and none were found to be naturally 

fluorescent; therefore, the compounds were not further tested under Protocol A. 

Supplementary testing through the FDA-Pesticide Analytical Methods Multi-Residue testing 

program (Chapters 3 and 4) in accordance with OPPTS test guideline 860.1360 was conducted in 

response to the U.S. EPA review of the above study (MRID 47701673). The new study presents 

data concerning Protocol B testing of metabolites M-1, M-3, and M-25 via methyl derivatives 

and the recovery of KIH-485 from a high moisture matrix, sweet corn kernel + cob with husks 

removed (K+CWHR) through Protocol D testing. None of the three acidic metabolite 

compounds, M-1, M-3, or M-25, was successfully recovered through Protocol B.

KIH-485 was partially to completely recovered from sweet corn K+CWHR using Protocol D, 

extraction method E-2, and cleanup method C5 with average recoveries of 71.68% and 92.39% at

fortification levels of 0.026 and 0.208 ppm. A slight analytical interference was observed.

With the submission of these supplementary data, the requirements for multiresidue methods 

testing of pyroxasulfone and its metabolites have been satisfied (T. Morton D396692, 12/8/11). 

The data indicate that the PAM Vol. I multiresidue methods, including Protocol D (report IIA 

4.3/14) and Protocols E and F (report IIA 4.3/11) may be applicable for determination of 

pyroxasulfone per se; however, the FDA multiresidue methods are not suitable for determination 

of the metabolites M-1, M-3, and M-25.

None of the metabolite compounds could be successfully chromatographed under Protocol C; 

pyroxasulfone chromatographed by GLC/ECD with adequate selectivity, sensitivity, and 

linearity. 

Pyroxasulfone was found to be fully recovered from soybean hay through PAM Section 303 

(Protocol E) with extraction procedure E4 and cleanup method C1; average recovery was 91.85%

in samples fortified at 0.545 and 0.0545 ppm. In addition, pyroxasulfone was recovered from 

soybean seed and oil through PAM Section 304 (Protocol F) with extraction procedure E5 and 

either cleanup method C1 or C2; average recovery was 90.05% for seed fortified at 0.218 and 

0.0218 ppm and 67.1% for oil fortified at 0.363 and 0.0363 ppm. The petitioner did not test 

Protocol D (PAM Section 302) because the sample matrix used for testing (soybean hay) did not 

have a high moisture content. 
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Because pyroxasulfone and its metabolites are not substituted ureas, no testing under Protocol G 

is required.

Conclusions. The submitted studies are adequate to satisfy data requirements. In addition, if 

metabolite M-28 is determined to be a residue of concern in soybeans, it will need to be tested

also. 

The data have been sent to FDA for evaluation. 

860.1380 Storage Stability

Crop commodities

Monograph for Pyroxasulfone, Section B.7.6.2 (MRIDs 47701656, 47701657, 48430011)

K-I Chemical submitted interim reports for two ongoing storage stability studies: one study with 

corn commodities and one study with soybean commodities. 

In the corn study, samples of corn forage, grain, stover, starch, flour, meal, and oil were fortified 

with pyroxasulfone, M-1, M-3, and M-25 at 0.10 or 0.05 ppm each. The fortified samples were 

stored in glass jars at <0 °C for periods including 3-4 months, 6-7 months, and the longest period 

necessary to encompass total storage time of field samples. The study was conducted 

concurrently with the corn field trial study.

At each storage interval, residues of pyroxasulfone and its metabolites were determined using the 

proposed LC/MS/MS enforcement method for corn commodities. The mean of the concurrent 

recoveries for all matrices at all tested intervals was within the acceptable range of 70-120%, 

with the exception of M-1 in oil at the 4-month interval (average of 65%) and M-3 in starch at 

the 4-month interval (average of 69%) and M-25 in oil (4-, 6-, 13-, and 17-month intervals; 

average of 50%, 69%, 69% and 68%, respectively) and starch (7-month interval; average of 

64%). 

Pyroxasulfone (KIH-485) and metabolites M-1 and M-3 were found to be stable in corn stover 

through 12 months of frozen storage and in corn grain and forage through 13 months of frozen 

storage. Pyroxasulfone, M-1, and M-3 were found to be stable in corn processed commodities 

during 6 months (oil) or 7 months (starch, flour, and meal) of frozen storage. M-25 residues were 

stable in forage for 24 months, grain for 26 months, stover for 25 months, starch for 16 months, flour 

for 23 months, and meal for 18 months. M-25 residues in com oil were moderately stabile at 67% 

remaining after 17 months of frozen storage. 

 

The aged recovery samples showed excess recovery of M-1 (i.e., >100%) in each RAC matrix at 

some storage intervals. The petitioner stated that this may be due to LC/MS/MS enhancement 

from aged matrix. When corrected for fresh fortification recovery, M-1 recovery in stover at the 

12-month storage interval was low (62%); the uncorrected recovery was adequate. 

In the soybean study, samples of soybean forage, seed, hay, meal, hulls, and refined oil were 

fortified with pyroxasulfone, M-1, M-3, and M-25 at 0.05, 0.10, or 0.20 ppm each. The fortified 

samples were stored in glass jars at <0 °C for periods including 3-6 months, 6-7 months, and the 
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longest period necessary to encompass total storage time of field samples. The study was 

conducted concurrently with the soybean field trial study.

At each storage interval, residues of pyroxasulfone and its metabolites were determined using the 

proposed LC/MS/MS enforcement method for soybean commodities. The mean of the 

concurrent recoveries for all matrices at all tested intervals was within the acceptable range of 

70-120%, with the exception of M-3 in hay at the 4- and 6-month intervals (average of 161% and 

65%, respectively) and M-25 in hay, meal, and hulls at the 5/6-month storage interval (average of 

59-63%). 

Pyroxasulfone was found to be stable in soybean forage and hay through as much as 17 months 

of storage, where no significant degradation of the residue was observed. Pyroxasulfone was 

found to be stable during up to 19 months frozen storage in seed, up to 7 months in refined oil, 

and up to 10 months storage in meal and hulls. M-1 was found to be stable in forage and hay for 

up to 17 months, up to 6 months in seed, up to 7 months in oil, and up to 10 months in meal and 

hulls. M-1 declined by approximately 40% in soybean seed at 19 months of frozen storage. M-3 

was found to be stable in forage and hay up to a 17-month period of storage up to a 19-month 

storage interval in seed, and up to 10 months in oil, meal, and hulls. Some decline in M-1 and 

M-3 was detected within 7 months and 10 of frozen storage, respectively, in refined oil, while 

both analytes were found to be stable in meal and hulls for up to 10 months of frozen storage. 

M-25 was found to be stable in forage hay, and seed after 12 months of frozen storage, in oil 

after 13 months of frozen storage, and in hulls and meal after 14 months of frozen storage.

The petitioner stated that the remaining time points for M-25 necessary to bracket sample storage 

prior to extraction will be added to the report by report amendment.

The storage durations and conditions of samples from the crop field trial, processing studies, and 

field rotational crop studies submitted to support this petition are presented in Table 5.

Table 5. Summary of Storage Conditions and Durations of Samples from Crop Field Trial, 

Processing, and Field Rotational Crop 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
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Table 5. Summary of Storage Conditions and Durations of Samples from Crop Field Trial, 

Processing, and Field Rotational Crop Studies. 

Matrix Storage 

Temperature

(°C)

Maximum Storage 

Duration

Interval of Demonstrated Storage

Stability

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)

Rotated field pea forage Frozen 34 weeks (7.8 months) 17 months (soybean forage)

Rotated field pea seed and 

straw

Frozen 14 weeks (3.2 months) 17 months (soybean hay)

19 months (soybean seed)

Rotated wheat forage Frozen 34 weeks (7.8 months) 13 months (corn forage)

Rotated wheat grain and 

straw

Frozen 14 weeks (3.2 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)

Rotated field pea forage Frozen 34 weeks (7.8 months) 12 months (soybean forage)

Rotated field pea seed and 

straw

Frozen 14 weeks (3.2 months) 12 months (soybean hay)

12 months (soybean seed)

Rotated wheat forage Frozen 34 weeks (7.8 months) 12 months (corn forage)

Rotated wheat grain and 

straw

Frozen 14 weeks (3.2 months) 12 months (corn grain and stover)

Conclusions. The submitted data are not adequate to completely satisfy data requirements 

because the available data represent storage intervals shorter than those of samples from the 

residue trials. The final reports of the ongoing storage stability studies must be submitted. The 

final reports should include data for M-25 in soybean raw agricultural commodities and soybean

processed commodities. 

With submission of the final reports, the petitioner should include additional information/data 

pertaining to the procedures used for the storage stability studies, including identification of the 
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fortification levels for each analyte in each matrix, a correct listing of the fortification dates (and 

storage intervals) for each of the spiked samples, and a discussion of any problems encountered 

during completion of the studies. An explanation should be provided for not using the data from 

the 3-month storage interval for M-1 in soybean forage. All residue data spreadsheets for storage 

stability analyses should be provided.

HED notes that no zero-day data were provided with the study. The petitioner should note for 

future submissions that storage stability studies should always include a zero-day sampling 

interval to establish the residue levels present at the time samples are placed into storage [see 

OPPTS 860.1380(d)(6)(i)]. 

Livestock commodities

Monograph for Pyroxasulfone, Section B.7.8.3 (MRID 47701659)

K-I Chemical submitted a storage stability study with cattle matrices in conjunction with the 

cattle feeding study. 

Samples of cattle milk, muscle, liver, kidney, and fat were fortified with pyroxasulfone, M-1, and 

M-3 at 0.01 ppm each for milk and 0.10 ppm each for tissues. The fortified samples were stored 

frozen (temperature unspecified) for periods of 189 days for milk, 112 days for muscle, up to 120 

days for liver, 113 days for kidney, and 91 days for fat. The study was conducted concurrently 

with the cattle feeding study.

At each storage interval, residues of pyroxasulfone and its metabolites were determined using the 

LC/MS/MS data collection method for cattle commodities. The mean of the concurrent 

recoveries for all matrices at the tested intervals was within the acceptable range of 70-120%. 

The data indicate that residues of pyroxasulfone, M-l, and M-3 are stable through 6 months of 

frozen storage in milk, 3 months of frozen storage in fat, and 3.7 months of frozen storage in 

muscle and kidney. Residues of M-1 and M-3 were stable in liver during up to 4 months of 

frozen storage. Pyroxasulfone was found to degrade in liver, yielding 40% recovery after 120 

days of frozen storage. Short-term storage stability was adequate for pyroxasulfone in liver, 

where 94% was recovered after 15 days of frozen storage.

In the cattle feeding study, the maximum frozen storage intervals were 154 days for milk 

samples, 186 days for cream samples, and 87 days for muscle, liver, kidney and fat samples. 

Conclusions. The submitted data are adequate to satisfy data requirements. The data indicate 

that pyroxasulfone residues in liver may need to be adjusted to account for potential decline 

during storage.

HED notes that as for the crop commodity storage stability studies, no zero-day data were 

provided with the study. 

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

Monograph for Pyroxasulfone, Sections B.7.8.1 and B.7.8.2 (MRID 47701659)

There are several livestock feedstuffs associated with the proposed uses of pyroxasulfone: 

aspirated grain fractions; field and sweet corn forage, silage, and stover; field corn grain and 

milled byproducts; sweet corn cannery waste. The dietary burdens of pyroxasulfone to livestock 

were calculated using the procedures of the most recent guidance developed by HED (June 

2008); see Table 6. The estimated dietary burdens are 0.048 ppm for beef cattle, 0.074 ppm for 

dairy cattle, 0.019 ppm for poultry, and 0.021 ppm for swine. K-I Chemical submitted a feeding 

study with cattle, which is summarized below, and requested a waiver of the requirement for a 

poultry feeding study.

Table 6. Calculation of Dietary Burdens of Pyroxasulfone Residues to Livestock.

Feedstuff Type1 % Dry 

Matter2 % Diet2 Highest Residue(ppm)

Dietary Contribution 

(ppm)3

Beef Cattle

Corn, field, stover R 83 15 0.139 0.025

Corn, field, grain CC 88 80 0.025 0.023

Untreated Protein Concentrate PC NA 5 0 0

TOTAL BURDEN -- -- 100 -- 0.048

Dairy Cattle

Corn, field, forage/silage R 40 45 0.054 0.061

Corn, field, grain CC 88 45 0.025 0.013

Untreated Protein Concentrate PC NA 10 0 0

TOTAL BURDEN -- -- 100 -- 0.074

Poultry

Corn, field, grain CC 88 75 0.025 0.019

Untreated Protein Concentrate PC NA 25 0 0

TOTAL BURDEN -- -- 100 -- 0.019

Swine

Corn, field, grain CC 88 85 0.025 0.021

Untreated Protein Concentrate PC NA 15 0 0

TOTAL BURDEN -- -- 100 -- 0.021

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.

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 
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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 ~38x, 110x, and 370x, respectively, the maximum 

estimated dietary burden to beef cattle and 24x, 73, and 240x, 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, 

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 
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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 7 below. 

Table 7. Maximum Residues in Samples from Cows Dosed at 18 ppm.

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. HED

note that radiovalidation data for the analytical method have not yet been submitted (refer to 

860.1340) and that the results of the goat metabolism study indicated that radioactivity was not 

readily extractable from milk and tissues using organic solvents.

The submitted data indicate that tolerances are not needed for cattle tissues and milk at this time 

for the corn use. Residues of each analyte were <0.01 ppm at a dosing level corresponding to 

240x the estimated dietary burden to dairy cattle. Pending submission of radiovalidation data for 

the analytical method, HED concludes that the proposed uses of pyroxasulfone fall under 

category 3 of 40 CFR 180.6(a) for ruminant tissues; there is no reasonable expectation of finite 

residues in cattle, goat, hog, horse, and sheep tissue commodities.

Typically, for a conclusion to be made that no tolerances are needed for livestock commodities, 

the feeding study data need to indicate that residues are below the LOQ at a 10x dosing level. 
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For this study, quantifiable residues of parent were found in milk, at up to 0.004 ppm, at a 240x 

dosing level. If these residues are adjusted to a 10x dosing level (~0.00017 ppm), they are below

the LOQ 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 ~780x (based on the 

14.8-ppm dosing level and a dietary burden of 0.019 ppm), expected residues of M-1 at a 10x 

feeding level would be <0.0001 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. In addition, tolerances on livestock commodities may 

be needed in the future, if use on additional feed stuffs are requested.

860.1500 Crop Field Trials

Monograph for Pyroxasulfone, Section B.7.6.1.1 (MRID 47701656; field and sweet corn)

Monograph for Pyroxasulfone, Section B.7.6.1.2 (MRID 47701657; soybean)

Monograph for Pyroxasulfone, Section B.7.6.1.3 (MRIDs 47701669, and 47701670; wheat)

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

and wheat field trials conducted in Australia. The results from these field trials are discussed 

below and summarized in Table 8. The LOQ for corn grain residues of concern (pyroxasulfone 

and M-3) is 0.013 ppm.

For all three studies, 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, and 1.321 

for M-25 were used. The full LOQ value was used for residues <LOQ for calculating total 

residues. 

HED notes that K-I Chemical also submitted field trial data for barley and triticale to support use 

of pyroxasulfone on these crops on Australia. Because pyroxasulfone is not proposed for use on 

barley or triticale in the U.S., these data will not be discussed herein.
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Table 8. Summary of Residue Data from Crop Field Trials with Pyroxasulfone.

Crop matrix Target Applic. 

Rate

(lb ai/A)

[g ai/ha]

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 (proposed use = 0.267 lb ai/A total application rate, 37-day PHI for sweet corn K+CWHR, 7-day 

PGI for corn forage)

Field corn forage 0.148-0.268

[166-300]4

37-95 44 <0.025 <0.054 0.053 0.025 0.028 0.007

Field corn grain 69-146 43 <0.025 <0.025 0.025 0.025 0.025 NA

Field corn stover 85-146 44 <0.025 <0.139 0.131 0.025 0.031 0.022

Sweet corn forage 0.148-0.268

[166-300]4

43-97 24 <0.025 <0.063 0.063 0.032 0.035 0.011

Sweet corn 

K+CWHR

43-132 24 <0.025 <0.028 0.028 0.025 0.026 0.001

Sweet corn stover 70-132 24 <0.025 0.115 0.112 0.025 0.0.41 0.028

SOYBEAN (proposed use = 0.267 lb ai/A total application rate, 15-day PHI for seed, 7-day PGI for forage, 

hay, or straw)

Soybean forage 0.112-0.186

[125-209]5

15-44 44 <0.025 0.781 0.723 0.114 0.207 0.212

Soybean hay 21-63 44 <0.030 1.901 1.849 0.119 0.283 0.424

Soybean seed 88-137 44 <0.03 <0.050 0.049 0.032 0.033 0.004

WHEAT (proposed use = 0.267 lb ai/A total application rate, 42-day PGI)

Wheat forage 0.112

[125]6

40-98 36 <0.05 <0.21 0.21 0.08 0.08 0.04

Wheat grain 153-183 20 <0.05 <0.05 0.05 0.05 0.05 NA

Wheat straw 153-183 20 <0.06 <0.18 0.18 0.09 0.10 0.04

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.

3

 NA = Not applicable.

4

 Applications were made at early postemergence of the crop (~V4 growth stage). Actual application rates ranged 

97.6-102.9% of the target rate.

5

 Applications were made at early postemergence of the crop (third trifoliate leaf stage). Actual application rates 

ranged 96.4-103.9% of the target rate.

6

 Actual application rates were within 1.6% of target rate.

Field and sweet corn

Pyroxasulfone was applied to field corn and sweet corn as an 85% WG formulation at a total of 

37 sites in the U.S. representing regions 1, 2, 3, 5, 6, 10, 11 and 12. The application rate was 

related to soil type: 0.148 lb ai/A (166 g ai/ha) for coarse-textured soil and 0.268 lb ai/A (300 g 

ai/ha) for medium- and fine-textured soil. The proposed labels specify single application rates up 

to 0.11 lb ai/A (120 g ai/ha) for coarse-textured soil, up to 0.15 lb ai/A (160 g ai/ha) for 

medium-textured soil, and up to 0.21 lb ai/A (240 g ai/ha) for fine-textured soil for preplant, 

preemergence applications, and early postemergence application; a maximum seasonal rate of 

0.267 lb ai/A (300 g ai/ha) is proposed (independent of soil type). Therefore, the field trials 
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conducted at 0.148 lb ai/A represent ~1.3x the proposed maximum single application rate for that 

soil type and ~0.6x the maximum proposed seasonal rate, and the field trials conducted at 0.268 

lb ai/A represent ~1.3x the proposed maximum single application rate for that soil type and ~1x 

the maximum proposed seasonal rate.

At twenty field corn trials and eleven sweet corn trials, a single postemergence application was 

made at the rates indicated above at approximately the V4 growth stage of the plant. The field 

corn trials were conducted in Zones 1 (2 trials), 2 (1 trial), 5 (16 trials), and 6 (1 trial); and the 

sweet corn trials were conducted in Zones 1 (2 trials), 2 (1 trial), 3 (1 trial), 5 (4 trials), 10 (1 

trial), 11 (1 trial), and 12 (1 trial). One field corn trial included an additional plot treated at an 

exaggerated rate to generate samples for processing; refer to 860.1520 for a discussion of these 

data. In addition, there were three trials (two field corn and one sweet corn) conducted in Zone 5 

that measured residue decline in RAC matrices; applications were made postemergence at ~0.268 

lb ai/A at these trials (conducted at sites with fine-textured soils). 

At three additional trials with three different soil types (fine, medium, and coarse), five different 

application types were compared: (1) preplant surface application; (2) preplant incorporated 

application; (3) post-planting preemergence application; (4) early postemergence application; and 

(5) split preemergence and postemergence applications. The application rates for types (1), (2), 

(3), and (4) were 0.268, 0.186, and 0.148 lb ai/A (300, 209, and 166 g ai/ha) for fine, medium, 

and coarse soils, respectively. The split application was made at 0.178 + 0.089, 0.125 + 0.062, 

and 0.093 + 0.050 lb ai/A (200 + 100, 140 + 69, and 110 + 56 g ai/ha) for fine, medium, and 

coarse soils, respectively. For the split application trials, the retreatment interval was 14 to 23 

days. 

Applications were made in 13-25 gal/A spray volumes using ground equipment; no adjuvant was 

used. 

Duplicate samples of field corn forage were harvested at the late dough/early dent stage, 37-95 

days following application. Duplicate samples of sweet corn forage and K+CWHR were 

collected at normal harvest, 43-132 days following application; sweet corn stover samples were 

collected 70-132 days following application. Duplicate samples of field corn grain and stover 

were collected at normal harvest, 85-146 days after application. In the residue decline trials, 

duplicate forage samples were collected 0, 3, 7, 15-16, 21, 29-30, 40, and 60 days following 

application; duplicate samples of field corn grain and stover were collected at normal harvest and 

15 and 30 days after normal harvest, and duplicate samples of sweet corn K+CWHR and stover 

were collected at normal harvest and 7 and 14 days following normal harvest.

Samples were analyzed for residues of pyroxasulfone and its metabolites M-1, M-3, and M-25 

using the proposed LC/MS/MS enforcement method for corn commodities. The LOQ was 0.005

ppm for each analyte in each commodity. The LOQ for combined residues in parent equivalents 

was 0.025 ppm for each commodity.

Sample storage conditions and durations are reported in Table 5. The available storage stability 

data support the field corn field trial study. 
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The results of the field trials reflecting postemergence application are summarized in Table 8. 

Residues of pyroxasulfone and its metabolites M-1, M-3, and M-25 were below the LOQ in/on 

all samples of field corn grain; combined residues in parent equivalents were <0.025 ppm

(<0.013 ppm for pyroxasulfone and M-3). In sweet corn K+CWHR samples, residues of 

pyroxasulfone and its metabolites were below the LOQ in/on all but two samples, from one trial, 

which had quantifiable residues of M-3 at 0.006 and 0.007 ppm; combined residues were <0.014-

0.016 ppm (pyroxasulfone and M-3). Residues of pyroxasulfone were below the LOQ in/on all 

samples of corn forage, with the exception of two field corn forage samples (residues of 0.010 

and 0.012 ppm) and two sweet corn forage samples (residues of 0.006 and 0.007 ppm). 

Quantifiable residues of M-1 were observed in forage from five of the twenty field corn sites and 

eight of eleven sweet corn field sites; maximum residues of M-1 were 0.014 ppm in field corn 

forage and 0.018 ppm in sweet corn forage. Residues of M-3 were below the LOQ in all forage 

samples, except two samples of sweet corn forage (0.006 ppm in both samples). Quantifiable 

residues of M 25 were observed in/on forage from six of the twenty field corn sites and eight of 

eleven sweet corn sites; maximum residues of M-25 were 0.021 ppm in field corn forage and 

0.024 ppm in sweet corn forage. Combined residues in parent equivalents ranged <0.025-<0.054 

ppm in/on field corn forage and <0.025-<0.063 ppm in/on sweet corn forage. 

Residues of pyroxasulfone were below the LOQ in/on all samples of stover, with the exception 

of one sample each of field corn and sweet corn stover (0.010 ppm in field corn stover and 0.015 

ppm in sweet corn stover). Quantifiable residues of M-1 were observed in stover from four of 

twenty field corn sites and four of eleven sweet corn sites; maximum residues of M-1 were 0.060 

ppm for field corn stover and 0.039 ppm for sweet corn stover. Residues of M-3 were below the 

LOQ in/on all stover samples, with the exception of two field corn stover samples (0.012 and 

0.015 ppm), and three sweet corn stover samples (0.005-0.010 ppm). Quantifiable residues of 

M-25 were observed in stover from two of twenty field corn sites and six of eleven sweet corn 

sites; maximum residues were 0.029 ppm in field corn stover and 0.044 ppm in sweet corn 

stover. Combined residues in parent equivalents ranged <0.025-<0.139 ppm in/on field corn 

stover and <0.025-0.115 ppm in/on sweet corn stover. 

The application comparison trials indicated that there were no major differences in residues in 

samples treated by the different methods and that soil type and environment seemed to have the 

major influence on residues. Quantifiable residues were only observed in/on forage and stover 

samples from the application comparison trials conducted on coarse-textured soil. In forage from

these trials, samples receiving preplant surface application, early postemergence application, or

split preemergence and postemergence applications had similar total residues (<0.119-0.148 

ppm), with lower residues found in samples receiving preplant incorporated application or postplanting preemergence application (<0.072-0.085 ppm). In stover, samples from the preplant 

surface application, preplant incorporated application, early postemergence application, or split 

preemergence and postemergence applications had similar total residues (<0.070-0.109 ppm), 

with lower residues found in samples receiving post-planting preemergence application (<0.051 

and <0.064 ppm). 

The decline trials showed that initial high residues of pyroxasulfone in/on forage immediately 

after application decline to levels below the LOQ at 30 days after application. Residues of M-1 

appeared to increase from the day of application to ~7 days after application, and then decrease 

after that to below the LOQ by 30 days after application (although quantifiable residues were 
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observed at 60 days posttreatment at one site, at 0.006 and 0.007 ppm). Residues of M-25 were 

quantifiable at 3 and 7 days after treatment at all three sites; no residues of M-25 were found after 

16 days after treatment. No quantifiable residues of M-3 were found in forage, except in one 

sample at 60 days posttreatment (0.009 ppm). Residues of pyroxasulfone, M-1, M-3, and M-25 

were below the LOQ in/on all field corn grain and sweet corn K+CWHR samples from the 

decline trials. No quantifiable residues of pyroxasulfone, M-1, M-3, or M-25 were found in corn 

stover from the decline trials, except 0.007 ppm M-3 at 15 days after normal harvest from one 

field corn trial, and 0.010 ppm declining to 0.006 ppm M-1 (over the decline period of 30 days 

after normal harvest) from the other field corn trial.

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

for field and sweet corn. The number and locations of the field trials are in accordance with 

OPPTS Guideline 860.1500 for field and sweet corn. Field trials were generally conducted at 

~1x the proposed maximum seasonal rate, and the application timing represents the latest 

proposed timing. The petitioner must amend the product label as required per 860.1200 to 

correlate the maximum seasonal application rate with soil texture.

The available data support the following tolerances for combined residues of pyroxasulfone, 

M-1, M-3, and M-25 (pyroxasulfone and M-3 for corn grain), expressed as parent equivalents: 

0.06 ppm for field corn forage; 0.015 ppm for field corn grain; 0.15 ppm for field corn stover; 

0.10 ppm for sweet corn forage; 0.015 ppm for sweet corn K+CWHR; and 0.15 ppm for sweet 

corn stover; refer to Appendix II for tolerance calculations.

No residue data for aspirated grain fractions were provided. These data are not required to 

support the proposed use of pyroxasulfone on corn because application is to be made before the 

reproduction stage begins and seed heads are formed. 

No residue data were submitted for popcorn commodities (grain and stover). As the proposed 

uses on all types of corn are identical, the submitted data for field corn grain and stover may be 

translated to popcorn grain and stover. Separate tolerances are needed for popcorn commodities. 

The petitioner must propose tolerances for pyroxasulfone residues of concern in/on popcorn 

grain, at 0.015 ppm, and popcorn stover, at 0.15 ppm.

Soybean

Pyroxasulfone was applied to soybean, as an 85% WG formulation, at a total of 25 sites in the 

U.S. representing Zones 2, 4 and 5. The application rate was related to soil type: as low as 0.11 

lb ai/A (125 g ai/ha) for coarse-textured soil, up to 0.186 lb ai/A (209 g ai/ha) for 

medium-textured soil, and up to 0.268 lb ai/A (300 g ai/ha) for fine-textured soil. The proposed 

labels specify application rates up to 0.11 lb ai/A (120 g ai/ha) for coarse-textured soil and up to 

0.21 lb ai/A (240 g ai/ha) for fine-textured soil for preplant/preemergence applications, and up to 

0.08 lb ai/A (89 g ai/ha) for coarse-textured soil and up to 0.19 lb ai/A (210 g ai/ha) for finetextured soil for postemergence application; a maximum seasonal rate of 0.267 lb ai/A (300 g 

ai/ha) is proposed (independent of soil type). 

At twenty trials, a single postemergence application was made at approximately the third 

trifoliate leaf stage of the plant, at 0.186 lb ai/A (209 g ai/ha) for medium- and fine-textured soils 
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or at 0.112 lb ai/A (125 g ai/ha) for coarse-textured soils; the application rates represent ~1x and 

1.4x the proposed maximum single application rate for this type of application to fine- and 

coarse-textured soils, respectively, and 0.7x and 0.4x, respectively, the maximum proposed 

seasonal rate. The trials were conducted in Zones 2 (2 trials), 4 (4 trials), and 5 (14 trials). One 

trial included an additional plot treated at an exaggerated rate to generate samples for processing; 

refer to 860.1520 for a discussion of these data. In addition, there were two trials conducted in 

Zone 5 that measured residue decline in RAC matrices; applications were made postemergence at 

~0.186 lb ai/A at these trials (conducted at sites with fine-textured soils). 

At three additional trials with three different soil types (fine, medium, and coarse), five different 

application types were compared: (1) preplant surface application; (2) preplant incorporated 

application; (3) post-planting preemergence application; (4) early postemergence application; and 

(5) split preemergence and postemergence applications. The application rates for types (1), (2), 

and (3) were 0.268, 0.186, and 0.148 lb ai/A (300, 209, and 166 g ai/ha) for fine, medium, and 

coarse soils, respectively. The application rates for type (4) were 0.186, 0.148, and 0.112 lb ai/A 

(209, 166, and 125 g ai/ha) for fine, medium, and coarse soils, respectively. The split application 

was made at 0.178 + 0.089, 0.125 + 0.062, and 0.098 + 0.050 lb ai/A (200 + 100, 140 + 69, and 

110 + 56 g ai/ha) for fine, medium, and coarse soils, respectively. For the split application trials, 

the retreatment interval was 23-26 days. 

Applications were made in 10-23 gal/A spray volumes using ground equipment; no spray 

adjuvant was used. 

Duplicate samples were harvested at the R2-R3 stage for forage (15 to 44 days after application), 

at mid to full bloom for hay (21 to 63 days after application), and at normal harvest for seed (88 

to 137 days after application). Hay was field dried to estimated 10-20% moisture content before 

collection; dry times were not reported. In the residue decline trials, duplicate forage samples 

were collected 0, 3, 7, 16, 21, 30, and 49-50 days following application; duplicate samples of 

seed and hay were collected at normal harvest and 5-7, 12-14, and 28-30 days after normal 

harvest.

Samples were analyzed for residues of pyroxasulfone and its metabolites M-1, M-3, and M-25 

using the proposed LC/MS/MS enforcement method for soybean commodities. The LOQ was 

0.005 ppm for each analyte in each commodity, with the exception of M-1 in seed for which the 

LOQ was 0.01 ppm. The LOQ for combined residues in parent equivalents was 0.025 ppm for 

soybean forage and hay and 0.03 ppm for soybean seed.

Sample storage conditions and durations are reported in Table 5. The available interim storage 

stability data do not support the soybean field trial study. Additional storage stability data are 

needed reflecting maximum storage intervals of 12 months for pyroxasulfone, M-1, and M-3 in 

seed, and 26 months, 24 months, and 29 months for M-25 in forage, seed, and hay, respectively. 

No additional storage stability data are needed for residues of pyroxasulfone, M-1, or M-3 in 

soybean forage or hay.

The results of the field trials reflecting postemergence application are summarized in Table 8. 

Quantifiable residues of pyroxasulfone, M-1, M-3, and M-25 were detected in soybean forage, at 

<0.005-0.690 ppm for pyroxasulfone, <0.005-0.196 ppm for M-1, <0.005-0.011 ppm for M-3, 
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and <0.005-0.029 ppm for M-25. Combined residues in parent equivalents ranged <0.025-0.781 

ppm in/on soybean forage. Quantifiable residues of pyroxasulfone, M-1, M-3 and M-25 were 

detected in soybean hay, at <0.005-1.168 ppm for pyroxasulfone, 0.009-0.647 ppm for M-1, 

<0.005-0.028 ppm for M-3, and <0.005-0.063 ppm for M-25. Combined residues in parent 

equivalents ranged <0.030-1.901 ppm in/on soybean hay. Residues of pyroxasulfone, M-1, M-3, 

and M-25 were below the LOQ in/on all samples of soybean seed, except for three samples, one 

bearing quantifiable M-25 residues at 0.006 ppm and two bearing quantifiable M-3 residues at

0.016 and 0.017 ppm. Combined residues in parent equivalents ranged <0.03-<0.050 ppm in/on 

soybean seed.

The application comparison trials generally indicated that early postemergence and split 

preemergence and postemergence application yielded the highest residues in forage and hay; 

residues of all analytes were less than or close to the LOQ in/on all seed samples from these 

trials. Soil type and environment seemed to also have an influence on residues. At the trials 

conducted on fine- and medium-textured soils, average combined residues resulting from 

preplant surface, preplant incorporated, or post-planting preemergence applications (<0.028-

0.063 ppm in/on forage and <0.041-0.055 ppm in/on hay) were much lower than those resulting 

from early postemergence and split preemergence and postemergence application (<0.082-0.502 

ppm in/on forage and <0.072-0.171 in/on hay). At the trial conducted on coarse-textured soil, 

there was less difference in average residues; <0.341-0.480 ppm in/on forage and <0.482-0.897 

in/on hay from the preplant surface, preplant incorporated, or post-planting preemergence 

applications versus <0.373-0.501 ppm in/on forage and <0.775-1.169 ppm in/on hay from early 

postemergence and split preemergence and postemergence application.

The decline trials showed that initial high residues of pyroxasulfone in/on forage immediately 

after application dissipate rapidly and are below or near LOQ at the times of normal harvest 

(similar to the residues seen in the majority of the trials). The concentrations of the metabolites 

M-1 and M-25 increase in forage over time and then generally decrease to concentrations just 

above LOQ by the final sampling time so at normal harvest intervals, residues could be seen just 

above LOQ. Residues of M-3 in forage were less than or close to the LOQ in/on all samples. 

Residues of all analytes were found to decline with increasing sampling intervals in soybean hay. 

Residues of all analytes were less than or close to the LOQ in/on all seed samples from these 

trials.

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

requirements for soybean, pending submission of the final report of the storage stability study. 

The number and locations of the field trials are in accordance with OPPTS Guideline 860.1500 

for soybean. Field trials were generally conducted at ~1x the proposed maximum single 

application rate and the application timing represents the latest proposed timing. The petitioner 

must amend the proposed label as specified per 860.1200 to correlate maximum seasonal 

application rate with soil texture and to reduce the proposed maximum seasonal application rate 

to conform with the use pattern of the field trials.

It has been determined soybean seed samples need to be reanalyzed for metabolite M-28. After 

review of residue data, M-28 may need to be added to the tolerance expression. In addition, 

additional data are required for the soybean use. Once these data are submitted and found 

adequate, tolerances for soybean RACs will be recommended.
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No residue data for aspirated grain fractions were provided. These data are not required to 

support the proposed use of pyroxasulfone on soybeans because application is to be made before 

the reproduction stage begins and seed heads are formed. 

Wheat

A total of 8 field trials (all of which were decline trials with respect to forage) were conducted in 

Australia to measure the magnitude of pyroxasulfone residues in/on wheat forage, grain, and 

straw following either incorporation by sowing (IBS) treatment, or post-sowing preemergence

(PSPE) treatment with the 85% WG formulation of pyroxasulfone. 

Wheat was treated at 8 locations, reflecting four field trials conducted in 2007-2008 (MRID 

47701669) at Yerong Creek, New South Wales; Walla Walla, New South Wales; Roseworthy, 

South Australia; and Northam, Western Australia; and four feed trials conducted in 2008-2009 

(MRID 47701770) at Culcairn, New South Wales; Moree, Northern New South Wales; 

Templers, South Australia; and Toodyay, Western Australia. In the trials reported in MRID 

47701669, separate treatment plots received a single application of the 85% WG formulation at 

an application rate of 0.112 or 0.223 lb ai/A (125 or 250 g ai/ha) as either an IBS or PSPE 

treatment; the application rates are 1.4x and 2.8x the maximum proposed single application rate 

for coarse- and medium-textured soils and 1x and 2x the maximum proposed single application 

rate for medium-fine and fine soils. In the trials reported in MRID 47701770, the 85% WG was 

applied to three separate treatment plots at 0.112, 0.134, or 0.223 lb ai/A (125, 150, or 250 g 

ai/ha) according to the same use patterns; the application rate of 0.134 lb ai/A corresponds to 

1.7x the maximum proposed single application rate for coarse- and medium-textured soils and 

1.2x the maximum proposed single application rate for medium-fine and fine soils. For the IBS 

plots, the seed was planted as soon as possible after applying the test substance to the soil; for 

both IBS and PSPE plots, the seed was planted the same day as test substance application. All 

applications were made using ground-based equipment, and spray volumes ranged 100-109 L/ha 

(11-12 gal/A). A control plot was also included for each trial. Although the petitioner provided 

information pertaining to soil type at each trial, the soil texture (fine, medium, coarse) was not 

provided. The trials included coarse-, medium-, and fine-textured soils types.

The soil types were identified as red brown earth (three trials), grey clay, gravelly clay, clay loam, 

loam, and sandy loam (one trial for each of these types). Based on a document found here

(http://www.dpi.nsw.gov.au/agriculture/horticulture/vegetables/soil/soilpak), red brown earth 

soils have a layer of sandy loam to light clay loam overlying clay subsoil. Because the top layer 

is sandy loam, we considered these soils to be coarse textured. 

Single control samples and single or duplicate treated samples of wheat forage, grain, and straw 

were harvested from both sets of trials. Wheat forage was sampled at PHIs of 28-30, 34-37 and 

40-42 days in the trials reported in MRID 47701669. Based on the results from these trials, 

which did not consistently demonstrate residue decline, forage sampling was extended for the 

second season of trials reported in MRID 47701670, with wheat forage sampled at PHIs of 41-

43, 56-58 and 70-71 days (and 83 and 98 days at one site). The crop growth stage of the wheat 

plants at forage sampling was not reported. Grain and straw were collected at mature harvest, 

with PHIs ranging 153-176 days. 
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Samples were analyzed for residues of pyroxasulfone and its metabolites M-1, M-3, and M-25 

using LC/MS/MS Method ATM-0031. The validated LOQ for each analyte was 0.01 ppm in 

wheat forage, grain, and straw. The LOQ for total residues was 0.05 ppm, expressed as 

pyroxasulfone equivalents, in all matrices analyzed. 

Note that for trials reported in MRID 47701669, samples from both treatment rates (0.112 and 

0.223 lb ai/A) were analyzed; however, for trials reported in MRID 47701670, only samples from

the 0.112-lb ai/A rate were analyzed for forage, and samples from the 0.112- and 0.134-lb ai/A 

rates were analyzed for grain and straw.

Sample storage conditions and durations are reported in Table 5. The available interim storage 

stability data do not support the wheat field trial studies. Additional storage stability data are 

needed reflecting maximum storage intervals of 13 months for M-25 in forage and 8 months in 

grain and straw (stover). No additional storage stability data are needed for residues of 

pyroxasulfone, M-1, or M-3 to support the wheat field trials.

The results of the field trials are summarized in Table 8. The results include both application 

scenarios, IBS and PSPE. The proposed U.S. label allows both preplant and post-plant 

preemergence applications. Because trials were conducted by spraying the IBS plots, then 

planting the entire trial area, then spraying the PSPE plots, all on the same day, the data have 

been treated as a whole irrespective of application timing in relation to planting.

Total residues of pyroxasulfone and its metabolites generally decreased with time in wheat 

forage; however, in some trials, a degree of variability was observed going from short to longer 

sampling times (i.e., higher residues were observed at longer sampling intervals in some cases). 

Only results reflecting sampling intervals of ≥40 days are included in Table 8, in accordance with 

the proposed PGI of 42 days for wheat. In forage samples harvested 40-98 days following 

treatment at 0.112 lb ai/A, residues of pyroxasulfone were below the LOQ in/on all samples with 

the exception of one in which residues were observed at 0.01 ppm. Residues of M-1, M-3, and 

M-25 ranged <0.01-0.09, <0.01-0.10, and <0.01-0.04 ppm, respectively. Combined residues 

ranged <0.05-0.20 ppm in/on forage samples. The moisture content of wheat forage across the 

trials ranged from 80 to 85%. 

Residues of pyroxasulfone, M-1, M-3, and M-25 were below the LOQ (<0.01 ppm each) in/on all 

samples of wheat grain harvested 167-183 days following treatment at 0.112 or 0.223 lb ai/A (in 

the four trials reported in MRID 47701669) and wheat grain harvested 153-176 days following 

treatment at 0.112 or 0.134 lb ai/A (in the four trials reported in MRID 47701670). 

In straw samples harvested 153-183 days following treatment at 0.112 lb ai/A, residues of 

pyroxasulfone and M-3 were below the LOQ in/on all samples with the exception of one sample 

in which quantifiable residues of pyroxasulfone were observed at 0.01 ppm. Residues of M-1 

and M-25 ranged 0.02-0.09 and <0.01-0.03 ppm, respectively. Combined residues ranged <0.06-

0.18 ppm in/on straw samples. The moisture content of wheat hay samples ranged 10.6-22.8%. 

Conclusions. The submitted wheat data are not adequate to satisfy data requirements because the 

geographic representation of the wheat field trials is incomplete. In addition, no samples of 
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wheat hay were collected in any of the field trials; HED requires residue data and a tolerance for 

wheat hay to support a use on wheat. 

HED has determined that the locations of the 8 Australian field trials correspond to EPA Zones 

2, 3, 4, 6, 8, and 10 (based on plant hardiness zones). To support a use on wheat in the U.S. in 

which quantifiable residues are observed, HED requires a total of 20 field trials, in Zones 1 (1 

trial), 2 (1 trial), 5 (5 trials), 6 (1 trial), 7 (5 trials), 8 (6 trials), and 11 (1 trial). Therefore, the 

petitioner must submit 16 additional field trials on wheat, conducted in Zones 1 (1 trial), 5 (5 

trials), 7 (5 trials), 8 (4 trials), and 11 (1 trial). In these trials, the petitioner should collect and 

analyze samples of wheat forage, hay, grain, and straw; samples should be collected at normal 

harvest times, and the crop growth stage at harvest should be reported for each sample. The 

texture of the soil should be reported for each of the field trial sites. If these residue data show 

that residue levels in forage, grain, and straw are similar to those found in the Australian field 

trials, HED will not require additional field trial data for wheat hay (i.e., the 16 field trials 

conducted in the U.S. for wheat hay will be considered sufficient to support a tolerance). 

To fully support sample storage conditions and durations, the final report of the ongoing storage 

stability study with metabolite M-25 must be submitted. No additional storage stability data are 

needed for pyroxasulfone, M-1, or M-3 to support the wheat field trials.

The study submissions included no raw data for the analytical portion of the study. Raw data 

from the sample analyses must be submitted; these data should include sample extraction and 

analysis dates to allow HED to verify sample storage intervals.

No residue data for aspirated grain fractions were provided. These data are not required to 

support the proposed use of pyroxasulfone on wheat because application is to be made before the 

reproduction stage begins and seed heads are formed. 

Additional data are required for the wheat use. Once these data are submitted and found 

adequate, tolerances for wheat RACs will be recommended.

860.1520 Processed Food and Feed

Monograph for Pyroxasulfone, Sections B.7.6.1.1 and B.7.7.2 (MRID 47701656; field and sweet corn)

Monograph for Pyroxasulfone, Sections B.7.6.1.2 and B.7.7.2 (MRID 47701657; soybean)

K-I Chemical submitted processing study data for field corn and soybean. No processing study 

data for wheat were submitted. A summary of the average processing factors found for the 

processed commodities of field corn and soybean is presented in Table 9. 
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Table 9. 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 --

Soybean Meal NC NC >2.6x2 NC 1.4x

Hulls NC NC >1.4x NC 0.9x

Refined 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.

2

 This value exceeds the maximum theoretical concentration of 2.2x for soybean meal.

Field corn

A field corn processing trial was conducted in conjunction with the corn field trials. At one site 

in IA (fine-textured soil), a single postemergence application of the 85% WG formulation was 

made to field corn at 1.328 lb ai/A (1488.4 g ai/ha), which is 5x the proposed maximum seasonal 

rate. A single bulk sample of field corn was collected 136 days following the last application and 

processed into grits, meal, flour, starch, and wet and dry milled refined oil using simulated 

commercial processing procedures. Dates of actual processing were not provided; based on 

sample shipping dates, processing was completed within 133 days of harvest.

Samples were analyzed for residues of pyroxasulfone and its metabolites M-1, M-3, and M-25 

using the proposed LC/MS/MS enforcement method for corn commodities. The LOQ was 0.005 

ppm for each analyte in each commodity, with the exception of M-3 in meal and M-1 in oil (dry 

and wet milled) for which the LOQ was 0.01 ppm. The LOQ for combined residues in parent 

equivalents was 0.025 ppm for grain, grits, flour, and starch, and 0.03 ppm for meal and refined 

oil. 

Sample storage conditions and durations are reported in Table 5. The available storage stability 

data supports the field corn processing study. 

Residues of pyroxasulfone, M-1, M-3, and M-25 were below the LOQ in/on field corn grain from 

the exaggerated rate plot. Residues were also below the LOQ in grits, meal, flour, starch, and 

wet and dry milled oil. Because residues were below the LOQ in all samples, processing factors 

could not be calculated.

Soybean

A soybean processing trial was conducted in conjunction with the soybean field trials. At one 

site in IA (fine-textured soil), a single postemergence application of the 85% WG formulation 

was made to soybeans at 0.571 lb ai/A (640 g ai/ha), which is 3x the proposed maximum single 

application rate for this type of application. A single bulk sample of soybean seed was collected 

113 days following the last application and processed into grits, meal, hulls, and refined oil using 
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simulated commercial processing procedures. Dates of actual processing were not provided; 

based on sample shipping dates, processing was completed within 90 days of harvest.

Samples were analyzed for residues of pyroxasulfone and its metabolites M-1, M-3, and M-25 

using the proposed LC/MS/MS enforcement method for soybean commodities. The LOQ was 

0.005 ppm for each analyte in each commodity, with the exception of M-1 in seed and meal for 

which the LOQ was 0.01 ppm. The LOQ for combined residues in parent equivalents was 0.025 

ppm for soybean hulls and oil and 0.03 ppm for soybean seed and meal. 

Sample storage conditions and durations are reported in Table 5. The available interim storage 

stability data do not support the soybean processing study. Additional storage stability data are 

needed reflecting maximum storage intervals of 29 months for M-25 in seed, and 16-19 months 

for M-25 in soybean processed commodities. No additional storage stability data are needed for 

pyroxasulfone, M-1, and M-3 in soybean processed commodities.

Residues of pyroxasulfone, M-1, M-3, and M-25 were below the LOQ in/on soybean seed from 

the exaggerated rate plot. Residues were also below the LOQ in meal, hulls and refined oil, 

except that M-3 was found in soybean meal at 0.013 ppm and in hulls at 0.007 ppm, yielding 

processing factors of 2.6x for M-3 in meal and 1.4x for M-3 in hulls. Total pyroxasulfone 

residue (parent, M-1, M-3, and M-25) processing factors would be 1.4x for meal and <1x for 

hulls. However, M-28 has been determined to be a residue of concern at this time and no 

processing data has been submitted for M-28. Processing data for M-28 are required. After 

submittal of these data, the soybean processing study will be re-evaluated for adequacy.

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

However, the soybean processing study is partially adequate to satisfy data requirements for the 

soybean use. Once the additional data are submitted for the soybean processing study, the 

adequacy will be determined.

The corn processing data indicate that no quantifiable residues of pyroxasulfone or metabolites 

M-1, M-3, and M-25 would be expected in field corn processed commodities following treatment 

at 1x. No tolerances are needed for the processed commodities of field corn.

The soybean processing data indicate that residues of concern for pyroxasulfone concentrate in 

soybean meal. Using the HAFT of 0.049 ppm, as well as the processing factors of 1.4x, the 

expected total residues in soybean meal following treatment at 1x would be 0.069 ppm. 

However, M-28 has been determined to be a residue of concern and no processing data has been 

submitted for M-28. Processing data for M-28 are required. After submittal of these data, the 

soybean processing study will be re-evaluated for adequacy.

The interim results of the storage stability study indicate that residues of M-1 may decline in 

soybean oil during storage (~30% after 7 months of storage). Because the residues of this analyte 

were below the LOQ in oil processed from seed treated at an exaggerated rate, HED concludes 

that potential decline during storage is not of concern at this time. This conclusion will be reevaluated when the final results of the storage stability study have been submitted.
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No processing data were submitted for wheat. A processing study for wheat must be submitted 

as a condition of registration.

860.1650 Submittal of Analytical Reference Standards

Analytical standards for pyroxasulfone and its metabolites M-1, M-3, M-25, M-28, and 

Metabolite C are not currently available in the EPA National Pesticide Standards Repository

(personal communication with Dallas Wright, ACB, 11/18/09). Analytical reference standards of 

pyroxasulfone and metabolites M-1, M-3, M-25, M-28, and Metabolite C 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 or 

Thuy Nguyen 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

Monograph for Pyroxasulfone, Section B.7.9.1 (MRID 47701674)

The metabolism of pyroxasulfone was investigated in rotated soybean, radish, and wheat. The 

test substance, radiolabeled pyroxasulfone (pyrazole and isoxazoline labels applied in separate 

plots), was formulated as a WG formulation and applied to 12 plots (six plots each radiolabel; 

plus six non-treated plots) containing clay loam soil at a rate equivalent to 0.268 lb ai/A (300 g 

ai/ha). The application rate is 1x the proposed maximum seasonal rate. The soil surface was 

treated directly with the formulated product and aged for 30, 120 and 365/490 days (nominal) 

prior to planting the rotational crops soybean, radish, and wheat. For soybean, the plants in the 

365-day isoxazoline-label plot were destroyed by pests, and the plot was replanted at 490 days 

after treatment. All crops were grown under natural conditions. The petitioner stated that clay 

loam soil was chosen for the study because the highest application rate on the label is associated 

with this soil type (fine-textured soil). The petitioner noted that phytotoxicity caused small root 

samples for radish planted in the 30-day plots. 

TRR were >0.01 ppm in all rotated crops matrices from the 30-, 120-, and 365/490-day plantback 

intervals. The highest residue levels were found in 30-day wheat straw and hay samples, with 

values as high as 5.2 ppm. The next highest TRR were found in 30-day soybean hay, at 1.2 ppm 

and 1.6 ppm for isoxazoline and pyrazole labels, respectively. Residues decreased in soybean 

and radish matrices, and wheat forage, as plantback intervals increased. Residues in wheat hay, 

straw, and grain matrices declined from the 30-day to 120-day interval but increased slightly or 

remained at similar levels at 365 days. 

The majority of the radioactive residues (generally >70% of TRR) were extracted using 

conventional organic and polar solvents (ACN, acidic ACN, and 0.1 N NaOH). Additional 

amounts were extracted using acid, base, lignin and/or enzymatic treatments. Nonextractable 
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residues after exhaustive extraction were <10% TRR and/or <0.05 ppm in all rotated crop 

matrices. 

For samples collected from plots treated with the pyrazole-label test substance, HPLC and TLC 

analysis of plant extracts confirmed the presence of parent and two main metabolites (M-1 and 

M-25), as well as lesser amounts of M-3, M-6, and M-9 in rotated crop matrices. Pyroxasulfone

was found at levels <5% TRR (<0.01 ppm) in 30-day wheat straw and radish roots and foliage, 

and 120-day radish roots and foliage; the parent was not detected in any rotated crop matrix at the

365-day plantback interval. Metabolite M-1 was a major residue accounting for 10-38% TRR in 

30-day wheat forage, hay, and straw, soybean forage and hay, and radish roots and foliage 

(0.031-0.963 ppm); 120-day wheat forage, hay, and straw, soybean forage and hay, and radish 

foliage (0.013-0.182 ppm); and 365-day wheat forage, hay, and straw, soybean forage and hay, 

and radish roots and foliage (0.003-0.202 ppm). Metabolite M-1 was found at <10% TRR in all 

other rotational crop commodities. Metabolite M-25 (desmethyl M-1) was a major residue 

accounting for 10-28% TRR in 30-day wheat forage, hay, and straw, and soybean hay; and in 

120- and 365-day wheat grain and radish foliage (0.005-0.023 ppm). Metabolite M-3 was a 

major metabolite in 30-, 120-, and 365-day wheat grain, at 15-28% TRR (0.008-0.023 ppm), and 

in 120- and 365-day radish tops, at 11% TRR (0.012 and 0.005 ppm); it was found at <9% TRR 

in other rotational matrices. Metabolite M-9 was present at ≤8% TRR, except in 120-day 

soybean hay, where it was found at 11% TRR (0.118 ppm) and in 365-day soybean forage where 

it was found at 11% TRR (0.020 ppm). An unknown eluting at 26 minutes (RT26), determined 

to be M-9 malonyl glucoside, was a major residue in 30-day soybean forage and hay, and radish 

roots, accounting for 16-20% TRR (0.036-0.316 ppm); 120-day soybean forage, hay, and seed, 

accounting for 10-19% TRR (0.011-0.204 ppm); and 365-day soybean forage and hay, 

accounting for 12% TRR (0.023 and 0.111 ppm). Another unknown, RT24, which could not be 

identified, was a major residue in 30-day radish roots (22% TRR, 0.051 ppm), 120-day wheat 

forage, radish roots, and radish foliage (12-22% TRR, 0.014-0.027 ppm), and 365-day radish 

roots (10% TRR, 0.003 ppm). The only other identified metabolite, M-6, was found at <2.5% 

TRR in 30-day wheat hay, soybean hay, and radish roots and foliage. These metabolites were 

formed from the pyrazole portion of the molecule. 

For samples collected from plots treated with the isoxazoline-label test substance, several 

conjugates and cysteine derivatives of the isoxazoline group were detected (metabolites A-D and 

P1). Metabolites A, B, C, D, P1, and M-28 were major residues (>10% TRR) in these rotated 

crop matrices at all PBIs: metabolite A was found in 30-, 120-, and 365-day wheat and radish 

matrices (12-45% TRR, 0.01-1.218 ppm); metabolite B was found in 30-, 120-, and 365-day 

wheat and 120-day radish commodities (10-35% TRR, 0.027-1.085 ppm); metabolite C was 

found in 30-, 120-, and 365-day wheat commodities (10-30% TRR, 0.173-0.522 ppm); 

metabolite D was found in 30-, 120-, and 365-day wheat and 120 and 365-day radish 

commodities (13-29% TRR, 0.01-1.494 ppm); metabolite P1 was found in 30- and 120-day 

radish and soybean commodities and 30-day wheat commodities (11-34% TRR, 0.034-0.170 

ppm); and metabolite M-28 was found in 30-, 120-, and 365/490-day wheat and soybean 

commodities (14-29% TRR, 0.013-0.273 ppm). Parent pyroxasulfone was found at ≤2.5% in 30-

and 120-day radish roots and tops, and metabolite M-6, the only other identified metabolite, was 

found at <1% TRR in 30-day wheat hay, soybean seed, and radish foliage and 120-day wheat 

forage.
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Residues of M-1, M-3, and/or M-25 greater than 0.01 ppm were found in rotated radish, soybean, 

and wheat commodities from the 30- and 120-day PBIs; and in rotated soybean and wheat 

commodities from the 365-day PBI.

Samples were stored frozen from collection to analysis. Initial HPLC analyses were completed 

within 58 days of sample collection. No dates of analysis other than initial HPLC analyses were 

provided. The petitioner stated that repeat analyses of various extracts and isolated products 

yielded profiles comparable to those initially obtained. No data to support these statements were 

included in the submission.

Based on the results of the study, the petitioner proposed that in general, metabolism in rotational 

crops appears to occur via cleavage between the parent sulfone and isoxazoline ring and reaction 

of glutathione with the isoxazole ring to form a transitory glutathione conjugate (M-15, not 

observed). Subsequent oxidation and/or demethylation of the pyrazole cleavage product 

occurred, yielding metabolites M-1, M-3, M-9, and M-25; metabolite M-9 was further conjugated

to yield a malonyl glucose conjugate. The transitory glutathione conjugate was further conjugated 

to another transitory metabolite (M-26, not observed), which underwent further conjugation with 

malonate and/or glucose to form metabolites A, B, C, D, and M-28; oxidation of M-28 would 

yield metabolite P-1. Finally, hydroxylation of pyroxasulfone would yield metabolite M-6. 

Conclusions. The submitted confined rotational crop study is adequate to satisfy data 

requirements. 

The results of the 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. 

The residues of concern in rotational crops for risk assessment at this time are pyroxasulfone and 

its metabolites M-1, M-3, M-25, M-28, and Metabolite C. The residues of concern for tolerance 

enforcement cannot be elucidated at this time. No rotation is allowed at this time. 

Limited/Extensive field rotational crop field studies must be conducted with analysis of 

pyroxasulfone and its metabolites M-1, M-3, M-25, M-28, and Metabolite C. 

860.1900 Field Accumulation in Rotational Crops

Monograph for Pyroxasulfone, Section B.7.9.2 (MRIDs 47701675 and 47701676)

K-I Chemical is not proposing any tolerances for rotated crop commodities in the U.S. The 

petitioner submitted field rotational crop data from two studies conducted in Australia to support 

the establishment of rotational crop tolerances in Australia. One study was conducted with field 

pea at PBIs of 25-28 days, and the other study was conducted with field pea and wheat at PBIs of 

348-357 days. The results of the field rotational crop studies are discussed below.

MRID 47701675: Three field rotational crop trials were conducted in Australia to measure the 

magnitude of total pyroxasulfone residues in field peas planted as a rotational crop 25 to 28 days 

following the use of the 85% WG formulation on wheat. A single broadcast spray application of 

the 85% WG formulation was made to soil post-planting preemergence, within 3 days of 
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planting, to wheat at target rates of 0.134 and 0.223 lb ai/A (150 and 250 g ai/ha) using spray 

volumes ranging 100-102 L/ha (11 gal/A). The application was made using ground equipment. 

The wheat crop was treated with glyphosate 21 to 22 days after sowing to achieve “failure” of the 

wheat crop. Field peas were planted 6 or 7 days later, at a 25 to 28-day PBI. Single control and 

treated samples of field pea forage, fodder, and seed were collected by hand (forage) or harvester 

(seed and fodder) at normal commercial harvest; forage was collected at intervals of 42-43, 56-58 

and 69-72 days after planting, and fodder and seed were collected 144-159 days after planting. 

The petitioner noted phytotoxicity in the form of stunted plant growth at two of the three trials; 

phytotoxicity information was not recorded for the third trial. 

The soil textures at the field trial sites were not identified by the petitioner. Based on the soil 

types, the soil at one of the trials was coarse textured, and the soil at the other two trials was 

medium textured. The application rates of 0.134 and 0.223 lb ai/A represent 0.5x and 0.8x the 

proposed maximum seasonal rate for pyroxasulfone.

Samples were analyzed for residues of pyroxasulfone and its metabolites M-1, M-3, and M-25 

using LC/MS/MS Method ATM-0031. For calculating total residues, the individual analyte 

residues were converted to parent molar equivalents and summed. The validated LOQ for each 

analyte was 0.01 ppm in field pea forage, fodder, and seed. The LOQ for total residues was 0.05 

ppm, expressed as pyroxasulfone equivalents, in all matrices analyzed. Note that analysis was 

restricted to samples treated at a single rate from each site; the 0.134 lb ai/A rate from two sites

(coarse- and medium-textured soils), and the 0.223 lb ai/A rate from one site (medium-textured 

soil).

Sample storage conditions and durations are reported in Table 5. The available interim storage 

stability data for soybean commodities support the sample storage conditions and durations of the 

field pea rotational crop study. 

Residues of pyroxasulfone and metabolite M-25 were each below the LOQ in/on all samples of 

field pea forage from crops treated at 0.134 lb ai/A (two sites) and 0.223 lb ai/A (one site). 

Residues of M-1 were <0.01-0.02 ppm in/on forage from sites treated at 0.134 lb ai/A and were 

<0.01-0.02 ppm in/on forage from the site treated at 0.223 lb ai/A. Residues of M-3 were below 

the LOQ in/on forage samples from the sites treated at 0.134 lb ai/A and were <0.01-0.01 ppm

in/on forage from the site treated at 0.223 lb ai/A. Combined residues in/on forage ranged <0.05-

<0.06 ppm for both treatment rates.

For field pea seed harvested at maturity, residues of pyroxasulfone, M-1, M-3, and M-25 were 

each below the LOQ in/on all tested samples from all three trial sites. For field pea fodder, 

residues of pyroxasulfone, M-3, and M-25 were each below the LOQ in/on all tested samples 

from all three trial sites. Residues of M-1 were 0.05 and 0.08 ppm in/on fodder from sites treated 

at 0.134 lb ai/A and 0.02 ppm in/on fodder from the site treated at 0.223 lb ai/A. Combined 

residues in/on fodder ranged <0.05-<0.14 ppm from sites treated at 150 g ai/ha and were 0.06 

ppm in/on fodder from the site treated at 0.223 lb ai/A.

MRID 47701676: Four field rotational crop trials were conducted in Australia to measure the 

magnitude of total pyroxasulfone residues in wheat and field peas grown as rotational crops

following the use of the 85% WG formulation on wheat and triticale in the season before 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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planting of the rotational crops. A single broadcast spray application of the 85% WG 

formulation was made to the soil either by preplant incorporation or post-planting preemergence 

to wheat or triticale at target rates of 0.112 and 0.223 lb ai/A (125 and 250 g ai/ha) using spray 

volumes ranging 100-109 L/ha (11-12 gal/A). These cereal crops were grown to harvest. In the 

winter season after the cereal harvest, 348-357 days after application, both field peas and wheat 

were planted at each of the four sites. Single control and treated samples of the wheat forage, 

grain, and straw, and field pea forage, seed, and fodder were collected by hand (forage) or by 

harvester (grain, seed, straw, and fodder) at normal commercial harvest times. The forage 

collection interval for wheat and field pea was 42-43 days after planting. Seed/grain and 

fodder/straw were sampled at mature harvest, 172-182 days after planting. The petitioner stated 

that no phytotoxicity effects were observed during the trial period.

The soil textures at the field trial sites were not identified by the petitioner. Based on the soil 

types, the soil at two of the trials was coarse textured, and the soil at the other two trials was 

medium textured. The application rates of 0.112 and 0.223 lb ai/A represent 0.4x and 0.8x the 

proposed maximum seasonal rate for pyroxasulfone.

Samples were analyzed for residues of pyroxasulfone and its metabolites M-1, M-3, and M-25 

using LC/MS/MS Method ATM-0031. For calculating total residues, the individual analyte 

residues were converted to parent molar equivalents and summed. The validated LOQ for each 

analyte was 0.01 ppm in each commodity. The LOQ for total residues was 0.05 ppm, expressed 

as pyroxasulfone equivalents, in all matrices analyzed. For forage, analysis of samples from both 

the 0.112 and 0.223 lb ai/A treatments was conducted; however for fodder/straw and seed/grain, 

analysis was restricted to samples from the 0.223 lb ai/A treatment.

Sample storage conditions and durations are reported in Table 5. The available interim storage 

stability data do not support the wheat and field pea rotational crop studies. Additional storage 

stability data are needed reflecting maximum storage intervals of 8 months for M-25 in wheat 

forage. No additional storage stability data are needed for residues of pyroxasulfone, M-1, or 

M-3 to support the field rotational crop trials.

Residues of pyroxasulfone, M-3, and M-25 were below the LOQ in/on all samples of wheat and 

field pea forage from both treatment rates. In wheat forage from crops treated at 0.112 lb ai/A, 

residues of M-1 were <0.01-0.02 ppm, and in wheat forage from crops treated at 0.223 lb ai/A, 

residues of M-1 were <0.01-0.05 ppm. For field peas, no residues of M-1 were found in forage 

from crops treated at 0.112 lb ai/A; residues of M-1 were <0.01-0.05 ppm in/on samples from the 

0.223 lb ai/A treatment. Combined residues in/on wheat forage ranged <0.05-<0.06 ppm for 

samples treated at 0.112 lb ai/A; and <0.05-<0.10 ppm for samples treated at 0.223 lb ai/A; 

combined residues in/on pea forage were <0.05 ppm for samples treated at 0.112 lb ai/A and 

<0.05-<0.10 ppm for samples treated at 0.223 lb ai/A.

In wheat grain and field pea seed harvested at maturity, residues of each analyte were each below 

the LOQ in/on all samples from the 0.223 lb ai/A treatment plots. For wheat straw and pea 

fodder, residues of pyroxasulfone, M-3, and M-25 were each below the LOQ in/on all samples 

from the0.223 lb ai/A treatment plots. Residues of M-1 were 0.02-0.03 ppm in/on wheat straw at 

three sites, and 0.02 and 0.04 ppm in/on field pea fodder at two sites; residues of M-1 were <0.01 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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ppm in all other wheat straw and field pea fodder samples. Combined residues in/on wheat straw 

ranged <0.05-<0.08 ppm and combined residues in/on pea fodder ranged <0.05-<0.09 ppm.

Conclusions. Under the conditions used in the trials, the field rotational crop studies are partially 

adequate to satisfy data requirements. To fully support storage conditions and durations for 

forage samples, the final report of the ongoing storage stability study with metabolite M-25 must 

be submitted. 

Although no North American field trials were conducted, the petitioner does not intend to use 

these data to support rotational crop tolerances in North America. Instead, the petitioner has 

proposed an 18-month plantback interval for all crops other than corn, soybean, and wheat. The 

proposed plantback interval is based on the results of the confined rotational crop study, which 

indicated the potential for quantifiable residues of concern in/on rotated radish, soybean, and 

wheat commodities from 30- and 120-day PBIs; and in rotated soybean and wheat commodities 

from a 365-day PBI. The results of the confined rotational crop study indicate that no 

quantifiable pyroxasulfone residues of concern would be expected in root crops planted 12 

months following treatment at 1x the proposed maximum seasonal rate of 0.267 lb ai/A. No data 

are available demonstrating that residues of concern will be below the LOQ in/on other rotated 

crop commodities at a PBI of 18 months.

The petitioner must submit a limited field rotational crop study with pyroxasulfone. The study 

must be conducted in the U.S. and should reflect application at the maximum proposed seasonal 

rate (0.267 lb ai/A) and planting of rotated crops at plantback intervals 1, 6, and 12 months. If 

quantifiable residues are found at the 12-month interval, then extensive field trials will be 

required to set rotational crop tolerances. Pyroxasulfone, M-1, M-3, M-25, M-28, and 

Metabolite C must be determined in these studies. HED notes that the limited field rotational 

crop study does not need to include a root crop. If quantifiable residues of concern are observed 

in rotated crop commodities from the limited field rotational crop study, extensive field rotational

crop studies will be required.

Until the required rotational crop data have been submitted, the petitioner must modify the labels 

for both products to specify that only crops on the label may be planted after pyroxasulfone 

application; crops on the label may be planted any time after application and root crops after 12 

months.

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 for corn forage and corn stover. However, the 

tolerance expression for corn grain should be pyroxasulfone and its metabolite M-3. The 

tolerance expression for plants 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 
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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.

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

The tolerances proposed by K-I Chemical are listed in Table 10, 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. 

Adequate field trial data are available to support the proposed tolerances for: corn, field, grain; 

corn, field, forage; corn, field, stover; corn, sweet, kernel plus cob with husks removed; corn, 

sweet forage; corn, sweet, stover. The data indicate that the proposed tolerances for field corn 

grain and sweet corn K+CWHR are too low; tolerances of 0.015 ppm would be appropriate. The 

data indicate that the proposed tolerances for field corn forage and sweet corn forage are too 

high; tolerances of 0.06 ppm and 0.10 ppm, respectively, would be appropriate. The available 

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

processed commodities. 

No residue data were submitted for popcorn commodities (grain and stover). As the proposed 

uses on all types of corn are identical, the submitted data for field corn grain and stover may be 

translated to popcorn grain and stover. Separate tolerances are needed for popcorn commodities. 

The petitioner must propose tolerances for pyroxasulfone residues of concern in/on popcorn 

grain, at 0.015 ppm, and popcorn stover, at 0.15 ppm

The adequacy of the proposed soybean tolerances will be evaluated pending submission of the 

final reports of the storage stability studies and additional residue data. 

The proposed tolerances should be revised to reflect the correct commodity definitions as 

specified in Table 10.

Table 10. Tolerance Summary for Pyroxasulfone.

Commodity Proposed Tolerance 

(ppm)

HED Recommended

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Field Corn Grain 0.01 0.015 Corn, field, grain

Field Corn Forage 0.15 0.06 Corn, field, forage

Field Corn Stover 0.15 0.15 Corn, field, stover

Sweet Corn Ears 0.02 0.015 Corn, sweet, kernel plus cob with 

husks removed

Sweet Corn Forage 0.15 0.10 Corn, sweet, forage

Sweet Corn Stover 0.15 0.15 Corn, sweet, stover

Field Corn Grits 0.01 Remove Tolerances are not needed for the 
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Table 10. Tolerance Summary for Pyroxasulfone.

Commodity Proposed Tolerance 

(ppm)

HED Recommended

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Field Corn Meal 0.01 Remove processed commodities of corn.

Field Corn Flour 0.01 Remove

Field Corn Starch 0.01 Remove

Field Corn Oil (wet and 

dry milled)

0.01 Remove

Corn, pop, grain -- 0.015 The submitted data for field corn 

grain and stover may be translated to 

popcorn grain and stover

Corn, pop, stover -- 0.15

Attachments: 

Appendix I - Chemical Name and Structure Table

Appendix II - Tolerance Assessment Calculations

Appendix III - REFERENCES

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

F

F

O

N

N

CF3

CH3

S

O

O

N

O

CH3

H3C

M-1

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

(trifluoromethyl)-1H-pyrazol-4-

yl]methanesulfonic acid 

N/A

F

F

O

N

N

CF3

S

O

O

HO

CH3

M-3

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

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

F

F

O

N

N

CF3

CH3

HO

O

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

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 N

N

O

F

F F

F F

H

C184

O

HO

O

OH

OH

OH

OH

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

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-3023-cyano-2-hydroxy-2-methylpropanoic acid N/A

HO

H C3 COOH

CN

Metabolite A1 None provided (cysteine glucose conjugate of 

isoxazoline-ring metabolite) N/A

S

O

H3C

CH3

NH2

O

O-Glucose

Metabolite B1 None provided (dimethylpropyl cysteine sulfoxide 

derivative) N/A

S

NH2

O

OH

O

H3C

CH3

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

S

NH2

O

H3C OH

O

HO

P11

None provided (malonyl cysteine conjugate of 

isoxazoline-ring products following reaction of 

pyroxasulfone or metabolites with glutathione)

N/A

S

O N

H3C N

H

HO O

OH

O O

OH

1

 Proposed structure.

2

 Tentatively identified.
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Appendix II. Tolerance Assessment Calculations.

For each of the crops listed below, the OECD MRL Calculator User Guide (SOP), along with the 

tolerance spreadsheet, was used for calculating recommended tolerances. As specified in the 

SOP, the tolerance calculation is in the region of the 95th percentile of the underlying residue 

distribution, and is more likely to overestimate rather than underestimate the 95th percentile. The 

rounding procedures specified in the SOP were also used. The OECD tolerance spreadsheet does 

not require the use of maximum-likelihood estimation (MLE) procedures for values <LOQ.

Field corn

The dataset used to establish a tolerance for pyroxasulfone on field corn commodities consisted 

of field trial data representing application at the V4 growth stage at 0.148 or 0.268 lb ai/A, 

depending on soil type, with PHIs of 37-95 days for forage, 69-146 days for grain, and 85-146 

days for stover. The field trial application rates are within 25% of the maximum label 

application rate and the application timing represents the latest proposed timing. The residue 

values that were entered into the tolerance spreadsheet are provided in Table II-1. The residue 

values were obtained from the field trials, discussed in the monograph document, in which 

samples were treated early postemergence (Table B.7.6-1); the results from the “normal” harvest 

interval in the decline trials (Table B.7.6-3) were included.

Residues of each analyte were below the LOQ in 28 of 44 forage samples, 35 of 44 stover 

samples, and all 43 grain samples (combined LOQ = 0.025 ppm, pyroxasulfone equivalents, for 

all matrices). The OECD MRL calculator was used and the recommended tolerances are 0.06 

ppm for field corn forage, 0.015 ppm for field corn grain, and 0.15 ppm for field corn stover. 
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Table II-1. Residue data used to calculate tolerance for pyroxasulfone on field corn forage, grain, and 

stover. 

Regulator: EPA EPA EPA

Chemical: Pyroxasulfone Pyroxasulfone Pyroxasulfone

Crop: Field corn forage Field corn grain Field corn stover

PHI: 37-95 days 69-146 days 85-146 days

App. Rate: 0.148-0.268 lb ai/A 0.148-0.268 lb ai/A 0.148-0.268 lb ai/A

Submitter: K-I Chemical K-I Chemical K-I Chemical

MRID Citation: MRID 47701656 MRID 47701656 MRID 47701656

Combined Residues of Pyroxasulfone and Metabolites M-1, M-3, and M-25 in 

forage and stover; Pyroxasulfone and M-3 in grain (ppm)1

<0.025 <0.013 <0.025

<0.028 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.028 <0.013 <0.025

<0.028 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.044 <0.013 <0.030

<0.045 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.054 <0.013 <0.139

<0.053 <0.013 <0.123

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 <0.029

<0.028 <0.013 <0.028

<0.029 <0.013 <0.031
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Table II-1. Residue data used to calculate tolerance for pyroxasulfone on field corn forage, grain, and 

stover. 

Regulator: EPA EPA EPA

Chemical: Pyroxasulfone Pyroxasulfone Pyroxasulfone

Crop: Field corn forage Field corn grain Field corn stover

PHI: 37-95 days 69-146 days 85-146 days

App. Rate: 0.148-0.268 lb ai/A 0.148-0.268 lb ai/A 0.148-0.268 lb ai/A

Submitter: K-I Chemical K-I Chemical K-I Chemical

MRID Citation: MRID 47701656 MRID 47701656 MRID 47701656

Combined Residues of Pyroxasulfone and Metabolites M-1, M-3, and M-25 in 

forage and stover; Pyroxasulfone and M-3 in grain (ppm)1

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.028 <0.013 <0.025

<0.029 <0.013 <0.025

<0.033 <0.013 <0.039

<0.032 <0.013 <0.036

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.028 <0.013 <0.025

<0.027 <0.032

1

 Results in which all analytes were below the LOQ are shaded.

Pyroxasulfone
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Field Corn Forage

Region / Country

GAP

Total number of data (n) 22

Percentage of censored data 59%

Number of non-censored data 9

Lowest residue 0.025

Highest residue 0.054

Median residue 0.025

Mean 0.028

Standard deviation (SD) 0.007

Correction factor for censoring (CF) 0.606

Proposed MRL estimate

- Highest residue 0.054

- Mean + 4 SD 0.057

- CF x 3 Mean 0.051

Unrounded MRL 0.057

Rounded MRL 0.06

High uncertainty of MRL estimate.

[High level of censoring]

Residues (mg/kg) n

< 0.025 13

0.025 1

0.027 1

0.028 2

0.029 2

0.033 1

0.045 1

0.054 1

Pyroxasulfone
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Field Corn Stover

Region / Country

GAP

Total number of data (n) 22

Percentage of censored data 73%

Number of non-censored data 6

Lowest residue 0.025

Highest residue 0.131

Median residue 0.025

Mean 0.031

Standard deviation (SD) 0.023

Correction factor for censoring (CF) 0.515

Proposed MRL estimate

- Highest residue 0.131

- Mean + 4 SD 0.121

- CF x 3 Mean 0.048

Unrounded MRL 0.131

Rounded MRL 0.15

High uncertainty of MRL estimate.

[High level of censoring]

Residues (mg/kg) n

< 0.025 16

0.027 1

0.028 1

0.029 1

0.03 1

0.038 1

0.131 1

Pyroxasulfone

Field Corn Grain
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Region / Country

GAP

Total number of data (n) 20

Percentage of censored data 100%

Number of non-censored data 0

Lowest residue 0.013

Highest residue 0.013

Median residue 0.013

Mean 0.013

Standard deviation (SD) 0.000

Correction factor for censoring (CF) 0.333

Proposed MRL estimate

- Highest residue 0.013

- Mean + 4 SD 0.013

- CF x 3 Mean 0.013

Unrounded MRL 0.013

Rounded MRL 0.015

High uncertainty of MRL estimate.

[High level of censoring]

Residues (mg/kg) n

< 0.013 20

Sweet corn

The dataset used to establish a tolerance for pyroxasulfone on sweet corn commodities consisted 

of field trial data representing application at the V4 growth stage at 0.148 or 0.268 lb ai/A, 

depending on soil type, with PHIs of 43-97 days for forage, 43-132 days for K+CWHR, and 70-

132 days for stover. The field trial application rates are within 25% of the maximum label 

application rate, and the application timing represents the latest proposed timing. The residue 
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

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values that were entered into the tolerance spreadsheet are provided in Table II-2. The residue 

values were obtained from the field trials, discussed in the monograph document, in which 

samples were treated early postemergence (Table B.7.6-1); the results from the “normal” harvest 

interval in the decline trials (Table B.7.6-3) were included.

For sweet corn commodities, residues of each analyte were below the LOQ in 5 of 24 forage 

samples, 22 of 24 K+CWHR samples, and 13 of 24 stover samples (combined LOQ = 0.025 

ppm, pyroxasulfone equivalents, for all matrices (0.013 ppm for K+CWHR pyroxasulfone and 

M-3)). 

Using the OECD MRL calculator, the recommended tolerances are 0.10 ppm for sweet corn 

forage, 0.15 ppm for sweet corn stover, and sweet corn K+CWHR is 0.015 ppm. 

Table II-2. Residue data used to calculate tolerance for pyroxasulfone on sweet corn forage, K+CWHR, 

and stover. 

Regulator: EPA EPA EPA

Chemical: Pyroxasulfone Pyroxasulfone Pyroxasulfone

Crop: Sweet corn forage Sweet corn K+CWHR Sweet corn stover

PHI: 43-97 days 43-132 days 70-132 days

App. Rate: 0.148-0.268 lb ai/A 0.148-0.268 lb ai/A 0.148-0.268 lb ai/A

Submitter: K-I Chemical K-I Chemical K-I Chemical

MRID Citation: MRID 47701656 MRID 47701656 MRID 47701656

Combined Residues of Pyroxasulfone and Metabolites M-1, M-3, and M-25 

(ppm)1

<0.038 <0.013 <0.028

<0.039 <0.013 <0.045

<0.063 <0.013 <0.025
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Table II-2. Residue data used to calculate tolerance for pyroxasulfone on sweet corn forage, K+CWHR, 

and stover. 

Regulator: EPA EPA EPA

Chemical: Pyroxasulfone Pyroxasulfone Pyroxasulfone

Crop: Sweet corn forage Sweet corn K+CWHR Sweet corn stover

PHI: 43-97 days 43-132 days 70-132 days

App. Rate: 0.148-0.268 lb ai/A 0.148-0.268 lb ai/A 0.148-0.268 lb ai/A

Submitter: K-I Chemical K-I Chemical K-I Chemical

MRID Citation: MRID 47701656 MRID 47701656 MRID 47701656

Combined Residues of Pyroxasulfone and Metabolites M-1, M-3, and M-25 

(ppm)1

<0.063 <0.013 <0.025

<0.050 <0.013 <0.075

<0.047 <0.013 <0.088

<0.025 <0.013 <0.025

<0.025 <0.013 <0.025

<0.025 <0.013 0.115

<0.026 <0.013 <0.109

<0.042 <0.014 <0.025

<0.042 <0.016 <0.025

<0.034 <0.013 <0.025

<0.035 <0.013 <0.025

<0.028 <0.013 <0.025

<0.029 <0.013 <0.025

<0.034 <0.013 <0.025

<0.033 <0.013 <0.025

<0.025 <0.013 <0.053

<0.025 <0.013 <0.053

<0.029 <0.013 <0.031

<0.025 <0.013 <0.032

<0.031 <0.013 <0.025

<0.025 <0.013 <0.025

1

 Results in which all analytes were below the LOQ are shaded.

Pyroxasulfone

Sweet Corn Forage
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 84 of 87

Region / Country

GAP

Total number of data (n) 12

Percentage of censored data 17%

Number of non-censored data 10

Lowest residue 0.025

Highest residue 0.063

Median residue 0.032

Mean 0.035

Standard deviation (SD) 0.012

Correction factor for censoring (CF) 0.889

Proposed MRL estimate

- Highest residue 0.063

- Mean + 4 SD 0.081

- CF x 3 Mean 0.094

Unrounded MRL 0.094

Rounded MRL 0.1

Residues (mg/kg) n

< 0.025 2

0.026 1

0.027 1

0.028 1

0.029 1

0.034 1

0.035 1

0.039 1

0.042 1

0.049 1

0.063 1

Pyroxasulfone

Sweet Corn Stover

Region / Country

GAP
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 85 of 87

Total number of data (n) 12

Percentage of censored data 50%

Number of non-censored data 6

Lowest residue 0.025

Highest residue 0.112

Median residue 0.025

Mean 0.041

Standard deviation (SD) 0.028

Correction factor for censoring (CF) 0.667

Proposed MRL estimate

- Highest residue 0.112

- Mean + 4 SD 0.154

- CF x 3 Mean 0.082

Unrounded MRL 0.154

Rounded MRL 0.15

Residues (mg/kg) n

< 0.025 6

0.025 1

0.032 1

0.037 1

0.053 1

0.082 1

0.112 1

Pyroxasulfone

Sweet corn K+CWHR

Region / Country

GAP
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 86 of 87

Total number of data (n) 12

Percentage of censored data 92%

Number of non-censored data 1

Lowest residue 0.013

Highest residue 0.015

Median residue 0.013

Mean 0.013

Standard deviation (SD) 0.001

Correction factor for censoring (CF) 0.389

Proposed MRL estimate

- Highest residue 0.015

- Mean + 4 SD 0.015

- CF x 3 Mean 0.015

Unrounded MRL 0.015

Rounded MRL 0.015

High uncertainty of MRL estimate.

[High level of censoring]

Residues (mg/kg) n

< 0.013 11

0.015 1

Appendix III. REFERENCES
Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 87 of 87

DP#: D389415

Subject: Pyroxasulfone. Review of Residue Data for the New Active Ingredient 

Pyroxasulfone.

From: T. Morton

To: M. Walsh

Dated: 5/12/11

MRIDs: 48430006 & 48430011

DP#: D389651

Subject: Pyroxasulfone. Review of Enforcement Method Amendments for the New 

Active Ingredient Pyroxasulfone.

From: T. Morton

To: M. Walsh

Dated: 5/25/11

MRIDs: 48430001

DP#: D394353

Subject: Pyroxasulfone. Review of Residue Data for the New Active Ingredient 

Pyroxasulfone. 

From: T. Morton

To: M. Walsh

Dated: 10/13/11

MRIDs: 48430015

DP#: D395720

Subject: Pyroxasulfone. Review of Residue Data for the New Active Ingredient 

Pyroxasulfone.

From: T. Morton

To: M. Walsh

Dated: 11/17/11

MRIDs: 48430009 & 48430010

DP#: D396692

Subject: Pyroxasulfone. Review of Residue Data for the New Active Ingredient 

Pyroxasulfone.

From: T. Morton

To: M. Walsh

Dated: 12/8/11

MRIDs: 48466203