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

Page 3 of 87 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

- long

chain fatty acid (VLCFA) biosynthesis , similar in mode to the K3 group of herbicides (Group 15).
Under PP # 9F 7560, K

- I Ch emical, 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, a nd 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 Gri ts

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

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

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

................................ ................................ ........... 0.01 ppm Field Corn O il (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 t ri

- lateral r eview 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 product s 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 post emergence 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 prep lant 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 perta ining to immature soybean crop commodities along with additional storage stability related data are needed. The nature of thePyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 4 of 87 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 metabolite s 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 Know ledge

- 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 r esidues of concern for corn grain are parent and M

- 3. Thus, t he residue definition for corn grain will be harmonized with Canad a 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.
T he 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, foll owed by o xidation , to yield metabolite M

- 3, and/or demethylation, to yield metabolites M

- 12 and M

- 9. The parent compound may also undergo demethylation, h ydroxylation 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. R esidues 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

. T he 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 commoditie s
. The methods are adequate to determine residues of pyroxasulfone and metabolites M

- 1, M

- 3, and M

- 25 in corn, soybean, and wheat commodities

. T he methods have b e e n 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 soybea n 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 method s for crop commodities ha ve 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 e nforcement method for livestock commodities is needed. However, in the future a lives tock 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 fo und to be stable in corn stover through 12 months of frozen storage and in corn grain and forage through 13 months of frozenPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 5 of 87 storage. Pyroxasulfone, M

- 1, and M

- 3 were found to be stable in corn processed commodities during 6 months (oil) or 7 months (star ch, 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 6 7% 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 fo r 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.
A n a dequate cattle feeding stud y has been submitted . The data indicate that tolerances for livestock commoditi es 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 fiel d trial data requirements for wheat; additional data from field trials conducted in the U.S., which include data for wheat hay, must be submitted. A dequate field trial data are available to support the proposed tolerances for: corn, field, grain; corn, f ield, forage; corn, field, stover; corn, sweet, kernel plus cob with husks removed (K+CWHR) ; corn, sw eet forage; corn, sweet, stover . The data indicate that the proposed tolerance for field corn grain is too low; tolerance of 0.0 15 ppm would be appropriat e. 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, po p, and sweet) are identical. Tolerances are needed for popcorn commodities, at 0.0 15 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 processingPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 6 of 87 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 wil l 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 commod ities 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 m ust 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, extens ive 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 crop s 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 contain s 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 requirement s 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 preclud e 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 metabolit es and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of pyroxasulfone [ 3

- [[[5

- (difluoromethoxy)

- 1

- methyl

- 3

- (trifluoromethyl)

- 1 H

- pyrazol

- 4

- yl]meth yl]sulfonyl]

- 4,5

- dihydro

- 5,5

- dimethylisoxazole ] and its metabolite, 5

- ( difluoromethoxy )

- 1

- methyl

- 3

- ( trifluoromethyl )

- 1 H

- p yrazol

- 4

- carboxylic acid (M

- 3) calculated as the stoichiometric equivalent of pyroxasulfone, in or on the commodity

. Corn, field, g rain

................................ ................................ .......... 0.0 15 ppm Corn, sweet, kernel plus cob with husks removed

........................ 0.0 15 ppmPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 7 of 87 Corn, pop, grain

................................ ................................ ........... 0.0 15 ppm Tolerances are established for residues of the herbicide pyroxasulfone , including its metabolites and degradates, in or on the commodities in the table bel ow. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of pyroxasulfone [ 3

- [[[5

- (difluoromethoxy)

- 1

- methyl

- 3

- (trifluoromethyl)

- 1 H

- pyrazol

- 4

- yl]methyl]sulfonyl]

- 4,5

- dihydro

- 5,5

- dimethylisoxazole ] and its meta bolites [ 5

- ( difluoromethoxy )

- 1

- methyl

- 3

- ( trifluoromethyl )

- 1 H

- pyrazol

- 4

- yl ] methanesulfonic acid (M

- 1), 5

- ( difluoromethoxy )

- 1

- methyl

- 3

- ( trifluoromethyl )

- 1 H

- pyrazol

- 4

- carboxylic acid (M

- 3), and [ 5

- ( difluoromethoxy )

- 3

- ( trifluoromethyl )

- 1 H

- pyrazol

- 4

- yl ] methane sulfonic 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
T he product label s for the 85% WG and 42.5% WG formulation s 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 formulati on 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 l abel 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 ame nd 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 t he 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

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

Page 8 of 87 The proposed rotational crop restrictions for the 85% WG and 42.5% WG formulations are not supported by the available rotational crop data. Unti l 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 applic ation and root crops after 12 months

. 860.1550 Proposed Tolerances
P roposed tolerances for the following commodities are too low ; increased tolerances must be proposed:
o field corn grain (0.0 15 ppm)
P roposed 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)
P roposed 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 (0.0 15 ppm) o popcorn stover (0. 15 ppm)
P roposed 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 pyrox asulfone 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 recomm end for a n un conditional reg istration for the requested use on corn
. HED cannot at this time recommend for registration for the requested uses on soybean and wheat due to out standing 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 sufficientlyPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 9 of 87 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 me tabolism 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 det ermine 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 Residu e Analytical Methods
Livestock commodities
Radiovalidation data must be submitted for the method for livestock

. 860.1380 Storage Stability Crop commodities
F inal report s of the ongoing storage stability studies must be submitted. The final repo rts 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 samp les, 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 bePyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 10 of 87 reporte d 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 ad ditional field trial data for wheat hay (i.e., the 1 6 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, M

1 , 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 cla ss of selective herbicides . It provides contact and residual control of a broad spectrum of broadleaf weeds and grasses, including glyphosate

resistant varieties. Pyroxasulfone acts as a potential inhibitor of VLCFA biosynthesis similar in mode to the K3 group of herbicides (Group 15)

. Pyroxasulfone has little effect on germination , yet potentially inhibits shoot elongation of the germinating seed. Pyroxasulfone is translocated in plants through xylem and is apoplastic. K

- I Chemical is proposing pyroxa sulfone 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 te chnical grade of pyroxasulfone are presented in Table 2 . This petition represents the first food/feed uses of pyroxasulfone proposed in the U.S.
The chemical names and structures of pyroxasulfone metabolites are presented in Appendix 1.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 11 of 87 Table 1. Pyroxas ulfone Nomenclature

. Chemical structure of Pyroxasulfone

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

- ox azole CAS name 3

- [[[5

- (difluoromethoxy)

- 1

- methyl

- 3

- (trifluoromethyl)

- 1 H

- pyrazol

- 4

- yl]methyl]sulfonyl]

- 4,5

- dihydro

- 5,5

- dimethylisoxazole CAS registry number 447399

- 55

- 5 End

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

- OE ) V

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

- OG ) Chemical structure of M

- 1 metabolite

[ 5

- ( difluoromethoxy )

- l

- methyl

- 3

- ( trifluoromethyl )

- l H

- pyrazol

- 4

- yl) ] methanesulfonic acid Chemical structure of M

- 3 metabolite

5

- ( difluoromethoxy )

- l

- methyl

- 3

- ( trifluoromethyl )

- l H

- pyrazole

- 4

- carboxylic acid Chemical structure of M

- 25 metabolite

[ 5

- ( difluoromethoxy )

- 3

- ( trifluoromethyl )

- 1 H

- pyrazol

- 4

- yl) ] methanesulfonic acidPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 12 of 87 Table 1. Pyroxas ulfone 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 Reference 1 Melting po int 130.7 oC MRID 4770 1 615 pH 5.03 at 22 oC MRID 4770 1 61 3 Density 1.60 g/c M

- 3 MRID 47701616 Water solubility 3.49 x 10 - 3 g/L at 20.0 ± 0.5 o C MRID 477016 19 Solvent solubility g/L at 20 oC Methanol: 11.4 Acetone: > 250 Ethyl acetate: 97.0 n
- Hexane: 0 .0721 Toluene: 11.3 Dichloromethane: 151 MRID 47701620

Vapor pressure 2.4 x 10 - 6 Pa at 25 o C MRID 47701621 Dissociation constant, pK a Not applicable ( pyroxasulfone N

containing rings are not expected to be protonated in a practical pH range ) MRID 4770161 7

Octanol/water partition coefficient, Log( P OW ) log P OW = 2.39 at 25 oC, pH 8.7 MRID 47701618 UV/visible absorption spectrum at pH 1.13 : λ max = 225.5 nm ; ε = 7291 Lmol - 1 c m - 1 at pH 7.23 : λ max = 225.0 nm; ε = 7340 Lmol - 1 c m - 1 at pH 10.91 : λ max = 225.5 nm ; ε = 7334 Lmol - 1 c m - 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 label s 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 ) for mulations 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

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

Page 13 of 87 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

[6 3588

- 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 4 th 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

Page 14 of 87 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 = Mediu m
- fine soil texture; F = Fine soil texture. NA = Not applicable. NS = Not specified.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 15 of 87 For the 85% WG formulation, the proposed label specifies that the product may only be applied using ground equipment. Application throug h 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 so ils 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 tha t 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). Appl ications 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 indicate s 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, Extre me ® ( imazethapyr and glyphosate ), Gangster FR® ( cloransula m
- methyl ), Gangster V® ( flumioxazin ), glyphosate, Lorox® ( linuron ), Outlook® ( dimethenamid

- P ), Prowl® ( pendimethalin ), Pursuit® ( imazethapyr ), Python® ( flumetsu lam ), 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 whe at.
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® ( cloransula M

- methyl ), glyph osate, 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 glyp hosate and/or dicamba for application to field corn.
A 12

- hour re stricted 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, soybea n, 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 fiel d 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 anPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 16 of 87 18

- month PBI is proposed for a ll 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

- cr op 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 rate s are generally supported by the submitted field trial data. HED has determined th at 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, s weet 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 c orn, 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

- d ay 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 be en 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 coars e
- 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

- , an d medium

- textured soils, and a maximum seasonal rate of 0.112 lb ai/A for soybean grown in coarse
- textured soils.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 17 of 87 Based on the use pattern information included with the OECD dossier submission for the 85% WG formulation, the petitioner intends that only o ne application be made in the spring to corn, soybean, and wheat . F or 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 0.1 1 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 ad juvant 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 soy

beans. 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 fie ld 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 modif y the labels for both products to specify that only root crop s 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 radiolabe ls were used in the plant studies; the label positions are presented below:Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 18 of 87 [pyrazole

- 5

- 14 C ] pyroxasulfone [isoxazoline

- 3

- 14 C ] pyroxasulfone

A number of metabolites were identified in these studies. The chemical structures and report names for thes e metabolites are provided in Appendix I. Field corn (MRID 47701649) : The metabolism of pyroxasulfone was investigated in field corn following a single application of [ 14 C ] 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 co rn grain ( kernels ) harvested at BBCH 79 and 99, respectively, following preemergence application of [pyrazole

- 5

- 14 C] 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 an d 0.101 ppm in corn grain harvested at BBCH 79 and 99, respectively, following preemergence application of [isoxazoline

- 3

- 14 C] pyroxasulfone

. Following postemergence applications with [pyrazole

- 5

- 14 C] pyroxasulfone , TRR were 1.905, 5.118, and 3.315 ppm in c orn 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 an d 0.048 ppm in corn grain harvested at BBCH 79 and 99, respectively, following postemergence application of [isoxazoline

- 3

- 14 C] pyroxasulfone

. TRR levels in the foliage treated postemergence were higher than th ose 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 radioactivit y 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 hyd rochloric 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

Page 19 of 87 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 eluci date 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 postem ergence 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 a s minor residues in stove r treated postemergence , each at <10% TRR (<0.30 ppm). Approximately 73

- 76% TRR was identified in stover treated with [pyrazole

- 5

- 14 C] pyroxasulfone and 16

- 43% TRR was identified in stover treated with [isoxazoline

- 3

- 14 C] 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 o f 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

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

- 3

- 14 C] pyroxasulfone

. Unidentified minor me tabolites 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 meth yl 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 demethyl ation of M

- 1. For the other py razole

- ring metabolites, the carboxylic acid metabolite M

- 3 likely form s from metabolites M

- 8 and M

- 10, with subsequent demethyl ation to form M

- 9 , which may be further conjugated

. In the case of the isoxazoline

- ring metabolites, an intermediate cysteine c onjugate ( M

- 26 , which was not found) may form from pyroxasulfone; subsequent deamination of M

- 26 w ould result in the formation of the conjugate M

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

Page 20 of 87 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 confirmato ry 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 pre
emergence and post
- emergence treatment with KIH
- 485Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 21 of 87 Soybean (MRID 477016 50 ) : The metabolism of pyroxasulfone was investigated in soybean following a single application of [ 14 C ] pyroxasulfone (pyrazole or isoxazoline labeled) , formulated as a WG formulation , in w ater 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

- 14 C ] pyroxasulfone . TRR were 3.700, 1.142, 0.498, and 3.347 ppm in soybean foliage harvested at BB CH 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

- 14 C ] pyroxasulfone

. Following postemergence application of [pyrazole

- 5

- 14 C ] pyroxasu lfone , 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 harve sted 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 postemergencePyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 22 of 87 application of [isoxazoline

- 3

- 14 C ] pyroxasulfone . During the subsequent characterization and identificatio n of the residues , it became evident that there had been a mix

- up during the sampling procedure s . In general, the composite samples from the postemergence treatment plots contained a mixture of plant material that had been treated with [pyrazole

- 5

- 14 C ] pyr oxasulfone and [isoxazoline

- 3

- 14 C ] 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

- 14 C ] pyroxasulfone

. After preemergence treatment w ith the [pyrazole

- 5

- 14 C ]

- label or the [isoxazoline

- 3

- 14 C ]

- 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 t he 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 hea lth 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 radiolabelle d 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 T RR was removed with acetone/ water and water extractions, with levels of recovered radioactivity ran ging 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 extrac tability 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 mas ses 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 identifiedPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 23 of 87 in mid

- fruit harvest foliage. The major r esidues 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

- 1 4 % (0.20

- 0.30 ppm) , 5.1

- 1 3 % (0.17

- 0.27 ppm) , and 38

- 55% TRR (0. 63

- 2.46 ppm) , respectively, in first flower harvest foliage, and 1 3

- 16% (0.07

- 0.20 ppm) , 6.8

- 1 2 % (0.055

- 0.17 ppm) , and 3 5 % 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

- 3 1 % TRR (0.15

- 0.30 ppm) ; this metabolite was a minor residue (~8% TRR, 0.26 p pm) 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 tre ated with [pyrazole

- 5

- 14 C] pyroxasulfone, there was no sample available of mid

- fruit harvest foliage treated with [isoxazoline

- 3

- 14 C]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 3 2 % 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 , ≤1.4 9 ppm) and mature seeds (≤52.0% TRR , ≤0.65 ppm ), following pre

- and postemergence application. The conjugate M

- 29 (co

eluting with M

- 1) was also considered a ma jor 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 ma ture foliage and 43

- 5 2 % TRR was identified in seed, except seed treated preemergence with [ pyrazole

- 5

- 14 C] pyroxasulfone , in which only 5.5% TRR was identified. The petitioner proposed that pyroxasulfone is metabolized in soybean via cleavage of the meth yl 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 demethyl ation of M

- 1. For the other pyrazole

- ring metabolites, the carboxylic acid metabolite M

- 3 likely form s from metabolites M

- 8 and M

- 10, with subsequent demethyl ation to form M

- 9 , which may be further conjugated

. In the case of the isoxazoline

- ring metabolites, an intermediate cystein e conjugate ( M

- 26 , which was not found) may form from pyroxasulfone; subsequent deamination of M

- 26 w ould 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 n o 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 mo nths prior to completion of analysis. The petitioner stated that because i nitial analyse s of the treated samplesPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 24 of 87 w ere not completed within three months of harvest , sub

- samples of the mature foliage ( pre
- and postemergence ) were re
- extracted and analyzed; c omparison of the HPLC profile s to the original data reportedly confirmed the stability of the sample s 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, t he 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 we re available of soybean hay from plots treated with [isoxazoline

- 3

- 14 C] pyroxasulfone. B ased on the sample used in the radiovalidation study (MRID 47701665), the petitioner appears to have initiated another soybean metabolism study. When the required add itional 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

- 14 C] pyroxasulfone are needed.

Postulated pathways of f ormation of metabolites iden tified in soybean following pre
emergence and post
- emergence treatment with KIH
- 485Pyroxasulfone 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 me tabolites 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.
HenPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 26 of 87 MRID 47701651 : The absorption, distribution and excretion of [ 14 C ] pyroxasulfone were investigated follo wing repeated oral administration to the laying hen. [Pyrazole

14 C] P yroxasulfone 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 twic e daily. Approximately 23 hours following the final dose administration, the hens were sacrificed , and l iver, skin, muscle and fat were either excised or sampled as appropriate. Radioactivity was determined in all samples by direct liquid scintillation c ounting (LSC) or LSC following solubilization. The actual mean dose was 2.129 mg/animal/day, equiv alent to 14.8 ppm in the diet, which is

~ 78 0 x the estimated dietary burden to poultry (see Table 6 ). T he mean recovery of radioactivity was 88% of the adm inistered 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 ; c oncentrations 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 releas ed 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 NH 3 ) , which extracted 32

- 40% TRR in to tal 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 differen t 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 putat ive 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 unidentifi ed peaks, n one of which accounted for greater than 0.037 ppm in an individual matrix

. Samples were stored frozen prior to analysis but n o 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 rin gs 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 47 701652 : The absorption, distribution and excretion of [isoxazoline

- 3

- 14 C ] pyroxasulfone were investigated following repeated oral admi nistration 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 ~ 61 0 x 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

- 0.0 976 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 ; c oncentrations 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 o rganic ( EtOAc , ACN , acidified ACN , and methanol) or more polar solvents (water, 1 M HCl, and 1M NH 3 ) , 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 morePyroxasulfone 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. Nonextractabl e 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 identif ied 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 metabolit e 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 id entified 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 n o 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 sa mple 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 comp letion of analysis. Based on the observed metabolites, the petitioner proposed that pyroxasulfone is metabolized in hens via dem e thylation to form metabolite M

- 5 or hydroxylation to form metabolite M

- 11; further oxidation of M

- 11 would yield M

- 13.
Co nclusions

. 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 [pyrazo le
14 C]
- KIH
- 485 (equivalent to 15 ppm in the diet) over 10 daysPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 29 of 87 Goat
MRID 47 701653 : The absorption, distribution, metabolism and excretion of [ 14 C ] pyroxasulfone were investigated following repeated oral administration to the lactating goat. [Pyr azole

14 C ] 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 ad ministration, the goat was sacrificed and l iver, 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 die t , equivalent to ~ 25 0x and 160 x the estimated dietary burden to beef and dairy cattle, respectively (see Table 6 ). The recovery of radioactivity was 91.9% of the administered dose ; t he majority of radioactivity (84%) was excreted in the urine , with minima l 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 NH 3 ) ; 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 radioactiv ity 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 i dentified 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 m etabolites 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 pro perties 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 go ats 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 metab olites 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 [ 14 C]
- KIH
- 485 at a daily dose l evel of 19 mg/ animal/day (equivalent to 12 ppm in the diet) over 5 days

MRID 47 701654 : 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 [pyrazole

14 C ] 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 47 701655 : The absorption, distribution, metabolism and excretion of [isoxazoline

- 3

- 14 C ] 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. Approximate ly 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 ~ 21 0x and 140 x 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 th e 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 du ring the study; the highest residues observed in milk were obtained on the last sampling day. Radioactivity was detected in all tissues ; c oncentrations 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 pp m 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 m ore polar solvents (water, 1 M HCl, and 1 M NH 3 ) ; 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 hydrolys is (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 ; n eit her 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 ex ceeded 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, 0.00 18 ppm)

. Only residues which were not retained on the HPLC column individually a ccounted 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 Nu mber 0535/138) indicated that the un
retained 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 m etabolites, 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 [ 14 C]
- KIH
- 485 at a daily dose level of 13.6 mg/ animal/day (equivalent to 10 ppm in the diet) over 3 days

Samples were stored frozen prior to analysis but n o dates of extraction and/or analys is 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 indicate d stability of the residue s 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 pr ior to completion of analysis.

Conclusions. The submitted goat metabolism studies are adequate to satisfy data requirements for nature of the residue in ruminants. Initially, f or the study conducted with [isoxazoline

- 3

- 14 C] pyroxasulfone, the peti tioner was required to provide additional discussion and supporting data for their statements that un

- retained radioactivity accounting for >0.05 ppm was likelyPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 34 of 87 multicomponent and contained M

- 30 and 5

- methyl

- 5

- isoxazoline carboxylic acid . The petitioner w as 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 supp orting data if available) of the attempts to identify residues by LC/MS. No dates of sample collection, extraction, or analysis were provided. T he 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), i f the required data indicate d that final sample analysis was not completed within 6 months of sample collection, evidence should be provide d that the identity of residues did not change during the period between collection and final analysis. For the hen and goat studies reflecting iso x azoline labeling (MRIDs 47701652 and 47701655), t he petitioner was required to provide the comparative chro matographic data that were cited in the stud ies

. 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 conclu ded 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

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

Page 35 of 87 Table 4. Summary of Residue Analytical Methods. Matrix Analytes Method Limit of q uantitation ( 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 anal ytes 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 d ata generation method (Australia) Wheat forage , g rain , s traw Pyroxasulfone M

- 1 M

- 3 M

- 25 LC/MS /MS

(Method No. AT M

- 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 p yroxasulfone, M

- 1, M

- 3 in milk ; 0.010 for p yroxasulfone, 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, Section s B.5.2.1 and B.5.2.3 (MRIDs 47701656

- 47 701658, 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 s oybean 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 A gricultural 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 ). T he extract is partitioned with hexane , and the hexane phase is discarded . The aqueous layer is diluted to v olume 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 NaHCO 3 and , for grain and oil , saturated NaCl solution, and partitioned twice with hexane. The combined hexane layers, containing pyroxasulfone , are concentrated to near drynessPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 36 of 87 and reconstituted in ACN. The aqueous phase, containing M

- 3, is acidifie d (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) car tridges; 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 analy sis [ 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 NH 2 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, s amples 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 evapor ated 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 c orn meal , s amples 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 aliq uots; 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 u sed 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. F or pyroxasulfone and M

- 3 in grain, forage, starch, oil, and flour andPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 37 of 87 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 s tandards. The method did not include any information about converting residues of metabolites to parent equivalents.

The io n 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 transit ions 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 d ue to the difficulties encountered in the determination of pyroxasulfone , M

- 1, M

- 3 and M

- 25, some of th e analyses were conducted with solvent

- based calibrants while others were based on calibrants prepared in control matrix final extract ; t he matrix

- based calibrants were necessary when mass spectral ionization demonstrated significant matrix enhancement or matrix suppression of the signal. The petitioner stated that m atrix blanks (controls) were analyzed concurrently to evaluate potential analytical interferences and that t here 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, a nd at 0.005 and 0.05 ppm for M

- 25; corn forage was additionally fortified with pyroxasulfone at 50 ppm. A verage 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 recoverie s of 69% and 57%, respectively)

. The overall r elative 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 al l matrices ranged 60

- 120 % for pyroxasulfone (average of 88 % ; four recoveries <70% ), 52

- 157 % for M

- 1 (average of 9 9 % ; 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 8 6 % ; 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% ave rage 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 ( lowerPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 38 of 87 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 enhanceme nt 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 quantit ation, 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 flo ur, 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 0.0 1 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 co rn 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 Herbic ide 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 aliquo ts, 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 NaHCO 3 and saturated NaCl solution [seed, hay, hulls, meal , oil ] or with 0.5 M NaHCO 3 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, ev aporated 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 se ed ; M

- 1Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 39 of 87 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 a nalysis [ 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 NH 2 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 met hanol, 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 inform ation 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 we re 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 d ue to the difficulties encountered in th e 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 ; t he matrix

- based calibrants were necessary when mass spe ctral ionization demonstrated significant matrix enhancement or matrix suppression of the signal. The petitioner stated that m atrix 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, a pparent 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 u ntreated soybean forage, at 0.00 7

- 0.0 27 ppm ; (2) a pparent 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 s ample 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 th e 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 valida ted 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

. A verage recoveries were within acceptable limits ( 70

- 120% ) for all analytes in allPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 40 of 87 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 RSD s were <2 0% at for all analytes in all matrices at all fortification levels. Recoveries from all matrices ranged 63

- 108 % for pyroxasulfone (average of 83 %; one recover y <70%), 66

- 120 % for M

- 1 (average of 94 %; one recover y <70% ), 63

- 116 % for M

- 3 (average of 84 %; fo ur 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 pp m 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 conclu ded 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 NaHCO 3 . The registrant has submitted MRID 48430001 which contains the recommendation of the ILV laboratory pertaini ng to a warning regarding emulsions forming. Adequate r adiovalidation data for this method were submitted using a sample of soybean hay from soybean plants treated postemergence with pyrazole

- label [ 14 C]pyroxasulfone (from a soybean metabolism study w hich does not appear to have been submitt ed 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, h ulls, 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 recoveri es of 36% and 59%, respectively, and soybean oil fortified with M

- 1 at 0.10 ppm yielded a recovery of 69%.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 41 of 87 Data collection method: An LC/MS/MS method similar to the enforcement methods was used for the determination of residues of pyroxasulfone and its m etabolites 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, AT M

- 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 pyroxasulfon e , M

- 1 and M

- 3 by LC/MS/MS. For the determination of the M

- 25 analyte, a n 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 st andard 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 sp ecify 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; t he petitioner did not identify the crop used for method validation studies. Samples were fortified with each analyte at the LOQ and 10xLOQ. A verage recoveries were within acceptable limits ( 70

- 120% ) and RSD s 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 method s 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 method s 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 the se 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.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 42 of 87 Livestock commod ities
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 commoditi es 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 commoditi es 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, s amples 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 concentrate d 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 aq ueous 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 tissue s 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 extract s are combined, brought to vol ume (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 i s basified (using 0.5 M NaHCO 3 ), mixed with saturated NaCl soluti on, and partitioned with hexane to extract pyroxasulfone . The hexane phase i s concentrated to dryness and reconstituted in ACN for further Envi

- Carb SPE cleanup; the extract i s 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 i s acidified (using 0.5 M citric acid) then partitioned with hexane: EtOAc (3:7, v:v) to extract M

- 3. The extract i s 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. T he 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 i s mixed with NaCl , and residues of M

- l a re partitioned into ACN. The ACN extract i s evaporated to dryness and reconstituted in ACN:water (2:8, v:v, containing 0.5% acetic acid) for analysis by LC/MS /MS.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 43 of 87 LC/MS /MS analyses were conduct ed 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 quant ified 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 . Th e petitioner stated that m atrix blanks (controls) were analyzed concurrently to evaluate potential analytical interferences , and i n 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, a pparent residues of each an alyte were below the LOQ in/on all samples of milk, skim milk, cream, muscle, fat, liver, and kidney from the undosed cattl e. 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 m uscle, liver, kidney and fat by fortification with each analyte at 0.01 and 0.10 ppm each. Average recoveries were wit hin acceptable limits (70

- 120%) for all analytes in all matrices. The RSD s 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 (averag e 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. 0 1 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 ana lyses (≤ 4.7 % RSD). The ILV laboratory stated that o ne 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 preparati on 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 a re homogeni zed 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 a re 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 i s concentrated , basified (using 0.5 M NaHCO 3 ) , mixed with saturated NaCl so lution , andPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 44 of 87 partitioned three times with hexane. The combined hexane extract i s concentrated to dryness and reconstituted in ACN for further purification by Envi

- Carb SPE; the extract i s evaporated to dryness and reconstituted in ACN:water (2:8, v:v, cont aining 0.5% acetic acid) for LC/MS /MS analysis for pyroxasulfone . The aqueous portion remaining after the hexane partition i s acidified (using 0.5 M citric acid) , and M

- 3 i s partitioned into hexane: EtOAc (3:7, v:v). The organic phase is evaporated to dry ness 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 i s concentrated, acidified to pH 5 (using 0.2 M acetate buffer) , and partitioned with EtOAc . The remaining aqueo us phase i s purified by NH 2 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 methan ol, 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 L OQ was 0.01 ppm for each analyte in poultry egg. The petitioner stated that m atrix blanks (controls) were analyzed concurrently to evaluate potential analytical interferences ; n o analytical interferences were detected in matrix blanks (t he limit of detect ion 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 t h e RSD s 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 sampl es 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 recover y 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 i ntegrated response for M

- 3 matrix blanks

. The ILV laboratory stated that o ne 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 method s data are partially adequate to satisfy data requirements. Radiovalidation data must be submitted fo r 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 feed ing study data are required to support this petition.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 45 of 87 The petitioner is not proposing tolerances for li vestock 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, radio

validation data are required.
860.1360 Multiresidue Methods Monograph for Pyroxasulfone, Section B.5.2 .4 (MRID 47 701673 )
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 substanc es 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 a nd 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 w as 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 meth ods, 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

. P yroxasulfone was found to be fully recovered from soybean h ay 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 30 4 (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.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 46 of 87 Because pyroxasulfone and its metabolites are not substituted ureas, no testing under Protocol G is required.
Conclusions

. The submitted stud ies are a dequate 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 477016 56 , 4770165 7 , 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 stu dy, 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 pro posed 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%) an d 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 an d 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 ag ed 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 refin ed 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 thePyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 47 of 87 longest period necessary to encompass total storag e 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 commoditi es. 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 interval s (average of 1 6 1 % and 6 5 %, 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 foun d 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, an d 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 wa s 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 b racket sample storage prior to extraction will be added to the report by report amendment. The storage duration s and conditions of samples from the crop field trial , processing studies , and field rotational crop studie s submitted to support this petition are presented in Table 5

.
Table 5. Summary of Storage Conditions and Duration s 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) Co rn 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 monthsPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 48 of 87 Table 5. Summary of Storage Conditions and Duration s 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 fo rage 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 p ea 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 Fr ozen 747 days (24.5 months) 25 months Corn starch Frozen 479 days (15.7 months) 1 6 months Corn grits, flour, and meal Frozen 520 days (17.1 months) 1 8 months (meal) 2 3 months (flour) Corn oil Frozen 575 days (18.9 months) 1 7 months (33% degradation) So ybean 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 d ays (17.1 months) 14 months Soybean meal Frozen 567 days (18.6 months) 1 4 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) 1 2 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 da ta 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 report s , the petitioner should include additional information/data pertaining to the procedures used for the storage stability stud ies , including identification of thePyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 49 of 87 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 stud ies . An explanation should be provided for not usi ng 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 Pyroxa sulfone, Section B.7. 8.3 (MRID 477016 59 )
K

- I Chemical submitted a storage stability stud y 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 reco veries 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 muscl e, 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 tha t 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

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

Page 50 of 87 860.1460 Food Handling
There are no proposed uses that are relevant to this guideline topic. 860.1480 Meat, Milk, Poultry, and Eggs Monograph for Pyroxasulfone, Section s B.7. 8 .1 and B.7.8.2 (MRID 4770165 9 )
The re are several livestock feedstuffs associated with the proposed uses of pyroxas ulfone: aspirated grain fractions; field and sweet corn forage, silage, and stover; field corn grain and milled bypro ducts; sweet corn cannery waste

. The dietary burdens of pyroxasulfone to livestock were calculated using the procedures of the most recen t guidance developed by HED (June 2008); see Table 6

. The estimated dietary burdens are 0.0 48 ppm for beef cattle, 0. 074 ppm for dairy cattle, 0.0 19 ppm for poultry, and 0.0 21 ppm for swine. K

- I Chemical submitted a fe eding stud y with cattle, which is su mmarized 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 Type 1 % Dry Matter 2 % Diet 2 Highest Residue (ppm) Dietary Contribution

(ppm) 3 Beef Cattle Corn, field, stover R 83 1 5 0. 139 0.0 25 Corn, field, grain CC 88 8 0 0.0 25 0.0 23 Untreated Protein Concentrate PC NA 5 0 0 TOTAL BURDEN

-- -- 100

-- 0.0 48 Dairy Cattle Corn, field, forage/silage R 40 4 5 0. 05 4 0.0 61 Corn, field, grain C C 88 45 0.025 0 .013 Untreated Protein Concentrate PC NA 10 0 0 TOTAL BURDEN

-- -- 100

-- 0. 074 Poultry Corn, field, grain CC 8 8 75 0 .025 0 .019 Untreated Protein Concentrate PC NA 25 0 0 TOTAL BURDEN

-- -- 100

-- 0.0 19 Swine Corn, field, grain CC 88 85 0.0 25 0.0 21 Untreated Protein Concentrate PC NA 15 0 0 TOTAL BURDEN

-- -- 100

-- 0.0 21 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 thePyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 51 of 87 petitioner to be 1x, designated “group 2”) and at exaggerated target dose levels of 5.4 ppm (designated “group 3”) and 18 ppm (desig nated “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 grou p 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 ~ 38 x, 110 x, and 370 x, respectively, the maximum estimated dietary burden to beef cattle and 24 x, 73 , and 240 x, 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 dai ly. 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 cre am 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 r esidue 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 st ability 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; recover y 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 we re 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 s amples.
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 contro l 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 per iod (including samplesPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 52 of 87 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 Ta ble 7 below.

Table 7. Maximum Residues in Samples from Cows Dosed at 18 ppm
. Samples Residues (ppm) P yroxasulfone M

- 1 M

- 3 Whole milk <0.004 1 <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 D ay 7 samples only ; residues in samples from all other samp ling 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.
Conclusi ons
. 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 tha t radioactivity was not readily extractable from milk and tissues using organic solvents.
T he 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 d osing level corresponding to 2 40 x 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 rumina nt 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 ind icate that residues are below the LOQ at a 10x dosing level.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 53 of 87 For this study, quantifiable residues of parent were found in milk, at up to 0.004 ppm, at a 2 40 x dosing level. If these residues are adjusted to a 10x dosing level (~0.00 0 1 7 ppm), they are bel ow the LOQ for milk. Poultry : The petitioner conclud ed 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 tria ls, 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 t he 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 ~ 780 x (based on the 14.8

- ppm dosing level and a dietary burden of 0.0 19 ppm), expected residues of M

- 1 at a 10x feeding level would be <0.00 01 ppm. Therefore, HED concludes that a poultry feeding study is not needed at this time. T he 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 ne eded 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 Pyroxasulf one, Section B.7. 6.1.1 (MRID 4770165 6 ; field and sweet corn ) Monograph for Pyroxasulfone, Section B.7. 6.1.2 (MRID 4770165 7; soybean ) Monograph for Pyroxasulfone, Section B.7.6.1.3 (MRID s 47701669, and 47701670; wheat )
K

- I Chemical submitted field trial da ta 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 f or 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 o n barley or triticale in the U.S. , these data will not be discussed herein.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 54 of 87 Table 8. Summary of Residue Data from Crop Field Trials with Pyroxasulfone
. Crop matrix T arget Applic. Rate (lb ai/A) [g ai/ha] PHI

(days) Total Residues of Pyroxasulfo ne and Metabolites M

- 1, M

- 3, and M

- 25 (ppm) 1

n Min. Max. HAFT 2 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 0.0 35 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 to tal application rate, 42
- day P G I) 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 (12 0 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 (2 40 g ai/ha) for fine

- textured soil for preplant, preemergence applications, and early postemergence application; a maximum season al rate of 0.267 lb ai/A (300 g ai/ha) is proposed (independent of soil type)

. Therefore, the field trialsPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 55 of 87 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 r ate, 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 postemergen ce 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 Zo nes 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 preemerg ence 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 0.09 3 + 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 ret reatment interval was 1 4 to 23 days. Applications were made in 13

- 25 gal/A spray volumes using ground equipment ; no adjuvant was used. Duplicate s amples of field corn forage were harvested at the late dough/early dent stage, 37

- 95 days following appl ication. Duplicate s amples of sweet corn forage and K+CWHR were collected at normal harvest, 43

- 132 days following application; sweet co r n stover samples were collected 70

- 132 days following application. Duplicate s amples of field corn grain and stover w ere 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 0.0 05 ppm for each analyte in each commodity. The LOQ for combined residues in parent equivalents was 0.025 ppm for each commodity. Samp le storage conditions and durations are reported in Table 5 . The available storage stability data support the field corn field trial study.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 56 of 87 The results of the field trials reflecting postemergence application are summarized in Table 8

. Residues of pyr oxasulfone 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 s weet corn K+CWHR samples, residues of pyroxasul fone 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 <0.0 14

- 0.0 16 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 fi ve 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 s weet 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 ; maxi mum 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 stov er 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 difference s in residues in samples treated by the differen t methods and that soil type and environment seemed to have the major influence on residues . Q uantifiable 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 inco rporated application or post

planting 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 applic ations had similar total residues (<0.07 0

- 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 immed iately after application decline to levels below the LOQ at 30 days after application. R esidues 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 applicatio n ( although quantifiable residues werePyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 57 of 87 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 ; n o residues of M

- 25 were found after 16 days after treatm ent. No quantifiable residues of M

- 3 were found in forage, except in one sample at 60 days posttreatment ( 0.009 ppm ). R esidues 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 decli ne 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 d ecline period of 30 days after normal harvest ) f

rom 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 l abel 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) , expr essed as parent equivalents: 0.06 ppm for field corn forage ; 0.0 15 ppm for field corn grain ; 0.15 ppm for field corn stover ; 0. 10 ppm for sweet corn forage ; 0.0 15 ppm for sweet corn K+CWHR; and 0.15 ppm for sweet corn stover ; refer to Appendix II for tole rance 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 fo rmed. No residue data were submitted for po p corn 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 tolera nces are needed for popcorn commodities. The petitioner must propose tolerances for pyroxasulfone residues of concern in/on popcorn grain, at 0.0 15 ppm, and popcorn stover, at 0.15 ppm. Soybean Pyroxasulfone was applied to soybean, as an 85% WG formulat ion, 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 0.2 68 lb ai/A (300 g ai/ha) for fine

- textured soil. The proposed labels specify application rates up to 0.11 lb ai/A (12 0 g ai/ha) for coarse
- textured soil and up to 0.21 lb ai/A (2 40 g ai/ha) for fine

- textured soil for preplant/ preemergence applications, an d up to 0.08 lb ai/A (89 g ai/ha) for coarse
- textured soil and up to 0. 19 lb ai/A (2 10 g ai/ha) for fine

textured 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 twent y 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 soilsPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 58 of 87 or at 0.112 lb ai/A (125 g ai/ha) for coarse

- textured soils; the applica tion 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 an d 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 (2 09, 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, respectiv ely. 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 s amples were harvested at the R2

- R3 stage for forage (1 5 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 0.0 05 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 1 2 months for pyroxasulfone, M

- 1, and M

- 3 in seed, and 26 months, 24 months, and 29 months for M

- 25 i n 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

. Q uantifiable 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,Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 59 of 87 and <0.005

- 0.029 ppm for M

- 25. Combined residues in parent equivalents ra nged <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. C ombined 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 preemergen ce 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 mu ch 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 re sidues; <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 s plit 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 re sidues 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 co uld be seen just above LOQ . R esidues 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 clos e to the LOQ in/on all seed samples from these trials.
Conclusions

. The submitted soybea n 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 timi ng. 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 ar e submitted and found adequate, tolerances for soybean RACs will be recommended

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

Page 60 of 87 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 b e 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 200 7

- 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 Ne w South Wales; Templers, South Australia; and Toodyay, Western Australia. In the trials reported in MRID 47701669, separate treatment p lots received a single application of the 85% WG formulation at an application rate of 0.112 or 0.223 lb ai/A ( 125 or 25 0 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 so ils

. 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 in cluded for each trial. Although the petitioner provided information pertaining to soil type at each trial, the soil texture (fine, medium, coarse) was not provided. T he 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. W heat 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 de cline, 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. G rain and straw were collected at mature harvest , with PHIs ranging 153

- 176 days

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

Page 61 of 87 Samples were analyzed for residues of pyroxasulfone and its metabolites M

- 1, M

- 3, and M

- 25 using LC/MS/MS Method AT M

- 0031. The validated LOQ for each a nalyte 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 a nd 0.223 lb ai/ A ) were analyzed ; howeve r , 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 rate s were analyzed for grain and straw. Sample storage condit ions and durations are reported in Table 5 . The available interim storage stability data do not support the wheat field trial stud ies

. 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 applic ation scenarios , IBS and PSPE. T he proposed U.S. label allows both preplant and post

- plant preemergence applications. Because trials were conducted by spraying the IBS plots, then planti ng the entire trial area, then spraying the PSPE plots, all on the s ame day , the data have been treated as a whole irrespective of application timing in relation to plant ing. 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, a nd 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, a nd M

- 25 were below the LOQ (<0.01 ppm each) in/on all samples of wheat grain harvested 1 67

- 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

- 1 76 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 i n 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 t he geographic representation of the wheat field trials is incomplete. In addition, no samples ofPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 62 of 87 wheat hay were collected in any of the fie ld 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 supp ort 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, t he 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 sho uld 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, gra in, 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 1 6 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 in tervals. 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.
A dditional 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, Section s B.7. 6.1.1 and B.7.7.2 (MRID 4770165 6; field and sweet corn ) Monograph for Pyroxasulfone, Section s B.7. 6.1.2 and B.7.7.2 (MRID 4770165 7; 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 avera ge processing factors found for the processed commodities of field corn and soybean is presented in Table 9

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

Page 63 of 87 Table 9. Summary of Processing Factors for Pyroxasulfone
. RAC Processed Commodity Processing Factor Pyroxasulfone M

- 1 M

- 3 M

- 25 Total Field c orn Grits NC 1 NC NC NC

-- Meal NC NC NC NC

-- Flour NC NC NC NC

-- Starch NC NC NC NC

-- Dry

- m illed Oil NC NC NC NC

-- Wet

- m illed Oil NC NC NC NC

-- Soybean Meal NC NC >2.6x 2 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 cor n 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 5 x the proposed maximum seasonal rate . A singl e bulk s ample of field corn was collected 13 6 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 provi ded; based on sample shipping dates, processing was completed with in 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 cor n 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 star ch, and 0.03 ppm for meal and refined oil. Sample storage conditions and durations are reported in Table 5

. The available storage stability data support s the field corn processing study

. Residues of pyroxasulfone, M

- 1, M

- 3, and M

- 25 were below the L OQ 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, process ing 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 s ample of soybean seed was collected 113 days following the last application and processed into grits, meal, hulls, and refined oil usingPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 64 of 87 simulated commercial process ing procedures. Dates of actual processing were not provided; based on sample shipping dates, processing was completed with in 90 days of harvest. Samples were analyzed for residues of pyroxasulfone and its metabolites M

- 1, M

- 3, and M

- 25 using the propose d 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 d ata are needed reflecting maximum storage interval s of 2 9 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. Resid ues 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 resi due 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 stud y 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 b e 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 c ommodities of field corn.
The soybean processing data indicate that residues of concern for pyroxasulfone concentrate in soybean mea l . Using the HAFT of 0.0 49 ppm , as well as the processing factors of 1.4 x, the expected total residues in soybean meal fol lowing treatment at 1x would be 0.0 69 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 stud y will be re

- evaluated for adequacy. The interim results of the storage stability study indicate that residues of M

- 1 may decline in soybe a n oil during storage (~30% after 7 months of storage). Because the residues of this analyte were below the LOQ in o il 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 re

evaluated when the final results of the storage stability study have been submitted.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 65 of 87 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 cur

rently 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 Metabol ite 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 addres s:
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 Rotati onal Crops Monograph for Pyroxasulfone, Section B.7. 9.1 (MRID 477016 74 ) The metabolism of pyroxasulfone was investigated in rotated soybean, radish, and wheat. The test substance, radiolabeled pyroxasulfone (pyrazole and isoxazoline labels applied in se parate 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 maximu m 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

- da y isoxa zoline

- label plot were destroyed by pests , and the plot was replanted at 490 day s 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 plantbac k 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. Re sidues decreased in soybean and radish matrices, and wheat forage, as plantback interval s 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 treatment s. NonextractablePyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 66 of 87 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 rad ish 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 foli age (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 matrice s. 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 malo nyl 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, acco unting 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 sampl es 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

- 1.08 5 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 f ound 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.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 67 of 87 Residues of M

- 1, M

- 3, and/or M

- 25 greate r than 0.01 ppm were found in rotated radish, soybean, and wheat commodities from the 30

- and 120

- day PBI s ; and in rotated soybean and wheat commodities from the 365

- day PBI. Samples were stored frozen from collection to analysis. I nitial HPLC analyses w ere 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 ob tained. No data to support these statements were included in the submission. Based on the results of the study, the petitioner proposed that i n general, metabolism in rotational crops appears to occur via cleavage between the parent sulfone and isoxazoli ne 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, h ydroxylation of pyroxasulfone would yield metabolite M

- 6

. Conclusions

. The submitted confined rotational crop study is adequate to satisfy data requirem ents. 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 foun d 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 f or tolerance en forcement 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.
860.19 00 Field Accumulation in Rotational Crops Monograph for Pyroxasulfone, Section B.7. 9.2 (MRID s 477016 75 and 47701676 )
K

- I Chemical is not proposing any tolerances for rotated crop commodities in the U.S. The petitioner submitted field rotational crop dat a from two studies conducted in Australia to support the establishment of rotational crop tolerances in Australia

. One study was conducted with field pea at PBI s of 25

- 28 days , and the other study was conducted with field pea and wheat at PBI s 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 ofPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 68 of 87 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. F ield peas were pl anted 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

- 4 3, 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 t hird 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 o f 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 AT M

- 0031. For calculating total resid ues, 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 equival ents, 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 soi l)

. 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 pyroxasul fone 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 w ere <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 fodd er, r esidues 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 treat ed 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 Austra lia to measure the magnitude of total pyroxasulfone residues in wheat and field peas grown as rotational crop s following the use of the 85% WG formulation on wheat and triticale in the season beforePyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 69 of 87 planting of the rotational crops. A single broadcast spr ay 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 1 00

- 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 pla nting . 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 0.1 12 and 0.223 lb ai/A represent 0. 4 x and 0.8x the proposed maximum seasonal r ate for pyroxasulfone. Samples were analyzed for residues of pyroxasulfone and its metabolites M

- 1, M

- 3, and M

- 25 using LC/MS/MS Method AT M

- 0031. For calculating total residues, the individual analyte residues were converted to parent molar equivalents a nd 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 stud ies

. 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 pyroxasulfon e, 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 , residu es 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 i n/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 fo r 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, r esidues of pyroxasulfone , M

- 3, and M

- 25 were each below the LOQ in /on all samples from the 0.223 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 f ield pea fodder at two sites; residues of M

- 1 were <0.01Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 70 of 87 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

. Un der 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 wit h 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 plant back 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, soybea n, 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 roo t 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 pe titioner 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 interval s 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 studie s. 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 s tudies 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 tolerance s for pyroxasulfone residues of concern in crop commodities be expressed in terms of combined residues of pyroxasulfo ne 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 pyroxasulfo ne 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. Co mpliance with the tolerance levels specified below is to be determined by measuring only the sumPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 71 of 87 of pyroxasulfone [ 3

- [[[5

- (difluoromethoxy)

- 1

- methyl

- 3

- (trifluoromethyl)

- 1 H

- pyrazol

- 4

- yl]methyl]sulfonyl]

- 4,5

- dihydro

- 5,5

- dimethylisoxazole ] and its metabolites [ 5

- ( difluoromethoxy )

- 1

- methyl

- 3

- ( trifluoromethyl )

- 1 H

- pyrazol

- 4

- yl ] methanesulfonic acid (M

- 1), 5

- ( difluoromethoxy )

- 1

- methyl

- 3

- ( trifluoromethyl )

- 1 H

- pyrazol

- 4

- carboxylic acid (M

- 3), and [ 5

- ( difluoromethoxy )

- 3

- ( trifluoromethyl )

- 1 H

- pyrazol

- 4

- yl ] methanesulfoni c 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 , al ong 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 toleran ce calculations.
A dequate 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, sw eet forage; corn, sweet, stover

. Th e data indicate that the proposed tolerances for field corn grain and sweet corn K+CWHR are too low; tolerances of 0.0 15 ppm would be appropriate. The data indicate that the proposed tolerances for field corn forage and sweet corn forage are too high; tol erances of 0.0 6 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 po p corn commod ities (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 m ust propose tolerances for pyroxasulfone residues of concern in/on popcorn grain, at 0.0 15 ppm, and popcorn stover, at 0.15 ppm The adequacy of the proposed soybean tolerances will be evaluated p ending submission of the final reports of the storage stabil ity 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 ; C orrect Commodity

D efinition Field Corn Grain 0.01 0.0 15 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 0.0 15 Corn, sweet, kernel plus c ob 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 thePyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 72 of 87 Table 10. Tolerance Summary for Pyroxasulfone. Commodity Proposed Tolerance (ppm) HED Recommended

Tolerance (ppm) Comments ; C orrect Commodity

D efinition Field Corn Meal 0.01 Remove processed commodities of corn. Field Corn Flour 0.01 Remove Field Corn Starch 0.01 Remove Field Corn O il (wet and dry milled) 0.01 Remove Corn, pop, grain

-- 0.0 15 T he 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 2005Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 73 of 87 APPENDIX I. Chemical Names and Structures of Pyroxasulfone and Metabolites. Code I UPAC Name Common Name Chemical Structure

KIH

- 485 3

- [[[5

- (difluoromethoxy)

- 1

- methyl

- 3

-

(trifluoromethyl)

- 1 H

- pyrazol

- 4

- yl]methyl]sulfonyl]

- 4,5

- dihydro

- 5,5

- dimethylisoxazole Pyroxasulfone

M

- 1 [ 5

- ( Difluoromethoxy )

- 1

- methyl

- 3

-

( trifluoromethyl )

- 1 H

- pyrazol

- 4

- y l ] methanesulfonic acid N/A

M

- 3 5

- ( Difluoromethoxy )

- 1

- methyl

- 3

-

( trifluoromethyl )

- 1 H

- pyrazol

- 4

- carboxylic acid N/A

M

- 5 3

- (5

- Difluoromethoxy

- 3

- trifluoromethyl

- 1 H

pyrazol

4

- ylmethanesulfonyl)

- 4,5

- dihydro

- 5,5

- dimethylisoxazole N/A

M

- 6 3

- (5

- Difluorom ethoxy

- 1

- methyl

- 3

-

trifluoromethyl

- 1 H

- pyrazol

- 4

- ylmethanesulfonyl)

- 4,5

- dihydro

- 5,5

- dimethylisoxazol

- 4

- ol N/A

M

- 8 (5

- Difluoromethoxy

- 1

- methyl

- 3

- trifluoromethyl

1 H

- pyrazol

- 4

- yl)methanol N/A

M

- 9 5

- Difluoromethoxy

- 3

- trifluoromethyl

- 1 H

pyrazole

- 4

- carboxyli c acid N/A

M

- 9 malonyl glucoside (RT26) 1 None provided NAPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 74 of 87 APPENDIX I. Chemical Names and Structures of Pyroxasulfone and Metabolites. Code I UPAC Name Common Name Chemical Structure

N

- glycoside of M

- 9 (Unknown @ 13 mins.) 1 None provided NA

M

- 10 5

- Difluoromethoxy

- 1

- methyl

- 3

- trifluoromethyl

1 H

- pyrazole

- 4

- carbaldehyde N/A

M

- 11 [3

- (5

- Difluoromethoxy

- 1

- methyl

- 3

-

trifluoro methyl

- 1 H

- pyrazol

- 4

- ylmethanesulfonyl)

- 4,5

- dihydro

- 5

- methylisoxazol

- 5

- yl] methanol N/A

M

- 12 (5

- Difluoromethoxy

- 3

- trifluoromethyl

- 1 H

pyrazol

- 4

- yl) methanol N/A

M

- 13 3

- (5

- Difluoromethoxy

- 1

- methyl

- 3

-

trifluoromethyl

- 1 H

- pyrazol

- 4

- ylmethanesulfonyl)

- 4,5

- di hydro

- 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

-

d ihydroisoxazol

- 3

- ylthio)propanoic acid N/A

M

- 22 5,5

- Dimethyl

- 4,5

- dihydroisoxazole N/A

M

- 25 [ 5

- ( Difluoromethoxy )

- 3

- ( trifluoromethyl )

- 1 H

pyrazol

- 4

- yl ] methanesulfonic acid N/APyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 75 of 87 APPENDIX I. Chemical Names and Structures of Pyroxasulfone and Metabolites. Code I UPAC 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

- 30 2 3

- cyano
- 2

- hydroxy

- 2

- methylpropanoic acid N/A

Metabolite A 1 None provided (cysteine glucose conjugate of

isoxazoline

- ring metabolite) N/A

Metabolite B 1 None provided (dimethylpropyl cysteine sulfoxide

derivative) N/A

Metabolite C 1 None provided (malonyl dehydrogenated cysteine

derivative of isoxazoline group) N/A

Metabolite D 1 None provided (cysteine conjugate of dimethyl

acrylic ac id) N/A

P1 1 None provided (malonyl cysteine conjugate of

isoxazoline

- ring products following reaction of pyroxasulfone or metabolites with glutathione) N/A

1 Proposed structure. 2 Tentatively identified.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 76 of 87 Appendix II. Tolerance Assessment Calculat ions. 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 95 th per centile of the underlying residue distribution, and is more likely to overestimat e rather than underestimate the 95 th percentile . The rounding procedures specified in the SOP were also used. The OECD tolerance spreadsheet does not require the use of maxi mum
- 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 l b 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 postemergenc e (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, 0.0 15 ppm for field corn grain, and 0.15 ppm for field corn stover.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 77 of 87 Table II
- 1. Re sidue 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 <0.0 25 <0.013 <0.0 25 <0.0 28 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 28 <0.013 <0.0 25 <0.0 28 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 44 <0.013 <0.0 30 <0.0 45 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0 .0 25 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 54 <0.013 < 0.139 <0.0 53 <0.013 < 0.123 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 2 5 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 29 <0.0 28 <0.013 <0.0 28 <0.0 29 <0.013 <0.0 31Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 78 of 87 Table II
- 1. Re sidue 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 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 28 <0.013 <0.0 25 <0.0 29 <0.013 <0.0 25 <0.0 33 <0.013 <0.0 39 <0.0 32 <0.013 <0.0 36 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 28 <0.013 <0.0 25 <0.0 27 <0.0 32 1 Results in which all analytes were below the LOQ are shaded

.

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

Page 79 of 87 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

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

Page 80 of 87 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 Standar d 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 GrainPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 81 of 87 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 0.01 3

- 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 t rial application rates are within 25% of the maximum label application rate , and the application timing represents the latest proposed timing. The residuePyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 82 of 87 values that were entered into the tolerance spreadsheet are provided in Table II

- 2 . The residue val ues 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 (0.01 3 ppm for K+CWHR pyroxasulfone and M

- 3 ) ). Using the OECD MRL calculator , t he recommended tolerances are 0. 10 ppm for sweet corn forage , 0.15 ppm for sweet corn stover , and sweet corn K+CWHR is 0.0 15 ppm.

Table II
- 2. Residue data used to calculate tolerance for pyroxas ulfone 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 <0.0 38 <0.01 3 <0.0 28 <0.0 39 <0.013 <0.0 45 <0.0 63 <0.013 <0.0 25Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 83 of 87 Table II
- 2. Residue data used to calculate tolerance for pyroxas ulfone 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 <0.0 63 <0.013 <0.0 25 <0.0 50 <0.013 <0.0 75 <0.0 47 <0.013 <0.0 88 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 <0.0 25 <0.013 0.115 <0.0 26 <0.013 < 0.109 <0.0 42 <0.0 14 <0.0 25 <0.0 42 <0.0 16 <0.0 25
< 0.0 34 <0.013 <0.0 25 <0.0 35 <0.013 <0.0 25 <0.0 28 <0.013 <0.0 25 <0.0 29 <0.013 <0.0 25 <0.0 34 <0.013 <0.0 25 <0.0 33 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 53 <0.0 25 <0.013 <0.0 53 <0.0 29 <0.013 <0.0 31 <0.0 25 <0.013 <0.0 32 <0.0 31 <0.013 <0.0 25 <0.0 25 <0.013 <0.0 25 1 Results in which all analytes were below the LOQ are shaded

.

Pyroxasulfone Sweet Corn ForagePyroxasulfone 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 Unround ed 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 GAPPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 85 of 87 Total number of da ta (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 GAPPyroxasulfone 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/k g) n < 0.013 11 0.015 1

Appendix III. REFERENCESPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 365229

Page 87 of 87 DP#: D 389415 Subject: Pyroxasulfone. Review of Residue Data for the New Active Ingredient

Pyroxasulfone. From: T. Morton To: M. Walsh Dated: 5/ 1 2/ 11 MRIDs: 48430006 & 48430011
DP#: D389 651 Subject: Pyroxasulfone. Review of Enforcement Method Amendments for the New

Active Ingredient Pyroxasulfone. From: T. Morton To: M. Walsh Dated: 5/ 25 / 11 MRIDs: 4843000 1
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