### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460 Office o f Chemical Safety and Pollution Prevention 

### MEMORANDUM Date: May 22,2014. 

### SUBJECT : Pyroxasulfone. Application for Amended Section 3 Registration for Use on Com. Summary of Analytical Chemistry and Residue Data. 

### PC Code: 090099 

### Decision No.: 482174 

### DP Barcode: D414667 

### Registration No.: 63588 - 91, 63588-92 and 63588 - 93 

### Petition No.: 3F8196 

### Regulatory Action: Amended Section 3 Registration 

### Risk Assessment Type: NA 

### Case No.: NA 

### TXR No.: NA 

### CAS No.: 447399 -55-5 

### MRID No.: None 40 

### CFR:

## 180.**:5~** /1

## .~ / 

# r4-- Ver.Apr.os

## ~ /

## ~· 

# ;,/v[/'{ FROM: Thurston G. Morton, Chemist

# ~~f/"" Risk Assessment Branch IV /Hea lth Effects Division (RABIV /HED; 7509P) 

### THROUGH: E lis sa Reaves, PhD, C hief Risk Assessment Branch 4 Health Effects Division (7509P) 

### TO : Bethany Benbow Herbici de Branch/RD (7505P)

The registrant is currently requesting to amend the com use pattern to include the addition of adjuvants to the product s. The additional com field trials conducted with the addition of adjuvants resulted in a need for increased tolerances from those established.

Page 1 of27Pyroxa s ulfone Summary of Analytical Chemistry and Residue Data DP #: 414667 

### Executive Summary Pyroxasu lfon e is an herbicide belonging to the pyrazole class of selective herbicides. 

### It provides contact and residua l control of a broad spectrum of broad leaf weeds and grasses, includ in g g lyph osate-resistant varieties. Pyroxasulfone acts as a potential inhib itor of very-long-chain fatty acid ( VLCFA) biosynthesis , simi lar in mode to th e K3 group of herbicides (Gro u p 15). Under PP # 3F8196 , K-1 Chemical , U.S.A. Inc. is propos in g tolerances are establ i s h ed for residues of the herbicide pyroxasulfone, includin g its metabolites and degradates, in or on the commodi ti es in the table below. Compliance with the tolerance levels specified be l ow i s to be determined by measuring on l y the su m ofpyroxasulfone [3-([[5- ( difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1 H-pyrazol-4-yl]methyl]sulfonyl]-4 , 5- dihydro-5 , 5-dimethylisoxazole] and its metabolites [5-(difluoromethoxy)-1-methyl-3- (trifluoromethyl)-1 H -p yrazo l-4 -y l]m ethanesulfonic acid (M -1 ) , 5 - ( di fluoromethoxy )-1- meth y l-3-(trifluoromethyl)-lH-pyrazol-4-carboxylic acid (M-3), and [5- (difluoromethoxy)-3-(trifluoromethyl)-1H-pyrazol-4-yl]methanesulfonic acid (M-25) , calculated as the stoichiometric equivalent of pyroxasulfone, 

### in or on the commodity. Com , field , forage .................................................... : .. 0.09 ppm Tolerances are established for residues of the herbi cide pyroxa s ulfone, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels s p ecified below is to be determined by measuring on l y the sum of pyroxasulfone [3-[[[5-( difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1 H -p yrazol-4- yl)methyl]sulfonyl]-4,5-dihydro-5,5-dimethylisoxazole] and its metabolite [5- ( difluoromethoxy)-1-methyl-3-(trifluoromethyl ) -1 H-pyrazol-4-carboxylic ac id (M-3) ca lcul ated as the stoic hi ometric equivalent of pyro xas ulfone , i n or on the commodity. Corn, field, grain .................. . ........ . .......... . ....... .. ...... . .. 0.02 ppm The nature of the residue in plants is ten ta tively adequately understood based on metabolism studies with field com and soybeans. The nature of the residue in rotational c rop s is adequately under s tood based o n confined rotational crop studies with ro tated soybean, radish , and wheat. The metabolic pathway of pyroxasulfone is similar in primary and rotational crops , and mainly involves cleavage of the methyl sulfone bridge of the parent compound, oxidation and/or demethylation of the pyrazole cleavage product to yield metabolites M-1 and M-25 , and reaction of the isoxazoline cleavage product wit h cysteine and/or glutathione ; further demethylation , deamination, and/or conjugation ofthese metabolites occurs, yield add i tion a l metabolites including M-3. The residues of concern in wheat hay, forage , and straw for tolerance enforc . ement in the U.S. are pyroxasulfone and its metabolites M- 1 , M-3, and M-25. The RABIV Risk Assessme nt team h as determined the residues of concern in wheat grain for tolerance enforcement a re pyroxasulfone and its metabolite M - 3. These residues of concern are similar to the r es idu es of concern for com raw agricultura l commodities (RACs). The n ature of the residue in livestock is adequately understood based on metabolism studies wit h goats and hens. Metabo li sm of pyroxasu l fone in 

### livestock occurs primarily via cleavage between the rings, to form metabolites M- 1, M-8, M-10, and/or M-15, followed by oxidation, to yie ld metabolite M - 3 , and / or demethylation , to yie ld metabolites M- 1 2 and M-9. The parent compound may also undergo demethylation , hydroxylation followed by oxidation, or oxidation Page 2 of27Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 3 of 27 followed by ring cleavage . HED has determined that the residues of concern in livestock commodities for tolerance enforcement in the U.S. are pyroxasulfone and its metabolites M - 1, and M - 3. R esidues of concern in livestock commodities for risk assessment in the U.S. are pyroxasu lfone and its metabolites M - 1, M - 3, M - 25, and M - 28. However, at this time no livestock tolerances are required except for milk . T he petitioner has proposed high performance liquid chromatography/triple quadrupole mass spectrometry (LC / MS/MS) method s 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, M - 25, and M - 2 8 in corn, soybean, and wheat commodities . F or the methods to be considered adequate for enforcement purposes, the methods must be amended to define confirmatory analysis procedures . The validated limit of quantitation (LOQ) is 0.005 ppm for each analyte in corn and soybean commodities, with the exception of M - 3 in co rn 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 previously deemed acceptable by the Analytical Chemistry Branch of the Biological and Economic Analysis Division (ACB). Enforcement methods for livestock commodities are not needed at this time but may be required in the future . Adequate LC/MS/MS methods were used for data collection for crop and livestock commodities. The FDA multiresidue methods of PAM Vol. I. are suitable for the determination of pyroxasulfone (using Section s 30 3 and 304 . Storage stability of KIH - 485, M - 1, M - 3 , and M - 25 was assessed over periods fully encompassing the total storage time for each analyte in corn commodities . A n a dequate cattle feeding stud y has been previously submitted. The data indicate that tolerances for livestock commodities (except for milk) are not needed to support the proposed pyroxasulfone wheat and cotton use. A poultry feeding study is not needed at this time. The data indicate that the proposed amended tolerances for corn, field , grain and corn, field, forage are adequate . There are no corn processed commodity tolerances and none are needed with this amended use . The field rotational crop study submitted (D402247, T. Morton, 1/10/13) is adequate and supports a plantback interval (PBI) of 120 days.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 4 of 27 Regulatory Recommendations and Residue Chemistry Defi ciencies HED has examined the residue chemistry database for pyroxasulfone. Pending submission of a revised Section B (see requirem ents under Directions for Use) and analytical reference standards (see requirements under Submittal of Analytical Reference Standards), there are no residue chemistry issues that would preclude granting this amended Section 3 registration for the requested use of pyroxasulfone, or establishment of tolerances for residues of pyroxasulfone as follow: T olerances are established for residues of the herbicide pyroxasulfone, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of pyroxasulfone [3 - [[[5 - (difluoromethoxy) - 1 - methyl - 3 - (trifluoromethyl) - 1H - pyrazol - 4 - yl]methyl]sulfonyl] - 4,5 - dihydro - 5,5 - dimethylisoxazole] and its metabolites [5 - (difluoromethoxy) - 1 - methyl - 3 - (trifluoromethyl) - 1H - pyrazol - 4 - yl]methanesulfonic acid (M - 1), 5 - (difluoromethoxy) - 1 - meth yl - 3 - (trifluoromethyl) - 1H - pyrazol - 4 - carboxylic acid (M - 3), and [5 - (difluoromethoxy) - 3 - (trifluoromethyl) - 1H - pyrazol - 4 - yl]methanesulfonic acid (M - 25), calculated as the stoichiometric equivalent of pyroxasulfone, in or on the commodity. Corn, field, forage ................................ ....................... 0.09 ppm Tolerances are established for residues of the herbicide pyroxasulfone, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of pyroxasulfone [3 - [[[5 - (difluoromethoxy) - 1 - methyl - 3 - (trifluoromethyl) - 1H - pyrazol - 4 - yl]methyl]sulfonyl] - 4,5 - dihydro - 5,5 - dimethylisoxazole] and its metabolite [5 - (difluoromethoxy) - 1 - methyl - 3 - (trifluoromethyl) - 1H - pyrazol - 4 - carboxylic acid (M - 3) calculated as the stoichiometric equivalent of pyroxasulfone, in or on the commodity. Corn, field , grain ................................ ......................... 0.02 ppm A human health risk assessment is forthcoming. 860.1200 Directions for Use  The field rotational crop study submitted (D402247, T. Morton, 1/10/13) is adequate and supports a plantback interval (PBI) of 120 days. 860.1550 Proposed Tolerances  The proposed tolera nces are adequate.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 5 of 27 860.1650 Submittal of Analytical Reference Standards  Analytical standards for metabolite M - 28 are not currently available in the EPA National Pesticide Standards Repository. Analytical reference standards of pyroxasulfone and metabolites M - 1, M - 3, M - 25, and M - 2 8 must be supplied and supplies re plenished as requested by the Repository. 860.1360 Multiresidue Methods  The petitioner should test pyroxasulfone under Protocol D using a matrix of higher moisture content than soybean hay, such as sweet corn K+CWHR . Background Pyroxasulfone is a new herbicide in the pyrazole class of selective herbicides . It provides contact and residual control of a broad spectrum of broadleaf weeds and grasses, including glyphosate - resistant varieties. Pyroxasulfone acts as a potential inhibitor of VLCFA biosynthesis similar in mode to the K3 group of herbicides (Group 15) . Pyroxasulfone has little effect on germination , yet potentially inhibits shoot elongation of the germinating seed. Pyroxasulfone is translocated in plants through xylem and is apopla stic. K - I Chemical is proposing pyroxasulfone for use on soybean in the U.S. The chemical structure and nomenclature of pyroxasulfone and its metabolites proposed for regulation are presented in Table 1 , and the physicochemical properties of the technica l grade of pyroxasulfone are presented in Table 2 . This petition represents the first food/feed uses of pyroxasulfone proposed in the U.S. The chemical names and structures of pyroxasulfone metabolites are presented in Appendix 1.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 6 of 27 Table 1. Pyroxasulfone Nomenclature . Chemical structure

Common name Pyroxasulfone Company experimental name KIH - 485 ; AE 2196191 IUPAC name 3 - [5 - (difluoromethoxy) - 1 - methyl - 3 - (trifluoromethyl)pyrazol - 4 - ylmethylsulfonyl] - 4,5 - dihydro - 5,5 - dimethyl - 1,2 - oxazole CAS name 3 - [[[5 - (difluoromethoxy) - 1 - methyl - 3 - (trifluoromethyl) - 1H - pyrazol - 4 - yl]methyl]sulfonyl] - 4,5 - dihydro - 5,5 - dimethylisoxazole CAS regi stry number 447399 - 55 - 5 End - use product (EP) Pyroxasulfone 85 WG Herbicide (85% WG; EPA File Symbol 63588 - OE ) V - 10233 Herbicide (42.5% WG; EPA File Symbol 63588 - OG ) Chemical structure of M - 1 metabolite

[ 5 - ( difluoromethoxy ) - l - methyl - 3 - ( trifluoromethyl ) - lH - pyrazol - 4 - yl) ] methanesulfonic acid Chemical structure of M - 3 metabolite

5 - ( difluoromethoxy ) - l - methyl - 3 - ( trifluoromethyl ) - lH - pyrazole - 4 - carboxylic acid Chemical structure of M - 25 metabolite

[ 5 - ( difluoromethoxy ) - 3 - ( trifluoromethyl ) - 1H - pyrazol - 4 - yl) ] methanesulfonic acidPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 7 of 27 Table 1. Pyroxasulfone Nomenclature . Chemical structure of M - 28 metabolite 3 - [1 - Carboxy - 2 - (5,5 - dimethyl - 4,5 - dihydroisoxazol - 3 - ylthio)ethylamino] - 3 - oxopropanoic acid Chemical structure of Metabolite C None provided (malonyl dehydrogenated cysteine derivative of isoxazoline group) Table 2. Physicochemical Properties of Pyroxasulfone. Parameter Value Reference 1 Melting point 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 47701617 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 A summary of the proposed amended use pattern on corn is presented in Table 3 .Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 8 of 27 Table 3. Summary of Directions for Use of Pyroxasulfone. 1 Applic. Timing, Type, and Equip. Formulation

[EPA File Symbol ] Applic. Rate

(lb ai/A) Max. No.

Applic. per Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations Corn (Field, Pop, Sweet, and Seed) Fall application Broadcast Ground 85% WG

[63588 - OE] C: NA

M: 0.11 - 0.15 MF: 0.15 - 0.19 F: 0.19 - 0.21 NS

0.267 37 (sweet corn ears) Application may be

made in the fall to minimum or no tillage fields to be planted to corn the following spring. Preplant Broadcast surface or incorporated Ground 85% WG

[63588 - OE] C: 0.08 - 0.11

M: 0.11 - 0.15 MF: 0.15 - 0.19 F: 0.19 - 0.21 NS Surface application may be made up to 45 days prior to planting, and soil incorporated application may be made up to 14 days prior to plant ing. Preemergence Broadcast Ground 85% WG

[63588 - OE] C: 0.08 - 0.11

M: 0.11 - 0.15 MF: 0.15 - 0.19 F: 0.19 - 0.21 NS Early postemergence Broadcast Ground 85% WG

[63588 - OE] C: 0.08 - 0.11

M: 0.11 - 0.15 MF: 0.15 - 0.19 F: 0.19 - 0.21 NS Application may be made up to V4 stage (visible 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. 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. 

### Conclusions . The use directions are adequate to allow evaluation of the residue data relative to the propose d use in the U.S. The proposed maximum seasonal rate s are s upported by the submitted field trial data.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 9 of 27 860.1300 Nature of the Residue - Plants (MRIDs 47701649 and 47701650 ) 

### The petitioner submitted studies pertaining to the metabolism of pyroxasulfone in corn and soybean. Two different radiolabels were used in the plant studies; the label positions are presented below: [pyrazole - 5 - 14 

### C ] pyroxasulfone [isoxazoline - 3 - 14 

### C ] pyroxasulfone

A number of metabolites were identified in these studies. The chemical structures and report names for these metabolites are provided in Appendix I. A summary of the nature of the pyroxasulfone residue s in/on corn and soybean (first study) are summarized in the following memorandum (T. Morton, D365229, 12/15/2011). Soybean (MRID 48390903) Second Study : The metabolism of KIH - 485 was investigated in soybean following a single application of [14C] - KIH - 485 (pyrazole or isoxazoline labeled ) diluted with a formulation blank and water at a rate of ca 300 g ai/ha (0.268 lb ai/A) pre - emergence or ca 209 g ai/ha (0.186 lb ai/A) post emergence, in an application volume of 500 or 700 L/ha, respectively. Total radioactive residues (TRR) following pre - emergence applications with [pyrazole - 5 - 14C]KIH - 485 were 0.369 mg/kg in soybean forage (growth stage R1 to R2), 0.280 mg/kg in hay (mid - full bloom), and 0.157 mg/kg in seed (maturity BBCH 99). Following pre - emergence application with [isoxazoline - 3 - 14 C]KIH - 485, TRR were 0.427, 0.172, and 0.219 mg/kg in soybean forage, hay, and seed, respectively. Following post - emergence applications with [pyrazole - 5 - 14C]KIH - 485, TRR were 0.431 mg/kg in soybean forage (growth stage R1 to R2), 0.354 mg/kg in hay (mid - f ull bloom), and 0.042 mg/kg in seed (maturity BBCH 99). Following post - emergence application with [isoxazoline - 3 - 14C]KIH - 485, TRR were 0.462, 0.185, and 0.080 mg/kg in soybean forage, hay, and seed, respectively. Surface washes removed up to 3.1% TRR fro m forage and up to 1.7% from hay; no radioactivity was removed from seed with the surface rinse. The majority of the remaining TRR was removed with the acetone:water and water extractions, with levels of recovered radioactivity ranging from 78.0 - 82.6% TRR (0.302 - 0.363 mg/kg) in forage, 75.6 - 91.4% TRR (0.130 - 0.323 mg/kg) in hay, and 59.7 - 89.4% TRR (0.035 - 0.169 mg/kg) in seed. Further sequential extractions of forage, hay, and seed samples with 0.1M hydrochloric acid and/or sodium hydroxide, 2M hydrochloric acid and/or sodium hydroxide, and acetone individually released up to 16.3% TRR. No radioactivity was extracted with 2M hydrochloric acid and sodium hydroxide from post - emergence seedPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 10 of 27 samples (pyrazole label) and with acetone from pre - emergence and post - emergence seed samples (pyrazole label) and post - emergence forage samples (isoxazoline label). Levels of unextracted residue ranged from 6.6 to 11.7% TRR (0.029 to 0.052 mg/kg) in forage, 4.7 to 14.2% TRR (0.017 to 0.026 mg/kg) in hay, and 5.8 to 8.2% TRR (0.003 to 0.017 mg/kg) in the seed. The highest unextracted residue levels (14.2% TRR) were in hay, with the lower levels being in forage and seed. In general, there were no significant differences in the radioactivity extracted between the two radiol abelled forms or between the pre - and post - emergence applications. For the acetone:water extractions, the radioactivity recovered was similar, though slightly higher for the pyrazole - label as compared to the isoxazoline - label; radioactivity recovered was also similar, though slightly higher for post - emergence applications as compared to pre - emergence applications, except for seed. Unextracted residues were generally higher in the isoxazoline - labeled samples as compared to the corresponding pyrazole - labele d samples, especially for hay. Similar unextracted residue levels were found in the pre - and post - emergence applications. The nonextractable residues from the isoxazoline - labeled forage and hay samples following pre emergence application underwent bound r esidue fractionation. Soxhlet extraction with acetonitrile released only 0.8% TRR in forage and no radioactivity in hay. Incorporation into pectin accounted for 4.3 - 5.8% in forage and hay and incorporation into lignin accounted for 1.5 - 2.2% TRR in forage and hay. Remaining residues in forage and hay were characterized as hemicellulose, accounting for 1.5 - 1.7% TRR, or as cellulose, accounting for 0.4 - 0.6% TRR. Nonextractable residues remaining following these procedures were 2.6% TRR for forage and 2.3% TRR for hay. Samples of soybean forage, hay, and seed were analyzed for metabolite characterization/identification. Metabolites were identified and quantitated by HPLC. The parent, KIH - 485, was not identified in forage, hay, and seed following either pr e - emergence or post - emergence application of [pyrazole - 5 - 14C] - KIH - 485 and [isoxazoline - 3 - 14C] - KIH - 485. Following pre - emergence or post - emergence application of [pyrazole - 5 - 14C] - KIH - 485, KIH - 485 was extensively metabolized to M - 1 and M - 25 and the unknown m etabolites @ 24 minutes and 29 minutes (tentatively characterized as a conjugate of M - 9). Following pre - emergence and post - emergence application of [isoxazoline - 3 - 14C] - KIH - 485, KIH - 485 was extensively metabolized to M - 28 and M - 29 and a number of unknown m etabolites characterized as being more polar than KIH - 485. Specifically, in forage and hay following pre - emergence or post - emergence application of [pyrazole - 5 - 14C] - KIH - 485, M1 was the major metabolite identified, accounting for 18.2 - 22.6% TRR (0.079 - 0.08 4 mg/kg) in forage and 26.6 - 39.5% TRR (0.075 - 0.140 mg/kg) in hay. M - 25 accounted for 7.2 - 8.6% TRR (0.031 - 0.032 mg/kg) in forage and 12.5 - 18.6% TRR (0.035 - 0.066 mg/kg) in hay. Minor metabolites identified were M - 3, M - 8, and M - 9. M - 3 accounted for 2.1 - 3.7 % TRR (0.008 - 0.016 mg/kg) in forage and 2.5 - 2.6% TRR (0.007 - 0.009 mg/kg) in hay. M - 8 and M - 9 accounted for 1.3 - 2.5% TRR (0.006 - 0.009 mg/kg) and 3.7 - 5.2% TRR (0.013 - 0.022 mg/kg), respectively, in forage. In hay, M - 8 and M - 9 were 2.6% TRR (0.007 mg/kg) and 3.2% TRR (0.009 mg/kg), respectively, following pre - emergence application and were not detected following post - emergence application. A number of unknown metabolites were also detected in these samples. They included unknowns @ 13, 24 and 29 minutes, pre sent at levels equivalent to 1.0 - 3.1, 4.1 - 10.5, and 10.2 - 22.1% TRR, respectively, in forage and 1.9 - 2.3, 2.9 - 3.2, and 11.5 -Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 11 of 27 12.9% TRR, respectively, in hay. Unknown metabolite @ 13 minutes was tentatively identified as N - glycoside of M - 9 and unknown metabo lite @ 29 minutes was tentatively characterized as a conjugate of M - 9. The remaining radioactivity was characterized as unresolved background or other unknown metabolites; other unknown metabolites accounted for 14.6 - 20.1% TRR (0.063 - 0.074 mg/kg) in forag e and 12.6 - 21.1% TRR (0.044 - 0.060 mg/kg) in hay. In seed following pre - emergence or post - emergence application of [pyrazole - 5 - 14C] - KIH - 485, M - 3 and M - 25 were the only metabolites identified, accounting for 2.6 - 3.5% TRR (0.001 - 0.005 mg/kg) and 4.6 - 11.1% TR R (0.005 - 0.007 mg/kg), respectively. A number of unknown metabolites were also detected in the seed samples, including unknowns @ 13, 24 and 29 minutes, present at levels equivalent to 1.7 - 4.7, 2.8 - 6.7, and 7.1 - 10.1% TRR, respectively. The remaining radi oactivity was characterized as unresolved background or other unknown metabolites; other unknown metabolites accounted for 22.4 - 49.2% TRR (0.009 - 0.078 mg/kg). Following pre - emergence or post - emergence application of [isoxazoline - 3 - 14C] - KIH - 485, M - 28 and M - 29 were the only metabolites identified in forage, hay, and seed. M - 28 accounted for 12.6 - 15.7% TRR (0.058 - 0.067 mg/kg) in forage, 12.7 - 13.3% TRR (0.023 - 0.024 mg/kg) in hay, and 7.5 - 9.8% TRR (0.008 - 0.017 mg/kg) in seed. M - 29 accounted for 12.8 - 16.1% TRR (0.059 - 0.069 mg/kg) in forage, 10.6 - 13.4% TRR (0.020 - 0.023 mg/kg) in hay, and 2.6% TRR (0.006 mg/kg) in seed (pre - emergence only); M - 29 was not detected in seed following post - emergence application. Conclusions . The submitted data are partially adequate to satisfy data requirements for the use of pyroxasulfone on soybeans

. HED has concluded that , for the purposes of this petition, the residues of concern for risk assessment and tolerance enforcement in soybean forage and hay consist of pyroxasulfone and its metabolites M - 1, M - 3, and M - 25. R esidues of concern for risk assessment and tolerance enforcement in soybean s eed consist of pyroxasulfone and its metabolites M - 3, M - 25, and M - 28. 860.1300 Nature of the Residue - Lives tock There are several livestock feedstuffs associated with the proposed use of pyroxasulfone. The petitioner provided livestock metabolism studies with lactating goats and laying hens, which are summarized in the following memorandum (T. Morton, D365229 , 12/15/2011) . 860.1340 Residue Analytical Methods A summary of the analytical methods associated with pyroxasulfone and the method validations are summarized in the following memorandum (T. Morton, D365229, 12/15/2011). 860.1360 Multiresidue Method s A summary of the analytical methods associated with pyroxasulfone are summarized in the following memorandum (T. Morton, D365229, 12/15/2011). 860.1380 Storage Stability The previously submitted corn magnitude of the residue studies are supported by adequate storage stability data. This data was reviewed previously.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 12 of 27 Table 4 . Summary of Storage Conditions and Durations of Samples from Crop Field Trial and

Processing Studies. Matrix Storage Temperature (°C) Maximum Storage

Duration Interval of Demonstrated Storage Stability Pyroxasulfone, M - 1, and M - 3 determination Corn forage Frozen 332 days (10.9 months) 13 months Corn grain and K+CWHR Frozen 391 days (12.8 months) 13 months (grain) Corn grain for processing Frozen 337 days ( 11.1 months) 13 months (grain) Corn stover Frozen 357 days (11.7 months) 12 months Corn processed commodities Frozen 196 days (6.4 months) 6 months (oil) 7 months (starch, flour, and meal) Soybean forage Frozen 466 days (15.3 months) 17 months Soybean hay Frozen 452 days (14.9 months) 17 months Soybean seed Frozen 359 days (11.8 months) 19 months Soybean seed for processing Frozen 364 days (12.0 months) 19 months Soybean meal and hulls Frozen 231 days (7.6 months) 10 months Soybean oil Frozen 220 days (7.2 months) 7 months Wheat forage Frozen 58 weeks (13.3 months) 13 months (corn forage) Wheat grain and straw Frozen 36 weeks (8.3 months) 13 months (corn grain) 12 months (corn stover) M - 25 determination Corn forage Frozen 710 days (23.3 months) 24 months Corn grain and K+CWHR Frozen 777 days (25.5 months) 26 months (grain) Corn grain for processing Frozen 689 days ( 22.6 months) 26 months (grain) Corn stover Frozen 747 days (24.5 months) 25 months Corn starch Frozen 479 days (15.7 months) 16 months Corn grits, flour, and meal Frozen 520 days (17.1 months) 18 months (meal) 23 months (flour) Corn oil Frozen 575 days (18.9 months) 17 months (33% degradation) Soybean forage Frozen 799 days (26.3 months) 12 months Soybean hay Frozen 727 days (23.9 months) 12 months Soybean seed Frozen 891 days (29.3 months) 12 months Soybean seed for processing Frozen 720 days (23.7 months) 12 months Soybean hulls Frozen 519 days (17.1 months) 14 months Soybean meal Frozen 567 days (18.6 months) 14 months Soybean oil Frozen 497 days (16.3 months) 13 months Wheat forage Frozen 58 weeks (13.3 months) 12 months (corn forage) Wheat grain and straw Frozen 36 weeks (8.3 months) 12 months (corn grain and stover) 

### 860.1400 Water, Fish, and Irrigated Crops There are no proposed uses that are relevant to this guideline topic .Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 13 of 27 860.1460 Food Handling There are no proposed uses that are relevant to this guideline topic. 860.1480 Meat, Milk, Poultry, and Eggs ( MRID 4770165 9 ) 

### The dietary burdens of pyroxasulfone to livestock were calculated using the procedures of the most recent guidance developed by HED (June 2008); see Table 5 . The estimated dietary burdens are 0.0 3 6 ppm for beef cattle, 3.05 ppm for dairy cattle, 0.0 18 ppm for poultry, and 0.0 16 ppm for swine. K - I Chemical previously submitted a fe eding stud y with cattle, which is summarized below , and requested a waiver of the requirement for a poultry feeding study . Table 5 . Calculation of Dietary Burdens of Pyroxasulfone Residues to Livestock. Feedstuff Type 1 % Dry Matter 2 % Diet 2 Residue (ppm) HR or STMR 4 Dietary Contribution (ppm) 3 Beef Cattle Corn, field, stover R 83 5 0.139 HR 0.0084 Corn, field, forage R 40 10 0.054 HR 0.014 Corn, field, grain CC 88 40 0.025 STMR 0.0060 Corn, field, milled byproducts CC 85 40 0.05 STMR 0.0061 Soybean, meal PC 92 5 0.0 32 STMR 0.00 17 TOTAL BURDEN -- -- 100 -- 0.03 6 Dairy Cattle Corn, field, stover R 83 5 0.139 HR 0.0 08 Wheat , forage R 25 2 0 3.2 HR 2.56 Soybean, forage/silage R 35 20 0.781HR 0.446 Corn, field, milled byproducts CC 85 25 0.025 STMR 0.00 74 Corn, sweet, cannery waste CC 30 10 0.063 STMR 0.021 Soybean, seed CC 89 10 0.0 32 STMR 0.00 36 Soybean, meal PC 92 10 0.0 32 STMR 0.00 35 TOTAL BURDEN -- -- 100 -- 3.05 Poultry Corn, field, grain CC 88 75 0.013 STMR 0.0 098 Soybean, meal PC 92 25 0.0 32 STMR 0.0 08 TOTAL BURDEN -- -- 100 -- 0.0 18Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 14 of 27 Table 5 . Calculation of Dietary Burdens of Pyroxasulfone Residues to Livestock. Feedstuff Type 1 % Dry Matter 2 % Diet 2 Residue (ppm) HR or STMR 4 Dietary Contribution (ppm) 3 Swine Corn, field, grain CC 88 35 0.013 STMR 0.0046 Corn, field, milled byproducts CC 85 50 0.013 STMR 0.0065 Soybean, meal PC 92 15 0.0 32 STMR 0.00 48 TOTAL BURDEN -- -- 100 -- 0.0 16 1 R: Roughage; CC: Carbohydrate concentrate; PC: Protein concentrate. 2 OPPTS 860.1000 Table 1 Feedstuffs ( June 2008 ). 3 Contribution = ([tolerance /% DM] X % diet) for beef and dairy cattle; contribution = ([tolerance] X % diet) for poultry and swine. 4 H R: Highest Residue; STMR : Trial Median Residue . 

### Cattle : The magnitude of the residue of pyroxasulfone and metabolites M - 1 and M - 3 in dairy cow tissues and milk was determined in a feeding study. For 28 consecutive days, lactating dairy cows were administered pyroxasulfone at a target dose level of 1.8 ppm (estimated by the petitioner to be 1x, designated “group 2”) and at exaggerated target dose levels of 5.4 ppm (designated “group 3”) and 18 ppm (designated “group 4”). A control group (designated “ group 1 ”) was not dosed. A total of 14 cows were include d in the study, two in group 1, three each in groups 2 and 3, and six in group 4. The average daily dose of pyroxasulfone was 36.3 mg/cow/day for group 2, 109.3 mg/cow/day for group 3 and 364.2 mg/cow/day for group 4. The dose levels of 1.8, 5.4, and 18 ppm represent 50 x, 150 x, and 500 x, respectively, the maximum estimated dietary burden to beef cattle and 0.6 x, 1.8 x, and 5.9 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 daily. Milk samples from each animal were collected twice daily and combined as one pooled sample . On da ys 13 and 28 , milk samples from all cows, except those cows designated for the depuration phase and cows from the mid dose group, were separated into cream and skim milk for separate analysis. Animals were sacrificed within 24 hours after the final dosing , and tissue samples were taken, except for three cows of the high dose group which were sacrificed 4, 8, and 15 days after the final dose to determine residue levels post dosing. All samples were stored frozen prior to analysis . Samples were analyzed fo r 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 i nterval from sampling until analysis for any matrix was 186 days for cream samples, 87 days for tissue samples and 154 days for milk samples. Storage stability analyses showed that all analytes were stable in milk for up to 6 months frozen storage and tis sues for up to at least 3 months of frozen storage, except for pyroxasulfone in liver which showed only a 40% recovery after 120 days of storage; recovery was 94% after 15 days of storage. Samples of milk from day 7 were the only milk samples analyzed for the low and mid dose groups. For the control and high dose groups, milk samples from study days 1, 2, 3, 4, 5, 6, 7,Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 15 of 27 10, 13, 16, 19, 22, 25, and 28 were analyzed. There were no residues o f pyroxasulfone or its metabolites M - 1 or M - 3 in milk greater than the LOQ (0.001 ppm) at any dose level (including the control) except for three milk samples from cows at the high dosing level where pyroxasulfone was found at 0.002 - 0.004 ppm on study day 7. Skim milk and cream samples from study days 13 and 28 for the control, low, and high dose groups were analyzed. No residues of pyroxasulfone or its metabolites M - 1 or M - 3 were found above LOQ (0.001 ppm) in any samples. No residues of pyroxasulfone or its metabolites M - 1 or M - 3 were found greater than the LOQ (0.01 ppm) in any tissue samples (liver, kidney, subcutaneous fat, abdominal fat, perinephric fat, loin muscle , and round muscle) from cattle in the control and high dose groups. No tissue samples from the low and mid dose group were analyzed. No residues of pyroxasulfone or its metabolites M - 1 or M - 3 were found greater than the LOQ in any of the samples taken fr om cows sacrificed during the depuration period (including samples from the control group). Milk samples were collected 3, 7, and 14 days following the end of dosing. The results for maximum residues of pyroxasulfone and its metabolites detected at the h igh dose level (18 ppm ) are summarized in Table 6 below. Table 6 . Maximum Residues in Samples from Cows Dosed at 18 ppm (5.9x) . Samples Residues (ppm) 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 sampling days were <0.001 ppm . 

### If the nonquantifiable residues of pyroxasulfone in liver from the high - dose cattle are adjusted for potential decline during storage of 45% (estimated decline after 3 mont hs of storage), residues would be <0.02 ppm. Conclusions . The submitted cattle feeding study is adequate to satisfy data requirements. R adiovalidation data for the analytical method were not submitted , however, the extraction procedures for the analyt ical method is similar to the method used in the nature of the residue study in livestock . T he submitted data indicate that n o tolerances are needed for livestock tissues. Residues of each analyte were <0.01 ppm at a dosing level corresponding to 5.9 x th e estimated dietary burden to dairy cattle. HED concludes that the proposed uses of pyroxasulfone fall under category 3 of 40Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 16 of 27 CFR 180.6(a) for ruminant tissues ; there is no reasonable expectation of finite residues in cattle, goat, hog, horse, and sheep tissue commodities. However, a tolerance is required for milk. Poultry : The petitioner 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. I n the corn, soybean, and wheat field trials, residues of pyroxasulfone, M - 1, M - 3, and M - 25 were below the LOQ in/on all samples of grain and seed , except one soybean trial in which residues of M - 3 in seed were approximately twice the LOQ and two other tria ls 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 st udy 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 indivi dual identified metabolite were 0.039 ppm of M - 1 in liver. Assuming a feeding level of ~ 820 x (based on the 14.8 - ppm dosing level and a dietary burden of 0.0 1 8 ppm), expected residues of M - 1 at a 10x feeding level would be <0.002 ppm. Therefore, HED concl udes 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 not e that a poultry feeding study may be needed in the future if additional uses with poultry feedstuffs are proposed. 860.1500 Crop Field Trials K - I Chemical previously submitted field trial data from corn field trials conducted in the U.S. The purpose of this study was to obtain Raw Agricultural Commodity (RAC) residue data for pyroxasulfone (KIH - 485) and its metabolites M - 1, M - 3, and M - 25 on corn commodities following the addition of adjuvants to the regi stered products . The results from these field trials along are discussed previously (D402247, T. Morton, 1/10/13) . A summary is provided in Table 7. HED converted residues of metabolites to parent equivalents f or calculation of total residues; molecular weight conversion factors of 1.262 for M - 1, 1.504 for M - 3, 1.321 for M - 25 , and 1.286 for M - 28 were used. The full LOQ value was used for residues <LOQ for calculating total residues.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 17 of 27 Table 7 . Summary of Residue Data from Corn Crop Field Trials wi th Pyroxasulfone 85 WG. Crop matrix Target Applic. Rate (lb ai/A) PHI

(days) Total Residues of Pyroxasulfone and Metabolites M - 1, M - 3, and M - 25 (ppm) 1 n Min. Max. HAFT 2 Median Mean Std. Dev. 3 Corn forage 0.147 - 0.270 59 - 68 36 <0.025 0.099 0.086 0.036 0.043 0.019 Corn stover 105 - 113 36 0.025 0.051 0.047 0.025 0.030 0.007 Corn grain 105 - 113 36 <0.025 <0.028 <0.026 0.025 0.025 0.001 1 For the purposes of calculating total residues, HAFT, median, mean, and standard deviation, the LOQ was used for residues reported as <LOQ. Metabolite residues were converted to parent equivalents. 2 HAFT = Highest average field trial result. 

### Conclusions . The submitted corn field trial data are adequate to satisfy crop field trial data requirements. The number and locations of the field trials are in accordance with OPPTS Guideline 860.1500 for corn . Field trials were generally conducted at ~1x the prop osed maximum single application rate and the application timing represents the latest proposed timing. 860.1520 Processed Food and Feed K - I Chemical previously submitted processing study data for corn . A summary of the average processing factors found for the processed commodities of corn is presented in Table 8 . Table 8 . Summary of Processing Factors for Pyroxasulfone. RAC Processed Commodity Processing Factor Pyroxasulfone M - 1 M - 3 M - 25 Total Field corn Grits 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 -- 1 NC = Not calculated; residues of this analyte were below the LOQ in both the RAC and the processed commodity. 

### Conclusions . The corn processing stud y is adequate to satisfy data requirements . The available processing data indicate that no tolerances are neede d for pyroxasulfone residues in the processed commodities of corn .Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 18 of 27 860.1650 Submittal of Analytical Reference Standards Analytical standards for pyroxasulfone metabolite M - 28 is not currently available in the EPA National Pesticide Standa rds Repository (personal communication with Theresa Cole , ACB, 6 / 27 / 1 3 ). This analytical standard must be submitted to the address below. The Repository has the following from Kumiai Company: pyroxasulfone, expiration date 7 / 21 /201 5 pyroxasulfone metabolite M - 1, expiration date 11/ 19 /201 5 pyroxasulfone metabolite M - 25, expiration date 11/ 19 /201 5 pyroxasulfone metabolite M - 3, expiration date 4/9/2014 Analytical reference standards of pyroxasulfone and metabolites M - 1, M - 3, M - 25, and M - 2 8 must be s upplied and supplies replenished as requested by the Repository. The reference standards should be sent to the Analytical Chemistry Lab, which is located at Fort Meade, to the attention of Theresa Cole at the following address: USEPA National Pesticide Standards Repository/Analytical Chemistry Branch/OPP 701 Mapes Road Fort George G. Meade, MD 20755 - 5350 (Note that the mail will be returned if the extended zip code is not used.) 860.1850 Confined Accumulation in Rotational Crops The results of the previously submitted study indicate that the metabolism of pyroxasulfone in rotated crops is similar to that for primary crops. However, several conjugates and cysteine derivatives of the isoxazoline group (metabolites A, B, C, D, and P1) were found in r otated crops that were not found in primary crops. 860.1900 Field Accumulation in Rotational Crops The field rotational crop study submitted (D402247, T. Morton, 1/10/13) is adequate and supports a plantback interval (PBI) of 120 days.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 19 of 27 860.1550 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 pyroxasulfone and its major metabolites M - 1, M - 3, and M - 25 , calculated as pyroxasulfone. HED has concluded that the proposed tolerance expression is appropriate. The tolerance expression should be stated as follows: T olerances are established for residues of the herbicide pyroxasulfone, including its metabolite s and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of pyroxasulfone [3 - [[[5 - (difluoromethoxy) - 1 - methyl - 3 - (trifluoromethyl) - 1H - pyrazol - 4 - yl]methy l]sulfonyl] - 4,5 - dihydro - 5,5 - dimethylisoxazole] and its metabolites [5 - (difluoromethoxy) - 1 - methyl - 3 - (trifluoromethyl) - 1H - pyrazol - 4 - yl]methanesulfonic acid (M - 1), 5 - (difluoromethoxy) - 1 - methyl - 3 - (trifluoromethyl) - 1H - pyrazol - 4 - carboxylic acid (M - 3), and [5 - (d ifluoromethoxy) - 3 - (trifluoromethyl) - 1H - pyrazol - 4 - yl]methanesulfonic acid (M - 25), calculated as the stoichiometric equivalent of pyroxasulfone, in or on the commodity. Corn, field, forage ................................ ....................... 0.09 ppm Tolerances are established for residues of the herbicide p yroxasulfone, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of pyroxasulfone [3 - [[[5 - (difluoromethoxy) - 1 - methyl - 3 - ( trifluoromethyl) - 1H - pyrazol - 4 - yl]methyl]sulfonyl] - 4,5 - dihydro - 5,5 - dimethylisoxazole] and its metabolite [5 - (difluoromethoxy) - 1 - methyl - 3 - (trifluoromethyl) - 1H - pyrazol - 4 - carboxylic acid (M - 3) calculated as the stoichiometric equivalent of pyroxasulfone, in o r on the commodity. Corn, field , grain ................................ ......................... 0.02 ppm There are no Codex MRLs established for residues of pyroxasulfone in any commodities. The tolerances proposed by K - I Chemical are listed in Table 9 , along with the tolerance levels recommended by HED . Th e Agency’s Guidance for Setting Pesticide Tolerances Based on Field Trial Data was utilized for determining appropriate tolerance levels for raw agricultural crop commodities; see Appendix II for tolerance calculations. The data indicate that the propos ed tolerances for corn, field , grain and corn, field, forage are adequate . Table 9 . Tolerance Summary for Pyroxasulfone. Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments ; C orrect Commodity

D efinition Corn, field, forage 0.09 0.09 Corn, field, grain 0.02 0.02Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 20 of 27 Attachments: Appendix I - Chemical Name and Structure Table Appendix II - Tolerance Assessment Calculations Template Version September 2005Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 21 of 27 APPENDIX I. Chemical Names and Structures of Pyroxasulfone and Metabolites. Code IUPAC Name Common Name Chemical Structure KIH - 485 3 - [[[5 - (difluoromethoxy) - 1 - methyl - 3 -

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

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

( trifluoromethyl ) - 1H - pyrazol - 4 - yl ] methanesulfonic acid N/A

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

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

M - 5 3 - (5 - Difluoromethoxy - 3 - trifluoromethyl - 1H pyrazol 4 - ylmethanesulfonyl) - 4,5 - dihydro - 5,5 - dimethylisoxazole N/A

M - 6 3 - (5 - Difluoromethoxy - 1 - methyl - 3 -

trifluoromethyl - 1H - pyrazol - 4 - ylmethanesulfonyl) - 4,5 - dihydro - 5,5 - dimethylisoxazol - 4 - ol N/A

M - 8 (5 - Difluoromethoxy - 1 - methyl - 3 - trifluoromethyl 1H - pyrazol - 4 - yl)methanol N/A

M - 9 5 - Difluoromethoxy - 3 - trifluoromethyl - 1H pyrazole - 4 - carboxylic acid N/A M - 9 malonyl glucoside (RT26) 1 None provided NAPyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 22 of 27 APPENDIX I. Chemical Names and Structures of Pyroxasulfone and Metabolites. Code IUPAC Name Common Name Chemical Structure N - glycoside of M - 9 (Unknown @ 13 mins.) 1 None provided NA

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

M - 11 [3 - (5 - Difluoromethoxy - 1 - methyl - 3 -

trifluoromethyl - 1H - pyrazol - 4 - ylmethanesulfonyl) - 4,5 - dihydro - 5 - methylisoxazol - 5 - yl] methanol N/A

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

M - 13 3 - (5 - Difluoromethoxy - 1 - methyl - 3 -

trifluoromethyl - 1H - pyrazol - 4 - ylmethanesulfonyl) - 4,5 - dihydro - 5 - methylisoxazole - 5 - carboxylic acid N/A

M - 15 2 - Amino - 5 - [1 - (carboxymethylamino) - 3 - (5,5 -

dimethyl - 4,5 - dihydroisoxazol - 3 - ylthio) - 1 - oxopropan - 2 - ylamino] - 5 - oxopentanoic acid N/A

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

dihydroisoxazol - 3 - ylthio)propanoic acid N/A

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

M - 25 [ 5 - ( Difluoromethoxy ) - 3 - ( trifluoromethyl ) - 1H pyrazol - 4 - yl ] methanesulfonic acid N/APyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 23 of 27 APPENDIX I. Chemical Names and Structures of Pyroxasulfone and Metabolites. Code IUPAC Name Common Name Chemical Structure M - 28 3 - [1 - Carboxy - 2 - (5,5 - dimethyl - 4,5 -

dihydroisoxazol - 3 - ylthio)ethylamino] - 3 - oxopropanoic acid N/A

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

hydroxypropanoic acid N/A M - 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 acid) N/A P1 1 None provided ( malonyl cysteine conjugate of

isoxazoline - ring products following reaction of KIH - 485 or metabolites with glutathione) N/A 1 Proposed structure. 2 Tentatively identified.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 24 of 27 Appendix II. Tolerance Assessment Calculations. 

## International Residue Limits

Pyroxasulfone (090099; 3/13/2013) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 

### Codex 40 CFR 180.659 General (1) Plant: determined by measuring only the sum of pyroxasulfone [3 - [[[5 - (difluoromethoxy) - 1 - methyl - 3 - (trifluoromethyl) - 1H - pyrazol - 4 - yl]methyl]sulfonyl] - 4,5 - dihydro - 5,5 - dimethylisoxazole] and its metabolite [5 - (difluoromethoxy) - 1 - methyl - 3 - (trifluoromethyl) - 1H - pyrazol - 4 - carboxylic acid (M - 3) calculated as the stoichiome tric equivalent of pyroxasulfone None None



### Commodity 1 

### Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 

### Codex Corn, field , grain 0.0 2 40 CFR 180.659 (2) Plant: determined by measuring only the sum of pyroxasulfone [3 - [[[5 - (difluoromethoxy) - 1 - methyl - 3 - (trifluoromethyl) - 1H - pyrazol - 4 - yl]methyl]sulfonyl] - 4,5 - dihydro - 5,5 - dimethylisoxazole] and its metabolites [5 - (difluoromethoxy) - 1 - methyl - 3 - (trifluoromethyl) - 1H - pyrazol - 4 - yl]methanesulfonic acid (M - 1), 5 - (difluoromethoxy) - 1 - methyl - 3 - (trifluoromethyl) - 1H pyrazol - 4 - carboxylic acid (M - 3), and [5 - (difluoromethoxy) - 3 - (trifluoromethyl) - 1H - pyrazol - 4 - yl]methanesulfonic acid (M - 25), calculated as the stoichiometric equivalent of pyroxasulfone None None



### Commodity 1 

### Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 

### Codex Corn , forage 0.09 

### US Canada Mexico 2 

### Codex 40 CFR 180.659 Livestock: determined by measuring only the sum of pyroxasulfone [3 - [[[5 - (difluoromethoxy) - 1 - methyl - 3 - (trifluoromethyl) - 1H - pyrazol 4 - yl]methyl]sulfonyl] - 4,5 - dihydro - 5,5 - dimethylisoxazole] and its metabolites [5 - (difluoromethoxy) - 1 - methyl - 3 - (trifluoromethyl) - 1H pyrazol - 4 - yl]methanesulfonic acid (M - 1) and 5 - (difluoromet hoxy) - 1 - methyl - 3 - (trifluoromethyl) - 1H - pyrazol - 4 - carboxylic acid (M - 3), calculated as the stoichiometric equivalent of pyroxasulfone None None



### Commodity 1 

### Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 

### Codex Completed: M. Negussie; 03/13/13 1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant. 2 Mexico adopts U.S. tolerances and/or Codex MRLs for its export purposes.Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 25 of 27 Pyroxasulfone Field Corn Forage US Parent, M1, M3, M25 with Adjuvant Total number of data (n) 31 Percentage of censored data 48% Number of non - censored data 16 Lowest residue 0.025 Highest residue 0.086 Median residue 0.026 Mean 0.033 Standard deviation (SD) 0.014 Correction factor for censoring (CF) 0.677 Proposed MRL estimate

- Highest residue 0.086

- Mean + 4 SD 0.087

- CF x 3 Mean 0.066 Unrounded MRL 0.087 Rounded MRL 0.09 Residues (mg/kg) n < 0.025 15 0.026 1 0.027 1 0.028 2 0.029 2 0.03 1 0.033 1 0.034 1 0.037 1 0.038 1 0.045 1 0.053 1 0.054 1 0.059 1 0.086 1Pyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 26 of 27 Pyroxasulfone Field Corn Stover US Parent, M1, M3, M25 with Adjuvant Total number of data (n) 31 Percentage of censored data 58% Number of non - censored data 13 Lowest residue 0.025 Highest residue 0.131 Median residue 0.025 Mean 0.031 Standard deviation (SD) 0.019 Correction factor for censoring (CF) 0.613 Proposed MRL estimate

- Highest residue 0.131

- Mean + 4 SD 0.108

- CF x 3 Mean 0.057 Unrounded MRL 0.131 Rounded MRL 0.15 High uncertainty of MRL estimate. [High level of censoring] Residues (mg/kg) n < 0.025 18 0.026 2 0.027 3 0.028 1 0.029 1 0.03 1 0.034 1 0.037 1 0.038 1 0.047 1 0.131 1 PyroxasulfonePyroxasulfone Summary of Analytical Chemistry and Residue Data DP#: 414667



### Page 27 of 27 Field Corn Grain US Parent, M3 with Adjuvant Total number of data (n) 31 Percentage of censored data 97% Number of non - censored data 1 Lowest residue 0.013 Highest residue 0.016 Median residue 0.013 Mean 0.013 Standard deviation (SD) 0.001 Correction factor for censoring (CF) 0.355 Proposed MRL estimate

- Highest residue 0.016

- Mean + 4 SD 0.015

- CF x 3 Mean 0.014 Unrounded MRL 0.016 Rounded MRL 0.02 High uncertainty of MRL estimate. [High level of censoring] Residues (mg/kg) n < 0.013 30 0.016 1