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                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                       
                                                  OFFICE OF CHEMICAL SAFETY AND
                                                                                               POLLUTION PREVENTION
                                                                               

MEMORANDUM

Date:	April 29, 2015

Subject:	Oxathiapiprolin.  Petition for the Establishment of Permanent Tolerances and Registration for Use of the New Active Ingredient on a Number of Crops.  Summary of Analytical Chemistry and Residue Data.

PC Code:  128111
DP Barcode:  D426128
Decision No.: 485920
Registration Nos.:  352-IOR, 352-IOE, 
                               100-RLGE, 100-RLGG
Petition No.:  3F8220
Regulatory Action:  Section 3
Risk Assessment Type:  NA
Case No.:  None
TXR No.:  NA
CAS No.:  1003318-67-9
MRID No.:  See Appendix K
40 CFR:  New Active Ingredient

From:	Elizabeth Holman, Physical Scientist
	Risk Assessment Branch II 
	Health Effects Division (HED; 7509P)

Through:	Douglas A.  Dotson, Ph.D., Senior Chemist
	Risk Assessment Branch II; HED (7509P)

	Danette Drew, ChemSAC Designated Reviewer (HED; 7509P)
	Donna S. Davis, ChemSAC Chair (HED; 7509) 
	Julie L. Van Alstine, M.P.H., ChemSAC Chair (HED; 7509)

To: 	Marcel Howard/Tony Kish
	Fungicide Branch 
	Registration Division (7505P)

                               Table of Contents

1.0	Executive Summary	3
2.0	Regulatory Recommendations	4
2.1	Data Deficiencies/Data Needs	4
2.2	Tolerance Considerations	4
2.2.1	Enforcement Analytical Method	4
2.2.2	Recommended Tolerances	6
2.2.3	Revisions to Petitioned-For Tolerances	7
2.2.4	International Harmonization	8
3.0	Introduction	8
3.1	Chemical Identity	8
3.2	Physical/Chemical Characteristics	9
3.3	Pesticide Use Pattern/Directions for Use (860.1200)	9
4.0	Metabolite/Degradate Residue Profile	10
4.1	Nature of the Residue	10
4.1.1	Summary of Plant Metabolism (860.1300)	13
4.1.2	Summary of Livestock Metabolism (860.1300)	17
4.1.3	Summary of Confined Rotational Crops (860.l850)	21
4.1.4	Summary of Metabolites and Degradates	23
4.2	Comparison of Metabolic Pathways	23
4.3	Residues of Concern Summary and Rationale	23
5.0	Residue Profile	25
5.1	Residue Analytical Methods (860.1340)	25
5.1.1	Data Collection Methods	25
5.1.2	Multi-Residue Methods (860.1360)	27
5.1.3	Tolerance Enforcement Methods	28
5.1.4	Submittal of Analytical Reference Standards (860.1650)	29
5.2	Storage Stability (860.1380)	30
5.3	Residue Data	30
5.3.1	Crop Field Trials (860.1500)	30
5.3.2	Field Rotational Crops (860.1900)	39
5.3.3	Processed Food and Feed (860.1520)	41
5.3.4	Meat, Milk, Poultry and Eggs (860.1480)	44
5.3.5.	Food Handling (860.1460)	44
5.3.6	Water, Fish, and Irrigated Crops (860.1400)	45
5.4	Food Residue Profile	45
6.0	Tolerance Derivation	45
7.0	ChemSAC Reference	46

1.0	Executive Summary

Oxathiapiprolin {1-[4-[4-[5-(2,6-Difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-ethanone} is a piperidinyl thiazole isoxazoline fungicide for control of crop diseases caused by oomycetes (downy mildew and late blight).  Syngenta is proposing this chemical for use on turf and ornamentals, whereas Dupont Chemical Company is proposing uses on a number of crops.  With the exception of grapes, all crops are proposed for Section 3 use in the U.S.  Grapes are being proposed for a tolerance without a US registration (import tolerance) based on a proposed use in the European Union (EU).  The proposed agricultural crop uses include ginseng, tuberous and corm vegetables, bulb vegetables, fruiting vegetables, leafy greens, head and stem Brassica vegetables, succulent peas, cucurbits, and tobacco.  For tomatoes, peppers, and edible-peel cucurbits, both field and greenhouse uses are proposed, with the use pattern being identical for these uses.  
HED is performing this assessment as a joint review with global partners PMRA/Canada and APVMA/Australia, with Japan and China/ICAMA acting as observers.  

Two agricultural products, formulated as an oil dispersion (OD) or suspension concentrate (SC), are proposed for use on these various crops.  The OD formulation contains 10.2% of the active ingredient (0.83 lb ai/gal), whereas the SC formulation contains 18.7% of the active ingredient (1.67 lb ai/gal).   

Oxathiapiprolin is generally applied 2-4 times per growing season with a minimum 3- to 14-day retreatment interval depending on crop, pest, and country/region.  The single application rates for the U.S. use pattern range from 35 to 280 g ai /ha (0.03-0.25 lb ai/A) for crop uses.  The maximum seasonal application rate is 560 g ai/ha (0.50 lb ai/A) for crop uses.  Preharvest intervals (PHI) range from 0 to 14 days.  

The residue chemistry database includes submissions addressing analytical methods; metabolism in target crops, rotational crops, and livestock; storage stability; residues from field trials; and residues in processed commodities.  Based on the requested uses, feeding studies and tolerances in livestock are not required at this time and the database is considered to be complete.  In rotational crops, HED is recommending establishing tolerances for inadvertent residues at 0.10 ppm for the purposes of harmonization with global partners.  

The proposed analytical enforcement method for crop commodities includes instructions for quantification of parent and seven metabolites.  The seven metabolites are IN-E8S72, IN-WR791, IN-RDG40, IN-Q7H09, IN-SXS67, IN-RZB20 and IN-RZD74.  Analytical methods suitable for enforcement and data gathering have been developed and validated.  The limit of quantitation (LOQ) is 0.01 ppm for parent and all seven metabolites.  

Crop field trials with oxathiapiprolin were conducted according to Good Agricultural Practice (GAP) in the U.S. and Canada with potato, tomato, pepper (bell and non-bell), cucumber, summer squash, cantaloupe, tobacco, ginseng, succulent pea, lettuce, spinach, Brassica vegetables, and bulb and green onion.  In addition, adequate EU field trial data on grape have been submitted to support the proposed tolerance without a US registration.  With the exception of the potato field trials where no quantifiable oxathiapiprolin residues were observed, one or more field trials from all other primary crops had quantifiable oxathiapiprolin residues.  These oxathiapiprolin residues were generally substantially higher than residues of any of the seven metabolites listed above.  Consequently, the residue of concern in plant commodities (treated as primary crops) is solely parent oxathiapiprolin.  Based on the submitted decline trial data, residues of oxathiapiprolin generally decline with increasing PHI.  All residue study results are supported by adequate storage stability data, and these field trial studies were conducted using an adequately validated analytical enforcement method.  

The registrant also submitted potato, tomato, and grape processing studies which were conducted at exaggerated use rates.  Based on a review of these processing studies, separate tolerances are not required for processed potato or grape commodities.  Based on the tomato processing study results, oxathiapiprolin is not expected to concentrate in tomato juice, paste, or puree  -  the commodities for which HED typically makes tolerance recommendations.  However, oxathiapiprolin concentrates in sundried tomato, with a median processing factor of 6.9X.  Based on the tomato HAFT oxathiapiprolin residue of 0.31 ppm, the anticipated residue of oxathiapiprolin is 2.1 ppm in dried tomato (0.31 ppm x median PF (6.9) = 2.1 ppm).  Although HED would not normally set tolerances in dried tomato, the registrant has petitioned for a dried fruiting vegetable tolerance.  For simplicity purposes in tolerance setting, the anticipated residue in dried tomato of 2.1 ppm is rounded up to the HED-recommended value of 3.0 ppm.  Although HED would not normally set such a tolerance, HED concludes that setting a tolerance value of 3.0 ppm for dried tomato would be appropriate (ChemSAC minutes 04/01/2015).  However, HED has concluded that setting a crop group tolerance for all dried fruiting vegetables is not appropriate, as our regulations do not currently permit setting a crop group processed commodity tolerance (ChemSAC minutes 04/01/2015).  
  
2.0	Regulatory Recommendations

There are no residue chemistry considerations that would preclude granting the requested registration and establishing the recommended tolerances for oxathiapiprolin residues on the proposed crops.  The specific tolerance recommendations are discussed in Section 2.2. 

2.1	Data Deficiencies/Data Needs

There are no residue chemistry data deficiencies at this time.  The HED notes that livestock feeding studies will likely be necessary to support any future use requests that involve crops which are significant livestock feeds.  

2.2	Tolerance Considerations

Due to the lack of toxicity from oxathiapiprolin, USEPA would normally grant a tolerance exemption for this chemical.  However, given that this chemical is being assessed as part of a global joint review and is intended to be registered in other countries, the Agency is setting tolerances for the purposes of harmonization.  

2.2.1	Enforcement Analytical Method

MRID No. 49011136 (Plants)
MRID No. 49011145 (Livestock)

Suitable methods for tolerance enforcement have been developed and independently validated.  For all matrices and analytes, the LOQ, defined as the lowest level of method validation (LLMV) or lowest spiking level where acceptable precision and accuracy data were obtained, was determined to be 0.01 ppm.  The limit of detection (LOD) was defined to be 30% of the LOQ (i.e., 0.003 ppm).  The FDA multi-residue methods are not suitable for detection and enforcement of oxathiapiprolin residues or associated metabolites.  However, the European Multiresidue Method (DFG Method S19) and the QuEChERS Multiresidue Method have shown success in some matrices (please see Section 5.1.2 for further details).  

2.2.1.1.  PLANT MATRICES

Proposed Enforcement Method.  The proposed analytical enforcement method for plant commodities is a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method that can be used to analyze for parent oxathiapiprolin and the following metabolites concurrently:  IN-E8S72, IN-WR791, IN-RDG40, IN-Q7H09, IN-SXS67, IN-RZB20 and IN-RZD74.  Crop samples are extracted using a solution of formic acid, water and acetonitrile, and diluted with aqueous formic acid solution and methanol.  An aliquot of supernatant is filtered/centrifuged and analyzed by reverse-phase HPLC-MS/MS in positive ion mode using a gradient elution with 0.05% formic acid in water/methanol and 0.01% formic acid in methanol as the mobile phases.  

Two ion transitions are available for parent and all seven metabolites.  Quantitation was performed using the mass transition 222-->192 for IN-RZB20; 341-->135 for IN-SXS67; 165-->65 for IN-RZD74; 207-->143 for IN-WR791; 179-->65 for IN-E8S72; 556-->174 for IN-RDG40; 556-->155 for IN-Q7H09; and 540-->163 for oxathiapiprolin.  Confirmation was performed using the mass transition 222-->42 for IN-RZB20; 341-->297 for IN-SXS67; 165-->135 for IN-RZD74; 207-->163 for IN-WR791; 179-->40 for IN-E8S72; 556-->163 for IN-RDG40; 556-->538 for IN-Q7H09; and 540-->500 for oxathiapiprolin.

2.2.1.2.  LIVESTOCK MATRICES

The proposed analytical enforcement method for livestock commodities is an HPLC-MS/MS method that can be used to analyze for parent oxathiapiprolin and the following metabolites concurrently:  IN-RAB06, IN-RLB67, IN-RDG40 and IN-Q7H09.  Residues of oxathiapiprolin and metabolites IN-RAB06, IN-RLB67, IN-RDG40 and IN-Q7H09 are extracted from livestock tissue, milk and egg samples in acetonitrile and hexane using a Genogrinder extractor.  Following centrifugation, the extracts are diluted with an aqueous formic acid solution and methanol and then analyzed.  After extraction, the samples are centrifuged and subjected to clean-up procedures depending on the matrix and analytes.  An aliquot of supernatant is filtered/centrifuged and analyzed by reverse-phase HPLC-MS/MS in positive ion mode using a gradient elution with 0.05% formic acid in water/methanol and 0.01% formic acid in methanol as the mobile phases.  

For residues of parent oxathiapiprolin and each metabolite in livestock matrices, the LOQ was 0.01 ppm, with a LOD estimated to be 0.003 ppm.  Two ion transitions are available for parent and the four metabolites.  Quantitation was performed using the mass transition 568-->524 for IN-RAB06; 572-->554 for IN-RLB67; 556-->174 for IN-RDG40; 556-->155 for IN-Q7H09; and 540-->163 for oxathiapiprolin. Confirmation was performed using the mass transition 568-->135 for IN-RAB06; 572-->163 for IN-RLB67; 556-->163 for IN-RDG40; 556-->538 for IN-Q7H09; and 540-->500 for oxathiapiprolin. 

2.2.2	Recommended Tolerances
 
HED has reviewed the available residue data and has determined the appropriate tolerance levels for residues of oxathiapiprolin.  HED has concluded that tolerances in livestock commodities are not required, given that there is no expectation of finite residues in these matrices.  The recommended tolerance expression for primary crops and livestock commodities is as follows:

      (a) Tolerances are established for residues of the fungicide oxathiapiprolin, 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 oxathiapiprolin, 1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-ethanone, in or on the commodity.
For inadvertent residues in rotational crops, the recommended tolerance expression is as follows: 

      (d) Indirect or inadvertent residues.  A tolerance of 0.10 ppm is established for indirect or inadvertent residues of the fungicide oxathiapiprolin, including its metabolites and degradates, in or on all other food commodities/feed commodities (other than those covered by a higher tolerance as a result of use on growing crops).  Compliance with the tolerance level is to be determined by measuring only oxathiapiprolin, 1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-ethanone, in or on the commodity.
TABLE 2.2.2.	Tolerance Summary for Oxathiapiprolin.  
                                   Commodity
                           Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
                    Comments; Correct Commodity Definition
Grape Berries
                                      0.7
                                     0.70
Grape
Crop Subgroup 1C, Tuberous and Corm vegetables
                                     0.01
                                     0.01
Vegetable, tuberous and corm, subgroup 1C
Crop Subgroup 3-07A, Bulb Onion

                                     0.04
                                     0.04
Onion, bulb, subgroup 3-07A
Crop Subgroup 3-07B, Green Onion

                                       2
                                      2.0
Onion, green, subgroup 3-07B
Crop Group 8-10, Fruiting Vegetables

                                      0.2
                         Dried fruiting vegetables 0.9
                                     0.50
                                       
                               Tomato, dried 3.0
Vegetable, fruiting, group 8-10

Tomato, dried   
Crop Group 9, Cucurbit Vegetables

                                      0.2
                                     0.20
Vegetable, cucurbit, group 9
Crop Subgroup 5A, Head and Stem Brassica Vegetables

                                      1.5
                                      1.5
Brassica, head and stem, subgroup 5A
Crop Subgroup 4A, Leafy Greens
                                      15
                                      15
Leafy greens subgroup 4A
Peas, edible-podded
                                       1
                                      1.0
Pea, edible-podded
Peas, succulent, shelled
                                     0.05
                                     0.05
Pea, succulent shelled
Ginseng root
                                      0.4
                                     0.15
Ginseng
Tobacco, dried leaves
                                      30
                                     None
Tobacco is a non-food use and therefore no tolerance is recommended.  
         Rotational Crops (To be established under a separate section)
All other food commodities/feed commodities (other than those covered by a higher tolerance as a result of use on growing crops)
                                     None
                                     0.10
Being established to harmonize with Canada's PMRA generic action MRL.  

2.2.3	Revisions to Petitioned-For Tolerances

As summarized below, some of the proposed tolerances are different from those recommended by HED.  The registrant should submit a revised Section F in which the proposed tolerances are the same as those recommended by HED and the correct commodity definitions are used.

For tobacco, succulent shelled peas, leafy greens, head and stem Brassica vegetables, tuberous and corm vegetables, and bulb onion, the proposed and recommended tolerances are identical.  For grape, green onion, cucurbit vegetables, and edible-podded peas, the recommended tolerances include an additional significant figure (such as 1.0 ppm rather than 1 ppm).  This is in order to avoid the situation where rounding of a residue result to the level of precision of the tolerance expression would be considered non-violative (such as 1.4 ppm being rounded to 1 ppm).  

In the case of Crop Group 8-10, Fruiting Vegetables, the registrant proposed excluding a tomato field trial (Trial 18) from the tolerance calculation.  If this trial is excluded, all representative commodities (bell pepper, non-bell pepper, and tomato) support a crop group tolerance of 0.20 ppm.  However, HED has concluded that this trial cannot be excluded from the tolerance derivation (see Section 5.3.1. for further details).  With the inclusion of Trial 18, the recommended tomato tolerance becomes 0.50 ppm and, consequently, the recommended Fruiting Vegetable Crop Group 8-10 tolerance becomes 0.50 ppm.  

Similarly, with the inclusion of tomato Trial 18, the dried tomato tolerance is also increased from the proposed value of 0.9 ppm to the recommended value of 3.0 ppm.  This dried fruiting vegetable tolerance is based on concentration in sundried tomatoes in the submitted tomato processing study.  HED would normally not set a tolerance on dried tomato, but has concluded that setting this petitioned-for-tolerance is appropriate.  Following the HED Processing Factor Focus Group (PFFG) Guidance Document (2014, in draft), this tolerance is recommended for harmonization.  It is also noted that the setting of this dried tomato tolerance is consistent with the approach used for other recent global joint reviews (P. Savoia, D422374, 01/15/2015).  However, HED has concluded that setting a crop group tolerance for all dried fruiting vegetables is not appropriate, as our regulations do not currently permit setting a crop group processed commodity tolerance (ChemSAC minutes 04/01/2015).  

In the case of ginseng, the registrant submitted four field trials at the GAP proposed use rate and two field trials at ~2X the GAP.  The registrant indicated that this was done because ginseng is a multi-year crop, often being harvested only after multiple growing seasons.  For tolerance derivation purposes, the registrant has proposed using the residue data from the 2X trials and proportionally adjusting the residue data from the 1X trials (where side-by-side treatment was not undertaken) to be 2 times higher.  Using the 2X trial data, a tolerance of 0.40 ppm is derived.  However, based on a review of the data and consultation with the global partners, HED has concluded that using the 1X data is more appropriate for tolerance-setting, yielding a 0.15 ppm recommended tolerance.  

The registrant did not petition for rotational crop tolerances.  However, HED has concluded that for harmonization purposes, it is appropriate to set a value of 0.10 ppm for inadvertent residues in rotational crops.  

2.2.4	International Harmonization

Oxathiapiprolin is the subject of a joint data review with global partners PMRA/Canada and APVMA/Australia, with Japan and China/ICAMA acting as observers.  There are currently no established regulatory levels for any organization, including from Codex.  The recommended regulatory levels are harmonized among the joint review partners.  

2.3	Label Recommendations

None.

3.0	Introduction

Oxathiapiprolin is a new piperidinyl thiazole isoxazoline fungicide for control of crop diseases caused by oomycetes (downy mildew and late blight).  

3.1	Chemical Identity

Table 3.1.  Oxathiapiprolin Nomenclature.
Chemical Structure

Common name
Oxathiapiprolin
Identity
1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-ethanone
CAS no.
1003318-67-9
Company experimental name
DPX-QGU42
IUPAC name
1-(4-{4-[(5RS)-5-(2,6-difluorophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}-1-piperidyl)-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone
CAS name
1-[4-[4-[5-(2,6-Difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-ethanone
End-use products (EP)
Oxathiapiprolin FHG OD (18.7% active ingredient)
Oxathiapiprolin FHG SC (10.2% active ingredient)
Zorvec[TM] Epicaltrin[TM]
ZorvecTM Enicade[T][M] 

Oxathiapiprolin is a racemic mixture of IN-Q7N24 and IN-Q7N25, with these structures provided below.  Chiral chromatographic analysis in livestock and crop matrices confirmed that the enantiomeric ratio remained at 1:1 throughout the studies.  

                                       

3.2	Physical/Chemical Characteristics

Table 3.2.  Physicochemical Properties of Oxathiapiprolin

Parameter

Value

Reference
Physical State (pure active substance)
crystalline solid, powder at 20C.
Petition Administrative Materials
Melting point (pure active substance)
~146C

Relative Density at 20°C
(pure active substance)  
1.4645  0.007

Water solubility at 20°C

Water 	0.1749 g/mL
pH 4 buffer 	0.2111 g/mL
pH 7 buffer 	0.1844 g/mL
pH 9 buffer   0.2060 g/mL

Solvent solubility at 20°C

 Acetonitrile 	129.9 +- 7.7
Methanol 	13.5 +- 0.2
Acetone 	              162.8 +- 11.3
Ethyl acetate 	33.9 +- 0.8
Dichloromethane 	352.9 +- 7.9
o-Xylene 	5.8 +- 0.1
n-Octanol 	0.03 +- 0.00
n-Hexane 	0.01 +- 0.00

Vapor pressure at 20°C 
1.141 x 10[-6] Pa at 20C (8.6 x 10[-9] mm Hg)

Henry's law constant at pH 7, 20°C
 3.521 x 10[-3] Pa m[3]/mol or 
3.474 x 10[-8] atm m[3]/mol
(negligible escaping tendency from dilute aqueous solution)

Dissociation constant (pKa) at 20°C 
No dissociation at pH 1.0 to 9.1

Octanol/water partition coefficient
Log (KOW) at 20°C
log Kow = 3.6
no pH effect



3.3	Pesticide Use Pattern/Directions for Use (860.1200)

Oxathiapiprolin is a piperidinyl thiazole isoxazoline fungicide developed for control of crop diseases caused by oomycetes (downy mildew and late blight).  In addition to the proposed use on turf and ornamentals, the proposed agricultural crop uses include ginseng, tuberous and corm vegetables, bulb vegetables, fruiting vegetables, leafy greens, head and stem Brassica vegetables, succulent peas, cucurbits, and tobacco.  As previously noted, there is also a proposed tolerance without a US registration for use on grapes in the EU.  A summary of the use directions on crops is provided in Table 3.3.  

Two agricultural products are proposed for use in North America (NA) on the various crops: Zorvec[TM] Epicaltrin[TM], and Zorvec[TM] Enicade[TM].  

Zorvec[TM] Enicade[TM] and Zorvec[TM] Epicaltrin[TM] are proposed for use on various crops only in commercial and farm plantings.  Zorvec[TM] Enicade[TM] is formulated as an oil dispersion and contains 10.2% ai, whereas Zorvec[TM] Epicaltrin[TM] is formulated as a suspension concentrate and contains 18.7% ai.  Different application methods (foliar and soil) must not be combined when protecting a crop during a growing season.  For tomatoes, peppers, and edible-peel cucurbits, both field and greenhouse uses are proposed, with the use pattern being identical for these uses.  

All of these end-use products may be applied through a variety of application methods including: aerial, ground, chemigation, and handheld equipment.  

Oxathiapiprolin is generally applied 2-4 times per growing season with a minimum 3- to 14-day retreatment interval depending on crop, pest, and country/region.  The single application rates for the U.S. use pattern range from 35 to 280 g ai /ha (0.03-0.25 lb ai/A) for crop uses, turf, and landscape ornamentals.  The maximum seasonal application rate is 560 g ai/ha (0.50 lb ai/A) for crop uses, turf, and landscape ornamentals.  PHIs range from 0 to 14 days.  

Conclusions.  

The proposed labels are adequate for purposes of evaluating the residue chemistry database.  The use directions, including application rates, are supported by the available supervised residue trials.  The label properly denotes the proposed greenhouse uses on tomatoes, peppers, and edible-peel cucurbits.  

4.0	Metabolite/Degradate Residue Profile

4.1	Nature of the Residue

A large number of oxathiapiprolin metabolism studies have been submitted including six primary plant metabolism studies, three livestock metabolism studies, two confined rotational crop studies, and two rat metabolism studies.  Figure 4.1 provides a summary of the major metabolites observed across these studies.  


Table 3.3.  Summary of Proposed Use Pattern.  EU = European Union; NA = North America.  
                                  Crop/
Group
                                    Region
                                Formulation[a]
                              Application Type[b]
                             Max # Applications[c]
                            Max Rate/appl
(lb ai/A)
                          Max Rate/
season
(lb ai/A)
                     Minimum Retreatment Interval 
(days)
                                  PHI 
(days)
                                     Grape
                                      EU
                                      OD
                                    foliar
                                       2
                                    0.0535
                                     0.107
                                      10
                                      14
                                    Potato
                                      EU
                                      SE
                                    foliar
                                       4
                                    0.01338
                                    0.0535
                                       7
                                       1
                                    Potato
                                      NA
                                      OD
                                    foliar
                                       4
                                    0.0445
                                     0.178
                                       5
                                       5
                            Cucurbits;
Fruiting Veg
                                      EU
                                      OD
                                    foliar
                                       3
                                    0.02677
                                    0.0803
                                       7
                                       3
                 Head/Stem Brassicas;
Bulb Veg;
Succulent peas
                                      NA
                                      OD
                                    foliar
                                       4
                                    0.03125
                                     0.125
                                       5
                                       0
                                    Ginseng
                                      NA
                                      OD
                                    foliar 
                                       2
                                     0.25
                                     0.50
                                      14
                                      14
                                    Lettuce
                                      EU
                                   OD or SE
                                    foliar
                                       2
                                    0.01338
                                    0.02677
                                       7
                                       7
                                Leafy Green Veg
                                      NA
                                     OD
SC
                                  foliar
soil
                              4 (foliar)
2 (soil)
                         0.03125 (foliar)
0.25 (soil)
                                0.125 (foliar)
                                  0.50 (soil)
                                      3
7
                                       0
                          Cucurbits;
Fruiting Veg[d]
                                      NA
                                     OD
SC
                                  foliar
soil
                              4 (foliar)
2 (soil)
                         0.03125 (foliar)
0.25 (soil)
                                0.125 (foliar)
                                  0.50 (soil)
                                   3 or 5
7
                                       0
                                    Tobacco
                                      NA
                                      OD
                                  foliar
soil
                              4 (foliar)
2 (soil)
                               0.03125 (foliar)
                                  0.25 (soil)
                                0.125 (foliar)
                                  0.50 (soil)
                                      5
7
                                       7
[a] OD = Oil Dispersion. SC = Suspension Concentrate. SE = Suspo-emulsion.  [b] Different application methods (foliar and soil) must not be combined when protecting a crop during a growing season.  [c] Maximum # of applications at the maximum single application rate are listed here.  For each NA crop use, 2-4 applications are allowed on the labels, with the single application rate varying depending on the specific situation, and the maximum seasonal application rate being the same regardless of the number of applications.  [d] For tomatoes, peppers, and edible-peel cucurbits, both field and greenhouse uses are proposed, with the use pattern being identical for these uses.    
Figure 4.1  -  Oxathiapiprolin Comparative Metabolic Pathway.  G = Goat; H = Hen; P = Plants; R = Rat.  



4.1.1	Summary of Plant Metabolism (860.1300)
MRID No. 49011205 (Lettuce  -  Foliar Application)
MRID No. 49011206 (Lettuce  -  Soil Application)
MRID No. 49011207 (Grape  -  Foliar Application)
MRID No. 49011208 (Potato  -  Foliar Application)
MRID No. 49011209 (Potato  -  Soil Application)
MRID No. 49011210 (Courgette  -  Soil Application)
MRID No. 49011236 (Tobacco Pyrolysis)

Data depicting the metabolism of oxathiapiprolin in lettuce, potato, grape, and courgette (summer squash) were submitted.  The registrant submitted six primary crop metabolism studies, three using foliar applications (lettuce, potato, grape) and three using soil applications (lettuce, potato, courgette).  In the foliar application studies, three 70 g ai/ha (0.062 lb ai/A) foliar spray applications were made to precultivated lettuce, potato, or grape vines, with a 14-day retreatment interval (RTI) and a total application rate of 210 g ai/ha (0.187 lb ai/A).  In the soil application studies, lettuce seed, seed potatoes, or courgette seed was sown into soil treated with a single application of oxathiapiprolin at a nominal application rate of 600 g ai/ha (0.534 lb ai/A).  The application rates used in the plant metabolism studies adequately represent the GAP rate, with all studies being conducted with at least ~1X the GAP rate.  Table 4.1.1.1 summarizes the sample collection for each plant metabolism study.  

Table 4.1.1.1.  Summary of Plant Collection in Oxathiapiprolin Plant Metabolism Studies.  
Plant Matrix
Application Method
(Comparison to U.S. GAP[a])
Summary of Plant Collection
Lettuce
Foliar
(1.5X)
Whole lettuce plants were sampled immediately after each application once the treatment formulations had been allowed to dry (0DAT1, 0DAT2 and 0DAT3), immediately before the second and third applications (10DAT1 and 10DAT2) and at intervals following the final application (3DAT3, 7DAT3 and 14DAT3).  
Lettuce
Soil
(1.1X)
Whole lettuce plants were sampled at three timepoints: 30 days after soil treatment (30DAT; BBCH 17), immature (BBCH 45; 44DAT) and at crop maturity (BBCH 49; 57DAT).  The 30DAT samples were collected as contingency samples and were not analyzed.  
Potato
Foliar
(1.1X)
Immature potato foliage samples (whole plants) were taken immediately after the first application, before and after the second and third (final) applications and fourteen days after the final application.  The final (maturity) harvest was taken 28 days after the final application.  Potato tuber samples were taken before the third (final) treatment, 14 days after the final treatment (14 DAT3) and at final harvest (28 DAT3).
Potato
Soil
(Not applicable[a])
Whole potato plants were sampled at two timepoints: 37 days after soil treatment (37DAT; BBCH 65, immature), and at crop maturity (BBCH 91, 72DAT).  Samples were separated into foliage and tubers at each sampling point.  
Grape
Foliar
(1.75X)
Grape foliage samples were taken at 0 days after treatment 1 (0DAT1), 0DAT2, 14DAT2, 0DAT3, 14DAT3 and 76DAT3 (maturity).  Berry (fruit) samples were taken at 14DAT2, 0DAT3, 14DAT3 and 76DAT3 (maturity).  
COURGETTE[a]
Soil
(1.1X)
Whole courgette plants were sampled at two timepoints: 44 days after soil treatment (44DAT; BBCH 71, immature), and at crop maturity (BBCH 89, 79DAT).  Samples were separated into foliage and fruit at each sampling point.  
[a] Comparison of application rate to maximum proposed GAP seasonal use rate (see Table 3.3).  Soil application methods have not been proposed on potato.  Courgette is a cucurbit vegetable.  

The pyrazole, thiazole, or isoxazoline rings were labeled separately in the metabolism studies (please see structure labeling depiction below).  HED has concluded that this labeling was sufficient to capture the metabolism of oxathiapiprolin.  

For each of these studies, separate analyses were conducted using two labels.  In the metabolism studies using foliar application, the radiolabelled forms were [pyrazole-5-[14]C]oxathiapiprolin and [thiazole-5-[14]C]oxathiapiprolin.  In the metabolism studies using soil application, [pyrazole-5-14C] oxathiapiprolin and [isoxazoline-5-[14]C]oxathiapiprolin were used.  Oxathiapiprolin is a racemic mixture of IN-Q7N24 and IN-Q7N25.  Chiral chromatographic analysis confirmed that the enantiomeric ratio of IN-Q7N24 and IN-Q7N25 remained at 1:1 unchanged throughout the studies.












   1. [pyrazole-5-[14]C]oxathiapiprolin
   2. [thiazole-5-[14]C]oxathiapiprolin
   3. [isoxazoline-5-[14]C]oxathiapiprolin
     

For each radiolabel, samples of each plant matrix (immature and mature) were harvested, homogenized, and analyzed for total radioactive residues by combustion/liquid scintillation counting (LSC).  Residues were extracted with acetonitrile and acetonitrile:water.  In only the potato foliar and grape foliar application studies, a range of exhaustive extraction procedures was also undertaken (water and acetone extraction; enzymatic, acid and base hydrolyses).  The extracts were analyzed by HPLC-UV and/or HPLC-MS in order to characterize and identify oxathiapiprolin residues.  The analytical methods used in the studies are acceptable.  Samples were analyzed within approximately 1 month of harvest; therefore, storage stability data are not required to support these studies.  All six studies are classified as acceptable guideline studies.  

Table 4.1.1.2 summarizes the major and minor residues observed across the plant metabolism studies.  Parent and seven metabolites (IN-E8S72, IN-WR791, IN-RDG40, IN-Q7H09, IN-SXS67, IN-RZB20 and IN-RZD74) were major residues in one or more studies (see Appendix A for identity and structure of oxathiapiprolin metabolites).  For a more detailed summary of the plant metabolism study results, please see Appendix B. 
 
In addition, due to the proposed use on tobacco, a tobacco pyrolysis study was submitted (MRID 49011236).  The purpose of this study was to examine the distribution of [[14]C]oxathiapiprolin (DPX-QGU42) pyrolysis products in main stream and side stream cigarette smoke of commercial cigarettes spiked with either of two radiolabelled forms, [pyrazole-5-[14]C]oxathiapiprolin and [isoxazoline-5-[14]C]oxathiapiprolin.  The pyrolysis of oxathiapiprolin in cigarettes resulted primarily in degradation to [14]CO2, averaging a total of 13.5 and 14.4% of the applied radioactivity for [pyrazole-5-[14]C] and [isoxazoline-[14]C] label sets, respectively.  Unchanged oxathiapiprolin was the major component present in the butt and filter extracts, averaging 49.6 and 58.1% of the applied radioactivity in the [pyrazole-5-[14]C] and [isoxazoline-5-[14]C] labels, respectively.  The remaining radioactivity was recovered as bound residues and minor volatile components, none representing >2.9% of the applied dose.  This study has adequately characterized the tobacco pyrolysis of oxathiapiprolin and is classified as acceptable guideline.  

Conclusions. 
The submitted primary plant metabolism studies and the tobacco pyrolysis study are considered to be acceptable guideline studies.  

Table 4.1.1.2.  Summary of Plant Metabolism Study Results.  Values listed are the maximum % TRR observed in each study across both labels used, with the application method listed in parentheses for each matrix.  Italicized compounds were tested for in the crop field trials.  Minor metabolites (<10% TRR) are shaded in grey.  

Lettuce (Foliar)
Lettuce (Soil)
Potato Foliage (Foliar)[b]
Potato Foliage (Soil)
Potato Tubers (Soil)
Grape Foliage (Foliar)
Grape Berries (Foliar)
Courgette  Foliage (Soil)
Courgette Fruit (Soil)
Oxathiapiprolin
                                      85
                                       
                                      59
                                       9
                                       7
                                      98
                                      74
                                      24
                                     <1
IN-Q7H09
                                       5
                                       
                                       2
                                       
                                       
                                       5
                                       2
                                      19
                                       
IN-RDG40
                                       
                                       
                                     <1
                                       
                                       
                                       2
                                       3
                                       
                                       
IN-RZB20
                                       
                                       7
                                       
                                      13
                                      12
                                       6
                                       
                                      17
                                       3
IN-WR791
                                       
                                      30
                                       
                                      13
                                      25
                                       1
                                      19
                                      28
                                      74
IN-RZB21/
IN-RDZ74[a]
                                       
                                      21
                                       
                                      19
                                       6
                                       
                                       
                                      13
                                       4
IN-E8S72
                                       
                                      21
                                       
                                      12
                                      14
                                       2
                                      14
                                      24
                                       5
IN-SX67
                                       
                                       4
                                       
                                       6
                                       7
                                       4
                                       4
                                       7
                                       4
IN-Q7D41
                                       1
                                       
                                       2
                                       
                                       
                                       2
                                     <1
                                       
                                       
IN-KJ552
                                       
                                       3
                                       
                                       4
                                       7
                                     <1
                                       1
                                       3
                                       3
IN-RAB06
                                       
                                       
                                       
                                       
                                       
                                       2
                                       2
                                       
                                       
IN-Q9L80
                                       
                                       
                                       
                                       
                                       
                                     <1
                                     <1
                                       
                                       
IN-Q9PS10
                                       
                                       
                                       
                                       
                                       
                                       1
                                     <1
                                       
                                       
IN-Q9R70
                                       
                                       
                                       
                                       
                                       
                                      --
                                     <1
                                       
                                       
[a] In most of the plant metabolism studies, similar metabolites IN-RZB21 and IN-RDZ74 could not be resolved from one another for identification purposes.  They were therefore reported together.  Only IN-RDZ74 was tested for in the crop field trials.  
[b] Low levels of extractable radioactivity in potato tuber extracts (<=0.012 ppm) were associated with plant natural products, thus precluding further analysis of potato tuber residues.

4.1.2	Summary of Livestock Metabolism (860.1300) 
MRID No. 49011148 Poultry Metabolism - Oxathiapiprolin
MRID No. 49011147 Lactating Ruminant (Goat) Metabolism - Oxathiapiprolin
MRID No. 49011211 Lactating Ruminant (Goat) Metabolism  -  Metabolite IN-SXS67

Data depicting the metabolism of oxathiapiprolin in laying hens and lactating goats were submitted.  A second goat metabolism study was also performed using metabolite IN-SXS67.  IN-SXS67 and related metabolite IN-E8S72 were either major or minor metabolites in the primary and rotational crop field trial studies.  However, IN-SXS67 was not observed in the livestock metabolism studies and IN-E8S72 was only seen in a single livestock matrix (goat liver).  Therefore, the additional goat metabolism study was conducted to further elucidate the breakdown of IN-SXS67 in livestock.   

Oxathiapiprolin, radiolabeled in the thiazole or pyrazole ring, was administered orally via gelatin capsule to the test animals.  This radiolabelling is considered sufficient to capture the livestock metabolism of oxathiapiprolin.  Study parameters are summarized in Table 4.1.2.1, below.

Table 4.1.2.1.  Summary of Hen and Goat Metabolism Studies Experimental Parameters.
Experimental Parameter
Laying Hens
Lactating Goats
Number of Animals
5 per radiolabel position
1 per radiolabel position (Oxathiapiprolin study)
1 total in pyrazole ring (IN-SXS67 study)
Dosing Period
14 days
7 days
Dosing Level
~2.4 mg/day 
(Pyrazole label - 17.4 mg/kg feed/day)
(Thiazole label  -  17.8 mg/kg feed/day)
~36X MRDB
Oxathiapiprolin Study
Pyrazole: ~21 mg/day (14.2 mg/kg feed/day)
Thiazole: ~18 mg/day (14.3 mg/kg feed/day)
~174X MRDB

IN-SXS67 Study
Pyrazole: ~27 mg/day (18.95 mg/kg feed/day)
Egg/Milk Collection
Daily (morning and evening)
Daily (morning and evening)
Excreta Collection
Daily (morning, prior to dosing)
Daily (morning, prior to dosing)
Time from Last Dose to Sacrifice
~6 hours
12 hours
Tissues Harvested and Analyzed
Muscle (breast and thigh)
Liver
Fat (omental and subcutaneous)
Carcass collected and frozen until study completion (but not analyzed)
Muscle (Oxathiapiprolin study: loin, hind, and fore quarter; IN-SXS67 study: loin and flank)
Liver
Kidney
Fat (omental, subcutaneous, renal)
Carcass collected and frozen until study completion (but not analyzed)
Sample Storage Duration
<6 months
<4 months (Oxathiapiprolin study)
57 days (IN-SXS67 study)

In the oxathiapiprolin hen metabolism study, triplicate aliquots of each of the homogenized matrices were taken and analyzed by combustion/LSC or solubilised for LSC.  Daily excreta were composited separately by taking 5% from Days 1-14 collections for each radiolabel group; eggs were composited by taking 10% of whole egg from Days 10-14 for each radiolabel group.  Subsamples (ca. 30-50 g) of composite samples of tissues, whole egg and excreta were prepared for metabolite extraction and analysis.  Tissue and excreta samples were extracted with acetonitrile and acetonitrile/water (4/1 and 1/1, v/v).  Whole egg and fat samples were extracted with dichloromethane, acetonitrile and acetonitrile/water (4/1, v/v).  The resulting extracts were combined by matrix, concentrated, and analyzed by LSC and HPLC.  All liver post-extracted solids (PES) were further treated with protease (37°C; 120 hr) to release unextracted residues.  The samples were extracted with acetonitrile after protease digestion and the resulting extracts analyzed by LSC and HPLC.  All extracts were stored at -20°C prior to HPLC analysis.
In the goat metabolism study for oxathiapiprolin, tissue and fat samples were homogenized in dry ice.  Triplicate aliquots of each matrix were then taken and analyzed by combustion/LSC or solubilized for LSC.  Equal amounts of feces, urine, and milk from Days 1-7 were pooled by radiolabel.  Subsamples (ca. 30-100 g) of tissues, milk and feces were prepared for metabolite extraction and analysis.  Samples were extracted with dichloromethane, acetonitrile and acetonitrile/water (4/1, v/v).  The resulting extracts were combined by matrix, concentrated and analyzed by LSC and HPLC.  The liver PES from both goats were further treated with protease (37°C; 120 hr) to release unextracted residues.  The samples were extracted with acetonitrile after protease digestion and the resulting extracts analyzed by LSC and HPLC.  All extracts were stored at -20°C prior to HPLC.

In the goat metabolism study for metabolite IN-SXS67, tissue and fat samples were homogenized in dry ice.  Liver, kidney, muscle and fat samples were mixed with tissue solubilizer, and incubated at 50°C overnight.  Acetic acid and LSC cocktail were added, and the samples were analyzed by LSC.  Aliquots of milk, urine, and cage wash samples were analyzed for total radioactivity by LSC.  Aliquots of the feces and GI tract samples were subjected to combustion analysis and LSC.  Individual aliquots (30-50 g) of tissues and feces (Day 1-7 composite) samples were extracted with acetonitrile/water (1/1, v/v) followed by acetonitrile.  Radioactivity remaining in the pellets was determined by combustion analysis following the final extraction.  The combined extracts were concentrated, and the radioactive content was determined by LSC analysis.  Since coextractives in the liver sample made further concentration difficult, the liver extracts were purified by C18 solid phase extraction prior to HPLC-MS analysis.
Results  -  Poultry.  Oxathiapiprolin and metabolites were readily eliminated in the hen excreta (including cage wash), where 95-100% of the dose was recovered.  Total radioactive residues (TRR) plateaued within 10-11 days in whole eggs.  Transfer of radioactive residues to the eggs was very low with 0.02% or less of the dose eliminated via this route over the 14 days.  Approximately 0.02% or less of the dose was found in the liver, muscle, and fat 6 hours after the last dose indicating no bioaccumulation potential.  Total radioactive residues in the liver were 0.096 ppm and 0.103 ppm for the [pyrazole-5-[14]C] and [thiazole-5-[14]C]oxathiapiprolin dosed hens, respectively.  Total residues were below 0.030 ppm in whole eggs, muscle, and fats.  Greater than 45% of the radioactivity in the tissues and eggs could be extracted, with the majority of residues identified or characterized.  Intact oxathiapiprolin was detected in most tissues and eggs.  Metabolites present in the tissues and eggs included IN-RAB06, IN-QFD61, IN-RDG40, IN-Q7H09, and IN-Q7D41. 
  
Table 4.1.2.2 provides a summary of the hen metabolism study results.  For a detailed breakdown of these results, please see Appendix E.  Since the results across the labels were similar, Table 4.1.2.2 presents the highest residue identified across the labels for each matrix.  

Table 4.1.2.2.  Summary of Identified Residues from Oxathiapiprolin Hen Metabolism Study in %TRR (ppm).  For each compound, matrix and across both labels studied, the maximum observed %TRR and ppm residue is listed.  ND = Not detected.  
 
Whole eggs
 
Liver
 
Abdominal fat
 
Skin with fat
 
Oxathiapiprolin
                                     21.9
                                    (0.003)
                                      8.2
                                    (0.008)
                                     66.2
                                    (0.01)
                                     36.9
                                    (0.004)
IN-RAB06
                                      ND
                                       
                                     13.5
                                    (0.014)
                                      ND
                                       
                                      ND
                                       
IN-QFD61
                                      ND
                                       
                                      9.8
                                    (0.01)
                                      ND
                                       
                                      ND
                                       
Hydroxy metabolites[a]
                                      4.8
                                    (0.001)
                                      7.6
                                    (0.007)
                                     15.4
                                    (0.005)
                                     33.2
                                    (0.004)
IN-Q7D41
                                      7.1
                                    (0.001)
                                      ND
                                       
                                      4.9
                                    (0.002)
                                     10.1
                                    (0.001)
[a]  Reference standards for hydroxyl metabolites IN-RDG40 and IN-Q7H09 were not fully resolved in the majority of tissue extracts using the routine HPLC method.

Results  -  Goats  -  Oxathiapiprolin Study.  The study results showed that oxathiapiprolin and metabolites are readily eliminated in the urine and feces where 84.3-86.4% of the dose (including cage wash) was recovered.  Total radioactive residues plateaued within 5 days in milk.  Transfer of radioactive residues to the milk was very low with 0.2% or less of the dose eliminated via this route over the 7 days.  Less than 1.2% of the dose was found in the liver, kidney, muscle, and fat combined at sacrifice 12 hours after the last dose, indicating that there is no bioaccumulation potential.  Approximately 94.0-99.6% of the total dose was recovered when the radioactivity found in gastrointestinal contents (8.4-12.3% dose) was included.  

Table 4.1.2.3 provides a summary of the identified residues in the oxathiapiprolin goat metabolism study.  For a more detailed breakdown of these results, please see Appendix E.  Since the results across the labels were similar, Table 4.1.2.3 presents the highest residue observed across the labels for each matrix.  Total radioactive residues in liver and kidneys were 0.857 and 0.087 ppm for the [pyrazole-5-[14]C]oxathiapiprolin dosed goat, and 0.834 and 0.073 ppm for the [thiazole-5-[14]C]oxathiapiprolin dosed goat, respectively.  Total residues were below 0.029 ppm in milk, muscle, and fat.  Greater than 52.4% of the radioactivity in the tissues and milk was extracted, with the majority of residues identified or characterized.  Residues of unmetabolized oxathiapiprolin were detected in most tissues including milk (at ca. 0.002 ppm).  Metabolites present at greater than 5% of the TRR in the various tissues and/or milk included IN-E8S72, IN-RAB06, IN-RLB67, IN-QFD61 IN-RDG40, IN-Q7H09, and IN-Q7D41.  Oxathiapiprolin was present at 59.0% and 56.4% dose in the feces from [pyrazole-5-[14]C]- and [thiazole-5-[14]C]oxathiapiprolin goats.






Table 4.1.2.3.  Summary of Identified Residues from Oxathiapiprolin Goat Metabolism Study in %TRR (ppm).  For each compound, matrix and across both labels studied, the maximum observed %TRR and ppm residue is listed.  ND = Not detected.  
 
Milk
 
Liver 
 
Kidney
 
Muscle
 
Fat (all matrices)
 
Oxathiapiprolin
                                                                           10.8
                                                                        (0.002)
                                                                           11.8
                                                                        (0.114)
                                                                           13.8
                                                                        (0.011)
                                                                           42.6
                                                                        (0.004)
                                                                           57.6
                                                                        (0.016)
Hydroxy Metabolites[a]
                                                                              4
                                                                        (0.001)
                                                                           13.3
                                                                        (0.129)
                                                                           20.6
                                                                        (0.013)
                                                                           30.1
                                                                        (0.004)
                                                                           25.7
                                                                        (0.007)
IN-E8S72
                                                                             ND
                                                                             ND
                                                                           24.4
                                                                        (0.021)
                                                                             ND
                                                                             ND
IN-Q7D41
                                                                            2.9
                                                                        (0.001)
                                                                            0.9
                                                                        (0.008)
                                                                             ND
                                                                            5.5
                                                                        (0.001)
                                                                           15.3
                                                                        (0.004)
IN-QFD61
                                                                            8.6
                                                                        (0.002)
                                                                            0.6
                                                                        (0.004)
                                                                             ND
                                                                             ND
                                                                             ND
IN-RAB06
                                                                           11.1
                                                                        (0.002)
                                                                            1.8
                                                                        (0.016)
                                                                            4.8
                                                                        (0.003)
                                                                             ND
                                                                             ND
IN-RLB67
                                                                             ND
                                                                            5.2
                                                                        (0.051)
                                                                             ND
                                                                             ND
                                                                             ND
[a]  Reference standards for hydroxy metabolites IN-RDG40 and IN-Q7H09 were not resolved in the routine HPLC method.  A modified method was used during LC-MS analysis to resolve these components in liver, however this was not done in other tissues due to low levels detected.  This method showed a further 2 minor unidentified hydroxy components were also present at similar retention time to IN-RDG40 and IN-Q7H09.  


Results  -  Goat  -  Metabolite IN-SXS67 Study.  In the IN-SXS67 goat metabolism study, [Pyrazole-5-14C]IN-SXS67 was administered to a lactating goat at an average dose of 18.95 mg/kg feed.  IN-SXS67 and the metabolite IN-E8S72 are readily eliminated with 59.1% of the administered dose recovered in the feces and 26.0% in the urine.  Edible tissues and milk contain negligible amounts of radioactivity (<0.1% of the AD).  An additional 12.5% of the dose was found in the GI tract at sacrifice.  Total radioactive residues in milk plateaued within two days (0.002-0.004 ppm).  Transfer of radioactive residues to the milk was very low, with less than 0.02% of the dose eliminated via this route over the seven days.  Samples of milk fat and skim milk prepared from whole milk contained equal concentrations of residues (0.003 ppm), indicating no selective partitioning of IN-SXS67 to the lipid fraction of milk.  Less than 0.1% of the dose was found in the liver, kidney, muscle, and fat combined at sacrifice six hours after the last dose, indicating that there is no bioaccumulation potential.  Residues in fat were low (0.002-0.006 ppm) and no selective accumulation of IN-SXS67 residues in the various fat types (omental, subcutaneous and renal fat) was observed.  Kidney and liver contained total radioactive residues of 0.483 ppm and 0.038 ppm, respectively.  Overall, 97.7% of the administered dose was recovered.

IN-SXS67 was the principal component of the residue in kidney (0.278 ppm, 57.6% of the TRR) and liver (0.030 ppm, 78.9% of the TRR).  IN-E8S72 was present at 0.186 ppm (38.5% of the TRR) in kidney, and 0.005 ppm (13.2% of the TRR) in liver.  IN-SXS67 and metabolite IN-E8S72 were the only components in urine and feces.  IN-E8S72 was the major component of the excreted residues (51.7% of the dose), with IN-SXS67 accounting for 30.6% of the dose.  Overall, IN-SXS67 metabolized primarily to IN-E8S72.  The total radioactive residues in the milk, muscle and fat were low.  There was no significant potential for accumulation of IN-SXS67 or its biotransformation products.

Conclusions. 
The submitted livestock metabolism studies are considered to be acceptable guideline studies

4.1.3	Summary of Confined Rotational Crops (860.l850)
MRID No. 49011241 Confined Rotational Crop Study  -  210 g ai/ha
MRID No. 49011240 Confined Rotational Crop Study  -  600 g ai/ha

Two confined rotational crop studies were conducted.  One study had soil treated at 210 g ai/ha (0.187 lb ai/A; ~0.4X), the other at 600 g ai/ha (0.534 lb ai/A; ~1X).  The soil in each study was then aged 30, 120 and 365 days prior to planting lettuce, turnips, and wheat at each aging period.  A single application of either [pyrazole-5-14C]oxathiapiprolin, [thiazole-5-[14]C]oxathiapiprolin or [isoxazoline-5-[14]C] oxathiapiprolin was used, with all analyses from each study submitted for both labels.  

In the 210 g ai/ha study, the TRR was highest in the food commodities in the soil treated with [Py-14C]-label: 0.258 ppm (grain), 0.028 ppm (lettuce) and 0.023 ppm (turnip tubers).  Oxathiapiprolin was a minor residue (<0.01 ppm) in the food commodities.  Metabolites included IN-WR791 (<=0.098 ppm), IN-E8S72 (<=0.039 ppm), IN-RZB20 (<=0.022 ppm), IN-RZB21/IN-RZD74 (<=0.012 ppm), IN-SXS67 (<=0.011 ppm) and, in immature lettuce, IN-Q7D41 (<=0.01 ppm).  Low levels of radioactivity were also associated with multiple unidentified components, characterized fractions and the terminal unextracted residues (all individually <=0.01 ppm).  

In the 560 g ai/ha study, the TRR were highest in the food commodities from soil treated with [Py-14C]: <=0.191 ppm (grain), <=0.036 ppm (lettuce) and <=0.020 ppm (turnip tubers).  Oxathiapiprolin was a minor residue (<=0.001 ppm) in the extracts of food commodities.  Metabolites included IN-WR791 (<=0.047 ppm), IN-E8S72 (<=0.019 ppm), IN-RZB20 (<=0.017 ppm), IN-RZB21/IN-RZD74 (<=0.011 ppm), IN-SXS67 (<=0.015 ppm), and IN-KJ552 (<=0.004 ppm).  Radioactivity was also detected in multiple unidentified components, unprofiled fractions and the terminal unextracted residues (all individually <=0.05 ppm).  

The maximum %TRR observed in each crop matrix across studies, labels, and plant back intervals is summarized in Table 4.1.3.  The minimum and maximum %TRR is also listed in Appendix A, which includes the chemical structure of each observed metabolite.  For a detailed breakdown of these confined rotational crop study results, please see Appendix C.  

Conclusions. 

The confined rotational crop studies are considered to be acceptable guideline studies.  


Table 4.1.3.  Summary of Confined Rotational Study Results.  Values listed are the maximum % TRR observed across studies and both labels used.  Italicized compounds were tested for in the crop field trials.  Minor metabolites (<10% TRR) are shaded in grey.  
 
Wheat grain
Wheat forage
Wheat hay
Wheat straw
Turnip tubers
Turnip foliage
Lettuce leaves
Oxathiapiprolin and non-polar metabolites
                                      1.9
                                      6.1
                                     16.4
                                     12.5
                                     15.2
                                      1.7
                                      5.8
IN-E8S72
                                     20.1
                                     12.1
                                     16.7
                                     13.5
                                     18.6
                                     72.7
                                     48.1
IN-WR791
                                     37.7
                                     42.2
                                     18.7
                                      8.3
                                     48.8
                                     52.1
                                     34.3
IN-SXS67
                                     11.8
                                     58.8
                                     55.7
                                     57.2
                                      7.2
                                      9.9
                                      5.2
IN-RZB20
                                     13.2
                                     55.1
                                     42.5
                                      27
                                       4
                                     11.6
                                     13.9
IN-RZB21/
IN-RZD74b
                                      8.6
                                     13.5
                                     14.4
                                      15
                                     13.7
                                      32
                                     20.8
IN-Q7H09
                                      ND
                                      ND
                                      4.2
                                      8.2
                                      ND
                                      ND
                                      ND
IN-RDG40
                                      ND
                                      ND
                                      ND
                                      4.8
                                      ND
                                      0.5
                                      ND
IN-KJ552
                                      2.9
                                      7.9
                                      4.6
                                      4.2
                                      9.9
                                      2.5
                                      4.9
IN-QPS10
                                      ND
                                      ND
                                      ND
                                     12.4
                                      ND
                                      ND
                                      ND
IN-Q7D41
                                      ND
                                      ND
                                      ND
                                      ND
                                      ND
                                      ND
                                       6
a  In some cases, the HPLC system did not separate oxathiapiprolin from non-polar reference standards IN-Q7H09, IN-RDG40, IN-Q9R70, IN-RAB06 and IN-Q7D41.  
b In most cases, similar metabolites IN-RZB21 and IN-RDZ74 could not be resolved from one another for identification purposes.  They were therefore reported together.  Only IN-RDZ74 was tested for in the primary and rotational crop field trials.
4.1.4	Summary of Metabolites and Degradates

The nature of the residue in the proposed crops and livestock is adequately understood for regulatory purposes.  The confined rotational crop study may be interpreted as being reflective of results that would be expected from studies designed to examine metabolism in target crops following early season soil application.  As such, metabolism data are available from the root vegetable, leafy crop, fruit, and cereal crop categories.  The results of those studies are all similar and cover four of the five crop categories (pulses/oilseeds are not covered).  A summary of the metabolites and degradates of oxathiapiprolin in plant, livestock, and environmental matrices is included in Appendix A.  

4.2	Comparison of Metabolic Pathways

A comparative metabolic pathway of oxathiapiprolin (DPX-QGU42) is presented in Figure 4.1, with the matrix-specific metabolic pathways presented in Appendix F.  The major metabolic pathways of oxathiapiprolin in the monogastric hen and rat, ruminant goat, and plants occurred primarily through hydroxylation and further oxidation reactions.  Hydroxylation of the phenyl moiety formed two metabolites, IN-Q7H09 and IN‑RDG40.  A transitory metabolite (IN-RPD37) may have formed by hydroxylation of the pyrazole methyl carbon, which further oxidized to carboxylic acid, IN-RAB06, mainly in animals.  The cleavage of the bond between piperidine ring nitrogen and pyrazole moiety of IN-RAB06 gave IN-E8S72, which formed an N-glucoside conjugate in the plants from foliar (mainly grape vines) as well as soil treatments.  Hydrolysis of the piperidine-2-carbon followed by ring opening may have resulted in formation of IN-RZB21 (amide), which further hydrolyzed to IN-RZB20 in the plants.  IN-RZB20 via multiple metabolic reactions may also have yielded IN-E8S72.

Hydroxylation in the isoxazoline ring followed by dehydration resulted in a non-polar metabolite, IN-Q7D41 in both animals and plants.  Hydrolysis of the isoxazoline ring formed a transitory metabolite, which further degraded to IN-RLD51 in the hen.  Piperidine-2-carbon hydroxylation followed by ring opening gave rise to IN‑RLB26, which may have further degraded through a transient amide, which served as a precursor to IN‑WR791.  Further degradation of IN-WR791 gave rise to IN-KJ552 mainly in the plants grown in the oxathiapiprolin treated soils.  Dihydroxylated metabolites, such as IN-RLB67 and IN-RLB27, were also observed in the animals.  Additionally, several minor metabolites were tentatively identified in the animals and plants and not discussed here as they were present in low levels.

4.3	Residues of Concern Summary and Rationale
ROCKS Report: D425280, I. Negrón-Encarnación, 04/29/2015

The Residues of Concern Knowledgebase Subcommittee (ROCKS) met on 22 January 2015 to discuss the residue definitions for oxathiapiprolin.  Their recommendations are summarized below.  

Radiolabelling approach:  The ROCKS was asked by the oxathiapiprolin team to weigh in on the registrant rationale for radiolabelling only three (pyrazole, thiazole or isoxazoline) of the five rings of oxathiapiprolin.  The registrant indicated that the most stable positions of radiolabels were selected based on the results of a rat metabolism study.  This study did not show significant cleavage of the bonds between the isoxazoline and difluorophenyl rings, or between the thiazole and piperidine rings, or between thiazole and isoxazoline moieties.  Studies with plants and animals showed that the bridge between the pyrazole and piperidine moieties was labile; however, metabolism studies with the radiolabeled pyrazole were conducted and the transformation of the pyrazole moiety was followed.  Overall, the ROCKS did not identify specific concerns with the selection of the radiolabels of oxathiapiprolin. 

Table 4.3. Summary of Metabolites and Degradates to be Included in the Risk Assessment and Tolerance Expression.
Matrix
Residues Included in Risk Assessment
Residues Included in Tolerance Expression for Compliance Monitoring
Plants
Primary Crop
Not applicable.
Oxathiapiprolin

Rotational Crop
Not applicable.
Oxathiapiprolin 
Livestock
Ruminant
Not applicable.  
Oxathiapiprolin

Poultry
Not applicable.  
Oxathiapiprolin
Drinking Water
Not applicable.  
Not Applicable
Oxathiapiprolin is 1-[4-[4-[5-(2,6-Difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-ethanone 
[1] Refer to Appendix A for the names and/or chemical structures of the metabolites/degradates.

Hazard Considerations

In the toxicity studies for oxathiapiprolin, no treatment related effects were seen in any species at doses up to the limit dose (1000 mg/kg/day).  The only treatment related effects were observed in offspring in rat reproduction studies at doses above the limit dose.  Human exposure at this level is not anticipated in conjunction with the use of products containing oxathiapiprolin in accordance with proposed labels.  Due to the limited toxicity in the oxathiapiprolin toxicological database, HED has determined that a quantitative risk assessment is not needed (i.e., no doses or endpoints were selected for risk assessment).  Therefore, a qualitative human health risk assessment will be conducted to support the proposed uses of oxathiapiprolin.  Consequently, HED has concluded that residues of concern are only required for tolerance enforcement and do not need to be set for risk assessment, as there will not be a quantitative dietary risk assessment.  Due to the lack of toxicity from oxathiapiprolin, USEPA would normally grant a tolerance exemption for this chemical.  However, given that this chemical is being assessed as part of a global joint review and is intended to be registered in additional countries, the Agency is setting tolerances for harmonization purposes.  

Exposure Considerations

Primary Crops:  For the vast majority of crops, parent oxathiapiprolin was the primary residue present in field trial samples across all crop field trials.  For potato, it is noted that there were no quantifiable residues of parent oxathiapiprolin or any metabolite at the proposed PHI or at any PHI tested.  Therefore, oxathiapiprolin is recommended as a residue of concern for tolerance enforcement on primary crops.  
Rotational Crops:  Average residues of metabolites IN-E8S72 and IN-SXS67 ranged from <LOQ in several commodities up to 0.30 ppm in wheat hay.  In general, the metabolites IN-E8S72 and IN-SXS67 were at higher concentrations than parent oxathiapiprolin and more consistently observed across all crops.  Given that tolerances are being set solely for the purposes of harmonization with global partners, HED has concluded that it is appropriate to align the residue of concern for tolerance enforcement with the global partners.  PMRA has set the residue of concern as parent oxathiapiprolin only in rotational crops and will be setting a generic action MRL of 0.10 ppm on all crops not currently proposed on the label.  This generic action MRL of 0.10 ppm will be used to provide coverage for inadvertent residues in rotational crops.  HED concludes that this approach is adequate for the purposes of tolerance enforcement in rotational crops and that this aligned approach will avoid future trade irritants with global partners.  

Ruminants:  There is no expectation of finite residues for ruminant matrices and no ruminant tolerances have been proposed at this time.  Parent oxathiapiprolin was a major residue across all goat matrices; therefore, it is considered an adequate indicator of misuse.  The ROCKS recommends parent only for tolerance enforcement.  This decision may need to be revisited depending on the results of any future submissions of ruminant feeding studies.
Poultry:  There is no expectation of finite residues for poultry matrices and no poultry tolerances have been proposed at this time.  Parent oxathiapiprolin is recommended as the residue of concern for tolerance enforcement on poultry commodities.  This decision may need to be revisited in the future if uses resulting in a higher livestock dietary burden are proposed.  

5.0	Residue Profile

5.1	Residue Analytical Methods (860.1340) 

5.1.1	Data Collection Methods

MRID No. 49011136 (Plants)

DuPont Method 30422, Supplement No.1, was used for all crop residue studies.  Table 5.1.1 summarizes the analytical method parameters.  

Table 5.1.1.  Summary of Oxathiapiprolin Analytical Method for Plant Commodities.
Method ID
DuPont-30422, Supplement No. 1, Analytical Method for the Determination of DPX-QGU42 and Metabolites in Crops Using LC/MS/MS
Analyte(s)
Oxathiapiprolin and metabolites (IN-Q7H09, IN-RDG40, IN-E8S72, IN-RZB20, IN-RZD74, IN-SXS67, and IN-WR791) 
Extraction Solvent/Technique
12:4:0.1 acetonitrile:water:formic acid
Cleanup Strategies 
(If Needed)
Filtration through a Envi(TM)-Carb SPE 6 cc 250 mg cartridge 
Chromatography
HPLC:  Waters Acquity HSST3, 2.1 mm  50 mm, 1.8 m particle size diameter
Detection
Triple quadrupole mass spectrometer (MS/MS) - using an electrospray (ESI) interface
LOQ
0.010 mg/kg

In analytical method DuPont-30422 Supplement 1 residues of oxathiapiprolin and metabolites IN-SXS67, IN-RZB20, IN-RZD74, IN-E8S72, IN-WR791, IN-RDG40, and IN-Q7H09 are extracted from crop samples using a solution of formic acid, water and acetonitrile, and diluted with aqueous formic acid solution and methanol.  An aliquot of supernatant is filtered/centrifuged and analyzed by reverse-phase HPLC-MS/MS in positive ion mode using a gradient elution with 0.05% formic acid in water/methanol and 0.01% formic acid in methanol as the mobile phases.  The analytes are determined via LC-MS/MS.  

For some matrices, ion suppression or matrix interference was observed.  For these matrices, a solid-phase extraction (SPE) clean-up using a graphitized carbon cartridge was used.  Due to the selectivity of graphitized carbon cartridges, the polar (IN-SXS67, IN-RZB20, IN-RZD74, IN-WR791 and IN-E8S72) and non-polar (IN-RDG40, IN-Q7H09 and oxathiapiprolin) compounds were eluted separately.  For these matrices, the analysis was divided into two injections, polar compounds and non-polar compounds.  For the analysis of oranges, grapes, wheat straw and canola, the SPE clean-up was used for the polar compounds.  For the analysis of ginseng, the SPE clean-up was used for the analysis of polar and non-polar compounds.

Method validation results showed that mean recoveries for residues of oxathiapiprolin and metabolites IN-SXS67, IN-RZB20, IN-RZD74, IN-E8S72, IN-WR791, IN-RDG40, and IN-Q7H09 in canola, grape, orange, tomato, potato, ginseng, wheat grain and wheat straw were 76-115% at fortification levels of 0.01 and 0.10 ppm.

Confirmatory data with a second ion using method Dupont-30422 Supplement 1 for all eight analytes were submitted with Dupont-30422 Supplement 2.  The data were reported separately, but were generated simultaneously with the DuPont-30422 Supplement 1 study.  Using confirmatory ion transitions, mean recoveries for residues of oxathiapiprolin and metabolites IN-SXS67, IN-RZB20, IN-RZD74, IN-E8S72, IN-WR791, IN-RDG40, and IN-Q7H09 in canola, grape, orange, tomato, potato, ginseng, wheat grain and wheat straw were 76-117% (except three recovery values of 54%, 69% and 127%) at fortification levels of 0.01 and 0.10 ppm.

Two ion transitions are available for parent and all seven metabolites.  Quantitation was performed using the mass transition 222-->192 for IN-RZB20; 341-->135 for IN-SXS67; 165-->65 for IN-RZD74; 207-->143 for IN-WR791; 179-->65 for IN-E8S72; 556-->174 for IN-RDG40; 556-->155 for IN-Q7H09; and 540-->163 for oxathiapiprolin.  Confirmation was performed using the mass transition 222-->42 for IN-RZB20, 341-->297 for IN-SXS67, 165-->135 for IN-RZD74, 207-->163 for IN-WR791, 179-->40 for IN-E8S72, 556-->163 for IN-RDG40, 556-->538 for IN-Q7H09, 540-->500 for oxathiapiprolin.

The method underwent ILV by different laboratories, which showed similar results to the validation tests.  Oxathiapiprolin, IN-SXS67, IN-E8S72 and IN-WR791 were analyzed in wheat grain, grape and tomato.  Residues of oxathiapiprolin, IN-SXS67, IN-RZB20, IN-RZD74, IN-E8S72, IN-WR791, IN-RDG40, and IN-Q7H09 were analyzed in carrot roots, spinach leaves, hops, wheat (forage, grain, straw), potato, potato chip, grape, grape dry pomace, tomato, tomato juice, spinach, broccoli, whole pepper, dried soybean seed, dried beans, dry bulb onion, dried ginseng and dried tobacco leaves.  Overall, mean ILV recoveries were 71-120% at fortification levels of 0.01 and 0.10 ppm.

The residue profiles obtained by extracting bio-incurred residues of radiolabelled test substance from samples of lettuce, grape berries and wheat grain using the DuPont-30422 Supplement 1 extraction procedures were compared with those obtained for the same samples in the plant metabolism study.  The levels of oxathiapiprolin and metabolites obtained using Method DuPont-30422 Supplement 1 were within 80-120% of those found in the metabolism study, indicating that Method DuPont-30422 Supplement 1 provides acceptable extraction efficiency.

The method LOQ, defined as the lowest limit of method validation, is 0.01 ppm for each analyte.  The analytical method DuPont-30422 Supplement 1 is considered suitable for enforcement purposes of oxathiapiprolin and metabolites IN-SXS67, IN-RZB20, IN-RZD74, IN-E8S72, IN-WR791, IN-RDG40, and IN-Q7H09 in high water, high acid, high starch, high oil and high protein content matrices.

Conclusions.

The analytical method used for data collection has been adequately validated.  The results are within generally recognized limits for analytical methods (mean recoveries between 70 and 120% with a relative standard deviation of <= 20%).  Furthermore, the solvent used for extraction was shown to efficiently extract incurred residues in the metabolism studies.  

5.1.2	Multi-Residue Methods (860.1360)

MRID No. 49011133 (DFG Method S19)
MRID No. 49011142 (QuEChERS)
MRID No. 49011143 (U.S. FDA MRM testing)

U.S. Multiresidue Methods.  FDA multiresidue protocols were evaluated for their ability to analyze for oxathiapiprolin and the metabolites IN-SXS67, IN-E8S72, and IN-WR791.  Protocols A, B, and C were not suitable because of poor sensitivity and/or because of degradation in the gas chromatography (GC) detector.  Without an appropriate determinative step from Protocols A, B, or C, the remaining Protocol D, E, and F testing was suspended as per the PAM protocol.  

European Multiresidue Method (DFG Method S19).  The European multiresidue analytical method DFG S19 has been successfully validated for the analysis of oxathiapiprolin and metabolites IN-RZB20, IN-RZD74, IN-E8S72, IN-WR791, IN-RDG40, and IN-Q7H09 in high water, high acid and high starch content crop matrices in terms of specificity, linearity, precision, accuracy and LOQ.  The method is considered acceptable for enforcement purposes in terms of materials, equipment and analysis time. It is not suitable for the analysis of metabolite IN-SXS67 in crop matrices, or for the detection of oxathiapiprolin and metabolites IN-RDG40 and IN-Q7H09 in high oil content matrices.

Method S19 was also found to be successful for the determination of oxathiapiprolin and metabolites IN-Q7H09, IN-RDG40, IN-RLB67, and IN-RAB06 in livestock matrices (milk, meat (muscle), liver, fat and eggs).  

QuEChERS Multiresidue Method.  The multiresidue analytical method QuEChERS has been successfully validated for the analysis of oxathiapiprolin in high water, high acid, high starch and high oil content crop matrices in terms of specificity, linearity, precision, accuracy and LOQ.  The method is considered acceptable for enforcement purposes in terms of materials, equipment, and analysis time, for all crop matrices except dry crop matrices.

Conclusions.    

The FDA multi-residue protocols are not suitable for the analysis of oxathiapiprolin and associated metabolites.  Depending on the crop matrix, HED notes that the QuEChERS and/or DFG Method S19 multi-residue methods may be suitable for the analysis of these compounds based on extraction solvents and clean-up strategies being similar to the analytical method described above.  The QuEChERS and DFG Method S19 multi-residue methods were found to be unsuitable for the analysis of oxathiapiprolin and associated metabolites in dry crop matrices and high oil crop matrices, respectively.  

5.1.3	Tolerance Enforcement Methods

MRID No. 49011145 (Livestock)

Plant Commodities: The enforcement method is the same as the data collection method described in Section 5.1.1.

Livestock Commodities: A method titled "Analytical method for the determination of DPX-QGU42 and metabolites in livestock tissues, milk and eggs using LC/MS/MS" (Report No: DuPont-31138) was submitted as an enforcement method for residues of oxathiapiprolin and associated metabolites in livestock commodities.  The method is similar to that used for plant commodities, but with modifications depending on the matrix and analyte.

Residues of oxathiapiprolin and metabolites IN-RAB06, IN-RLB67, IN-RDG40 and IN-Q7H09 are extracted from livestock tissue, milk and egg samples in acetonitrile and hexane using a Genogrinder extractor.  The extracts are diluted with an aqueous formic acid solution and methanol.  The analytes are determined via LC-MS/MS.

Method validation results showed that mean recoveries for residues of oxathiapiprolin and metabolites IN-RAB06, IN-RLB67, IN-RDG40 and IN-Q7H09 in whole eggs, whole milk, heavy cream, beef fat, beef muscle, beef kidney and beef liver were 82-119% at fortification levels of 0.01 and 0.10 ppm.

The method underwent an ILV.  Mean ILV recoveries were 91-119% for residues of oxathiapiprolin, IN-RAB06, IN-RLB67, IN-RDG40, and IN-Q7H09 in whole eggs, whole milk, beef muscle and liver at fortification levels of 0.01 and 0.10 ppm, except in liver for IN-RDG40 at fortification level of 0.01 ppm (mean recovery of 124%).  As a result of the ILV investigations, a change to the HPLC conditions was recommended for the determination of IN-RDG40 in bovine liver and poultry eggs due to interference levels, and determination using the secondary ion transition was recommended for IN-RLB67 and IN-RDG40 in bovine liver.

The residue analytical method uses the same solvents (acetonitrile and hexane) as the goat and hen metabolism studies.  The only difference is that the metabolism extraction protocol used a homogenizing probe while in the analytical residue method extraction, samples are extracted using a Genogrinder.  Since the extraction protocols are similar, it can be concluded that Method DuPont-31138 provides acceptable extraction efficiency.

In order to ensure unambiguous identification, two mass transitions for each analyte were monitored.  Quantitation was performed using the mass transition 568-->524 for IN-RAB06; 572-->554 for IN-RLB67; 556-->174 for IN-RDG40; 556-->155 for IN-Q7H09; and 540-->163 for oxathiapiprolin.  Confirmation was performed using the mass transition 568-->135 for IN-RAB06; 572-->163 for IN-RLB67; 556-->163 for IN-RDG40; 556-->538 for IN-Q7H09; and 540-->500 for oxathiapiprolin.

The method LOQ is 0.01 ppm for each analyte.  The analytical method DuPont-31138 is considered suitable for enforcement purposes of oxathiapiprolin and metabolites IN-RAB06, IN-RLB67, IN-RDG40, and IN-Q7H09 in livestock matrices.

Conclusions.

The analytical methods for enforcement are adequate in terms of the tolerance expression and have passed both independent laboratory and Agency validation.  

5.1.4	Submittal of Analytical Reference Standards (860.1650)

A supply of oxathiapiprolin analytical standard is available in the National Pesticides Standards Repository.  The standard has an expiration date of 04 June 2018.  As a reminder to the petitioner, supplies of analytical standards must be replenished as requested by the repository as long as the tolerance is published in 40 CFR.  The repository address is listed below and shipment should be sent to the attention of either Theresa Cole or Thuy Nguyen.  Note that the full 9-digit ZIP code is mandatory or the mail will be returned to the sender.  
      USEPA
      National Pesticide Standards Repository/Analytical Chemistry Branch/OPP
      701 Mapes Road
      Fort George G.  Meade, MD  20755-5350


5.2	Storage Stability (860.1380)

MRID No. 49011204

The storage stability study on wheat forage, tomato, potato tuber, wheat grain, grape, dry bean seed, soybean seed, grape dry pomace, and wheat straw is considered to be scientifically acceptable.  Normalized recoveries showed that residues of oxathiapiprolin and metabolites IN-Q7H09, IN-RDG40, IN-E8S72, IN-RZB20, IN-RZD74, IN-SXS67, and IN-WR791 are stable for up to 18 months in crop matrices stored at or below -20°C.  Samples were analyzed at various time points throughout the course of the storage period, including a 0-day time point for the RAC samples.  Since the results of the study suggest that oxathiapiprolin and all seven metabolites investigated are stable in crop matrices with high water, high starch, high protein, high oil, and high acid content, stability is assumed for all crop commodities, including processed fractions, for up to 18 months when samples are stored frozen.  Almost all recovery values were within the acceptable range of 70-120%; only 11 individual samples had recoveries outside the acceptable range at 121-135%.  The normalized recoveries for oxathiapiprolin and metabolites IN-Q7H09, IN-RDG40, IN-E8S72, IN-RZB20, IN-RZD74, IN-SXS67, and IN-WR791 in crop samples stored frozen at -20+-10°C for up to 18 months ranged from 73 to 120%, demonstrating stability of residues in plant matrices under the given conditions.  

For a detailed summary of the concurrent recoveries of oxathiapiprolin and the associated seven metabolites, please see Appendix H.  

In the submitted livestock metabolism studies, samples were generally stored for six months or less prior to analysis; therefore, additional storage stability data are not required to support these data.  

Conclusions.

The submitted storage stability data are adequate to support the metabolism, field trials, and processing studies.  The data demonstrate that residues of oxathiapiprolin and all seven metabolites investigated are stable in crop matrices with high water, high starch, high protein, high oil and high acid content, including processed fractions, for up to 18 months when samples are stored frozen.  The seven metabolites included in the storage stability study are IN-Q7H09, IN-RDG40, IN-E8S72, IN-RZB20, IN-RZD74, IN-SXS67, and IN-WR791.    


5.3	Residue Data

5.3.1	Crop Field Trials (860.1500)

See Appendix K for a listing of MRID references for each Crop Field Trial Study.

Supervised residue trials with oxathiapiprolin were conducted in the U.S. and Canada with ginseng, tuberous and corm vegetables (potato), bulb vegetables (green onion and dry bulb onion), fruiting vegetables (tomato and pepper), leafy greens (lettuce and spinach), head and stem Brassica vegetables (broccoli, cauliflower, and cabbage), succulent peas (shelled seed and edible-podded), cucurbits (cantaloupe, summer squash, and cucumber), and tobacco.  Adequate data were submitted to support the proposed greenhouse uses on tomato, pepper, and edible-peel cucurbits.  For leafy greens, adequate data were submitted on representative crops, including head lettuce and leaf lettuce, as well as spinach.  In support of the proposed tolerance on imported grapes, adequate trials were also conducted in the EU.  The number of field trials are adequate based on the North American Free Trade Agreement (NAFTA) Guidance Document on Data Requirements for Tolerances on Imported Commodities in the United States and Canada (December 2005). According to the guidance, twelve trials to support imported grape would be acceptable and data from eighteen trials are available.   

All matrices were assayed for residues of oxathiapiprolin and associated metabolites according to the data collection method described in Section 5.1.1.  In the NAFTA field trials, with the exception of the EU grape and NAFTA potato study, all crop field trials tested for parent oxathiapiprolin and seven metabolites (IN-E8S72, IN-WR791, IN-RDG40, IN-Q7H09, IN-SXS67, IN-RZB20, and IN-RZD74).  For the potato field trials, oxathiapiprolin, IN-E8S72, and IN-WR791 were tested for, whereas the EU grape field trials tested for oxathiapiprolin, IN-E8S72, IN-WR791, IN-RDG40, and IN-Q7H09.    

The geographic distribution of the NAFTA field trials is summarized in Appendix I.  Sufficient numbers of trials were conducted in geographically appropriate regions to support the establishment of tolerances in the proposed commodities.

With the exception of potato and summer squash, parent oxathiapiprolin was the predominant residue across all crop field trials.  The field trials were generally conducted in a manner that was consistent with the proposed use pattern, both in terms of the proposed PHI and application rates/methods.  Please see Table 5.3.1.2 for the GAP proposed use rates and PHI.  For the same crop, field trials conducted using a foliar application method had generally higher residues than those conducted using direct soil application methods.  Of the seven metabolites that were tested for, four metabolites were not detected above the LOQ in any of the field trials at the proposed PHI: IN-Q7H09, IN-RDG40, IN-RZB20, and IN-SXS67.  At the proposed PHI, the remaining three metabolites (IN-E8S72, IN-RZD74, and IN-WR791) were relatively rarely observed in the field trials above the LOQ and generally at low levels compared to parent.  At the proposed PHI, IN-E8S72 and IN-WR791 were quantifiable in ginseng, grape vine leaves, tobacco, and summer squash.  IN-E8S72 was also at trace levels (<= LOQ) in tomato; IN-WR791 was also quantifiable in succulent pea and non-bell pepper (up to 0.013 ppm); and IN-RZD74 was only quantifiable in tobacco matrices.

In the case of summer squash, metabolite IN-E8S72 was observed at slightly higher levels than oxathiapiprolin in the field trials conducted with only soil application methods (maximum IN-E8S72 residue of 0.021 ppm vs. oxathiapiprolin residue of 0.015 ppm).  In the case of potato, no quantifiable residues were observed for oxathiapiprolin or any of the metabolites at the proposed PHI or at any other PHI assessed.  As noted previously, for the potato field trials only oxathiapiprolin, IN-E8S72, and IN-WR791 were tested for, whereas the EU grape field trials tested for only oxathiapiprolin, IN-WR791, IN-RDG40, IN-E8S72, and IN-Q7H09.    

Table 5.3.1.2 summarizes the North America crop field trial data at the GAP proposed PHIs, as well as the EU grape field trial data.  Given that the residue of concern in primary crops has been defined as oxathiapiprolin only (see Section 4.3 for further details), Table 5.3.1.2. only captures the oxathiapiprolin residues.  The registrant also submitted EU crop field trial data for the other EU proposed uses (see Table 3.3 for proposed EU use pattern; detailed field trial results not summarized here).  Specifically, additional EU trials were conducted with edible and inedible peel cucurbits, tomatoes, lettuce, and potato.  This EU crop field trial data is consistent with North American crop field trial data, with parent oxathiapiprolin being the predominant residue across the dataset.  Metabolites were only rarely detected above the LOQ in any of the EU field trials.     

In the case of Crop Group 8-10, Fruiting Vegetables, the registrant has proposed excluding a tomato field trial (Trial 18) from the summary statistics and tolerance calculation.  The registrant has provided a rationale for excluding this trial.  Specifically, they indicate that the results from this trial "do not agree with the current body of knowledge for this active ingredient based both on physical-chemical properties and supervised field residue tests in multiple crops.  In particular, the following anomalies were observed:  Oxathiapiprolin residues in tomato fruit were much higher at this trial following foliar application than at any other tomato or pepper supervised residue trial.  Oxathiapiprolin residue in tomato fruit were higher at this trial than in the three tomato processing trials where oxathiapiprolin was applied at exaggerated rates.  Oxathiapiprolin residues in tomato fruit were equally high following late-season soil applications as following late-season foliar applications.  Oxathiapiprolin residues in tomato fruit were near 0.1 mg/kg following early-season soil applications."  The tomato field trial HAFT from foliar application is 0.14 ppm if one excludes this trial and 0.31 ppm if one includes this trial.  While HED agrees that the results from this trial do not appear to be consistent with the results of the rest of the fruiting vegetable trials, the registrant has not provided sufficient evidence to exclude the trial (e.g., evidence that an error occurred in conducting the trial, such as misapplication of the fungicide at exaggerated non-GAP use rates, or that irregular weather conditions occurred that resulted in these residues).  Therefore, HED has decided not to exclude this trial from the tomato field trial dataset.  

In the case of grape, ten EU trials conducted in 2010 and 2011 used a PHI of 9-11 days, whereas the proposed PHI is 14 days.  However, eight additional trials were conducted in 2013 with a PHI of 14-15 days.  The use rates in the grape trials were also slightly lower than the proposed use rate (0.8x-0.9x of GAP rate for 60% of the total submitted trials, with the remaining 40% conducted at ~1x).  Overall, the 2010 and 2011 residue data is similar to that of the 2013 trials, with the combined dataset being considered adequate to support the proposed tolerance without a US registration.  

In the case of ginseng, the registrant submitted four field trials at the GAP proposed use rate and two field trials at ~2X the GAP.  The registrant indicated that this was done because ginseng is a multi-year crop, often being harvested only after multiple growing seasons.  At the two trials where a 2X rate was used, side-by-side plots were established with one plot receiving the maximum application allowed for one season and a second plot receiving simulated multiple season applications.  The multiple season scenario involved the maximum applications of oxathiapiprolin allowed for one season followed 45 days later by the maximum applications of oxathiapiprolin allowed for a second season.  The resulting residues were exaggerated since there was only a 45-day window between "growing seasons" as compared to an 11-month separation of applications under realistic use.  The oxathiapiprolin residues following the simulated multi-season treatment averaged 2X the oxathiapiprolin residues following the maximum single-season GAP treatment.  The residue results from both approaches (GAP and 2X) are listed in Table 5.3.1.2.  For tolerance derivation purposes, the registrant has proposed using the residue data from the 2X trials and proportionally adjusting the residue data from the 1X trials (where side-by-side treatment was not undertaken) to be 2 times higher.  Please see Section 6.0 for HED's conclusions regarding this registrant proposal.  Overall, HED concludes that there is sufficient ginseng field trial data to support the proposed use.    

Conclusions.  

The crop field trials are adequate for regulatory purposes, including for setting tolerances.  For the NAFTA proposed uses, the number of trials is sufficient and the geographic distribution of the trials captures the major growing regions in the U.S., per OCSPP Series 860 Guidelines.  Adequate data is available to support the proposed greenhouse uses on tomato, peppers, and edible-peel cucurbits.  While residue data was submitted on tobacco (and is summarized in Table 5.3.1.2), as tobacco is a non-food use, no tolerance is recommended for tobacco.  The submitted grape field trial data is also sufficient to support the proposed tolerance without a US registration based on a proposed EU use.  Data from the trials are representative of worst-case residues expected to result from application of oxathiapiprolin according to the proposed use patterns, and the residue data are supported by adequate analytical method performance and storage stability data.
Table 5.3.1.2.  Summary of Oxathiapiprolin Field Trial Residue Data under GAP Proposed Conditions
                                   Commodity
                                      EPa
                             (Application Method)
                   Total Application Rate

lb ai/A
(g ai/ha)
                               DALA/ PHI (days)
                         Residue Levels in ppm (mg/kg)
                                       
                                       
                                       
                                       
                                      nb
                                     Min.b
                                     Max.b

                                       
                                     LAFTb
                                     HAFTb
                                Medianb (STMdR)
                                 Meanb (STMR)
                                  Std. Dev.b
                Crop Subgroup 1C, Tuberous and Corm Vegetables
(Proposed GAP: PHI = 5 days; Foliar application only; 0.178 lb ai/A maximum total application rate)
                                 Potato Tubers
                                  100 g/L OD
                                   (Foliar) 
                           0.125 - 0.195
(140 - 219)
                                     4 - 5
                                      22
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      NA
           Grape (Import Tolerance Use Only Based on EU use pattern)
(Proposed GAP: PHI = 14 days; Foliar application only; 0.107 lb ai/A maximum total application rate)
                                Grape (Berries)
                                  NEU and SEU
                                  100 g/L OD
                                   (Foliar)
                                  0.087-0.112
                                (97.51-125.09)
                                     9-15
                                      18
                                     0.021
                                     0.41
                                     0.021
                                     0.41
                                     0.12
                                     0.15
                                     0.123
                        Crop Subgroup 3-07A, Bulb Onion
(Proposed GAP: PHI = 0 days; Foliar application only; 0.125 lb ai/A maximum total application rate)
                                Dry Bulb Onion
                                  100 g/L OD
                                   (Foliar)
                          0.12-0.13
(134.94 - 145.72)
                                       0
                                      12
                                   <0.01
                                     0.026
                                     0.01
                                     0.026
                                     0.011
                                     0.014
                                     0.005
                       Crop Subgroup 3-07B, Green Onion
(Proposed GAP: PHI = 0 days; Foliar application only; 0.125 lb ai/A maximum total application rate)
                            Whole Plant Green Onion
                                  100 g/L OD
                                   (Foliar)
                         0.122-0.133
(137.81 - 149.5)
                                       0
                                       5
                                     0.38
                                     0.86
                                     0.40
                                     0.85
                                     0.57
                                     0.58
                                     0.18
                                Peas, succulent
(Proposed GAP: PHI = 0 days; Foliar application only; 0.125 lb ai/A maximum total application rate)
                                 Shelled Seed
                                  100 g/L OD
                                   (Foliar)
                                 0.125-0.137 
                                  (140 - 153)
                                       0
                                       6
                                   <0.01
                                     0.029
                                   <0.01
                                     0.026
                                     0.011
                                     0.016
                                     0.008
                                       
                                       
                                   Whole Pea
                                       
                                       
                                  100 g/L OD
                                   (Foliar)
                                 0.127-0.137  
                                  (142 - 153)
                                       0
                                       6
                                     0.20
                                     0.55
                                     0.20
                                     0.55
                                     0.29
                                     0.315
                                     0.121
                                    Ginseng
(Proposed GAP: PHI = 14 days; Foliar application only; 0.50 lb ai/A maximum total application rate)
                                   Ginseng, 
                                  Dried Roots
                                  100 g/L OD
                                   (Foliar)
                                   0.49-0.51
                                  [548 - 571]
                                    13 - 14
                                       4
                                     0.025
                                     0.058
                                     0.041
                                     0.049
                                     0.044
                                     0.044
                                     0.003
                                       
                                       
                                   0.98-1.00
                                 [1102 - 1125]
                                    13 - 14
                                       2
                                     0.064
                                     0.15
                                     0.072
                                     0.14
                                      NA
                                      NA
                                      NA
              Crop Subgroup 5A, Head and Stem Brassica Vegetables
(Proposed GAP: PHI = 0 days; Foliar application only; 0.125 lb ai/A maximum total application rate)
                                 Broccoli Head
                                  100 g/L OD 
                                   (Foliar)
                            0.124-0.127
(139 - 142)
                                       0
                                       5
                                     0.056
                                     0.84
                                     0.066
                                     0.81
                                     0.21
                                     0.297
                                     0.294
                               Cauliflower Head
                                  100 g/L OD 
                                   (Foliar)
                            0.124-0.128
(139 - 143)
                                       0
                                       5
                                     0.073
                                     0.17
                                     0.077
                                     0.14
                                     0.082
                                     0.094
                                     0.026
                                 Cabbage Head
                                  100 g/L OD
                                   (Foliar) 
                            0.122-0.128
(137 - 143)
                                       0
                                       
                                      10
                                       
                                     0.043
                                     0.46
                                     0.044
                                     0.42
                                     0.14
                                     0.178
                                     0.129
                        Crop Subgroup 4A, Leafy Greens
(Proposed Gap: PHI = 0 days; Foliar application = 0.125 lb ai/A maximum application rate; Soil application = 0.50 lb ai/A maximum application rate)
                                Spinach Leaves
                                  100 g/L OD
                                   (Foliar)
                         0.122 - 0.129
(136.4 - 144.7)
                                       0
                                      10
                                      1.3
                                      7.0
                                      1.4
                                      6.5
                                      3.4
                                      3.7
                                      1.9
                                Spinach Leaves
                                  200 g/L SC
                                 (Direct Soil)
                         0.490 - 0.513
(549.4 - 575.4)
                                       0
                                      10
                                   <0.01
                                      2.1
                                   <0.01
                                      2.1
                                     0.11
                                     0.75
                                     0.92
                       Head Lettuce with Wrapper Leaves
                                  100 g/L OD
                                   (Foliar)
                                 0.125 - 0.133
                                  (140 - 149)
                                       0
                                      11
                                     0.20
                                      1.5
                                     0.23
                                      1.4
                                     0.57
                                     0.66
                                     0.40
                       Head Lettuce with Wrapper Leaves
                                 200 g/L SC /
                                  100 g/L OD
                                 (Direct Soil)
                                 0.499 - 0.515
                                  (560 - 578)
                                       0
                                      11
                                   <0.01
                                     0.47
                                   <0.01
                                     0.43
                                     0.010
                                     0.081
                                     0.16
                       Leaf Lettuce Plant without Roots
                                  100 g/L OD
                                   (Foliar)
                                 0.125 - 0.132
                                  (140 - 148)
                                       0
                                      11
                                     0.41
                                      3.1
                                     0.53
                                      3.0
                                      1.8
                                      1.5
                                     0.78
                       Leaf Lettuce Plant without Roots
                                 200 g/L SC /
                                  100 g/L OD
                                 (Direct Soil)
                                 0.486 - 0.515
                                  (545 - 578)
                                       0
                                      11
                                   <0.01
                                     0.38
                                     0.01
                                     0.37
                                     0.01
                                     0.057
                                     0.11
                                 Leaf Lettuce
                                  200 g/L SC
       (Soil application - in-furrow/drip/drench/shank/basal in-season)
                                  0.491-0.499
                                   (556-560)
                                       0
                                       3
                                   <0.01
                                      3.7
                                   <0.01
                                      2.9
                                     0.01
                                      1.0
                                      1.7
                     Crop Group 8-10, Fruiting Vegetables
(Proposed Gap: PHI = 0 days; Foliar application = 0.125 lb ai/A maximum application rate; Soil application = 0.50 lb ai/A maximum application rate)
Tomato fruit  -  field and greenhouse- grown c
                                       
                                  100 g/L OD
                                   (Foliar)
                                       
                                       
                          0.122-0.131
(136.3 - 146.8)
                                       
                                       0
                                      23
                                   <0.01
                                     0.35
                                   <0.01
                                     0.31
                                     0.035
                                     0.057
                                     0.065
Tomato fruit  -  field grown c
                                  200 g/L SC
                                 (Direct Soil)
                           0.49-0.55
(553.8 - 610.9)
                                       0
                                      18
                                   <0.01
                                     0.44
                                   <0.01
                                     0.24
                                     0.010
                                     0.010
                                     0.010
Tomato fruit  -  field grown
                                  200 g/L SC
       (Soil application - in-furrow/drip/drench/shank/basal in-season)
                                  0.499-0.504
                                   (560-566)
                                       0
                                       3
                                   <0.01
                                     0.070
                                   <0.01
                                     0.054
                                     0.010
                                     0.025
                                     0.025
Bell Pepper
Whole Fruit Field-grown and greenhouse
                                       
                                  100 g/L OD
                                   (Foliar)

                             0.123-0.132
(138-147)
                                       0
                                      12
                                     0.013
                                     0.14
                                     0.016
                                     0.12
                                     0.032
                                     0.045
                                     0.037
Bell Pepper
Whole Fruit Field-grown 
                                 200 g/L SC /
                                  100 g/L OD
                                 (Direct Soil)
                             0.498-0.593
(558-665)
                                       0
                                      10
                                   <0.01
                                     0.019
                                   <0.01
                                     0.017
                                     0.010
                                     0.011
                                     0.002
Non-Bell Pepper
Whole Fruit
Field-grown
                                       
                                  100 g/L OD
                                   (Foliar)

                                       
                             0.125-0.139
(140-156)
                                       
                                       0
                                       6
                                     0.019
                                     0.13
                                     0.028
                                     0.12
                                     0.057
                                     0.063
                                     0.035
Non-Bell Pepper
Whole Fruit
Field-grown
                                 200 g/L SC /
                                  100 g/L OD
                                 (Direct Soil)
                                       
                              0.49-0.51
(546-568)
                                       0
                                       6
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      NA
                       Crop Group 9, Cucurbit Vegetables
(Proposed Gap: PHI = 0 days; Foliar application = 0.125 lb ai/A maximum application rate; Soil application = 0.50 lb ai/A maximum application rate)
Cantaloupe, Whole Fruit
                                  100 g/L OD
                                   (Foliar)
                                  0.123-0.130
                                  (138 - 146)
                                       0
                                      12
                                     0.012
                                     0.13
                                     0.014
                                     0.12
                                     0.045
                                     0.054
                                     0.033
Cantaloupe,
Whole Fruit
                                    200 SC/
                                    100 OD
                                 (Direct Soil)
                                   0.50-0.52
                                  (558 - 578)
                                       0
                                      12
                                   <0.01
                                     0.034
                                     0.01
                                     0.024
                                     0.01
                                     0.012
                                     0.004
Cucumber Fruit, Field and Greenhouse Grown
                                  100 g/L OD
                                   (Foliar)
                                  0.121-0.127
                                   (136-142)
                                       0
                                      16
                                   <0.01
                                     0.096
                                   <0.01
                                     0.09
                                     0.030
                                     0.032
                                     0.022
Cucumber Fruit,
Field-grown
                                   200 SC / 
                                    100 OD
                                 (Direct Soil)
                                   0.46-0.52
                                  (518 - 578)
                                       0
                                      11
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.010
                                     0.010
                                      NA
Summer Squash
                                  100 g/L OD
                                   (Foliar)
                                  0.123-0.133
                                  (138 - 149)
                                       0
                                      10
                                   <0.01
                                     0.13
                                     0.01
                                     0.12
                                     0.032
                                     0.043
                                     0.033
Summer Squash
                            200 g/L SC / 100 g/L OD
                                 (Direct Soil)
                                   0.50-0.52
                                  (557 - 578)
                                       0
                                      10
                                   <0.01
                                     0.042
                                   <0.01
                                     0.026
                                     0.010
                                     0.012
                                     0.005
Summer Squash
                                  200 g/L SC
       (Soil application - in-furrow/drip/drench/shank/basal in-season)
                                  0.499-0.504
                                  (560-566) 
                                       0
                                       3
                                   <0.01
                                     0.015
                                   <0.01
                                     0.013
                                     0.010
                                     0.011
                                    0.0017
                            Tobacco, dried leaves 
(Proposed GAP: PHI = 7 days; Foliar application = 0.125 lb ai/A maximum application rate; Soil application = 0.50 lb ai/A maximum application rate)
Tobacco, 
Dried Leaves
                                  100 g/L OD
                                   (Foliar)
                                  0.125-0.13
                                (140.0 - 145.4)
                                      6-7
                                       5
                                      3.8
                                      17
                                      4.5
                                      15
                                      7.6
                                      8.4
                                      4.0
Tobacco, 
Dried Leaves
                                  200 g/L SC
                                 (Direct Soil)
                                   0.50-0.51
                                (557.2 - 571.1)
                                     7-42
                                       5
                                   <0.01
                                      4.1
                                     0.015
                                      2.8
                                     0.18
                                      1.1
                                      1.4
Note:  For the computation of the median, mean, and standard deviation: values < LOQ are assumed to be at the LOQ (0.01 ppm).  
a 	EP = End-use Product 
b	n = Number of independent field trials; Min = Minimum individual specimen residue; Max = Maximum individual specimen residue; HAFT = Highest Average residue from one Field Trial; Median = Median based on per trial averages; Mean = Mean based on per trial averages; Std Dev = Standard deviation of mean.  
c      Tomato crop field trial 18, with mean residues of 0.31 ppm (foliar trial) and 0.24 ppm (soil trial), was proposed as an outlier by the registrant.  However, HED has concluded that this trial cannot be excluded and has therefore included this trial in the summary statistics.  If Trial 18 were excluded, the tomato HAFT for foliar application is 0.14 ppm and for soil application is 0.028 ppm.  


5.3.2	Field Rotational Crops (860.1900)

Two separate field rotational crop studies were conducted.  The study design and summary of residue data results are provided below.  Detailed tables of these residue data are available in Appendix C.    

Field Rotational Crop Study #1 (MRID 49011244) - Study Design
Application information:
Bare soil was treated with these targeted conditions:
Formulation:  Oxathiapiprolin 100 g/L OD (DPX-QGU42-203)
Trt 2:  2 applications, 2 oz ai/A (57 g ai/A or 140 g ai/ha ; 0.125 lb ai/A) per application, 7-day retreatment interval.
Trt 3:  2 applications, 4 oz ai/A (113 g ai/A or 280 g ai/ha ; 0.25 lb ai/A) per application, 7-day retreatment interval.
No adjuvants were included for these soil applications.
No test substance was applied to untreated control plots (with the exception of Trial 01 60-day PBI wheat).
Prior to rotational crop planting, the plots were tilled. 
Three (rotational) crops were subsequently planted in the treated and untreated soil at the following targeted intervals after the last application (plantback intervals).
Rotational Crop
Representation
Raw Agricultural Commodities
Targeted Plantback Intervals (days)
                                Root vegetables
                                  Root crops
                                  tops, roots
                                    7 - 30
                                   60 - 120
                                   300 - 365
                              Small grain cereals
                                 Cereal crops
                           forage, hay, grain, straw
                                       
                                    Soybean
                               Legume vegetables
          forage, hay, immature seeds with pod, mature shelled seeds
                                       
Sampling information: 
For each targeted plantback interval, each rotational crop:
Treated plots:  Duplicate samples of immature or commercially mature specified commodities.
Untreated control plots:  Single samples of immature or commercially mature specified commodities.

Study #1 results - Residue analyses were conducted for parent plus metabolites IN-E8S72, IN-WR791, IN-RDG40, IN-Q7H09, IN-SXS67, IN-RZB20 and IN-RZD74.  The residue data demonstrated the following:
   * Average IN-Q7H09, IN-RDG40, IN-RZB20, IN-RZD74, and IN-WR791 residues are <LOQ (0.01 ppm) in all rotational crop commodities at all PBIs.
   * With the exception of soybean forage (maximum residue of 0.033 ppm at the 560 g ai/ha seasonal rate), average oxathiapiprolin residues were <LOQ in all commodities.  
   * Average IN-E8S72 residues in rotational crop commodities range from <LOQ in several commodities up to 0.16 ppm in soybean hay (at PBIs ranging from 7-30 days) at the 560 g ai/ha rate (maximum seasonal rate).
   * Average IN-SXS67 residues in rotational crop commodities range from <LOQ in several commodities up to 0.090 ppm in cereal grain hay (at PBIs ranging from 7-30 days) at the 560 g ai/ha rate (maximum seasonal rate).
      
Field Rotational Crop Study #2 (MRID 49011245) - Study Design
Application information:
Bare soil was treated with these targeted conditions:
Formulation:  Oxathiapiprolin 100 g/L OD (DPX-QGU42-203) or 
Oxathiapiprolin 200 g/L SC (DPX-QGU42-213) (Trial 31 only)
Trt 2: 2 applications, 2 oz ai/A (57 g ai/A, 140 g ai/ha, 0.126 lb ai/A) per application, 7-day retreatment interval.
Adjuvants were included for these soil applications.
No test substance was applied to untreated control plots.
Prior to rotational crop planting, the plots were tilled. 
Rotational crops were subsequently planted in the treated and untreated soil at the following targeted intervals after the last application (plantback intervals).
Rotational Crop
Crop Group
Representation
Raw Agricultural Commodities
Targeted Plantback Interval (days)
                                  Sugar Beet
                                       2
                      Leaves of Root and Tuber Vegetables
                                     Tops
                                     5-10
                                    Lettuce
                                      4A
                      Leafy Vegetables (except Brassica)
                            Immature leaves, leaves
                                       
                                    Celery
                                      4B
                                       
                               Petioles (stalk)
                                       
                                Mustard Greens
                                      5B
                                   Brassica
                                    Leaves
                                       
                                    Soybean
                                     6, 7
                                    Legumes
             R6 Immature pod, 
R6 Immature seed, forage, hay, seed
                                       
                                  Corn, Sweet
                                    15, 16
                   Cereal Grains, Forage, Fodder, and Straw
          Forage, ears (kernels plus cob with husks removed), stover
                                       
                                  Corn, Field
                                       
                                       
       Forage, ears (immature grain plus cob with husks removed), stover
                                       
                                    Sorghum
                                       
                                       
                                Forage, stover
                                       
                                     Wheat
                                       
                                       
                              Forage, hay, straw
                                       
                                    Canola
                                      20A
                                    Oilseed
                                     Seed
                                       
                                  Strawberry
                                    13-07G
                            Berries and Small Fruit
                                    Berries
                                       
Sampling information: 
For each targeted plantback interval, each rotational crop had:
Treated plots:  duplicate samples of immature or commercially mature specified commodities.
Untreated control plots:  single samples of immature or commercially mature specified commodities.

Study #2 Results - Residue analyses were conducted for parent plus metabolites IN-E8S72, IN-WR791, IN-RDG40, IN-Q7H09, IN-SXS67, IN-RZB20 and IN-RZD74.  The residue data demonstrated the following in rotational crops grown in fields previously treated with oxathiapiprolin following 2 applications of oxathiapiprolin at 140 g ai/ha (0.126 lb ai/A) for a seasonal application rate of 280 g ai/ha (0.251 lb ai/A; 0.5X the maximum seasonal use rate):
   * Average oxathiapiprolin, IN-Q7H09, IN-RDG40, IN-RZB20, and IN-RZD74 residues are <0.010 ppm in all rotational crop commodities at all PBI.
   * Average IN-WR791 residues are 0.012 ppm in all rotational crop commodities.
   * Average IN-E8S72 and IN-SXS67 residues in rotational crop commodities range from ND (<0.003 ppm) in several commodities up to 0.30 ppm in wheat hay at a 5-9 day PBI. 
Proposed Plant Back Interval Restrictions (Directly from the Proposed Labels)
 Crop, Crop Group, or Crop Subgroup*
Plantback Restriction (in Days) following Last Application
Root and Tuber Vegetables (Group 1)
                                                                              0
Bulb Vegetables (Group 3-07)
                                                                              0
Leafy vegetables (Group 4)
                                                                              0
Brassica Vegetables (Group 5)
                                                                              0
Peas, succulent
                                                                              0
Fruiting Vegetables (Group 8-10)
                                                                              0
Cucurbit Vegetables (Group 9)
                                                                              0
Strawberries
                                                                              0
Herbs and Spices (Group 19)
                                                                              0
Oilseed (Group 20)
                                                                              0
Ginseng
                                                                              0
Tobacco
                                                                             30
Cereals (Group 15, 16)
                                                                             30
Grass animal feeds (Group 17)
                                                                            180
Legume Vegetables  except succulent peas (Group 6)
                                                                            180
Non-grass Animal feed (Group 18)
                                                                            180
Peanuts
                                                                            180
All other crops not listed
                                                                           180
*Crop, Crop Group, or Crop Subgroup is given as listed on the proposed labels.  

Conclusions.  Based on the residue definition for rotational crops being defined as parent oxathiapiprolin only, the submitted field rotational crop study data is adequate and the PBIs listed on the proposed labels are considered sufficient.  Due to the lack of toxicity from oxathiapiprolin, USEPA would normally grant a tolerance exemption for this chemical.  However, given that this chemical is being assessed as part of a global joint review and is intended to be registered in additional countries, the Agency is setting tolerances for harmonization purposes.  Given that tolerances are being set solely for the purposes of harmonization with global partners, HED has concluded that it is appropriate to align the residue of concern for tolerance enforcement with the global partners.  PMRA has set the residue of concern as parent oxathiapiprolin only in rotational crops and will be setting a generic action MRL of 0.10 ppm on all crops not currently proposed on the label.  This generic action MRL of 0.10 ppm will be used to provide coverage for inadvertent residues in rotational crops.  HED concludes that this approach is adequate for the purposes of tolerance enforcement in rotational crops and that this aligned approach will avoid future trade irritants with global partners.  

5.3.3	Processed Food and Feed (860.1520)

MRID 49011237 Grape
MRID 49011238 Potato
MRID 49011239 Tomato

Processing studies in grape, potato, and tomato were submitted with the petition. 

Grape

In the submitted grape processing study, four separate field trials were conducted, with two in Northern EU (NEU) and two in Southern EU (SEU).  Three trials were conducted at ~1.2X the proposed maximum seasonal use rate, whereas the fourth trial was conducted at ~4.5X the proposed maximum seasonal use rate.  Samples were assayed for residues of oxathiapiprolin and associated metabolites according to the method described in Section 5.1.1, and the residue results are supported by adequate storage stability data.  Overall, consistent residue behavior was found in these NEU and SEU trials, providing data appropriate for assessing residues and processing factors through processing (Appendix J).  It is noted that the GAP proposed PHI is 14 days, whereas these processing field trials were conducted at a 19-21 day PHI.  Despite this mismatch, these data are considered adequate for the purpose of evaluating the concentration of residues in grape processed commodities.  
Each processed grape commodity (wine, juice, and raisin) showed a predictable residue profile consistent with the physical-chemical properties of oxathiapiprolin and with the loss of water to produce some commodities.  Oxathiapiprolin residues concentrated in raisins (average processing factor of 2) relative to the raw fruit and reduced in juice, red wine, and white wine relative to the raw fruit, with average processing factors of 0.17, 0.14, and 0.13, respectively (Appendix J).  
Grape Conclusions.  

The submitted grape processing study data is adequate for assessing the concentration of residues in processed commodities.  Based on the above results, oxathiapiprolin residues are not expected to concentrate in grape juice or wine.  Residues of oxathiapiprolin may concentrate in raisin.  A tolerance value of 0.62 ppm (i.e., 0.41 ppm (HAFT) x 1.5 (median PF) = 0.62 ppm) is calculated for raisin.  However, as this value is less than the recommended tolerance for grape (0.70 ppm), HED does not recommend in favor of a tolerance for raisin.  

Potato

The target study design for the submitted potato processing study included at-plant and mid-season applications at a very exaggerated rate (1400 g ai/ha) in addition to exaggerated (175 g ai/ha) late-season foliar applications resulting in a total seasonal application of 3500 g ai/ha.  After this processing study was conducted, the proposed GAP for potato was finalized with only 4 applications at 50 g ai/ha for a seasonal application of 200 g ai/ha (0.176 lb ai/A).  Hence, the potatoes for processing were treated at an exaggerated rate of ~17.5 for the season.  Three separate potato processing trials were conducted with this target study design, with the actual use rates resulting in exaggerated rates of 17.8-18.8x compared to GAP.  Samples were assayed for residues of oxathiapiprolin and associated metabolites according to the method described in Section 5.1.1 and the residue results are supported by adequate storage stability data.  
Overall, consistent residue behavior was found for applications conducted according to the specified exaggerated use pattern consisting of both soil and foliar applications.  The data provided are adequate for assessing residues and processing factors through processing (see Appendix J for full details on deriving these processing factors).  
Processed potato commodities showed a predictable residue profile consistent with the physical-chemical properties of oxathiapiprolin and with the loss of water to produce some commodities.  Oxathipiprolin concentrated in waste from the peeling processes (average/median processing factors of 1.6/1.1 and 1.4/0.4 for steam-peeling and abrasion-peeling, respectively), and being reduced or greatly reduced in all other commodities.  Average processing factors ranged from <0.1 to 0.3 per commodity for washed tubers, culls, steam-peeled tubers, abrasion-peeled tubers, potato dried flakes, potato chips, peeled French fries, unpeeled French fries, boiled unpeeled potatoes, boiled peeled potatoes, and microwaved unpeeled (baked) potatoes.  

Potato Conclusions. 
The submitted potato processing study data is adequate for assessing the concentration of residues in processed commodities.  In the 22 primary crop field trials for potato, which were conducted at the GAP proposed use rate and PHI, no quantifiable residues were observed in the potato RAC.  If one multiples the median PF for potato waste from steam by the HAFT for the potato RAC (<0.01 ppm x 1.1), one would obtain 0.011 ppm.  Given the lack of quantifiable residues in the primary crop potato field trial studies, this 0.011 ppm value for steam waste is conservative and likely an overestimate of residues in potato waste.  Therefore, separate tolerances in processed potato commodities are not required.  The potato RAC tolerance of 0.01 ppm, which is being set at the tolerance enforcement method LOQ, should adequately cover processed potato commodities.  

Tomato 

The submitted tomato processing study included three separate field trials.  The use pattern for these trials combined the soil application rate per season (0.62 lb ai/A, equivalent to 1x) with foliar application rate per application (0.62 lbs ai/A, 1.25x), for an overall seasonal application rate equivalent to 2.25x.  Samples were assayed for residues of oxathiapiprolin and associated metabolites according to the method described in Section 5.1.1, and the residue results are supported by adequate storage stability data.  

Oxathipiprolin residues concentrated in sun-dried tomatoes and wet tomato pomace (median processing factors of 6.9 and 13, respectively), remained constant in paste (average processing factor of 1.0) and were reduced in puree, washed tomatoes, juice, and peeled and canned tomatoes, with average processing factors of 0.5, 0.5, 0.2, <0.04, and <0.03, respectively.  Please see Appendix J for more details on the derivation of these processing factors.    

Tomato Conclusions.  

The submitted tomato processing study data is adequate for assessing the concentration of residues in processed commodities.  Based on the above results, oxathiapiprolin is not expected to concentrate in tomato juice, paste, or puree  -  the commodities for which HED typically makes tolerance recommendations.  Residues of oxathiapiprolin may concentrate in wet pomace and sun-dried tomato.  Based on the tomato HAFT oxathiapiprolin residue of 0.31 ppm, the anticipated residue of oxathiapiprolin is 4.0 ppm in wet pomace and 2.1 ppm in dried tomato.  Although HED would not normally set tolerances in dried tomato, it is noted that the registrant has petitioned for a dried fruiting vegetable tolerance based on these results.  For simplicity purposes in tolerance setting, the anticipated residue in dried tomato of 2.1 ppm is rounded up to the HED-recommended value of 3.0 ppm, with this rounding to 3.0 ppm being consistent with OECD rounding guidelines.  Based on a review of the data and current policy on setting tolerances on non-standard processed commodities (ChemSAC minutes 04/01/2015), HED concludes that setting a tolerance value of 3.0 ppm for dried tomato would be appropriate.  Following the HED Processing Factor Focus Group (PFFG) Guidance Document (2014, in draft), this tolerance is recommended for harmonization.  It is noted that the setting of this dried tomato tolerance is consistent with the approach used for other recent global joint reviews (P. Savoia, D422374, 01/15/2015).  However, HED concludes that a crop group tolerance of 3.0 ppm for all dried fruiting vegetables is not appropriate, as our regulations do not currently permit setting a crop group processed commodity tolerance (ChemSAC minutes 04/01/2015).  

5.3.4	Meat, Milk, Poultry and Eggs (860.1480)

As summarized in Table 5.3.4.1, maximum reasonable dietary burdens (MRDBs) were calculated by for cattle, poultry, and swine based on the proposed tolerances and use pattern.  The estimated MRDBs are 0.260 ppm, 0.393 ppm, 0.100 ppm, and 0.100 ppm in dairy cattle, beef cattle, swine, and poultry, respectively.  These MRDB calculations include an assumption of tolerance level residues of 0.10 ppm in rotational crops, as well as the sole livestock feed items from the primary crop uses (potato culls and potato process waste).  Potato culls and potato process waste were assumed to be present at LOQ levels (0.01 ppm), which is a worst case scenario assumption.  Overall, HED considers these MRDBs to be very conservative.  

TABLE 5.3.4.1	Calculation of Dietary Burdens of Oxathiapiprolin Residues to Livestock.
                                   Feedstuff
                                    Type[1]
                                % Dry Matter[2]
                                   % Diet[2]
                          Recommended Tolerance (ppm)
                         Dietary Contribution (ppm)[3]
                                  Beef Cattle
Corn gluten feed
                                      CC
                                      40
                                      75
                                     0.10
                                     0.188
Corn gluten meal
                                      CC
                                      40
                                       5
                                     0.10
                                     0.013
Canola meal
                                      PC
                                      88
                                       5
                                     0.10
                                     0.006
Pineapple process residue
                                       R
                                      25
                                      10
                                     0.10
                                     0.040
Sorghum forage
                                       R
                                      35
                                       5
                                     0.10
                                     0.014
                                                                   TOTAL BURDEN
                                      --
                                      --
                                      100
                                      --
                                     0.260
                                 Dairy Cattle
Carrot culls
                                      CC
                                      12
                                      10
                                     0.10
                                     0.083
Sweet corn cannery waste
                                      CC
                                      30
                                      10
                                     0.10
                                     0.033
Corn gluten feed
                                      CC
                                      40
                                      25
                                     0.10
                                     0.063
Peanut meal
                                      PC
                                      85
                                      10
                                     0.10
                                     0.012
Lespedeza forage
                                      RR
                                      22
                                      40
                                     0.10
                                     0.182
Field pea vine
                                      RR
                                      25
                                       5
                                     0.10
                                     0.020
                                                                   TOTAL BURDEN
                                      --
                                      --
                                      100
                                      --
                                     0.393
                                     Swine
Barley grain
                                      CC
                                      88
                                      20
                                     0.10
                                     0.020
Rice grain
                                      CC
                                      88
                                      20
                                     0.10
                                     0.020
Sorghum grain
                                      CC
                                      86
                                      45
                                     0.10
                                     0.045
Field pea seed
                                      PC
                                      90
                                      15
                                     0.10
                                     0.015
                                                                   TOTAL BURDEN
                                      --
                                      --
                                      100
                                      --
                                     0.100
                                    Poultry
Rye grain
                                      CC
                                      88
                                      35
                                     0.10
                                     0.035
Barley grain
                                      CC
                                      88
                                      40
                                     0.10
                                     0.040
Field pea seed
                                      PC
                                      90
                                      20
                                     0.10
                                     0.020
Soybean seed
                                      PC
                                      89
                                       5
                                     0.10
                                     0.005
                                                                   TOTAL BURDEN
                                      --
                                      --
                                      100
                                      --
                                     0.100
1. R = Roughage; CC = Carbohydrate Concentrate; PC = Protein Concentrate.  
2. Revisions of Feedstuffs in Table 1 of OPPTS Test Guideline 860.1000 and Guidance on Constructing Maximum Reasonably Balanced Diets (MRBD).; ChemSAC memorandum; 30 June 2008.  
3. Contribution = ([tolerance / %DM] x %diet) for beef and dairy cattle.  Contribution = (tolerance x %diet) for poultry and swine.  

Based on the low residues of oxathiapiprolin and all metabolites in the goat metabolism study, a cattle feeding study was not conducted.  The majority of the administered dose (>85%) was eliminated in the excreta.  Overall low residues of parent oxathiapiprolin and metabolites were observed in the other goat matrices, with a maximum residue of 0.129 ppm.  Given that the goat metabolism study was conducted at ~36X the anticipated dietary burden in ruminants, there is no expectation of finite residues in ruminant commodities and no ruminant tolerances have been proposed.  

In the hen metabolism study, oxathiapiprolin and metabolites were readily eliminated in the excreta (including cage wash), where 95-100% of the dose was recovered.  Overall the highest residue observed in the other hen matrices was 0.014 ppm in liver for unresolved oxathiapiprolin hydroxy metabolites.  Parent oxathiapiprolin was the predominant residue across hen matrices.  Given that the hen metabolism study was conducted at ~174 the anticipated dietary burden of the proposed uses, there is no expectation of finite residues for poultry matrices and no poultry tolerances have been proposed at this time.  

Conclusions.  At this time, based on the livestock metabolism studies and the anticipated livestock dietary burden, no detectable residues of oxathiapiprolin are expected in livestock commodities (category 6(a)3); therefore, there are no oxathiapiprolin-related residues expected in livestock commodities and HED concludes that tolerances for livestock commodities are unnecessary.  

If future uses of oxathiapiprolin are requested on crops which serve as significant livestock feedstuffs, livestock feeding studies may be required.  

5.3.5.	Food Handling (860.1460)

At this time, there are no food-handling establishment uses associated with oxathiapiprolin.

5.3.6	Water, Fish, and Irrigated Crops (860.1400)

At this time, there are no water, fish, or irrigated crop uses associated with oxathiapiprolin.

5.4	Food Residue Profile

The submitted residue chemistry studies were generally well conducted and are adequate for supporting regulatory conclusions, establishing appropriate tolerance levels for enforcement, and for purposes of risk assessment.  Analysis of residues can be accomplished through standard analytical techniques, and residues do not show any trends for dissipation during frozen storage.  With the exception of the potato field trials where no quantifiable oxathiapiprolin residues were observed, one or more field trials from all other primary crops had quantifiable oxathiapiprolin residues.  These oxathiapiprolin residues were generally substantially higher than any of the seven metabolites listed above.  The registrant also submitted a large amount of residue decline data which generally demonstrated that residues of oxathiapiprolin decrease with increasing PHI (results not presented here; see study specific MRID DERs for further details).  All residue study results are supported by adequate storage stability data and these field trial studies were conducted using the proposed analytical enforcement method.  

Due to the lack of toxicity from oxathiapiprolin, USEPA would normally grant a tolerance exemption for this chemical.  However, given that this chemical is being assessed as part of a global joint review and is intended to be registered in additional countries, the Agency is setting tolerances for harmonization purposes.  Given that tolerances are being set solely for the purposes of harmonization with global partners, HED has concluded that it is appropriate to align the residue of concern for tolerance enforcement with the global partners.  PMRA has set the residue of concern as parent oxathiapiprolin only in rotational crops and will be setting a generic action MRL of 0.10 ppm on all crops not currently proposed on the label.  This generic action MRL of 0.10 ppm will be used to provide coverage for inadvertent residues in rotational crops.  HED concludes that this approach is adequate for the purposes of tolerance enforcement in rotational crops and that this aligned approach will avoid future trade irritants with global partners.  

Also, if there are future uses on crops that are significant livestock feedstuffs, then livestock feeding studies may be necessary.

6.0	Tolerance Derivation

The recommended tolerance levels for RAC commodities were obtained using the OECD calculation procedures.  With the exception of grape and ginseng, average residues of oxathiapiprolin from field trials conducted according to the proposed label were used in the calculations.  Please see Table 5.3.1.2 for the GAP proposed use rates and PHI.  

For the crop group tolerance calculations (fruiting vegetables, cucurbit vegetables, leafy greens, and Brassica vegetables), within each crop group, the residue levels between the representative commodities did not vary by more than 5-fold, indicating that crop-group tolerances are appropriate.  Residues from each representative commodity were used to get commodity-specific tolerance levels and the maximum commodity-specific tolerance within the crop group was selected as the recommended tolerance for the entire group.  The residue data and calculation procedure outputs for each representative commodity are included in Appendix M.

For the crop uses where both foliar and soil application methods are proposed (leafy greens, cucurbits, fruiting vegetables, tobacco), the proposed labels do not allow foliar and soil application methods to be used interchangeably within the same season.  Therefore, it is not appropriate to merge the field trial results from foliar and soil application methods.  The foliar application trials yielded higher residues than the soil application trials across commodities.  Therefore, the tolerances were derived using the foliar trials and these tolerances are protective of the residues observed in the soil application method field trials.  

As discussed previously, in the case of grape, the EU trials conducted in 2010 and 2011 used a PHI of 9-11 days, whereas the proposed PHI is 14 days.  For tolerance derivation purposes, these 2010 and 2011 trials were combined with eight 2013 trials conducted at a PHI of 14-15 days.  The 2010 and 2011 residue data is similar to that of the 2013 trials, with the combined dataset being considered adequate to support the proposed tolerance.  Please see Table 5.3.1.2 for the GAP proposed use rates and PHI.  

The registrant also submitted EU crop field trial data for the other EU proposed uses (see Table 3.3 for proposed EU use pattern; detailed field trial results not summarized here).  Specifically, additional EU trials were conducted with edible and inedible peel cucurbits, tomatoes, lettuce, and potato.  This EU crop field trial data is consistent with North American crop field trial data, with parent oxathiapiprolin being the predominant residue across the dataset and generally lower residues being observed in the EU field trial dataset.  Only the NAFTA field trial data was used in the tolerance calculations, with this NAFTA data being protective of the residues observed in the EU studies.   

In the case of ginseng, the registrant submitted four field trials at the GAP proposed use rate and two field trials at ~2X the GAP.  The registrant indicated that this was done because ginseng is a multi-year crop, often being harvested only after multiple growing seasons.  Please see section 5.3.1 for further details on these trials.  For tolerance derivation purposes, the registrant has proposed using the residue data from the 2X trials and proportionally adjusting the residue data from the 1X trials (where side-by-side treatment was not undertaken) to be 2 times higher.  Using the 2X trial data, a tolerance of 0.40 ppm is derived.  However, based on a review of the data and consultation with the global partners, HED has concluded that using the 1X data is more appropriate for tolerance-setting, yielding a 0.15 ppm recommended tolerance.  

In the case of Crop Group 8-10, Fruiting Vegetables, the registrant proposed excluding a tomato field trial (Trial 18) from the tolerance calculation.  If this trial is excluded, all representative commodities (bell pepper, non-bell pepper, and tomato) support a crop group tolerance of 0.20 ppm.  However, HED has decided not to exclude this trial from the tolerance derivation (see Section 5.3.1. for further details).  With the inclusion of Trial 18, the recommended tomato tolerance becomes 0.50 ppm and, consequently, the recommended Fruiting Vegetable Crop Group 8-10 tolerance becomes 0.50 ppm.  It is noted that if both small and standard tomato cultivars are included together in the tolerance calculations, the recommended tomato tolerance is 0.40 ppm (as presented in Appendix M).  However, Canada's PMRA has concluded that tolerance calculations must be conducted separately for small and standard tomato cultivars.  Using the 11 field trials for small tomato cultivars, they derived a 0.50 ppm tolerance.  While HED would not normally calculate a tomato tolerance in this manner, given that HED is setting tolerances solely for the purposes of harmonization with global partners, a value of 0.50 ppm is considered adequate.   

As discussed previously (see section 5.3.3), separate tolerances in processed potato and grape commodities are not required.  Additionally, oxathiapiprolin is not expected to concentrate in tomato juice, paste, or puree  -  the commodities for which HED typically makes tolerance recommendations.  Residues of oxathiapiprolin may concentrate in wet pomace and sun-dried tomato.  Based on the tomato HAFT oxathiapiprolin residue of 0.31 ppm, the anticipated residue of oxathiapiprolin is 2.1 ppm in dried tomato.  Although HED would not normally set tolerances in dried tomato, it is noted that the registrant has petitioned for a dried fruiting vegetable tolerance based on these results.  For simplicity purposes in tolerance setting, the anticipated residue in dried tomato of 2.1 ppm is rounded up to the HED-recommended value of 3.0 ppm, with this rounding to 3.0 ppm being consistent with OECD rounding guidelines (ChemSAC minutes 04/01/2015).  Based on a review of the data and current policy on setting tolerances on non-standard processed commodities (ChemSAC minutes 04/01/2015), HED concludes that setting a tolerance value of 3.0 ppm for dried tomato would be appropriate.  Following the HED Processing Factor Focus Group (PFFG) Guidance Document (2014, in draft), this tolerance is recommended for harmonization.  It is also noted that the setting of this dried tomato tolerance is consistent with the approach used for other recent global joint reviews (P. Savoia, D422374, 01/15/2015).  However, HED concludes that a crop group tolerance of 3.0 ppm for all dried fruiting vegetables is not appropriate, as our regulations do not currently permit setting a crop group processed commodity tolerance (ChemSAC minutes 04/01/2015).  

7.0	ChemSAC Reference

This memorandum was reviewed by the Chemistry Science Advisory Council (ChemSAC) on April 1, 2015 and has been revised to reflect the recommendations of that group.  
