Document ID: EPA-HQ-OPP-2014-0149-0009
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-04-02T04:00Z

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

MEMORANDUM

Date:  October 15, 2014  

SUBJECT:	Difenoconazole.  New Foliar Uses on Pea and Bean, Dried Shelled, Except Soybean, Subgroup 6C and Bushberry Subgroup 13-07B.  Summary of Analytical Chemistry and Residue Data.

PC Code:  128847
DP Barcodes:  D418479 and D421194
Decision Nos.:  486674 and 486691
Registration No.:  100-1262, 100-1312, 100-1313, 100-1317
Petition No.:  4F8231
Regulatory Action:  Amended Section 3 Registration
Risk Assessment Type:  Not Applicable
Case No.:  7014
TXR No.:  Not Applicable
CAS No.:  119446-68-3
MRID No.:  See MRID Summary Table
40 CFR:  §180.475
	Ver.Apr.08

FROM:			Bonnie Cropp-Kohlligian, Environmental Scientist
				Risk Assessment Branch IV (RABIV)
				Health Effects Division (HED) (7509P)		
		
THROUGH:	Thurston Morton, Senior Chemist
				RABIV, HED (7509P)
	
TO:				Rosemary Kearns/Tony Kish (RM 22)
				Fungicide Branch
				Registration Division (7505P)

MRID Summary Table
MRID No.
Study Type
Comments
49227601
860.1500 Dried Pea and Dried Bean
New DER 49227601.der.docx
49227602
860.1500 Blueberry 
New DER 49227602.der.docx

Executive Summary

Difenoconazole is a broad spectrum fungicide belonging to the triazole group of fungicides.  The mode of action of difenoconazole is as a demethylation inhibitor of sterol biosynthesis which disrupts membrane synthesis by blocking demethylation.  It is currently registered in the U.S. for use as a seed treatment on a number of cereal grain crops, cotton, canola, and potato seed pieces and/or for multiple late-season foliar applications on numerous crops and for post-harvest use on members of tuberous and corm vegetables subgroup 1C.

Tolerances for difenoconazole are currently established under 40 CFR §180.475.  Tolerances for plant commodities are listed under §180.475(a)(1) and are expressed in terms of difenoconazole per se.  Tolerances for livestock commodities are listed under §180.475(a)(2) and are expressed in terms of difenoconazole and its metabolite, CGA-205375.  Tolerances are currently established in/on numerous crop commodities ranging from 0.01 ppm to 95 ppm and in meat, milk, and egg ranging from 0.01 ppm to 0.40 ppm.  [Note:  The current tolerance expression is in accordance with current guidance (Knizner, 5/27/09).]

Under PP#4F8231 (revised Section F dated 4/29/14; D421194), Syngenta Crop Protection, LLC (hereafter referred to as Syngenta or petitioner) is requesting the establishment of tolerances for residues of difenoconazole in/on the following raw agricultural commodities:

          Pea and bean, dried shelled (except soybean), subgroup 6C	0.2 ppm
          Peas, vines	10 ppm
          Peas, hay	40 ppm
          Bushberry, subgroup 13-07B	3.0 ppm
          
Concomitantly, Syngenta is requesting the deletion of the currently established tolerance for residues of difenoconazole in/on chickpea (0.08 ppm).

In conjunction with PP#4F8231, Syngenta is proposing an amended Section 3 registration for a 2.08 lb ai/gal emulsifiable concentrate (EC) formulation (Inspire(TM) Fungicide; EPA Reg. No. 100-1262) to add uses on members of pea and bean, dried shelled, except soybean, subgroup 6C and bushberry subgroup 13-07B.  In addition, Syngenta is proposing to add some or all of the proposed uses to the following multiple active ingredient (MAI) products:  a 2.08 lb ai/gal MAI EC formulation with propiconazole (Inspire(TM) XT Fungicide; EPA Reg. No. 100-1312); a 1.05 lb ai/gal MAI suspension concentrate (SC) formulation with azoxystrobin (Quadris Top(TM) Fungicide; EPA Reg. No. 100-1313); and a 0.73 lb ai/gal MAI emulsion oil in water (EW) formulation with cyprodinil (Inspire Super (TM) Fungicide; EPA Reg. No. 100-1317).  The proposed uses are for multiple foliar applications at up to 0.115 lb ai/A/application for maximum seasonal rates of 0.46 lb ai/A on dried peas (EPA Reg Nos. 100-1262 and 100-1313 only), dried beans and bushberries with a 7-day minimum retreatment interval (RTI) and preharvest intervals (PHIs) of 14-days for dried peas/beans and 7-day for bushberries.  [Note:  Because there are no currently established tolerances for residues of propiconazole and cyprodinil in/on dried peas, Syngenta is not proposing use of Inspire(TM) XT Fungicide (EPA Reg. No. 100-1312) and Inspire Super (TM) Fungicide (EPA Reg. No. 100-1317) on dried peas.]

Three of the difenoconazole products addressed herein contain a second active ingredient (propiconazole, azoxystrobin, or cyprodinil).  This review addresses the proposed uses for difenoconazole only.  
Because difenoconazole is a triazole compound, HED requires that samples from any metabolism, field trial, and/or processing study be analyzed for the triazole metabolites, triazolyl alanine (TA), triazolyl acetic acid (TAA), and 1,2,4-triazole (1,2,4-T), for dietary risk assessment purposes.  HED issued guidance on the residue chemistry data requirements for the triazole-based metabolites (DP# 327788, 4/25/06, M. Doherty).  The field trial data submitted with this petition reflect analysis for the three triazole metabolites and are discussed later in the body of this review but not in this summary section.

The nature of the residue in primary crops is adequately understood based on acceptable plant metabolism studies reflecting foliar treatments to canola, grape, potato, tomato and wheat, and seed treatment in wheat.  The HED Residues of Concern Knowledgebase Sub-committee (ROCKS) has determined that only the parent compound needs to be considered as a residue of concern in/on primary crop commodities for both tolerance enforcement and risk assessment (ROCKS Report Memo; DP#391350, 9/19/2011, W. Irwin).  

The nature of the residue in rotational crops is adequately understood.  The metabolism of difenoconazole in rotational crops is similar to that of primary crops.  The HED ROCKS (ROCKS Report Memo; DP#391350, 9/19/2011, W. Irwin) has determined that only the parent compound needs to be considered as a residue of concern in/on rotational crops.  The available confined and limited field rotational crop data support a 30-day plantback interval (PBI) for cereal and root/tuber crops not already registered for foliar use with difenoconazole and a 60-day PBI for all other crops not already registered for foliar use with difenoconazole.  With these PBIs, tolerances for residues of difenoconazole are not needed for rotational crops.  The minimum PBIs proposed with the current petition are adequate for difenoconazole.

The nature of the residue in livestock is adequately understood based on acceptable goat and hen metabolism studies.  The HED ROCKS has determined that the parent compound and the CGA-205375 metabolite are the residues of concern in livestock commodities for both tolerance enforcement and the risk assessment (ROCKS Report Memo; DP#391350, 9/19/2011, W. Irwin).  In addition, metabolite OH-CGA-169374 should be considered as a residue of concern in milk for the dietary risk assessment.  Adequate cattle and poultry feeding study data were previously submitted for difenoconazole.  There are several livestock feedstuffs associated with the proposed uses.  Based on the re-calculated livestock dietary burdens and the available feeding study data, HED concludes that the currently established tolerance in milk should be increased from 0.01 ppm to 0.02 ppm to support the proposed new uses on dried peas.  Other currently established livestock commodity tolerances remain adequate.

An adequate tolerance enforcement method, Method AG-575B, is available for crop commodities.  The method determines residues of difenoconazole per se in/on crop commodities by gas chromatography with nitrogen-phosphorus detection (GC/NPD).  The method limits of quantitation (LOQs) are 0.01-0.05 ppm.  A confirmatory GC method with mass-selective detection (MSD) is also available for crop commodities.

An adequate tolerance enforcement method, Method REM 147.07b, is available for livestock commodities.  The method determines residues of difenoconazole and CGA-205375 in livestock commodities by liquid chromatography with tandem mass spectrometry detection (LC/MS/MS).  The method LOQs are 0.01 ppm (for each analyte) for livestock tissues and 0.005 ppm (for each analyte) for milk.  Adequate confirmatory methods, Method AG-544A and Method REM 147.06, are available for the determination of residues of difenoconazole and CGA-205375, respectively.  
Provided the petitioner amends the labels/Section B of the petition as required, the submitted dried bean and dried pea field trial data and previously submitted chickpea field trial data, conducted with an EC formulation of difenoconazole, are adequate to support the proposed use for difenoconazole on members of pea and bean, dried shelled, except soybean, subgroup 6C.  These data were collected with adequate data-collection methods and supported by adequate storage stability data.  Using the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures, the recommended tolerances are 0.05 ppm in/on dried bean seed, 0.20 ppm in/on dried pea seed, 40 ppm in/on pea hay and 10 ppm in/on pea vines.  Since the maximum field trial residues, highest average field trial residues and recommended tolerances for dried bean seed and dried pea seed are within 5x, a crop group tolerance can be set for pea and bean, dried shelled, except soybean, subgroup 6C and is recommended at 0.20 ppm based on the dried pea seed data.  The recommended tolerances are the same as the petitioned-for tolerances.  

No data were submitted for bean forage and hay.  Although cowpea forage and hay are not designated as under grower control according to Table 1 of GLN 860.1000, ChemSAC (meeting 8/24/11) has determined that, for a number of practical reasons, a label restriction such as the following is acceptable in lieu of data:  "To be grown for bean, dry seed only.  Do not feed or harvest cowpea forage and hay."  Without this restriction, cowpea forage and hay data would be required to support the proposed use on dried bean.

The submitted blueberry field trial data, conducted with an EC formulation of difenoconazole, are adequate to support the proposed use for difenoconazole on members of bushberry subgroup 13-07B.  The number and locations of field trials reflecting the proposed use for members of bushberry subgroup 13-07B is in accordance with Guideline 860.1500.  However, an analysis of the field trials found that two of the eleven trials submitted (North American Free Trade Agreement (NAFTA) Growing Region 1; Trials T162 and T163 conducted in PE, Canada) were not independent field trials being less than 20 miles apart and reflecting the same variety and application timing resulting in substantially similar residue levels.  Hence, only the trial with the higher residue of difenoconazole (T162) was used to calculate the tolerance for residues of difenoconazole in/on bushberry subgroup 13-07B.  Using the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures, the recommended tolerance for residues of difenoconazole in/on bushberry subgroup 13-07B is 4.0 ppm.  The recommended tolerance is not the same as the petitioned-for tolerance (3.0 ppm) due to the independent field trial determination.

With regards to the proposed uses of the SC and EW formulation of difenoconazole, having considered the submitted/available bridging data comparing residues of difenoconazole from use of an EC formulation with that of an SC formulation or an EW formulation and given that the recommended tolerances are well above the highest average field trial (HAFT) levels found in the supporting magnitude of the residue data, HED concludes that the recommended tolerances for residues of difenoconazole are likely to cover the proposed uses of the SC and EW formulations of difenoconazole.  The submitted field trial data representing an EC formulation of difenoconazole are, therefore, deemed adequate to support the proposed uses of the SC and EW formulations of difenoconazole provided the petitioner amends the labels/Section B of the petition as required.

Codex maximum residue limits (MRLs) are not established for residues of difenoconazole in/on members of the pea and bean, dried shelled, except soybean, subgroup 6C and harmonization with the established Canadian MRLs in/on a variety dried pea seeds and dried bean seeds (all at 0.03 ppm) is not possible because the Canadian MRL would not be adequate to cover residues expected from the proposed foliar uses in the U.S.  There are no established Codex, Canadian or Mexican MRLs for residues of difenoconazole in/on members of the bushberry subgroup 13-07B, pea hay and pea vines so harmonization is not possible.  For milk, the residue definition (sum of parent and its metabolite, CGA-205375) and recommended milk tolerance increase (from 0.01 ppm to 0.02 ppm) will harmonize with the established Codex MRL in milk but not the established Canadian MRL (0.01 ppm) which is limited to residues of parent only.  An International Residue Limit Status Sheet is attached in Appendix I.

Regulatory Recommendations and Residue Chemistry Deficiencies

HED has examined the residue chemistry database for difenoconazole.  With regards to difenoconazole, pending submission of a revised Section B (see requirements under Directions for Use) and Section F (see requirements under Proposed Tolerances) of the petition there are no residue chemistry issues that would preclude granting the proposed foliar uses on pea and bean, dried shelled, except soybean, subgroup 6C and bushberry subgroup 13-07B or establishment of tolerances for residues of difenoconazole in/on the following:

          Pea and bean, dried shelled, except soybean, subgroup 6C	0.20 ppm
          Pea, field, hay	40 ppm
          Pea, field, vines	10 ppm
          Bushberry subgroup 13-07B	4.0 ppm

In addition, with the establishment of a tolerance in/on pea and bean, dried shelled, except soybean, subgroup 6C (0.20 ppm), the currently established tolerance for residues of difenoconazole in/on chickpea (0.08 ppm) should be deleted.  

Although not petitioned-for, the new pea hay and vine feedstuffs significantly increased the dietary burden calculation for dairy cattle.  Based on the re-calculated livestock dietary burdens and available feeding study data, HED concludes that the currently established tolerance for residues of difenoconazole and its metabolite CGA-205375, expressed as difenoconazole equivalents, in milk should be increased from 0.01 ppm to 0.02 ppm to support the proposed new uses on dried peas.  Other currently established livestock commodity tolerances remain adequate.

A human health risk assessment is forthcoming.

Notes to PM:  

(1)  Syngenta submitted eleven blueberry field trials conducted in Canada and the United States to support the proposed use of difenoconazole on members of bushberry subgroup 13-07B.  However, an analysis of the field trials found that two of the trials conducted in Canada and representing NAFTA Growing Region 1 (Trials T162 and T163) were not independent according to criteria agreed to by EPA and Health Canada's Pesticide Management Regulatory Authority (PMRA) (i.e., Replicate trial guidance presented in draft memo 568 - _Criteria for Independence of Trials 04/23/2013).  Hence, only three independent field trials were conducted in NAFTA Growing Region 1 (PE and NS; 3 trials).  While this finding was not a deficiency for EPA which only requires 1 blueberry field trial from NAFTA Growing Region 1, it could be a deficiency for PMRA which requires 4 blueberry field trials from NAFTA Growing Region 1.  Furthermore, since the present action is not being conducted as a joint review with PMRA and there is no indication that the subject data are under review by PMRA, HED cannot coordinate with PMRA regarding harmonization of the bushberry subgroup 13-07B tolerance level.

(2)  Previously required additional soybean field trials conducted with the SC formulation of difenoconazole at the maximum use rate have not been submitted (PP#9F7676; DP# 378829, 2/23/11, B. Cropp-Kohlligian).  These data would have been useful for the subject dried bean/pea seeds.   

860.1200 Directions for Use  -  Pertains to Difenoconazole Only
The recommended amendments to the directions for use are present below in relation to the submitted revised draft supplemental labels for Inspire(TM) Fungicide (EPA Reg. No. 100-1262; draft dated 10/2/14), Inspire(TM) XT Fungicide (EPA Reg. No. 100-1312; draft dated 10/2/14), Quadris Top(TM) Fungicide (EPA Reg. No. 100-1313; draft dated 10/2/14) and Inspire Super (TM) Fungicide (EPA Reg. No. 100-1317; draft dated 10/10/14).  However, Section B of the petition should also be amended, as needed, to be consistent with the final version of the directions for use on the amended labels, including the plant-back intervals (PBI) which were specified on the supplemental labels but not in Section B of the petition.
   * The proposed labels for Inspire(TM) Fungicide (EPA Reg. No. 100-1262; draft dated 10/2/14) and Quadris Top(TM) Fungicide (EPA Reg. No. 100-1313; draft dated 10/2/14) should be amended to specify a total maximum use rate of 0.23 lb ai/A on pea vines and hay consistent with the supporting field trial data.  
   * The proposed labels for Inspire(TM) Fungicide (EPA Reg. No. 100-1262; draft dated 10/2/14), Inspire(TM) XT Fungicide (EPA Reg. No. 100-1312; draft dated 10/2/14), Quadris Top(TM) Fungicide (EPA Reg. No. 100-1313; draft dated 10/2/14) and Inspire Super (TM) Fungicide (EPA Reg. No. 100-1317; draft dated 10/10/14) should be amended to specify a 14-day minimum retreatment interval for uses on members of pea and bean, dried shelled, except soybeans, subgroup 13-07B consistent with the supporting field trial data.  In the absence of supporting cowpea hay and forage field trial data, these proposed labels must also be amended to include the following restriction for uses on dried beans:  "To be grown for bean, dried seed only.  Do not feed or harvest cowpea forage and hay."  An unqualified restriction on the use of difenoconazole on cowpea is not required since cowpea seed may be harvested.  

860.1550 Proposed Tolerances

Section F (revised 4/29/14; D421194) must be further revised as follows.  The recommended tolerance for residues of difenoconazole in/on bushberry subgroup 13-07B (4.0 ppm) is not the same as the petitioned-for tolerance (3.0 ppm) due to the independent field trial determination.  The petitioned-for tolerance for residues of difenoconazole in/on pea and bean, dried shelled, except soybean, subgroup 6C tolerance (0.2 ppm) must be corrected to 0.20 ppm, consistent with current practices for setting tolerances.  Also, although not petitioned-for, because of the new pea hay and vine feedstuffs which significantly increased the maximum reasonably balanced dietary estimate for dairy cattle, the currently established tolerance in milk will need to be increased from 0.01 ppm to 0.02 ppm.  There are also some minor changes needed to the commodity definitions.  See Table 13 for details.

Background

The chemical structure and nomenclature of difenoconazole and its regulated livestock metabolite CGA-205375, and the physicochemical properties of the technical grade of difenoconazole are presented in Tables 1 and 2.  

Table 1.  Difenoconazole Nomenclature.
Chemical structure of parent
                                mol. wt. 406.3
Common name
Difenoconazole
Company experimental name
CGA-169374
IUPAC name
1-[2-[2-chloro-4-(4-chloro-phenoxy)-phenyl]-4-methyl-[1,3]dioxolan-2-ylmethyl]-1H-[1,2,4]triazole
CAS name
1-[[2-[2-chloro-4-(4-chlorophenoxy)phenyl]-4-methyl-1,3-dioxolan-2-yl]methyl]- 1H-1,2,4-triazole
CAS registry number
119446-68-3
Chemical structure of 
CGA-205375 livestock metabolite
                                mol. wt. 349.2
Chemical structure of 
1,2,4-Triazole (1,2,4-T)
                                       
Chemical structure of Triazolyl alanine (TA)
                                       
Chemical structure of
Triazolyl acetic acid (TAA)
                                       

Table 2.  Physicochemical Properties of Difenoconazole.
Parameter
Value
Reference
Melting point
78.6 ºC
DP#s 172067 and 178394, 10/26/92, R. Lascola
pH
6-8 at 20 ºC (saturated solution)

Density
1.37 g/cm[3] at 20 ºC

Water solubility
3.3 ppm at 20 ºC

Solvent solubility
	g/100 mL at 25 ºC:
n-hexane:	0.5
1-octanol:	35
toluene:	77
acetone:	88
ethanol:	89

Vapor pressure
2.5 x 10[-10] mm Hg at 25 ºC

Dissociation constant, pKa 
pure grade (99.3% +- 0.3%) difenoconazole in water (with 4% methanol) at 20ºC is 1.1  
DP# 375159, 5/26/10, B. Cropp-Kohlligian
Octanol/water partition coefficient, Log(KOW)
4.2 at 25 ºC
DP#s 172067 and 178394, 10/26/92, R. Lascola
UV/visible absorption spectrum
max at about 200 and 238 nm (in methanol at 26 ºC)
PMRA Proposed Regulatory Decision Document on Difenoconazole, 4/14/99 (PRDD99-01)

860.1200 Directions for Use

Under Section B of the petition, Syngenta has submitted directions for use on members of pea and bean, dried shelled, except soybean, subgroup 6C and bushberry subgroup 13-07B for the 2.08 lb ai/gal EC formulation of difenoconazole (Inspire(TM) Fungicide; EPA Reg. No. 100-1262) and the following multiple active ingredient (MAI) products:  a 2.08 lb ai/gal MAI EC formulation with propiconazole (Inspire(TM) XT Fungicide; EPA Reg. No. 100-1312); a 1.05 lb ai/gal MAI suspension concentrate (SC) formulation with azoxystrobin (Quadris Top(TM) Fungicide; EPA Reg. No. 100-1313); and a 0.73 lb ai/gal MAI emulsion oil in water (EW) formulation with cyprodinil (Inspire Super (TM) Fungicide; EPA Reg. No. 100-1317).  In addition, Syngenta submitted revised draft supplemental labels after the petition.  The subject end-use products are identified in Table 3, and the use directions based on revised draft supplemental labels are summarized in Table 4.

Table 3.  Summary of End-Use Products and Crops Under Consideration.
Trade Name
                                 EPA Reg. No.
                                  ai Content
                               Formulation Type
                                 Target Crops
Source of Use
Directions 
Inspire(TM) Fungicide
                                   100-1262
                                Difenoconazole
                            2.08 lb ai/gal (23.2%)
                           Emulsifiable concentrate
                                     (EC)
Pea and bean, dried, shelled (except soybean), subgroup 6C:  dried cultivars of bean (Lupinus); bean (Phaseolus) (includes field bean, kidney bean, lima bean (dry), navy bean, pinto bean, tepary bean); bean (Vigna) (includes adzuki bean, blackeyed pea, catjang, cowpea, crowder pea, moth bean, mung bean, rice bean, southern pea, urd bean); broad bean (dry); chickpea; guar; lablab bean; lentil; pea (Pisum) (includes field pea); pigeon pea.

Bushberry subgroup 13-07B:  
Aronia berry; blueberry, highbush; blueberry, lowbush; buffalo currant; Chilean guava; cranberry, highbush; currant, black; currant, red; elderberry; European barberry; gooseberry; honeysuckle, edible; huckleberry; jostaberry; Juneberry (Saskatoon berry); lingonberry; native currant; salal; sea buckthorn; cultivars, and/or hybrids of these.
Revised Draft Supplemental Label
Dated 10/2/14

Quadris Top(TM) Fungicide
                                   100-1313
                                Difenoconazole
                            1.05 lb ai/gal (11.4%)
                                       
                                 Azoxystrobin
                            1.67 lb ai/gal (18.2%)
                            Suspension concentrate
                                     (SC)

Inspire(TM)  XT Fungicide
                                   100-1312
                                Difenoconazole
                            2.08 lb ai/gal (22.8%)
                                       
                                 Propiconazole
                            2.08 lb ai/gal (22.8%)
                                      EC
Bean, dried, except cowpeas:  dried cultivars of bean (Lupinus); bean (Phaseolus) (includes field bean, kidney bean, lima bean (dry), navy bean, pinto bean, tepary bean); bean (Vigna) (includes adzuki bean, blackeyed pea, catjang, crowder pea, moth bean, mung bean, rice bean, southern pea, urd bean); broad bean (dry); chickpea; lablab bean.

Bushberry subgroup 13-07B:  
Aronia berry; blueberry, highbush; blueberry, lowbush; buffalo currant; Chilean guava; cranberry, highbush; currant, black; currant, red; elderberry; European barberry; gooseberry; honeysuckle, edible; huckleberry; jostaberry; Juneberry (Saskatoon berry); lingonberry; native currant; salal; sea buckthorn; cultivars, and/or hybrids of these.
Revised Draft Supplemental Label
Dated 10/2/14

Inspire Super(TM) Fungicide
                                   100-1317
                                Difenoconazole
                             0.73 lb ai/gal (8.4%)
                                       
                                  Cyprodinil
                            2.09 lb ai/gal (24.1%)
                          Emulsion oil in water (EW)

Revised Draft Supplemental Label
Dated 10/10/14

Table 4.  Summary of Directions for Use of Difenoconazole.
Appl. Timing, Type, and Equip.
                                  Formulation
                                [EPA Reg. No.]
                               Max. Appl. Rate 
                                   (lb ai/A)
                           Max. No. Appl. per Season
                           Max. Seasonal Appl. Rate
                                   (lb ai/A)
                                      PHI
                                    (days)
                        Use Directions and Limitations
Pea and bean, dried shelled (except soybean), subgroup 6C.   
Foliar,
Broadcast, Ground (>=15 gal/A), aerial (>=10 gal/A) or chemigation (0.1-0.25 inches/A)
                               2.08 lb ai/gal EC
                                  [100-1262]
                                  0.114-0.115
                              Not Specified (NS)
                                     0.46
                                      14
The minimum retreatment interval is 7 days.  Make no more than 2 sequential applications before alternating to another fungicide with a different mode of action.

                             1.05 lb ai/gal MAI SC
                                  [100-1313]
                                       
                                       
                                       
                                       
Same as for 100-1262.
 
Bean, dried (except cowpeas)
Note:  Because there are no currently established tolerances for residues of propiconazole and cyprodinil in/on dried peas, Syngenta is not proposing use of Inspire(TM) XT Fungicide (EPA Reg. No. 100-1312) and Inspire Super (TM) Fungicide (EPA Reg. No. 100-1317) on dried peas.
Foliar,
Broadcast, Ground (>=15 gal/A), aerial (>=10 gal/A) or chemigation (0.1-0.25 inches/A)
                             2.08 lb ai/gal MAI EC
                                  [100-1312]
                                  0.114-0.115
                                      NS
                                     0.46
                                      14
The minimum retreatment interval is 7 days.  Make no more than 2 sequential applications before alternating to another fungicide with a different mode of action.

                             0.73 lb ai/gal MAI EW
                                  [100-1317]
                                       
                                       
                                       
                                       
Same as for 100-1312.

Bushberry subgroup 13-07B
Foliar,
Broadcast, Ground (>=15 gal/A) or aerial (>=10 gal/A)
                               2.08 lb ai/gal EC
                                  [100-1262]
                                  0.114-0.115
                                      NS
                                     0.46
                                       7
The minimum retreatment interval is 7 days.  Make no more than 2 sequential applications before alternating to another fungicide with a different mode of action.

                             2.08 lb ai/gal MAI EC
                                  [100-1312]
                                       
                                       
                                       
                                      30
Same as for 100-1262.

                             1.05 lb ai/gal MAI SC
                                  [100-1313]
                                       
                                       
                                       
                                       7
Same as for 100-1262.

                             0.73 lb ai/gal MAI EW
                                  [100-1317]
                                       
                                       
                                       
                                       7
Same as for 100-1262.
PHI = preharvest interval.

The revised draft supplemental label dated 10/2/14 for Inspire(TM) Fungicide (EPA Reg. No. 100-1262) specifies the following rotational crop restrictions:

	0-day PBI for Bean and Pea, Dried Shelled (except soybean) Subgroup 6C; Berry, Bushberry Subgroup 13-07B; Berry, Low Growing Subgroup 13-07G, except Cranberry; Brassica (Cole) leafy vegetables; Bulb vegetables; Carrot; Chickpea; Cucurbit vegetables; Fruiting vegetables; Potato; Soybean; Strawberry; Sugar beet; Tomatoes and tomatillos; Tuberous and corm vegetable subgroup 1C.

	30-day PBI for Cereals (wheat, barley, triticale, oats, rye, millet, and buckwheat); Root and Tuber Vegetables, Crop Group 1 (except Carrot, Sugar Beet and Tuberous Corm Vegetables Subgroup 1C).

	60-day PBI for all other crops intended for food and feed.

The revised draft supplemental label dated 10/2/14 for Inspire(TM) XT Fungicide (EPA Reg. No. 100-1312) specifies the following rotational crop restrictions:

	0-day PBI for Bean, Dried; Berry, Bushberry Subgroup 13-07B; Berry, Low Growing Subgroup 13-07G (except Cranberry); Bulb vegetables; Carrot; Soybean; Strawberry; Sugar beet.

	30-day PBI for Cereals (wheat, barley, triticale, oats, rye).

	60-day PBI for Cilantro; Corn; Corn, Sweet; Garden Beet; Parsley; Peanut; Rice.

	105-day PBI for all other crops intended for food and feed.

The revised draft supplemental label dated 10/2/14 for Quadris Top(TM) Fungicide (EPA Reg. No. 100-1313) specifies the following rotational crop restrictions:

	0-day PBI for Bean and Pea, Dried Shelled (except soybean) Subgroup 6C; Berry, Bushberry Subgroup 13-07B; Berry, Low Growing, Subgroup 13-07G, except Cranberry; Brassica (Cole) leafy vegetables; Bulb vegetables; Carrot; Chickpea; Cucurbit vegetables; Eggplant; Fruiting Vegetables Crop Group 8-10; Okra; Pepper; Potato; Soybean; Strawberry; Sugar beet; Tomato; Tuberous and corm vegetables subgroup 1C.

	30-day PBI for Cereals (wheat, barley, triticale, oats, rye); Root and Tuber Vegetables, Crop Group 1 (except Carrot, Sugar Beet and Tuberous Corm Vegetables Subgroup 1C).

	60-day PBI for all other crops intended for food and feed.

	365-day PBI for Buckwheat; Millet.

The revised draft supplemental label dated 10/10/14 for Inspire Super (TM) Fungicide (EPA Reg. No. 100-1317) specifies the following rotational crop restrictions:

	0-day PBI for Bean, Dried; Berry, Bushberry Subgroup 13-07B; Brassica (Cole) leafy vegetables; Bulb vegetables; Carrot; Chickpea; Cucurbit vegetables; Fruiting Vegetables; Pepper; Strawberry; Tomato and tomatillo.

	30-day PBI for Cereals (wheat, barley, triticale, oats, rye, millet and buckwheat); Potato; Soybean; Sugar beet; Sweet corn; Root and tuber vegetable crop group 1, except carrot.

	60-day PBI for all other crops intended for food and feed.

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

No bean forage and hay field trial data were submitted.  Although cowpea forage and hay are not designated as under grower control in Table 1 of GLN 860.1000, ChemSAC (meeting 8/24/11) determined that, for a number of practical reasons, a label restriction such as the following is acceptable in lieu of data:  "To be grown for bean, dry seed only.  Do not feed or harvest cowpea forage and hay."  Without this restriction, cowpea forage and hay data and tolerances would be required to support a use on cowpea grown for forage and hay.

The minimum proposed plant-back intervals are adequate.

The recommended amendments to the directions for use are present below in relation to the submitted draft supplemental labels for Inspire(TM) Fungicide (EPA Reg. No. 100-1262; draft dated 10/2/14), Inspire(TM) XT Fungicide (EPA Reg. No. 100-1312; draft dated 10/2/14), Quadris Top(TM) Fungicide (EPA Reg. No. 100-1313; draft dated 10/2/14) and Inspire Super (TM) Fungicide (EPA Reg. No. 100-1317; draft dated 10/10/14).  However, Section B of the petition should also be amended, as needed, to be consistent with the final version of the directions for use on the amended labels, including the plant-back intervals (PBI) which were specified on the supplemental labels but not in Section B of the petition.
   * The proposed labels for Inspire(TM) Fungicide (EPA Reg. No. 100-1262; draft dated 10/2/14) and Quadris Top(TM) Fungicide (EPA Reg. No. 100-1313; draft dated 10/2/14) should be amended to specify a total maximum use rate of 0.23 lb ai/A on pea vines and hay consistent with the supporting field trial data.  
   * The proposed labels for Inspire(TM) Fungicide (EPA Reg. No. 100-1262; draft dated 10/2/14), Inspire(TM) XT Fungicide (EPA Reg. No. 100-1312; draft dated 10/2/14), Quadris Top(TM) Fungicide (EPA Reg. No. 100-1313; draft dated 10/2/14) and Inspire Super (TM) Fungicide (EPA Reg. No. 100-1317; draft dated 10/10/14) should be amended to specify a 14-day minimum retreatment interval for uses on members of pea and bean, dried shelled, except soybeans, subgroup 13-07B consistent with the supporting field trial data.  In the absence of supporting cowpea hay and forage field trial data, these proposed labels must also be amended to include the following restriction for uses on dried beans:  "To be grown for bean, dried seed only.  Do not feed or harvest cowpea forage and hay."  An unqualified restriction on the use of difenoconazole on cowpea is not required since cowpea seed may be harvested.  

860.1300 Nature of the Residue - Plants
ROCKS Report Memo; DP#391350, 9/19/2011, W. Irwin  

The nature of the residue in primary crops is understood based on acceptable plant metabolism studies reflecting foliar applications in canola, grape, potato, tomato, and wheat.  An acceptable wheat metabolism study reflecting seed treatment is also available.  Based on the results of available plant metabolism studies, difenoconazole is metabolized in plants by the hydroxylation of the phenyl ring and/or cleavage of the dioxolane ring followed by cleavage of the carbon-carbon bridge between the phenyl and triazole rings.  

The HED Residues of Concern Knowledgebase Sub-committee (ROCKS) has determined that only the parent compound needs to be considered as a residue of concern in/on primary crop commodities for both tolerance enforcement and risk assessment (ROCKS Report Memo; DP#391350, 9/19/2011, W. Irwin).  Residues of metabolite CGA-205375 are higher in primary crops as the preharvest interval (PHI) increases; however, with the current/proposed crops/PHIs, the parent is sufficient to consider.  If, additional uses on new crops with longer PHIs are proposed in the future, then the CGA-205375 metabolite may need to be considered for those uses/crops.

860.1300 Nature of the Residue - Livestock
ROCKS Report Memo; DP#391350, 9/19/2011, W. Irwin 
Residue Chemistry Memo DP#s 172067 and 178394, 10/26/92, R. Lascola (MRID 42090042)

The nature of the residue in livestock is understood based on acceptable goat and hen metabolism studies.  The HED Residues of Concern Knowledgebase Sub-committee (ROCKS) has determined that the parent compound (difenoconazole, CGA-169374) and the CGA-205375 metabolite are the residues of concern in livestock commodities for both tolerance enforcement and risk assessment (ROCKS Report Memo; DP#391350, 9/19/2011, W. Irwin).  The metabolite CGA-205375 is the major residue in livestock and is considered to have toxicity comparable to the parent.  In addition, metabolite OH-CGA-169374 (hydroxy-difenoconazole), which comprised 15.2% of the TRR in goat milk from the phenyl-labeled goat study (MRID 42090042; DP#s 172067 and 178394, 10/26/92, R. Lascola) when the combined residues of difenoconazole and the metabolite CGA-205375 comprised 29.9% of the TRR, should be considered as a residue of concern for risk assessment (ROCKS Report Memo; DP#391350, 9/19/2011, W. Irwin).  Based on a simple ratio of TRR values, residues of OH-CGA-169374 in milk are expected to be approximately 0.5x the combined residues of difenoconazole and the metabolite CGA-205375.  Therefore, based on available goat metabolism data, total residues of concern in milk for dietary risk assessments (parent, CGA-205375, and OH-CGA-169374), should be calculated by multiplying the tolerance in milk by 1.5x.

860.1340 Residue Analytical Methods

Crop Commodities
Residue Chemistry Memo DP# 356135, 9/17/09, B. Cropp-Kohlligian
Residue Chemistry Memo DP# 340379, 8/9/07, W. Wassell and M. Sahafeyan

Enforcement methods:  An adequate enforcement method, GC/NPD method AG-575B, is available for the determination of residues of difenoconazole per se in/on plant commodities.  An adequate enforcement method, GC/MSD method AG-676A, is also available for the determination of residues of difenoconazole per se in/on canola and barley commodities.  A confirmatory method, GC/MSD method AG-676, is also available.  The LOQs are 0.01-0.05 ppm.  

Data collection methods:  Samples were analyzed for residues of difenoconazole using Analytical Method No. REM 147.08, a high performance liquid chromatography method with tandem mass spectrometry detection (LC/MS/MS).  Samples were analyzed for triazole metabolites (1,2,4-triazole (1,2,4-T), triazolyl alanine (TA) and triazolyl acetic acid (TAA)) using Morse Laboratories Meth-160, also a LC/MS/MS method.  Acceptable method validation and concurrent recoveries were reported for dried pea vine, hay, seed and dried bean seed samples at fortification levels of 0.01-15 ppm, thus validating the methods.  Acceptable method validation and concurrent recoveries were reported for blueberry samples at fortification levels of 0.01-2.5 ppm for difenoconazole and 0.01 and 0.10 ppm for triazole metabolites, thus validating the methods.  The limit of quantitation (LOQ; determined as the lowest level of method validation, LLMV) was 0.01 ppm for difenoconazole and each metabolite in all matrices, with the exception of an LOQ of 0.20 ppm for metabolite TA in/on dried bean seeds.  

Previously submitted chickpea data (MRID 47929805; PP#9F7676; DP# 378829, 2/23/11, B. Cropp-Kohlligian) were collected with the same analytical methods.  Acceptable concurrent recoveries were report for chickpea seed samples at fortification levels of 0.01 and 0.10 ppm for difenoconazole, 1,2,4-T and TA and 0.05 and 0.50 ppm for TAA, thus validating the methods.  The LOQ was 0.01 ppm for all analytes in/on chickpea seeds.

Livestock Commodities
Residue Chemistry Memo DP# 374898, 3/3/10, B. Cropp-Kohlligian
Residue Chemistry Memo DP#s 361054 and 362648, 9/17/09, B. Cropp-Kohlligian
Analytical Chemistry Branch Memo, 10/29/07, C. Stafford
Residue Chemistry Memo DP# 340379, 8/9/07, W. Wassell and M. Sahafeyan

Enforcement methods:   An adequate tolerance enforcement method, Method REM 147.07b, is available for livestock commodities.  The method determines residues of difenoconazole and CGA-205375 in livestock commodities by liquid chromatography with tandem mass spectrometry detection (LC/MS/MS).  The method LOQs are 0.01 ppm (for each analyte) for livestock tissues and 0.005 ppm (for each analyte) for milk.  Adequate confirmatory methods, Method AG-544A and Method REM 147.06, are available for the determination of residues of difenoconazole and CGA-205375, respectively, in livestock commodities. 

860.1360 Multiresidue Methods
Residue Chemistry Memo DP#s 172067 and 178394, 10/26/92, R. Lascola
Email from C. Stafford (Analytical Chemistry Branch) to B. Cropp-Kohlligian dated 9/2/09

Multiresidue methods (MRM) testing data (MRID 42090054) were previously submitted in conjunction with PP#2E4051 (DP#s 172067 and 178394, 10/26/92, R. Lascola).  The study investigated the recovery of difenoconazole and its metabolites CGA-205374, CGA-205375, and CGA-189138 through the MRM methods of PAM Vol. I.  Based on the study results, HED concluded, as did the petitioner, that the MRM methods were not likely to be appropriate for determining residues of difenoconazole and its related compounds in plant and livestock tissues.  The study was forwarded to FDA for further review.  Difenoconazole is not listed in the most recent PESTDATA (1999).

In contradiction to the MRM study evidence, Analytical Chemistry Branch (ACB) has noted (Email from C. Stafford (ACB) to B. Cropp-Kohlligian dated 9/2/09) that (1) FDA routinely monitors for difenoconazole by GC/MS using their current modified Luke procedures which are not in the published PAM I manual; (2) difenoconazole has also been tested through the QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) method which is just beginning to be implemented in the FDA field labs using LC/MS/MS; and (3) the USDA-PDP program labs monitor for difenoconazole; the California Department of Food and Agriculture (CDFA), a participating laboratory, uses a multiresidue method with LC/MS analysis.  Based on these facts, HED accepts that difenoconazole is recoverable through existing multiresidue methods, although the evidence is non-guideline and a conclusion concerning whether recovery is complete (>80%) cannot be reached.  No additional MRM testing data are required at this time.  

860.1380 Storage Stability

Crop Commodities
Residue Chemistry Memo DP# 363016, 1/12/12, D. Drew
Residue Chemistry Memo DP#s 361054 and 362648, 9/17/09, B. Cropp-Kohlligian
Residue Chemistry Memo DP# 356135, 9/17/09, B. Cropp-Kohlligian
Residue Chemistry Memo DP# 340379, 8/9/07, W. Wassell and M. Sahafeyan

Samples of bean seed, pea seed, pea hay, pea vines and blueberries from the new magnitude of the residue studies were stored frozen for up to 9.8, 10.1, 12.3, 11.0 and 8.0 months, respectively, prior to analysis for residues of parent.  Samples of chickpea seed from the previously submitted chickpea field trial study (MRID 47929805; PP#9F7676; DP# 378829, 2/23/11, B. Cropp-Kohlligian) were stored for up to 6.0 months prior to analysis for residues of parent.  All samples were maintained frozen at the testing facility, during shipping to the laboratory, and at the laboratory until analysis.  No new storage stability data for difenoconazole were submitted with the current petition.  Based on previously submitted storage stability data, residues of difenoconazole have been shown to be stable under frozen conditions in/on representative raw agricultural commodities (RACs) for up to 1 year and in/on cotton seed, potato tuber, tomato, wheat forage, wheat grain, and wheat straw for up to 2 years.  

Samples of bean seed, pea seed, pea hay, pea vines and blueberries from the new magnitude of the residue studies which were analyzed for residues of the triazole metabolites were stored for up to 12.3 months prior to analysis.  Samples of chickpea seed from the previously submitted chickpea field trial study (MRID 47929805; PP#9F7676; DP# 378829, 2/23/11, B. Cropp-Kohlligian) were stored for up to 5.2 months prior to analysis for residues of the triazole metabolites.  No new supporting storage stability data for the triazole metabolites were submitted with the current petition.  However, the U.S. Triazole Task Force has submitted a 4-year storage stability study for the triazole metabolites (1,2,4-T, TA, and TAA) in various crop matrices and processed commodities (DP# 363016, 1/12/12, D. Drew).  HED generally considers residues to be stable under storage if 70% or more of the applied residue remains (<30 % residue decline).  The subject storage stability data indicate that residues of 1,2,4-T are relatively stable for up to four years of frozen storage in/on canola oil, canola meal, tomato paste, turnip roots, and on wheat grain, straw and flour and up to one year on wheat bran.  However, at one year of storage, residues of 1,2,4-T had declined in/on mustard greens, tomato and wheat forage to 53%, 67% and 57%, respectively.  Residues of TA and TAA were stable for at least four years of frozen storage in/on all commodities tested, except for TA in canola oil, where stability was demonstrated for up to 8 months.  Hence, residue levels of 1,2,4-T found in/on blueberries and pea vines from the submitted field trials should be adjusted for a potential decline to 53% and 57%, respectively, due to storage. 

The storage durations and conditions of samples from the magnitude of the residue studies submitted to support this petition are presented in Table 5.  

Table 5.  Summary of Storage Conditions and Durations of Samples from the Submitted Crop Field Trials.  
Matrix 
                              Storage Temperature
                                     (°C)
                        Maximum Actual Storage Duration
                                   (months)
                  Interval of Demonstrated Storage Stability
Difenoconazole - Raw Agricultural Commodities
Bean, seed
                                    <-10
                                    5.9-9.8
None provided with the current petition.  Based on previously submitted storage stability data, when stored under frozen conditions, residues of difenoconazole per se are stable in/on all raw agricultural commodities (RACs) for up to one year.  In addition, residues are stable for up to two years in/on cotton seed, potato tuber, tomato, wheat forage, wheat grain, and wheat straw.
Pea, seed
                                       
                                   7.5-10.1

Pea, hay
                                       
                                   8.9-12.3

Pea, vines
                                       
                                   8.8-11.0

Blueberry
                                       
                                    5.1-8.0

Chickpea. Seed[1] (previously submitted)
                                       
                                      6.0

1,2,4-triazole (1,2,4-T), triazolyl alanine (TA), and triazolyl acetic acid (TAA) - Raw Agricultural Commodities
Bean, seed
                                    <-10
                                   7.5-10.0
None provided with the current petition; however, the U.S. Triazole Task Force has submitted a 4-year storage stability study for the triazole metabolites in various crop matrices and processed commodities (MRID 47606601; DP# 363016, 1/12/12, D. Drew).  

Residues of 1,2,4-T are relatively stable for up to four years of frozen storage in/on canola oil, canola meal, tomato paste, turnip roots, and on wheat grain, straw and flour.  Residues of 1,2,4-T are stable for up to one year on wheat bran, up to four months on wheat forage and mustard greens, and up to one month on tomato fruit.  1,2,4-T residues were not stable on canola seed at the first storage interval tested (four months).  Note:  At one year of storage, residues of 1,2,4-T had declined in/on mustard greens, tomato and wheat forage to 53%, 67% and 57%, respectively.  

Residues of TA and TAA were stable for at least four years of frozen storage in/on all commodities tested, except for TA in canola oil, where stability was demonstrated for up to 8 months. 
Pea, seed
                                       
                                   8.7-11.3

Pea, hay
                                       
                                   9.7-12.3

Pea, vines
                                       
                                   9.9-12.3

Blueberry
                                       
                                   9.2-11.7

Chickpea, seed[1] (previously submitted)
                                       
                                      5.2

[1]  Chickpea seed from the previously submitted chickpea field trial study (MRID 47929805; PP#9F7676; DP# 378829, 2/23/11, B. Cropp-Kohlligian).

Conclusions.  With regards to difenoconazole, samples of bean seed, pea seed, pea hay, pea vines, blueberries and previously submitted chickpea seed (DP# 378829) were stored frozen for up to 9.8, 10.1, 12.3, 11.0, 8.0 and 6.0 months, respectively, prior to analysis for residues of difenoconazole.  Available storage stability data indicate that residues of difenoconazole per se are stable under frozen conditions in/on all RACs for up to 1 year and in/on cotton seed, potato tuber, tomato, wheat forage, wheat grain, and wheat straw for up to 2 years.  These data are deemed adequate to support the storage intervals and conditions of these samples for residues of difenoconazole.
With regards to the triazole metabolites, samples of bean seed, pea seed, pea hay, pea vines, blueberries and previously submitted chickpea seed (DP# 378829) were stored frozen for up to a maximum period of approximately 1 year prior to analysis.  No new storage stability data for the triazole metabolites (1,2,4-T, TA, and TAA) were submitted to support the storage conditions and intervals of these samples; however, the U.S. Triazole Task Force has submitted a 4-year storage stability study for the triazole metabolites in various crop matrices and processed commodities (MRID 47606601; DP# 363016, 1/12/12, D. Drew).  These data are deemed adequate to support the storage intervals and conditions of these samples for residues of the triazole metabolites.  Based on these data, residue levels of 1,2,4-T found in/on treated blueberries and pea vine samples from the submitted field trials should be adjusted for a potential decline to 53% and 57%, respectively, due to storage. 

Livestock Commodities
Residue Chemistry Memo DP# 375194, 6/17/10, B. Cropp-Kohlligian 
Residue Chemistry Memo DP#s 361054 and 362648, 9/17/09, B. Cropp-Kohlligian
Residue Chemistry Memo DP# 340379, 8/9/07, W. Wassell and M. Sahafeyan

No new meat, milk, poultry, and egg data and/or supporting storage stability data for difenoconazole and/or its metabolites in/on livestock commodities were provided in the subject submissions.

Conclusions.  With regards to residues of difenoconazole (CGA-169374) and its metabolite CGA-205375, the available storage stability data (47957201.der) and supplemental storage stability information provided in Report Number ABR-93012 (MRID 47957202) and Report Number 202/99 (MRID 47957203) are deemed adequate to support the storage intervals and conditions of samples collected from the cattle and poultry feeding studies previously submitted, reviewed by HED under PP# 6F7115 (D340379, 8/9/07, W. Wassell and M. Sahafeyan).  The information in Report Numbers ABR-93012 and 202/99 is considered supplemental since study details and raw data were not provided. 

With regards to the triazole metabolites, supporting storage stability data for residues of 1,2,4-triazole (1,2,4-T) are required to support the storage conditions (frozen) and intervals (up to 10 months) of livestock commodity samples collected for the cattle and poultry feeding studies.  However, storage stability data for these compounds has been requested as part of the Human Health Aggregate Risk Assessment for the triazole metabolites (M. Doherty, et al., 2/7/06) and these data, when submitted, are expected to satisfy storage stability data requirements for the subject petition.

860.1400 Water, Fish, and Irrigated Crops

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

860.1460 Food Handling

There are no proposed uses that are relevant to this guideline topic.
860.1480 Meat, Milk, Poultry, and Eggs
ROCKS Report Memo; DP#391350, 9/19/2011, W. Irwin 
Residue Chemistry Memo PP#1E7852; DP# 389912, 5/30/12, B. Cropp-Kohlligian (meat and milk tolerances)
Residue Chemistry Memo PP#9F7676; DP# 378829, 2/23/11, B. Cropp-Kohlligian (egg tolerance)
Residue Chemistry Memo DP# 375194, 6/17/10, B. Cropp-Kohlligian
Residue Chemistry Memo DP# 340379, 8/9/07, W. Wassell and M. Sahafeyan
Residue Chemistry Memo DP#s 172067 and 178394, 10/26/92, R. Lascola

No new livestock feeding study data were submitted with the current petition.  Adequate cattle and poultry feeding studies were previously submitted and are the basis for the currently established tolerances for difenoconazole residues of concern in meat, milk, and egg.  There are no tolerances for difenoconazole residues of concern in poultry tissues.  The currently established livestock commodity tolerances reflect the maximum reasonably balanced diets (MRBDs) for beef cattle (7.4 ppm), dairy cattle (2.8 ppm), poultry (0.11 ppm) and swine (0.09 ppm) for difenoconazole calculated using the most recent guidance on constructing reasonably balanced livestock diets (ChemSAC memo, 6/30/08).  See DP#s 378829 and 389912 for details.

There are new feedstuffs associated with the proposed uses of difenoconazole for dairy cattle, poultry and swine but not for beef cattle.  Field pea vines/silage and field pea hay are roughages (R) which may be fed to dairy cattle.  Cowpea and field pea seed are protein concentrates (PC) which may be fed to poultry and swine.  [Note:  No cowpea forage and hay data were submitted with this petition and tolerances in/on these commodities will not be established.]  In accordance with ChemSAC recommendations concerning blended and nonblended feedstuffs (ChemSAC meeting minutes 8/26/09, 9/21/11 and 12/21/11), the difenoconazole residue estimates in/on field pea hay/vines/silage for dairy cattle MRBD calculations should be based on the highest average field trial (HAFT) values and the estimates in/on cowpea/field pea seed for poultry and swine MRBD calculations should be based on the median field trial values.

Since there are no new feedstuffs for beef cattle, the previously calculated MRBD for beef cattle (7.4 ppm) remains unchanged.  The previously calculated MRBDs for poultry and swine included the potential contributions from other difenoconazole treated protein concentrates:  soybean seed and/or meal.  Since the estimated median difenoconazole residue level in treated cowpea/field pea seed (0.01 ppm for cowpea and 0.03 ppm for field pea) is lower than in/on treated soybean seed/meal (0.15 ppm), previously calculated MRBDs for poultry (0.11 ppm) and swine (0.09 ppm) will not need to be increased due to the proposed uses.  The MRBD for dairy cattle was re-calculated for the subject petition and increased from 2.8 ppm to 7.2 ppm; the results are presented in Table 6.  Hence, the adequacy of the currently established tolerance in milk was also reassessed.

Table 6.	Calculation of Dietary Burdens of Difenoconazole Residues to Livestock.
Feedstuff  1
                                    Type[2]
                                % Dry Matter[3]
                                   % Diet[3]
                          Residue Estimates[4] (ppm)
                         Dietary Contribution (ppm)[5]
Beef Cattle (15%R; 80%CC; 5%PC)
Sugar beet, dried pulp
                                       R
                                      88
                                      15
                                      1.9
                                     0.32
Potato, processed waste
                                      CC
                                      15
                                      30
                                    3.5[6]
                                      7.0
Barley, grain
                                      CC
                                      88
                                      50
                                      0.1
                                     0.06
Soybean, meal (seed)
                                      PC
                                      92
                                       5
                                     0.15
                                     0.01
TOTAL BURDEN
                                      --
                                      --
                                      100
                                      --
                                      7.4
Dairy Cattle (45%R; 45%CC; 10%PC)
Wheat, forage
                                       R
                                      25
                                      10
                                      0.1
                                     0.04
Sugar beet, dried pulp
                                       R
                                      88
                                      15
                                      1.9
                                     0.32
Field pea, hay
                                       R
                                      88
                                      10
                                    17.1[6]
                                     1.94
Field pea, vines
                                       R
                                      25
                                      10
                                    4.85[6]
                                     1.94
Apple, wet pomace[7]
                                      CC
                                      40
                                      10
                                   11.6[6,7]
                                    2.9[7]
Barley, grain
                                      CC
                                      88
                                      35
                                      0.1
                                     0.04
Soybean, meal (seed)
                                      PC
                                      92
                                      10
                                     0.15
                                     0.02
TOTAL BURDEN
                                      --
                                      --
                                      100
                                      --
                                      7.2
Swine (85%CC; 15%PC)
Wheat, milled byprdts[8]
                                      CC
                                      88
                                      50
                                    0.1[8]
                                     0.050
Barley, grain
                                      CC
                                      88
                                      20
                                      0.1
                                     0.020
Untreated
                                      CC
                                      --
                                      15
                                      --
                                     0.000
Soybean, seed
                                      PC
                                      89
                                      15
                                     0.15
                                     0.022
TOTAL BURDEN
                                      --
                                      --
                                      100
                                      --
                                     0.09
Poultry (75%CC; 25%PC)
Wheat, grain
                                      CC
                                      89
                                      75
                                      0.1
                                     0.075
Soybean, seed
                                      PC
                                      89
                                      20
                                     0.15
                                     0.030
Soybean, meal[9]
                                      PC
                                      92
                                       5
                                    0.15[9]
                                     0.008
TOTAL BURDEN
                                      --
                                      --
                                      100
                                      --
                                     0.11
1	According to Guideline 860.1000 Table 1 Feedstuffs (June 2008), only one of the following alternative feedstuffs is to be included in any theoretical livestock diet:  almond hulls, wet apple pomace, aspirated grain fractions, carrot culls, dried citrus pulp, sweet corn cannery waste, cotton gin byproducts, pineapple process residue, and potato processed waste.
2	R:  Roughage; CC:  Carbohydrate concentrate; PC:  Protein concentrate.
3	Guideline 860.1000 Table 1 Feedstuffs (June 2008).  
4	Residue Estimates = Tolerance level residues unless otherwise noted.
5	Contribution = ([tolerance/% DM] X % diet) for beef and dairy cattle.
  Contribution = (tolerance X % diet) for swine and poultry.
6	In accordance with ChemSAC recommendations concerning feedstuffs consider blended or nonblended for MRBD calculations (ChemSAC meeting minutes 8/26/09, 9/21/11 and 12/21/11):
   * Potato processed waste (3.5 ppm):  Difenoconazole residue estimate based on the median residue value for potato reflecting postharvest use (1.13 ppm) and the average concentration factor for potato wet peel (3.1x).
   * Pea, field, hay (17.1 ppm) and Pea, field, vines (4.85 ppm):  Difenoconazole residue estimates based on the highest average field trial (HAFT) value.
   * Apple, wet pomace (11.6 ppm):  Difenoconazole residue estimates was based on the median residue value for apple reflecting postharvest use (1.22 ppm from dip + spray) and the average concentration factor for apple, wet pomace (9.5x).
7	Residue estimate/dietary contribution based on new apple magnitude of the residue data submitted under pending petition 3F8209.  Note:  In the prior MRBD calculation for dairy cattle, processed potato waste (CC) constituted the major portion of the dietary burden and was estimated at 2.6 ppm for dietary contribution.  Hence, the dietary contribution for apple, wet pomace constitutes a minor increase in the MRBD calculation for dairy cattle when compared to the contributions from field pea hay and vines.
8	Residue estimate translated from wheat grain.
9	Residue estimate translated from soybean seed.

Cattle

Syngenta previously submitted a cattle feeding study with difenoconazole (MRID 46950226) which was reviewed by HED (PP# 6F7115; D340379, 8/9/07, W. Wassell and M. Sahafeyan).  These data are the basis for the established tolerances for residues of difenoconazole and its metabolite CGA-205375 in cattle, goat, hog, horse, and sheep commodities.  [Note:  Syngenta also previously submitted a report of a second cattle feeding study (Report Number 202/99; MRID 47957203) which was reviewed by HED (D375194, 6/17/10, B. Cropp-Kohlligian) and deemed supplemental.]

Three treatment groups of three dairy cows each were dosed orally with gelatin capsules containing difenoconazole at target dose rates of 1, 5, and 15 ppm in the diet (dry-weight basis) for 29-30 consecutive days; actual dose rates were 0.94, 4.24, and 14.26 ppm.  The actual dosing rates correspond to approximately 0.1x, 0.6x, and 1.9x the dietary burden for beef cattle (7.4 ppm) and 0.1x, 0.6x, and 2.0x the dietary burden for dairy cattle (7.2 ppm).  Cows were milked twice daily, and samples were composited daily for each cow.  One cow from each treatment group was sacrificed on Day 29 and the remaining two cows from each treatment group were sacrificed on Day 30.  All cows were sacrificed 20-23 hours after the final dose.  Samples of liver, kidney, renal fat, mesenterial fat, subcutaneous fat, round muscle, tenderloin muscle, and diaphragm muscle were collected from each cow.  Samples of milk collected on study days 0, 2, 5, 8, 12, 15, 19, 22, 26, and 28 from all dose levels were retained for analysis.

Milk and tissue samples were analyzed for residues of difenoconazole and CGA-205375 using an LC/MS/MS method, REM 147.07 (precursor to the current enforcement Method 147.07b), and for residues of 1,2,4-T using an LC/MS/MS method, RAM 455/01.  These methods remain adequate for data collection based on acceptable method recoveries.  The validated LOQs for REM 147.07, determined as the lowest level of method validation (LLMV), were 0.005 ppm for each analyte in milk and 0.01 ppm for each analyte in tissues.  The validated LOQ for RAM 455/01, determined as the LLMV, was 0.01 ppm in all matrices.  No LODs were reported for either method.  

The maximum residues of difenoconazole, CGA-205375, and 1,2,4-T in milk and tissues at each dosing level are presented in Table 7 below.

Table 7.	Maximum Residues of Difenoconazole, CGA-205375, and 1,2,4-Triazole in Cattle Milk and Tissues by Feeding Level.
Matrix
                    Maximum Residues by Feeding Level (ppm)

                                   0.94 ppm
                               0.1x MRBD cattle
                                   4.24 ppm
                               0.6x MRBD cattle
                                   14.3 ppm
                             1.9x MRBD beef cattle
                            2.0x MRBD dairy cattle
Difenoconazole (mol. wt. 406.3) Residues Found
Milk
                                   <0.005
                                   <0.005
                                   <0.005
Fat (renal, mesenterial, and subcutaneous)
                                   <0.01
                                   <0.01
                                   <0.01
Kidney
                                   <0.01
                                   <0.01
                                   <0.01
Liver
                                   <0.01
                                     0.02
                                     0.03
Muscle (round, tenderloin, and diaphragm)
                                   <0.01
                                   <0.01
                                   <0.01
CGA-205375 (mol. wt. 349.2) Residues Found
[CGA-205375 residues calculated as parent equivalents using ratio of mol. wts. (1.16x)]
Milk
                                   <0.005
                                     0.007
                                     0.020
                                  [0.023][1]
Fat, renal
                                     0.01
                                     0.05
                                     0.13
Fat, mesenterial
                                     0.01
                                     0.04
                                     0.14
                                   [0.16][1]
Fat, subcutaneous
                                     0.02
                                     0.04
                                     0.13
Kidney
                                     0.01
                                     0.04
                                     0.12
                                   [0.14][1]
Liver
                                     0.07
                                     0.23
                                     0.66
                                   [0.77][1]
Muscle, round
                                   <0.01
                                     0.01
                                     0.04
Muscle, tenderloin
                                   <0.01
                                     0.01
                                     0.04
Muscle, diaphragm
                                   <0.01
                                     0.01
                                     0.05
                                   [0.06][1]
1,2,4-Triazole Residues
Milk
                                   <0.01
                                     0.03
                                     0.05
Fat, renal
                                   <0.01
                                   <0.01
                                   <0.01
Fat, mesenterial
                                   <0.01
                                   <0.01
                                   <0.01
Fat, subcutaneous
                                   <0.01
                                   <0.01
                                   <0.01
Kidney
                                   <0.01
                                     0.02
                                     0.05
Liver
                                   <0.01
                                     0.01
                                     0.03
Muscle, round
                                   <0.01
                                     0.01
                                     0.04
Muscle, tenderloin
                                   <0.01
                                     0.02
                                     0.04
Muscle, diaphragm
                                   <0.01
                                     0.01
                                     0.04
1  CGA-205375 residues calculated as parent equivalents using ratio of mol. wts. (1.16x) of difenoconazole (mol. wt. 406.3) and CGA-205375 (mol. wt. 349.2).

Residues of CGA-205375 were found to have a linear relationship with the dosing levels in fat, liver, and kidney.  Residues of CGA-205375 in milk and muscle, and residues of difenoconazole and 1,2,4-T in milk and all tissues were too low to allow determination of the linearity of the dose response.  Residues of CGA-205375 and 1,2,4-T appeared to reach a plateau in milk by dosing days 5 and 8, respectively.  

Conclusions.  There are new feedstuffs associated with the proposed uses of difenoconazole for dairy cattle, poultry and swine but not for beef cattle.  While these new feedstuffs did not change previously calculated maximum reasonably balanced diets (MRBDs) for beef cattle (7.4 ppm), poultry (0.11 ppm) and swine (0.09 ppm), the new pea hay and vine feedstuffs significantly increased the MRBD for dairy cattle.  Based on the MRBDs for livestock and the available feeding study data, HED concludes that the currently established tolerance for residues of difenoconazole and its metabolite CGA-205375, expressed as difenoconazole equivalents, in milk should be increased from 0.01 ppm to 0.02 ppm to support the proposed new use on dried peas.  Other currently established livestock commodity tolerances remain adequate.

With regards to the dietary risk estimate for residues of concern in milk, the HED Residues of Concern Knowledgebase Sub-committee (ROCKS) has determined that in addition to the parent compound (difenoconazole or CGA-169374) and metabolite CGA-205375, metabolite OH-CGA-169374 (hydroxyl-difenoconazole) is a residue of concern in milk for risk assessment.  Based on available goat metabolism data (MRID 42090042; DP#s 172067 and 178394, 10/26/92, R. Lascola), residues of OH-CGA-169374 in milk are expected to be approximately 0.5x the combined residues of difenoconazole and the metabolite CGA-205375.  Therefore, the combined residues of parent, CGA-205375 and OH-CGA-169374 in milk may be estimated at 0.03 ppm by multiplying the recommended increased milk tolerance (0.02 ppm) by 1.5x.  This is a conservative estimate.

860.1500 Crop Field Trials
Residue Chemistry Memo PP#9F7676; DP# 378829, 2/23/11, B. Cropp-Kohlligian (chickpea; MRID 47929805)
49227601.der.docx (dried pea and dried bean)
49227602.der.docx (blueberry)

Pea and Bean, Dried Shelled, Except Soybean, Subgroup 6C

Syngenta has submitted a full field trial database for difenoconazole on dried peas and dried beans using a 2.08 lb ai/gal emulsifiable concentrate (EC) formulation of difenoconazole.  Five independent dried pea field trials were conducted during the 2011 growing season in the United States, encompassing North American Free Trade Agreement (NAFTA) Growing Regions 5 (ND; 1 trial), 10 (CA; 1 trial) and 11 (ID and OR; 3 trials).  Ten independent dried bean field trials were conducted during the 2011 growing season in the United States, encompassing NAFTA Growing Regions 5 (IA, NE, MO and MN; 5 trials), 7 (NE; 1 trial), 8 (OK; 1 trial), 10 (CA; 1 trial) and 11 (ID; 2 trials).  

Each trial consisted of one untreated plot and one treated plot. Each trial location received four foliar broadcast applications of the EC formulation of difenoconazole at 0.1117-0.1222 lb ai/A/application, for a total seasonal rate of 0.4587-0.4708 lb ai/A.  Applications were made at retreatment intervals (RTIs) of 12-16 days using spray volumes of 1.97-28.04 gal/A.  A nonionic surfactant (NIS) or crop oil concentrate (COC) was included in spray mixtures for all applications.  [Note:  At two of the ten dried bean trials (Trial 8 in MO and Trial 11 in OK), an additional application may have been made based on deviations reported in the field trial reports.  Not enough information was provided to determine the exact use pattern at these sites, including the timing and rate of the fifth application.] 

Samples of dried pea seed and dried bean seed were harvested after the fourth application, at a preharvest interval (PHI) of 13-15 days for dried pea seed and 13-18 days for dried bean seed, with the exception of dried bean Trials 8 and 11.  At Trials 8 and 11, dried bean seed was harvested at a PHI of 31 or 48 days based on the date of the fourth application.  Samples of dried pea vine and hay were harvested at 0 days after the second application (42 days before normal harvest); however, no samples of dried bean forage and hay were collected from the dried bean field trials.  To assess residue decline in/on seed, additional seed samples were collected at one dried pea and one dried bean trial each at PHIs of 0, 3, 7 and 21 days. To assess residue decline in/on dried pea vine and hay, additional samples were collected at one trial at PHIs of 3, 7, and 10 days.  The submitted field trial data were collected with adequate data-collection methods and are supported by adequate storage stability data which indicate that residue levels of 1,2,4-T found in/on pea vines from the submitted field trials should be adjusted for a potential decline to 57% due to storage.

Difenoconazole residues:  Individual sample (and per-trial average) residues of difenoconazole were <0.01-0.134 ppm (<0.01-0.0894 ppm) in/on dried pea seed and <0.01-0.0356 ppm (<0.01-0.0297 ppm) in/on dried bean seed collected at a PHI of 13-18 days.  In dried bean Trials 8 and 11, in which seed samples were harvested 31 or 48 days after the fourth application, and it is unclear if a fifth application (unknown date and rate) may have been used,  individual residues of difenoconazole were <0.01-0.0115 ppm in/on dried bean seed.  [Note:  Since dried bean seed data for Trials 8 and 11 reportedly do not adequately reflect the proposed PHI, they were not used to calculate the tolerance for residues of difenoconazole in/on dried bean seed.]  Individual sample (and per-trial average) residues of difenoconazole were 1.17-5.28 ppm (1.49-4.85 ppm) in/on pea vines and 3.98-17.4 ppm (4.43-17.1 ppm) in/on pea hay collected at a PHI of 0-days.  Residue decline data in seed show that residues of difenoconazole generally increased with increasing PHI to a maximum level on the 7-day PHI (dried bean seed) or 14-day PHI (dried pea seed), and then decreased with increasing PHI.  Residue decline data in pea vine and hay show that residues of difenoconazole decreased overall with increasing PHIs, although a slight increase was observed between the 7- and 10-day PHI.

1,2,4-T metabolite residues: Residues were <0.02 ppm in/on pea vines (corrected for potential decline to 57% due to sample storage) and <0.01 ppm in/on all other commodities.  Residue decline could not be assessed.

TA metabolite residues:  The highest average field trial (HAFT) residues were 0.835 ppm in/on dried pea seed, 2.47 ppm in/on dried bean seed, 0.213 ppm in/on pea hay and 0.191 in/on pea vines.  The average field trial residues were 0.344 ppm in/on dried pea seed, 0.685 ppm in/on dried bean seed, 0.126 ppm in/on pea hay and 0.0591 in/on pea vines.  Residues of TA in dried pea seed generally increased with increasing PHI.  Residue decline in dried bean seed could not be assessed.  Residues of TA in pea vine and hay showed an overall increase between the 0- and 10-day PHI, with residues remaining generally stable between the 0- and 7-day PHI.

TAA metabolite residues:  Residues were <0.01 ppm in/on dried pea seed and pea vines.  The HAFT residues were 0.0342 ppm in/on dried bean seed and 0.0588 ppm in/on pea hay.  The average field trial residues were 0.0167 ppm in/on dried bean seed and 0.0261 ppm in/on pea hay.  Residue decline in dried bean seed could not be assessed.  Residues of TAA generally increased with increasing PHI in pea hay. 

Table 8.	Summary of Residues from Dried Pea and Dried Bean Field Trials with EC Formulation of Difenoconazole.
Crop Matrix
                            Total Application Rate
                                   (lb ai/A)
                                  PHI (days)
                                     n[1]
                                Residues (ppm)
                                       
                                       
                                       
                                       
                                    Min.[2]
                                    Max.[2]
                                    LAFT[3]
                                    HAFT[3]
                                   Median[3]
                                    Mean[3]
                                     SD[3]
                                Difenoconazole
Dried Pea, vines
                                 0.2290-0.2369
                                       0
                                       5
                                     1.17
                                     5.28
                                     1.49
                                     4.85
                                     3.69
                                     3.47
                                     1.31
Dried Pea, hay
                                 0.2290-0.2369
                                       0
                                       5
                                     3.98
                                     17.4
                                     4.43
                                     17.1
                                     9.93
                                     10.7
                                     4.63
Dried Pea, seed
0.4592-0.4659
                                     13-15
                                       5
                                   <0.01
                                     0.134
                                   <0.01
                                    0.0894
                                    0.0277
                                    0.0342
                                    0.0319
Dried Bean, seed[4]
                                 0.4590-0.4708
                                     13-18
                                     8[4]
                                   <0.01
                                    0.0356
                                   <0.01
                                    0.0297
                                    0.0106
                                    0.0131
                                    0.0061
                                    1,2,4-T
Dried Pea, vines[5]
                                 0.2290-0.2369
                                       0
                                       5
                                  <0.02[5]
                                  <0.02[5]
                                  <0.02[5]
                                  <0.02[5]
                                    0.02[5]
                                    0.02[5]
                                      NA
Dried Pea, hay
                                 0.2290-0.2369
                                       0
                                       5
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      NA
Dried Pea, seed
0.4592-0.4659
                                     13-15
                                       5
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      NA
Dried Bean, seed [4]
                                 0.4587-0.4708
                                     13-48
                                      10
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      NA
                                      TA
Dried Pea, vines
                                 0.2290-0.2369
                                       0
                                       5
                                    0.0161
                                     0.196
                                    0.0194
                                     0.191
                                    0.0271
                                    0.0591
                                    0.0739
Dried Pea, hay
                                 0.2290-0.2369
                                       0
                                       5
                                    0.0227
                                     0.214
                                    0.0286
                                     0.213
                                     0.140
                                     0.126
                                    0.0677
Dried Pea, seed
0.4592-0.4659
                                     13-15
                                       5
                                     0.131
                                     0.840
                                     0.140
                                     0.835
                                     0.292
                                     0.344
                                     0.285
Dried Bean, seed[4]
                                 0.4587-0.4708
                                     13-48
                                      10
                                   <0.20
                                     2.48
                                   <0.20
                                     2.47
                                     0.514
                                     0.685
                                     0.655
                                      TAA
Dried Pea, vines
                                 0.2290-0.2369
                                       0
                                       5
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      NA
Dried Pea, hay
                                 0.2290-0.2369
                                       0
                                       5
                                    0.0118
                                    0.0635
                                    0.0133
                                    0.0588
                                    0.0214
                                    0.0261
                                    0.0188
Dried Pea, seed
0.4592-0.4659
                                     13-15
                                       5
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      NA
Dried Bean, seed[4]
                                 0.4587-0.4708
                                     13-48
                                      10
                                   <0.01
                                    0.0373
                                   <0.01
                                    0.0342
                                     0.01
                                    0.0167
                                    0.0087
[1] n = number of field trials.
[2]  Values based on total number of samples.
[3]  Values based on per-trial averages.  LAFT = lowest average field trial, HAFT = highest average field trial, SD = standard deviation.  For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ are assumed to be at the LOQ.  The LOQ was 0.01 ppm for difenoconazole and each metabolite in all matrices, with the exception of an LOQ of 0.20 ppm for metabolite TA in dried bean seed.  
[4]  Dried bean seed field trials 8 and 11 data for residues of difenoconazole are not included in this table or included in the tolerance determination for residues of difenoconazole in/on dried bean seed since they do not adequately reflected the proposed use.  At these sites a fifth application was made, according to deviations in the field site reports.  The date, timing, and rate of the fifth application were not provided.  Samples were harvested at PHIs of 31 or 48 days and; therefore, do not adequately reflect the proposed PHI (14-days) for dried bean seed. 
[5]  Available storage stability data indicate that residue levels of 1,2,4-T found in/on pea vines (<0.01 ppm) from the submitted field trials should be adjusted for a potential decline to 57% due to storage.

Previously Submitted Chickpea Field Trial Data (MRID 47929805; PP#9F7676; DP# 378829, 2/23/11, B. Cropp-Kohlligian):  Syngenta previously submitted three field trials for difenoconazole on chickpeas reflecting the same maximum use rate (i.e., four foliar applications of a 2.08 lb ai/gal EC formulation of difenoconazole at 0.115 lb ai/A/application (0.46 lb ai/A total seasonal rate) with 14-day RTI and 14-day PHI).  Three chickpea field trials were conducted in the United States encompassing NAFTA Growing Regions 10 (CA; 1 trial) and 11 (OR; 2 trials) during the 2007 growing season.  The per trial average residue values for difenoconazole were <0.01, <0.01, and 0.031 ppm in/on chickpea seed; the currently established tolerance in/on chickpea (0.08 ppm) is based on these data.  Samples were also analyzed for 1,2,4-T, TA, and TAA with the following residues:  1,2,4-T and TAA:  <0.01 ppm in/on all samples; TA:  0.116-0.385 ppm.  These field trial data were collected with adequate data-collection methods and are supported by adequate storage stability data.

Table 9.	Summary of Previously Submitted (DP# 378829) Residues from Chickpea Field Trials with EC Formulation of Difenoconazole. 
Commodity
                              Total Applic. Rate
                                   (lb ai/A)
                                       
                                    DALA[1]
                                Residue Levels
                                    (ppm)[2]

                                     N[1]
                                     Min.
                                     Max.
                                    HAFT[3]
                                    Median
                                    (STMdR)
                                     Mean
                                    (STMR)
                                   Std. Dev.
                                Difenoconazole
                                Chickpea, seed
                                 0.4613-0.4627
                                      14
                                       6
                                   <0.01
                                     0.032
                                     0.031
                                     0.01
                                     0.017
                                     0.011
                           1,2,4-Triazole (1,2,4-T)
                                Chickpea, seed
                                 0.4613-0.4627
                                      14
                                       6
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                      NA
                            Triazolyl alanine (TA)
                                Chickpea, seed
                                 0.4613-0.4627
                                      14
                                       6
                                     0.116
                                     0.385
                                     0.383
                                     0.181
                                     0.228
                                     0.124
                          Triazolyl acetic acid (TAA)
                                Chickpea, seed
                                 0.4613-0.4627
                                      14
                                       6
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                      NA
  1 	 DALA = Days after the last application.  N = number of samples; not field trials.
  2 	Mean, median, HAFT, and standard deviations were calculated by the reviewer.  The LOQ (0.01 ppm for all analytes) was used for calculations for any results reported as <LOQ.
  3	HAFT = Highest Average Field Trial.

Conclusions.  With the exception of the proposed retreatment interval (7-day RTI) and the total maximum use rate on pea hay and vines (0.46 lb ai/A), the submitted dried bean and dried pea field trial data and previously submitted chickpea field trial data, conducted with an EC formulation of difenoconazole, are adequate to support the proposed use pattern for members of pea and bean, dried shelled, except soybean, subgroup 6C.  No data were submitted for bean forage and hay.  Although cowpea forage and hay are not designated as under grower control in Table 1 of GLN 860.1000, ChemSAC (meeting 8/24/11) determined that, for a number of practical reasons, a label restriction such as the following is acceptable in lieu of data:  "To be grown for bean, dry seed only.  Do not feed or harvest cowpea forage and hay."

The number of field trials reflecting the proposed use on members of pea and bean, dried shelled, except soybean, subgroup 6C are in accordance with Guideline 860.1500 and the locations are also in accordance with the exception of missing one dried bean seed field trial from NAFTA Growing Region 8.  However, this is not an issue for the subject action since all other NAFTA growing regions for dried bean seed are adequately represented, the available dried bean seed trials reflect multiple years, and the recommended tolerance in/on pea and bean, dried shelled, except soybean, subgroup 6C is based on the dried pea seed data.  See tolerance discussion below.

The submitted field trial data were collected with adequate data-collection methods and are supported by adequate storage stability data which indicate that residue levels of 1,2,4-T found in/on pea vines from the submitted field trials should be adjusted for a potential decline to 57% due to storage.

Using the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures, the recommended tolerances are 0.05 ppm in/on dried bean seed, 0.20 ppm in/on dried pea seed, 40 ppm in/on pea hay and 10 ppm in/on pea vines.  [Note:  Since dried bean seed data for Trials 8 and 11 reportedly do not adequately reflect the proposed PHI, they were not used to calculate the tolerance for residues of difenoconazole in/on dried bean seed.]  Since the maximum field trial residues, highest average field trial residues and recommended tolerances for dried bean seed and dried pea seed are within 5x, a crop group tolerance can be set for pea and bean, dried shelled, except soybean, subgroup 6C and is recommended at 0.20 ppm based on the dried pea seed data.  The recommended tolerances are the same as the petitioned-for tolerances.  

Syngenta is also requesting the use of a suspension concentrate (SC) formulation of difenoconazole (Quadris Top(TM) Fungicide; EPA Reg. No. 100-1313) and an emulsion oil in water (EW) formulation of difenoconazole (Inspire Super (TM) Fungicide; EPA Reg. No. 100-1317) on members of pea and bean, dried shelled, except soybean, subgroup 6C with essentially the same use pattern and minimum PHI.  The adequacy of the submitted field trial data conducted with an EC formulation of difenoconazole to support the proposed uses for the SC and EW formulations is discussed later under a separate heading entitled, "Adequacy of the submitted data for the EC formulation to support the proposed uses for the SC and EW formulations."  

Bushberry Subgroup 13-07B

Syngenta has submitted a full field trial database for difenoconazole on blueberries using a 2.08 lb ai/gal emulsifiable concentrate (EC) formulation of difenoconazole.  Eleven field trials were conducted in Canada and the United States during the 2012 growing season.  An analysis of the field trials found that two of the eleven trials submitted (NAFTA Growing Region 1; Trials T162 and T163 conducted in PE, Canada) were not independent being less than 20 miles apart and reflecting the same variety and application timing resulting in substantially similar residue levels.  Hence, ten independent field trials were conducted encompassing North American Free Trade Agreement (NAFTA) Growing Regions 1 (PE and NS; 3 trials), 2 (NC, PA and GA; 3 trials), 5 (QC and ON; 3 trials) and 12 (BC; 1 trial).  [Note:  Only the trial with the higher residue of difenoconazole (T162) was used to calculate the tolerance for residues of difenoconazole in/on bushberry subgroup 13-07B.]    

Although highbush blueberry is listed as the representative crop for bushberry subgroup 13-07B, some of the submitted trials were conducted on lowbush blueberry varieties; however, combining these trials is deemed acceptable (email B. Schneider to B. Cropp-Kohlligian dated 4/15/14).  The submitted field trial data were collected with adequate data-collection methods and are supported by adequate storage stability data which indicate that residue levels of 1,2,4-T found in/on blueberries from the submitted field trials should be adjusted for a potential decline to 53% due to storage.  

In addition, Syngenta submitted bridging data in support of the proposed use of the EW formulation of difenoconazole on bushberry subgroup 13-07B.  At three trial locations, a second treated plot reflected application of a 335 g ai/L multiple active ingredient (MAI) oil in water emulsion (EW) formulation (Inspire Super EW) containing 249 g ai/L cyprodinil and 86 g ai/L (0.72 lb ai/gal) difenoconazole.  Application rates in the submission were reported in terms of total g ai/ha for combined application of cyprodinil and difenoconazole.  Individual application rates for difenoconazole were calculated by the study reviewer based on the ratio of the active ingredient in the product (reported rate x 0.257).  

Each treated plot received four foliar broadcast applications of the 2.08 lb ai/gal EC or the 0.72 lb ai/gal EW formulation (3 of the 11 trials) at 0.1052-0.1276 lb ai/A/application (118-143 g ai/ha), for a total seasonal rate of 0.4318-0.4845 lb ai/A (484-543 g ai/ha).  Applications to all plots were made using ground equipment in spray volumes of 29.9- 96.2 gal/A (280-900 L/ha), at retreatment intervals (RTIs) of 6-9 days.  A nonionic surfactant (NIS) was included in spray mixtures for all applications.  Samples of blueberries were harvested at a preharvest interval (PHI) of 1 day.  Additional samples were collected from two sites at PHIs of 3/4, 8/9 and 12/13 days to assess residue decline.   

Following four applications of the EC formulation of difenoconazole at a total application rate of 0.4461-0.4845 lb ai/A, individual sample (and per-trial average) residues in/on blueberries harvested at a PHI of 1 day were 0.30-2.2 ppm (0.33-1.9 ppm) for difenoconazole.  The highest average field trial (HAFT) residues in/on samples of blueberries were <0.02 ppm of 1,2,4-T (corrected for potential residue decline to 53% during storage), 0.041 ppm of TA and <0.01 ppm of TAA.  Residue decline data show that residues of difenoconazole decrease in blueberries with increasing PHIs.  Residues of the triazole metabolites were not assessed in the decline trial samples.

Regarding the bridging data, following four applications of the 0.72 lb ai/gal EW formulation at a total application rate of 0.4318-0.4666 lb ai/A (484-523 g ai/ha), individual sample (and per-trial average) residues of difenoconazole in/on blueberries harvested at a PHI of 1-day were 0.17-1.2 ppm (0.18-0.99 ppm).  These data are discussed under a separate heading entitled, "Adequacy of the submitted data for the EC formulation to support the proposed uses for the SC and EW formulations."  See Table 11.

Table 10.  Summary of Residues from Blueberry Field Trials with EC Formulation of Difenoconazole.
Crop Matrix
                                      EP
                            Total Application Rate
                                   (lb ai/A)
                                  PHI (days)
                                     n[1]
                                Residues (ppm)
                                       
                                       
                                       
                                       
                                       
                                    Min.[2]
                                    Max.[2]
                                    LAFT[3]
                                    HAFT[3]
                                   Median[3]
                                    Mean[3]
                                     SD[3]
                                Difenoconazole
Blueberries
                               2.08 lb ai/gal EC
                                 0.4461-0.4845
                                       1
                                     10[4]
                                     0.30
                                      2.2
                                     0.33
                                      1.9
                                     0.92
                                      1.0
                                     0.53
                                    1,2,4-T
Blueberries
                               2.08 lb ai/gal EC
                                 0.4461-0.4845
                                       1
                                      10
                                  <0.02[5]
                                  <0.02[5]
                                  <0.02[5]
                                  <0.02[5]
                                    0.02[5]
                                    0.02[5]
                                      NA
                                      TA
Blueberries
                               2.08 lb ai/gal EC
                                 0.4461-0.4845
                                       1
                                      10
                                   <0.01
                                     0.041
                                   <0.01
                                     0.041
                                     0.01
                                     0.016
                                     0.011
                                      TAA
Blueberries
                               2.08 lb ai/gal EC
                                 0.4461-0.4845
                                       1
                                      10
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                     0.01
                                      NA
[1] n = number of field trials.
[2] Values based on total number of samples.
[3] Values based on per-trial averages.  LAFT = lowest average field trial, HAFT = highest average field trial, SD = standard deviation.  For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ are assumed to be at the LOQ.  The LOQ was 0.01 ppm for each analyte.
[4]  Residues of difenoconazole from Trial T163 were not included in this table.  An analysis of the field trials found that two of the eleven trials (NAFTA Growing Region 1; Trials T162 and T163 conducted in PE, Canada) were not independent being less than 20 miles apart and reflecting the same variety and application timing resulting in substantially similar residue levels.  Hence, only the trial with the higher residue of difenoconazole (T162) was used to calculate the tolerance for residues of difenoconazole in/on bushberry subgroup 13-07B.
[5]  Available storage stability data indicate that residue levels of 1,2,4-T found in/on blueberries (<0.01 ppm) from the submitted field trials should be adjusted for a potential decline to 53% due to storage.

Conclusions.  The submitted blueberry field trial data, conducted with an EC formulation of difenoconazole, are adequate to support the proposed use pattern for members of bushberry subgroup 13-07B.  Although highbush blueberry is listed as the representative crop for bushberry subgroup 13-07B, some of the submitted trials were conducted on lowbush blueberry varieties; however, combining these trials is deemed acceptable (email B. Schneider to B. Cropp-Kohlligian dated 4/15/14).  The submitted field trial data were collected with adequate data-collection methods and are supported by adequate storage stability data which indicate that residue levels of 1,2,4-T found in/on blueberries from the submitted field trials should be adjusted for a potential decline to 53% due to storage.  

The number and locations of field trials reflecting the proposed use for members of bushberry subgroup 13-07B is in accordance with Guideline 860.1500.  However, an analysis of the field trials found that two of the eleven trials submitted (NAFTA Growing Region 1; Trials T162 and T163 conducted in PE, Canada) were not independent field trials being less than 20 miles apart and reflecting the same variety and application timing resulting in substantially similar residue levels.  Hence, only the trial with the higher residue of difenoconazole (T162) was used to calculate the tolerance for residues of difenoconazole in/on bushberry subgroup 13-07B.  Using the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures, the recommended tolerance for residues of difenoconazole in/on bushberry subgroup 13-07B is 4.0 ppm.  The recommended tolerance is not the same as the petitioned-for tolerance (3.0 ppm) due to the independent field trial determination.

Syngenta is also requesting the use of a suspension concentrate (SC) formulation of difenoconazole (Quadris Top(TM) Fungicide; EPA Reg. No. 100-1313) and an emulsion oil in water (EW) formulation of difenoconazole (Inspire Super (TM) Fungicide; EPA Reg. No. 100-1317) on bushberry subgroup 13-07B with essentially the same use pattern and minimum PHI.  The adequacy of the submitted field trial data conducted with an EC formulation of difenoconazole to support the proposed uses for the SC and EW formulations is discussed later under a separate heading entitled, "Adequacy of the submitted data for the EC formulation to support the proposed uses for the SC and EW formulations."  

Adequacy of the submitted data for the EC formulation to support the proposed uses for the SC and EW formulations

The petitioner has proposed uses of EC, SC, and EW formulations of difenoconazole on members of pea and bean, dried shelled, except soybean, subgroup 6C and bushberry subgroup 13-07B with essentially the same use patterns.  The full data sets submitted for dried bean seed, dried pea seed, pea hay, pea vines and blueberry reflect applications of an EC formulation of difenoconazole.  No field trial data for the SC were provided in the subject submissions.  Syngenta did submitted three bridging field trials for blueberry comparing residues of difenoconazole resulting from use of an EC formulation with that of an EW formulation but none of the dried bean/pea field trials were conducted with an EW formulation.  

Syngenta submitted three side-by-side blueberry field trials at the proposed maximum use rate on bushberry subgroup 13-07B using a 2.08 lb ai/gal emulsifiable concentrate (EC) formulation or a 0.72 lb ai/gal EW formulation of difenoconazole.  On comparison of the results by formulation type, residues of difenoconazole were similar for the EC and EW trials.  

Table 11.	Summary of Residue Data from Side-by-Side Blueberry Field Trials Comparing Residues of Difenoconazole from an EC Formulation to a EW Formulation.
Commodity
                                Formulation [1]
                              Total Applic. Rate
                                   (lb ai/A)
                                     PHI 
                                    (days)
                            Residue Levels (ppm) 2

                                       
                                       
                                       
                                       N
                                     Min.
                                     Max.
                                   HAFT [3]
                                    Median
                                    (STMdR)
                                     Mean
                                    (STMR)
                                   Std. Dev.
                             EC vs. EW Formulation
                                   Blueberry
                               2.08 lb ai/gal EC
                                 0.4461-0.4604
                                       1
                                       3
                                     0.30
                                      1.2
                                      1.0
                                     0.40
                                     0.58
                                     0.37
                                       
                               0.72 lb ai/gal EW
                                 0.4318-0.4666
                                       1
                                       3
                                     0.17
                                      1.2
                                     0.99
                                     0.28
                                     0.48
                                     0.44
  1	The EW is a MAI formulation containing 249 g ai/L cyprodinil and 86 g ai/L (0.72 lb ai/gal) difenoconazole.
  2	The LOQ is 0.01 ppm in/on each commodity.
  3	HAFT = Highest Average Field Trial.

Syngenta previously submitted side-by-side field trial data for leaf lettuce, mustard greens, and tomatoes comparing residues of difenoconazole per se resulting from use of a 2.08 lb ai/gal EC formulation with that of a 2.08 lb ai/gal SC formulation (DP# 354013, 3/20/09, B. Cropp-Kohlligian).  For each crop, three side-by-side tests were conducted in different regions and samples were harvested at a 0-day PHI.  Side-by-side field trial data were also previously submitted for the same crops comparing residues of difenoconazole per se resulting from use of a 2.08 lb ai/gal EC formulation with that of a 0.73 lb ai/gal EW formulation.  For each crop, three side-by-side tests were conducted in different regions; samples of leaf lettuce and tomato were harvested at a 0-day PHI and samples of mustard greens were harvested at a 7-day PHI.  These previously submitted side-by-side field trial data are summarized in Table 12 below.  

When comparing the highest average field trial (HAFT) and mean residue levels from the side-by-side field trial data for the EC and SC formulations, residues of difenoconazole per se were found to be higher for the EC formulation than for the SC formulation.  Given that all samples were harvested at 0-day PHI, these data are not capable of determining residual differences between the two formulations resulting from significantly longer PHIs. 

When comparing the HAFT and mean residue levels from the side-by-side field trial data for the EC and EW formulations, residues of difenoconazole per se were found to be higher for the EW formulation than for the EC formulation; HAFT residue levels were found to be 28-54% for the EW formulation than for the EC formulation.  Furthermore, the HED ChemSAC (meeting 01/27/2010) considered these side-by-side field trial data for the EC and EW formulations and noted that the crops are not sufficiently diverse and that before these formulations can be considered equivalent for all crops, a third diverse crop such as grapes should be compared in similar side-by-side trials. 

Table 12.	Summary of Previously Submitted (DP# 354013) Residue Data from Side-by-side Crop Field Trials Comparing Residues of Difenoconazole from an EC formulation to a SC formulation or EW formulation.
Commodity
                                Formulation [1]
                              Total Applic. Rate
                                   (lb ai/A)
                                     PHI 
                                    (days)
                            Residue Levels (ppm) 2

                                       
                                       
                                       
                                       N
                                     Min.
                                     Max.
                                   HAFT [3]
                                    Median
                                    (STMdR)
                                     Mean
                                    (STMR)
                                   Std. Dev.
                             EC vs. SC Formulation
                                 Leaf lettuce
                               2.08 lb ai/gal EC
                                  0.454-0.473
                                       0
                                       6
                                     0.84
                                      5.6
                                      5.6
                                     3.65
                                     3.42
                                     2.07
                                       
                               2.08 lb ai/gal SC
                                  0.452-0.465
                                       0
                                       6
                                     0.66
                                      5.5
                                      5.4
                                     2.55
                                     3.01
                                     1.99
                                Mustard greens
                               2.08 lb ai/gal EC
                                  0.459-0.464
                                       0
                                       6
                                     3.50
                                     23.0
                                     20.5
                                     7.90
                                     10.9
                                     7.85
                                       
                               2.08 lb ai/gal SC
                                  0.458-0.462
                                       0
                                       6
                                     3.20
                                     18.0
                                     16.0
                                     6.10
                                     8.82
                                     5.81
                                    Tomato
                               2.08 lb ai/gal EC
                                  0.461-0.480
                                       0
                                       6
                                     0.08
                                     0.26
                                     0.25
                                     0.12
                                     0.15
                                     0.08
                                       
                               2.08 lb ai/gal SC
                                  0.454-0.486
                                       0
                                       6
                                     0.09
                                     0.18
                                     0.17
                                     0.14
                                     0.14
                                     0.04
                             EC vs. EW Formulation
                                 Leaf lettuce
                               2.08 lb ai/gal EC
                                  0.459-0.474
                                       0
                                       6
                                     2.38
                                     6.68
                                     6.23
                                     4.17
                                     4.40
                                     1.62
                                       
                               2.82 lb ai/gal EW
                                  0.454-0.470
                                       0
                                       6
                                     2.57
                                     9.68
                                     9.60
                                     3.99
                                     5.51
                                     3.21
                                Mustard greens
                               2.08 lb ai/gal EC
                                  0.456-0.479
                                       7
                                       6
                                     0.53
                                     3.38
                                     1.96
                                     0.68
                                     1.32
                                     1.17
                                       
                               2.82 lb ai/gal EW
                                  0.445-0.477
                                       7
                                       6
                                     0.61
                                     2.96
                                     2.51
                                     1.17
                                     1.45
                                     0.90
                                    Tomato
                               2.08 lb ai/gal EC
                                  0.462-0.467
                                       0
                                       6
                                     0.08
                                     0.22
                                     0.20
                                     0.16
                                     0.15
                                     0.06
                                       
                               2.82 lb ai/gal EW
                                  0.453-0.467
                                       0
                                       6
                                     0.08
                                     0.31
                                     0.27
                                     0.14
                                     0.17
                                     0.09
  1	The EW is a MAI formulation containing 2.09 lb ai/gal of cyprodinil and 0.73 lb ai/gal of difenoconazole.
  2	The LOQ is 0.01 ppm in/on each commodity.
  3	HAFT = Highest Average Field Trial.

Conclusions.  Given the limited scope and nature of the previously submitted side-by-side field trial data on leaf lettuce, mustard greens, and tomatoes comparing residues of difenoconazole per se resulting from use of a 2.08 lb ai/gal EC formulation with that of a 2.08 lb ai/gal SC formulation discussed above, HED has been reluctant to draw too many conclusions from these data out of context.  However, with regards to the crops included in this petition and in consideration of the specific use proposals for the EC and SC formulations of difenoconazole, HED concludes that, collectively, these side-by-side field trial data indicate that residue levels of difenoconazole per se in/on the crops included in this petition, with the exception of dried bean seed and dried pea seed, resulting from the proposed multiple late-season foliar applications of a SC formulation should not exceed those resulting from the same use of an EC formulation.  Furthermore, having considered the available residue database which indicates that the recommended tolerance for residues of difenoconazole in/on pea and bean, dried shelled, except soybean, subgroup 6C (0.20 ppm) is well above the highest average field trial (HAFT) residue level found in the supporting magnitude of the residue data (0.0894 ppm in/on dried pea seed), HED concludes that the recommended tolerances for residues of difenoconazole are likely to cover the proposed uses of the 1.05 lb ai/gal SC formulation of difenoconazole.  Hence, HED concludes that the submitted field trial data for the EC formulation may be translated to support the proposed uses of the 1.05 lb ai/gal SC formulation on members of pea and bean, dried shelled, subgroup 6C and bushberry subgroup 13-07B provided the petitioner amends the labels/Section B of the petition as required under Directions for Use.

Based on the submitted side-by-side blueberry field trial data comparing residues of difenoconazole per se resulting from use of a 2.08 lb ai/gal EC formulation with that of a 0.72 lb ai/gal EW formulation and reflecting a 1-day PHI, HED concludes that the submitted field trial data for the EC formulation may be translated to support the proposed uses of the 0.73 lb ai/gal EW formulation on members of bushberry subgroup 13-07B.

Given the limited scope and nature of the previously submitted side-by-side field trial data on leaf lettuce, mustard greens, and tomatoes comparing residues of difenoconazole per se resulting from use of a 2.08 lb/gal EC formulation with that of a 0.73 lb/gal EW formulation discussed above, HED has been reluctant to draw too many conclusions from these data out of context.  HED concludes that the available bridging data comparing residues of difenoconazole per se resulting from use of an EC formulation with that of an EW formulation, discussed above, indicate that the field trial data for the EC formulation are not adequate to support the proposed uses of the EW formulation.  Collectively, these side-by-side field trial data, which represent multiple late-season, foliar applications and 0-7 day PHIs, indicate the potential for significantly higher residue levels of difenoconazole per se in/on field crops from the use of the EW formulation when compared to the same use of an EC formulation.  The highest average field trial (HAFT) residue levels from the side-by-side field trials were 28-54% higher for the EW formulation than for the EC formulation.  However, having considered the available residue database for difenoconazole which indicates that the recommended tolerance for residues of difenoconazole in/on pea and bean, dried shelled, subgroup 6C (0.20 ppm) is well above the HAFT residue levels found in the supporting magnitude of the residue data (i.e., 0.0894 ppm for dried pea seed), HED concludes that the recommended tolerances are likely to cover the proposed uses of the EW formulation of difenoconazole on dried beans.  [Note:  Syngenta is not proposing use of Inspire Super (TM) Fungicide (EPA Reg. No. 100-1317) on dried peas.]  Hence, HED concludes that the submitted field trial data for the EC formulation may be translated to support the proposed uses of the 0.73 lb ai/gal EW formulation on dried beans provided the petitioner amends the labels/Section B of the petition as required under Directions for Use.

860.1520 Processed Food and Feed

There are no processed commodities associated with the proposed new uses.

860.1650 Submittal of Analytical Reference Standards

Analytical standards for difenoconazole (expiration 11/30/15) and its metabolite CGA-205375 (expiration 8/31/15) are currently available in the EPA National Pesticide Standards Repository.  

860.1850 and 860.1900 Confined and Field Accumulation in Rotational Crops
ROCKS Report Memo; DP#391350, 9/19/2011, W. Irwin  
Residue Chemistry Memo DP# 382946, 12/7/11, B. Cropp-Kohlligian

The nature of the residue in rotational crops is adequately understood.  The metabolism of difenoconazole in rotational crops is similar to that of primary crops.  The proposed metabolic pathway for difenoconazole (Company experimental name CGA-169374) involved the degradation of the dioxolane ring to CGA-205374 followed by reduction to CGA-205375.  Alternatively, oxidative cleavage of CGA-205374 would lead to CGA-189138.  
The HED Residues of Concern Knowledgebase Sub-committee (ROCKS) considered the subject difenoconazole confined rotational crop data and, in consideration of the PBIs indicated by the limited field rotational crop data, determined that only the parent compound needs to be considered as a residue of concern in/on rotational crops at this time (ROCKS Report Memo; DP#391350, 9/19/2011, W. Irwin).  

The available difenoconazole confined and limited field rotational crop trials are deemed adequate to satisfy data requirements under Guidelines 860.1850 and 860.1900.   Taken together, these data support a 30-day plantback interval (PBI) for cereal and root/tuber crops not already registered for foliar use with difenoconazole and a 60-day PBI for all other crops not already registered for foliar use with difenoconazole.  With these PBIs, tolerances for residues of difenoconazole are not needed for rotational crops.   

Note:  HED has previously determined, in several reviews, that based on available confined rotational crop data a 30-day PBI for all crops not already registered for use with difenoconazole is appropriate for currently registered/proposed seed treatment uses of difenoconazole.  These decisions remain unaltered.   

860.1550 Proposed Tolerances

Tolerances for plant commodities are established under §180.475(a)(1), and are expressed in terms of difenoconazole per se.  The tolerance expression proposed by Syngenta is in terms of difenoconazole per se.

The tolerances proposed by Syngenta are listed in Table 13, along with the tolerance levels recommended by HED and correct commodity definitions.

Provided the petitioner amends the labels/Section B of the petition as required, the submitted dried bean and dried pea field trial data and previously submitted chickpea field trial data, conducted with an EC formulation of difenoconazole, are adequate to support the proposed uses for difenoconazole on pea and bean, dried shelled, except soybean, subgroup 6C.  No data were submitted for bean forage and hay.  Although cowpea forage and hay are not designated as under grower control in Table 1 of GLN 860.1000, ChemSAC (meeting 8/24/11) determined that, for a number of practical reasons, a label restriction such as the following is acceptable in lieu of data:  "To be grown for bean, dry seed only.  Do not feed or harvest cowpea forage and hay."
Using the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures, the recommended tolerances are 0.05 ppm in/on dried bean seed, 0.20 ppm in/on dried pea seed, 40 ppm in/on pea hay and 10 ppm in/on pea vines.  Since the maximum field trial residues, highest average field trial residues and recommended tolerances for dried bean seed and dried pea seed are within 5x, a crop group tolerance can be set for pea and bean, dried shelled, except soybean, subgroup 6C and is recommended at 0.20 ppm based on the dried pea seed data.  The recommended tolerances for residues of difenoconazole in/on legume commodities are the same as the petitioned-for tolerances.  

The submitted blueberry field trial data, conducted with an EC formulation of difenoconazole, are adequate to support the proposed uses for difenoconazole on bushberry subgroup 13-07B.  The number and locations of field trials reflecting the proposed use for members of bushberry subgroup 13-07B is in accordance with Guideline 860.1500.  However, an analysis of the field trials found that two of the eleven trials submitted (NAFTA Growing Region 1; Trials T162 and T163 conducted in PE, Canada) were not independent field trials being less than 20 miles apart and reflecting the same variety and application timing resulting in substantially similar residue levels.  Hence, only the trial with the higher residue of difenoconazole (T162) was used to calculate the tolerance for residues of difenoconazole in/on bushberry subgroup 13-07B.  Using the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures, the recommended tolerance for residues of difenoconazole in/on bushberry subgroup 13-07B is 4.0 ppm.  The recommended tolerance is not the same as the petitioned-for tolerance (3.0 ppm) due to the independent field trial determination.

Tolerances are established for the combined residues of difenoconazole and metabolite CGA-250375 in livestock commodities.  Acceptable cattle and poultry feeding study data are available.  Based on the re-calculated livestock dietary burdens and the available feeding study data, HED concludes that the currently established tolerance in milk should be increased from 0.01 ppm to 0.02 ppm to support the proposed new uses on dried peas.  Other currently established livestock commodity tolerances remain adequate.

Codex maximum residue limits (MRLs) are not established for residues of difenoconazole in/on members of the pea and bean, dried shelled, except soybean, subgroup 6C and harmonization with the established Canadian MRLs in/on a variety dried pea seeds and dried bean seeds (all at 0.03 ppm) is not possible because the Canadian MRL would not be adequate to cover residues expected from the proposed foliar uses in the U.S.  There are no established Codex, Canadian or Mexican MRLs for residues of difenoconazole in/on members of the bushberry subgroup 13-07B, pea hay and pea vines so harmonization is not possible.  For milk, the residue definition (sum of parent and its metabolite, CGA-205375) and recommended milk tolerance increase (0.02 ppm) will be harmonized with the established Codex MRL in milk but not the established Canadian MRL (0.01 ppm) which is limit to residues of parent only.  An International Residue Limit Status Sheet is attached in Appendix I.

Table 13. 	Tolerance Summary for Difenoconazole.
Commodity
                           Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
Correct Commodity Definition;
Comments
Bushberry, subgroup 13-07B
                                      3.0
                                      4.0
Bushberry subgroup 13-07B
Pea and bean, dried shelled (except soybean), subgroup 6C
                                      0.2
                                     0.20
Pea and bean, dried shelled, except soybean, subgroup 6C
Peas, hay
                                      40
                                      40
Pea, field, hay
Peas, vines
                                      10
                                      10
Pea, field, vines
Chickpea
                                     0.08
                                    delete
With the establishment of a tolerance in/on pea and bean, dried shelled, except soybean, subgroup 6C (0.20 ppm), this tolerance is not appropriate and should be deleted.
Milk
                                      --
                                     0.02
The new dried pea hay and vine feedstuffs significantly increased the maximum reasonably balance diet (MRBD) for dairy cattle (from 2.8 ppm to 7.2 ppm).  Based on the MRBDs for livestock and the available feeding study data, HED concludes that the currently established tolerance for residues of difenoconazole and its metabolite CGA-205375, expressed as difenoconazole equivalents, in milk should be increased from 0.01 ppm to 0.02 ppm to support the proposed new uses on dried peas.  Other currently established livestock commodity tolerances remain adequate.
References

DP#s:	172067 and 178394
Subject:	PP#2E4051.  CGA-169374 (Difenoconazole, Dividend(R)) in Imported Wheat, Barley, and Rye Grain.  First Food Use.  CBTS#s 9029, 9895.
From:	R. Lascola
To:	J. Stone/C. Giles-Parker
Dated:	10/26/92
MRIDs:	42090001-42090004, 42090032-42090059, and 42303901

DP#:	327788
Subject:	Triazole-Based Metabolites:  Guidance On Residue Chemistry Data Submissions.
From:	M. Doherty
To:	C. Giles-Parker
Date:	4/25/06
MRIDs:	None

DP#:	340379
Subject:	PP#6F7115; Difenoconazole.  Petition for Establishment of Tolerances on Fruiting Vegetables, Pome Fruit, Sugar Beets, Tuberous and Corm Vegetables, and Imported Papaya.  Summary of Analytical Chemistry and Residue Data.
From:	W. Wassell/M. Sahafeyan
To:	D. Rosenblatt/S. Brothers
Dated:	8/9/07
MRIDs:	46950215-46950237

DP#:	None (ACB memo)
Subject:	Review of Proposed Tolerance Enforcement Method for Difenoconazole.  ACB Project # B07-26.
From:	C. Stafford
To:	D. Vogel
Dated:	10/29/07
MRIDs:	None

DP#	356135
Subject:	Difenoconazole.   Submission of Residue Analytical Methods Data in Response to DP#265858.  Submission of Storage Stability Data in Response to DP#307059.  Summary of Analytical Chemistry and Residue Data.
From:	B. Cropp-Kohlligian
To:	J. Bazuin/T. Kish
Dated:	9/17/09
MRIDs:	47413501 and 47413502

DP#s	361054 and 362648
Subject:	Difenoconazole.  Application for Amended Section 3 Registration to Add Uses on Bulb Vegetables, Brassica Leafy Vegetables, Cucurbit Vegetables, Citrus Fruits, Grapes, Pistachios, and Tree Nuts.  Submission of Residue Analytical Methods Data in Response to DP#340379.  Summary of Analytical Chemistry and Residue Data.
From:	B. Cropp-Kohlligian
To:	R. Kearns/T. Kish
Dated:	9/17/09
MRIDs:	47586101-47586107 and 47648604-47648605

DP#	374898
Subject:	Difenoconazole.  The Need for Additional Independent Laboratory Validation (ILV) Information for the Livestock Enforcement Method REM 147.07.
From:	B. Cropp-Kohlligian
To:	R. Kearns/T. Kish
Dated:	3/3/10
MRIDs:	None

DP#	375159
Subject:	Difenoconazole.  Dissociation Constant in Water Data to Satisfy OPPTS 830.7370 Guideline Requirements.
From:	B. Cropp-Kohlligian
To:	R. Kearns/T. Kish
Dated:	5/26/10
MRIDs:	47957001

DP#	375194
Subject:	Difenoconazole.  Submission of Storage Stability Data in Livestock Commodities in Response to DP# 340379.  Submission of a Report of a New Cattle Feeding Study.  Summary of Analytical Chemistry and Residue Data.
From:	B. Cropp-Kohlligian
To:	R. Kearns/T. Kish
Dated:	6/17/10
MRIDs:	47957201-47957203

DP#	378829
Subject:	Difenoconazole.  Application for Amended Section 3 Registration to Add Uses on Carrots, Chickpeas, Soybeans, Stone Fruits (Group 12), Strawberries, and Turnip Greens.  Summary of Analytical Chemistry and Residue Data.
From:	B. Cropp-Kohlligian
To:	R. Kearns/T. Kish
Dated:	2/23/11
MRIDs:	47929801-47929805

DP#:		391350
Subject:	Difenoconazole:  Report of the Residues of Concern Knowledgebase Sub-committee (ROCKS).
From:		W. Irwin, ROCKS Member
Through:	C. Olinger and E. Scollon, ROCKS Co-Chairs
To:		HED Difenoconazole Risk Assessment Team
Dated:		9/19/11
MRIDs:	NA

DP#	382946
Subject:	Difenoconazole.  Submission of Confined Rotational Crop Data in Response to Data Deficiencies Identified as a Condition of Registration Under Previous Petitions.  Summary of Analytical Chemistry and Residue Data.
From:	B. Cropp-Kohlligian
To:	R. Kearns/T. Kish
Dated:	12/7/11
MRID:	48203402

DP#	363016
Subject:	Storage Stability of 1,2,4-Triazole, Triazolylalanine and Triazolylacetic Acid in Various Crop Matrices and Processed Commodities (up to four years under frozen storage). 
From:	D. Drew
To:	T. Gibson
Dated:	1/12/12
MRID:	47606601

DP#	389912
Subject:	Difenoconazole.  Petition for Postharvest Use on Tuberous and Corm Vegetables Subgroup 1C and Foliar Uses on Fruiting Vegetables Group 8-10, Citrus Fruits Group 10-10, Pome Fruits Group 11-10, and Low growing Berry Subgroup 13-07G, Except Cranberry.  Summary of Analytical Chemistry and Residue Data.
From:	B. Cropp-Kohlligian
To:	S. Jackson/B. Madden
Dated:	5/30/12
MRID:	48437101

Attachments:  
Appendix I - International Residue Limit Status Sheet
Appendix II - Tolerance Assessment Calculations

Template Version September 2005

Appendix I.  International Residue Limit Status Sheet.

                        Difenoconazole (128847; 7/1/14)
Summary of US and International Tolerances and Maximum Residue Limits 
Residue Definition:
US
Canada
Mexico[2]
Codex[3]
40 CFR 180.475:
Plant: difenoconazole, 1-[2-[2-chloro-4-(4-chlorophenoxy)phenyl]-4-methyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole

Livestock:  sum of difenoconazole, 1-[2-[2-chloro-4-(4-chlorophenoxy)phenyl]-4-methyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole, and its metabolite, CGA-205375, 1-[2-chloro-4-(4-chloro-phenoxy)phenyl]-2-[1,2,4]triazol-1-yl-ethanol, calculated as the stoichiometric equivalent of difenoconazole

Difenoconazole, 1-[2-[4-(4-chlorophenoxy)-2-chlorophenyl]-4-methyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole.

Plants: difenoconazole

Animal commodities: sum of difenoconazole and 1-[2-chloro-4-(4-chloro-phenoxy)-
phenyl]-2-(1,2,4-triazol)-1-yl-ethano), expressed as difenoconazole.
The residue is fat-soluble.
Commodity[1]
Tolerance (ppm) /Maximum Residue Limit (mg/kg)

                                      US
Canada
Mexico[2]
Codex[3]
Bushberry, subgroup 13-07B
4.0

Pea and bean, dried shelled, except soybean, subgroup 6C
0.20
0.03 Dry (adzuki beans, beans, blackeyed peas, 
 broad beans, catjang seeds, chickpeas, cowpea seeds, field peas, guar seeds, kidney beans, lablab beans, lentils, lima beans, moth beans, mung beans, navy beans, pigeon peas, pink beans, pinto beans, rice beans, southern peas, tepary beans, urd beans, grain lupin

Pea, field, hay
40

Pea, field, vines
10

Milk
0.02
0.01

0.02
Completed:  M. Negussie; 07/07/14
[1] Includes only commodities of interest for this action.  Tolerance values should be the HED recommendations and not those proposed by the applicant.
2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains.  PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

Appendix II.  Tolerance Assessment Calculations.

The Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures were used for calculating the recommended tolerances.  As specified in the OECD document, the average residue from each field trial was used.  The rounding procedures specified in the OECD guidelines were also used.

Pea and bean, dried shelled, except soybean, subgroup 6C

The dataset used to establish the tolerance for residues of difenoconazole in/on peas and beans, dried shelled, except soybean, subgroup 6C consisted of dried bean seed and dried pea seed field trial data representing four foliar applications of an EC formulation of difenoconazole at 0.115 lb ai/A/application with a 14-day RTI and a 14-day PHI.  Previously submitted chickpea seed field trial data (MRID 47929805; PP#9F7676; DP# 378829, 2/23/11, B. Cropp-Kohlligian) reflecting the same formulation and use rate were also used.

The dataset used to establish the tolerances for residues of difenoconazole in/on pea hay and pea vines consisted of pea field trial data for hay and vines representing two foliar applications of an EC formulation of difenoconazole at 0.115 lb ai/A/application with a 14-day RTI and a 0-day PHI.

The residue values which were used to calculate the tolerance are provided below in Table II-1.  Using the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures, the recommended tolerances are 0.05 ppm in/on dried bean seed, 0.20 ppm in/on dried pea seed, 40 ppm in/on pea hay and 10 ppm in/on pea vines.  (Figure II-1)  Since the maximum field trial values, highest average field trial values and recommended tolerances for dried bean seed and dried pea seed are within 5x, a crop group tolerance can be set for pea and bean, dried shelled, except soybean, subgroup 6C and is recommended at 0.20 ppm based on the dried pea seed data.  The recommended tolerances are the same as the petitioned-for tolerances.

Table II-1.	Residue data used to calculate tolerance for difenoconazole in/on dried bean, seed; dried pea, seed; pea, hay; and pea, vines.
Regulator:
EPA
Chemical:
Difenoconazole
Crops:
Dried bean, seed; Dried pea, seed; Pea hay; Pea vines
PHI:
14-days for seed and 0-days for pea hay/vines 
App. Rate:
4 x 0.115 lb ai/A/application for seed and 2 x 0.115 lb ai/A/application for pea hay/vines; 14-day RTI.
Submitter:
Syngenta
MRID Citation:
MRID 49227601
MRID 47929805; PP#9F7676; DP# 378829, 2/23/11, B. Cropp-Kohlligian

Figure II-1.	Tolerance spreadsheet summary of difenoconazole magnitude of the residue data for legume 			commodities.
Compound
                                Difenoconazole
Crop
                               Dried Bean, seed
                                Dried Pea, seed
                                   Pea, Hay
                                  Pea, Vines
Region/Country
                                      USA
                                      USA
                                      USA
                                      USA
GAP
                                 0.46 lb ai/A
                                4@0.115 lb ai/A
                                  14-day RTI
                                  14-day PHI
                                 0.46 lb ai/A
                                4@0.115 lb ai/A
                                  14-day RTI
                                  14-day PHI
                                 0.23 lb ai/A
                                2@0.115 lb ai/A
                                  14-day RTI
                                   0-day PHI
                                 0.23 lb ai/A
                                2@0.115 lb ai/A
                                  14-day RTI
                                  0-day PHI 
Total number of data (n)
                                      11
                                       5
                                       5
                                       5
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
Percentage of censored data
                                      45%
                                      20%
                                      0%
                                      0%
Number of non-censored data
                                       6
                                       4
                                       5
                                       5
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
Lowest residue
                                     0.010
                                     0.010
                                     4.430
                                     1.490
Highest residue
                                     0.031
                                     0.089
                                    17.100
                                     4.850
Median residue
                                     0.010
                                     0.028
                                     9.930
                                     3.690
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
Mean
                                     0.014
                                     0.034
                                    10.672
                                     3.468
Standard deviation (SD)
                                     0.008
                                     0.032
                                     4.631
                                     1.304
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
Correction factor for censoring (CF)
                                     0.697
                                     0.867
                                     1.000
                                     1.000
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
Highest residue
                                     0.031
                                     0.089
                                    17.100
                                     4.850
Mean + 4 SD
                                     0.046
                                     0.162
                                    29.197
                                     8.683
CF x 3 mean
                                     0.030
                                     0.089
                                    32.016
                                    10.404
Unrounded MRL
                                     0.046
                                     0.162
                                    32.016
                                    10.404
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                  Rounded MRL
                                     0.05
                                      0.2
                                      40
                                      10

 
High uncertainty of MRL estimate due to small dataset.
High uncertainty of MRL estimate due to small dataset.
High uncertainty of MRL estimate due to small dataset.

Residues (mg/kg)
Residues (mg/kg)
Residues (mg/kg)
Residues (mg/kg)
                                       
                                     0.030
                                       
                                     0.015
                                       
                                     9.930
                                       
                                     4.310
                                       
                                       
                                     0.013
                                       
                                     0.089
                                       
                                     4.430
                                       
                                     3.690
                                       
                                       
                                     0.010
                                       
                                     0.029
                                       
                                    12.500
                                       
                                     3.000
                                       
                                       
                                     0.010
                                       *
                                     0.010
                                       *
                                     9.400
                                       
                                     1.490
                                       
                                       
                                     0.012
                                       
                                     0.028
                                       
                                    17.100
                                       
                                     4.850
                                       
                                       
                                     0.010
                                       *
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                     0.010
                                       *
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                     0.011
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                     0.031
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                     0.01
                                       *
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                     0.01
                                       *
                                       
                                       
                                       
                                       
                                       
                                       
Bushberry subgroup 13-07B

The dataset used to establish the tolerance for residues of difenoconazole in/on bushberry subgroup 13-07B consisted of blueberry field trial data representing four foliar applications of an EC formulation of difenoconazole at 0.115 lb ai/A/application and a 7-day RTI and a 1-day PHI.
An analysis of the field trials found that two of the eleven trials submitted (NAFTA Growing Region 1; Trials T162 and T163 conducted in PE, Canada) were not independent field trials being less than 20 miles apart and reflecting the same variety and application timing resulting in substantially similar residue levels.  Hence, only the trial with the higher residue of difenoconazole (T162) was used to calculate the tolerance for residues of difenoconazole in/on bushberry subgroup 13-07B.

The residue values which were used to calculate the tolerance are provided below in Table II-2.  Using the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures, the recommended tolerance is 4.0 ppm in/on bushberry subgroup 13-07B (Figure II-2).  The recommended tolerance is not the same as the petitioned-for tolerance (3.0 ppm) due to the independent field trial determination.

Table II-2.	Residue data used to calculate tolerance for difenoconazole in/on bushberry subgroup 13-07B.
Regulator:
EPA
Chemical:
Difenoconazole
Crop:
Blueberry
PHI:
1-day 
App. Rate:
4 x 0.115 lb ai/A/application; 7-day RTI.
Submitter:
Syngenta
MRID Citation:
MRID 49227602

Figure II-2.	Tolerance spreadsheet summary of difenoconazole magnitude of the residue data for 					bushberries.
                                   Compound
                                Difenoconazole
                                     Crop
                                   Blueberry
                                Region/Country
                                   USA/PMRA
                                      GAP
                                 0.46 lb ai/A
                                4@0.115 lb ai/A
                                   7-day RTI
                                   1-day PHI

 
                                       
                           Total number of data (n)
                                      10
                                       
                                       
                                       
                          Percentage of censored data
                                      0%
                          Number of non-censored data
                                      10
                                       
                                       
                                       
                                Lowest residue
                                     0.330
                                Highest residue
                                     1.900
                                Median residue
                                     0.920
                                       
                                       
                                       
                                     Mean
                                     1.009
                            Standard Deviation (SD)
                                     0.534
                                       
                                       
                                       
                     Correction factor for censoring (CF)
                                     1.000
                                       
                                       
                                       

 
                                       
                                       
                                       
                                       
                                Highest residue
                                     1.900
                                  Mean + 4 SD
                                     3.144
                                  CF x 3 Mean
                                     3.027
                                 Unrounded MRL
                                     3.144
                                       
                                       
                                       
                                  Rounded MRL
                                       4

 
                                       

Residues (mg/kg)
                                       
                                   1.200[1]
                                       
                                       
                                     1.400
                                       
                                       
                                     1.900
                                       
                                       
                                     0.840
                                       
                                       
                                     1.000
                                       
                                       
                                     0.650
                                       
                                       
                                     0.400
                                       
                                       
                                     0.670
                                       
                                       
                                     0.330
                                       
                                       
                                     1.700
                                       
1  Average Residue from Trial T162.  An analysis of the field trials found that two of the eleven trials submitted (NAFTA Growing Region 1; Trials T162 and T163 conducted in PE, Canada) were not independent field trials being less than 20 miles apart and reflecting the same variety and application timing resulting in substantially similar residue levels.  Hence, only the trial with the higher residue of difenoconazole (T162) was used to calculate the tolerance for residues of difenoconazole in/on bushberry subgroup 13-07B.