
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460




	OFFICE OF CHEMICAL SAFETY 
	AND POLLUTION PREVENTION


MEMORANDUM

Date:		14-April-2011

Subject:	Tetraconazole.  Residue Chemistry Summary for Application of Tetraconazole to Field Corn, Popcorn, Small Fruit Vine Climbing (Except Fuzzy Kiwifruit) Subgroup 13-07F, and Low-growing Berry Subgroup 13-07G (except cranberry).  

PC Code:  120603
DP Barcode:  D382300
Decision No.:  435873
Registration Nos.:  80289-7 and 80289-8
Petition Nos.:  0E7735 (13-07F and 03-07G) and 0F7737 (field corn and popcorn)
Regulatory Action:  Section 3
Risk Assessment Type:  not applicable
Case No.:  7043
TXR No.:  not applicable
CAS No.:  112281-77-3
MRID Nos.:  48131301, 48135102, 48135103, 48135104, 48135105, and 48135106 
40 CFR:  180.557 

From:		Tom Bloem, Chemist
         Risk Assessment Branch 1, Health Effects Division (RAB1/HED); 7509P

Through:	George F. Kramer, Ph.D., Senior Chemist
         RAB1/HED (7509P)

To:			Mary Waller/Lisa Jones (RM 21)
			Barbara Madden (RM 05)
         Registration Division (7505P) 

The subsequent text references the "free triazole metabolites" and the "non-free-triazole metabolites."  These terms refer to the following compounds:  free triazole metabolites - 1,2,4-triazole (T; PC Code 600074), triazolyl alanine (TA; PC Code 600011), triazolyl acetic acid (TAA; PC Code 600082), triazolyl hydroxypropionic acid (THP), and/or all labile conjugates of these compounds and non-free-triazole metabolites - tetraconazole metabolites of concern for risk assessment other than T, TA, TAA, THP and/or all labile conjugates of these compounds.  
EXECUTIVE SUMMARY

Background:  Tetraconazole (1-[2-(2,4-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethoxy)propyl]-1H-1,2,4-triazole) is a systemic fungicide and is a member of the conazole/triazole class of pesticides.  Tetraconazole acts by inhibiting the metabolic pathway leading to fungal sterol production (sterol-demethylation inhibitor (DMI)) and is currently registered for application to sugar beets, grapes, peanuts, pecans, and soybeans with tolerances ranging from 0.03-1.0 ppm (40 CFR 180.557).  Tolerances as a result of secondary residues are also established in/on hog, poultry, and ruminant commodities at 0.01-0.25 ppm.  

The Interregional Research Project No. 4 (IR-4; Princeton, NJ) proposed a Section 3 Registration (PP# 0E7735) for application of tetraconazole to the small fruit vine climbing (except fuzzy kiwifruit) subgroup 13-07F and low-growing berry subgroup 13-07G (except cranberry) and Isagro (Morrisville, NC) proposed a Section 3 Registration (PP# 0F7737) for application of tetraconazole to field corn and popcorn.  In conjunction with these requests, the following tolerances for residues of tetraconazole per se were proposed (180.557(a)):  small fruit vine climbing, except fuzzy kiwifruit subgroup 13-07F - 0.20 ppm; low-growing berry subgroup 13-07G, except cranberry - 0.25 ppm; corn field, forage - 1.0 ppm; corn field, grain - 0.01 ppm; corn field, stover - 1.5 ppm; corn pop, grain - 0.01 ppm; and corn pop, stover - 1.5 ppm.  IR-4 also requested the removal of the currently-established 0.20 ppm grape tolerance. 

IR-4 initially requested a Section 3 Registration for application to the low-growing berry subgroup 13-07G.  Since it was evident that residues in water from the cranberry use would alone result in dietary exposures greater than HED's level of concern, IR-4  submitted a letter and revised Section F withdrawing the request for a tolerance on cranberry as part of the 13-07G subgroup.  A revised Section B was not submitted.

Directions for Use:  IR-4 proposed application of Mettle 125ME Fungicide (microemulsion formulation; 1 lb ai/gallon; EPA Reg. No. 80289-8) to the small fruit vine climbing (except fuzzy kiwifruit) subgroup 13-07F and the low-growing berry subgroup 13-07G for control of powdery mildew, black rot, anthracnose, leaf spot, leaf blight, and/or Oidium spp.  Isagrow proposed application of Domark(R)230ME Fungicide (1.9 lb ai/gallon; EPA Reg. No. 80289-7) to popcorn and field corn (including field corn grown for seed) for control of ray leaf spot, rust (common and southern), anthracnose leaf blight, eye spot, northern/southern corn leaf blight, northern corn leaf spot, physoderma brown spot, and yellow leaf blight.  Table 3 is a summary of the proposed application scenarios.  

As indicated above, a revised Section B with the cranberry instructions removed is requested.  In addition, since the grape and strawberry field trial data did not include an adjuvant with the spray solution, HED requests that the revised Section B also prohibit the additional of adjuvant to the spray solutions for application to crops in subgroups 13-07F and 13-07G. 

Nature of the Residue - Plants:  The HED Metabolism Assessment Review Committee (MARC) reviewed the sugar beet (triazole ring labeled study), grape (triazole and phenyl ring labeled studies), and wheat (triazole and phenyl ring labeled studies) metabolism studies (D264157, W. Donovan, 19-Apr-2000).  The MARC tentatively concluded that the residue of concern in banana, peanut, and sugar beet was tetraconazole per se.  This decision was not finalized due to uncertainty concerning the toxicity of the free triazole metabolites, incomplete identification of residues in wheat straw, and the lack of a phenyl-labeled sugar beet metabolism study.  HED has subsequently determined that the free triazole metabolites are of toxicological concern (TXR No. 0052011) and received/reviewed the requested metabolism studies.  Since the MARC was disbanded prior to the submission/review of the requested data and prior to the submission of the triazole-labeled soybean metabolism study, a final conclusion pertaining to the residues of concern in plants was not made by the MARC.  

Based on the tentative conclusions made by the MARC, the results of the metabolism studies, and toxicological considerations, HED concludes that the residue of concern for tolerance enforcement in all crops is tetraconazole per se and the residues of concern for risk assessment are as follows:  (1) shelled pea and bean (succulent and dried):  tetraconazole and T, TA, TAA, and all labile conjugates of these compounds and (2) all remaining crops:  tetraconazole, M14360-alcohol (free and conjugated), M14360-acid, M14360-DFA, M14360-hydroxydetriazolyl-O-malonyldiglucoside, and T, TA, TAA and all labile conjugates of these compounds.  HED notes that Syngenta developed a common moiety method for propiconazole which employs base hydrolysis followed by oxidation and that a similar method would be appropriate for determination of the tetraconazole non-free-triazole metabolites (non-free-triazole metabolites hydrolyzed/oxidized to 2,4-dichlorobenzoic acid).  For a full discussion pertaining to the residues of concern in plants see the HED risk assessment document D321751 (M. Clock-Rust et al., 26-Jan-2007).

Nature of the Residue - Livestock:  The MARC reviewed the goat metabolism studies and tentatively determined that the residues of concern in livestock were tetraconazole and T (D264157, W. Donovan, 19-Apr-2000).  This decision was not finalized due to uncertainty concerning the toxicity of T and due to the lack of a poultry metabolism study.  HED has subsequently determined that the free triazole metabolites are of toxicological concern (TXR No. 0052011) and received/reviewed a poultry metabolism study (D282558, W. Donovan, 17-May-2002).  Since the MARC was disbanded prior to the submission and/or review of these data, a final conclusion pertaining to the residues of concern in livestock was not made by the MARC.  

Based on the tentative conclusions made by the MARC, the results of the metabolism studies, and toxicological considerations, HED concludes that the residue of concern in livestock for tolerance enforcement is tetraconazole per se and the residues of concern for risk assessment are tetraconazole, M14360-alcohol (free and conjugated), M14360-acid, M14360-DFA, M14360(C-1)-alcohol (free and conjugated), M14360-hydroxydetriazolyl-O-malonyldiglucoside, and T, TA, THP, and TAA and all labile conjugates of these compounds.  HED included as residues of concern the free triazole metabolites (excluding T) and non-free-triazole metabolites as these were identified as significant residues in plants; T was included as it was a significant metabolite in the livestock and plant metabolism studies.  For a full discussion pertaining to the residues of concern in livestock see the HED risk assessment document D321751 (M. Clock-Rust et al., 26-Jan-2007).

Magnitude of the Residue - Proposed Primary Crops:  Adequate grape (representative crop for 13-07F subgroup), strawberry (representative crop for 13-07G subgroup), and field corn magnitude of the residue data were submitted.  The field trials were geographically distributed as suggested in Table 5 of 860.1500, were conducted with the proposed formulation, and employed the proposed application scenario.  Adequate grape and field corn processing studies were also submitted and these studies indicate that separate tolerances in/on the grape and field corn processed commodities are unnecessary.  Provided a revised Section B is submitted which eliminates the cranberry application instructions and prohibits the addition of adjuvants to the spray solutions for 13-07F and 13-07G crops, HED concludes that the following tolerances for residues of tetraconazole per se are appropriate (the currently established grape tolerance should be deleted; revised Section F is requested):  small fruit vine climbing (except fuzzy kiwifruit) subgroup 13-07F - 0.20 ppm; low-growing berry subgroup 13-07G (except cranberry) - 0.25 ppm; is appropriate; ): corn, field, grain - 0.01 ppm; corn, field, forage - 1.1 ppm; corn, field, stover - 1.7 ppm; corn, pop - 0.01 ppm; and corn, pop, stover - 1.7 ppm.  The following storage stability data are needed to validate the magnitude of the residue data:  T, TA, and TAA in strawberry (516 days); tetraconazole in corn grain, forage, and stover (266 days; grain data will be translated to all processed commodities excluding refined oil); T in corn forage and stover (263 days); and tetraconazole, T, TA, and TAA in refined corn oil (198 days).

Magnitude of the Residue - Livestock:  Tolerances for residues of tetraconazole per se are currently established in/on ruminant (cattle, goat, horse, and sheep) fat (0.02 ppm), liver (0.20 ppm), meat (0.01 ppm), and meat byproducts (except liver; 0.01 ppm) and milk (0.01 ppm) and milk fat (0.25 ppm).  Tolerances are also established in/on hog fat (0.01 ppm), hog liver (0.05 ppm), and hog meat (0.01 ppm) and in/on poultry fat (0.05 ppm), meat (0.01 ppm), meat byproducts (0.01 ppm), and egg (0.02 ppm).  Based on the residues in/on the proposed/registered crops, the livestock maximum reasonably balanced dietary burdens (MRBDBs) are as follows:  beef cattle - 0.519 ppm, dairy cattle - 1.292 ppm, hog - 0.035 ppm, and poultry - 0.050 ppm.  Based on the MRBDBs and the previously submitted and reviewed dairy cattle (D254411, W. Donovan, 18-May-2000) and poultry (46614307.der.doc; D329379, T. Bloem, 23-Jan-2007) feeding studies, HED concludes that the following tolerances are appropriate (the currently established hog, egg, poultry meat and fat, and ruminant meat tolerances remain appropriate; a revised Section F is requested):  milk - 0.03 ppm; milk, fat - 0.75 ppm; fat (cattle, goat, horse, and sheep) - 0.15 ppm; liver (cattle, goat, horse, and sheep) - 1.5 ppm; meat byproducts (except liver; cattle, goat, hog, horse, and sheep) - 0.15 ppm; and poultry, meat byproducts - 0.05 ppm (currently established hog, ruminant meat, and poultry meat and fat tolerances remain appropriate).  

Nature/Magnitude of the Residue - Rotational Crops:  Based on the results of the confined rotational crop studies and toxicological considerations, HED concluded that the residue of concern in rotational crops for tolerance enforcement is tetraconazole per se and the residues of concern for risk assessment are tetraconazole, M14360-acid, M14360-DFA, M14360(C-1)-alcohol (free and conjugated), and TA, THP, and TAA and all labile conjugates of these compounds (for a full discussion see D331476, M. Clock-Rust et al., 26-Jan-2007).  The petitioner previously submitted data concerning the magnitude of tetraconazole per se residues in rotational crops and these data, as well as HED's conclusions concerning the magnitude of tetraconazole per se residues in rotational crops following treatment at the proposed rates, are summarized below.  

The field rotational crop studies resulted in tetraconazole per se residues of <0.02 ppm in all studied rotational crops (wheat grain, pea, potato, canola seed, sugar beet (top and root)), excluding wheat straw, planted 7-9 days after a bare soil application at 1.4-17x the proposed seasonal rates (D278236, W. Donovan, 22-Oct-2001).  Residues of tetraconazole per se were <0.02-0.05 ppm in wheat straw when planted in fields treated at 4.2-17x.  Based on these data, the proposed plant-back intervals, and proposed application rates, HED concludes that residues of tetraconazole per se in rotational crops planted in fields treated at the proposed rate will be insignificant.  

Analytical Methods:  Adequate analytical methods are available to enforce the currently established tetraconazole per se plant and livestock tolerances (D280006, W. Donovan, 10-Jan-2002, D267481, 12-Oct-2000; D278236, W. Donovan, 22-Oct-2001).  As part of the corn petition, Isagro submitted adequate method validation and independent laboratory validation (ILV) data which indicates that the QuEChERS multi-residue method L 00.00-115 (48135104.der.docx) is capable of quantifying tetraconazole residues in/on a variety of fruit, cereal grain, root, oilseed, and livestock commodities (note that mean recoveries in/on wheat straw were 50-70%;).  Based on these data and since the extraction solvent employed in the QuEChERS method (acetonitrile) is similar to the extraction solvent employed in the radiovalidated enforcement methods (acetone), HED concludes that the QuEChERS method is adequate for enforcement of the tolerances recommended in the current document and forwarded the method to the Food and Drug Administration (FDA; D386650, T. Bloem, 14-Apr-2011)

Multiresidue Methods (MRMs) Testing:  HED has previously reviewed information concerning the MRMs testing of tetraconazole and forwarded these data to the FDA (D278236, W. Donovan, 22-Oct-2001; D332231, T. Bloem, 13-Sep-2006).  Tetraconazole was not recovered through the MRM Protocols.  

Recommendation:  IR-4 proposed a Section 3 Registration (PP# 0E7735) for application of tetraconazole to the small fruit vine climbing (except fuzzy kiwifruit) subgroup 13-07F and low-growing berry subgroup 13-07G (except cranberry) and Isagro proposed a Section 3 Registration (PP# 0F7737) for application of tetraconazole to field corn and popcorn.  The following are HED recommendations for each of these petitions.  A human-health risk assessment will be prepared as a separate document.

PP# 0E7735 (subgroups 13-07F and 13-07G (except cranberry)):  Provided revised Sections B and F are submitted, HED concludes that the residue chemistry database supports a conditional registration for application of the proposed tetraconazole formulation to the small fruit vine climbing (except fuzzy kiwifruit) subgroup 13-07F and low-growing berry subgroup 13-07G (except cranberry).  HED recommends that the following permanent tolerances for residues of tetraconazole per se be established as a result of this registration (currently established grape tolerance should be removed):  small fruit vine climbing (except fuzzy kiwifruit) subgroup 13-07F - 0.20 ppm and low-growing berry subgroup 13-07G (except cranberry) - 0.25 ppm.  The residue chemistry database may support an unconditional registration upon submission of storage stability data demonstrating the stability of T, TA, and TAA residues in/on strawberry (516 days).  

PP# 0F7737 (field corn and popcorn):  Provided a revised Section F is submitted, HED concludes that the residue chemistry database supports a conditional registration for application of the proposed tetraconazole formulation to field corn and popcorn.  HED recommends that the following permanent tolerances for residues of tetraconazole per se be established as a result of this registration:  corn, field, grain - 0.01 ppm; corn, field, forage - 1.1 ppm; corn, field, stover - 1.7 ppm; corn, pop - 0.01 ppm; corn, pop, stover - 1.7 ppm; milk - 0.03 ppm; milk, fat - 0.75 ppm; fat (cattle, goat, horse, and sheep) - 0.15 ppm; liver (cattle, goat, horse, and sheep) - 1.5 ppm; meat byproducts (except liver; cattle, goat, hog, horse, and sheep) - 0.15 ppm; poultry, meat byproducts - 0.05 ppm.  The residue chemistry database may support an unconditional registration upon submission of the following storage stability data:  tetraconazole in corn grain, forage, and stover (266 days); T in corn forage and stover (263 days); and tetraconazole, T, TA, and TAA in refined corn oil (198 days).  HED notes that MRID 47606601, which presents information concerning the stability of T, TA, and TAA in several matrices, has been submitted to the Agency but has not yet been reviewed.  Provided these data demonstrate the stability of T, TA, and TAA in the above matrices, no additional information will be required for these analytes.  

HED also recommends that the tetraconazole tolerance expression be changed to the following (40 CFR 180.557(a)):  

   180.557(a):  Tolerances are established for residues of tetraconazole, including its metabolites and degradates, in or on the commodities listed below.  Compliance with the following tolerance levels is to be determined by measuring only tetraconazole (1-[2-(2,4-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethoxy)propyl]-1H-1,2,4-triazole).
DETAILED CONSIDERATIONS

Background

Tetraconazole is a systemic fungicide and is a member of the conazole/triazole class of pesticides. Tetraconazole acts by inhibiting the metabolic pathway leading to fungal sterol production (sterol DMI). 

Table 1:  Test Compound Nomenclature.
Chemical Structure
                                       
Common name
Tetraconazole
Company experimental name
None Specified in Submission
IUPAC name
(+-)-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propyl-1,1,2,2-tetrafluoroethyl ether
CAS name
1-[2-(2,4-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethoxy) propyl]-1H-1,2,4-triazole
CAS #
112281-77-3

Table 2:  Physicochemical Properties of the Technical Grade Tetraconazole.
Melting point/range
Not applicable - test is a viscous liquid 
MRID 44268104; D259842, B. Kitchens, 11-Apr-2000.
pH
5.48 in DI H2O; 5.47 for saturated solution at 20°C

Density
1.4382 g/ml at 20°C
1.4252 g/ml at 30°C 

Water solubility (PAI >94.16%)
159.31 mg/L at 25°C

Solvent solubility
                                 not available
Vapor pressure (PAI >99.65%)
0.13 x 10[2] Pa at 35.5°C; 0.58 x 10[2] Pa at 46.5°C; 2.985 x 10[2] Pa at 60°C
MRID 44305301; D259842, B. Kitchens, 11-Apr-2000.
Dissociation constant (Ka)
0.158 - 0.316
MRID 46055603; D294198, B. Kitchens, 26-Jan-2004.
Octanol/water partition coefficient (PAI >99.65%)
log Pow = 3.53 at 25°C
MRID 44305301; D259842, B. Kitchens, 11-Apr-2000.
UV/visible absorption spectrum
                                 not available

OPPTS GLN 860.1200  Directions for Use

IR-4 proposed application of Mettle 125ME Fungicide (ME; 1 lb ai/gallon; EPA Reg. No. 80289-8) to the small fruit vine climbing (except fuzzy kiwifruit) subgroup 13-07F and the low-growing berry subgroup 13-07G for control of powdery mildew, black rot, anthracnose, leaf spot, leaf blight, and/or Oidium spp.  Isagrow proposed application of Domark(R)230ME Fungicide (ME; 1.9 lb ai/gallon; EPA Reg. No. 80289-7) to popcorn and field corn (including field corn grown for seed) for control of ray leaf spot, rust (common and southern), anthracnose leaf blight, eye spot, northern/southern corn leaf blight, northern corn leaf spot, physoderma brown spot, and yellow leaf blight.  Table 3 is a summary of the proposed application scenarios.  

IR-4 initially requested a Section 3 Registration for application to the low-growing berry subgroup 13-07G.  Since it was evident that residues in water from the cranberry use would alone result in dietary exposures greater than HED's level of concern, IR-4  submitted a letter and revised Section F withdrawing the request for a tolerance on cranberry as part of the 13-07G subgroup.  A revised Section B was not submitted.  Therefore, HED requests a revised section B with the cranberry application instructions removed.  In addition, since the grape and strawberry field trial data did not include an adjuvant with the spray solution, HED requests that the revised Section B also prohibit the additional of an adjuvant to the 13-07F and 13-07G spray solutions.

Table 3:  Proposed Application Scenarios.
                                  Formulation
                                  Single Rate
                                 (lb ai/acre)
                                 Seasonal Rate
                                 (lb ai/acre)
                                   No. Apps
                                 RTI[1] (days)
                                 PHI[1] (days)
                                   Comments
small fruit vine climbing (except fuzzy kiwifruit) subgroup 13-07F (grape, gooseberry, Amur river grape, 
hardy kiwifruit, maypop, schisandra berry, and cultivars, varieties, and/or hybrids of these)
Mettle 125 ME Fungicide (EPA Reg. No. 80289-8; 1 lb ai/gallon
                                  0.023-0.039
                                     0.08
                                       2
                                      14
                                      14
-Ground (sufficient volume for through coverage), aerial (>=10 GPA), and chemigation applications are permitted.
-Do not apply more than 0.08 lb ai/acre/season. 
-The label indicates the following rotational crop restrictions: registered/proposed crops may be planted 0 days after the last application; all other crops may be planted 15 days after the last application.  
low-growing berry subgroup 13-07G (strawberry, lowbush blueberry, bearberry, bilberry, cloudberry, 
cranberry, lingonberry, muntries, partridgeberry, and cultivars, varieties, and/or hybrids of these)
Mettle 125 ME Fungicide (EPA Reg. No. 80289-8; 1 lb ai/gallon
                                  0.023-0.039
                                     0.16
                                       4
                                      14
                                       0
-Ground (sufficient volume for through coverage), aerial (>=10 GPA), and chemigation applications are permitted.
-Do not apply more than 0.16 lb ai/acre/season. 
-The label indicates the following rotational crop restrictions: registered/proposed crops may be planted 0 days after the last application; all other crops may be planted 15 days after the last application.  
         popcorn and field corn (including field corn grown for seed)
Domark(R)230ME Fungicide (EPA Reg. No. 80289-7; 1.9 lb ai/gallon)
                                  0.045-0.090
                                     0.09
                                       2
                                       7
                                 not specified
-Do not apply after corn growth stage R3 (brown silk/milk).
- Ground (sufficient volume for through coverage), aerial (>=2 GPA), and chemigation applications are permitted.
-The label indicates the following rotational crop restrictions: registered/proposed crops may be planted 0 days after the last application; sugarcane and small grains (barley, buckwheat, millet, oats, rice, rye, triticale, and wheat) - 45 days after the last application; and all other crops - 120 days after the last application.  
[1]  PHI = preharvest interval; RTI = retreatment interval.

 OPPTS GLN 860.1300  Nature of the Residue  - Plants/Livestock
 
 See Executive Summary.  
 
 OPPTS GLN 860.1340  Residue Analytical Method
 48135102.der1.docx (field corn field trial); 48135102.der2.docx (field corn processing); 48131301.der.docx (strawberry); 
 48135104.der.docx (QuEChERS method)

Enforcement Method:  Adequate analytical methods are available to enforce the currently established tetraconazole per se plant and livestock tolerances (D280006, W. Donovan, 10-Jan-2002, D267481, 12-Oct-2000; D278236, W. Donovan, 22-Oct-2001).  As part of the corn petition, Isagro submitted adequate method validation and ILV data which indicates that the QuEChERS multi-residue method L 00.00-115 (48135104.der.docx) is capable of quantifying tetraconazole residues in/on a variety of fruit, cereal grain, root, oilseed, and livestock commodities (note that mean recoveries in/on wheat straw were 50-70%;).  Since the extraction solvent employed in the QuEChERS method (acetonitrile) is similar to the extraction solvent employed in the radiovalidated enforcement methods (acetone), HED concludes that the radiovalidation of the QuEChERS method is unnecessary.  HED concludes that the QuEChERS method is adequate for enforcement of the tolerances recommended in the current document.  Since the ILV study indicated that slight modifications to the QuEChERS method was necessary for quantification of tetraconazole, the ILV study was forwarded to the FDA (D386650, T. Bloem, 14-Apr-2011).    
Analytical Methods Employed in the Field Trial and Processing Studies:  The grape, strawberry, and field corn samples from the magnitude of the residues studies were analyzed for residues of tetraconazole, T, TA, and TAA using adequately validated methods (see below for summaries of these methods).  Based on the LLMV, the LOQ was 0.05 ppm for tetraconazole in/on strawberry, 0.01 ppm for T, TA, and TAA in/on strawberry, and 0.01 ppm for tetraconazole, T, TA, and TAA in/on all field corn and grape matrices.  The method employed for determination of tetraconazole per se in strawberry, grape, and field corn commodities used the same or a sufficiently similar solvent as the current radiovalidated enforcement method (D280006, W. Donovan, 10-Jan-2002).  The method used for determination of T, TA, and TAA is identical to method previously determined to be acceptable (D329379, T. Bloem, 23-Jan-2007).  HED concludes that these methods are appropriate for data-collection purposes.  

Tetraconazole - Strawberry:  The homogenized samples were extracted with acetone and filtered.  After rinsing the flask and filter cake with acetone, the acetone in the filtrate was rotary evaporated to obtain an aqueous extract.  The aqueous extract was partitioned with dichloromethane/saturated sodium chloride.  The organic phase was filtered through a drying agent and cleaned up using an activated carbon/silica gel column.  The column eluant was rotary evaporated to dryness and the residues were dissolved in ethyl acetate.  Analysis of the extracts was performed using a gas chromatograph/nitrogen-phosphors detector (GC/NPD). 

Tetraconazole  -  Grape RAC and Processed Commodities:  The grape and grape juice samples were extracted by homogenizing with acetone and the raisin samples were extracted by homogenizing with acetone:water (7:3).  The samples were centrifuged, concentrated to dryness, reconstituted in methanol:water:formic acid (65:35:0.1), and analyzed via liquid chromatography/mass spectrometer/mass spectrometer (LC/MS/MS).  

Tetraconazole - QuEChERS Method used for Field Corn RAC and Processed Commodities Excluding Corn Oil:  The homogenized samples were shaken and centrifuged with acetonitrile containing anhydrous magnesium sulfate, sodium chloride, sodium citrate tribasic dehydrate, and sodium citrate dibasic sesquihydrate.  The extracts were purified through a column containing anhydrous magnesium sulfate, primary secondary amines (PSA), and carbon and analyzed for tetraconazole using LC/MS.

Tetraconazole - Modified QuEChERS Method used for Field Corn Oil - Tetraconazole:  Corn oil samples were extracted with acetonitrile saturated with n-hexane and then purified through a column containing anhydrous magnesium sulfate, PSA, carbon, and C18 and analyzed for tetraconazole using LC/MS.

T, TA, and TAA - Field Corn (all RACs) and Strawberry (Pyxant Method 1572.02):  The homogenized samples were extracted with methanol/water (80:20, v/v) followed by derivatization with 3N HCl in n-butanol solution and subsequent derivatization with heptafluorobutyric anhydride for TA and TAA and dansyl chloride for T.  The derivatized extracts were analyzed for metabolites T, TA, and TAA using LC/MS/MS.

OPPTS 860.1360  -  MRM

HED has previously reviewed information concerning the MRMs testing of tetraconazole and forwarded these data to FDA (D278236, W. Donovan, 22-Oct-2001; D332231, T. Bloem, 13-Sep-2006).  Tetraconazole was not recovered through the MRM Protocols.  

OPPTS GLN 860.1380 - Storage Stability Data
 48135102.der1.docx (field corn field trial); 48135102.der2.docx (field corn processing); 48131301.der.docx (strawberry); 47270101.der.doc (grape)
 
Samples from the field trial and processing studies submitted in support of the current petition were frozen upon collection and remained frozen until analysis.  Table 4 is a summary of the storage intervals from collection to analysis and the available data validating these intervals.  The following storage stability data are needed to validate the relevant residue data:  T, TA, and TAA in strawberry (516 days); tetraconazole in corn grain, forage, and stover (266 days; grain data will be translated to all processed commodities excluding refined oil); T in corn forage and stover (263 days); and tetraconazole, T, TA, and TAA in refined corn oil (198 days).  HED notes that MRID 47606601, which presents information concerning the stability of T, TA, and TAA in several matrices, has been submitted to the Agency but has not yet been reviewed.  Provided these data demonstrate the stability of T, TA, and TAA in the above matrices, no additional information will be required for these analytes.  

Table 4:  Summary of Storage Conditions/Intervals and Available Data validating these Conditions Intervals.  
                                    Matrix
                                    Analyte
                                 Storage Temp.
                            Actual Storage Duration
                  Interval of Demonstrated Storage Stability
strawberry
                                 tetraconazole
                                    frozen
                                  <=203 days
245 days in/on strawberry; 48131301.der.docx.

                                  T, TA, TAA
                                       
                                  <=516 days
Not provided.
grape
                                 tetraconazole
                                    frozen
                                  <=236 days
245 days in/on strawberry; 48131301.der.docx.

                                  T, TA, TAA
                                       
                                  <=236 days
12 months in apple (46568301.der).
grape juice and raisin
                                 tetraconazole
                                    frozen
                                64 days (juice)
                               91 days (raisin)
69 days in grape juice and 91 days in raisin; 47435201.der.doc.

                                  T, TA, TAA
                                       
                                       
12 months in apple (46568301.der) and  130 days in apple juice (47090446.der). 
corn forage
                                 tetraconazole
                                    -20°C
                                  <=266 days
Not provided; note that grain storage stability data will be translated to all processed commodities excluding refined oil.  
corn grain and grain  processed commodities (excluding corn oil)
                                       
                                       
                                  <=235 days

corn stover
                                       
                                       
                                  <=229 days

corn grain and grain  processed commodities (excluding corn oil)
                                  T, TA, TAA
                                    -20°C
                                  <=263 days
T  - 12 months in/on wheat grain (D361110, D. Soderberg, 26-Feb-2010).
TA and TAA - 26 months on wheat grain (D361110, D. Soderberg, 26-Feb-2010); 13 months in/on wheat forage and hay; and 13 months in/on corn cob, forage, and straw (D338246, M. Doherty, 28-May-2008; declined ~3% per month in/on wheat straw).

The wheat grain storage stability data was translated to all corn grain commodities excluding refined corn oil.
corn forage and stover
                                       T
                                    -20°C
                                  <=263 days
Not provided.

                                  TA and TAA
                                    -20°C
                                  <=263 days
TA and TAA - 26 months on wheat grain (D361110, D. Soderberg, 26-Feb-2010); 13 months in/on wheat forage and hay; and 13 months in/on corn cob, forage, and straw (D338246, M. Doherty, 28-May-2008; declined ~3% per month in/on wheat straw).
refined corn oil
                         tetraconazole, T, TA, and TAA
                                    -20°C
                                  <=198 days
Not provided.

OPPTS 860.1480 - Meat/Milk/Poultry/Eggs

Tolerances for residues of tetraconazole per se are currently established in/on ruminant (cattle, goat, horse, and sheep) fat (0.02 ppm), liver (0.20 ppm), meat (0.01 ppm), and meat byproducts (except liver; 0.01 ppm) and milk (0.01 ppm) and milk fat (0.25 ppm).  Tolerances are also established in/on hog fat (0.01 ppm), hog liver (0.05 ppm), and hog meat (0.01 ppm) and in/on poultry fat (0.05 ppm), meat (0.01 ppm), meat byproducts (0.01 ppm), and egg (0.02 ppm).  

Table 5 is a summary of the tetraconazole per se MRBDBs calculations for beef cattle (0.519 ppm), dairy cattle (1.292 ppm), hog (0.035 ppm), and poultry (0.050 ppm).  The dietary burdens were calculated using the guidance developed as part of the OPPTS 860.1000 Table 1 Feedstuff Revisions (J. Stokes, HED; June-2008).  Note that the labels prohibit feeding peanut hay and soybean forage/hay to livestock.  The following text is a summary of the magnitude of tetraconazole per se residues in livestock; information concerning the magnitude of the remaining residues of concern can be found in the dietary exposure (D381912, T. Bloem, 14-Apr-2011) and/or risk assessment (D380618, A. Nowotarski et al., in draft) documents.

Ruminants:  A cattle feeding/depuration study depicting residues of tetraconazole per se incurred in dairy cattle milk and tissues following dosing with tetraconazole was previously submitted and reviewed (D254411, W. Donovan, 18-May-2000).  Dairy cows were orally dosed for 28-30 days with tetraconazole at 0.34 ppm, 1.02 ppm, and 3.4 ppm.  These doses are 0.3x, 0.8x, and 2.6x the dairy cattle MRBDB.  Cows were milked twice daily (a.m. and p.m.) and the morning and evening milk collections were composited daily for each cow.  Subsamples of milk collected on Days 14 and 28 were separated into cream and skim milk.  Cattle were sacrificed within 24 hours of the final dose and samples of liver, kidney, fat (pooled perirenal and omental), subcutaneous fat, and skeletal muscle (pooled pectoralis and adductor muscle of the thigh) were collected after sacrifice.  The samples were analyzed for residues of tetraconazole per se using an adequately validated method (storage interval has also been validated).  Residues in milk reached a plateau by the third day of dosing.  Table 6 is a summary of the maximum tetraconazole per se residues in each of the ruminant matrices from the feeding study and the estimated residue based on the dairy cattle MRBDB.  The dairy cattle MRBDB was used for estimation of residues in all ruminant commodities (milk and tissues) as it is higher than that for beef cattle.

Based on the submitted ruminant feeding study and the MRBDB for dairy cattle, HED concludes that the following tolerances for residues of tetraconazole per se in ruminants and milk are appropriate (the currently established ruminant meat tolerances remain appropriate; a revised Section F is requested):  milk - 0.03 ppm; milk, fat - 0.75 ppm; fat (cattle, goat, horse, and sheep) - 0.15 ppm; liver (cattle, goat, horse, and sheep) - 1.5 ppm; meat byproducts (except liver; cattle, goat, hog, horse, and sheep) - 0.15 ppm.  Due to the high residue in liver as compared to the other tissue residues, HED concluded that a separate tolerance on liver and meat byproducts was appropriate.  

Hog:  Based on the hog MRBDB and the cattle feeding study, HED concludes that the currently established hog tolerances remain appropriate.  

Poultry:  A poultry feeding/depuration study depicting residues of tetraconazole per se incurred in eggs and poultry tissues following dosing with tetraconazole was previously submitted and reviewed (46614307.der.doc; D329379, T. Bloem, 23-Jan-2007).  Hens were orally dosed for 40 days with tetraconazole at 0.069 ppm, 0.241 ppm, and 0.714 ppm.  These doses are equivalent to 1.4x, 4.8x, and 14x the poultry MRBDB.  Eggs were collected twice daily throughout the feeding study.  Hens were sacrificed within 16-24 hours of the final dose and samples of liver, kidney, skeletal muscle, abdominal fat, and skin/subcutaneous fat were collected.  The samples were analyzed for residues of tetraconazole per se using an adequately validated method (storage interval has also been validated).  Tetraconazole residues in egg reached a plateau by the tenth day of dosing.  Table 6 is a summary of the maximum tetraconazole residues in each of the poultry matrices from the feeding study and the estimated residue based on the poultry MRBDB.  

HED concludes that the currently established egg, poultry fat, and poultry meat tolerances remain appropriate.  Since the meat byproduct tolerances is based on the highest residue in tissue (muscle, fat, liver, and kidney), HED concludes that the poultry meat byproduct tolerance should be increased to 0.05 ppm.  A revised Section F is requested. 

Table 5:  Livestock MRBDB Calculations.
                                 Commodity[1]
                                   % diet[2]
                                 % dry matter
                        HED-recommended tolerance (ppm)
                               dietary burden[3]
                                  beef cattle
field corn forage (R)
                                      15
                                      40
                                      1.1
                                     0.412
aspirated grain fractions (CC)
                                       5
                                      85
                                      1.0
                                     0.059
sugar beet molasses (CC)
                                      10
                                      75
                                     0.25
                                     0.033
field corn grain (CC)
                                      65
                                      88
                                     0.01
                                     0.007
soybean seed (PC)
                                       5
                                      89
                                     0.15
                                     0.008
total
                                      100
                                      --
                                      --
                                     0.519
                                 dairy cattle
field corn forage (R)
                                      45
                                      40
                                      1.1
                                     1.238
sugar beet molasses (CC)
                                      10
                                      75
                                     0.25
                                     0.033
field corn grain (CC)
                                      35
                                      88
                                     0.01
                                     0.004
soybean seed (PC)
                                      10
                                      89
                                     0.15
                                     0.017
total
                                      100
                                      --
                                      --
                                     1.292
                                    Poultry
field corn grain (CC)
                                      75
                                      --
                                     0.01
                                     0.009
soybean meal (PC)
                                      25
                                      --
                                     0.15
                                     0.041
total
                                      100
                                      --
                                      --
                                     0.050
                                      Hog
field corn grain (CC)
                                      85
                                      --
                                     0.01
                                     0.010
soybean seed (PC)
                                      15
                                      --
                                     0.15
                                     0.025
total
                                      100
                                      --
                                      --
                                     0.035
[1]  R = roughage, CC = carbohydrate concentrate, PC = protein concentrate; label prohibits feeding peanut hay and soybean forage to
livestock. 
[2]  From revised Table 1 (J. Stokes, HED; June-2008).
[3]  Beef/dairy cattle dietary burden = residue x % diet / % dry matter; poultry/swine dietary burden = residue x (% diet / 100).
.

Table 6:  Livestock Residues.
                                    matrix
             max tetraconazole residue from feeding study[1] (ppm)
                     tetraconazole transfer coeffcients[2]
                       estimated residue at 1x MRBDB[3]
                                       
                             lowest dietary burden
                             middle dietary burden
                            highest dietary burden 
                             lowest dietary burden
                             middle dietary burden
                            highest dietary burden
                                       
dairy cattle MRBDB = 1.292 ppm (0.3x, 0.8x, 2.6x); hog MRBDB = 0.035 ppm (10x, 29x, 97x)
milk[4]
                                   <0.003
                                     0.016
                                     0.048
                                      --
                                     0.016
                                     0.014
                                     0.021
skimmed milk
                                   <0.003
                                   <0.003
                                     0.003
                                      --
                                      --
                                    0.0009
                                     0.001
cream
                                     0.023
                                     0.125
                                     0.391
                                     0.068
                                     0.122
                                     0.115
                                     0.158
subcutaneous fat
                                     0.003
                                     0.033
                                     0.205
                                      --
                                     0.032
                                     0.060
                                 beef = 0.041
                                 swine = 0.001
peritoneal fat
                                     0.029
                                     0.069
                                     0.199
                                     0.085
                                     0.068
                                     0.059
                                 beef = 0.110
                                 swine = 0.003
kidney
                                     0.007
                                     0.039
                                     0.067
                                     0.021
                                     0.038
                                     0.020
                                 beef = 0.049
                                 swine = 0.001
liver
                                     0.371
                                     0.662
                                     1.636
                                     1.091
                                     0.649
                                     0.481
                                 beef = 1.410
                                 swine = 0.038
muscle
                                   <0.003
                                     0.006
                                     0.015
                                      --
                                     0.006
                                     0.004
                                 beef = 0.008
                                swine = 0.0002
                 poultry (MRBDB = 0.050 ppm; 1.4x, 4.8x, 14x)
liver
                                     0.011
                                     0.029
                                     0.081
                                     0.159
                                     0.120
                                     0.113
                                     0.008
kidney
                                   <0.01
                                   <0.01
                                     0.049
                                      --
                                      --
                                     0.069
                                     0.003
skeletal muscle
                                   <0.01
                                   <0.01
                                     0.021
                                      --
                                      --
                                     0.029
                                     0.001
abdominal fat
                                     0.045
                                     0.140
                                     0.456
                                     0.652
                                     0.581
                                     0.639
                                     0.033
skin and subcutaneous fat
                                     0.019
                                     0.044
                                     0.181
                                     0.275
                                     0.183
                                     0.253
                                     0.014
egg[5]
                                     0.011
                                     0.034
                                     0.135
                                     0.159
                                     0.141
                                     0.189
                                     0.009
[1]  Ruminant feeding study - D254411, W. Donovan, 18 May-2000 (dietary burdens of 0.34 ppm, 1.02 ppm, and 3.4 ppm); poultry feeding study - 46614307.der.wpd (dietary burdens of 0.069 ppm, 0.241 ppm, and 0.714 ppm).
[2]  Transfer coefficient = tetraconazole residue / dietary burden.
[3]  Residue estimate = dietary burden x transfer coefficient; the highest transfer coefficient derived from a dosing level which resulted in quantifiable residues was used; since the dairy cattle MRBDB is higher than that for beef, it was used to estimate residues in ruminant tissue.
[4]  Residues in milk peaked on the third day of dosing.
[5]  Residues in egg peaked on the tenth day of dosing.

 OPPTS 860.1500 - Crop Field Trials:  
 48135102.der1.docx (field corn); 48131301.der.docx (strawberry); 47270101.der.doc (grape)

The petitioners requested registration for application of Mettle 125ME Fungicide (ME; 1 lb ai/gallon; EPA Reg. No. 80289-8) to the small fruit vine climbing (except fuzzy kiwifruit) subgroup 13-07F and the low-growing berry subgroup 13-07G (except cranberry) and Domark(R)230ME Fungicide (ME; 1.9 lb ai/gallon; EPA Reg. No. 80289-7) to popcorn and field corn (including field corn grown for seed).  Below are HED's conclusions concerning the adequacy of the field trial data submitted in support of these proposals.  HED notes that the submitted field trial studies monitored for residues of tetraconazole, T, TA, and TAA; information concerning the magnitude of the remaining residues of concern can be found in the dietary exposure (D381912, T. Bloem, 14-Apr-2011) and/or risk assessment (D380618, A. Nowotarski et al., in draft) documents.

Small Fruit Vine Climbing (except fuzzy kiwifruit) Subgroup 13-07F:  HED previously approved a petition for application of tetraconazole to grape, the representative crop for the 13-07F subgroup, and recommended for a 0.20 ppm tolerance for residues of tetraconazole per se (D384213, T. Bloem, 13-Jan-2011).  The grape field trials were geographically distributed as suggested in Table 5 of 860.1500, were conducted with the proposed formulation, and employed the proposed application scenario (see below for a summary of these data).  HED notes that the field trials did not include an adjuvant in the spray solution.  Provided a revised Section B is submitted prohibiting the addition of adjuvants to the spray solutions for 13-07F crops, HED concludes that a tolerance of 0.20 ppm for residues of tetraconazole per se in/on the small fruit vine climbing (except fuzzy kiwifruit) subgroup 13-07F is appropriate.  The currently established grape tolerance should be deleted.  A revised Section F is requested,

Low-growing Berry Subgroup 13-07G (except cranberry):  As part of the current submission, IR-4 submitted adequate strawberry field trial data (strawberry is the representative crop for the 13-07G subgroup; see below for summary).  The field trials were geographically distributed as suggested in Table 5 of 860.1500, were conducted with the proposed formulation, and employed the proposed application scenario.  HED notes that the field trials did not include an adjuvant in the spray solution.  The tetraconazole residue data were entered in the tolerance spreadsheet as specified by the Guidance for Setting Pesticide Tolerances Based on Field Trial Data (see attachment 2) with a resulting recommended tolerance of 0.25 ppm.  Provided a revised Section B is submitted prohibiting the addition of adjuvants to the spray solutions for 13-07F crops and with elimination of the application instructions for cranberry (see next paragraph), HED concludes that a tolerance of 0.25 ppm for residues of tetraconazole per se in/on the low-growing berry subgroup 13-07G (except cranberry) is appropriate (T, TA, and TAA storage stability data are required to validate the field trial data; see Section 860.1380).  A revised Section F is requested.

IR-4 initially requested a Section 3 Registration for application to the entire low-growing berry subgroup 13-07G.  Since it was evident that residues in water from the cranberry use would alone result in dietary exposures greater than HED's level of concern, IR-4  submitted a letter and revised Section F withdrawing the request for a tolerance on cranberry as part of the 13-07G subgroup.  A revised Section B was not submitted.  
Field Corn and Popcorn:  As part of the current submission, Isagro submitted field corn field trial data (see below for summary; field corn is an acceptable surrogate for popcorn).  The field trials were geographically distributed as suggested in Table 5 of 860.1500, were conducted with the proposed formulation, and employed the proposed application scenario.  HED notes that the field trials included a nonionic surfactant (NIS) or crop oil concentrate (COC) in the spray solution.  The tetraconazole residue data were entered in the tolerance spreadsheet as specified by the Guidance for Setting Pesticide Tolerances Based on Field Trial Data (see attachment 2); the resulting recommended tolerances are as follows (field corn grain data were not entered as all residues were <LOQ; grain (tetraconazole), stover/forage (tetraconazole and T) storage stability data are required to validate the field trial data; see Section 860.1380):  corn, field, grain - 0.01 ppm; corn, field, forage - 1.1 ppm; corn, field, stover - 1.7 ppm; corn, pop - 0.01 ppm; and corn, pop, stover - 1.7 ppm.  A revised Section F is requested.

The field corn and popcorn label prohibits application after the R3 crop growth stage with no specified PHIs. Since the R3 crop growth stage represents a mid-season application and the field trial data employed application at the R3 crop growth stage (forage, grain, and stover samples were collected at the normal harvest time), HED concludes that proposed label is adequate and PHIs are unnecessary.  

Grape (47270101.der.doc):  Twelve field trials were conducted in North American Free Trade Agreement (NAFTA) Growing Zones 1 (n=2), 10 (n=8), and 11 (n=2).  Each field trial consisted of a single control plot and two treated plot (plots A and B).  Treatment plots A and B received two foliar applications (RTI = 14-16 days) of a ME tetraconazole formulation (1.04 lb ai/gal) at ~0.040 lb ai/acre (1x proposed single/seasonal rate; adjuvants were not added).  Treatment plot A received the first application 43-47 days prior to harvest and samples were harvested 28-32 days after the last application (DALA).  Treatment plot B received the first application 28-32 days prior to harvest and samples were harvested 14-16 DALA (proposed PHI).  At one of the field trial sites, additional samples were harvested from treatment plots A (0, 7, 15, 22, and 37 DALA) and B (0, 5, 10, and 22 DALA).  

The samples were analyzed for residues of tetraconazole, T, TA, and TAA using adequately validated methods (only samples from treatment B plot were analyzed for T, TA, and TAA).  Table 7 is a summary of the residues in/on the treated samples.  The residue decline data indicated that tetraconazole per se residues decreased with increasing PHI (T, TA, and TAA residues were <LOQ at all intervals).  

Strawberry (48131301.der.docx):  Eight field trials were conducted in NAFTA Growing Zones 1 (n=1), 2 (n=1), 3 (n=1), 5 (n=1), 10 (n=3), and 11 (n=1).  In addition, two greenhouse trials were conducted in the United States encompassing NAFTA Growing Zones 6 and 9.  Except for the greenhouse trial conducted in Growing Zone 9, the trials employed four foliar applications of a ME tetraconazole formulation (1.0 lb ai/gal) at 0.0430-0.0463 lb ai/acre (1x proposed single/seasonal rate; adjuvants were not added).  The CO greenhouse trial employed four foliar applications of a ME tetraconazole formulation (1.0 lb ai/gal) at 0.0206-0.0212 lb ai/acre (0.5x proposed single/seasonal rate).  The RTIs were 12-16 days for all except between the third and fourth application at the NY trial which was conducted with a RTI of 8 days due to rapidly maturing strawberries.  Strawberry samples were harvested at 0 and 1 day after the last application.  A decline trial was carried out and samples were also harvested at 4-, 7-, and 14-day PHIs.

The samples were analyzed for residues of tetraconazole, T, TA, and TAA using adequately validated methods.  Table 7 is a summary of the residue data (CO greenhouse trial is not included in the summary).  In the decline trial, maximum residue of tetraconazole was 0.09 ppm at 0 and 1 day, and <0.05 ppm at 4, 7, and 14 days (residues of T, TA, and TAA were <LOQ at all intervals in the residue decline trial).  Tetraconazole, T, TA, and TAA residues were <LOQ in the CO greenhouse trial which employed four applications at 0.0206-0.0212 lb ai/A (PHI = 0 and/or 1 day).  Data demonstrating the stability of T, TA, and TAA residues in/on strawberry (516 days) should be submitted.  

Field Corn (48135102.der1.docx):  Twenty-one field trials were conducted in NAFTA Growing Zones 1 (n=1), 2 (n=1), 4 (n=1), 5 (n=17), and 6 (n=1).  The trials employed a single broadcast application of a ME tetraconazole formulation (1.9 lb ai/gal) at 0.091 lb ai/acre (1x the proposed single/seasonal rate).  All applications included either a COC or a NIS in the spray solution.  Field corn forage, grain, and stover were harvested from each plot at commercial harvest maturity. At three trial sites (MS, IL, and IA), additional samples of forage, grain, and stover were harvested at 7 and 3 days prior to normal harvest, at normal harvest, and at 3 and 7 days after normal harvest to assess residue decline.  

The samples were analyzed for residues of tetraconazole, T, TA, and TAA using adequately validated methods.  Samples from the individual trials were analyzed for T, TA, and TAA excluding the 12 trials conducted in Growing Zone 5 where a composite blended sample was analyzed.  Table 7 is a summary of the residue data.  The tetraconazole residue decline data for field corn forage and stover did not result in a discernable pattern (residues were variable over the sampling interval) while resides in field corn grain were <LOQ at all sampling intervals.  The following storage stability data should be submitted:  tetraconazole in corn grain, forage, and stover (266 days) and T in corn forage and stover (263 days).  HED notes that MRID 47606601, which presents information concerning the stability of T, TA, and TAA in several matrices, has been submitted to the Agency but has not yet been reviewed.  Provided these data demonstrate the stability of T, TA, and TAA in the above matrices, no additional information will be required for these analytes.  

Table 7:  Summary of Residue Data from Crop Field Trials.
                                   Commodity
                                  Total Rate
                                 (lb ai/acre)
                                      PHI
                                    (days)
                            Residue Levels (ppm)[2]
                                       
                                       
                                       
                                       n
                                     Min.
                                     Max.
                                    HAFT[3]
                                    Median
                                     Mean
                                   Std. Dev.
                                 Tetraconazole
Grape[1]
                                plot A - ~0.080
                                     28-31
                                      24
                                   <0.01
                                     0.091
                                     0.056
                                     0.013
                                     0.022
                                     0.019

                                plot B - ~0.080
                                     14-16
                                      24
                                   <0.01
                                     0.096
                                     0.095
                                     0.019
                                     0.031
                                     0.027
Strawberry
                                 0.174 - 0.182
                                       0
                                      18
                                   <0.05
                                     0.21
                                     0.20
                                     0.08
                                     0.091
                                     0.047

                                       
                                       1
                                      18
                                   <0.05
                                     0.18
                                     0.16
                                     0.07
                                     0.086
                                     0.044
Corn forage
                                  0.088-0.094
                                     7-30
                                      42
                                     0.041
                                     0.962
                                     0.907
                                       
                                     0.401
                                      0.2
Corn grain
                                       
                                     48-95
                                      42
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                      --
Corn stover
                                       
                                    56-107
                                      42
                                   <0.01
                                     1.722
                                     1.548
                                       
                                     0.453
                                      0.3
                                       T
Grape
                                plot B - ~0.080
                                      15
                                      24
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
Strawberry
                                 0.174 - 0.182
                                       0
                                       2
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                      --

                                       
                                       1
                                      18
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                      --
Corn forage
                                  0.088-0.094
                                     7-30
                                      42
                                   <0.01
                                     0.019
                                     0.015
                                       
                                     0.010
                                      0.0
Corn grain
                                       
                                     48-95
                                      15
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                      --
Corn stover
                                       
                                    56-107
                                      42
                                   <0.01
                                     0.060
                                     0.035
                                       
                                     0.011
                                      0.0
                                      TA
Grape
                                plot B - ~0.080
                                      15
                                      24
                                   <0.01
                                     0.053
                                     0.051
                                     0.01
                                     0.016
                                     0.012
Strawberry
                                 0.174 - 0.182
                                       0
                                       2
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                      --

                                       
                                       1
                                      18
                                   <0.01
                                     0.041
                                     0.039
                                   <0.01
                                     0.015
                                     0.010
Corn forage
                                  0.088-0.094
                                     7-30
                                      42
                                     0.018
                                     0.286
                                     0.272
                                       
                                     0.083
                                      0.1
Corn grain
                                       
                                     48-95
                                      15
                                     0.075
                                     1.151
                                     1.106
                                       
                                     0.456
                                      0.4
Corn stover
                                       
                                    56-107
                                      42
                                   <0.01
                                     0.663
                                     0.510
                                       
                                     0.075
                                      0.1
                                      TAA
Grape
                                plot B - ~0.080
                                      15
                                      24
                                   <0.01
                                     0.017
                                     0.016
                                     0.01
                                     0.011
                                     0.002
Strawberry
                                 0.174 - 0.182
                                       0
                                       2
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                      --

                                       
                                       1
                                      18
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                      --
Corn forage
                                  0.088-0.094
                                     7-30
                                      42
                                   <0.01
                                     0.025
                                     0.021
                                       
                                     0.013
                                      0.0
Corn grain
                                       
                                     48-95
                                      15
                                   <0.01
                                     0.022
                                     0.022
                                       
                                     0.013
                                      0.0
Corn stover
                                       
                                    56-107
                                      42
                                   <0.01
                                     0.060
                                     0.039
                                       
                                     0.014
                                      0.0
[1]  Plots A and B both received two (RTI = 14-16 days) airblast applications of the 125 g/L tetraconazole formulation (1.04 lb ai/gal; EC) at ~0.04 lb ai/acre (1x).  Plot A received the first application 43-47 days prior to normal harvest while plot B received the first application 28-32 days prior to normal harvest.  Only samples from plot B were analyzed for T, TA, and TAA.
[2]  The median, mean, and standard deviation were calculated assuming LOQ residues for residues <LOQ.  
[3]  HAFT = highest-average field trial.

OPPTS 860.1520 - Processed Food/Feed:  
 47270101.der.doc (grape);  48135102.der2.docx (field corn)

The petitioner previously submitted a grape processing study (47270101.der.doc; D353020, T. Bloem, 26-June-2008) and submitted a field corn processing study as part of the current petition (48135102.der2.docx). The grape study indicated that residues of tetraconazole per se do not concentrate in grape juice or raisin (conducted at 5x seasonal rate).  The corn processing study resulted in tetraconazole per se residues <LOQ in both the RAC and processed commodities (conducted at 5x seasonal rate); therefore, processing factors could not be calculated.  Based on these data, HED concludes that tolerances for the grape and field corn processed commodities are unnecessary.  The grape and field corn processing studies also monitored for residues of T, TA, and TAA and these data, as well as the tetraconazole data, are summarized below.  Information concerning the magnitude of the remaining residues of concern can be found in the dietary exposure (D381912, T. Bloem, 14-Apr-2011) and/or risk assessment (D380618, A. Nowotarski et al., in draft) documents.  Storage stability data are required to validate field corn (tetraconazole, T, TA, and TAA) processing studies (see Section 860.1380).  

HED notes the field corn aspirated grain fraction residue data were not provided.  Residues of tetraconazole and T were <LOQ in/on all the field corn grain samples thereby eliminating the need for aspirated grain fraction residue data for these analytes (see guidance for OPPTS 860.1000 Table 1 Feedstuff Revisions, J. Stokes, June-2008).  However, residues of TA (0.456 ppm) and TAA (0.013 ppm) were found in/on corn grain; HED does have soybean aspirated grain fraction data (2 x 0.09+ lb ai/acre R3-R5 crop stage) which did not demonstrate significant concentration of T, TA, or TAA residues in the aspirated grain fractions.  Since aspirated grain fractions are a minor feed commodity, HED concludes that the soybean aspirated grain fraction T, TA, and TAA residue are an adequate surrogate for field corn.  

Grape (47270101.der.doc):  Two field trials were established during 2006 in NAFTA growing zones 10 and 11.  The treated plots received two applications (RTI = 14-15 days) of a 125 g/L liquid tetraconazole formulation at ~0.200 lb ai/acre (5x).  The first application was made 28-32 days prior to harvest and bulk grape samples were harvested 14-16 days after the last application.  The bulk grape samples (n=2) were processed into grape juice (cold press) and raisin (<14% moisture) using simulated commercial processing procedures.  The resulting samples were analyzed for tetraconazole, T, TA, and TAA residues using adequately validated methods.  Table 8 is a summary of the tetraconazole, T, TA, and TAA processing factors.  

Field Corn (48135102.der2.docx):  Two field trials were established during 2009 in NAFTA growing zones 5 and 6.  The treated plots received a single application of a ME tetraconazole formulation (1.9 lb ai/gal) at 0.452-0.457 lb ai/A (R3 crop stage; 5x).  Field corn grain was harvested at commercial harvest maturity and processed into starch, refined oil (wet and dry milling), grits, flour, and meal using simulated commercial procedures.  The resulting samples were analyzed for residues of tetraconazole, T, TA, and TAA using adequately validated methods.  Table 8 is a summary of the tetraconazole, T, TA, and TAA processing factors.  Data demonstrating the stability of tetraconazole in/on field corn grain (266 days) and refined oil (198 days) and T, TA, and TAA in/on refined field corn oil (198 days) should be submitted.  HED notes that MRID 47606601, which presents information concerning the stability of T, TA, and TAA in several matrices, has been submitted to the Agency but has not yet been reviewed.  Provided these data demonstrate the stability of T, TA, and TAA in the above matrices, no additional information will be required for these analytes.  


Table 8:  Residue Data from Grape and Field Corn Processing Studies.
                                     Crop
                                   Commodity
                                  Total Rate
                                   (lb ai/A)
                                      PHI
                                    (days)
                                Residues (ppm)
                            Processing Factor[1,2]
                                       
                                       
                                       
                                       
                                 Tetraconazole
                                      TA
                                      TAA
                                       T
                                 Tetraconazole
                                      TA
                                      TAA
                                       T
                           Traver, CA; 2006; CA4; 10
Grape
Grape (RAC)
                                     ~0.40
                                      15
                                     0.077
                                   <0.01
                                   <0.01
                                   <0.01
                                      --
                                      --
                                      --
                                      --

Juice
                                       
                                       
                                     0.008
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.01
                                      NC
                                      NC
                                      NC

Raisin
                                       
                                       
                                     0.070
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.91
                                      NC
                                      NC
                                      NC
                          Ephrata, WA; 2006; WA1; 11
Grape 
Grape (RAC)
                                     ~0.40
                                      14
                                     0.579
                                   <0.01
                                   <0.01
                                   <0.01
                                      --
                                      --
                                      --
                                      --

Juice
                                       
                                       
                                     0.035
                                   <0.01
                                   <0.01
                                   <0.01
                                     0.06
                                      NC
                                      NC
                                      NC

Raisin
                                       
                                       
                                     0.411
                                     0.020
                                   <0.01
                                   <0.01
                                     0.71
                                    >2.0
                                      NC
                                      NC
                      Richland, IA; 2009 (22P; V-32894-V)
Field Corn
Grain (RAC)
                                     ~0.45
                                      89
                                   <0.01
                                     0.906
                                   <0.01
                                   <0.01
                                      --
                                      --
                                      --
                                      --

Starch
                                       
                                       
                                   <0.01
                                     0.030
                                   <0.01
                                   <0.01
                                      NC
                                     0.03x
                                      NC
                                      NC

Refined oil (wet milling)
                                       
                                       
                                   <0.01
                                    <LOQ
                                   <0.01
                                   <0.01
                                      NC
                                   <0.01x
                                      NC
                                      NC

Grits
                                       
                                       
                                   <0.01
                                     0.491
                                   <0.01
                                   <0.01
                                      NC
                                     0.5x
                                      NC
                                      NC

Flour
                                       
                                       
                                   <0.01
                                     0.387
                                   <0.01
                                   <0.01
                                      NC
                                     0.4x
                                      NC
                                      NC

Meal
                                       
                                       
                                   <0.01
                                     0.527
                                   <0.01
                                   <0.01
                                      NC
                                     0.6x
                                      NC
                                      NC

Refined oil (dry milling)
                                       
                                       
                                   <0.01
                                     0.016
                                   <0.01
                                   <0.01
                                      NC
                                     0.02x
                                      NC
                                      NC
                       Hinton, OK; 2009 (23P; V-32894-X)
Field Corn
Grain (RAC)
                                     ~0.45
                                      50
                                   <0.01
                                     0.436
                                   <0.01
                                   <0.01
                                      --
                                      --
                                      --
                                      --
                                       
Starch
                                       
                                       
                                   <0.01
                                     0.023
                                   <0.01
                                   <0.01
                                      NC
                                     0.05x
                                      NC
                                      NC
                                       
Refined oil (wet milling)
                                       
                                       
                                   <0.01
                                   <0.01
                                   <0.01
                                   <0.01
                                      NC
                                   <0.02x
                                      NC
                                      NC
                                       
Grits
                                       
                                       
                                   <0.01
                                     0.172
                                   <0.01
                                   <0.01
                                      NC
                                     0.4x
                                      NC
                                      NC
                                       
Flour
                                       
                                       
                                   <0.01
                                     0.160
                                   <0.01
                                   <0.01
                                      NC
                                     0.4x
                                      NC
                                      NC
                                       
Meal
                                       
                                       
                                   <0.01
                                     0.220
                                   <0.01
                                   <0.01
                                      NC
                                     0.5x
                                      NC
                                      NC
                                       
Refined oil (dry milling)
                                       
                                       
                                   <0.01
                                     0.013
                                   <0.01
                                   <0.01
                                      NC
                                     0.03x
                                      NC
                                      NC
      [1]  NC = Not calculated; residues were below the LOQ (<0.01 ppm for all in analytes) in both RAC and processed fraction.
[2]  Processing Factor = (residue in the processed fraction) / (residue in the RAC).  

860.1850 and 860.1900 Confined/Field Accumulation in Rotational Crops

Based on the results of the confined rotational crop studies and toxicological considerations, HED concluded that the residue of concern in rotational crops for tolerance enforcement is tetraconazole per se and the residues of concern for risk assessment are tetraconazole, M14360-acid, M14360-DFA, M14360(C-1)-alcohol (free and conjugated), and TA, THP, and TAA and all labile conjugates of these compounds (for a full discussion see D331476, M. Clock-Rust et al., 26-Jan-2007).  The petitioner has submitted data concerning the magnitude of tetraconazole per se residues in rotational crops and these data are summarized below.

A field rotational crop study has been previously submitted which monitored for residues of tetraconazole per se in spring wheat (straw and grain), peas (seed), potato (tuber), canola (seed), and sugar beet (root and top) planted 7-9 days following application of tetraconazole to bare soil at 0.112 lb ai/acre, 0.223 lb ai/acre, 0.669 lb ai/acre, and 1.34 lb ai/acre (D278236, W. Donovan, 22-Oct-2001).  These application rates represent 1.2x, 2.5x, 7.4x, and 15x the seasonal rate for field corn and popcorn; 1.4x, 2.8x, 8.4x, and 17x the seasonal rate for 13-07F crops; and 0.7x, 1.4x, 4.2x, 8.4x the seasonal rate for 13-07G crops.  Residues of tetraconazole per se were <0.02 ppm (<LOQ) in all samples except spring wheat straw harvested from the 7.4x/8.4x/4.2x and 15x/17x/8.4x treated plots (<0.02-0.05 ppm).  

A supplemental field rotational crop study was also submitted which provided tetraconazole per se residues in rotational crops planted in fields in which the primary crop was treated with 2-4 applications of tetraconazole at 0.11 lb ai/acre for three consecutive years (2.8-5.5x, 1.4-2.8x,  and 2.4-4.9x the 13-07F, 13-07G, and field/pop corn seasonal application rates, respectively; MRID 45320902).  In this study, the plantback intervals (PBIs) ranged from 76-328 days and the rotational crops were barley, onion, canola, bean, pea, potato, and sugar beet.  In all rotational crop samples analyzed, tetraconazole per se residue levels were below the LOD of 0.01 ppm (D278236, W. Donovan, 22-Oct-2001).  

Based on these data, the proposed PBIs, and proposed application rates, HED concludes that residues of tetraconazole per se in rotational crops planted in fields treated at the proposed rate will be insignificant.  Information concerning the magnitude of the remaining residues of concern can be found in the dietary exposure (D381912, T. Bloem, 14-Apr-2011) and/or risk assessment (D380618, A. Nowotarski et al., in draft) documents.

OPPTS 860.1550 Proposed and HED Recommended Tolerances
 
Table 9 is a summary the proposed and HED-recommended tolerances for residues of tetraconazole per se (40 CFR 180.557).  A revised Section F is requested specifying the correct tolerance expression (see below), commodity definition, and/or tolerance levels.  HED notes that there are no Canadian or Codex maximum residue limits for tetraconazole; therefore, harmonization is not an issue.  HED recommends that the tetraconazole tolerance expression be changed to the following (40 CFR 180.557(a)):  

   180.557(a):  Tolerances are established for residues of tetraconazole, including its metabolites and degradates, in or on the commodities listed below.  Compliance with the following tolerance levels is to be determined by measuring only tetraconazole (1-[2-(2,4-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethoxy)propyl]-1H-1,2,4-triazole).

Table 9.  Tolerance Summary.
                                   Commodity
                           Proposed Tolerance (ppm)
                        HED-Recommended Tolerance (ppm)
                                   Comments
Small fruit vine climbing, except fuzzy kiwifruit, subgroup 13-07F
                                     0.20
                                     0.20
                      A revised Section F is requested.  
Low-growing berry subgroup 13-07G (except cranberry)
                                     0.25
                                     0.25
                                       
Corn, field, forage
                                      1.0
                                      1.1
                                       
Corn, field, grain
                                     0.01
                                     0.01
                                       
Corn, field, stover
                                      1.5
                                      1.7
                                       
Corn, pop, grain
                                     0.01
                                     0.01
                                       
Corn, pop, stover
                                      1.5
                                      1.7
                                       
Milk
                                 Not proposed
                                     0.03
                                       
Milk, fat
                                 Not proposed
                                     0.75
                                       
Fat (cattle, goat, horse, sheep)
                                 Not proposed
                                     0.15
                                       
Liver (cattle, goat, horse, sheep)
                                 Not proposed
                                      1.5
                                       
Meat byproducts, except liver (cattle, goat, horse, sheep)
                                 Not proposed
                                     0.15
                                       
Poultry, meat byproducts
                                 Not proposed
                                     0.05
                                       

RDI: RAB1 chemists (9-Feb-2011)
T. Bloem:S10945:PY1:(703)-605-0217

Attachment 1:  Chemical Structures
Attachment 2:  Tolerance Calculations
Attachment 3:  International Residue Limit Status

Attachment 1: Chemical Structures

                          Common Name; Chemical Name
                                   Structure
Tetraconazole
CAS:  1-[2-(2,4-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethoxy)
propyl]-1H-1,2,4-triazole
IUPAC:  (+-)-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propyl 1,1,2,2-tetrafluoroethyl ether
                                       
Triazole (T)
1,2,4-triazole
                                       
Triazolyl alanine (TA)
3-(1H-1,2,4-triazol-1-yl)alanine
                                       
Triazolyl acetic acid (TAA)
(1H-1,2,4-triazol-1-yl)acetic acid 
                                       
Triazolyl hydroxypropionic acid (THP)
2-hydroxy-3-(1H-1,2,4-triazol-1-y)propionic acid
                                       
M14360-acid
2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)-propionic acid
                                       
M14360-difluoroacetic acid (M14360-DFA)
5-(2,4-dichlorophenyl)-2,2-difluoro-6-(1H-1,2,4-triazol-1-yl)-oxahexanoic acid
                                       
M14360-alcohol
2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1-propanol
                                       

Attachment 2:	Tolerance Calculations (MLE spreadsheet and Tolerance Calculations)

Strawberry

Corn Forage



Corn Stover

Attachment 3:  International Residue Limit Status

                    Tetraconazole (120603; 19-January-2011)
Summary of US and International Tolerances and Maximum Residue Limits 
Residue Definition:
                                      US
                                    Canada
                                   Mexico[2]
                                   Codex[3]
40 CFR 180.557(a): tetraconazole (1-[2-(2,4-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethoxy)propyl]-1H-1,2,4-triazole)
                                     None
                                       
                                     None
Tolerance (ppm) /Maximum Residue Limit (mg/kg)
Commodity[1]
                                      US
                                    Canada
                                   Mexico[2]
                                     Codex
Corn, field, forage
                                      1.1
                                       
                                       
                                       
Corn, field, grain
                                     0.01
                                       
                                       
                                       
Corn, field, stover
                                      1.7
                                       
                                       
                                       
Corn, pop, grain
                                     0.01
                                       
                                       
                                       
Corn, pop, stover
                                      1.7
                                       
                                       
                                       
Small fruit vine climbing, except fuzzy kiwifruit subgroup 13-07F
                                     0.20
                                       
                                       
                                       
Low-growing berry subgroup 13-07G
                                     0.25
                                       
                                       
                                       
Milk
                                     0.03
                                       
                                       
                                       
Milk, fat
                                     0.75
                                       
                                       
                                       
Fat (cattle, goat, horse, sheep)
                                     0.15
                                       
                                       
                                       
Liver (cattle, goat, horse, sheep)
                                      1.5
                                       
                                       
                                       
Meat byproducts, except liver (cattle, goat, horse, sheep)
                                     0.15
                                       
                                       
                                       
Poultry, meat byproducts
                                     0.05
                                       
                                       
                                       
Completed:  M. Negussie; 01/19/2011
[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.



