Tetraconazole Residue Chemistry Summary Document D3 8 2 300

page 1 of 24 **UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

WA SHINGTON, 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 Lo w - growing Berry

Subgroup 13 - 07G (except cranberry ) . **PC Code:** 120603 **DP Barcode:** D38 2300 **Decision No.:** 435873 **Registration No s**  **. :**  80289 - 7 and 80289 - 8 **Petition No s**  **.:** 0E7735 (13 - 07F and 03 - 07G) and 0F7737 (field corn and popcorn) **Regulatory Action:** Section 3 **Risk Assessment Type:** not applicable **Case No.:** 7043 **T XR No.:**  not applicable **CAS No.:** 112281 - 77 - 3 **MRID No s**  **.:** 48131301, 48135102, 48135103, 48135104, 48135105, and 48135106 **40 CFR:** 180. 557 From: Tom Bloem, Chemist

Risk Assessment Branch 1, Health Effects Division (RAB1/HED); 7509 P Through: George F. Kramer, Ph.D., Senior Chemist

RAB1/HED (7509 P ) To: Mary

Waller/Lisa Jones (RM 21) Barbara Madden (RM 05) Registration Division (7505 P ) 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 hydroxy

propionic acid (THP), and/or all labile conjugates of these compounds and non - free triazole metabolites - tetraconazole met abolites of concern for risk assessment other than T, TA, TAA, THP and/or all labile conjugates of these compounds.Tetraconazole Residue Chemistry Summary Document D3 8 2 300

page 2 of 24 **E XECUTIVE SUMMARY**  **Background:** Tetraconazole (1 - [2 - (2,4 - dichlorophenyl) - 3 - (1,1,2,2 - tetrafluoroethoxy )propyl] - 1 H

- 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 beet s , grape s , peanut s , pecan s , and soy

bean s with tolerance s ranging from 0.0 3 - 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 0.0 1 - 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 s mall fruit vine climbing (except fuzzy kiwifruit) subgroup 13 - 07F and low - growing berry subgroup 13 - 07G ( except cranberry ) and I sagro (Morrisville, NC) proposed a Section 3 Registration (PP# 0F7737) for application of tetraconazole to field corn and popcorn. Inconjunction 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 - 0 7G. 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. **Direction s**  **for Use:** IR - 4 proposed application of Mettle  125ME Fungicide (microemulsion formulation ; 1 lb ai/gallon; EPA Reg. No. 80289 - 8) to the s mall 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. Is agrow propos ed application of Domark®230ME Fungicide (1.9 lb ai/gallon; EPA Reg. No. 8 0289 - 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 yel low 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 request s 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 resid ues 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 requestedTetraconazole Residue Chemistry Summary Document D3 8 2 300

page 3 of 24 metabolism studies. Si nce the MARC was disbanded prior to the submission/review of the requested data and prior to the submission of the triazole - labeled soy bean 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 - ac id, M14360 - DFA, M14360 - hydroxydetriazolyl - O - malonyldiglucoside, and T, TA, TAA and all labile conjugates of these compounds. HED notes that Sy ngenta 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 hydroly

zed/oxidized to 2,4 - dichlorobenzoic acid). For a full discussion pertaining to the residues of concern i n plants see the HED risk assessment document D3 21751 (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 tetracon azole 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 t oxicological 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 distribute d 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 cro ps , 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): s mall fruit vine climbing (except fuzzy

kiwifruit) subgroup 13 - 07F - 0.20 ppm; low - growing berry subgroup 13 - 07G (exceptTetraconazole Residue Chemistry Summary Document D3 8 2 300

page 4 of 24 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 by

products (except liver; 0.01 ppm) and milk (0.01 ppm) and milk fat (0.25 ppm). Tolerances are also established in/on h og 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 by products (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 revise d 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 by products (except liver; cattle, goat, hog, horse, and sheep) - 0.15 ppm; and poultr y, meat by

products - 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 toxic ological 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 c rops (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 - 1 7 x the proposed seasonal rate s (D27 8236, W. Donovan, 22 - Oct - 2001) . Residues of tetraconazole per se were <0.02 - 0.05 ppm in wheat straw when planted in field s treated at 4.2 - 1 7 x. Based on the se data, the proposed plant - back intervals, and proposed application rates, HED concludes that resi dues of tetraconazole per se in rotational crop s planted in field s treated at the proposed rate will be insignificant. **Analytical Methods:** Adequate analy tical 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, I sagro submitted adequate method validation and independent laboratory validation (ILV) data which in dicates 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 extractionTetraconazole Residue Chemistry Summary Document D3 8 2 300

page 5 of 24 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 a dequate for enforcement of the tolerances recommended in the current document and forwarded the method to the Food and Drug Administration (FDA; D 386650 , T. Bloem, 14 - Apr - 2011) **Multiresidue Methods (MRMs) Testing:** HED has previously reviewed information concerning the MRMs tes ting 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 . **Reco mmendation:**  IR - 4 proposed a Section 3 Registration ( PP# 0E7735) for application of tetraconazole to the s mall fruit vine climbing (except fuzzy kiwifruit) subgroup 13 - 07F and low - growing berry subgroup 13 - 07G ( except cranberry ) and I sagro 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 Section s B and F are submitted, HED concludes that the residue chemistry database supports a conditional registration for application of the proposed tetraconazole formulati on to the s mall 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 o f this registration (currently established grape tolerance should be removed): s mall fruit vine climbing (except fuzzy

kiwifruit) subgroup 13 - 07F - 0.20 ppm and low - growing berry s ubgroup 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 revis ed 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 fo r 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 by products (except liver; cattle, goat, hog, horse, and sheep) - 0.15 ppm; poultry, meat by products - 0.05 ppm. The residue chemistry datab ase 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 oi l (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 analy tes. 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 - tetraf luoroethoxy

)propyl] - 1 H

- 1,2,4 - triazole).Tetraconazole Residue Chemistry Summary Document D3 8 2 300

page 6 of 24 **D ETAILED 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 Com pound Nom**  **enclature.** Chemical Structure N N N O C F 2 C F 2H Cl Cl Common name Tetraconazole Company experimental name None Specified in Submission IUPAC name (±) - 2 - (2,4 - dichlorophenyl) - 3 - (1 H - 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] - 1 H - 1,2,4 - triazole CAS # 112281 - 77 - 3 **Table 2 :**  **Physicochem ical**  **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 H 2 O ; 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 n ot 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 P ow = 3.53 at 25 °C MRID 44305301; D259842, B. Kitchens, 11 - Apr - 2000. UV/visible absorption spectrum n ot available **OPPTS GLN 860.1200 Directions for Use** IR - 4 propos ed application of Mettl e  125ME Fungicide ( ME ; 1 lb ai/gallon; EPA Reg. No. 80289 - 8 ) to the s mall 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 . Is agrow propos ed application of Domark®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 summ ary 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 inc lude an adjuvant with the spray solution, HED request s that the revised Section B also prohibit the additional of an adjuvant to the 13 - 07F and 13 - 07G spray solutions .Tetraconazole Residue Chemistry Summary Document D3 8 2 300

page 7 of 24 **Table 3**  **: Proposed Application Scenario**  **s.** Formulation Single Rate

(lb ai/acre) Seasonal Rate

(lb ai/acre) No.

Apps RTI 1 (days) PHI 1 (days) Comments s mall 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 no t 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 no t 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®230ME Fungicide (EPA Reg. No. 80289 - 7; 1.9 lb ai/gallon) 0.045 - 0.090 0.09 2 7 not specifi ed - 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 analy tical 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, I sagro 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 method s ( acetone ) , HED concludes that the radiovalidation of the QuEChERS meth od 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 Q uEChERS method was necessary for quantification o f tetraconazole, the ILV study was forwarded to the FDA (D 386650 , T. Bloem, 14 - Apr - 2011).Tetraconazole Residue Chemistry Summary Document D3 8 2 300

page 8 of 24 **Analytical Methods Employed in the F ield Trial**  **and Processing**  **Studies:** The grape, strawberry, and field corn samples from the magnitude of the residues studies were analy zed for residues of tetraconazole, T, TA, and TAA using adequately validated method s (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 strawb erry, 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 strawberr y, 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. B loem, 23 - Jan - 2007). HED concludes that thes e methods are appropriate for data collection purposes. Tetraconazole - Strawberry : The h omogenized 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 dry

ness 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 dry ness, reconstituted in methanol:water:formic acid (65:35:0.1), and analy zed 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 centri fuged 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

secon dary

amines (PSA), and carbon and analy zed for tetraconazole using L C/MS. Tetraconazole - Modified QuEChERS Method used for F ield 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 analy zed for tetraconazole using LC /MS. T, TA, and TAA - Field Corn (all RACs) and Strawberry (Py xant 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 heptafluorobuty ric anhydride for TA and TAA and dansyl chloride for T. The derivatized extracts were analy zed for metabolites T, TA, and TAA using LC /MS/MS. **OPPTS 860.1360 –**  **MR M**  HED has previously

reviewed information concerning the MRMs testing of tetraconazole and forwarded these data to FDA ( D278 236, W. Donovan, 22 - Oct - 2001; D3 32231 , T. Bloem, 13 - Sep 2006). Tetraconazole was not recovered through the MRM P rotocols.Tetraconazole Residue Chemistry Summary Document D3 8 2 300

page 9 of 24 **OPPTS GLN 860.138 0**  **- 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 an d remained frozen until analysis. T able 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 valid ate 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 ref ined corn oil (19 8 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 analy tes. **T able**  **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 t etraconazole 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). c orn forage t etraconazole - 20 °C ≤266 days **Not provided** ; note that grain storage stability data will be translated to all processed commodities excluding refined oil. c orn grain and grain processed commodities (excluding corn oil) ≤235 days c orn stover ≤229 days

c orn 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/o n wheat forage and hay ; and 13 months in/on corn cob, forage, and straw (D338246, M. Doherty, 28 - May2008 ; 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.

c orn 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/o n wheat forage and hay ; and 13 months in/on corn cob, forage, and straw (D338246, M. Doherty, 28 - May2008 ; declined ~3% per month in/on wheat straw) . r efined c orn oil tetraconazole, T, TA, and TAA - 20 °C ≤ 198 days **Not provided .** Tetraconazole Residue Chemistry Summary Document D3 8 2 300

page 10 of 24 **OPPTS 860.1480 -**  **Meat/Milk/Poultry/Eggs** T olerances for residues of tetraconazole per se are currently established in/ on ruminant (cattle, goat, horse, and sheep ) fat ( 0.0 2 ppm), liver (0 .20 ppm), meat (0.0 1 ppm), and meat by products ( except liver ; 0.0 1 ppm) and milk (0.0 1 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 (0.0 5 ppm), meat (0.0 1 ppm), meat by products (0.0 1 ppm) , and egg (0.0 2 ppm). Table 5 is a summary

of the tetraconazole per se MRBDB s 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 Feed stuff Revisions (J. Stokes, HED; June - 2008). Note that the labels prohibit feeding peanut hay and soy bean 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 ( D 380618, 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

dos ed for 28 - 30 days with tetraconazole at 0.34 ppm, 1.02 ppm, and 3.4 ppm. These doses are 0 . 3 x, 0 . 8 x, and 2 .6 x 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 analy zed 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 residue s i n 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 fo r 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 - 0.0 3 ppm; milk, fat - 0. 7 5 ppm; fat (cattle, goat, horse, and sheep) - 0. 15 ppm; liv er (cattle, goat, horse, and sheep) - 1.5 ppm; meat by products (except liver; cattle, goat, hog, horse, and sheep) - 0.1 5 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 by products was appropriate . **Hog:** Based on the hog MRBD B 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; D 329379 , T. Bloem, 23 - Jan - 20 07 ). Hens were oral ly dosed for 40 days with tetraconazole at 0.069 ppm, 0.241 ppm, and 0.714 ppm. These doses are equivalent to 1. 4 x, 4 .8 x, andTetraconazole Residue Chemistry Summary Document D3 8 2 300

page 11 of 24 1 4 x 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 analy zed for residues of tetraconazole per se using an adequately validated method (storage interval has also been val idated). 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 by product tolerances is based on the highest residue in tissue (muscle, fat, liver, and kidney

) , HED concludes that the poultry meat by product tolerance should be increased to 0.05 ppm. A revised Section F is requested. **Table 5 : Livestock M**  **RB DB Calculations**  **.**

C ommodity 1 % diet2 % dry matter HED - recommended tolerance (ppm) dietary burden 3 beef cattle f ield corn forage (R) 15 40 1.1 0.412 a spirated grain fractions (CC) 5 85 1.0 0.059 s ugar beet molasses (CC) 10 75 0.25 0.033 f ield corn grain (CC) 65 88 0.01 0.007 s oybean seed (PC) 5 89 0.15 0.008 t otal 10 0 -- -- 0.519 d airy cattle f ield corn forage (R) 45 40 1.1 1.238 s ugar beet molasses (CC) 10 75 0.25 0.033 f ield corn grain (CC) 35 88 0.01 0.004 s oybean seed (PC) 10 89 0.15 0.017 t otal 100 -- -- 1.292 P oultry f ield corn grain (CC) 75 -- 0.01 0.009 s oybean meal (PC) 25 -- 0.15 0.041 t otal 100 -- -- 0.050 H og f ield corn grain (CC) 85 -- 0.01 0.010 s oybean seed (PC) 15 -- 0.15 0.025 t otal 100 -- -- 0.035 1 R = roughage, CC = carbohydrate concentrate, PC = protein concentrate; label prohibits feeding peanut hay and soybean forage to livestock. 2 F rom revised Table 1 (J. Stokes, HED; June - 2008) . 3 B eef/dairy cattle dietary burden = residue x % diet ÷ % dry matter; poultry/swine dietary burden = residue x (% diet ÷ 100).

.Tetraconazole Residue Chemistry Summary Document D3 8 2 300

page 12 of 24 **Table 6 : Livestock Residues**  **.** matrix max tetraconazole residue from feeding study 1 (ppm) tetraconazole transfer coeffcients 2 estimated residue at 1x M RB DB 3 lowest dietary burden middle dietary burden highest dietary burden lowest dietary burden middle dietary burden highest dietary burden dairy cattle M RB DB = 1.292 ppm ( 0 . 3 x, 0 . 8 x, 2.6 x) ; hog MRBDB = 0.035 ppm ( 10x, 29x, 97x) milk 4 <0.003 0.016 0.048 -- 0.016 0.014 0.0 21 skimmed milk <0.003 <0.003 0.003 -- -- 0.0009 0.00 1 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 = 0.0 41 swine = 0.00 1 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 0.0 20 beef = 0.0 49 swine = 0.001 liver 0.371 0.662 1.636 1.091 0.649 0.481 beef = 1.410 swine = 0.0 38 muscle <0.003 0.006 0.015 -- 0.00 6 0.004 beef = 0.00 8 swine = 0.0002 poultry (M RB DB = 0.050 ppm; 1.4 x, 4.8 x, 1 4 x) liver 0.011 0.029 0.081 0.159 0.120 0.113 0.0 08 kidney <0.01 <0.01 0.049 -- -- 0.069 0.00 3 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 0.0 33 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 R uminant 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 wa s 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 .Tetraconazole Residue Chemistry Summary Document D3 8 2 300

page 13 of 24 **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 s mall fruit vine climbing (exc ept fuzzy kiwifruit) subgroup 13 - 07F and the low - growing berry subgroup 13 - 07G (except cranberry ) and Domark®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 conc lusion s 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 remainin g residues of concern can be found in the dietary exposure (D381912, T. Bloem, 14 - Apr 2011 ) and/or risk assessment ( D 380618, 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 ( D3 84213 , T. Bloem, 13 - J an - 20 11 ). The grape field trials were geo graphically 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 s mall 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 f ormulation , 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.Tetraconazole Residue Chemistry Summary Document D3 8 2 300

page 14 of 24 **Field Corn and Popcorn:** As part of the current submission, Is agro submitted field corn field trial data (see below for summary ; field corn is an acceptable surrogate for popcorn). The field trials were geograp hically

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 include d a nonionic surfactant (NI S) or crop oil concentrate (COC) in th e 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 (fie ld 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, fie ld, 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 prohibit s application after the R3 crop growth stage with no specified PHI s . 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 PHI s 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 analy

zed for residues of tetraconazole, T, TA, and TAA using adequately validated methods (only

samples from treatment B plot were analy zed 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 in creasing 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 Zone s 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 RTI s 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 PHI s.Tetraconazole Residue Chemistry Summary Document D3 8 2 300

page 15 of 24 The samples were analy

zed 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 n ot included in the summary

). Inthe 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 NI S in the spray solution . Field c orn 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 analy

ze d for residues of tetraconazole, T, TA, and TAA using adequately validated methods. Samples from the individual trials were analy zed for T, TA, and TAA excluding the 12 trials conducted in Growing Zone 5 wh ere a composite blended sample was analy zed . Tab le 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 s ampling 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 s tability 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 analy tes.Tetraconazole Residue Chemistry Summary Document D3 8 2 300

page 16 of 24 **Table 7**  **: Sum ma**  **ry 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. **T etraconazole**  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 S trawberry 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 C orn forage 0.088 - 0.094 7 - 30 42 0.041 0.962 0.907 0.401 0.2 C orn grain 48 - 95 42 <0.01 <0.01 <0.01 <0.01 <0.01 -- C orn 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 S trawberry 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 -- C orn forage 0.088 - 0.094 7 - 30 42 <0.01 0.019 0.015 0.010 0.0 C orn grain 48 - 95 15 <0.01 <0.01 <0.01 <0.01 <0.01 -- C orn 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 S trawberry 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 C orn forage 0.088 - 0.094 7 - 30 42 0.018 0.286 0.272 0.083 0.1 C orn grain 48 - 95 15 0.075 1.151 1.106 0.456 0.4 C orn 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 S trawberry 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 -- C orn forage 0.088 - 0.094 7 - 30 42 <0.01 0.025 0.021 0.013 0.0 C orn grain 48 - 95 15 <0.01 0.022 0.022 0.013 0.0 C orn 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 = h ighest - average f ield 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 unne cessary . 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 f ound in the dietary

exposure (D381912, T. Bloem, 14 - Apr - 2011 ) and/or risk assessment ( D 380618, A. Nowotarski et al. , in draft) documents. Storage stability data areTetraconazole Residue Chemistry Summary Document D3 8 2 300

page 17 of 24 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. R esidues 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 analy tes (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 soy bean 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 fe ed commodity, HED concludes that the soy bean 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 z ones 10 and 11. The treated plots received two applications (RTI = 14 - 15 days) of a 1 25 g/L liquid tetraconazole formulation at ~0.200 lb ai/acre (5x) . The first application was made 28 - 32 days prior to harvest and b ulk grape samples were harvested 14 - 16 days after the l ast application. The bulk grape sample s (n=2) were processed into grape juice (cold press) and raisin (<14% moisture) using simulated commercial processing procedures. The resulting samples were analy zed for tetraconazole, T, TA, and TAA residues using a dequately validated method s . 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 sin gle 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 analy zed 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 (19 8 days) and T, TA, and TAA in/on refined field corn oil (19 8 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. P rovided these data demonstrate the stability of T, TA, and TAA in the above matrices, no additional information will be required for these analy tes.Tetraconazole Residue Chemistry Summary Document D3 8 2 300

page 18 of 24 **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 Tetracona zole TA TAA T Tetracona zole 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. 4 x , 2.8 x, 8 .4x, and 1 7 x 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 7.4 x/ 8.4x/4.2x and 15x/ 17 x/ 8.4x treated plots (<0.02 - 0.05 ppm). A supplemental field rotational crop study was also submitted which pro vided 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 - 4.9 x the 13 - 07F, 13 -Tetraconazole Residue Chemistry Summary Document D3 8 2 300

page 19 of 24 07G , and field

/pop corn seasonal application rates, respectively ; MRID 45320902). In this study, the plantback intervals ( PBI s ) ranged from 76 - 328 days and the rotational crops were barley, onion, canola, bean, pea, potato, and sugar beet. In all rotational crop samples analy zed, tetraconazole per se residue levels were below the LOD of 0.01 ppm (D278236, W. Donovan, 22 - Oct - 2001). Based on the se data, the proposed PBI s , 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. In formation 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 ( D 380618, 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 i s 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 co mmodities 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] - 1 H

- 1,2,4 - triazole). **Table 9**  **. Tolerance Sum**  **ma ry**  **.** 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 - 20 11 ) T. Bloem: S10945 : PY1 :(703) - 605 - 0217 Attachment 1: Chemical Structures Attachment 2: Tolerance Calculations Attachment 3: International Residue Limit StatusTetraconazole Residue Chemistry Summary Document D3 8 2 300

page 20 of 24 **A ttachment 1: Chemical Structures** 

**Com mon Name**  ; Chemical Name **Structure Tetraconazole**  CAS: 1 - [2 - (2,4 - dichlorophenyl) - 3 - (1,1,2,2 - tetrafluoroethoxy) propyl] - 1 H

- 1,2,4 - triazole IUPAC: (±) - 2 - (2,4 - dichlorophenyl) - 3 - (1 H - 1,2,4 - triazol - 1 - yl)propyl 1,1,2,2 - tetrafluoroethyl ether N N N O C F 2 C F 2 H Cl Cl **Triazole (T)**  1,2,4 - triazole N N N H **Triazolyl alanine (TA)**  3 - (1 H - 1,2,4 - triazol - 1 - yl)alanine N N N N H 2

O O H **Triazolyl acetic acid (TAA)**  (1 H - 1,2,4 - triazol - 1 - yl)acetic acid N N N H O O C **T riazolyl hydroxypropionic acid**  **(THP)** 2 - hydroxy- 3 - ( 1 H

- 1,2,4 - triazol - 1 - y) propionic acid N N N O H H O O C **M14360 -**  **acid** 2 - (2,4 - dichlorophenyl) - 3 - (1 H - 1,2,4 - triazol - 1 - yl) - propionic acid N N N Cl Cl C O O H **M14360 -**  **difluoroacetic acid (M14360 -**  **DFA)** 5 - (2,4 - dichlorophenyl) - 2,2 - difluoro - 6 - (1 H - 1,2,4 - triazol - 1 - yl) - oxahexanoic acid N N N O C F 2 C O O H Cl Cl **M14360 -**  **alcohol** 2 - (2,4 - dichlorophenyl) - 3 - (1 H - 1,2,4 - triazol - 1 - yl) - 1 - propanol N N N O H Cl ClTetraconazole Residue Chemistry Summary Document D3 8 2 300

page 21 of 24 Attachment 2: Tolerance Calculations ( MLE spreadsheet and Tolerance Calculations) **Strawberry**

**Regulator:** EPA **Chemical:** tetraconaozle **Crop:** strawberry **PHI: App. Rate:**  **Submitter:**

**n:** 18 **min:** 0.05 **max:** 0.21 **median:** 0.08 **average:** 0.09 **95th Percentile 99th Percentile**  **99.9th Percentile** 0.20 0.20 0.25 (0.25) (0.25) (--) 0.20 **0.25** 0.35 **(0.25)** (0.40) (--) 0.25 **0.25 0.45**  0.9167 p-value > 0.05 : Do not reject lognormality assumption **Approximate Shapiro-Francia**  **Normality Test EU Method I**  **Normal**

**UCLMedian95th 95/99 Rule**  **EU Method II Distribution-Free**  **Mean+3SD**Tetraconazole Residue Chemistry Summary Document D3 8 2 300

page 22 of 24 **Corn Forage**

**Regulator:** EPA **Chemical:** tetraconaozle **Crop:** field corn forage **PHI: App. Rate:**  **Submitter:**

**n:** 42 **min:** 0.04 **max:** 0.96 **median:** 0.38 **average:** 0.41 **95th Percentile 99th Percentile**  **99.9th Percentile** 0.80 1.0 1.2 (0.90) (1.1) (--) 1.1 **1.7** 3.0 **(1.5)** (3.0) (--) 1.1 **1.1 1.9**  0.9082 p-value <= 0.01: Reject lognormality assumption **Approximate Shapiro-Francia**  **Normality Test EU Method I**  **Normal**

**UCLMedian95th 95/99 Rule**  **EU Method II Distribution-Free**  **Mean+3SD**Tetraconazole Residue Chemistry Summary Document D3 8 2 300

page 23 of 24 **Corn Stover**

**Regulator:** EPA **Chemical:** tetraconaozle **Crop:** field corn stover **PHI: App. Rate:**  **Submitter:**

**n:** 42 **min:** 0.01 **max:** 1.72 **median:** 0.42 **average:** 0.50 **95th Percentile 99th Percentile**  **99.9th Percentile** 1.2 1.5 1.8 (1.4) (1.7) (--) 2.5 **5.0** 12 **(4.0)** (10) (--) 1.3 **1.7 2.5**  0.8086 p-value <= 0.01: Reject lognormality assumption **Approximate Shapiro-Francia**  **Normality Test EU Method I**  **Normal**

**UCLMedian95th 95/99 Rule**  **EU Method II Distribution-Free**  **Mean+3SD**Tetraconazole Residue Chemistry Summary Document D3 8 2 300

page 24 of 24 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] - 1 H - 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 no t been finalized by the CCPR and the CAC.