EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: [Mary Waller (PM#21), 703 -305-9354 ]

INST RUCTIONS: Please utilize this outline in preparing the pesticide petition. In cases where the outline element does not apply, please insert “NA-Remove” and maintain the outline. Please do not change the margins, font, or format in your pesticide petition . Simply replace the instructions that appear in green and brackets, i.e., “ [insert company name] ,” with the information specific to your action. TEMPLATE: [ Isagro S.p.A. ] [Insert petition number] EPA has received a pesticide petition ( [insert petition number] ) from [Isagro S.p.A. ] , [430 Davis Drive, Suite 240, Morrisville, NC 27560 ] proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180. (Options (pick one) 1. by establishing a tolerance for residues of [tetraconazole] in or on the raw agricultural commodity [Corn: field, forage; field, grain; field, stover; pop, grain; and pop, stover] at [1.0 , 0. 01, 1. 5, 0.01 and 1 .5 , respectively] parts per million (ppm)

. EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition. A. Residue Chemistry
1. Plant metabolism. [T he metabolism of tetraconazole is adequately understood for the purposes of establishing the proposed tolerances. T etraconazole metabolites include 1,2,4-triazole, and two conjugates, triazolylalanine and triazolyl acetic acid, which are common to most of the triazole fungicides. B ased on the available metabolism and toxicology data, parent tetraconazole is proposed to be considered as the residue of concern in plant and animal matrices. Tolerances have previously been approved for many crop and animal matrices. ]2

2. Analytical method. [Adequate enforcement methodology (capillary gas chromatography with electron capture detector (GC/ECD)) is available to enforce the tolerance expression. T he method may be requested from: Chief, Analytical Chemistry Branch, Environmental Science center, 701 Mapes Rd., Ft. Meade, MD 20755-5350. Plus an additional new enforcement method using LC/MS -MS detection is submitted] 3. Magnitude of residues. [Fo r a Field Corn magnitude of residue study a total of twenty-one (21 ) residue trials , scattered over 5 residue regions, were conducted to evaluate the magnitude of the residues of tetraconazole followin g one application of Domark 230 ME at the maximum use rate of 0.091 lbs of active ingredient (ai) per acre. T he raw agricultural commodities (RAC s) harvested and analyzed for residues were forage, grain and stover. Fo rage had a mean residue level of 0.404 ppm with a minimum residue level of 0.044 ppmand a maximum residue level of 0.907 ppm. All grain samples had no detectable residue levels even in 5X exaggerated trials with a detection limit of 0.005 ppm. Stover had a mean residue level of 0.453 ppm with a minimum residue level of not detectable (LOD = 0.005 ppm) and a maximum residue level of 1.548 ppm. Both of the two processing studies at a 5X rate had no detectable residues in the grain. The processed fractions were analyzed anyway with again no detectable residues in any of the fractions (flour, grits, meal, oil starch). T here were some exaggerated 2X and 5X samples of the RACs and they had increased residues with the higher rates. T he three dissipation studies did not show any significant residue decline over time. All trials included an adjuvant of either a crop oil concentrate (COC) or a non-ionic surfactant (NIS). ] B. Toxicological Profile 1. Acute toxicity. [Acute oral lethal dose (LD 50) = 1,031 milligrams/kilogram (mg/kg) (toxicity category III); acute dermal LD 50 > 2,000 mg/kg (toxicity category III); acute inhalation lethal concentration (LC 50) > 3. 66 mg/liter (toxicity category IV); primary eye irritation – slight eye irritant (toxicity category III); primary skin irritation

– not a dermal irritant (toxicity category IV); and dermal sensitization

– not a dermal sensitizer. ] 2. Genotoxicty. [Numerous mutagenicity studies were conducted with tetraconazole and no genotoxic effects were reported

. ] 3. Re productive and developmental toxicity. [A two-generation reproduction study was conducted in rats at dietary concentrations of 0, 10, 70 or 490 ppm. The LOAEL for parental toxicity = 70 ppm, equivalent to 4.9/5.9 (male/female) mg/kg/day based on increased mortality in P generation females. The NOAEL = 10 ppm, equivalent to 0.7/0.8 (M/F) mg/kg/day. The LOAEL for off spring toxicity = 490 ppm (40.6 mg/kg/day from the P generation female intake) based on decreased litter weight and mean pup weight in litters of all generations before weaning and3

increased relative liver weights at weaning in both sexes of all litters. The NOAEL = 70 ppm (5.9 mg/kg/day). The LOAEL for reproductive toxicity = 70 ppm, equivalent to 4.9/5.9 (M/F) mg/kg/day based on increased mean gestation duration in P generation parental females and related evidence of compound toxicity in the parturition process. The NOAEL was 10 ppm (0.7 mg/kg/day for males and 0.8 for females). A developmental toxicity study was conducted using rats gavaged with doses of 0, 5, 22.5, and 100 mg/kg/day from days 2 through 15 of gestation. The maternal toxicity LOAEL is 100 mg/kg/day based on decreased body weight gain, and food consumption and increased liver and kidney weights. The maternal toxicity NOAEL is 22.5 mg/kg/day. Developmental toxicity was noted at 100 mg/kg/day and consisted of an increased incidence of small fetuses, and supernumerary ribs. The LOAEL and NOAEL for developmental toxicity were 100 and 22.5 mg/kg/day, respectively. A developmental toxicity study was conducted using rabbits gavaged with doses of 0, 7.5, 15, or 30 mg/kg/day. The maternal toxicity NOAEL = 13 mg/kg/day and LOAEL = 30 mg/kg/day, based upon decreased body weight gain. T he developmental toxicity NOAEL = 30 mg/kg/day and the LOAEL was not established. ] 4. Subchronic toxicity. [Ninety-day feeding studies were conducted in rats and mice. The rat study was conduced at dietary concentrations of 0, 10, 60, or 360 ppm. The NOAEL = 4.1/5.5 (M/F) mg/kg/day. The LOAEL = 23.9/28.7 (M/F) mg/kg/day, based on single liver cell degeneration in males, and increased SGPT and SGOT, decreased BUN levels, increased absolute and relative liver weights and presence of hepatocellular single cell necrosis in females. The mouse study was co nducted at dietary concentrations of 0, 5, 25, 125, or 625 ppm. The NOAEL = 4 (M/F) mg/kg/day. The LOAEL = 16/20 (M/F) mg/kg/day, based on single liver cell degeneration in males, and increased SGPT and SGOT, decreased BUN levels, increased absolute and relative liver weights and presence of hepatocellular single cell necrosis in females. ]

5. Chronic toxicity. [A two year combined chronic toxicity/carcinogenicity study was conducted in rats at dietary concentrations of 0, 10, 80, 640 or 1280 ppm. T he NOAEL = 3.4/4.4 (M/F) mg/kg/day. T he LOAEL = 27.7/39.4 (M/F) mg/kg/day, based upon histopathology of the bone (osseous hypertrophy of the cranium/parietal bone), pale and thickened incisors, and decreased absolute and relative adrenal and pituitary weights in males; decreased body weight (at terminal sacrifice) in females. No treatment- related increases in tumor incidence were observed. A 52 -week chronic toxicity study was conducted in dogs at dietary concentrations of 0, 22.5, 90 or 360 ppm. The NOAEL = 0.73/0.82 (M/F) mg/kg/day. The LOAEL = 27.7/39.4 (M/F) mg/kg/day, based upon increased absolute and relative kidney weights and histopathological changes in the male kidney.4 Carcinogenicity; an 80 week mouse oncogenicity study was conducted at dietary concentrations of 0, 10, 90, 800, or 1250 ppm. T he NOAEL = 1.4/1.5 (M/F) mg/kg/day. T he LOAEL = 12/14.5 (M/F) mg/kg/day, based upon increased liver weights and hepatocellular vacuolation in both sexes and increased kidney weights in males. T reatment-related increased incidences of combined benign and malignant liver tumors in both sexes were observed. ] 6. Animal metabolism. [The nature of tetraconazole residues is adequately understood. T etraconazole is extensively metabolized very quickly and eliminated from the body by fecal and urinary routes. ]

7. Metabolite toxicology

. [ 1,2 -4-Triazole is the major metabolite identified in urine and feces with minor amounts of triazole acid and alcohol. The most conservative toxicology endpoint for 1,2,4-triazole is 15 mg/kg/day, based on body weight decreases in male rats in the reproductive study. ] 8. Endocrine disruption

. [Tetraconazole did not have effects on endocrine organs or tissues, nor were there any indications of effects on fetal development in either rats or rabbits, or on reproductive performance in rats. Therefore, at doses likely to be encountered, tetraconazole in not likely to be an endocrine disruptor. ] C. Aggregate Exposure 1. Dietary exposure. [ (food and drinking water combined) : a. Acute risk: Using 100% crop treated, all existing RAC tolerances plus the presently proposed corn tolerances for residue exposure assumptions; the acute dietary exposure from food and water to tetraconazole will occupy < 1.0% of the aPAD for the population group (females 13 to 49 years old) receiving the greatest exposure. No acute toxicity endpoint was identified for the remaining population subgroups. b. C hronic risk: Using 100% crop treated for all food commodities, incorporated empirical p rocessing factors, average field trial residues for all crops, and average residues in meat and meat by-products derived from feeding studies; the exposure to tetraconazole from food and water will utilize 7.7 % of the cPAD for the population group all inf ants < 1 year old (the most sensitive subpopulation). c. C ancer risk: Using actual and projected percent crop treated estimates for crops, empirical processing factors plus average field trial residues for all crops, and average residues in meat and meat by-products derived from feeding studies; the estimated cancer risk for the proposed use of tetraconazole on corn, low growing berry subgroup 13 -07G, peanut, pecan, small fruit vine climbing subgroup 13 -07F, soybeans, sugar beet and water is under 3x 10 -6

. T his aggregate risk is the sumo f the risk from food and water and falls within the Agency 's acceptable risk standard for cancer. i. Food. [given above]5

ii. Drinking water

. [given above] 2. Non

-dietary exposure

. [Tetraconazole is currently not registered for use on any residential non-food site. Therefore, residential exposure to tetraconazole residues will be through dietary exposure only. ] D. Cumulative Effects [EPA has not made a common mechanism of toxicity finding as to tetraconazole and any other substance. However, the Agency does have concern about potential toxicity to 1,2,4-triazole and two conjugates, triazolylalanine and triazolyl acetic acid. T o support the extension of existing parent triazole-derivative fungicide tolerances, EPA conduced an interim human health assessment for aggregate exposure to 1,2,4-triazole. B ased on this assessment EPA concluded that for all exposure durations and population subgroups, aggregate exposures to 1,2,4- triazole are not expected to exceed its level of concern. ] E. Safety Determination 1. U.S. population. [Based on the exposure assumptions described above and on the completeness of the toxicology database, it can be concluded that total aggregate exposure from food and water to the U.S. population and all evaluated population subgroups from tetraconazole exposure from all proposed uses will be below 100% of the RfDs. E PA generally has no concerns for estimated exposures below 100% of the RfD, since the RfD represents the level at or below which daily aggregate exposure will not pose an appreciable risk to human health. T hus, ISAGRO believes it can be concluded that there is reasonable certainty that no harm will result from aggregate exposure to tetraconazole residues for the registered and proposed uses on grape

. ] 2. Infants and children

. [In assessing the potential for additional sensitivity of infants and children to residues of tetraconazole, the data from developmental toxicity studies in both the rat and rabbit and a two generation reproduction study in rats have been considered. T hese toxicity studies indicate the offspring are not mo re sensitive and all developmental and reproductive effects were secondary to severe maternal toxicity. Thus, ISAGRO believes that infants and children are protected and that an additional uncertainty factor for infants and children is not warranted

. ] F. International Tolerances

[Maximum residue levels (MRL) have been established for tetraconazole in the following countries (in ppm): Belgium : sugar beet root, 0.05; wheat grain, 0.05; wheat straw, 2.0. Brazil : apple, 0.4; banana, 0.2; coffee, 0.08; grape, 0.3; mango, 0.1; soybean, 0.1.6

France : apple, 0.2; barley grain, 0.02; grape, 0.2; wine, 0.01; sugar beet root, 0.05; wheat grain, 0.02. Italy : apple, 0.5; artichoke, 0.2; barley grain, 0.1; courgette, 0.2; cucumber, 0.2; grape, 0.5; melon, 0.05; peach, 0.2; pear, 0.2; pepper, 0.2; tomato, 0.2, watermelon, 0.05; wheat grain, 0.05 Portugal : apple, 0.3; grape, 0.2; melon, 0.1; peach, 0.2; pear, 0.3; strawberry, 0.2; sugar beet root, 0.05. Spain : apple, 0.2; artichoke, 0.05; cucurbit fruit & edible peel, 0.2; nectarine, 0.2; peach, 0.2; pear, 0.2; sugar beet leaves, 0.3; sugar beet root; 0.05; tomato, 0.1. United Kingdom : barley grain, 0.2; barley straw, 10; oat grain, 0.1; oat straw, 2; wheat grain, 0.05; wheat straw, 5. Czech Republic : apple, 0.5; grape, 0.05 Hungary : apple, 0.2; grape, 0.5; sugar beet root & leaves, 0.5; sugar beet root, 0.1; wheat grain, 0.05; wheat straw, 3. Poland : apple, 0.5; cereal grain, 0.05; cereal straw, 3; cucumber edible peel, 0.2. Japan : wheat, 0.05; barley; 0.2 other cereal grain, 0.1; sugar beet, 0.5; artichoke, 0.2; tomato, 1; cucumber, 0.5; pumpkin (including squash), 1; oriental cucurbitaceous vegetables, 0.2; apple, 0.5, Japanese pear, 0.5, pear, 0.5 quince, 0.5 peach, 0.3, nectarine, 0.2; apricot, 0.2; Japanese plum (including prune); 0.2; cherry, 0.2; strawberry, 2; watermelon, 0.2, melon, 0.2; makuwauri, 0.2; grape, 0.5; tea, 20. No CODEX maximum residue levels (MRL) have been established for residues of tetraconazole on any crops at this time

. ]