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]

INSTRUCTIONS: 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. [The metabolism of tetraconazole is adequately 

understood for the purposes of establishing the proposed tolerances. Tetraconazole 

metabolites include 1,2,4-triazole, and two conjugates, triazolylalanine and triazolyl 

acetic acid, which are common to most of the triazole fungicides. Based 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.]
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2. Analytical method. [Adequate enforcement methodology (capillary gas 

chromatography with electron capture detector (GC/ECD)) is available to enforce 

the tolerance expression. The 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. [For 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 following one application of 

Domark 230 ME at the maximum use rate of 0.091 lbs of active ingredient (ai) per 

acre. The raw agricultural commodities (RACs) harvested and analyzed for 

residues were forage, grain and stover. Forage had a mean residue level of 0.404 

ppm with a minimum residue level of 0.044 ppm and 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). There were some exaggerated 2X and 5X samples of 

the RACs and they had increased residues with the higher rates. The 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 (LD50) = 1,031 milligrams/kilogram 

(mg/kg) (toxicity category III); acute dermal LD50 > 2,000 mg/kg (toxicity category 

III); acute inhalation lethal concentration (LC50) > 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. Reproductive 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 and 
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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. The 

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 

conducted 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. The NOAEL = 3.4/4.4 (M/F) mg/kg/day. The 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.
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Carcinogenicity; an 80 week mouse oncogenicity study was conducted at 

dietary concentrations of 0, 10, 90, 800, or 1250 ppm. The NOAEL = 1.4/1.5 (M/F) 

mg/kg/day. The 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. Treatment-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. Tetraconazole 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. Chronic risk: Using 100% crop treated for all food commodities,

incorporated empirical processing 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 infants < 1 year old 

(the most sensitive subpopulation). 

c. Cancer 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 3x10-6. This aggregate risk is the sum of the risk from food 

and water and falls within the Agency's acceptable risk standard for cancer. 

i. Food. [given above]
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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. To 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. Based 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. EPA 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. Thus, 

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. These toxicity studies indicate the offspring are not 

more 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. 
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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.]