COMPANY NOTICE OF FILING FOR TETRACONAZOLE NEW USES 

PESTICIDE PETITION

EPA Registration Division contact: Sidney Jackson, (703) 305-7610

Interregional Research Project Number 4

Pesticide Petition Number 0E7735

EPA has received a pesticide petition (PP 0E7735) from the Interregional 

Research Project Number 4 (IR-4), 500 College Road East, Suite 201W, Princeton, 

NJ 08540 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 180.557 by establishing a 

tolerance for residues of tetraconazole in or on the raw agricultural commodities small 

fruit vine climbing, except fuzzy kiwifruit subgroup 13-07F at 0.20 parts per million 

(ppm) and low growing berry subgroup 13-07G at 0.25 ppm. Additionally, the petition 

proposes to delete the existing tolerance for grape at 0.20 ppm since grape is included in 

the proposed subgroup 13-07F. The 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.

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.

3. Magnitude of residues. For grape group 13-07F, a total of twelve (12) 

residue trials were conducted to evaluate the magnitude of the residues of 

tetraconazole following two applications of METTLE 125ME at 0.04 lbs of active 
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ingredient (ai) per acre (a) with treatments 14 days apart and harvest at 14 days 

after the last application. The grape fruit raw agricultural commodity (RAC) mean 

was 0.030 ppm with a minimum residue level of 0.005 ppm and a maximum residue 

level of 0.091 ppm. Both of the two processed fractions grape juice and raisins did 

not concentrate having residue levels less than their corresponding grape fruit 

(RAC). A tolerance has previously been established on grape at 0.20 ppm.

For strawberry group 13-07G, a total of ten (10) residue trials were conducted to 

evaluate the magnitude of the residues of tetraconazole following two applications of 

METTLE 125ME at 0.05 lbs of active ingredient (ai) per acre (a) with treatments 14 

days apart and harvest at 0 days after the last application. The strawberry fruit 

raw agricultural commodity (RAC) mean was 0.0787 ppm with a minimum residue 

level of less than 0.005 ppm and a maximum residue level of 0.211 ppm. No 

processing studies are required.

B. Toxicological Profile

1. Acute toxicity. For formulated product; Acute oral lethal dose (LD50) = 

>5000 (combined) milligrams/kilogram (mg/kg) (toxicity category III); acute dermal 

LD50 < 2,000 mg/kg (toxicity category III); acute inhalation lethal concentration 

(LC50) = 3.17 mg/liter (toxicity category IV); primary eye irritation - clear by 72 

hours - Minimal irritant (toxicity category III); primary skin irritation – not an 

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

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.
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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.

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 
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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 Small fruit vine climbing subgroup 13-07F and 

Low growing berry subgroup 13-07G RAC tolerance 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 projected percent crop treated estimates for all 

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 small fruit vine climbing subgroup 13-07F, low growing 

berry subgroup 13-07G, peanuts, pecans, soybeans, sugar beet and water is 

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. As discussed above

ii. Drinking water. As discussed 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 
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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. 

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.
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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.