 

<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.]

>

<	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
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.

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]>

<	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.  

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.]>

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