Document ID: EPA-HQ-OPP-2006-0576-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-03-23T04:00Z

FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE

NOTICE OF FILING 

EPA Registration Division Contact: Mary Waller (PM#21), 703-305-9354

Sipcam Agro USA, Inc.

	In 1999 the U.S. EPA received a pesticide petition (PP#9F5066) from
Sipcam Agro USA, Inc., 300 Colonial Center Parkway, #230, Roswell, GA 
30076, proposing, pursuant to section 408(d) of the Federal Code, Drug,
and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part
180.557 by establishing tolerances for residues of tetraconazole in or
on raw agricultural commodities pertaining to sugarbeets.  The EPA
subsequently acted upon the petition, and published [Fed. Reg. 70, No.
77; 20821] the requisite tolerances under 40 CFR § 180.557 as they
pertained to regional registrations.  At this time the EPA is
eliminating the regional restrictions pertaining to these tolerances in
conjunction with non-regionalized registrations of tetraconazole on
sugarbeets. 

Residue Chemistry

	1. Plant and animal metabolism.  In plants and animals, the metabolism
of tetraconazole is adequately understood.  Tetraconazole metabolites
include 1,2,4-triazole, and two conjugates, triazolylalanine and
triazolyl acetic acid, which are common to the triazole derivative
fungicides.  Based on the available metabolism and toxicology data,
parent tetraconazole is the residue of concern in plant and animal
matrices.

	2. Analytical method. In plants and animals, the residue of concern,
parent tetraconazole, can be determined using High Pressure Liquid
Chromatography (HPLC) with a Mass Spectrometer (MS) detector.  The limit
of quantitation (LOQ) for the method is 0.01 ppm for sugarbeet raw and
processed commodities.

	3. Magnitude of the residues. A magnitude of residue study was
conducted at a total of twelve field sites, encompassing all
geographical regions where sugarbeets are grown, to evaluate the
magnitude of the residues of tetraconazole in sugarbeet raw agricultural
commodities following six applications of Eminent 125SL at 0.107 lbs of
active ingredient (ai) per acre, throughout the growing season until 14
days prior to harvest.  Residues of tetraconazole in sugarbeet roots
ranged from non-detectable (<0.010) to 0.09 ppm [HAFT] among thirty-four
samples taken from the twelve field sites. A subset of dissipation
samples taken from one of the field sites demonstrated that
tetraconazole residues were detectable at 0.02 and 0.014 ppm in
sugarbeet roots when the preharvest interval was zero (0) and three (3)
days, respectively, but thereafter were non-detectable (<0.010) as the
preharvest interval ranged from seven (7) to sixty (60) days.

Residues of tetraconazole on sugarbeet tops (leaves) ranged from 1.44 to
4.90 ppm [HAFT] among thirty-four samples taken from the twelve field
sites. A subset of dissipation samples taken from one of the field sites
demonstrated that the magnitude of tetraconazole residues declined in
sugarbeet tops with a calculated half-life of 39 days (R*2 = 0.83) as
the preharvest interval ranged from zero (0) to sixty (60) days.

A second magnitude of residue study was conducted at a thirteenth field
site to evaluate the magnitude of the residue of tetraconazole in
sugarbeet roots and tops following six applications of tetraconazole at
0.107 lbs active ingredient per acre, as compared with three
applications at the same rate, with applications throughout the growing
season until 14 days prior to harvest.  Residues of tetraconazole in the
roots and tops were present in approximately direct proportion with the
number of applications that were made to the crop (in roots 0.04 vs.
0.012 ppm; in tops 1.71 vs. 0.79 ppm, respectively with six vs. three
applications).

A processing study conducted upon bulked sugarbeet roots taken from a
fourteenth field site determined that residues of tetraconazole
concentrated in sugarbeet pulp (dry) by a factor of 2.1, and in
sugarbeet molasses by a factor of 2.8.

Toxicological Profile

The toxicological database for tetraconazole is complete.  The EPA’s
assessments of potential exposure and risks associated with the proposed
tolerances are categorized as follows:

1. Acute toxicity. Acute oral lethal dose (LD)50 = 1,031
milligrams/kilogram (mg/kg) (toxicity category III); acute dermal LD50 <
2,000 mg/kg (toxicity category III); acute inhalation lethal
concentration (LC)50 = 3.66 mg/liter (toxicity category IV); primary eye
irritation - clear by 72 hours (toxicity category III); primary skin
irritation - slight irritation (toxicity category IV); and dermal
sensitization - negative.

  

2. Genotoxicity. A battery of mutagenicity studies yielded negative
results in Salmonella typhimurium, cultured Chinese hamster ovary (CHO)
cells, and mouse lymphoma cells. There was no evidence of clastogenicity
in vitro or in vivo and tetraconazole did not induce unscheduled DNA
synthesis in human HeLa cells.

	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 was 70 ppm,
equivalent to 4.9/5.9 (male/female) mg/kg/day based on increased
mortality in P generation females. The NOAEL was 10 ppm, equivalent to
0.7/0.8 (M/F) mg/kg/day. The LOAEL for off spring toxicity was 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 was 70 ppm (5.9 mg/kg/day). The LOAEL for
reproductive toxicity was 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 wa100 mg/kg/day based on
decreased body weight gain, and food consumption and increased liver and
kidney weights. The maternal toxicity NOAEL was 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 was
13 mg/kg/day, and LOAEL was 30 mg/kg/day, based upon decreased body
weight gain.  The developmental toxicity NOAEL was 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 was 4.1/5.5 (M/F) mg/kg/day.  The
LOAEL was 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 was 4 (M/F) mg/kg/day.  The LOAEL was 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 was 3.4/4.4
(M/F) mg/kg/day.  The LOAEL was 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 was 0.73/0.82 (M/F)
mg/kg/day.  The LOAEL was 27.7/39.4 (M/F) mg/kg/day, based upon
increased absolute and relative kidney weights and histopathological
changes in the male kidney.      

6. Carcinogenicity.  An 80 week mouse oncogenicity study was conducted
at dietary concentrations of 0, 10, 90, 800, or 1250 ppm.  The NOAEL was
1.4/1.5 (M/F) mg/kg/day.  The LOAEL was 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.

7. 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.

8. 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
reproduction study.

9. Endocrine disruption. Tetraconazole did not affect 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.  Using 100% crop treated scenarios and existing
sugar beet, milk, cattle, horse, goat, and sheep tolerances, plus the
pending peanut, pecan, soybean and poultry tolerances, acute dietary
exposure to tetraconazole from food occupies only 0.5% of the aPAD
(0.225 mg/kg at UF = 100) for females 13 to 49 years old, the only
population subgroup for which an acute toxicity endpoint was determined.
 Using the same exposure assumptions, chronic dietary exposure from food
to tetraconazole occupies 3.9% and 11.1% of the cPAD (0.0073 mg/kg/day
at UF = 100) for the U.S. population and the most sensitive
subpopulation, non-nursing infants, respectively.  The estimated
aggregate oncogenic risk from dietary exposure from all existing and
proposed uses is 0.21 x 10-6, a value that falls within the Agency's
acceptable oncogenic risk standard of <1 x 10-6. 

	i. Food. The cRfD and aRfD values of 0.0073 mg/kg bw and 0.225 mg/kg
bw, respectively, were used to assess risk from dietary exposure.  Tier
1 dietary risk assessments indicate that the highest chronic and acute
exposures never exceed 11.1% and 0.5% (at the 99.9th percentile of
exposure) for the cRfD and aRfD, respectively.

	ii. Drinking water. The standard EPA Mississippi soybean PRZM/EXAMS
modeling scenario with index reservoir (IR) was used to conservatively
estimate concentrations of tetraconazole in drinking water resulting
from a proposed use on soybeans, which also applies to the presently
proposed use on peanuts.  The drinking water estimated concentrations
(DWECs) from the Mississippi soybean scenario model were 2.19 ppb
(acute), 0.578 ppb (chronic) and 0.441ppb (30 year lifetime average). 
These are 6 to 28 times greater than the highest level of tetraconazole
“detected” in Minnesota surface water, which was 0.075 ppb (1/2
limit of quantitation).  Thus, the Mississippi DWECs were used to assess
dietary risks from exposure to drinking water for uses on soybeans and
peanuts.  The DWECs are lower than the lowest drinking water level of
comparison (DWLOC) values of 6,720 ppb (acute), 69 to 249 ppb (chronic),
and 1.516 ppb (cancer).  When DWLOC values are not exceed by DWEC values
it can be concluded that dietary risks from exposure to drinking water
are acceptable.

	2. Non-dietary exposure. Tetraconazole is currently not registered or
proposed for use on any residential non-food site.  Therefore,
residential exposure to tetraconazole residues would be through dietary
exposure only.

D. Cumulative Effects

	EPA has not determined that a common mechanism of toxicity pertains to
tetraconazole as compared with any other substance.  

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 it can be concluded that
there is reasonable certainty that no harm will result from aggregate
exposure to tetraconazole residues for registered and proposed uses,
including the presently proposed use on peanuts.

	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 maternal
toxicity. Thus infants and children are protected, and an additional
uncertainty factor pertaining to 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.

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.

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