Document ID: EPA-HQ-OPP-2007-0311-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-06-27T04:00Z

<>

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

 

<Interregional Research Project Number 4> (IR-4)

<PP# 6E7097>

<	EPA has received a pesticide petition (PP) [6E7093] from the IR-4, 500
College Road East, Suite 201 W, 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 180.474, by
establishing a tolerance for residues of><< the fungicide tebuconazole (
alpha -[2-(4-chlorophenyl)-ethyl]- alpha -(1,1-dimethylethyl)-1 H
-1,2,4-triazole-1-ethanol)   in or on the raw agricultural commodity
vegetable, bulb, group 3 at 1.3 parts per million (ppm); brassica, leafy
greens, subgroup 5B at 2.5 ppm; beet, garden, root at 0.7 ppm; and beet,
garden, leaves at 5.0 ppm.  EPA has determined that the petition
contains data or information regarding the elements set forth in section
408 (d)(2) of the 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   SEQ CHAPTER \h \r 1 The nature of the residue in
plants and animals is adequately understood.  The residue of concern is
the parent compound only, as specified in 40 CFR 180.474.>

<	2. Analytical method.   SEQ CHAPTER \h \r 1 An enforcement method for
plant commodities has been validated on various commodities.  It has
undergone successful EPA validation and has been submitted for inclusion
in PAM II.  The animal method has also been approved as an adequate
enforcement method.>

<	3. Magnitude of residues. Green Onions

IR-4 received a request from Agricultural Experimental Stations of
California, Oregon, Washington, and New Jersey for the use of
tebuconazole on green onions.  To support this request, magnitude of
residue data were collected from field trials conducted in the United
States (New Jersey, EPA region 2; and Oregon, region 12) and Canada
(Ontario).  In each trial, the test substance was applied four times as
a foliar broadcast spray at a rate of approximately 0.169 lb ai/A each. 
In all trials, the total amount of test substance applied was
approximately 0.676 lb ai/A.  The applications were made 8 to 14 days
apart, and green onions were collected 7 to 8 days after the final
application.  

	onazole exhibits moderate toxicity. The rat acute oral LD50 = 3,933
milligram/kilogrSamples were analyzed for residues of tebuconazole by
the National Food Safety and Toxicology Center, East Lansing, MI.  In
treated samples from New Jersey and Oregon, residues of tebuconazole
ranged from 0.06 to 0.11 ppm.  The highest residues (0.79 ppm and 0.80
ppm) were observed in the samples from Ontario.  

Dry Bulb Onions

IR-4 received requests from Oregon, Washington, New York, and the
American Dehydrated Onion and Garlic Association for the use of
tebuconazole on dry bulb onions.  To support these requests, magnitude
of residue data were collected from foliar and in-furrow field trials.
Foliar trials were conducted in New Jersey (EPA region 2), Texas (region
6), Ohio (region 5), California (region 10, two trials), Washington
(region 11), Oregon (region 12), and Colorado (region 8). In-furrow
trials were conducted in Colorado (Region 9), California (Region 10, two
trials), Washington (Region 11), and each of the Canadian provinces of
Ontario and Quebec (equivalent to Regions 5 and 5B, respectively).  

Each foliar treated plot received four foliar applications of the test
substance at a rate of approximately 0.165 lb ai/A each, for a total of
approximately 0.660 lb ai/A.  All applications were made 10 to 14 days
apart, and mature dry bulb onions were collected 6 to 7 days following
the final application.  Samples were analyzed for residues of
tebuconazole by the National Food Safety and Technology Center, East
Lansing, MI.  No residues above the lowest level of method validation
(LLMV) of 0.05 ppm were observed in treated samples from four trials. 
Residues ranged from 0.06 to 0.09 ppm in samples from New Jersey,
California, and Oregon. 

In-furrow traials were treated with one in-furrow application of
Folicur® 3.6F at a rate of approximately 0.576 lb ai/A followed by two
foliar applications at a rate of approximately 0.165 lb ai/A each.  No
adjuvant was added to the spray mixtures.  The in-furrow application was
made at planting, and the first foliar application was made 56 to 146
days later.  The foliar applications were made 12 to 14 days apart, and
samples were collected 5 to 7 days following the last application.

Samples were analyzed for residues of tebuconazole by the USDA ARS ANRI
Environmental Quality Laboratory—IR-4 Program, Beltsville, MD. 
Results from the nine in-furrow trials show that the maximum residue in
tebuconazole following a total application of approximately 0.906 lb
ai/A and a pre-harvest interval (PHI) of 7 days was 0.101 ppm.  

Leafy Brassica

Seven field trials on mustard greens were conducted in New Jersey (EPA
Region 2), North Carolina (Region 2), Tennessee (Region 4), Michigan
(Region 5), Texas (Region 6), and in California (Region 10).  In each
trial, four foliar applications of Folicur® 3.6F at a rate of
approximately 0.1125 lb ai/A each were made, for a total of
approximately 0.4500 lb ai/A.  The applications were made 12 to 16 days
apart, and samples were collected 6 to 7 days following the last
application.  

Samples were analyzed for residues of tebuconazole by the Food and
Environmental Toxicology Laboratory, Gainesville, FL.  Results from the
seven trials show that the maximum residue in tebuconazole following a
total application of approximately 0.4500 lb ai/A and a pre-harvest
interval (PHI) of 7 days was 1.40 ppm.  

Garden Beets

Seven field trials were conducted for this study in Georgia (EPA Region
2), Texas (Region 6), Tennessee (Region 2), New Jersey (Region 2), and
Oregon (Region 12), and in Ohio (Region 5).  In each trial, four foliar
applications of Folicur 3.6F at a rate of approximately 0.203 lb ai/A
(corresponds to 3.24 oz ai/A) each were applied, for a total of
approximately 0.812 lb ai/A (12.96 oz ai/A).  In each trial, beet tops
and roots were harvested separately.  

Samples were analyzed for residues of tebuconazole by the Food and
Environmental Toxicology Laboratory, Gainesville, FL.  Results from the
trials show that the maximum residues in beet roots following a total
application of approximately 0.812 lb ai/A and a pre-harvest interval
(PHI) of approximately 7 days were 0.474 ppm.  Maximum residues in beet
tops samples treated with three applications (approximately 0.609 lb
ai/A) were 2.02 ppm, while maximum residues in beet tops treated with
four applications were 3.76 ppm.>

<B. Toxicological Profile>

<	1. Acute toxicity.    SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1
Tebucam (mg/kg) (category III); the rabbit acute dermal LD50 > 5,000
mg/kg (category IV); and the rat acute inhalation LC50 > 0.371
milligram/ Liter (mg/L) (category II). Technical tebuconazole was
slightly irritating to the eye (category III) and was not a skin
irritant (category IV) in rabbits. Tebuconazole was not a dermal
sensitizer.>

<	2. Genotoxicty.   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 An Ames
test with Salmonella sp., a mouse micronucleus assay, a sister chromatid
exchange assay with Chinese hamster ovary cells, and an unscheduled DNA
synthesis assay with rat hepatocytes provided no evidence of
mutagenicity.>

<	3. Reproductive and developmental toxicity.   SEQ CHAPTER \h \r 1  
SEQ CHAPTER \h \r 1 

a. 	In a developmental toxicity study, pregnant female rats were gavaged
with technical tebuconazole at levels of 0, 30, 60, or 120 mg/kg/day
between days 6 and 15 of gestation. The maternal NOAEL was 30 mg/kg/day
and the maternal LOAEL was 60 mg/kg/day based on increased absolute and
relative liver weights. The developmental NOAEL was 30 mg/kg/day and the
developmental LOAEL was 60 mg/kg/day based on delayed ossification of
thoracic, cervical and sacral vertebrae, sternum and limbs plus an
increase in supernumerary ribs.

b.	In a developmental toxicity study, pregnant female rabbits were
gavaged with technical tebuconazole at levels of 0, 10, 30, or 100
mg/kg/day between days 6 and 18 of gestation. The maternal NOAEL was 30
mg/kg/day and the maternal LOAEL was 100 mg/kg/day based on minimal
depression of body weight gains and food consumption. The developmental
NOAEL was 30 mg/kg/day and the developmental LOAEL was 100 mg/kg/day
based on increased postimplantation losses, malformations in 8 fetuses
out of 5 litters (including peromelia in 5 fetuses/4 litters;
palatoschisis in 1 fetus/1 litter), hydrocephalus and delayed
ossification.

c.	In a developmental toxicity study, pregnant female mice were gavaged
with technical tebuconazole at levels of 0, 10, 30, or 100 mg/kg/day
between days 6 and 15 of gestation (part 1 of study) or at levels of 0,
10, 20, 30, or 100 mg/kg/day between days 6 and 15 of gestation (part 2
of study). The maternal NOAEL was 10 mg/kg/day and the maternal LOAEL
was 20 mg/kg/day. Maternal toxicity (hepatocellular vacuolation and
elevations in AST, ALP and alkaline phosphatase) occurred at all dose
levels but was minimal at 10 mg/kg/day. Reduction in mean corpuscular
volume in parallel with reduced hematocrit occurred at doses greater
than or equal to 20 mg/kg/day. The liver was the target organ. The
developomental NOAEL was 10 mg/kg/day and the developmental LOAEL was 30
mg/kg/day based on an increase in the number of runts.    

d.	In a developmental toxicity study, pregnant female mice were
administered dermal doses of technical tebuconazole applied at levels of
0, 100, 300, or 1,000 mg/kg/day between days 6 and 15 of gestation.
Equivocal maternal toxicity was observed 1,000 mg/kg/day.  The maternal
NOAEL was <nearly-eq> 1,000 mg/kg/day. The developmental NOAEL was 1,000
mg/kg/day.

e.	In a 2-generation reproduction study, rats were fed technical
tebuconazole at levels of 0, 100, 300, or 1,000 ppm, (0, 5, 15, or 50
mg/kg/day, males and females). The parental maternal NOAEL was 15
mg/kg/day and the parental LOAEL was 50 mg/kg/day based on depressed
body weights, increased spleen hemosiderosis and decreased liver and
kidney weights. The reproductive NOAEL was 15 mg/kg/day and the
reproductive LOAEL of 50 mg/kg/day based on decreased pup body weights
from birth through 3 - 4 weeks. In a developmental neurotoxicity study,
pregnant female rats were fed a nominal concentration of 0, 100, 300 or
1000 ppm of tebuconazole in the diet.  The NOAEL for maternal toxicity
in this study was 300 ppm (based on mortality, body weight and feed
consumption reductions, and prolonged gestation in the1000 ppm dosage
group).  The 1000 ppm dose level was considered to be excessively toxic
for the F1 offspring, based on mortality, marked reductions in pup body
weight and body weight gain, reduction in pup absolute brain weight (at
postpartum day (PD) 12 and adult), a developmental delay in vaginal
patency, and decreased cerebellar thickness.  The effects on brain
weight and morphology are considered to represent incomplete
compensation for the marked decrease in body weight gain during
development.  By approximately day 80 postpartum, the body weight had
completely recovered in the females but was still reduced (89% of the
control group value) in the males.  The brain weights had shown an
incomplete recovery (90% to 93% of the control group values) in both
sexes. The EPA has determined that the  LOAEL for offspring toxicity in
this study is 100  ppm..  Technical grade tebuconazole did not cause any
specific neurobehavioral effects in the offspring when administered to
the dams during gestation and lactation at dietary concentrations up to
and including 1000 ppm.>

<	4. Subchronic toxicity.   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 

a. 	In a 90-day oral feeding study, rats were administered technical
tebuconazole at levels of 0, 100, 400, or 1,600 ppm (0, 8, 34.8, or
171.7 mg/kg/day for males or 0, 10.8, 46.5, or 235.2 mg/kg/day for
females). In males, the no observed adverse effect level (NOAEL) was
34.8 mg/kg/day and the lowest observed adverse effect level (LOAEL) was
171.7 mg/kg/day based on decreased body weight and decreased body weight
gain, adrenal vacuolation and spleen hemosiderosis. In females, the
NOAEL was 10.8 mg/kg/day and the LOAEL of 46.5 mg/kg/day was based on
adrenal vacuolation.

b.	In a 90-day oral feeding study, Beagle dogs were administered
technical tebuconazole at levels of 0, 200, 1,000, or 5,000 ppm (0, 74,
368, or 1,749 mg/kg/day for males or 0, 73, 352, or 1,725 mg/kg/day for
females). In females, the NOAEL was 73 mg/kg/day and the LOAEL was 352
mg/kg/day based on decreased body weight and decreased body weight gain,
decreased food consumption and increased liver N-demethylase activity.
At the highest dose tested (HDT), lens opacity was seen in all males and
in one female and cataracts were seen in three females.

c.	In a 21-day dermal toxicity study, rabbits were exposed dermally to
technical tebuconazole 5 days a week at doses of 0, 50, 250, or 1,000
mg/kg/day. No significant systemic effects were seen. The systemic NOAEL
> 1,000 mg/kg/day.

d.	In a 21-day inhalation toxicity study, rats were exposed to technical
tebuconazole (15 exposures - 6 hours/day for 3 weeks) at airborne
concentrations of 0, 0.0012, 0.0106, or 0.1558 mg/L/day. The NOAEL was
0.0106 mg/L/day and the LOAEL was 0.1558 mg/L/day based on piloerection
and induction of liver N-demethylase. >

<	5. Chronic toxicity.   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 

a.	 In a 2-year combined chronic feeding/carcinogenicity study, rats
were administered technical tebuconazole at levels of 0, 100, 300, or
1,000 ppm (0, 5.3, 15.9, or 55 mg/kg/day for males or 0, 7.4, 22.8, or
86.3 mg/kg/day for females). In males, the NOAEL was 5.3 mg/kg/day and
the LOAEL was 15.9 mg/kg/day based on C-cell hyperplasia in the thyroid
gland. In females, the NOAEL was 7.4 mg/kg/day and the LOAEL was 22.8
mg/kg/day based on body weight depression, decreased hemoglobin,
hematocrit, mean corpuscular volume and mean corpuscular hemoglobin
concentration and increased liver microsomal enzymes. No evidence of
carcinogenicity was found at the levels tested.

b.	In a 1-year chronic feeding study, Beagle dogs were administered
technical tebuconazole at levels of 0, 40, 200, or 1,000 (weeks 1-39)
and 2,000 ppm (weeks 40-52) (0, 1, 5 or 25/50 mg/kg/day for males and
females). The NOAEL was 1 mg/kg/day and the LOAEL was 5 mg/kg/day based
on ocular lesions (lenticular and corneal opacity) and hepatic toxicity
(changes in the appearance of the liver and increased siderosis).

c.	In a 1-year chronic feeding study, Beagle dogs were administered
technical tebuconazole at levels of 0, 100, or 150 ppm (0, 3.0, or 4.4
mg/kg/day for males or 0, 3.0 or 4.5 mg/kg/day for females). The NOAEL
was 3.0 mg/kg/day and the LOAEL was 4.4 mg/kg/day based on adrenal
affects in both sexes. In males there was hypertrophy of adrenal zona
fasciculata cells amounting to 4/4 at 150 ppm and to 0/4 at 100 ppm and
in controls. Other adrenal findings in males included fatty changes in
the zona glomerulosa (3/4) and lipid hyperplasia in the cortex (2/4) at
150 ppm vs. (1/4) for both effects at 100 ppm and control dogs. In
females there was hypertrophy of zona fasciculata cells of the adrenal
amounting to 4/4 at 150 ppm and to 0/4 at 100 ppm and 1/4 in controls.
Fatty changes in the zona glomerulosa of the female adrenal amounted to
2/4 at 150 ppm and to 1/4 at 100 ppm and in controls.

d.	In a 91-week carcinogenicity study, mice were administered technical
tebuconazole at levels of 0, 500, or 1,500 ppm (0, 84.9, or 279
mg/kg/day for males or 0, 103.1, or 365.5 mg/kg/day for females).
Neoplastic histopathology consisted of statistically significant
increased incidences of hepatocellular neoplasms; adenomas (35.4%) and
carcinomas (20.8%) at 1,500 ppm in males and carcinomas (26.1%) at 1,500
ppm in females. Statistically significant decreased body weights and
increased food consumption were reported that were consistent with
decreased food efficiency at 500 and 1,500 ppm in males and at 1,500 ppm
in females. Clinical chemistry values (dose-dependent increases in
plasma GOT, GPT and Alkaline Phosphatase) for both sexes were consistent
with hepatotoxic effects at both 500 and 1,500 ppm. Relative liver
weight increases reached statistical significance at both 500 and 1,500
ppm in males and at 1,500 ppm in females. Non-neoplastic histopathology
included dose-dependent increases in hepatic pancinar fine fatty
vacuolation, statistically significant at 500 and 1,500 ppm in males and
at 1,500 ppm in females. Other histopathology included significant oval
cell proliferation in both sexes and dose-dependent ovarian atrophy that
was statistically significant at 500 and 1,500 ppm. The Maximum
Tolerated Dose (MTD) was achieved at or around 500 ppm.>

<	6. Animal metabolism.   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 Rats
were gavaged with 1 or 20 mg/kg radio-labeled technical tebuconazole.
98.1 % of the oral dose was absorbed. Within 72 hours of dosing, over
87% of the dose was excreted in urine and feces. At sacrifice (72 hours
post dosing), total residue (-GI tract) amounted to 0.63% of the dose. A
total of 10 compounds were identified in the excreta. A large fraction
of the identified metabolites corresponded to successive oxidations
steps of a methyl group of the test material. At 20 mg/kg, changes in
detoxication patterns may be occurring.

>

<	<	7. Endocrine disruption. [  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r
1 No special studies investigating potential estrogenic or endocrine
effects of tebuconazole have been conducted. However, the standard
battery of required studies has been completed. These studies include an
evaluation of the potential effects on reproduction and development, and
an evaluation of the pathology of the endocrine organs following
repeated or long-term exposure. These studies are generally considered
to be sufficient to detect any endocrine effects but no such effects
were noted in any of the studies with either tebuconazole or its
metabolites.>

<C. Aggregate Exposure>

<	1. Dietary exposure.   SEQ CHAPTER \h \r 1 Assessments, using the DEEM
FCID Version 2.0, 1994-1996,98 CSFII software,  were conducted to
evaluate potential risks due to chronic and acute dietary (food and
water) exposure of the U.S. population and selected population subgroups
to residues of tebuconazole.  These analyses cover all registered crops,
current Section 18 uses, pending uses listed in EPA’s Multi-Year
Workplan for Registration of Conventional Pesticides with an OPP
expected completion date of 1st quarter 2007, plus the following new
uses proposed by IR-4 for tebuconazole: bulb vegetables group 3, leafy
brassica greens subgroup 5B, and garden beets. 

The EPA used the LOAEL of 8.8 mg/kg/day from a tebuconazole rat
developmental neurotoxicity study and an uncertainty factor of 1,000 to
establish the acute and chronic population adjusted doses (aPAD and
cPAD, respectively) at 0.0088 mg/kg. 

Results from the acute and chronic dietary exposure analyses described
below demonstrate a reasonable certainty that no harm to the overall
U.S. population or any population subgroup will result from the use of
tebuconazole on currently registered uses, Section 18 uses, and pending
uses.>

<	i. Food.   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 An acute and
chronic, Tier 3 dietary (food) risk assessments were conducted using
data from field trials and data from PDP where appropriate. The acute
analysis indicated that the most highly exposed population subgroup was
all infants < 1 year with an exposure equal to 82.8% of the aPAD. The
U.S. total population had an exposure equal to 53.4% of the aPAD. The
chronic analysis also showed that the most highly exposed population
subgroup was infants <1 year with an exposure equal to 12.7% of the
cPAD. The total U.S. population had a chronic exposure equal to 4.9% of
the cPAD. These exposure estimates are below EPA’s level of concern.>

<	ii. Drinking Food. Acute and chronic exposure estimates from water are
included in the exposure values given above for food. These exposure
extimates are below EPA’s level of concern.>

<	2. Non-dietary exposure.   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1
Tebuconazole is currently registered for use on the following
residential non-food sites: residential application to roses, flowers,
trees and shrubs; the formulation of wood-based composite products; wood
products for in-ground contact; plastics; exterior paints, glues and
adhesives.  Residential exposure to homeowners who mix, load and apply
tebuconazole to roses, flowers, trees and shrubs as well as
post-application exposure of adults and youth (age 10-12) to
tebuconazole residues from this use was assessed. (Based on the US EPA
residential exposure SOPs, the use pattern precludes likely
post-application exposure to younger age groups.)  Short-term and
intermediate-term margins of exposure for homeowners mixing, loading and
applying tebuconazole using pump  sprayers and hose-end sprayers were
3040 and 218, respectively. Chronic margins-of-exposure for the
homeowner mixer/loader/applicator using the same equipment were 14,900
and 1070 ppm, respectively. Short-term and intermediate-term margins of
post-application exposure for adults ranged from 408 - 2120. The
margins-of exposure for youth ranged from 712 to 3700. Chronic margins
of post-application exposure exceeded 4930 for adults and youth.  

For the remaining uses (wood treatment, plastics, paints, glues and
adhesives) EPA has determined that exposure via incidental ingestion (by
children) and inhalation is not a concern for these products which are
used outdoors.  A non-dietary assessment of exposure to tebuconazole
from the copper tebuconazole-treated wood showed all tebuconazole MOEs
exceeding 10,000. Therefore, there is no unacceptable risk associated
with this use for tebuconazole.>

<D. Cumulative Effects>

<	  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 Tebuconazole is a member
of the triazole class of systemic fungicides. At this time, the EPA has
not made a determination that tebuconazole and other substances that may
have a common mechanism of toxicity would have cumulative effects.
Therefore, for this tolerance petition, it is assumed that tebuconazole
does not have a common mechanism of toxicity with other substances and
only the potential risks of tebuconazole in its aggregate exposure are
considered. The cumulative effects of the primary common metabolites
(1,2,4-triazole and its TA and TAA conjugates are being addressed by the
US Triazole Task Force.>

<E. Safety Determination>

<	1. U.S. population.   SEQ CHAPTER \h \r 1 Based on the information
supplied under Aggregate Exposure describe above, there is reasonable
certainty that exposure from tebuconazole will not result in harm to the
adult U.S. population.>

<	2. Infants and children.   SEQ CHAPTER \h \r 1 Based on the
information supplied under Aggregate Exposure describe above, there is
reasonable certainty that exposure from tebuconazole will not result in
harm to infants and children.>

<F. International Tolerances>

<	No Codex MRLs have been established for tebuconazole on the pending
crops bulb vegetables group 3, leafy brassica greens subgroup 5B, and
garden beets. MRLs for tebuconazole have been established for these
crops in various countries as follows:

Bulb vegetables group 3 or members of the group: Austria, Brazil,
France, Germany, Japan, Korea, Netherlands, South Africa, and Spain

Leafy brassica greens subgroup 5B: Germany, Japan, Netherlands, and
Spain

Garden beets: Brazil (beet root).>