Document ID: EPA-HQ-OPP-2012-0427-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-08-22T04:00Z

EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR PESTICIDE
PETITION  

Docket ID Number:  EPA-HQ-OPP-2012-0427

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

Interregional Research Project Number 4 

Pesticide Petition Number:  PP 2E8012

	EPA has received a pesticide petition (PP 2E8012) from  [Interregional
Research Project No. 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 amending the tolerances for residues of tebuconazole,
alpha-[2-(4-chlorophenyl)ethyl]-alpha-(1,1-dimethylethyl)-1H-1,2,4-triaz
ole-1-ethanol, including its metabolites and degradates, in or on the
raw agricultural commodity barley, grain at 0.3 parts per million (ppm);
vegetable, cucurbit group 9 at 0.4 parts per million (ppm); and
vegetable, fruiting group 8-10 at 1.3 ppm.  Further, this petition
proposes to delete the existing tolerance vegetable, fruiting, group 8
at 1.3 ppm once the proposed tolerance has been established since the
proposed new tolerance will supersede the existing tolerance. 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 support 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. 

Bayer CropScience has previously provided US EPA with residue studies
which support the existing US tolerances of 0.09 ppm on cucurbits and
0.15 ppm on barley grain. Additional trials to fulfill conditional
requirements of registration were conducted. As a result, this petition
proposes increasing the US tolerances for cucurbit vegetables to 0.4 ppm
and for barley grain to 0.3 ppm.

In a magnitude of residue study on cantaloupe conducted by IR-4, two
trials were conducted in California (region 10) as requested by US EPA
as a condition of registration.  In each trial, three broadcast foliar
applications of Folicur 3.6F were made at a target label rate of 0.225
lb a.i./A/application for a total target application rate of 0.675 lb
ai/A.  The actual total amount applied in each trial was 0.684 and 0.695
lb ai/A.  Applications were made 10 – 13 days apart with a 6 or 7 day
PHI.

A magnitude of residue study was also conducted by IR-4 on Barley.  In
this study, three trials were conducted, one in region 10 (California)
and two in region 11 (Idaho and Washington) as requested by US EPA as a
condition of registration.  In each trial, one foliar application of
Folicur 3.6F was made at a target label rate of 0.1125 lbs ai/A.  Actual
application rates ranged from 0.1088 to 0.1149 lb ai/A with a PHI of 29
or 31 days.     

Residues in trials conducted according to the critical GAP range on
cantaloupe from 0.05 to 0.24 ppm (n=4), and on barley from 0.0666 ppm to
0.280 ppm (n=6).

B. Toxicological Profile

	1. Acute toxicity.    SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1
Tebuconazole exhibits moderate toxicity. The rat acute oral LD50 = 3,933
milligram/kilogram (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. 

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 no-observed adverse
effect level (NOAEL) was 30 mg/kg/day and the maternal lowest-observed
adverse effect level (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. 

f.	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 NOAEL was 34.8 mg/kg/day and the 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. 

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. Metabolite toxicology. Not applicable

	8. Endocrine disruption. Tebuconazole was one of the chemicals included
in List 1 of the EPA Endocrine Disruptor Screening Program (EDSP). BCS
has received the EDSP Test Order and has committed to fulfilling the
requirements as appropriate.

C. Aggregate Exposure

	1. Dietary exposure. 

  SEQ CHAPTER \h \r 1 The EPA’s April 18, 2008 Tebuconazole Human
Health Risk Assessment used the LOAEL of 8.8 mg/kg/day from a
tebuconazole rat developmental neurotoxicity study and an uncertainty
factor of 300 to establish the acute and chronic population adjusted
doses (aPAD and cPAD, respectively) at 0.029 mg/kg/day. 

The higher residue values for cucurbit vegetables and barley grain were
included in the dietary exposure assessment. A tier 3 dietary assessment
was conducted to evaluate exposure for the U.S. population and all
appropriate subgroups. Results of this assessment show that no harm to
the overall U.S. population or any population subgroup will result from
the use of tebuconazole on currently registered uses when incorporating
the additional residue results.>

<	i. Food. A tier 3 dietary assessment (using DEEM FCID Version 2.0,
1994-1996, 98 CSFII)  including all of the current and pending uses of
tebuconazole showed that the most highly exposed population subgroup for
food only for the acute assessment was children 1-2 with an exposure
equal to 19.3% of the aPAD. The U.S. total population had an exposure
for food only equal to 11.5% of the aPAD. The chronic analysis for food
only showed that the most highly exposed population subgroup was
children 1-2 with an exposure equal to 1.2% of the cPAD. The total U.S.
population had a chronic exposure equal to 0.6% of the cPAD. These
exposure estimates are below EPA’s level of concern.>

<	ii. Drinking water. Acute and chronic exposure estimates for combined
food plus water intake are also below EPA’s level of concern. Assuming
an acute drinking water level of 33.8 ppb,  the most highly exposed
population subgroup for food plus water was infants <1 year with an
exposure equal to 25.1% of the aPAD.  The U.S. total population had an
exposure for food plus water equal to 13.5% of the aPAD.  Assuming a
chronic drinking water level of 15.2 ppb, the chronic analysis for food
plus water showed that the most highly exposed population subgroup was
infants < 1 year with an exposure equal to 4.5% of the cPAD. The total
U.S. population had a chronic exposure equal to 2.8% of the cPAD.>

	

	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; glues and adhesives.  EPA in
their April 18 2008 Human Health Risk Assessment assessed residential
handler, post-application and other exposures (drift etc.) to
homeowners. EPA concluded that exposures to homeowners do not exceed the
level of concern.

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
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

International tolerances/MRLs for tebuconazole have been established for
many crops including, barely and cucurbits. Codex MRLs have been
established on barley grain at 0.2 ppm, on cucumber at 0.2 ppm and on
summer squash at 0.02 ppm. EU MRLs are 2 ppm for barley, 0.5 ppm for
cucumber, 0.2 ppm for muskmelon and 0.2 ppm on summer squash.

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