Document ID: EPA-HQ-OPP-2005-0097-0019
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-12-03T05:00Z

EPA Registration Division contact: Laura Nollen, (703) 305-7390

Interregional Research Project Number 4 (IR-4)

Petition Number (PP#) 8E7428

EPA has received a pesticide petition 8E7428 from IR-4, IR-4 Project
Headquarters, Rutgers, The State University of NJ, 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 raising the existing tolerance
for residues of the fungicide tebuconazole
(alpha-[2-(4-chlorophenyl)-ethyl]-alpha-(1,1-dimethylethyl)-1H-1,2,4-tri
azole-1-ethanol), in or on the raw agricultural commodity cherry from
4.0 to 5.0 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 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. IR-4 received requests from South Carolina,
New Jersey, Illinois, Alabama, California, Texas, Oklahoma, and New York
for the use of tebuconazole as a minor post-harvest treatment on fresh
market cherries. To support these requests, magnitude of residue data
were collected from EPA regions 5, 10, and 11. Field trials were
conducted in Michigan (region 5), California (region 10), and Washington
(two trials, region 11). Tebuconazole residues in treated samples ranged
from 0.33 to 3.55 ppm.

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.   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. 

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 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. Metabolite toxicology.   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1
NA

	8. 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 The EPA’s April 18, 2008
Tebuconazole Human Health Risk Assessment included all uses including
the pending use for post-harvest use on cherries. This 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. 

Results from EPA’s April 18, 2008 Tebuconazole Human Health Risk
Assessment show that that no harm to the overall U.S. population or any
population subgroup will result from the use of tebuconazole on
currently registered uses and pending uses including post-harvest
applications to cherries.

	i. Food. EPA’s acute dietary analysis reported in their April 18,
2008 Tebuconazole Human Health Risk Assessment showed that the most
highly exposed population subgroup was all infants < 1 year with an
exposure equal to 53% of the aPAD. The U.S. total population had an
exposure equal to 28% of the aPAD. The chronic analysis also showed that
the most highly exposed population subgroup was infants <1 year with an
exposure equal to 11% of the cPAD. The total U.S. population had a
chronic exposure equal to 4% 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; 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
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 Tolerance

	International tolerances/MRLs for tebuconazole have been established
for many crops including cherries and other stone fruit in many
countries. Codex and EU MRLs have been established for tebuconazole on
cherries at 5 ppm.