Document ID: EPA-HQ-OPP-2006-0075-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-06-11T04:00Z

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE

(1/1/2005)

EPA Registration Division contact: Dan Peacock (703) 305-5407	

		

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Gowan Company

9E5059

	EPA has received a pesticide petition (9E5059) from Gowan Company, 370
S. Main Street, Yuma, AZ 85364 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 by establishing a tolerance for residues of
fenazaquin in or on the raw agricultural commodity apples at 0.2 parts
per million (ppm), pears at 0.2 ppm and citrus fruits at 0.5 ppm. EPA
has determined that the petition contains data or information regarding
the elements set forth in section 408(d)(2) of the FFDCA; 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.

                                      

. 

Apples:  Two studies were conducted.  In the first study, apple trees
were foliar-treated with C14-fenazaquin (two positions) using a 2x
maximum label rate when the apples were approximately 2.5 cm in size
(early treatment) and 5 weeks later (late treatment).  Apples were
harvested at maturity approximately 15 weeks after the early treatment
and 10 weeks after the late treatment.  Depending on position of the
label the TRR (total radioactive residue) was 0.136 ppm and 0.161 ppm in
whole apples treated early in the season.  The TRR of the apples treated
later was 0.367 and 0.498 ppm depending upon the position of the
radiolabel.  At both application times, 85 to 90% of the TRR was in the
peel.  Parent fenazaquin was identified as the major component of the
TRR (20%).  The remaining extractable radioactivity was identified as 
photoproducts.  Approximately 40 to 55% of the peel TRR was
nonextractable and appeared to be located in the cutin fraction of the
peel.  None of the extractable metabolites in the pulp were present at
high enough levels for identification.

In the second study, apple trees were foliar-treated with approximately
1.3x the maximum use rate in an early and late treatment as described
above.  The TRR (total radioactive residue) were 0.048 ppm or 0.040 ppm
depending upon the position of the radiolabel in whole apples treated
early in the season.  In the late season treatment, the TRR was 0.120 or
0.168 ppm.  Regardless of the application time, 74 to 91% of the TRR was
in the peel and solvent surface wash with only 9 to 26% in the pulp. 
Fenazaquin and Metabolite A (a labile dimer of fenazaquin that converts
back to parent) are the major substances identified in apples.  These
accounted for approximately 24.7 to 34.6% of the TRR (0.01 to 0.016 ppm)
in apples receiving the early application and approximately 47.1 to
55.7% of the TRR (0.067 to 0.078ppm) in apples receiving the late
application.

Oranges:  Orange trees were foliar treated with radiolabeled fenazaquin
(two positions) at approximately 4x the maximum use rate.  Two trees
were treated 191 days before fruit harvest (early treatment) and two
trees were treated 63 days before fruit harvest (late treatment).  The
mean TRR was equivalent to 0.313 ppm and 0.580 ppm in the early and late
treatments, respectively.  Approximately 90% and 98% of the TRR was
located in the peel in the early and late applications, respectively.

Parent fenazaquin was the major metabolite  constituting 46% of the TRR
in the early application and 60% in the late application.  A metabolite
hydroxylated in the quinazoline ring represented approximately 7% of the
TRR in the early treatment.

Conclusion:  These metabolism studies support the import tolerances on
apples, pears and citrus.  The similarities of metabolic patterns for
fenazaquin in these two crops is sufficient to define the pathway of
fenazaquin metabolism in plants.  These studies show the breakdown of
fenazaquin occurs primarily by photodegradation; therefore the metabolic
pathway in other crops is likely to be similar.

. 

	

A method for the determination of fenazaquin residues in raw and
processed commodities has been developed and validated.  The general
method includes extraction with acetonitrile:water and partitioning into
hexane.  Cleanup is accomplished by solid phase chromatography using
Florisel and aminopropyl cartridges.  The final eluate is evaporated and
the residuum is reconstituted in trimethylpentane containing
1,4-dibromonapthlene, an internal standard.  Resides of fenazaquin are
quantified using gas chromatography/mass spectrometry (GC/MS) with
selected ion monitoring.  The limit of quantitation (LOQ) is 0.01 mg/kg
for all matrices tested.

. 

Field trials have been conducted in apples, pears, oranges, mandarins,
and lemons. 

Apples and Pears:  Magnitude of the Residue trials have been conducted
in Argentina, Chile, France, Germany, Italy, New Zealand, Spain, South
Africa and the United Kingdom.  The data indicate that an import
tolerance of 0.2 ppm is appropriate to support the typical use patterns
of fenazaquin in these commodities.  

.  

The acute oral toxicity of technical fenazaquin in the rat is 134 mg/kg
in males and 136 mg/kg in females.

A battery of genotoxicity studies has been performed on fenazaquin.  

. 

In vitro Gene Mutation:  A Salmonella typhimurium gene mutation assay
was performed with and without activation in strains TA98, TA100,
TA1535, and TA 1537 at concentrations up to 3 mg/plate.  An Escherichia
coli test using strain WP2 uvrA was also performed.  These tests were
negative both in the presence and absence of metabolic activation
systems.  A mouse lymphoma L5178Y TK+/- assay was done at concentrations
up to 12 ug/ml in the presence of S9 activation and up to 20 ug/ml
without activation.    There was an increase in mutation frequency in
the activated treatments that also displayed high cytotoxicity and low
cloning efficiency.  Fenazaquin was tested in an in vitro Unscheduled
DNA Synthesis assay (UDS) at concentrations up to 5 ug/ml.  Fenazaquin
was not genotoxic in this UDS assay.

In vitro Chromosomal Aberration:  Fenazaquin was evaluated in two
independent Chinese hamster ovary cell (CHO) chromosome aberration
assays at concentrations up to 1 or 4 ug/ml without activation and up to
60 or 50 ug/ml in the presence of activation.  Fenazaquin was negative
in both tests.  

In vivo Gene Mutation:  It was shown that fenazaquin did not induce in
vivo unscheduled DNA synthesis in rat liver in rats exposed to up to 600
mg/kg.

In vivo Chromosomal Aberration:  In a mouse bone marrow micronucleus
study, fenazaquin was administered to ICR mice by gavage in two doses
separated by 24 hours.  Micronuclei were evaluated 24 hours following
the second dose.  No micronuclei were observed at the highest dose of
1600 males or 1200 females.  An in vivo sister chromatid exchange (SCE)
study was performed in CD-1 male mice at doses up to 2000 mg/kg. 
Fenazaquin did not induce SCEs in bone marrow even at overtly toxic
doses.

Overall:  Based on a weight of the evidence evaluation, fenazaquin is
non-genotoxic.

Rat Dietary: Groups of ten male and ten female Fischer 344 rats were fed
98% fenazaquin for three months at dietary levels of 0, 15, 45, 150, or
450 ppm (1.0, 3.0, 9.6, or 28.7 mg/kg/day and 1.2, 3.5, 11.5, or 33.0
mg/kg/day males and females, respectively).  The predominant
toxicological effects observed were decreases in growth and food
consumption at 450 ppm.  The NOAEL was judged to be 150 ppm (9.6 mg/kg/d
in the males, 11.5 mg/kg/d in the females).

Rat Gavage: Male and female Fischer 344 rats were administered 98%
fenazaquin in 10% aqueous acacia by gavage for three months at dosages
of 0, 1, 3, 10, or 30 mg/kg/day.  Toxicologically significant decreases
in growth, food consumption and food utilization efficiency were
observed at 30 mg/kg/day.  The NOAEL was considered to be 10 mg
fenazaquin/kg/day.

Hamster Gavage:  Syrian golden hamsters (15/sex/dose) were administered
98% fenazaquin in 10% acacia by gavage at dosages of 0, 5, 25, 75, or
150 mg/kg/day in the males and 0, 5, 25, 50, or 100 mg/kg/day in the
females.  Although the mouse is generally the species of choice, the
hamster was used based on pharmacokinetic considerations. The mouse
excreted fenazaquin much more rapidly than either the rat or hamster.  
Severe decreases in body weight gain were observed at 75/50 and 175/100
mg/kg/day in both males and females.  Although minor increases in
hepatic enzyme activity occurred at doses equal to or grater than 25
mg/kg/day, these changes were not correlated with any histopathologic
findings and were therefore, considered to be toxicologically
insignificant.  Statistically significant histopathological changes of
testicular atrophy were noted in the 75 and 150 mg/kg/day males.  Based
on body weight and related effects, the NOAEL was considered to be 25
mg/kg/day.

Dog Dietary:  Groups of four male and four female six-month old Beagle
dogs were administered diets containing technical fenazaquin (98%) at 0,
1, 5, or 15 mg/kg/day.  Body weight, weight gain and food consumption
were all decreased in the 15 mg/kg/day dose groups.  Cholesterol and
potassium levels in the high-dose groups were significantly lowered and
elevated, respectively.  A decrease in vacuolation of hepatocytes was
observed in the 15 mg/kg/day animals.  Based on these effects, the NOAEL
was judged to be 5 mg/kg/day.

Syrian golden hamster:  Male and female Syrian golden hamsters were
administered daily gavage doses of 0, 2, 25, 30 (male) and 35 (female)
mg/kg/day of 97-98% fenazaquin in 10% acacia for 18 months.  The study
was divided into two parts.  Each study part consisted of 50
controls/sex and 40 animals/sex/treated group.  The studies were
combined for statistical analysis.  Survival was unaffected in the males
and improved in treated females.  The occurrence of Clostridium
difficile on-study required the use of vancomycin to control the
infection.  Body weight gain was reduced in both sexes at doses equal to
and greater than 15 mg/kg/day during the first third of the study;
terminal body weigh was reduced only in the 30 mg/kg/day treated males. 
Treatment related changes were noted in hematology and clinical
chemistry at doses of 15 mg/kg/day and above but were of minimal
toxicological significance.  

Statistically significant changes in both absolute and/or relative organ
weights were observed in the spleen and kidneys of males and females and
the thyroid of females treated with doses 15 mg/kg/day and above. 
Increases in relative heart, brain and testes weights in the high dose
males are considered secondary to the reduced body weight in this group.
 The only treatment related pathologic changes were decreases in the
incidence and severity of amyloidosis in both sexes and an increase in
the incidence of enterotoxic enteritis.  The NOAEL was considered to be
2 mg/kg/day based on reduced body weight gain and changes in hematology
and clinical chemistry parameters.

Dog:  In a 1-year study, 98% fenazaquin was fed to groups of 4
beagles/sex/dose at doses of 0, 1, 5, and 15 mg/kg/day.  Due to
palatability problems, the 15 mg/kg/day dose was lowered to 10 mg/kg/day
on day 95 giving an overall time-weighted consumption value of 12
mg/kg/day.   Body weight gain was reduced at the intermediate and top
doses compared to controls, however this was attributed primarily to a
single large control male.   Food consumption appeared to be reduced at
the top dose.  High dose males showed increased ALT and creatine kinase
activities and reduced cholesterol values throughout the study.  No
treatment related pathological abnormalities were recorded.  Based on
reduced body weights, the NOEL was judged to be 5 mg/kg/day.  Since the
reduction in body weight observed in the high dose group was associated
with decreased food consumption and was not associated with any other
toxicological change or histopathological finding, it was concluded that
the NOAEL was 12 mg/kg/day.

Rat:  In a two year chronic/oncogenicity study, groups of 60 male and 60
female Fischer 344 rats were administered diets containing 0, 10, 100,
200, and 400 ppm males or 450 ppm females.  There were no
treatment-related effects on survival or clinical signs of toxicity for
any treated group.  Body weight, body weight gain, food consumption and
efficiency of food utilization were significantly decreased throughout
most of the treatment period for animals receiving fenazaquin at dose
levels of 200 ppm and above.  There were mild to moderate dose
responsive decreases in serum cholesterol and triglyceride
concentrations at dosages of 200 ppm and above.  

The only lesion which was associated with treatment was hepatocellular
atypia in males receiving  100 ppm fenazaquin and higher.  The incidence
but not the severity was increased compared to control males.  Foci of
hepatic cellular alteration are spontaneous in Fischer 344 rats. 
Although these lesions may be precursors of hepatocellular neoplasia,
this was not observed after 24 months of exposure,  indicating that the
hepatic cellular changes were not a preneoplastic condition.  The NOAEL 
for fenazaquin in this study was considered to be 10 ppm (0.46 mg/kg/day
males, 0.57 mg/kg/day females) based on the finding of hepatocellular
atypia in males at 100 ppm fenazaquin.

The metabolism of fenazaquin is well understood.  Several metabolism
studies were performed in rats using mixtures of fenazaquin, labeled
uniformly in either the t-butyl phenyl ring or the quinazoline-phenyl
ring at doses of 1, 10, or 30 mg/kg.  

Absorption occurs within 8 hours and excretion in 24 hours with 75%
excreted within 48 hours and 84-98% within 72 hours.  The majority of
the fenazaquin is excreted in the feces (approximately 80%) with the
remainder in the urine.  Less than 2% of the radioactivity remained in
the carcass.  No radioactivity was exhaled within 48 hours of dosing
indicating that the phenyl rings were not cleaved.  Tissue levels after
7 days were low with the highest levels found in the ovaries and fat
(<0.01%).  There was no difference in excretion patterns based on sex or
dosing regime.   Fenazaquin represented between 1.2 to 20.6% of the
total fecal radioactivity.  Three major metabolites were identified in
the feces.  Two were the result of oxidation of one of the methyl groups
on the dimethylethyl sidechain to either an alcohol or carboxylic acid. 
The third was the result of oxidation of the same methyl group on the
dimethylethyl sidechain plus oxidation of the two position of the
quinazoline ring to give a phenolic-like hydroxyl group.  The
characterized urinary metabolite is produced by cleavage of the ether
bridge.  None of the metabolites found in urine were observed in feces. 

The pharmacokinetics of fenazaquin was compared in F344 rats, CD-1 mice
and Syrian golden hamsters.  Based on the relative toxicity of
fenazaquin to each species, doses in rats were 1, 10, and 30 mg/kg; in
hamsters 5, 25, and 125 mg/kg; in mice 30, 300 and 750 mg/kg.  Results
show doses of  < 30 mg/kg are rapidly absorbed in mice and hamsters with
relatively slow but prolonged absorption in the rats.  There is evidence
of saturation of the metabolism of fenazaquin at 125 mg/kg in hamsters
and at 750 mg/kg in mice.  In mice, plasma concentrations dropped
rapidly at 30 mg/kg but at 300 and 750 mg/kg the decline was slower and
more extended, with evidence of a second peak in plasma concentrations
at approximately 48 hours.  In rats and hamsters, plasma half lives and
profiles were similar irrespective of administered dose, although
hamsters showed a longer half life. 

No toxicological studies on presumptive metabolites were performed.

No evidence of estrogenic or anti-estrogenic activity was present in the
available animal studies. The developmental toxicity and reproductive
toxicity studies showed no effects suggestive of endocrine disruption
(i.e., change in fetal sex ratios, change in estrous cyclicity or mating
performance, change in fertility, or malformed or altered reproductive
organ development.

.

 

Screening level acute and chronic dietary exposure assessments were
conducted using Dietary Exposure Evaluation Model (DEEM) software
systems, Version 2.04 (acute) and Version 2.00 (chronic).   The 1994-98
USDA food consumption data (CSFII) were used in the assessments.  

Proposed tolerance levels were used for the raw agricultural
commodities.  Based on the processing studies,  fenazaquin does not
concentrate in most processed products for human consumption, with the
exception of citrus peel (10x) and citrus oil (25x).   For the processed
commodities, the proposed tolerances were either set at 1x or were
increased by the appropriate concentration factor.    The highly
conservative assumption of 100% treated crops was assumed for both the
acute and chronic screening assessments.

Acute:   The highest sub-population exposure was to children aged 1 to 2
years, with an exposure estimate of 0.015 mg/kg at the 95th percentile
of exposure and 0.039 mg/kg at the 99.9th percentile of exposure.  
Based on the acute endpoint selected, the most relevant sub-population
group is females 13-50 years.  For this population sub-group the
estimated exposure is 0.0032 mg/kg at the 95th percentile of exposure
and 0.012 mg/kg at the 99.9th percentile.  

Chronic:   The highest exposure was to children 1-2 years, at 0.0042
mg/kg/day.

Both the acute and chronic screening assessments greatly overestimate
the actual anticipated dietary exposures because tolerance values were
used as the basis for the residue inputs and it was assumed that all
imported apples, pears, and citrus were treated with fenazaquin.  				

There is no drinking water exposure to fenazaquin associated with the
proposed import tolerances.

. 

	There is no evidence of increased sensitivity of infants and children
to fenazaquin in the developmental and reproductive toxicity studies.

1.  Acute Risk

To estimate acute exposure risk, the exposure value from food was
compared to the acute Population Adjusted Dose (aPAD).  The acute
endpoint selected was the maternal toxicity NOAEL of 10 mg/kg/day in the
rat developmental study.   Based on an uncertainty factor of 100x, the
aPAD was calculated to be 0.1 mg/kg/day.  

The DEEM assessment predicts that at the 95th percentile, fenazaquin
exposure will comprise 4.6% of the aPAD for the U.S. population, 14.7%
for children aged 1 to 2 years, and 3.3% for females aged 13 to 50 (the
most relevant population subgroup, based on the endpoint selected).   At
the 99.9th percentile, the DEEM assessment predicts that fenazaquin
exposure will comprise 20.6%, 11.7% and 39.1% of the aPAD for the U.S.
population, children aged 1 to 2 years and  females aged 13 to 50,
respectively.   Since acute levels of concern are not reached in a Tier
1 assessment, refinements were not performed.  Based on a screening
level assessment, it can be concluded that there is a reasonable
certainty of no harm to the U.S. population or any population subgroup
from acute dietary exposure to fenazaquin.

2.  Chronic Risk

To estimate chronic exposure risk, the exposure value from food was
compared to the  chronic Population Adjusted Dose (cPAD).   The chronic
endpoint selected was the male rat NOAEL of 0.46 mg/kg/day, based on the
increased incidence of non-neoplastic hepatocellular atypia..  An
uncertainty factor of 100 was assumed, yielding a cPAD of 0.0046
mg/kg/day.  

The DEEM assessment predicts fenazaquin exposure will comprise 21.2% of
the cPAD for the U.S. population and 90.8% for children aged 1 to 2
years.  These estimates represent exposures at tolerance and assume 100%
crop treated.  Since chronic levels of concern are not reached in a
screening assessment, refinements were not performed.   It can be
concluded that there is a reasonable certainty of no harm to the U.S.
population or any population subgroup from chronic dietary exposure to
fenazaquin.

No Codex tolerances have been set for fenazaquin.  For apples, MRLs have
been established in Luxemburg, France Greece, Italy, Spain, Portugal and
 Korea at 0.1 ppm, in Argentina at 0.2 ppm and in Taiwan at 0.5 ppm. 
For pears, MRLs were similar to apples with the exception of Korea which
has an MRL of 0.3 ppm in pears.  Citrus fruits have established MRLs of
0.2 ppm in Spain and  Italy and 0.5 ppm in Greece and Portugal.  Korea
has an established MRL of 0.7 ppm for tangerines.

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