Document ID: EPA-HQ-OPP-2008-0838-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-04-13T04:00Z

<COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE  (9/21/07)>

<EPA Registration Division contact: [insert name and telephone number
with area code]>

 

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<TEMPLATE:>

<[E. I. duPont de Nemours and Company, DuPont Crop Protection]>

<[Insert petition number]>

<	EPA has received a pesticide petition ([insert petition number]) from
[E. I. duPont de Nemours and Company, DuPont Crop Protection], [P. O.
Box 30, Newark, DE 19714-0030] 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.>

<(Options (pick one)>

<	1. by establishing a tolerance for residues of>

<	>

<	[flusilazole
(1[[bis(4-fluorophenyl)methyl-silyl]methyl]-1H-1,2,4-triazole) and its
metabolite IN-F7321 (bis(4-fluorophenyl)methylsilanol) in or on the raw
agricultural commodities [soybean,] at [0.04] parts per million (ppm);
soybean, aspirated grain fractions at 2.6 ppm; soybean, refined oil at
0.1 ppm; wheat, grain at 0.15 ppm; wheat, forage at 25  ppm, wheat,
straw at 7.0 ppm; wheat, aspirated grain fractions at 6.0 ppm; cattle,
fat at 1.5 ppm; cattle, kidney at 5.0 ppm; cattle, liver at 2.0 ppm;
cattle, meat and cattle meat byproducts at 0.40 ppm; goat, fat at 1.5
ppm; goat, kidney at 5.0 ppm; goat, liver, at 2.0 ppm; goat, meat and
goat, meat byproducts at 0.40 ppm; hog, fat at 1.5 ppm; hog, kidney at
5.0 ppm; hog, liver at 2.0 ppm; hog, meat and hog, meat byproducts at
0.40 ppm; horse, fat at 1.5 ppm; horse, kidney at 5.0 ppm; horse, liver
at 2.0 ppm; horse, meat and horse, meat byproducts a 0.40 ppm; milk at
0.20 ppm; milk, fat at 1.3 ppm; sheep, fat at 1.5 ppm; sheep, kidney at
5.0 ppm; sheep, liver at 2.0 ppm; sheep, meat and sheep, meat byproducts
at 0.40 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.>

The metabolic fate of flusilazole in plants is adequately understood. 
Plant metabolism studies conducted with apples, bananas, grapes,
soybeans, sugar beets, and wheat show qualitatively similar metabolism
among the crops.  The metabolic pathway in plants involves
hydroxylations, conjugations, and cleavage between the silicon and the
triazole ring.  As the interval between treatment and sampling
increases, there are decreasing residues of unchanged flusilazole and
increased metabolism and conjugation.  A major metabolic route in plants
is cleavage of the Si-CH2 bond to form a silanol (IN-F7321), which may
be further metabolized to two silane diols or to a disiloxane. 
Hydroxylation can occur on the phenyl ring of intact flusilazole or
IN-F7321 resulting in phenolic metabolites.  The phenolic groups become
the sites for conjugation reactions.  The major plant metabolite arising
from triazole-labeled flusilazole is triazolyl alanine, which is
subsequently metabolized to triazole acetic acid.  Due to the extensive
degradation of flusilazole by multiple mechanisms to many minor
metabolites, there are no major flusilazole metabolites in plants, other
than triazolyl alanine.  Flusilazole and IN-F7321 are proposed to be
included in the tolerance expression.  Triazolyl amine is not included
as it is a common metabolite to all triazole-containing fungicides. 
IN-F7321, while a relatively minor plant metabolite, is unique to
flusilazole and was found to be present in magnitude of the residue
studies in various crops and in livestock feeding studies at low levels.

<	2. Analytical method. [An adequate enforcement method (gas
chromatography/mass-selective detector) is available to enforce the
tolerance expression.  The limit of quantitation (LOQ) is 0.01 ppm for
flusilazole and IN-F7321 for all applicable wheat and soybean
commodities (except wheat straw where the LOQ is 0.02 ppm).  The
estimated limit of detection (LOD) is 0.003 ppm for both flusilazole and
IN-F7321 for all applicable wheat and soybean commodities (except wheat
straw where the LOD is 0.006 ppm).]>

<	3. Magnitude of residues. [Twenty-three field magnitude of residue
trials (including decline at 2 trials) were conducted on soybeans. 
Additional treated plots and larger control plots were included at one
site to produce samples for processing and production of aspirated
grain.  Two applications were made at the use rate of 0.1 lb active
ingredient per acre (ai/A) per application and soybeans were harvested
30 days after the last application (DALA).  The highest average field
trial residue (HAFT) was 0.033 ppm and the average field residue was
0.017 ppm on soybeans for applications at critical label application
parameters.  Aspirated grain fraction (AGF) residues were 0.91 ppm for
flusilazole and 0.12 ppm for IN-F7321.  Processing factors for
flusilazole showed a concentration of residues in soybean oil and AGF of
2.2 and 65 fold, respectively.    Processing factors for IN-F7321 showed
a concentration of residues in soybean oil and AGF of 2.7 and 40 fold,
respectively.    

Twenty-two field residue trials were conducted on wheat.   Two
applications were made at the use rate of 0.125 lb ai/A, the first at
flag-leaf expansion and the second at heading.  Wheat was harvested
21-55 days after the last application.  The maximum flusilazole field
residues were 8.7 ppm, 0.078 ppm, and 2.5 ppm in/on forage (0 DALA),
grain (21-55 DALA), and straw (21-55 DALA), respectively.  The
corresponding maximum IN-F7321 field residues were 1.5 ppm, 0.023 ppm,
and 1.8 ppm in/on forage (0 DALA), grain (21-55 DALA), and straw (21-55
DALA), respectively.  There is no concentration of flusilazole or
IN-F7321 residues in wheat bran, middlings, shorts, low grade flour,
patent flour or in bread baked using the patent flour.  Flusilazole
residues concentrated in light impurity and large screenings by
56.55-and 1.69-fold, respectively, in a grain processing study. 
IN-F7321 residues concentrated in light impurities by 51.85-fold and did
not concentrate in large screenings.  The light impurities fraction
would best represent a wheat aspirated grain fraction sample.]>

<B. Toxicological Profile>

<	1. Acute toxicity.  

[Acute Oral LD50 in Rats		1110 mg/kg M		III>

					  674 mg/kg F

Acute Dermal LD50 in Rabbits	>2000 mg/kg	    		III

Acute Inhalation LC50 in Rats	> 5 mg/L	    		IV

Eye Irritation in Rabbits		Slight	    			IV

Skin Irritation in Rabbits		Mild    			IV

Guinea Pig Skin Sensitization	Not a sensitizer]

<	2. Genotoxicity.

 [Flusilazole was non-genotoxic based on negative results in the
following assays:

	In vitro

	Bacterial gene mutation in with Salmonella typhimurium

		Clastogenicity:  Chromosomal aberrations in cultured human
lymphocytes.

	Mammalian gene mutation assay (CHO/HGPRT)

	Unscheduled DNA Synthesis in cultured rat hepatocytes

	In vivo

	Mouse micronucleus test in mice dosed orally with 375 mg/kg 

	No chromosomal aberrations in bone marrow of rats dosed oral up to 150
mg/kg]>

<3. Reproductive and developmental toxicity.>

[Developmental toxicity of flusilazole has been evaluated by the oral
(feeding and gavage) and dermal routes in rats and by the oral (feeding
and gavage) routes in rabbits. 

The rat maternal and developmental NOAELs in the feeding study were both
100 ppm (9 mg/kg/day) based on reduced weight gain and increased
resorptions and stunted fetuses at the next highest concentration (300
ppm).  There were no increases in malformations at any concentration.

The collective results from several rat gavage studies indicated that
2.0 mg/kg was the lowest maternal NOAEL. This was based on reduced
weight gain and food consumption, clinical signs, and liver and
placental weight increases.  The weight of evidence from these studies
indicated a developmental NOAEL of 2.0 mg/kg/day, based on increased
incidence of skeletal variations at 10 mg/kg/day or above and
malformations at the maternally toxic doses of 50 or 250 mg/kg/day. 

In the rat dermal developmental study, the maternal NOAEL was near 2
mg/kg/day since the only effect observed were microscopic placental
changes without accompanying adverse fetal effects. At the next highest
dose, 10 mg/kg/day, maternal effects included minimal to mild
centrilobular hepatocellular hypertrophy and enlarged placenta. Fetal
effects at 10 mg/kg/day were enlarged livers and increased variations
(rudimentary ribs and unossified sternebra).

In a rabbit dietary developmental study, the NOAEL for the dam was 21.2
mg/kg/day.  The developmental NOAEL was 8.3 mg/kg/day based on decreased
litters and increased resorptions.  The combined results from three
rabbit gavage studies indicated the lowest maternal NOAEL to be 7
mg/kg/day based on increased clinical signs as 15 mg/kg/day.  The lowest
developmental NOAEL was 15 mg/kg/day based on increased resorptions at
higher doses.

The effects of flusilazole on reproductive parameters were investigated
in two multigeneration studies.  The collective results from these
studies indicate a parental NOAEL of 50 ppm (2.85 mg/kg/day) based on
body weight effects at 250 ppm (the highest dose tested). The
reproductive and offspring NOAELs were both 50 ppm (2.85 mg/kg/day)
based on increased gestation length, dystocia and periparturient deaths,
decreased number of pups born alive, and lower pup body weights on
lactation days 14 and 21 at 250 ppm.]

<	4. Subchronic toxicity. 

[Subchronic studies were conducted by feeding in rats, mice and dogs and
by dermal application in rabbits.  In a 90-day feeding study in rats,
the NOAEL was 125 ppm flusilazole (9-11 mg/kg/day) based on elevated
serum cholesterol, increased liver weights, mild liver degeneration, and
mild bladder mucosal hyperplasia at higher doses.

The combined results of two 90-day feeding studies in mice resulted in a
NOAEL of 25 ppm (4-5 mg/kg/day), based on effects on body weight, food
efficiency, mild hematologic changes, increased liver weights, reduced
kidney weights, and histopathologic changes of the liver and/or urinary
bladder at higher doses.

	

In the 90-day study in dogs the NOAEL was 25 ppm (0.9 mg/kg/day). 
Effects observed at higher dose were body weight, clinical chemistry and
liver weight changes and evidence of cellular proliferation in the
urinary bladder.  

In a 21-day dermal study in rabbits, the NOAEL for systemic effects was
200 mg/kg/day, the highest dose tested.  Indicators of dermal irritation
were observed at this dose, but there was no histopathology related to
systemic effects.  

>

In summary, in subchronic studies, the targets identified were blood,
liver, and urinary bladder.  The most sensitive species was the dog,
with a NOAEL of 0.9 mg/kg/day.]

<	5. Chronic toxicity. 

[Chronic studies with flusilazole have been conducted in rats, mice, and
dogs and again the dog was the most sensitive species.  The NOEL of
flusilazole in the one-year dog feeding study was 5 ppm (0.2 mg/kg/day)
based on minimal effects at the next higher dose, 20 ppm (0.7
mg/kg/day).  Because these effects primarily reflected a reversible,
adaptive response of the liver, it was concluded that the NOAEL was 0.7
mg/kg/day.  A mechanistic study conducted to define the nature of these
liver effects supports this assignment.  Effects at higher doses in the
chronic dog study were mild to moderate hepatotoxicity, mild
leucocytosis (inflammatory) response, and changes in clinical chemistry.

Two 2-year feeding studies were conducted in rats. Target organs were
consistent with the subchronic administration studies, i.e., liver and
bladder.  At higher doses, bladder transitional cell neoplasia was
increased in both sexes and testicular Leydig cell adenomas in males. 
There was evidence for proliferative effect of the test substance in the
bladder transitional epithelium.  Therefore, it can be concluded that
the urinary bladder tumors were caused by an epigenetic,
threshold-associated mechanism.  Mechanistic studies indicated
interference of flusilazole with hypothalmic-pituitary-gonadal (HPG)
axis is a possible mechanism of testicular tumor induction.  Thus it is
reasonable to conclude that a threshold exists for the induction Leydig
cell adenomas by flusilazole.  The NOAEL for neoplasms was 125 ppm in
males (5.03 mg/kg/day) and 375 ppm (20.5 mg/kg/day) in females.  The
NOAEL for chronic toxicity (non-neoplastic hepatotoxicity) is 50 ppm (2
mg/kg/day).

Based on two chronic feeding studies in mice, target organs were the
liver, kidney, urinary bladder, and urethra.  Increased incidences of
liver tumors (hepatocellular adenomas and carcinomas) occurred at doses
in excess of the MTD.  Significant histopathological changes were
observed in the liver at doses below those resulting in oncogenicity.
The NOAEL for oncogenicity was 200 ppm (36 mg/kg/day) in females and 500
ppm (73.1 mg/kg/day) for males. Histopathological changes consistent
with hepatotoxicity were observed at lower doses and considered to be
precursors to tumor development.  Considering these observations and the
lack of genotoxic potential, it is reasonable to conclude that the
induction of such tumors was associated with cytotoxicity and
subsequently increased cell turnover.  These events suggest a threshold
for flusilazole-induced mouse liver tumors.  The NOAEL for chronic
effects (non-neoplastic hepatotoxicity) in mice is 100 ppm (14.3/19.4
mg/kg/day in males and females, respectively).]

>

<	6. Animal metabolism. 

[Flusilazole is extensively metabolized and excreted in the rat.  In a
metabolism study, male and female rats were given either a single dose
of phenyl- or triazole-labeled flusilazole.  Excretion was high in all
groups, 78% -99%.  Excretion of the phenyl label was divided between
feces and urine, with a greater proportion in the feces.  With the
triazole-label, excretion was primarily urinary, 72-81%. Tissue
retention was low, ranging from 1.3-3.5%.

A considerable proportion of administered flusilazole was found to be
excreted from the GI tract unchanged (from 2-10%).  Eight metabolites
were identified.  Cleavage and rapid excretion of the triazole moiety is
the primary step in the proposed metabolic pathway for flusilazole.  The
silane molecule may then be excreted or further metabolized to non-polar
fatty acid conjugates (males>females), ((-D-glucopyranuronic acid
conjugate (females), and may in addition further degrade to more polar
molecules.  The metabolites found in goats and hens indicated a similar
metabolic pathway to the rat, with little evidence of tissue
retention.]>

<7. Metabolite toxicology. The major flusilazole metabolites in plant
and animal tissue components of the human diet were also significant
mammalian metabolites and were intrinsically assessed for relative
safety in the flusilazole toxicology tests.  In addition, some of these
metabolites were also process impurities and were present in toxicology
test samples of flusilazole.  Therefore, the impact of trace dietary
residue exposures to flusilazole metabolites has been indirectly
assessed during the development of the toxicology database for this
active ingredient.>

<	8. Endocrine disruption. 

[The effects of flusilazole have been evaluated in a battery of
subchronic, chronic, developmental, and reproduction studies.  Endocrine
organs have been evaluated on those studies and appropriate NOAELS
determined.  When needed, studies were conducted to define the
mechanisms of action and the threshold exposures for flusilazole-induced
effects of concern.  These mechanistic studies included targeted
assessments of hormone-mediated modes of action for tumor induction,
which follows the best currently available practices and facilitates a
risk-based approach to safety assessment.  An endocrine disrupter
screening program is being developed and validated.  When the
appropriate screening and/or testing protocols have been are available,
flusilazole may be subjected to additional screening and or testing.]>

<C. Aggregate Exposure>

Flusilazole is a fungicide with proposed uses in the United States on
soybeans and wheat.  This tolerance petition proposes the following new
uses in the United States: soybean and wheat. There are no residential
uses.

<	1. Dietary exposure. [The chronic dietary RfD (cRfD) of 0.007
mg/kg/day is based on a NOAEL of 0.7 mg/kg/day from the two-year dog
feeding study and an uncertainty factor of 100.  EPA selected an acute
dietary RfD (aRfD) of 0.02 mg/kg for females 13-50 based on a NOAEL of
2.0 mg/kg/day in a rat developmental study.  An aRfD was not established
for other populations since an effect attributable to a single exposure
was not observed in the oral toxicity studies.]>

<	i. Food. [a. Chronic Dietary Exposure Assessment

Chronic dietary flusilazole exposure risk resulting from the proposed
use of flusilazole on soybean and wheat was estimated using the Dietary
Exposure Evaluation Model with the Food Commodity Intake Database
(DEEM-FCIDTM, Exponent, Inc.). The analysis employed overall-mean
field-trial values and employed projections of the 5-year annual average
percent crop treated values.  The results of the chronic dietary
exposure analysis indicate that the predicted exposure to the general
U.S. population is 0.000089 mg/kg/day, or 1% of the cRfD.  The predicted
exposure to the most sensitive population, children 1-2 years old, was
0.000366 mg/kg/day, or 5% of the cRfD.  This chronic dietary risk
estimate for flusilazole shows that an adequate margin of safety exists
for all population subgroups, and that no effects would result from
dietary exposure to flusilazole. 

The chronic module of the DEEM-FCIDTM software was also used to assess
lifetime risk of cancer.  A Q* value of 2.84x10-3 was applied to the
predicted chronic exposure for the general U.S. population; the
resulting lifetime cancer risk was 2.5x10-7, which is below the level of
concern. 

                                                       

b. Acute Dietary Exposure Assessment

The Tier 3 acute dietary exposure analysis resulting from the proposed
use of flusilazole on soybean and wheat was conducted with the acute
module of the DEEM-FCIDTM software.  The acute dietary analysis used
field trial residue data for soybean and wheat and considered meat and
milk in a probabilistic assessment, which also employed processing
factors and projected 5-year maximum annual percent crop treated values.

     

The acute exposure analysis demonstrates that an adequate margin of
safety exists for the only population group of interest, adult females. 
The results of the acute dietary exposure analysis for flusilazole
indicate that the predicted exposure to the only relevant population
group, females 13-50 years, is 0.000803 mg/kg/day, 4% of the aRfD at the
99.9th percentile.  Flusilazole clearly meets the Food Quality
Protection Act (FQPA) standard of reasonable certainty of no harm.]>

<	ii. Drinking Water. [Surface water exposure was estimated using the
FIRST screening model version 1.0.  Ground water exposure was estimated
using SCI-GROW version 2.3.  These are screening level models used for
determining upper bound concentrations of pesticides in surface water
and ground water. Results indicate that a reasonable certainty exists
that flusilazole residues in drinking water will not contribute
significantly to the acute and chronic human risk. 

     

The predicted chronic concentration for flusilazole under worst-case
conditions was 0.021 parts per billion (ppb) in ground water and 1.85
ppb in surface water.  When the higher surface water concentration is
included in the chronic dietary risk assessment, the predicted exposure
to the general U.S. population is 0.000128 mg/kg/day, or 2% of the cRfD.
The predicted exposure to the most sensitive population, children 1-2
years old, is 0.000424 mg/kg/day, or 6% of the cRfD.  This chronic
aggregate risk estimate for flusilazole shows that an adequate margin of
safety exists for all population subgroups, and that no effects would
result from chronic aggregate (food and water) exposure to flusilazole. 
The lifetime cancer risk was considered with the inclusion of drinking
water.  A Q* value of 2.84x10-3 was applied to the predicted chronic
exposure including drinking water for the general U.S. population; the
resulting lifetime cancer risk was 3.6x10-7, which is below the level of
concern. 

The predicted acute concentration for flusilazole under worst-case
conditions was 0.021 parts per billion (ppb) in ground water and 4.126
ppb in surface water.  When the higher surface water concentration was
included in the acute dietary risk assessment, the predicted exposure at
the 99.9th percentile for the only relevant population, females (13-50
years), is 0.000867 mg/kg/day, 4% of the aRfD.  Since the % aRfD for the
only relevant population group is well below 100%, the acute dietary
safety of flusilazole, including the contribution of drinking water,
clearly meets the standard of reasonable certainty of no harm.]>

<	2. Non-dietary exposure. [Flusilazole products are not labeled for
residential non-food uses, thereby eliminating the potential for
residential exposure. Non-occupational, non-dietary exposure for
flusilazole has not been estimated because the proposed products are
limited to commercial crop production. Therefore, the potential for
non-occupational exposure is insignificant.]>

<D. Cumulative Effects>

<	[Flusilazole is a member of the triazole-containing class of
pesticides.  Although triazole pesticides act similarly in plants
(fungi) by inhibiting ergosterol biosynthesis, there is not necessarily
a relationship between this pesticidal activity and their mechanism of
toxicity in mammals. Structural similarities do not constitute a common
mechanism of toxicity.  Evidence is needed to establish that the
chemicals operate by the same, or essentially the same sequence of major
biochemical events (EPA, 2002). In triazoles a variable pattern of
toxicological responses is found. Some are hepatotoxic and
hepatocarcinogenic in mice. Some induce thyroid tumors in rats. Some
induce developmental, reproductive, and neurological effects in rodents.
Furthermore, the triazoles produce a diverse range of biochemical events
including altered cholesterol levels, stress responses, and altered DNA
methylation. It is not clearly understood whether these biochemical
events are directly connected to their toxicological outcomes. Thus,
there is currently no evidence to indicate that triazoles share common
mechanisms of toxicity and EPA is not following a cumulative risk
approach based on a common mechanism of toxicity for the triazole
pesticides. For information regarding EPA’s procedures for cumulating
effects from substances found to have a common mechanism of toxicity,
see EPA’s website at http://  HYPERLINK
"http://www.epa.gov/pesticides/cumulative" 
www.epa.gov/pesticides/cumulative . 

Flusilazole is a triazole-derived pesticide. This class of compounds can
form the common metabolites 1,2,4-triazole conjugates (triazole alanine
and triazole acetic acid). To support existing tolerances and to
establish new tolerances for triazole-derived pesticides, EPA conducted
a human health risk assessment for exposure to 1,2,4-triazole, triazole
alanine, and triazole acetic acid resulting from the use of all current
and pending uses of any triazole-derived fungicide. The risk assessment
is highly conservative, screening-level evaluation in terms of hazards
associated with common metabolites (e.g., use of a maximum combination
of uncertainty factors) and potential dietary and non-dietary exposures
(i.e., high end estimates of both dietary and non-dietary exposures).

In addition, on the assessment involving the 1,2,4-triazole metabolites,
the Agency retained the additional 10X FQPA safety factor for the
protection of infants and children. The assessment includes evaluations
of risks for various subgroups, including those comprised of infants and
children. The Agency’s complete risk assessment may be found at  
HYPERLINK "http://www.epa.gov/opprd001/factsheets/tetraHHRA.pdf" 
http://www.epa.gov/opprd001/factsheets/tetraHHRA.pdf .  

In that risk assessment, EPA concluded that, based upon the available
information and on conservative estimates of hazard and exposure, there
are no human health risk issues associated with 1,2,4-triazole or its
metabolites that would preclude re-registration of the
triazole-derivative fungicides registered to date or conditional
registrations of the  triazole derivative fungicides that have been
proposed as of September 1, 2005, which included the use of flusilazole
on soybean.]>

<E. Safety Determination>

<	1. U.S. population. 

[This chemical has not yet been evaluated by the Cancer Peer Review
Committee.  In the interim EPA has selected a conservative Q* of 2.84 x
10-3 mg/kg/day based on female mouse liver adenoma and carcinoma
combined tumor rate.  For an acute dietary exposure EPA has selected an
ARfD of 0.02 mg/kg/day for females 13 or older based on an NOAEL of 2
mg/kg/day on rat developmental studies and an uncertainty factor of
100x.  No acute reference dose was selected for the general population,
since no endpoint of concern attributable to a single dose was
identified for the general population.  EPA has selected an incidental
short-term oral/inhalation NOAEL of 2.85 mg/kg/day and a short-term
dermal NOAEL of 2.85 mg/kg/day from the rat reproduction studies and an
uncertainty factor of 100 to be used in residential and occupational
risk assessment.  Based on the completeness and reliability of the
toxicity data and the conservative exposure assessments, there is
reasonable certainty that no harm will result from the aggregate
exposure of residues of flusilazole.  No additional safety factors are
warranted.]>

<	2. Infants and children. 

[The endpoints selected are considered protective of infants and
children since short-term endpoints are based on NOAELs for fetal
effects in developmental toxicity studies or offspring effects in
reproduction studies.  The chronic reference doses based on another
endpoint (oncogenicity) is adequately protective because they are lower
than those identified for developmental toxicity.  Based on the
completeness and reliability of the toxicity data base, the lack of
toxicological endpoints of special concern, the lack of any indication
that children are more sensitive than adults to flusilazole, and the
conservative exposure assessment, there is a reasonable certainty that
no harm will result to infants and children from the aggregate exposure
of residues of flusilazole, including all anticipated dietary exposure
and all other non-occupational exposures. Accordingly, there is no need
to apply an additional safety factor for infants and children.]>

<F. International Tolerances>

<[International Codex values are established for apricot; banana;
barley; barley straw and fodder, dry; cattle fat, meat. milk, and edible
offal; chicken eggs, meat, and edible offal; dried grapes (=currants,
raisins and sultanas); grapes; nectarine; peach; pome fruit; rape seed;
rye; rye straw and fodder, dry; sugar beet; wheat; and wheat straw and
fodder, dry.]>