 

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE  

                                                          (8/7/2007)

EPA Registration Division contact: Shaja R. Brothers 703.308.3194

 

TEMPLATE:

Interregional Research Project Number 4 (IR-4)

7E7256

	EPA has received a pesticide petition 7E7256 from Interregional
Research Project Number 4 (IR-4), Technology Center and Rutgers State
University of New Jersey, 500 College Road East Suite 201 W. ,
Princeton, New Jersey 08450 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 180.381 by establishing a tolerance for residues of
fenbuconazole,
(alpha-(2-(4-chlorophenyl)ethyl]-alpha-phenyl-3-(1H-1,2,4-triazole)-1-pr
opanenitrile) and its metabolites cis and
trans-5-(4-chlorophenyl)-dihydro-3-phenyl-3-(1H-1,2,4-triazole-1-ylmethy
l)-2-3H-furanone)  in or on the raw agricultural commodities pepper 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 support granting of the
petition.

A. Residue Chemistry

	1. Plant metabolism.   The qualitative nature of fenbuconazole residues
in plants is adequately understood based on acceptable metabolism
studies on wheat, peaches, sugarbeets and peanuts.  The metabolism of
fenbuconazole was qualitatively similar in all crops and proceeded via
three pathways.  Based on these metabolism studies, the residue of
concern for dietary exposure and tolerance setting purposes in bell and
non-bell pepper is the combined residues of the parent compound,
fenbuconazole and its lactone metabolites, RH-9129 and RH-9130 [cis and
trans-5-(4-chlorophenyl)-dihydro-3-phenyl-3-(1H-1,2,4-triazole-1-ylmethy
l)-2-3H-furanone)].  The total residue is expressed as fenbuconazole. 

	2. Analytical method. Adequate analytical methods are available to
enforce the tolerances of fenbuconazole residues in plant commodities. 
The analytical methods vary depending on the matrices being analyzed. 
These methods had undergone successful independent laboratory
validation.

For pepper, samples from the residue trials were analyzed for
fenbuconazole (RH-7592) and its lactone metabolites, RH-9129 and
RH-9130, using Rohm & Haas analytical method Technical Report Number 
34-90-47 or Technical Report Number 34-90-47R.  The method had undergone
an independent method validation and was also successfully validated by
EPA with minor modifications suggested by the Agency that included
procedure for the standardization of the silica gel and Florisil column
clean-up elution pattern (TR-34-90-47R).  The limits of quantitation and
detection of the method are 0.01 µg/g and 0.003 µg/g, respectively.

	3. Magnitude of residues.  Magnitude of residue studies were conducted
by USDA’s program IR-4 at field sites located within the major growing
regions in the U.S. as recommended by the EPA’s guidelines.  In total,
nine trials (six bell and three non-bell) were conducted for this study
during the 2000 growing season. Bell peppers were grown in Maryland,
Georgia, Florida, Texas, Ohio, and California.  Non-bell peppers were
grown in Texas, Florida, and California. These studies have been
previously submitted to the Agency. 

In each trial, at least four foliar applications of RH-7592 75WP at a
rate of approximately 0.167 lb ai/A each were made for a total of
approximately 0.668 lb ai/A.  In Georgia and Florida, five applications
were made to allow the peppers to mature.  A total of approximately
0.835 lb ai/A was applied in these trials.  A nonionic surfactant at 1
pt/100 gal was added to the spray mixtures.  The applications were made
at 12- to 16-day intervals and timed so that samples could be collected
approximately 7 days after the final application.  In both Florida and
the Texas trials, additional samples were collected following the final
application and 14 days later for decline determination.

The lowest level of method validation (LLMV) in this study was
approximately 0.01 ppm (0.0101 ppm fenbuconazole, 0.00992 ppm RH-9129,
and 0.00988 ppm RH-9130).  Based on recoveries of both sample types
fortified at the LLMV, the estimated limit of detection (LOD) and limit
of quantitation (LOQ) were calculated as 0.003 ppm and 0.0082 ppm,
respectively, for fenbuconazole.  For those fortified with RH-9129, the
LOD and LOQ were calculated as 0.003 ppm and 0.0099 ppm, respectively. 
The LOD and LOQ for RH-9130 were calculated as 0.004 ppm and
0.011 ppm, respectively. 

Treated samples were analyzed within 8 days of extraction.  Analytical
sets typically consisted of calibration standards, unfortified controls,
fortified controls, and treated samples.  

The results from the trials show that the maximum residue in both sample
types following a total application of approximately 0.668 lb ai/A and a
pre-harvest interval (PHI) of 6 to 7 days was 0.20 ppm fenbuconazole
and 0.01 ppm RH-9129.  No RH-9130 residues above the LLMV of 0.01 ppm
were observed.  The maximum fenbuconazole residue in 7-day samples
treated with five applications (approximately 0.835 lb ai/A) was 0.15
ppm in bell peppers and 0.21 ppm in non-bell peppers.  One bell pepper
sample contained 0.01 ppm RH-9130; no RH-9129 or RH-9130 residues above
the LLMV were observed.  

In bell peppers treated with four applications, the highest
fenbuconazole residue at 0 days was 0.27 ppm; residues had declined to a
maximum of 0.17 ppm by 14 days.  In samples treated with five
applications, the maximum 0-day residue was 0.24 ppm (bell) and 0.52 ppm
(non-bell).  By 14 days, the maximum residue was 0.08 ppm (bell) and
0.15 ppm (non-bell). 

 

Bell peppers treated with four applications yielded RH-9129 residues of
0.01 ppm at 0 days and 0.01 to 0.02 ppm at 14 days.  No RH-9129 residues
> 0.01 ppm were observed in bell peppers treated with five applications,
but non-bell peppers contained 0.01 ppm at both 0 and 14 days.  RH-9130
residues > 0.01 ppm were observed in 0-day non-bell peppers treated with
five applications (0.09 ppm) and in 14-day bell pepper samples treated
with four applications (0.01 ppm and 0.13 ppm).  Samples yielded
residues < 0.01 ppm upon reanalysis. 

B. Toxicological Profile

	1. Acute toxicity.   The toxicological profile and endpoints for
fenbuconazole which supports this petition to establish tolerances were
previously published in the Federal Register of July 20, 2005 (70
FRL-7702-7). For acute dietary risk assessments, EPA has established a
reference dose (acute RfD) of 0.3 mg/kg/day for females 13+ years old,
the population sub-group of concern.  The aRfD is based on the
developmental toxicity study in the rat with a maternal and
developmental NOAEL of 30 mg/kg/day and an uncertainty factor of 100.  A
decrease in maternal body weight, an increase in post-implantation loss
and a significant decrease in the number of live fetuses per dam were
observed at the LOAEL of 75 mg/kg/day.  No appropriate endpoint was
available for analyzing the acute exposure of the overall U. S.
population. Fenbuconazole is practically non-toxic after  
administration by the oral and dermal routes, and was not significantly
toxic to rats after a 4 hour inhalation exposure. Fenbuconazole is
classified as not irritating to skin and inconsequentially irritating to
the eyes. It is not a skin sensitizer.

	2. Genotoxicty. Fenbuconazole was negative (non-mutagenic) in an Ames
assay with and without hepatic enzyme activation. Fenbuconazole was
negative in a hypoxanthine guanine phosphoribosyl transferase (HGPRT)
gene mutation assay using Chinese hamster ovary (CHO) cells in culture
when tested with and without hepatic enzyme activation. In isolated rat
hepatocytes, fenbuconazole did not induce unscheduled DNA synthesis
(UDS) or repair. Fenbuconazole did not produce chromosome effects in
rats in vivo. On the basis of the results from this battery of tests, it
is concluded that, fenbuconazole is not mutagenic or genotoxic.

	3. Reproductive and developmental toxicity. i. Developmental toxicity
in the rat. In the developmental study in rats, the maternal (systemic)
no observed adverse effect level (NOAEL) was 30 mg/kg/day based on
decreases in body weight and body weight gain at the lowest observed
adverse effect level (LOAEL) of 75 mg/kg/day. The developmental (fetal)
NOAEL was 30 mg/kg/day based on an increase in post implantation loss
and a significant decrease in the number of live fetuses per dam at the
LOAEL of 75 mg/kg/day. 

 

    ii. Developmental toxicity in the rabbit. In the developmental study
in rabbits, the maternal (systemic) NOAEL was 10 mg/kg/day based on
decreased body weight gain at the LOAEL of 30 mg/kg/day. The
developmental (fetal) NOAEL was 30 mg/kg/day based on increased
resorptions at the LOAEL of 60 mg/kg/day.

    iii. Reproductive toxicity. In the 2-generation reproduction
toxicity study in rats, the maternal (systemic) NOAEL was 4 mg/kg/day
based on decreased body weight and food consumption, increased number of
dams delivering nonviable offspring, and increases in adrenal and
thyroid weights at the LOAEL of 40 mg/kg/day. The reproductive (pup)
NOAEL was 40 mg/kg/day, the highest dose tested.]

	4. Subchronic toxicity. i. Rat 90-day oral study. A Subchronic feeding
study in rats conducted for 13-weeks resulted in a NOAEL of 80 parts per
million (ppm) (5.1 and 6.3 mg/kg/day in males and females,
respectively). The only effect observed at 80 ppm was minimal
centrilobular hypertrophy (seen in one male) and hepatocytic
centrilobular vacuolation (3 males) with no concomitant increase in
liver weight or clinical chemistry correlates and no analogous effects
in females. As such, these observations are not considered to be
adverse. Increased liver weight, hepatic hypertrophy, thyroid
hypertrophy, and decreased body weight were observed at the higher doses
of 400 and 1,600 ppm.

    ii. Dog 90-day oral study. A subchronic feeding study in dogs
conducted for 13-weeks resulted in a NOAEL of 100 ppm (3.3 and 3.5
mg/kg/day in males and females, respectively). At the LOAEL of 400 ppm,
increased liver weight, clinical chemistry parameters, and liver
hypertrophy (males) were observed.

    iii. Rat 4-week dermal study. In a 21-day dermal toxicity in the rat
study, the NOAEL was greater than 1,000 mg/kg/ day, with no effects seen
at this limit dose.  

	5. Chronic toxicity. i. Dog. A 1-year feeding study in dogs resulted in
a NOAEL of 15 ppm (0.62 mg/kg/day) for females and 150 ppm (5.2
mg/kg/day) for males. Decreased body weight, increased liver weight,
liver hypertrophy, and pigment in the liver were observed at the LOAEL
of 150 and 1,200 ppm in females and males, respectively.

    ii. Mouse. A 78-week chronic/oncogenicity study was conducted in
male and female mice at 0, 10, 200 (males only), 650, and 1,300 ppm
(females only). The NOAEL was 10 ppm (1.4 mg/kg/day), and the LOAEL was
200 ppm (26.3 mg/kg/day) for males and 650 ppm (104.6 mg/kg/day) for
females based on increased liver weight and histopathological effects on
the liver, which were consistent with chronic enzyme induction.  There
was no statistically significant increase of any tumor type in males.
However, there was a statistically significant increase in combined
liver adenomas and carcinomas in females at the high dose only (1,300
ppm; 208.8 mg/kg/day). There were no liver tumors in the control
females, and liver tumor incidences in the high-dose females just
exceeded the historical control range. In ancillary mode-of-action
studies in female mice, the increased tumor incidence was associated
with changes in several parameters in mouse liver following high doses
of fenbuconazole, including an increase in P450 enzymes (predominately
of the CYP 2B type), an increase in cell proliferation, an increase in
hepatocyte hypertrophy, and an increase in liver weight. Changes in
these liver parameters, as well as the occurrence of the low incidence
of liver tumors, were non-linear with respect to dose (i.e., effects
were observed only at high dietary doses of fenbuconazole). Similar
findings have been shown with several pharmaceuticals, including
phenobarbital, which is not carcinogenic in humans. The non-linear dose
response relationship observed with respect to liver changes (including
the low incidence of tumors) in the mouse indicates that these findings
should be carefully considered in deciding the relevance of high-dose
animal tumors to human dietary exposure.

    iii. Rat. A 24-month chronic/oncogenicity study in male and female
rats was conducted at 0, 8, 80, and 800 ppm fenbuconazole, and a second
24-month chronic/oncogenicity study was conducted in male rats at 0,
800, and 1,600 ppm. The NOAEL was 80 ppm (3 and 4 mg/kg/day in males and
females, respectively), and the LOAEL was 800 ppm (31 and 43 mg/kg/day
in males and females, respectively) based on decreased body weight,
increased liver and thyroid weights, and liver and thyroid hypertrophy.
Fenbuconazole produced a minimal but statistically significant increase
in the incidence of combined thyroid follicular cell benign and
malignant tumors. These findings occurred only in male rats following
life-time ingestion of very high levels (800 and 1,600 ppm in the diet)
of fenbuconazole.

    iv. Carcinogenicity. The Agency has concluded, that the available
data provide limited evidence of the carcinogenicity of fenbuconazole in
both mice and rats and has classified fenbuconazole as a Group C
carcinogen (possible human carcinogen with limited evidence of 
carcinogenicity in animals) in accordance with Agency guidelines,
published in the Federal Register (51 FR 33992, September 24, 1986), and
recommended that for the purpose of risk characterization a low-dose
extrapolation model applied to the experimental animal tumor data should
be used for quantification of human risk (Q*). EPA's 26 Feb 1998 Hazard
Identification Assessment Review Committee (HIARC) report concluded that
0.00359 (mg/kg/day)-1 is the appropriate Q* for fenbuconazole; this Q*
is based on the fenbuconazole mouse liver tumor data, along with a power
surface area scaling factor.

	6. Animal metabolism. The absorption, distribution, excretion, and
metabolism of fenbuconazole in rats, goats, and hens were investigated. 
Following oral administration, fenbuconazole was completely and rapidly
absorbed, extensively metabolized by oxidation/hydroxylation and
conjugation, and rapidly and essentially completely excreted,
predominately in the feces. Fenbuconazole did not accumulate in tissues.

	7. Metabolite toxicology. There are no toxicological concerns for
fenbuconazole based on differential metabolic pathways in plants and
animals. Triazole fungicides are known to produce three common
metabolites, 1,2,4-triazole, triazolylalanine and triazole acetic acid.
To support the extension of existing parent triazole-derivative
fungicide tolerances, EPA conducted an interim human health assessment
for aggregate exposure to 1,2,4-triazole. This interim assessment was
summarized in the Federal Register notice dated August 4, 2004 and
titled Propiconazole; Time-Limited Pesticide Tolerances. EPA concluded,
that for all exposure durations and population subgroups, aggregate
exposures to 1,2,4-triazole are not expected to exceed its level of
concern.

	8. Endocrine disruption. The mammalian endocrine system includes
estrogen and androgens as well as other hormonal systems. Fenbuconazole
is not known to interfere with reproductive hormones; thus,
fenbuconazole should not be considered to be estrogenic or androgenic.
There are no known instances of proven or alleged adverse reproductive
or developmental effects to people, domestic animals, or wildlife as a
result of exposure to fenbuconazole or its residues.

C. Aggregate Exposure

	1. Dietary exposure. The exposure and risk resulting from agricultural
uses of fenbuconazole was considered for the U.S. population and special
sub-populations.  There are two direct sources of exposure to humans
considering fenbuconazole’s uses across all labels:  from food intake
and from consuming drinking water.  The exposure and risk are estimated
in this report for different durations of both routes of exposure and
their aggregated contribution.  In an aggregate assessment, exposures
from food residues were combined with conservative estimates of
potential water residues.  The current approach of the EPA Office of
Pesticide Programs (OPP) is to use a tiered approach for acute dietary
risk assessment that proceeds from very conservative assumptions about
food residues, to inclusion of more realistic residue values measured
closer to the point of consumption.

	i. Food.  The process of dietary risk assessment of pesticides
considers chronic and acute exposures to the U.S. population and
sensitive population sub-groups.  Critical to any dietary assessment is
residue and consumption data.  Because of the number of years
fenbuconazole has been used on crops, a substantial public dataset
exists of food residues as measured by the USDA's Pesticide Data Program
(PDP).  The PDP monitoring data realistically estimate the magnitude of
pesticide residue on food as it is purchased by the consumer, since
samples are taken closer to the point of consumption, and more
accurately represent actual patterns of use and food distribution than
measurements from a typical field trial.  Additional exposures from
potential residues in drinking water were also estimated.

The Dietary Exposure Evaluation Model (DEEM-FCID, version 2.14), a
commercially available software package, was used to estimate exposure
to fenbuconazole via food consumption by the general U.S. population and
certain subgroups.  The model combined the consumption data and residue
data for a given pesticide to analyze dietary risk.  

Food consumption data from the USDA Continuing Survey of Food Intakes by
Individuals (CSFII) conducted from 1994 through 1998 including the
children's supplemental survey were used in this assessment.  The food
consumption data, i.e., foods as consumed, were translated into raw
agricultural commodities and their food forms using recipe translation
files contained within the DEEM software.  For chronic assessments, food
consumption values averaged across the populations of interest were
used. Because of the number of years that fenbuconazole has been used in
agriculture, the PDP data provides the best available information on
residues that may result from established uses on food crops.  It should
be noted that a number of the fenbuconazole uses are supported by
residue data supplied by the IR-4 program.  The section 3 tolerance
value was used for those foods that were not sampled by the PDP residue
program, and for which there is no established policy for surrogation
from another crop.  These crops include such uses as lime; plum, prune,
dried; pummelo; and tangerine.

a.  Acute dietary exposure.  Although, no acute adverse effect was
observed as a result of exposure to a single dose, EPA has established
an acute reference dose (aRfD) for the purpose of the acute dietary
assessment. This aRfD was set at 0.3 mg/kg/day for females 13+ years
old, the population sub-group of concern. This was based on the
developmental rat toxicity study with a NOAEL of 30 mg/kg/day and an
uncertainty factor of 100. The 100-fold safety factor includes
intraspecies and interspecies variations. Exposures from all existing
and proposed residues result in very low acute exposures. Using the
above assumptions for Tier 1 assessment, the food exposure to
fenbuconazole for females 13+ years old at the 95th percentile was
estimated to be 0.0133 mg/kg/day that utilized less that 5% of the aRfD.

b.  Chronic dietary exposure. EPA has established a chronic reference
dose (cRfD) for fenbuconazole at 0.03 mg/kg/day for all population
subgroups. The cRfD is based on the 2-year combined chronic
feeding-carcinogenicity study in rats with a NOAEL of 3.03 and 4.02
mg/kg/day in males and females respectively, and an uncertainty factor
of 100. The 100-fold safety factor includes intraspecies and
interspecies variations. No additional FQPA safety factor is required.
The food exposure for the overall U.S. population was estimated for the
Tier 1 assessment to be 0.0044 mg/kg/day that utilized 14.9% of the cRfD
using the Tier 1 conservative exposure assumptions of 100% crop treated
and residues at tolerance levels. The population subgroup with the
highest potential for exposure was children 1-2 years old with food
exposure of 0.018888 mg/kg/day that represented 63% of the cRfD.  For
the Tier 2 assessment, the estimated food exposure was reduced to less
than 3.0 % of the cRfD for the general population and 9.5% of the cRfD
for children 1-2 years.

 c.  Cancer dietary exposure. EPA has classified fenbuconazole as a
Group C carcinogen (possible human carcinogen with limited evidence of
carcinogenicity in animals) and has established a Q* of 0.00359
(mg/kg/day)-1 in human equivalents.  The group used in this analysis was
the general U. S. population.  A Tier I assessment using very
conservative assumptions of: 1) use of tolerance residues 2) 100% CT,
and 3) default processing factors, produces a dietary exposure that
exceeds the Agency threshold of a negligible cancer risk of 1 x 10-6.. A
more realistic estimate of the dietary exposure is obtained based on
using the actual residue values rather than the tolerance, average field
trial residues, available PDP monitoring data, actual processing factors
and estimates of the fraction of the crops actually exposed to
fenbuconazole.  Incorporation of these data into the Tier 3 assessment
resulted in an estimated food exposure of 0.000084 mg/kg/day including
pepper use with a cancer risk estimate of 3.01 x 10-7 . 

Drinking Water.  Direct measurements of fenbuconazole in drinking water
were not available.  Estimates of potential water concentrations
resulting from agricultural use of fenbuconazole were estimated using
three environmental models, assuming certain environmental degradation
properties for fenbuconazole and modeled dynamics of ground water and
surface water bodies.  The acute drinking water estimates were estimated
using PRZM/EXAMS and SCI-GRO models and are known to overestimate
potential water residues.  These three models provide conservative,
screening level estimates of water concentrations.  PRZM/EXAMS  is used
for surface water while SCI-GROW is used to give estimates of ground
water concentrations.  Such water estimates are very sensitive to the
input parameters; however, they can still serve as a screening estimate
for exposure considerations. Based on the PRZM/EXAMS and SCI-GROW models
the US EPA estimated EECs of fenbuconazole for acute exposures to be
20.3 parts per billion (ppb) for surface water and 0.031 ppb for ground
water. The EECs for chronic (non-cancer) and for cancer exposures are
estimated to be 16.5 ppb for surface water and 0.031 ppb for
groundwater.   The potential, acute, aggregate exposures from food and
drinking water for females of child bearing age is approximately
0.013930 mg/kg-bw/day or 4.64 % of the acute reference dose (aRfD) for
the upper 95th %tile of the population using a Tier 1 assessment.

Potential chronic exposure to water residues was estimated using 16.5
ppb for the two commodities, i.e., “water, direct, all sources” and
“water, indirect, all sources” for input to DEEM-FCID for chronic
water (Tier III) analysis. After considering all existing and proposed
uses, the exposure to fenbuconazole residues is 5.0 % of the chronic
reference  dose for the most exposed population sub-group, non-nursing
infants.  Although this is much below the acceptable level, it is a very
conservative assessment, since about 96 % of the total dietary exposure
to non-nursing infants (4.8% of the cRfD) comes from the addition of
direct and indirect drinking water sources as estimated for the worst
possible scenario.  For the US population, direct and indirect drinking
water sources represent 81% of the total exposure and approximately 1%
of the cRfD.

Cancer dietary exposure with water was also calculated. Incorporation of
water at 16.5 ppb into the Tier 3 assessment resulted in an estimated
exposure of 0.000432 mg/kg/day including pepper use with a cancer risk
estimate of 1.55 x 10-6.     

	2. Non-dietary exposure.  Fenbuconazole is not currently registered for
use on any sites that would result in residential exposure. Thus, the
risk from non-dietary exposure would be considered negligible.

D. Cumulative Effects.  Fenbuconazole is a member of the triazole class
of fungicides.  At this time, EPA does not have available data to
determine whether fenbuconazole exhibits a common mechanism of toxicity
with other triazole fungicides.  However, a cumulative risk assessment
was submitted to the Agency by the United States Triazole Task Force
(USTTF) on behalf of its members (of which, DAS is a member). Cumulative
exposure to triazole metabolites triazole alanine (TA), + triazole
acetic acid (TAA), and 1,2,4-triazole (1,2,4-T) derived from all uses of
triazole-derivative products registered in US was proved to be below the
Agency’s levels of concerns for dietary, drinking water, residential
and aggregated risk to adults and children. More details have been
published in EPA’s FR / Vol 70, No. 45 / March 9, 2005.

	

E. Safety Determination

	1. U.S. population. Using the above conservative exposure assumptions
and taking into account the completeness and reliability of the toxicity
data, chronic dietary exposure to fenbuconazole from all registered and
proposed uses and drinking water will utilize 14.9% of the cRfD for the
U. S. population (total).  Slight refinement (Tier 2) of the tolerance
residues by adjusting for the percent crop treated resulted in reduced
risk estimates of 2.7% of cRfD for the general U. S. population when
bell and non-bell was included in the assessment with all existing uses
of fenbuconazole.  Generally, EPA has no concern for exposures below
100% of the cRfD because the chronic RfD represents the level at or
below which daily dietary exposures over a lifetime will not pose
appreciable risks to human health. 

 Likewise, the acute dietary food exposure at 95th percentile (Tier 1)
for females 13+ yrs, the population sub-group of concern is 4.45 % of
aRfD which is well below 100% of the aRFD.  Therefore, there is no
concern for exposure because the acute RfD represents the level at or
below which a single daily exposure will not pose appreciable risks to
human health.  

When pepper use was included in the assessment with all existing and
pending uses of fenbuconazole, the cancer risk estimate was 1.55 x 10-6.
 Generally, the Agency has no concern for exposures that result in a
cancer risk estimate below 1 x 10-6.  Considering the conservative
assumptions of this assessment and the screening level exposure from
drinking water, the cancer risk is not expected to exceed 1 x 10-6 for
the U.S. population as a whole. However, for the US population,
estimates of direct and indirect drinking water sources represent 81% of
the total exposure. 

Therefore, based on these risk assessments, Dow AgroSciences concludes
that there is reasonable certainty that no harm will result to the U. S.
population from aggregate exposure to fenbuconazole residues from all
supported registered and proposed uses.

	2. Infants and children. EPA uses a weight evidence approach in
determining what safety factor is appropriate for assessing risks to
infants and children.  This approach takes into account the nature and
severity of the effects observed in pre- and post-natal studies and
other information such as epidemiological data.  The completeness and
adequacy of the toxicity database is also considered.

Toxicity database and exposure data for fenbuconazole are complete.  No
indication of increased susceptibility of rats or rabbits to in utero
and/or postnatal exposure was noted in the acceptable developmental
toxicity studies in rats and rabbits as well as in a 2-generation
reproductive toxicity study in rats.  EPA has previously determined that
no additional safety factor to protect infants and children is necessary
for fenbuconazole and that the RfD at 0.03 mg/kg/day is appropriate for
assessing risk to infants and children.

Using the conservative assumptions (Tier 1) described above, the chronic
dietary exposure to fenbuconazole will utilize 28.3 % of the cRfD for
all infants (<1 yr old), 33.2 % of the cRfD for non-nursing infants,
63.0 % of the cRfD for children 1-2 yrs old and 43.4 % of the cRfD for
children 3-5 yrs old.

Slight refinement (Tier 2) by adjusting residues for % CT reduced the
risk estimates to 9.5% of the cRfD for children 1-2 yrs old, the
population sub-group with the highest potential exposure.  Similarly,
when bell and non-bell was included in the Tier 2 assessment with all
existing uses of fenbuconazole, the risk estimates were 4.0% of the cRfD
for all infants (<1 yr old), 4.6% of the cRfD for non-nursing infants,
and 6.8% of the cRfD for children 3-5 yrs old.  

Even when considering the potential exposure to drinking water, the
aggregate exposure is not expected to exceed 100% of the cRfD.
Therefore, based on the completeness and reliability of the toxicity
data and the conservative exposure assessment, Dow AgroSciences
concludes with reasonable certainty that no harm will result to infants
and children from the aggregate exposure to fenbuconazole from all
current and proposed pending uses.   

F. International Tolerances

	Codex MRL's are established on bananas and pecans at 0.05 ppm, wheat
grain at 0.1 ppm, peach at 0.5 ppm, cherries at 1.0 ppm, and wheat straw
at 3.0 ppm. Although the residue definitions differ (i.e., Codex does
not include the metabolites), the U.S. tolerances for pecans and wheat
grain match the Codex limits numerically. The U.S. stone fruit crop
group tolerance of 1.0 ppm is consistent with the highest Codex MRL on
an individual member (cherries) of that crop group. In the cases of
bananas and wheat straw, the levels of total residues in the U.S.
tolerance expression (which includes fenbuconazole metabolites) are
higher than the Codex MRL (which excludes these metabolites). Therefore,
EPA has not harmonized these values.

	

