Document ID: EPA-HQ-OPP-2012-0515-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-08-23T04:00Z

FILE NAME:   DFB-A357 citrus 2012 NOF  

                     

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Commodity Vocabulary database (http://www.epa.gov/pesticides/foodfeed/).

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2F8015

 Summary of Petitions

	EPA has received a pesticide petition (2F8015) from [Chemtura
Corporation], [199 Benson Road, Middlebury, CT 06749] 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 (1)

1. by establishing a tolerance for residues of

 

[N-[[(4-chlorophenyl)amino]-carbonyl]-2,6-difluorobenzamide (DFB) and
its metabolites 4-chlorophenylurea (CPU) and 4-chloroaniline (PCA) in or
on the raw agricultural commodities [orange, grapefruit, and lemon
(citrus fruits crop group 10), at 1.3 ppm, and citrus oil processed
commodity at 39 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.

A. Residue Chemistry                                       

	1. Plant metabolism. The nature of the residue in plants is adequately
understood.  In plants, the metabolism of diflubenzuron was investigated
in soybeans, citrus, mushroom, and rice.  The main component of residues
in rice was CPU; levels of PCA were negligible to non-detectable.  The
main component of the residues in soybeans and oranges was the parent
diflubenzuron. A considerable portion of the residues were bound.
Diflubenzuron showed very limited absorption and translocation in plants
with most of the residues remaining on the surface. The Agency has
concluded that the residues of concern are diflubenzuron and its
metabolites CPU and PCA.

	2.  Analytical method. A practical analytical method for detecting and
quantifying levels of diflubenzuron in or on food with a limit of
detection that allows monitoring of the residue at or above the level
set in the tolerance was used to determine residues in citrus RAC and
processed commodities.  

Residues of the individual analytes are detectable and quantifiable
using three separate analytical methods. Residues of diflubenzuron (DFB)
were quantitated by LC-MS/MS, and residues of the metabolites
4-chlorophenylurea (CPU) and 4-chloroaniline (PCA) were derivatized with
HFBA and quantitated by GC/MS. 

 

Residues of diflubenzuron were repeatedly extracted with methylene
chloride in the presence of anhydrous sodium sulfate and the extracts
combined. The volume was adjusted to measurable volume and a 50% aliquot
was removed for further clean-up. The extract was roto-evaporated to
dryness and reconstituted in acetonitrile. The resultant solvent mixture
was partitioned with hexane by shaking for ~1 minute and the
acetonitrile layer was collected in a concentration flask. After
concentration, the residue was dissolved with 2 mL acetonitrile and 8 mL
water. Using a preconditioned C18-SPE cartridge, the reconstituted
acetonitrile extract was passed through the cartridge for clean-up
followed by additional clean-up using a Si SPE cartridge. The solvent
was evaporated and the residue was reconstituted in acetonitrile and
water. An appropriate volume was transferred to a gas chromatography
(GC) vial for analysis. The DFB method for citrus juice was slightly
different in that no second filtration was required. The DFB method for
orange oil involved repeated partition of the oil with acetonitrile and
hexane. The combined acetonitrile extracts were analyzed without further
cleanup. The samples were analyzed by LC-MS/MS. The limit of
quantitation was 0.05 ppm in citrus matrices, except for orange oil with
an LOQ of 1.0 ppm.

CPU was repeatedly extracted with ethyl acetate in the presence of
anhydrous sodium sulfate and the extracts combined. The volume was
adjusted to measurable volume and a 50% aliquot was removed for further
clean-up. The extract was roto-evaporated to dryness and reconstituted
in acetone and petroleum ether. Using a preconditioned Si SPE cartridge,
the reconstituted organic extract was passed through the cartridge for
clean-up with gradient elution. The solvent was evaporated and the
residue was reconstituted in hexane. The CPU residue method for oil
involved a partition of the oil between hexane and acetonitrile:water.
The combined acetonitrile:water phases were concentrated and were
cleaned up by means of a C18-SPE cartridge followed by a Si-SPE
cartridge. The CPU was derivatized with HFBA and submitted for analysis
by GC/MS. The limit of quantitation was 0.01 ppm in citrus.

The determination of PCA residues in citrus matrices utilizes an
internal standard method. Samples of matrix to be analyzed are fortified
with an internal standard.  Residues of PCA and the internal standard
are subjected to acid and base hydrolysis. The extraction was repeated
two more times and the extracts were combined. The pH of the combined
extracts was adjusted to pH>12 and the sample was repeatedly partitioned
with hexane. The combined organic phases were partitioned with a small
volume of aqueous acid. The aqueous acid phase was basified to pH >12
and was repeatedly partitioned with a small volume of hexane. The
resultant extract was passed through a Florisil SPE cleanup prior to
derivatization with HFBA. All citrus matrices were conducted by the same
method, with the exception that filtration was not required for orange
juice or oil. The PCA present was determined by GC/MS analysis. The
limit of quantitation was 0.005 ppm (5.0 ppb) in citrus. 

The methods were successfully validated on orange fruit, orange juice,
orange dried pulp, and orange citrus oil prior to or concurrently with
sample analysis.

3. Magnitude of residues  A complete crop residue program has been
completed for diflubenzuron and its metabolites in the major citrus
growing areas of the US. Raw agricultural commodities, treated according
to the proposed label, were sampled.  The analytical data demonstrated
that residues in crops are not expected to exceed the proposed tolerance
levels.   

A total of 23 citrus fruit trials (12 orange, 6 grapefruit, and 5 lemon)
were conducted in EPA Regions 3, 6, and 10 during the 2008 and 2009
growing seasons.  Twelve orange trials were conducted in U.S. EPA
Regions 3 (FL, 8 trials), 6 (TX, 1 trial), and 10 (CA, 3 trials).  Six
grapefruit trials were conducted in U.S. EPA Regions 3 (FL, 3 trials), 6
(TX, 1 trial), and 10 (CA, 2 trials).  Five lemon trials were conducted
in Regions 3 (FL, 1 trial) and 10 (CA, 4 trials).  One decline orange
trial was conducted in EPA Region 3, one decline lemon trial and one
decline grapefruit trial were conducted in EPA Region 10.  A further 5
trials (3 orange and 2 grapefruit) were also conducted using ultra low
volume (ULV) equipment.  Additionally, data on orange processed
commodities were provided from one site in EPA Region 10.  The number
and geographic locations of field trials are adequate to support a
revised U.S. tolerance for residues of diflubenzuron (DFB) and its
4-chlorophenylurea (CPU) and 4-chloroaniline (PCA) metabolites in the
citrus fruits crop group, based on the proposed field use conditions.  

Chemtura Corporation is proposing a citrus crop group tolerance of 1.3
ppm, and a tolerance of 39 ppm on citrus oil processed commodity.

B. Toxicological Profile

1. Acute toxicity.  Studies for diflubenzuron technical indicate the
acute oral toxicity in rats and mice is >4,640 mg/kg, and the acute
dermal toxicity in rats is >10,000 mg/kg.  The acute inhalation LC50 in
rats is >35 mg/l (6 hours). Diflubenzuron technical is not an eye or
skin irritant to rabbits, and is not a dermal sensitizer in guinea pigs.

	2. Genotoxicity.  Diflubenzuron did not show any mutagenic activity in
point mutation assays employing S. typhimurium, S. cerevisiae, or L5178Y
Mouse Lymphoma cells.  Diflubenzuron did not induce chromosomal
aberrations in Chinese Hamster Ovary cells and did not induce
unscheduled DNA synthesis in human WI-38 cells.  Diflubenzuron was also
negative in Mouse Micronucleus and Mouse Dominant Lethal assays and it
did not induce cell transformation in Balb/3T3 cells.

3. Reproductive and developmental toxicity.  In a rat developmental
toxicity study, diflubenzuron was administered by oral gavage to
pregnant female rats at dosage levels of 0, 1, 2 and 4 mg/kg/day. No
treatment related effects were seen. A subsequent study was conducted in
pregnant Sprague Dawley rats at a dose of  0 and 1,000 mg/kg/day. No
maternal toxicity was observed. The incidence of fetuses with skeletal
abnormalities was slightly increased in the treated group, but was
within historical background range. The NOEL for maternal and
developmental toxicity in rats was greater than 1,000 mg/kg/day. 

Diflubenzuron was also administered by oral gavage to pregnant New
Zealand White rabbits at dosage levels of 0, 1, 2 and 4 mg/kg/day. No
treatment related effects were seen. A subsequent study was conducted in
pregnant rabbits at a dose of 0 and 1,000 mg/kg/day. No maternal or
developmental toxicity was seen. The NOEL for maternal and developmental
toxicity in rabbits was greater than 1,000 mg/kg/day.

In a rat reproduction study, diflubenzuron was fed to two generations of
male and female rats at dietary concentrations of 0, 10, 20, 40, and 160
ppm. No effects were seen on parental body weight gain and there were no
reproductive effects. In a subsequent study, diflubenzuron was fed to
two generations of male and female rats at dietary concentrations of
500, 5,000 and 50,000 ppm.  Systemic adult toxicity was seen at all
dosage levels.  No effects were seen on reproductive  parameters,
however, litter and mean pup weights of F1 offspring were reduced at
50,000.  The NOEL for reproductive toxicity in rats was 50,000 ppm (2.5
g/kg/day), and for pre-weaning development it was 5,000 ppm (250
mg/kg/day).	

4. Subchronic toxicity.[To assess subchronic toxicity, a four-week
inhalation study and a three-week dermal study were conducted.  In the
inhalation study rats were exposed nose only to 10, 30 or 100 mg/m3 for
6 hours per day, 5 days per week for 4 weeks.  Treatment related
findings  were a slight reduction in erythrocytes, hemoglobin and
hematocrit in male and female rats at a concentration of 100 mg/m3 and
an increase in total bilirubin in high dose female rats.  There was no
effect on methemoglobin concentration at any dose level.  The NOEL for
subchronic inhalation toxicity was 30 mg/m3. 

In the dermal toxicity study, diflubenzuron was applied to the backs of
male and female CD rats for three weeks at dose levels of 20, 500 and
1,000 mg/kg/day. Hematology evaluation showed reductions in red blood
cell (RBC), hemoglobin (Hgb) and hematocrit values at 500 and 1,000
mg/kg/day.  An increased incidence of polychromasia, hypochromasia and
anisocytosis was seen at 500 and 1,000 mg/kg/day.  An increase in
methemoglobin and sulfhemoglobin values was seen at 1,000 mg/kg/day. 
The NOEL for systemic toxicity was 20 mg/kg/day. Also, a dermal
absorption factor of 0.5% for systemic absorption, was derived from a
study where rats were dosed with either 0.005 or 0.05 mg/cm2 of [14C]
diflubenzuron technical. This value can be used for converting dermal
exposure to oral equivalents.

5. Chronic toxicity.  Diflubenzuron was given by capsule to male and
female Beagle dogs for one year at dose levels of 0, 2, 10, 50 and 250
mg/kg/day.  Body weight gain was slightly reduced in females at 250
mg/kg/day.  Absolute liver and spleen weights were increased in males
given 50 and 250 mg/kg/day.  A reduction in hemoglobin and mean
corpuscular hemoglobin concentration, with an elevation in reticulocyte
count, was seen at 50 and 250 mg/kg/day.  Methemoglobin and
sulfhemoglobin values were increased at doses of 10 mg/kg/day and
greater.  Histopathological findings were limited to pigmented
macrophages and Kupffer cells in the liver at doses of 50 and 250
mg/kg/day. The NOEL for chronic toxicity in dogs was 2 mg/kg/day.

Diflubenzuron was fed to male and female Sprague Dawley rats for two
years at dose levels of  0, 156, 625, 2,500 and 10,000 ppm.
Methemoglobin values were elevated in female rats at all dose levels and
in male rats at the two highest dose levels.  Sulfhemoglobin was
elevated in females, only, at dose levels of 2,500 and 10,000 ppm.  Mean
corpuscular volume (MCV) and reticulocyte counts were increased in high
dose females. Spleen and liver weights were elevated at the two highest
doses.  Histopathological examination demonstrated an increase in
hemosiderosis of the liver and spleen, bone marrow and erythroid
hyperplasia and areas of cellular alteration in the liver.  In another
study diflubenzuron was administered to male and female CD rats for two
years at dose levels of 0, 10, 20, 40 and 160 ppm. Elevated
methemoglobin levels were seen in high dose males and females.  No
additional effects, including carcinogenic findings, were observed.  The
NOEL for chronic toxicity in rats was 40 ppm (2 mg/kg/day).

     A ninety-one week oncogenicity study in CFLP mice was conducted at
doses of 0, 16, 80, 400, 2,000 and 10,000 ppm.  There was no increase in
tumor incidence as a result of diflubenzuron administration.  Target
organ effects included: increased methemoglobin and sulfhemoglobin
values, Heinz bodies, increased liver and spleen weight, hepatocyte
enlargement and vacuolation, extramedullary hemopoiesis in the liver and
spleen, siderocytosis in the spleen and pigmented Kupffer cells.  A NOEL
for these effects was 16 ppm (2 mg/kg/day).  

Diflubenzuron was fed to male and female Sprague Dawley rats for two
years at dose levels of 0, 156, 625, 2,500 and 10,000 ppm. 
Methemoglobin values were elevated in female rats at all dose levels and
in male rats at the two highest dose levels.  Blood sulfhemoglobin was
elevated in females, only, at dose levels of 2,500 and 10,000 ppm.  MCV
and reticulocyte counts were increased in high dose females. Spleen and
liver weights were elevated at the two highest doses.  Histopathological
examination demonstrated an increase in hemosiderosis of the liver and
spleen, bone marrow and erythroid hyperplasia and areas of cellular
alteration in the liver. There was no increase in tumor formation.  In
another study diflubenzuron was administered to male and female CD rats
for two years at dose levels of 0, 10, 20, 40 and 160 ppm. Elevated
methemoglobin levels were seen in high dose males and females.  No
additional effects, including carcinogenic findings, were observed.

Immunotoxicity.  Diflubenzuron was fed to mice at concentrations of 0,
80, 400, 2,000 and 10,000 ppm for 28 days.  There was no observed effect
of diflubenzuron, at any dose tested, on the anti-SRBC IgM response. 
The immunotoxicity NOAEL for this study was the highest dose tested dose
concentration of 10,000 ppm.  

6. Animal metabolism. The qualitative nature of the residues in
livestock is adequately understood based on data from ruminant and
poultry metabolism studies. The Agency has concluded that the residues
of concern are diflubenzuron and its metabolites CPU and PCA.

DFB in rats at a single dose of 100 mg/kg and 5 mg/kg single and
multiple oral doses depicted limited absorption from the
gastrointestinal tract.  No major difference was observed between the
single and multiple doses.  In single dose  treatments, after 7 days, 
20% and 3% of the applied dose 5 and 100 mg/kg, respectively were
excreted in urine, while 79% and 98% of the applied dose 5 and 100
mg/kg, respectively, were eliminated in the feces.  Very little
bioaccumulation in the tissues was observed.  In the feces, only
unchanged parent compound was detected.  Several metabolites were
observed in the urine which are, among others, 2-6-difluorobenzoic acid
(DFBA), 2,6-diflurophippuric acid, 2-6-difluorobenzamide (DFBAM), and 
2-hydroxydiflubenzuron (2-HDFB).  An unresolved peak that was
characterized as p-chloroaniline (PCA) and/or p-chlorophenylurea (CPU)
was  found.  This latter peak accounted for about 2% of the administered
dose (5 mg/kg).  To resolve if PCA and CPU are indeed metabolites of
DFB, rats were administered a single oral dose, 100 mg/kg of 14C DFB. 
The major metabolites identified in rat urine were
4-chloroaniline-2-sulfate, accounting  for almost 50% of the total
radioactive residue (TRR) in the urine and N-(4-chlorophenyl)oxamic acid
which accounted  for about 15% of the (TRR).  Neither CPU, PCA nor their
N-hydroxylderivatives  were found in rat urine at a limit of detection
of 23 parts per billion (ppb).  As in the previous study, DFB was the
only residue found in the feces.

7. Metabolite toxicology. NCI/NTP conducted chronic feeding and gavage
studies with p-chloroaniline (PCA), a minor potential metabolite of
diflubenzuron, in Fischer 344 rats and  B6C3F1 mice.

PCA was administered in the diet to Fischer 344/N rats at dietary
concentrations of 250 and 500 ppm for 78 weeks, followed by a 24 week
observation period.  A slight body weight depression was seen in high
dose females rats, compared to controls.  Survival was reduced in high
dose males compared to controls.  In male rats there was a slight
increase in uncommon fibromas or fibrosarcomas of the spleen, which was
not statistically significant.  Non-neoplastic proliferative and chronic
inflammatory lesions were found in spleens of treated rats.  It was
concluded that, under the conditions of the assay, sufficient evidence
was not found to establish the carcinogenicity of PCA for Fischer 344/N
rats.

PCA was administered 5 days/week by oral gavage, as a hydrochloride salt
in water, to male and female F344/N rats at doses of 0, 2, 6 or 18
mg/kg/day.  Mean body weights of dosed rats were generally within 5% of
those of controls throughout the study.  High dose animals generally
showed mild hemolytic anemia and dose-related methemoglobinemia. 
Non-neoplastic lesions seen were bone marrow hyperplasia, hepatic
hemosiderosis and splenic fibrosis, suggesting treatment related effects
on the hematopoietic system.  Adrenal medullary hyperplasia was observed
in high dose female rats.  The incidence of uncommon sarcomas of the
spleen was significantly increased in high dose male rats.  A marginal
increase in pheochromocytomas of the adrenal gland was seen in high dose
male and female rats.  It was concluded that, under the conditions of
this 2 year gavage study, there was clear evidence of carcinogenic
activity of PCA hydrochloride for male Fischer 344/N rats and equivocal
evidence of carcinogenic activity of PCA hydrochloride for female
Fischer 344/N rats.

PCA was administered in the diet to B6C3F6 mice at dietary
concentrations of 2500 and 5000 ppm for 78 weeks followed by a 13-week
observation period.  A body weight depression was seen in treated mice
of both sexes, compared to controls.  An increased incidence of
hemangiomas and hemangiosarcomas in spleen, kidney, liver  and other
sites was seen in treated mice of both sexes; however this increase was
not statistically significant compared to controls.  Non-neoplastic
proliferative and chronic inflammatory lesions were found in spleens of
treated mice.  The evidence was considered insufficient to conclusively
relate the hemangiomatous tumors in mice to compound administration.  It
was concluded that, under the conditions of the assay, sufficient
evidence was not found to establish the carcinogenicity of PCA for
B6C3F1 mice.

PCA hydrochloride was administered 5 days/week by oral gavage to male
and female B6C3F1 mice at doses of 0, 3, 10, or 30 mg/kg/day.  Mean body
weights of high dose male and female mice were generally within 5% of
those of controls throughout the study.  The incidence of hepatocellular
adenomas or carcinomas (combined) was increased in a non-dose-dependent
manner in treated male mice. Metastasis of carcinoma to the lung was
seen in the high dose group.  An increased incidence of hemangiosarcomas
of the liver or spleen was seen in high dose male mice. It was concluded
that, under the conditions of this 2-year gavage study, there was some
evidence of carcinogenic activity of PCA hydrochloride for male B6C3F1
mice and no evidence of carcinogenic activity of PCA hydrochloride for
female B6C3F1 mice. 

In addition to PCA, 4-chlorophenylurea (CPU) is also a potential minor
metabolite of diflubenzuron.  By association with Monuron, the EPA had
assumed that CPU has oncogenic potential with the same carcinogenic
potency (q1*) as Monuron. 

9.  Endocrine disruption.  The standard battery of required studies has
been completed and evaluated to determine potential estrogenic or
endocrine effects of diflubenzuron. 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. No such effects were noted
in any of the studies with diflubenzuron.

C. Aggregate Exposure

1.  Dietary Exposure. An evaluation of chronic dietary exposure,
including drinking water, has been performed for the U.S. population and
various population subgroups including infants and children.  One day
single dose oral studies in rats and mice indicated there were no
significant acute effects observed.  As only marginal effects were
noted, an acute exposure assessment is not needed for diflubenzuron.

 i. Food

The dietary exposure from diflubenzuron was estimated based on the
average residue values from the various currently labeled raw
agricultural commodities (RAC’s), and the proposed citrus crop group
uses.  Percent of crop treated was also factored into the estimate. 
Residues in meat, milk and egg products were obtained from extrapolation
of metabolism study data to anticipated  livestock dietary burdens.  

A chronic dietary exposure assessment was conducted on diflubenzuron
using DEEM-FCIDTM Version 2.14, which incorporates consumption data
fromUSDS’s CSFII, 1994-1996 and 1998. Chemtura predicts that 28% of
citrus crops will be treated at market maturity (~5 years following
introduction of the new use pattern on citrus).  Percent crop treated
for mushrooms has declined considerably over the years from 31%
(previous EPA’s assessments) to no more than 3.2% for a 5-year
average. A partially refined assessment in which the percent crop
treated information for citrus and mushroom was incorporated, while the
percent crop treated values for all other crops were maintained at 100%.
 With this refinement, the chronic dietary exposure to the US Population
(total) was estimated was 12.4% of the cPAD (0.00248 mg/kg/day). The
most highly exposed subpopulation, children 1-2 years, has an estimated
total exposure of 39.9% of the cPAD. The total chronic dietary exposure
associated with current and proposed uses of diflubenzuron on citrus has
been demonstrated to be less than the cPAD (0.02 mg/kg/day) and are
therefore not of concern. Using updated percent crop treated estimates
on all crops would further refine the exposure estimate. Use of percent
crop treated information for all crops and switching to average residues
rather than tolerances would further refine the exposure downward.  

Incremental cancer risk assessments were conducted for CPU and PCA with
the proposed modified uses on citrus. When the 28% crop treated factor
is included in the analysis for citrus, the incremental cancer risks are
estimated to be 0.000042 mg/kg bw/day for CPU and 0.000007 mg/kg bw/day
for PCA. 

ii. Drinking water. Diflubenzuron degrades in soil relatively quickly
with an aerobic half-life ranging from 3-7 days. Major degradates
include difluorobenzoic acid (DFBA) and CPU. DFBA is further metabolized
through decarboxylation and ring cleavage by soil microbes whereas CPU
is slowly degraded to soil-bound entities. Under anaerobic aquatic
conditions, diflubenzuron has a half-life of 34 days with the main
degradates being DFBA and CPU. In surface water, diflubenzuron is
degraded by microbes with a half-life of 5-10 days. 

Based on EPA’s SCI-GRO and Tier II PRZM-EXAM modeling, the average
annual mean concentration of diflubenzuron in ground and surface water
sources is not expected to exceed the level of concern.  The DWLOC for
chronic (cancer) exposure to diflubenzuron and CPU in surface/drinking
water was determined as 2.76 ppb for the U.S. population (total). The
groundwater estimate from SCIGROW is 0.208 ppb. The estimated maximum
concentrations of diflubenzuron and CPU in ground and surface water are
less than the DWLOC’s as a contribution to chronic aggregate exposure.

2. Non-dietary exposure. Diflubenzuron is a restricted use pesticide
based on its toxicity to aquatic invertebrates. This restricted use
classification makes it unavailable for use by homeowners. Occupational
uses of diflubenzuron may expose people in residential locations, parks,
or forests treated with diflubenzuron. Based on very low residues
detected in forestry dissipation studies, a low dermal absorption rate
(0.5%), and extremely low dermal and inhalation toxicity, these uses are
expected to result in insignificant risk, and are therefore not included
in the aggregate risk assessment.

D. Cumulative Effects

The registrant has considered the potential for cumulative effects of
diflubenzuron and other substances with a common mechanism of toxicity. 
The mammalian toxicity of diflubenzuron is well defined.  Chemtura is
not aware of any other pesticide product registered in the United States
that could be metabolized to p-chloroaniline. For this reason,
consideration of potential cumulative effects of residues from
pesticidal substances with a common mechanism of action as diflubenzuron
is not appropriate. Thus, only the potential exposures to diflubenzuron
were considered in the total exposure assessment.

E. Safety Determination

1. U.S. population. Based on the available toxicology and exposure
database for diflubenzuron, the registrant has determined that the total
non-occupational aggregate exposure from diflubenzuron would occur from
food and drinking water routes.  Based on the 0.02 mg/kg/day RfD
(reference dose) derived from the dog chronic NOEL of 2 mg/kg/day and a
100-fold safety factor, chronic dietary exposure to the U.S. population
(total) is 12.4% of the RfD. Aggregate exposure does not exceed 100% of
the RfD when the potential theoretical residues in drinking water are
included.  

     For PCA, the total non-occupational aggregate exposure would occur
from the dietary route.  The risk from diflubenzuron-derived PCA can be
estimated using a linear extrapolation of the dose-response from the rat
chronic study conducted by the National Toxicology Program in which rats
were dosed via gavage with p-chloroaniline [hydrochloride] for 24
months.  EPA has determined the Q* as 0.112 based on the combined
incidence of liver adenomas and carcinomas in male mice.   Using this
Q*, the theoretical risk to the U.S. population (total) from dietary
exposure to diflubenzuron-derived PCA was estimated at 7.87 x 10-7.  

         For CPU, total aggregate exposure could occur from food and
drinking water. The EPA has determined that since CPU is structurally
related to Monuron the most potent Q* of 1.52 x 10-2 (based on male rat
liver neoplastic nodule and/or carcinoma combined tumor rates) from the
NTP carcinogenesis data for Monuron should be used for assessing cancer
risk from CPU.  Using this Q* the theoretical risk to the U.S.
population (total) from dietary exposure to CPU was estimated at 6.41 x
10-7. The aggregate cancer risk including drinking water does not exceed
the level of concern.

2. Infants and children. The dietary exposure of diflubenzuron was
calculated as 0.000986 and 0.002911 mg/kg/day respectively for nursing
and non-nursing infants. These values are 4.9% and 14.6% respectively of
the RfD for diflubenzuron.  The dietary exposure from diflubenzuron in
children 1-6 and 7-12 years old was determined as  0.006601 mg/kg/day
and 0.003509 mg/kg/day, respectively. These values are 33.0% and 17.5%
of the RfD, respectively.  Aggregate exposure from food and drinking
water does not exceed the level of concern. 

          As previously discussed, the NOEL’s for maternal and
developmental toxicity in rats and rabbits were greater than 1,000
mg/kg/day, and the NOEL for reproductive toxicity was greater than 5,000
mg/kg/day.  Therefore, based on the completeness and reliability of the
toxicity data and the conservative exposure assessment, the registrant
concludes that there is reasonable certainty that no harm will result in
infants and children from aggregate exposure to residues of
diflubenzuron and its conversion products containing the p-chloroaniline
moiety.

F. International Tolerances

Codex MRLs have been established for diflubenzuron per se on many
commodities including : citrus fruit (0.5 ppm), mushrooms (0.3 ppm),
pome fruits (5 ppm), rice (0.01 ppm), rice straw and fodder (dry; 0.7
ppm), edible offal (mammalian) (0.1 ppm), eggs (0.05 ppm), poultry meat
(0.05 ppm), milk (0.02 ppm). MRLs have been established for
diflubenzuron in the EU for citrus (1.0 ppm), pome fruit (5 ppm),
apricot (1 ppm), strawberry (2 ppm), grapes (1 ppm), and brassica
vegetables (1 ppm). 

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