Document ID: EPA-HQ-OPP-2013-0010-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-02-15T05:00Z

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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Cynthia Giles-Parker; Acting Product
Manager, Team 20; (703) 305-7740 

TEMPLATE:

KIM-C1, LLC

2F8055

	EPA has received a pesticide petition (2F8055) from KIM-C-1, LLC, 2547
West Shaw Avenue, Suite 116, Fresno, CA 93711 requesting, 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

	1. by establishing a temporary tolerance for residues of 

	N-(2-chloro-4-pyridinyl-N’-phenylurea (forchlorfenuron) in or on the
raw agricultural commodity almond, cherry (sweet), fig, pear, pistachio,
plum/prune at 0.01 parts per million (ppm).  EPA has determined that the
petition contains data or information regarding the elements set forth
in section 408 (d)(2) of  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. One plant metabolism study on each of three crops,
including grapes, kiwi fruit and apple fruit, were conducted.  Based on
all three studies the residue of concern was defined as forchlorfenuron
parent compound.

	2. Analytical method. Two analytical methods, both based on high
performance liquid chromatography (HPLC) procedures have been developed.
 The first method used a visible ultraviolet (UV) detector, while the
second method used a mass spectrophotometer (MS) detector.  Since the MS
detector is capable of both qualitative as well as quantitative
measurement, it is the preferred method.  The level of quantification
(LOQ) in all of the crops (i.e., almond, cherry, fig, pear, pistachio
and plum/prune) is 0.01 ppm.

	3. Magnitude of residues. Ten field magnitude of residue trials with
florchlorfenuron were conducted in five counties in California during
the 2006 growing season.  This included residue trials on sweet cherry,
fig, pear, pistachio and plum/prune.  In addition, three almond trials
were conducted in three counties in California during the 2005 and 2006
growing seasons.  Applications on almonds were made at 11.4 grams a.i./A
while applications on the other five crops were made at 10 grams a.i./A.
 Treatments were made with the shortest possible interval between
application and harvest to maximize the residue level.  All commodities
were analyzed for parent compound.  The validated limit of
quantification (LOQ) for forchlorfenuron was set at 0.01 ppm.  The limit
of detection (LOD) was defined as 1/3 of the LOQ or 0.003 ppm for each
matrix.  Residues of forchlorfenuron were < LOQ (0.01 ppm) on all
cherry, fig, pear, pistachio and plum/prune matrices.  No residues of
forchlorfenuron were found in the almond nut in shell samples (<0.01). 
Non-detectable to low levels of forchlorfenuron were found in almond
hulls, with the highest level being 0.0841 ppm (0.0935 ppm corrected for
concurrent mean procedural recovery).   

B. Toxicological Profile

Acute toxicity. 

 Acute toxicity endpoints for forchlorfenuron technical are as follows:

Guideline No./Study  Type	Results	Toxicity Category

870.1100

Acute Oral – Rat	LD50 (mg/kg bw):

M = 4904; F = 4899; Combined = 4918	III

870.1200

Acute Dermal – Rabbit	LD50 (mg/kg bw):

M = >2000; F = >2000	III

870.1300

Acute Inhalation – Rat	LC50 (mg/L):

M = >3.0; F = >3.0	IV

870.2400

Primary Eye Irritation - Rabbit	Mild eye irritant	III

870.2500

Primary Skin Irritation – Rabbit	Non-irritant	IV

870.2600

Dermal Sensitization – Guinea Pig	Non-sensitizer	N/A

Genotoxicty. 

The genotoxic potential of forchlorfenuron was studied in vitro in
bacteria and mammalian cells and in vivo in the unscheduled DNA
synthesis test.  The test systems assayed did not show any evidence of
genotoxicity except in the bacterial mutagenicity assay, strain TA1535,
without metabolic activation.  The weight of evidence indicates that
forchlorfenuron does not possess significant genotoxicity concerns.

Reproductive and developmental toxicity. 

A developmental toxicity study was conducted with forchlorfenuron using
rats gavaged with levels of 0, 100, 200 and 400 mg/kg/day.  The maternal
and developmental NOAELs were 200 mg/kg/day based on reduced body
weights, body weight gain, food consumption, and an increased incidence
of alopecia in dams.  There were no developmental effects.

A developmental toxicity study was conducted with forchlorfenuron using
rabbits gavaged with doses of 0, 25, 50 and 100 mg/kg/day.  Maternal
toxicity (decreased body weight and body weight gains) were observed at
50 mg/kg/day and above.  The maternal NOAEL was 25 mg/kg/day and the
developmental NOAEL was 100 mg/kg/day.  There were no developmental
effects.

A two generation reproduction study was conducted in rats in which
forchlorfenuron was administered in the diet at levels of 0, 150, 2,000
and 7,500 ppm.  There were no adverse effects of forchlorfenuron on
reproductive success.  Parental toxicity consisted of clinical signs,
inhibition of body weight gain, reduced food consumption, and
macroscopic and microscopic effects in the kidney.  Reproductive
toxicity in the highest dose consisted of slightly reduced live litter
sizes in the F2 litters.  In the pups, body weights and survival (late
lactation period) were reduced and at the high dose, pup mortality and
emaciation were increased.  The parental, pup and reproductive NOAELs
were 150 ppm, 150 ppm and 2,000 ppm, respectively.

 

Subchronic toxicity. 

Forchlorfenuron was tested in rats in a 3-month study at 

dietary levels of 0, 200, 1,000 and 5,000 ppm   Observations were
decreased body weight, body weight gain and food efficiency.  The NOAEL
for males was 5,000 ppm (400 mg/kg/day) and in females was 1,000 ppm (84
mg/kg/day).

Forchlorfenuron was tested in a 13-week dietary toxicity study in mice  

conducted at dose levels of 0, 900, 1,800, 3,500 and 7,000 ppm.  Effects

included decreased body weight and food consumption, increased relative 

liver weight and lymphocytic cell infiltration in the kidneys.  The
NOAEL 

was 3,500 ppm (609 mg/kg/day in males and 788 mg/kg/day in females).

A 13-week dietary toxicity study was conducted with forchlorfenuron in 

beagle dogs at dose levels of 0, 50, 500 and 5,000 ppm.  Effects
included 

decreased body weight gain, food consumption, and food efficiency.  The 

NOAEL for both sexes was 500 ppm (16.8 mg/kg/day in males and 19.1 

mg/kg/day in females).

Chronic toxicity. 

In a 104-week combined chronic/oncogenicity study in rats,
forchlorfenuron was administered in the diet at dose levels of 0, 150,
2,000 and 7,500 ppm.  Findings were decreased body weight and body
histopathological effects in the kidney.  No oncogenicity was found. 
The NOAEL for this study was 150 ppm (7 mg/kg/day in males and 9
mg/kg/day in females).

Forchlorfenuron was administered in the diet to mice for 78-weeks at
dose 

levels of 0, 10, and 1,000 mg/kg/day.  Observations were decreased body 

weight, body weight gain, food consumption, increased kidney weights and

incidence of chronic kidney histopathological lesions.  The NOAEL for
both 

sexes was 10 mg/kg/day.  No oncogenicity was found.

In a 12-month study, forchlorfenuron was administered in the diet given
to 

dogs at dose levels of 0, 150, 3,000 and 7,500 ppm.  Observations
included 

reduced body weight, body weight gain, food consumption, and various 

hematology changes.  The NOAEL for both sexes was 3,000 ppm (87 

mg/kg/day in males and 91 mg/kg/day in females).

Animal metabolism. 

A rat metabolism study indicated that forchlorfenuron is almost
completely 

absorbed and most of the 14C-forchlorfenuron-derived radioactivity is
rapidly 

eliminated primarily via the urine.  The majority of the metabolism of 

forchlorfenuron was via hydroxylation of the phenyl ring.  The sulfate 

conjugate of the hydroxyl forchlrofenuron was the major metabolite
excreted 

in the urine, accounting for as much as approximately 96% of the urinary

radioactivity.  Tissue residues accounted for less than 1% of the
administered 

dose at 168 hours post-dosing.

Metabolite toxicology. 

Metabolites occur at levels below 0.1 ppm and, therefore, are below
levels 

required to be assayed in animal testing.  Nevertheless, the toxicity of
sulfate 

conjugate (and any other animal metabolites) was assessed during the
conduct 

of the CPPU required mammalian toxicity studies.

Endocrine disruption. 

No special studies to investigate the potential for endocrine effects of
forchlorfenuron have been performed.  However, a large, detailed
toxicology data base exists for the compound with studies in all
required categories.  Included are acute, sub-chronic, chronic,
developmental and reproductive toxicology studies, with detailed
histology and histopathology of numerous tissues, including endocrine
organs, following repeated or long-term exposures.  These studies are
considered capable of revealing endocrine effects.  The results of all
of these studies show no evidence of any endocrine-mediated effects and
no pathology of the endocrine organs.  Consequently, it is concluded
that forchlorfenuron does not possess estrogenic or endocrine disrupting
properties.

C. Aggregate Exposure

Dietary exposure. 

A dietary exposure assessment was conducted looking at a number of crops
including almond, fig, pear and prune (as well as apples, blueberries,
grapes and kiwifruit).  This assessment was conducted in connection with
a previous EUP that was obtained for development of efficacy data on the
above listed crops.  The following information was published by EPA in
FR, Vol. 69, No. 67, pp. 18375-18380,  4/7/04.  

Food. 

A reference dose (RfD) was calculated using the most sensitive species
data available from the toxicological testing. The calculated RfD of
0.08 mg/kg/day was used to calculate the impact of the estimated residue
with results from treatment of the total acreage of all crops included
in the prior EUP.  Making the same risk exposure calculations, it was
shown that there was no significant impact on reducing the RfD by using
almonds, apples, blueberries, figs, grapes, kiwifruit, pears and plums
in aggregate.

Drinking water. 

 EPA stated the following in FR Vol. 73, No. 159, pp. 47841-47847, under
“Forchlorfenuron; Permanent and Time-Limited Pesticide Tolerances”
wherein EPA established permanent tolerances for residues of
forchlorfenuron in or on bushberry subgroup 13-07B and time-limited
tolerances under Petition No. 7F7246 for use on almond, cherry (sweet),
fig, pear, pistachio and plum/prune (see FR pp. 47844);  

“The Agency used screening level water exposure models in the dietary

exposure analysis and risk assessment for forchlorfenuron in drinking 

water.  Forchlorfenuron is persistent and moderately mobile in soils.  

Forchlorfenuron is also a substituted urea plant growth regulator that
is 

essentially stable to all routes of dissipation except sensitized 

photodegradation in water. Based on the Pesticide Root Zone Model / 

Exposure Analysis Modeling System (PRZM/EXAMS) and Screening 

Concentration in Ground Water (SCI-GROW) models, the Estimated 

Environmental Concentrations (EECs) of forchlorfenuron from the newly 

proposed use on bushberries and the uses on almonds, sweet cherries,
figs, 

 pears, plums and pistachios under the EUP will not exceed the EECs from

the grape and kiwi uses previously assessed by the Agency in document 

titled Drinking Water Assessment for Forchlorfenuron for Grape and Kiwi 

Uses. Therefore, the Agency has incorporated the drinking water EEC 

from the grape and kiwi analysis directly into this dietary assessment. 
For 

chronic dietary risk assessment, the water concentration of value 0.003 

ppb was used to assess the contribution to drinking water.”

Non-dietary exposure. 

EPA noted the following in FR Vol. 73, No. 159, 8/15/08 in the notice 

establishing the prior temporary tolerances under PP 7F7246 in almonds, 

sweet cherries, figs, pears, plums and pistachios in regard to
non-dietary 

exposure:

“The term ‘‘residential exposure’’ is used in this document to
refer to non-occupational, non-dietary exposure (e.g., for lawn and
garden pest control,

indoor pest control, termiticides, and flea and tick control on pets). 
Forchlorfenuron is not registered for any specific use patterns that
would

result in residential exposure.”

D. Cumulative Effects

EPA noted the following in FR Vol. 73, No. 159, 8/15/08 in the FR Notice
establishing prior temporary tolerances under PP 7F7246 in almonds,
sweet cherries, figs, pears, plums and pistachios in regard to
cumulative effects:

“Section 408(b)(2)(D)(v) of FFDCA requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency consider
‘‘available information’’ concerning the cumulative effects of a
particular pesticide’s residues and ‘‘other substances that have a
common mechanism of toxicity.’’  EPA has not made a common mechanism
of toxicity finding as to forchlorfenuron and any other substances and
forchlorfenuron does not appear to produce a toxic metabolite produced
by other substances. For the purposes of this tolerance action,
therefore, EPA has not assumed that forchlorfenuron has a common
mechanism of toxicity with other substances.”

E. Safety Determination

EPA noted the following in FR Vol. 73, No. 159, 8/15/08 in the notice
establishing prior temporary tolerances under PP 7F7246 in almond, sweet
cherry, fig, pear, pistachio and plum/prune relative to the Agency’s
conclusions regarding the safety of the proposed uses under the proposed
temporary tolerances for forchlorfenuron (which are the same tolerance
levels proposed in this Petition):

“EPA has determined that reliable data show the safety of infants and
children would be adequately protected if the FQPA SF were reduced to
1X. That decision is based on the following findings: 

The toxicity database for forchlorfenuron is complete.

There is no indication that forchlorfenuron is a neurotoxic chemical and
there is no need for a developmental neurotoxicity study or additional
UFs to account for neurotoxicity.

There is no evidence that forchlorfenuron results in increased
susceptibility in in 

utero rats or rabbits in the prenatal developmental studies or in young
rats in the 2–generation reproduction study.  

There are no residual uncertainties identified in the exposure
databases.  EPA made conservative (protective) assumptions in the ground
and surface water modeling used to assess exposure to forchlorfenuron in
drinking water.  EPA used similarly conservative assumptions to assess
exposure to forchlorfenuron residues in food. These assessments will not
underestimate the exposure and risks posed by forchlorfenuron.

EPA determines whether acute and chronic pesticide exposures are safe by

comparing aggregate exposure estimates to the aPAD and cPAD. The aPAD
and cPAD represent the highest safe exposures, taking into account all
appropriate SFs. EPA calculates the aPAD and cPAD by dividing the POD by
all applicable UFs. For linear cancer risks, EPA calculates the
probability of additional cancer cases given the estimated aggregate
exposure. Short-term, intermediate-term, and chronic-term risks are
evaluated by comparing the estimated aggregate food, water, and

residential exposure to the POD to ensure that the margin of exposure

(MOE) called for by the product of all applicable UFs is not exceeded.

1. Acute risk. An acute aggregate risk assessment takes into account
exposure estimates from acute dietary consumption of food and drinking

water. No adverse effect resulting from a single-oral exposure was
identified and no acute dietary endpoint was selected. Therefore,
forchlorfenuron is not expected to pose an acute risk. 

2. Chronic risk. Using the exposure assumptions described in this unit
for

chronic exposure, EPA has concluded that chronic exposure to
forchlorfenuron from food and water will utilize <1% of the cPAD for the

general U.S. population and all subpopulations. There are no residential

uses for forchlorfenuron.

3. Short-term and intermediate-term risk. Short-term and
Intermediate-term aggregate exposure takes into account short-term and
intermediate-term residential exposure plus chronic exposure to food and
water (considered to be a background exposure level).  Forchlorfenuron
is not registered for any use patterns that would result in short-term
and intermediate-term residential exposure. Therefore, the short-term
and intermediate-term aggregate risk, individually is the sum of the
risk from exposure to forchlorfenuron through food and water, which has
already been addressed, and will not be greater than the chronic
aggregate risk.

4. Aggregate cancer risk for U.S. population. Since forchlorfenuron has

been classified as not likely to be carcinogenic, aggregate cancer risk
is

not a concern.

5. Determination of safety-U.S. population and Infants & Children. 
Based on these risk assessments, EPA concludes that there is a
reasonable certainty that no harm will result to the general population
or to infants and children from aggregate exposure to

forchlorfenuron residues.

F. International Tolerances

The following international tolerances exist for forchlorfenuron:

Australia: An MRL of 0.01 ppm has been established for grapes and as a
temporary MRL level for blueberries, mango and plum/prune.

European Union: Forchlorfenuron MRLs are set for table grapes and
kiwifruit at 0.05 ppm.  However, a new EU MRL of 0.01 ppm is proposed
because sufficient trials are available showing residues below 0.01 ppm

Israel: An MRL of 0.01 ppm has been established for table grapes, wine
grapes and kiwifruit.

Japan: An MRL of 0.01 has been set for almonds.

Mexico: Has deferred to the U.S. Tolerances.  Therefore, all
forchlorfenuron tolerances established in the U.S. apply to Mexico. 

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