Document ID: EPA-HQ-OPP-2007-1065-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-02-13T05:00Z

<COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE  (7/1/2006)>

<EPA Registration Division contact: [Mr. Tony Kish, Product Manager
(22), (703) 308-9443]>

 

<INSTRUCTIONS:  Please utilize this outline in preparing tolerance
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<TEMPLATE:>

<[KIM-C1, LLC]>

<[Insert petition number]>

<	EPA has received a pesticide petition ([insert petition number]) from
[KIM-C1, LLC], [c/o Siemer & Associates, Inc. 135 W. Shaw, Suite 102,
Fresno, CA  93704] 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>

<	>< [Forchlorfenuron (KT-30)] in or on the raw agricultural commodity
[Almond, Cherry, 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
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 primary residue of forchlorfenuron is parent
material.  Three plant metabolism studies were conducted, one on grapes
(MRID #44394601), one on kiwifruit (MRID #44359501), and one on apples
(MRID #44394602), all showed parent material to be the primary residue. 
There were two hydroxy metabolites in all > three radio label studies at
very low levels.  That is why the parent material is considered the
primary residue.  There have been 30+ residue studies conducted
(cumulatively) on grapes, raisins and kiwifruit that have been
previously submitted to US EPA to support the Section 3 registration on
grapes, raisin, and kiwifruit.  Tolerances are established at 0.03 for
grapes, 0.02 for raisins, and 0.01 for kiwifruit.  Sixteen additional
residue studies were conducted for this EUP request, six on almonds, two
on cherry, two on fig, two on pear, two on pistachio and two on prune. 
Residue levels were at or below the level of quantification (0.01) on
fruits and nuts in all sixteen studies.]

<	2. Analytical method. [Two analytical methods, both based on high
performance liquid chromotography (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 lowest level of
quantification (LOQ) in all of the crops (i.e. almond, cherry, fig,
pear, pistachio and prune) was 0.01 ppm.]>

<	3. Magnitude of residues. [The magnitude of residues in almond,
cherry, fig, pear, pistachio and prune are all at or below the LOQ.  All
analyzed samples had residue levels below detectable levels.]>

<B. Toxicological Profile>

	[A full battery of toxicology testing including studies of acute,
subchronic, chronic, oncogenicity, developmental, reproductive and
genotoxicity effects is available for KT-30 Technical active ingredient.
 The acute toxicity of KT-30 is low by all routes.  The lowest
subchronic study showed a no observable adverse effect level (NOAEL)
value of 16.8 milligrams/kilogram/day (mg/kg/day) obtained from the dog
90-day toxicity study.  Chronic studies in other animals indicated that
KT-30 is not carcinogenic.  The lowest chronic dietary NOAEL is 7
mg/kg/day from male rats fed KT-30 for 104 weeks.  KT-30 showed no
evidence of developmental toxicity in rats and rabbits.  In a rat
reproduction study, reproductive effects were only observed at
maternally toxic doses.  Finally, genetic toxicity studies indicated
that KT-30 was not genotoxic.  For the purpose of dietary risk analysis,
0.07 mg/kg/day is proposed for the chronic population adjusted dose
(cPAD).  The cPAD is based on a chronic endpoint of 7 mg/kg/day, which
is the NOAEL for male rats  from the chronic/oncogenicity feeding study
and with an uncertainty factor of 100.  No acute toxicity endpoint could
be identified and, therefore, an acute dietary risk assessment is
considered unnecessary.]

<	1. Acute toxicity.  [These toxicity studies were run with KT-30
Technical as well as the end use formulation (ABG-3207 Plant Growth
Regulator).  The acute toxicity of KT-30 is low by all routes.  The
battery of acute toxicity studies place KT-30 into Toxicity Category
III.  KT-30 has low acute toxicity when administered orally, dermally or
via inhalation to rats.  It is not a skin irritant and is only a mild
eye irritant.  KT-30 is not a skin sensitizer.]>

<	2. Genotoxicity. [The genotoxic potential of KT-30 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 the evidence indicates that
KT-30 does not possess significant genotoxicity concerns.]>

<	

3. Reproductive and developmental toxicity. [Developmental effects of
KT-30 were studied in rats and rabbits and multigenerational effects on
reproduction were studied in rats.

i.  Rat developmental.  In the developmental toxicity study conducted
with rats, KT-30 was administered by gavage at levels of 0, 100, 200,
and 400 mg/kg/day.  The maternal and developmental NOAELs are 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.

ii.  Rabbit developmental.  In the rabbit developmental toxicity study,
gavage doses of 0, 25, 50, and 100 mg/kg/day were administered. 
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.

iii.  Reproduction.  In the rat reproduction study, KT-30 was
administered in the diet at levels of 0, 150, 2,000 and 7,500 ppm for
two generations.  There were no adverse effects of KT-30 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.]>

<	4. Subchronic toxicity. [Subchronic studies have been conducted with
KT-30 in the rat, mouse and dog.

i.  Rats.  KT-30 Technical 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).

ii.  Mice.  A 13-week dietary toxicity study in mice was 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).

iii. Dogs.  A 13-week dietary toxicity study was conducted 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).]

>

<	5. Chronic toxicity. [KT-30 has been tested in chronic studies with
rats, mice and dogs.

i.  Rats.  In a 104-week combined chronic/oncogenicity study in rats,
KT-30 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).

ii.  Mice.  KT-30 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.

iii.  Dogs.  In a 12-month study, KT-30 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).

iv.  Carcinogenicity.  KT-30 did not produce carcinogenicity in chronic
studies with rats or mice.  The oncogenicity classification of KT-30
will be “E” (no evidence of carcinogenicity for humans).]>

<	6. Animal metabolism. [A rat metabolism study indicated that KT-30 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 KT-30 was via hydroxylation of the phenyl
ring.  The sulfate conjugate of hydroxyl KT-30 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.]>

<	7. Metabolite toxicology. [Metabolites occur at levels below 0.1 ppm
and, therefore, are below levels required to be assayed in animal
testing.]>

<	8. Endocrine disruption. [Potential endocrine effects.  No special
studies to investigate the potential for endocrine effects of KT-30 have
been performed.  However, as summarized above, a large and detailed
toxicology data base exists for the compound including studies in all
required categories.  These studies include acute, sub-chronic, chronic,
developmental, and reproductive toxicology studies, including 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 KT-30 does not possess estrogenic or endocrine disrupting
properties.]>

<C. Aggregate Exposure>

<	1. Dietary exposure. [The dietary exposure assessment was conducted by
Environs for foods containing forchlorfenuron: CAS Number: 68157-60-8
(KT-30).]>

<	i. Food. [Reference is made to a document that shows a Dietary
Exposure Assessment that was conducted for KIM-C1 by ENVIORNS, looking
at a number of crops, some of which were almond, fig, pear, and prune. 
This work was done for KIM-C1 in connection with a previous EUP that
KIM-C1 obtained for development of efficacy data on the crops listed
below.  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 levels with results from treatment of the total acreage of all
crops included in the 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.  Combining the RfD consumption from the group of
crops with that of apples would exceed 1% of the reference dose only
slightly if the total acreage of all crops were treated.  (This study is
referenced in the Notice of Filing published by EPA at: Federal
Register: Forchlorfenuron; Notice of Filing a Pesticide Petition… [FR.
DOC 04-7651 Filed 4-6-04])]>

<	ii. Drinking Water. [The very low use rate of KT-30, i.e., 10 grams
active ingredient (a.i.) or less per acre if used constantly once a year
for 20 years would apply less than a pound of KT-30 per acre during that
20 year period.  Computer modeling, using the conservative pesticide
root zone model (PRZM) means of analysis has shown that no KT-30 would
reach ground water, even in sandy loam soils.  The results of this risk
analysis supported an unambiguous conclusion of “essentially zero risk
to ground water” even under reasonable worst-case assumptions. 
Concentrations are not predicted to exceed 15 to 20 ppb of KT-30 in the
soil in the upper soil horizons, even following yearly applications for
as long as 30 years.  No secondary exposure is anticipated as a result
of contamination of drinking water.]>

<	2. Non-dietary exposure. [No non-dietary exposure is expected since
KT-30 is not anticipated to be found in the drinking water.  This
material does not translocate in plants and thus secondary exposure
through plants growing in soil receiving KT-30 is not anticipated.  The
extremely low application rates will not result in significant buildup
in the environment.  Data indicate that any parent material of KT-30
left in the soil will be strongly bound to soil particles and will not
move.]>

<D. Cumulative Effects>

<	[There are no cumulative effects expected since KT-30 is not taken up
by plants from the soil.  It slowly degrades to mineral end points.  Its
low use rates and infrequent applications are not conducive to buildup
in the environment.]>

<E. Safety Determination>

<	1. U.S. population. [As pointed out above in dietary exposure-food,
the percentage of the RfD consumed by treating the subject crops
represents only 1% of the estimated safe level for the most sensitive
segment of the population, non-nursing infants.]>

<	2. Infants and children. [No developmental, reproductive or fetotoxic
effects have been associated with KT-30.  The calculation of safety
margins with respect to these segments of the population were taken into
consideration in the TMRC estimates with respect to the risk associated
with the percentage of the reference dose being consumed.]>

<F. International Tolerances>

<	[There is no Codex maximum residue level established for KT-30. 
However, KT-30 is registered for use on grapes and kiwifruit in the
U.S., and has a pending registration for blueberries.  Forchlorfenuron
is registered for use on grapes and other crops in Japan, Chile, Mexico,
and South Africa.  In Italy, forchlorfenuron is registered on
kiwifruit.]>