Document ID: EPA-HQ-OPP-2016-0519-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2017-06-08T04:00Z

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

EPA Registration Division Contact:  RD

Interregional Research Project No. 4

PP# 6E8450

The U.S. Environmental Protection Agency (EPA) has received a pesticide
petition (PP# 6E8450) from Interregional Research Project Number 4
(IR-4), Rutgers, The State University of New Jersey, 500 College Road
East, Suite 201W, Princeton, NJ  08540, 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. § 180.614 by establishing tolerances for the
residues of Kasugamycin,
(3-O-[2-amino-4-[(carboxyimino-methyl)amino]-2,3,4,6-tetradeoxy-α-D-ara
bino-hexopyranosyl]-D-chiro-inositol), in or on the following raw
agricultural commodities:  Fruit, stone, subgroup 12-12A at 0.6 ppm and
Walnut at 0.04 ppm.  EPA has determined that the petition contains data
or information regarding the elements set forth in FFDCA Section
408(d)(2), however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data support granting of the
petition. Additional data may be needed before EPA rules on the
petition.

A. 	Residue Chemistry

1.   Metabolism in plants. The metabolism of kasugamycin in tomatoes has
been investigated and is well understood as published in the Federal
Register of April 8, 2005 (67 Fed. Reg. 17997). The nature of residues
of kasugamycin in tomatoes was investigated using 14C radiolabeled
kasugamycin. Parent kasugamycin was the primary component in both fruit
and foliage. The main metabolite in fruit, present at a maximum level of
0.01 part per million (ppm), was identified as kasugamycinic acid,
resulting from the conversion of the iminomethyl function to a
carboxylic acid; conjugates of kasugamycin and kasugamycinic acid were
also found in fruit at very low levels.  Investigation of extracts from
foliage indicated the presence of 2-N-acetyl kasugamycin,
kasuganobiosamine, and conjugates of kasugamycin and kasugamycinic acid.

2.  Metabolism in livestock.  The metabolism of kasugamycin in the
lactating goat has been investigated using 14C radiolabeled kasugamycin
and is well understood; 14C-kasugamycin was fed at an exaggerated level
(14.4X) of 12.6 mg/kg (dry feed basis) to a goat for 5 days. 

The majority of the label was excreted as unchanged kasugamycin in the
urine and feces.  Residues ranged from 0.003 ppm in skim milk to 0.024
ppm in milk fat. Residues in other tissues ranged from 0.002 ppm
(omental fat) to 0.013 ppm (liver). The kidney contained 0.262 ppm
kasugamycin. Of the residues found in kidney, 92.9% was identified as
unchanged kasugamycin.

The goat study indicated that kasugamycin is poorly absorbed and those
residues that are retained comprise only parent compound.

3.  Analytical method.  A practical analytical method for detecting and
measuring levels of kasugamycin has been developed and validated in all
appropriate agricultural commodities. This analytical method is suitable
for monitoring of food with residues at the levels proposed for the
tolerances. The limit of quantitation (LOQ) for this method is 0.04 ppm.
An independent laboratory validation of the residue analytical method
was successful. 

	4.  Magnitude of residue.  Eight trials (four tart and four sweet) were
conducted for this study, one in New York (tart cherry, EPA Region 1),
four in Michigan (two tart and two sweet cherry, EPA Region 5), one in
Colorado (tart cherry, EPA Region 9), and two in California (both sweet
cherry, EPA Region 10).  The number of trials and geographic
representation (when combined with trials conducted for study
AAFC07-073R) are adequate for obtaining a tolerance in cherry.  

At all trials, four foliar (directed) applications of Kasumin 2L at a
rate of approximately 0.084 lb ai/A each were applied, for a total
application of approximately 0.34 lb ai/A.  A spreader/sticker type
adjuvant was added to the spray tank mix during each application.  The
applications were made at 7 (+/- 1) day intervals starting at
approximately 51 days before harvest.  The applications were timed so
that commercially mature sweet and tart cherries could be collected 30
(+/- 3) days after the final application.  

Control samples were fortified and analyzed both prior to and
concurrently with field-treated samples.  Fortification levels ranged
from 0.04 to 4.0 ppm.  Method validation recoveries ranged from
94 to 101% at the lowest level of method validation (LLMV), and from
82 to 101% overall.  The average recovery of all kasugamycin
fortifications at 0.04 ppm was 98 ± 4% (n = 9).  The average recovery
of all kasugamycin method validation and concurrent fortifications at
0.4 ppm was 83 ± 8% (n = 10).  The limit of detection (LOD) and LOQ
were statistically calculated as 0.0045 ppm and 0.0137 ppm,
respectively, for kasugamycin.  A five-point standard curve was
generated each time an analysis set was run; the correlation coefficient
was always (0.95.  Note: Matrix in trial CA 112 had a significant
interference; for control sample A and treated sample C, the peak of
interest was partially resolved and quantitation was possible. For
sample D, however, the resolution of kasugamycin could not be achieved
and quantitation was impossible.

The maximum storage interval for field-treated samples in this study was
303 days.  Storage stability testing was performed after 307 days of
frozen storage; results demonstrated stability.

The results from the trials show that the maximum residues in cherry
fruit following a total application of approximately 0.34 lb ai/A and a
PHI of 30 (+-3) days were 0.358 ppm (29 PHI) (NY18 trial, tart cherry). 
The mean residue in all eight trials was 0.172 ppm. The decline study
(MI04) did not show significant residue loss from 7 to 30 days after
treatment.  The highest residue detected was 0.365 ppm for the 0 day
sample in the MI04 trial (tart cherry).

Three field trials (6 samples) were conducted in walnuts according to
the proposed use pattern (i.e., 4 foliar directed applications at 0.083
lb ai/A with 7 day retreatment interval). Walnuts were harvested
approximately 100 days after the last application. Quantifiable residues
were observed in one sample (0.0400 ppm from 07-CA60). All other
residues were below the LLMV of 0.04 ppm.  The tolerance for walnuts is
proposed at the limit of quantitation (0.04 ppm).

B. 	Toxicological Profile

1.  Acute toxicity.  Kasugamycin has a low order of acute toxicity.  The
acute oral and dermal LD50 values for kasugamycin are greater than 5,000
milligrams per kilogram (mg/kg) for rats regardless of gender. In acute
inhalation testing in the rat, kasugamycin’s LC50 is greater than 2.05
milligram/liter (mg/L). Further, kasugamycin was mildly irritating to
the eyes, non-irritating to the skin of rabbits, and non-sensitizing to
the skin of the guinea pig.  This technical label will carry the EPA
signal word “CAUTION.”

2.  Genotoxicity.  A battery of mutagenicity studies yielded negative
results in bacteria and mammalian cells; kasugamycin was negative in the
following assays:  bacterial reverse mutation, Chinese hamster ovary
(CHO), chromosomal aberration (in vitro), mammalian erythrocyte
micronucleus, unscheduled DNA synthesis, and in vitro mammalian cell
gene mutation.  Overall, it is unlikely that kasugamycin presents a
genetic hazard

3.  Reproductive and developmental toxicity.  

i.  Rat developmental.  In the developmental toxicity study conducted
with rats, for maternal toxicity, the no observed adverse effect level
(NOAEL) is 200 mg/kg/day and the lowest observed adverse effect level
(LOAEL) is 1000 mg/kg/day based on decreased body weights, body weight
gains, and food consumption; increased incidence of loose stool; and
distention of the large intestine with stool in the cecum. 

For developmental toxicity, the NOAEL is 1000 mg/kg/day and the LOAEL is
≥1000 mg/kg/day.

ii. Rabbit developmental.  In the developmental toxicity study conducted
with rabbits, the maternal NOAEL is 10 mg/kg/day and the LOAEL is = 30
mg/kg/day based on the range-finding study results of maternal weight
loss, decreased food consumption during treatment and abortion (three or
four females).

For developmental toxicity, the NOAEL is 10 mg/kg/day and the LOAEL is =
30 mg/kg/day based on the decrease in fetal body weight in the
range-finding study.

iii.  Reproduction.  In the rat reproduction study the parental/systemic
NOAEL is 70.3/82.9 mg/kg/day (M/F) and the LOAEL is 425.3/503.4
mg/kg/day (M/F) based on decreased body weights and body weight gains in
P males, and red and swollen skin around the anal opening (M&F)(P and F1
animals).

For reproductive toxicity, the NOAEL is 70.3/82.9 mg/kg/day (M/F) and
the LOAEL is 425.3/503.4 mg/kg/day (M/F) based on testicular
atrophy/degeneration in F1 males, decreased fertility and fecundity in
the F1 parents for both litters, and increased pre-coital interval
during the mating period for the F2 litter. 

For offspring toxicity, the NOAEL is 425.3/503.4 mg/kg/day (M/F) and the
LOAEL is >425.3/503.4 mg/kg/day (M/F).  

4.  Subchronic toxicity. 

≥1,000 ppm male but were not considered adverse.

ii.  Rat 21-day dermal toxicity.  A 21-day dermal toxicity study was
conducted in the rate.  For systemic effects, NOAEL is >500 mg/kg/day
for male and ≥500/200 mg/kg/day for female.  The LOAEL was not
determined as no effects were noted at the highest dose tested.  

For dermal effects, the NOAEL is 250 mg/kg/day for males and 250/100
mg/kg/day for females.  The LOAEL was 500 mg/kg/day for males and
500/200 mg/kg/day for females based on erytherma, edema, eschar,
ulceration, scabbing, microscopic findings of acanthosis, inflammation,
and ulceration.

iii.  Rat 90-day dietary neurotoxicity.  A 90-day acute neural screen
battery was conducted in the rat.  For systemic effects, the NOAEL was
210/238 mg/kg/day (M/F). The LOAEL was 439/486 mg/kg/day (M/F) based on
decreased body weight and body weight gain.  

For neurotoxicity, the NOAEL was ≥439/486 mg/kg/day (M/F). The LOAEL
was not determined as no neurotoxic effects were observed at the highest
dose tested.

iv.  Mouse 90-day oral toxicity.  A 13-week subchronic feeding study was
conducted in the mouse.  The NOAEL is 135.4/170.9 mg/kg/day (M/F) and
the LOAEL is 408.5/565.6 mg/kg/day (M/F) based on increased mortality
and anal lesions (M/F), and kidney lesions (F). At 1,559/1,834 mg/kg/day
(M/F), decreased body weights and body weight gains (M/F), testicular
tubular dilatation and degeneration, perianal/perigenital staining (F),
and extramedullary hematopoiesis of the spleen (M) were seen.

v.  Dog 90-day oral toxicity.  A 13-week subchronic feeding study was
conducted in the dog. The NOAEL is 99.6/103.6 mg/kg/day (M/F) and the
LOAEL is 99.6/103.6 mg/kg/day (M/F) based on tongue lesions, few feces,
swollen mouth, excessive salivation, and thickened skin at the
commissure of the mouth. At 182/170 mg/kg/day (M/F), decreased body
weights, body weight gains, and food consumption were seen.  

           5.  Chronic toxicity.  Kasugamycin has been tested in chronic
studies with dogs, rats, and mice. 

                      i.  Rat combined chronic toxicity/carcinogenicity.
 A 24-month combined chronic/oncogenicity study was conducted in rats. 
The NOAEL was 11.3/140 mg/kg/day (M/F).  The LOAEL was 116/≥140
mg/kg/day (M/F) based on increased testicular softening and atrophy in
males.  No evidence of carcinogenicity was observed.  

                   ii.  Carcinogenicity mouse.  A 78-week chronic
feeding study was conducted in mice. The NOAEL was 186.3/215.2 mg/kg/day
and the LOAEL was >186.3/215.2 mg/kg/day with no evidence of
carcinogenicity. 

           6.  Dog chronic toxicity.  A 52-week chronic toxicity study
was carried out in dogs.  The NOAEL was 99.6/103.6 mg/kg/day (M/F) and
the LOAEL was >99.6/103.6 mg/kg/day with no evidence of carcinogenicity.
 

           7.  Immunotoxicity.  An immunotoxicity study was carried out
in female mice.  The systemic NOAEL is 755/691 mg/kg/day (AFC group/NK
group).  The LOAEL is 2,468/2,531 mg/kg/day (AFC group/NK group) based
on clinical observations, decreased mean body weights, and decreased
hematological parameter.

The immunotoxicity NOAEL is ≥2,468/2,531 mg/kg/day and the LOAEL was
not determined.  A significant decrease (p≤0.05) in Total Spleen
Activity (AFC/spleen) was only observed at a dose causing excessive
toxicity (HDT) and that exceeded the limit dose.

	8.  Carcinogenicity.  Kasugamycin did not produce carcinogenicity in
adequately designed chronic studies with rats or mice; additionally, no
mutagenic potential was noted in any of the five mutagenicity studies.
Classification of kasugamycin is “not likely to be carcinogenic to
humans.”

	9.  Animal metabolism.  A metabolism and pharmacokinetics study was
carried out in the rats.  The mean radioactivity recovery 168 hours
after exposure ranged between 90.6-96.7%, with the majority of the dose
recovered within 48 hours in the feces (81.9-93.9%) and urine
(1.26-3.07%).  The maximum concentration found in the plasma of both
males and females occurred approximately one hour after the
administration of a single low or high dose.  More kasugamycin
accumulated in the kidneys, urinary bladder, and lymph nodes than in the
blood, but after 168 hours, little or no kasugamycin was found in these
tissues.  The absorption and metabolism of kasugamycin in rats was
limited (<5% dose) and was not affected by sex, dose level, or duration
of dosing.  Parent compound was the major component identified in the
urine, feces, liver, kidney, and plasma.  Minor amounts (<1% dose) of
the metabolite kasuganobiosamine were identified in urine, liver,
kidney, and plasma but none detected in the feces.  Elimination occurred
primarily in the feces (87.7-94.5%, however, kasugamycin was not
excreted in the bile (enterohepatic circulation did not occur).

	10.  Metabolite toxicology.  No metabolites of significant expected
toxicity were identified in the animal metabolism study.

11.  Endocrine disruption.  Beyond testicular softening seen in the rat
combined chronic toxicity/carcinogenicity study, there is no evidence
that kasugamycin has any effect on endocrine function.  

C. 	Aggregate Exposure

1.   Dietary exposure.  Tier I chronic dietary exposure evaluations were
conducted for the active ingredient fungicide/bactericide, kasugamycin,
using EPA’s DEEM-FCID/Calendex v.4.02/10.00.  Default processing
factors were used in these assessments.  All food consumption data were
from the 2005-06, 2007-08, and 2009-10 cycles of the National Health and
Nutrition Examination Survey/“What We Eat in America” (NHANES/WWEIA)
dietary survey.  These exposure assessments included tolerance values as
proposed for current uses on pome fruits and the maximum residue levels
(MRL) as established in Canada for fruiting vegetables and walnuts, in
addition to the proposed use on cherries and assumed 100% of the crops
were treated.  Secondary residues in animal commodities were not
considered as anticipated residues and transfer information from
metabolism studies indicate that tolerances for kasugamycin in animal
commodities are not required.  Drinking water estimates were
incorporated directly into the dietary exposure assessment using the
value of 1.1781 ppb derived for the surface water estimated drinking
water concentrations (EDWC) previously by EPA.  This value was chosen
for the risk assessment as it exceeds the 0.116 ppb value obtained for
groundwater.

For acute dietary exposures, no appropriate dose and endpoint could be
identified from the submitted studies for females ages 13-49 or the
general population. Consequently, an acute dietary exposure assessment
was not conducted.  

For chronic dietary exposures, the reference dose (RfD) is 0.113
mg/kg/day, based on the NOAEL for males (11.3 mg/kg/d) in the combined
chronic toxicity/oncogenicity study in rats and an uncertainty factor of
100. No additional Food Quality Protection Act (FQPA) safety factor was
applied.  The toxic effect of concern is increased testicular softening
observed in males at 116 mg/kg/d. No effects were observed in females at
the maximum dose (140 mg/kg/d).

Chronic exposure to the most exposed subpopulation (children 1-2 years)
resulted in exposure equivalent to 3.0% of the chronic RfD of 0.113
mg/kg-bw/day.  EPA generally has no concern for exposures below 100% of
the RfD; there is a reasonable certainty that no harm will result from
dietary (food) exposure to residues arising from the proposed uses for
kasugamycin

Cancer:  EPA classified kasugamycin as “not likely to be a human
carcinogen.”  Due to the classification, no quantitative cancer
exposure assessment was performed.	

2.  Non-dietary exposure.  

          i.  Occupational handler (mixer/loader/applicator) exposure. 
Products containing kasugamycin will be registered for agricultural uses
only and will not be available for any residential or public uses.
Kasumin 2L will be applied only by professionals; assessment of
occupational handler exposures potential post-application exposure is
required. These exposures are anticipated to be of short-term or
intermediate-term duration. The exposure related hazards are:

For dermal exposure of any duration, EPA determined there was no need to
conduct an occupational risk assessment in 2012.  Based on this
determination and the similarity of use pattern between pome fruit and
cherries, no dermal assessments were conducted.

For inhalation exposures (short- and intermediate-term), the dog
subchronic (NOAEL = 10.6/11.4 mg/kg/day (M/F); LOAEL = 106.0/107.9
mg/kg/day) and the rabbit developmental studies (NOAEL = 10 mg/kg/day;
LOAEL = 30 mg/kg/day) were selected as co-critical studies.  The NOAELs
were comparable and believed to be protective of both portal of entry
effects to the lung from irritation as well as systemic effects.  For
the assessment, a NOAEL of 11 mg/kg/day with LOAELs of 106 mg/kg/day was
utilized.  Complete absorption of inhaled exposures is assumed.

Applications of Kasumin 2L to cherries will be made with airblast
equipment. 

The highest rate, maximum number of applications, shortest intervals,
and shortest PHI on the proposed label were modeled individually for
handlers making applications to cherries.

EPA default assumptions for the maximum daily area treated were also
employed in the assessment (40 acres/day for airblast applications; EPA,
2001). Inhalation unit exposures were obtained from EPA’s
“Occupational Pesticide Handler Unit Exposure Surrogate Reference
Table” (EPA, 2013). Handler exposure estimates assume a 70 kg body
weight. Complete (100%) absorption of inhaled exposures is assumed.

Short-/intermediate-term inhalation exposures and margins of exposure
(MOE) calculated for occupational handlers mixing/loading and applying
kasugamycin range from 58,000 to 1,300,000.  MOEs greater than 100
indicate that occupational handler exposures associated with
applications of kasugamycin to cherries are not of concern.

Walnuts: Maximum spray concentration of 0.00083 lb ai/gal sprayed at a
rate of 100gal/A (i.e., 0.083 lb ai/A). No more than 4 applications can
be made per season with a minimum interval between applications of 7
days. The PHI on walnuts is 100 days.

Applications of Kasumin 2L to walnuts will be made with airblast
equipment. The highest rates, maximum number of applications, shortest
intervals and shortest PHI on the proposed label were modeled
individually for handlers making applications to walnuts.

EPA default assumptions for the maximum daily area treated were also
employed in the assessment; these being, 40 acres/day for airblast
applications (EPA, 2001).  Dermal and inhalation unit exposures were
obtained from the PHED Surrogate Exposure Guide (EPA, 1997). Handler
exposure estimates assume a 60 kg body weight. Complete (100%)
absorption of inhaled exposures is assumed. A dermal absorption fraction
was not applied in the calculation because the endpoint of concern is
from a dermal toxicity study.

Short-/intermediate-term dermal and inhalation exposures and margins of
exposure (MOEs) calculated for occupational handlers applying
kasugamycin range from 78,600 to 1,510,000.  Short-/intermediate-term
dermal, and short-/intermediate-term inhalation MOEs range from 7,530 to
402,000. 

MOEs greater than 100 indicate that occupational handler exposures
associated with applications of kasugamycin to walnuts are not of
concern.

D. 	Cumulative effects.  FFDCA Section 408(b)(2)(D)(v) requires that,
when considering whether to establish, modify, or revoke a tolerance,
EPA consider “available information” concerning the cumulative
effects of a particular pesticide’s residues and other substances that
have a “common mechanism of toxicity.”   EPA does not have, at this
time, available data to determine whether kasugamycin has a common
mechanism of toxicity with other substances or how to include this
pesticide in a cumulative risk assessment.  For the purposes of this
tolerance action, EPA has not assumed that kasugamycin has a common
mechanism of toxicity with other substances.

E. 	Safety determination. 

1.   U.S. population.  The chronic dietary exposure analysis (food plus
water) showed that exposure from all proposed uses of kasugamycin would
result in an exposure equal to 0.000564 mg/kg body wt/day (0.5% of the
chronic RfD of 0.113 mg/kg/day) for the general U.S. population.  A
chronic cancer exposure analysis was not performed, since there is no
evidence of human carcinogenic potential for kasugamycin.  Short-term
aggregate and intermediate-term aggregate risk was not assessed because
there are no current, pending, or proposed residential uses for
kasugamycin.  Based on the completeness and reliability of the toxicity
data supporting these petitions, there is a reasonable certainty that no
harm will result from aggregate exposure to residues arising from the
proposed kasugamycin tolerances, including anticipated dietary exposure
from food and water exposures.

2.   Infants and children.  The chronic dietary exposure analysis (food
plus water) showed that exposure from all established and proposed uses
of kasugamycin would result in an exposure equal to 0.00338 mg/kg body
wt/day (3.0% of the chronic RfD of 0.113 mg/kg/day) for the most
sensitive subpopulation, children (1-2 years old). A chronic cancer
exposure analysis was not performed since there is no evidence of human
carcinogenic potential for kasugamycin.  Short-term aggregate and
intermediate-term aggregate risk was not assessed because there are no
current, pending, or proposed residential uses for kasugamycin.  Based
on the completeness and reliability of the toxicity data supporting
these petitions, there is a reasonable certainty that no harm will
result from aggregate exposure to residues arising from all proposed
kasugamycin tolerances, including anticipated dietary exposure from food
and water exposures.  Considering the potential aggregate exposure from
food and water exposure routes, aggregate exposure is not expected to
exceed 100% of the chronic RfD and there is a reasonable certainty that
no harm will result to infants and children from the aggregate exposure
to kasugamycin.

F. 	International tolerances.  There are no Codex MRLs established for
kasugamycin.  Kasugamycin is currently not included on Annex 1 and has a
default MRL of 0.01 within the European Union.  

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& peas, broad beans, dried peanuts, other legumes/pulses, potatoes,
Japanese radish, roots (including radish), Japanese radish, leaves
(including radish), Chinese cabbage, cabbage, broccoli, other
cruciferous vegetables, burdock, lettuce (including cos lettuce and leaf
lettuce), onions, welsh (including leek), garlic, carrots, celery,
pimento (sweet pepper), melons, Japanese pears, pears, loquat, peaches,
mume plum, kiwifruit, and tea at 0.04 ppm; sugar beets, turnips, roots
(including rutabaga), turnip, leaves (including rutabaga), watercress,
brussels sprouts, kyona, cauliflower, shungiku, other composite
vegetables, mitsuba, other umbelliferous vegetables, other solanaceous
vegetables, cucumbers (including gherkin), pumpkins (including squash),
watermelon, other cucurbitaceous vegetables, okra, ginger, other
vegetables, unshu orange, pulp, citrus natsudaidai, whole lemons,
oranges (including navel oranges), grapefruits, limes, other citrus
fruits, other fruits, other spices, and other herbs at 0.05 ppm.

Canada has established MRLs as follows: black walnuts and English
walnuts at 0.04 ppm; African eggplants, scarlet eggplants, bell peppers,
currant tomatoes, eggplants, bush tomatoes, goji berries, tomatoes,
naranjullas, non-bell peppers, garden huckleberrires, martynias,
sunberries, tree tomatoes, pepinos, okras, coconas, broundcherries
roselles, tomatillos, and  pea eggplants at 0.1 ppm; and Loquats,
Chinese quinces, apples, medlars, Japanese quinces, Asian pears,
tejocotes quinces, azaroles, mayhaw, crabapples, and pears at 0.2 ppm.

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