Flonicamid; Pesticide Tolerance, 51604-51615 [05-17128]
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51604
Federal Register / Vol. 70, No. 168 / Wednesday, August 31, 2005 / Rules and Regulations
Dated: August 19, 2005.
Lois Rossi,
Director, Registration Division, Office of
Pesticide Programs.
1. The authority citation for part 180
continues to read as follows:
I
Authority: 21 U.S.C. 321(q), 346a and 371.
Therefore, 40 CFR chapter I is
amended as follows:
I
2. In § 180.554, the table in paragraph
(b) is amended by alphabetically adding
commodities to read as follows:
I
PART 180—[AMENDED]
§ 180.544 Methoxyfenozide; tolerance for
residues.
*
Commodity
*
*
(b) * * *
Parts per million
sorghum, grain
sorghum, grain, forage
sorghum, grain, stover
*
*
*
*
*
BILLING CODE 6560–50–S
ENVIRONMENTAL PROTECTION
AGENCY
40 CFR Part 180
[OPP–2005–0217; FRL–7731–6]
Flonicamid; Pesticide Tolerance
Environmental Protection
Agency (EPA).
ACTION: Final rule.
AGENCY:
SUPPLEMENTARY INFORMATION:
I. General Information
SUMMARY: This regulation establishes a
tolerance for combined residues of
flonicamid and its metabolites in or on
certain plant and livestock
commodities. ISK Biosciences requested
this tolerance under the Federal Food,
Drug, and Cosmetic Act (FFDCA), as
amended by the Food Quality Protection
Act of 1996 (FQPA).
DATES: This regulation is effective
August 31, 2005. Objections and
requests for hearings must be received
on or before October 31, 2005.
ADDRESSES: To submit a written
objection or hearing request follow the
detailed instructions as provided in
Unit VI. of the SUPPLEMENTARY
INFORMATION. EPA has established a
docket for this action under Docket
identification (ID) number OPP–2005–
0217. All documents in the docket are
listed in the EDOCKET index athttps://
www.epa.gov/edocket. Although listed
in the index, some information is not
publicly available, i.e., CBI or other
information whose disclosure is
restricted by statute. Certain other
material, such as copyrighted material,
is not placed on the Internet and will be
publicly available only in hard copy
form. Publicly available docket
materials are available either
electronically in EDOCKET or in hard
copy at the Public Information and
Records Integrity Branch (PIRIB), Rm.
119, Crystal Mall #2, 1801 S. Bell St.,
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Arlington, VA. This docket facility is
open from 8:30 a.m. to 4 p.m., Monday
through Friday, excluding legal
holidays. The docket telephone number
is (703) 305–5805.
FOR FURTHER INFORMATION CONTACT: Ann
Sibold, Registration Division (7505C),
Office of Pesticide Programs,
Environmental Protection Agency, 1200
Pennsylvania Ave., NW., Washington,
DC 20460–0001; telephone number:
(703) 305–6502; e-mail
address:sibold.ann@epa.gov.
A. Does This Action Apply to Me?
You may be potentially affected by
this action if you are an agricultural
producer, food manufacturer, or
pesticide manufacturer. Potentially
affected entities may include, but are
not limited to:
• Crop production (NAICS 111), e.g.,
agricultural workers; greenhouse,
nursery, and floriculture workers;
farmers.
• Animal production (NAICS 112),
e.g., cattle ranchers and farmers, dairy
cattle farmers, livestock farmers.
• Food manufacturing (NAICS 311),
e.g., agricultural workers; farmers;
greenhouse, nursery, and floriculture
workers; ranchers; pesticide applicators.
• Pesticide manufacturing (NAICS
32532), e.g., agricultural workers;
commercial applicators; farmers;
greenhouse, nursery, and floriculture
workers; residential users.
This listing is not intended to be
exhaustive, but rather provides a guide
for readers regarding entities likely to be
affected by this action. Other types of
entities not listed in this unit could also
be affected. The North American
Industrial Classification System
(NAICS) codes have been provided to
assist you and others in determining
whether this action might apply to
certain entities. If you have any
questions regarding the applicability of
this action to a particular entity, consult
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[FR Doc. 05–17131 Filed 8–30–05; 8:45 am]
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12/31/2007
12/31/2007
12/31/2007
the person listed underFOR FURTHER
INFORMATION CONTACT.
B. How Can I Access Electronic Copies
of this Document and Other Related
Information?
In addition to using EDOCKET (https://
www.epa.gov/edocket/), you may access
this Federal Register document
electronically through the EPA Internet
under the ‘‘Federal Register’’ listings at
https://www.epa.gov/fedrgstr/. A
frequently updated electronic version of
40 CFR part 180 is available at E-CFR
Beta Site Two at https://
www.gpoaccess.gov/ecfr/. To access the
OPPTS Harmonized Guidelines
referenced in this document, go directly
to the guidelines athttps://www.epa.gpo/
opptsfrs/home/guidelin.htm/.
II. Background and Statutory Findings
In the Federal Register of May 23,
2003 (68 FR 28218) (FRL–7307–5), EPA
issued a notice pursuant to section
408(d)(3) of FFDCA, 21 U.S.C.
346a(d)(3), announcing the filing of a
pesticide petition (PP 3F6552) by ISK
Biosciences, 7470 Auburn Road, suite
A, Concord, Ohio 44077. The petition
requested that 40 CFR part 180 be
amended by establishing a tolerance for
the combined residues of the insecticide
flonicamid, [N-(cyanomethyl)-4trifluoromethylnicotinamide] and its
metabolites, TFNA, (4trifluoromethylnicotinic acid), TFNAAM, (4-trifluoromethylnicotinamide)
and TFNG, [N-(4trifluoromethylnicotinoyl)glycine] in or
on the raw agricultural commodities:
Celery, at 1.2 parts per million (ppm);
cotton, at 0.5 ppm; cotton, gin trash, at
6.0 ppm; cotton, hulls, at 1.0 ppm;
cotton, meal, at 1.0 ppm; fruit, pome,
group 11, at 0.2 ppm; fruit, stone, group
12, except plum and fresh prune plum,
at 0.7 ppm; lettuce, head, at 1.0 ppm;
lettuce, leaf, at 4.0 ppm; plum, at 0.1
ppm; potato, at 0.2 ppm; potato, flakes,
at 0.4 ppm; prune, fresh, at 0.1; spinach,
at 9.0 ppm; tomato, paste, at 2.0 ppm;
tomato, puree, at 0.5 ppm; vegetable,
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Federal Register / Vol. 70, No. 168 / Wednesday, August 31, 2005 / Rules and Regulations
cucurbit, group 9, at 0.4 ppm; vegetable,
fruiting, group 8, at 0.4 ppm; by
establishing tolerances for the combined
residues of the insecticide flonicamid,
[N-(cyanomethyl)-4trifluoromethylnicotinamide] and its
metabolite TFNA-AM, (4trifluoromethylnicotinamide) in animal
tissues and poultry meat
byproducts:Cattle, fat, at 0.01 ppm;
cattle, meat, at 0.04 ppm; eggs, at 0.02
ppm; goat, fat, at 0.01 ppm; goat, meat,
at 0.04 ppm; hog, fat, at 0.01; hog, meat,
at 0.01 ppm; horse, fat, at 0.01 ppm;
horse, meat, at 0.04 ppm; milk, at 0.02
ppm; poultry, fat, at 0.01 ppm; poultry,
meat, at 0.01 ppm; poultry, meat
byproducts, at 0.01 ppm; sheep, fat, at
0.01 ppm; sheep, meat, at 0.04 ppm; by
establishing tolerances for the combined
residues of the insecticide flonicamid
[N-(cyanomethyl)-4trifluoromethylnicotinamide] and its
metabolites TFNA, (4trifluoromethylnicotinic acid) and
TFNA-AM, (4trifluoromethylnicotinamide) in the
animal meat byproducts: cattle, meat
byproducts, at 0.06 ppm; goat, meat
byproducts, at 0.06 ppm; hog, meat
byproducts, at 0.01 ppm; horse, meat
byproducts, at 0.06 ppm; and sheep,
meat byproducts, at 0.06 ppm. That
notice included a summary of the
petition prepared by ISK Biosciences,
the registrant. One comment was
received on the notice of filing. EPA’s
response to this comment is discussed
in Unit IV.C.
Section 408(b)(2)(A)(i) of FFDCA
allows EPA to establish a tolerance (the
legal limit for a pesticide chemical
residue in or on a food) only if EPA
determines that the tolerance is ‘‘safe.’’
Section 408(b)(2)(A)(ii) of FFDCA
defines ‘‘safe’’ to mean that ‘‘there is a
reasonable certainty that no harm will
result from aggregate exposure to the
pesticide chemical residue, including
all anticipated dietary exposures and all
other exposures for which there is
reliable information.’’ This includes
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exposure through drinking water and in
residential settings, but does not include
occupational exposure. Section
408(b)(2)(C) of FFDCA requires EPA to
give special consideration to exposure
of infants and children to the pesticide
chemical residue in establishing a
tolerance and to ‘‘ensure that there is a
reasonable certainty that no harm will
result to infants and children from
aggregate exposure to the pesticide
chemical residue. . . .’’
EPA performs a number of analyses to
determine the risks from aggregate
exposure to pesticide residues. For
further discussion of the regulatory
requirements of section 408 of FFDCA
and a complete description of the risk
assessment process, see the final rule on
Bifenthrin Pesticide Tolerances (62 FR
62961, November 26, 1997, FRL–5754–
7)
III. Aggregate Risk Assessment and
Determination of Safety
Consistent with section 408(b)(2)(D)
of FFDCA, EPA has reviewed the
available scientific data and other
relevant information in support of this
action. EPA has sufficient data to assess
the hazards of and to make a
determination on aggregate exposure,
consistent with section 408(b)(2) of
FFDCA, for a tolerance for combined
residues of flonicamid and its
metabolites on various crop and
livestock commodities at levels set forth
in the list below.
Tolerances for combined residues of
flonicamid and its metabolites in/on
crops and livestock commodities.
1. Recommended tolerances for
combined residues of flonicamid and its
metabolites TFNA, TFNG and TFNAAM in/on crops.
Cotton, undelinted seed at 0.50 ppm
Cotton, gin byproducts at 6.0 ppm
Cotton, hulls at 2.0 ppm
Cotton, meal at 1.0 ppm
Fruit, pome, group 11 at 0.20 ppm
Fruit, stone, group at 12 0.60 ppm
Potato 0.20 at ppm
Potato, granular/flakes at 0.40 ppm
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Spinach at 9.0 ppm
Tomato, paste at 2.0 ppm
Tomato, puree at 0.50 ppm
Vegetable, cucurbit, group at 0.40
ppm
Vegetable, fruiting, group at 0.40 ppm
Vegetable, leafy except Brassica group
4, except spinach at 4.0 ppm
2. Recommended tolerances for
combined residues of flonicamid and its
metabolites TFNA and TFNA-AM in/on
livestock commodities.
Cattle, fat at 0.02 ppm
Cattle, meat at 0.05 ppm
Egg at 0.03 ppm
Goat, fat at 0.02 ppm
Goat, meat at 0.05 ppm
Horse, fat at 0.02 ppm
Horse, meat at 0.05 ppm
Milk at 0.02 ppm
Poultry, fat at 0.02 ppm
Poultry, meat at 0.02 ppm
Poultry, meat byproducts at 0.02 ppm
Sheep, fat at 0.02 ppm
Sheep, meat at 0.05 ppm
Cattle, meat byproducts at 0.08 ppm
Goat, meat byproducts at 0.08 ppm
Horse, meat byproducts at 0.08 ppm
Sheep, meat byproducts at 0.08 ppm
EPA’s assessment of exposures and
risks associated with establishing the
tolerance follows.
A. Toxicological Profile
EPA has evaluated the available
toxicity data and considered its validity,
completeness, and reliability as well as
the relationship of the results of the
studies to human risk. EPA has also
considered available information
concerning the variability of the
sensitivities of major identifiable
subgroups of consumers, including
infants and children. Specific
information on the studies received and
the nature of the toxic effects caused by
flonicamid as well as the no observed
adverse effect level (NOAEL) and the
lowest observed adverse effect level
(LOAEL) from the toxicity studies are
discussed in Table 1 of this unit.
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Federal Register / Vol. 70, No. 168 / Wednesday, August 31, 2005 / Rules and Regulations
TABLE 1.—SUBCHRONIC, CHRONIC AND OTHER TOXICITY OF FLONICAMID
Guideline No.
Study Type
Dose Levels
Results
870.3100
90–Day oral toxicity rodents (rats)
28–day range-finding
0, 50 (males), 200,
1,000,2,000 (males),
or 5,000(females)
ppm (3.08,
12.11,60.0, or 119.4
mg/kg/day,males and
14.52, 72.3, or340.1
mg/kg/day, females)
0, 50 (males), 100,
500, 1,000,5,000 or
10,000 (females)ppm
(3.61, 7.47,
36.45,73.8, or 353.4
mg/kg/day,males and
8.36, 41.24,
81.9,372.6, or 642
mg/kg/day,females)
NOAEL is 200 ppm (12.11 mg/kg/day) formales
and 1,000 ppm (72.3 mg/kg/day) forfemales
LOAELs were 1,000 ppm (60.0 mg/kg/day)
formales based on changes in the kidney
(hyalinedeposition) and 5,000 ppm (340 mg/
kg/day) forfemales based on kidney (hyaline
deposition)and liver changes (centrilobular
hypertrophy)
NOAEL is 100 ppm (7.47 mg/kg/day) for
malesand 1,000 ppm (81.9 mg/kg/day) for females.
LOAELs were 500 ppm (36.45 mg/kg/day)
formales based on changes in the kidney
(hyalinedeposition) and 5,000 ppm for females (372.6mg/kg/day) based on kidney
(hyalinedeposition),
liver
changes
(centrilobularhypertrophy), hematological effects (anemia)and clinical chemistry (increased cholesterol)
870.3100
90–Day oral toxicity rodents (mice)
0, 100, 1,000 or 7,000
ppm(0, 15.25, 153.9
or 1,069mg/kg bw/
day in males,and 0,
20.10, 191.5, or
1,248mg/kg bw/day
in females)
NOAEL is 100 ppm (males: 15.25 mg/kgbw/
day, females: 20.10 mg/kg bw/day)
LOAEL is 1,000 ppm in (males: 153.9 mg/
kgbw/day; females: 191.5 mg/kg bw/day)
basedon extramedullary hematopoiesis of
the spleen
Many of the tissues/organs recommended
byGuideline
870.3100
were
not
histologicallyexamined in any dose group,
but this study isnot required and serves as a
range-findingstudy for the mouse carcinogenicity study.Therefore, it is classified as
acceptable, non-guideline study
870.3150
90–Day oral toxicity
(nonrodents- dogs)
0, 3, 8, 20, or 50 (females) mg/kg bw/day
NOAEL is 8 mg/kg/day in males and 20 mg/kg/
day for female
LOAEL is 20 mg/kg/day in males and 50 mg/
kg/day in females, based on acute clinical
signs in males and females (vomiting, first
observed on Day 1 and last observed on
Day 90), clinical pathology at 7 weeks (increased total protein levels in males, lower
red
blood
cells
and
higher
reticulocytescounts in females), increased
adrenal weights in males, decreased
thymusgland weights in males, and increased kidney tubular vacuolation infemales
at study termination
870.3200
28–Day dermal toxicity
(rats)
0, 20, 150, or 1,000
mg/kg/day
NOAEL is 1,000 mg/kg/day
LOAEL is >1,000 mg/kg/day
870.3700
Prenatal developmental
toxicity (rats)
0, 20, 100 or 500 mg/
kg bw/day
Maternal
NOAEL is 100 mg/kg bw/day
LOAEL is 500 mg/kg bw/day, based
onincreased liver weight, and liver and
kidneypathological changes (hypertrophy
ofcentrilobular
hepatocytes
in
liver
andvacuolation of proximal tubular cell
inkidneys)
Developmental
NOAEL is 100 mg/kg bw/day
LOAEL is 500 mg/kg bw/day, based on the increased incidence of cervical rib
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51607
TABLE 1.—SUBCHRONIC, CHRONIC AND OTHER TOXICITY OF FLONICAMID—Continued
Guideline No.
Study Type
Dose Levels
Results
870.3700
Prenatal
developmentaltoxicity
(rabbits)
0, 2.5, 7.5, or 25 mg/
kg/day
Maternal
NOAEL is 7.5 mg/kg/day
LOAEL is 25 mg/kg, based on decreased
bodyweights, body weight gains, and food
consumption
Developmental
NOAEL is ≥ 25 mg/kg/day
LOAEL is not established
870.3800
Reproduction and fertility effects (rats)
0, 50, 300, or 1,800
ppm(0/0, 3.7/4.4,
22.3/26.5, and132.9/
153.4 mg/kg bw/day
[M/F]
Parental
NOAEL is 50 ppm (equivalent to 3.7/4.4mg/kg/
day [M/F]
LOAEL is 300 ppm (equivalent to 22.3/26.5mg/
kg/day
[M/F]
based
on
increased
relativekidney weight and hyaline droplet
depositionin the proximal tubules of the kidneys in themales and increased blood serum
LH levels inthe F1 females
Offspring
NOAEL is 300 ppm (equivalent to 22.3/26.5mg/
kg/day
[M/F].
LOAEL
is
1,800
ppm(equivalent to 132.9/153.4 mg/kg/day [M/
F]based on decreased absolute and relative
tobody
uterus
weights
and
delayed
sexualmaturation in the F1 females
Reproductive Performance
NOAEL is 1,800 ppm (equivalent to 132.9/
153.4mg/kg/day [M/F]
LOAEL for reproductive performance was
notobserved
870.4100
Chronic toxicity (dogs)
0, 3, 8, or 20 mg/kg/
day
NOAEL is 8 mg/kg/day
LOAEL is 20 mg/kg/day, based on acute clinical signs(vomiting, mostly within the first
week), clinical pathology at 12 months (higher reticulocytes counts) in males and females
870.4200
Carcinogenicity (mice)
0, 250, 750, or 2250
ppm(0/0, 29/38, 88/
112, or261/334 mg/
kg/day [M/F]
NOAEL was not established
LOAEL is 250 ppm (equivalent to 29/38mg/kg/
day [M/F]), based on minimal tomoderate
centrilobular hepatocellularhypertrophy, minimal to severeextramedullary hematopoiesis,
minimal tomoderate pigment deposition in
the sternalbone marrow, and increased incidence of tissuemasses/nodules in the lungs
in the males, andminimal to moderate decreased cellularity inthe femoral bone marrow andhyperplasia/hypertrophy of the
epithelial cellsof the terminal bronchioles of
the females
At the doses tested, the carcinogenic
potentialof IKI-220 (flonicamid) is positive at
250 ppmin males and females based on the
increasedincidence of alveolar/bronchiolar
adenomas,carcinomas,
and
combinedadenomas/carcinomas. Dosing was
consideredadequate based on increased incidence of tissuemasses/nodules in the lungs
and microscopicfindings in the liver, spleen,
bone marrow, andlungs. However, data were
providedsuggesting this effect is specific to
sensitivestrains of mice
Carcinogenic in mice
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Federal Register / Vol. 70, No. 168 / Wednesday, August 31, 2005 / Rules and Regulations
TABLE 1.—SUBCHRONIC, CHRONIC AND OTHER TOXICITY OF FLONICAMID—Continued
Guideline No.
Study Type
Dose Levels
Results
870.4200
Carcinogenicity (mice)
0, 10, 25, 80, 250
ppmmales: 0, 1.20,
3.14, 10.0,30.3 mg/
kg/day; females:
0,1.42, 3.67, 11.8,
36.3 mg/kg/day
NOAEL is 80 ppm (equivalent to 10/12mg/kg/
day in males/females)
LOAEL is 250 ppm (equivalent to 30/36mg/kg/
day in males/females) based on lungmasses
and
terminal
bronchiole
epithelial
cellhyperplasia/hypertrophy in both sexes
At the doses tested, the carcinogenic
potentialof IKI-220 (flonicamid) is positive in
males andfemales based on the incidences
ofalveolar/bronchiolar
adenomas,
carcinomas,and combined adenomas and/or
carcinomas. Dosing was consideredadequate
based on lung masses and terminal bronchiole epithelialcell hyperplasia/hypertrophy
in both sexes
Carcinogenic in mice
870.4300
Combined Chronic/carcinogenicity (rats)
0, 50 (males), 100
(males),200, 1,000,
or 5,000 (females)
ppm (0/0, 1.84,3.68,
7.32/8.92, 36.5/44.1,
and 219 mg/kg/day
[M/F]
NOAEL is 200 ppm (equivalent to 7.32/8.92mg/
kg/day in males/females)
LOAEL is 1,000 ppm (equivalent to 36.5/
44.1mg/kg/day in males/females) based
ondecreased body weights and body weight
gains,and increased incidences of keratitis in
malesand striated muscle fiber atrophy in females
At the high dose there was an incidence
(12%)of nasolacrimal duct squamous cell
carcinomasslightly outside the historical control range (0-10%) in male rats. A correlation
between theincidence of inflammation and
the fluctuatingincidence of nasal tumors was
made acrossdose groups. EPA did not consider thenasolacrimal duct tumors to be treatment-related
Female rats had a significant increasing trendin
nasolacrimal
duct
squamous
cell
carcinomasat <0.05, and at the high dose
was slightlyabove the historical control mean
(0.8%) andrange (0-4%). EPA considered the
nasolacrimal duct squamouscell carcinomas
to be possibly treatment related, but that a
clearassociation with treatment could not be
made
870.5100
Bacterial reverse mutation
61.7 to 5,000 µg/plate
+/-S9
Negative
870.5100
Bacterial system, mammalian
activationgene mutation
33 to 5,000 µg/plate +/S9
Negative for metabolite TFNA
870.5100
Bacterial system, mammalian
activationgene mutation
33 to 5,000 ug/plate +/S9
Negative for metabolite TFNA-AM
870.5100
Bacterial system, mammalian
activationgene mutation
33 to 5,000 ug/plate +/S9
Negative for metabolite TFNG-AM
870.5100
Bacterial system, mammalian
activationgene mutation
33 to 5,000 µg/plate +/S9
Negative for metabolite TFNA-OH
870.5100
Bacterial system,mammalian activation gene mutation
5 to 5000 ug/plate +/S9
Negative for metabolite TFNG
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51609
TABLE 1.—SUBCHRONIC, CHRONIC AND OTHER TOXICITY OF FLONICAMID—Continued
Guideline No.
Study Type
Dose Levels
Results
870.5300
In vitro mammalian
cellgene mutation
28.3 to 2,290 µg/mL
initialtest, and 143 to
2,290µg/mL repeat
Negative
870.5375
In vitro Cytogenetics
573, 1145 and 2290
µg/mL
Negative
870.5395
In vivo cytogenetic(micronucleus) test
in mice
Twice orally by
intragastricgavage at
doses of 250,
500and 1,000 mg/kg/
day formales and
125, 250 and 500mg/
kg/day for females
Negative
Non-guideline
Other genotoxicity, in
vivo Comet assay
Single doses of 375,
750 and 1,500 mg/kg
Was not positive for nuclear migration up
to1,500 mg/kg
Non-guideline
Unscheduled DNA synthesis
Once orally at 600 and
2,000 mg/kg
Is not genotoxic in hepatocytes from treated
rats
870.6200
Acute
neurotoxicityscreening battery (rats)
0, 100, 300, 600
(males), or 1,000 mg/
kg/day
NOAEL is 600 mg/kg in males and 300 mg/
kgin females
LOAEL is 1,000 mg/kg based on mortality
andsigns of toxicity (decreased motor activity,tremors,
impaired
respiration,
and
impairedgait) in males
This
acute
neurotoxicity
study
is
unacceptablebecause interval motor activity
data were notprovided as specified according
to guidelines,FOB handling and open-field
observationswere incomplete, and positive
data providedwere from a lab other than the
performing labfor this study. This study is not
required forthis risk assessment and additional informationis not required
870.6200
Subchronic
neurotoxicity
screeningbattery
(rats)
0, 200, 1000, or 10,000
ppm(0/0, 13/16, 67/
81, or625/722 mg/kg/
day [M/F]
NOAEL is 200/1,000 ppm (equivalent to 13/
81mg/kg/day [M/F]
LOAEL is 1,000/10,000 ppm (equivalent to67/
722
mg/kg/day
[M/F]
based
on
decreasedmotor activity, rearing, and foot
splay inmales, decreased body weights,
body weightgains, and food consumption in
males andfemales
870.7485
Metabolism
andpharmacokinetics
(rats)
Pilot excretion study,
singleoral dose 0.85
or 21 mg/kgand pilot
pharmacokineticstudy, single oral dose of
2or 50 mg/kg
IKI-220 (flonicamid) was rapidly absorbed
andexcreted with no apparent differences
betweenthe sexes. By 48 hours after treatment, 93%of the administered dose had
been eliminatedand by 168 hours ∼96% was
eliminated. Theprimary route of elimination
was the urine,accounting for ∼90% of the
dose. The feces oftreated rats accounted for
∼5% of theadministered dose, with no significant amountsof radiolabel detected in expired air of eithersex. After 168 hours of a
single high or lowdose of the test material,
<3% of theradioactivity was recovered in the
carcass and<0.05% in the blood, irrespective
of dose orsex
The
pharmacokinetic
parameters
were
alsosimilar between the dose levels (2 and
50mg/kg) and sexes. The radiolabel was
rapidlyabsorbed and excreted. The apparent
plasmahalf-life (TW) was 4.8-6.0 hours and
theelimination followed first order kinetics.
Thetime of maximum plasma concentration(Tmax) for individual animals ranged
from0.25 to 1 hour after treatment (with a
mean foreach group of 0.3-0.6 hours)
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TABLE 1.—SUBCHRONIC, CHRONIC AND OTHER TOXICITY OF FLONICAMID—Continued
Guideline No.
Study Type
870.7485
Dose Levels
Metabolism and pharmacokinetics (rats)
B. Toxicological Endpoints
For hazards that have a threshold
below which there is no appreciable
risk, the dose at which no adverse
effects are observed (the NOAEL) from
the toxicology study identified as
appropriate for use in risk assessment is
used to estimate the toxicological level
of concern (LOC). However, the lowest
dose at which adverse effects of concern
are identified (the LOAEL) is sometimes
used for risk assessment if no NOAEL
was achieved in the toxicology study
selected. An uncertainty factor (UF) is
applied to reflect uncertainties inherent
in the extrapolation from laboratory
animal data to humans and in the
variations in sensitivity among members
of the human population as well as
other unknowns. An UF of 100 is
routinely used, 10X to account for
interspecies differences and 10X for
intraspecies differences.
Three other types of safety or
uncertainty factors may be used:
‘‘Traditional uncertainty factors;’’ the
Results
2 or 400 mg/kg
Appears that the overall recovery ofradioactive
dose from all group was 94-99% by168
hours post-dose. Absorption was rapidand
extensive, detected in plasma within
10minutes of dosing, with maximum
plasmaconcentrations within 24-54 minutes.
By 168hours post-dose, total urinary excretion was72-78%, cage rinse was 10-21%,
and fecalexcretion was 4-7% dose. Parent
(IKI-220)(flonicamid) and 9 metabolites accounted for80-94% of the dose for all
groups. Parent wasdetected primarily in the
urine, 46-73% of thedose in excreta in all
groups. The primarymetabolite was 4trifluoromethylnicotinamide(TFNA-AM),
1827% dose in all dose groups,along with
minor amounts of TFNA-AM N-oxide (1-4%
dose).Other metabolites in urine and feces
were detected atless than or equal to 2.5%
of the dose.IKI-220 (flonicamid) was excreted
primarily unchangedin the urine, but biotransformation of IKI-220(flonicamid) in rats included
nitrile
hydrolysis,N-oxidation,
hydroxylation of the pyridine ring and
amidehydrolysis
‘‘special FQPA safety factor;’’ and the
‘‘default FQPA safety factor’’ By the
term ‘‘traditional uncertainty factor,’’
EPA is referring to those additional
factors used prior to FQPA passage to
account for database deficiencies. These
traditional uncertainty factors have been
incorporated by the FQPA into the
additional safety factor for the
protection of infants and children. The
term ‘‘Special FQPA safety factor refers
to those safety factors that are deemed
necessary for the protection of infants
and children, primarily as a result of the
FQPA.’’ The ‘‘default FQPA safety
factor’’ is the additional 10X safety
factor that is mandated by the statute
unless it is decided that there are
reliable data to choose a different
additional factor (potentially a
traditional uncertainty factor or a
special FQPA safety factor).
For dietary risk assessment (other
than cancer) the Agency uses the UF to
calculate an acute or chronic reference
dose (acute RfD or chronic RfD) where
the RfD is equal to the NOAEL divided
by an UF of 100 to account for
interspecies and intraspecies differences
and any traditional uncertainty factors
deemed appropriate (RfD = NOAEL/UF).
Where a special FQPA safety factor or
the default FQPA safety factor is used,
this additional safety factor is applied to
the RfD by dividing the RfD by such
additional factor. The acute or chronic
Population Adjusted Dose (aPAD or
cPAD) is a modification of the RfD to
accommodate this type of safety factor.
For non-dietary risk assessments
(other than cancer) the UF is used to
determine the LOC. For example, when
100 is the appropriate UF (10X to
account for interspecies differences, and
10X for intraspecies differences) the
LOC is 100. To estimate risk, a ratio of
the NOAEL to exposure (margin of
exposure (MOE) = NOAEL/exposure) is
calculated and compared to the LOC.
A summary of the toxicological dose
and endpoints for flonicamid used for
human risk assessment is shown in
Table 2 of this unit:
TABLE 2.—TOXICOLOGICAL DOSES AND ENDPOINTS FOR FLONICAMID HUMAN HEALTH RISK ASSESSMENTS
Acute dietary
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Special FQPA SF*
andLevel of Concern for
Risk Assessment
Dose Used in
RiskAssessment, UF
Exposure Scenario
None
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FQPA SF = NA
aPAD = NA
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Study and Toxicological Effects
Quantitative risk assessment is notrequired
since there are no acute dietarytoxicity concerns
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TABLE 2.—TOXICOLOGICAL DOSES AND ENDPOINTS FOR FLONICAMID HUMAN HEALTH RISK ASSESSMENTS—Continued
Dose Used in
RiskAssessment, UF
Special FQPA SF*
andLevel of Concern for
Risk Assessment
Study and Toxicological Effects
NOAEL = 3.7 mg/kg/day
UF = 100
Chronic RfD = 0.04mg/kg/
day
FQPA SF = 1
aPAD = chronic RfD/
FQPA SF= 0.04 mg/
kg/day
2–Generation Reproduction rat
Parental
LOAEL = 22 mg/kg/day basedon increased
kidney weights, kidney hyaline deposition,
increased blood serum LH (F1 females)
Exposure Scenario
Chronic dietary
Cancer
Suggestive evidence of carcinogenic potential
UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = level of
concern, NA = Not Applicable
C. Exposure Assessment
1. Dietary exposure from food and
feed uses. Tolerances are being
proposed for the combined residues of
flonicamid and its metabolites, in or on
a variety of raw agricultural
commodities. Risk assessments were
conducted by EPA to assess dietary
exposures from flonicamid and its
metabolites in food as follows:
i. Acute exposure. Quantitative acute
dietary exposure and risk assessments
are performed for a food-use pesticide,
if a toxicological study has indicated the
possibility of an effect of concern
occurring as a result of a 1–day or single
exposure. No such effects were
identified in the toxicological studies
for flonicamid; therefore, a quantitative
acute dietary exposure assessment is
unnecessary.
ii. Chronic exposure. In conducting
the chronic dietary exposure assessment
EPA used the Dietary Exposure
Evaluation Model software with the
Food Commodity Intake Database
(DEEM-FCIDTM Version 2), which
incorporates food consumption data as
reported by respondents in the USDA
1994–1996 and 1998 Nationwide
Continuing Surveys of Food Intake by
Individuals (CSFII), and accumulated
exposure to the chemical for each
commodity. The following assumptions
were made for the chronic exposure
assessments: 100% crop treated,
tolerance level residues, and drinking
water estimated concentration of 0.94
parts per billion (ppb).
2. Dietary exposure from drinking
water. The Agency lacks sufficient
monitoring exposure data to complete a
comprehensive dietary exposure
analysis and risk assessment for
flonicamid and its metabolites in
drinking water. Because the Agency
does not have comprehensive
monitoring data, drinking water
concentration estimates are made by
reliance on simulation or modeling
taking into account data on the physical
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characteristics of flonicamid and its
metabolites.
The Agency uses the Generic
Estimated Environmental Concentration
(GENEEC) or the Pesticide Root Zone
Model/Exposure Analysis Modeling
System (PRZM/EXAMS) to estimate
pesticide concentrations in surface
water and Screening Concentrations in
Groundwater (SCI-GROW), which
predicts pesticide concentrations in
ground water. In general, EPA will use
GENEEC (a Tier 1 model) before using
PRZM/EXAMS to estimate pesticide
concentrations (a Tier 2 model) for a
screening-level assessment for surface
water. The GENEEC model is a subset of
the PRZM/EXAMS model that uses a
specific high-end runoff scenario for
pesticides. GENEEC incorporates a farm
pond scenario, while PRZM/EXAMS
incorporate an index reservoir
environment in place of the previous
pond scenario. The PRZM/EXAMS
model includes a percent crop area
factor as an adjustment to account for
the maximum percent crop coverage
within a watershed or drainage basin.
None of these models include
consideration of the impact processing
(mixing, dilution, or treatment) of raw
water for distribution as drinking water
would likely have on the removal of
pesticides from the source water. The
primary use of these models by the
Agency at this stage is to provide a
screen for sorting out pesticides for
which it is unlikely that drinking water
concentrations would exceed human
health levels of concern.
In order to fully implement the
requirements of FQPA, EPA determined
that chronic estimated drinking water
concentrations (EDWCs) can be used
directly in chronic dietary exposure
assessments to calculate aggregate
dietary (food + water) risk. This is done
by using the relevant PRZM-EXAMS
value as a residue for water (all sources)
in the dietary exposure assessment. The
principal advantage of this approach is
that the actual individual body weight
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and water consumption data from the
CSFII are used, rather than assumed
weights and consumption for broad age
groups. This refinement has been used
for the flonicamid chronic aggregate risk
assessment for surface water.
Based on the PRZM/EXAMS and SCIGROW models, the EDWCs of combined
residues of flonicamid and its
metabolites for chronic exposures are
estimated to be 0.94 ppb for surface
water and 0.00137 ppb for ground
water.
3. From non-dietary exposure. The
term ‘‘residential exposure’’ is used in
this document to refer to nonoccupational, non-dietary exposure
(e.g., for lawn and garden pest control,
indoor pest control, termiticides, and
flea and tick control on pets).
Flonicamid is not registered for use
on any sites that would result in
residential exposure.
4. Cumulative effects from substances
with a common mechanism of toxicity.
Section 408(b)(2)(D)(v) of the 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.’’
Unlike other pesticides for which EPA
has followed a cumulative risk approach
based on a common mechanism of
toxicity, EPA has not made a common
mechanism of toxicity finding as to
flonicamid and any other substances,
and flonicamid does not appear to
produce a toxic metabolite produced by
other substances. EPA considered that
there might be a common mechanism
among flonicamid and other pesticides.
EPA concluded that the evidence did
not support a finding of common
mechanism for flonicamid and other
pesticides. For the purposes of this
tolerance action, therefore, EPA has not
assumed that flonicamid has a common
mechanism of toxicity with other
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substances. For information regarding
EPA’s efforts to determine which
chemicals have a common mechanism
of toxicity and to evaluate the
cumulative effects of such chemicals,
see the policy statements released by
EPA’s Office of Pesticide Programs
concerning common mechanism
determinations and procedures for
cumulating effects from substances
found to have a common mechanism on
EPA’s website at https://www.epa.gov/
pesticides/cumulative/.
D. Safety Factor for Infants and
Children
1. In general. Section 408 of FFDCA
provides that EPA shall apply an
additional tenfold margin of safety for
infants and children in the case of
threshold effects to account for prenatal
and postnatal toxicity and the
completeness of the data base on
toxicity and exposure unless EPA
determines based on reliable data that a
different margin of safety will be safe for
infants and children. Margins of safety
are incorporated into EPA risk
assessments either directly through use
of a MOE analysis or through using
uncertainty (safety) factors in
calculating a dose level that poses no
appreciable risk to humans. In applying
this provision, EPA either retains the
default value of 10X when reliable data
do not support the choice of a different
factor, or, if reliable data are available,
EPA uses a different additional safety
factor value based on the use of
traditional uncertainty factors and/or
special FQPA safety factors, as
appropriate.
2. Prenatal and postnatal sensitivity.
There was no evidence for quantitative
or qualitative susceptibility following
oral or dermal exposures to rats in utero
or oral exposure to rabbits in utero.
Following oral exposures to rats,
developmental effects were seen only in
the presence of maternal toxicity. No
developmental effects were seen in
rabbits.
The degree of concern for prenatal
and/or postnatal susceptibility is low
due to the lack of evidence of qualitative
and quantitative susceptibility. This is
because developmental effects were
only seen in one species, only at the
maternal toxicity dose, and effects seen
in offspring were not more severe than
those seen in the maternal toxicity.
Thus, neither qualitative nor
quantitative susceptibility issues are of
concern for flonicamid. The database for
required developmental and
reproductive studies is complete, thus
there are no residual uncertainties.
3. Conclusion. The FQPA Safety
Factor is reduced to 1X because:
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i. There is a complete toxicity
database;
ii. There is a lack of susceptibility
evidence in the developmental studies
and reproductive study (The effects seen
in offspring were mild and occurred
only in one species.);
iii. The dietary food exposure
assessment utilizes proposed tolerance
level or higher residues and 100% CT
information for all commodities; and
iv. The dietary drinking water
assessment (Tier 1 estimates) utilizes
values generated by model and
associated modeling parameters which
are designed to provide conservative,
health protective, high-end estimates of
water concentrations.
E. Aggregate Risks and Determination of
Safety
1. Acute risk. No acute risk is
expected for the following reasons: No
acute toxicity endpoint was identified.
There was no endpoint noted in the
database from a single dose exposure
that could be used for risk assessment.
This included the acute neurotoxicity
and developmental toxicity studies as
well as other short- and long-term
studies. Body weight decreases were
consider inappropriate for this acute
endpoint since in these studies they
occur later then the acute time interval.
The observed vomiting in either the
acute or subchronic dog studies
occurred without manifestations of any
other acute clinical signs or related
pathology. Thus acute clinical effects
seen in the dog studies were considered
not appropriate. The acute neurotoxicity
study was also not appropriate for the
general population since the effects
observed only occurred in the high
doses tested where mortality was also
observed, and therefore the
neurotoxicity signs were probably part
of the death response. While death can
be an acute response, the dose at which
death occurred was in EPA’s judgement,
so high that it is unlikely to happen. In
addition, the acute neurotoxicity study
did not have all the required
observations. The effects observed in the
developmental studies were not
attributable to an acute response, and
therefore the developmental studies
were not used for an acute endpoint for
females of reproductive age. Thus, an
acute dietary endpoint was not
considered appropriate.
2. Chronic risk. Using the exposure
assumptions described in this unit for
chronic exposure, EPA has concluded
that exposure to flonicamid and its
metabolites from food and drinking
water will utilize 11% of the cPAD for
the U.S. population, 15% of the cPAD
for all infants <1 year old, and 25% of
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the cPAD for children 1-2 years old.
There are no residential uses for
flonicamid that result in chronic
residential exposure to flonicamid.
3. Short-term and intermediate term
risk. Short-term aggregate exposure
takes into account residential exposure
plus chronic exposure to food and water
(considered to be a background
exposure level). Intermediate-term
aggregate exposure takes into account
residential exposure plus chronic
exposure to food and water (considered
to be a background exposure level).
Flonicamid is not registered for use on
any sites that would result in residential
exposure. Therefore, the aggregate risk
is the sum of the risk from food and
water, which do not exceed the
Agency’s level of concern.
4. Aggregate cancer risk for U.S.
population. In assessing the
carcinogenic potential of flonicamid,
EPA took into account the following
weight-of-the-evidence considerations:
i. Flonicamid is not mutagenic.
ii. The treatment-related CD-1 mouse
lung tumors (benign and malignant)
which occurred in both sexes were due
to an established mitogenic mode of
action that occurred in a susceptible
mouse strain with a high background. A
clear species difference was observed
between mice and rats in the incidence
of lung tumors and the BrdU Index
studies. (Bromodeoxyuridine (BrdU)
Index studies are used to quantify rates
of cell proliferation). No tumors were
seen in the lungs of rats. The flonicamid
induced increase in the BrdU Index
appears to be related to the different
sensitivity of strains of mice, with the
CD-1 mice being a relatively sensitive
strain.
iii. The only other tumor response
was nasolacrimal duct tumors which
occurred in female rats at the high dose
which were considered to be possibly
treatment-related, but a clear association
with treatment could not be made.
Unlike male rats, the nasal tumor
response in females could not be clearly
associated with spontaneous
inflammation related to malocclusion of
incisor teeth, due to the low incidence
of both the neoplastic and nonneoplastic lesions. Given these findings
in the cancer and mutagenicity studies,
EPA regards the carcinogenic potential
of flonicamid as very low and concludes
that it poses no greater than a negligible
cancer risk to humans.
5. Determination of safety. Based on
these risk assessments, EPA concludes
that there is a reasonable certainty that
no harm will result to the general
population, and to infants and children
from aggregate exposure to flonicamid
residues.
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IV. Other Considerations
A. Analytical Enforcement Methodology
Adequate enforcement methods are
available to enforce the proposed
tolerances of flonicamid and the major
metabolites in plants and livestock. The
proposed method for plants uses a LC/
MS/MS (FMC No. P-3561M) to
determine the residues of flonicamid
and its major metabolites, TFNA-AM (4trifluoromethylnicotinamide), TFNA (4trifluoromethylnicotinic acid), and
TFNG [N-(4trifluoromethylnicotinoyl)glycine]. The
reported LOQ was 0.01 ppm and the
reported LOD was 0.005 ppm for peach,
potato, processed commodities of
apples, plums, potatoes, and tomatoes.
The reported LOQ was 0.02 ppm and
the LOD was 0.01 ppm for each analyte
in/on wheat; cotton seed, hulls, and
refined oil. The method was adequately
validated by an independent laboratory.
For livestock, three methods were
proposed: LC/MS/MS method (RCC No.
844743) for residues in eggs and
livestock tissues, LC/MS method (RCC
No. 842993) for residues in milk, and
LC/MS/MS method (FMC P3580) which
include an acid hydrolysis step for
residues in cattle muscle, kidney and
liver. The three livestock methods
recommend the use of calibration
standards, prepared by using control
matrix extracts for all or some of the
analyze/matrix combinations to remove
matrix enhancement effects. The
methods were adequately validated by
an independent laboratory. These
methods may be used for the
determination of residues of flonicamid
and its metabolites TFNA-AM, TFNG,
and TFNA. The validated LOQ was 0.01
ppm and LOD was 0.005 ppm for
methods 844743 and 842993; the
reported validated LOQ was 0.025 ppm
and the LOD was 0.005 ppm for method
FMC P3580.
Enforcement methodology may be
requested from: Chief, Analytical
Chemistry Branch, Environmental
Science Center, 701 Mapes Rd., Ft.
Meade, MD 20755–5350; telephone
number: (410) 305–2905; e-mail address:
residuemethods@epa.gov.
B. International Residue Limits
No Codex, Mexican or Canadian
MRLs or tolerances have been
established. Therefore no compatibility
questions exist with respect to Codex.
C. Response to Comments
EPA received one comment from the
National Cotton Council, which stated
that it supports ISK Bioscience’s request
for the establishment of tolerances in
the listed food and feed items. In today’s
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action, EPA is responding affirmatively
to this comment.
V. Conclusion
Therefore, tolerances are established
for the combined residues of flonicamid
[N-(cyanomethyl)-4-trifluoromethyl)-3pyridinecarboxamide], and its
metabolites TFNA [4trifluoromethylnicotinic acid], TFNAAM [4-trifluoromethylnicotinamide]
and TFNG [N-(4trifluoromethylnicotinoyl)glycine] in or
on the crops at tolerance levels listed in
Unit III.
Tolerances are established for the
combined residues of flonicamid [N(cyanomethyl)-4-(trifluoromethyl)-3pyridinecarboxamide], and its
metabolites TFNA [4trifluoromethylnicotinic acid] and
TFNA-AM [4trifluoromethylnicotinamide] in or on
the livestock commodities at tolerance
levels listed in Unit III.
VI. Objections and Hearing Requests
Under section 408(g) of FFDCA, as
amended by FQPA, any person may file
an objection to any aspect of this
regulation and may also request a
hearing on those objections. The EPA
procedural regulations which govern the
submission of objections and requests
for hearings appear in 40 CFR part 178.
Although the procedures in those
regulations require some modification to
reflect the amendments made to FFDCA
by FQPA, EPA will continue to use
those procedures, with appropriate
adjustments, until the necessary
modifications can be made. The new
section 408(g) of FFDCA provides
essentially the same process for persons
to ‘‘object’’ to a regulation for an
exemption from the requirement of a
tolerance issued by EPA under new
section 408(d) of FFDCA, as was
provided in the old sections 408 and
409 of FFDCA. However, the period for
filing objections is now 60 days, rather
than 30 days.
A. What Do I Need to Do to File an
Objection or Request a Hearing?
You must file your objection or
request a hearing on this regulation in
accordance with the instructions
provided in this unit and in 40 CFR part
178. To ensure proper receipt by EPA,
you must identify docket ID number
OPP–2005–0217 in the subject line on
the first page of your submission. All
requests must be in writing, and must be
mailed or delivered to the Hearing Clerk
on or before October 31, 2005.
1. Filing the request. Your objection
must specify the specific provisions in
the regulation that you object to, and the
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51613
grounds for the objections (40 CFR
178.25). If a hearing is requested, the
objections must include a statement of
the factual issue(s) on which a hearing
is requested, the requestor’s contentions
on such issues, and a summary of any
evidence relied upon by the objector (40
CFR 178.27). Information submitted in
connection with an objection or hearing
request may be claimed confidential by
marking any part or all of that
information as CBI. Information so
marked will not be disclosed except in
accordance with procedures set forth in
40 CFR part 2. A copy of the
information that does not contain CBI
must be submitted for inclusion in the
public record. Information not marked
confidential may be disclosed publicly
by EPA without prior notice.
Mail your written request to: Office of
the Hearing Clerk (1900L),
Environmental Protection Agency, 1200
Pennsylvania Ave., NW., Washington,
DC 20460–0001. You may also deliver
your request to the Office of the Hearing
Clerk in Suite 350, 1099 14th St., NW.,
Washington, DC 20005. The Office of
the Hearing Clerk is open from 8 a.m.
to 4 p.m., Monday through Friday,
excluding legal holidays. The telephone
number for the Office of the Hearing
Clerk is (202) 564–6255.
2. Copies for the Docket. In addition
to filing an objection or hearing request
with the Hearing Clerk as described in
Unit VI.A., you should also send a copy
of your request to the PIRIB for its
inclusion in the official record that is
described in ADDRESSES. Mail your
copies, identified by docket ID number
OPP–2005–0217, to: Public Information
and Records Integrity Branch,
Information Resources and Services
Division (7502C), Office of Pesticide
Programs, Environmental Protection
Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460–0001. In person
or by courier, bring a copy to the
location of the PIRIB described in
ADDRESSES. You may also send an
electronic copy of your request via email to: opp-docket@epa.gov. Please use
an ASCII file format and avoid the use
of special characters and any form of
encryption. Copies of electronic
objections and hearing requests will also
be accepted on disks in WordPerfect
6.1/8.0 or ASCII file format. Do not
include any CBI in your electronic copy.
You may also submit an electronic copy
of your request at many Federal
Depository Libraries.
B. When Will the Agency Grant a
Request for a Hearing?
A request for a hearing will be granted
if the Administrator determines that the
material submitted shows the following:
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There is a genuine and substantial issue
of fact; there is a reasonable possibility
that available evidence identified by the
requestor would, if established resolve
one or more of such issues in favor of
the requestor, taking into account
uncontested claims or facts to the
contrary; and resolution of the factual
issue(s) in the manner sought by the
requestor would be adequate to justify
the action requested (40 CFR 178.32).
VII. Statutory and Executive Order
Reviews
This final rule establishes a tolerance
under section 408(d) of FFDCA in
response to a petition submitted to the
Agency. The Office of Management and
Budget (OMB) has exempted these types
of actions from review under Executive
Order 12866, entitled Regulatory
Planning and Review (58 FR 51735,
October 4, 1993). Because this rule has
been exempted from review under
Executive Order 12866 due to its lack of
significance, this rule is not subject to
Executive Order 13211, Actions
Concerning Regulations That
Significantly Affect Energy Supply,
Distribution, or Use (66 FR 28355, May
22, 2001). This final rule does not
contain any information collections
subject to OMB approval under the
Paperwork Reduction Act (PRA), 44
U.S.C. 3501 et seq., or impose any
enforceable duty or contain any
unfunded mandate as described under
Title II of the Unfunded Mandates
Reform Act of 1995 (UMRA) (Public
Law 104–4). Nor does it require any
special considerations under Executive
Order 12898, entitled Federal Actions to
Address Environmental Justice in
Minority Populations and Low-Income
Populations (59 FR 7629, February 16,
1994); or OMB review or any Agency
action under Executive Order 13045,
entitled Protection of Children from
Environmental Health Risks and Safety
Risks (62 FR 19885, April 23, 1997).
This action does not involve any
technical standards that would require
Agency consideration of voluntary
consensus standards pursuant to section
12(d) of the National Technology
Transfer and Advancement Act of 1995
(NTTAA), Public Law 104–113, section
12(d) (15 U.S.C. 272 note). Since
tolerances and exemptions that are
established on the basis of a petition
under section 408(d) of FFDCA, such as
the tolerance in this final rule, do not
require the issuance of a proposed rule,
the requirements of the Regulatory
Flexibility Act (RFA) (5 U.S.C. 601 et
seq.) do not apply. In addition, the
Agency has determined that this action
will not have a substantial direct effect
on States, on the relationship between
VerDate Aug<18>2005
16:14 Aug 30, 2005
Jkt 205001
the national government and the States,
or on the distribution of power and
responsibilities among the various
levels of government, as specified in
Executive Order 13132, entitled
Federalism (64 FR 43255, August 10,
1999). Executive Order 13132 requires
EPA to develop an accountable process
to ensure ‘‘meaningful and timely input
by State and local officials in the
development of regulatory policies that
have federalism implications.’’ ‘‘Policies
that have federalism implications’’ is
defined in the Executive Order to
include regulations that have
‘‘substantial direct effects on the States,
on the relationship between the national
government and the States, or on the
distribution of power and
responsibilities among the various
levels of government.’’ This final rule
directly regulates growers, food
processors, food handlers and food
retailers, not States. This action does not
alter the relationships or distribution of
power and responsibilities established
by Congress in the preemption
provisions of section 408(n)(4) of
FFDCA. For these same reasons, the
Agency has determined that this rule
does not have any ‘‘tribal implications’’
as described in Executive Order 13175,
entitled Consultation and Coordination
with Indian Tribal Governments (65 FR
67249, November 6, 2000). Executive
Order 13175, requires EPA to develop
an accountable process to ensure
‘‘meaningful and timely input by tribal
officials in the development of
regulatory policies that have tribal
implications.’’ ‘‘Policies that have tribal
implications’’ is defined in the
Executive Order to include regulations
that have ‘‘substantial direct effects on
one or more Indian tribes, on the
relationship between the Federal
Government and the Indian tribes, or on
the distribution of power and
responsibilities between the Federal
Government and Indian tribes.’’ This
rule will not have substantial direct
effects on tribal governments, on the
relationship between the Federal
Government and Indian tribes, or on the
distribution of power and
responsibilities between the Federal
Government and Indian tribes, as
specified in Executive Order 13175.
Thus, Executive Order 13175 does not
apply to this rule.
VIII. Congressional Review Act
The Congressional Review Act, 5
U.S.C. 801 et seq., as added by the Small
Business Regulatory Enforcement
Fairness Act of 1996, generally provides
that before a rule may take effect, the
agency promulgating the rule must
submit a rule report, which includes a
PO 00000
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Fmt 4700
Sfmt 4700
copy of the rule, to each House of the
Congress and to the Comptroller General
of the United States. EPA will submit a
report containing this rule and other
required information to the U.S. Senate,
the U.S. House of Representatives, and
the Comptroller General of the United
States prior to publication of this final
rule in the Federal Register. This final
rule is not a ‘‘major rule’’ as defined by
5 U.S.C. 804(2).
List of Subjects in 40 CFR Part 180
Environmental protection,
Administrative practice and procedure,
Agricultural commodities, Pesticides
and pests, Reporting and recordkeeping
requirements.
Dated: August 19, 2005.
Lois A. Rossi,
Acting Director, Office of Pesticide Programs.
Therefore, 40 CFR chapter I is
amended as follows:
I
PART 180—AMENDED
1. The authority citation for part 180
continues to read as follows:
I
Authority: 21 U.S.C. 321(q), 346a and 371.
2. Section 180.613 is added to read as
follows:
I
§ 180.613 Flonicamid; tolerances for
residues.
(a) General. (1) Tolerances are
established for the combined residues of
flonicamid [N-(cyanomethyl)-4(trifluoromethyl)-3pyridinecarboxamide] and its
metabolites TFNA [4trifluoromethylnicotinic acid], TFNAAM [4-trifluoromethylnicotinamide]
TFNG [N-(4trifluoromethylnicotinoyl)glycine] in or
on the following raw agricultural
commodities:
Commodity
Cotton, gin byproducts ....................
Cotton, hulls ..........
Cotton, meal .........
Cotton, undelinted
seed ..................
Fruit, pome, group
11 ......................
Fruit, stone, group
12 ......................
Potato ...................
Potato, granular/
flakes .................
Spinach .................
Tomato, paste .......
Tomato, puree ......
Vegetable,
cucurbit, group ..
Vegetable, fruiting,
group .................
E:\FR\FM\31AUR1.SGM
31AUR1
Parts per million
6.0
2.0
1.0
0.50
0.20
0.60
0.20
0.40
9.0
2.0
0.50
0.40
0.40
Federal Register / Vol. 70, No. 168 / Wednesday, August 31, 2005 / Rules and Regulations
Commodity
Parts per million
Vegetable, leafy
except Brassica
group 4, except
spinach ..............
4.0
(2) Tolerances are established for
combined residues of flonicamid [N(cyanomethyl)-4-(trifluoromethyl)-3pyridinecarboxamide], and its
metabolites TFNA [4trifluoromethylnicotinic acid], TFNAAM [4-trifluoromethylnicotinamide] in
or on the following raw agricultural
commodities:
Commodity
Parts per million
Cattle, fat ..............
Cattle, meat ..........
Cattle, meat byproducts ............
Egg .......................
Goat, fat ................
Goat, meat ............
Goat, meat byproducts ....................
Horse, fat ..............
Horse, meat ..........
Horse, meat byproducts ............
Milk .......................
Poultry, fat ............
Poultry, meat ........
Poultry, meat byproducts ............
Sheep, fat .............
Sheep, meat .........
Sheep, meat by
products ............
0.02
0.05
0.08
0.03
0.02
0.05
0.08
0.02
0.05
0.08
0.02
0.02
0.02
0.02
0.02
0.05
0.08
(b) Section 18 emergency exemptions.
[Reserved]
(c) Tolerances with regional
registrations. [Reserved]
(d) Indirect or inadvertent residues.
[Reserved]
[FR Doc. 05–17128 Filed 8–30–05; 8:45 am]
BILLING CODE 6560–50–S
ENVIRONMENTAL PROTECTION
AGENCY
I. General Information
40 CFR Part 180
[OPP–2005–0165; FRL–7719–8]
Halosulfuron-methyl; Pesticide
Tolerances for Emergency Exemptions
Environmental Protection
Agency (EPA).
ACTION: Final rule.
AGENCY:
SUMMARY: This regulation establishes a
time-limited tolerance for residues of
halosulfuron-methyl in or on sweet
potatoes. This action is in response to
EPA’s granting of an emergency
exemption under section 18 of the
VerDate Aug<18>2005
16:14 Aug 30, 2005
Jkt 205001
Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA) authorizing
use of the pesticide on sweet potatoes.
This regulation establishes a maximum
permissible level for residues of
halosulfuron-methyl in this food
commodity. The tolerance will expire
and is revoked on December 31, 2008.
DATES: This regulation is effective
August 31, 2005. Objections and
requests for hearings must be received
on or before October 31, 2005.
ADDRESSES: To submit a written
objection or hearing request follow the
detailed instructions as provided in
Unit VII. of the SUPPLEMENTARY
INFORMATION. EPA has established a
docket for this action under docket
identification (ID) number OPP–2005–
0165. All documents in the docket are
listed in the EDOCKET index at https://
www.epa.gov/edocket/. Although listed
in the index, some information is not
publicly available, i.e., Confidential
Business Information (CBI) or other
information whose disclosure is
restricted by statute. Certain other
material, such as copyrighted material,
is not placed on the Internet and will be
publicly available only in hard copy
form. Publicly available docket
materials are available either
electronically in EDOCKET or in hard
copy at the Public Information and
Records Integrity Branch (PIRIB), Rm.
119, Crystal Mall #2, 1801 S. Bell St.,
Arlington, VA. This docket facility is
open from 8:30 a.m. to 4 p.m., Monday
through Friday, excluding legal
holidays. The docket telephone number
is (703) 305–5805.
FOR FURTHER INFORMATION CONTACT:
Andrew Ertman, Registration Division
(7505C), Office of Pesticide Programs,
Environmental Protection Agency, 1200
Pennsylvania Ave., NW., Washington,
DC 20460–0001; telephone number:
(703) 308–9367; e-mail address:
ertman.andrew@epa.gov.
SUPPLEMENTARY INFORMATION:
A. Does this Action Apply to Me?
You may be potentially affected by
this action if you are an agricultural
producer, food manufacturer, or
pesticide manufacturer. Potentially
affected entities may include, but are
not limited to:
• Crop production (NAICS code 111).
• Animal production (NAICS code
112).
• Food manufacturing (NAICS code
311).
• Pesticide manufacturing (NAICS
code 32532).
This listing is not intended to be
exhaustive, but rather provides a guide
PO 00000
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Fmt 4700
Sfmt 4700
51615
for readers regarding entities likely to be
affected by this action. Other types of
entities not listed in this unit could also
be affected. The North American
Industrial Classification System
(NAICS) codes have been provided to
assist you and others in determining
whether this action might apply to
certain entities. If you have any
questions regarding the applicability of
this action to a particular entity, consult
the person listed under FOR FURTHER
INFORMATION CONTACT.
B. How Can I Access Electronic Copies
of this Document and Other Related
Information?
In addition to using EDOCKET (https://
www.epa.gov/edocket/), you may access
this Federal Register document
electronically through the EPA Internet
under the ‘‘Federal Register’’ listings at
https://www.epa.gov/fedrgstr/. A
frequently updated electronic version of
40 CFR part 180 is available on E-CFR
Beta Site Two at https://
www.gpoaccess.gov/ecfr/.
II. Background and Statutory Findings
EPA, on its own initiative, in
accordance with sections 408(e) and
408(l)(6) of the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. 346a,
is establishing a tolerance for residues of
the herbicide halosulfuron-methyl, in or
on sweet potatoes at 1.0 parts per
million (ppm). This tolerance will
expire and is revoked on December 31,
2008. EPA will publish a document in
the Federal Register to remove the
revoked tolerance from the Code of
Federal Regulations (CFR).
Section 408(l)(6) of FFDCA requires
EPA to establish a time-limited
tolerance or exemption from the
requirement for a tolerance for pesticide
chemical residues in food that will
result from the use of a pesticide under
an emergency exemption granted by
EPA under section 18 of FIFRA. Such
tolerances can be established without
providing notice or period for public
comment. EPA does not intend for its
actions on FIFRA section 18 related
tolerances to set binding precedents for
the application of section 408 of FFDCA
and the new safety standard to other
tolerances and exemptions. Section
408(e) of FFDCA allows EPA to
establish a tolerance or an exemption
from the requirement of a tolerance on
its own initiative, i.e., without having
received any petition from an outside
party.
Section 408(b)(2)(A)(i) of FFDCA
allows EPA to establish a tolerance (the
legal limit for a pesticide chemical
residue in or on a food) only if EPA
determines that the tolerance is ‘‘safe.’’
E:\FR\FM\31AUR1.SGM
31AUR1
]]>Agencies
[Federal Register Volume 70, Number 168 (Wednesday, August 31, 2005)]
[Rules and Regulations]
[Pages 51604-51615]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 05-17128]
-----------------------------------------------------------------------
ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[OPP-2005-0217; FRL-7731-6]
Flonicamid; Pesticide Tolerance
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
-----------------------------------------------------------------------
SUMMARY: This regulation establishes a tolerance for combined residues
of flonicamid and its metabolites in or on certain plant and livestock
commodities. ISK Biosciences requested this tolerance under the Federal
Food, Drug, and Cosmetic Act (FFDCA), as amended by the Food Quality
Protection Act of 1996 (FQPA).
DATES: This regulation is effective August 31, 2005. Objections and
requests for hearings must be received on or before October 31, 2005.
ADDRESSES: To submit a written objection or hearing request follow the
detailed instructions as provided in Unit VI. of the SUPPLEMENTARY
INFORMATION. EPA has established a docket for this action under Docket
identification (ID) number OPP-2005-0217. All documents in the docket
are listed in the EDOCKET index athttps://www.epa.gov/edocket. Although
listed in the index, some information is not publicly available, i.e.,
CBI or other information whose disclosure is restricted by statute.
Certain other material, such as copyrighted material, is not placed on
the Internet and will be publicly available only in hard copy form.
Publicly available docket materials are available either electronically
in EDOCKET or in hard copy at the Public Information and Records
Integrity Branch (PIRIB), Rm. 119, Crystal Mall 2, 1801 S.
Bell St., Arlington, VA. This docket facility is open from 8:30 a.m. to
4 p.m., Monday through Friday, excluding legal holidays. The docket
telephone number is (703) 305-5805.
FOR FURTHER INFORMATION CONTACT: Ann Sibold, Registration Division
(7505C), Office of Pesticide Programs, Environmental Protection Agency,
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone
number: (703) 305-6502; e-mail address:sibold.ann@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does This Action Apply to Me?
You may be potentially affected by this action if you are an
agricultural producer, food manufacturer, or pesticide manufacturer.
Potentially affected entities may include, but are not limited to:
Crop production (NAICS 111), e.g., agricultural workers;
greenhouse, nursery, and floriculture workers; farmers.
Animal production (NAICS 112), e.g., cattle ranchers and
farmers, dairy cattle farmers, livestock farmers.
Food manufacturing (NAICS 311), e.g., agricultural
workers; farmers; greenhouse, nursery, and floriculture workers;
ranchers; pesticide applicators.
Pesticide manufacturing (NAICS 32532), e.g., agricultural
workers; commercial applicators; farmers; greenhouse, nursery, and
floriculture workers; residential users.
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in this unit could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether this action might apply to certain entities. If you have any
questions regarding the applicability of this action to a particular
entity, consult the person listed underFOR FURTHER INFORMATION CONTACT.
B. How Can I Access Electronic Copies of this Document and Other
Related Information?
In addition to using EDOCKET (https://www.epa.gov/edocket/), you may
access this Federal Register document electronically through the EPA
Internet under the ``Federal Register'' listings at https://www.epa.gov/
fedrgstr/. A frequently updated electronic version of 40 CFR part 180
is available at E-CFR Beta Site Two at https://www.gpoaccess.gov/ecfr/.
To access the OPPTS Harmonized Guidelines referenced in this document,
go directly to the guidelines athttps://www.epa.gpo/opptsfrs/home/
guidelin.htm/.
II. Background and Statutory Findings
In the Federal Register of May 23, 2003 (68 FR 28218) (FRL-7307-5),
EPA issued a notice pursuant to section 408(d)(3) of FFDCA, 21 U.S.C.
346a(d)(3), announcing the filing of a pesticide petition (PP 3F6552)
by ISK Biosciences, 7470 Auburn Road, suite A, Concord, Ohio 44077. The
petition requested that 40 CFR part 180 be amended by establishing a
tolerance for the combined residues of the insecticide flonicamid, [N-
(cyanomethyl)-4-trifluoromethylnicotinamide] and its metabolites, TFNA,
(4-trifluoromethylnicotinic acid), TFNA-AM, (4-
trifluoromethylnicotinamide) and TFNG, [N-(4-
trifluoromethylnicotinoyl)glycine] in or on the raw agricultural
commodities: Celery, at 1.2 parts per million (ppm); cotton, at 0.5
ppm; cotton, gin trash, at 6.0 ppm; cotton, hulls, at 1.0 ppm; cotton,
meal, at 1.0 ppm; fruit, pome, group 11, at 0.2 ppm; fruit, stone,
group 12, except plum and fresh prune plum, at 0.7 ppm; lettuce, head,
at 1.0 ppm; lettuce, leaf, at 4.0 ppm; plum, at 0.1 ppm; potato, at 0.2
ppm; potato, flakes, at 0.4 ppm; prune, fresh, at 0.1; spinach, at 9.0
ppm; tomato, paste, at 2.0 ppm; tomato, puree, at 0.5 ppm; vegetable,
[[Page 51605]]
cucurbit, group 9, at 0.4 ppm; vegetable, fruiting, group 8, at 0.4
ppm; by establishing tolerances for the combined residues of the
insecticide flonicamid, [N-(cyanomethyl)-4-trifluoromethylnicotinamide]
and its metabolite TFNA-AM, (4-trifluoromethylnicotinamide) in animal
tissues and poultry meat byproducts:Cattle, fat, at 0.01 ppm; cattle,
meat, at 0.04 ppm; eggs, at 0.02 ppm; goat, fat, at 0.01 ppm; goat,
meat, at 0.04 ppm; hog, fat, at 0.01; hog, meat, at 0.01 ppm; horse,
fat, at 0.01 ppm; horse, meat, at 0.04 ppm; milk, at 0.02 ppm; poultry,
fat, at 0.01 ppm; poultry, meat, at 0.01 ppm; poultry, meat byproducts,
at 0.01 ppm; sheep, fat, at 0.01 ppm; sheep, meat, at 0.04 ppm; by
establishing tolerances for the combined residues of the insecticide
flonicamid [N-(cyanomethyl)-4-trifluoromethylnicotinamide] and its
metabolites TFNA, (4-trifluoromethylnicotinic acid) and TFNA-AM, (4-
trifluoromethylnicotinamide) in the animal meat byproducts: cattle,
meat byproducts, at 0.06 ppm; goat, meat byproducts, at 0.06 ppm; hog,
meat byproducts, at 0.01 ppm; horse, meat byproducts, at 0.06 ppm; and
sheep, meat byproducts, at 0.06 ppm. That notice included a summary of
the petition prepared by ISK Biosciences, the registrant. One comment
was received on the notice of filing. EPA's response to this comment is
discussed in Unit IV.C.
Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a
tolerance (the legal limit for a pesticide chemical residue in or on a
food) only if EPA determines that the tolerance is ``safe.'' Section
408(b)(2)(A)(ii) of FFDCA defines ``safe'' to mean that ``there is a
reasonable certainty that no harm will result from aggregate exposure
to the pesticide chemical residue, including all anticipated dietary
exposures and all other exposures for which there is reliable
information.'' This includes exposure through drinking water and in
residential settings, but does not include occupational exposure.
Section 408(b)(2)(C) of FFDCA requires EPA to give special
consideration to exposure of infants and children to the pesticide
chemical residue in establishing a tolerance and to ``ensure that there
is a reasonable certainty that no harm will result to infants and
children from aggregate exposure to the pesticide chemical residue. . .
.''
EPA performs a number of analyses to determine the risks from
aggregate exposure to pesticide residues. For further discussion of the
regulatory requirements of section 408 of FFDCA and a complete
description of the risk assessment process, see the final rule on
Bifenthrin Pesticide Tolerances (62 FR 62961, November 26, 1997, FRL-
5754-7)
III. Aggregate Risk Assessment and Determination of Safety
Consistent with section 408(b)(2)(D) of FFDCA, EPA has reviewed the
available scientific data and other relevant information in support of
this action. EPA has sufficient data to assess the hazards of and to
make a determination on aggregate exposure, consistent with section
408(b)(2) of FFDCA, for a tolerance for combined residues of flonicamid
and its metabolites on various crop and livestock commodities at levels
set forth in the list below.
Tolerances for combined residues of flonicamid and its metabolites
in/on crops and livestock commodities.
1. Recommended tolerances for combined residues of flonicamid and
its metabolites TFNA, TFNG and TFNA-AM in/on crops.
Cotton, undelinted seed at 0.50 ppm
Cotton, gin byproducts at 6.0 ppm
Cotton, hulls at 2.0 ppm
Cotton, meal at 1.0 ppm
Fruit, pome, group 11 at 0.20 ppm
Fruit, stone, group at 12 0.60 ppm
Potato 0.20 at ppm
Potato, granular/flakes at 0.40 ppm
Spinach at 9.0 ppm
Tomato, paste at 2.0 ppm
Tomato, puree at 0.50 ppm
Vegetable, cucurbit, group at 0.40 ppm
Vegetable, fruiting, group at 0.40 ppm
Vegetable, leafy except Brassica group 4, except spinach at 4.0 ppm
2. Recommended tolerances for combined residues of flonicamid and
its metabolites TFNA and TFNA-AM in/on livestock commodities.
Cattle, fat at 0.02 ppm
Cattle, meat at 0.05 ppm
Egg at 0.03 ppm
Goat, fat at 0.02 ppm
Goat, meat at 0.05 ppm
Horse, fat at 0.02 ppm
Horse, meat at 0.05 ppm
Milk at 0.02 ppm
Poultry, fat at 0.02 ppm
Poultry, meat at 0.02 ppm
Poultry, meat byproducts at 0.02 ppm
Sheep, fat at 0.02 ppm
Sheep, meat at 0.05 ppm
Cattle, meat byproducts at 0.08 ppm
Goat, meat byproducts at 0.08 ppm
Horse, meat byproducts at 0.08 ppm
Sheep, meat byproducts at 0.08 ppm
EPA's assessment of exposures and risks associated with
establishing the tolerance follows.
A. Toxicological Profile
EPA has evaluated the available toxicity data and considered its
validity, completeness, and reliability as well as the relationship of
the results of the studies to human risk. EPA has also considered
available information concerning the variability of the sensitivities
of major identifiable subgroups of consumers, including infants and
children. Specific information on the studies received and the nature
of the toxic effects caused by flonicamid as well as the no observed
adverse effect level (NOAEL) and the lowest observed adverse effect
level (LOAEL) from the toxicity studies are discussed in Table 1 of
this unit.
[[Page 51606]]
Table 1.--Subchronic, Chronic and Other Toxicity of Flonicamid
----------------------------------------------------------------------------------------------------------------
Guideline No. Study Type Dose Levels Results
----------------------------------------------------------------------------------------------------------------
870.3100 90-Day oral toxicity 0, 50 (males), 200, NOAEL is 200 ppm (12.11 mg/
rodents (rats) 1,000,2,000 (males), kg/day) formales and 1,000
28-day range-finding.. or 5,000(females) ppm ppm (72.3 mg/kg/day)
(3.08, 12.11,60.0, or forfemales
119.4 mg/kg/day,males LOAELs were 1,000 ppm (60.0
and 14.52, 72.3, mg/kg/day) formales based
or340.1 mg/kg/day, on changes in the kidney
females) (hyalinedeposition) and
0, 50 (males), 100, 5,000 ppm (340 mg/kg/day)
500, 1,000,5,000 or forfemales based on kidney
10,000 (females)ppm (hyaline deposition)and
(3.61, 7.47, liver changes
36.45,73.8, or 353.4 (centrilobular
mg/kg/day,males and hypertrophy)
8.36, 41.24, NOAEL is 100 ppm (7.47 mg/
81.9,372.6, or 642 mg/ kg/day) for malesand 1,000
kg/day,females). ppm (81.9 mg/kg/day) for
females.
LOAELs were 500 ppm (36.45
mg/kg/day) formales based
on changes in the kidney
(hyalinedeposition) and
5,000 ppm for females
(372.6mg/kg/day) based on
kidney
(hyalinedeposition), liver
changes
(centrilobularhypertrophy)
, hematological effects
(anemia)and clinical
chemistry (increased
cholesterol)
-------------------------------------------------------------------------------------
870.3100 90-Day oral toxicity 0, 100, 1,000 or 7,000 NOAEL is 100 ppm (males:
rodents (mice) ppm(0, 15.25, 153.9 15.25 mg/kgbw/day,
or 1,069mg/kg bw/day females: 20.10 mg/kg bw/
in males,and 0, day)
20.10, 191.5, or LOAEL is 1,000 ppm in
1,248mg/kg bw/day in (males: 153.9 mg/kgbw/day;
females) females: 191.5 mg/kg bw/
day) basedon
extramedullary
hematopoiesis of the
spleen
Many of the tissues/organs
recommended byGuideline
870.3100 were not
histologicallyexamined in
any dose group, but this
study isnot required and
serves as a range-
findingstudy for the mouse
carcinogenicity
study.Therefore, it is
classified as acceptable,
non-guideline study
-------------------------------------------------------------------------------------
870.3150 90-Day oral toxicity 0, 3, 8, 20, or 50 NOAEL is 8 mg/kg/day in
(nonrodents- dogs) (females) mg/kg bw/ males and 20 mg/kg/day for
day female
LOAEL is 20 mg/kg/day in
males and 50 mg/kg/day in
females, based on acute
clinical signs in males
and females (vomiting,
first observed on Day 1
and last observed on Day
90), clinical pathology at
7 weeks (increased total
protein levels in males,
lower red blood cells and
higher reticulocytescounts
in females), increased
adrenal weights in males,
decreased thymusgland
weights in males, and
increased kidney tubular
vacuolation infemales at
study termination
-------------------------------------------------------------------------------------
870.3200 28-Day dermal toxicity 0, 20, 150, or 1,000 NOAEL is 1,000 mg/kg/day
(rats) mg/kg/day LOAEL is >1,000 mg/kg/day
-------------------------------------------------------------------------------------
870.3700 Prenatal developmental 0, 20, 100 or 500 mg/ Maternal
toxicity (rats) kg bw/day NOAEL is 100 mg/kg bw/day
LOAEL is 500 mg/kg bw/day,
based onincreased liver
weight, and liver and
kidneypathological changes
(hypertrophy
ofcentrilobular
hepatocytes in liver
andvacuolation of proximal
tubular cell inkidneys)
Developmental
NOAEL is 100 mg/kg bw/day
LOAEL is 500 mg/kg bw/day,
based on the increased
incidence of cervical rib
-------------------------------------------------------------------------------------
[[Page 51607]]
870.3700 Prenatal 0, 2.5, 7.5, or 25 mg/ Maternal
developmentaltoxicity kg/day NOAEL is 7.5 mg/kg/day
(rabbits) LOAEL is 25 mg/kg, based on
decreased bodyweights,
body weight gains, and
food consumption
Developmental
NOAEL is >= 25 mg/kg/day
LOAEL is not established
-------------------------------------------------------------------------------------
870.3800 Reproduction and 0, 50, 300, or 1,800 Parental
fertility effects ppm(0/0, 3.7/4.4, NOAEL is 50 ppm (equivalent
(rats) 22.3/26.5, and132.9/ to 3.7/4.4mg/kg/day [M/F]
153.4 mg/kg bw/day [M/ LOAEL is 300 ppm
F] (equivalent to 22.3/26.5mg/
kg/day [M/F] based on
increased relativekidney
weight and hyaline droplet
depositionin the proximal
tubules of the kidneys in
themales and increased
blood serum LH levels
inthe F1 females
Offspring
NOAEL is 300 ppm
(equivalent to 22.3/26.5mg/
kg/day [M/F]. LOAEL is
1,800 ppm(equivalent to
132.9/153.4 mg/kg/day [M/
F]based on decreased
absolute and relative
tobody uterus weights and
delayed sexualmaturation
in the F1 females
Reproductive Performance
NOAEL is 1,800 ppm
(equivalent to 132.9/
153.4mg/kg/day [M/F]
LOAEL for reproductive
performance was
notobserved
-------------------------------------------------------------------------------------
870.4100 Chronic toxicity 0, 3, 8, or 20 mg/kg/ NOAEL is 8 mg/kg/day
(dogs) day LOAEL is 20 mg/kg/day,
based on acute clinical
signs(vomiting, mostly
within the first week),
clinical pathology at 12
months (higher
reticulocytes counts) in
males and females
-------------------------------------------------------------------------------------
870.4200 Carcinogenicity (mice) 0, 250, 750, or 2250 NOAEL was not established
ppm(0/0, 29/38, 88/ LOAEL is 250 ppm
112, or261/334 mg/kg/ (equivalent to 29/38mg/kg/
day [M/F] day [M/F]), based on
minimal tomoderate
centrilobular
hepatocellularhypertrophy,
minimal to
severeextramedullary
hematopoiesis, minimal
tomoderate pigment
deposition in the
sternalbone marrow, and
increased incidence of
tissuemasses/nodules in
the lungs in the males,
andminimal to moderate
decreased cellularity
inthe femoral bone marrow
andhyperplasia/hypertrophy
of the epithelial cellsof
the terminal bronchioles
of the females
At the doses tested, the
carcinogenic potentialof
IKI-220 (flonicamid) is
positive at 250 ppmin
males and females based on
the increasedincidence of
alveolar/bronchiolar
adenomas,carcinomas, and
combinedadenomas/
carcinomas. Dosing was
consideredadequate based
on increased incidence of
tissuemasses/nodules in
the lungs and
microscopicfindings in the
liver, spleen, bone
marrow, andlungs. However,
data were
providedsuggesting this
effect is specific to
sensitivestrains of mice
Carcinogenic in mice
-------------------------------------------------------------------------------------
[[Page 51608]]
870.4200 Carcinogenicity (mice) 0, 10, 25, 80, 250 NOAEL is 80 ppm (equivalent
ppmmales: 0, 1.20, to 10/12mg/kg/day in males/
3.14, 10.0,30.3 mg/kg/ females)
day; females: 0,1.42, LOAEL is 250 ppm
3.67, 11.8, 36.3 mg/ (equivalent to 30/36mg/kg/
kg/day day in males/females)
based on lungmasses and
terminal bronchiole
epithelial cellhyperplasia/
hypertrophy in both sexes
At the doses tested, the
carcinogenic potentialof
IKI-220 (flonicamid) is
positive in males
andfemales based on the
incidences ofalveolar/
bronchiolar adenomas,
carcinomas,and combined
adenomas and/or
carcinomas. Dosing was
consideredadequate based
on lung masses and
terminal bronchiole
epithelialcell hyperplasia/
hypertrophy in both sexes
Carcinogenic in mice
-------------------------------------------------------------------------------------
870.4300 Combined Chronic/ 0, 50 (males), 100 NOAEL is 200 ppm
carcinogenicity (males),200, 1,000, (equivalent to 7.32/8.92mg/
(rats) or 5,000 (females) kg/day in males/females)
ppm (0/0, 1.84,3.68, LOAEL is 1,000 ppm
7.32/8.92, 36.5/44.1, (equivalent to 36.5/44.1mg/
and 219 mg/kg/day [M/ kg/day in males/females)
F] based ondecreased body
weights and body weight
gains,and increased
incidences of keratitis in
malesand striated muscle
fiber atrophy in females
At the high dose there was
an incidence (12%)of
nasolacrimal duct squamous
cell carcinomasslightly
outside the historical
control range (0-10%) in
male rats. A correlation
between theincidence of
inflammation and the
fluctuatingincidence of
nasal tumors was made
acrossdose groups. EPA did
not consider
thenasolacrimal duct
tumors to be treatment-
related
Female rats had a
significant increasing
trendin nasolacrimal duct
squamous cell carcinomasat
<0.05, and at the high
dose was slightlyabove the
historical control mean
(0.8%) andrange (0-4%).
EPA considered the
nasolacrimal duct
squamouscell carcinomas to
be possibly treatment
related, but that a
clearassociation with
treatment could not be
made
-------------------------------------------------------------------------------------
870.5100 Bacterial reverse 61.7 to 5,000 [mu]g/ Negative
mutation plate +/-S9
-------------------------------------------------------------------------------------
870.5100 Bacterial system, 33 to 5,000 [mu]g/ Negative for metabolite
mammalian plate +/- S9 TFNA
activationgene
mutation
-------------------------------------------------------------------------------------
870.5100 Bacterial system, 33 to 5,000 ug/plate +/ Negative for metabolite
mammalian - S9 TFNA-AM
activationgene
mutation
-------------------------------------------------------------------------------------
870.5100 Bacterial system, 33 to 5,000 ug/plate +/ Negative for metabolite
mammalian - S9 TFNG-AM
activationgene
mutation
-------------------------------------------------------------------------------------
870.5100 Bacterial system, 33 to 5,000 [mu]g/ Negative for metabolite
mammalian plate +/- S9 TFNA-OH
activationgene
mutation
-------------------------------------------------------------------------------------
870.5100 Bacterial 5 to 5000 ug/plate +/- Negative for metabolite
system,mammalian S9 TFNG
activation gene
mutation
-------------------------------------------------------------------------------------
[[Page 51609]]
870.5300 In vitro mammalian 28.3 to 2,290 [mu]g/mL Negative
cellgene mutation initialtest, and 143
to 2,290[mu]g/mL
repeat
-------------------------------------------------------------------------------------
870.5375 In vitro Cytogenetics 573, 1145 and 2290 Negative
[mu]g/mL
-------------------------------------------------------------------------------------
870.5395 In vivo Twice orally by Negative
cytogenetic(micronucl intragastricgavage at
eus) test in mice doses of 250, 500and
1,000 mg/kg/day
formales and 125, 250
and 500mg/kg/day for
females
-------------------------------------------------------------------------------------
Non-guideline Other genotoxicity, in Single doses of 375, Was not positive for
vivo Comet assay 750 and 1,500 mg/kg nuclear migration up
to1,500 mg/kg
-------------------------------------------------------------------------------------
Non-guideline Unscheduled DNA Once orally at 600 and Is not genotoxic in
synthesis 2,000 mg/kg hepatocytes from treated
rats
-------------------------------------------------------------------------------------
870.6200 Acute 0, 100, 300, 600 NOAEL is 600 mg/kg in males
neurotoxicityscreenin (males), or 1,000 mg/ and 300 mg/kgin females
g battery (rats) kg/day LOAEL is 1,000 mg/kg based
on mortality andsigns of
toxicity (decreased motor
activity,tremors, impaired
respiration, and
impairedgait) in males
This acute neurotoxicity
study is
unacceptablebecause
interval motor activity
data were notprovided as
specified according to
guidelines,FOB handling
and open-field
observationswere
incomplete, and positive
data providedwere from a
lab other than the
performing labfor this
study. This study is not
required forthis risk
assessment and additional
informationis not required
-------------------------------------------------------------------------------------
870.6200 Subchronic 0, 200, 1000, or NOAEL is 200/1,000 ppm
neurotoxicity 10,000 ppm(0/0, 13/ (equivalent to 13/81mg/kg/
screeningbattery 16, 67/81, or625/722 day [M/F]
(rats) mg/kg/day [M/F] LOAEL is 1,000/10,000 ppm
(equivalent to67/722 mg/kg/
day [M/F] based on
decreasedmotor activity,
rearing, and foot splay
inmales, decreased body
weights, body weightgains,
and food consumption in
males andfemales
-------------------------------------------------------------------------------------
870.7485 Metabolism Pilot excretion study, IKI-220 (flonicamid) was
andpharmacokinetics singleoral dose 0.85 rapidly absorbed
(rats) or 21 mg/kgand pilot andexcreted with no
pharmacokineticstudy, apparent differences
single oral dose of betweenthe sexes. By 48
2or 50 mg/kg hours after treatment,
93%of the administered
dose had been
eliminatedand by 168 hours
~96% was eliminated.
Theprimary route of
elimination was the
urine,accounting for ~90%
of the dose. The feces
oftreated rats accounted
for ~5% of theadministered
dose, with no significant
amountsof radiolabel
detected in expired air of
eithersex. After 168 hours
of a single high or
lowdose of the test
material, <3% of
theradioactivity was
recovered in the carcass
and<0.05% in the blood,
irrespective of dose orsex
The pharmacokinetic
parameters were
alsosimilar between the
dose levels (2 and 50mg/
kg) and sexes. The
radiolabel was
rapidlyabsorbed and
excreted. The apparent
plasmahalf-life
(T[frac1s2]) was 4.8-6.0
hours and theelimination
followed first order
kinetics. Thetime of
maximum plasma
concentration(Tmax) for
individual animals ranged
from0.25 to 1 hour after
treatment (with a mean
foreach group of 0.3-0.6
hours)
-------------------------------------------------------------------------------------
[[Page 51610]]
870.7485 Metabolism and 2 or 400 mg/kg Appears that the overall
pharmacokinetics recovery ofradioactive
(rats) dose from all group was 94-
99% by168 hours post-dose.
Absorption was rapidand
extensive, detected in
plasma within 10minutes of
dosing, with maximum
plasmaconcentrations
within 24-54 minutes. By
168hours post-dose, total
urinary excretion was72-
78%, cage rinse was 10-
21%, and fecalexcretion
was 4-7% dose. Parent (IKI-
220)(flonicamid) and 9
metabolites accounted
for80-94% of the dose for
all groups. Parent
wasdetected primarily in
the urine, 46-73% of
thedose in excreta in all
groups. The
primarymetabolite was 4-
trifluoromethylnicotinamid
e(TFNA-AM), 18-27% dose in
all dose groups,along with
minor amounts of TFNA-AM N-
oxide (1-4% dose).Other
metabolites in urine and
feces were detected atless
than or equal to 2.5% of
the dose.IKI-220
(flonicamid) was excreted
primarily unchangedin the
urine, but
biotransformation of IKI-
220(flonicamid) in rats
included nitrile
hydrolysis,N-oxidation,
hydroxylation of the
pyridine ring and
amidehydrolysis
----------------------------------------------------------------------------------------------------------------
B. Toxicological Endpoints
For hazards that have a threshold below which there is no
appreciable risk, the dose at which no adverse effects are observed
(the NOAEL) from the toxicology study identified as appropriate for use
in risk assessment is used to estimate the toxicological level of
concern (LOC). However, the lowest dose at which adverse effects of
concern are identified (the LOAEL) is sometimes used for risk
assessment if no NOAEL was achieved in the toxicology study selected.
An uncertainty factor (UF) is applied to reflect uncertainties inherent
in the extrapolation from laboratory animal data to humans and in the
variations in sensitivity among members of the human population as well
as other unknowns. An UF of 100 is routinely used, 10X to account for
interspecies differences and 10X for intraspecies differences.
Three other types of safety or uncertainty factors may be used:
``Traditional uncertainty factors;'' the ``special FQPA safety
factor;'' and the ``default FQPA safety factor'' By the term
``traditional uncertainty factor,'' EPA is referring to those
additional factors used prior to FQPA passage to account for database
deficiencies. These traditional uncertainty factors have been
incorporated by the FQPA into the additional safety factor for the
protection of infants and children. The term ``Special FQPA safety
factor refers to those safety factors that are deemed necessary for the
protection of infants and children, primarily as a result of the
FQPA.'' The ``default FQPA safety factor'' is the additional 10X safety
factor that is mandated by the statute unless it is decided that there
are reliable data to choose a different additional factor (potentially
a traditional uncertainty factor or a special FQPA safety factor).
For dietary risk assessment (other than cancer) the Agency uses the
UF to calculate an acute or chronic reference dose (acute RfD or
chronic RfD) where the RfD is equal to the NOAEL divided by an UF of
100 to account for interspecies and intraspecies differences and any
traditional uncertainty factors deemed appropriate (RfD = NOAEL/UF).
Where a special FQPA safety factor or the default FQPA safety factor is
used, this additional safety factor is applied to the RfD by dividing
the RfD by such additional factor. The acute or chronic Population
Adjusted Dose (aPAD or cPAD) is a modification of the RfD to
accommodate this type of safety factor.
For non-dietary risk assessments (other than cancer) the UF is used
to determine the LOC. For example, when 100 is the appropriate UF (10X
to account for interspecies differences, and 10X for intraspecies
differences) the LOC is 100. To estimate risk, a ratio of the NOAEL to
exposure (margin of exposure (MOE) = NOAEL/exposure) is calculated and
compared to the LOC.
A summary of the toxicological dose and endpoints for flonicamid
used for human risk assessment is shown in Table 2 of this unit:
Table 2.--Toxicological Doses and Endpoints for Flonicamid Human Health Risk Assessments
----------------------------------------------------------------------------------------------------------------
Special FQPA SF* and
Exposure Scenario Dose Used in Risk Level of Concern for Study and Toxicological
Assessment, UF Risk Assessment Effects
----------------------------------------------------------------------------------------------------------------
Acute dietary None FQPA SF = NA Quantitative risk
aPAD = NA............. assessment is notrequired
since there are no acute
dietarytoxicity concerns
-------------------------------------------------------------------------------------
[[Page 51611]]
Chronic dietary NOAEL = 3.7 mg/kg/day FQPA SF = 1 2-Generation Reproduction
UF = 100.............. aPAD = chronic RfD/ rat
Chronic RfD = 0.04mg/ FQPA SF= 0.04 mg/kg/ Parental
kg/day. day. LOAEL = 22 mg/kg/day
basedon increased kidney
weights, kidney hyaline
deposition, increased
blood serum LH (F1
females)
-------------------------------------------------------------------------------------
Cancer Suggestive evidence of carcinogenic potential
----------------------------------------------------------------------------------------------------------------
UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL =
lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference
dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable
C. Exposure Assessment
1. Dietary exposure from food and feed uses. Tolerances are being
proposed for the combined residues of flonicamid and its metabolites,
in or on a variety of raw agricultural commodities. Risk assessments
were conducted by EPA to assess dietary exposures from flonicamid and
its metabolites in food as follows:
i. Acute exposure. Quantitative acute dietary exposure and risk
assessments are performed for a food-use pesticide, if a toxicological
study has indicated the possibility of an effect of concern occurring
as a result of a 1-day or single exposure. No such effects were
identified in the toxicological s
