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Adverse
Effects
ACTIVITY:
Insecticide
(pyridinecarboxamide)
CAS Name:
N-(cyanomethyl)-4-(trifluoromethyl)-3-pyridinecarboxamide
Structure:
US
Federal Register |
Date
published |
Docket
Control No. |
Brief
review |
June 27, 2007 |
EPA-HQ-OPP-2007-0338 |
IR-4. Pesticide
Petition. PP 6E7081. Proposal to establish a tolerance
for combined residues of the insecticide flonicamid and its
metabolites TFNA [4-trifluoromethylnicotinic acid], TFNA-AM
[4-trifluoromethylnicotinamide], TFNG [N-(4-trifluoromethylnicotinoyl)glycine]
in or on food commodities:
Brassica, leafy greens (subgroup
5B)
This subgroup includes 8 commodities.
broccoli raab • cabbage, chinese bok choy •
collards • kale • mizuna • mustard
greens • mustard spinach • rape greens
|
16.0 ppm |
hop |
7.0 ppm |
okra |
0.4 ppm |
radish, tops |
16.0 ppm |
turnip greens |
16.0 ppm |
vegetables, tuberous and corm, (subgroup
1C)
This subgroup includes
22 commodities.
arracacha • arrowroot • artichoke, chinese
• artichoke, jerusalem • canna, edible
• cassava • chayote root • chufa
• dasheen • ginger • leren •
potato • potato culls • potato granules
flakes • potato peel, wet • potato processed
potato waste • potato, specialty • sweet
potato • tanier • turmeric • yam
bean • yam, true
|
0.2 ppm |
Vegetables, root, except sugarbeet,
(subgroup 1B)
This subgroup includes
19 commodities.
beet, garden • burdock, edible • carrot
• carrot culls • celeriac • chervil,
turnip rooted • chicory root • ginseng
• horseradish • parsley, turnip rooted
• parsnip • radish • radish, oriental
• rutabaga • salsify • salsify,
black • salsify, spanish • skirret •
turnip
|
0.45 ppm |
Analytical methodology has been developed
to determine the residues of flonicamid and its three major
metabolites (TFNA, TFNG, and TFNA-AM) in various crops. The
residue analytical method for the majority of crops includes
an initial extraction with acetonitrile/deionized water (ACN/DI),
followed by a liquid/liquid partition with ethyl acetate.
The residue method for wheat straw is similar, except that
a C18 solid phase extraction (SPE) is added prior to the liquid/liquid
partition. The final sample solution is quantitated using
LC equipped with a reverse phase column and a triple quadruple
mass spectrometer (MS/MS). |
March
29, 2006 |
EPA-HQ-OPP-2004-0132 |
ISK
Biosciences.
Pesticide Tolerance.
FINAL RULE.
This
regulation establishes a tolerance for combined residues of
flonicamid and
its metabolites
TFNA [4-trifluoromethylnicotinic acid],
TFNA-AM [4-trifluoromethylnicotinamide]
TFNG [N-(4-trifluoromethylnicotinoyl)glycine]
in or on
Commodity |
Parts
per million |
Brassica,
head and stem, subgroup 5A
This
subgroup includes 10 commodities.
broccoli
• broccoli, cavalo • broccoli, chinese
• brussels sprout • cabbage • cabbage,
chinese mustard • cabbage, chinese napa •
cauliflower • cavalo broccolo • kohlrabi
|
1.5 |
Mustard
greens |
11 |
This Rule
refers to the Final Rule of August 31, 2005 (see below) for
• toxicological endpoints for
flonicamid used for human risk assessment
• dietary exposure from drinking water
• the nature of the toxic effects caused by flonicamid
and its metabolites as well as the no observed adverse effect
level (NOAEL), and
• the lowest observed adverse effect level (LOAEL) from
the toxicity studies.
In
that document, first-time tolerances
were approved for food and EPA stated
•
Suggestive evidence of carcinogenic potential
(Lung and Nasolacrimal
duct) |
August
31, 2005 |
OPP-2005-0217 |
ISK
Biosciences.
Pesticide tolerances.
FINAL RULE.
• First-time tolerances for food
• Cancer.
Suggestive
evidence of carcinogenic potential
(Lung and Nasolacrimal
duct)
• The FQPA Safety
Factor is reduced to 1X
• 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.
Section
180.613 is added to read as follows:
Sec. 180.613 Flonicamid; tolerances for residues.
(a) General. (1) Tolerances are established for the combined
residues of flonicamid [N-(cyanomethyl)-4-(trifluoromethyl)-3-pyridinecarboxamide]
and its metabolites
TFNA [4-trifluoromethylnicotinic acid],
TFNA-AM [4-trifluoromethylnicotinamide]
TFNG [N-(4-trifluoromethylnicotinoyl)glycine]
in or on the following raw agricultural commodities: |
Commodity |
Parts
per million |
Cotton,
gin byproducts |
6.0 |
Cotton,
hulls |
2.0 |
Cotton,
meal |
1.0 |
Cotton,
undelinted seed |
0.50 |
Fruit,
pome, group 11
This
group includes 10 commodities.
apple • apple, dried pomace • apple, juice
• apple, wet pomace • crabapple •
fruit, pome • loquat • mayhaw •
pear • pear, oriental • quince
|
0.20 |
Fruit,
stone, group 12
This
group includes 14 commodities.
apricot • cherry, sweet • cherry, tart
• fruit, stone • fruit, stone, except
plum, prune, dried • nectarine • peach
• plum • plum, chickasaw • plum,
damson • plum, japanese • plum, prune
• plum, prune, dried • plum, prune, fresh
|
0.60 |
Potato |
0.20 |
Potato,
granular/flakes |
0.40 |
Spinach
|
9.0 |
Tomato,
paste |
2.0 |
Tomato,
puree |
0.50 |
Vegetable,
cucurbit, group
This
group (group 9) includes
19 commodities.
balsam apple • balsam pear • cantaloupe
• chayote, fruit • cucumber • cucumber,
chinese • cucurbits • gherkin, west indian
• gourd, edible • melon • melon,
citron • muskmelon • pumpkin • squash
• squash, summer • squash, winter •
vegetable, cucurbit, group • watermelon •
waxgourd, chinese
|
0.40 |
Vegetable,
fruiting, group
This
group (group 8) includes
17 commodities.
chili, postharvest • eggplant • groundcherry
• pepino • pepper • pepper, bell
• pepper, nonbell • pepper, nonbell, sweet
• tomatillo • tomato • tomato, concentrated
products • tomato, dried pomace • tomato,
paste • tomato, puree • tomato, wet pomace
• vegetable, fruiting • vegetable, fruiting,
group
|
0.40 |
Vegetable,
leafy except Brassica group 4,
except spinach
This
group includes 37 commodities.
amaranth, leafy • arugula • cardoon •
celery • celery, chinese • celtuce •
chervil • chervil, fresh leaves • chrysanthemum,
edible leaved • chrysanthemum, garland •
corn salad • cress, garden • cress, upland
• dandelion, leaves • dock • endive
• fennel, florence • fennel, florence,
fresh leaves and stalk • kale, sea • lettuce,
head • lettuce, leaf • orach • orach,
leaves • parsley • parsley, leaves •
purslane, garden • purslane, winter •
radicchio • rhubarb • spinach •
spinach, chinese • spinach, new zealand •
spinach, vine • swiss chard • tampala
• vegetable, leafy • vegetable, leafy,
except brassica, group
|
4.0 |
(2)
Tolerances are established for combined
residues of flonicamid
[N-(cyanomethyl)-4-(trifluoromethyl)-3-pyridinecarboxamide],
and its metabolites
TFNA [4-trifluoromethylnicotinic acid],
TFNA-AM [4-trifluoromethylnicotinamide]
in or on the following raw agricultural commodities: |
Commodity |
Parts
per million |
Cattle,
fat |
0.02 |
Cattle,
meat |
0.05 |
Cattle,
meat byproducts |
0.08 |
Egg |
0.03 |
Goat,
fat |
0.02 |
Goat,
meat |
0.05 |
Goat,
meat byproducts |
0.08 |
Horse,
fat |
0.02 |
Horse,
meat |
0.05 |
Horse,
meat byproducts |
0.08 |
Milk |
0.02 |
Poultry,
fat |
0.02 |
Poultry,
meat byproducts |
0.02 |
Sheep,
fat |
0.02 |
Sheep,
meat |
0.05 |
Sheep,
meat by products |
0.08 |
|
July
7, 2004 |
OPP-2004-0132 |
ISK
Biosciences.
Pesticide tolerance
petition PP 4F6832; by
establishing tolerances for the combined residues of the insecticide
flonicamid (N-(cyanomethyl)-4-trifluoromethyl)-3-pridinecarboxamide
(CA) or N-cyanomethyl-4- trifluoromethylnicotinamide (IUPAC)
and its
metabolites, TFNA [4-trifluoromethylnicotinic acid,
TFNA-AM (4-
trifluoromethylnicotinamide) and TFNG
N-(4-trifluoromethylnicotinoyl)-
glycine) in or on the raw agricultural commodities:
Brassica,
head and stem, subgroup 5-A, at 1.5 ppm and
Mustard greens at 11 ppm.
•
Acute toxicity. In an acute neurotoxicity study,
the no observed adverse effect levels (NOAELs) for neurotoxicity
were 600
milligrams/kilogram (mg/kg) in males
and 1,000 mg/kg in
female highest doses tested (HDT). The systemic NOAELs
were
600 mg/kg in
males and 300 mg/kg in
females.
• Reproductive and developmental toxicity
-- A developmental toxicity study in rats resulted
in the maternal and developmental no observed effect levels
(NOELs) of 100 mg/kg/day. The maternal lowest observed effect
level (LOEL) was 500 mg/kg/day based on the treatment-related
effects observed on the liver and kidney
of the dams in the highest dose group. The
developmental LOEL was 500 mg/kg/day based on the increases
in placental weights and incidences of fetal skeletal variations
seen only at maternally toxic doses of 500 mg/kg/day.
-- In the rabbit developmental toxicity
study, the maternal and
developmental NOELs were 7.5 mg/kg/day and 25 mg/kg/day HDT,
respectively. The maternal LOEL was 25 mg/kg/day based on
decreased body weights and food consumption
...
-- In the multigeneration rat reproduction
study, the NOAEL was 300 ppm for both parental animals
(13.5-32.8 and 16.3-67.0 mg/kg/day, respectively, for males
and females) and their offspring. The effects at the highest
dose of 1,800 ppm included the following: Increased
kidney weights and gross and histopathological alterations
in the kidney. Findings noted in the top dose females
included delayed vaginal opening and
increased liver, kidney and spleen weights in the F1
generation and reduced ovary and adrenal
weights in the parental generation and decreased
uterine weights in the F1 female weanlings. There was
an increase in the follicle stimulating
hormone (FSH) and luteinizing hormone (LH) levels in
F1 females tested for these endpoints.
•
Subchronic toxicity.
-- In a 90-day rat feeding study
the NOAEL was established at 200 ppm
(12.11 mg/kg/day) for males and 1,000 ppm (72.3 mg/kg/day)
for females. The NOAELs were based on
effects on hematology, triglycerides, and pathology in the
liver and kidney.
-- In a 13-week mouse study,
the NOAEL was 100 ppm (15.25 mg/kg/day in males and 20.1 mg/kg/day
in females). The LOAEL is 1,000 ppm (153.9 mg/kg/day in males
and 191.5 mg/kg/day in females) based
on hematology effects and changes in glucose, creatinine,
bilirubin, sodium, chloride and potassium levels, increased
liver and spleen weights and histopathology findings in the
bone marrow, spleen and kidney.
-- In a subchronic toxicity study in
dogs with capsule administration, the NOAEL was
20 mg/kg/day based on findings of severe toxicity at a dose
exceeding the maximum tolerated dose; symptoms included collapse,
prostration and convulsions leading to early sacrifice
at the LOAEL of 50 mg/kg/day.
-- In a subchronic neurotoxicity study
in rats, the NOAEL for dietary
administration was 1,000 ppm (67 mg/kg/day in males and 81
mg/kg/ day in females) for
systemic toxicity based on body weight and food
consumption effects.
•
Chronic
toxicity.
--
In the chronic dog study with
administration via using capsules, the NOEL was 8 mg/kg/day.
The LOAEL was 20 mg/kg/
day based on reduced
body weights in females and effects on the
circulating red blood cells.
• In a rat 24-month combined chronic
and oncogenicity study,
flonicamid technical was not carcinogenic in rats.
The NOAEL was 200
ppm (7.32 mg/kg/day) for males
and 1,000 ppm (44.1 mg/kg/day) for
females. The LOAEL was 1,000 ppm for males and 5,000
ppm for females based on histopathology
in the kidney, hematology effects, hepatic effects including
changes in biochemical parameters, increased organ weights,
and histopathological changes. Atrophy of striated muscle
fibers, cataract and retinal atrophy observed in the high
dose females were considered to be due to acceleration of
spontaneous age-related lesions.
-- In the 18-month mouse study,
effects were observed in the lung,
liver, spleen and bone marrow at 250
ppm or higher. Findings
included
centrilobular hepatocellular hypertrophy, extramedullary hematopoiesis
and pigment deposition in the spleen and decreased cellularity
(hypocellularity) in the bone marrow. There
were statistically
significant increases
in the incidence of alveolar/bronchiolar adenomas
in both sexes of treated groups with hyperplasia/hypertrophy
of
epithelial cells in terminal bronchioles. There was a statistically
significant increase in the incidence of alveolar/bronchiolar
carcinomas in males at 750 ppm and 2,250 ppm and in females
at 2,250
ppm only. Mechanism-of-action
studies have indicated that
the lung effects are unique to the mouse and are not likely
to
translate to other species including the rat.
-- A second 18-month mouse
study was conducted in CD-1 mice at
dose levels ranging from 10 to 250 ppm to establish a NOAEL
for hyperplasia/hypertrophy of epithelial cells in terminal
bronchioles and for the incidence of alveolar/bronchiolar
adenomas and carcinomas in both sexes. There
was a statistically significant
increase in the incidence of alveolar/bronchiolar
adenomas in males
at 250 ppm. In females, there was no statistically
significant increase in the incidence of pulmonary neoplastic
lesions at any dose level. The incidence
of hyperplasia/hypertrophy of epithelial cells lining the
terminal bronchioles of the lungs was
statistically increased at 250 ppm in both
sexes. |
June
1, 2004 |
OPP-2004-0153 |
ISK
and FMC. Pesticide
Product Registrations; Conditional Approval.
This notice announces Agency approval of applications
submitted by ISK Biosciences Corporation and FMC Corporation,
to conditionally register the pesticide products Technical
Flonicamid Insecticide
and F1785 GH 50 WG Insecticide containing
a new active ingredient not included in any previously registered
products.
-- A paper copy of the fact sheet, which provides more detail
on this registration, may be obtained from the National Technical
Information Service (NTIS), 5285 Port Royal Rd., Springfield,
VA 22161.
-- A conditional registration may be granted
under section 3(c)(7)(C)
of FIFRA for a new active ingredient where certain data are
lacking, on
condition that such data are received by the end of the conditional
registration period and do not meet or exceed the risk criteria
set
forth in 40 CFR 154.7; that use of the pesticide during the
conditional
registration period will not cause unreasonable adverse effects;
and
that use of the pesticide is in the public interest. The Agency
has
considered the available data on the risks associated with the
proposed
use of flonicamid, and information on social, economic, and
environmental benefits to be derived from such use. Specifically,
the
Agency has considered the nature and its pattern of use, application
methods and rates, and level and extent of potential exposure.
Based on
these reviews, the Agency was able to make basic health and
safety
determinations which show that use of flonicamid during the
period of
conditional registration will not cause any unreasonable adverse
effect
on the environment, and that use of the pesticide is in the
public
interest. |
May
28, 2003 |
OPP-2003-
0174 |
ISK
and FMC -
Pesticide Products;
Registration Applications.
-- File
Symbol: 71512-O. Applicant: ISK Biosciences
Corporation 7470 Auburn Road, Suite A, Concord, OH
44077. Product Name: Flonicamid 50 WG.
Insecticide. Active ingredient: Flonicamid
at 50%. Proposed classification/Use: None. For
use on potatoes, pome fruit, cotton, stone fruit, fruiting
vegetables, cucurbits, and leafy vegetables.
-- File Symbol: 279-GETT. Applicant: FMC
Corporation 1735 Market Street, Philadelphia, PA 19103.
Product Name: F1785 N 50 WG. Insecticide. Active ingredient:
Flonicamid at 50%. Proposed classification/Use: None. For
ornamental uses in nurseries and landscapes. |
May
23, 2003 |
OPP-2003-0172 |
ISK
BIOSCIENCES
- Petition for pesticide
tolerances;
--
for the combined residues of the insecticide
flonicamid 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 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, 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
and its metabolite TFNA-AM,
(4-trifluoromethylnicotinamide)
in animal tissues and poultry meat byproducts:
|
--
FAT: Cattle,Goat, Hog, Horse, Poultry, Sheep, at 0.01
ppm;
-- MEAT: Cattle, Goat, Horse, Sheep, at 0.04 ppm;
-- MEAT: Hog, Poultry, at 0.01 ppm;
-- eggs, at 0.02 ppm;
-- milk, at 0.02 ppm;
-- poultry, meat byproducts, at 0.01 ppm. |
--
by establishing tolerances for the combined residues of
the insecticide flonicamid
and its metabolites TFNA
and TFNA-AM in the animal
meat byproducts: |
--
MBYP: Cattle,Goat, Horse, Sheep, at 0.06 ppm;
-- Hog, meat byproducts, at 0.01 ppm. |
--
In an acute neurotoxicity study, the no observed adverse effect
levels (NOAELs) for neurotoxicity were 600 milligrams/kilogram
(mg/kg) in males
and 1,000 mg/kg in female
(highest doses tested). The systemic NOAELs were 600 mg/kg
in males
and 300 mg/kg in females.
-- In a 90-day rat feeding study the NOAEL was established
at 200 ppm (12.11 mg/kg/day) for males
and 1,000 ppm (72.3 mg/kg/day) for females. The NOAELs were
based on effects on
hematology, triglycerides, and pathology
in the liver and kidney.
-- In a 13-week mouse study,
the NOAEL was 100 ppm (15.25 mg/kg/day in males
and 20.1 mg/kg/day in females). The LOAEL is 1,000 ppm (153.9
mg/kg/day in males and 191.5
mg/kg/day in females) based on hematology
effects and changes in glucose,
creatinine, bilirubin, sodium, chloride and potassium levels,
increased liver and spleen weights
and histopathology findings in the bone marrow, spleen
and kidney.
-- In a rat 24-month combined chronic and oncogenicity study,
flonicamid technical was not carcinogenic in rats. The NOAEL
was 200 ppm (7.32 mg/kg/day) for males
and 1,000 ppm (44.1 mg/kg/day) for females. The LOAEL was
1,000 ppm for males and 5,000
ppm for females based on histopathology
in the kidney, hematology effects,
hepatic effects including changes in biochemical parameters,
increased organ weights, and histopathological changes.
Atrophy of striated muscle fibers, cataract
and retinal atrophy observed in the high dose females were
considered to be due to acceleration of spontaneous age-related
lesions.
-- In
the 18-month mouse study, effects were observed in the
lung, liver, spleen and bone marrow at 250 ppm or higher.
Findings included, centrilobular
hepatocellular hypertrophy, extramedullary hematopoiesis and
pigment deposition in the spleen and
decreased cellularity (hypocellularity) in the bone
marrow. There were statistically
significant increases in
the incidence of alveolar/bronchiolar adenomas
in both sexes of treated groups with hyperplasia/hypertrophy
of epithelial cells in terminal bronchioles There
was a statistically significant
increase in the incidence of
alveolar/bronchiolar carcinomas in males
at
750 ppm and 2,250 ppm and in females at 2,250 ppm only.
-- Reproductive and developmental toxicity. A developmental
toxicity study in rats resulted in the maternal and developmental
no observed adverse effect levels (NOAELs) of 100 mg/kg/day.
The maternal lowest
observed adverse effect level (LOAEL) was 500 mg/kg/day based
on the treatment-related effects observed on the liver
and kidney of the dams in the highest dose group. The
developmental LOAEL was 500 mg/kg/ day based on the increases
in placental weights and incidences of fetal skeletal variations
seen only at maternally toxic doses
of 500 mg/kg/ day.
-- In the rabbit developmental toxicity study, the maternal
and developmental NOAELs were 7.5 mg/kg/day and 25 mg/kg/day
highest dose tested (HDT), respectively. The maternal LOAEL
was 25 mg/kg/day based on decreased
body weights and food consumption.
-- In the multi-generation rat reproduction study, the NOAEL
was 300 ppm for both parental animals (13.5-32.8 and 16.3-67.0
mg/kg/day, respectively, for males and females) and their
offspring. The effects at the highest dose of 1,800 ppm included
the following: increased kidney weights
and gross and histopathological alterations in the kidney.
Findings noted in the top dose females included delayed
vaginal opening and increased
liver, kidney and spleen weights in
the F1 generation and reduced ovary and
adrenal weights in the parental
generation and decreased uterine weights in
the F1 female weanlings. There
was an increase in the FSH and
LH levels in F1 females tested for these
endpoints.
-- In a subchronic toxicity study in dogs with capsule administration,
the NOAEL was 20 mg/kg/day based on findings of severe
toxicity at a dose exceeding the maximum
tolerated dose; symptoms included collapse, prostration
and convulsions leading to early sacrifice
at the LOAEL of 50 mg/kg/day.
-- Chronic toxicity. In the chronic dog study with administration
via using capsules, the NOAEL was 8 mg/kg/day. The LOAEL was
20 mg/kg/ day based on reduced body
weights in females and
effects on the circulating red blood cells.
-- In the 18-month mouse study, effects
were observed in the lung, liver,
spleen and bone marrow at 250 ppm or higher. Findings
included, centrilobular hepatocellular
hypertrophy, extramedullary hematopoiesis and
pigment deposition in the spleen and
decreased cellularity (hypocellularity) in the bone
marrow. There were statistically
significant increases in
the incidence of alveolar/bronchiolar adenomas
in both sexes of treated groups with hyperplasia/hypertrophy
of epithelial cells in terminal bronchioles.
There was a statistically significant
increase in the incidence
of alveolar/bronchiolar carcinomas in males
at 750 ppm and 2,250 ppm and in females at 2,250 ppm only.
-- Endocrine disruption. No
special studies investigating potential estrogenic or other
endocrine effects of flonicamid have been conducted.
Some suggestions of possible endocrine
effects were reported at the highest dose tested (1,800 ppm)
in the multi-generation reproduction study which showed increased
FSH and LH levels, a delay in the time to vaginal opening
in the F1 generation, and reduced ovary and adrenal weights
in the parental generation. |
July
10, 2002 |
OPP-2002-0119 |
FMC
and ISK - Registration
applications for two pesticide products:
File
Symbol: 279-GEAU. Applicant: FMC Corporation,
Agricultural Products Group, 1735 Market Street, Philadelphia,
PA 19103. Product name: F1785
GH 50 WG Insecticide. Insecticide. Active ingredient:
Flonicamid at 50%. Proposed classification/Use: None. For
greenhouse use.
File
Symbol: 71512-T. Applicant: ISK Biosciences
Corporation, 7470 Auburn Road, Suite A, Concord, OH
44077. Product name: Technical
Flonicamid Insecticide. Insecticide. Active
ingredient: Flonicamid at 98.4%. Proposed classification/Use:
None. For manufacturing use only. |
|