Return to Flonicamid
Index Page
Activity:
Insecticide
(Pyridinecarboxamide)
Structure:
Adverse
Effects:
Ataxia
Blood
Body Weight Decrease
Bone
Brain
Cancer: Lung and Nasal
acrimal duct
Convulsions
Developmental
Endocrine: Adrenal
Endocrine: Ovary
Endocrine: Sex Ratios
Endocrine: Thymus
Endocrine: Vagina
Eye
Kidney
Liver
Lung
Muscle
Neurotoxicity
Reproductive
Spleen
ISK
Biosciences is actively seeking approval for the use of
Flonicamid on several food commodities in the US.
On
April 9, 2002, EPA granted organophosphate (OP) alternative
status to ISK Biosciences and FMC's insecticide, flonicamid
(F 1785 GH), for use on ornamentals grown in indoor greenhouses.
Flonicamid is an alternative to the OP's chlorpyrifos, acephate,
dimethoate, and oxydemeton methyl; the carbamate, fenoxycarb;
and the pyrethroids, bifenthrin and fluvalinate, for use
on indoor greenhouse ornamentals to control sucking insects
(e.g. aphids, thrips, and whiteflies). Flonicamid is a systemic
insecticide that immediately suppresses the feeding of sucking
insects. It's mode of action, although unknown, appears
to be unique and should help with pest resistance management.
(USDA
Release, 4/16/02).
|
Ataxia
(click
on for all fluorinated pesticides)
CHRONIC
TOXICITY, DOG. Subchronic Oral Toxicity Study: 52964-0013; 208802;
“A 90-Day Oral Toxicity Study in Dogs with IKI-220 Technical”;
(W.E. Ridder, M. Watson; Toxicology and Pharmacology, Ricerca
LLC, Painesville, OH; Report No. 011509-1; 9/5/01); Four beagle
dogs/sex/group received 0, 3, 8, or 20 mg/kg/day of IKI-220 Technical
(lot no. 9809, purity: 98.7%) in capsules for 13 weeks. An additional
group of 4 females received 50 mg/kg/day of the test material
for the same duration. Both the males and females in the 20 mg/kg
group and the females in the 50 mg/kg group demonstrated treatment-related
signs of vomiting. Ataxia was also noted
for some of the animals in these groups....
Reference:
April 28, 2005 - Summary of toxicology data. California EPA, Department
of Pesticide Regulation, Medical Toxicology Branch.
http://www.fluorideaction.org/pesticides/flonicamid.ca.epa.2005.pdf
Blood
(click on for all fluorinated pesticides)
-- 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.
-- 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 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.
Ref:
Federal Register: May 23, 2003 (Volume 68, Number 100)] [Notices]
[Page 28218-28222]. Flonicamid; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food.
http://www.fluorideaction.org/pesticides/Flonicamid.FR.May23.2003.htm
-- 90-Day
oral toxicity rodents (rats). 28-day range-finding. NOAEL
is 100 ppm (7.47 mg/kg/day) for males and 1,000 ppm (81.9 mg/kg/day)
for females.
LOAELs were 500 ppm (36.45 mg/kg/day) for males based on changes
in the kidney (hyaline deposition) and 5,000
ppm for females (372.6mg/kg/day) based on kidney (hyaline deposition),
liver changes (centrilobularhypertrophy),
hematological effects (anemia)
and clinical chemistry (increased cholesterol)
--
90-Day oral toxicity (nonrodents- dogs).
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 reticulocytes
counts in females), increased adrenal
weights in males, decreased thymus gland weights in males, and
increased kidney tubular vacuolation in females at study termination
-- Chronic
toxicity (dogs). 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.
-- Carcinogenicity
(mice). NOAEL
was not established. LOAEL is 250 ppm (equivalent to 29/38mg/kg/
day [M/F]), based on minimal to moderate centrilobular
hepatocellular hypertrophy, minimal to severe
extramedullary hematopoiesis, minimal to moderate
pigment deposition in the sternal bone marrow, and
increased incidence of tissue masses/nodules in the lungs in the
males, and minimal to moderate decreased
cellularity in the femoral bone marrow and hyperplasia/hypertrophy
of the epithelial cells of the terminal bronchioles of the females.
At the doses tested, the carcinogenic potential of IKI-220 (flonicamid)
is positive at 250 ppm in males and females based on the increased
incidence of alveolar/bronchiolar adenomas, carcinomas, and combined
adenomas/carcinomas. Dosing was considered adequate based on increased
incidence of tissue masses/nodules in the lungs and microscopic
findings in the liver, spleen, bone marrow, and lungs. However,
data were provided suggesting this effect is specific to sensitive
strains of mice. Carcinogenic in
mice.
--
Chronic dietary.
2-Generation Reproduction
rat. Parental LOAEL = 22 mg/kg/day based on increased kidney
weights, kidney hyaline deposition, increased
blood serum LH (F1 females)
Ref:
August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule.
Federal Register.
http://www.fluoridealert.org/pesticides/flonicamid.fr.aug.31.2005.html
Brain
(click on for all fluorinated pesticides)
“IKI-220
Technical: Combined Chronic Toxicity and Carcinogenciity Study
in Rats,” (M. Kuwahara; IET 98-0142; 8/16/04). ... This
volume contains discussion of questions concerning the bone/bone
marrow effects and cerebellar granular tumors
observed in the original study.... In this document the U.S. EPA
also questioned whether the cerebellar granular
cell tumors (observed histopathologically) were treatment related.
It was reported that GCT involving the meninges of the brain is
the most frequently reported benign neoplasm occurring in many
strains of rat. Historical controls obtained from 38 2-year studies
in Wistar rats (1981 - 2000) at RCC Ltd., Switzerland showed a
range of 0 - 7.14% (M) and 0 - 4.35% (F). The report concluded
that since GCTs of meninges are observed only microscopically,
small ones may be included in the sections examined only by chance.
The tumors do not metastasize and are possibly underreported.
Thus their true incidence is not really known. The report considered
these observations to be incidental and unrelated to treatment.
DPR considers the GCTs to be marginally
increased in females when compared to historical controls but
essentially equivocal. (Silva, 4/11/05)
Reference:
April 28, 2005 - Summary of toxicology data. California EPA, Department
of Pesticide Regulation, Medical Toxicology Branch.
http://www.fluorideaction.org/pesticides/flonicamid.ca.epa.2005.pdf
Body
Weight Decrease
(click on for all fluorinated pesticides)
-- 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. No adverse effects on
the fetuses were observed at the highest dose.
-- 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.
Ref:
Federal Register: May 23, 2003 (Volume 68, Number 100)] [Notices]
[Page 28218-28222]. Flonicamid; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food.
http://www.fluorideaction.org/pesticides/Flonicamid.FR.May23.2003.htm
--
Combined Chronic/ carcinogenicity (rats).
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 on decreased body weights and body
weight gains, and increased incidences
of keratitis in males and striated muscle
fiber atrophy in females. At the high dose there was an incidence
(12%)of nasolacrimal duct squamous cell carcinomas
slightly outside the historical control
range (0-10%) in male rats. A correlation between the incidence
of inflammation and the fluctuating incidence of nasal tumors
was made across dose groups. EPA did not consider the nasolacrimal
duct tumors to be treatment-related. Female rats had a significant
increasing trend in nasolacrimal duct squamous cell carcinomas
at < 0.05, and at the high dose was slightly above the historical
control mean (0.8%) and range (0-4%). EPA considered the nasolacrimal
duct squamous cell carcinomas to be possibly treatment related,
but that a clear association with treatment could not be made.
--
Subchronic
neurotoxicity screening battery (rats).
NOAEL is 200/1,000 ppm (equivalent to 13/81mg/kg/day [M/F].
LOAEL is 1,000/10,000 ppm (equivalent to 67/722 mg/kg/day [M/F]
based on decreased motor activity, rearing,
and foot splay in males, decreased body
weights, body weight gains,
and food consumption in males and females.
Ref:
August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule.
Federal Register.
http://www.fluoridealert.org/pesticides/flonicamid.fr.aug.31.2005.html
--
CHRONIC TOXICITY, DOG. Subchronic Oral Toxicity Study: 52964-0013;
208802; “A 90-Day Oral Toxicity Study in Dogs with IKI-220
Technical”; (W.E. Ridder, M. Watson; Toxicology and Pharmacology,
Ricerca LLC, Painesville, OH; Report No. 011509-1; 9/5/01); Four
beagle dogs/sex/group received 0, 3, 8, or 20 mg/kg/day of IKI-220
Technical (lot no. 9809, purity: 98.7%) in capsules for 13 weeks.
An additional group of 4 females received 50 mg/kg/day of the
test material for the same duration. Both the males and females
in the 20 mg/kg group and the females in the 50 mg/kg group demonstrated
treatment-related signs of vomiting. Ataxia was also noted for
some of the animals in these groups. Incidences of diarrhea and
excessive salivation were observed for the females in the high
dose group. The females in the high dose group were so affected
as to refuse to eat the certified dog chow. One
female in the 50 mg/kg was euthanized due to severe anorexia on
study day 20. Food consumption was
significantly lower for the females in the 50 mg/kg group (p<0.05).
...
-- Definitive Study: 52964 - 0064 216038 “A 52-Week Oral
Toxicity Study in Dogs With IKI-220 Technical, Amended Report,”
(Ridder, W.E., Watson, M.; Toxicology and Pharmacology, Ricerca
Biosciences, LLC, Painesville, OH; Document #: 012075-1-1; 11/15/02
(amended report 1/2/03)). Flonicamid technical (IKI-220, N-cyanomethyl-4-trifluoromethyl
nicotinamide: 98.7% pure) was administered by capsules to beagle
dogs (6/sex/dose) at 0 (capsule only), 3, 8 and 20 mg/kg/day
for 1 year (365 consecutive days). NOEL
= 8 mg/kg/day (Body weight gains were significantly decreased
in females at 20 mg/kg/day during weeks 2-4.
Although the body weight gains were not statistically different
from controls for the remainder of the study, the body
weight gain decrease was 30% at termination for females at 20
mg/kg/day (4.90 kg for controls vs. 3.41 kg at 20 mg/kg/day).
Males at 9 and 12 months had statistically significantly increased
MCV and MCH and at 12 months increased reticulocytes (%) at 20
mg/kg/day. NOTE that at pretest males at 20 mg/kg/day had a statistically
significantly decreased RBC, HGB and HCT. Throughout the test,
however these parameters were comparable to controls.
** 52964
- 0061 216035 “IKI-220 Technical: A Teratogenicity Study
in Rabbits,” (Takahashi, K.; Institute of Environmental
Toxicology, Ibaraki, Japan; Laboratory Study #: IET 00-0025; 2/21/02
& final report amended 11/28/02). Flonicamid technical (98.7%
pure) was administered via oral gavage to artificially inseminated
SPF Japanese White rabbits (Kbl:JW) (25/dose) at 0 (1% sodium
carboxymethyl cellulose), 2.5, 7.5 and 25 mg/kg/day during gestation
days 6 through 27. Maternal NOEL = 7.5 mg/kg/day
(Body weight gains at 25 mg/kg/day were statistically significantly
decreased during the interval of GD 6 - 28 (throughout treatment).
At 25 mg/kg/day there was statistically significantly decreased
food consumption on GD 9 - 12, 12 - 15, 15 - 18 and 18 - 21. Developmental
NOEL = 25 mg/kg/day (There were no treatment-related effects at
any dose.) Acceptable. No adverse effect. (Silva, 2/11/05)
Reference:
April 28, 2005 - Summary of toxicology data. California EPA, Department
of Pesticide Regulation, Medical Toxicology Branch.
http://www.fluorideaction.org/pesticides/flonicamid.ca.epa.2005.pdf
Bone
(click
on for all fluorinated pesticides)
-- 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 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 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...
Ref:
Federal Register: May 23, 2003 (Volume 68, Number 100)] [Notices]
[Page 28218-28222]. Flonicamid; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food.
http://www.fluorideaction.org/pesticides/Flonicamid.FR.May23.2003.htm
-- Developmental.
NOAEL is 100 mg/kg bw/day. LOAEL is 500 mg/kg bw/day, based on
the increased incidence of cervical rib
-- Carcinogenicity
(mice). NOAEL
was not established. LOAEL is 250 ppm (equivalent to 29/38mg/kg/
day [M/F]), based on minimal to moderate centrilobular
hepatocellular hypertrophy, minimal to severe extramedullary hematopoiesis,
minimal to moderate pigment deposition
in the sternal bone marrow, and increased
incidence of tissue masses/nodules in the lungs in the males,
and minimal to moderate decreased
cellularity in the femoral bone marrow and hyperplasia/hypertrophy
of the epithelial cells of the terminal bronchioles of the females
At the doses tested, the carcinogenic potential of IKI-220 (flonicamid)
is positive at 250 ppm in males and females based on the increased
incidence of alveolar/bronchiolar adenomas, carcinomas, and combined
adenomas/carcinomas. Dosing was considered adequate based
on increased incidence of tissue masses/nodules in the lungs and
microscopic findings in the liver, spleen, bone
marrow, and lungs. However, data were provided suggesting
this effect is specific to sensitive strains of mice. Carcinogenic
in mice.
-- Aggregate cancer risk for U.S.
population... 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 non-neoplastic lesions.
Ref:
August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule.
Federal Register.
http://www.fluoridealert.org/pesticides/flonicamid.fr.aug.31.2005.html
“IKI-220 Technical: Combined Chronic Toxicity and Carcinogenciity
Study in Rats,” (M. Kuwahara; IET 98-0142; 8/16/04). This
volume contains discussion of questions concerning the bone/bone
marrow effects and cerebellar granular tumors observed in the
original study. This document was a response to U.S. EPA
questions about an apparent increase incidence in hematopoiesis
in bone marrow (femur). This effect was observed primarily as
a compensatory response for a decrease in blood cell components
due to spontaneous lesions at other sites and observed mainly
in animals receiving unscheduled necropsies. Tables 1 and 2 (pages
10 - 11) in the volume list the causes or probable causes for
increased hematopoiesis in the bone marrow (femur). The
U.S. EPA reviewer asked whether fluorine from flonicamid could
cause the bone effects. Metabolism studies have shown that free
fluorine is not released and therefore the bone effects were not
related to free fluorine. ... (Silva, 4/11/05)
Reference:
April 28, 2005 - Summary of toxicology data. California EPA, Department
of Pesticide Regulation, Medical Toxicology Branch.
http://www.fluorideaction.org/pesticides/flonicamid.ca.epa.2005.pdf
Cancer
(click
on for all fluorinated pesticides)
Suggestive
Evidence of Carcinogenicity, but not sufficient to assess human
carcinogenic potential. Nasal
lacrimal duct squamous cell carcinomas possibly
treatment-related in female Wistar rats; Mitogenesis MOA accepted
for lung tumors in CD-1 mice (both
sexes).
Ref: April
26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the
Office of Pesticide Programs. From: Jess Rowland, Chief Science
Information Management Branch Health Effect Division (7509C) Office
of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf
--
Cancer. Suggestive
evidence of carcinogenic potential.
-- Carcinogenicity (mice).
NOAEL was not established. LOAEL is 250 ppm (equivalent to 29/38mg/kg/
day [M/F]), based on minimal to moderate centrilobular
hepatocellular hypertrophy, minimal
to severe extramedullary hematopoiesis, minimal to moderate
pigment deposition in the sternal bone marrow,
and increased incidence of tissue masses/nodules
in the lungs in the males, and minimal
to moderate decreased cellularity in the femoral bone marrow and
hyperplasia/hypertrophy of the epithelial
cells of the terminal bronchioles of the females At the doses
tested, the carcinogenic potential of IKI-220 (flonicamid) is
positive at 250 ppm in males and females based on the increased
incidence of alveolar/bronchiolar adenomas, carcinomas, and combined
adenomas/carcinomas. Dosing was considered adequate based
on increased incidence of tissue masses/nodules in the lungs and
microscopic findings in the liver, spleen, bone marrow, and lungs.
However, data were provided suggesting this effect is specific
to sensitive strains of mice. Carcinogenic
in mice.
--
Combined Chronic/ carcinogenicity (rats).
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 on decreased body weights and body
weight gains,and increased incidences of keratitis in males and
striated muscle fiber atrophy in females. At the high dose
there was an incidence (12%)of nasolacrimal
duct* squamous cell carcinomas
slightly outside the historical control
range (0-10%) in male rats. A correlation between the incidence
of inflammation and the fluctuating incidence of nasal tumors
was made across dose groups. EPA did not consider the nasolacrimal
duct tumors to be treatment-related. Female rats had a significant
increasing trend in nasolacrimal duct squamous cell carcinomas
at < 0.05, and at the high dose was slightly above the
historical control mean (0.8%) and range (0-4%). EPA
considered the nasolacrimal duct squamous cell carcinomas to be
possibly treatment related, but that a clear association with
treatment could not be made.
-- 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 non-neoplastic 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.
Ref:
August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule.
Federal Register.
http://www.fluoridealert.org/pesticides/flonicamid.fr.aug.31.2005.html
-- In the 18-month
mouse study... 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. These effects in the lungs of mice
were not life threatening as most of effects were observed at
the terminal sacrifice and there was no effect of treatment on
mortality in the study. A NOAEL could not be determined from the
dose levels administered. 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. Flonicamid technical
was not carcinogenic in the rat.
Ref:
Federal Register: May 23, 2003 (Volume 68, Number 100)] [Notices]
[Page 28218-28222]. Flonicamid; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food.
http://www.fluorideaction.org/pesticides/Flonicamid.FR.May23.2003.htm
-- 52964 - 0068, 0069 & 0070 216042, 216043, 216044 “Vol
0068: Dietary Carcinogenicity of IKI-220 Technical in Mice; Vol
0069: Pathology Sub-Report (Supplemental) for Dietary Carcinogenicity
of IKI220 Technical in Mice; Vol 0070: Historical Data for Dietary
Carcinogenicity of IKI-220 Technical in Mice,” (Nagaoka,
T., Nakashima, N.; Shin Nippon Biomedical Laboratories, Ltd.,
Kagoshima, Japan; The Institute of Environmental Toxicology, Ibaraki,
Japan; 1/22/04, 3/30/04, 1/22/04 for volumes 0068, 0069 &
0070, respectively). Flonicamid technical (IKI-220: 98.7% pure)
was fed in diet to Charles River Crj:CD-1®(ICR)BR mice
(50/sex/dose) at 0, 10, 25, 80 and 250 ppm (equivalent
doses: M = 1.20, 3.14, 10, 30.3 mg/kg/day; F = 1.42, 3.67, 11.8,
36.3 mg/kg/day) for 78 weeks. Systemic NOEL = 80 ppm (There was
an increase in lung hyperplasia and hypertrophy (both sexes) and
liver fatty change in centrilobular hepatocytes (F) at 250 ppm.
There was a statistically significant decrease in absolute kidney
weights in females at 250 ppm. There was
a statistically significant increase in lung masses--pulmonary
adenomas and carcinomas in males at 250 ppm.) Not acceptable
(There were numerous deficiencies in this study (see A., above).
There were no interim kills, nor were all target organs examined
and weighed as recommended by FIFRA Guidelines.), not upgradeable.
Possible adverse effect indicated (There
was a statistically significant increase in pulmonary adenomas
and carcinomas in males at 250 ppm. Silva, 4/29/05
-- Rationale for Regulation by Reference Dose,” (Cohen,
S.M., Hardisty, J.F., McCarty, J.D.; FMC Corporation, Agricultural
Products Group, Princeton, NJ; Document #: flonicamid 04-04, 8/31/04).
This report contains a complete discussion (along with a presentation
of summary data) on the mechanism and potential for oncogenicity
of flonicamid. All studies discussed in this report were presented
for review to DPR. Many of the potential adverse effects, primarily
regarding the incidence of nasal and lung cancer in rats and mice,
respectively, were initially noted in worksheets provided by USEPA.
Upon re-evaluation of the noted effects, the nasal cancers in
rats were found to originate in the nasal-lacrimal duct, which
is more common than the squamous cell carcinomas. The nasolacrimal
duct tumors were determined to be unilateral and not bilateral
which indicated they were spontaneous and not due to treatment.
Based on the low spontaneous incidence of these tumors in humans
versus rats, the potential for their initiation in humans after
flonicamid exposure, were negligible. Lung tumors (observed only
in mice) appeared to be due to mitogenesis, non-linear, non-genotoxic
mode of action for which a threshold dose has been established.
Historical controls were presented for all potential adverse effects.
Included also were complete discussions of all questions raised
by USEPA. This information is supplemental. No worksheet was performed
for this data volume. Silva, 2/2/05.
Reference:
April 28, 2005 - Summary of toxicology data. California EPA, Department
of Pesticide Regulation, Medical Toxicology Branch.
http://www.fluorideaction.org/pesticides/flonicamid.ca.epa.2005.pdf
*
Note: The
nasolacrimal duct carries tears from the
lacrimal sac into the nasal cavity.
Convulsions
(click
on for all fluorinated pesticides)
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.
Ref:
Federal Register. Jully 7, 2004. Flonicamid; Notice of Filing
a Pesticide Petition to Establish a Tolerance for a Certain Pesticide
Chemical in or on Food. [OPP-2004-0132; FRL-7362-5].
http://www.fluoridealert.org/pesticides/flonicamid.fr.july7.2004.htm
Developmental
(click
on for all fluorinated pesticides)
Prenatal
developmental toxicity (rats).
-- Developmental: NOAEL is 100 mg/kg
bw/day. LOAEL is 500 mg/kg bw/day, based on the increased
incidence of cervical rib
--
Maternal. NOAEL
is 100 mg/kg bw/day. LOAEL is 500 mg/kg bw/day, based on increased
liver weight, and liver
and kidney pathological changes
(hypertrophy of centrilobular hepatocytes
in liver and vacuolation of proximal tubular cell in kidneys)
Ref:
August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule.
Federal Register.
http://www.fluoridealert.org/pesticides/flonicamid.fr.aug.31.2005.html
Endocrine:
Adrenal
(click on for all fluorinated
pesticides)
--
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. These findings did
not affect the reproductive performance or survival of offspring
in the study.
-- 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. However, there were no effects on
reproductive performance or survival of the offspring in the study.
At levels that are expected to be found in the environment, flonicamid
will not cause any endocrine-related effects.
Ref:
Federal Register: May 23, 2003 (Volume 68, Number 100)] [Notices]
[Page 28218-28222]. Flonicamid; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain
Pesticide Chemical in or on Food.
http://www.fluorideaction.org/pesticides/Flonicamid.FR.May23.2003.htm
--
90-Day oral toxicity (nonrodents- dogs).
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 reticulocytes
counts in females), increased adrenal
weights in males, decreased thymus
gland weights in males, and increased
kidney tubular vacuolation in females at study termination.
Ref:
August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule.
Federal Register.
http://www.fluoridealert.org/pesticides/flonicamid.fr.aug.31.2005.html
Endocrine:
Ovary
(click on for all fluorinated
pesticides)
-- 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. These
findings did not affect the reproductive performance or survival
of offspring in the study.
-- 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. However, there were no effects on
reproductive performance or survival of the offspring in the study.
At levels that are expected to be found in the environment, flonicamid
will not cause any endocrine-related effects.
Ref:
Federal Register: May 23, 2003 (Volume 68, Number 100)] [Notices]
[Page 28218-28222]. Flonicamid; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food.
http://www.fluorideaction.org/pesticides/Flonicamid.FR.May23.2003.htm
Endocrine:
Sex Ratios (click
on for all fluorinated pesticides)
-- TERATOLOGY, RABBIT
Rangefinding Study: 52964 - 0060 216034 “IKI-220 Technical:
A Teratogenicity Study in Rabbits Preliminary Study,” (Takahashi,
K.; Institute of Environmental Toxicology, Ibaraki, Japan; Laboratory
Study #: IET 000024; 2/21/02). Flonicamid technical (98.7% pure)
was administered via oral gavage to artificially inseminated SPF
Japanese White rabbits (Kbl:JW) (6/dose)
at 0 (1% sodium carboxymethyl cellu- lose), 3, 10 and 30 mg/kg/day
during gestation days 6 through 27. Maternal NOEL = 10 mg/kg/day
(There were slight effects on body weight, body weight gain, clinical
signs, abortion (2/6 does at 30 mg/kg), food consumption, gravid
uterine weights and placental weights at 30 mg/kg/day.) Developmental
NOEL = 10 mg/kg/day (There were lowered
sex ratios, and fewer implants and live fetuses at 30 mg/kg/day.)
There were no major deficiencies in this study. It was for the
purpose of dose rangefinding for the definitive study. No adverse
effect indicated. These data are supplemental. Silva, 2/10/05
Definitive Study:
Reference:
April 28, 2005 - Summary of toxicology data. California EPA, Department
of Pesticide Regulation, Medical Toxicology Branch.
http://www.fluorideaction.org/pesticides/flonicamid.ca.epa.2005.pdf
Endocrine:
Thymus
(click
on for all fluorinated pesticides)
90-Day
oral toxicity (nonrodents- dogs).
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 reticulocytes
counts in females), increased adrenal
weights in males, decreased thymus gland
weights in males, and increased kidney tubular vacuolation
in females at study termination.
Ref:
August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule.
Federal Register.
http://www.fluoridealert.org/pesticides/flonicamid.fr.aug.31.2005.html
Endocrine:
Vagina
(click on for all fluorinated pesticides)
-- 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.
These findings did not affect the reproductive performance or
survival of offspring in the study.
-- 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. However, there
were no effects on reproductive performance or survival of the
offspring in the study. At levels that are expected to be found
in the environment, flonicamid will not cause any endocrine-related
effects.
Ref:
Federal Register: May 23, 2003 (Volume 68, Number 100)] [Notices]
[Page 28218-28222]. Flonicamid; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food.
http://www.fluorideaction.org/pesticides/Flonicamid.FR.May23.2003.htm
Eye
(click on for all fluorinated pesticides)
--
Combined Chronic/ carcinogenicity (rats).
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 on decreased body weights and body
weight gains, and increased incidences of
keratitis*
in males and striated muscle fiber
atrophy in females. At the high dose there was an incidence
(12%)of nasolacrimal duct**
squamous cell carcinomas slightly
outside the historical control range (0-10%) in male rats.
A correlation between the incidence of inflammation and the fluctuating
incidence of nasal tumors was made across dose groups. EPA did
not consider the nasolacrimal duct tumors to be treatment-related.
Female rats had a significant increasing
trend in nasolacrimal duct squamous cell carcinomas at < 0.05,
and at the high dose was slightly above the historical control
mean (0.8%) and range (0-4%). EPA considered
the nasolacrimal duct squamous cell carcinomas to be possibly
treatment related, but that a clear association with treatment
could not be made.
Ref:
August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule.
Federal Register.
http://www.fluoridealert.org/pesticides/flonicamid.fr.aug.31.2005.html
Definitions:
* Keratitis: A term used to define
a wide variety of corneal infections, irritations, and inflammations
** The
nasolacrimal duct carries tears from the
lacrimal sac into the nasal cavity.
Kidney
((click
on for all fluorinated pesticides)
-- 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...
-- 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...
-- 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.
Ref:
Federal Register: May 23, 2003 (Volume 68, Number 100)] [Notices]
[Page 28218-28222]. Flonicamid; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food.
http://www.fluorideaction.org/pesticides/Flonicamid.FR.May23.2003.htm
-- 90-Day
oral toxicity rodents (rats). 28-day range-finding. NOAEL
is 100 ppm (7.47 mg/kg/day) for males and 1,000 ppm (81.9 mg/kg/day)
for females.
LOAELs were 500 ppm (36.45 mg/kg/day) for males based on changes
in the kidney (hyaline deposition)
and 5,000 ppm for females (372.6mg/kg/day) based on kidney
(hyaline deposition), liver changes
(centrilobularhypertrophy), hematological effects (anemia)
and clinical chemistry (increased cholesterol)
--
90-Day oral toxicity (nonrodents- dogs).
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 reticulocytes
counts in females), increased adrenal
weights in males, decreased thymus gland weights in males,
and increased kidney tubular vacuolation
in females at study termination
-- Prenatal
developmental toxicity (rats).
Maternal.
NOAEL is 100 mg/kg bw/day. LOAEL is 500 mg/kg bw/day, based on
increased liver weight, and liver
and kidney pathological changes
(hypertrophy of centrilobular hepatocytes in liver and
vacuolation of proximal tubular cell in kidneys)
--
Chronic dietary.
2-Generation Reproduction
rat. Parental LOAEL = 22 mg/kg/day based on increased kidney
weights, kidney hyaline deposition,
increased blood serum LH (F1 females).
Ref:
August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule.
Federal Register.
http://www.fluoridealert.org/pesticides/flonicamid.fr.aug.31.2005.html
Liver
(click on for
all fluorinated pesticides)
-- 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 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...
-- 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...
Ref:
Federal Register: May 23, 2003 (Volume 68, Number 100)] [Notices]
[Page 28218-28222]. Flonicamid; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain
Pesticide Chemical in or on Food.
http://www.fluorideaction.org/pesticides/Flonicamid.FR.May23.2003.htm
-- 90-Day
oral toxicity rodents (rats). 28-day range-finding. NOAEL
is 100 ppm (7.47 mg/kg/day) for males and 1,000 ppm (81.9 mg/kg/day)
for females.
LOAELs were 500 ppm (36.45 mg/kg/day) for males based on changes
in the kidney (hyaline deposition) and 5,000
ppm for females (372.6mg/kg/day) based on kidney (hyaline deposition),
liver changes (centrilobularhypertrophy),
hematological effects (anemia) and clinical chemistry (increased
cholesterol)
--
Prenatal
developmental toxicity (rats).
Maternal.
NOAEL is 100 mg/kg bw/day. LOAEL is 500 mg/kg bw/day, based on
increased liver weight,
and liver
and kidney pathological
changes (hypertrophy of centrilobular hepatocytes in liver
and vacuolation of proximal tubular cell in kidneys).
--
Carcinogenicity
(mice). NOAEL
was not established. LOAEL is 250 ppm (equivalent to 29/38mg/kg/
day [M/F]), based on minimal to moderate
centrilobular hepatocellular hypertrophy,
minimal to severe extramedullary hematopoiesis,
minimal to moderate pigment
deposition in the sternal bone marrow, and
increased incidence of tissue masses/nodules in the lungs in the
males, and minimal to moderate decreased
cellularity in the femoral bone marrow and hyperplasia/hypertrophy
of the epithelial cells of the terminal bronchioles of the females.
At the doses tested, the carcinogenic potential of IKI-220 (flonicamid)
is positive at 250 ppm in males and females based on the increased
incidence of alveolar/bronchiolar adenomas, carcinomas, and combined
adenomas/carcinomas. Dosing was considered adequate based on increased
incidence of tissue masses/nodules in the lungs and microscopic
findings in the liver, spleen, bone
marrow, and lungs. However, data were provided suggesting this
effect is specific to sensitive strains of mice. Carcinogenic
in mice.
Ref:
August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule.
Federal Register.
http://www.fluoridealert.org/pesticides/flonicamid.fr.aug.31.2005.html
Lung
(click on for
all fluorinated pesticides)
Suggestive
Evidence of Carcinogenicity, but not sufficient to assess human
carcinogenic potential. Nasal
lacrimal duct squamous cell carcinomas possibly
treatment-related in female Wistar rats; Mitogenesis MOA accepted
for lung tumors in CD-1 mice (both
sexes).
Ref: April
26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the
Office of Pesticide Programs. From: Jess Rowland, Chief Science
Information Management Branch Health Effect Division (7509C) Office
of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf
-- In the 18-month
mouse study... 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. These effects in the lungs of mice were not life threatening
as most of effects were observed at the terminal sacrifice and
there was no effect of treatment on mortality in the study. A
NOAEL could not be determined from the dose levels administered.
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.
Flonicamid technical was not carcinogenic in the rat.
Ref:
Federal Register: May 23, 2003 (Volume 68, Number 100)] [Notices]
[Page 28218-28222]. Flonicamid; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food.
http://www.fluorideaction.org/pesticides/Flonicamid.FR.May23.2003.htm
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. There were no treatment-related
increases in neoplastic or non-neoplastic lesions at dose levels
of 80 ppm or lower in either sex. The NOAEL was 80 ppm, equivalent
to 10.0 and 11.8 mg/kg body weight/day for males and females,
respectively. This study confirmed a threshold for these effects
at 80 ppm, which had been indicated in studies on the mechanism.
Ref:
Federal Register. Jully 7, 2004. Flonicamid; Notice of Filing
a Pesticide Petition to Establish a Tolerance for a Certain Pesticide
Chemical in or on Food. [OPP-2004-0132; FRL-7362-5].
http://www.fluoridealert.org/pesticides/flonicamid.fr.july7.2004.htm
--
Carcinogenicity
(mice). NOAEL
was not established. LOAEL is 250 ppm (equivalent to 29/38mg/kg/
day [M/F]), based on minimal to moderate centrilobular
hepatocellular hypertrophy, minimal to severe extramedullary hematopoiesis,
minimal to moderate pigment deposition
in the sternal bone marrow, and increased
incidence of tissue masses/nodules in the lungs in the males,
and minimal to moderate decreased
cellularity in the femoral bone marrow and hyperplasia/hypertrophy
of the epithelial cells of the terminal bronchioles of the females.
At the doses tested, the carcinogenic potential
of IKI-220 (flonicamid) is positive at 250 ppm in males and females
based on the increased incidence of alveolar/bronchiolar adenomas,
carcinomas, and combined adenomas/carcinomas. Dosing was
considered adequate based on increased incidence
of tissue masses/nodules in the lungs and microscopic findings
in the liver, spleen, bone marrow, and lungs.
However, data were provided suggesting this effect is specific
to sensitive strains of mice. Carcinogenic
in mice.
-- Carcinogenicity
(mice). NOAEL
is 80 ppm (equivalent to 10/12 mg/kg/day in males/females). LOAEL
is 250 ppm (equivalent to 30/36mg/kg/day in males/females) based
on lung masses and terminal bronchiole epithelial
cellhyperplasia/ hypertrophy in both sexes. At the doses
tested, the carcinogenic potential of IKI-220
(flonicamid) is positive in males and females based on the incidences
of alveolar/ bronchiolar adenomas, carcinomas,and combined adenomas
and/or carcinomas. Dosing was considered adequate based
on lung masses and terminal bronchiole epithelialcell hyperplasia/
hypertrophy in both sexes. Carcinogenic
in mice.
Ref:
August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule.
Federal Register.
http://www.fluoridealert.org/pesticides/flonicamid.fr.aug.31.2005.html
-- 52964 - 0068, 0069 & 0070 216042, 216043, 216044 “Vol
0068: Dietary Carcinogenicity of IKI-220 Technical in Mice; Vol
0069: Pathology Sub-Report (Supplemental) for Dietary Carcinogenicity
of IKI220 Technical in Mice; Vol 0070: Historical Data for Dietary
Carcinogenicity of IKI-220 Technical in Mice,” (Nagaoka,
T., Nakashima, N.; Shin Nippon Biomedical Laboratories, Ltd.,
Kagoshima, Japan; The Institute of Environmental Toxicology, Ibaraki,
Japan; 1/22/04, 3/30/04, 1/22/04 for volumes 0068, 0069 &
0070, respectively). Flonicamid technical (IKI-220: 98.7% pure)
was fed in diet to Charles River Crj:CD-1®(ICR)BR mice
(50/sex/dose) at 0, 10, 25, 80 and 250 ppm (equivalent
doses: M = 1.20, 3.14, 10, 30.3 mg/kg/day; F = 1.42, 3.67, 11.8,
36.3 mg/kg/day) for 78 weeks. Systemic NOEL = 80 ppm (There was
an increase in lung hyperplasia and hypertrophy (both sexes) and
liver fatty change in centrilobular hepatocytes (F) at 250 ppm.
There was a statistically significant decrease in absolute kidney
weights in females at 250 ppm. There was
a statistically significant increase in lung masses--pulmonary
adenomas and carcinomas in males at 250 ppm.) Not acceptable
(There were numerous deficiencies in this study (see A., above).
There were no interim kills, nor were all target organs examined
and weighed as recommended by FIFRA Guidelines.), not upgradeable.
Possible adverse effect indicated (There
was a statistically significant increase in pulmonary adenomas
and carcinomas in males at 250 ppm. Silva, 4/29/05.
Reference: April 28, 2005 - Summary of toxicology data. California
EPA, Department of Pesticide Regulation, Medical Toxicology Branch.
http://www.fluorideaction.org/pesticides/flonicamid.ca.epa.2005.pdf
Muscle
(click
on for all fluorinated pesticides)
--
Combined Chronic/ carcinogenicity (rats).
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 on decreased body weights and body
weight gains, and increased incidences of keratitis
in males and striated muscle fiber atrophy
in females. At the
high dose there was an incidence (12%)of nasolacrimal duct squamous
cell carcinomas slightly outside
the historical control range (0-10%) in male rats. A correlation
between the incidence of inflammation and the fluctuating incidence
of nasal tumors was made across dose groups. EPA did not consider
the nasolacrimal duct tumors to be treatment-related. Female rats
had a significant increasing trend in nasolacrimal duct squamous
cell carcinomas at < 0.05, and at the high dose was slightly
above the historical control mean (0.8%) and range (0-4%). EPA
considered the nasolacrimal duct squamous cell carcinomas to be
possibly treatment related, but that a clear association with
treatment could not be made.
Ref:
August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule.
Federal Register.
http://www.fluoridealert.org/pesticides/flonicamid.fr.aug.31.2005.html
Neurotoxicity
(click
on for all fluorinated pesticides)
--
Acute neurotoxicity screening battery (rats). NOAEL
is 600 mg/kg in males and 300 mg/kg in females. LOAEL is 1,000
mg/kg based on mortality and signs of toxicity (decreased
motor activity, tremors, impaired respiration, and impaired gait)
in males. This acute neurotoxicity
study is unacceptable because interval motor activity data
were not provided as specified according to guidelines,FOB handling
and open-field observations were incomplete, and positive data
providedwere from a lab other than the performing lab for this
study. This study is not required for this
risk assessment and additional information is not required.
-- Subchronic
neurotoxicity screening battery (rats).
NOAEL is 200/1,000 ppm (equivalent to 13/81mg/kg/day [M/F].
LOAEL is 1,000/10,000 ppm (equivalent to 67/722 mg/kg/day [M/F]
based on decreased motor activity, rearing,
and foot splay in males, decreased body
weights, body weight
gains, and food consumption in males and females.
Ref:
August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule.
Federal Register.
http://www.fluoridealert.org/pesticides/flonicamid.fr.aug.31.2005.html
Reproductive
(click
on for all fluorinated pesticides)
--
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.
-- 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. However,
there were no effects on reproductive performance
or survival of the offspring in the study. At levels that are
expected to be found in the environment, flonicamid will not cause
any endocrine-related effects.
Ref:
Federal Register. Jully 7, 2004. Flonicamid; Notice of Filing
a Pesticide Petition to Establish a Tolerance for a Certain Pesticide
Chemical in or on Food. [OPP-2004-0132; FRL-7362-5].
http://www.fluoridealert.org/pesticides/flonicamid.fr.july7.2004.htm
--
Reproduction and fertility effects (rats).
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 to body uterus
weights and delayed sexual maturation
in the F1 females
-- Chronic
dietary. 2-Generation
Reproduction rat. Parental LOAEL = 22 mg/kg/day based on increased
kidney weights, kidney
hyaline deposition, increased blood
serum LH (F1 females).
Ref:
August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule.
Federal Register.
http://www.fluoridealert.org/pesticides/flonicamid.fr.aug.31.2005.html
Spleen
(click on for all fluorinated pesticides)
-- 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. These findings did not affect the reproductive
performance or survival of offspring in the study.
-- 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 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...
Ref:
Federal Register: May 23, 2003 (Volume 68, Number 100)] [Notices]
[Page 28218-28222]. Flonicamid; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food.
http://www.fluorideaction.org/pesticides/Flonicamid.FR.May23.2003.htm
90-Day
oral toxicity rodents (mice).
LOAEL is 1,000 ppm in
(males: 153.9 mg/kgbw/day; females: 191.5 mg/kg bw/ day) based
on extramedullary hematopoiesis of the spleen.
Many of the tissues/organs recommended by
Guideline 870.3100 were not histologically examined in any dose
group, but this study is not required and serves as a range-finding
study for the mouse carcinogenicity study.Therefore, it is classified
as acceptable, non-guideline study.
Ref:
August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule.
Federal Register.
http://www.fluoridealert.org/pesticides/flonicamid.fr.aug.31.2005.html
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