Adverse Effects
Flonicamid
CAS No.
158062-67-0
 
 

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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