EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR PESTICIDE 

PETITION

Docket ID Number: EPA-HQ-OPP-2016-0013

EPA Registration Division Contact: Sidney Jackson, (703) 305-7610 

Interregional Research Project Number 4 (IR-4)

Pesticide Petition Number: 5E8428

EPA has received a pesticide petition (PP# 5E8428) from IR-4 Project Headquarters, 500 

College Road East, Suite 201W, Princeton, New Jersey, 08540, proposing, pursuant to section 

408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 

CFR part 180 by establishing a tolerance for residues of the combined residues of the insecticide 

flonicamid [N-(cyanomethyl)-4-trifluoromethyl)-3-pyridinecarboxamide (CA) or Ncyanomethyl-4-trifluoromethylnicotinamide (IUPAC)] and its metabolites, TFNA [4-

trifluoromethylnicotinic acid], TFNA-AM [4-trifluoromethylnicotinamide] and TFNG [N-(4-

trifluoromethylnicotinoyl)-glycine] in or on the raw agricultural commodities Vegetable, legume, 

edible podded, subgroup 6A at 4.0 parts per million (ppm), Pea and bean, succulent shelled, 

subgroup 6B at 6.0 parts ppm, Pea and bean, dried shelled, except soybean, subgroup 6C at 3.0 

ppm, and Vegetable, fruiting, group 8-10 at 1.50 ppm (revision of established tolerance of 0.40 

ppm). EPA has determined that the petition contains data or information regarding the elements 

set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency 

of the submitted data at this time or whether the data support granting of the petition. Additional 

data may be needed before EPA rules on the petition.

A. Residue Chemistry

 

1. Plant metabolism. Wheat, potato and peach metabolism studies were conducted using 

[14C]-pyridyl-flonicamid. The metabolic profile was similar for all three matrices. The major 

metabolites for the various crops were: TFNA in peach, TFNA and TFNG in potato and TFNG 

in wheat. The metabolism of flonicamid in plants shows the main pathway of metabolism 

involves hydrolysis of -CN and BCONH2 functional groups in the molecule. The metabolism of 

flonicamid in plants is well understood. 

2. Analytical method. Analytical methodology has been developed to determine the 

residues of flonicamid and its three major plant metabolites, TFNA, TFNG, and TFNA-AM in 

various crops. The residue analytical method for the majority of crops includes an initial 

extraction with acetonitrile (ACN)/deionized (DI) water, followed by a liquid-liquid partition 

with ethyl acetate. The residue method for wheat straw is similar, except that a C18 solid phase 

extraction (SPE) is added prior to the liquid-liquid partition. The final sample solution is 
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quantitated using a liquid chromatograph (LC) equipped with a reverse phase column and a triple 

quadruple mass spectrometer (MS/MS).

3. Magnitude of residues. Residue data were collected on edible podded and succulent 

shelled peas and beans, and dry shelled peas and beans during field trials (total of 12 dry shelled 

bean field trials, 5 dry pea field trials, 6 lima bean field trials, 7 snap bean field trials, and 13 

edible podded and succulent pea field trials). Maximum total residues ranged from <0.08 to 

1.2881 parts per million (ppm) in dry bean samples, 0.1208 to 0.9192 ppm in lima bean samples, 

0.4542 to 1.3677 ppm in dry pea samples, 0.6543 to 1.420 ppm in snap bean samples, 0.356 to 

2.03 ppm in edible podded pea samples, and 0.471 to 2.96 ppm in succulent shelled pea samples. 

Residue data were collected on greenhouse peppers during field trials (total of 4 trials in 

Canada). Maximum total residues ranged from 0.170 to 0.886 ppm.

B. Toxicological Profile

1. Acute toxicity. A battery of acute toxicity studies was conducted which placed 

flonicamid technical in Toxicity Category III for oral lethal dose (LD)50, Category IV for dermal 

LD50, inhalation lethal concentration (LC)50, dermal irritation, and eye irritation. Flonicamid 

technical is not a dermal sensitizer. In an acute neurotoxicity study, the no observed adverse 

effect levels (NOAELs) for neurotoxicity were 600 milligram per kilogram (mg/kg) in males and 

1000 mg/kg in female (highest doses tested). The systemic NOAELs were 600 mg/kg in males 

and 300 mg/kg in females.

2. Genotoxicity. Flonicamid technical did not cause mutations in the bacterial reverse 

mutation or mouse lymphoma tests with or without metabolic activation, chromosome damage in 

the mouse micronucleus or cytogenetics tests with and without metabolic activation, an increase 

in DNA damage in the comet assay or in an in vivo rat unscheduled DNA synthesis (UDS) study. 

Based on the weight of evidence, it is concluded that flonicamid technical is not genotoxic.

3. 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 incidences of fetal 

skeletal variations seen only at maternally toxic doses of 500 mg/kg/day. 

In the rabbit developmental toxicity study, the maternal and developmental NOAELs 

were 7.5 mg/kg/day and > 25 mg/kg/day highest dose tested (HDT), respectively. The maternal 

LOEL was 25 mg/kg/day based on decreased body weights, body weight gains and food 

consumption. No adverse effects on the fetuses were observed at the highest dose. 

In the multigeneration rat reproduction study, the NOAEL was 50 ppm for parental 

animals (3.7 and 4.4 mg/kg/day, respectively, for males and females) and 300 ppm for their 

offspring (22.3 and 26.5 mg/kg/day, respectively, for males and females). The effects at the 

highest dose of 1800 ppm included the following: increased kidney weights and gross and 
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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. 

4. Subchronic toxicity. The NOAEL for flonicamid technical in the rat 28-day dermal 

toxicity study was 1000 mg/kg/day, which was the highest dose tested.

In a 90-day rat feeding study the NOAEL was established at 200 ppm (12.11 mg/kg/day) for 

males and 1000 ppm (72.3 mg/kg/day) for females. The LOAELs were 1000 ppm (60.0 

mg/kg/day) for males and 5000 ppm (340 mg/kg/day) for females 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 1000 ppm (153.9 mg/kg/day in males and 191.5 

mg/kg/day in females) based on hematology effects and changes in glucose, creatinine, bilirubin, 

sodium, chloride and potassium levels, increased liver and spleen weights and histopathology 

findings in the bone marrow, spleen and kidney. 

In a subchronic toxicity study in dogs with capsule administration, the NOAEL was 8 

mg/kg/day in males and 20 mg/kg/day in females based on findings of severe toxicity at a dose 

exceeding the maximum tolerated dose; symptoms included collapse, prostration and 

convulsions leading to early sacrifice at the LOAEL of 50 mg/kg/day.

In a subchronic neurotoxicity study in rats, the NOAEL for dietary administration was 200 

ppm for males and 1000 ppm for females (13 mg/kg/day in males and 81 mg/kg/day in females). 

The LOAEL was 1000 and 10,000 ppm (67 and 722 mg/kg/day) in males and females, 

respectively (highest dose tested) based on decreased motor activity, body weight and food 

consumption effects.

5. Chronic toxicity. In the chronic dog study with administration via using capsules, the 

NOEL was 8 mg/kg/day. The LOAEL was 20 mg/kg/day based on reduced body weights in 

females and effects on the circulating red blood cells.

In a rat 24-month combined chronic and oncogenicity study, flonicamid technical was not 

carcinogenic in rats. The NOAEL was 200 ppm (7.32 mg/kg/day) for males and 1000 ppm (44.1 

mg/kg/day) for females. The LOAEL was 1000 ppm for males and 5000 ppm for females based 

on histopathology in the kidney, hematology effects, hepatic effects including changes in 

biochemical parameters, increased organ weights, and histopathological changes. Atrophy of 

striated muscle fibers, cataract and retinal atrophy observed in the high dose females were 

considered to be due to acceleration of spontaneous age-related lesions.

In the 18-month mouse study, effects were observed in the lung, liver, spleen and bone 

marrow at 250 ppm or higher. Findings included centrilobular hepatocellular hypertrophy, 

extramedullary hematopoiesis and pigment deposition in the spleen and decreased cellularity 

(hypocellularity) in the bone marrow. There were statistically significant increases in the 

incidence of alveolar/bronchiolar adenomas in both sexes of treated groups with 
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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 

2250 ppm and in females at 2250 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 no observed adverse effect level (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. 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 increase 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 

NOAELs were 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. Flonicamid technical was not 

carcinogenic in the rat.

6. Animal metabolism. Rat, goat and poultry metabolism studies were conducted using 

[

14C]-pyridyl-flonicamid. The majority of the dose was rapidly excreted. Flonicamid was a 

major component of rat urine 48 hours after dosing. TFNA-AM was the major metabolite found 

in rats (urine), goats (milk and tissues) and in laying hens (tissues and eggs). TFNG was found 

between 8 - 24% of the total radioactive residue (TRR) in the livers of rats sacrificed at intervals 

between 0.5 - 6 hours after dosing. The liver samples at these time intervals had 14C-residues of 

2.3% - 4.6% of the dose. TFNA was not a major component in animal tissues. The metabolism 

of flonicamid in animals shows the main pathway of metabolism involves hydrolysis of -CN and 

-CONH2 functional groups in the molecule, identical to plant metabolism. The main metabolic 

reactions were hydrolysis of cyano to the amide function and ring hydroxylation. In rats 

flonicamid was further metabolized by several routes, including nitrile hydrolysis, amide 

hydrolysis, N-oxidation, and hydroxylation of the pyridine ring, leading to multiple metabolites. 

The metabolism of flonicamid in animals is well understood. 

7. Metabolite toxicology. The main metabolites of flonicamid were examined in acute 

oral toxicity studies in rats and bacterial reverse mutation tests. All the metabolites were less 

toxic than flonicamid and not mutagenic.

8. 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 (1800 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, 
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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 endocrinerelated effects.

C. Aggregate Exposure.

1. Dietary exposure

i. Food. 

Tier 1 chronic dietary exposure assessments on flonicamid were conducted using the Dietary

Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID 

TM, Version 2.14), which uses food consumption data from the U.S. Department of Agriculture’s 

Continuing Surveys of Food Intakes by Individuals (CSF II) from 1994-1996 and 1998. Overall 

dietary exposure to flonicamid was expressed in mg/kg/day and was calculated as a percent of 

Chronic Population Adjusted Dose (cPAD).

Proposed tolerances for residues of flonicamid representing Crop Subgroups 6A (4.0 ppm), 

6B (6.0 ppm), 6C, except soybeans (3.0 ppm) and Crop Group 8-10 (1.5 ppm) were incorporated 

into the DEEM-FCID residue file for dietary exposure assessment. 

The Chronic Reference Dose (cRfD) was established at 0.04 mg/kg/day. The cRfD was 

based on a 2-generation reproduction rat study with a NOAEL of 3.7 mg/kg/day. The uncertainty 

factor of 100 was applied to the NOAEL to derive cRfD. The cPAD is equivalent to the cRfD of 

0.04 mg/kg/day (FQPA SF = 1).

ii. Drinking water. 

A Tier II drinking water assessment was conducted to represent drinking water exposure 

(SCI-GROW2 for groundwater and Pesticide Root Zone Model/ Exposure Analysis Modeling 

System (PRZM/EXAMS) for surface water). The maximum chronic Estimated Environmental 

Concentration (EEC) from PRZM/EXAMS was 1.5 ppb, derived from the ME potato and CA 

lettuce standard EPA scenarios (see “Flonicamid: Human health risk assessment for proposed 

uses on root vegetables (except sugarbeet; Subgroup 1B), tuberous corm vegetables (subgroup 

1C), leafy Brassica green vegetables (subgroup 5B), turnip greens, hops and okra. PC Code: 

128016, Petition No: 6E7081, DP Barcode: D347805. December 21, 2007”). Using the Tier 1 

Screening Concentration in Ground Water (SCI-GROW)2 model, the ground water EEC for 

flonicamid was 0.00132 ppb, which was considered appropriate for chronic EEC. To be 

protective of all drinking water systems, the predicted chronic EEC for surface water (1.5 ppb) 

was incorporated in the DEEM dietary assessment modeling.

2. Non-dietary exposure. Based upon the product label, EPA assumes that the proposed 

food-use sites are commercial in nature, and that the applications on landscape ornamentals 

would only be made by professional pest control operators. Therefore, residential handler 

scenarios are not expected and need not be assessed. Flonicamid label language should preclude 

use by non-professionals (e.g., homeowners), particularly regarding landscape ornamentals.
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D. Cumulative Effects. 

 The 2007 EPA assessment (refer to Section C) was conducted for food and water exposure 

only. There are no expected long-term residential exposures. Because drinking water estimates 

have been combined with dietary exposures, the dietary assessment serves as the aggregate 

exposure and risk assessment for flonicamid. The addition of the proposed uses is not expected 

to change the nature of the aggregate assessment. Because aggregated food and drinking water 

exposures from this conservative Tier I assessment for the most highly exposed population

subgroup (Children 1-2 years old) only amount to 23.1% of the chronic Population Adjusted 

Dose (cPAD), exposure to flonicamid from the all current and proposed uses should not exceed 

EPA’s level of concern.

E. Safety Determination.

 1. U.S. population. Using the conservative Tier 1 assumptions described in Section C., 

based on the completeness and reliability of the toxicology data, it is estimated that the chronic 

dietary exposure (food plus drinking water) at the 95th percentile general U.S. population 

comprises 15.9 % of the cPAD. These conservative estimates include exposure to flonicamid 

from tolerance-level residues representing the proposed uses. The EPA generally has no concern 

for exposures below 100% of the acute Population Adjusted Dose (aPAD)/cPAD because it 

represents the level at or below which daily aggregate dietary exposure over a lifetime will not 

pose any unacceptable risks to human health. It is concluded that there is a reasonable certainty 

that no harm will result from aggregate exposure to residues of flonicamid, including all 

anticipated dietary exposure.

2. Infants and children. The FQPA safety factor was set at 1 to derive the cPAD (i.e. 0.04 

mg/kg/day) for chronic dietary risk assessment to infants and children as well as adults. Using 

the conservative Tier 1 assumptions described in Section C and based on the completeness and 

reliability of the toxicology data, it is estimated that the chronic dietary exposure (food plus 

drinking water) at the 95th percentile for the most sensitive sub-population (Children 1-2 years 

old) comprises 37.5 % of the cPAD. The risk from incorporating the proposed tolerances into 

the dietary risk assessment increased the cPAD by less than 2% for the most sensitive population 

subgroup (Children 1-2 years old). 

Based on the above information, there is reasonable certainty that no harm will result to 

infants, children, or adults from dietary (food plus drinking water) exposure to flonicamid 

residues from the proposed uses, as well as all other existing flonicamid-treated human dietary

food sources.

F. International Tolerances

Canada has established MRLs for flonicamid and its metabolites on head and stem 

brassica, leafy brassica greens, leafy vegetables (except brassica), tuberous and corm vegetables, 
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fruiting vegetables, cucurbits, stone fruits, pome fruits, vegetable root crops except sugarbeet, 

radish tops, turnip greens, hops, and resulting secondary residues in meat, milk, poultry and eggs.

There are no Mexican residue limits or Codex MRLs for the insecticide flonicamid and 

its metabolites TFNA, TFNA-AM and TFNG.