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`

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date: 10/2/2012

SUBJECT: Revised: Flonicamid: Human Health Risk Assessment for the Proposed Use on 

Low Growing Berry, Rapeseed, and Greenhouse Grown Cucumbers. 

PC Code: 128016 DP Barcode: D397277

Decision No.: 457726 Registration Nos.: 71512-9 & 71512-10

Petition No.: 1E7942 Regulatory Action: Section 3 Registration

Risk Assessment Type: Single Chemical/Aggregate Case No.: 7436

TXR No.: NA CAS No.: 158062-67-0

MRID No.: NA 40 CFR: §180.613

FROM: Barry O’Keefe, Senior Biologist

Amelia Acierto, Chemist

Cassi Walls, Chemist

Myron Ottley, Senior Toxicologist

Risk Assessment Branch III

Health Effects Division (7509P)

THROUGH: Jeff Dawson, Acting Branch Chief

Risk Assessment Branch III

Health Effects Division (7509P)

TO: Barbara Madden

Risk Integration, Minor Use and Emergency Response Branch, RM 05

Registration Division (7505P)

This document and attachments provide an assessment of the human health risk resulting from 

the proposed and registered uses of flonicamid. The toxicology reevaluation was performed by 

Myron Ottley, the drinking water assessment was conducted by James Hetrick (EPA 

Environmental Fate and Effects Division (EFED)), and the review of the residue chemistry data 

by Amelia Acierto, the dietary, occupational and residential exposure assessments were

conducted by Cassi Walls, and the overall human health risk assessment was conducted by Barry

O’Keefe. 
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Table of Contents

1.0 Executive Summary........................................................................................................... 4

2.0 HED Recommendations.................................................................................................... 7

2.1 Data Deficiencies ............................................................................................................ 8

2.2.1 Enforcement Analytical Method ............................................................................... 8

2.2.2 International Harmonization..................................................................................... 8

2.2.3 Recommended Tolerances......................................................................................... 8

2.2.4 Revisions to Petitioned-For Tolerances.................................................................... 9

2.3 Label Recommendations................................................................................................ 9

3.0 Introduction........................................................................................................................ 9

3.1 Chemical Identity ......................................................................................................... 10

3.2 Physical/Chemical Characteristics ............................................................................. 10

3.3 Pesticide Use Pattern.................................................................................................... 11

3.4 Anticipated Exposure Pathways................................................................................. 12

3.5 Consideration of Environmental Justice.................................................................... 12

4.0 Hazard Characterization and Dose-Response Assessment.......................................... 13

4.1 Summary of Toxicological Effects.............................................................................. 13

4.2 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 15

4.2.1 Completeness of the Toxicology Database.............................................................. 15

4.2.2 Evidence of Neurotoxicity........................................................................................ 15

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal........ 16

4.2.4 Residual Uncertainty in the Exposure Database ................................................... 16

4.3.1 Summary of Points of Departure and Toxicity Endpoints Used in Human Health 

Risk Assessment ...................................................................................................................... 16

5.0 Dietary Exposure and Risk Assessment......................................................................... 18

5.1 Metabolite/Degradate Residue Profile ....................................................................... 18

5.1.1. Summary of Metabolism Studies, Environmental Degradation, and Metabolic 

Pathway Comparison.............................................................................................................. 18

5.1.2 Residues of Concern Summary ............................................................................... 19

5.2 Food Residue Profile .................................................................................................... 19

5.3 Water Residue Profile.................................................................................................. 21

5.4 Dietary Risk Assessment.............................................................................................. 22

5.4.1 Description of Residue Data & Percent Crop Treated Used in Dietary 

Assessment............................................................................................................................... 22

5.4.2 Acute Dietary Risk Assessment............................................................................... 22

5.4.3 Chronic Dietary Risk Assessment........................................................................... 23

5.4.4 Summary Table......................................................................................................... 23

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 23

6.1 Residential Bystander Post-Application Inhalation Exposure ................................ 23

6.2 Spray Drift.................................................................................................................... 24

7.0 Aggregate Exposure/Risk Characterization.................................................................. 24

7.1 Acute Aggregate Risk................................................................................................... 24

7.2 Short-Term Aggregate Risk........................................................................................ 24

7.3 Intermediate-Term Aggregate Risk ........................................................................... 24

7.4 Chronic Aggregate Risk .............................................................................................. 25
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7.5 Cancer Aggregate Risk ................................................................................................ 25

8.0 Cumulative Exposure/Risk Characterization ............................................................... 25

9.0 Occupational Exposure/Risk Characterization ............................................................ 25

9.1 Short-/Intermediate-Term Handler Risk................................................................... 25

9.2 Short-/Intermediate-Term Post-Application Risk .................................................... 28

9.2.1 Dermal Post-Application Risk................................................................................. 28

9.2.2 Inhalation Post-Application Risk............................................................................ 28

10.0 References......................................................................................................................... 28

Appendix A. Toxicology Profile................................................................................................ 29

A.1 Toxicology Data Requirements................................................................................... 29

A.2 Toxicity Profiles............................................................................................................ 30

Appendix B. Physical/Chemical Properties & Structures ..................................................... 36

Appendix C. International Residue Limit Status Sheet. ........................................................ 39

Appendix D. Review of Human Research ............................................................................... 40
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1.0 Executive Summary

Flonicamid is a systemic insecticide that immediately suppresses the feeding of sucking insects

on plants. From its chemical structure (a nicotinic acid derivative), it would be expected to 

exhibit the same mode of action as similarly structured neo-nicotinoid pesticides. However, 

flonicamid has not been found to activate acetylcholine esterase (like organophosphates and 

carbamates), or nicotinic acetylcholine receptors (like neo-nicotinoids).

Flonicamid is registered for use on a variety of agricultural crops, including: cotton, cucurbits, 

fruiting vegetables, leafy vegetables, pome fruits, stone fruits, potatoes, root vegetables (except 

sugar beet; subgroup 1B), tuberous and corm vegetables (subgroup 1C), leafy Brassica green 

vegetables (subgroup 5B), turnip greens, hops and okra. Flonicamid is also registered for use on 

commercial ornamentals, interiorscapes, and nurseries; but these labels do not allow use in home 

gardens and greenhouses or in any residential settings.

IR-4 has requested flonicamid be registered for use on low growing berry subgroup 13-07G, 

rapeseed subgroup 20A, and greenhouse grown cucumbers. Note rapeseed is synonymous with 

canola. The proposed uses of flonicamid are expected to result in occupational exposure only; 

no residential exposure is expected from the proposed uses of flonicamid. Only short- and 

intermediate-term occupational exposures were assessed for the proposed uses of flonicamid. 

The formulated end use products (EPs) evaluated in this assessment are Beleaf 50SG Insecticide

(EPA Reg. No. 71512-10) and Flonicamid 50WG, EPA Reg. No. 71512-9).

The most recent human health risk assessment was conducted to evaluate flonicamid use on root 

vegetables (except sugar beet; subgroup 1B), tuberous and corm vegetables (subgroup 1C), leafy

Brassica vegetables (subgroup 5B), turnip greens, hops, and okra (DP347805, S. Piper, 

12/21/07). 

Use Profile

Flonicamid is proposed for use as a foliar spray using ground, aerial, and chemigation equipment

on the low growing berry subgroup 13-07G, rapeseed subgroup 20A, and greenhouse grown 

cucumbers. It is also proposed as a soil drench for greenhouse grown cucumbers. The use 

profile is summarized in Table 3.3. The proposed maximum single application rate for all

proposed crops or crop groups is 0.089 lb ai/A (2.8 oz/A) with either Beleaf 50SG Insecticide or 

Flonicamid 50WG. Up to three seasonal applications can be made to crops in the low growing 

berry subgroup 13-07G and rapeseed subgroup 20A. Two seasonal applications can be made to 

greenhouse grown cucumbers. The retreatment interval for all proposed crops is 7 days. The 

pre-harvest intervals (PHIs) are 0 days for low growing berry subgroup 13-07G and greenhouse 

grown cucumbers, and 7 days for rapeseed subgroup 20A.

Exposure Profile

The proposed agricultural uses of flonicamid would result in new exposures from both food and 

drinking water. There are no existing or proposed residential uses, and therefore, there are no 

non-occupational exposures expected. However, the proposed agricultural uses will result in 
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occupational exposures from handler and post-application activities. Exposures are expected to 

occur for short- and intermediate-term durations.

Toxicity/Hazard

Since the last risk assessment, additional toxicity data have not been submitted. In accordance 

with the 2007 revised 40 CFR Part 158 Toxicology data requirements, an immunotoxicity study

and a subchronic inhalation toxicity study were required for flonicamid. An immunotoxicity

study which is currently underway, and is expected to be submitted to the Agency in a few 

months, remains required for flonicamid. Previously, the registrant, ISK Biosciences 

Corporation, submitted waiver requests for the 28-day and 90-day subchronic inhalation toxicity

studies, which HED granted (DP290408, J. Arthur, 5/9/05 and DP297602, J. Arthur, 5/9/05). 

The waivers were granted based on flonicamid’s low acute inhalation toxicity (Toxicity Category

IV) and inhalation MOEs extrapolated from oral points of departure (PODs) that exceeded the 

target inhalation MOE of 1,000. However, based on current conditional requirements for 

inhalation toxicity data, the need for a subchronic inhalation study was reassessed by the HED 

Hazard and Science Policy Council (HASPOC). Based upon a weight of evidence approach the 

HASPOC concluded that a subchronic 28-day inhalation study is required at this time (TXR No. 

0056400, K. Rury, 7/30/12). In the absence of a route specific inhalation study, a 10X database 

uncertainty factor has been applied to assess risks for inhalation exposure scenarios.

The flonicamid toxicity/hazard database is nearly complete, with the exception of a subchronic 

inhalation toxicity study and an immunotoxicity study. The kidney and liver are the target 

organs for flonicamid toxicity via the oral route in rats and dogs. Increased kidney weight and 

hyaline droplet deposition were observed as well as liver centrilobular hypertrophy in the rat 28-

day oral range-finding, 90-day oral, developmental, and reproductive studies. The 90-day dog 

study showed kidney tubular vacuolation, as well as increased adrenal weights, increased 

reticulocytes and decreased thymus weights. Increased reticulocyte count was noted in both the 

subchronic and chronic dog studies. In the 28-day dermal study, with flonicamid technical, no 

dermal or systemic toxicity was seen at the limit dose (1000 mg/kg/day).

In rats, developmental effects (increased incidence of cervical ribs) were observed at maternally 

toxic (liver and kidney effects) dose levels. In rabbits, developmental effects were not observed 

at any dose level including maternally toxic doses. Because effects were seen only at maternally 

toxic doses in rats, there is no concern for increased susceptibility of developing young for 

flonicamid. Additionally, there are no concerns for neurotoxicity. The adverse effects noted in 

the acute neurotoxicity study (death, decreased motor activity, tremors, impaired respiration and 

gait) and the subchronic neurotoxicity study (decreased body weight and food consumption, 

decreased rearing and motor activity, rearing and foot-splay) are at levels substantially above the 

levels where HED is currently regulating. Based on the toxicity data, HED recommended the 

Food Quality Protection Act (FQPA) safety factor (SF) be reduced to 1X because there are no

residual uncertainties with regard to susceptibility with pre- and/or postnatal toxicity. 

Mutagenicity studies with flonicamid were negative, and flonicamid is classified by the Cancer 

Assessment Review Committee as “suggestive evidence of carcinogenicity, but not sufficient to 

assess human carcinogenic potential”, based on increased incidences of lung tumors in CD-1 
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mice. These tumors are species and strain specific and do not correlate well with tumors in 

humans. 

Flonicamid has a low acute toxicity via the oral (Tox Category III), dermal (Tox Category IV), 

and inhalation (Tox Category IV) routes of exposure. It is not an eye or skin irritant and is not a 

skin or dermal sensitizer. 

Dietary Exposure (Food and Water)

The residue chemistry data and environmental fate data are adequate to assess human exposure. 

The assessments are based on reliable data and will not underestimate exposure or risk. 

The drinking water assessment was conducted by the Environmental Fate and Effects Division 

(EFED) using a parent only and total toxic residue (TTR) approach. TTRs include 4-

trifluoromethylnicotinic acid (TFNA), 4-trifluoromethylnictinamide (TFNA-AM), 6-hydro-4-

trifluoromethylnicotinic acid (TFNA-OH), N-(4-trifluoromethylnicotinoyl) glycine (TFNG), and 

N-(4-trifluoromethylnicotinoyl) glycinamide (TFNG-AM). The predicted concentrations of 

flonicamid TTRs for the proposed uses are lower than estimated drinking water concentrations 

(EDWCs) in previous drinking water assessments. An EDWC of 1.9 μg/L (ppb) was used in the 

chronic dietary assessment.

The EDWCs were incorporated directly into the dietary exposure assessments.

There was no acute endpoint identified in the toxicity studies; therefore, no acute dietary

assessment is needed. An unrefined chronic dietary assessment was conducted using 100% crop 

treated (%CT) estimates, tolerance-level residues for all commodities, and empirical or Dietary

Exposure Evaluation Model–Food Commodity Intake Database (DEEM-FCIDTM) default 

processing factors. The results of the chronic dietary analysis for food and drinking water 

assessment show that the chronic dietary risk estimates are below the Agency’s level of concern

(LOC) (<100% of the chronic population adjusted dose (cPAD)) for all population subgroups

and were estimated at 11% of the cPAD for the general U.S. population and 28% of the cPAD 

for the most highly exposed population subgroup (children 1-2 years old). Flonicamid is 

classified as “suggestive evidence of carcinogenicity, but not sufficient to assess human 

carcinogenic potential”, therefore, a cancer dietary risk assessment was not performed.

Residential Exposure

No new residential uses were requested in this petition. Additionally, flonicamid is not currently 

registered for use in residential settings. 

Occupational Exposure

Based on the proposed use pattern of flonicamid, there is a potential for short- and intermediateterm occupational exposure during handling (mixing, loading, and applying) and post-application 

activities. For personal protective equipment (PPE), the proposed labels require handlers to wear 

long-sleeved shirt and long pants, shoes plus socks, and waterproof gloves. No dermal hazard 
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was identified for flonicamid; therefore, only a quantitative inhalation exposure assessment was 

performed for handlers. Most of the occupational handler exposure scenarios result in short- and 

intermediate-term MOEs that range from 2,200 to 450,000 and are not of concern to HED (i.e. an 

MOE > 1000) with baseline attire. However, the short-/intermediate-term MOEs for two 

scenarios result in risk estimates that exceed HED’s level of concern; i.e. 1) the scenario of 

mixing/loading/applying for soil drench applications to greenhouse grown cucumbers using a 

mechanically pressurized handgun results in an MOE of 440, and 2) the scenario of 

mixing/loading/applying sprays to greenhouse grown cucumbers using a mechanically

pressurized handgun results in an MOE of 600. With the addition of a dust/mist respirator the 

MOEs for these two scenarios are 2,200 and 3,100, respectively, which do not exceed HED’s 

level of concern. Therefore, the proposed labels should be amended to include the requirement 

for a dust mist respirator.

Although occupational dermal exposure is expected following treatment of crops, no dermal 

hazard was identified for flonicamid. Therefore, a quantitative post-application dermal risk 

assessment was not conducted. HED assumes that post-application inhalation exposures are 

minimal following applications of an active ingredient (ai) with low vapor pressure. Since 

flonicamid has low acute inhalation toxicity (Toxicity Category IV) and a low vapor pressure, 

post-application inhalation exposures and risks were not quantitatively assessed. Although a 

quantitative occupational post-application inhalation exposure assessment was not performed, an 

inhalation exposure assessment was performed for occupational handlers. Handler exposure 

resulting from application of pesticides outdoors and in well ventilated greenhouses is likely to 

result in higher exposure than post-application exposure. Therefore, it is expected that these 

handler inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.

Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, including studies from the 

Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler 

Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force 

(ORETF) database; and the Agricultural Re-entry Task Force (ARTF) database, are subject to 

ethics review pursuant to 40 CFR 26, have received that review, and are compliant with 

applicable ethics requirements. For certain studies that review may have included review by the 

Human Studies Review Board. Descriptions of data sources as well as guidance on their use can 

be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

2.0 HED Recommendations

HED recommends the registration request be granted for flonicamid use on low growing berry

subgroup 13-07G, rapeseed subgroup 20A, and greenhouse grown cucumbers.
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2.1 Data Deficiencies

The following data are required:

870.7800 Immunotoxicity Study

 In 2007, the Agency revised 40 CFR Part 158.500 Toxicology data requirements to 

include functional immunotoxicity testing and granted a 2-year grace period to allow time 

for registrants to develop the required data. ISK Biosciences Corporation has committed 

to submitting an adequate functional immunotoxicity study that is currently underway

and expected to be submitted to the Agency later in 2012.

870.3465 28-Day Inhalation Study

 In 2007, the Agency revised 40 CFR Part 158.500 Toxicology data requirements to 

include a 28-day inhalation toxicity study. The HED Hazard and Science Policy Council 

(HASPOC) reassessed the need for a subchronic inhalation toxicity study. Based upon a 

weight of evidence approach the HASPOC concluded that a subchronic 28-day inhalation 

study is required at this time.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method 

Adequate LC/MS/MS methods are available for both collecting and enforcing tolerances for 

flonicamid and the major metabolites TFNA-AM, TFNA, and TFNG in plants (FMC No. P3561M). The method has been adequately validated by an independent laboratory in conjunction 

with a previous petition. For enforcement of tolerances for livestock commodities, three 

methods are available: LC/MS/MS method (RCC No. 844743) for residues in eggs and livestock 

tissues; LC/MS method (RCC No. 842993) for residues in milk; and LC/MS/MS method (FMC 

P3580) which includes an acid hydrolysis step for residues in cattle muscle, kidney, and liver. 

2.2.2 International Harmonization

There are currently no Canadian or Codex Maximum Residue Limits (MRLs) for residues of 

flonicamid on the proposed crops and crop groups. See Appendix C for the International 

Residue Limit Status sheet. 

2.2.3 Recommended Tolerances 

Pending submission of a revised Section F and Section B, and revised labels, there are no residue 

chemistry issues that will preclude establishment of permanent tolerances for flonicamid in/on 

the crops and crop groups specified in Table 2.2.3. 
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Table 2.2.3. Tolerance Summary for Flonicamid

Commodity Established

Tolerance

(ppm)

Proposed 

Tolerance

(ppm)

Recommended 

Tolerance 

(ppm)

Comments (correct 

commodity definition)

Berry, low growing, subgroup 13-07G - 1.4 1.5

1

Cucumber for greenhouse use only 0.4 1.3 1.52 Vegetable, cucurbit, group 9

Rapeseed subgroup 20A - 1.5 1.53

1

The representative commodity for the berry, low growing, subgroup 13-07G is strawberry. The Organization of 

Economic Cooperation and Development (OECD) tolerance calculation procedure gave values of 1.5 ppm for

strawberry.

2 A tolerance was established on cucumber at 0.4 ppm (as a member of the cucurbit vegetable group 9). The current 

petition is to increase the tolerance to 1.3 ppm for cucumber grown in greenhouse only. The OECD spreadsheet 

calculation procedure gave a value of 1.5 ppm for cucumber grown in the greenhouse treated at the proposed label 

rate by foliar spray. The OECD spreadsheet calculation procedure gave a value of 0.7 ppm for cucumber treated by 

chemigation. This tolerance value and the existing tolerance of 0.40 ppm in 40 CFR §180.613 will be covered under 

the foliar spray treatment in greenhouse.

3

The representative commodity for the rapeseed, subgroup 20A is canola. The OECD spreadsheet calculation 

procedure gave a value of 1.5 ppm for canola. 

2.2.4 Revisions to Petitioned-For Tolerances

Based on the OECD tolerance calculation procedure, HED recommends increasing the proposed 

tolerance from 1.4 ppm to 1.5 ppm for berry, low growing, subgroup 13-07G and from 1.3 ppm 

to 1.5 ppm for greenhouse grown cucumber (as “Vegetable, cucurbit, group 9”).

2.3 Label Recommendations

860.1200 Directions for Use

The submitted labels for BeleafTM 50SG Insecticide and Flonicamid 50WG have a restriction for 

greenhouse use. The labels should be revised to change the statement “Do not use this product in 

greenhouses” to “Do not use this product in greenhouses, except on cucumbers”.

For the proposed use on greenhouse grown cucumbers the requirement to wear a PF5 dust/mist 

respirator needs to be added to the Beleaf 50SG Insecticide (EPA Reg. No. 71512-10) and 

Flonicamid 50WG, EPA Reg. No. 71512-9) labels. A PF5 dust/mist respirator is assumed to 

reduce inhalation exposure by 80%.

3.0 Introduction

Flonicamid is a systemic insecticide that immediately suppresses the feeding of sucking insects

on plants. From its chemical structure (a nicotinic acid derivative), it would be expected to 

exhibit the same mode of action as similarly structured neo-nicotinoid pesticides. However, 

flonicamid has not been found to activate acetylcholine esterase (like organophosphates and 

carbamates), or nicotinic acetylcholine receptors (like neo-nicotinoids).

Flonicamid is currently registered on head and stem Brassica vegetables, cotton, cucurbit 

vegetables, fruiting vegetables, hops, leafy Brassica greens, leafy vegetables, okra, potato, pome 
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fruit, root vegetables, stone fruit, tuberous and corm vegetables, and turnip greens. It is also 

currently registered on landscape ornamentals. 

IR-4 has requested flonicamid be registered for use on low growing berry subgroup 13-07G, 

rapeseed subgroup 20A, and greenhouse grown cucumbers. The proposed uses of flonicamid are 

expected to result in occupational exposure only; no residential exposure is expected from the 

proposed uses of flonicamid. Only short- and intermediate-term occupational exposures were 

assessed for the proposed uses of flonicamid. The formulated end use products (EPs) evaluated 

in this assessment are Beleaf 50SG Insecticide (EPA Reg. No. 71512-10) and 50WG formulation 

(Flonicamid 50WG, EPA Reg. No. 71512-9).

3.1 Chemical Identity

Table 3.1 Flonicamid Nomenclature.

Chemical Structure

Empirical Formula C3H6F3N3O

Common Name Flonicamid

Company Experimental Name IKI-220; F-1785

IUPAC Name N-cyanomethyl-4-(trifluoromethyl)nicotinamide

CAS Name N-(cyanomethyl)-4-(trifluoromethyl)-3-pyridinecarboxamide

CAS Registry Number 158062-67-0

End Use Product/EP Beleaf 50SG Insecticide (EPA Reg. No. 71512-10) and Flonicamid 

50WG (EPA Reg. No. 71512-9)

Chemical Class Pyridincarboxamids

The chemical structure and nomenclature of flonicamid and its metabolites are presented in 

Appendix B.

3.2 Physical/Chemical Characteristics

Flonicamid has a log octanol/water partition coefficient (log Pow) of 0.3 and is considered very

soluble in water (5 g/L at 20 oC), and is therefore highly mobile with a very low persistence in 

soil. Flonicamid is considered to be not very volatile, with a vapor pressure of 7.05 x 10-9 mm

Hg at 20oC and a Henry’s Law Constant of 4.2 x 10-8Pa m3/mol at 25oC. With a molecular 

weight of 229.2 g/mol, the potential to cross biological barriers is somewhat limited. In animal 

livestock studies flonicamid is rapidly metabolized and excreted with very low detectable levels 

in edible animal tissues. The physicochemical properties of flonicamid are summarized in 

Appendix B. 

N

CF3

N

H

O

N
Page 11 of 40

3.3 Pesticide Use Pattern

The petitioner has submitted amended labels for a 50SG formulation (Beleaf 50SG Insecticide,

EPA Reg. No. 71512-10) and for the 50WG formulation (Flonicamid 50WG, EPA Reg. No. 

71512-9). A summary of the proposed use patterns on berry, low growing (subgroup 13-07G), 

greenhouse grown cucumbers, and rapeseed (subgroup 20B) is detailed in Table 3.3. Flonicamid 

is proposed for use as a foliar spray using ground, aerial, and chemigation equipment on the low 

growing berry subgroup 13-07G, rapeseed subgroup 20A, and greenhouse grown cucumbers. It 

is also proposed as a soil drench for greenhouse grown cucumbers. The use profile is 

summarized in Table 3.3. The proposed single maximum application rate for each proposed crop 

or crop group is 0.089 lb ai/A (2.8 oz/A) with either of the Beleaf 50SG Insecticide or 

Flonicamid 50WG labels. Up to three seasonal applications can be made to crops in the low 

growing berry subgroup 13-07G and rapeseed subgroup 20A. Two seasonal applications can be 

made to the greenhouse grown cucumbers. The retreatment interval for all proposed crops is 7 

days. The pre-harvest intervals (PHIs) are 0 days for low growing berry subgroup 13-07G and 

greenhouse grown cucumbers, and 7 days for rapeseed subgroup 20A.

Table 3.3. Summary of Directions for Use of Flonicamid.

Application, 

Timing, 

Type and 

Equipment

Formulation 

(EPA Reg. 

Nos.).

App. Rate 

(lb ai/A)

[oz /A]

Max. No. 

App. per 

Season

RTI

(days)

Max. 

Seasonal 

App. 

Rate

(lb ai/A)

[oz /A]

PHI

(days) Use Directions and other Limitations

Berry, low growing, subgroup 13-07G [Bearberry, bilberry, blueberry, lowbush, cloudberry, cranberry, lingonberry, muntries 

partridgeberry, strawberry, cultivars, varieties, and/or hybrids of these]1.

Foliar spray 

ground or air

Beleaf 50SG

(EPA Reg.

No. 71512-

10) or

Flonicamid 

50WG (EPA 

Reg. No. 

71512-9)

0.089

[2.8]

3 7 0.267

[8.4]

0 Apply when Aphids or Lygus first appear in the field 

and before populations reach high levels. Flonicamid 

will stop Aphids or Lygus feeding rapidly but it may 

take several days to see reduction in Aphids or Lygus 

numbers. Reapply when new insects are detected. 

Two sequential applications of flonicamid result in 

better Aphids or Lygus control than a single 

application. Do not make more than 2 applications of 

flonicamid without rotating to an insecticide with a 

different mode of action. 

Greenhouse Cucumbers

Foliar 

directed

Beleaf 50SG

(EPA Reg.

No. 71512-

10) or

Flonicamid 

50WG (EPA 

Reg. No. 

71512-9)

0.089

[2.8]

2 7 4.28 

oz/A or 

0.1 oz per 

1000 ft2

0 1) For Aphids Plant Bugs. Begin applications before 

populations begin to build and before damage is 

evident, according to local pest management 

guidelines. Use LOWER RATE for building 

populations and HIGHER RATE for greater 

populations and/or dense foliage. Rapidly growing 

plants may need retreatment. Check plants often and 

retreat as necessary to maintain population below 

damaging levels.

2) For Greenhouse Whitefly. Apply when adult 

whiteflies first appear. Do not allow population to 

increase unchecked before making the first 

application. Application provides SUPPRESSION 

only. Apply in combination with other effective 

products for control. Check plants often and retreat as 

necessary to maintain population below damaging 

levels. 
Page 12 of 40

Table 3.3. Summary of Directions for Use of Flonicamid.

Application, 

Timing, 

Type and 

Equipment

Formulation 

(EPA Reg. 

Nos.).

App. Rate 

(lb ai/A)

[oz /A]

Max. No. 

App. per 

Season

RTI

(days)

Max. 

Seasonal 

App. 

Rate

(lb ai/A)

[oz /A]

PHI

(days) Use Directions and other Limitations

Chemigation

(to soil (soil 

drench) or 

growth 

media)

Beleaf 50SG

(EPA Reg.

No. 71512-

10) or

Flonicamid 

50WG (EPA 

Reg. No. 

71512-9)

0.089

[2.8]

2 7 4.28 oz/A 

or 2.8 

g/1000 ft2

0 Begin applications before populations begin to build 

and before damage is evident according to local pest 

management guidelines. Apply using a drench by 

hand, drip irrigation or with motorized calibrated 

irrigation equipment to the base of the plants.2

Rapeseed Subgroup 20A [Borage, crambe, cuphea, echium, flax seed, gold of pleasure, hare’s ear mustard, lesquerella, lunaria, meadowfoam, 

milkweed, mustard seed, oil raddish, poppy seed, rapeseed, sesame, sweet rocket, cultivars varieties, and/or hybrids of these].

Foliar spray 

ground or air

Beleaf 50SG

(EPA Reg.

No. 71512-

10) or

Flonicamid 

50WG (EPA 

Reg. No. 

71512-9)

0.089

[2.8]

3 7 0.267

[8.4]

7 Apply when Aphids or Lygus first appear in the field 

and before populations reach high levels. Flonicamid 

will stop Aphids or Lygus feeding rapidly but it may 

take several days to see reduction in Aphids or Lygus 

numbers. Reapply when new insects are detected. 

Two sequential applications result in better Aphids or 

Lygus control than a single application. Do not make 

more than 2 applications of flonicamid without 

rotating to an insecticide with a different mode of 

action.3

1

Spray adjuvants may improve coverage but do not use binder or sticker-type surfactants. Only use adjuvants known to be safe on strawberries.

2 Use a minimum of 25 gal/1000 plants but do not exceed the holding capacity of soil or growth media. Do not apply more than 4.28 oz/A (0.44 

oz/1000 plants based on 1 plant/4.5 ft2or 9712 plants/A) of flonicamid per application. 

3

Spray adjuvants may improve coverage but do not use binder or sticker-type surfactants. Only use adjuvants known to be safe on canola

3.4 Anticipated Exposure Pathways

Humans may be exposed to flonicamid in drinking water, since application may result in 

azoxystrobin reaching surface and ground water sources of drinking water. Humans may also be 

exposed through their diet from applications to agricultural commodities. There are no 

residential uses of flonicamid, so exposure to flonicamid does not occur in residential or nonoccupational settings. In an occupational setting, handlers may be exposed while handling the 

pesticide prior to application, as well as during application. There is also a potential for postapplication exposure for workers re-entering treated sites.

Risk assessments have been completed for the existing uses of flonicamid. This risk assessment 

considers all of the aforementioned exposure pathways based on the proposed new uses of 

flonicamid, but also considers existing uses of flonicamid, particularly in the dietary exposure 

assessment. 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 
Page 13 of 40

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary

exposures based on home use of pesticide products and associated risks for adult applicators and 

for children 3 to < 6 years old, youths and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary

patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

- Flonicamid: Human Health Risk Assessment for Proposed Uses on Root Vegetables (Except Sugar beet; 

Subgroup 1B), Tuberous and Corm Vegetables (Subgroup 1C), Leafy Brassica Green Vegetables (Subgroup 

5B), Turnip Greens, Hops, and Okra. PC Code: 128016, Petition No. 6E7081. S. Piper, DP347805, 12/21/2007.

A detailed hazard characterization with a list of available toxicity studies for flonicamid is 

presented in the most recent flonicamid risk assessment (DP347805, S. Piper, 12/21/2007). The 

submitted studies are of good quality and provide sufficient information to determine whether 

flonicamid poses a human health hazard. 

Since the last risk assessment, additional hazard data have not been submitted. In accordance 

with the 2007 revised 40 CFR Part 158 Toxicology data requirements, an immunotoxicity study

and a subchronic inhalation toxicity study were required for flonicamid. An immunotoxicity

study which is currently underway, and is expected to be submitted to the Agency in a few 

months, remains required for flonicamid. Previously, the registrant, ISK Biosciences 

Corporation, submitted waiver requests for the 28-day and 90-day subchronic inhalation toxicity

studies, which HED granted (DP290408, J. Arthur, 5/9/05 and DP297602, J. Arthur, 5/9/05). 

The waivers were granted based on flonicamid’s low acute inhalation toxicity (Toxicity Category

IV) and inhalation MOEs extrapolated from oral points of departure (PODs) that exceeded the 

target inhalation MOE of 1,000. However, based on current conditional requirements for 

inhalation toxicity data, the need for a subchronic inhalation study was reassessed by the HED 

Hazard and Science Policy Council (HASPOC). Based upon a weight of evidence approach the 

HASPOC concluded that a subchronic 28-day inhalation study is required at this time (TXR No. 

0056400, K. Rury, 7/30/12). In the absence of a route specific inhalation study, a 10X database 

uncertainty factor has been applied to assess risks for inhalation exposure scenarios.

4.1 Summary of Toxicological Effects

The oral studies in rats and dogs with flonicamid indicate the kidney and liver are the target 

organs for flonicamid toxicity. Increased kidney weight and hyaline droplet deposition and liver 

centrilobular hypertrophy were seen in the rat 28-day oral range-finding study, 90-day oral study, 
Page 14 of 40

developmental study and reproductive study. The 90-day dog study showed kidney tubular 

vacuolation, as well as increased adrenal weights, increased reticulocytes and decreased thymus 

weights. Increased reticulocyte counts were noted in both the subchronic and chronic dog 

studies. In the 28-day dermal study no dermal or systemic toxicity was seen at the limit dose 

(1000 mg/kg/day) for flonicamid technical.

Developmental effects (increased incidence of cervical ribs) were only observed at maternally 

toxic doses (liver and kidney gross and histopathological effects). No developmental effects 

were seen in rabbit fetuses. Offspring effects (decreased body weight and delayed sexual 

maturation) in the multi-generation study were seen only in the presence of parental toxicity

(kidney effects in males, blood effects in females). Thus, there is no concern for increased 

susceptibility of developing young for flonicamid. 

In an acute neurotoxicity study, signs of toxicity such as decreased motor activity, tremors, 

impaired gait and respiration were observed at lethal dose levels (1000 mg/kg). In a subchronic 

study, decreased body weight, body weight gain and food consumption, foot splay, rearing and 

decreased motor activity were seen in males at 67 mg/kg/day and above, and in females at 722 

mg/kg/day.

Preliminary results of an immunotoxicity study, submitted to EPA (J. Setser. 2012. “A 28-day

oral (dietary) immunotoxicity study of technical flonicamid in female CD-1 mice.”) suggest that 

flonicamid is not an immuno-suppressant, either structurally or functionally up to and including 

dose levels exceeding the Limit Dose. These results will be confirmed upon submission and 

detailed review of the study data.

Mutagenicity studies were negative for flonicamid and its metabolites TFNA, TFNA-AM, 

TFNG, TFNG-AM, and TFNA-OH. Flonicamid is carcinogenic in CD-1 mice, based on 

increased incidences of lung tumors associated with Clara cell activation. This tumor type, 

however, is associated with species and strain sensitivity and is not directly correlated with 

cancer risks in humans. Nasal cavity tumors in male Wistar rats were linked to incisor 

inflammation data and were not sufficient to make a similar determination in female rats. These 

nasolacrimal duct tumor findings for males were confounded by the lack of a dose-response and 

the biological significance is questionable; doses were at 1.84, 3.68, 7.32, and 36.8 mg/kg/day. 

The Cancer Assessment Review Committee (CARC) did not consider the nasolacrimal duct 

tumors in rats to be treatment related. The determination of carcinogenicity potential for 

flonicamid was made by the CARC on January 5, 2005 based on the weight of the evidence 

approach and resulted in the classification “suggestive evidence of carcinogenicity, but not 

sufficient to assess human carcinogenic potential” (TXR# 0052013, J. Kidwell, 2/24/05). The 

RAB3 risk assessment team determined that quantification of risk using a non-linear approach 

(i.e., using a chronic reference dose (cRfD)) adequately accounts for all chronic toxicity, 

including carcinogenicity that could result from exposure to flonicamid. Therefore, the cRfD is 

protective for carcinogenic effects. As a result, separate cancer risk assessments were not 

conducted. The cRfD was based on an endpoint of toxicity from a two generation reproduction 

study in rats. The NOAEL in this study was 3.7 mg/kg/day; the LOAEL of 22.3 mg/kg/day is 

based on increased kidney weights, kidney hyaline deposition, and increased blood serum 

luteinizing hormone in F1 females. 
Page 15 of 40

Flonicamid has a low acute toxicity via the oral (Tox Category III), dermal (Tox Category IV), 

and inhalation (Tox Category IV) routes of exposure. It is not an eye or skin irritant and is not a 

skin or dermal sensitizer. Flonicamid metabolites TFNA, TFNA-AM, TFNG, TFNG-AM, and 

TFNA-OH, likewise are classified as Category III for acute oral toxicity. The acute toxicity

category and toxicology profile of technical flonicamid are presented in the appendix (A1.0 and 

A 2.0).

4.2 Safety Factor for Infants and Children (FQPA Safety Factor)

HED has determined that reliable data show it would be safe for infants and children to reduce 

the FQPA safety factor to 1X for sort-term, intermediate-term, and dietary risk assessments. 

This determination is based on the considerations and reasons listed in the sections below.

4.2.1 Completeness of the Toxicology Database

The toxicity database for flonicamid is complete except for an immunotoxicity study and a 

subchronic inhalation study. Changes to 40 CFR §158 make immunotoxicity testing (OPPTS 

Guideline 870.7800) and a subchronic inhalation study required for pesticide registration. An 

immunotoxicity study has been conducted and will be submitted to EPA shortly. However, the 

existing data are sufficient for endpoint selection for exposure/risk assessment scenarios, and for 

evaluation of the requirements under the FQPA. While spleen weights were decreased in the 

subchronic dog study, there are no other indications in the available studies that organs 

associated with immune function are affected by flonicamid, and preliminary results of the 

above-mentioned immunotoxicity study suggested that flonicamid is not an immunosuppressant. 

EPA does not believe that the final results of the immunotoxicity study will result in a dose less 

than the point of departure already used in this risk assessment, and an additional database 

uncertainty factor for potential immunotoxicity does not need to be applied.

As explained above a subchronic 28-day inhalation study is required at this time (TXR No. 

0056400, K. Rury, 7/30/12). In the absence of a route specific inhalation study, the HASPOC 

recommended that a 10X database uncertainty factor be applied to assess risks for inhalation 

exposure scenarios.

4.2.2 Evidence of Neurotoxicity

The current data base includes acute and subchronic neurotoxicity studies. The clinical effects 

seen in these studies, while suggestive of an adverse effect on nervous tissue and/or function, did 

not occur in the absence of other effects. In the acute study, the increase in mortality suggests 

the animals were in an extreme condition. In the subchronic study, food consumption and body 

weight measurements suggest the animals were otherwise compromised and in a state of general 

malaise. Also, these types of effects were not observed in the other subchronic or chronic studies 

in mice, rats or dogs. Thus, there is not clear evidence of neurotoxicity. Lastly, clear NOAELs 

and LOAELs were defined for these effects, which are above the levels currently used for risk 

assessment purposes, the current risk assessment is protective of these effects, and a 

developmental neurotoxicity study is not required.
Page 16 of 40

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There was no evidence for quantitative or qualitative susceptibility following oral exposures to 

rats in utero or oral exposure to rabbits in utero. Following oral exposures to rats, developmental 

effects (cervical ribs) were seen only in the presence of maternal toxicity (liver and kidney

effects). No developmental effects were seen in rabbits. In the multi-generation reproduction 

study, developmental delays in the offspring (decreased body weights, delayed sexual 

maturation) were seen only in the presence of parental toxicity (kidney and blood effects). Also, 

there are clear NOAELs and LOAELs for all effects. The degree of concern for pre and/or postnatal susceptibility is, therefore, low due to the lack of evidence of qualitative and quantitative 

susceptibility.

4.2.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the flonicamid exposure database. An unrefined 

conservative chronic dietary exposure assessment for food and drinking water was conducted, 

assuming tolerance level residues for all existing and proposed commodities and 100% of 

registered and proposed crops treated. The drinking water assessment utilized water 

concentration values generated by models and associated modeling parameters which are 

designed to produce conservative, health protective, high-end estimates of water concentrations 

which are not likely to be exceeded. The dietary (food and drinking water) exposure assessment 

does not underestimate the potential exposure for infants, children, or women of child bearing 

age. 

4.3 Toxicity Endpoint and Point of Departure Selections

4.3.1 Summary of Points of Departure and Toxicity Endpoints Used in Human Health 

Risk Assessment 

The toxicological doses and endpoints supporting this petition remain unchanged and have been 

summarized in the previous human health risk assessment (DP347805, S. Piper, 12/21/2007). 

The toxicity endpoints and PODs are presented in Tables 4.3.1. and 4.3.2.

Table 4.3.1. Summary of Toxicological Dose and Endpoints for Flonicamid for Use in 

Dietary and Non-Occupational Human Health Risk Assessments.

Exposure Scenario

Point of 

Departure 

Uncertainty/FQ

PA Safety 

Factors

RfD, PAD, Level 

of Concern for 

Risk Assessment

Study and Toxicological 

Effects

Acute Dietary None NA aPAD = NA No toxicological effects seen in 

a single dose study.

Chronic Dietary NOAEL = 3.7

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Chronic RfD = 

0.04 mg/kg/day

cPAD = 0.04

mg/kg/day

2-Gen Reproduction rat

Parental LOAEL = 22

mg/kg/day based on increased 

kidney weights, kidney hyaline 

deposition, increased blood 

serum LH (F1 females). 
Page 17 of 40

Table 4.3.1. Summary of Toxicological Dose and Endpoints for Flonicamid for Use in 

Dietary and Non-Occupational Human Health Risk Assessments.

Exposure Scenario

Point of 

Departure 

Uncertainty/FQ

PA Safety 

Factors

RfD, PAD, Level 

of Concern for 

Risk Assessment

Study and Toxicological 

Effects

Incidental Oral (All 

time intervals) None NA Residential LOC for MOE = NA

No hazard was indentified,

since incidental oral exposure 

is not expected based on use 

pattern.

Short-Term (1 to 30 

days) & IntermediateTerm Dermal (1 to 6 

months)

None NA Residential LOC 

for MOE = NA

No hazard was indentified,

since the 28-day dermal study 

did not show any dermal or 

systemic effects at the limit 

dose of 1000 mg/kg/day.

Short-Term (1 to 30 

days) & IntermediateTerm Inhalation (1 to 

6 months)

NOAEL = 12

mg/kg/day

UFA = 10X

UFH = 10X

UFDB = 10X

FQPA SF = 1X

Residential LOC 

for MOE = 1000

90-Day oral rat

LOAEL = 60 mg/kg/day based 

on kidney hyaline deposition.

Cancer Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic 

Potential

Point of Departure (POD) = A data point or estimated point that is derived from observed dose-related data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant 

human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. 

UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFDB = database uncertainty factor. FQPA SF

= FQPA safety factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = 

margin of exposure. LOC = level of concern. NA = Not Applicable.

Table 4.3.2. Summary of Toxicological Dose and Endpoints for Flonicamid for Use in 

Occupational Human Health Risk Assessments.

Exposure Scenario

Point of 

Departure 

Uncertainty

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Short-Term (1 to 30 

days) & IntermediateTerm Dermal (1 to 6 

months)

None NA

Occupational 

LOC for MOE = 

NA

No hazard was indentified, since 

the 28-day dermal study did not 

show any dermal or systemic 

effects at the limit dose of 1000 

mg/kg/day.

Short-Term (1 to 30 

days) & IntermediateTerm Inhalation (1 to 

6 months)

Oral NOAEL = 

12 mg/kg/day

UFA = 10X

UFH = 10X

UFDB = 10X

Occupational

LOC for MOE = 

1000

90-Day oral rat

LOAEL = 60 mg/kg/day based on 

kidney hyaline deposition.

Cancer Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic 

Potential

Point of Departure (POD) = A data point or estimated point that is derived from observed dose-related data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant 

human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. 

UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFDB = database uncertainty factor. MOE = 

margin of exposure. LOC = level of concern. NA = Not Applicable.
Page 18 of 40

Based on the available toxicological database and the Agency's current practices, the inhalation 

risk for flonicamid was assessed using an oral toxicity study. The Agency sought expert advice 

and input on issues related to this route to route extrapolation approach (i.e. the use of oral 

toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and 

Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the 

SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, re-examine and develop new 

policies and procedures for conducting inhalation risk assessments, including route to route 

extrapolation of toxicity data. If any new policies or procedures are developed, the Agency may

revisit the need for an inhalation toxicity study for flonicamid and/or re-examine the inhalation 

toxicity risk assessment.

5.0 Dietary Exposure and Risk Assessment 

References:

Flonicamid: Human Health Risk Assessment for Proposed Uses on Root Vegetables (Except Sugar beet; Subgroup 

1B), Tuberous and Corm Vegetables (Subgroup 1C), Leafy Brassica Green Vegetables (Subgroup 5B), Turnip 

Greens, Hops and Okra. DP347805, S. Piper, 12/21/07.

Revised: Flonicamid: Petition for the Establishment of Permanent Tolerances and Registration for Use on Berry 

Low-Growing Subgroup 13-07G, Cucumber for Greenhouse Use Only, and Rapeseed Sub-group 20A. Summary of 

Analytical Chemistry and Residue Data. DP396902, A. Acierto, 10/2/12.

Drinking Water Assessment to Assess Flonicamid Use on Low Growing Berries Subgroup 13-07G, Greenhouse 

Cucumbers, and Rapeseed 20A. DP396906, J. Hetrick, 4/25/12.

Revised: Flonicamid Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for an 

IR-4 Section 3 Registration Action on Berry Low-Growing Subgroup 13-07G, Cucumber for Greenhouse Use Only, 

and Rapeseed Sub-group 20A. DP397279.dr1, C. Walls, 9/27/12.

5.1 Metabolite/Degradate Residue Profile

5.1.1. Summary of Metabolism Studies, Environmental Degradation, and Metabolic 

Pathway Comparison

The nature of the residue in plants and livestock are adequately understood for the purposes of 

this petition. Based on the metabolism studies conducted in plants, the major metabolic pathway 

of flonicamid in plants involves hydrolysis of the cyano (-CN) and amide (-CONH) functional 

groups and ring hydroxylation. The residues of concern in plants for tolerances and risk 

assessment are flonicamid and its metabolites TFNA, TFNA-AM, and TFNG. In livestock 

commodities, HED has determined that the residues of concern for the tolerances and risk 

assessment are flonicamid, TFNA and TFNA-AM. A more detailed description of the plant and 

animal metabolism studies is presented in the previous risk assessment (DP347805, S. Piper, 

12/21/07).
Page 19 of 40

5.1.2 Residues of Concern Summary

A summary of the metabolites and degradates of flonicamid for human health risk assessment is 

summarized in Table 5.1.2. 

Table 5.1.2. Summary of Metabolites and Degradates included in the Flonicamid Risk Assessment and 

Tolerance Expression

Matrix

Residues included in 

Risk Assessment

Residues included in 

Tolerance Expression

Plants

Primary Crop Flonicamid, TFNA, TFNA-AM and 

TFNG

Flonicamid, TFNA, TFNA-AM and 

TFNG

Rotational Crop Flonicamid, TFNA, TFNA-AM and 

TFNG

Flonicamid, TFNA, TFNA-AM and 

TFNG

Livestock

Ruminant Flonicamid, TFNA and TFNA-AM Flonicamid, TFNA and TFNA-AM

Poultry Flonicamid, TFNA and TFNA-AM Flonicamid, TFNA and TFNA-AM

Drinking Water

Flonicamid, TFNA, TFNG-AM, 

TFNG, TFNA-OH, TFNA-AM Not Applicable

5.2 Food Residue Profile

Adequate residue data are available to support dietary risk assessment as well as the proposed 

tolerances of flonicamid. Adequate field trial data were submitted on strawberries, greenhouse 

grown cucumbers, and canola supporting the use of the flonicamid 50SG formulation on the 

proposed crops/crop groups. An adequate number of field trials were conducted on the required 

representative crops in the appropriate geographic regions. The crop field trial data reflect the 

proposed multiple application rates and PHIs. Summaries of the residue data from the field and 

greenhouse trials are presented in Tables 5.2.1, 5.2.2, and 5.2.3.

Table 5.2.1. Summary of Residue Data from Strawberry Field Trials with Flonicamid.

Commodity Analyte Total

Rate

(lb ai/A)

PHI 

(days)

Residue Levels (ppm flonicamid equivalents)

n Sampl

e Min.

Sampl

e Max.

LAFT1 HAFT1 Media

n

Mean Std. 

Dev.

Strawberry, 

Berries with 

caps 

removed

Flonicamid

0.263-0.280 0 7

0.11 0.66 0.13 0.54 0.34 0.34 0.16

TFNA <0.02 0.12 <0.02 0.12 0.052 0.051 0.035

TFNA-AM <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A

TFNG <0.02 0.083 <0.02 0.080 0.026 0.036 0.022

Combined2<0.17 <0.79 <0.19 <0.73 0.41 0.45 0.20

1

LAFT: Lowest average field trial; HAFT: highest average field trial

2 Combined residues of flonicamid, TFNA, TFNA-AM, and TFNG, calculated at flonicamid equivalents.
Page 20 of 40

Table 5.2.2. Summary of Residue Data from Cucumber Greenhouse Trials with Flonicamid.

Commodity Analyte Total Rate

lb ai/A

[kg ai/ha]

PHI 

(days)

Residue Levels (ppm)

n Min. Max. LAFT* HAFT* Median

(STMdR)

Mean

(STMR)

Std. 

Dev.

Foliar

Cucumber 

fruit

Flonicamid 0.262-

0.291 

[0.294-

326]

0 4

<0.046 0.69 0.054 0.54 0.101 0.2 0.23-

TFNA <0.02 0.034 <0.02 0.031 0.02 0.23 0.005

TFNA-AM <0.02 <0.02 <0.02 <0.02 0.02 0.02 0

TFNG <0.02 0.03 <0.02 0.028 0.02 0.23 0.004

Chemigation

Cucumber 

fruit

Flonicamid 0.264-

0.269 

[0.296-

0.302]

0 4

0.012 0.2 0.013 0.2 0.112 0.11 0.073

TFNA <0.02 0.023 0.02 0.023 0.02 0.021 0.001

TFNA-AM <0.02 <0.02 <0.02 <0.02 0.02 0.02 0

TFNG <0.02 0.11 <0.02 0.11 0.02 0.043 0.04

*LAFT = Lowest average field trial; HAFT = Highest average field trial. 

Table 5.2.3. Summary of Residue Data from Canola Field Trials with Flonicamid.

Commodity Analyte Total

Rate

(lb ai/A)

PHI 

(days)

Residue Levels (ppm flonicamid equivalents)1,2

n Sample 

Min.

Sample 

Max.

LAFT2 HAFT2 Media

n

Mean Std. 

Dev.

Canola seed

Flonicamid

0.261-0.272 6-8 8

<0.2 0.333 <0.2 0.333 0.2 0.215 0.048

TFNA <0.24 <0.24 <0.24 <0.24 0.24 0.24 0

TFNA-AM <0.24 <0.24 <0.24 <0.24 0.24 0.24 0

TFNG <0.18 0.287 <0.18 0.287 0.18 0.195 0.039

Combined3<0.86 1.10 <0.86 1.1 0.86 0.650 0.245

1 The LOQ was 0.2 ppm for all analytes. Values reflect per trial averages; n = no. of field trials. Data reflect conversion of 

quantifiable residues of TFNA, TFNA-AM, and TFNG to parent equivalents by the study reviewer.

2 LAFT = lowest average field trial; HAFT = highest average field trial.

3 Combined residues of flonicamid, TFNA, TFNA-AM, and TFNG calculated using molecular weight conversion factors of 1.20, 

1.21, and 0.92, respectively.

Field trial decline studies demonstrate that the combined residues of flonicamid and its 

metabolites in strawberry decline with increasing pre-harvest intervals (PHIs). Residue decline 

was observed in greenhouse grown cucumber treated by foliar spray but not in crops treated by 

chemigation where the residues increased from the 0- to 7-day PHIs. A decline study was not 

submitted for canola.

Adequate processing studies in/on canola are available. The processing data indicate that the 

combined residues of flonicamid, TFNG, TFNA, and TFNA-AM do not concentrate in canola 

meal and canola oil (each have 0.27x average processing factor). The reported processing 

factors do not exceed the theoretical concentration factor of 1.0x for canola meal and 3.0x for 

canola oil (OCSPP §860.1520, Table 3). Based on these results, the tolerances for livestock 

commodities will not change. Residue data from the canola processing study are reported in 

Table 5.2.4. 
Page 21 of 40

Table 5.2.4. Residue Data from Canola Processing Study with Flonicamid.

RAC Processed 

Commodity

Total 

Rate

(lb ai/A)

PHI Residues (ppm)1[Average] Processing Factor2

FlonicamidTFNA TFNAAM TFNG Combined3FlonicamidTFNA TFNAAMTFNG Combined3

Canola

Seed

(RAC)

0.821 8

--

4

,

0.232

[0.232]

<0.02,

<0.02

[<0.02]

<0.02,

<0.02

[<0.02]

<0.02,

<0.02

[<0.02]

<0.292

[<0.292]

NA5- NA -- -- --

Meal

<0.02,

<0.02

[<0.02]

<0.02,

<0.02

[<0.02]

<0.02,

<0.02

[<0.02]

<0.02,

<0.02

[<0.02]

<0.08,

<0.08

[<0.08]

<0.09x NC5 NC NC <0.27x

Oil <0.02 <0.02 <0.02 <0.02 <0.08 <0.09x NC NC NC <0.27x

1 The LOQ was 0.02 ppm for all analytes. Averages and combined residues were calculated by the study reviewer using the LOQ 

for values reported as <LOQ. The second value for seed and meal reflects the results of re-dilution (seed) or reinjection (meal). 

Residues of the metabolites were <LOQ in/on all samples and therefore were not converted to parent equivalents.

2

Processing Factor = [Measured residue for analyte in the processed fraction] / [Measured residue for analyte in the RAC]. 

3 Combined residues of flonicamid, TFNA, TFNA-AM, and TFNG.

4 The first value obtained for seed (0.143 ppm) was rejected by the study director because it was outside the linearity range.

5 NC = Not calculated; residues were below the LOQ (<0.02 ppm for all in analytes) in the RAC and processed fraction; NA= not 

available

The submitted storage stability data demonstrate that residues of flonicamid, TFNA, TFNA-AM, 

and TFNG are stable in/on the RAC samples of strawberry, cucumber and canola stored frozen 

for up to 460, 336 and 735 days, respectively. The available data on five diverse crops (oil seed, 

non-oily grain, root and tuber crop, leafy vegetables, and fruiting vegetables) support the storage 

conditions and durations on strawberry, cucumber and canola.

Rotational Crops

No new rotational crop data were submitted and none are required with the use of flonicamid on 

rapeseed, cucumber and berry. 

5.3 Water Residue Profile

The drinking water assessment was conducted by the EFED using a parent only and total toxic 

residue (TTR) approach. TTRs include 4-trifluoromethylnicotinic acid (TFNA), 4-

trifluoromethylnictinamide (TFNA-AM), 6-hydro-4-trifluoromethylnicotinic acid (TFNA-OH), 

N-(4-trifluoromethylnicotinoyl) glycine (TFNG), and N-(4-trifluoromethylnicotinoyl) 

glycinamide (TFNG-AM). Tier I ground water EDWCs were calculated using SCI-GROW 

model. Tier II surface water EDWCs were calculated using PRZM and EXAMS models. All 

Tier II surface water modeling was corrected for percent cropped area (PCA). EFED estimates 

drinking water concentrations of a chemical based on the highest rate of application of the 

chemical on all registered and proposed crops. The predicted concentrations of flonicamid total 

toxic residues for the proposed uses, except for cranberry, are lower than EDWCs in previous 

drinking water assessments. The EDWCs for cranberry were estimated using the Tier 1 rice 

model which does not account for dilution and degradation. Because flonicamid and it 

degradation products degrade rapidly in aerobic soil (t1/2=5.2 days), the EDWCs for cranberry

are expected to be highly conservative. The conservative nature of the EDWCs for cranberry

uses limit their use as Tier 1 screening concentrations (94.93 μg/L for single application and 
Page 22 of 40

285.44 μg/L for annual application rate). EFED, therefore, recommended that HED continue to 

use the 1 in 10 year annual average and 30 year annual average EDWCs from previous drinking 

water assessments. The 1 in 10 year daily peak, however, should be changed to reflect the peak 

EDWC for flonicamid TTR from the Florida strawberry scenario in this assessment. The 

concentration of total toxic residues of flonicamid (flonicamid TTR) should not exceed 9.031

μg/L for a 1 in10 year daily peak, 1.9 μg/L for 1 in 10 year annual average, and 0.94 μg/L for 30 

year annual average. 

Based on Tier II surface water modeling for the proposed uses, other than cranberries, the 

concentration of flonicamid should not exceed 7.00 μg/L for a 1 in10 year daily peak, 0.141

μg/L for 1 in 10 year annual average, and 0.065 μg/L for 30 year annual average. The 

concentration of total toxic residues of flonicamid (flonicamid TTR) should not exceed 9.031

μg/L for a 1 in10 year daily peak, 0.968 μg/L for 1 in 10 year annual average, and 0.488 μg/L for 

30 year annual average. 

Tier 1 rice modeling was conducted to assess flonicamid residues from use on cranberries. The 

estimated drinking water concentrations (EDWCs) of flonicamid TTR in edge of bog surface 

water concentrations are not expected to exceed 94.93 μg/L and 285.44 μg/L for an application 

rate of 0.089 lbs/A and 0.2676 lbs/A, respectively. These concentrations are expected to be 

extremely conservative because the Tier 1 rice model does not account for dilution and 

degradation. 

Tier I ground water modeling indicates that concentrations flonicamid and flonicamid TTR in 

ground water concentrations should not exceed 0.000753 μg/L and 0.00132 μg/L, respectively,

for peak and long-term average concentrations. No monitoring data are available to assess 

flonicamid concentrations in ground and surface waters. 

The surface water EDWC of 1.9 μg/L (ppb) was used in the chronic dietary assessment.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data & Percent Crop Treated Used in Dietary Assessment

An acute dietary risk assessment was not performed as flonicamid has no acute toxicological 

endpoint. Tolerance level residues combined with 100% crop treated were used to determine the 

chronic dietary exposure and risk estimates. Separate tolerances were established for dried 

potatoes, tomato paste, and tomato puree based on processing studies. The adjustment factor #1 

was set to 1.0 for these commodities; the DEEM default processing factors were used for the 

other processed commodities for which default processing factors are available.

5.4.2 Acute Dietary Risk Assessment

There was no acute endpoint identified in the toxicity studies; and therefore, no acute dietary

assessment is needed. 
Page 23 of 40

5.4.3 Chronic Dietary Risk Assessment

A chronic dietary exposure assessment was conducted for the general U.S. population and all 

population subgroups. The chronic dietary exposure for food and drinking water utilized 11% of 

the cPAD for the general U.S. population. The chronic dietary exposure for the highest reported 

exposed population subgroup, children 1-2 years old, utilized 28% of the cPAD. The results are 

reported in table 5.4.4. All population subgroups were below the LOC. 

5.4.4 Summary Table

Table 5.4.4. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Flonicamid

Population Subgroup*

cPAD 

(mg/kg/day)

Dietary Exposure 

(mg/kg/day) % cPAD**

General U.S. Population

0.04

0.004455 11

All Infants (< 1 year old) 0.006272 16

Children 1-2 years old 0.011236 28

Children 3-5 years old 0.008413 21

Children 6-12 years old 0.004999 11

Youth 13-19 years old 0.003184 8

Adults 20-49 years old 0.003864 10

Females 13-49 years old 0.003962 10

Adults 50+ years old 0.004270 11

*The values for the highest exposed population are bolded.

** Report % cPAD to 2 significant figures.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

This document addresses the proposed new agricultural uses of flonicamid on low growing berry

subgroup 13-07G, rapeseed subgroup 20A, and greenhouse grown cucumbers. Therefore, no 

new residential exposure is expected. There are registered labels with use on commercial 

ornamentals, interiorscapes, and nurseries; but these labels do not allow use in home gardens and 

greenhouses or in any residential settings. Therefore, residential handler scenarios are not 

expected and need not be assessed. Additionally, because no dermal toxicity endpoint was 

identified for flonicamid, a post-application residential exposure/risk assessment is not 

necessary.

6.1 Residential Bystander Post-Application Inhalation Exposure

Although a quantitative residential post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational handlers. This 

exposure scenario is representative of a worse case inhalation exposure and should be considered 

protective of most post-application inhalation exposure scenarios.
Page 24 of 40

6.2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for flonicamid. The 

Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks

associated with drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g. a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure. For flonicamid, potential exposures from food and drinking water 

scenarios were aggregated. 

7.1 Acute Aggregate Risk

An endpoint attributable to a single oral dose was not identified in the toxicity database; 

therefore, an acute dietary risk RfD was not established and an acute aggregate risk assessment 

was not conducted. 

7.2 Short-Term Aggregate Risk

A short-term aggregate risk assessment was not conducted because residential exposure is not 

expected from the use pattern proposed in this registration request, or from any registered uses.

7.3 Intermediate-Term Aggregate Risk

An intermediate-term aggregate assessment was not conducted because residential exposure is 

not expected from the use pattern proposed in this registration request, or from any registered 

uses.
Page 25 of 40

7.4 Chronic Aggregate Risk

This assessment was conducted for food and drinking water exposures only. There are no 

expected long-term residential exposures. Because drinking water estimates have been 

combined with dietary exposures, the dietary assessment described earlier (see Section 5.4) 

serves as the aggregate exposure and risk assessment for flonicamid. Because aggregated food 

and drinking water exposures from this conservative assessment for the most highly exposed 

population subgroup (Children 1-2 years old) only amount to 25% of the cPAD, exposure to 

flonicamid from the uses subject to this registration action do not exceed HED’s level of 

concern.

7.5 Cancer Aggregate Risk

This assessment was not deemed necessary because evidence of flonicamid’s carcinogenicity is 

only suggestive and not sufficient to assess human carcinogenic potential.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to flonicamid and any other substances and flonicamid does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that flonicamid has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

References: FLONICAMID: Occupational and Residential Exposure/Risk Assessment for Use on Berry LowGrowing Subgroup 13-07G, Cucumber for Greenhouse Use Only, and Rapeseed Sub-group 20A. DP397278, C. 

Walls, 7/17/12.

9.1 Short-/Intermediate-Term Handler Risk

Flonicamid is proposed for use on low growing berries, greenhouse grown cucumbers, and 

rapeseed/canola. Application methods, maximum application rates and use sites are summarized 

in Table 3.3. Based on the proposed use patterns of flonicamid, there is a potential for short- and 

intermediate-term dermal and inhalation occupational exposures during handling (mixing, 

loading, and applying) and post-application activities. Chronic exposure is not expected for the 

proposed use patterns. PPE was assessed at baseline (long pants, a long-sleeved shirt, shoes, 

socks, no chemical-resistant gloves, and no respirator). Both the Beleaf 50SG Insecticide and 

Flonicamid 50WG formulations require handlers to wear long sleeved shirts, long pants, 

waterproof gloves, shoes, and socks. 
Page 26 of 40

A summary of the short- and intermediate-term risk estimates for occupational handlers mixing, 

loading, and applying flonicamid to low growing berries, greenhouse cucumbers, and 

rapeseed/canola are presented in Table 9.1. Dermal hazard was not identified for flonicamid; 

therefore, only a quantitative inhalation exposure assessment was performed. HED’s LOC for 

the inhalation MOE is defined by the uncertainty factors that are applied to the assessment. HED 

applies a 10X factor to account for interspecies extrapolation, a 10X factor to account for 

intraspecies sensitivity, and an additional 10X database uncertainty factor because the endpoint 

and point of departure chosen are derived from an oral toxicity study. Therefore, the total 

uncertainty factor that has been applied to the non-cancer risk assessment for flonicamid is 

1000X for occupational short-/intermediate-term inhalation exposure. Occupational inhalation 

exposure and risk estimates resulting in MOEs ≥1000 will not be of concern to HED.

The results of the occupational handler exposure and risk assessment indicate that most scenarios 

result in short- and intermediate-term MOEs that range from 2,200 to 450,000 and are not of 

concern to HED (i.e. an MOE > 1000) with baseline attire. However, the short-/intermediateterm MOEs for two scenarios result in risk estimates that exceed HED’s level of concern; i.e. 1) 

the scenario of mixing/loading/applying for soil drench applications to greenhouse grown 

cucumbers using a mechanically pressurized handgun results in an MOE of 440, and 2) the 

scenario of mixing/loading/applying sprays to greenhouse grown cucumbers using a 

mechanically pressurized handgun results in an MOE of 600. With the addition of a PF5 

dust/mist respirator the MOEs for these two scenarios are 2,200 and 3,100, respectively, which 

do not exceed HED’s level of concern. A PF5 dust/mist respirator is assumed to reduce 

inhalation exposure by 80%. Therefore, the proposed labels should be amended to include the 

requirement for a PF5 dust/mist respirator.

Table 9.1: Short- and Intermediate-Term Agricultural Handler Exposure and Risk for Flonicamid

Exposure 

Scenario Crop App Rate (lb ai/A)1

Amount Treated 

Daily

Unit Exposure3 Dose MOEs5

Baseline 

inhalation 

(μg/lb ai)

Baseline 

Inhalation

(mg/kg/Day)4

Baseline 

Inhalation

Mixer/Loader

M/L WDG to 

Support Aerial 

Application

Canola

Strawberry 0.089 350 acres 8.96 0.0035 3,400

M/L WDG to 

Support 

Chemigation 

Canola

Strawberry 0.089 350 acres 8.96 0.0035 3,400

Greenhouse 

cucumbers 0.13 60 acres 8.96 0.00090 14,000

M/L WDG to 

Support 

Groundboom 

Application

Canola

Strawberry 0.089 80 acres 8.96 0.00080 15,000

Applicator
Page 27 of 40

Table 9.1: Short- and Intermediate-Term Agricultural Handler Exposure and Risk for Flonicamid

Exposure 

Scenario Crop App Rate (lb ai/A)1

Amount Treated 

Daily

Unit Exposure3 Dose MOEs5

Baseline 

inhalation 

(μg/lb ai)

Baseline 

Inhalation

(mg/kg/Day)4

Baseline 

Inhalation

Applying Sprays 

via Aerial 

Equipment

Canola

Strawberry 0.089 350 acres 0.068 0.000026 450,000

Applying Sprays 

via Groundboom 

Equipment

Canola,

strawberry 0.089 80 acres 0.34 0.000030 400,000

Flagger

Flagging for 

Aerial Sprays

Canola

Strawberry 0.089 350 acres 0.35 0.00014 88,000

Mixer/Loader/Applicator

Manually 

Pressurized 

Handwand WDG

Greenhouse 

cucumbers 0.013e

40 gallons 30 0.00020 60,000

Backpack Sprayer 

WDG

Greenhouse 

cucumbers 0.013e

40 gallons 140 0.00094 13,000

Mechanically 

Pressurized 

Handgun WDG

Greenhouse 

cucumbers 0.013e

1000 gallons

120 0.020 600

24 (with 

Respirator) 0.0039 3,100

Mechanically 

Pressurized 

Handgun WDG

Greenhouse 

cucumbers 

(drench)

0.00055f1000 gallons

3,931 0.027 440

786 (with 

Respirator) 0.0054 2,200

Mechanically 

Pressurized 

Handgun WDG

Strawberry 0.0018 g1000 gallons 3.9 0.000085 140,000

Mechanically 

Pressurized 

Handgun WDG

Canola 0.0088 h1000 gallons 3.9 0.00043 28,000

a Application rates are the maximum application rates determined from proposed labels for flonicamid.

b Amount handled per day values are HED estimates of acres treated per day based on Exposure SAC SOP #9 “Standard 

Values for Daily Acres Treated in Agriculture,”

c Baseline Inhalation: no respirator.

d Inhalation ST/IT MOE = NOAEL (12 mg/kg/day) / inhalation daily dose (mg/kg/day), where inhalation dose = daily 

unit exposure (μg/lb ai) x 0.001 mg/1 μg x application rate (lb ai/A) x area treated (A/day) / body weight (80 kg adult). 

LOC = 100

e Application rate 0.013 lb ai/gal = 4.28 oz/A x A/10 gal x 1 lb/16 oz x 50%ai

f Application rate 0.00055 lb ai/gal = 0.44oz/1000 plants x 1000 plants/25 gal x 1 lb/16 oz x 50% ai

g Application rate 0.0018 lb ai/gal = 2.8oz/A x A/50 gal x 1 lb/16 oz x 50%ai

h Application rate 0.0088 lb ai/gal = 2.8 oz/A x A/10 gal x 1 lb/16 oz x 50%ai
Page 28 of 40

9.2 Short-/Intermediate-Term Post-Application Risk

9.2.1 Dermal Post-Application Risk

The proposed occupational uses for flonicamid addressed in this document involve application to 

crops, resulting in the potential for exposure to flonicamid during post-application activities. 

However, an appropriate dermal endpoint was not identified for flonicamid. Therefore, an 

assessment of occupational dermal post-application exposure to flonicamid was not conducted.

9.2.2 Inhalation Post-Application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for flonicamid at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV) and low vapor pressure (7.05 x 10-9 mmHg at 20 oC). 

However, there are multiple potential sources of post-application inhalation exposure to 

individuals performing post-application activities in previously treated fields. These potential 

sources include volatilization of pesticides and resuspension of dusts and/or particulates that 

contain pesticides. The Agency sought expert advice and input on issues related to volatilization 

of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory

Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for flonicamid.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational handlers. 

Handler exposure resulting from application of pesticides outdoors is likely to result in higher 

exposure than post-application exposure. Therefore, it is expected that these handler inhalation 

exposure estimates would be protective of most occupational post-application inhalation 

exposure scenarios.

Restricted Entry Interval: Technical flonicamid is classified as toxicity category IV for acute 

dermal toxicity, primary eye, and skin irritation. Under the WPS, active ingredients classified as 

acute toxicity categories III or IV for these routes are assigned a 12-hour REI. For all activities 

and crops, the REI of 12 hours on the proposed labels is appropriate to protect workers. 

10.0 References

Flonicamid: Human Health Risk Assessment for Proposed Uses on Root Vegetables (Except Sugar beet; Subgroup 

1B), Tuberous and Corm Vegetables (Subgroup 1C), Leafy Brassica Green Vegetables (Subgroup 5B), Turnip 

Greens, Hops and Okra. DP347805, S. Piper, 12/21/07.
Page 29 of 40

Revised: Flonicamid: Petition for the Establishment of Permanent Tolerances and Registration for Use on Berry 

Low-Growing Subgroup 13-07G, Cucumber for Greenhouse Use Only, and Rapeseed Sub-group 20A. Summary of 

Analytical Chemistry and Residue Data. DP396902, A. Acierto, 5/16/12.

Drinking Water Assessment to Assess Flonicamid Use on Low Growing Berries Subgroup 13-07G, Greenhouse 

Cucumbers, and Rapeseed 20A. DP396906, J. Hetrick, 4/25/12.

Revised: Flonicamid Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for an 

IR-4 Section 3 Registration Action on Berry Low-Growing Subgroup 13-07G, Cucumber for Greenhouse Use Only, 

and Rapeseed Sub-group 20A. DP397279.dr1, C. Walls, 9/27/12.

FLONICAMID: Occupational and Residential Exposure/Risk Assessment for Use on Berry Low-Growing Subgroup 

13-07G, Cucumber for Greenhouse Use Only, and Rapeseed Sub-group 20A. DP397278, C. Walls, 7/17/12.

Appendix A. Toxicology Profile 

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for non-food use for flonicamid are in Table 1. Use of the 

new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1. Toxicology Data Requirements for Flonicamid.

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation ..............................................

870.2600 Dermal Sensitization......................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

870.3150 Oral Subchronic (nonrodent).........................................

870.3200 21-Day Dermal ..............................................................

870.3250 90-Day Dermal ..............................................................

870.3465 28-Day Inhalation..........................................................

yes

yes

yes

no

yes

yes

yes

yes

-

no

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (nonrodent).............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse)....................................................

870.4300 Chronic/Oncogenicity....................................................

yes

yes

no

yes

yes

yes

yes

-

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5375 Mutagenicity—Structural Chromosomal Aberrations...

870.5385 Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes
Page 30 of 40

Table A.1. Toxicology Data Requirements for Flonicamid.

Study

Technical

Required Satisfied

870.6100a Acute Delayed Neurotoxicity (hen)...............................

870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotoxicity Screening Battery (rat) .................

870.6200b 90-Day Neurotoxicity Screening Battery (rat)...............

870.6300 Develop. Neurotoxicity .................................................

no

no

yes

yes

no

-

-

yes

yes

no

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity .............................................................

yes

no

yes

yes

-

no

Special Studies for Ocular Effects

Acute Oral (rat)...........................................................

Subchronic Oral (rat) ..................................................

Six-month Oral (dog)..................................................

-

-

-

-

-

-

A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity Data on Technical Flonicamid.

Guideline

No. Study Type MRID No. Results Toxicity Category

870.1100 Acute Oral - Rat 45656707 LD50 = 884 mg/kg (Males), 

LD50 = 1768 mg/kg (Females) III

870.1200 Acute Dermal - Rat 45656708 LD50 > 5000 mg/kg IV

870.1300 Acute Inhalation - Rat 45656709 LC50 > 4.9 m/L IV

870.2400 Primary Eye Irritation - Rabbit 45656710 None or very low effects. IV

870.2500 Primary Skin Irritation - Rabbit 45656711 Erythema & edema scores were zero. IV

870.2600 Dermal Sensitization - Guinea Pig 45656712 Not a sensitizer. NA

870.1100 Acute Oral – Rat

Flonicamid metabolite TFNA

45854605 LD50  2000 mg/kg III

870.1100 Acute Oral – Rat

Flonicamid metabolite TFNA-AM

45854606 LD50  2000 mg/kg III

870.1100 Acute Oral – Rat

Flonicamid metabolite TFNG

45854607 LD50  2000 mg/kg III

870.1100 Acute Oral – Rat

Flonicamid metabolite TFNG-AM

45854608 LD50  2000 mg/kg III

870.1100 Acute Oral – Rat

Flonicamid metabolite TFNA-OH

45854609 LD50  2000 mg/kg III

Table A.2.2. Flonicamid Toxicity Results From Repeated Dosing and Other Studies.

Study 

Guideline/Study

MRID Results

870.3100a

90-Day oral 

toxicity in rats

45656721 (2002)/ 

acceptable-guideline/ 

0, 50 (males) , 200, 1000, 2000 

(males), or 5000 (females) ppm 

(3.08, 12.11, 60.0, or 119.4 

mg/kg/day, males & 14.52, 72.3, or 

NOAEL = 200 ppm (12.11 mg/kg/day, males); 1000 

ppm (72.3 mg/kg/day, females) 

LOAELs = 1000 ppm (60.0 mg/kg/day, males) based 

on hyaline deposition in the kidney; 5000 ppm (340 

mg/kg/day, females) based on hyaline deposition in 

the kidney and centrilobular hypertrophy in the liver.
Page 31 of 40

Table A.2.2. Flonicamid Toxicity Results From Repeated Dosing and Other Studies.

Study 

Guideline/Study

MRID Results

340.1 mg/kg/day, females) 

28-day range-finding: 45656720 

(2002)/ acceptable (non-guideline)/ 

0, 50 (males), 500, 1000, 5000 or 

10000 (females) ppm ( 3.61, 7.47, 

36.45, 73.8, or 353.4 mg/kg/day, 

males & 8.36, 41.24, 81.9, 372.6, 

or 642 mg/kg/day, females)

28-day range-finding: 

NOAEL = 100 ppm (7.47 mg/kg/day, males); 1000 

ppm (81.9 mg/kg/day, females) 

LOAELs = 500 ppm (36.45 mg/kg/day, males);

based on hyaline deposition in the kidney; 5000 ppm 

(372.6 mg/kg/day, females) based on hyaline 

deposition in the kidney, centrilobular hypertrophy in 

the liver, anemia and increased cholesterol. 

870.3100b

90-Day oral 

toxicity rodents 

(mice)

45656719 (2001)/ 

acceptable (non-guideline)/ 

0, 100, 1000 or 7,000 ppm (0, 

15.25, 153.9 or 1069 mg/kg bw/day 

in males, and 0, 20.10, 191.5, or 

1248 mg/kg bw/day in females)

NOAEL is 100 ppm (males: 15.25 mg/kg bw/day, 

females: 20.10 mg/kg bw/day)

LOAEL is 1000 ppm (males: 153.9 mg/kg bw/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.

870.3150

90-Day oral 

toxicity in dogs

45646722 (2001)/ 

acceptable - guideline/ 

0, 3, 8, 20, or 50 (females) mg/kg 

bw/day

NOAEL is 8 mg/kg/day in males and 20 mg/kg/day 

for females. 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. 

870.3200

21-Day dermal 

toxicity in rats

45656723 (2001)/ acceptable -

guideline/ 0, 20, 150, or 1000 

mg/kg/day

NOAEL is 1000 mg/kg/day

LOAEL is >1000 mg/kg/day. 

870.3700a

Prenatal 

developmental in 

rats

45656724 (2002)/ acceptable -

guideline/ 0, 20, 100 or 500 mg/kg 

bw/day

Maternal 

NOAEL is 100 mg/kg bw/day

LOAEL is 500 mg/kg bw/day, based on increased 

liver weight, and liver and kidney pathological 

changes (hypertrophy of centrilobular hepatocytes in 

liver and vacuolation of proximal tubular cell in 

kidneys). 

Developmental 

NOAEL is 100 mg/kg bw/day 

LOAEL is 500 mg/kg bw/day, based on the 

increased incidence of cervical rib. 

870.3700b

Prenatal 

developmental in 

45854611 & 45854610 (2002)/ 

acceptable - guideline/ 0, 2.5, 7.5, or 

25 mg/kg/day

Maternal 

NOAEL is 7.5 mg/kg/day 

LOAEL is 25 mg/kg/day, based on decreased body 
Page 32 of 40

Table A.2.2. Flonicamid Toxicity Results From Repeated Dosing and Other Studies.

Study 

Guideline/Study

MRID Results

rabbits weights, body weight gains, and food consumption. 

Developmental 

NOAEL is  25 mg/kg/day 

LOAEL is not established.

870.3800

Reproduction and 

fertility effects in 

rats

45854613 and 45854612 (2002)/ 

acceptable - guideline/ 0, 50, 300, or 

1800 ppm (0/0, 3.7/4.4, 22.3/26.5, 

and 132.9/153.4 mg/kg bw/day 

[M/F])

Parental

NOAEL is 50 ppm (equivalent to 3.7/4.4 mg/kg/day 

[M/F]). 

LOAEL is 300 ppm (equivalent to 22.3/26.5 

mg/kg/day [M/F]) based on increased relative kidney 

weight and hyaline droplet deposition in the 

proximal tubules of the kidneys in the males and 

increased blood serum LH levels in the F1 females. 

Offspring

NOAEL is 300 ppm (equivalent to 22.3/26.5 

mg/kg/day [M/F]). LOAEL is 1800 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. 

Reproductive Performance

NOAEL is 1800 ppm (equivalent to 132.9/153.4 

mg/kg/day [M/F]). 

LOAEL for reproductive performance was not 

observed. 

870.4100b

Chronic toxicity 

in dogs

45854614 (2003)/ 

acceptable - guideline/ 

0, 3, 8, or 20 mg/kg/day

NOAEL is 8 mg/kg/day. 

LOAEL is 20 mg/kg/day, based on acute clinical 

signs (vomiting, mostly within the first week), 

clinical pathology at 12 months (higher reticulocytes 

counts) in males and females. 

870.4200b

Carcinogenicity in 

mice

45854615 & 45854616 (2003)/ 

acceptable - guideline/ 0, 250, 750, 

or 2250 ppm (0/0, 29/38, 88/112, or 

261/334 mg/kg/day [M/F])

NOAEL was not established. 

LOAEL is 250 ppm (equivalent to 29/38 mg/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 IKI220 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 
Page 33 of 40

Table A.2.2. Flonicamid Toxicity Results From Repeated Dosing and Other Studies.

Study 

Guideline/Study

MRID Results

is specific to sensitive strains of mice.

Carcinogenic in mice.

870.4200b

Carcinogenicity in 

mice

46205801 (2004)/acceptable -

guideline/ 0, 10, 25, 80, 250 ppm 

[males: 0, 1.20, 3.14, 10.0, 30.3 

mg/kg/day; females: 0, 1.42, 3.67, 

11.8, 36.3 mg/kg/day]

NOAEL is 80 ppm (equivalent to 10/12 mg/kg/day 

in males/females). 

LOAEL is 250 ppm (equivalent to 30/36 mg/kg/day 

in males/females) based on lung masses and terminal 

bronchiole epithelial cell hyperplasia/hypertrophy in 

both sexes. 

At the doses tested, the carcinogenic potential of IKI220 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 epithelial 

cell hyperplasia/hypertrophy in both sexes.

Carcinogenic in mice.

870.4300

Combined 

Chronic toxicity/ 

Carcinogenicity in 

rats

45863801 (2002)/ acceptable -

guideline/ 0, 50 (males), 100 

(males), 200, 1000, or 5000 

(females) ppm (0/0, 1.84, 3.68, 

7.32/8.92, 36.5/44.1, and 219 

mg/kg/day [M/F])

NOAEL is 200 ppm (equivalent to 7.32/8.92 

mg/kg/day in males/females). 

LOAEL is 1000 ppm (equivalent to 36.5/44.1 

mg/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. The CARC 

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 

p<0.05, and at the high dose was slightly above the 

historical control mean (0.8%) and range (0-4%). 

The CARC considered the nasolacrimal duct 

squamous cell carcinomas to be possibly treatment 

related, but that a clear association with treatment 

could not be made.

870.5100

Bacterial reverse 

gene mutation

45656725 (2002)/ acceptable -

guideline/ 61.7 to 5000 μg/plate +/-

S9 

Negative

870.5100

Bacterial reverse 

gene mutation

45854617 (2002)/ acceptable -

guideline/ 33 to 5000 ug/plate +/-

S9

Negative for metabolite TFNA

870.5100 45854618 (2002)/ acceptable - Negative for metabolite TFNA-AM 
Page 34 of 40

Table A.2.2. Flonicamid Toxicity Results From Repeated Dosing and Other Studies.

Study 

Guideline/Study

MRID Results

Bacterial reverse 

gene mutation

guideline/ 33 to 5000 ug/plate +/-

S9

870.5100

Bacterial reverse 

gene mutation

45854619 (2002)/ acceptable -

guideline/ 33 to 5000 ug/plate +/-

S9

Negative for metabolite TFNG-AM 

870.5100

Bacterial reverse 

gene mutation

45854620 (2002)/ acceptable -

guideline/ 33 to 5000 ug/plate +/-

S9

Negative for metabolite TFNA-OH

870.5100

Bacterial reverse 

gene mutation

45854621 (2002)/ acceptable -

guideline/ 5 to 5000 ug/plate +/- S9

Negative for metabolite TFNG

870.5300

In vitro

mammalian cell 

gene mutation

45656726 (2002)/ acceptable -

guideline/ 28.3 to 2290 μg/mL 

initial test, and 143 to 2290 μg/mL 

repeat.

Negative

870.5375

In vitro

Cytogenetics

45656727 (2002)/ acceptable -

guideline/ 573, 1145 and 2290 

μg/mL

Negative

870.5395

In vivo

cytogenetic 

(micronucleus) 

test in mice

45656728 (2002)/ acceptable -

guideline/ twice orally by 

intragastric gavage at doses of 250, 

500 and 1000 mg/kg/day for males 

and 125, 250 and 500 mg/kg/day for 

females

Negative

Non-guideline

Other 

genotoxicity, in 

vivo Comet assay

45854622 (2002)/ unacceptable 

(non-guideline)/ single doses of 

375, 750 and 1500 mg/kg

Was not positive for nuclear migration up to 1500 

mg/kg

Non-guideline

Unscheduled 

DNA synthesis

45854623 (2002)/ acceptable (nonguideline)/ once orally at 600 and 

2000 mg/kg

Is not genotoxic in hepatocytes from treated rats

870.6200a

Acute 

neurotoxicity 

screening battery 

(rats)

45854624 (2002)/ unacceptable -

guideline/ 0, 100, 300, 600 (males), 

or 1000 mg/kg/day

NOAEL is 600 mg/kg in males and 300 mg/kg in 

females. 

LOAEL is 1000 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 provided were from a 

lab other than the performing lab for this study. 

870.6200b

Subchronic 

neurotoxicity 

screening battery 

(rats)

45854702 (2003)/ acceptable -

guideline/ 0, 200, 1000, or 10,000 

ppm (0/0, 13/16, 67/81, or 625/722 

mg/kg/day [M/F])

NOAEL is 200/1000 ppm (equivalent to 13/81 

mg/kg/day [M/F]). 

LOAEL is 1000/10,000 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 
Page 35 of 40

Table A.2.2. Flonicamid Toxicity Results From Repeated Dosing and Other Studies.

Study 

Guideline/Study

MRID Results

males and females. 

870.7485

Metabolism and 

pharmacokinetics 

(rats)

45656729 (2001)/ acceptable -

guideline/ pilot excretion study, 

single oral dose 0.85 or 21 mg/kg

and pilot pharmacokinetic study, 

single oral dose of 2 or 50 mg/kg 

IKI-220 was rapidly absorbed and excreted with no 

apparent differences between the sexes. By 48 hours 

after treatment, ~93% of the administered dose had 

been eliminated and by 168 hours ~96% was 

eliminated. The primary route of elimination was the 

urine, accounting for ~90% of the dose. The feces of 

treated rats accounted for ~5% of the administered 

dose, with no significant amounts of radiolabel 

detected in expired air of either sex. After 168 hours 

of a single high or low dose of the test material, <3% 

of the radioactivity was recovered in the carcass and 

<0.05% in the blood, irrespective of dose or sex.

The pharmacokinetic parameters were also similar 

between the dose levels (2 and 50 mg/kg) and sexes. 

The radiolabel was rapidly absorbed and excreted. 

The apparent plasma half-life (T1⁄2) was 4.8-6.0 

hours and the elimination followed first order 

kinetics. The time of maximum plasma 

concentration (Tmax) for individual animals ranged 

from 0.25 to 1 hour after treatment (with a mean for 

each group of 0.3-0.6 hours).

870.7485

Metabolism and 

pharmacokinetics 

(rats)

45863802 to -5, 45854703 (2002)/ 

acceptable - guideline/ 2 or 400 

mg/kg

Appears that the overall recovery of radioactive dose 

from all group was 94-99% by 168 hours post-dose. 

Absorption was rapid and extensive, detected in 

plasma within 10 minutes of dosing, with maximum 

plasma concentrations within 24-54 minutes. By 168 

hours post-dose, total urinary excretion was 72-78%, 

cage rinse was 10-21%, and fecal excretion was 4-

7% dose. Parent (IKI-220) and 9 metabolites 

accounted for 80-94% of the dose for all groups. 

Parent was detected primarily in the urine, 46-73% 

of the dose in excreta in all groups. The primary 

metabolite was 4-trifluoromethylnicotinamide 

(TFNA-AM), 18-27% dose in all dose groups, along 

with minor amounts of TFNA-AM N-oxide (1-4% 

dose). Other metabolites in urine and feces were 

detected at less than or equal to 2.5% of the dose. 

IKI-220 was excreted primarily unchanged in the 

urine, but biotransformation of IKI-220 in rats 

included nitrile hydrolysis, N-oxidation, 

hydroxylation of the pyridine ring an amide 

hydrolysis.
Page 36 of 40

Appendix B. Physical/Chemical Properties & Structures

Table B.1. Physicochemical Properties of Flonicamid*

Parameter Value Reference

Melting point/range 157.5 C MRID 45854601

pH, 1% aqueous 

suspension

4.5 (25 C) MRID 45854601

Density 1.531 (20 C) MRID 45854601

Water solubility 5.2 g/L (20 C) MRID 45854601

Solvent solubility Solvent g/100 mL (20 C)

acetone 17.32

acetonitrile 12.04

dichloromethane 0.40

ethyl acetate 3.57

hexane 0.00003

isopropyl alcohol 1.46

methanol 9.76

n-octanol 0.26

toluene 0.03

MRID 45656705

Vapor pressure 9.43 x 10-7

Pa (20 C)

2.55 x 10-6Pa (25 C)

MRID 45854601

Dissociation constant, 

pKa

11.60 ± 0.03 (20 ± 1 C) MRID 45656705

Octanol/water 

partition coefficient

1.9 (Log POW = 0.3) (29.8 C) MRID 45854601

UV/visible absorption 

spectrum

Acidic and neutral aqueous solutions exhibited similar 

spectra with an absorption maximum near 265 nm and a 

molar absorptivity of 3,900 L/cm mol. A basic solution 

exhibited two absorption peaks. The peak observed in 

acidic and neutral solutions was present at a slightly longer 

wavelength, 270 nm, with an absorptivity of 4,200 L/cm 

mol. The second peak had an absorption maxima at 204 nm 

with an absorptivity of 13,200 L/cm mol.

MRID 45854601

*Reviewed by RD, Dr. Shyam Mathur, D285457, 9/30/2003.
Page 37 of 40

Table B.2. Chemical Names and Structures of Flonicamid and its Transformation Products

Company Name Chemical Name Structure

Flonicamid N-(cyanomethyl)-(4-trifluoromethyl)-

3-pyridinecarboxamide

TFNA 4-trifluoromethylnicotinic acid

TFNA-AM 4-trifluoromethylnicotinamide

TFNG N-(4- trifluoromethylnicotinoyl) 

glycine

TFNG-AM N-(4-trifluoromethylnicotinoyl)-

glycinamide

N-oxide of 

flonicamid

N

CF3

N

H

O

N

N

CF3

OH

O

N

CF3

NH2

O

N

CF3

N

H

O

O

OH

N

CF3

N

H

O

O

NH2
Page 38 of 40

Table B.2. Chemical Names and Structures of Flonicamid and its Transformation Products

Company Name Chemical Name Structure

N-oxide of TFNG

OH-TFNA-AM 6-hydroxy-4-

trifluoromethylnicotinamide

TFNA-OH 6-hydroxy-4-trifluoromethylnicotinic 

acid

N

CF3

OH

O

HO
Page 39 of 40

Appendix C. International Residue Limit Status Sheet.

Flonicamid (PC Code 128016)

Table C.1. Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

40 CFR 180.613:

Plant : flonicamid [N -(cyanomethyl)-4-

(trifluoromethyl)-3-pyridinecarboxamide] and its 

metabolites TFNA [4-trifluoromethylnicotinic acid], 

TFNA-AM [4-trifluoromethylnicotinamide], and TFNG 

[N -(4-trifluoromethylnicotinoyl)glycine]

Livestock: residues of flonicamid [N -(cyanomethyl)-4-

(trifluoromethyl)-3-pyridinecarboxamide], and its 

metabolites TFNA [4-trifluoromethylnicotinic acid] and

TFNA-AM [4-trifluoromethylnicotinamide] 

None None

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex3

Berry, low growing, subgroup 

13-07G 1.5

Vegetable, cucurbit, group 9 1.5

Rapeseed Subgroup 20A 1.5

Completed: M. Negussie; 05/01/2012

1

Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and 

not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

1

Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and 

not those proposed by the applicant.
Page 40 of 40

Appendix D. Review of Human Research

Studies reviewed for ethical conduct:

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. 

Electronic Database. Task Force members Health Canada, U. S. Environmental Protection 

Agency, and the National Agricultural Chemicals Association, released February, 1995.

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler 

Unit Exposure Surrogate Reference Table. U.S. Environmental Protection Agency. Released 

June 21, 2011.

Data from the Outdoor Residential Exposure Task Force (ORETF).