UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: November 25, 2014 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Flonicamid. Human Health Scoping Document in Support of Registration Review. 

PC Code: 128016 

Decision No.: 493129 

Petition No.: NA 

DP Barcode: D421511 

Registration No~: NA 

Regulatory Action: Registration Review 

Risk Assessment Type: NA Case No.: 7436 

TXRNo.:NA 

MRIDNo.:NA 

CAS No.: 158062-67-0 

40 CFR: §180.613 

FROM: Barry O'Keefe, Senior Biologist /J, 0 tJ<.u}p 

Cassi Walls, Senior Biologist {}~ .£~ 

Nancy 

Risk 

Myron 

Assessment 

Dodd, 

Ottley, 

Chemist 

Senior 

Branch 

Biologist 

~ 

III (RAB3) 

~ 

~ 

~ 

Health Effects Division (7509P) 

Office of Pesticide Programs 

THROUGH: Christine Olinger, Branch Chief ~~e:___ 

Risk Assessment Branch Ill (RAB3 /- ' 

. Health Effects Division (7509P) 

Office of Pesticide Programs 

TO: Ricardo Jones, Chemical Review Manager 

Neil Anderson, Branch Chief 

Risk Management and Implementation Branch I (RMIB 1) 

Pesticide Re-Evaluation Division (PRD) (7508P) 

Office of Pesticide Programs 

Executive Summary 

Following is the Health Effects Division's (HED's) human health scoping document for the 

insecticide flonicamid to support Registration Review. To evaluate the scope of work necessary 

to support Registration Review, HED has considered recent risk assessments for flonicamid, 

updates to its toxicity, exposure and usage databases, and the latest Agency science policy and 

risk assessment methodologies. The most recent risk assessment for flonicamid was conducted 

in 2013 for several new uses, increased application rates, and crop group revisions (D408549, B. 

O'Keefe, 08/20/2013). 

Page 1 of25 
Flonicamid is registered for use on a variety of agricultural crops, including: alfalfa and clover 

grown for seed, cotton, cucurbits, fruiting vegetables, greenhouse grown cucumbers and 

tomatoes, hops, leafy Brassica greens (subgroup 5B), leafy vegetables, low growing berry 

subgroup 13-070, mint, okra, pome fruits, potatoes, rapeseed subgroup 20A, root vegetables 

(except sugar beet; subgroup 1B), stone fruits, tuberous and corm vegetables (subgroup 1C), tree 

nuts, and turnip greens. Flonicamid is also registered for use on commercial ornamentals, 

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

in any residential settings. 

The toxicology database for flonicamid is adequate for risk assessment. However, a subchronic 

inhalation study is required because the use of an oral point of departure (POD) results in 

margins of exposure (MOEs) which do not meet the target MOE for a waiver (MOE= 1 000). 

The HED Hazard and Science Policy Council (HASPOC) has determined that this inhalation 

study will provide a more accurate evaluation of inhalation risk to flonicamid (HASPOC, 

TXR0056400, K. Rury, 07/30/2012). Therefore, in the absence of a subchronic inhalation 

toxicity study, a 1 OX database uncertainty factor has been added for inhalation exposure 

assessment. 

In repeated dose studies, the primary target organs are the liver and the kidney in rats and dogs. 

There are no concerns for neurotoxicity, immunotoxicity, or mutagenicity. The Cancer 

Assessment Review Committee (CARC) classified flonicamid as "suggestive evidence of 

carcinogenicity, but not sufficient to assess human carcinogenic potential" (TXR0052013, J. 

Kidwell, 02/24/2005). 

Based on the available data, toxicity endpoints and PODs have been selected for chronic dietary, 

and short- and intermediate-term inhalation exposure scenarios. Since no observed effects could 

be attributed to a single dose, an acute endpoint for acute dietary exposure was not established. 

No dermal or systemic toxicity was observed up to the limit dose in a 28-day dermal study, so 

dermal endpoints were not selected. The Food Quality Protection Act (FQPA) Safety Factor can 

be reduced to 1X because there is no concern for increased susceptibility and no residual 

uncertainties for pre- and post-natal toxicity, and there are no residual uncertainties in the 

exposure database. 

The residue chemistry database is sufficient to support current registrations of flonicamid. A 

tolerance revision was recommended in a previous assessment (D408549, B. O'Keefe, 8/20/13) 

that has not been made. The nature of the residue in plants and livestock has been adequately 

defined. Adequate field trial, rotational crop, livestock feeding, analytical/enforcement methods, 

primary crop processing, and storage stability data are available. 

New dietary exposure and aggregate risk assessments are not expected to be needed during 

Registration Review, unless there are significant increases to the drinking water exposure 

estimates that need to be incorporated. 

New occupational handler and post-application exposure and risk assessments are not anticipated 

to be needed during Registration Review. However, if results from the required subchronic 

Page 2 of25 
inhalation study change the endpoints and result in lower PODs for occupational handler 

exposures, then new occupational handler exposure and risk assessments may be needed. 

The Agency will examine the need for spray drift and volatilization assessments during 

Registration Review for flonicamid based on the potential for exposure to bystanders from 

agricultural applications. 

Introduction 

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

on plants. Based on 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 interact with acetylcholine esterase (like organophosphates and 

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

The most recent human health risk assessment for flonicamid was finalized in 2013 for several 

new uses (D408549, B. O'Keefe, 08/20/2013). Flonicamid is currently registered for use on a 

variety of agricultural crops, including: alfalfa and clover grown for seed, cotton, cucurbits, 

fruiting vegetables, greenhouse grown cucumbers and tomatoes, hops, leafy Brassica greens 

(subgroup 5B), leafy vegetables, low growing berry subgroup 13-070, mint, okra, pome fruits, 

potatoes, rapeseed subgroup 20A, root vegetables (except sugar beet; subgroup IB), stone fruits, 

tuberous and corm vegetables (subgroup IC), tree nuts, and turnip greens. Flonicamid is also 

registered for use on commercial ornamentals, interiorscapes, and nurseries; but these labels do 

not allow use in home gardens, greenhouses, or in any residential settings. 

Flonicamid end use products are formulated as soluble granules and water dispersible granules. 

Applications can be made with ground, aerial, airblast, chemigation, or hand-held equipment. 

Refer to Attachment 1 (Table 1) for the chemical identity offlonicamid. 

Hazard Identification/Toxicology 

The toxicology database for flonicamid is adequate for risk assessment. Refer to Attachment 4 

for a summary of the toxicity endpoints and PODs for flonicamid. Refer to Attachment 5 for the 

complete toxicity profile tables for flonicamid. Except for a subchronic inhalation study, all 

toxicity data requirements for conventional pesticide registration under the current 40 CFR 

§ 158.500 have been satisfied. All studies needed to assess susceptibility concerns, such as 

developmental and reproduction studies, have been submitted. The subchronic inhalation study 

is required because the use of an oral POD results in MOEs as low as 440 for occupational 

exposure, which does not meet the target MOE of 1000 for a waiver (HASPOC, TXR0056400, 

K. Rury, 07/30/2012). Therefore, in the absence of a subchronic inhalation toxicity study, a lOX 

database uncertainty factor has been added for inhalation exposure. 

The repeated dose oral studies in rats and dogs indicate that 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, 

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

Page 3 of25 
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 dose levels up to 

the limit dose (1 000 mg!kg/day). 

Developmental effects in rats (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 (ACN), signs of toxicity such as decreased motor activity, 

tremors, impaired gait, and impaired respiration were observed at lethal dose levels (1000 

mg!kg). However, no histopathological correlates in nervous system tissues were observed. In a 

subchronic neurotoxicity study, decreased body weight, foot splay, food consumption, and motor 

activity were seen in males at doses of 67 mg!kg/day higher, and in females at 722 mg!kg/day. 

As in the ACN, microscopic examination of nervous tissue revealed no anomalies. Therefore, 

the adverse effects observed in these two studies were not considered evidence of neurotoxicity. 

In addition, there was no evidence of neurotoxicity in the other studies in the database. 

Therefore, there is no concern for neurotoxicity 

An immunotoxicity study showed that flonicamid is not an immuno-suppressant, either 

structurally or functionally, at dose levels up to and exceeding the limit dose. 

Mutagenicity studies were negative for flonicamid. Flonicamid is classified as "suggestive 

evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential" based on 

a weight of evidence approach (TXR00520 13, J. Kidwell, 02/24/2005). The RAB3 risk 

assessment team determined that quantification of risk using a non-linear approach (i.e., using a 

chronic reference dose) adequately accounts for all chronic toxicity, including carcinogenicity 

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

No Observable Adverse Effect Level (NOAEL) in this study was 3.7 mg!kg/day; the Lowest 

Observable Adverse Effect Level (LOAEL) of22.3 mg!kg/day is based on increased kidney 

weights, kidney hyaline deposition, and increased blood serum luteinizing hormone in F 1 

females. 

Flonicamid has a low acute toxicity via the oral (Toxicity Category Ill), dermal (Toxicity 

Category IV), and inhalation (Toxicity Category IV) routes of exposure. It is not an eye or skin 

irritant (Toxicity Category IV) and is not a skin or dermal sensitizer. Flonicamid metabolites 

TFNA ( 4-trifluoromethylnicotinic acid), TFNA-AM ( 4-trifluoromethylnicotinamide ), and 

TFNG, N-( 4-trifluoromethylnicotinoyl)glycine, TFNG-AM (N-( 4-triflouromethylnicotinoyl)-

glycinamide), and TFNA-OH (6-hydroxy-4-triflouromethylnicotinamide) are all classified as 

Toxicity Category III for acute oral toxicity. 

Page 4 of25 
HED has determined that the FQPA safety factor for infants and children can be reduced to IX 

because: 

• the toxicity data base is complete with the exception of a subchronic inhalation study, and 

in the absence of this study a 1 OX database uncertainty factor has been applied to 

occupational inhalation exposure scenarios; 

• there are no concerns for neurotoxicity based on the results of the acute and subchronic 

neurotoxicity studies; 

• the degree of concern for pre- and/or post-natal susceptibility is low due to the lack of 

evidence of qualitative and quantitative susceptibility in the developmental and 

reproductive toxicity studies; and 

• there are no residual uncertainties in the flonicamid exposure database. 

Conclusions: The toxicology database of flonicamid is adequate for risk assessment. However, 

a subchronic inhalation study is required. In the absence of the subchronic inhalation study, a 

1 OX database uncertainty factor has been added for inhalation exposure. The inhalation toxicity 

endpoints and PODs will be re-evaluated upon receipt of the subchronic inhalation study. 

Dietary Exposure 

A tolerance change needs to be made; refer to "Data Deficiencies" below and the last HED risk 

assessment fordetails (D408549, B. O'Keefe, 8/20/13). 

The residue chemistry data and drinking water data are adequate to assess dietary exposure and 

sufficient to support current registrations. The nature of the residue in plants and livestock has 

been defined. For purposes of tolerance and dietary risk assessments, the residues of concern in 

plant and rotational crop commodities include parent flonicamid and its metabolites TFNA, 

TFNA-AM, and TFNG. The residues of concern in livestock commodities include flonicamid 

and its metabolites TFNA and TFNA-AM. The residues of concern for drinking water are 

flonicamid and its' degradates TFNA, TFNG-AM, TFNG, TFNA-OH, and TFNA-AM. 

There are adequate residue analytical methods for tolerance enforcement. The enforcement 

method for plant commodities is a liquid chromatography/tandem mass spectrometry 

(LC/MS/MS) method (FMC Method No. P-3561M). The method determines residues of 

flonicamid and its metabolites TFNA-AM, TFNA, and TFNG. Three enforcement methods are 

used for livestock commodities: (1) an LC/MS/MS method (RCC No. 844743) for determination 

of residues in eggs, poultry tissues, and fat of cattle, goat, hog, horse, and sheep; (2) an LC/MS 

method (RCC No. 842993) for determination of residues in milk; and (3) an LC/MS/MS method 

(FMC No. P-3580), which includes an acid hydrolysis step, for determination of residues in meat 

and meat products (kidney and liver) of cattle, goat, hog, horse, and sheep. All three methods 

determine flonicamid and the metabolites OH-TFNA-AM, TFNA-AM, TFNG, and TFNA. 

Adequate crop field trials and processing studies are available to support existing uses. 

Adequate field rotational crop studies are available supporting the existing tolerances for indirect 

residues of flonicamid in rotational crops. These data support the 30-day plant-back interval 

currently specified for crops without flonicamid uses. Adequate storage stability data are 

Page 5 of25 
available to support storage durations for flonicamid in/on plant commodities and livestock 

commodities. 

The most recent dietary (food and drinking water) exposure assessment was conducted in 2013 

(D413405, N. Dodd, 08/14/2013) using the Dietary Exposure Evaluation Model (DEEM-FCID, 

Version 3.16), which uses 2003-2008 food consumption data from the U.S. Department of 

Agriculture's National Health and Nutrition Examination Survey, What We Eat in America 

(NHANES/WWEIA). An acute endpoint attributable to a single dose was not identified; 

therefore, an acute dietary exposure assessment was not conducted. The chronic dietary 

exposure assessment was a conservative assessment, using tolerance-level residues and assuming 

that 1 00% of the crops were treated. The assessment did not indicate risks of concern for the 

general U.S. population or any of the population subgroups. A cancer dietary assessment was 

not conducted as the flonicamid database has been classified as showing "suggestive evidence of 

carcinogenicity, but not sufficient to assess human carcinogenic potential." The estimated 

drinking water concentration (EDWC) used in the assessment (9.92 pg/L) was from the Pesticide 

Root Zone Model-Ground Water (PRZM-GW) model. 

The chronic dietary (food and drinking water) exposure estimates were below the Agency's level 

of concern for all population subgroups. The dietary exposure estimates utilized 12% of the 

chronic Population Adjusted Dose ( cP AD) for the general US population and 30% of the cPAD 

for children 1-2 years old, the population subgroup with the highest estimated chronic dietary 

exposure to flonicamid. 

Conclusions: Since the dietary assessment was recently conducted it will not need to be updated 

during Registration Review, unless there are significant increases to the drinking water exposure 

estimates. 

Residential Exposure 

Residential exposure is not expected. There are registered labels allowing flonicamid use on 

commercial ornamentals, interiorscapes, and nurseries; but these labels prohibit flonicamid use 

in home gardens, greenhouses, or in any residential settings. Therefore, residential handler 

scenarios are not expected, nor assessed. Additionally, because a dermal toxicity endpoint was 

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

necessary. 

Spray Drift or Volatilization 

Residential bystander exposures resulting from off-site transport (e.g., spray drift or 

volatilization) may occur as a result of appiications of flonicamid. The potential for spray drift 

will be evaluated for each pesticide during the Registration Review process which ensures that 

all uses for that pesticide will be considered concurrently. The approach is outlined in the 

~evised (2012) Standard Operating Procedures for Residential Risk Assessment (SOPs)-

Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of 

Spray Drift. This document outlines the quantification of indirect non-occupational exposure to 

drift. In terms of volatilization, the agency has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

Page 6 of25 
(http://www .regulations. gov /#! docketDetail;D= EPA-HQ-0 PP-2014-021 9). During Registration 

Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analysis is required for flonicamid. 

Conclusions: There are no registered residential uses and no residential exposures are expected. 

Additionally, the Agency will examine the need for a volatilization assessment, as well as 

evaluate the potential for exposure from spray drift during Registration Review. Residential 

bystander exposures resulting from off-site transport (i.e., spray drift or volatilization) may occur 

as a result of occupational applications of flonicamid. The need for a bystander risk assessment 

for flonicamid will be considered during Registration Review. 

Aggregate Risk Assessment 

Aggregate assessments consider exposures from food, drinking water, and residential uses. 

Since there are no residential uses of flonicamid, aggregate risk for all exposure durations 

considers only exposures from food and drinking water. 

In the most recent human health risk assessment (D408549, B. O'Keefe, 08/20/2013), an acute 

aggregate risk assessment, which is equivalent to the acute dietary risk assessment, was not 

conducted, since no observed effects could be attributed to a single dose, and therefore, an acute 

endpoint was not established. A cancer dietary assessment was not conducted as flonicamid has 

been determined to be in the category "Suggestive Evidence of Carcinogenicity, but Not 

Sufficient to Assess Human Carcinogenicity Potential". For flonicamid, only potential chronic 

exposures from food and drinking water were aggregated. Therefore, the chronic aggregate risk 

(food and drinking water) is equivalent to the chronic dietary (food and drinking water) exposure 

estimate. 

Conclusions: Aggregate exposure to flonicamid is currently not of concern to HED. New 

aggregate assessments are not anticipated to be needed during Registration Review. 

Occupational Exposure 

Flonicamid is registered for use on numerous agricultural use sites. It is also registered for 

occupational use on several non-agricultural use sites. There is potential for short- and 

intermediate-term occupational exposure to flonicamid during handling (mixing, loading, and 

applying) and post-application activities. 

Occupational Handlers 

Previous occupational handler exposure and risk assessments for flonicamid were conducted at 

the maximum application rate, updated body weights, updated unit exposures, and assumed the 

maximum area treated per day for all the registered use sites. The registered flonicamid labels 

require occupational handlers to wear long-sleeved shirts, long pants, shoes, socks, and chemical 

resistant gloves. Additionally, some labels require the use of protective eyewear. Applications 

can be made with ground, aerial, airblast, chemigation, and hand held equipment. For some 

inhalation exposure scenarios, risk estimates at baseline personal protective equipment (PPE) 

(single layer clothing, no gloves, and no respirator) are of concern (MOEs <1000). 

Page 7 of25 
Mixing/loading/applying for soil drench applications to greenhouse grown cucumbers using a 

mechanically pressurized handgun results in the highest inhalation exposure to flonicamid (MOE 

= 440). Mixing/loading/applying sprays to greenhouse grown cucumbers or tomatoes using a 

mechanically pressurized handgun results in the second highest inhalation exposure (MOE= 

600). With the addition of a dust/mist respirator the MOEs for these two scenarios are 3,100 and 

2,200, respectively. The occupational inhalation MOEs for all other existing handler scenarios 

range from 3,400 to 520,000. 

Occupational Post-Application 

Occupational post-application short- and intermediate-term dermal and inhalation exposures are 

possible for workers tending treated food crops. However, since hazard was not identified for 

the dermal route of exposure, dermal post-application risks were not assessed; and consequently, 

dislodgeable foliar residue (DFR) data are not needed. 

Conclusions: There is sufficient information available to assess occupational handler and postapplication exposures. Updated occupational handler and post-application exposure assessments 

are not anticipated to be needed during Registration Review. However, if results from the 

required subchronic inhalation study change the endpoints and result in lower PODs for 

occupational exposures, then new occupational handler exposure and risk assessments may be 

needed. 

Public Health and Pesticide Epidemiology Data 

Based on the low frequency and severity of incident cases reported for flonicamid in both the 

OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National 

Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System 

for Occupational Risk-Pesticides (SENSOR), there does not appear to be a concern at this time 

that would warrant further investigation. 

For the Main IDS, from January 1, 2009 to May 28, 2014, there were zero incidents reported 

involving flonicamid. In the Aggregate IDS, from January 1, 2009 to May 28, 2014, there was 

one incident reported involving flonicamid. It was classified as minor severity. 

A query of the SENSOR-Pesticides database for 1998-2010 identifies no cases involving 

flonicamid. 

The Agricultural Health Study (AHS) is a high quality, prospective epidemiology study 

evaluating the link between pesticide use and various health outcomes, including cancer. The 

AHS includes private and commercial pesticide applicators and their spouses. If there are AHS 

findings relevant to a particular pesticide going through registration review, the Agency will 

ensure they are considered in the problem formulation/scoping phase of the process and, if 

appropriate, fully reviewed in the risk assessment phase of the process. The AHS includes 

information on use of 50 different pesticide active ingredients commonly used in agriculture. 

Flonicamid is not included in the AHS, and therefore, this study does not provide information for 

this report. 

Page 8 of25 
Conclusion: Based on the low frequency and low severity of incident cases reported for 

flonicamid in both IDS and SENSOR-Pesticides databases, there does not appear to be a concern 

at this time that would warrant further investigation. The Agency will continue to monitor the 

incident information, and if a concern is triggered, additional analysis will be included in the risk 

assessment. 

Tolerance Assessment and International Harmonization 

Tolerances are established for plant and livestock commodities under 40 CFR § 180.613 for 

residues of the insecticide flonicamid, including its metabolites and degradates. Compliance 

with the tolerance levels for plant commodities under 40 CFR §180.613(a)(l) is to be determined 

by measuring only the sum offlonicamid, N-(cyanomethyl)-4-(trifluoromethyl)-3-

pyridinecarboxamide, and its metabolites, TFNA ( 4-trifluoromethylnicotinic acid), TFNA-AM 

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

as the stoichiometric equivalent of flonicamid. Compliance with the tolerance levels for 

livestock commodities under 40 CFR §180.613(a)(2) is to be determined by measuring only the 

sum of flonicamid, N-( cyanomethyl)-4-(trifluoromethyl)-3-pyridinecarboxamide, and its 

metabolites, TFNA (4-trifluoromethylnicotinic acid), and TFNA-AM (4-

trifluoromethylnicotinamide ), calculated as the stoichiometric equivalent of flonicamid. Refer to 

Attachment 1 for structures of flonicamid and its metabolites. 

There are no Codex maximum residue limits (MRLs) established for flonicamid; therefore, there 

are no harmonization issues with Codex at this time. There are Canadian MRLs, with the same 

tolerance expressions as the US, and at the same levels as the US for most commodities. The 

exceptions are cucurbits (1.5 ppm for the US; 0.4 ppm for Canada) and milk (0.05 ppm for the 

US; 0.03 ppm for Canada). The US established a tolerance of 1.5 ppm for the crop group 9 

(cucurbit vegetables). Canada established separate tolerances of0.4 ppm for most cucurbits and 

1.5 ppm for cucumber. Tolerance harmonization issues will be evaluated during registration 

review. 

The tolerance on okra needs to be deleted, because okra is already covered by the tolerance for 

vegetable, fruiting, group 8-10. Tolerance harmonization issues will be evaluated during 

Registration Review. 

Cumulative 

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 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/. 

Page 9 of25 
Human Studies 

The risk assessments which have been previously conducted for flonicamid relied in part on data 

from studies in which adult human subjects were intentionally exposed to a pesticide to 

determine their dermal and inhalation exposure. Many such studies, involving exposure to many 

different pesticides, comprise generic pesticide exposure databases such as the Pesticide 

Handlers Exposure Database (PHED) and the Agricultural Reentry Task Force (ARTF) 

Database. EPA has reviewed all the studies supporting these multi-pesticide generic exposure 

databases, and has found no clear and convincing evidence that the conduct of any of them was 

either fundamentally unethical or significantly deficient relative to the ethical standards 

prevailing at the time the research was conducted. All applicable requirements of EPA's Rule 

for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and 

there is no regulatory barrier to continued reliance on these studies. 

Data Deficiencies 

Toxicology 

870.3465 Subchronic Inhalation study 

• A subchronic inhalation study is required because the use of an oral point of departure for 

inhalation exposure results in MOEs as low as 440 for occupational exposure, which is 

not sufficient to alleviate concern (HASPOC, TXR0056400, K. Rury, 07/30/2012). 

Therefore, a 1 OX database uncertainty factor has been added for inhalation exposures. 

Residue Chemistry 

Tolerances 

Since a tolerance for the cucurbit vegetable crop group at 1.5 ppm has been established, the 

tolerance for cucumber at 1.5 ppm should be removed from 40 CFR §180.613. 

Occupational/Residential Exposure 

Additional exposure data are not needed to support the registered uses of flonicamid at this time. 

References 

Memoranda Relevant to Re2istration Review of Flonicamid. 

Author DPffXR# Date Title 

Risk Assessment 

J. Arthur 0289592 5/25/05 Flonicamid: Human Health Risk Assessment for Proposed Uses 

on Cotton, Cucurbit Vegetables, Fruiting Vegetables, Leafy 

Vegetables, Pome Fruit, Stone Fruit, Potatoes, and Nursery and 

Landscape Ornamentals. PC Code: 128016, Petition No:3F6552, 

DP Barcode: 0289592. 

Page 10 of25 
Memoranda Relevant to Registration Review of Flonicamid. 

Author DP/I'XR# Date Title 

S. Piper D332317 2/29/08 Flonicamid: Amendment to D347805 Human Health Risk 

Assessment for Proposed Uses on Root Vegetables (Except 

Sugarbeet; 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, DP Barcode: D332317. 

S. Piper D347805 12/21/07 Flonicamid: Human Health Risk Assessment for Proposed Uses 

on Root Vegetables (Except Sugarbeet; 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, DP Barcode: D347805. 

B. O'Keefe D397277 10/2112 Revised: Flonicamid: Human Health Risk Assessment for the 

Proposed Use on Low Growing Berry, Rapeseed, and Greenhouse 

Grown Cucumbers. 

B. O'Keefe D408549 8/20/13 Flonicamid - Human Health Risk Assessment for a Section 3 

Registration of New Uses on Alfalfa and Clover Grown for Seed, 

Mint, Greenhouse Grown Tomatoes, and Tree Nuts. 

Residue Chemistry 

A. Acierto D290386 4/22/05 Flonicamid. Petition for the Establishment of Permanent 

Tolerances for Use on Cotton, Cucurbit Vegetables, Fruiting 

Vegetables, Leafy Vegetables, Pome Fruit, Potato, and Stone 

Fruit. Summary of Analytical Chemistry and Residue Data. 

PP#3F6552. 

A. Acierto D329381 8/28/08 Flonicamid 50WG Insecticide (EPA Reg. No. 71512-9). 

Conditional Registration Follow-Up Data. 

A. Acierto D332316 11/16/07 Flonicamid. IR-4 Petition for the Establishment of Permanent 

Tolerances for Use on Root Vegetables (Except Sugar Beet; 

Subgroup 1B), Tuberous and Corm Vegetables (Subgroup 1C), 

Leafy Brassica Greens (Subgroup 5B), Turnip Greens, Hops, and 

Okra. Summary of Analytical Chemistry and Residue Data. 

PP#6E7081. 

N. Dodd D413404 8/14/13 Flonicamid. Petition for the Establishment of Permanent 

Tolerances and Registration for New Uses on Alfalfa, Clover, 

Spearmint, Peppermint; Inclusion of Cucumber in Cucurbit Group 

9; and Crop Group Conversions for Fruiting Vegetable Group 8-

10, Pome Fruit Group 11-10, and Stone Fruit Group 12-12. 

Summary of Analytical Chemistry and Residue Data. 

N. Dodd D413407 8/14/13 Flonicamid. Petition for the Establishment of Permanent 

Tolerances and Registration for Use on Tree Nuts. Summary of 

Analytical Chemistry and Residue Data. 

Dietary Exposure Assessment 

N. Dodd D413405 8/14/13 Flonicamid Chronic Aggregate Dietary (Food and Drinking 

Water) Exposure and Risk Assessments for the Section 3 

Registration Actions on Tree Nuts, Alfalfa, Clover, Spearmint, 

Peppermint, and Cucurbit Group 9, and Crop Group Conversions 

for Fruiting Vegetable Group 8-10, Pome Fruit Group 11-10, and 

Stone Fruit Group 12-12. 

Occupational Residential Exposure 

C. Walls D408738 08/05/2013 Flonicamid: Occupational and Residential Exposure/Risk 

Assessment for Use on Alfalfa, Clover, Mint, Greenhouse 

Tomatoes, and Tree Nuts. 

Page 11 of25 
Memoranda Relevant to Resdstration Review of Flonicamid. 

Author DPffXR# Date Title 

Toxicolo2y 

K.Rury TXR0056400 07/30/2012 Flonicamid: Summary of Hazard and Science Policy Council 

(HASPOC) Meeting of July 12,2012: Recommendations on the 

Waiver Request for the Subchronic Inhalation Study. 

J. Kidwell TXR0052013 02/24/2005 Flonicamid: Report of the Cancer Assessment Review Committee 

PC Code: 128016 

Incident Report 

S. Recore D432122 09/30/2014 Flonicamid: Tier I Review of Human Incidents 

Attachments 

1. Chemical Identity Table 

2. Physicochemical Properties of Technical Grade Flonicamid Table 

3. Tolerance/MRL Swnmary Table 

4. Endpoint Selection Tables 

5. Toxicity Profile Tables 

Page 12 of25 
Attachment 1 

Chemical Identity Table 

TABLE 1. Flonicamid Nomenclature. ~.,. ... , .... :.;; ,:"''...~~ .\,"'J._J''~ ,8 ,~ 

"'· -~ 

Compound . CF3 0 

cr~~CN N 

Common name flonicamid 

Company experimental name IKI-220 

IUPACname N-cyanomethyl-4-(trifluoromethyl)nicotinamide 

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

CAS# 158062-67-0 

Compound CF3 0 ({oH 

N 

Common name TFNA 

Chemical name 4-trifluoromethylnicotinic acid 

Compound CF3 0 

erN~ N 

Common name TFNA-AM 

Chemical name 4-trifluoromethylnicotinamide 

Compound 

~~T(" 0 

N 

Common name TFNG 

Chemical name N-( 4-trifluoromethylnicotinoyl)glycine 

Compound CF3 0 

if~rrNH, 0 N 

Common Name TFNG-AM 

Chemical Name N-(4-triflouromethylnicotinoyl)-glycinamide 

Page 13 of25 
TABLEt. ' Flonicamid Nomenclature. ~: ~. ., .' "'' ~ '•' ~ 'L ~ 

. 

Compound NOH ~ 

HO N 

Common Name TFNA-OH 

Chemical Name 6-hydroxy-4-triflouromethylnicotinamide 

Attachment 2 

TABLEl. Physicochemical Properties of Technical Grade Flonicamid. .~ 

~--

Parameter Value Reference1 , ' 

Molecular weight (g/mole) 229.16 

Melting point 157.5 oc MRID 45854601 

pH 4.5 (25 °C} 

Relative Density 1.531 (20 °C} 

Water solubility 5.2 giL (20 °C} 

Solvent solubility Solvent gLJ 00 mL (20 °C) MRID 45656705 

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 

Vapor pressure 9.43 x 10·7 Pa (20 °C} or 7.07 x IQ-9 mm Hg MRID 45854601 

2.55 x IQ-6 Pa (25 °C} or 1.91 x 10·8 mm Hg 

Dissociation constant, pKa 11.60 ± 0.03 (20 ± 1 °C) MRID 45656705 

Octanol/water partition coefficient, 1.9 (Log P = 0.3) (29.8 °C) MRID 45854601 

Log(Kow) 

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 Llcm 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 Llcm mol. The second peak had 

an absorption maxima at 204 nm with an absorptivity 

of 13,200 L/cm mol. 

1 RD Memo, DP# 285457, 9/30/2003, S. Mathur 

Page 14 of25 
Attachment 3 

Tolerance/MRL Tables 

Flonicamid (128016; Date of Request 09-08-2014) 

Table 3. Summary of US and International Tolerances and Maximum Residue Limits. 

Residue Definition: 

us Canada Mexico' Codex 

40 CFR § 180.613(a) General. (1) sum of Plants: N-(cyanomethyl)-4- None 

flonicamid, N-( cyanomethyl)-4- (trifluoromethyl)-3-

(trifluoromethyl)-3-pyridinecarboxamide, pyridinecarboxamide, including the 

and its metabolites, TFNA (4- metabolites 4-trifluoromethylnicotinic 

trifluoromethylnicotinic acid), TFNA- acid, N-(4-

AM ( 4-trifluoromethylnicotinamide), and trifluoromethylnicotinoyl)glycine and 4-

TFNG, N-(4- trifluoromethylnicotinamide 

trifluoromethylnicotinoyl)glycine, 

calculated as the stoichiometric 

equivalent of flonicamid. 

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/k :) 

us Canada Mexico' Codex 

Alfalfa, forage 10.0 

Alfalfa, hay 1.0 

Alfalfa, seed 1.5 

Almond, hulls 9.0 

Berry, low growing, 1.5 

subgroupl3-07G 

Brassica, head and stem, 1.5 1.5 broccoli, brussels sprouts, cabbages, 

subgroup 5A cauliflowers, Chinese broccoli, Chinese 

mustard cabbages, kohlrabies, 

napa Chinese cabbages 

Brassica, leafy greens, 16 16 broccoli raab, bok choy Chinese I' 

subgroup 58 cabbages, collards, kales, mustard 

greens, mustard spinach, rape leaves 

Cotton, gin byproducts 6.0 

Cotton, hulls 2.0 

Cotton, meal 1.0 

Cotton, undelinted seed 0.50 

Cucumber 1.5 1.5 

Fruit, pome, group 11-1 0 0.20 0.2 apples, Asian pears, azaroles, 

Chinese quinces, crabapples, Japanese 

quinces, Joquats, mayhaws, medlars, 

pears, quinces, tejocotes 

Fruit, stone, group 12-12 0.60 0.6 American plums, Apricots, beach 

plums, black cherries, Canada plums, 

capulins, cherry plums, chicksaw plums, 

Chokecherries, damson plums, fresh 

prune plums, Japanese apricots, 

Japanese plums, klamath plums, nanking 

cherries, nectarines, peaches, plumcots, 

plums, sloes, sweet cherries, tart cherries 

Hop, dried cones 7.0 7 

Nut, tree, group 14-12 0.15 

Okra 0.40 0.4 

Page 15 of25 
Table 3. Summary of US and International Tolerances and Maximum Residue Limits. 

Peppermint, tops 7.0 

Potato, granules/flakes 0.40 0.4 

Radish, tops I6 16 

Rapeseed subgroup 20A 1.5 

Spearmint, tops 7.0 

Spinach 9.0 9 

Tomato, paste 2.0 2 

Tomato, puree 0.50 0.5 

Turnip, greens I6 

Vegetable, cucurbit, group 9 1.5 0.4 balsam apples, balsam pears, 

cantaloupes, chayote fruit, Chinese 

cucumbers, Chinese waxgourds, citron 

melons, edible gourds and muskmelons 

(other than those listed in this item), 

pumpkins, summer squash, 

watermelons, west Indian gherkins, 

winter squash 

I.5 cucumbers 

Vegetable, fruiting, group 8- 0.40 0.4 African eggplants, bell peppers, bush 

IO tomatoes, coconas, currant tomatoes, 

eggplants, garden huckleberries, goji 

berries, groundcherries, martynias, 

naranjillas, nonbell peppers, okras, pea 

eggplants, pepinos, roselles, scarlet 

eggplants, sunberries, tomatillos, 

tomatoes, tree tomatoes 

Vegetable, leafy, except 4.0 4 Amaranth, arugula, cardoon, celery, 

brassica, group 4, except celtuce, Chinese celery, com salad, 

spinach dandelion leaves, dock, edible leaved 

0 chrysanthemum, endives, fresh chervil 

leaves, fresh Florence fennel leaves and 

stalks, fresh parsley leaves, garden cress, 

garden purslane , garland 

chrysanthemum, head lettuce, leaf 

lettuce, orach, radicchio, rhubarb, swiss 

chard, upland cress, winter purslane 

9 spinach 

Vegetable, root, except sugar 0.60 0.6 Roots (black salsify, carrot, celeriac, 

beet, subgroup I B chicory, edible burdock, garden beet, 

ginseng, horseradish, radish, oriental 

radish, parsnip, rutabaga, salsify, skirret, 

Spanish salsify, turnip, turnip-rooted 

chervil, turnip-rooted parsley 

Vegetable, tuberous and 0.20 0.2 arracacha, arrowroot, cassava roots, 

corm, subgroup I C chayote roots, Chinese artichokes, 

chufa, edible canna, ginger roots, 

Jerusalem artichokes, Ierens, potatoes, 

sweet potato roots, tanier corms, taro 

corms, true yam tubers, turmeric roots, 

yam bean roots 

Page 16 of25 
Table 3. Summary of US and International Tolerances and Maximum Residue Limits. 

Residue Definition: 

us Canada Mexico1 Codex 

40 CFR §180.613(a) General. (2) sum of Livestock: N-( cyanomethyl)-4- None 

flonicamid, N-( cyanomethyl)-4- (trifluoromethyl)-3-

( trifluoromethy 1)-3 -pyridinecarboxamide, pyridinecarboxamide, including the 

and its metabolites, TFNA (4- metabolites 4-trifluoromethylnicotinic 

trifluoromethylnicotinic acid), and acid and 4-trifluoromethylnicotinamide 

TFNA-AM (4-

trifluoromethylnicotinamide ), calculated 

as the stoichiometric equivalent of 

flonicamid. 

Commodity Tolerance (ppm) /Maximum Residue Limit (mglkg) 

us Canada Mexico1 Codex 

Cattle, fat 0.03 0.03 

Cattle, meat 0.08 0.08 

Cattle, meat byproducts 0.08 0.08 

Egg 0.04 

Goat, fat 0.03 0.03 

Goat, meat 0.08 0.08 

Goat, meat byproducts 0.08 0.08 

Hog, fat 0.03 

Hog, meat 0.03 

Hog, meat byproducts 0.03 

Horse, fat 0.03 0.03 

Horse, meat 0.08 0.08 

Horse, meat byproducts 0.08 0.08 

Milk 0.05 0.03 

Poultry, fat 0.03 

Poultry, meat 0.03 

Poultry, meat byproducts 0.03 

Sheep, fat 0.03 0.03 

Sheep, meat 0.08 0.08 

Sheep, meat byproducts 0.08 0.08 

Completed: M. Negussie; 09/10/14 1 Mexico adopts US tolerances and/or Codex MRLs for Its export purposes. 

Page 17 of25 
Attachment 4 

Summary of Toxicity Endpoints and Points of Departure of Flonicamid 

. Table 4.1. Summary of Toxicological Dose and Endpoints for Flonicamid for Use in Dietary and Non- 1!;· 

Occupational Human Health Risk Assessments. l;, 

Point of" U ncertainty/FQ RID, PAD, Level Study and Toxicological Exposure Scenario Departure PA Safety of Concern for Effects .. Factors Risk Assessment 

No toxicological effects seen in 

Acute Dietary None NA aPAD=NA a single dose study, except at 

dose levels near the acute LDso. 

Chronic RID = 2-Gen Reproduction rat 

Parental LOAEL = 22 

NOAEL=3.7 UFA=lOX 0.04 mg/kg/day mglkg/day based on increased Chronic Dietary mglkg/day UFH= lOX kidney weights, kidney hyaline FQPA SF =IX cPAD=0.04 deposition, increased blood 

mg/kg/day serum LH (Fl females). 

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

Potential 

Pomt of Departure (POD)= A data pomt or estimated pomt that IS denved 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. UF A= extrapolation from animal to human (interspecies). UFH =potential variation in 

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

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

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

:,; 

i:. 

Table 4.2. Summary of Toxicological Dose and Endpoints for Flonic~mid for Use in Occupational Human -

Health Risk Assessments. 

Point of Uncertainty Level of Concern 

Exposure Scenario Departure Factors for Risk Study and Toxicological Effects 

Assessment 

Short-Term (1 to 30 

No hazard was indentified, since 

the 28-day dermal study did not 

days) & Intermediate- None NA LOC for MOE= show any dermal or systemic Term Dermal (1 to 6 NA effects at the limit dose of I 000 

months) mglkg/day. 

Short-Term (1 to 30 UFA= lOX 90-Day oral rat 

days) & Intermediate- OralNOAEL= UFH= lOX LOCforMOE= LOAEL = 60 mg/kg/day based on 

Term Inhalation (1 to 12 mglkg/day UFos= lOX 1000 kidney hyaline deposition. 6 months) 

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

Potential 

Pomt of Departure (POD)= A data pomt or estimated pomt that IS denved 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). UFos =database uncertainty factor. MOE= 

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

Page 18 of25 
Attachment 5 

Toxicity Profile for Flonicamid 

Table 5.1. Acute Toxicity Data on Technical Flonicamid and Flonicamid Degradates and Metabolites. 

Guideline MRID ,, Toxicity 

No. Study Type No. Results CateEOI"Y 

870.1100 Acute Oral • Rat 45656707 LDso = 884 mglkg (Males), III LDso = 1768 mglkg (Females) 

870.1200 Acute Dermal • Rat 45656708 LDso > 5000 mglkg IV 

870.1300 Acute Inhalation • Rat 45656709 LCso > 4.9 miL 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 45854605 LDso ~ 2000 mglkg III 

Flonicamid metabolite TFNA 

870.1100 Acute Oral - Rat 45854606 LDso ~ 2000 mglkg III 

Flonicamid metabolite TFNA-AM 

870.1100 Acute Oral - Rat 45854607 LDso ~ 2000 mglkg III 

Flonicamid metabolite TFNG 

870.1100 Acute Oral - Rat 45854608 LDso ~ 2000 mglkg III 

Flonicamid metabolite TFNG-AM 

870.1100 Acute Oral - Rat 45854609 LDso ~ 2000 mglkg III 

Flonicamid metabolite TFNA-OH 

Table 5.2. Flonicamid Toxicity Results From Repeated Dosin2 and Other Studies. · .• .- ,. •. - < 

Study MRID Results 

Guideline/Study ,. 

870.3100a 45656721 (2002) NOAEL = 200 ppm (12.11 mglkg/day, males); 1000 

90-Day oral ppm (72.3 mglkglday, females) 

toxicity in rats acceptable-guideline/ LOAELs = 1000 ppm (60.0 mg/kg/day, males) based 

0, 50, 200, 1000, 2000 (males), or on hyaline deposition in the kidney; 5000 ppm (340 

5000 (females) ppm mg/kg/day, females) based on hyaline deposition in 

0, 3.08, 12.11, 60.0, or 119.4 the kidney and centrilobular hypertrophy in the liver. 

mglkg/day (males) 

0, 14.52, 72.3, or 340.1 mg/kg/day 

(females) 28-day range-finding: 

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

28-day range-finding: 45656720 ppm (81.9 mg!kglday, females) 

(2002)/ acceptable (non-guideline)/ LOAELs = 500 ppm (36.45 mg!kg/day, males); 

0, 50 (males), 500, 1000, 5000 or based on hyaline deposition in the kidney; 5000 ppm 

10000 (females) ppm ( 3.61, 7.47, (372.6 mg!kg/day, females) based on hyaline 

36.45, 73.8, or 353.4 mglkg/day, deposition in the kidney, centrilobu1ar hypertrophy in 

males & 8.36, 41.24, 81.9, 372.6, the liver, anemia and increased cholesterol. 

or 642 mg!kg/day, females) 

Page 19 of25 
Table 5.2. Flonicamid Toxicity Results From Repeated Dosin2 and Other Studies. 

Study MRID Results 

Guideline/Study _:, 

870.3IOOb 456567I9 (200I) NOAEL is I 00 ppm (males: I5.25 mglkg bw/day, 

90-Day oral females: 20.IO mglkg bw/day) 

toxicity rodents acceptable (non-guideline)/ LOAEL is 1000 ppm (males: I53.9 mg/kg bw/day; 

(mice) 0, IOO, 1000 or 7,000 ppm females: 191.5 mglkg bw/day) based on 

0, I5.25, 153.9 or I069 mglkg extramedullary hematopoiesis of the spleen. 

bw/day in males, 

Many of the tissues/organs recommended by 0, 20.10, I91.5, or I248 mglkg Guideline 870.3IOO were not histologically bw/day in females examined in any dose group, but this study is not 

required and serves as a range-fmding study for the 

mouse carcinogenicity study. Therefore, it is 

classified as acceptable, non-guideline study. 

870.3I50 45646722 (200I) NOAEL is 8 mglkg/day in males and 20 mg/kg/day 

90-Day oral for females. LOAEL is 20 mglkg/day in males and 

toxicity in dogs acceptable - guideline 50 mglkg/day in females, based on acute clinical 

signs in males and females (vomiting, first observed 

0, 3, 8, 20, or 50 (females) mglkg on Day 1 and last observed on Day 90), clinical 

bw/day 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 45656723 (200I) NOAEL is I 000 mg/kg/day 

2I-Day dermal acceptable - guideline LOAEL is >1000 mg/kg/day. 

toxicity in rats 0, 20, I 50, or 1000 mglkg/day 

870.3700a 45656724 (2002) Maternal 

Prenatal acceptable- guideline NOAEL is I 00 mg/kg bw/day 

developmental in 0, 20, I 00 or 500 mglkg bw/day LOAEL is 500 mg/kg bw/day, based on increased 

rats 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 IOO mg/kg bw/day 

LOAEL is 500 mglkg bw/day, based on the 

increased incidence of cervical rib. 

870.3700b 458546I1, 458546IO (2002) Maternal 

Prenatal acceptable - guideline NOAEL is 7.5 mglkg/day 

developmental in 0, 2.5, 7.5, 25 mglkg/day LOAEL is 25 mg/kg/day, based on decreased body 

rabbits weights, body weight gains, and food consumption. 

Developmental 

NOAEL is~ 25 mglkg/day 

LOAEL is not established. 

Page 20 of25 
Table 5.2. Flonicamid Toxicity Results From Repeated Dosinsr; and Other Studies. 

Study MRID Results "'' .,. 

Guideline/Study .,t 'lt.. ~·. " 

870.3800 45854613, 45854612 (2002) Parental 

Reproduction and acceptable_ guideline NOAEL is 50 ppm (equivalent to 3.7/4.4 mglkglday 

fertility effects in [MIF]). 

rats O, 50' 300, 1800 ppm LOAEL is 300 ppm (equivalent to 22.3/26.5 

(0/0, 3.7/4.4, 22.3/26.5, 132.9/153.4 mglkglday [M/F]) based on increased relative kidney 

870.4100b 

Chronic toxicity 

in dogs 

870.4200b 

Carcinogenicity in 

mice 

mglkg bw/day [M/F]) weight and hyaline droplet deposition in the 

proximal tubules of the kidneys in the males and 

increased blood serum LH levels in the Fl females. 

45854614 (2003) 

acceptable - guideline 

0, 3, 8, or 20 mglkglday 

45854615,45854616 (2003) 

acceptable- guideline 

0, 250, 750, 2250 ppm 

(0/0, 29/38, 88/112, 261/334 

mglkglday [M/F]) 

Offspring 

NOAEL is 300 ppm (equivalent to 22.3/26.5 

mglkglday [M/F]). LOAEL is 1800 ppm (equivalent 

to 132.9/153.4 mglkglday [M/F]) based on decreased 

absolute and relative to body uterus weights and 

delayed sexual maturation in the Fl females. 

Reproductive Performance 

NOAEL is 1800 ppm (equivalent to 132.9/153.4 

mglkglday [M/F]). 

LOAEL for reproductive performance was not 

observed. 

NOAEL is 8 mglkglday. 

LOAEL is 20 mglkglday, based on acute clinical 

signs (vomiting, mostly within the first week), 

clinical pathology at 12 months (higher reticulocytes 

counts) in males and females. 

NOAEL was not established. 

LOAEL is 250 ppm (equivalent to 29/38 mglkglday 

[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 ofthe females. 

At the doses tested, the carcinogenic potential ofiKI220 is positive at 250 ppm in males and females 

based on the increased incidence of 

alveolar/bronchiolar adenomas, carcinomas, and 

combined adenomas/carcinomas. Dosing was 

considered adequate based on increased incidence of 

tissue masses/nodules in the lungs and microscopic 

findings in the liver, spleen, bone marrow, and lungs. 

However, data were provided suggesting this effect 

is specific to sensitive strains of mice. 

Carcinogenic in mice. 

Page 21 of25 
Table 5.2. Flonicamid Toxicity Results From Repeated Dosing and Other Studies. ... ~., '~ " 

Study MRID Results .. 

Guideline/Study 

870.4200b 

Carcinogenicity in 

mice 

870.4300 

Combined 

Chronic toxicity/ 

Carcinogenicity in 

rats 

870.5100 

Bacterial reverse 

gene mutation 

870.5100 

Bacterial reverse 

gene mutation 

870.5100 

Bacterial reverse 

gene mutation 

46205801 (2004) 

acceptable - guideline 

0, 10, 25, 80, 250 ppm 

males: 0, 1.20, 3.14, 10.0, 30.3 

mglkglday; 

females: 0, 1.42, 3.67, ll.8, 36.3 

mg/kglday 

45863801 (2002) 

acceptable - guideline 

0,50, 100,200, 1000,or5000 

(females) ppm 

010, 1.84, 3.68, 7.32/8.92, 36.5/44.1, 

219 mg/kglday [MIF] 

45656725 (2002) 

acceptable- guideline 

61.7 to 5000 Jlg/plate +/- S9 

45854617 (2002) 

acceptable- guideline 

33 to 5000 uglplate +/- S9 

45854618 (2002) 

acceptable- guideline 

33 to 5000 uglplate +/- S9 

NOAEL is 80 ppm (equivalent to 10/12 mg/kglday 

in males/females). 

LOAEL is 250 ppm (equivalent to 30/36 mg/kglday 

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. 

NOAEL is 200 ppm (equivalent to 7.32/8.92 

mg/kglday in males/females). 

LOAEL is 1000 ppm (equivalent to 36.5/44.1 

mg/kglday in males/females) based on decreased 

body weights and body weight gains, and increased 

incidences ofkeratitis 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. 

Negative 

Negative for metabolite TFNA 

Negative for metabolite TFNA-AM 

Page 22 of25 
Table 5.2. Flonicamid Toxicity Results From Repeated Dosine; and Other Studies. ~~-~ - ·..,.' 

Study MRID Results ,... -.-. 

Guideline/Study ... ,. -~ ·~ . ,. 

870.5100 45854619 (2002) Negative for metabolite TFNO-AM 

Bacterial reverse acceptable- guideline 

gene mutation 33 to 5000 ug/plate +/- 89 

870.5100 45854620 (2002) Negative for metabolite TFNA-OH 

Bacterial reverse acceptable - guideline 

gene mutation 33 to 5000 ug/plate +/- 89 

870.5100 45854621 (2002) Negative for metabolite TFNG 

Bacterial reverse acceptable- guideline 

gene mutation 5 to 5000 ug/plate +/- 89 

870.5300 45656726 (2002) Negative 

In vitro acceptable - guideline 

mammalian cell 28.3 to 2290 ~g/mL initial test, and 

gene mutation 143 to 2290 ~g/mL repeat. 

870.5375 45656727 (2002) Negative 

In vitro acceptable - guideline 

Cytogenetics 573, 1145 and 2290 ~g/mL 

870.5395 45656728 (2002) Negative 

In vivo acceptable- guideline cytogenetic 250, 500, 1000 mglkg/day for males (micronucleus) 

test in mice 125, 250, 500 mglkg/day for 

females 

Non-guideline 45854622 (2002) Was not positive for nuclear migration up to 1500 

Other unacceptable (non-guideline) mglkg 

genotoxicity, in single doses of375, 750, 1500 vivo Comet assay mglkg 

Non-guideline 45854623 (2002) Is not genotoxic in hepatocytes from treated rats 

Unscheduled a~ceptable (non-guideline) 

DNA synthesis once orally at 600 and 2000 mglkg 

870.6200a 45854624 (2002) NOAEL is 600 mglkg in males and 300 mglkg in 

Acute acceptable -non-guideline females. 

neurotoxicity 0, 100,300,600 (males), 1000 LOAEL is 1000 mglkg based on mortality and signs 

screening battery mglkg/day of toxicity (decreased motor activity, tremors, 

(rats) impaired respiration, and impaired gait) in males. 

This acute neurotoxicity study is not classified as a 

guideline study 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. However, dosing was very high, 

near or above the LDso, and the study produced data 

that are useful for risk assessment. 

Page 23 of25 
Table 5.2. Flonicamid Toxicity Results From Repeated Dosing and Other Studies. ·;, 

Study MRID Results 

Guideline/Study ~ 

870.6200b 45854702 (2003) 

Subchronic 

neurotoxicity 

screening battery 

(rats) 

870.7485 

Metabolism and 

pharmacokinetics 

(rats) 

870.7485 

Metabolism and 

pharmacokinetics 

(rats) 

870.7800 

Immunotoxicity 

acceptable - guideline 

0, 200, 1000, 10,000 ppm 

(010, 13/16, 67/81, or 625/722 

mglkg/day [M/F]) 

45656729 (2001) 

acceptable - guideline 

pilot excretion study, single oral 

dose 0.85 or 21 mglkg and pilot 

pharmacokinetic study, single oral 

dose of2 or 50 mglkg 

45863802 to -5, 45854703 (2002) 

acceptable- guideline 

2 or 400 mglkg 

48870201 (2012) 

NOAEL is 200/1000 ppm (equivalent to 13/81 

mglkg/day [M/F]). 

LOAEL is 1000/10,000 ppm (equivalent to 67/722 

mglkg/day [M/F]) based on decreased motor activity, 

rearing, and foot splay in males, decreased body 

weights, body weight gains, and food consumption in 

males and females. 

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 mglkg) and sexes. 

The radiolabel was rapidly absorbed and excreted. 

The apparent plasma half-life (T~) 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 I hour after treatment (with a mean for 

each group of0.3-0.6 hours). 

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 I 0 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 I 0-21%, 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 ofTFNA-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 ofiKI-220 in rats 

included nitrile hydrolysis, N-oxidation, 

hydroxylation of the pyridine ring an amide 

hydrolysis. 

NOAEL = 1540.2 mglkg/day 

Page 24 of25 
Table 5.2. Flonicamid Toxicity Results From Repeated Dosing and Other Studies. 

Study MRID Results 

Guideline/Study •l, ....... (mouse) LOAEL not established 

Acceptable - guideline 

0, 100, 600, 6000 ppm 

0, 23 .2, 141.8, 1540.2 mglkglday) 

Page 25 of25