### 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 ofRegistration Review.

PC Code: 128016 Decision No.: 493129 Petition No.: NA DPBarcode: D421511 Registration**No~:** 

### NA Regulatory Action: Registration Review CaseNo.: 7436 RiskAssessment Type: NA 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, SeniorBiologist

### {}~**.£~** Nancy Dodd, Chemist

### ~**~** Myron Ottley, Senior Biologist**~ ~**  

### Risk Assessment Branch III (RAB3) Health Effects Division (7509P) Office ofPesticide Programs

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

### Risk Assessment Branch Ill (RAB3 /- '

. Health Effects Division (7509P) Office ofPesticide Programs
TO: Ricardo Jones, Chemical Review Manager Neil Anderson, Branch Chief Risk Management and ImplementationBranch I (RMIB1) Pesticide Re-Evaluation Division (PRD) (7508P) Office ofPesticide Programs
Executive Summary Following is the Health Effects Division's (HED's) humanhealth scoping document for the insecticide flonicamid to support Registration Review. To evaluatethe scope ofwork necessary to support Registration Review, HED has consideredrecent risk assessments for flonicamid, updates to its toxicity, exposure and usage databases, and the latestAgency science policy and risk assessment methodologies. The mostrecent risk assessment for flonicamid was conducted in 2013 for several newuses, increased applicationrates, and crop group revisions (D408549, B. 

### O'Keefe, 08/20/2013).

Page 1of25

### Flonicamid is registered for use on a variety ofagricultural crops, including: alfalfa and clover grown for seed, cotton, cucurbits, fruiting vegetables, greenhouse grown cucumbers and tomatoes, hops, leafyBrassica

### greens (subgroup 5B), leafy vegetables, low growing berry subgroup 13-070,mint, okra, pome fruits, potatoes, rapeseed subgroup 20A, root vegetables (except sugarbeet; subgroup 1B), stone fruits, tuberous and corm vegetables (subgroup 1C), tree nuts, and turnip greens. Flonicamid is also registered for use oncommercial ornamentals, interiorscapes, and nurseries; butthese labels do not allowuse inhome 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 ofan oral point ofdeparture (POD) results in margins ofexposure (MOEs) which do not meetthe target MOE for a waiver (MOE= 1000). The HED Hazard and Science Policy Council (HASPOC) has determined thatthis inhalation study will provide a more accurate evaluation ofinhalationrisk to flonicamid (HASPOC, TXR0056400, K. Rury, 07/30/2012). Therefore, inthe absence ofa subchronic inhalation toxicity study, a 1OX database uncertainty factor has been added for inhalation exposure assessment.

In repeated dose studies, the primarytarget organs are the liver and the kidney inrats and dogs. There are no concerns for neurotoxicity, immunotoxicity, or mutagenicity. The Cancer Assessment Review Committee (CARC) classified flonicamid as "suggestive evidence of carcinogenicity, butnot sufficient to assess human carcinogenicpotential" (TXR0052013, J. Kidwell, 02/24/2005).

Based onthe 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 notestablished. 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-nataltoxicity, and there are no residual uncertainties in the exposure database.

The residue chemistrydatabase is sufficientto support currentregistrations offlonicamid. A tolerance revision was recommended in aprevious assessment (D408549, B. 

### O'Keefe, 8/20/13) thathas notbeenmade. The nature ofthe residue inplants and livestockhas been adequately defined. Adequate field trial, rotational crop, livestock feeding, analytical/enforcementmethods, primary crop processing, and storage stability data are available.

Newdietary 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 thatneed to be incorporated.

Newoccupational handler andpost-application exposure and risk assessments are not anticipated to be needed during Registration Review. However, ifresults from the required subchronic

Page 2 of25

### inhalation study change the endpoints and result in lowerPODs for occupational handler exposures, then new occupational handler exposure and risk assessments may be needed.

The Agency will examinethe 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 ofsucking insects
onplants. Based on its chemical structure (anicotinic acid derivative), itwouldbe expected to exhibitthe same mode ofaction as similarly structured neo-nicotinoidpesticides. However, flonicamid has notbeen found to interact with acetylcholine esterase (like organophosphates and carbamates), or nicotinic acetylcholine receptors (like neo-nicotinoids).

The mostrecent 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 ona variety ofagricultural crops, including: alfalfa and clovergrown 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 sugarbeet; subgroup IB), stone fruits, tuberous and corm vegetables (subgroup IC), tree nuts, and turnip greens. Flonicamid is also registered for use oncommercial ornamentals, interiorscapes, and nurseries; butthese labels do not allowuse in home gardens, greenhouses, orin any residential settings.

Flonicamid end use products are formulated as soluble granules and water dispersible granules. Applications canbe made with ground, aerial, airblast, chemigation, orhand-held equipment. Referto 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 ofthe 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 current40 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 ofan oral POD results inMOEs as low as 440 for occupational exposure, which does not meetthe target MOE of 1000 for a waiver (HASPOC, TXR0056400, K. Rury, 07/30/2012). Therefore, inthe absence ofa subchronic inhalationtoxicity study, a 

### lOX database uncertainty factor has been added for inhalation exposure.
The repeated dose oral studies inrats 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 inthe rat 28-day oral range-finding study, 90-day oral study, developmental study, and reproductive study. The 90-daydog study showedkidney tubular

Page 3 of25

### vacuolation, as well as increased adrenal weights, increasedreticulocytes and decreased thymus weights. Increased reticulocyte counts were noted in boththe 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 (1000 mg!kg/day). Developmental effects inrats (increased incidence ofcervical 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) inthe multi-generation study were seen only in the presence ofparental toxicity (kidney effects in males, blood effects in females). Thus, there is no concern for increased susceptibility ofdeveloping young for flonicamid.

In an acute neurotoxicity-study (ACN), signs oftoxicity such as decreased motor activity, tremors, impaired gait, and impaired respiration were observed atlethal dose levels (1000 mg!kg). However, no histopathological correlates innervous 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 of67 mg!kg/day higher, and in females at 722 mg!kg/day. As in the ACN, microscopic examination ofnervous tissue revealed no anomalies. Therefore, the adverse effects observed in these two studies were not considered evidence ofneurotoxicity. In addition, there was no evidence ofneurotoxicity in the other studies in the database. Therefore, there is no concernfor neurotoxicity

Animmunotoxicity 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 ofcarcinogenicity, butnot sufficientto assess human carcinogenicpotential" based on a weight ofevidence approach (TXR0052013, J. Kidwell, 02/24/2005). The RAB3 risk assessmentteam determined that quantification ofrisk using a non-linear approach (i.e., using a chronic reference dose) adequately accounts for all chronic toxicity, including carcinogenicity that couldresult from exposure to flonicamid. Therefore, the cRfD is consideredprotective for carcinogenic effects. As a result, separate cancerrisk assessments were not conducted. The cRfD was based on anendpoint oftoxicity from a two generationreproduction study inrats. The No Observable Adverse Effect Level (NOAEL) inthis study was 3.7 mg!kg/day; the Lowest Observable Adverse EffectLevel (LOAEL) of22.3 mg!kg/day is based on increased kidney weights, kidney hyaline deposition, and increased blood serum luteinizinghormone inF1 

### females.

Flonicamid has a low acute toxicity viathe oral (Toxicity Category Ill), dermal (Toxicity Category IV), and inhalation (Toxicity Category IV) routes ofexposure. It is not an eye or skin irritant (Toxicity Category IV) and is not a skin ordermal sensitizer. Flonicamid metabolites TFNA ( 4-trifluoromethylnicotinic acid), TFNA-AM ( 4-trifluoromethylnicotinamide), and TFNG, N-( 

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

### 4-triflouromethylnicotinoyl)- glycinamide), andTFNA-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 bereduced to IX because:

• the toxicity data base is complete withthe exception ofa subchronic inhalation study, and inthe absence ofthis study a 1 

### OX database uncertainty factor has been applied to occupational inhalation exposure scenarios;
• there are no concerns for neurotoxicitybased onthe results ofthe acute and subchronic neurotoxicity studies;
• the degree ofconcern for pre- and/orpost-natal susceptibility is low due to the lack of evidence ofqualitative and quantitative susceptibilityinthe developmental and reproductive toxicity studies; and
• there are no residual uncertainties in the flonicamid exposure database.


### Conclusions: The toxicology database offlonicamid is adequate for risk assessment. However,
a subchronic inhalation study is required. In the absence ofthe 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 ofthe subchronic inhalation study. Dietary Exposure



### A tolerance change needs to be made; refer to "DataDeficiencies" 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 sufficientto support currentregistrations. The nature ofthe residue in plants and livestock has been defined. Forpurposes oftolerance and dietary risk assessments, the residues ofconcern in plant and rotational crop commodities includeparentflonicamid and its metabolites TFNA, TFNA-AM, and TFNG. The residues ofconcern in livestock commodities include flonicamid and its metabolites TFNA and TFNA-AM. Theresidues ofconcern 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/tandemmass spectrometry (LC/MS/MS) method (FMC MethodNo. P-3561M). The method determines residues of flonicamid and its metabolites TFNA-AM, TFNA, and TFNG. Three enforcementmethods are used for livestock commodities: (1) an LC/MS/MS method (RCC No. 844743) for determination ofresidues in eggs, poultry tissues, and fat ofcattle, goat, hog, horse, and sheep; (2) an LC/MS method (RCC No. 842993) for determination ofresidues in milk; and (3) an LC/MS/MS method (FMC No. P-3580), which includes an acid hydrolysis step, for determination ofresidues inmeat and meatproducts (kidney and liver) ofcattle, 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 supportingthe existing tolerances for indirect residues offlonicamid inrotational crops. These data supportthe 30-dayplant-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 plantcommodities and livestock commodities.

The mostrecent 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 andNutritionExamination 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% ofthe crops were treated. The assessment did not indicate risks ofconcern for the general U.S. population or any ofthe population subgroups. A cancer dietary assessment was not conducted as the flonicamid database has been classified as showing "suggestive evidence of carcinogenicity, butnot sufficientto assess human carcinogenicpotential." The estimated drinking water concentration (EDWC) used in the assessment (9.92 pg/L) was from the Pesticide RootZone Model-Ground Water (PRZM-GW) model.

The chronic dietary (food and drinking water) exposure estimates were belowthe Agency's level ofconcern for all population subgroups. The dietary exposure estimates utilized 12% ofthe chronic PopulationAdjusted Dose (cPAD) for the general US population and 30% ofthe cPAD for children 1-2 years old, the population subgroup with the highest estimated chronic dietary exposure to flonicamid.

Conclusions: 

### Since the dietary assessmentwas recently conducted it will not need to be updated during Registration Review, unless there are significantincreases 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; butthese labels prohibitflonicamid use inhome gardens, greenhouses, orin any residential settings. Therefore, residential handler scenarios are notexpected, nor assessed. Additionally, because a dermal toxicity endpoint was not identifiedfor flonicamid, apost-applicationresidential exposure/risk assessment is not necessary. SprayDrift or Volatilization 

### Residential bystander exposures resulting from off-site transport (e.g., spray drift or volatilization) may occur as a result ofappiications offlonicamid. The potential for spray drift will be evaluatedfor eachpesticide during the Registration Reviewprocess which ensures that all uses for thatpesticide 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 ofindirect non-occupational exposure to drift. In

### terms ofvolatilization, the agencyhas developed a Volatilization Screening Tool and a subsequentVolatilization ScreeningAnalysis

Page 6 of25(http://www.regulations.gov /#!docketDetail;D=EPA-HQ-0PP-2014-0219). During Registration Review, the agency will utilize this analysis to determine ifdata (i.e., flux studies, route-specific inhalationtoxicological studies) orfurther analysis is required for flonicamid.



### Conclusions: There are no registered residential uses and no residential exposures are expected. Additionally, the Agency will examinethe 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-sitetransport (i.e., spray drift orvolatilization) mayoccur as a result ofoccupational applications offlonicamid. The need for a bystanderrisk assessment for flonicamid will beconsideredduring Registration Review. 

### Aggregate RiskAssessment Aggregate assessments consider exposures from food, drinking water, and residential uses. Since there are no residential uses offlonicamid, aggregate risk for all exposure durations considers only exposures from food and drinking water.

In the mostrecent human healthrisk assessment (D408549, 

### B. O'Keefe, 08/20/2013), an acute aggregate risk assessment, which is equivalentto the acute dietary risk assessment, was not conducted, since no observed effects could be attributed to a single dose, andtherefore, an acute endpoint was not established. A cancerdietary assessment was not conducted as flonicamid has been determined to be inthe category "Suggestive Evidence ofCarcinogenicity, butNot Sufficient to Assess Human CarcinogenicityPotential". Forflonicamid, onlypotential chronic exposures from food and drinking water were aggregated. Therefore, the chronic aggregaterisk (food and drinking water) is equivalent to the chronic dietary (food and drinking water) exposure estimate.



### Conclusions: Aggregate exposure to flonicamid is currentlynot ofconcernto HED. New aggregate assessments are not anticipatedto be needed during Registration Review. 

### OccupationalExposure

Flonicamid is registered for use onnumerous agricultural use sites. Itis 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) andpost-application activities. Occupational Handlers Previous occupational handler exposure andrisk assessments for flonicamid were conducted at the maximum applicationrate, updatedbody weights, updated unit exposures, and assumed the maximum areatreated perday for all theregistered 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 ofprotective eyewear. Applications
can be made with ground, aerial, airblast, chemigation, andhandheld equipment. Forsome inhalation exposure scenarios, risk estimates at baseline personal protective equipment (PPE) (single layer clothing, no gloves, andno respirator) are ofconcern (MOEs <1000).

Page 7 of25

### Mixing/loading/applying for soil drench applications to greenhouse grown cucumbers using a mechanicallypressurized handgun results inthe highest inhalation exposure to flonicamid (MOE

= 440). Mixing/loading/applying sprays to greenhouse grown cucumbers or tomatoes using a mechanicallypressurizedhandgunresults in the second highest inhalation exposure (MOE= 600). Withthe additionofa dust/mistrespiratorthe MOEs for these two scenarios are 3,100 and 2,200, respectively. The occupational inhalation MOEs for all other existinghandler 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 ofexposure, dermal post-applicationrisks were not assessed; and consequently, dislodgeable foliar residue (DFR) data are not needed.

Conclusions: 

### There is sufficient information available to assess occupational handler andpostapplication exposures. Updated occupationalhandler and post-applicationexposure assessments are not anticipated to be needed during Registration Review. However, ifresults from the required subchronic inhalation study changethe endpoints and result inlower PODs for occupational exposures, then new occupational handler exposure and risk assessments may be needed.

Public Health and Pesticide Epidemiology Data


### Based onthe lowfrequency and severity ofincident cases reported for flonicamid inboththe OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel EventNotification System for Occupational Risk-Pesticides (SENSOR), there does not appear to be a concern at this time that would warrant further investigation.

Forthe Main IDS, from January 1, 2009 to May 28, 2014, there were zero incidents reported involving flonicamid. Inthe Aggregate IDS, from January 1, 2009 to May 28, 2014, there was one incidentreported involving flonicamid. It

### was classified as minor severity.

A query ofthe SENSOR-Pesticides database for 1998-2010 identifies no cases involving flonicamid.

The Agricultural Health Study (AHS) is ahigh quality, prospective epidemiology study evaluatingthe linkbetweenpesticide use and various health outcomes, including cancer. The AHS includes private and commercial pesticide applicators and their spouses. Ifthere are AHS findings relevantto aparticularpesticide going through registration review, the Agency will
ensure they are considered inthe problem formulation/scoping phase ofthe process and, if appropriate, fully reviewed inthe risk assessment phase ofthe process. The AHS includes information onuse of50 different pesticide active ingredients commonlyused in agriculture. Flonicamid is not included inthe AHS, and therefore, this study does notprovide information for this report.

Page 8 of25

### Conclusion: 

### Based onthe lowfrequency and low severity ofincident 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 monitorthe incidentinformation, and ifa concern is triggered, additional analysis will be included inthe risk assessment.
ToleranceAssessment and International Harmonization



### Tolerances are established for plant and livestock commodities under40 CFR §180.613 for residues ofthe insecticide flonicamid, including its metabolites and degradates. Compliance with the tolerance levels for plant commodities under40 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 offlonicamid. Compliance with the tolerance levels for livestock commodities under40 CFR §180.613(a)(2) is to be determined by measuring only the
sum offlonicamid, N-( 

### cyanomethyl)-4-(trifluoromethyl)-3-pyridinecarboxamide, and its metabolites, TFNA (4-trifluoromethylnicotinic acid), and TFNA-AM (4- trifluoromethylnicotinamide), calculated as the stoichiometric equivalent offlonicamid. Refer to Attachment 1for structures offlonicamid and its metabolites.

There are no Codex maximum residue limits (MRLs) established for flonicamid; therefore, there
are no harmonization issues with Codex atthis time. There are Canadian MRLs, with the same tolerance expressions as the US, and atthe same levels as the US for mostcommodities. 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 ppmfor the crop group 9 (cucurbitvegetables). Canadaestablished separate tolerances of0.4ppmfor most cucurbits and 1.5 ppm for cucumber. Tolerance harmonization issues will be evaluated during registration review.

The tolerance on okraneeds to be deleted, because okrais already covered by the tolerance for vegetable, fruiting, group 8-10. Tolerance harmonization issues will be evaluated during Registration Review.

Cumulative


### Unlike otherpesticides for which EPA has followed a cumulative risk approachbased on a commonmechanism oftoxicity, EPAhas notmade a commonmechanism oftoxicity finding as to flonicamid and any other substances and flonicamid does not appear to produce a toxic metaboliteproduced by other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism oftoxicity and to evaluatethe cumulative effects of such chemicals, see the policy statements released by EPA's Office ofPesticide Programs concerning common mechanism determinations andprocedures for cumulating effects from substances found to have a commonmechanism onEPA'swebsite at http://www.epa.gov/pesticides/cumulative/.

Page 9 of25

### Human Studies


### The risk assessments which have beenpreviously conducted for flonicamid relied inpart on data from studies in which adulthuman subjects were intentionally exposedto apesticide 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. EPAhas reviewed all the studies supporting these multi-pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct ofany ofthem was eitherfundamentally unethical or significantly deficient relative to the ethical standards prevailing atthe time the research was conducted. All applicable requirements ofEPA's Rule for the Protection ofHuman Subjects ofResearch (40 CFRPart 26) have been satisfied, and there is no regulatory barrierto continuedreliance onthese studies.

Data Deficiencies Toxicology


### 870.3465 Subchronic Inhalation study

• A subchronic inhalation study is required because the use ofan oral point ofdeparture for inhalation exposure results inMOEs 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 dataare not neededto supportthe registered uses offlonicamid at this time.

References

Memoranda Relevant to Re2istration Review ofFlonicamid.
Author DPffXR# Date Title
Risk Assessment J

.Arthur 0289592 5/25/05 Flonicamid: Human Health Risk Assessment for Proposed Uses
on Cotton, CucurbitVegetables, 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 of25Memoranda Relevant to Registration Review ofFlonicamid.
Author DP/I'XR# Date Title
S. Piper D332317 2/29/08 Flonicamid: Amendmentto D347805 Human Health Risk Assessmentfor Proposed Uses on Root Vegetables (Except Sugarbeet; Subgroup 1B), Tuberous and Corm Vegetables (Subgroup 1C), LeafyBrassica 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), LeafyBrassica 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 Assessmentfor a Section 3 Registration ofNew Uses on Alfalfa and CloverGrown for Seed, Mint, Greenhouse Grown Tomatoes, and TreeNuts. Residue Chemistry A. Acierto D290386 4/22/05 Flonicamid. Petition for the Establishment ofPermanent Tolerances for Use on Cotton, Cucurbit Vegetables, Fruiting Vegetables, Leafy Vegetables, Pome Fruit, Potato, and Stone Fruit. Summary ofAnalytical 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 ofPermanent Tolerances for Use on Root Vegetables (Except SugarBeet; Subgroup 1B), Tuberous and Corm Vegetables (Subgroup 1C), LeafyBrassica Greens (Subgroup 5B), Turnip Greens, Hops, and Okra. Summary ofAnalytical Chemistry and Residue Data. PP#6E7081. N. Dodd D413404 8/14/13 Flonicamid. Petition for the Establishment ofPermanent Tolerances and Registration for NewUses onAlfalfa, Clover, Spearmint, Peppermint; Inclusion ofCucumber in Cucurbit Group 9; and Crop Group Conversions for FruitingVegetable Group 8- 10, Pome Fruit Group 11-10, and Stone FruitGroup 12-12. SummaryofAnalytical Chemistry and Residue Data. N. Dodd D413407 8/14/13 Flonicamid. Petition for the Establishment ofPermanent Tolerances and Registration for Use on TreeNuts. 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 TreeNuts, 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 TreeNuts.



### Page 11 of25Memoranda Relevant to Resdstration Review ofFlonicamid.
Author DPffXR# Date Title Toxicolo2y K.Rury TXR0056400 07/30/2012 Flonicamid: Summary ofHazard and Science Policy Council (HASPOC) Meeting ofJuly 12,2012: Recommendations on the Waiver Request for the Subchronic Inhalation Study. J. Kidwell TXR0052013 02/24/2005 Flonicamid: Report ofthe CancerAssessment Review Committee PCCode: 128016

Incident Report S. Recore D432122 09/30/2014 Flonicamid: Tier I Review ofHuman Incidents
Attachments 1. Chemical Identity Table 2. Physicochemical Properties ofTechnical Grade Flonicamid Table 3. Tolerance/MRL Swnmary Table 4. Endpoint Selection Tables 5. ToxicityProfile 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

CommonName TFNG-AM Chemical Name N-(4-triflouromethylnicotinoyl)-glycinamide



### Page 13 of25TABLEt. ' Flonicamid Nomenclature.**~: ~.**  ., .' "''**~** '•'**~** 

### 'L**~**

. Compound 

# NOH**~** HO N

Common Name TFNA-OH Chemical Name 6-hydroxy-4-triflouromethylnicotinamide

Attachment 2

TABLEl. PhysicochemicalProperties ofTechnical 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 gLJ00 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 Vaporpressure 9.43 x 10·7 Pa(20 °C} or7.07 x IQ-9 mmHg 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 of3,900 Llcm mol. A basic solution exhibited two absorption peaks. Thepeak observed in acidic and neutral solutions was present at
a slightly longer wavelength, 270 nm, with an absorptivity of4,200 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 of25Attachment3 Tolerance/MRL Tables


### Flonicamid (128016; Date ofRequest 09-08-2014)

Table3. Summary ofUS and International Tolerances and Maximum Residue Limits. ResidueDefinition: 

## 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, includingthe 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 offlonicamid. Commodity Tolerance (ppm) /Maximum ResidueLimit (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, bokchoy 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 11-10 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, chicksawplums, 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 of25Table3. Summary ofUS 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 (otherthanthose 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, gardenpurslane , 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, edibleburdock, 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, cassavaroots, corm, subgroup I C chayote roots, Chinese artichokes, chufa, edible canna, gingerroots, Jerusalem artichokes, Ierens, potatoes, sweetpotato roots, tanier corms, taro corms, true yam tubers, turmeric roots, yam beanroots



### Page 16 of25Table3. SummaryofUSand 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- (trifluoromethy1)-3-pyridinecarboxamide, pyridinecarboxamide, including the and its metabolites, TFNA (4- metabolites 4-trifluoromethylnicotinic trifluoromethylnicotinic acid), and acid and4-trifluoromethylnicotinamide TFNA-AM (4- trifluoromethylnicotinamide), calculated
as the stoichiometric equivalent of flonicamid. Commodity Tolerance (ppm)/Maximum Residue Limit (mglkg) 

### us Canada Mexico 1 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, meatbyproducts 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 1Mexico adopts US tolerances and/or Codex MRLs for Its exportpurposes.



### Page 17 of25

### Attachment 4 Summary ofToxicity Endpoints and Points ofDeparture ofFlonicamid



# . Table4.1. Summary ofToxicologicalDose and Endpoints for Flonicamid for Use in Dietary and Non- 1!;· Occupational Human Health RiskAssessments. 

### l;,

Pointof " Uncertainty/FQ RID, PAD, Level Study and Toxicological Exposure Scenario Departure PA Safety ofConcern for Effects

.. Factors RiskAssessment Notoxicological effects seen in Acute Dietary None NA aPAD=NA a single dose study, except at dose levels nearthe 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 ofCarcinogenicity, butNot Sufficient to Assess Human Carcinogenic Potential Pomt ofDeparture (POD)=A data pomt orestimatedpomtthat IS denved from observed dose-related data and used to mark the beginning ofextrapolation 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 ofthe human population (intraspecies). UFos =databaseuncertainty factor. FQPA SF

= FQPA safety factor. PAD=population adjusted dose (a= acute, c =chronic). RID=reference dose. MOE= margin ofexposure. LOC = level ofconcern. NA =NotApplicable. :,;

i:.

Table4.2. Summary ofToxicologicalDose and Endpoints for**Flonic~mid** for Use in Occupational Human 

### - Health RiskAssessments. Point of Uncertainty Level ofConcern

Exposure Scenario Departure Factors for Risk Study and ToxicologicalEffects 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 ofI000 months) mglkg/day. Short-Term (1 to 30 UFA= lOX 90-Day oralrat 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 ofCarcinogenicity, butNot Sufficientto Assess Human Carcinogenic Potential Pomt ofDeparture (POD)=A data pomt orestimatedpomtthat IS denved from observed dose-related data and used to markthe beginning ofextrapolationto 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 ofthe human population (intraspecies). UFos =database uncertainty factor. MOE= margin ofexposure. LOC =level ofconcern. NA =NotApplicable.



### 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 orvery 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 centrilobularhypertrophy 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 = 500ppm (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 onhyaline 36.45, 73.8, or 353.4 mglkg/day, deposition in the kidney, centrilobu1arhypertrophy in males & 8.36, 41.24, 81.9, 372.6, the liver, anemia and increased cholesterol.
or 642 mg!kg/day, females)



### Page 19 of25Table 5.2. Flonicamid Toxicity Results From Repeated Dosin2and Other Studies. Study MRID Results Guideline/Study _:, 870.3IOOb 456567I9 (200I) NOAEL is I00 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/kgbw/day; (mice) 0, IOO, 1000 or7,000 ppm females: 191.5 mglkg bw/day) based on 0, I5.25, 153.9 or I069 mglkg extramedullary hematopoiesis ofthe spleen. bw/day in males, Many ofthe 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 onDay 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 studytermination. 870.3200 45656723 (200I) NOAEL is I000 mg/kg/day 2I-Day dermal acceptable

- guideline LOAEL is >1000 mg/kg/day. toxicity in rats 0, 20, I50, or 1000 mglkg/day 870.3700a 45656724 (2002) Maternal Prenatal acceptable- guideline NOAEL is I00 mg/kg bw/day developmental in 0, 20, I00 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 ofcentrilobular hepatocytes in liver and vacuolation ofproximal tubular cell in kidneys). Developmental NOAEL is IOO mg/kgbw/day LOAEL is 500 mglkg bw/day, based onthe increased incidence ofcervical 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 of25Table 5.2. Flonicamid Toxicity Results From Repeated Dosinsr; and OtherStudies. 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 increasedrelative kidney

870.4100b Chronic toxicity in dogs

870.4200b Carcinogenicity in mice mglkgbw/day [M/F]) weight and hyaline droplet deposition in the proximal tubules ofthe kidneys in the males and increasedblood serum LH levels in the Fl females.

45854614 (2003) acceptable

- guideline 0, 3, 8, or20 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 (equivalentto 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 (equivalentto 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 (higherreticulocytes counts) in males and females. NOAELwas not established. LOAEL is 250 ppm (equivalentto 29/38 mglkglday [M/F]), based onminimal to moderate centrilobular hepatocellularhypertrophy, minimal to severe extramedullaryhematopoiesis, minimal to moderate pigment deposition inthe sternal bone marrow, and increased incidence oftissue masses/nodules in the lungs in the males, and minimal to moderate decreased cellularity in the femoral bone marrow and hyperplasia/hypertrophy ofthe epithelial cells ofthe terminal bronchioles ofthe females.

Atthe doses tested, the carcinogenic potential ofiKI220 is positive at 250 ppm in males and females based onthe 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 wereprovided suggestingthis effect is specific to sensitive strains ofmice. Carcinogenic in mice.



### Page 21 of25Table 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 (equivalentto 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 ofIKI220 is positive in males and females based on the incidences ofalveolar/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 correlationbetweenthe incidence of inflammation andthe fluctuating incidence ofnasal 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, butthat a clear association with treatment could notbe made. Negative

Negative for metabolite TFNA

Negative for metabolite TFNA-AM



### Page 22 of25Table5.2. 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 screeningbattery mglkg/day oftoxicity (decreased motoractivity, tremors, (rats) impaired respiration, and impaired gait) in males.

This acute neurotoxicity study is not classified as a guideline studybecause 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 otherthantheperforming lab for this study. However, dosing was very high,
near orabove the LDso, and the study produced data that are useful for risk assessment.



### Page 23 of25Table 5.2. Flonicamid ToxicityResults From Repeated Dosingand OtherStudies. ·;, Study MRID Results Guideline/Study**~** 870.6200b 45854702 (2003) Subchronic neurotoxicity screeningbattery (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 or21 mglkg and pilot pharmacokinetic study, single oral dose of2 or50 mglkg

45863802 to -5, 45854703 (2002) acceptable- guideline 2 or400 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 aftertreatment, -93% ofthe administered dose had been eliminated and by 168 hours -96% was eliminated. The primaryroute ofelimination was the urine, accounting for -90% ofthe dose. The feces of treated rats accounted for -5% ofthe administered dose, with no significant amounts ofradiolabel detected in expired air ofeither sex. After 168 hours ofa single high or low dose ofthe testmaterial, <3% ofthe radioactivity was recovered in the carcass and <0.05% in the blood, irrespective ofdose orsex.
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 ofmaximum plasma concentration (Tmax) for individual animals ranged from 0.25 to I hour aftertreatment (with a mean for each group of0.3-0.6 hours). Appears that the overall recovery ofradioactive dose from all group was 94-99% by 168 hours post-dose. Absorption was rapid and extensive, detected in plasma within I0 minutes ofdosing, with maximum plasma concentrations within 24-54 minutes. By 168 hours post-dose, total urinary excretion was 72-78%, cage rinse was I0-21%, and fecal excretion was 4- 7% dose. Parent (IKI-220) and 9 metabolites accounted for 80-94% ofthe dose for all groups. Parent was detected primarily in the urine, 46-73% ofthe 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-AMN-oxide (1-4% dose). Other metabolites in urine and feces were detected at less than orequal to 2.5% ofthe dose. IKI-220 was excreted primarily unchanged in the urine, but biotransformation ofiKI-220 in rats included nitrile hydrolysis, N-oxidation, hydroxylation ofthe pyridine ring an amide hydrolysis. NOAEL = 1540.2 mglkg/day



### Page 24 of25Table5.2. Flonicamid ToxicityResults FromRepeated Dosing and OtherStudies. 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