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` UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA** **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM Date**  **:** 10 /2 /2012 **SUBJECT: Revised:**  Flonicamid : Human Health Risk Assessment for the Proposed Use on

Low Growing Berry , Rapeseed, and Greenhouse Grown Cucumbers . **PC Code:** 12 80 16 **DP Barcode:** D39 7277 **Decision No.:** 45 7726 **Registration No s**  **. :**  71512 - 9 & 71512 - 10 **Petition No .:**  1 E 79 42 **Regulatory Action**  **:** Section 3 Registration **Risk A**  **ss essment Typ**  **e :**  Single Chemical/Aggregate **Case No.:** 7436 **T XR No.:**  NA **CAS No.:** 1 58062 - 67 - 0 **MRID No.:** NA **40 CFR:** §180. 613 **FROM:** Barry

O’Keefe , Senior Biologist Amelia Acierto , Chemist Cassi Walls , Chemist My ron Ottley , Senior Toxicologist Risk Assessment Branch III Health Effects Division (7509P) **THROUGH:** Jeff Dawson , Acting Branch Chief

Risk Assessment Branch III Health Effects Division (7509P) **TO:** Barbara Madden

Risk Integration, Minor Use and Emergency Response Branch, RM 05 Registration Division (7505P) This document and attachments provide an assessment of the human health risk resulting from the proposed and registered uses of flonicamid . The toxicology reevaluation was performed b y My ron Ottley , the drinking water assessment was conducted by James Hetrick (EPA Environmental Fate and Effects Division (EFED)) , and the review of the residue chemistry data by Amelia Acierto, the dietary , occupational and residential exposure assessment s were conducted b y Cassi Walls , and the overall human health risk assessment w as conducted b y Barry O’Keefe .Page **2** of **40 Table of Contents**  **1.0 Executive Summary**  **................................ ................................**  **................................ ...........**  **4 2.0**  **HED Recommendations ................................**  **................................ ................................**  **.... 7**  **2.1 Data**  **Deficiencies** ................................ ................................ ................................ ............ 8 **2.2.1 Enforcement Analytical Method**  ................................ ................................ ............... 8 **2.2.2 International Harmonization**  ................................ ................................ ..................... 8 **2.2.3 Recommended Tolerances**  ................................ ................................ ......................... 8 **2.2.4 Revisions to Petitioned**  **- For Tolerances**  ................................ ................................ .... 9 **2.3 Label Recommendations**  ................................ ................................ ................................ 9 **3.0 Intr**  **oduction ................................**  **................................ ................................**  **........................ 9**  **3.1 Chemical Identity**  ................................ ................................ ................................ ......... 10 **3.2 Physical/Chemical Characteristics**  ................................ ................................ ............. 10 **3.3 Pesticide Use Pattern**  ................................ ................................ ................................ .... 11 **3.4 Anticipated Exposure Pathways**  ................................ ................................ ................. 12 **3.5 Consideration of Environmental Justice**  ................................ ................................ .... 12 **4.0 Hazard Characterization and Dose**  **- Response Assessment**  **................................ ..........**  **13 4.1**  **Summary of Toxicological Effects** ................................ ................................ .............. 13 **4.2 Safety Factor for Infants and Children (FQPA Safety Factor)**  ............................... 15 **4.2.1 Completeness of the Toxicology Database**  ................................ .............................. 15 **4.2.2 Evidence of Neurotoxicity**  ................................ ................................ ........................ 15 **4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  ........ 16 **4.2.4 Residual Uncertainty in the Exposure Database**  ................................ ................... 16 **4.3.1 Summary of Points of Departure and Toxicity Endpoints Used in Human Health**  **Risk Assessment** ................................ ................................ ................................ ...................... 16 **5.0 Dietary**  **Exposure and Risk Assessment ................................**  **................................ .........**  **18 5.1**  **Metabolite/Degradate Residue Profile** ................................ ................................ ....... 18 **5.1.1. Summary of Metabolism Studies, Environmental Degradation, and Metabolic**  **Pathway Comparison** ................................ ................................ ................................ .............. 18 **5.1.2 Residues of Conc**  **ern Summary** ................................ ................................ ............... 19 **5.2 Food Residue Profile**  ................................ ................................ ................................ .... 19 **5.3 Water Residue Profile**  ................................ ................................ ................................ .. 21 **5.4 Di**  **etary Risk Assessment** ................................ ................................ .............................. 22 **5.4.1 Description of Residue Data & Percent Crop Treated Used in Dietary**  **Assessment** ................................ ................................ ................................ ............................... 22 **5.4.2 Acute Dietary Risk Assessment**  ................................ ................................ ............... 22 **5.4.3 Chronic Dietary Risk Assessment**  ................................ ................................ ........... 23 **5.4.4 Summary Table**  ................................ ................................ ................................ ......... 23 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  **............................. 23**  **6.1 Residential Bystander Post**  **- Application Inhalation Exposure**  ................................ 23 **6.2 Spray Drift**  ................................ ................................ ................................ .................... 24 **7.0 Aggregate Exposure/Risk Characterization**  **................................ ................................**  **.. 24**  **7.1 Acute Aggregate Risk**  ................................ ................................ ................................ ... 24 **7.2 Shor** **t -**  **Term Aggregate Risk** ................................ ................................ ........................ 24 **7.3 Intermediate**  **- Term Aggregate Risk**  ................................ ................................ ........... 24 **7.4 Chronic Aggregate Risk**  ................................ ................................ .............................. 25Page **3** of **40**

**7.5 Ca**  **ncer Aggregate Risk** ................................ ................................ ................................ 25 **8.0 Cumulative Exposure/Risk Characterization**  **................................ ...............................**  **25 9.0**  **Occupational Exposure/Risk Characterization ................................**  **............................ 25**  **9.1 Short** **- /Intermediate**  **- Term Handler Risk**  ................................ ................................ ... 25 **9.2 Short** **- /Intermediate**  **- Term Post** **- Application Risk**  ................................ .................... 28 **9.2.1 Dermal Post**  **- Application Risk**  ................................ ................................ ................. 28 **9.2.2 Inhalation Post** **- Application Risk**  ................................ ................................ ............ 28 **10.0 References**  **................................ ................................**  **................................ .........................**  **28 Appendix A. Toxicology Profile**  **................................ ................................**  **................................ 29**  **A.1 Toxicology Data Requirements**  ................................ ................................ ................... 29 **A.2 Toxicity Profiles**  ................................ ................................ ................................ ............ 30 **Appendix B. Physical/Chemical Properties & Structures ................................**  **..................... 36**  **Appendix C. International Residue Limit Status Sheet. ................................**  **........................ 39**  **Appendix D. Review of Human Research ................................**  **................................ ...............**  **40**Page **4** of **40**

**1.0 Executive Summary**  Flonicamid is a s ys temic insecticide that immediately suppresses the feeding of sucking insects on plants . From its chemical structure ( a nicotinic acid derivative ) , it would be expected to exhibit the same mode of action as similarly structured neo - nicotinoid pesticides. However, flonicamid has not been found to activate a cetyl choline esterase (like organophosphate s and carbamates), or nicotinic acetyl cholin e recept ors ( like neo - nicotinoids). Flonicamid is registered for use on a variety of agricultural crops, including: cotton, cucurbits, fruiting vegetables, leafy

vegetables, pome fruit s , stone fruit s , potatoes, root vegetables (except sugar beet ; subgroup 1B), tuberous and corm vegetables (subgroup 1C), leafy Brassica g reen vegetables (subgroup 5B), turnip greens, hops and okra. Flonicamid is also registered for use on commercial ornamentals, interiorscapes, and nurseries; but these labels do not allow use in hom e gardens and greenhouses or in any residential settings. IR - 4 has requested flonicamid be registered for use on low growing berry subgroup 13 - 07G, rapeseed subgroup 20A, and greenhouse grown cucumbers. Note rapeseed is sy nony mous with canola. The propo sed uses of flonicamid are expected to result in occupational exposure only ; no residential exposure is expected from the proposed uses of flonicamid. Only short - and intermediate - term occupational exposures were assessed for the proposed uses of flonicam id . The formulated end use product s (EP s ) evaluated in this assessment are Beleaf 50SG Insecticide ( EPA Reg. No. 71512 - 10) and Flonicamid 50WG, EPA Reg. No. 71512 - 9) . The most recent human health risk assessment was conducted to evaluate flonicamid use o n root vegetables (except sugar beet ; subgroup 1B), tuberous and corm vegetables (subgroup 1C), leafy Brassica vegetables (subgroup 5B), turnip greens, hops, and okra (DP347805, S. Piper, 12/21/07). Use Profile Flonicamid is proposed for use as a foliar spray using ground, aerial, and chemigation equipment on the low growing berry subgroup 13 - 07G, rapeseed subgroup 20A, and greenhouse grown cucumbers . It is also proposed as a soil drench for greenhouse grown cuc umbers. The use profile is summarized in Table 3 .3 . The proposed maximum s ingle application rate for all proposed crop s or crop group s is 0.089 lb ai/A (2.8 oz/A) with either Beleaf 50SG Insecticide or Flonicamid 50WG. Up to three seasonal applications can be made to crops in the low growing berry subgroup 13 - 07G and rapeseed subgroup 20A . Two seasonal applications can be made to greenhouse grown cucumbers. The retreatment interval for all proposed crops is 7 day s. The pre - harvest intervals (PHIs) are 0 day s for low growing berry subgroup 13 - 07G and greenhouse grown cucumbers , and 7 day s for rapeseed subgroup 20A . Exposure Profile The proposed agricultural uses of flonicamid would result in new exposures from both food and drinking water. There are no existing or proposed residential uses, and therefore, there are no non - occupational exposures expected. However, the proposed agricultural uses w ill result inPage **5** of **40**

occupational exposure s from handl er and post - application activities. Exposures are expected to o ccur for short - and intermediate - term durations . Toxicity/Hazard Since the last risk assessment, additional toxicity data have not been submitted. In accordance with the 2007 revised 40 CFR Part 158 Toxicology data requirements, an immunot oxicity study and a subchronic inhalation toxicity study were required for flonicamid . An immunotoxicity study which is currentl y underway , and is expected to be submitted to the Agency in a few months, remains required for flonicamid . Previously , the re gistrant, I SK Biosciences Corporation, submitted waiver requests for the 28 - day and 90 - day

subchronic inhalation toxicity studies, which HED granted (DP290408, J. Arthur, 5/9/05 and DP297602, J. Arthur, 5/9/05). The waivers were granted based on flonicami d’s low acute inhalation toxicity (Toxicity Category IV ) and inhalation MOE s extrapolated from oral points of departure ( PODs ) that e xceed ed the target inhalation MOE of 1 , 000. However, based on current conditional requirements for inhalation toxicity

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

the HED Hazard and Science Policy Council (HASPOC). Based upon a weight of evidence approach the HASPOC concluded that a subchronic 28 - day inhalation study

is required at this time (TXR No. 0056400, K. Rury , 7/30/12). In the absence of a route specific inhalation study , a 10X database uncertainty factor has be en applied to assess risks for inhalation exposure scenarios. The f lonicamid toxicity

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

study and an immunotoxicity

study . The kidney

and liver are the target organs for flonicamid toxicity via the oral route in rats and dogs. Increased kidney weight and hyaline droplet deposition were observed as well as liver centrilobular hy pertrophy in the rat 28 - day oral range - finding, 90 - day oral, developmental , and reproductive studies. The 90 - day dog study showed kidney

tubular va cuolation, as well as increased adrenal weights, increased reticulocy tes and decreased thy

mus weights. Increased reticulocy te count was noted in both the subchronic and chronic dog studies. In the 28 - day dermal study , with flonicamid technical , no dermal or s ys temic toxicity was seen at the limit dose (1000 mg/kg/day). In rats, d evelopmental effects (increased incidence of cervical ribs) were observed at maternall y toxic (liver and kidney

effects) dose levels. In rabbits, d evelopmental effects were not observed at any dose level including maternall y toxic doses. Because effects were seen only at maternall y toxic doses in rats , there is no concern for increased susceptibility of developing young for flonicamid. Additionally, there are no concerns for neurotoxicity . The adverse effects noted in the acute neurotoxicity

study (death, decreased motor activity , tremors, impaired respiration and gait) and the subchronic neurotoxicity study (decreased body weight and food consumption, decreased rearing and moto r activity , rearing and foot - splay) are at levels substantially above the levels where HED is currently regulating. Based on the toxicity data, HED recommended the Food Quality Protection Act ( FQPA) safety factor (SF) be reduced to 1X because there are no residual uncertainties with regard to susceptibility with pre - and/or postnatal toxicity . Mutagenicity

studies with flonicamid were negative, and flonicamid is classified by the Cancer Assessment Review Committee as “suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential”, based on increased incidences of lung tumors in CD - 1Page **6** of **40**

mice. These tumors are species and strain specific and do not correlate well with tumors in humans. Flonicamid has a low acute toxicity via the oral (Tox Category III) , dermal (Tox Category IV), and inhalation (Tox Category IV) routes of exposure. It is not an eye or skin irritant and is not a skin or dermal sensitizer. Dietary Exposure (Food and W ater) The residue chemistry

data and environmental fate data are adequate to assess human exposure. The assessments are based on reliable data and will not underestimate exposure or risk. The drinking water assessment was conducted b y the Environmental Fate and Effects Division (EFED) using a parent only and total toxic residue (TTR) approach. T TRs include 4 - trifluoromethylnicotinic acid ( TFNA), 4 - trifluoromethylnictinamide (TFNA - AM), 6 - hydro - 4 - trifluoromethylnicotinic acid (TFNA - OH), N - (4 - trifluoromethylnicotinoyl) gl ycine (TFNG), and N - (4 - trifluoromethylnicotinoyl) glycinamide (TFNG - AM). The predicted concentrations of flonicamid TTRs for the proposed uses are lower than estimated drinking water concentrations (EDWC s ) in previous drinking water assessments . An EDWC of 1.9 μg/L(ppb) was used in the chronic dietary

assessment. The EDWCs were incorporated directly into the diet ary exposure assessments. There was no acute endpoint identified in the toxicity studies; therefore, no acute dietary assessment is needed. An unrefined chronic dietary assessment was conducted using 100% crop treated (%CT) estimates , tolerance - level residues for all commodities , and empirical or Dietary Exposure Evaluation Model

–Food Commodity Intake Database ( DEEM - FCIDTM ) default processing factors. The results of the chronic dietary anal ys is for food and drinking water assessment show that the chron ic dietary risk estimates are below the Agency ’s level of concern (LOC) (<100% of the chronic population adjusted dose ( c PAD ) ) for all population subgroups and were estimated at 1 1 % of the c PAD for the general U.S. population and 2 8 % of the c PAD for the most highl y exposed population subgroup (children 1 - 2 years old). Flonicamid is classified as “suggestive evidence of carcinogenicity , but not sufficient to assess human carcinogenic potential”, therefore, a cancer dietary ris k assessment was not performe d. Residential Exposure No new residential uses were requested in this petition. Additionally, flonicamid is not currentl y registered for use in residential settings. Occupational Exposure Based on the proposed use pattern of flonicamid , there is a potential for short - and intermediate term occupational exposure during handling (mixing , loading , and applying) and post - application activities. For personal protective equipment (PPE), the proposed labels require handlers to wear long - sleeved shirt and long pants, shoes plus socks, and waterproof gloves. No dermal hazardPage **7** of **40**

was identified for flonicamid; therefore, onl y a quantitative inhalation exp osure assessment was performed for handlers . Most of the occupational handler exposure scenarios result in short - and intermediate - term MOEs that range from 2,200 to 450,000 and are not of concern to HED (i.e. an MOE > 10 0 0) with baseline attire. However , the short - /intermediate - term MOEs for two scenarios result in risk estimates that exceed HED’s level of concern; i.e. 1) the scenario of mixing/loading/appl yi ng for soil drench applications to greenhouse grown cucumbers using a mechanically

pressurized h andgun results in an MOE of 440, and 2) the scenario of mixing/loading/appl yi ng spray s to greenhouse grown cucumbers using a mechanically pressurized handgun results in an MOE of 600. With the addition of a dust/mist respirator the MOEs for these two scen arios are 2,200 and 3,100, respectivel y, which do not exceed HED’s level of concern. Therefore, the proposed labels should be amended to include the requirement for a dust mist respirator . Although occupational dermal exposure is expected following treatment of crops , no dermal hazard was identified for flonicamid . Therefore, a quantitative post - application dermal risk assessment was not conducted. HED assumes that post - application inhalation exposures are minimal following applications of an active ingredient (ai) with low vapor pressure. Since flonicamid has low acute inhalation toxicity (Toxicity Category IV ) and a low vapor pressure, post - application inhalation exposures and risks were not quantitatively assessed. Although a quantitative occupation al post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational handlers. Handler exposure resulting from application of pesticides outdoors and in well ventilated greenhouses is likel y to result in higher exposure than post - application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post - application inhalation exposure scenarios. Review of Human Research This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These data , including studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database; and the Agricultural Re - entry Task Force (ARTF) database, are subject to ethics review pursuant to 40 CFR 26, have received that review, a nd are compliant with applicable ethics requirements. For certain studies that review may have included review by the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler- exposure - data.html and http://www.epa.gov/pesticides/science/post - app - exposure - data.html . **2.0 HED**  **Recommendations** HED recommends the registration request be granted for flonicamid use on low growing berry subgroup 13 - 07G, rapeseed subgroup 20A, and greenhouse grown cucumbers .Page **8** of **40**

**2.1 Data Deficiencies**  **The following data are required :**  870.7800 Immunotoxicity Study

 In 2007, the Agency

revised 40 CFR Part 158.500 Toxicology data requirements to include functional immunotoxicity testing and granted a 2 - ye ar grace period to allow time for registrants to develop the required data. ISK Bioscience s Corporation has committed to submitting an adequate functional immunotoxicity study that is currently

underway and expected to be submitted to the Agency later in 2012 . 870.3465 28 - Day

Inhalation Study

 In 2007, the Agency

revised 40 CFR Part 158.500 Toxicology data requirements to include a 28 - day

inhalation toxicity

study . The HED Hazard and Science Policy Council (HASPOC) reassessed the need for a subchronic inhalation toxicity study . Based upon a we ight of evidence approach the HASPOC concluded that a subchronic 28 - day inhalation study is required at this time. **2. 2**  **Tolerance Considerations 2.2.1**  **Enforcement Analytical Method** Adequate LC/MS/MS methods are available for both collecting and enforcin g tolerances for flonicamid and the major metabolites TFNA - AM, TFNA, and TFNG in plants (FMC No. P 3561M). The method has been adequatel y validated by an independent laboratory in conjunction with a previous petition. For enforcement of tolerances for livestock commodities, three methods are available: LC/MS/MS method (RCC No. 844743) for residues in eggs and livestock tissues; L C/MS method (RCC No. 842993) for residues in milk; and L C/MS/MS method (FMC P3580) which includes an acid hydrol ys is step for residues in cattle muscle, kidney , and liver. **2.2.2 International Harmonization**  There are currently no Canadian or Codex Maximum Residue Limits (MRLs) for residues of flonicamid on the proposed crops and crop groups . See Appendix C for the International Residue Limit Status sheet. **2.2.3 Recommended Tolerances**  Pending submission of a revised Section F and Section B , and revised label s, there are no residue chemistry issues that will preclude establishment of permanent tolerances for flonicamid in/on the crops and crop groups specified in Table 2.2.3 .Page **9** of **40**

**Table 2.2.3**  **. Tolerance Summary for Flonicam id**  **Comm odity**  **Established Tolerance**  **(ppm )**  **Proposed**

**Tolerance (ppm)**  **Recommended**

**Tolerance (ppm)**  **Comments (correct**

**comm odity definition)**  Berry, low

growing, subgroup 13 - 07G - 1.4 1 . 5 1 Cucumber for greenhouse use only 0.4 1.3 1.5 2 Vegetable, cucurbit, group 9 Rapeseed subgroup 20A - 1.5 1.5 3 1 The representative commodity for the berry , low growing, subgroup 13 - 07G is straw berry. The Organization of Economic Cooperation and Development ( OECD ) tolerance calculation procedure gave values of 1.5 ppm for straw berry . 2 A tolerance wa s established on cucumber at 0.4 ppm (as a member of the cucurbit vegetable group 9) . The current petition is to increase the tolerance to 1.3 ppm for cucumber grown in greenhouse only. The OECD spreadsheet calculation procedure gave a value of 1.5 ppm for cucumber grown in the greenhouse treated at the proposed label rate by foliar spray. The OECD spreadsheet calculation procedure gave a value of 0.7 ppm for cucumber treated by chemigation . This tolerance value and the existing tolerance of 0.40 ppm in 40 CFR §180.613 will be covered under the foliar spray treatment in greenhouse . 3 The representative commodity for the rapeseed , subgroup 20A is canola. The OECD spreadsheet calculation procedure gave a value of 1.5 ppm for canola. **2.2.4 Revisions to Petitioned**  **- For Tolerances**  Based on the OECD tolerance calculation procedure, HED recommends increasing the proposed tolerance from 1.4 ppm to 1.5 ppm for berry , low growing, subgroup 13 - 07G and from 1.3 ppm to 1.5 ppm for greenhouse grown cucumber (as “Vegetable, cucurbit, group 9”) . **2. 3**  **Label Recommendatio ns**  860.1200 Directions for Use The submitted la

bels for BeleafTM 50SG Insecticide and Flonicamid 50WG have a restriction for greenhouse use. The labels should be revised to change the statement “Do not use this product in greenhouses” to “Do not use this product in greenhouses , except on cucumber s ”. For the proposed use on greenhouse grown cucumbers the requirement to wear a PF5 dust/mist respirator needs to be added to the Beleaf 50SG Insecticide ( EPA Reg. No. 71512 - 10) and Flonicamid 50WG, EPA Reg. No. 71512 - 9) labels. A PF5 dust/mist respirator is assumed to reduce inhalation exposure b y 80%. **3.0 In**  **troduction** Flonicamid is a s ys temic insecticide that immediately suppresses the feeding of sucking insects on plants . From its chemical structure ( a nicotinic acid derivative ) , it would be expected to exhibit the same mode of action as similarly structured neo - nicotinoid pesticides. However, flonicamid has not been found to activate a cetyl choline esterase (l ike organophosphate s and carbamates), or nicotinic acetyl cholin e receptors (like neo - nicotinoids). Flonicamid is currently

registered on head and stem Brassica vegetables, cotton, cucurbit vegetables, fruiting vegetables, hops, leafy Brassica greens, leaf y vegetables, okra, potato, pomePage **10** of **40**

fruit, root vegetables, stone fruit , tuberous and corm vegetables, and turnip greens . It is also currentl y registered on landscape ornamentals. IR - 4 has requested flonicamid be registered for use on low growing berry subgroup 13 - 07G, rapeseed subgroup 20A, and greenhouse grown cucumbers . The propose d uses of flonicamid are expected to result in occupational exposure only ; no residential exposure is expected from the proposed uses of flonicamid . Only s hort - and intermediate - term occupational exposure s w ere assessed for the proposed uses of flonicamid . The formulated end use product s (EP s ) evaluated in this assessment are Beleaf 50SG Insecticide ( EPA Reg. No. 71512 - 10) and 50WG formulation (Flonicamid 50WG, EPA Reg. No. 71512 - 9) . **3.1 Chemical Identity**  Table 3.1 Flonicamid Nomenclature. Chemical Structure

Empirical Formula C 3 H 6 F 3 N 3 O Common Name Flonicamid Company Experimental Name IK I - 220; F - 1785 IUPAC Name N - cyanomethyl - 4 - (trifluoromethyl)nicotinamide CAS Name N - (cyanomethyl) - 4 - (trifluoromethyl) - 3 -pyridinecarboxamide CAS Registry Number 158062 - 67 - 0 End Use Product/EP Beleaf 50SG Insecticide (EPA Reg. No. 71512 - 10) and Flonicamid 50WG ( EPA Reg. No. 71512 - 9) Chemical Class P yridincarboxamids The chemical structure and nomenclature of flonicamid and its metabolites are presented in Appendix B . **3.2 Physical/Chemical Characteristics**  Flonicamid has a log octanol/water partition coefficient ( log P ow) of 0 . 3 and is considered very soluble in water (5 g/L at 20 o C), and is therefore highl y mobile with a very low persistence in soil. Flonicamid is considered to be not very volatile, with a vapor pressure of 7.05 x 10 - 9 mm Hg at 20 o C and a Henry ’s L aw Constant of 4.2 x 10 - 8 Pa m 3 /mol at 25 o C. With a molecular weight of 229.2 g/mol , the potential to cross biological barriers is somewhat limited . In animal livestock studies flonicamid is rapidly metabolized and excreted with very low detectable levels in edible animal tissues. The phy si c ochemical properties of flonicamid are summarized in Appendix B . 

### N C F 3 

### N

H O NPage **11** of **40**

**3.3 Pesticide Use Pattern**  The petitioner has submitted amended label s for a 50SG formulation ( Beleaf 50SG Insecticide, EPA Reg. No. 71512 - 10 ) and for the 50WG formulation (Flonicamid 50WG, EPA Reg. No. 71512 - 9) . A summary

of the proposed use patterns on berry , low growing (subgroup 13 - 07G), greenhouse grown cucumbers, and rapeseed (subgroup 20B) is detailed in Table 3.3 . Flonicamid is propose d for use as a foliar spray using ground, aerial, and chemigation equipment on the low growing berry

subgroup 13 - 07G, rapeseed subgroup 20A, and greenhouse grown cucumbers . It is also proposed as a soil drench for greenhouse grown cucumbers. The use prof ile is summarized in Table 3.3. The proposed single maximum application rate for each proposed crop or crop group is 0.089 lb ai/A (2.8 oz/A) with either of the Beleaf 50SG Insecticide or Flonicamid 50WG labels. Up to three seasonal applications can be m ade to crops in the low growing berry

subgroup 13 - 07G and rapeseed subgroup 20A . Two seasonal applications can be made to the greenhouse grown cucumbers. The retreatment interval for all proposed crops is 7 day s. The pre - harvest intervals (PHIs) are 0 d ay s for low growing berry subgroup 13 - 07G and greenhouse grown cucumbers , and 7 day s for rapeseed subgroup 20A . **Table 3.3 . Summ**  **ary of Directions for Use of Flonicamid**  **. Application,**  **Tim ing,**  **Type and Equipment**  **Form ulation** 

**(EPA Reg. No**  **s .).**  **App. Rate** 

**(lb ai/A)**  **[oz /A] Max. No.** 

**App. per Season**  **RTI**

**(days) Max.**  **Seasonal App.**  **Rate (lb ai/A)**  **[oz /A] PHI** 

**(days) Use Directions and other Limitations**  Berry, low growing, subgroup 13 - 07G [Bearberry, bilberry, blueberry, lowbush, cloudberry, cranberry, lingonberry, muntries partridgeberry, strawberry, cultivars, varieties, and/or hybrids of these] 1

. Foliar spray ground or air Beleaf 50SG

( EPA Reg . No . 71512 - 1 0 ) or Flonicamid 50WG (EPA Reg. No. 71512 - 9) 0.089

[ 2.8 ] 3 7 0.267 [ 8.4 ] 0 Apply when Aphids or Lygus first appear in the field

and before populations reach high levels. Flonicamid will stop Aphids or Lygus feeding rapidly but it may take several days to see reduction in Aphids or Lygus numbers. Reapply when new insects are detected. Two sequential application s of flonicamid result in better Aphids or Lygus control than a single application. Do not make more than 2 applications of flonicamid without rotating to an insecticide with a different mode of action. Gr eenhouse Cucumber s Foliar directed Beleaf 50SG

( EPA Reg . No . 71512 - 10 ) or Flonicamid 50WG (EPA Reg. No. 71512 - 9) 0.089

[ 2.8 ] 2 7 4.28 oz/A or 0.1 oz per 1000 ft2 0 1) For Aphids Plant Bugs. Begin applications before

population s begin to build and before damage is evident, according to local pest management guidelines. Use LOWER RATE for building populations and HIGHER RATE for greater populations and/or dense foliage. Rapidly growing plants may need retreatment. Check plants o ften and retreat as ne c essary to maintain population below damaging levels. 2) For Greenhouse White f ly . Apply when adult whiteflies first appear. Do not allow population to increase unchecke d before making the first application. Application provides SUPPRE SSION only. Apply in combination with other effective products for control. Check plants often and retreat as necessary to maintain population below damaging levels.Page **12** of **40**

**Table 3.3 . Summ**  **ary of Directions for Use of Flonicamid**  **. Application,**  **Tim ing,**  **Type and Equipment**  **Form ulation** 

**(EPA Reg. No**  **s .).**  **App. Rate** 

**(lb ai/A)**  **[oz /A] Max. No.** 

**App. per Season**  **RTI**

**(days) Max.**  **Seasonal App.**  **Rate (lb ai/A)**  **[oz /A] PHI** 

**(days) Use Directions and other Limitations**  Chemigation (to soil (soil drench) or growth media) Beleaf 50SG

( EPA Reg . No . 71512 - 10 ) or Flonicamid 50WG (EPA Reg. No. 71512 - 9) 0.089

[ 2.8 ] 2 7 4.28 oz/A or 2.8 g/1000 ft2 0 Begin applications before populations begin to build

and before damage is evident according to local pest management guidelines. Apply using a drench by hand, drip irrigation or with motorized calibrated irrigation equipment to the base of the plants. 2 Rapeseed Subgroup 20 A [Borage, crambe, cuphea, echium, flax seed, gold of pleasure, hare’s ear mustard, lesquerella, lunaria, meadowfoam, milkweed, mustard seed, oil raddish, poppy seed, rapeseed, sesame, sweet rocket, cultivars varieties, and/or hybrids of these ]. Foliar spray ground or air Beleaf 50SG

( EPA Reg . No . 71512 - 10 ) or Flonicamid 50WG (EPA Reg. No. 71512 - 9) 0.089

[ 2.8 ] 3 7 0.267 [ 8.4 ] 7 Apply when A phids or Lygus first appear in the field and before populations reach high levels. Flonicamid will stop Aphids or Lygus feeding rapidly but it may take several days to see reduction in Aphids or Lygus numbers. Reapply when new insects are detected. Two sequential applications result in better Aphids or Lygus control than a single application. Do not make more than 2 applications of flonicamid without rotating t o an insecticide with a different mode of action. 3 1 Spray adjuvants may improve coverage but do not use binder or sticker- type surfactants. Only use adjuvants known to be safe on strawberries. 2 Use a minimum of 25 gal/1000 plants but do not exceed the holding capacity of soil or growth media. Do not apply more than 4. 28 oz/A (0.44 oz/1000 plants based on 1 plant/4.5 ft2 or 9712 plants/A) of flonicamid per application. 3 Spray adjuvants may improve coverage but do not use binder or sticker- type surfactants. Only use adjuvants known to be safe on canola **3.4 Anticipated Exposure Pathways**  Humans may

be exposed to flonicamid in drinking water, since application may result in azoxystrobin reaching surface and ground water sources of drinking water . Humans may also be exposed through their diet from applications to agricultural commodities . There are no residential uses of flonicamid , so exposure to flonicamid does not occur in residential or non occupational settings. Inan occupational setting, handlers may be exposed while handling the pesticide prior to application, as well as during application. There is also a potential for post application exposure for workers re - entering treated sites. Risk assessments have been complete d for the existing uses of flonicamid . This risk assessment considers all of the aforementioned exposure pathway s bas ed on the proposed new uses of flonicamid , but also considers existing uses of flonicamid , particularl y in the dietary exposure assessment. **3.5 Consideration of Environmental Justice**  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a p art of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well - established procedures. In line with OPP policy, HED estimates risks to population subgroups fromPage **13** of **40**

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by In dividuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group and region of the country . Additionally , OPP is able to assess dietary

exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non - dietary exposures based on home use of pesticide products and associated risks for adult applicators and for children 3 to < 6 ye ars old , youths and adults entering or playing on treated areas post application are evaluated. Further considerations are currentl y in development as OPP has committed resources and expertise to the developm ent of specialized software and models that consider exposure to b ys tanders and farm workers as well as lifestyl e and traditional dietary patterns among specific subgroups. **4.0 Hazard Characterization and Dose**  **- Response Assessment** 

- Flonicamid: Human Health Ri sk Assessment for Proposed Uses on Root Vegetables (Except Sugar beet ; Subgroup 1B), Tuberous and Corm Vegetables (Subgroup 1C), Leafy Brassica Green Vegetables (Subgroup 5B), Turnip Greens, Hops, and Okra. PC Code: 128016, Petition No. 6E7081 . S. Piper , DP3 47805, 1 2 /2 1/20 07 . A detailed hazard characterization with a list of available toxicity studies for flonicamid is presented in the most recent flonicamid risk assessment ( DP347805 , S. Piper , 1 2 /2 1/20 07 ). The submitted studies are of good quality and p rovide sufficient information to determine whether flonicamid poses a human health hazard. Since the last risk assessment, additional hazard data have not been submitted. In accordance with the 2007 revised 40 CFR Part 158 Toxicology data requirements, an immunotoxicity study and a subchronic inhalation toxicity study were required for flonicamid . An immunotoxicity study which is currentl y underway , and is expected to be submitted to the Agency in a few months, remains required for flonicamid . Previou sly , the registrant, I SK Biosciences Corporation, submitted waiver requests for the 28 - day and 90 - day

subchronic inhalation toxicity studies, which HED granted (DP290408, J. Arthur, 5/9/05 and DP297602, J. Arthur, 5/9/05). The waivers were granted based o n flonicamid’s low acute inhalation toxicity (Toxicity Category IV ) and inhalation MOE s extrapolated from oral points of departure (PODs) that e xceed ed the target inhalation MOE of 1 , 000. However, based on current conditional requirements for inhalation toxicity

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

the HED Hazard and Science Policy Council (HASPOC). Based upon a weight of evidence approach the HASPOC concluded that a subchronic 28 - day inhalation study

is required at this time (TXR No. 0056400, K. Rury , 7/30/12). In the absence of a route specific inhalation study , a 10X database uncertainty factor has be en applied to assess risks for inhalation exposure scenarios. **4. 1**  **Summary of Toxicological Effects**  The oral studies in rats and dogs with flonicamid indicate the kidney and liver are the target organs for flonicamid toxicity . Increased kidney weight and hyaline droplet deposition and liver centrilobular hypertrophy were seen in the rat 28 - day oral range - finding study , 90 - day oral study,Page **14** of **40**

developmental study

and reproductive study . The 90 - day dog study

showed kidney

tubular vacuolation, as well as increased adrenal weights, increased reticulocy tes and decreased thy

mus weights. Increased reticulocy te counts were noted in both the subchronic and chronic dog studies. In the 28 - day

dermal study

no dermal or sy stemic toxicity was seen at the limit dose (1000 mg/kg/day) for flonicamid technical. Developmental effects (increased incidence of cervical ribs) were onl y observed at maternall y toxic doses (liver and kidney gross and histopathological effects). No developmental effects were seen in rabbit fetuses. Offspring effects (decreased body weight and delayed sexual maturation) in the multi - generation study were seen only in the presence of parental toxicity (kidney effects in males, blood effects in females). Thus, there is no concern for increased susceptibility of developing young for flonicamid. In an acute neurotoxicity

study , signs of toxicity

such as decreased motor activity , tremors, impaired gait and respiration were observed at lethal dose levels (1000 mg/kg). In a subchronic study , decreased body weight, body weight gain and food c onsumption, foot splay , rearing and decreased motor activity

were seen in males at 67 mg/kg/day and above, and in females at 722 mg/kg/day . Preliminary

results of an immunotoxicity study , submitted to EPA (J. Setser. 2012. “A 28 - day oral (dietary) immunot oxicity study of technical flonicamid in female CD - 1 mice.”) suggest that flonicamid is not an immuno - suppressant, either structurall y or functionally up to and including dose levels exceeding the Limit Dose. These results will be confirmed upon submissio n and detailed review of the study data. Mutagenicity

studies were negative for flonicamid and its metabolites TFNA, TFNA - AM, TFNG, TFNG - AM, and TFNA - OH. Flonicamid is carcinogenic in CD - 1 mice, based on increased incidences of lung tumors associated with Clara cell activation. This tumor ty pe, however, is associated with species and strain sensitivity and is not directly

correlated with cancer risks in humans. Nasal cavity tumors in male Wistar rats were linked to incisor inflammation data and were not sufficient to make a similar determination in female rats. These nasolacrimal duct tumor findings for males were confounded b y the lack of a dose - response and the biological significance is questionable; doses were at 1.84, 3.68, 7.32, and 36.8 mg/kg/day . The Cancer Assessment Review Committee (CARC) did not consider the nasolacrimal duct tumors in rats to be treatment related. The determination of carcinogenicity potential for flonicamid was made b y the CARC on January 5, 2005 b ased on the weight of the evidence approach and resulted in the classification “ suggestive evidence of carcinogenicity , but not sufficient to assess human carcinogenic potential” (TXR# 0052013, J. Kidwell, 2/24/05). The RAB3 risk assessment team determine d that quantification of risk using a non - linear approach (i.e., using a chronic reference dose (c RfD ) ) adequately account s for all chronic toxicity, including carcinogenicity that could result from exposure to fl onicamid . Therefore, the cRfD is protectiv e for carcinogenic effects . As a result, separate cancer risk assessments were not conducted. The cRfD was based on an endpoint of toxicity from a two generation reproduction study in rats. The NOAEL in this study was 3.7 mg/kg/day ; the LOAEL of 22.3 mg/kg/day is based on increased kidney weights, kidney hyaline deposition, and increased blood serum luteinizing hormone in F 1 females .Page **15** of **40**

Flonicamid has a low acute toxicity via the oral (Tox Category III) , dermal (Tox Category IV), and inhalation (Tox Cate gory IV) routes of exposure. It is not an eye or skin irritant and is not a skin or dermal sensitizer. Flonicamid metabolites TFNA, TFNA - AM, TFNG, TFNG - AM, and TFNA - OH, likewise are classified as Category III for acute oral toxicity . The acute toxicity category and toxicology

profile of technical flonicamid are presented in the appendix (A1.0 and A 2.0). **4. 2**  **Safety F**  **actor for Infants and Children (FQPA Safety Factor)** HED has determined that reliable data show it would be safe for infants and children to reduce the FQPA safety factor to 1X for sort - term, intermediate - term, and dietary risk assessments. This determination is based on the considerations and reasons liste d in the sections below. **4. 2**  **.1 Completeness**  **o f**  **the Toxicology Database**  The toxicity

database for flonicamid is complete except for an immunotoxicity study and a subchronic inhalation study . Changes to 40 CFR § 158 make immunotoxicity testing (OPPTS Guide line 870.7800) and a subchronic inhalation study required for pesticide registration . An immunotoxicity

study has been conducted and will be submitted to EPA shortly . However, the existing data are sufficient for endpoint selection for exposure/risk asse ssment scenarios, and for evaluation of the requirements under the FQPA. While spleen weights were decreased in the subchronic dog study, there are no other indications in the available studies that organs associated with immune function are affected b y f lonicamid, and preliminary results of the above - mentioned immunotoxicity study suggested that flonicamid is not an immunosuppressant. EPA does not believe that the final results of the immunotoxicity study will result in a dose less than the point of departure already used in this risk assessment, and an additional database uncertainty factor for potential immunotoxicity does not need to be applied. As explained above a subchronic 28 - day inhalation study

is required at this time (TXR No. 0056400, K. Rury , 7/30/12). In the absence of a route specific inhalation study , the HASPOC recommended that a 10X database uncertainty factor be applied to assess risks for inhalation exposure scenarios. **4. 2**  **.2 Evidence of N**  **eurotoxicity** The current data base includes acute and subchronic neurotoxicity studies. The clinical effects seen in these studies, while suggestive of an adverse effect on nervous tissue and/or function, did not occur in the absence of other effects. In the acute study , the increase in mortality sug gests the animals were in an extreme condition. In the subchronic study, food consumption and body weight measurements suggest the animals were otherwise compromised and in a state of general malaise. Also, these types of effects were not observed in the other subchronic or chronic studies in mice, rats or dogs. Thus, there is not clear evidence of neurotoxicity . Lastly , clear NOAELs and LOAELs were defined for these effects, which are above the levels currently used for risk assessment purposes, the current risk assessment is protective of these effects, and a developmental neurotoxicity study is not required.Page **16** of **40**

**4. 2**  **.3 Evidence**  **o f Sensitivity/Su**  **sceptibility in the Developing o r Young Animal**  There was no evidence for quantitative or qualitative susceptibility following oral exposures to rats in utero or oral exposure to rabbits in utero . Following oral exposures to rats, developmental effects (cervical ribs) were seen onl y in the presence of maternal toxicity (liver and kidney effects). No developmental effects were seen in rabbits. In the multi - generation reproduction study , developmental delay s in the offspring (decreased body weights, delayed sexual maturation) were seen only in the presence of parental toxicity (kidney and blood effects). Also, there are clear NOAELs and LOAELs for all effects. The degree of concern for pre and/or post natal susceptibility

is, therefore, low due to the lack of evidence of qualitative and quantitative su sceptibility . **4. 2**  **.4 Residual**  **Uncertainty in the Exposure Datab ase**  There are no residual uncertainties in the flonicamid exposure database. An unrefined conservative chronic dietary exposure assessment for food and drinking water was conducted, assuming tolerance level residues for all existing and proposed commodities and 100% of registered and proposed crops treated. The drinking water assessment utilized water concentration values generated b y models and associated modeling parameters which are design ed to produce conservative, health protective, high - end estimates of water concentrations which are not likel y to be exceeded. The dietary (food and drinking water) exposure assessment does not underestimate the potential exposure for infants, children , o r women of child bearing age. **4. 3**  **Toxicity Endpoint and Point of D**  **eparture Selections 4.**  **3 .1**  **Summary of Points of Departure and Toxicity Endpoints Used in Human Health Risk Assessment**  The toxicological doses and endpoints supporting this petition remain unchanged and have been summarized in the previous human health risk assessment (DP347805, S. Piper , 12/21/2007) . The toxicity

endpoints and PODs are presented in Table s 4. 3.1 . and 4.3.2. **Table 4.3.1. Summary of Toxicological Dose and Endpoints for Flonicamid for Use in**  **Dietary and Non -**  **Occupational Human Health Risk Assessments. Exposure Scenario**  **Point of Departure**  **Uncertainty/FQ**

**PA Safety Factors**  **RfD, PAD, Level**

**of Concern for Risk Assessment**  **Study and Toxicological Effects**  Ac ute Dietary None NA aPAD = NA N o toxicological effects seen in a single dose study . Chronic Dietary NOAEL = 3.7 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X C hronic RfD =

0.04 mg/kg/day cPAD = 0.04 mg/kg/day 2 - Gen Reproduction rat

Parental LOAEL = 22 mg/kg/day based on increased kidney weights, kidney hyaline deposition, increased blood serum LH (F1 females).Page **17** of **40**

**Table 4.3.1. Summary of Toxicological Dose and Endpoints for Flonicamid for Use in**  **Dietary and Non -**  **Occupational Human Health Risk Assessments. Exposure Scenario**  **Point of Departure**  **Uncertainty/FQ**

**PA Safety Factors**  **RfD, PAD, Level**

**of Concern for Risk Assessment**  **Study and Toxicological Effects**  Incidental Oral (All time intervals) None NA Residential LOC for MOE = NA No hazard was indentified,

since incidental oral exposure is not expected based on use pattern. Short - Term

(1 to 30 days) & Intermediate Term Dermal (1 to 6 mo nths) None NA Residential LOC for MOE = NA No hazard was indentified,

since the 28 - day

dermal study did not show

any dermal or systemic effects at the limit dose of 1000 mg/kg/day. Short - Term

(1 to 30 days) & Intermediate Term Inhalation (1 to 6 months) NOAEL = 12 mg/kg/day UF A = 10X

UF H = 10X UF DB = 10X FQPA SF = 1X Residential LOC

for MOE = 1000 90 - Day oral rat LOAEL = 60 mg/kg/day based on kidney hyaline deposition. Cancer Suggestive Evidence of Carcinogenic ity, but Not Sufficient to Assess Human Carcinogenic Pot ential Point of Departure (POD) = A data point or estimated point that is derived from observed dose - related data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level . LOAEL = lowes t observed adverse effect level. UF = uncertainty factor . UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF DB = database uncertainty factor. FQPA SF = FQPA safety factor . PAD = population adjusted dose (a = acute, c = chronic) . RfD = reference dose . MOE = margin of exposure . LOC = level of concern . NA = Not Applicable . **Table 4.3. 2**  **. Summary of Toxicological Dose and Endpoints for Flonicamid for Use in Occupational Human Health Risk**  **Assessments. Exposure Scenario**  **Point of Departure**  **Uncertainty**

**Factors Level of Concern** 

**for Risk Assessment**  **Study and Toxicological Effects** Short - Term

(1 to 30 days) & Intermediate Term Dermal (1 to 6 mo nths) None NA Occupational LOC for MOE = NA No hazard was indentified, since

the 28 - day

dermal study did not show any dermal or systemic effects at the limit dose of 1000 mg/kg/day. Short - Term

(1 to 30 days) & Intermediate Term Inhalation (1 to 6 months) Oral NOAEL = 12 mg/kg/day UF A = 10X

UF H = 10X UF DB = 10X Occupational

LOC for MOE = 1000 90 - Day

oral rat LOAEL = **60** mg/kg/day based on kidney hyaline deposition. Cancer Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential Point of Departure (POD) = A data point or estimated point that is derived from observed dose - related data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAE L = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF DB = database uncertainty facto r. MOE = margin of exposure. LOC = level of concern. NA = Not Applicable.Page **18** of **40**

Based on the available toxic ological database and the Agency's current practices, the inhalation risk for flonicamid was assessed using an oral toxicity study . The Agency

sought expert advice and input on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may , as appropriate, re - examine and develop new policies and procedures for conducting inhalation risk assessments, including route to route extrapolation of toxicity

data. If any

new polic ies or procedures are developed, the Agency may revisit the need for an inhalation toxicity study for flonicamid and/or re - examine the inhalation toxicity risk assessment. **5.0 Dietary Exposure and Risk Assessment**  **References:** Flonicamid: Human Health Ri sk Assessment for Proposed Uses on Root Vegetables (Except Sugar beet ; Subgroup 1B), Tuberous and Corm Vegetables (Subgroup 1C), Leafy Brassica Green Vegetables (Subgroup 5B), Turnip Greens, Hops and Okra. DP347805, S. Piper, 12/21/07. **Revised:** Flonicamid: Petition for the Establishment of Permanent Tolerances and Registration for Use on Berry Low- Growing Subgroup 13 - 07G, Cucumber for Greenhouse Use Only, and Rapeseed Sub -group 20A. Summary of Analytical Chemistry and Residue Data. DP396902, A. Acierto, 10 / 2/12. Drinking Water Assessment to Assess Flonicamid Use on Low Growing Berries Subgroup 13 - 07G, Greenhouse Cucumbers, and Rapeseed 20A. DP396906, J. Hetrick, 4/25/12. **Revised:** Flonicamid Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for an IR - 4 Section 3 Registration Action on Berry Low- Growing Subgroup 13 - 07G, Cucumber for Greenhouse Use Only, and Rapeseed Sub -group 20A. DP397279 .dr1 , C. Walls, 9 / 27 /12 . **5.1 Metabolite/Degradate Residue Profile**  **5.1.1. Summary of Metabolism Studies**  **, Environmental Degradation, and Metabolic Pathway Comparison**  The nature of the residue in plants and livestock are adequatel y understood for the purposes of th is petition. Based on the metabolism studies conducted in plants, the major metabolic pathway of flonicamid in plants involves hydrol ys is of the cyano ( - CN) and amide ( - CONH) functional groups and ring hydrox yl ation. The residues of concern in plants for tolerance s an d risk assessment are flonicamid and its metabolites TFNA, TFNA - AM, and TFNG. In livestock commodities, HED has determined that the residues of concern for the tolerance s and risk assessment are flonicamid, TFNA and TFNA - AM. A more detailed description o f the plant and animal metabolism studies is presented in the previous risk assessment (DP347805, S. Piper, 12/21/07).Page **19** of **40**

**5.1. 2**  **Residues of Concern Summary** A summary

of the metabolites and degradates of flonicamid for human health risk assessment is summarized in Table 5.1.2. **Table 5.1.**  **2 .**  **Summary of Metabolites and Degradates included in the Flonicamid Risk Assessment and Tolerance Expression** 

**Matrix Residues included in**  **Risk Assessment Residues included in**  **Tolerance Expression** Plants Primary Crop Flonicamid, TFNA, TFNA - AM and TFNG Flonicamid, TFNA, TFNA - AM and TFNG Rotational Crop Flonicamid, TFNA, TFNA - AM and TFNG Flonicamid, TFNA, TFNA - AM and TFNG Livestock R

uminant Flonicamid, TFNA and TFNA - AM Flonicamid, TFNA and TFNA - AM Poultry Flonicamid, TFNA and TFNA - AM Flonicamid, TFNA and TFNA - AM Drinking Water Flonicamid, TFNA, TFNG - AM, TFNG, TFNA - OH, TFNA - AM Not Applicable **5.2 Food Residue Profile**  Adequate residue data are available to support dietary risk assessment as well as the proposed tolerances of flonicamid. Adequate field trial data were submitted on strawberries, greenhouse grown cucumbers, and canola supporting the use of the flonicamid 50SG formulation on the proposed crop s /crop groups. An adequate number of field trials were conducted on the required representative crops in the appropriate geographic regions . The crop field trial data reflect the proposed multiple application rates an d PHI s . Summaries of the residue data from the field and greenhouse trials are presented in Tables 5. 2 .1, 5.2.2, and 5.2.3. **T able**  **5.2.1 . Summary of Residue Data from** **Strawberry Field Trials with Flonicamid. Commodity**  **Analyte Total**  **Rate (lb ai/A)**  **PHI**

**(days) Residue Levels (ppm**  **flonicam id equivalents)**  **n Sampl**  **e Min. Sampl**  **e Max. LAFT**  **1 HAFT**  **1 Media**  **n Mean**  **Std.**

**Dev.** Strawberry, Berries with caps removed Flonicamid 0.263 - 0.280 0 7 0.11 0.66 0.13 0.54 0.34 0.34 0.16

TFNA <0.02 0.12 <0.02 0.12 0.052 0.051 0.035 TFNA - AM <0.02 <0.02 <0.02 <0.02 0.02 0.02 N/A TFNG <0.02 0.083 <0.02 0.080 0.026 0.036 0.022 Combined2 <0.17 <0.79 <0.19 <0.73 0.41 0.45 0.20 1 LAF T: Lowest average fiel d trial; HAFT: highest average field trial 2 Combined residues of flonicamid, TFNA, TFNA - AM, and TFNG , calculated at flonicamid equivalents.Page **20** of **40**

**T able**  **5.2.2 .**  **Summary of Residue Data from**  **Cucumber Greenhouse Trials with Flonicam** **id. Commodity**  **Analyte Total Rate**  **lb a i** **/A [k** **g ai/ha] PHI** 

**(days) Residue Levels**  **(ppm )** 

**n Min.**  **Ma x.**  **LAFT*** **HAFT*** **Median (STMdR)**  **Mean**

**(STMR) Std.** 

**Dev.** Foliar Cucumber fruit Flonicamid 0.262 - 0.291 [0.294 - 326 ] 0 4 <0. 046 0.69 0.054 0.54 0.101 0.2 0.23 - TFNA <0.02 0.034 <0.02 0.031 0.02 0.23 0.005 TFNA - AM <0.02 <0.02 <0.02 <0.02 0.02 0.02 0 TFNG <0.02 0.03 <0.02 0.028 0.02 0.23 0.004 Chemigation Cucumber fruit Flonicamid 0.264 - 0.269 [0.296 - 0.302] 0 4 0.012 0.2 0.013 0.2 0.112 0.11 0.073 TFNA <0.02 0.023 0.02 0.023 0.02 0.021 0.001 TFNA - AM <0.02 <0.02 <0.02 <0.02 0.02 0.02 0 TFNG <0.02 0.11 <0.02 0.11 0.02 0.043 0.04 *LAFT = Lowest average field trial; HAFT = Highest average field trial. **T able**  **5.2.3 . Summary of Residue Data from** **Canola Field Trials with Flonicamid. Commodity**  **Analyte Total**  **Rate (lb ai/A)**  **PHI**

**(days) Residue Levels (ppm**  **flonicam id equivalents)**  **1,2 n**  **Sample Min.**  **Sample Ma** **x. LAFT**  **2 HAFT**  **2 Media**  **n Mean**  **Std.**

**Dev.** Canola seed Flonicamid 0.261 - 0.272 6 - 8 8 < 0. 2 0. 333 < 0. 2 0.333 0. 2 0. 215 0. 048

TFNA <0.2 4 <0.24 <0.2 4 <0.24 0.24 0.24 0 TFNA - AM <0.2 4 <0.24 <0.2 4 < 0. 24 0.24 0.24 0 TFNG <0. 18 0. 287 <0. 18 0. 287 0.18 0. 195 0.039 Combined 3 <0. 86 1.10 <0. 86 1.1 0. 86 0. 650 0. 245 1 The LOQ was 0.2 ppm for all analytes. V alues reflect per trial averages; n = no . of field trials . Data reflect conversion of quantifiable residues of TFNA, TFNA - AM, and TFNG to parent equivalents by the study reviewer. 2 LAFT = lowest average field trial; HAFT = highest average field trial. 3 Combined residues of flonicamid, TFNA, TFNA - AM, and TFNG calculated using molecular weight conversion factors of 1. 20, 1.21, and 0.92, respectively. Field trial decline studies demonstrate that the combined residues of flonicamid and its metabolites in strawberry decline with increasing pre - harvest intervals ( PHIs ) . Residue decline was observed in greenhouse grown cucumber treated by foliar spray

but not in crops treated b y chemigation where the residues increased from the 0 - to 7 - day PHIs. A decline study

was not submitted for canola. Adequate processing studies in/on canola are available. The processing data indicate that the combined residues of flonicamid, TFNG, TFNA, and TFNA - AM do not concentrate in canola meal and canola oil (each have 0.27x average processing factor). The reported processing factors do not exceed the theoretical concentration factor of 1.0x for canola meal and 3.0x for canol a oil (OCSPP §860.1520, Table 3) . Based on these results, the tolerances for livestock commodities will not change. Residue data from the canola processing study are reported in Table 5.2.4 .Page **21** of **40**

**T able**  **5.2.4. Residue Data from Canola Processing Study with**  **Flonicamid. RAC**  **Processed Commodity**  **Total**

**Rate (lb ai/A)**  **PHI Residues (ppm)**  **1 [Average]**  **Processing Factor 2** 

**Flonic**   ** amid** **TFNA TFNA**  ****

**AM TFNG**  **Com******

**bined 3**  **Flonic**  

** amid** **TFNA TFNA**  ****

**AM TFNG**  **Com******

**bined 3** 

Canola Seed

(RAC) 0.821 8 -- 4 , 0.232 [0.232] <0.02,

<0.02 [<0.02] <0.02,

<0.02 [<0.02] <0.02,

<0.02 [<0.02] <0.292 [<0.292] NA 5

- NA -- -- --

Meal <0.02, <0.02 [<0.02] <0.02,

<0.02 [<0.02] <0.02,

<0.02 [<0.02] <0.02,

<0.02 [<0.02] <0.08,

<0.08 [<0.08] <0.09x NC 5 NC NC <0.27x Oil <0.02 <0.02 <0.02 <0.02 <0.08 <0.09x NC NC NC <0.27x 1 The LOQ was 0.02 ppm for all analytes. Averages and combined residues were calculated by the study reviewer using the LOQ for values reported as <LOQ. The second value for seed and meal reflects the results of re - di lution (seed) or reinjection (meal). Residues of the metabolites were <LOQ in/on all samples and therefore were not converted to parent equivalents. 2 Processing Factor = [Measured residue for analyte in the processed fraction] / [Measured residue for analyte in the RAC]. 3 Combined residues of flonicamid, TFNA, TFNA - AM, and TFNG . 4 The first value obtained for seed (0.143 ppm) was rejected by the study director because it was outside the linearity range. 5 NC = Not calculated; residues were below the LOQ (<0.02 ppm for all in analytes) in the RAC and processed fraction ; NA= not available The submitted storage stability data demonstrate that residues of flonicamid, TFNA, TFNA - AM, and TFNG are stable in/on the RAC samples of strawberry , cucumber and canola stored frozen for up to 460, 336 and 735 day s, respectively . The available data on five diverse crops (oil seed, non - oily grain, root and tuber crop, leafy vegetables, and fruiting vegetables) support the storage conditions and durations o n strawberry , cucumber and canola. Rotational Crops No new rotational crop data were submitted and none are required w ith the use of flonicamid on rapeseed, cucumber and berry . **5. 3**  **Water Residue Profile** The drinking water assessment was conducted b y the EFED using a parent only and total toxic residue (TTR) approach. T TRs include 4 - trifluoromethylnicotinic acid ( TFNA), 4 - trifluoromethylnictinamide (TFNA - AM), 6 - hydro - 4 - trifluoromethylnicotinic acid (TFNA - OH), N - (4 - trifluoromethylnicotinoyl) glycine (TFNG), and N - (4 - trifluoromethyl nicotinoyl) gl ycinamide (TFNG - AM). Tier I ground water EDWCs were calculated using S C I - GROW model. T ier II surface water EDWCs were calculated using PRZM and EXAMS models . All Tier II surface water modeling was corrected for percent cropped area (PCA) . EFED estimates drinking water concentrations of a chemical based on the highest rate of application of the chemical on all registered and proposed crops. The predicted concentrations of flonicamid total toxic residues for the proposed uses , except for cranberry , are lower than EDWCs in previous drinking water assessments . The EDWCs for c ranberry were estimated using the Tier 1 rice model which does not account for dilution and degradation. Because flonicamid and it degradation products degrade rapidly in aerobic soil (t 1/2 =5.2 day s), the EDWCs for cranberry are expected to be highl y cons ervative. The conservative nature of the EDWCs for cranberry uses limit their use as Tier 1 screening concentrations (94.93 μg/L for single application andPage **22** of **40**

285.44 μg/L for annual application rate) . EFED, therefore, recommended that HED continue to use th e 1 in 10 year annual average and 30 year annual average EDWCs from previ ous drinking water assessments. The 1 in 10 year dail y peak, however, should be changed to reflect the peak EDWC for flonicamid TTR from the Florida strawberry scenario in this asses sment. The concentration of total toxic residues of flonicamid (flonicamid TTR) should not exceed 9.031 μg/L for a 1 in10 year daily peak, 1.9 μg/L for 1 in 10 year annual average, and 0.94 μg/L for 30 ye ar annual average. Based on Tier II surface water modeling for the proposed uses, other than cranberries, the concentration of flonicamid should not exceed 7.00 μ g/L for a 1 in10 year daily peak, 0.141 μg/L for 1 in 10 ye ar annual average, and 0.065 μg/L for 30 year annual average. The concentration of total toxic residues of flonicamid (flonicamid TTR) should not exceed 9.031 μ g/L for a 1 in10 year daily peak, 0.968 μg/L for 1 in 10 year annual average, and 0.488 μg/L for 30 year annual average. Tier 1 rice modeling was conducted to assess flonicamid residues from use on cranberries. The estimated drinking water concentrations (EDWCs) of flonicamid TTR in edge of bog surface water concentrations are not expected to exceed 94.93 μg/L and 285.44 μg/L for an application rate of 0.089 lbs/A and 0.2676 lbs/A, respectivel y. These concentrations are expected to be extremely conservative because the Tier 1 rice model does not account for dilution and degradation. Tier I ground water modeling indicates that concentrations flonicamid and flonicamid TTR in ground water concentrations should not exceed 0.000753 μg/L and 0.00132 μg/L , respectivel y, for peak and long - term average concentrations. No monitoring data are available to assess flonicamid concentrations in ground and surface waters. The surface wat er EDWC of 1.9 μg/L (ppb) was used in the chronic dietary assessment. **5. 4**  **Dietary Risk Assessment 5.**  **4 .1**  **Description of Residue Data & Percent Crop Treated Used in Dietary Assessment** An acute dietary

risk assessment was not performed as flonicamid has no acute toxicological endpoint. Tolerance level residues combined with 100% crop treated were used to determine the chronic dietary

exposure and risk estimates. Separate tolerances were established for dried potatoes, tomato paste, and tomato puree based on processing studies. The adjustment factor #1 was set to 1.0 for these commodities; the DEEM default processing factors were used for the other processed commodities for which default processing factors are available. **5. 4**  **. 2**  **Acute Dietary Risk Assessment** There was no acute endpoint identified in the toxicity studies; and therefore, no acute dietary assessment is needed.Page **23** of **40**

**5. 4**  **. 3**  **Chronic Dietary Risk Assessment** A chronic dietary

exposure assessment was conducted for the general U.S. population and all population subgroups. The chronic dietary exposure for food and drinking water utilized 1 1 % of the cPAD for the general U.S. population. The chronic dietary expos ure for the highest reported exposed population subgroup, children 1 - 2 years old , utilized 2 8 % of the cPAD. The results are reported in table 5. 4.4 . All population subgroups were below the LOC . **5. 4**  **. 4**  **Summary Table Table**  **5.4.4 .**  **Summary of Dietary (Food and Drinking Water) Exposure and Risk for Flonicam id**  **Population Subgroup** ***** **cPAD (m**  **g/kg/day) Dietary**  **Exposure**

**(m g/kg/day)**  **% cPAD** ****** General U.S. Population

0.04 0.00 4 455 1 1 All Infants (< 1 year old) 0.00 6272 1 6 **Children 1 -**  **2 years old**  **0.0 1**  **1236 2**  **8** Children 3 - 5 years old 0.00 8413 2 1 Children 6 - 12 years old 0.00 49 99 11 Youth 13 - 19 years old 0.00 3 184 8 Adults 20 - 49 years old 0.00 38 64 10 Females 13 - 49 years old 0.00 39 62 10 Adults 50+ years old 0.00 4 270 1 1 *The values for the highest exposed population are bolded. ** Report % cPAD to 2 significant figures. **6.0 Residential**  **(Non -**  **Occupational) Exposure/Risk Characterization** This document addresses the proposed new agricultural use s of flonicamid on low growing berry subgroup 13 - 07G, rapeseed subgroup 20A, and greenhouse grown cucumbers . Therefore, no new residential exposure is expected. There are registered labels with use on commercial ornamentals, interiorscapes, and nurseries ; but these labels do not allow use in home gardens and greenhouses or in any

residential settings. Therefore, residential handler scenarios are not expected and need not be assessed. Additionally , b ecause no dermal toxicity endpoint was identified for flonicamid, a post - application residential exposure/risk assessment is not necessary . **6. 1**  **Residential Bystander Post -** **A pplication Inhalation Exposure**  Although a quantitative residential post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational handlers. This exposure scenario is representative of a worse case inhalation exposure and should be considered protective of most post - application inhalation exposure scenarios.Page **24** of **40**

**6. 2**  **Spray Drift** Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed f or flonicamid . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency ’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency ha s completed its evaluation of the new database submitted by

the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy

on how to appropriatel y apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y air, orchard airblast and ground hydraulic methods. After the policy

is in place, the Agency

may impose further refinements in spray drift management practices to reduce off - target drift with specific products with significant risks associated with drift. **7.0 Aggregate Exposure/Risk Characterization**  In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and c ompared to quantitative estimates of hazard (e.g. a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. For flonicamid , potential expo sures from food and drinking water scenarios were aggregated. **7.1 Acute Aggregate Risk**  An endpoint attributable to a single oral dose was not identified in the toxicity database ; therefore, an acute dietary risk RfD was not established and an acute aggregate risk assessment was not conducted. **7.2 Short** **- Term Aggregate Risk**  A short - term aggregate risk assessment was not conducted because residential exposure is not expected from the use pattern proposed in this registration request, or from any registered uses. **7.3 Intermediate**  **- Term Aggregate Risk**  An intermediate - term aggregate assessment was not conducted beca use residential exposure is not expected from the use pattern proposed in this registration request, or from any registered uses.Page **25** of **40**

**7.4 Chronic Aggregate Risk**  This assessment was conducted for food and drinking water exposures onl y. There are no expected long - term residential exposures. Because drinking water estimates have been combined with dietary

exposures, the dietary

assessment described earlier (see Section 5. 4 ) serves as the aggregate exposure and risk assessment for flonicamid. Because aggregated food and drinking water exposures from this conservative assessment for the most highly exposed population subgroup (Children 1 - 2 years old) only amount to 2 5 % of the cPAD, exposure to flonicamid from the uses subject to this registration action do not exceed HED’s level of concern. **7.5 Cancer Aggregate Risk**  This assessment was not deemed necessary because evidence of flonicamid’s carcinogenicity is only suggestive and not sufficient to assess human carcinogenic potential. **8.0 Cumulative Exposure/** **Risk Characterization** Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to flonicamid and any other substances and flonicamid does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that flonicamid has a common mechanism of toxicity with other substances. For information regarding EPA’s e fforts 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 proced ures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. **9.0 Occupational Exposure/Risk Characterization**  **Reference s**  **:** FLONICAMID: Occupational and Residential Exposure/Risk Assessment for Use on Berry LowGrowing Subgroup 13 - 07G, Cucumber for Greenhouse Use Only, and Rapeseed Sub -group 20A. DP397278, C. Walls, 7 / 17 /12 . **9 .1**  **Short -** **/Intermediate -**  **Term Handler Risk** Flonicamid is proposed for use on low growing berries, greenhouse grown cucumbers, and rapeseed/canola. Application methods, maximum application rates and use sites are summarized in Table 3.3 . Based on the proposed use pattern s of flonicamid , there is a potential for short - and intermediate - term dermal and inhalation occupational exposure s during handling (mixing , loading , and appl yi ng ) and post - application activities. Chronic exposure is not expected for the proposed use patterns. PPE was assessed at baseline ( long pants, a long - sleeved shirt, shoes, socks, no chemical - resistant gloves, and no respirator). Both the Beleaf 50SG Insecticide and Flonicamid 50WG formulations require handlers to wear long sleeved shirts, long pants, waterproof gloves, shoes, and socks.Page **26** of **40**

A summary

of the short - and intermediate - term risk estimates for occupational handlers mixing, loading, and appl yi ng flonicamid to low growing berries, greenhouse cucumbers, and rapeseed/canola are presented in Table 9.1. D er mal hazard was not identified for flonicamid; therefore, onl y a quantitative inhalation exposure assessment was performed. HED’s LOC for the inhalation MOE is defined by the uncertainty factors that are applied to the assessment. HED applies a 10X factor to account for interspecies extrapolation , a 10X factor to account for intraspecies sensitivity , and an additional 10X database uncertainty factor because the endpoint and point of departure chosen are derived from an oral toxicity study . The refore, the total uncertainty factor that has been applied to the non - cancer risk assessment for flonicamid is 100 0 X for occupational short - /intermediate - term inhalation exposure. Occupational inhalation exposure and risk estimates resulting in MOEs ≥ 10 0 0 will not be of concern to HED. The results of the occupational handler exposure and risk assessment indicate that most scenarios result in short - and intermediate - term MOEs that range from 2,200 to 450,000 and are not of concern to HED (i.e. an MOE > 10 0 0) with base line attire. However, the short - /intermediate term MOEs for two scenarios result in risk estimates that exceed HED’s level of concern; i.e. 1) the scenario of mixing/loading/appl yi ng for soil drench applications to greenhouse grown cucumbers using a mechanicall y pressurized handgun results in an MOE of 440, and 2) the scenario of mixing/loading/appl yi ng spray s to greenhouse grown cucumbers using a mechanically

pressurized handgun results in an MOE of 600. With the addition of a PF5 dust/mist respirator the MOEs for these two scenarios are 2,200 and 3,100, respe ctivel y , which do not exceed HED’s level of concern . A PF5 dust/mist respirator is assumed to reduce inhalation exposure by

80%. Therefore, the proposed labels should be amended to include the requirement for a PF5 dust/mist respirator . **Table 9.1**  **: Short -**  **and Intermediate -**  **Term Agricultural Handler Exposure and Risk for Flonicamid Exposure**  **Scenario Crop**  **App Rate (lb ai/A)**  **1 Am**  **ount Treated**

**Daily Unit Exposure**  **3 Dose**  **MOEs 5** 

**Baseline inhalation**  **(μg/lb ai) Baseline** 

**Inhalation (m** **g/k g/Day)**  **4 Baseline** 

**Inhalation Mi** **xer/Loader** M/L WDG to Support Aerial Application Canola

Strawberry 0.089 350 acres 8.96 0.0035 3,4 00 M/L WDG to Support Chemigation Canola

Strawberry 0.089 350 acres 8.96 0.0035 3,4 00 Greenhouse cucumbers 0.13 60 acres 8.96 0.000 90 14 , 000 M/L WDG to Support Groundboom Application Canola

Strawberry 0.089 80 acres 8.96 0.00080 15,0 00 **Applicator**Page **27** of **40**

**Table 9.1**  **: Short -**  **and Intermediate -**  **Term Agricultural Handler Exposure and Risk for Flonicamid Exposure**  **Scenario Crop**  **App Rate (lb ai/A)**  **1 Am**  **ount Treated**

**Daily Unit Exposure**  **3 Dose**  **MOEs 5** 

**Baseline inhalation**  **(μg/lb ai) Baseline** 

**Inhalation (m** **g/k g/Day)**  **4 Baseline** 

**Inhalation** Applying Sprays via Aerial Equipment Canola

Strawberry 0.089 350 acres 0.068 0.000026 450 , 000 Applying Sprays via Groundboom Equipment Canola,

strawberry 0.089 80 acres 0.34 0.000030 400 , 000 **Flagger** Flagging for Aerial Sprays Canola

Strawberry 0.089 350 acres 0.35 0.00014 88,0 00 **Mi xer/Loader/Applicator**  Manually Pressurized Handwand WDG Greenhouse

cucumbers 0.013 e 40 gallons 30 0.00020 60 , 000 Backpack Sprayer WDG Greenhouse

cucumbers 0.013 e 40 gallons 140 0.00094 13 , 000 Mechanically Pressurized Handgun WDG Greenhouse

cucumbers 0.013 e 1000 gallons 120 0.020 600 24 (with Respirator) 0.0039 3,100 Mechanically Pressurized Handgun WDG Greenhouse

cucumbers (drench) 0.00055 f 1000 gallons 3,9 31 0.027 4 40 786 (with Respirator) 0.0054 2,200 Mechanically Pressurized Handgun WDG Strawberry 0.0018 g 1000 gallons 3.9 0.000085 140,000 Mechanically Pressurized Handgun WDG Canola 0.0088 h 1000 gallons 3.9 0.00043 28,000

a Application rates are the maximum application rates determined from p roposed labels for flonicamid . b Amount handled per day values are HED estimates of acres treated per day based on Exposure SAC SOP #9 “Standard

Values for Daily Acres Treated in Agriculture,” c Baseline Inhalation: no respirator. d Inhalation ST/IT MOE = NOAEL (12 mg/kg/day) / inhalation daily dose (mg/kg/day), where inhal ation dose = daily unit exposure (μg/lb ai) x 0.001 mg/1 μg x applicatio n rate (lb ai/A) x area treated (A/day) / body weight (8 0 kg adult). LOC = 100 e Application rate 0.013 lb ai/gal = 4.28 oz/A x A/10 gal x 1 lb/16 oz x 50%ai f Application rate 0.00055 lb ai/gal = 0.44oz/1000 plants x 1000 plants/25 gal x 1 lb/16 oz x 50% ai g Application rate 0.0018 lb ai/gal = 2.8oz/A x A/50 gal x 1 lb/16 oz x 50%ai h Application rate 0.0088 lb ai/gal = 2.8 oz/A x A/10 gal x 1 lb/16 oz x 50%aiPage **28** of **40**

**9 .2**  **Short -** **/Int ermediate**  **- Te**  **rm Post** **- Application Risk**  **9 .2.1**  **Dermal Post -** **A pplication Risk**  The proposed occupational uses for flonicamid addressed in this document involve application to crops , resulting in the potential for exposure to flonicamid during post - application activities . However, an appropriate dermal endpoint was not identified for flonicamid . Therefore, an assessment of occupational dermal post - application exposure to flonicamid was not conducted. **9.2. 2**  **Inhalation Post** **- Application Risk**  Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for flonicamid at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV ) and low vapor pressure (7.05 x 10 - 9 mmHg at 20 o C) . However, there are multiple potential sources of post - application inhalation exposure to individuals performing post - application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post - application inhalation exposure data generated b y the Agricultural Reentry Task Force and may , as appropriate, develop policies and procedures, to identify the need for and, subsequently , the way to incorporate occupational post - application inhalation exposure into the Agency's risk asse ssments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for flonicamid . Although a quantitative occupational post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post - application exposure. Ther efore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post - application inhalation exposure scenarios. **Restricted Entry Interval:** Technical flonicamid is classified as toxicity category IV for acut e dermal toxicity, primary

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

categories III or IV for these routes are assigned a 12 - hour REI . For all ac tivities and crops, the REI of 12 hours on the proposed label s is a ppropriate to protect workers. **10 .0**  **References** Flonicamid: Human Health Risk Assessment for Proposed Uses on Root Vegetables (Except Sugar beet ; Subgroup 1B), Tuberous and Corm Vegetables (Subgroup 1C), Leafy Brassica Green Vegetables (Subgroup 5B ), Turnip Greens, Hops and Okra. DP347805, S. Piper, 12/21/07.Page **29** of **40**

**Revised:** Flonicamid: Petition for the Establishment of Permanent Tolerances and Registration for Use on Berry Low- Growing Subgroup 13 - 07G, Cucumber for Greenhouse Use Only, and Rapeseed Sub -group 20A. Summary of Analytical Chemistry and Residue Data. DP396902, A. Acierto , 5/16 /12 . Drinking Water Assessment to Assess Flonicamid Use on Low Growing Berries Subgroup 13 - 07G, Greenhouse Cucumbers, and Rapeseed 20A. DP396906, J. Hetrick, 4/25/ 12. **Revised:** Flonicamid Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for an IR - 4 Section 3 Registration Action on Berry Low- Growing Subgroup 13 - 07G, Cucumber for Greenhouse Use Only, and Rapeseed Sub -group 20A. DP397279 .dr1 , C. Walls, 9 / 27/ 12 . FLONICAMID: Occupational and Residential Exposure/Risk Assessment for Use on Berry Low- Growing Subgroup 13 - 07G, Cucumber for Greenhouse Use Only, and Rapeseed Sub -group 20A. DP397278, C. Walls, 7 / 17 /12 . **A ppendix**  **A .**  **Toxicology Profile A.1**  **Toxicology Data Requirements** The requirements (40 CFR 158. 500 ) for non - food use for flonicamid are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. **Table A.1. Toxicolo**  **gy Data Requirements for Flonicamid.**  **Study Technical**  **Required Satisfied**  870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Primary Eye Irritation ................................ .................... 870.2500 Primary Dermal Irritation ................................ .............. 870.2600 Dermal Sensitization ................................ ...................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent) ................................ ............... 870.3150 Oral Subchronic (nonrodent) ................................ ......... 870.3200 21 - Day

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

Dermal ................................ .............................. 870.3465 28 - Day

Inhalation ................................ .......................... yes yes yes no yes yes

yes yes

- no 870.3700a Developmental Toxicity (rodent) ................................ ... 870.3700b Developmental Toxicity (nonrodent) ............................. 870.3800 Reproduction ................................ ................................ . yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) ................................ .............. 870.4100b Chronic Toxicity (nonrodent) ................................ ........ 870.4200a Oncogenicity (rat) ................................ .......................... 870.4200b Oncogenicity (mouse) ................................ .................... 870.4300 Chronic/Oncogenicity ................................ .................... yes yes no yes yes yes

yes

- yes yes 870.5100 Mutagenicity

—Gene Mutation - bacterial ..................... 870.5300 Mutagenicity

—Gene Mutation - mammalian ................ 870.5375 Mutagenicity

— Structural Chromosomal Aberrations ... 870.5385 Mutagenicity

—Other Genotoxic Effects ....................... yes yes yes yes yes

yes yes yesPage **30** of **40**

**Table A.1. Toxicolo**  **gy Data Requirements for Flonicamid.**  **Study Technical**  **Required Satisfied**  870.6100a Acute Delayed Neurotoxicity (hen) ............................... 870.6100b 90 - Day

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

Neurotoxicity Screening Battery (rat) ............... 870.6300 Develop. Neurotoxicity ................................ ................. no no yes yes no -

- yes yes no 870.7485 General Metabolism ................................ ...................... 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity ................................ ............................. yes no yes yes

- no Special Studies for Ocular Effects

Ac ute Oral (rat) ................................ ........................... Subchronic Oral (rat) ................................ .................. Six - mo nth Oral (dog) ................................ .................. -

-

- -

-

- **A.2 Toxicity Profiles**  **Table A.2.1. Acute Toxicity Data on Technical Flonicamid**  **. Guideline**  **No. Study Type**  **MRID No.**  **Results Toxicity**  **Category** 870.1100 Ac ute Oral - Rat 45656707 LD 50 = 884 mg/kg (Males), LD 50 = 1768 mg/kg (Females) III 870.1200 Ac ute Dermal - Rat 45656708 LD 50 > 5000 mg/kg IV 870.1300 Ac ute Inhalation - Rat 45656709 LC 50 > 4.9 m/L IV 870.2400 Primary Eye Irritation - Rabbit 45656710 None or very low effects. IV 870.2500 Primary Skin Irritation - Rabbit 45656711 Erythema & edema scores were zero. IV 870.2600 Dermal Sensitization - Guinea Pig 45656712 Not a sensitizer. NA 870.1100 Ac ute Oral

– Rat

Flonicamid metabolite TFNA 45854605 LD 50  2000 mg/kg III 870.1100 Ac ute Oral

– Rat

Flonicamid metabolite TFNA - AM 45854606 LD 50  2000 mg/kg III 870.1100 Ac ute Oral

– Rat

Flonicamid metabolite TFNG 45854607 LD 50  2000 mg/kg III 870.1100 Ac ute Oral

– Rat

Flonicamid metabolite TFNG - AM 45854608 LD 50  2000 mg/kg III 870.1100 Ac ute Oral

– Rat

Flonicamid metabolite TFNA - OH 45854609 LD 50  2000 mg/kg III **Table A.2.2. Flonicam** **id Toxicity Results From** **Repeated Dosing and Other Studies. Study**  **Guideline/Study MRID**  **Results** 870.3100 a 90 - Day oral toxicity in rats 45656721 (2002)/

acceptable - guideline/ 0, 50 (males) , 200, 1000, 2000 (males), or 5000 (females) ppm (3.08, 12.11, 60.0, or 119.4 mg/kg/day, males & 14.52, 72.3, or NOAEL = 200 ppm (12.11 mg/kg/day , males ) ; 1000 ppm (72.3 mg/kg/day , females ) LOAELs = 1000 ppm (60.0 mg/kg/day , males ) based on hyaline deposition in the kidney; 5000 ppm (340 mg/kg/day , females ) based on hyaline deposition in the kidney and centri lobular hypertrophy in the liver.Page **31** of **40**

**Table A.2.2. Flonicam** **id Toxicity Results From** **Repeated Dosing and Other Studies. Study**  **Guideline/Study MRID**  **Results**

340.1 mg/kg/day, females) 28 - day range - finding: 45656720 (2002)/ acceptable (non - guideline)/ 0, 50 (males), 500, 1000, 5000 or 10000 (females) ppm ( 3.61, 7.47, 36.45, 73.8, or 353.4 mg/kg/day, males & 8.36, 41.24, 81.9, 372.6, or 642 mg/kg/day, fe males) 28 - day range - finding: NOAEL = 100 ppm

(7.47 mg/kg/day , males ) ; 1000 ppm (81.9 mg/kg/day , females ) LOAELs = 500 ppm (36.45 mg/kg/day , males ) ; based on hyaline deposition in the kidney; 5000 ppm (372.6 mg/kg/day , females ) based on hyaline deposition in the kidney , centrilobular hypertrophy in the liver , anemia and increased cholesterol. 870.3100b 90 - Day oral toxicity rodents (mice) 45656719 (2001)/

acceptable (non - guideline)/ 0, 100, 1000 or 7,000 ppm (0, 15.25, 15 3.9 or 1069 mg/kg bw/day in males, and 0, 20.10, 191.5, or 1248 mg/kg bw

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

females: 20.10 mg/kg bw /day) LOAEL is 1000 ppm (males: 153.9 mg/kg bw/day; females: 191.5 mg/kg bw /day) based on extramedullary hematopoiesis of the spleen. Many of the tissues/organs recommended by Guideline 870.3100 were not histologically examined in any dose group, but this study is not required and serves as a range - finding study for the mouse carcinogenicity study. Therefore, it is classified as acceptable, non - guideline study. 870.3150 90 - Day oral toxicity in dogs 45646722 (2001)/

acceptable - guideline/ 0, 3, 8, 20, or 50 (females) mg/kg bw /day NOAEL is 8 mg/kg/day in males and 20 mg/kg/day for females. LOAEL is 20 mg/kg/day in males and 50 mg/kg/day in females, based on acute clinical signs in males and females (vomiting, first observed on Day 1 and last observed on Day 90), clinical pathology at 7 weeks (increased total protein levels in males, lower red blood cells and higher reticulocytes counts in females), increased adrenal weights in males, decreased thymus gland weights in males, and increased kidney tubular vacuolation in females at study termination. 870.3200 21 - Day dermal toxicity in rats 45656723 (2001)/ acceptable -

guideline/ 0, 20, 150, or 1000 mg/kg/day NOAEL is 1000 mg/kg/day LOAEL is >1000 mg/kg/day. 870.3700a Prenatal developmental in rats 45656724 (2002)/ acceptable -

guideline/ 0, 20, 100 or 500 mg/kg bw /day Maternal NOAEL is 100 mg/kg bw /day LOAEL is 500 mg/kg bw/day, based on increased liver weight, and liver and kidney pathological changes (hypertrophy of centrilobular hepatocytes in liver and vacuolation of proximal tubular cell in kidneys). Developmental NOAEL is 100 mg/kg bw/day LOAEL is 500 mg/kg bw/day, based on the increased incidence of cervical rib. 870.3700b Prenatal developmental in 45854611 & 45854610 (2002)/

acceptable - guideline/ 0, 2.5, 7.5, or 25 mg/kg/day Maternal NOAEL is 7.5 mg/kg/day LOAEL is 25 mg/kg/day, based on decreased bodyPage **32** of **40**

**Table A.2.2. Flonicam** **id Toxicity Results From** **Repeated Dosing and Other Studies. Study**  **Guideline/Study MRID**  **Results** rabbits weights, body weight gains, and food consumption. Developmental NOAEL is  25 mg/kg/day LOAEL is not established. 870.3800 Reproduction and fertility effects in rats 45854613 and 45854612 (2002)/

acceptable - guideline/ 0, 50, 300, or 1800 ppm (0/0, 3.7/4.4, 22.3/26.5, and 132.9/153.4 mg/kg bw/day [M/F]) Parental NOAEL is 50 ppm (equivalent to 3.7/4.4 mg/kg/day [M/F]). LOAEL is 300 ppm (equivalent to 22.3/26.5 mg/kg/day [M/F]) bas ed on increased relative kidney weight and hyaline droplet deposition in the proximal tubules of the kidneys in the males and increased blood serum LH levels in the F1 females. Offspring NOAEL is 300 ppm (equivalent to 22.3/26.5 mg/kg/day [M/F]). LOAEL i s 1800 ppm (equivalent to 132.9/153.4 mg/kg/day [M/F]) based on decreased absolute and relative to body uterus weights and delayed sexual maturation in the F1 females. Reproductive Performance NOAEL is 1800 ppm (equivalent to 132.9/153.4 mg/kg/day [M/F]) . LOAEL for reproductive performance was not observed. 870.4100b Chronic toxicity in dogs 45854614 (2003)/

acceptable - guideline/ 0, 3, 8, or 20 mg/kg/day NOAEL is 8 mg/kg/day. LOAEL is 20 mg/kg/day, based on acute clinical signs (vomiting, mostly within the first week), clinical pathology at 12 months (higher reticulocytes counts) in males and females. 870.4200b Carcinogenicity in mice 45854615 & 45854616 (2003)/

acceptable - guideline/ 0, 250, 750, or 2250 ppm (0/0, 29/38, 88/112, or 261/334 mg/kg/day [M/F]) NOAEL was not established. LOAEL is 250 ppm (equivalent to 29/38 mg/kg/day [M/F]), based on minimal to moderate centrilobular hepatocellular hypertrophy, minimal to severe extramedullary hematopoiesis, minimal to moderate pigment deposition in the sternal bone marrow, and increased incidence of tissue masses/nodules in the lungs in the males, and minimal to moderate decreased cellularity in the femoral bone marrow and hyperplasia/hypertrophy of the epithelial cells of the terminal bronchioles of the females. At the doses tested, th e carcinogenic potential of IKI 220 is positive at 250 ppm in males and females based on the increased incidence of alveolar/bronchiolar adenomas, carcinomas, and com bined 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 effectPage **33** of **40**

**Table A.2.2. Flonicam** **id Toxicity Results From** **Repeated Dosing and Other Studies. Study**  **Guideline/Study MRID**  **Results** is specific to sensitive strains of mice. Carcinogenic in mice. 870.4200b Carcinogenicity in mi ce 46205801 (2004)/acceptable -

guideline/ 0, 10, 25, 80, 250 ppm [males: 0, 1.20, 3.14, 10.0, 30.3 mg/kg/day; females: 0, 1.42, 3.67, 11.8, 36.3 mg/kg/day] NOAEL is 80 ppm (equivalent to 10/12 mg/kg/day in males/females). LOAEL is 250 ppm (equivalent to 30/36 mg/kg/day in males/females) based on lung masses and terminal bronchiole epithelial cell hyperplasia/hypertrophy in both sexes. At the doses tested, the carcinogenic potential of IKI 220 is positive in males and fema les 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. Carcinog enic in mice. 870.4300 Com bined Chronic toxicity/ Carcinogenicity in rats 45863801 (2002)/ acceptable -

guideline/ 0, 50 (males), 100 (males), 200, 1000, or 5000 (females) ppm (0/0, 1.84, 3.68, 7.32/8.92, 36.5/44.1, and 219 mg/kg/day [M/F]) NOAEL is 200 ppm (equivalent to 7.32/8.92 mg/kg/day in males/females). LOAEL is 1000 ppm (equivalent to 36.5/44.1 mg/kg/day in males/females) based on decreased body weights and body weight gains, and increased incidences of keratitis in males and striated muscle fiber atrophy in females. At the high dose there was an incidence (12%) of nasolacrimal duct squamous cell carcinomas slightly outside the historical control range (0 - 10%) in male rats. A correlation between the incidence of inflammation and the fluctuati ng incidence of nasal tumors was made across dose groups. The CARC did not consider the nasolacrimal duct tumors to be treatment - related. Female rats had a significant increasing trend in nasolacrimal duct squamous cell carcinomas at p<0.05, and at the high dose was slightly above the historical control mean (0.8%) and range (0 - 4%). The CARC considered the nasolacrimal duct squamous cell carcinomas to be possibly treatment related, but that a clear association with treatment could not be made. 870.5100 Bacterial reverse gene mutation 45656725 (2002)/ acceptable -

guideline/ 61.7 to 5000 μg/plate +/ - S9 Negative 870.5100 Bacterial reverse gene mutation 45854617 (2002)/ acceptable -

guideline/ 33 to 5000 ug/plate +/ - S9 Negative for metabolite TFNA 870.5100 45854618 (2002)/ acceptable - Negative for metabolite TFNA - AMPage **34** of **40**

**Table A.2.2. Flonicam** **id Toxicity Results From** **Repeated Dosing and Other Studies. Study**  **Guideline/Study MRID**  **Results** Bacterial reverse gene mutation guideline/ 33 to 5000 ug/plate +/ -

S9 870.5100 Bacterial reverse gene mutation 45854619 (2002)/ acceptable -

guideline/ 33 to 5000 ug/plate +/ - S9 Negative for metabolite TFNG - AM 870.5100 Bacterial reverse gene mutation 45854620 (2002)/ acceptable -

guideline/ 33 to 5000 ug/plate +/ - S9 Negative for metabolite TFNA - OH 870.5100 Bacterial reverse gene mutation 45854621 (2002)/ acceptable -

guideline/ 5 to 5000 ug/plate +/ - S9 Negative for metabolite TFNG 870.5300 In vitro mammalian cell gene mutation 45656726 (2002)/ acceptable -

guideline/ 28.3 to 2290 μg/mL initial test, and 143 to 2290 μg/mL repeat. Negative

870.5375 In vitro Cy togenetics 45656727 (2002)/ acceptable -

guideline/ 573, 1145 and 2290 μg/mL Negative 870.5395 In vivo cy togenetic (micronucleus) test in mice 45656728 (2002)/ acceptable -

guideline/ twice orally by intragastric gavage at doses of 250, 500 and 1000 mg/kg/day for males and 125, 250 and 500 mg/kg/day for females Negative

Non - guideline Other genotoxicity, in vivo Comet assay 45854622 (2002)/ unacceptable

(non - guideline)/ single doses of 375, 750 and 1500 mg/kg Was not positive for nuc lear migration up to 1500 mg/kg Non - guideline Unscheduled DNA synthesis 45854623 (2002)/ acceptable (non guideline)/ once orally at 600 and 2000 mg/kg Is not genotoxic in hepatocytes from treated rats 870.6200a Ac ute neurotoxicity screening battery (rats) 45854624 (2002)/ unacceptable -

guideline/ 0, 100, 300, 600 (males), or 1000 mg/kg/day NOAEL is 600 mg/kg in males and 300 mg/kg in females. LOAEL is 1000 mg/kg based on mortality and signs of toxicity (decreased motor activity, tremors, im paired respiration, and impaired gait) in males. This acute neurotoxicity study is unacceptable because interval motor activity data were not provided as specified according to guidelines, FOB handling and open - field observations were incomplete, and positive d ata provided were from a lab other than the performing lab for this study. 870.6200b Subchronic neurotoxicity screening battery (rats) 45854702 (2003)/ acceptable -

guideline/ 0, 200, 1000, or 10,000 ppm (0/0, 13/16, 67/81, or 625/722 mg/kg/day [M/F]) NOAEL is 200/1000 ppm (equivalent to 13/81 mg/kg/day [M/F]). LOAEL is 1000/10,000 ppm (equivalent to 67/722 mg/kg/day [M/F]) based on decreased motor activity, rearing, and foot splay in males, decreased body weights, body weight gains, and food consumption inPage **35** of **40**

**Table A.2.2. Flonicam** **id Toxicity Results From** **Repeated Dosing and Other Studies. Study**  **Guideline/Study MRID**  **Results** males and females. 870.7485 Metabolism and pharmacokinetics (rats) 45656729 (2001)/ acceptable -

guideline/ pilot excre tion study, single oral dose 0.85 or 21 mg/kg and pilot pharmacokinetic study, single oral dose of 2 or 50 mg/kg IKI - 220 was r apidly 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 f

or ~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 radi oactivity was recovered in the carcass and <0.05% in the blood, irrespective of dose or sex. The pharmacokinetic parameters were also similar between the dose levels (2 and 50 mg/kg) and sexes. The radiolabel was rapidly absorbed and excreted. The appar ent plasma half - life (T1⁄2) was 4.8 - 6.0 hours and the elimination followed first order kinetics. The time of maximum plasma concentration (Tmax) for individual animals ranged from 0.25 to 1 hour after treatment (with a mean for each group of 0.3 - 0.6 hours). 870.7485 Metabolism and pharmacokinetics (rats) 45863802 to - 5, 45854703 (2002)/

acceptable - guideline/ 2 or 400 mg/kg Appears that the overall recovery of radioactive dose from all group was 94 - 99% by 168 hours post - dose. Absorption was rapid and e xtensive, detected in plasma within 10 minutes of dosing, with maximum plasma concentrations within 24 - 54 minutes. By 168 hours post - dose, total urinary excretion was 72 - 78%, cage rinse was 10 - 21%, and fecal excretion was 4 - 7% dose. Parent (IKI - 220) and 9 metabolites accounted for 80 - 94% of the dose for all groups. Parent was detected primarily in the urine, 46 - 73% of the dose in excreta in all groups. The primary metabolite was 4 - trifluoromethylnicotinamide (TFNA - AM), 18 - 27% dose in all dose groups, al ong with minor amounts of TFNA - AM N - oxide (1 - 4% dose). Other metabolites in urine and feces were detected at less than or equal to 2.5% of the dose. IKI - 220 was excreted primarily unchanged in the urine, but biotransformation of IKI - 220 in rats included nitrile hydrolysis, N - oxidation, hydroxylation of the pyridine ring an amide hydrolysis.Page **36** of **40**

**Appendix B**  **. Physical/Chemical Properties**  **& Structures Table**  **B.1. Physicochemical Properties of Flonicamid**  * **Parameter Value**  **Reference** Melting point/range 157.5  C MRID 45854601 pH, 1% aqueous suspension 4.5 (25  C) MRID 45854601 Density 1.531 (20  C) MRID 45854601 Water solubility 5.2 g/L (20  C) MRID 45854601 Solvent solubility Solvent g/100 mL (20  C)

acetone 17.32 acetonitrile 12.04 dichloromethane 0.40 ethyl acetate 3.57 hexane 0.00003 isopropyl alcohol 1.46 methanol 9.76 n - octanol 0.26 toluene 0.03 MRID 45656705

Vapor pressure 9.43 x 10 - 7 Pa (20  C)

2.55 x 10 - 6 Pa (25  C) MRID 45854601 Dissociation constant, pK a 11.60 ± 0.03 (20 ± 1  C) MRID 45656705 Octanol/water partition coefficient 1.9 (Log P OW = 0.3) (29.8  C) MRID 45854601 UV/visible absorption spectrum Acidic and neutral aqueous solutions exhibited similar

spectra with an absorption maximum near 265 nm and a molar absorptivity of 3,900 L/cm mol. A basic solution exhibited two absorption peaks. The peak observed in acidic and neutral solutions was present at a slightly longer wavelength, 270 nm, with an absorptivity of 4,200 L/cm mol. The second peak had an absorption maxima at 204 nm with an absorptivity of 13,200 L/cm mol. MRID 45854601

*Reviewed by RD, Dr. Shyam Mathur, D285457, 9/30/2003.Page **37** of **40**

**Table B.**  **2 .**  **Chemical Names and Structures of Flonicamid and its Transformation Products** Company Name Chemical Name Structure Flonicamid N - (cyanomethyl) - (4 - trifluoromethyl) -

3 -pyridinecarboxamide

TFNA 4 - trifluoromethylnicotinic acid

TFNA -AM 4 - trifluoromethylnicotinamide

TFNG N - (4 - trifluoromethylnicotinoyl)

glycine

TFNG -AM N - (4 - trifluoromethylnicotinoyl) -

glycinamide

N - oxide of flonicamid 

### N C F 3 

### N

H O N



### N C F 3 

### O H O

N C F 3 

### N H 2 

### O

N C F 3 N

H O O O H

N C F 3 N

H O O N H 2Page **38** of **40**

**Table B.**  **2 .**  **Chemical Names and Structures of Flonicamid and its Transformation Products** Company Name Chemical Name Structure

N - oxide of TFNG

OH - TFNA -AM 6 -hydroxy - 4 -

trifluoromethylnicotinamide

TFNA - OH 6 -hydroxy - 4 - trifluoromethylnicotinic

acid 

### N C F 3 

### O H O

O HPage **39** of **40**

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

### Flonicamid (PC Code 128016 ) **Table C.1. Summary of US and International Tolerances and Maximum Residue Limits** Residue Definition : US Canada Mexico 2 Codex 3 40 CFR 180.613: Plant : flonicamid [N - (cyanomethyl) - 4 - (trifluoromethyl) - 3 -pyridinecarboxamide] and its metabolites TFNA [4 - trifluoromethylnicotinic acid], TFNA -AM [4 - trifluoromethylnicotinamide] , and TFNG [N - (4 - triflu oromethylnicotinoyl)glycine] Livestock: residues of flonicamid [N - (cyanomethyl) - 4 - (trifluoromethyl) - 3 -pyridinecarboxamide], and its metabolites TFNA [4 - trifluoromethylnicotinic acid] and TFNA -AM [4 - trifluoromethylnicotinamide] None None

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex 3 Berry, low growing, subgroup 13 - 07G 1.5 Vegetable, cucurbit, group 9 1.5 Rapeseed Subgroup 20A 1.5 Completed: M. Negussie; 05/01/2012 1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant. 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. 3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.Page **40** of **40**

**Appendix D**  **. Review of Human Research**  **Studies reviewed for ethical conduct:**  The PHED Task Force, 1995. The Pesticide Handlers Exposure Database , Version 1.1. Electronic Database. Task Force members Health Canada, U. S. Environmental Protection Agency , and the National Agricultural Chemicals Association, rele ased February , 1995. The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit Exposure Surrogate Reference Table. U.S. Environmental Protection Agency . Released June 21, 2011. Data from the Outdoor Residential Exposure Task Force (ORETF).