Metaflumizone Human - Health Risk Assessment D 393447

Page 1 of 39 UNITED STATES ENVIRONMENTAL PROTECTI ON AGENCY WASHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION **Date:** December 2 1 , 2011 **S ubject**  **: Metaflumizone.**  **Revised** Human - Health Risk Assessment Associated with a Section

3 Registration for a Fire Ant Bait for Application to Citrus, Tree Nuts, and Grape , and a new Section 3 Registration for a Fl y Bait for Application around Industrial, Commercial, Agricultural and Recreational Facilities/Structures and Premises. **PC Code s**  **:** 281250 (E Isomer); 281251 (Z isomer) **DP Barcode:** D 393447 **Decision No.:** 3841 57 **Registration No. :**  7969 - 226 **Petition No.:** 7F7260 **Regulatory Action:** Section 3 **Risk Assessment Type:** single chemical aggregate **Case No.:** 7446 **T XR No.:**  not available **CAS No.:** 139968 - 49 - 3 **MRID No:** none **40 CFR:** 180.### **F rom**  **:** Kelly

M. Lowe, Environmental Scientist Tom Bloem, Chemist Chester E. Rodriguez, Ph.D., Toxicologist Risk Assessment Branch 1 (RAB 1 ) Health Effects Division ( HED, 7509 P ) **T hrough**  : Dana M. Vogel , Branch Chief

George F. Kramer, Ph.D., Senior Chemist RAB 1 /HED (7509P) **T o**  **:** Kable Davis (RM 07)

Registration D ivision ( RD, 7505 P ) **Note: This document supersedes D345134 (T. Bloem et al .**  **, 26 -** **Jan -**  **10) .**  **An immunotoxicity study has been received and reviewed by the**  **Agency and updates have been made to the Food Quality Protection Act (FQPA) Safety Factor (SF).**  **In addition, an assessment for a new Section 3 Registration for a fly bait product has been included in this document.**  The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and exposure data and conduct dietary , occupational, residential , and aggregate exposure assessments, as neede d, to estimate the risk to human health that will result from all registered/ proposed metaflumizone uses. The hazard characterization w as provided by Chester Rodriguez (RAB1) ; the residue chemistry review and dietary

exposure assessment were provided by Tom Bloem (RAB1); the occupational/residential exposure assessment and risk assessment was provided b y Kell y Lowe (RAB1 ); and the drinking water assessment was provided by Mohammed Ruhman of the Environmental Fate and Effects Division (EFED).Metaflumizone Human - Health Risk Assessment D 393447

Page 2 of 39 **Table of Con tents**  2.1 Summary of Registered/Proposed Uses ................................ ................................ ..................... 8 2.2 Structure and Nomenclature ................................ ................................ ................................ .... 10 3.1 Absorption, Distribution, Metabolism, Excretion (ADME) ................................ .................... 11 3.2 Mammalian Toxicology ................................ ................................ ................................ ........... 11 3.3 Toxi city Endpoint Selection ................................ ................................ ................................ .... 13 3.4 FQPA Safety Factor Considerations ................................ ................................ ........................ 17 3.4.1 Completeness of the Toxicology Database ................................ .............................. 17 3.4.2 Evidence of Neurotoxicity ................................ ................................ ....................... 17 3.4.3 Evidence of Sensitivity/Susceptibility in Developing Animals ............................... 17 3.4.4 Residual Uncertainty in the Exposure Database ................................ ...................... 18 4.1 Metabolism (Crops, Livestock, and Rotational Crops) and Environmental Degradation ........ 18 4.2 Analytical Methodology ................................ ................................ ................................ .......... 19 4.3 Comparative Metabolic Profile ................................ ................................ ................................ 19 4.4 Drinking Water Residue Profile ................................ ................................ ............................... 20 4.5 Food Residue Profile ................................ ................................ ................................ ................ 21 4.6 International Residue Limits and HED - Recommended Tolerances ................................ ........ 22 4.7 Dietary Exposure and Risk ................................ ................................ ................................ ...... 22 5.1 Residential Handler Exposure ................................ ................................ ................................ .. 23 5.2 Residential Post - application Exposure ................................ ................................ ..................... 24 5.3 Combined Residential Exposure ................................ ................................ .............................. 24 6.1 Acute Aggregate Risk ................................ ................................ ................................ .............. 26 6.2 Short -/Intermediate - Term Aggregate Risk ................................ ................................ ............. 26 6.3 Chronic Aggregate Risk ................................ ................................ ................................ ........... 27 6.4 Cancer Aggregate Risk ................................ ................................ ................................ ............ 27 8.1 Occupational Handler Exposure ................................ ................................ .............................. 27 8.2 Occupational Post - application Exposure ................................ ................................ ................. 31 8.3 Restricted Entry Interval ................................ ................................ ................................ .......... 31 9.1 Toxico logy ................................ ................................ ................................ ............................... 31 9.2 Residue Chemistry ................................ ................................ ................................ ................... 31 9.3 Occupational and Residential Exposure ................................ ................................ .................. 32 1.0 Executive Summary ................................ ................................ ................................ ................................ 3 2.0 Ingredient Profile ................................ ................................ ................................ ................................ .... 8 3.0 Hazard Characterization/Assessment ................................ ................................ ................................ .... 10

4.0 Dietary Exposure/Risk Characterization ................................ ................................ ............................... 18

5.0 Residential Exposure/Risk Characterization ................................ ................................ ......................... 23 6.0 Aggregate Risk Assessments and Risk Characterization ................................ ................................ ...... 25

7.0 Cumulative Risk Characterization/Assessment ................................ ................................ .................... 27 8.0 Occupational Exposure/Risk Characterization ................................ ................................ ..................... 27 9.0 Data Deficiencies ................................ ................................ ................................ ................................ .. 31 Appendix A. Toxicity Profile Tables ................................ ................................ ................................ ......... 33 Appendix B. Chemical Names and Structures ................................ ................................ ........................... 38Metaflumizone Human - Health Risk Assessment D 393447

Page 3 of 39 **1.0 Executive Summary**  Metaflumizone (2 - [2 - (4 - cyanophenyl) - 1 - [3 - (trifluoromethyl)phenyl]ethylidene] -N - [4 - (trifluoromethox y)phenyl ]hydrazinecarboxamide; E and Z isomers) is a semicarbazone insecticide that blocks the sodium channels of the nervous s ys tem in susceptible insects leading to inhibited feeding and paral ys is (Lepidoptera and Coleoptera) . The E and Z isomers are ty picall y present at an E:Z ratio of >9:1. HED previously reviewed a petition concerning the application of metaflumizone as a pet care product and fire ant bait for use on lawns, landscapes, golf courses, and other non - cropland ( D304496 , R. Mitkus et al. , 24 - Jan - 2006). Itshould be noted that the pet use currently registered for metaflumizone is in the process of being cancelled; however, the use has been included in this risk assessment. Existing stock of the registered product will continue to be sold, but registration will not be maintained beyond 2012. BASF Corporation is currently proposing the application of AltrevinTM Fire Ant Bait Insecticide (EPA File Sy

mbol No. 7969 - ###) to citrus fruits, grapes, and tree nuts and proposed th e establishment of the followi ng permanent tolerances for residues of metaflumizone (E and Z isomers): Citrus Fruits, Group 10 - 0.01 ppm; Tree Nuts, Group 14 - 0.01 ppm; Grapes, table - 0.01 ppm; and Grapes, wine - 0.01 ppm. In addition, BASF Corporatio n is also proposing the application of Metaflumizone Fly Bait (EPA Reg #7969 - xxx) for control of the adult common housefly around industrial buildings, commercial facilities, and agricultural structures and premises. It can also be used around recreational facilities and outdoor recreational areas. A previous risk assessment (D345134, T. Bloem et.al, 26 - Jan - 10) assessed risks from the proposed new fire ant bait uses; however, th e current risk assessment supersedes that document and reflects updates relate d to the FQPA SF and includes an assessment for the new Section 3 registration as a fl y bait product . **Hazard Characterization:** Hematotoxicity (toxicity of the blood) was the primary toxic effect of concern following subchronic or chronic oral exposures to metaflumizone . Splenic extramedullary

hematopoiesis, increased hemosiderin, and anemia were the most common hematotoxic effects reported after repeated oral dosing with metaflumizone. Chronic oral (gavage) exposures to dogs resulted in slight decreases in mean corpuscular hemoglobin concentration and total hemoglobin, leading to increased plasma bilirubin, increased urinary urobilinogen, and increased hemosiderin in the liver . In a chronic toxicity /carcinogenicity

study in mice, anemia was observed in the form of increased hemosiderin in the spleen, increased mean absolute reticulocyte count, decreased mean corpuscular volume, and mean corpuscular hemoglobin. The postulated pesticidal mode of action of metaflumizone involves inhibition of sodium channel s in target insect species; however, in mammals (rats), there were onl y clinical signs of neurotoxicity

(i.e., piloerection and body temperature variations) with no neuropathology and in the presence of s ys temic toxicity (e.g., recumbency and poor general state ) following acute or repeated exposures . Similarly , several immune s ystem organs seem to be affected following metaflumizone administration via the oral, dermal, and inhalation routes (e.g., the presence of macrophages in the thymus, ly mphocy te necro sis in the mesenteric ly mph nodes, and diffuse atrophy of the mandibular); however, there was no evidence of any functional deficits at the highest dose tested in a recentl y submitted and reviewed guideline immunotoxicity study . Therefore, the clinical neurotoxicity signs and the effects on the immune sy stem organs following metaflumizone administration are likel y to be secondary to the hematotoxic effects . Metaflumizone induced a malformation based on an absent subclavian artery at a relativel y high dose in the developmental toxicity study in rabbits. However, this was observed at the sameMetaflumizone Human - Health Risk Assessment D 393447

Page 4 of 39 dose as severe maternal toxicity, which included late - term abortions and other clinical signs of toxicity . There was no evidence (quantitative or qualitative) of incr eased susceptibility following in utero exposures to rats or rabbit and following pre - and post natal exposures to rats. There was no evidence that metaflumizone is genotoxic and carcinogenicity studies with mice and rabbits were negative. **Dose -**  **Response As sessment and FQPA SF Decision:**  The p oints of d epartures (PoDs ) and t oxicological endpoints of concern are the same as those described in the risk assessment document dated January

26, 2010 ( D345134 ) . The metaflumizone risk assessment team recommends that the FQPA SF be (a) reduced from 10x to 3x for all oral exposure scenarios, (b) retained at 10x for inhalation exposure scenarios, and (c) reduced from 10x to 1x for dermal exposure s cenarios . The reasons are as follows (for a more detailed discussion see Section 3.4): 1) Although metaflumizone shows evidence of potential immunotoxicity in the form of dose - related effects in the organs of the immune sy stem across multiple studies with either the parent compound (composed of both E and Z isomers) or the Z - iso mer of metaflumizone, evaluation of a recentl y submitted immunotoxicity study did not result in a point of departure lower than those from the last risk assessment and there were no immune sy stem functional deficits (D345134, T. Bloem et al. , 26 - Jan - 10). 2) Reducing the FQPA SF at 3x for a database uncertainty for all oral exposure scenarios is adequate to protect against any toxicity that might occur at 2 - fold lower doses in dietary exposures (absorption was noted to be 2 - fold greater in dietary versus oral gavage studies). 3) The FQPA SF of 10x is being retained for inhalation exposure scenarios for the use of a lowest - observed adverse - effect level (LOAEL) instead of a NOAEL . 4) The FQPA SF for dermal exposure scenarios is being reduced from 10x to 1x since there is a route - sp ecific study

with a clear NOAEL and the concern for developmental toxicity is low. 5) There are no residual concerns or uncertainties for pre - and/or postnatal toxicity . 6) There is no clear evidence that metaflumizone directly targets the nervous s ys tem in mammals. 7) The dietary

anal ys is is conservative in that tolerance - level residues, 100% crop treated, and modeled drinking water estimates were assumed. Therefore, HED concludes that while the submission of data/information b y the petitioner address ing the residue chemistry deficiencies may

conceivabl y result in adjustment of the maximum theoretical residue estimate, actual metaflumizone dietary exposure estimates will not be greater than those generated in the current risk assessment (i.e., incorporation of anticipated residues, percent crop treated estimates, and/or refined drinking water estimates will compensate for any increase in the maximum theoretical residue). 8) The residential anal ys is is conservative in that health - protective assumptions were assumed along with the use of the Residential SOPs. HED notes that route - specific toxicity studies were selected for assessment of short - /intermediate - term dermal, inhalation, and oral exposures. Short/intermediate - term dermal and inhalation exposures can be aggregated based on the effects on the immune sy stem organs seen at the LOAEL in the selected studies. Short/intermediate - term oral, dermal, and inhalation exposures can be aggregated based on the decreased body weight or decreased body- weight gai n effects seen at the LOAEL in the selected oral and dermal studies and at doses above the LOAELMetaflumizone Human - Health Risk Assessment D 393447

Page 5 of 39 in the selected inhalation study . **Dietary Exposure Assessment:** Acute and chronic metaflumizone dietary risk assessments were conducted using the Dietary Exposure Evaluation Model - Food Consumption Intake Database (DEEM - FCID  , ver. 2.03) model. DEEM - FCIDTM (ver. 2.03) incorporates consumption data from the United States Department of Agriculture (USDA) Continuing Survey s of Food Intakes by Individuals (CSFII ; 1994 - 1996 and 1998). The acute and chronic dietary anal ys es assumed tolerance - level residues, 100% crop treated, and modeled drinking water estimates from the Pesticide Root Zone Model - Exposure Anal ys is Modeling S ys tem (PRZM - EXAMS) . The drinking water estimates were based on the application of metaflumizone as a fly bait on use sites such as recreational facilities and outdoor recreational areas including parks, picnic grounds, and camp grounds , which are represented by the turf modeling scenario [this scenario resulted in the highest estimated drinking water concentration (EDWC)]. DEEMTM (ver. 7.81) default processing factors were assumed for all commodities excluding grape raisin, grape juice, and citrus juice, which were reduced to 1 based on empirical data. An acute dietary exposure estimate was generated for females 13 - 49 years old, but not for the remaining population subgroups since an endpoint attributed to a single dose was not identified for those populations. The acute dietary

exposure estimate for females 13 - 49 years old was <1% of the acute population - adjusted dose (aPAD) and, therefore, does not exceed HED’s level of concern (LOC). The chronic dietary

exposure estimates were <1% of the cPAD and, therefore, do not exceed HED’s LOC (c hildren 1 - 2 years old were the most highly exposed population subgroup). **Residential Risk :**  Residential exposure is no t anticipated from the proposed fire ant bait application s to citrus fruits, grapes and tree nuts ; however, residential post - applicatio n exposure is anticipated from the proposed fly bait application scenarios . The resulting dermal and incidental oral MOEs were greater than the LOC s of 100 and 300 , respectively , and, therefore, were not of concern. There are already registered pet care and fire ant bait ( for application to lawns, landscapes, golf courses, and other non - cropland) uses that may result in residential exposures. As was noted above, the pet care product is in the process of being cancelled; however, the use has been includ ed in this risk assessment. The MOEs for the fire ant bait use (lawns, landscapes, golf courses, and other non - cropland) are > 100 for dermal exposures, >300 for incidental oral exposures and >1000 for inhalation exposures and, therefore, do not exceed HED's LOC s . The MOEs for the pet care product are > 1 00 for dermal exposures and >300 for incidental oral exposures and, therefore, do not exceed HEDs LOC . **Aggregate Risk:** Inaccordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from dietary (food and water) and residential (dermal, inhalation, and incidental oral) sources. When aggregating exposures and risks from these sources, HED considers the route and duration of exposure as well as the toxicological effec ts for each route. S hort - /intermediate - term dermal, oral, and inhalation exposures can be aggregated based on a common toxic effect (decreased body weight or decreased body- weight gain). Based on th is and the proposed/registered use s , aggregate acute, short - /intermediate - term, and chronic assessments were conducted. An aggregate cancer risk assessment was not performed because metaflumizone is not considered to be a carcinogen. Acute/Chronic Aggregate Risk - Since there are no registered/proposed us es that result in acute or chronic residential exposure, the acute and chronic aggregate exposure assessment consists ofMetaflumizone Human - Health Risk Assessment D 393447

Page 6 of 39 exposure from food and water. The acute (<1% aPAD) and chronic (  1 % cPAD) dietary exposure estimates do not exceed HED's LOC . Short- /Intermediate - T

erm Aggregate Risk

– The short - term aggregate assessment combines food and drinking water exposure with the highest potential residential exposure. The pet care products result in the highest potential residential exposure estimates, with the fly bait products resulting in the second highest . Because the pet uses of metaflumizone are in the process of being cancelled, a short - term aggregate assessment was performed both for the pet care product and for the fl y bait product. Intermediate - t erm exposures are possible for the pet care product; however, since the points of departure for the short - and intermediate - term durations are the same for metaflumizone, the short - term aggregate assessment is protective of longer- term exposures for the pe t care product. For adults and the general U.S. population, the short - and intermediate - term aggregate assessment combines chronic dietary with residential post application dermal exposure. For young children, the short - and intermediate - term aggregate assessment combines chronic dietary exposure with incidental oral and dermal post - application exposure s . Since the LOC is different for dermal and oral exposures (100 and 300, respectivel y), the aggregate risk index (ARI) method was used to determine aggregate risk (ARI s > 1 are not a risk of concern). The aggregate ARIs from food, water, and non - occupational exposures are >1 for both the fl y bait and pet care uses for adults and children. Therefore, short - /intermediate - term aggregate risk estimates do no t exceed HED’s LOC . **Occupational Risk :**  The occupational handler assessment for the proposed uses (fire ant bait on citrus fruit, grapes and tree nut s , and fl y bait around industrial buildings, commercial facilities, agricultural structures and premises, recreational facilities and outdoor recreational areas) was completed assuming the maximum label application rate s . Broadcast applications were assumed to be made b y tractor - drawn spreaders, bell y grinders, and/or push - ty pe spreaders. Placing bait in bai t stations was assumed to be done using a cup/spoon or by hand. Based on the activity use pattern, the duration of exposure is expected to be short - and intermediate - term for occupational scenarios; long - term exposures (greater than 6 months) are not anti cipated. The same points of departure are used for short - and intermediate - term exposures; therefore, risks are the same for all durations of exposure. The proposed label s require long - sleeved shirt and long pants and chemical - resistant gloves as dermal PPE for all applicators and other handlers. Occupational handler dermal and inhalation risk estimates were calculated. The dermal and inhalation exposure risks for mixer/loaders, applicators, and mixer/loader/applicators are not of concern (i.e., MOEs > 100 for dermal exposures and >1000 for inhalation exposures) at baseline and with the addition of gloves as recommended by the label. Occupational dermal postapplication exposure was not assessed as it is not anticipated that workers will be exposed after application of the fly bait and/or the fire ant bait . HED believes the presence of commercial workers in treated areas (e.g., industrial and commercial buildings) is minimal after application of the fl y bait . In the case of the fire ant bait, all appli cations are directed towards the soil surface and workers are not expected to frequent areas infested with active fire ants. R estricted Entry Interval (REI ) : The proposed uses for the fl y bait product are non - agricultural sites; therefore, a REI is n ot required. For the fire ant bait product (citrus fruits, grapes and tree nuts) , s ince a quantitative post - application dermal risk assessment has not been conducted, the default Worker Protection Standard (WPS) REI applies and is based on the acute toxic ity category of the technical for dermal toxicity , skin irritation potential, and eye irritation potential. Metaflumizone has low acute toxicity (Category

IV) via the dermal route, and is neither a dermalMetaflumizone Human - Health Risk Assessment D 393447

Page 7 of 39 irritant (Category

IV), eye irritant (Category IV) , nor a dermal sensitizer. Therefore, the default REIof 12 hours would apply for metaflumizone. **Environmental**

**- Justice Considerations:**  Potential areas of environmental - justice concerns, to the extent possible, were considered in this human - health ris k 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.hss.energy .gov/nuclearsafety/ env/guidance/justice/eo12898.pdf). As a part of ev ery pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well - established procedures. In line with OPP policy , HED estimates risks to population subgroups from 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 CSFII and are used in pesticide risk assessments fo r all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country . Additionally, OPP is able to assess dietary exposure to smaller, specialized subgro ups 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 toddlers, youths, and adults enteri ng 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 development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. **HED Recommendation :**  P ending submission of a revised Section B , revised Section F , and anal ytical reference standards to the EPA National Pesticide Standards Repository ; the toxicological, residue chemistry , and occupational/residential exposure databases support granting a conditional registration for the proposed metaflumizone uses. In conjunction with this registration, the tolerances listed below should be established with the tolerance expression, commodity

definitions, and numerical tolerances described as follows: Tolerances are established for residues of the insecticide metaflumizone, including its metabolites and degradates, in or on the commodities listed below. Compliance with the tolerance levels specified below is to be determined by measuring only

the sum of metaflumizone (E and Z isomers; 2 - [2 - (4 - cyanophenyl) - 1 - [3 - (trifluoromethyl) phenyl]ethylidene] -N

- [4 - (trifluoromethox y)phenyl ] hydrazinecarboxamide) and its metabolite 4 - {2 - oxo - 2 - [3 - (trifluoromethyl) phenyl ]ethyl} - benzonitrile, calculated as the stoichiometric equivalent of metaflumizone , in or on the following commo dities: Fruit, citrus, group 10 - 0.04 ppm; Nut, tree, group 14 - 0.04 ppm; Almond, hulls - 0.04 ppm; and Grape - 0.04 ppm. The conditional registration may be made unconditional pending resolution of the following issues:

 Cabbage metabolism study (4 6264326.der.wpd) - In formation pertaining to sample extraction and anal ys is dates is required; if the interval from harvest to analy sis is greater than the currently

validated interval, then additional storage stability data will also be necessary .  Cotton metabolism study (46264324.der.wpd) - In dividual concentrations of the unknowns should be reported; if any unknown comprises >10% of the total radioactiveMetaflumizone Human - Health Risk Assessment D 393447

Page 8 of 39 residue (TRR), then further characterization/identification procedures may be required (based on the se data additional residues may be included for risk assessment).  Storage stability

data - To support the subject field trial and processing studies, the following storage stability data are required which demonstrate the stability of metaflumizone (E an d Z isomers) and M320I04: grapes - 4.8 months; citrus fruit - 5.6 months; almond hulls - 6.5 months; and almond nutmeat - 5.8 months. **2.0 Ingredient Profile**  **2.1 Summary of**  **Registered/ Proposed Uses**  **Registered:** HED previously reviewed a petition concerning the application of metaflumizone as a pet care product (maximum application rate of 0.002 lb ai/animal ; 12 applications/year) and fire ant bait product for application to lawns, landscapes, golf courses, and other non - cropland (maximum applicati on rate of 0.001 lb ai/acre ; 4 applications/year ; homeowner application permitted) (D304496, R. Mitkus et al. , 24 - Jan - 2006). Itshould be noted that the pet use currentl y registered for metaflumizone is in the process of being cancelled; however, the use has been included in this risk assessment. Existing stock of the registered product will continue to be sold, but registration will not be maintained beyond 2012. **Proposed:** The petitioner is proposing application of AltrevinTM Fire Ant Bait Insecticide ( EPA Reg. No. 7969 - ### ; granular (G); 0.063% active ingredient) to citrus fruits, grap es, and tree nuts (see Table 2.1.1). The label also includes directions for use in orchards and nurseries containing field - or container - grown nonbearing stone and pome f ruit trees (application within a year of harvest is prohibited) . The proposed label includes a 12 - hour REI . **On page 3 of the label, HED requests that the petitioner list the crops for each crop group as defined in 40 CFR**  **180.41 and eliminate the "includi ng but not limited to" phrase. A revised Section B is**  **requested.** In addition, the Registrant is proposing the use of metaflumizone as a granular fl y bait for control of the adult common housefly around industrial buildings, commercial facilities, and agricultural structures and premises. It can also be used around recreational facilities and outdoor recreational areas. The end - use product is Metaflumizone Fly Bait (EPA Reg #7969 - xxx; granular (G)), containing 0.063% active ingredient . The bait can be broadcast over large areas as a scatter bait or placed in bait stations/tray s. The maximum application rate proposed for broadcast applications (scatter bait) is 0.014 lb ai/A, and for bait stations/tray s is 2 oz bait/station hung or place d at a density of 8 - 10 stations/2000 square feet.Metaflumizone Human - Health Risk Assessment D 393447

Page 9 of 39 **Table 2.1.1: Summary of Proposed Directions for Metaflumizone.** Applic ation Timing; Type; and Equip ment Product;

Formulation [EPA Reg. No.] App lication

Rate Max. No.

App. per Season Max.

Seasonal App. Rate PHI

(days) Use Directions and Limitations **Citrus trees (citrus and Fortunella**  **spp.):** including but not limited to orange (sweet, sour), lemon, lime, grapefruit, citrus hybrids (chironja, tangelo, tangor), kumquat, Mandarin (tangerine), pummelo, and Satsuma mandarin **Nut trees** : including, but not limited to almond, beech nut, Brazil nut, butternut, cashew, chestnut, chinquapin, filbert, hickory nut, macadamia nut, pecan, and walnut **Grape vineyards ; and orchards and nurseries containing field**  **- or container**  **- grown nonbearing stone and pome fruit trees**  Postemergence; Broadcast; Ground AltrevinTM Fire

Ant Bait Insecticide; 0.063% G [7969 - ###] 0.0006 - 0.001

lb ai/acre 4 0.004 lb ai/acre 5 1 Broadcast applications are to be made in

areas having a mound density of at least 1 mound per 2,000 square feet. Otherwise, individual mound spot treatments are to be made (see below). A minimum retreatment interval ( RTI ) of 4 weeks is proposed. Postemergence; Spot; Ground AltrevinTM Fire

Ant Bait Insecticide; 0.063% G [7969 - ###] 0.000 04 -

0.000 08 lb ai/mound; not to exceed 0.001 lb ai/acre not

indicated 0.004 lb

ai/acre 5 1 Spot applications are to be made in areas

having a mound density of less than 1 mound per 2,000 square feet. Otherwise, broadcast applications are to be made (see above). A minimum RTI of 4 weeks is proposed. Around industrial buildings, commercial facilities, agricultural structures and premises, recreational facilities and outdoor recreational areas. Postemergence; Broadcast; Ground2 Metaflumizone

Fly Bait ; 0.063% G [7969 - ###] 0.014 lb

ai/acre not

indicated not indicated NA Do not apply in side homes. Apply in locations where children and pets cannot access or come into contact with bait granules. Do not apply in are where livestock can ingest or contact bait. Do not use (except for bait station use) in edible product areas where food is commercially prepared or process or in serving areas when food exposed. Do not place bait in piles or in wet/moist areas. Do not pile or heap bait in station or tray. Reapply as bait is consumed to maintain control. Postemergence; Spot; Ground 3 Metaflumizone

Fly Bait ; 0.063% G [7969 - ###] 0.000079 lb

ai/station and 8 - 10 stations/2000 ft2

1 . Application to non - bearing pome and stone fruit trees is permitted up to 1 - year before first harvest. 2. Locations include: (1) Outside of food and beverage plants, meat and poultry processing plants, food handling establishments, restaurants, cafes, fast - food establishments, supermarkets, farm markets, bakeries, commissaries, warehouses, and the refuse dumpsters associated with these establishments. (2) Outside of livestock handling and feeding facilities including broiler and layer houses, swine production facilities, livestock barns, horse stables, milking parlors, dairy barns, feed lots, feed stor ag e buildings, feed silos, and other animal handling and feeding facilities. (3) Indoors in livestock handling and feeding facilities. Only in areas where livestock cannot come in contact with or ingest bait granules; such as walkways or manure pits in cage d layer houses, dairy barns, and swine facilities. (4) Outdoors around recreational facilities and outdoor recreational areas including parks, picnic grounds, campgrounds , and outdoor latrines. 3. Locations include: (1) In and around food and beverage processing plants, meat and poultry processing plants, food handling establishments, restaurants, cafes, fast - food establishments, supermarkets, farm markets, bakeries, commissaries and warehouses. (2) In and around livestock handling and feeding facilities including broiler and layer houses, swine production facilities, livestock barns, horse stables, milking parlors, dairy barns, feed lots, feed storage buildings, feed silos and other animal handling and feeding facilities.Metaflumizone Human - Health Risk Assessment D 393447

Page 10 of 39 **2.2 Structure and Nomenclatur**  **e** The chemical structure and nomenclature of metaflumizone and the phy sicochemical properties of the technical grade of metaflumizone are presented in Tables 2.2.1 and 2.2.2, respectivel y. **Table 2.2.1: Metaflumizone Nom enclature**  . Chemical structure

Common name Metaflumizone Company experimental name BAS 320 I IUPAC name (EZ ) - 2' - [2 - (4 - cyanophenyl) - 1 - (α,α,α - trifluoro - m- tolyl)ethylidene] - 4 - (trifluoromethoxy)carbanilohydrazide CAS name 2 - [2 - (4 - cyanophenyl) - 1 - [3 - (trifluoromethyl)phenyl]ethylidene] -N - [4 - (trifluoromethoxy)phenyl]hydrazinecarboxamide CAS registry number 139968 - 49 - 3 End -use product (EP) Altrevin Fire Ant Bait Insecticide (0.063% G formulation; EPA Reg. No. 7969 - ###) **Table 2.2.2: Physicochem ical Properties of Metaflum** **izone.** Melting point Two melting points observed at approximately 127 oC and 186 oC. MRID 46264204 pH 6.48 at 25 oC (1% aqueous suspension) MRID 46264524 Density (20 oC) 1.461 g/cm3 MRID 46264204 Water solubility (20 oC) D.I. water 1.79 μg/L pH 5 1.35 μg/L pH 7 1.81 μg/L pH 9 1.73 μg/L MRID 46264208

Solvent solubility (20 oC) Acetone 142.7 mg/L Acetonitrile 60.3 mg/L DCM 92.7 mg/L EtOAc 159.7 mg/L Heptane 0.0084 mg/L Methanol 13.95 mg/L Toluene 3.96 mg/L MRID 46264212 Vapor pressure 1.24 x 10 - 8 Pa at 20 oC MRID 46264206 Dissociation constant, pKa None in pH range 2 - 12 MRID 46264217 Octanol/water partition coefficient, Log(KOW) Log P OW = 5.1 (Z isomer) Log P OW = 4.4 (E isomer) MRID 46264213 UV/visible absorption spectrum Molar absorptivity: 3.81×10 4 L/Mcm at 234 nm; 1.93×10 4 L/Mcm at 280 nm. MRID 46264207 **3.0 Hazard Characterization/Assessment** The hazard characterization and toxicity profile tables (Appendix A) for metaflumizone have been updated since the last risk assessment (D345134, T. Bloem , 26 - Jan - 10) in order to include an immunotoxicity

study recentl y submitted and reviewed b y the Agency. This document includes information related to that study and updates to the FQPA SF. Oral gavage and dietary exposures to metaflumizone are addressed wh en appropriate since an absorption study (MRID# 47249001) demonstrated an approximately 2 - fold greater absorption from dietary exposures as compared to oral gavage dosing. Because of this difference in absorption, toxicity via dietary exposure has the potential to occur at doses 2 - fold lower than those currently identified using CN N N H N H O O F 3 C C F 3Metaflumizone Human - Health Risk Assessment D 393447

Page 11 of 39 gavage dosing ( f

or more details, see D345134, T. Bloem, 26 - Jan - 10 ). **3.1 Absorption, Distribution, Metabolism, Excretion (ADME) Gavage Route:**  Metaflumizone was poorly absorbed fro m the gastrointestinal (GI) tract of rats following oral dosing via gavage at 30 and 1000 mg/kg with an apparent inverse dose - absorption relationship (up to 7% was absorbed following a 30 mg/kg dose; up to 2% after a 1000 mg/kg dose). Following a single d ose (30 mg/kg/day) of radioactive metaflumizone by gavage, residues (up to 0.6% of the dose) were detected in the liver only . After two weeks of repeated daily dosing at 30 mg/kg/day , the tissue distribution of metaflumizone was increased, with up to 1% o f the administered dose measured in the liver, kidney , muscle, fat, and plasma. Average concentrations in fat did not decrease b y 168 hrs following the last dose in a repeated dosing paradigm, a finding that is consistent with the lipophilic nature of metaflumizone (log KOW = 5.1). These observations, as well as the relativel y long elimination half - life of metaflumizone (up to 17 days, depending on which ring is labeled) and the very large volume of distribution of metaflumizone in rats (up to 156 L) indi cate that the small fraction of metaflumizone absorbed from the GI tract following gavage dosing is slowly eliminated from the body . There were no major sex - related differences in excretion . Approximately 90% of the administered dose was excreted in the feces as untransformed metaflumizone seven day s following a single dose, with 1 - 2% excreted in urine . The absorbed fraction of metaflumizone was extensively biotransformed, primarily b y h ydrox yl ation of the aniline or benzonitrile ring or hydroly sis of the central hydrazine carboxamide group, and all metabolites were excrete d in either the urine or bile. **3.2 Mammalian Toxicology** A summary

of the subchronic and chronic toxicity and genotoxicity

databases for m etaflumizone, its Z - isomer, and the goat/pl ant/soil metabolite M320I23 is found in Table A.2. Gavage Dosing with Metaflumizone Metaflumizone technical (96% metaflumizone; mixture of ~90% E - isomer:10% Z - isomer) demonstrated low acute toxicity via the oral, dermal, and inhalation routes of exposure (Category IV ) . It is neither a dermal irritant (Category IV), an eye irritant (Category IV), nor a dermal sensitizer. Acute toxicity testing of the Z - isomer and the goat/plant/soil metabolite M320I23 yi elded results similar to those for the technical product (Table A.1). Metaflumizone caused both hematotoxicity (toxicity of the blood) and immunotoxicity as primary toxic effects following subchronic or chronic oral exposure. Metaflumizone induced slight anemia and/or a compensatory extramedullary

hematopoiesis in the spleen in the 90 - day oral toxicity

study in rats. Similar hematological effects were not observed at the doses tested in the chronic toxicity

/carcinogenicity

study in rats, however, a negative finding may have been due to an adaptive resp onse to the anemia following long - term exposure in this species. In the chronic toxicity

study in dog, anemia was observed in the form of slight decreases in mean corpuscular hemoglobin concentration and total hemoglobin leading to increased plasma biliru bin, increased urinary

urobilinogen, and increased hemosiderin in the liver. In the chronic/carcinogenicity s tudy in mice, anemia in the form of increased hemosiderin in the spleen, increased mean absolute reticulocy te count, and decreased mean corpuscula r volume and mean corpuscular hemoglobin were observed in both males and females.Metaflumizone Human - Health Risk Assessment D 393447

Page 12 of 39 Hematotoxicity

and/or immunotoxicity

were also observed following dermal exposure to metaflumizone. In a rat 90 - day dermal toxicity

study , increased hemosiderin was observ ed in the livers of females, along with increased macrophages in the thy mus, l ymphocy

te necrosis in the mesenteric l ymph nodes, and diffuse atrophy of the mandibular l ymph node. Ly mphocy te necrosis in the mesenteric ly mph node was also the critical effect (i.e., observed at the lowest dose) reported in a rat 28 - day inhalation toxicity

study , thereby

supporting the conclusion that metaflumizone is immunotoxic across all routes of exposure tested. The potential neurotoxicity of metaflumizone was assessed in both acute and subchronic neurotoxicity

studies. There was no evidence of neurotoxicity in the acute neurotoxicity study in rats up to the highest dose tested (the limit dose). Piloerection and body temperature variations were noted in the subchronic neurotoxicity study in rats, and salivation and ataxia were observed at the high dose in a chronic study with dogs . However, reduced general condition and/or recumbency , indicators of general sy stemic toxicity , were also observed in both sexes in both studi es . Thus, although metaflumizone is postulated to operate b y way of a neurotoxic mechanism of action (sodium channel inhibition) in insect species, it is difficult to separate the clinical signs of neurotoxicity from a general s ys temic toxic effect in mammals . In the developmental toxicity study in rat, toxicity

to the offspring was not observed at any dose, whereas mild maternal toxicity (decreased body- weight gain) was observed at the highest dose tested. In the developmental toxicity study in rabbits, the malformation absent subclavian artery was observed at the same dose as severe maternal toxicity , which included late - term abortions and clinical signs of toxicity . In the 2 - generation reproductive toxicity study in rats, perinatal mortality was obser

ved in offspring. However, the mortality was most likely

the result of the improper nursing behavior, as well as the decreased body weight and clinical signs of toxicity , exhibited by

the parents at the same dose. Similar findings were observed in the range - finding developmental neurotoxicity study in rats, in which pup mortality was observed at the same dose as clinical signs of toxicity and total litter loss in maternal animals. There was no evidence indicating that metaflumizone is genotoxic and carci nogenicity studies with mice and rats were negative. Oral Gavage Dosing with the Z - isomer of Metaflumizone : In a 3 - month oral study

with the Z - isomer alone (99.7%), groups of 10 S 

### prague - Dawley rats/sex were gavaged daily

at doses of 0, 100, 300, or 1000 mg/kg/day for 90 day s. Mortality , reduced general condition, piloerection, and decreased overall motor activity were observed in females at the L OAEL of 300 mg/kg/day (NOAEL = 100 mg/kg/day). In males, decreased overall motor activity was observed at the highest dose tested only (LOAEL = 1000 mg/kg/day ; NOAEL = 300 mg/kg/day). A comparison with the subchronic (90 - day) neurotoxicity study in rats using metaflumizone technical (LOAEL = 150 mg/kg/day; NOAEL = 36 mg/kg/day), indicates that the Z - isomer is most likely

less potent than metaflumizone technical (predominantly E - isomer), because it caused toxicity at doses that were 2 - fold and 7 - fold higher than the technical active in females and male s, respectively . In addition, like metaflumizone technical, the Z - isomer of m etaflumizone was negative for mutagenicity with and without metabolic activation in an in vitro bacterial reverse mutation (Ames) assay . Oral Gavage Dosing with Metabolite M320I23 : M320I23 is a metabolite of metaflumizone that is generated in soil, plants (cotton, tomato, whiteMetaflumizone Human - Health Risk Assessment D 393447

Page 13 of 39 cabbage), and goats, but not in rats. No adverse effects were observed in a 3 - month oral (gavage) study of M320I23 in rats. M320I23 was negative for mutagenicity in an in vitro bacterial reverse mutation (Ames) test with and without metabolic activation and an in vitro mammalian gene mutation study at the h ypoxanthine - guanine phosphoribosyl transferase (HGPRT) locus in Chinese hamster ovary (CHO) cells without metabolic activation (inconclusive results were obtained in the presence of metabolic activation due to compound precipitation). M320I23 was also negative in an in vitro mammalian chromosomal aberration study with V79 cells without metabolic activation. Although the metabolite was positive in this in vitro study

with metabolic activation, it was negative in an in vivo mammalian cy togenetics assay (mouse micronucleus test), which would be considered a more relevant test sy stem for clastogenicity

since it was tested in a whole animal. The overall weight of the evidence for this metabolite, therefore, indicates that M320I23 is less toxic than metaflumizone technical and non mutagenic like the parent compound. Dietary Dosing with Metaflumizone Five short - term toxicity

studies, in which rats or mice were exposed to metaflumizone in the diet, were submitted to the Agency after the original data package submission. These studies were conducted earl y in the development of metaflumizone as an insecticide, and the results of these studies led to the (appropriate) decision by the registrant to conduct all of its guideline studies using gavage dosing. In every study , decreased body weight and body- weight gains were observed in the presence of decreased food consumption. Because the decreases in body weight were observed onl y in the presence of decreased food consumption at the doses tested in these studies (≥3.8 mg/kg bw/day), the effect on body weight could not be attributed to a direct effect of treatment, but rather was due to the decreased food consumption, which was most likely caused b y a lack of palatability of the test substance when administered in the diet. The results f rom these five studies were supported b y two additional studies, also later submitted to the Agency , which demonstrated that when given a preference in a free - choice feeding regimen, rats strongl y preferred untreated control feed and avoided diet that was treated with metaflumizone; and when given no preference in an alternate - day feeding regimen, rats ate less and lost weight on those days in which they were forced to eat diet treated with metaflumizone . The results of these seven studies were supported b y an eighth study in which no effect on body weight or food consumption was observed when rats were administered metaflumizone by gavage at doses that were similar to the dietary studies. Because the lower body weight observed in the dietary studies was c aused b y the animals eating less due to the unpalatability of metaflumizone, and not to direct toxicity

of the test compound (for example, on intermediary metabolism), they

are not relevant for endpoint selection for risk assessment. However, it would be anticipated that humans, like rodents, might also smell and not eat food that contained residues of metaflumizone at the levels tested in these additional animal toxicity studies, thereby

limiting ingestion of the compound. **3.3 Toxicity Endpoint Selection** A summary

of the toxicological endpoints and doses chosen for the exposure scenarios relevant for the current human - health risk assessment are summarized below and in Tables 3.3.1 (for dietary and residential exposure) and 3.3.2 (for occupational exposure) . Since the last risk assessment ( D345134, T. Bloem, 26 - Jan - 10 ), an immunotoxicity study was submitted and reviewed b y the Agency . The results of the study did not impact the toxicity endpoint selection from the last risk assessment; except for the FQP A factor , which was previously retained at 10 xMetaflumizone Human - Health Risk Assessment D 393447

Page 14 of 39 due to the absence of an immunotoxicity study (see FQPA considerations below ; Section 3.4 ). Since long - term dermal and inhalation exposures are not expected with the current use pattern, endpoints for these exposure scenarios are not presented. **Dietary and Residential Exposure** Acute Dietary Endpoint (General population including infants and children): An acute dietary endpoint was not established f or this population group since an endpoint of concern (effe ct) attributable to a single dose was not identified in the database. Studies considered for this endpoint included the acute neurotoxicity study for which a LOAEL was not observed. Acute Dietary Endpoint (Females 13 - 49 years old): This endpoint was es tablished based on a developmental effect observed in the rabbit developmental toxicity study that can be potentially due to a single dose of metaflumizone . The effects consisted of an absent subclavian artery in the offspring at the LOAELof 300 mg/kg bw/day metaflumizone (NOAEL = 100 mg/kg bw/day) . The rat developmental toxicity study was also considered for this endpoint; however, no developmental effects were observed in this study at the highest dose tested of 120 mg/kg bw/day metaflumizone. A combi ned uncertainty factor (UF) of 300 was applied to account for interspecies (10 x ) and intraspecies (10 x ) extrapolation and a FQPA SF of 3x was retained because the rabbit developmental toxicity study was performed via oral gavage dosing. Dietary exposures (which are more relevant for human exposures) exhibited an approximately 2 - fold greater absorption into the sy stemic circulation and , thus , can potentially lead to toxicity

at 2 - fold lower levels of exposure . Thus, the aPAD for females 13 - 49 years old is estimated to be 0.33 mg/kg bw/day . Chronic Dietary Endpoint: This endpoint was based on results of a chronic toxicity study in dogs via capsule administration . The effects at the LOAELof 30 mg/kg bw/day (NOAEL = 12 mg/kg bw/day) consisted of reduced gen eral health condition, slight to severe ataxia, recumbency , and severe salivation, decreases in MCHC and total Hb and increased bilirubin, increased urobilinogen, and increased hemosiderin in the liver . A combined UF of 300 was applied to account for interspecies (10 x ) and intraspecies (10 x ) extrapolation and an FQPA factor of 3x being retained for the higher absorption observed with dietary exposures to metaflumizone (see above) . Thus, the cPAD is estimated to be 0.040 mg/kg bw/day . Incidental Oral (Sho rt- and Intermediate - Term): This endpoint was selected on the basis of the maternal effects observed in the rat 2 - generation reproductive toxicity study at the LOAEL of 50 mg/kg bw/day

metaflumizone (NOAEL = 20 mg/kg bw/day) . M aternal toxicity consisted o f poor general health and body weight deficits that were also associated with improper nursing behavior . Similar effects were also noted in a developmental neurotoxicity study (gavage, range finding) also considered for this endpoint. In this study , poor maternal health was also observed at the LOAEL of 120 mg/kg bw/day metaflumizone (NOAEL = 80 mg/kg bw/day) . B oth studies considered for this endpoint achieved a clear NOAELfor the offspring effects, but the NOAEL of 20 mg/kg bw/day

for the 2 - generation reproductive toxicity study is considered more protective . A combined UF of 300 was applied to account for interspecies (10 x ) and intraspecies (10 x ) extrapolation and an FQPA SF of 3x to account for the 2 - fold greater absorption observed in dietary versus oral gavage exposures (see above) . The LOC is 300. Dermal (Short- and Intermediate - Term): This endpoint was based on a rat 90 - day dermal toxicity study in which deficits in body weight , body- weight gain and food consumption (inMetaflumizone Human - Health Risk Assessment D 393447

Page 15 of 39 males and females ); anogenital smearing; increased macrophages in the thymus; ly mphocy te necrosi s in the mesenteric ly mph nodes; diffuse atrop hy of the mandibular ly

mph node; and increased hemosiderin in the liver (females onl y) were observed at the LOAELof 300 mg/kg bw/day (NOAE L = 100 mg/kg bw/day)

. The LOC is 100 based on a combined UF of 100 for interspecies (10 x ) and intraspecies (10 x ) extrapolation. Inhalation (Short- and Intermediate - Term): There is a 28 - day inhalation study that is adequate for both exposure durations . There was no NOAEL identified for female rats. At the L OAEL of 0.10 mg/L metaflumizone (NOAEL = 0.03 mg/L), histopathology of the nasal tissues, lungs, thy mus, prostate, and adrenal cortex was observed in males . The LOAEL identified in females res ulted in ly

mphocy te necrosis in the mesenteric ly mph node . The FQPA of 10 x is being retained for lack of a NOAELfor females, in addition to the combined UF of 100 for interspecies (10 x ) and intraspecies (10 x ) extrapolation. HED notes that route - specific toxicity studies were selected for assessment of short - /intermediate - term dermal, inhalation, and oral exposures. Short/intermediate - term dermal and inhalation exposures can be aggregated based on the immunotoxic effects seen at the LOAEL in the selected studies. Short/intermediate - term oral, dermal, and inhalation exposures can be aggregated based on the decreased body weight or decreased body- weight gain effects seen at the LOAEL in the selected oral and dermal studies and at doses above the LOAELin the selected inhalation study . **Table 3.3.1: Summary of Toxicological Doses and Endpoints for Metaflum** **izone Used in Residential Hum an**  **** **Health Risk Assessments. 1**  Exposure Scenario Dose Used in Risk

Assessment, UF FQPA SF or LO C for Risk Assessment Study and Toxicological Effects Acute Dietary general population, including infants and children N/A N/A An endpoint of concern (effect) attributable to a single dose was not identified in the database. Quantification of acute risk to general population including infants and children is not required. Acute Dietary females 13 - 49 years old NOAEL = 100

mg/kg/day UF = 100 FQPA SF = 3x aPAD = aRfD = 0.33 mg/kg/day Developmental toxicity (rabbit; gavage dosing); Offspring LOAEL = 300 mg/kg/day based on absent subclavian artery. Chronic Dietarygeneral population, including infants and children NOAEL = 12 mg/kg/day

UF = 100 FQPA SF = 3x cPAD =c RfD = 0.04 mg/kg/day Chronic toxicity (dog; capsule dosing); LOAEL = 30 mg/kg/day based on reduced general health condition, slight to severe ataxia, recumbency, and severe salivation, decreases in MCHC and total Hb and increased bilirubin, increased urobilinogen, and increased hemosiderin in the liver. Short - (1 - 30 days) and Intermediate - (1 - 6 months) Term Incidental Oral NOAEL = 20 mg/kg/day LOC (residential) = MOE < 300 2 - generation reproduction (rat); Maternal LOAEL = 50 mg/kg/day based on poor general health and decreased body weight. Short - (1 - 30 days) and Intermediate - (1 - 6 months) Term Dermal NOAEL = 100

mg/kg/day LOC (residential) = MOE < 100 LOC (occupational) = MOE < 100 90 - day dermal (rat); LOAEL = 300 mg/kg/day based on decreased BW gain and food consumption (M&F); anogenital smearing, decreased BW, increased macrophages in the thymus, lymphocyte necrosis in the mesenteric lymph nodes, diffuse atrophy of the mandibular lymph node, and increased hemosiderin in the liver (F).Metaflumizone Human - Health Risk Assessment D 393447

Page 1 6 of 39 **Table 3.3.1: Summary of Toxicological Doses and Endpoints for Metaflum** **izone Used in Residential Hum an**  **** **Health Risk Assessments. 1**  Exposure Scenario Dose Used in Risk

Assessment, UF FQPA SF or LO C for Risk Assessment Study and Toxicological Effects Short - (1 - 30 days) and Intermediate - (1 - 6 months) Term Inhalation LOAEL = 0.03 mg/L *

NOAEL not observed L OC (residential) = MOE < 1000 (includes 10x FQPA SF in form of UF L) LOC (occupational) = MOE < 1000 (includes 10x UF L) 28 - day inhalation (rat); LOAEL = 0.03 mg/L * based lymphocyte necrosis in the mesenteric lymph node (F). Cancer (oral, dermal, inhalation) **Classification:** Not likely to be carcinogenic to humans. 1 UF = uncertainty factor, FQPA SF = FQPA Safety Factor, NOAEL = no - observed adverse - effect level, LOAEL = lowest observed adverse - effect level, RfD = reference dose (a = acute, c = chronic), PAD = population - adjusted dose, MOE = margin of exposure, LOC = level of concern, N/A = Not Applicable, UF L = uncertainty factor for lack of a NOAEL and extrapolation of a 28 - day study for longer durations. * 0.03 mg/L x 100% absorption x 45.2 L/hr/kg (conversion factor) x 6 hrs/day (exposure duration) x 1 (activity f actor) = 8 mg/kg bw/day **Occupational Exposure** Dermal (Short- and Intermediate - Term): This endpoint was based on a rat 90 - day dermal toxicity study in which deficits in body weight, body- weight gain and food consumption (in males and females); anogenital smearing; increased macrophages in the thymus; ly mphocy te necrosis in the mesenteric ly mph nodes; diffuse atrophy of the mandibular ly

mph node; and increased hemosiderin in the liver (females onl y) were observed at the LOAELof 300 mg/kg bw/day (NOAEL = 100 mg/kg bw/day)

. The LOC is 100 based on a combined UF of 100 for interspecies (10x) and intraspecies (10x) extrapolation. Inhalation (Short- and Intermediate - Term): There is a 28 - day inhalation study that is adequate for both exposure durations . There was no NOAEL identified for female rats. At the L OAEL of 0.10 mg/L metaflumizone (NOAEL = 0.03 mg/L), histopathology of the nasal tissues, lungs, thy mus, prostate, and adrenal cortex was observed in males . The LOAEL identified in females resulted i n ly

mphocy te necrosis in the mesenteric ly mph node . The FQPA of 10x is being retained for lack of a NOAELfor females, in addition to the combined UF of 100 for interspecies (10x) and intraspecies (10x) extrapolation. **Table 3.3.2: Summary of Toxicolog**  **ical Doses and Endpoints for Metaflum izone Used in Occupational**  **Hum an**  **- Health Risk Assessments.**  **1** Exposure Scenario Dose Used in Risk

Assessment, UF FQPA SF or LOC for Risk Assessment Study and Toxicological Effects Short - (1 - 30 days) and Intermediate - (1 - 6 months) Term Dermal NOAEL = 100

mg/kg/day LOC (residential) = MOE <100 LOC (occupational) = MOE <100 90 - day dermal (rat); LOAEL = 300 mg/kg/day based on decreased BW gain and food consumption (M&F); anogenital smearing, decreased BW, increased macrophag es in the thymus, lymphocyte necrosis in the mesenteric lymph nodes, diffuse atrophy of the mandibular lymph node, and increased hemosiderin in the liver (F). Short - (1 - 30 days) and Intermediate - (1 - 6 months) Term Inhalation LOAEL = 0.03 mg/L *

NOAEL not observed LOC (residential) = MOE <1000 (includes 10x FQPA SF in form of UF L) LOC (occupational) = MOE <1000 (includes 10x UF L) 28 - day inhalation (rat); LOAEL = 0.03 mg/L * based on lymphocyte necrosis in the mesenteric lymph node (F).

1 UF = uncertainty factor, FQPA SF = FQPA Safety Factor, NOAEL = no - observed adverse - effect level, LOAEL = lowest observed adverse - effect level, RfD = reference dose (a = acute, c = chronic), PAD = population - adjusted dose, MOE = margin ofMetaflumizone Human - Health Risk Assessment D 393447

Page 17 of 39 exposure, LOC = level of concern, N/A = Not Applicable, UF L = uncertainty factor for lack of a NOAEL and extrapolation of a 28 - day study for longer durations. * 0.03 mg/L x 100% absorption x 45.2 L/hr/kg (conversion factor) x 6 hrs/day (exposure duration) x 1 (activity f actor) = 8 mg/kg bw/day **3.4 FQPA Safety Factor**  **Considerations** The metaflumizone risk assessment team recommends that the FQPA SF be reduced from 10x to 3x for all oral exposure scenarios, be retained at 10x for inhalation exposure scenarios, and be reduced to 1x for dermal exposures. **3.4.1 Completeness of the Toxicology Database** The toxicology

database for metaflumizone is adequate for registration. In the last risk assessment (D345134, T. Bloem, 26 - Jan - 10) the only database deficiency

noted was an immunotoxicity

study . Since then, an immunotoxicity study has been received and evaluated b y the Agency . The results of the study did not result in a point of departure lower than those from the last risk assessment. A difference in absorption was n oted between oral gavage and dietary dosing. Absorption via the diet, a more relevant route of exposure for oral human risk assessments, was noted to be greater than via gavage b y a factor of 2. Therefore, toxicity via the diet can be expected at doses th at are approximately

2 - fold lower than those currentl y selected for dietary and incidental oral risk assessments , which are based on gavage dosing . Thus, an FQPA SF of 3x is being retained in the form of a database uncertainty factor for all oral exposure scenarios to protect against any toxicity that might result via the dietary (oral) route. In the case of inhalation exposure scenarios, the FQPA SF of 10x is being retained as an uncertainty factor for the use of a lowest - observed - adverse - effect level (L OAEL) in the absence of a NOAE L from a 28 - day inhalation study . The reduction of the FQPA SF from 10x to 1x for dermal exposure scenarios is justified since there is a route - specific study with a clear NOAEL . **3.4.2 Evidence of Neurotoxicity** C linical signs indicative of neurotoxicity were observed in several studies ; however, these signs were generally

observed in the presence of poor animal health (e.g., reduced general health condition , loss of body

weight, death) . In addition, no neuropatho logy was observed in any study with metaflumizone. No signs of abnormal offspring behavior, central nervous s ys tem (CNS) malfo **r**mations, effects on offspring brain weights, or effects on offspring sexual maturation were observed in the developmental or 2 - generation reproduction studies. No adverse effects were reported on motor activity or in the functional observational battery i n the chronic/carcinogenicity s tudy in rats. There was no evidence of neurotoxicity in the acute neurotoxicity

test in rat up to the limit dose. **3.4.3 Evidence of Sensitivity/Susceptibility in Developing Animals** There are no residual concerns or uncer tainties for increased sensitivity /susceptibility

in developing animals resulting from pre - and/or postnatal exposure.Metaflumizone Human - Health Risk Assessment D 393447

Page 18 of 39 **3.4.4 Residual Uncertainty in the Exposure Database** The dietary

anal ys is is conservative in that tolerance - level residues, 100% crop treated, and modeled drinking water estimates were assumed. Therefore, HED concludes that while the submission of data/information by the petitioner addressing the residue chemistry deficiencies may conceivably

result in adjustment of the maximum theoreti cal residue estimate, actual metaflumizone dietary

exposure estimates will not be greater than those generated in the current risk assessment (i.e., incorporation of anticipated residues, percent crop treated estimates, and/or refined drinking water estimates will compensate for any increase in the maximum theoretical residue). The residential anal ys is is conservative in that health - protective assumptions were assumed along with the use of the Residential SOPs. **4 .0 Dietary**  **Exposure/Risk Characterization** residue chemistry summary - D345540, T. Bloem, 26 - Jan - 10 dietary exposure - D393549 , T. Bloem, 20 - Sep - 11 drinking water - D367556, J. Melendez, 3 - Aug - 2011 **4 .1 Metabolism**  **(Crops, Livestock, and Rotational Crops) and Environmental Degradation**  The petitioner previousl y submitted cotton, cabbage, tomato, goat, and hen metabolism studies and confined rotational crop studies conducted with metaflumizone uniformly ring - labeled in the [benzonitrile 14 C] metaflumizone (B - label) and [trifluoromethoxy ph enyl 14 C] metaflumizone (T label) rings . Based on these data and information concerning environmental degradation of metaflumizone , HED concluded that the residue of concern in plants, livestock, rotational crops, and drinking water are as defined in Tabl e 4 .1.1. For further information concerning these conclusions, see the HED risk assessment document D304496 (R. Mitkus et al. , 24 - Jan - 06). HED notes that the residue of concern in ruminants is to be reevaluated i f the ruminant dietary burden increased significantly . Almond hulls (90% dry matter; dairy

onl y) and dried citrus pulp (91% dry matter; beef and dairy) are the onl y feed commodities associated with the current petition (maximum of 10% of the diet). HED previously estimated beef and dairy cattl e dietary burdens at 2.53 ppm and 0.36 ppm, respectivel y (D308394, T. Bloem, 30 - Nov - 05). Based on the recommended almond hull and citrus tolerances (0.04 ppm), the maximum contribution of almond hulls and/or dried citrus pulp to the beef/dairy cattle diet is 0.008 ppm. Therefore, the previous conclusions concerning the residues of concern in ruminants remain appropriate. The metabolites M320I04 , M320I23 , and M320I28 are not considered to cause greater toxicity than parent (metaflumizone) or toxicity other than the parent compound. M320I 04 lacks the T ring , which is thought to driv e the toxicity for metaflumizone . M320I23 and M320I28 contain th e T - ring ; however, they do not contain any additional functionalities that would enhance their toxicity above that of parent. Itis noted that the cotton (PHI= 21 day s) and tomato (PHI= 0 and 7 day s) metabolism studies and the environmental degradation studies indicated that selective metabolism and/or isomerization resulted in E:Z metaflumizone isomer ratios of ~1:1 (cotton and tomato) and 1.7:1 (environmental degradation). However, as stated in Section 3.2, HED concludes that the Z - isomer, even when enriched to 100%, is of lesser toxicity than metaflumizone technical, and, therefore, the toxic ological studies performed with the technical product (E:Z of >90%:10%) are protective of any potential enrichment of the Z - isomer. HED notes the initial metaflumizone human - health risk assessment (D304496, R. Mitkus et al. , 24 - Jan - 2006) indicated that metaflumizone (E and Z isomers) and M320I23 were the residues ofMetaflumizone Human - Health Risk Assessment D 393447

Page 19 of 39 concern in drinking water and EFED provided estimated drinking water concentrations (EDWCs) for these compounds (D319414, M. Ruhman, 13 - Mar - 2006). Subsequent ED WC memorandum from EFED provided concentrations for parent only and noted that previousl y a conservative approach was taken b y modeling parent plus M320I23. The environmental degradation section of the above referenced human - health risk assessment (Sectio n 5.1.4) indicated the following: “...due to their low concentrations and slow formation, the environmental degradates of metaflumizone are not expected to be threats to surface water”. Based on this and since the groundwater EDWC for combined parent and M 320I23 was orders of magnitude lower than that for surface water, HED concludes that EDWCs representing parent only are acceptable. **Table 4**  **.1.1 :**  **Residues of Concern for Tolerance Expression and Risk Assessment (see Appendix B.6 for**  **structures) .**  Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Pla nts 1 metaflumizone (E and Z isomers) and M320I04 metaflumizone (E and Z isomers) and M320I04 Livestock (excluding ruminant liver) 2 metaflumizone (E and Z isomers) metaflumizone (E and Z isomers) Livestock ruminant liver2 metaflumizone (E and Z isomers) and M320I28 3 metaflumizone (E and Z isomers) Rotational crops metaflumizone (E and Z isomers) and M320I04 metaflumizone (E and Z isomers) and M320I04 Drinking water metaflumizone (E and Z isomers) Not applicable 1 This decision is contingent on the petitioner submitting data which address the following: (1) c abbage metabolism study - information pertaining to sample extraction and analysis dates; if the interval is > currently validated interval, then additional storage stability data are required ; (2) c otton metabolism s tudy - individual concentrations of the unknowns is needed; if any unknown comprises >10% of the TRR, then further characterization/identific ation procedures may be required (based on these data additional residues may be included for risk assessment). 2 For future petitions, these conclusions will be re - evaluated; see Section 5.1. 6 of D304496 (R. Mitkus et al. , 24 - Jan - 2006 ) . 3 Acetonitrile and acetic acid microwave extraction of the methanol extracted liver residues results in the formation of M320I28 (microwave assisted cleavage and/or derivatization; common moiety method). **4 .2 Analytical**  **Methodology** HED previousl y determine d that the BASF liquid chromatograph y /mass spectrometer/mass spectrometer (LC/MS/MS) Method 531/0 is adequate for tolerance enforcement and forwarded this method to the Food and Drug Administration (FDA; D308394, T. Bloem, 30 -Nov - 05; D328915, T. Bloem, 17 - M ay- 06). Citrus, grape, and tree nut samples from the field trial and processing studies were analyzed for residues of metaflumizone (E and Z isomers; limit of quantitation ( LO Q ) = 0.01 ppm) and M320I04 (LOQ = 0.018 ppm) using BASF method 531/0. Based on the adequate validation data submitted with the field trial and processing studies, HED concludes that the current enforcement method is suitable for enforcement of the tolerances associated with the current petition. **4 .3 Comparative**  **Metabolic Profile** M320I 04 ( all structures found in Appendix B) is the only metabolite that is common to plants, livestock (hen and goat) , and the rat . In plants , it appears that metaflumizone is metabolized by way of the following reaction s: isomerization of the metaflumiz one E isomer to the Z isomer (cotton , tomato) ; ring closure to form metabolite M320I23 (circular parent ; in cotton, tomato, and cabbage ) ; cleavage of metaflumizone at the imine bridge, resulting in the formation of M320I 04 and a metabolite containing the p - trifluoromethoxyaniline moiety (cotton, tomato, cabbage, and rotational crops ) ; cleavage of M320 I23 to form M320I 05 ( p trifluoromethox yaniline ; cotton) ; and cleavage of M320I23 and/or M320I04 to form M320I 06Metaflumizone Human - Health Risk Assessment D 393447

Page 20 of 39 (4 - cyanobenzoic acid ; cotton, tomato, and cabba ge ) . Metabolites M320I 04/25/26/27 are common to both hen and goat . In hen , it appears that metaflumizone is metabolized via the following reactions: hydrox yl ation of metaflumizone at the 3 - trifluoromethylphenyl ring to form M320I27; formation of M320I04 and a metabolite containing the p - trifluoromethoxyaniline moiety (as in plants) ; and /or reduction of M320I04 to form M320I25 , which is conjugated with glutamic acid to form M320I26. In goat , metabolism of metaflumizone appears to occur in the following manner: hydrox yl ation of metaflumizone at the trifluoromethox yaniline ring forming M320I22 followed b y conjugation to glucuronic acid to form M320I24; hydroxylation of metaflumizone at the benzyl position to form M320I 07 followed b y oxidation and ri ng formation yielding M320I23; formation of M320I 04 and a metabolite containing the p - trifluoromethox yaniline moiety (as in plants and hen); cleavage of M320I 04 to form M320I06 , which is conjugated w ith gl ycine to form M320I 13; and/or reduction of M320I04 to form M320I25 , which is conjugated with glucuronic acid to form M320I10 or conjugated with glutamic acid to form M320I26. The petitioner isolated and identified M320I 17 (trifluoromethox yaniline derivative ) as a major residue in urine (53% TRR) , which indicates that free T - ring compounds are forming in significant concentrations. In the rat , metaflumizone is thought to be metabolized by several pathway s. M320I 04 (plus the p - trifluoromethox yaniline moiety) is formed in a similar manner as in plants and livestock . M320I 04 is then further metabolized to M320I 06 and then M320I13 and/or M320I 10 (without M320I25 intermediate) , as in goat. M320I05 is also formed from parent , as in cotton, but in one step (without cyclization). M320I23 (circular parent) is not formed in the rat as it is in certain plants and goat. Two metabolites were measured in the rat that were also found in goat (M320I07/17) . Metabolites that were unique to the rat included M320I21 (trifluoromethox yaniline derivative conjugated to glutathione and glucuronic acid) , M320I12 (product conjugated to glutathione and glucuronic acid after T - ring cleavage ), and M320I16 (trifluoromethox y

urea derivative). **4 .4 Drinking**  **Water Residue Profile** Metaflumizone has a low vapor pressure (9.30 x 10 - 11 torr) and very low solubility

in water (solubility

1.79 ppb at 20 o C). Metaflumizone was practicall y stable to aqueous hydrol ys is in neutral and alkaline conditions and to photolysis on soil (predicted e nvironmental soil photolysis half - life of 54 day s). It has also shown the same stability to metabolism in the aerobic soil sy stem (the 90 th percentile half - life of 134 day s), and the anaerobic aquatic water/sediment sy stems (half

- life of >378 day s). In f

ield studies, metaflumizone has shown similar persistence in planted terrestrial field studies (half - life of 6 - 24 day s in bare - ground plots and 174 - 618 day s in plots planted with cotton and potatoes). In contrast, relatively low persistence was observed i n highl y acidic aqueous s ystems or in aqueous s ys tems exposed to light energy (half - lives of 5 - 29 day s). For mobility, metaflumizone appears to have very high affinity

to soil and sediment particles rendering it to be immobile in systems with varied textures and organic matter content (Koc of 16,534 - 51,031 L Kg - 1 ). The chemical is not expected to partition into the air due to its very low vapor pressure. EFED provided surface and ground estimated drinking water concentrations generated using the Screenin g Concentration in Groundwater (SCI - GROW) and Pesticide Root Zone Model - Exposure Analy sis Modeling Sy stem ( PRZM - EXAMS) models, respectively ( D367556, J. Meléndez, 3 - Aug - 2011). The models were run using the fl y bait application scenario to turf toMetaflumizone Human - Health Risk Assessment D 393447

Page 21 of 39 represent application to use sites such as recreational facilities and outdoor recreational areas including parks, picnic grounds, and camp grounds (26 x 0.0137 lb ai/acre; yielded the highest EDWCs). The SCI - GROW model resulted in a point estimate of 2.14 x 10 - 3 ppb and the PRZM EXAMS model resulted in peak residue of 1.14 ppb and a 1 - in - 10 year annual mean concentr ation of 0.597 ppb for residues of metaflumizone (E and Z isomers). Therefore, the acute and chronic dietary exposure anal ys es assumed a drinking water estimate of 1.14 ppb and 0.597ppb, respectivel y. **4 .5 Food**  **Residue Profile Granular Fly Bait Applica**  **tion:** The proposed granular fl y bait application scenario does permit application in and around food handling establishments and agricultural structures and premises including inside livestock premises. However, the labels include the following restricti ons: Do not apply in areas where livestock can ingest or contact the bait and do not use (except for bait station use) in edible product areas where food is commerciall y prepared or processed or in serving areas when food is exposed. Considering these re strictions and since metaflumizone has a low vapor pressure (1.24 x 10 - 8 Pa at 20 oC), HED concludes that this use will not result in significant residues in/on food/feed. **Citrus, Grape, Tree Nuts , and Non**  **-**

**Bearing Stone and Pome Fruit Trees :**  The submitted citrus fruit, grape, and tree nut magnitude of the residue studies are adequate pending submission of supporting storage stability data. Residues of metaflumizone (E and Z isomers) and M320I04 were <LOQ (limit of quantitation) in/on all samples of citrus fruit, grape, tree nutmeat, and almond hulls harvested 5 day s following a single soil application of the test formulation at 0.004 lb ai/acre (4x/1x the maximum proposed single/seasonal application rate). The submitted data will support tolerances for the combined residues of metaflumizone (E and Z isomers) and the metabolite M320I 04 (expressed as parent) in/on citrus fruit, grape, tree nuts, and almond hulls at the combined LOQ of 0.04 ppm. **A revised Section F is requested.** The submitted grape and o range processing studies are adequate pending submission of supporting storage stability data. Residues of metaflumizone (E and Z isomers) and M320I04 were <LOQ in/on the orange and grape raw agricultural commodity (RAC) and orange oil following applicati on at 5x the proposed rate. Processing data for the grape processed commodities and the remaining orange processed commodities were not provided and are unnecessary

since residues were <LOQ in/on the RAC following treatment at 5x. The data indicate that no tolerances are needed for the processed commodities of grape or citrus fruit. Based on the submitted residue data and low application rate, HED concludes that application to non - bearing stone and pome fruit trees may be considered a non - food use (application within 1 ye ar of harvest is prohibited). **Livestock :**  Considering the proposed/registered uses, the only feedstuffs are almond hulls and dried citrus pulp , which may be fed to cattle (no poultry or hog feed commodities). Using the revised OPPTS 860.1000 Table 1, the maximum reasonabl y balanced diet (MRBD) for beef and dairy cattle is 0.004 ppm; based on these dietary burdens and the previously reviewed cattle feeding study (D308394, T. Bloem, 30 -Nov - 05), HED concludes that livestock tolerances are unnecessary .Metaflumizone Human - Health Risk Assessment D 393447

Page 22 of 39 **Rotational Crops :**  Citrus fruits, grapes, and tree nuts are typicall y not rotated; therefore, data pertaining to rotational crops are not required to support the proposed uses. **4 .6 International**  **Residue Limits and HED**  **- Recomme**  **nded Tolerances** There are no Canadian, Mexican, or Codex Maximum Residue Limits (MRL s) established for residues of metaflumizone; therefore, harmonization is not relevant. HED request s that the petitioner submit a revised Section F specifying the commodi ty definitions and numerical tolerances specified in Table 5.6.1 and the following tolerance definition: Tolerances are established for residues of the insecticide metaflumizone, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of metaflumizone (E and Z isomers; 2 - [2 - (4 - cy anophenyl) - 1 - [3 - (trifluoromethyl) phenyl]ethylidene] - N - [4 - (trifluoromethoxy)phenyl] hydrazinecarboxamide) and its metabolite 4 - {2 - oxo - 2 - [3 - (trifluoromethyl) phenyl]ethyl} - benzonitrile, calculated as the stoichiometric equivalent of metaflumizone , in or on the following commodities: **Table 4**  **. 6**  **.1 :**  **Tolerance Summary for Metaflum** **izone.**

Proposed HED - Recommended Comments Commodity Tolerance

(ppm) Commodity

Definition Tolerance (ppm) Citrus Fruits, Group 10 0.01 Fruit, citrus, group 10 0.04 Based on the field trial data, a higher tolerance is required . Tree Nuts, Group 14 0.01 Nut, tree, group 14 0.04 Grapes, table 0.01 Grape 0.04 Grapes, wine 0.01 -- none Based on the processing data, a separate tolerance for wine is not required. Al mond, hulls none Al mond, hulls 0.04 Based on the field trial data, a tolerance is required . **4 .7 Dietary**  **Exposure and Risk** Acute and chronic metaflumizone dietary risk assessments were conducted using DEEM - FCID  (ver. 2.03) model. DEEM - FCID TM (ver. 2.03) incorporates consumption data from the USDA CSFII (1994 - 1996 and 1998). The acute and chronic dietary analy ses assumed tolerance - level residues, 100% crop treated, and modeled drinking water estimates from the Pesticide Root Zone Model - Exposure Analysis Modeling Sy stem (PRZM - EXAMS). The drinking water estimates were based on the application of metaflumizone as a fly bait on use sites such as recreational facilities and outdoor recreational areas including parks, picnic grounds, and camp grounds rep resented b y the turf modeling scenario [this scenario resulted in the highest estimated drinking water concentration (EDWC)]. DEEMTM (ver. 7.81) default processing factors were assumed for all commodities excluding grape raisin, grape juice, and citrus jui ce, which were reduced to 1 based on empirical data. The acute dietary exposure estimate for females 13 - 49 ye ars old was <1% the aPAD and , therefore, does not exceed HED’s LOC . An endpoint attribut able to a single dose was not identified for the remainin g population subgroups. The chronic dietary

exposure estimates were  1 % the cPAD and, therefore, do not exceed HED’s LOC (children 1 - 2 years old were the most highly exposed population subgroup). Table 4 . 7 .1 is a summary

of the acute and chronic dietary exposure estimates for the various populations.Metaflumizone Human - Health Risk Assessment D 393447

Page 23 of 39 **Table 4**  **.7.1. Summary of Acute and Chronic Dietary Exposure and Risk for Metaflumizone (drinking water included).**  Population Subgroup Acute Chronic aPAD (mg/kg/day) Exposure

(mg/kg/day) %aPAD cPAD (mg/kg/day) Exposure

(mg/kg/day) %cPAD General U.S. Population no endpoint identified 0.04 0.000092 <1.0 All Infants (< 1 year old) 0.000102 <1.0 Children 1 - 2 years old 0.000323 <1.0 Children 3 - 5 years old 0.000239 <1.0 Children 6 - 12 years old 0.000132 <1.0 Youth 13 - 19 years old 0.000079 <1.0 Adults 20 - 49 years old 0.000066 <1.0 Adults 50+ years old 0.000071 <1.0 Females 13 - 49 years old 0.33 0.000329 <1.0 0.000071 <1.0 **5 .0 Residential**  **Exposure/Risk Characterization** D 393548 , K. Lowe , 20 - Sep - 11 D 393547 , K. Lowe, 20 - Sep - 11 The proposed fire ant bait product (citrus fruit, grapes, and tree nuts) is not expected to result in residential exposure since the proposed use sites are agricultural sites. **Note:** The proposed use as an agricultural fire ant bait was previousl y assessed (D367561, M. Dow, 07 - Dec - 09), but revisions have been made to account for the revisions to the hazard assessment of metaflumizone (D393547, K. Lowe, 20 - Sep - 11). The proposed fl y bait product can be used in areas where children could be present and, therefore, a residential assessment was performed for this use. There are already registered fire ant bait uses (lawns, landscapes, golf courses, and other non crop land) and pet uses (spot - on product) that would result in residential exposure that have been previously

assessed (D345154, T. Bloem et al ., 26 - Jan - 2010; D315785, M. Dow, 19 - Jan - 2006). The pet use product is in the process of being cancelled ; however, it has been included in this assessment. E xisting product will continue to be sold; but the registration will not be maintained past 2012. **5 .1 Residential**  **Handler Exposure Fly Bait (proposed):**  The proposed product is not anticipated to result in non - occupational use as it is proposed for commercial/recreational areas such as campgrounds and picnic grounds. It is expected that commercial handlers would appl y this product to areas such as these. Therefore, a residential handler assessment has not been performed for the proposed fl y bait product. **Fire Ant Bait**  **(registered on lawns, landscapes, golf courses, and other non**  **- cropland**  **) :**  Residential handler exposure was expected for homeowners who may apply the registered fire ant bait product to home l awns. Since the residential and commercial fire ant products have identical application rates, HED used the commercial loader/applicator dermal (no gloves) and inhalation exposure assumptions to calculate exposure and risk estimates for the homeowner load er/applicator scenario (commercial push - ty pe drop spreader; 5 acres/day ; onl y short - term exposures anticipated). Risks were not a concern for residential handlers (i.e., MOEs > the LOC of 100 for dermal exposures and 1000 for inhalation exposures; see Tab le 4.4). **Pet Care (registered**  **spot -**  **on product**

**) :**  Residential handler e xposure/risk from metaflumizone application to domestic pets was not assessed because handler contact is expected to beMetaflumizone Human - Health Risk Assessment D 393447

Page 24 of 39 negligible. The spot - on product is designed to be self - contained as it is applied directly from the tube to the pet with the tip of the applicator used to part the pet’s hair. **5 .2 Residential Post** **- application Exposure**  **Fly Bait (proposed):** The proposed fl y bait product can be used in areas where adults and children could be present, such as campgrounds and picnic grounds. For adults, dermal exposure was assessed and for children (3 to <6 ye ar olds), dermal and incidental oral exposure ( e.g ., hand - to - mouth exposure) was assessed for individuals contacting turf or soil treated with fl y bait granules . Short - term dermal and incidental oral exposures/risks have been assessed here and since the short - and intermediate - term PODs are the same, the short - term assessment is protective of longer- term exposures . Inaddition, the fly bait product is a granular product and; therefore, i ngestion of metaflumizone granules found in treated turf is also a potential source of exposure for children. This scenario is considered an episodic event b y HED and, therefore, is assessed as an acute exposure (i.e., acute dietary endpoints are used). Since there is no acute dietary endpoint applicable to children, no quantitative assessment was needed. The resulting dermal and incidental oral MOEs were greater than the L OC s of 100 and 300, respectivel y, and, therefore, were not of concern (see Table 6.4.1). **Fire Ant Bait (registered on lawns, landscapes, golf courses, and other non -**  **cropland) :**  Use of the fire ant b ait products may result in short - term post - application exposure to children (3 to <6 ye ar olds; dermal and incidental oral), adults (dermal), and adolescents (dermal) contacting treated turf

. As stated above, short - term exposures are expected; however, si nce the short - and intermediate - term PODs are the same, the short - term risk estimates are protective of any potential intermediate - term exposures. In gestion of metaflumizone granules found in treated lawns is also a potential source of exposure for children. This scenario is considered an episodic event b y HED and, therefore, is assessed as an acute exposure (i.e., acute dietary endpoints are used). Since there is no acute dietary endpoint applicable to children, no quantitative assessment was needed. The resulting dermal and incidental oral MOEs were greater than the LOC s of 100 and 300, respectivel y, and, therefore, were not of concern (see Table 6.4.1). **Pet Care (registered**  **spot -**  **on product**

**) :**  As mentioned above, the pet care products registered for metaflumizone are in the process of being cancelled; however, the uses have been included in this risk assessment. The pet care products may result in short - and intermediate - term post application d ermal (all populations) and incidental oral [children (3 to<6 year olds)] exposures. The resulting MOEs are > 100 for dermal exposure and >300 for incidental oral exposures and, therefore, exceed HED's LOC (see Table 6.4.1). HED notes that pet care produc t exposure calculations can be considered refined in that they are based on the assumptions that 0.78% of the application rate is available as dislo dgeable residue rather than the default 20%; for further information see D315785 (M. Dow, 19 - Jan - 06). **5 .**  **3 Combined Residential Exposure**  For residential handlers, dermal and inhalation exposures are combined since the endpoints are similar for these routes. For children (3 to <6 ye ar olds), post - application hand - to - mouth and dermal exposures are combined . D ermal exposure could be combined with all the incidental oral exposure scenarios (e.g., hand - to - mouth, object - to - mouth, soil ingestion) since it is assumed that these exposures do not occur as single, isolated events, but rather as a series of concurrent events that may overlap . However, combining all of the incidental oral exposures with dermal exposureMetaflumizone Human - Health Risk Assessment D 393447

Page 25 of 39 would be overl y conservative because each of these scenarios, independently, incorporates high end, health protective inputs or assumptions. C ombining p ost - application dermal exposure with only hand - to - mouth exposure is considered a protective estimate of children’s exposure to pesticides used in residential settings . S ince the LOCs for the dermal , inhalation and incidental oral routes are not the same ( dermal LOC = 100, i nhalation LOC = 1000 , and incidental oral LOC = 300 ), these routes were combined using the ARI approach. All of the combined risk estimates are greater than the L OC and, therefore, are not of concern. **Table 5**  **. 3**  **.1. Summary of Short -**  **ter m Residential Handler and Post**  **- application Exposures and Risks.**  Population Route of Exposure Dose (mg/kg/day) MOE 1 **Fire Ant Bait ( registered on lawns, landscapes, golf courses, and other non**  **- cropland;**  **D345154 /D315785**  **)** Adult -- Residential Handler Dermal 0.00021 480,000 Inhalation 0.00000045 18,000,000 Combined dermal and inhalation -- ARI 2 = 3,800 Adult

– Residential Post application Dermal 0.000232 430,000 Adult

– Golfer Post - application Dermal 0.000016 6,200,000 Adolescent

– Golfer Post application Dermal 0.0000272 3,700,000 Children (3 to <6 year olds)

– Post - application Incidental oral hand - to - mouth 0.000015 1,300,000 Incidental oral object - to - mouth 0.00000093 22,000,000 Dermal 0.00039 260,000 Combined incidental oral hand - to mouth and dermal -- ARI 3 = 1,600 **Pet Care ( registered spot**  **- on;**  **D345154 /D315785**  **)** Adults

– Post - application Dermal 0.29 340 Children (3 to <6 year olds)

– Post - application Incidental oral hand - to - mouth 0.035 570 Dermal 0.16 620 Combined incidental oral hand - to mouth and dermal -- ARI 3 = 1.5 **Fly Bait ( proposed;**  **D 393548**  **)** Adult

–Post - application Dermal 0.0033 31,000 Children (3 to <6 year olds)

– Post - application Incidental oral hand - to - mouth 0.00021 96,000 Incidental oral object - to - mouth 0.000052 380,000 Incidental soil ingestion 0.0000007 29,000,000 Dermal 0.0054 18,000 Combined incidental oral hand - to mouth and dermal -- ARI 3 = 120 1. MOE = NOAEL (mg/kg/day) ÷ Dose (mg/kg/day). 2. AR I = Aggregate Risk I ndex = 1 ÷ ((1 ÷ (MOE inhalation ÷ LOC inhalation )) + (1 ÷ (MOE dermal ÷ LOC dermal ))); ARI > 1 indicates an acceptable exposure. 3. AR I = Aggregate Risk I ndex = 1 ÷ ((1 ÷ (MOE incidental oral hand - to - mouth ÷ LOC incidental oral hand - to - mouth )) + (1 ÷ (MOE dermal ÷ LOC dermal ))); ARI > 1 indicates an acceptable exposure. **6 .0 Aggregate**  **Risk Assessments and Risk Characterization** In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from dietary

(food and water) and residential (dermal, inhalation, incidental oral) sources. When aggregating exposures and risks from these sources, HED considers the route and duration of exposure as well as the toxicological effects for each route. As indicated above, short - /intermediate - term dermal, oral, and inhalation exposures can be aggregated based on a common toxic effect (decreased body weight or decrease d body- weight gain). Based on this and the proposed/registered use s , aggregate acute, short - /intermediate - term, and chronic assessmentsMetaflumizone Human - Health Risk Assessment D 393447

Page 26 of 39 were conducted. **6 .1 Acute**  **Aggregate Risk** Since there are no registered/proposed uses that result in acute residenti al exposure to females 13 - 49 years old (acute endpoint was not identified for the remaining populations), the acute aggregate exposure assessment consists of exposure from onl y food and water. The acute dietary exposure estimate for females 13 - 49 years ol d was <1% the aPAD and, therefore, does not exceed HED’s LOC (see Section 5.2). **6 .2 Short**  **- /Intermediate**  **- T**  **erm Aggregate Risk** The short - term aggregate assessment combines food and drinking water exposure with the highest potential residential exposure. As seen in table 6.3.1, the pet care products result in the highest potential residential exposure estimates, with the fly bait products resulting in the second highest . Because the pet uses of metaflumizone are in the process of being cancelled, a s hort term aggregate assessment w as performed both for the pet care product and for the fl y bait product . Intermediate - term exposures are possible for the pet care product; however, since the points of departure for the short - and intermediate - term durations are the same for metaflumizone, the short - term aggregate assessment is protective of longer- term exposures for the pet care product. For adults and the general U.S. population , the short - and intermediate - term aggregate assessment s combine chronic dietary with residential post - application dermal exposure . For yo ung children, the short - and intermediate - term aggregate assessment s combine chronic dietary exposure with incidental oral and dermal post - application exposure. HED uses chronic dietary exposure when conducting short - and intermediate - term aggregate assessments since it has been determined that these will more accuratel y reflect exposure from food over the HED defined short - and intermediate - term interval than wil l acute exposure. Table 6 .2.1 is a summary of the short - term and intermediate - term aggregate risk estimates resulting from the fl y bait product and the pet care product . Since the LOCs for the dermal and oral routes are not the same (dermal LOC = 100 and oral LOC = 300), these routes were combined using the ARI approach. The aggregate ARI s are > 1; therefore, none of the calculated short - and intermediate - term aggregate risks are of concern . **Table 6**  **.2.1: Short -**  **and Intermediate -**  **Term Aggregate Risk**  Population Background Dietary + Incidental Oral Exposures Residential Exposures ARI (food, water, and residential) f Oral LOC Chronic Food

and Water Exposure (mg/kg/day) a Incidental

Oral Exposure (mg/kg/day) b Oral

MOE c Dermal

LOC Dermal

Exposure (mg/kg/day) d Dermal

MOE e **Pet Care Product** (Short and Intermediate - term) General U.S. Population 300 0.00008 NA 250 , 000 100 0.29 340 3 Children 1 - 2 years old 0.00031 0.035 570 0.16 620 2 **Fly Bait Product** (Short - term) General U.S. Population 300 0.00008 NA 250,000 100 0.0033 31,000 230 Children 1 - 2 years old 0.00031 0.00021 39,000 0.0054 18,000 75Metaflumizone Human - Health Risk Assessment D 393447

Page 27 of 39 a. See Table 5.7.1 for exposures. b. See Table 6.3.1 for exposures. I ncidental oral exposure only represents hand - to - mouth exposure for purposes of the aggregate assessment . c. Oral MOE = NOAEL (20 mg/kg/day) ÷ (chronic food/water exposure + incidental oral exposure). d. See Table 6.3.1 for exposures. e. Dermal MOE = NOAEL (100 mg/kg/day) ÷ (dermal exposure). f. AR I ( Aggregate Risk In dex) = 1 ÷ ((1 ÷ (Oral MOE ÷ Oral LOC)) + (1 ÷ (Dermal MOE ÷ Dermal LOC))); ARI > 1 indicates an acceptable

exposure. **6 .3 Chronic**  **Aggregate Risk** Since there are no registered/proposed uses that result in chronic residential exposure, the chronic aggreg ate exposure assessment consists of exposure from food and water. The chronic dietary exposure estimate was ≤ 1 % the cPAD and, therefore, do es not exceed HED’s LOC (see Section 5.2). **6 .4 Cancer**  **Aggregate Risk** An aggregate cancer risk assessment was not performed because metaflumizone is not considered to be a carcinogen. **7 .0 Cumulative**  **Risk Characterization/Assessment** 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 for metaflumizone and any other substances; and metaflumizone does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has assumed that metaflumizone does not have a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures fo r cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. **8 .0 Occupational**  **Exposure/Risk Characterization**  D 393547 , K. Lowe, 20 - Sep - 11 D 393548 , K. Lowe, 20 - Sep - 11 There are two pro posed products that may result in occupational handler and post - application exposure: (1) Metaflumizone Fly Bait for use around industrial buildings, commercial facilities, agricultural structures and premises, recreational facilities and outdoor recreati onal areas; and (2) Altrevin Fire Ant Bait Insecticide for use as a soil treatment in citrus orchards, tree nut orchards, grape vineyards, nonbearing stone and pome fruit orchards and in nurseries containing nonbearing container- or field - grown stone and p ome fruit tree stock. **Note:** The proposed use as an agricultural fire ant bait was previousl y assessed (D367561, M. Dow, 07 - Dec - 09), but revisions have been made to account for the revisions to the FQPA SF (D393547, K. Lowe, 20 - Sep - 11). **8 .1**  **Occupational Handler Exposure**  The proposed products are both solid bait formulations . Metaflumizone Fly Bait is to be used as a scatter bait for broadcast treatment or placed in bait stations/tray s. Altrevin Fire Ant BaitMetaflumizone Human - Health Risk Assessment D 393447

Page 28 of 39 Insecticide can be used for broadcast and in dividual mound applications. Dermal and inhalation exposures/risks were estimated for handlers involved in mixing/loading activities for granular formulations for tractor- drawn spreader equipment, applying granulars via tractor- drawn spreader or by hand , and mixing/loading/appl yi ng activities for handheld equipment , such as push - ty pe spreaders, bell y grinders and spoons. The metaflumizone product labels require long - sleeved shirt and long pants and chemical - resistant gloves as dermal PPE for all applicators and other handlers. No chemical - specific handler exposure data were submitted in support of this Section 3 registration. To assess handler exposures for regulatory actions when chemical - specific monitoring data are not available, HED relies on the most scientifically reliable surrogate data currentl y available from various sources such as PHED, AHETF, and ORETF. Some of this data, such as the industry task force data, is compensatory, subject to the data protection provisions of FIFRA. HED policy on use of surrogate data is described in more detail on the Agency's website (http://www.epa.gov/pesticides/science/handler - exposure - data.html ). Scenario - specific surrogate exposure data, including their sources, are presented in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/pesticides/science/handler - exposure - table.pdf ). Ty pically , HED completes short - and intermediate - term assessments for occupational scenarios in all cases because these kinds of exposures are likely and acceptable use/usage data are not available to justify

deleting intermediate - term scenarios. Based on use data and label instructions, HED believes that occupational exposures may occur over a single day

or up to weeks at a time for many use - patterns and that intermittent exposure over several weeks may also occur. Some applic ators may appl y these products over a period of weeks, because they are commercial applicators who are completing multiple applications for multiple clients. Long term exposures are not expected, therefore, a long - term assessment was not conducted. Der mal and inhalation risks were combined in this assessment, since the toxicological effects for these exposure routes were similar. A total ARI was used since the LOCs for dermal exposure (100) and inhalation exposure (1000) are different. The target ARI is 1; therefore, ARIs of less than 1 are risks of concern. Table 8 .1. 1 presents the exposure/risks for short - and intermediate - term dermal and inhalation exposures at baseline and with gloves . The dermal and inhalation exposure risks for mixer/loaders, applicators and mixer/loader/applicators are not of concern (i.e., MOEs >100 for dermal and >1000 for inhalation; ARI s >1) at baseline and with the addition of gloves.Metaflumizone Human - Health Risk Assessment D 393447

Page 29 of 39 **Table 8**  **.1.1. Short -** **/Interm ediate**  **- Term** **Occupational Exposure and Risk Estimates for Metaflum izone.**  Exposure Scenario Use Site Mitigation 1 Dermal Unit Exposure (ug/lb ai) 2 Inhalation

Unit Exposure (ug/lb ai) 2 Application

Rate 3 Amount

Treated Daily 4 Dermal Inhalation ARI 9 Dose (mg/kg/day) 5 MOE 6 Dose (mg/kg/day) 7 MOE 8 **MIXER/LOADER** Mixing / Loading Granules for Tractor Drawn Spreader Applications Fire Ant

Bait Baseline 8.4 1.7 0.001 lb ai/acre 40 acres 0.0000048 21,000,000 9.70E - 07 8,200,000 7,900 PPE - G 6.9 NA 0.0000039 25,000,000 NA NA 35,000 Fly Bait Baseline 8.4 1.7 0.014 lb ai/acre 40 acres 0.000067 1,500,000 1.40E - 05 590,000 570 PPE - G 6.9 NA 0.000055 1,800,000 NA NA 2,500 **APPLICATOR** Applying Granules via Tractor Draw

n Spreader Fire Ant

Bait Baseline 9.9 1.2 0.001 lb ai/acre 40 acres 0.0000057 18,000,000 6.90E - 07 12,000,000 11,000 PPE - G 7.2 NA 0.0000041 24,000,000 NA NA 47,000 Fly Bait Baseline 9.9 1.2 0.014 lb ai/acre 40 acres 0.000079 1,300,000 9.60E - 06 830,000 780 PPE - G 7.2 NA 0.000058 1,700,000 NA NA 3,400 Applying Granules by Hand Fire Ant

Bait Baseline 104000 470 0.000078 lb ai/mound 5

mo unds 0.00058 170,000 2.60E - 06 3,100,000 1,100 PPE - G 71000 NA 0.0004 250,000 NA NA 2,100 Fly Bait Baseline 104000 470 0.017 lb ai/acre 0.5 acre 0.013 7,900 5.70E - 05 140,000 51 PPE - G 71000 NA 0.0086 12,000 NA NA 100 **MIXER/LOADER/APPLICATOR** Mixing / Loading/Applying Granulars via "Push Ty pe" Rotary Spreader Fire Ant

Bait Baseline 440 10 0.001 lb ai/acre 5 acres 0.000031 3,200,000 7.10E - 07 11,000,000 8,200 PPE - G 240 NA 0.000017 5,800,000 NA NA 28,000 Fly Bait Baseline 440 10 0.014 lb ai/acre 5 acres 0.00044 230,000 1.00E - 05 800,000 590 PPE - G 240 NA 0.00024 420,000 NA NA 2,000 Applying Ready to Use Granular by Spoon (MRID #452507 - 01; Fipronil study) Fire Ant

Bait Baseline No Data 45 0.000078 lb ai/mound 5

mo unds No Data No Data 2.50E - 07 32,000,000 No Data PPE - G 2000 NA 0.000011 9,000,000 NA NA 58,000 Fly Bait Baseline No Data 45 0.017 lb ai/acre 0.5 acre No Data No Data 5.50E - 06 1,500,000 No Data PPE - G 2000 NA 0.00024 410,000 NA NA 2,600 Mixing / Fire Ant Baseline 10000 62 0.001 lb 1 acre 0.00014 700,000 8.90E - 07 9,000,000 3,900Metaflumizone Human - Health Risk Assessment D 393447

Page 30 of 39 **Table 8**  **.1.1. Short -** **/Interm ediate**  **- Term** **Occupational Exposure and Risk Estimates for Metaflum izone.**  Exposure Scenario Use Site Mitigation 1 Dermal Unit Exposure (ug/lb ai) 2 Inhalation

Unit Exposure (ug/lb ai) 2 Application

Rate 3 Amount

Treated Daily 4 Dermal Inhalation ARI 9 Dose (mg/kg/day) 5 MOE 6 Dose (mg/kg/day) 7 MOE 8 Loading/Applying Granulars via Belly Grinder Bait PPE - G 9300 NA ai/acre 0.00013 750,000 NA NA 6,400

Fly Bait Baseline 10000 62 0.014 lb ai/acre 1 acre 0.002 50,000 1.20E - 05 650,000 280 PPE - G 9300 NA 0.0019 54,000 NA NA 460 1 Level of mitigation: Baseline and PPE - G (gloves). Gloves are recommended PPE on proposed label. 2 PHED/ORETF/AHETF 3 Based on proposed label (Reg. No. #7969 - xxx) 4 Exposure Science Advisory Council Policy #9.1 5 Dermal Dose = Dermal Unit Exposure (mg/kg) × Application Rate (lb ai/acre) × Amount Treated (acres/day) / BW (70 kg) 6 Dermal MOE = Dermal NOAEL (100 mg/kg/day) ÷ Dermal Dose (mg/kg/d ay). LOC = 100. 7 Inhalation Dose = Inhalation Unit Exposure (mg/kg) × Application Rate (lb ai/acre) × Amount Treated (acres/day) ÷ BW (70 kg) 8 Inhalation MOE = Inhalation NOAEL (8 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). LOC = 1000. 9 ARI (Aggregated Risk Index) = 1 / ((1 ÷ (Dermal MOE ÷ Dermal LOC)) + (1 ÷ (Inhalation MOE ÷ Inhalation LOC))). Baseline dermal and PPE - G Dermal combined with Baseline Inhalation.Metaflumizone Human - Health Risk Assessment D 393447

Page 31 of 39 **8 .2**  **Occupational Post**  **- application**  **Exposure** Occupation al dermal postapplication exposure was not assessed. With regard to the fl y bait use, it is not anticipated that workers will be exposed after application of the fly bait. HED believes the presence of commercial workers in treated areas is minimal after application. With regard to the fire ant bait use, d ermal contact with treated surfaces is not expected; all applications are directed towards the soil surface. In addition, workers are not expected to frequent areas infested with active fire ants. For these reasons, a quantitative dermal post - application assessment has not been conducted. Based on the Agency's current practices, a quantitative occupational post - application inhalation exposure assessment was not performed for metaflumizone at this tim e. 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 (FIFRA) 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 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 assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for metaflumizone. **8 .3**  **Restricted Entry Interval** For the fl y bait product, a REIis not required since the proposed use sites are non - agricultural sites. For the fire ant bait (citrus fruit, grapes, and tree nuts) , a REI is required on the label and the draft label lists a 12 - hour REI . Metaflumizone is classified in Acute Toxicity Categ ory IV for acute dermal toxicity , acute inhalation toxicity, primary eye irritation, primary

dermal irritation and it is not a dermal sensitizer. Therefore, the interim WPS REI of 12 hours is adequate to protect agricultural workers from post - application exposures. **9 .0 Data**  **Deficiencies 9**  **.1 Toxicology**

 None. **9 .2 Residue**  **Chemistry**

 A revised Section B is requested which list the crops for each crop group as defined in 40 CFR 180.41 and eliminates the "including but not limited to" phrase.  A revised Section F with the tolerance expression, commodity definitions, and numerical tolerances described as follows: Tolerances are established for residues of the insecticide metaflumizone, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined b yMetaflumizone Human - Health Risk Assessment D 393447

Page 32 of 39 measuring only

the sum of metaflumizone (E and Z isomers; 2 - [2 - (4 - cyanophenyl) - 1 - [3 - (trifluoromethyl )phenyl ]ethylidene] -N - [4 - (trifluoromethox y) phenyl] hydrazinecarboxamide) and its metabolite 4 - {2 - oxo - 2 - [3 - (trifluoromethyl )phenyl]ethyl} - benzonitrile, calculated as the stoichiometric equivalent of metaflumizone , in or on the following commodities: Fruit, citrus, group 10 - 0.04 ppm; Nut, tree, group 14 - 0.04 ppm; Almond, hulls - 0.04 ppm; and Grape - 0.04 ppm.  Standards of the metaflumizone (E and Z isomers ) and 4 - {2 - oxo - 2 - [3 - (trifluoromethyl )phenyl ] ethyl} - benzonitrile should be submitted to the EPA National Pesticide Standards Repository .  Cabbage metabolism study (46264326.der.wpd) - In formation pertaining to sample extraction and anal ys is dates is required; if the interval from harvest to analy sis is gre ater than the currently

validated interval, then additional storage stability data will also be necessary .  Cotton metabolism study (46264324.der.wpd) - In dividual concentrations of the unknowns should be reported; if any unknown comprises >10% TRR, then f urther characterization/ identification procedures may be required (based on these data additional residues may

be included for risk assessment).  Storage stability

data - To support the subject field trial and processing studies, the following storage st ability data are required which demonstrate the stability of metaflumizone (E and Z isomers) and M320I04: grapes - 4.8 months; citrus fruit - 5.6 months; almond hulls - 6.5 months; and almond nutmeat - 5.8 months. **9 .3 Occupational**  **and Residential Expos ure**   None .Metaflumizone Human - Health Risk Assessment D 393447

Page 33 of 39 **Appendix A. Toxicity Profile Tables Table A.1**  **: Acute Toxicity Profile**  **- M**  **etaflum izone**  **Technical (96% ai** **), Z -**  **isomer, and Metabolite M320I23 .**  Guideline No./Study Type MRID No. Results Toxicity Category **M etaflum** **izone Technical (96% ai)**  870.1100/Acute oral toxicity rat 46264232 LD 50 => 5,000 mg/kg (males, females combined) IV 870.1100/Acute oral toxicity mouse 46264234 LD 50 => 5,000 mg/kg (males, females combined) IV 870.1200/Acute dermal toxicity rat 46264235 LD 50 > 5,000 mg/kg (males, females combined) IV 870.1300/Acute inhalation toxicity rat 46264236 LC 50 > 5.2 mg/L (males, females combined) IV 870.2400/Primary eye irritation rabbit 46264238 Conjunctivitis in 2/3, 1/3, 0/3 at 1, 24, and 48 hours, resp.; no positive effects IV 870.2500/Primary dermal irritation rabbit 46264237 non - irritant PII = 0 IV 870.2600/Dermal sensitization guinea pig 46264239 is not a sensitizer N/A **Z -**  **isomer** 870.1100/Acute oral toxicity rat 46264231 LD 50 => 5,000 mg/kg (males, females combined) IV **Metabolite M320I23** 870.1100/Acute oral toxicity rat 46264233 LD 50 => 2,000 mg/kg (HDT 1 ) (females) III 1 HDT=Highest Dose Tested **Table A.2: Subchronic and Chronic Toxicity and Genotoxicity Profile**  **– M**  **etaflum izone**  **Technical, Z -**  **isomer, and Metabolite M320I23.**  Guideline No./ Study Type MRID No. (Year)/Doses/ Classification Results

**M etaflum** **izone Technical**  4 - day palatability rats (Alternate - day feeding regimen) 47036907 (2007)

**Un acceptable/non**  **- guideline**  (individual animal data not submitted) Reduced food consumption and corresponding body weight losses occurred when treated diet was offered compared to control diet, indicating poor palatability of the diet when the test material i s incorporated as an admixture in feed. 5 - day palatability rats (Free - choice regimen) 47036908 (2007)

**Un acceptable/non**  **- guideline**  (individual animal data not submitted) When offered a choice of control feed or diet treated with 400 ppm of the test material, rats exhibited a strong preference for the control feed by avoidance of the treated diet. This avoidance indicates poor palatability of the diet when the test material is incorporated as an admixture in feed. 7 - day rats (gavage) 47036909 (2007)

0, 6, 16, or 28 mg/kg bw/day **Un acceptable/non**  **- guideline**  (individual animal and dose analysis data not submitted) No effects on food consumption or body- weight gain. In contrast, significant decreases in food consumption and body- weight gain were observed after 7 days of treatment at similar doses via the diet (MRID 47036902)

90 - day oral rats (dietary) 47036902 (19 99/2007)

0, 50, 100, 200, or 400 ppm (equivalent to 0, 3.8, 7.2, 13.7, or 26.3 mg/kg/day) **Acceptable (non -**  **guideline)** NOAEL not established LOAEL = 50 ppm (3.8 mg/kg/day) based on decreased food consumption, body weights, and body- weight gains, due to po or palatability of the test substance

28 - day oral rats (dietary) 47036903 (1999/2007)

0, 10, 20, or 40 ppm (equivalent to 0, 1.1, 2.2, or 4.3 mg/kg/day) **Acceptable (non -**  **guideline)** NOAEL = 20 ppm (2.2 mg/kg/day) LOAEL = 40 ppm (4.3 mg/kg/day) based on decreased food consumption, body- weight gains, and body weights, due to poor palatability of the test substance

28 - day oral rats (dietary) 47036904 (2000)

0, 250, 1000, 5000, or 10,000 ppm (equivalent to 0/0, 27.2/23.8, 86.4/83.2, 417.5/360.6, or 798.1/7 83.0 mg/kg/day [M/F] NOAEL not established LOAEL = 250 ppm ( 27.2/23.8 mg/kg/day) based on decreased food consumption, body- weight gains, and body weights, due to poor palatability of the test substanceMetaflumizone Human - Health Risk Assessment D 393447

Page 34 of 39 **Table A.2: Subchronic and Chronic Toxicity and Genotoxicity Profile**  **– M**  **etaflum izone**  **Technical, Z -**  **isomer, and Metabolite M320I23.**  Guideline No./ Study Type MRID No. (Year)/Doses/ Classification Results **Acceptable (non -**  **guideline)** 28 - day oral mice (dietary) 47036905 (1999/2007)

0, 50, 200, or 800 ppm (equivalent to 0, 10, 42, or 101 mg/kg/day **Acceptable (non -**  **guideline)** NOAEL = 50 ppm (10 mg/kg/day) LOAEL = 200 ppm ( 42 mg/kg/day) based on decreased food consumption, body- weight gains, and body wei ghts, due to poor palatability of the test substance 28 - day oral mice (dietary) 47036906 (2001/2007)

0, 10, 20, or 40 ppm (equivalent to 0, 2.0, 4.3, or 8.2 mg/kg/day) **Acceptable (non -**  **guideline)** NOAEL = 40 ppm (8.2 mg/kg/day) LOAEL not established

870.3100 90 - day oral rats (gavage) 46264241 (2002)

0, 100, 500 or 1000 mg/kg/day **Unacceptable (guideline)**  NOAEL (28 - day) = 100 mg/kg/day LOAEL (28 - day) = 500 mg/kg/day based on decreased BW, BW gain and food consumption, and splenic extramedullary hematopoiesis and hepatocellular hypertrophy NOAEL (90 - day) = not established LOAEL (90 - day) = not established It is noted that treatment - related effects were not identified in either sex at 100 mg/kg/day after 90 days. 870.3250 90 - day dermal rats 462643 03 (2004)

0, 100, 300 or 1000 mg/kg/day **Acceptable (guideline)** NOAEL = 100 mg/kg/day LOAEL = 300 mg/kg/day based on decreased BW gain and food consumption (M&F); anogenital smearing, decreased BW, increased macrophages in the thymus, lymphocyte necrosis in the mesenteric lymph nodes, diffuse atrophy of the mandibular lymph node, and increased hemosiderin in the liver (F) 8703465 28 - day inhalation rats 47839301 (2004)

0, 0.03, 0.10, or 0.70 mg/L **Acceptable (non -**  **guideline)** NOAEL= 0.03 mg/L (M) and not o bserved (F) LOAEL = 0.10 mg/L based on histopathology of the nasal tissues, lungs, thymus, prostate, and adrenal cortex (M); and 0.03 mg/L based on lymphocyte necrosis in the mesenteric lymph node (F). 870.3700 Developmental toxicity rats (gavage) 46264316 (2004)

0, 15, 40 or 120 mg/kg/day **Acceptable (guideline)** Maternal NOAEL = 40 mg/kg/day Maternal LOAEL = 120 mg/kg/day based on decreased corrected BW gain (corrected for uterine weights) Developmental NOAEL = 120 mg/kg/day (HDT) Developmental LOAEL > 120 mg/kg/day 870.3700 Developmental toxicity rabbits (gavage) 46264317 (2004)

0, 30, 100 or 300 mg/kg/day **Acceptable (guideline)** Maternal NOAEL = 100 mg/kg/day Maternal LOAEL = 300 mg/kg/day based on abortions (GD 22 and 28), ataxia (GD 23 - 28), lateral recumbency (GD 26 - 29), and poor health state (GD 27 - 29) Developmental NOAEL = 100 mg/kg/day Developmental LOAEL = 300 mg/kg/day, based on absent subclavian artery

870.3800 2 - generation reproduction rats (gavage) 46264315 (2004)

P generation: 0, 12, 30 or 75 mg/kg/day (mid and high doses reduced to 20 and 50 mg/kg/day, resp., after 17 weeks of treatment) F1 generation: 0, 12, 20 or 50 mg/kg/day **Acceptable (guideline)** Parental NOAEL = 20 mg/kg/day Parental LOAEL = 50 mg/kg/day based on poor h ealth state and decreased BW Reproductive NOAEL = 20 mg/kg/day Reproductive LOAEL = 50 mg/kg/day based on improper nursing behavior Offspring NOAEL = 20 mg/kg/day Offspring LOAEL = 50 mg/kg/day based on mortality (from birth to weaning) 870.4100 Chronic toxicity dogs (capsule) 46264302 (2004)

0, 6, 12 or 30 (60/40/30) mg/kg/day (dose level altered in high dose NOAEL = 12 mg/kg/day LOAEL = 30 mg/kg/day based on reduced general health condition, slight to severe ataxia, recum bency, and severe salivation (all clinical signs observed on ≥day 191); decreases in MCHC and total Hb andMetaflumizone Human - Health Risk Assessment D 393447

Page 35 of 39 **Table A.2: Subchronic and Chronic Toxicity and Genotoxicity Profile**  **– M**  **etaflum izone**  **Technical, Z -**  **isomer, and Metabolite M320I23.**  Guideline No./ Study Type MRID No. (Year)/Doses/ Classification Results group) **Acceptable (guideline)** increased bilirubin, increased urobilinogen, and increased hemosiderin in the liver 870.4200 Carcinogenicity mice (gavage) 46264314 (2003)

0, 100, 250 or 1000 mg/kg/day **Acceptable (guideline)** NOAEL = 250 mg/kg/day LOAEL = 1000 mg/kg/day (limit dose), based on incr. hemosiderin in the spleen, increased mean absolute reticulocyte count, and decreased mean corpuscular volume and mean corpuscular h emoglobin (M&F); and decreased BW gain (M). No evidence of carcinogenicity. 870.4300 Chronic Toxicity/Carcinogeni city rats (gavage) 46264240 (2003)

0, 30, 60 or 300/200 mg/kg/day (high dose reduced to 200 mg/kg/day in females after 2 weeks of treatment) **Acceptable (guideline)**  NOAEL = 30 (M) and 60 mg/kg/day (F) LOAEL = 60 mg/kg/day based on basophilic hepatocellular alterations and hepatocellular hypertrophy (M); 200 mg/kg/day based on decreased BW, BW gain, and food consumption (F). No evidence of carcinogenicity. 870.5100 In Vitro bacterial reverse mutation (S. typhimurium/E. coli) 46264304 (2001)

15, 50, 150, 500, or 5000  g/plate (std. plate test) ( - /+ activation) **Acceptable (guideline)** Negative.

870.5300 In Vitro mammalian gene mutation (CHO/HGPRT) 46264307 (2002)

0, 25.0, 50.0, 100.0, 156.3, 200.0, 312.5, 400.0, 625.0, 800.0, 1250.0, 2500.0 or 5000.0 μ g/mL ( - activation) 0, 50.0, 100.0, 156.3, 200.0, 312.5, 400.0, 625.0, 800.0, 1200.0, 1250.0, 2500.0 or 5000.0 μg/mL (+ activation) **Un acceptable**  **(guideline)** Inconclusive without metabolic activation due to compound precipitation at all concentrations tested Inconclusive with metabolic activation due to compound precipitation at all concentrations tested

870.5375 In Vitro mammalian chromosomal aberration (V79) 46264309 (2002)

0, 3.125, 6.25, 12.5, 25.0 or 50.0 μ g/mL ( - activation); 0, 25.0, 50.0 or 100.0 μ g/mL (+ activation) **Acceptable (guideline)** Positive without metabolic activation at soluble (12.5 μ g/mL) and insoluble ( ≥ 25 μ g/mL) concentrations. Negative with metabolic activation. 870.5395 In Vivo mammalian cy togenetics (mouse micronucleus) 46264311 (2002)

0, 500, 1000 or 2000 mg/kg **Acceptable (guideline)** Negative. 870.5550 UDS in mammalian cells 46264313 (2003)

0, 1000 or 2000 mg/kg **Acceptable (guideline)** Negative. 870.6200 Acute neurotoxicity rats (gavage) 46264318 (2003)

0, 125, 500, or 2000 mg/kg/day **Acceptable (guideline)** NOAEL = 2000 mg/kg/day (HDT) LOAEL > 2000 mg/kg/day 870.6200 46264319 (2003) NOAEL = 36 mg/kg/dayMetaflumizone Human - Health Risk Assessment D 393447

Page 36 of 39 **Table A.2: Subchronic and Chronic Toxicity and Genotoxicity Profile**  **– M**  **etaflum izone**  **Technical, Z -**  **isomer, and Metabolite M320I23.**  Guideline No./ Study Type MRID No. (Year)/Doses/ Classification Results Subchronic neurotoxicity rats (gavage) 0, 12, 36, 150 or 300 mg/kg/day

**Acceptable (guideline)** LOAEL = 150 mg/kg/day, based on death, reduced general condition, and piloerection (M&F); hyperthermia (M); abnormal squatting posture , hypothermia, decreased BW, BW gain, and food consumption (F) 870.6300 Developmental Neurotoxicity rats (gavage) (range finding) 47839302 (2005)

0, 50, 80, or 120 mg/kg bw/day Maternal NOAEL = 80 mg/kg/day Maternal LOAEL = 120 mg/kg/day, based on poor general state and total litter loss in both cohorts. Offspring NOAEL = 80 mg/kg/day Offspring LOAEL = 120 mg/kg/day based on pup mortality

870.7485 Metabolism rats (gavage) 46264230 (2002)

30 and 1000 mg/kg (single dose) 30 mg/kg (14 - day repeated dosing) **Acceptable (guideline)** Following a single oral dose of [benzonitrile ring - U 14 C] and [trifluoromethoxyphenyl ring - U 14 C] metaflumizone, the amount of absorption was <7.5% for the 30 mg/kg dose group and < 2% for the 1000 mg/kg dose group after 72 hours. The majority (>90%) of the 2 doses were excreted in the feces. Biliary excretion accounted for <5% of the low dose and <2% of the high dose. Urinary excretion was also low at 1 - 2%. The absorbed doses were distributed quickly to the muscle, liver, kidney, and fat within 0.5 - 2 hours. Total radioactivity in muscle, liver, kidney, blood, and plasma reached maximal levels at or near the blood T max irrespective of sex or dose. Near the blood T max , radioactivity was highest in fat or liver, followed by kidney and blood/plasma/muscle. Unchanged parent accounted for the majority of radioactive residue in muscle, liver, kidney, fat and plasma. BAS 320I was metabolized via hydroxylation of the aniline or benzonitrile ring and hydrolysis of the central hydrazine carboxamide group to yi eld the aniline derivatives and phenacyl benzoylnitrile derivatives. The trifluoromethoxyaniline was shown to conjugate with malonic and oxalic acids. Glycine conjugation occurred at the carboxyl group of the cyanobenzoic acid. Glutathione conjugation occurred by displacement of one of the fluorine atoms of the trifluoromethyl or trifluoromethoxy group to form S - (N - (N - γ - glutamyl)) - cysteinyl - , glycyl - conjugate. After 14 days of daily dosing at 30 mg/kg/day, metaflumizone concentrations were up to 26 (muscle), 13 (liver), 13 (kidney), 43 (fat), and 26 (plasma) times higher than those found after a single oral dose. [Trifluoromethoxyphenyl ring - U 14 C] - labeled parent/metabolite(s) appeared to partition into RBCs, rather than plasma, in both sexes after 14 days of dosing. Single, low - dose absorption study (gavage vs dietary) 47249001 (2007)

0.73 mg/kg bw (single - dose gavage) 0.76 mg/kg bw (single - dose dietary) Unacceptable/non - guideline (biliary excretion not measured) 10.8% absorption via gavage 23.0% absorption via diet Although measurement of radioactivity excreted into the bile was not made and is necessary for a complete characterization of absorption, s tudy data indicate that the relative percentage of administered dose excreted into bile under either dosing regimen would be similar 870.7800 Immunotoxicity 28 days (oral gavage) 48448601(2011)

0, 15, 40, or 75 mg/kg/day Immunotoxicity: NOAEL = 75 mg/kg bw /day LOAEL = not identified Systemic toxicity: NOAEL = 40 mg/kg bw/day LOAEL = 75 mg/kg bw/day based on decreases in body weights, body weight gains, and food consumption. **Z -**  **isomer** 870.3100 3 - month oral rats - gavage 46264301 (2004)

0, 100, 300 or 1000 mg/kg/day **Acceptable (guideline)** NOAEL = 100 (F) and 300 (M) mg/kg/day LOAEL = 300 (F) and 1000 (M) mg/kg/day, based on mortality, clinical signs (reduced general condition and piloerection), and lymphocyte necrosis in the mesenteric lymph node (F) and decreased motor activity (M&F) 870.5100 In Vitro bacterial reverse mutation (S. 46264305 (2002)

20 - 5000 μ g/plate (std. plate test) ( - Negative with and without metabolic activation. Negative with and without metabolic activation.Metaflumizone Human - Health Risk Assessment D 393447

Page 37 of 39 **Table A.2: Subchronic and Chronic Toxicity and Genotoxicity Profile**  **– M**  **etaflum izone**  **Technical, Z -**  **isomer, and Metabolite M320I23.**  Guideline No./ Study Type MRID No. (Year)/Doses/ Classification Results typhimurium/E. coli) /+ activation)

4 - 2500 μ g/plate (preincubation assay) ( - /+ activation) **Acceptable (guideline)**  **Metabolite M320I23** 870.3100 3 - month oral rats - gavage 46264242 (2004)

0, 50, 200, or 1000 mg/kg/day **Acceptable (guideline)** NOAEL = 1000 mg/kg/day (HDT) LOAEL > 1000 mg/kg/day

870.5100 In vitro bacterial reverse mutation (S. typhimurium, E. coli) 46264306 (2003)

20, 100, 500, 2500, or 5000 μg/plate (std. plate test) ( - /+ activation) 62.5, 125, 250, 500, 1500 μg/plate (preincubation assay) ( - /+ activation) **Acceptable (guideline)** Negative with and without metabolic activation. Negative with and without metabolic activation.

870.5300 In Vitro mammalian gene mutation (CHO/HGPRT) 46264308 (2004)

0, 0.125, 0.25, 0.5, 1.0, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, or 6.0 μ g/mL ( - activation) 0, 1.25, 2.5, 3.125, 5, 6.25, 10, 12.5, 15, 20, 25, 30, 40, 50, or 100 μ g/mL (+ activation) **Unacceptable (guideline)**  Negative without metabolic activation. Inconclusive with metabolic activation du e to compound precipitation at all concentrations tested

870.5375 In Vitro mammalian chromosomal aberration (V79) 46264310 (2004)

0, 0.25, 0.5 or 1.0 μg/mL ( - activation) 0, 1.0, 5.0, 7.5, 10.0 or 12.5 μg/mL (+ activation) **Acceptable (guideline)** Negative without metabolic activation. Positive with metabolic activation.

870.5395 In Vivo mammalian cy togenetics (mouse micronucleus) 46264312 (2004)

0, 500, 1000 or 2000 mg/kg **Acceptable (guideline)** Negative.Metaflumizone Human - Health Risk Assessment D 393447

Page 38 of 39 **Appendix B**  **. Chemical Names and**  **Structures Comm**  **on name/code Chemical name**  **Chemical structure**

Metaflumizone E isomer 4 - {(2E) - 2 - ({[4 - (trifluoromethoxy) - anilino]carbonyl}hydrazono) - 2 - [3 - (trifluoromethyl)phenyl]ethyl} - benzonitrile 2 - [2 - (4 - cyanophenyl) - 1 - [3 - trifluoromethyl)phenyl]ethylidene] -N - [4 - hydrazinecarboxamide (E) Metaflumizone Z isomer 2 - [2 - (4 - cyanophenyl) - 1 - [3 - trifluoromethyl)phenyl]ethylidene] -N - [4 - hydrazinecarboxamide (Z)

F 3 C N H N O C F 3

C N O

H N

M320I04 4 - {2 - oxo - 2 - [3 - (trifluoromethyl )phenyl]ethyl} - benzonitrile M320I05 (CL 65504) p - trifluoromethoxyaniline M320I06 (found in tomato and cattle urine) 4 - cyanobenzoic acid

M320I07 2 - [2 - (4 - cyanophenyl) - 2 - hydroxy- 1 - [3 - trifluoromethyl)phenyl]ethylidene] -N - [4 - hydrazinecarboxamide

M320I10

M320I13 {[(4_cyanophenyl)acetyl]amino}acetic acid M320I17 (isolated and identified in goat urine) oxo{[4_(trifluoromethoxy)phenyl]amino} acetic acid M320I22 (E and Z isomers) -- CN N N H N H O O F 3 C C F 3

N H 2 O C F 3

C N O O H

O OH OH

O H O C

O O H C N F 3 C

N H O O C

F 3 O H O

C N N N H N H O O F 3 C C F 3 O HMetaflumizone Human - Health Risk Assessment D 393447

Page 39 of 39 **Comm on name/code**  **Chemical name Chemical structure** 

M320I23 4 - {5 - hydroxy- 3 - oxo - 4 - [4 - (trifluoromethoxy)phenyl] - 6 - 3 - (trifluoromethyl)phenyl] - 2,3,4,5 - tetrahydro - 1,2,4 - triazin - 5 - yl}benzonitrile

M320I24 (E and Z isomers) --

M320I25 4 - {2 - hydroxy- 2 - [3 - (trifluoromethyl )phenyl]ethyl} - benzonitrile

M320I26 4 - amino - 5 - {2 - (4 - cyanophenyl) - 1 - [3 - (trifluoromethyl)phenyl]ethoxy} - 5 - oxopentanoic acid M320I28 (hydrolysis product of Metaflumizone) N - [4 - (trifluoromethoxy)phenyl] - acetamide C N N F 3 C N

H N O

O F 3 C O H

C N N N H N H O O F 3 C C F 3 O O O

H O H O H H O OC

CN O F 3 C O N H 2 C OO

H

C H 3 N H O O C

F 3