### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### MEMORANDUM

Date:

Subject:

From:

Through:

To: 21-November-2013



### Metaflumizone: Human-Health Risk Assessment for Tolerances in/on Imported Tomato, Pepper, and Eggplant.

!PC Codes: 281250 DP Barcode: D41 0219 Decision No.: 474810 Registration No.: none Petition No.: 3E8146**~egulatory** Action: tolerances with no U.S

. registration 

## !Risk Assessment Type: single chemical Case No.: 7446 TXR No.: not applicable CAS No.: 139968-49-3 MRID Nos.: not applicable 40 CFR: §180.657



### Tom Bloem,

# Chern**~~ ~** **~'"71** A 

### Chester Rodriguez, Ph.D., Pharmacologist 

# --z(;tu**~** 

# /

.._..**~~** Kelly Lowe, Environmental Scientist

## ~ Risk Assessment Branch 1/Health Effects Divtsion (RAB1/HED; 7509P)

Charles W

. Smith III, Branch Chief 

# C'

# (___)**~** George F. Kramer, Ph.D., Branch Senior

# Chemis**~~ ~·**  RAB1/HED (7509P)

John Herbert/Julie Chao, RM 07 Registration Division (RD; 7505P)

HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. RD of OPP has requested that HED evaluate hazard and
exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from all registered and proposed uses of metaflumizone (2-[2-( 4-cyanophenyl)-1-[3-(trifluoromethyl)phenyl] ethylidene ]-N-[ 

### 4-(trifluoromethoxy)phenyl]hydrazinecarboxamide; E:Z isomer ratio of >9: 1 ). A
summary of the findings and an assessment of the human risk resulting from the registered and proposed uses are provided in this document. The risk assessment, dietary risk assessment, and residue chemistry data review were provided by Tom Bloem (RAB1), the hazard characterization was provided by Chester Rodriguez (RAB 1 ), the residential exposure assessment by Kelly Lowe (RAB1), and the drinking water assessment by Jose Melendez of the Environmental Fate and Effects Division (EFED).

Page 1 of30Metaflumizone Human

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### Table of Contents

1.0 Executive Summary

................................ ................................ ................................ ................................ ................ 3

2.0 HED Recommendations

................................ ................................ ................................ ................................ ......... 5

2.1 Dat a Deficiencies/Conditions of Registration

................................ ................................ ................................ .... 5 2.2 Tolerance Considerations

................................ ................................ ................................ ................................ ... 5 2.2.1 Enforcement Analytical Method

................................ ................................ ................................ ................ 5 2.2.2 Recommended Tolerances

................................ ................................ ................................ ......................... 6 2.2.3 Revisions to Petitioned

- For Tolerances

................................ ................................ ................................ ..... 6 2.2.4 International Harmonization

................................ ................................ ................................ ...................... 6 2.3 Label Recommendations

................................ ................................ ................................ ................................ .... 7
3.0 Ingredient Profile

................................ ................................ ................................ ................................ .................... 7

3.1 Chemical Identify

................................ ................................ ................................ ................................ .............. 7 3.2 Physical/Chemical Properties

................................ ................................ ................................ ............................ 8 3.3 Proposed Use Pattern

................................ ................................ ................................ ................................ ......... 8 3.4 Anticipated Exposure Pathways

................................ ................................ ................................ ......................... 9 3.5 Consideration of Environmental Justice

................................ ................................ ................................ ............ 9

4.0 Hazard Characterization/Assessment

................................ ................................ ................................ ................... 10
4.1 Toxicology Studies Available for Analysis

................................ ................................ ................................ ..... 10 4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

................................ ................................ ...... 10 4.3 Toxicological Effects

................................ ................................ ................................ ................................ ....... 11 4.4 SF for Infants and Children (FQPA SF)

................................ ................................ ................................ .......... 13 4.4.1 Completeness of the Toxicology Database

................................ ................................ .............................. 13 4.4.2 Evidence of Neurotoxicity

................................ ................................ ................................ ....................... 13 4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

................................ ........... 14 4.4.4 Residual Uncertainty in the Exposure Database

................................ ................................ ...................... 14 4.5 Toxicity Endpoint and Point of Departure (POD) Selections

................................ ................................ .......... 14
5.0 Dietary Exposure and Risk Asses sment

................................ ................................ ................................ ............... 17
5.1 Metabolite/Degradate Residue Profile

................................ ................................ ................................ ............. 17 5.2 Food Residue Profile

................................ ................................ ................................ ................................ ........ 17 5.3 Drinking Water Residue Profile

................................ ................................ ................................ ....................... 18 5.4 Dietary (Food + Drinking Water) Risk Assessment

................................ ................................ ........................ 19
6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ ................................ ........ 19
6.1 Residential Bystander Post

- Application Inhalation Exposure

................................ ................................ ......... 21 6.2 Spray Drift

................................ ................................ ................................ ................................ ....................... 21
7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ................................ .......... 21
7.1 Acute Aggregate Risk

................................ ................................ ................................ ................................ ...... 21 7.2 Short

- Term Aggregate Risk

................................ ................................ ................................ ............................. 21 7.3 Chronic Aggregate Risk

................................ ................................ ................................ ................................ ... 22 7.4 Cancer Aggregate Risk

................................ ................................ ................................ ................................ .... 22

8.0 C umulative Exposure/Risk Characterization

................................ ................................ ................................ ........ 22
9.0 Occupational Exposure/Risk Characterization

................................ ................................ ................................ ..... 22

Appendix A. Toxicology Profile and Executive Summaries.

................................ ................................ ..................... 23
Appendix B: Chemical Names and Structures.

................................ ................................ ................................ ........... 28
Appendix C: Exposure to Metaflumizone in Fish/Shellfish at Consumption Levels Associated with Subsistence Fishing.

................................ ................................ ................................ ................................ ............................ 29Metaflumizone Human

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### 1.0 Executive Summary

Metaflumizone (2

- [2

- (4

- cyanophenyl)

- 1

- [3

- (trifluoromethyl)phenyl ]ethylidene]

- N

- [4

- (trifluoromethoxy)phenyl]hydrazinecarboxamide; E:Z isomer ratio of >9:1 ) is a semicarbazone insecticide which blocks the voltage

- dependent sodium channel s of susceptible insects leading to paralysis. Metaflumizone is currently registered for application to c itrus, t ree n uts, and g rape s with tolerances established for the combined residues of metaflumizone (E and Z isomers) and M320I04 at 0.04 ppm. Metaflumizone is also registered for application around i ndustrial,

c ommercial, a gricultura l

, and r ecreational f acilities/ s tructures and p remises

. A pplication of metaflumizone to pets was previously registered but was cancelled by the registrant in 201 1

. BASF requested tolerance s for the combined residues of metaflumizone (E and Z isomers) and M320I04 in/on imported tomato, pepper, and eggplant at 0.6 ppm. The most recent risk assessment for metaflumizone was conducted o n 21

- December

- 2011 (D393447, K. Lowe et al. )

Hazard Assessment: Hematotoxicity (toxicit y 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 repeat ed 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 hemo globin.

The postulated pesticidal mode of action of metaflumizone involves inhibition of sodium channels in target insect species; however, in mammals (rats), there were only clinical signs of neurotoxicity (i.e., piloerection and body temperature variat ions) with no neuropathology and in the presence of systemic toxicity (e.g., recumbency and poor general state) following acute or repeated exposures. Similarly, several immune system organs seem to be affected following metaflumizone administration via t he oral, dermal, and inhalation routes (e.g., the presence of macrophages in the thymus, lymphocyte necrosis in the mesenteric lymph nodes, and diffuse atrophy of the mandibular lymph node ); however, there was no evidence of any functional deficits at the highest dose tested in a g uideline immunotoxicity study. Therefore, the clinical neurotoxicity signs and the effects on the immune system organs following metaflumizone administration are likely to be secondary to the hematotoxic effects.

Metaflumizone induced a malformation based on an absent subclavian artery at a relatively high dose in the developmental toxicity study in rabbits. However, this effect was observed at the same dose as severe maternal toxicity, which included late

- term abortions and o ther clinical signs of toxicity. There was no evidence (quantitative or qualitative) of increased 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.

F ood Quality Protection Act (F QPA ) Safety Factor ( SF ) Decision: 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. A detailed discussion of these conclusions can be found in Section 4.4.Metaflumizone Human

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### Dose

- Response Assessment: T able 4.6 .1 is a summary of the points of departure (PODs) selected for assessment of dietary, inhalation, and dermal exposure. R oute

- 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 system organs seen at the lowest

- observed adverse

- effect level ( LOAEL ) in the selected studies. Short/intermediate

- term oral, dermal, and inhalation exp osures 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 LOAEL in the selected inhalation study. Since the PODs and level of concern (LOC) for the different exposure routes are different, the aggregate risks were calculated u sing the aggregate risk index (ARI) approach.

Residue Chemistry and Drinking Water Assessments: Adequate residue chemistry data have been submitted to support the establishment of tolerances in/on imported tomato, pepper, and eggplant. In addition, adequate data are available for the generation of modeled estimated drinking water concentrations (EDWCs).

Dietary Risk Estimates (Food + Drinking Water ): Acute and chronic dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model

- Food Consumption Intake Database (DEEM

- FCIDTM, ver. 3.16) which incorporates the food consumption data from the Un ited States Department of Agriculture (USDA) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA; 2003

- 2008). The acute and chronic analyses assumed tolerance

- level residues, 100% crop treated, and modeled drinking wate r estimates. Since adequate processing studies have been submitted which indicate that tolerances in/on grape raisin, grape juice, citrus juice, tomato puree, and tomato juice are unnecessary, the DEEM (ver. 7.81) default processing factors for these comm odities were reduced to 1. For tomato paste, the DEEM (ver. 7.81) default processing factor was also reduced to 1 as a separate tolerance in/on this commodity is recommended. For the remaining relevant commodities, the DEEM (ver. 7.81) default processing factors were retained. Based on an assessment by EFED , which concluded that metaflumizone has a high potential to bioaccumulat e in aquatic food webs, the current analysis included the K OW 

### (based) Aquatic Bioaccumulation Model (KABAM; ver. 1.0) piscivorou s fish residue estimate for fish/shellfish . The resulting acute (1.6% aPAD; assessment only necessary for females 13

- 49 years old) and chronic (≤5.8% cPAD; children 1

- 2 years old were the most highly exposed subgroup) analyses resulted in risk estimates t hat are not of concern to HED

.
Residential (Non

- Occupational) Exposure and Risk Assessment: There are no new residential uses associated with this regulatory action. Metaflumizone is registered for application as a fire ant bait to lawns, landscapes, golf courses, and other non

- cropland

, and as a granular fly bait around industrial buildings, commercial facilities, agricultural structures / premises , and recreational facilities/areas. As a result of these registered uses, residential handler (short

- term d ermal and inhalation exposures) and post

- application (short

- term dermal and incidental oral) exposures are expected and were assessed t o conform with the most recent policies and guidance

. No risks of concern were identified for any scenario

.
Aggrega te

- Risk Estimates: In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from dietary (food and water) and residential (dermal, inhalation, and/or incidental oral) sources. When aggregating exposures and risks from th ese sources, HED considers the route and duration of exposure as well as the toxicological effects for each route.Metaflumizone Human

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### As indicated above, short

- term dermal, incidental oral, and/or inhalation residential exposures are anticipated and these can be aggregated with dietary exposure based on a common toxic effect (decreased body weight or decreased body

- weight gain). Based on the proposed/registered uses, aggregate acute, short

- term, and chronic assessments were conducted. All aggregate assessments resulted in risk estimates which are not of concern to HED.

Occupational Exposure and Risk Assessment: The petitioner is proposing a tolera nce in/on imported tomato, pepper, and eggplant. Therefore, an occupational exposure assessment is unnecessary for the curre nt action.

Review of Human Research : This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from the Residential Standard Operating Procedures ( SOPs ; Turf SOP )

, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at http://www.epa.gov/pesticides/science/handler

- exposure

data.html an d http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

2.0 HED Recommendations

Provided a revised Section F is submitted, HED concludes that the toxicological and exposure database s are sufficient to support the establishment of the tomato, pepper, and eggplant tolerances listed in Table 2.2. 2.1 for the combined residues of metaflumizone (E and Z isomers) and M320I04. No additional data are required to support the establishment of these tolerances.

2.1 Data Deficiencies/Conditions of Registration

There are no data deficiencies for the current petition. Although not relevant to the current petition, BASF has not re sponded to the following two previously identified data deficiencies (D345540, T. Bloem, 26

- Jan

- 2010):

– Cabbage metabolism study (46264326.der.wpd)

- Information pertaining to sample extraction and analysis dates is required; if the interval from harves t to analysis is greater than the currently validated interval, then additional storage stability data will also be necessary.

– Cotton metabolism study (46264324.der.wpd)

- Individual concentrations of the unknowns should be reported; if any unknown compr ises >10% of the total radioactive residue (TRR), then further characterization/ identification procedures may be required (based on these data

, additional residues may be included for risk assessment).

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

HED previously reviewed method validation and independent laboratory validation (ILV) studies for the BASF liquid chromatograph/mass spectrometer/mass spectrometer (LC/MS/MS) analytical method 531/0 and forwarded the method to FDA for t olerance enforcement (46264221.der; D308394, T. Bloem, 30

- Nov

- 2005; D328915, T. Bloem, 17

- May

- 2006). It is noted that following methodMetaflumizone Human

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### validation, BASF incorporated several minor modifications to method 531/0 with this revised method specified as 531/1 (m ethod 531/1 is the current enforcement method). Since the tomato, pepper, and eggplant magnitude of the residue samples submitted in support of the current petition were analyzed using a method very similar to the current enforcement method and since adeq uate validation data were submitted, HED concludes that the current enforcement method is suitable for enforcement of the tolerances recommended herein.

Analytical standards for metaflumizone (E and Z isomers; expiration date 1

- June

- 2021) and M320I04 (expiration date 1

- July

- 2017) are currently available in the EPA National Pesticide Standards Repository (communication from Theresa Cole, BEAD, 5

- Apr

- 2013).

2.2.2 Recommended Toler ances
Table 2.2.2.1 is a summary of the proposed and HED

- recommended tolerances for the combined residues of metaflumizone (E and Z isomers) and M320I04 (expressed in parent equivalents).

Table 2.2.2.1: Tolerance Summary.

Commodity Proposed Tolerance (ppm) 1 HED

- Recommended Tolerance (ppm) 1 Comments

tomato 0.6 0.60 Based on the available field trial data and in order to harmonize with Codex, a tolerance of 0. 60 ppm is recommended.

tomato, paste

-- 1.2 ppm Based on the highest

- average field

- trial ( HAFT ) residue and the average tomato paste processing factor of 2.94x, a tomato paste tolerance of 1.2 ppm is recommended (0.39 x 2.94 = 1.15).

pepper 0.6 1. 5 Based on the available data, residues in/on imported pepper and by translation eggplant

, may be greater than the proposed 0.6 ppm tolerance; using the pepper data and the Organization for Economic Cooperation and Development ( OECD ) tolerance

- calculation procedure, a tolerance of 1.5 ppm is recommended. eggplant 0.6 1. 5



### 2.2.3 Revisions to Petitioned

- For Tolerances

Based on the HAFT tomato residue of 0.39 ppm and the average tomato paste processing factor of 2.94x , a tomato paste tolerance of 1.2 ppm is recommended (0.39 x 2.94 = 1.15). Based on the available data, residues in/on imported pepper , and by translation eggplant

, may be greater than 0.6 ppm; using the pepper data and the OECD tolerance

- calculation proc edure , a tolerance of 1.5 ppm is recommended (pepper data translated to eggplant per 40 CFR 180.41 fruiting vegetable crop group 8

- 10).

2.2.4 International Harmonization

HED concluded that the metaflumizone tolerance expression for crops should include metaflumizone (E and Z isomers) and M320I04. The Codex maximum residue limit (MRL) expression differs in that it does not include M320I04. HED determined that M320I04 shou ld be included as a residue of concern for risk assessment and tolerance enforcement purposes as it was identified at significant concentrations in the submitted metabolism study and is the primary residue in some processed commodities.

Based on the ava ilable field trial data, HED concluded that harmonization with the currently established 0.6

- ppm tomato Codex MRL was acceptable. However, based on the available field trial data, HED concluded that harmonization with the Codex pepper and eggplant MRLs wa s not appropriate (maximum residues in/on pepper of 0.66 ppm; pepper data translated to eggplant per 40 CFR 180.41 fruiting vegetable crop group 8

- 10). In addition, HED concluded that based on the available data, a tomato paste tolerance should be establi shed.Metaflumizone Human

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### HED notes that the currently established Codex MRLs are based on the 2009 Joint Food and Agricultural Organization/World Health Organization (FAO/WHO) Meeting on Pesticide Residues (JMPR) metaflumizone report and this report was utilized in the cu rrent residue chemistry review. The difference in the HED

- recommended tolerances and the Codex MRLs may be due to the following issues: (1) codex MRLs do not include M320I04 residues; (2) the codex MRLs were established using the North American Free Trad e Agreement ( NAFT A) tolerance

- calculation procedure which allowed the establishment of tolerances less than the highest residues; the OECD tolerance

- calculation procedure which was employed herein, does not permit this; and/or (3) the JMPR report indicated that only two applications were permitted to peppers grown in Mexico; based on the English translation of the Mexican labeled provided to HED, two sequential applications are permitted with no restriction on the number per season.

2.3 Label Recommendations

N ot relevant to the current petition as tolerances on imported commodities are being requested.

3.0 Ingredient Profile

3.1 Chemical Identify

The chemical structure and nomenclature of metaflumizone and M320I04 a re presented in Tables 3.1.1.

Table 3.1. 1 . Metaflumizone, M320I04, and M320I23 Nomenclature

.

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

Metabolite M320I04

4

- [2

- oxo

- 2

- [3

- (trifluoromethoxy)phenyl]ethyl]

- benzonitrile

Metabolite 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 C N N N

H N H O O

F 3 C C F 3

C N O F 3 C

C N N

F 3 C N H

N O

O F 3 C O HMetaflumizone Human

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### 3.2 Physical /Chemical Properties

Table 3.2.1 is a summary of the physical/chemical properties for metaflumizone. Metaflumizone has a low vapor pressure and a high Log K ow 

### .

Table 3. 2 .1

. Physicochemical Properties of Metaflumizone. Melting points 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/cm 3 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, pK a None in pH range 2

- 12 MRID 46264217 Octanol/water partition coefficient, Log(K OW ) 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



### 3.3 Proposed Use Pattern

The petitioner provided English translations of labels from the following countries concerning application of metaflumizone to tomato, pepper, and/or eggplant (see Table 3.3.1): Indonesia, Korea, Italy, Austria, M acedonia, Germany, Mexico, Chile , and Columbia. The countries and application scenarios provided by the petitioner are consistent with the countries and application scenarios summarized in the 2009 JMPR metaflumizone report for all countr ies excluding Macedonia and Mexico (the 2009 JMPR report was utilized as part of the current residue chemistry review) . The 2009 JMPR review did not include a summary concerning application of metaflumizone to tomato, pepper, and eggplant grown in Macedon ia. For Mexico, the JMPR review indicates a maximum of two applications per season to tomato and bell pepper while the Mexican label provided to HED indicates that only two sequential applications may be made

, but does not provide a limit concerning the n umber per season.Metaflumizone Human

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Page 9 of 30 Table 3.3.1. Summary of Application Scenarios

Crop Country Formulation Application PHI ( days ) Comments Method Rate kg a i ./ha RTI (days) Max no. of
apps. eggplant Italy SC 240 g ai/L foliar 0.24 7

- 10 2 x 0.24 3 x 0.06 3 field and greenhouse

pepper Austria SC 240 g ai/L foliar 0.12 (<50 cm) 0.18 (50

- 125 cm) 0.24 (>125 cm) 7

- 14 2 1 greenhouse only

Germany SC 240g ai/L foliar 0.12 (<50 cm) 0.18 (50

- 125 cm) 0.24 (>125 cm) 7

- 14 2 3 greenhouse only

Macedonia SC 240g ai/L foliar 0.24

-- 4 3

-- pepper, sweet Italy SC 240 g ai/L foliar 0.24 7

- 10 2 3 greenhouse only pepper, sweet (bell) Mexico SC 240 g ai/L foliar 0.29 4

- 7

-- 2 3

-- pepper, chili Indonesia SC 240 g ai/L foliar 0.031 kg ai/hL 1

-- -- -- -- pepper, red (chili) Korea SC 20% (w:w) foliar 0.016 kg ai/hL 1

-- 3 2

--

Tomato Austria SC 240 g ai/L foliar 0.12 (<50 cm) 0.18 (50

- 125 cm) 0.24 (>125 cm) 7

- 14 2 1 greenhouse only

Germany SC 240g ai/L foliar 0.12 (<50 cm) 0.18 (50

- 125 cm) 0.24 (>125 cm) 7

- 14 2 3 greenhouse only

Macedonia SC 240g ai/L foliar 0.24

-- 4 3

-- Italy SC 240 g ai/L foliar 0.24 7

- 10 2 3 field and greenhouse Mexico SC 240 g ai/L foliar 0.29 4

- 7

-- 2 3

--

Chile SC 240 g ai/L foliar 0.24 10

- 15 3 3 field and greenhouse Columbia SC 240 g ai/L foliar 0.32 7 2 3

-- 1 The English translation of the Indonesian and Korean labels did not provided application rates in kg ai/ha. The Indonesian label indicated that the spray solution should contain 0.5 ml of the formulated product per liter (0.12 g ai/L) and high volumes sprays should be used. The Korean label indicated that the spray solution should contain 13 ml of the formulated product per 20 L (0.16 g ai/L) and should be applied so as to ensure thorough coverage of foliage, bloom, and fruit. T he indicated kg ai/hL were taken from the 2009 JMPR review.
2 The Mexican label indicates that no more than two sequential applications may be made but does not indicate a maximum number of applications per season.



### 3.4 Anticipated Exposure Pathways

Based on the proposed/registered metaflumizone application scenarios

, dietary exposure is

a nticipated as residues may be found in/on crops and drinking water

. It is noted that the c urrent dietary assessment included residues in fish/shellfish as EFED con cluded that metaflumizone has t he potential to bioaccumulate substantially in aquatic food webs (D361157, K. Sappington , 21

- Dec

2011 ). Dermal , inhalation, and incidental oral residential exposure s are also anticipated as a result of the registered fly and fire ant bait application scenarios (handler and post application exposures).

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations,” ( http://www.epa.gov/compliance/environmentaljustice/ resources/policy/exec_order_12898. pdf ) . As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from 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 u nder the NHANES/WWEIA ( 2003

- 2008) and are used in pesticide risk assessments for all registered foodMetaflumizone Human

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Page 10 of 30 

### uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Addi tionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and ass ociated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the developme nt of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

It is noted that , based on analysis by EFED, metaflumizone has a high potential to bioaccumulate in aquatic food webs. As a result, the dietary risk assessment included a residue estimate for fish/shellfish with the resulting exposures less than HED’s LOC (see Section 5.4). HED also performed a separate analysis for exposure to metaflu mizone in fish/shellfish at the consumption level associated with subsistence fishing; the resulting exposure estimates were also less than HED’s LOC (see Appendix C ).

4.0 Hazard Characterization/Assessment

Metaflumizone is a semicarbazone insecticide which blocks the voltage

- dependent sodium channels of susceptible insects leading to paralysis

. For toxicity in mammals, metaflumizone seems to operate with a different mode of action leading to primary toxic effects more closely associated with hematoto xicity and immunotoxicity

. Clinical signs of neurotoxicity such as piloerection in some studies are likely to be secondary effects to a poor general state.

4.1 Toxicology Studies Available for Analysis

The toxicological database for metaflumizone is adequate for hazard characterization, toxicity endpoint selection, and FQPA SF evaluation

. In the last risk assessment ( D393447, K. Lowe et al.

, 21

- Dec

- 2011 ), no toxicity studies were noted to be missing

. N eurotoxicity (acute and subchronic), immunotoxicity, and inhalation studies have all been submitted and reviewed by the Agency

. Additionally, toxicity data for the goat/plant/soil metabolite M320I23 have also been submitted and reviewed for hazard charact erization.

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)
Following administration of a single oral gavage dose of radiolabeled metaflumizone, the fraction absorbed was estimated to be low at <7.5% and even lower at the highest dose test ed of 1000 mg/kg bw

. The majority of the unabsorbed dose was excreted in feces

. The absorbed radioactivity was distributed quickly to the muscle, liver, kidney, and fat within 0.5

- 2 hours

. Maximum levels in blood (C max 

### ) were attained at about 10 hrs and were prolonged to about 30 hours at the highest dose tested

. Elimination half

- lives were estimated at about 44 hours for both sexes and increased by more than 2

- fold at the highest dose tested

. Increases in both C max 

### and the area under the plasma

concen tration

- time curve (AUC) were less than proportional with respect to increases in dose.
In a comparative bioavailability study (oral gavage versus dietary), a difference in absorption was noted between oral gavage and dietary dosing

. Absorption via the diet, a more relevant route of exposure for dietary human risk assessments, was noted to be greater than via gavage by a factor of 2. Therefore, toxicity via the diet can be reasonably expected at doses that are approximately 2

- fold low er than those currently selected for dietary and incidental oral risk assessments, which are based on gavage dosing

.Metaflumizone Human

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### 4.3 Toxicological Effects

Metaflumizone technical (90% E

- isomer and 10% Z

- isomer) : Metaflumizone technical is a mixture of ~90% E

- isomer and 10% Z

- isomer which cause s hematotoxicity (toxicity of the blood) and immunotoxicity as primary toxic effects following subchronic or chronic oral
exposure s

. S light anemia and/or a compensatory extramedullary hematopoiesis in the spleen of
rats were o bserved in a 90

- day oral toxicity study , but not in the corresponding chronic toxicity /carcinogenicity study in rats suggestive of an adaptive response to the anemia following long

- term exposure in rats

. In a chronic toxicity study in dog s , anemia was obs erved in the form of slight decreases in mean corpuscular hemoglobin concentration and total hemoglobin leading to increased plasma bilirubin, increased urinary urobilinogen, and increased hemosiderin in the liver

. Following chronic exposures, anemia was observed in both sexes in mice as increased hemosiderin in the spleen, increased mean absolute reticulocyte count, and decreased mean corpuscular volume and mean corpuscular hemoglobin

.
In a developmental toxicity study in rats, toxicity to the offsprin g was not observed at any dose, whereas mild maternal toxicity (decreased body

- weight gain) was observed at the highest dose tested. In rabbits, the malformation absent subclavian artery was observed at the same dose as severe maternal toxicity, which inc luded late

- term abortions and clinical signs of toxicity. In the
two

- generation reproductive toxicity study in rats, perinatal mortality was observed 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 dos e as clinical signs of toxicity and total litter loss in maternal animals.

There was no evidence of neurotoxicity in an acute neurotoxicity study in rats up to the highest dose tested (the limit dose)

. Piloerection and body temperature variations were no ted 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 systemic toxicity, were also observed in both sexes in both studies

. Thus, although metaflumizone is postulated to operate by 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 syst emic toxic effect in mammals.

Dermal exposure to metaflumizone also resulted in h ematotoxicity and/or immunotoxicity. In a rat 90

- day dermal toxicity study, increased hemosiderin was observed in the livers of females, along with increased macrophages in the thymus, lymphocyte necrosis in the mesenteric lymph nodes, and diffuse atrophy of the mandibular lymph node.

The results of a 28

- day rat inhalation toxicity study also identified l ymphocyte necrosis in the mesenteric lymph node as the critical effec t (i.e., observed at the lowest dose)

. Although metaflumizone resulted in histopathological findings consistent with immunotoxicity, the results of a 28

- day immunotoxicity study in rats did not indicate any functional deficits in immune response; effects were limited t o deficits in body weight, body

- weight gains, and food consumption.Metaflumizone Human

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### The concern for genotoxicity following exposure to metaflumizone is low based on the resu lts of

an in vivo mouse micronucleus assay; and there was no evidence of carcinogenecity in the respective studies with mice and rats

. Metaflumizone was classified as Category IV for its low acute toxicity via the oral, dermal, and inhalation routes of ex posure. It was neither a dermal irritant, eye irritant, nor a dermal sensitizer.

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 led to the (appropriate) decision by the registrant to conduct all of its guideline studies using gavage dosing. In every dietary study, decreased body weight and body

- weight gains were observed in the pre sence of decreased food consumption. Because the decreases in body weight were observed only 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 dir ect effect of treatment, but rather was due to the decreased food consumption, which was most likely caused by a lack of palatability of the test substance when administered in the diet. The results from these five studies were supported by two additional studies, also submitted subsequent to the original package , which demonstrated that when given a preference in a free

- choice feeding regimen, rats strongly 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 by 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 caused by the animals eating less due to the unpalatability of metaflumizone, and not to direct toxi city of the test compound , they are not relevant for endpoint selection for risk assessment.

Metaflumizone (Z

- isomer alone) : The Z

- isomer of metaflumizone administered alone (99.7%) via oral gavage to rats resulted in m ortality, reduced general conditi on, piloerection, and decreased overall motor activity in females. In males, decreased overall motor activity was observed at the highest dose tested only. T he Z

- isomer of m etaflumizone was negative for mutagenicity with and without metabolic activation in an in vitro bacterial reverse mutation (Ames) assay.

When these findings for the Z

- isomer alone are compared to those from the subchronic (90

- day) neurotoxicity study in rats using metaflumizone technical ( 90% E

- isomer and 10% Z

- isomer ), it can be conc luded that the Z

- isomer is 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 males, respectively.

Metaflumizone Metabolite M 320I23: M320I23 is a metabolite of metaflumizone that is generated in soil, plants (cotton, tomato, white cabbage), and goats, but not in rats. No adverse effects were observed in a 3

- month oral (gavage) study of M320I23 in rats. This metabolite was als o 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 hypoxanthine

- guanine phosphoribosyl transferase (HGPRT) locus in Chinese hamster ov ary (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 vitroMetaflumizone Human

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Page 13 of 30 

### 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 cytogenetic assay (mouse micronucleus test), which would be considered a more relevant test system for cl astogenicity 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.

4. 4 SF for Infants and Children (FQPA SF)

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.

4. 4 .1 Completeness of the Toxicology Database

The toxicological database for metaflumizone is adequate for risk assessment and FQPA SF evaluation. The following acceptable studies are available for FQPA consideration: developmen tal toxicity studies in rats and rabbits; two

- generation reproduction study in rats; and acute neurotoxicity (ACN) and subchronic neurotoxicity (SCN) studies in rats

. An immunotoxicity study has also been submitted and reviewed by the Agency for FQPA SF

e valuation.

A difference in absorption was noted 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 by a factor of 2. Therefore, toxi city via the diet can be expected at doses that are approximately 2

- fold lower than those currently 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 data base uncertainty factor (UF) 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 re tained as an UF for the use of a LOAEL in the absence of a no

- observed adverse

- effect level (NOAEL ) 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

.
4. 4 .2 Evidence of Neurotoxicity

Clinical 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 neuropathology was observed in any study with metaflumizone. No signs of abnormal offspring behavior, central nervous system (CNS) malfo r mations, effects on offspring brain weights, or effects on offspring sexual maturation were observe d in the developmental or two

- generation reproduction studies. No adverse effects were reported on motor activity or in the functional observational battery in the chronic/carcinogenicity study in rats. There was no evidence of neurotoxicity in the acute neurotoxicity test in rat s up to the limit dose.Metaflumizone Human

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### 4. 4 .3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There are no residual concerns or uncertainties for increased sensitivity/susceptibility in developing animals resulting from pre

- and/or postnatal exposure.

4. 4 .4 Residual Uncertainty in the Exposure Database

The dietary analysis 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 identified in a pre vious petition ( PP#5F6944; D 308394, T. Bloem, 30

- Nov

- 2005 ) may conceivably 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 assess ment (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 analysis is conservative in that health

- protec tive assumptions were assumed along with the use of the Residential SOPs.

4. 5 Toxicity Endpoint and Point of Departure ( POD ) Selections

The PODs, UFs , and toxicity endpoints a re presented in Table 4. 3.1

. Since this is an import tolerance, the endpoin ts necessary for occupational exposure are not presented.

Acute Dietary Endpoint (General population including infants and children): An acute dietary endpoint was not established for this population group since an endpoint of concern (effect) attribut able 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 established 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 L OAEL of 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 met aflumizone. A combined UF of 300 was applied to account for interspecies (10x) and intraspecies (10x) 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 systemic 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 LOAEL of 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 inte rspecies (10x) and intraspecies (10x) extrapolation

, and an FQPA factor of 3x

was 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.Metaflumizone Human

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Page 15 of 30 

### Incidental Oral (Shor t

- and Intermediate

- Term): This endpoint was selected on the basis of the
matern al effects observed in the rat two

- generation reproductive toxicity study at the LOAEL of 50 mg/kg bw/day metaflumizone (NOAEL = 20 mg/kg bw/day). Maternal toxicity consisted of 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, poo r maternal health was also observed at the LOAEL of 120 mg/kg bw/day metaflumizone (NOAEL = 80 mg/kg bw/day). Both studies considered for this endpoint achieved a clear NOAEL for the offspring effects, but the NO AEL of 20 mg/kg bw/day for the two

- generati on reproductive toxicity study is considered more protective. A combined UF of 300 was applied to account for interspecies (10x) and intraspecies (10x) extrapolation

, and an FQPA SF of 3x to account for the 2

- fold greater absorption observed in dietary ve rsus 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 (in males and females); anogenital smearing; 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 (females only) were observed at the LOAEL of 300 mg/kg bw/day (NOAEL = 100 mg/kg bw/day) . T he 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 LOAEL of 0.10 mg/L metaflumizone (NOAEL = 0.03 mg/L), histopathology of the nasal tissues, lungs, thymus, prostate, and adrenal cortex was observed in males. The LOAEL identified in females resulted in lymphocyte necrosis in the mesenteric lymph node.

The methods and dosimetry equations described in EPA’s reference concentration (RfC) guidance (1994) are suited for calculating HECs (human

- equivalent concentration) based on the inhalation toxicity point of departure ( N OAEL , LOAEL, or BMDL) for use in MOE calculations. The regional

- deposited

- dose ratio (RDDR), which accounts for the particulate diameter (mass median aerodynamic diameter [MMAD] and geometric standard deviation [ σ g 

### ] of aerosols), can be used to estimate the different dose fractions deposite d along the respiratory tract. The RDDR is also based on interspecies differences in ventilation and r espiratory

- tract surface areas

. Thus, the RDDR can be used to adjust an observed inhalation particulate exposure of an animal to the predicted inhalatio n exposure for a human. For the subchronic inhalation toxicity study with metaflumizone

, an RDDR wa s estimated at 2.81 based on systemic effects ( lymphocyte necrosis in the mesenteric lymph node ) in females at the LOAEL of 0.03 mg/L (no NOAEL established) and a MMAD of 1.7 μ m and σ g 

### of 2.7

. For this action with metaflumizone, only residential handler scenarios are being assessed for which 2

- hr/day inhalation exposures are assumed. Adjustment to shorter exposure scenarios relative to the animal toxicity study duration ( e.g., 2 hr residential exposures) should only be made if there is time

- course information that would support a shorter time

- frame

. Since there is no such information available for metaflu mizone, the unadjusted animal PO D w as used to assess the shorter duration residential handler exposures

. Thus, the HEC equals the LOAEL from the study was calculated to be 0.0 84 mg/L

. The FQPA SF of 10x is being retained for lack of a NOAEL for females in the study. The standard interspecies extrapolatio n UF can be reduced from 10 x to 3 x due to the HEC calculation accounting for pharmacokinetic (notMetaflumizone Human

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Page 16 of 30 

### pharmacodynamic) interspecies differences

. The intraspecies UF remains at 10 x

. Therefore, t he LOC for this scenario is 30 0

, which includes the FQPA SF of 10 x , interspecies (3 x )

, and intraspecies (10 x ) extrapolation.

4.6 Recommendation for Combining Routes of Exposure for Risk Assessment

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 LOAEL in the selected inhalation study.

Table 4

. 6 .1: Summary of Toxicological Doses and Endpoints for Metaflumizone Used in Residential Human

Health Risk Assessments. 1

Exposure Scenario Dose Used in Risk Assessment, UF FQPA SF or LOC 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 Dietary

general 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 increase d 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 Two

- generation reproduction (rat); Maternal LOAEL = 50 mg/kg/day based on poor general health and decrea sed body weight.

Short

- (1

- 30 days) and Intermediate

- (1

- 6 months) Term Dermal NOAEL = 100 mg/kg/day LOC (residential) = 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).

Short

- (1

- 30 days) and Intermediate

- (1

- 6 months) T erm Inhalation LOAEL = 0.03 0 mg/L NOAEL not observed LOC (residential) = MOE < 300 28

- day inhalation (rat); LOAEL = 0.03 mg/L * based lymphocyte necrosis in the mesenteric lymph node (F). HEC = 0.084 mg/L 2 HED=2.4 mg/kg/day 3

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 = leve l of concern, N/A = n ot a pplicable, UF L = uncertainty factor for lack of a NOAEL and extrapolation of a 28

- day study for longer durations.
2 HEC = LOAEL x RDDR = 0.030 x 2.809 = 0.084
3 H ED = human

- equivalent dose = HEC x human specific conversion factor (CF) x relative activity factor (AF) x exposure duration = 0.084 mg/L x 11.8 L/hr/kg BW x 1.2 x 2 hrs = 2.4 mg/kg/dayMetaflumizone Human

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### 5.0 Dietary Exposure and Risk Assessment
D4 12301 , T. Bloem, 21

- Nov

- 2013 (residue chemistry summary for the current action) D4 13154 , T. Bloem, 21

- Nov

- 2013 (dietary exposure analysis for the current action)



### 5.1 Metabolite/Degradate Residue Profile

Table 5.1. 1 is a summary of the residues of concern in plants, livestock, rotational crops, and drinking water for risk assessment and/or tolerances expression ( for further information see D304496, R. Mitkus et al. , 24

- Jan

- 2006).

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 M32 0I23 were the residues of concern in drinking water and EFED provided EDWCs for these compounds (D319414, M. Ruhman, 13

- Mar

- 2006). Subsequent EDWC memorandum from EFED provided concentrations for parent only and noted that including parent plus M320I23 wa s a con servative approach. The environmental degradation section of the above referenced human

- health risk assessment (Section 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 M320I23 was orders of magnitude lower than that for surface water, HED concludes that EDWCs representing parent only

are a cceptable.

Table 5.1.1: Residues of Concern for Tolerance Expression and Risk Assessment

Matrix Residues I ncluded in Risk Assessment Residues I ncluded in Tolerance Expression

P lants 1 metaflumizone (E and Z isomers) and M320I04 metaflumizone (E and Z isomers) and M320I04
L ivestock (excluding ruminant liver) 2 metaflumizone (E and Z isomers) metaflumizone (E and Z isomers)
Livestock ruminant liver 2 metaflumizon e (E and Z isomers) and M320I28 3 metaflumizone (E and Z isomers)
R otational 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) cabbage m etabolism study

- information pertaining to sample extraction and analysis dates; if the interval is greater than the currently validated interval, then additional storage stability data are required ; and (2) cotton metabolism s tudy

- individual concentrations of the unknowns is needed; if any unknown comprises >10% of the total radioactive residue , then further characterization/identification 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 M320I2 8 (microwave assisted cleavage and/or derivatization; common moiety method).



### 5.2 Food Residue Profile

The number and geographical representation of the submitted field trial data are adequate. In addition, the petitioner submitted an adequate tomato processing study which indicated that the residues of concern concentrate in only tomato wet pomace, tomato peel, and tomato paste. All samples were analyzed using adequately validated methods and sufficient storage stability data are available. No additional magnitude of the residues data are required.

Table 2.2.2.1 is a summary of the petitioner proposed and HED recommended tolerance levels for the combined residues of metaflumizone (E and Z isomers) and M320I04 in/on imported tomato, pepper, and eggplant. The following paragraphs are summaries o f the residue data and methods used for derivation of the r ecommended tolerances.Metaflumizone Human

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Page 18 of 30 

### For tomato , the available EU and U.S. field trial data resulted in maximum combined residues of metaflumizone (E and Z isomers) and M320I04 of <0.60 ppm; therefore, HED concludes that harmonization with the currently established C odex MRL value is appropriate (tolerance expressions differ). However, based on the HAFT tomato residue of 0.39 ppm and the average tomato paste processing factor of 2.94x, a tomato paste tolerance of 1.2 ppm for the combined residues of metaflumizone (E and Z isomers) and M320I04 is recommended (0.39 x 2.94 = 1.15).

For peppers , the maximum combined metaflumizone (E and Z isomers) and M320I04 residues in/on bell peppers from the U.S. trials were ≤0.66 ppm (4 x 0.29 kg ai/hectare; RTI = 6

- 8 days; PHI = 3 days) and from the E.U. trials were ≤0.62 ppm (2 x 0.26 kg ai/hectare; RTI = 6

- 7 days; PHI = 3

- 4 days). Therefore, HED concludes that h armonization with the Codex 0.6

- ppm pepper MRL is not appropriate. Based on the U.S. pepper (bell and non

- bell) data and the OECD tolerance

- calculation procedure, a tolerance of 1.5 ppm for the combined residues of metaflumizone (E and Z isomers) and M320I04 is appropriate. HED used only the U.S. data to determine an appropriate pepper tolerance as the employed applicat ion scenario more closely matches the scenario registered in Mexico with Mexico having the highest registered application rate and is the major source of peppers imported into the U.S. HED notes that although Codex has established a MRL in/on dried pepper of 6.0 ppm, HED does not require tolerances in/on dried pepper.

For eggplant and based on translation from the U.S. non

- bell pepper field trial data (representative crop for eggplant; see 40 CFR 180.41 fruiting vegetable crop group 8

- 10), HED concludes that an eggplant tolerance of 1.5 ppm for the combined residues of metaflumizone (E and Z isomers) and M320I04 is appropriate. HED notes that, based on the information provided by the petitioner, application to eggplant is only registered in Italy with t he seasonal application scenario employed in the U.S. trials being ~2x the registered seasonal Italian application rate (1x single application ra te). Since the residue decline

- data indicated that, in general, residues decline with increasing PHI, HED

conc ludes that the U.S. data are sufficient.

HED notes that the currently established Codex MRLs are based on the 2009 JMPR report for metaflumizone and this report was utilized in the current residue chemistry review. The differences in the HED

- recommend ed tolerances and the Codex MRLs may be due to the following identified issues: (1) codex MRLs do not include M320I04 residues; (2) the codex MRLs were established using the NAFT A tolerance

- calculation procedure which allowed the establishment of toleranc es less than the highest residues; the OECD tolerance

- calculation procedure , which was employed herein, does not permit this; and/or (3) the JMPR report indicated that only two applications were permitted to peppers grown in Mexico; based on the English tr anslation of the Mexican labeled provided to HED, two sequential applications are permitted with no restriction on the number per season.

5.3 Drinking Water Residue Profile

The proposed tolerances in/on imported tomato, pepper, and eggplant will not impact residues in U.S. drinking water. Table 5 .3.1 is a summary of worst case metaflumizone surface

- /ground

- water EDWCs previously provided by EFED ( D367556, J. Meléndez, 3

- Aug

- 2011). These are the highest metaflumizone EDWCs and were incorporated into the current assessment. It is noted that EFED concluded that generation of EDWCs using PRZM

- groundwater is unnecessary as they would be less than the FIRST surface water EDWCs. The water models and their description are available at the EPA internet site : http://www.epa.gov/oppefed1/models/water/

.Metaflumizone Human

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Page 19 of 30 Table 5. 3 .1 : Maximum Tier I Metaflumizone EDWCs. 1

Model Yearly Application Rate Concentration (ppb) Groundwater ( SCI

- GROW ) 2 fly bait (26 x 0.0137 lb ai/acre) acute and chronic 0.00214
Surface water (FIRST) fly bait (26 x 0.0137 lb ai/acre) acute 1.14 chronic 0.597

1 Bolded numbers were incorporated into the current analyses.
2 EFED concluded that b ased on the metaflumizone environmental fate data and the SCI

- GROW estimate, generation of PRZM

- ground
water modeling estimates were unnecessary as they would be less then the available surface water estimates.



### 5.4 Dietary (Food + Drinking Water) Risk Assessment

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using DEEM

- FCIDTM ( ver. 3.16) which incorporates the food consumption data from the USDA NHANES/WWEIA ( 2003

- 2008)

. The acute and chronic analyses assumed tolerance

- level residues

, 100% crop treated, and modeled drinking water estimates. Since adequate processing studies have been submitted which indicate that tolerances in/on grape raisin, grape juice, citrus juice, tomato puree, and tomat o juice are unnecessary, the DEEM (ver. 7.81) default processing factors for these commodities were reduced to 1. F or tomato paste, the DEEM (ver. 7.81) default processing factor was also reduced to 1 as a separate tolerance in/on this commodity is

recomm ended. For the remaining relevant commodities, the DEEM (ver. 7.81) default processing factors were retained. Based on an assessment by EFED which concluded that metaflumizone has a high potential to bioaccumulat e in aquatic food webs, the current analys is included the KABAM ( ver. 1.0) piscivorous fish residue estimate for fish/shellfish. The resulting acute ( 1.6 % a PAD;
assessment only necessary for f emales 13

- 49 years old) and chronic (≤ 5.8 % cPAD; children 1

- 2 years old were the most highly exposed subgroup) analyses resulted in risk estimates that are not of concern to HED (see Table 5.4.1)

.

Table 5.4.1 : Summary of the Acute and Chronic Dietary Exposure and Risk.

Population aPAD (mg/kg/day) Exposure (mg/kg/day) 1 %aPAD cPAD (mg/kg/day) Exposure (mg/kg/day) %cPAD

General U.S. Population

An endpoint of concern (effect) attributable to a single dose was not identified in the database. Quantification of acute risk to these population s is not required

. 0.04 0.001463 3.7
All Infants 0.000489 1.2
Children 1

- 2 years old 0.00 2304 5.8
Children 3

- 5 years old 0.002131 5.3
Children 6

- 12 years old 0.001554 3.9
Youth 13

- 19 years old 0.001059 2.6
Adults 20

- 49 years old 0.001446 3.6
Adults 50

- 99 years old 0.001471 3.7
Females 13

- 49 years old 0. 33 0.005286 1.6 0.00 1236 3.1

1 95 th percentile (tier 1 analysis)



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no new residential uses associated with this regulatory action. Metaflumizone is registered for application as a fire ant bait to lawns, landscapes, golf courses, and other non

cropland and as a granular fly bait around industrial buildings, commercial facilities, agricultural
structures / premises , and recreational faci lities / areas. Res idential exposure resulting from these exist i ng uses were reassessed to conform with the most recent policies and guidance (D414616, K. Lowe, 21

- Nov

- 2013).Metaflumizone Human

- Health Risk Assessment D410219

Page 20 of 30 

### As a result of these registered uses, residential handler ( s hort

- term d ermal and inhalation
exposures ) and post

- application ( short

- term dermal and incidental oral ) exposures are expected and were assessed (see Table 6.0.1 and 6.0.2)

. No risks of concern w ere identified for any scenario

. Table 6.0.3 is a summary of the residential exposure scenario s which should be included in the aggregat e risk assessment

.
Table 6.0.1. Residential Handler Exposure and Risk Estimates for Existing Residential Uses.

Scenario Formulation Equipment Dose (mg/kg/day) 1 MOE 2
ARI 3 Dermal Inhalation Dermal (LOC < 100) Inhalation (LOC < 300 )

Lawns/

Turf Granule Push

- type rotary spreader 5.1E

- 06 1.6E

- 08 2.0E+07 1.5 E+08 140,000 Belly Grinder 1.2E

- 04 1.3E

- 08 8.1E+05 1.8 E+08 7,900
Spoon 1.8E

- 07 2.5E

- 09 5.6E+08 9.6 E+0 8 2,000,000 3.9E

- 05 5.4E

- 07 2.6E+06 4.4 E+0 6 9,400
Cup 3.2E

- 09 3.7E

- 10 3.2E+10 6.4 E+ 9 20,000,000 6.9E

- 07 8.1E

- 08 1.5E+08 3.0 E+07 92,000

1 Dose (mg/kg/day) equations provided in D414616 (K. Lowe, 21

- Nov

- 2013) . Application rates = 0.001 lb ai/A, 2.3 x 10

- 8 lb ai/ft 2 , or 0.0001 lb ai/mound based on fire ant bait product (see Table 4.1 in D414616 ).

2 MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day) , where dermal POD = 100 mg/kg/day and inhalation POD = 2.4 mg/kg/day.

3 ARI = 1÷ [(Dermal LOC ÷ Dermal MOE) + (Inhalation LOC ÷ Inhalation MOE)] , where dermal L OC = 100 and inhalation LOC = 3 00

. ARI>1 is not of concern.

Table 6.0.2. Residential Post

- application Exposure and Risk Estimates for Existing Residential Uses. Use/Target Lifestage Post

- application Exposure Scenario Dose 1 (mg/kg/day) MOE 2 A RI 3

Tur f Adult Dermal

- High

- contact (playing) 0.0012 86,000

N/A 0.00008 1,200,000 Dermal

- Mowing 1.5E

- 06 65,000,000 Dermal

- Golfing 5.9E

- 06 17,000,000

Child 11<16 yrs Dermal

- Mowing 1.8E

- 06 57,000,000
Dermal

- Golfing 6.9E

- 06 15,000,000 Child 6<11 yrs Dermal

- Golfing 8.1E

- 06 12,000,000

Child 1<2 yrs Dermal (high

- contact play) 0.0023 44,000 380 I ncidental o ral

- Hand to Mouth 2.1E

- 05 950,000
I ncidental o ral

- Object to Mouth 1.3E

- 06 15,000,000 N/A I ncidental o ral

- Incidental Soil Ingestion 4.7E

- 07 42,000,000

1 Dose (mg/kg/day) equations provided in D414616 (K. Lowe, 21

- Nov

- 2013) . Application rates = 0.001 lb ai/A based on fire ant bait product (see Table 4.1 ) and 0.014 lb ai/A based on the fly bait product (see Table 4.1 in D414616 )

. 2 MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day), where dermal POD = 100 mg/kg/day and incidental oral POD = 20 mg/kg/day.

3 ARI = Aggregate Risk Index = 1÷ [(Dermal LOC ÷ Dermal MOE) + ( Incidental ora l LOC ÷ Incidental oral MOE)] , where dermal LOC = 10 0 and incidental oral LOC = 300

. ARI>1 is not of concern.

Table 6.0.3. Recommendations for the Residential Exposures for Aggregate Assessment. 1

Lifestage (Scenario) Dose (mg/kg/day) 2,4 MOE 3,5

Dermal Inhalation Oral Dermal (LOC < 100) Inhalation (LOC < 300) Oral (LOC < 300) Total

Residential Handler
Adult Male (Belly Grinder) 1.2E

- 04 1.3E

- 08 N / A 8.1E+05 5.9E+08 N/A ARI = 7,900

Residential Post

- application
Adult Male ( h igh

contact activity on turf ) 0.0012 N/A N/A 86,000 N/A N/A 86,000

Child ( high

- contact

activity on turf) 0.0023 N / A 2.1E

- 05 44,000 N / A 950,000 ARI = 380

1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment.

2 Residential Handler Dose = the highest handler dose for each applicable lifestage of all residential handler scenarios assessed.

3 Residential Handler MOE = the MOEs associated with the highest residential handler doses. ARI = 1÷ [(Dermal LOC ÷ Dermal MOE) + (Inh alation LOC ÷ Inhalation MOE)].

4 Residential Post

- application Dose = the highest post

- application dose for each applicable lifestage of all post

- application scenarios assessed.

5 Residential Post

- application MOE = the MOEs associated with the highest post

- application doses. ARI = 1÷ [(Dermal LOC ÷ Dermal MOE) + (Incidental oral LOC ÷ Incidental oral MOE)]

. ARI>1 is not of concern.Metaflumizone Human

- Health Risk Assessment D410219

Page 21 of 30 

### 6 .1 Residential Bystander Post

- Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for metaflumizone at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (9.3 x 10 - 11 

### mmHg), and the low proposed use rate (0.014 lb ai/A). However, volatilization of pesticides may be a source of post

application inhalation exposure to individuals nearby pesticide applications. 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, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/ meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies a nd procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post

application inhalation exposure assessment for metaflumizone.

6.2 Spray Drift

Exposure as a result of spray drift is not anticipated since the registered products are all granular formulations.

7.0 Aggregate Exposure/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, and/or incidental oral) sources. When aggregating exposures and risks from these sources, HED con siders the route and duration of exposure as well as the toxicological effects for each route. As indi cated above, short

- term dermal, incidental oral, and /or inhalation residential exposures are anticipated and these can be aggregated with dietary exposur e based on a common toxic effect (decreased body weight or decreased body

- weight gain). Based on the proposed/registered uses, aggregate acute, short

term, and chronic assessments were conducted.

7.1 Acute Aggregate Risk

Since there are no registered /proposed uses that result in acute residential 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 only food and water. The acute dietary exposure estimate for females 13

- 49 years old was 1 .6 % the aPAD and, therefore, does not exceed HED’s LOC (see Section 5. 4 ).

7 .2 Short

- Term Aggregate Risk

The short

- term aggregate assessment combine d food and drinking water exposure with the highest potential residential exposure as outlined in Table 6.0.3 . Table 7 .2.1 is a summary of the short

- term aggregate risk estimates for metaflumizone

. Since the PODs and LOCs for the dermal and oral routes of exposure are different

, the aggregate risk estimates were calculated using the ARI approach. The aggregate ARIs are > 1 and are

, therefore, no t of concern to HED

.Metaflumizone Human

- Health Risk Assessment D410219

Page 22 of 30 Table 7 .2.1: Short

- and Intermediate

- Term Aggregate Risk

Population Background Dietary + Incidental Oral Exposures Residential Exposures ARI 4 Oral LOC Chronic Dietary Exp

. (mg/kg/day) 1 Incidental Oral Exp

. (mg/kg/day) 1 Oral MOE 2 Dermal LOC Dermal Exp. (mg/kg/day) 1 Dermal MOE 3

General U.S. Population 300 0.00 1463 NA 14,000

100 0.00 12 81,000 43

Adults 50

- 99 years old 0.001471 NA 14,000 0.0012 81,000 43

Children 1

- 2 years old 0.002304 0.000 0 21 8600 0.00 23 44,000 27

1 See Table s 5.4.1 (dietary) and Table 6 .0. 3 (residential)

. 2 Oral MOE = NOAEL (20 mg/kg/day) ÷ (chronic food/water exposure + incidental oral exposure).

3 Dermal MOE = NOAEL (100 mg/kg/day) ÷ (dermal exposure).

4 ARI ( Aggregate Risk Index) = 1 ÷ ((1 ÷ (Oral MOE ÷ Oral LOC)) + (1 ÷ (Dermal MOE ÷ Dermal LOC))); ARI > 1 indicates an acceptable exposure.



### 7.3 Chronic Aggregate Risk

Since there are no registered/proposed uses that result in chronic residential exposure, the chronic aggregate exposure assessment consists of exposure from food and water. The chronic dietar y exposure estimate was ≤ 5.8 % the cPAD and, therefore, does not exceed HED’s LOC (see Section 5. 4 ).

7.4 Cancer Aggregate Risk

An aggregate cancer risk assessment was not performed because metaflumizone is not considered to be a carcinogen.

8.0 Cum ulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to metaflumizone and any other substan ces and metaflumizone does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that metaflumizone has a common mechanism of toxicity with other substances. For inf ormation regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

The petitioner is proposing a tolerance in/on imported tomato, pepper, and eggplant . Therefore, an occupational exposure assessment is unnecessary for the current action.

RDI: RAB1 ( 20

- Nov

- 2013)

Appendix A. Toxicology Profile and Executive Summaries

. Appendix B: Chemical Names and Structures

. Appendix C : Exposure to Metaflumizone in Fish/Shellfish at Consumption Levels Associated with Subsistence Fishing

.Metaflumizone Human

- Health Risk Assessment D410219

Page 23 of 30 

### Appendix A. Toxicology Profile and Executive Summaries

.

Table A.1: Acute Toxicity Profile

- M etaflumizone Technical (96% ai), Z

- isomer, and Metabolite M320I23.
Guideline No./Study Type MRID No. Results Toxicity Category
M etaflumizone 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 etaflumizone Technical, Z

- isomer, and Metabolite M320I23.
Guideline No./

Study Type MRID No. (Year)/Doses/ Classification Results

M etaflumizone 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 is 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 avoidan ce 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) 4 7036902 (1999/2007)

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 poor 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 798.1/783.0 mg/kg/day [M/F] Acceptable (non

- guideline) 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 D410219

Page 24 of 30 Table A.2: Subchronic and Chronic Toxicity and Genotoxicity Profile

– M etaflumizone Technical, Z

- isomer, and Metabolite M320I23.
Guideline No./

Study Type MRID No. (Year)/Doses/ Classification Results

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, an d body weights, 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 extram edullary 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 46264303 (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, lymphocyt e necrosis in the mesenteric lymph nodes, diffuse atrophy of the mandibular lymph node, and increased hemosiderin in the liver (F)

870

. 3465 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 observed (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
arter y

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 health 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 Offs pring 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 group) Acceptable (guideline) NOAEL = 12 mg/kg/day LOAEL = 30 mg/kg/day based on reduced general health condition, slight to severe ataxia, recumbency, and severe salivation (all clinical signs observed on ≥day 191); decreases in MCHC and total Hb and increased bilirubin, increased urobilinogen, and increa sed hemosiderin in the liverMetaflumizone Human

- Health Risk Assessment D410219

Page 25 of 30 Table A.2: Subchronic and Chronic Toxicity and Genotoxicity Profile

– M etaflumizone Technical, Z

- isomer, and Metabolite M320I23.
Guideline No./

Study Type MRID No. (Year)/Doses/ Classification Results

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 hemoglobin (M&F); and decreased BW gain (M). No evidence of carcinogenicity.

870.4300 Chronic Toxicity/Carcinogeni city rats (gavage) 462 64240 (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 Φ 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)

Unacceptable (guideline) Inconclusive without 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 cytogenetics (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 Subchronic neurotoxicity rats (gavage) 46264319 (2003)

0, 12, 36, 150 or 300 mg/kg/day Acceptable (guideline) NOAEL = 36 mg/kg/day 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)Metaflumizone Human

- Health Risk Assessment D410219

Page 26 of 30 Table A.2: Subchronic and Chronic Toxicity and Genotoxicity Profile

– M etaflumizone Technical, Z

- isomer, and Metabolite M320I23.
Guideline No./

Study Type MRID No. (Year)/Doses/ Classification Results

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 two 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 yield the aniline derivatives and phenacyl benzoylnitrile derivatives. The trifluorometh oxyaniline 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 trifluoro methoxy 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 a fter 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, study 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) 4844 8601(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. typhimurium/E. coli) 46264305 (2002)

20

- 5000 μ g/plate (std. plate test) (

- /+ activation)

4

- 2500 μ g/plate (preincubation assay) (

- /+ activation) Acceptable (guideline) Negative with and without metabolic activation.Metaflumizone Human

- Health Risk Assessment D410219

Page 27 of 30 Table A.2: Subchronic and Chronic Toxicity and Genotoxicity Profile

– M etaflumizone Technical, Z

- isomer, and Metabolite M320I23.
Guideline No./

Study Type MRID No. (Year)/Doses/ Classification Results

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 due 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 cytogenetics (mouse micronucleus) 46264312 (2004)

0, 500, 1000 or 2000 mg/kg

Acceptable (guideline) Negative.Metaflumizone Human

- Health Risk Assessment D410219

Page 28 of 30 

### Appendix B: Chemical Names and Structures

.

Common 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

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

M320I28

(hydrolysis product of Metaflumizone) N

- [4

- (trifluoromethoxy)phenyl]

- acetamide C N N N H N H O O

F 3 C C F 3

C N N F 3 C N H

N O

O F 3 C O H

C H
3 N H O O C F 3Metaflumizone Human

- Health Risk Assessment D410219

Page 29 of 30 

### Appendix C : Exposure to Meta flumizone in Fish /Shellfish at Consumption Levels Associated with Subsistence Fishing

.
Based on an assessment by EFED which concluded that metaflumizone has a high potential to bioaccumulate in aquatic food webs, the dietary risk assessment conducted in support of the current uses included the KABAM ( ver. 1.0 ) piscivorous fish resi due estima te for fish/shellfish; the resulting exposure estimates are less than HED’s LOC (see Section 5.4)

. However, th e s e analys e s d id not consider fish/shellfish consumption rates associated with subsistence fishing. To account for these consumption rates, the assessment summarized below was conducted.

C onsumption rates associated with subsistence fishing were attained from the Fish Consumption Rates Technical Support Document (ver. 2.0; www.ecy.wa.goc/b iblio/1209058.html ) from the State of Washington Department of Ecology . The report addresses fish consumption in the State of Washington among the general population, tribal populations, and other groups such as Asian and Pacific Islanders and recreationa l anglers. Based on the consumption rates from this document and the KABAM (ver. 1.0) piscivorous fish residue estimate, exposure estimates were calculated and added to the DEEM

- FICD estimates (see Table D.1). T he resulting total exposure estimates are l ess than HED’s LOC.

HED notes that the exposure estimates presente d in Table D.1 can be considered conservative for the following reasons: ( 1 ) the KABAM (ver. 1.0) model assumes a farm pond ecosystem receiving runoff from an adjacent treated field ; thi s scenario is not typical for subsistence fishing; ( 2) the analysis assumes that all consumed fish/shellfish have the KABAM piscivor ous fish metaflumizone residue estimate ; and (3 ) the DEEM

- FCID exposure estimates considered residues in fish/shellfish and adding the s e estimate s to the exposure estimates from subsistence fishing results in fish/shellfish consumption levels great er than figures indicated in Table D.1

.

It is noted that t he lindane subsistence diet exposure analysis (D282455, T. Morton, 17

- Apr

2002) utilized consumption data from the Alaska Department of Fish and Game

- Division of Subsistence

- Community Profile Database (ver. 3.11; 27

- Mar

- 2001)

. Based on lindane ’s d emonstrated properties for long

- range transport and the documented conc entrations in terrestrial, freshwater, and marine habitats, the lindane analysis selected the three Alaskan communities with the highest consumption of seal, whale, or walrus. In contrast to lindane, metaflumizone is anticipated to effect only water bodie s in the vicinity of the application site (long range transport is not anticipated ; communication from EFED ). Therefore, it was concluded that the consumption estimates provided in the used in the lindane analysis were not applicable to the current assess ment.Metaflumizone Human

- Health Risk Assessment D410219

Page 30 of 30 Table D.1

. Summary of Subsistence Dietary Input s and Risks.

Population Fish/Shellfish Residue Estimate 1 (ppm) Body Weight (kg) Subsistence DEEM

- FCID Exposure 4 combined %PAD 5 Consumption ( g /day ) 2 Exposure (mg/kg/day) 3

Acute Chronic Acute Chronic Acute Chronic Acute Chronic

Children 1

- 2 years old

3.5 10

acute assessment is
unnecessary 25

acute assessment is
unnecessary 0.008750

acute assessment is
unnecessary 0.002304

acute assessment is
unnecessary 28

Children 3

- 5 years old 20 25 0.004375 0.002131 16

Children 6

- 12 years old 30 113 0.013183 0.001554 37

Adults 7 0 214 0.010700 0.001471 30

Adult Females 6 0 797 214 0.046492 0.012483 0.005286 0.001236 1 6 34

1 As part of EFED’s ecological risk assessment associated with the registered fly bait application scenario, a residue estimate for piscivorous fish of 3.5 ppm was generated using KABAM (ver. 1.0; D361157, K. Sappington, 21

- Dec

- 2011).
2 Consumption rate s derived from the Fish Consumption Rates Technical Support Document (ver. 2.0; www.ecy.wa.goc/biblio/1209058.html ) from the State of Washington Department of Ecology. The adult consumption figures w ere taken from Table 1 and the children (<6 years old) consumption figures were taken from Table A.1. The referenced document di d not include consumption figures for children ( 6

- 12 years old ), T he 113 g/day consumption figure for children 6

- 12 years old was derived by adjusting the adult consumption figure by 0.53 with the 0.53 factor based on the following reference: Heller, C., 1966. Meat Consumption at Three Northern Eskimo Villages. Environment of the Cape Thompson Region, Ala ska. Wilimovsky, Norman, & Wolfe, John, Editors. United States Atomic Energy Commission. pp. 1109

- 1111.
3 E xposure = consumption (g/day) ÷ body weight x fish residues (ppm) x (1 mg/1000 μg)
4 See Table 5.4.1.
5 C ombine d %PAD = (subsistence exposure + DEEM

- FCID exposure) ÷ PAD (aPAD = 0.33 mg/kg/day; cPAD = 0.04 mg/kg/day)

.