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 

Risk Assessment 

Lowe, Environmental 

Branch 1/Health 

Scientist 

Effects Divtsion 

~ 

(RAB1/HED; 7509P) 

RAB1/HED 

Charles 

George F. 

W

Kramer, 

. Smith 

(7509P) 

III, 

Ph.D., 

Branch 

Branch 

Chief 

Senior 

C' 

Chemis~~ 

(___)~ ~· 

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 of30 
Metaflumizone Human-Health Risk Assessment D410219

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Table of Contents

1.0 Executive Summary................................................................................................................................................3

2.0 HED Recommendations .........................................................................................................................................5

2.1 Data 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 Assessment ...............................................................................................................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 Cumulative 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.............................................................................................................................................................29
Metaflumizone Human-Health Risk Assessment D410219

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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 channels of susceptible insects leading to 

paralysis. Metaflumizone is currently registered for application to citrus, tree nuts, and grapes 

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 industrial, 

commercial, agricultural, and recreational facilities/structures and premises. Application of 

metaflumizone to pets was previously registered but was cancelled by the registrant in 2011. 

BASF requested tolerances 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 on 21-December-2011 (D393447, K. Lowe et al.)

Hazard Assessment: Hematotoxicity (toxicity of the blood) was the primary toxic effect of 

concern following subchronic or chronic oral exposures to metaflumizone. Splenic 

extramedullary hematopoiesis, increased hemosiderin, and anemia were the most common 

hematotoxic effects reported after repeated oral dosing with metaflumizone. Chronic oral 

(gavage) exposures to dogs resulted in slight decreases in mean corpuscular hemoglobin 

concentration and total hemoglobin, leading to increased plasma bilirubin, increased urinary 

urobilinogen, and increased hemosiderin in the liver. In a chronic toxicity/carcinogenicity study 

in mice, anemia was observed in the form of increased hemosiderin in the spleen, increased 

mean absolute reticulocyte count, decreased mean corpuscular volume, and mean corpuscular 

hemoglobin. 

The postulated pesticidal mode of action of metaflumizone involves inhibition of sodium 

channels in target insect species; however, in mammals (rats), there were only clinical signs of 

neurotoxicity (i.e., piloerection and body temperature variations) 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 the 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 guideline 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 other 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.

Food Quality Protection Act (FQPA) 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.
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Dose-Response Assessment: Table 4.6.1 is a summary of the points of departure (PODs) selected 

for assessment of dietary, inhalation, and dermal exposure. Route-specific toxicity studies were 

selected for assessment of short-/intermediate-term dermal, inhalation, and oral exposures. 

Short/intermediate-term dermal and inhalation exposures can be aggregated based on the effects 

on the immune system organs seen at the lowest-observed adverse-effect level (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. Since the PODs and level of concern (LOC) for the different exposure routes 

are different, the aggregate risks were calculated using 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 United 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 water 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 commodities 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 bioaccumulate in aquatic food webs, the current analysis 

included the KOW (based) Aquatic Bioaccumulation Model (KABAM; ver. 1.0) piscivorous 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 that 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

dermal and inhalation exposures) and post-application (short-term dermal and incidental oral) 

exposures are expected and were assessed to conform with the most recent policies and 

guidance. No risks of concern were identified for any scenario. 

Aggregate-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 these sources, HED 

considers the route and duration of exposure as well as the toxicological effects for each route. 
Metaflumizone Human-Health Risk Assessment D410219

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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 tolerance in/on 

imported tomato, pepper, and eggplant. Therefore, an occupational exposure assessment is 

unnecessary for the current 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-exposuredata.html and 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 

databases 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 responded 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 harvest 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 comprises >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 tolerance enforcement (46264221.der; D308394, 

T. Bloem, 30-Nov-2005; D328915, T. Bloem, 17-May-2006). It is noted that following method 
Metaflumizone Human-Health Risk Assessment D410219

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validation, BASF incorporated several minor modifications to method 531/0 with this revised method 

specified as 531/1 (method 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 adequate 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 Tolerances

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 procedure, 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 should 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 available 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 was 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 established. 
Metaflumizone Human-Health Risk Assessment D410219

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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 current 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 Trade Agreement (NAFTA) 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

Not 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 are 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

CN

N N

H N

H

O O

F3C

CF3

CN

O

F3C

CN

N F3C NH

N O

O F3C

HO
Metaflumizone Human-Health Risk Assessment D410219

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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 Kow.

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/cm3 MRID 46264204

Water solubility (20 oC)

D.I. water 1.79 μg/L

pH 5 1.35 μg/L

pH 7 1.81 μg/L

pH 9 1.73 μg/L

MRID 46264208

Solvent solubility (20 oC)

Acetone 142.7 mg/L

Acetonitrile 60.3 mg/L

DCM 92.7 mg/L

EtOAc 159.7 mg/L

Heptane 0.0084 mg/L

Methanol 13.95 mg/L

Toluene 3.96 mg/L

MRID 46264212

Vapor pressure 1.24 x 10-8 Pa at 20 oC MRID 46264206

Dissociation constant, pKa None in pH range 2-12 MRID 46264217

Octanol/water partition 

coefficient, Log(KOW)

Log POW = 5.1 (Z isomer)

Log POW = 4.4 (E isomer) MRID 46264213

UV/visible absorption 

spectrum

Molar absorptivity: 3.81×104 L/Mcm at 234 nm; 1.93×104 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, Macedonia, 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 countries 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 Macedonia. 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 number per season. 
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Table 3.3.1. Summary of Application Scenarios

Crop Country Formulation

Application PHI

(days) Comments Method Rate kg ai./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/hL1 -- -- -- --

pepper, red (chili) Korea SC 20% (w:w) foliar 0.016 kg ai/hL1 -- 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. The 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 

anticipated as residues may be found in/on crops and drinking water. It is noted that the current 

dietary assessment included residues in fish/shellfish as EFED concluded that metaflumizone has the 

potential to bioaccumulate substantially in aquatic food webs (D361157, K. Sappington, 21-Dec2011). Dermal, inhalation, and incidental oral residential exposures 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 under 

the NHANES/WWEIA (2003-2008) and are used in pesticide risk assessments for all registered food 
Metaflumizone Human-Health Risk Assessment D410219

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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. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups and exposure assessments are performed when conditions 

or circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of 

pesticide products and associated risks for adult applicators and for 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 development 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 metaflumizone 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 

hematotoxicity 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. Neurotoxicity (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 characterization.

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 tested 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 (Cmax) 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 Cmax and the area under the plasma 

concentration-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 

lower than those currently selected for dietary and incidental oral risk assessments, which are based 

on gavage dosing.
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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 causes hematotoxicity (toxicity of the 

blood) and immunotoxicity as primary toxic effects following subchronic or chronic oral 

exposures. Slight anemia and/or a compensatory extramedullary hematopoiesis in the spleen of 

rats were observed 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 dogs, anemia was observed 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 offspring 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 included 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 dose 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 noted in the 

subchronic neurotoxicity study in rats, and salivation and ataxia were observed at the high dose 

in a chronic study with dogs. However, reduced general condition and/or recumbency, indicators 

of general 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 systemic toxic effect in mammals.

Dermal exposure to metaflumizone also resulted in hematotoxicity 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 lymphocyte necrosis in the 

mesenteric lymph node as the critical effect (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 to deficits in body weight, body-weight gains, and food 

consumption.
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The concern for genotoxicity following exposure to metaflumizone is low based on the results 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 exposure. 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 presence 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 direct 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 toxicity 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 mortality, reduced general condition, piloerection, and 

decreased overall motor activity in females. In males, decreased overall motor activity was 

observed at the highest dose tested only. The Z-isomer of metaflumizone 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 concluded 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 M320I23: 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 

also 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 ovary 

(CHO) cells without metabolic activation (inconclusive results were obtained in the presence of 

metabolic activation due to compound precipitation). M320I23 was also negative in an in vitro
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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 clastogenicity since it was tested in a whole animal. 

The overall weight of the evidence for this metabolite, therefore, indicates that M320I23 is less 

toxic than metaflumizone technical and non-mutagenic like the parent compound.

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: 

developmental 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 

evaluation.

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, toxicity 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 database 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 retained 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) malformations, effects on offspring brain weights, or effects on offspring sexual 

maturation were observed 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 rats up to the limit dose. 
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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 previous petition (PP#5F6944; D308394, 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 assessment (i.e., incorporation of anticipated residues, percent crop treated estimates, and/or 

refined drinking water estimates will compensate for any increase in the maximum theoretical 

residue). The residential analysis is conservative in that health-protective 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 are presented in Table 4.3.1. Since this is an import 

tolerance, the endpoints 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) 

attributable to a single dose was not identified in the database. Studies considered for this 

endpoint included the acute neurotoxicity study for which a LOAEL was not observed. 

Acute Dietary Endpoint (Females 13-49 years old): This endpoint was 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 LOAEL 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 metaflumizone. 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 general health condition, slight to severe ataxia, recumbency, and 

severe salivation, decreases in MCHC and total Hb and increased bilirubin, increased 

urobilinogen, and increased hemosiderin in the liver. A combined UF of 300 was applied to 

account for interspecies (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.
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Incidental Oral (Short- and Intermediate-Term): This endpoint was selected on the basis of the 

maternal 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, poor 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 NOAEL 

of 20 mg/kg bw/day for the two-generation 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 versus oral gavage exposures (see above). The LOC is 300.

Dermal (Short- and Intermediate-Term): This endpoint was based on a rat 90-day dermal 

toxicity study in which deficits in body weight, body-weight gain and food consumption (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). The LOC is 100 based on a combined UF of 100 for 

interspecies (10x) and intraspecies (10x) extrapolation.

Inhalation (Short- and Intermediate-Term): There is a 28-day inhalation study that is adequate 

for both exposure durations. There was no NOAEL identified for female rats. At the 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 (NOAEL, 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 [σg] 

of aerosols), can be used to estimate the different dose fractions deposited along the respiratory 

tract. The RDDR is also based on interspecies differences in ventilation and respiratory-tract 

surface areas. Thus, the RDDR can be used to adjust an observed inhalation particulate exposure 

of an animal to the predicted inhalation exposure for a human. For the subchronic inhalation

toxicity study with metaflumizone, an RDDR was 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 1.7μm and σg 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 metaflumizone, the unadjusted animal POD was used to assess

the shorter duration residential handler exposures. Thus, the HEC equals the LOAEL from the 

study was calculated to be 0.084 mg/L. The FQPA SF of 10x is being retained for lack of a 

NOAEL for females in the study. The standard interspecies extrapolation UF can be reduced 

from 10x to 3x due to the HEC calculation accounting for pharmacokinetic (not 
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pharmacodynamic) interspecies differences. The intraspecies UF remains at 10x. Therefore, the 

LOC for this scenario is 300, which includes the FQPA SF of 10x, interspecies (3x), and 

intraspecies (10x) 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 HumanHealth Risk Assessments.1

Exposure Scenario Dose Used in Risk 

Assessment, UF

FQPA SF or LOC for Risk 

Assessment Study and Toxicological Effects

Acute Dietarygeneral 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 Dietaryfemales 13-49 years 

old

NOAEL = 100 

mg/kg/day

UF = 100

FQPA SF = 3x 

aPAD =aRfD = 0.33 mg/kg/day

Developmental toxicity (rabbit; gavage dosing); 

Offspring LOAEL = 300 mg/kg/day based on 

absent subclavian artery.

Chronic Dietarygeneral population, 

including infants and 

children

NOAEL = 12 mg/kg/day

UF = 100

FQPA SF = 3x 

cPAD =cRfD = 0.04 mg/kg/day

Chronic toxicity (dog; capsule dosing); LOAEL 

= 30 mg/kg/day based on reduced general 

health condition, slight to severe ataxia, 

recumbency, and severe salivation, decreases in 

MCHC and total Hb and increased bilirubin, 

increased urobilinogen, and increased 

hemosiderin in the liver.

Short- (1-30 days) 

and Intermediate-

(1-6 months) Term 

Incidental Oral 

NOAEL = 20 mg/kg/day LOC (residential) = MOE < 300

Two-generation reproduction (rat); Maternal 

LOAEL = 50 mg/kg/day based on poor general 

health and decreased body weight.

Short- (1-30 days) 

and Intermediate-(1-

6 months) Term 

Dermal

NOAEL = 100 

mg/kg/day LOC (residential) = MOE < 100 

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) Term 

Inhalation

LOAEL = 0.030 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/L2

HED=2.4 mg/kg/day3

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 = lowestobserved adverse-effect level, RfD = reference dose (a = acute, c = chronic), PAD = population-adjusted dose, MOE = margin of 

exposure, LOC = level of concern, N/A = not applicable, UFL = 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

 HED = 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/day
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5.0 Dietary Exposure and Risk Assessment

D412301, T. Bloem, 21-Nov-2013 (residue chemistry summary for the current action)

D413154, 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 M320I23 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 was a conservative 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 acceptable. 

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

Matrix Residues Included in Risk Assessment Residues Included in Tolerance Expression

Plants1 metaflumizone (E and Z isomers) and M320I04 metaflumizone (E and Z isomers) and M320I04

Livestock (excluding ruminant liver)2 metaflumizone (E and Z isomers) metaflumizone (E and Z isomers)

Livestock ruminant liver2 metaflumizone (E and Z isomers) and M320I283 metaflumizone (E and Z isomers)

Rotational crops metaflumizone (E and Z isomers) and M320I04 metaflumizone (E and Z isomers) and M320I04

Drinking water metaflumizone (E and Z isomers) Not applicable 1 This decision is contingent on the petitioner submitting data which address the following: (1) cabbage metabolism 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 study - 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 M320I28 

(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 of the residue data and methods used for 

derivation of the recommended tolerances. 
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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 Codex 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 harmonization 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 application 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 the seasonal application scenario employed in 

the U.S. trials being ~2x the registered seasonal Italian application rate (1x single application rate). 

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

concludes 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-recommended 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 NAFTA 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. 

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-Health Risk Assessment D410219

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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 based 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 tomato juice are unnecessary, the DEEM (ver. 7.81) default processing 

factors for these commodities 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 bioaccumulate in aquatic food webs, the current analysis included the KABAM

(ver. 1.0) piscivorous 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 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 

populations is not required.

0.04

0.001463 3.7

All Infants 0.000489 1.2

Children 1-2 years old 0.002304 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 0.001236 3.1 1

 95th 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 noncropland and as a granular fly bait around industrial buildings, commercial facilities, agricultural 

structures/premises, and recreational facilities/areas. Residential exposure resulting from these 

existing uses were reassessed to conform with the most recent policies and guidance (D414616, 

K. Lowe, 21-Nov-2013). 
Metaflumizone Human-Health Risk Assessment D410219

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As a result of these registered uses, residential handler (short-term dermal 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 were identified for any 

scenario. Table 6.0.3 is a summary of the residential exposure scenarios which should be 

included in the aggregate risk assessment.

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

Scenario Formulation Equipment

Dose (mg/kg/day)1 MOE2

ARI3

Dermal Inhalation Dermal

(LOC < 100)

Inhalation

(LOC < 300)

Lawns/

Turf Granule

Push-type rotary spreader 5.1E-06 1.6E-08 2.0E+07 1.5E+08 140,000

Belly Grinder 1.2E-04 1.3E-08 8.1E+05 1.8E+08 7,900

Spoon 1.8E-07 2.5E-09 5.6E+08 9.6E+08 2,000,000

3.9E-05 5.4E-07 2.6E+06 4.4E+06 9,400

Cup 3.2E-09 3.7E-10 3.2E+10 6.4E+9 20,000,000

6.9E-07 8.1E-08 1.5E+08 3.0E+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/ft2, 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 LOC = 100 and inhalation LOC = 300. 

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 Dose1 (mg/kg/day) MOE2 ARI3

Turf

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 Incidental oral - Hand to Mouth 2.1E-05 950,000

Incidental oral - Object to Mouth 1.3E-06 15,000,000 N/A Incidental oral - 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 oral LOC ÷ Incidental oral MOE)], where dermal LOC = 100 

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 MOE3,5

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 (highcontact 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) + 

(Inhalation 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

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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 postapplication 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 and 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 postapplication 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 considers the route and duration 

of exposure as well as the toxicological effects for each route. 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, shortterm, 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 combined 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, not of concern to HED. 
Metaflumizone Human-Health Risk Assessment D410219

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Table 7.2.1: Short- and Intermediate-Term Aggregate Risk

Population

Background Dietary + Incidental Oral Exposures Residential Exposures

ARI4

Oral 

LOC

Chronic Dietary 

Exp. (mg/kg/day)1

Incidental Oral 

Exp. (mg/kg/day)1

Oral 

MOE2

Dermal 

LOC

Dermal Exp.

(mg/kg/day)1

Dermal 

MOE3

General U.S. 

Population

300

0.001463 NA 14,000

100

0.0012 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 0.000021 8600 0.0023 44,000 27

1

 See Tables 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 dietary 

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 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to metaflumizone and any other substances 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 information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

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

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Appendix A. Toxicology Profile and Executive Summaries.

Table A.1: Acute Toxicity Profile - Metaflumizone Technical (96% ai), Z-isomer, and Metabolite M320I23.

Guideline No./Study Type MRID No. Results Toxicity 

Category

Metaflumizone Technical (96% ai)

870.1100/Acute oral toxicity rat 46264232 LD50 => 5,000 mg/kg (males, females combined) IV

870.1100/Acute oral toxicity mouse 46264234 LD50 => 5,000 mg/kg (males, females combined) IV

870.1200/Acute dermal toxicity rat 46264235 LD50 > 5,000 mg/kg (males, females combined) IV

870.1300/Acute inhalation toxicity rat 46264236 LC50 > 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 LD50 => 5,000 mg/kg (males, females combined) IV

Metabolite M320I23

870.1100/Acute oral toxicity rat 46264233 LD50 => 2,000 mg/kg (HDT1) (females) III 1 HDT=Highest Dose Tested

Table A.2: Subchronic and Chronic Toxicity and Genotoxicity Profile – Metaflumizone Technical, Z-isomer, 

and Metabolite M320I23.

Guideline No./

Study Type

MRID No. (Year)/Doses/ 

Classification Results

Metaflumizone Technical

4-day palatability rats 

(Alternate-day 

feeding regimen)

47036907 (2007)

Unacceptable/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)

Unacceptable/non-guideline

(individual animal data not 

submitted)

When offered a choice of control feed or diet treated with 400 ppm of the 

test material, rats exhibited a strong preference for the control feed by 

avoidance of the treated diet. This avoidance indicates poor palatability of 

the diet when the test material is incorporated as an admixture in feed.

7-day rats (gavage)

47036909 (2007)

0, 6, 16, or 28 mg/kg bw/day

Unacceptable/non-guideline

(individual animal and dose 

analysis data not submitted)

No effects on food consumption or body-weight gain. In contrast, 

significant decreases in food consumption and body-weight gain were 

observed after 7 days of treatment at similar doses via the diet (MRID 

47036902)

90-day oral rats 

(dietary)

47036902 (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 substance
Metaflumizone Human-Health Risk Assessment D410219

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Table A.2: Subchronic and Chronic Toxicity and Genotoxicity Profile – Metaflumizone 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, and 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 extramedullary hematopoiesis and 

hepatocellular hypertrophy

NOAEL (90-day) = not established

LOAEL (90-day) = not established

It is noted that treatment-related effects were not identified in either sex at 

100 mg/kg/day after 90 days.

870.3250

90-day dermal rats

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, lymphocyte 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 

artery

870.3800

2-generation 

reproduction rats 

(gavage)

46264315 (2004)

P generation: 0, 12, 30 or 75 

mg/kg/day (mid and high doses 

reduced to 20 and 50 mg/kg/day, 

resp., after 17 weeks of treatment)

F1 generation: 0, 12, 20 or 50 

mg/kg/day 

Acceptable (guideline)

Parental NOAEL = 20 mg/kg/day

Parental LOAEL = 50 mg/kg/day based on poor 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

Offspring LOAEL = 50 mg/kg/day based on mortality (from birth to 

weaning)

870.4100

Chronic toxicity dogs 

(capsule)

46264302 (2004)

0, 6, 12 or 30 (60/40/30) mg/kg/day 

(dose level altered in high dose 

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 increased hemosiderin in the liver
Metaflumizone Human-Health Risk Assessment D410219

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Table A.2: Subchronic and Chronic Toxicity and Genotoxicity Profile – Metaflumizone 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)

46264240 (2003)

0, 30, 60 or 300/200 mg/kg/day 

(high dose reduced to 200 

mg/kg/day in females after 2 weeks 

of treatment)

Acceptable (guideline)

NOAEL = 30 (M) and 60 mg/kg/day (F)

LOAEL = 60 mg/kg/day based on basophilic hepatocellular alterations 

and hepatocellular hypertrophy (M); 200 mg/kg/day based on decreased 

BW, BW gain, and food consumption (F). 

No evidence of carcinogenicity.

870.5100

In Vitro bacterial 

reverse mutation (S. 

typhimurium/E. coli)

46264304 (2001)

15, 50, 150, 500, or 5000 Φg/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

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Table A.2: Subchronic and Chronic Toxicity and Genotoxicity Profile – Metaflumizone Technical, Z-isomer, 

and Metabolite M320I23.

Guideline No./

Study Type

MRID No. (Year)/Doses/ 

Classification Results

870.6300

Developmental 

Neurotoxicity

rats (gavage) (rangefinding)

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-U14C] and 

[trifluoromethoxyphenyl ring-U14C] 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 

Tmax irrespective of sex or dose. Near the blood Tmax, 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 trifluoromethoxyaniline was 

shown to conjugate with malonic and oxalic acids. Glycine conjugation 

occurred at the carboxyl group of the cyanobenzoic acid. Glutathione 

conjugation occurred by displacement of one of the fluorine atoms of the 

trifluoromethyl or trifluoromethoxy group to form S-(N-(N-γ-glutamyl))-

cysteinyl-, glycyl-conjugate.

After 14 days of daily dosing at 30 mg/kg/day, metaflumizone 

concentrations were up to 26 (muscle), 13 (liver), 13 (kidney), 43 (fat), 

and 26 (plasma) times higher than those found after a single oral dose. 

[Trifluoromethoxyphenyl ring- U14C]-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)

48448601(2011)

0, 15, 40, or 75 mg/kg/day

Immunotoxicity: NOAEL = 75 mg/kg bw/day

LOAEL = not identified

Systemic toxicity: NOAEL = 40 mg/kg bw/day

LOAEL = 75 mg/kg bw/day based on decreases in body weights, bodyweight 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 – Metaflumizone 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

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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)

F3C

N

H

N OCF 3

CN

O

HN

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

CN

N N

H NH

O

O

F3C

CF3

CN

N F3C NH

N O

O F3C

HO

HC3 N

H

O

O

CF3
Metaflumizone Human-Health Risk Assessment D410219

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Appendix C: Exposure to Metaflumizone 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 residue estimate for fish/shellfish; 

the resulting exposure estimates are less than HED’s LOC (see Section 5.4). However, these

analyses did not consider fish/shellfish consumption rates associated with subsistence fishing. 

To account for these consumption rates, the assessment summarized below was conducted. 

Consumption rates associated with subsistence fishing were attained 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 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 recreational 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). The resulting total exposure 

estimates are less than HED’s LOC. 

HED notes that the exposure estimates presented 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; this scenario is not typical for subsistence fishing; 

(2) the analysis assumes that all consumed fish/shellfish have the KABAM piscivorous fish 

metaflumizone residue estimate; and (3) the DEEM-FCID exposure estimates considered 

residues in fish/shellfish and adding these estimates to the exposure estimates from subsistence 

fishing results in fish/shellfish consumption levels greater than figures indicated in Table D.1.

It is noted that the lindane subsistence diet exposure analysis (D282455, T. Morton, 17-Apr2002) 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

demonstrated properties for long-range transport and the documented concentrations 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 bodies 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 assessment. 
Metaflumizone Human-Health Risk Assessment D410219

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Table D.1. Summary of Subsistence Dietary Inputs and Risks.

Population Fish/Shellfish Residue 

Estimate1 (ppm)

Body 

Weight (kg)

Subsistence

DEEM-FCID Exposure4 combined %PAD5

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 70 214 0.010700 0.001471 30

Adult Females 60 797 214 0.046492 0.012483 0.005286 0.001236 16 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 rates 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 were taken from Table 1 and the children (<6 years old) consumption figures were taken from Table A.1. The referenced document did not 

include consumption figures for children (6-12 years old), The 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, Alaska. 

Wilimovsky, Norman, & Wolfe, John, Editors. United States Atomic Energy Commission. pp. 1109-1111. 3

 Exposure = consumption (g/day) ÷ body weight x fish residues (ppm) x (1 mg/1000 μg) 4

 See Table 5.4.1. 5 Combined %PAD = (subsistence exposure + DEEM-FCID exposure) ÷ PAD (aPAD = 0.33 mg/kg/day; cPAD = 0.04 mg/kg/day).