UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date 29-September-2015 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

Subject: Metaflumizone: Human Health Risk Assessment in Support of Section 3 

Registrations for Application of Metaflumizone to Pome Fruit (crop group (CG) 11-

10) and Stone Fruit (CG 12-12); Updating the CG Designation for Citrus to 10-10 

and Tree Nuts to 14-12; and Permitting Aerial Application to Citrus Fruits, Grapes, 

Tree Nuts, and Nurseries Containing Field-/Container-Grown Nonbearing Stone and 

Pome Fruit Trees. 

PC Codes: 281250 (E Isomer); 281251 (Z isomer) DP Barcodes: 0421321; 0425540 

Decision No.: 492130 Registration No.: 7969-270 

Petition No.: 4F8286 Regulatory Action: Section 3 

Risk Assessment Type: single chemical airn.regate Case No.: 7446 

TXR No.: not applicable CASNo.: 139968-49-3 

MRID No: not applicable - - 40 CFR: 180.657 

om Bloem, Chemist l - \ From: T ~" ;J / 

Anwar Y. Dunbar, .Ph.i?,Ph~acologist ~ "1 v~ ~ /},1 

James S. Miller, Environmental Engineer, Public Hct<lth, Service (PHS) < ~A:~ Risk Assessment Branch I/Health Effects Division (RABl/HED; 750 

;. .. ~ Through: Thurston Morton, Chemist, Acting Branch Chief ~ / 

George F. Kramer, Ph.D., Senior Chemist ~7' K--=--5?§ 

RABI/HED (7509P) 

To: Richard Gebken (RM 10) 

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 (RAB 1 ), the hazard 

characterization was provided by Anwar Dunbar (RAB 1 ), the residential/occupational exposure 

assessment by James Miller (RAB l ), and the drinking water assessment by Mohanuned Ruhman 

of the Environmental Fate and Effects Division (EFED). 

Page 1 of38 
Metatlumizone Human Health Risk Assessment 0421 321 

Table of Contents 

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

2.0 HED Recommendations ........................................................................................................................................ 6 

2. 1 Data Deficiencies/Data Needs ........................................................................................................................... 6 

2.2 Tolerance Considerations .................................................................................................................................. 6 

2.2. 1 Enforcement Analytical Method ............................................................................................................... 6 

2.2.2 Recommended Tolerances ........................................................................................................................ 7 

2.2.3 Revisions to Petitioned-For Tolerances ..................................................................................................... 7 

2.2.4 International Ham1onization ...................................................................................................................... 7 

2.3 Label Recommendations ........................................ ........................................................................................... 7 

3.0 Ingredient Profile ............................................... .................................................................................................... 8 

3. 1 Chemical Identify .............................................................................................................................................. 8 

3.2 Proposed Use Panern ........................................................................................................................................ 9 

3.3 Anticipated Exposure Pathways ....................................................................................................................... I 0 

3 .4 Consideration of Environmental Justice .......................................................................................................... I 0 

4.0 Hazard Characterization/Assessment .................................................................................................................... 11 

4.1 Toxicology Studies Available for Analysis ...................................................................................................... 11 

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME) ...................................................................... 11 

4.3 Toxicological Effects ....................................................................................................................................... 11 

4.4 SF for Infants and Children (FQPA SF) ........................................................................................................... 13 

4.4.1 Completeness of the Toxicology Database .............................................................................................. 14 

4.4.2 Evidence of Neurotoxicity ........................................................................................................................ 14 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ........................................... 14 

4.4.4 Residual Unce11ainty in the Exposure Database ....................................................................................... 14 

4.5 Toxicity Endpoint and Point of Departure (POD) Selections .......................................................................... 15 

5.0 Dietary Exposure and Risk Assessment.. .............................................................................................................. 19 

5.1 Metabolite/Degradate Residue Profile ............................................................................................................. 19 

5.2 Food Residue Profile ........................................................................................................................................ 19 

5.3 Drinking Water Residue Profile ....................................................................................................................... 20 

5.4 Dietary (Food + Drinking Water) Risk Assessment ........................................................................................ 20 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ........................................................................ 2 1 

6.1 Residential Bystander Post-Application Inhalation Exposure ......................................................................... 22 

6.2 Spray Drift ··· ·· ······ ·· ~· ······· ·· -. ··· ·· ··· ·· ·· ·· ··· ·· ················································ ·· ·· ·· ·· ····································· ·· ·22 - . 7 .0 Aggregate Exposure/Risk Characteriiation .......................................................................................................... 23 

7. I Acute Aggregate Risk ...................................................................................................................................... 23 

7.2 Short-Tenn Aggregate Risk ............................................................................................................................. 23 

7.3 Chronic Aggregate Risk ................................................................................................................................... 23 

7.4 Cancer Aggregate Risk .................................................................................................................................... 23 

8.0 Cumulative Exposure/Risk Characterization ........................................................................................................ 24 

9.0 Occupational Exposure/Risk Characterization ..................................................................................................... 24 

9.1 Occupational Handler Exposure/Risk Assessment .......................................................................................... 24 

9.2 Occupational Post-Application Exposure/Risk Assessment ............................................................................ 25 

Appendix A. Toxicology Profile and Executive Summaries ...................................................................................... 26 

Appendix B. Methodologies for HEC Calculations .................................................................................................... 3 1 

Appendix C: Physiochemical Properties ..................................................................................................................... 36 

Appendix D: Exposure to Metaflumizone in Fish/Shellfish at Consumption Levels Associated with Subsistence 

Fishing ............................................................................................................................................................. 37 

Page 2 of38 
Metaflumizone Human Health Risk Assessment D421321

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1.0 Executive Summary

Metaflumizone (2-[2-(4-cyanophenyl)-1-[3-(trifluoromethyl)phenyl]ethylidene]-N-[4-

(trifluoromethoxy)phenyl]hydrazinecarboxamide; E and Z isomers) is a semicarbazone insecticide 

which blocks the sodium channel and inhibits nerve impulses leading to inhibited feeding and 

paralysis in susceptible insects (Lepidoptera; Coleoptera; fire ants). The E and Z isomers are 

typically present at a >9:1 ratio (E:Z). 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 (see Table 3.1.1 for names and structures); tolerances 

without a U.S. registration are established in/on peppers, eggplant, tomato, and tomato paste at 

0.60-1.5 ppm. Metaflumizone is also registered for application around industrial, commercial, 

agricultural, and recreational facilities/structures/premises. The most recent risk assessment for 

metaflumizone was conducted on 21-November-2013 (D410219, T. Bloem et al.).

BASF is requesting application of metaflumizone to pome fruit (CG 11-10) and stone fruit (CG 12-

12) and is requesting the establishment of permanent tolerances in/on these crop groups for the 

combined residues of metaflumizone (E and Z isomers) and M320I04 at 0.04 ppm (see Table 3.1.1 

for names/structures). BASF is also requesting an update to the CG commodity definitions for citrus 

(from CG 10 to CG 10-10) and tree nut (from CG 14 to CG 14-12); permitting aerial application to 

citrus, grape, and tree nut; and permitting aerial application to nonbearing pome fruit and stone fruit. 

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 postnatal exposures to rats. There was no evidence 

that metaflumizone is genotoxic and carcinogenicity studies with mice and rabbits were negative.
Metaflumizone Human Health Risk Assessment D421321

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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.

Dose-Response Assessment: Tabled 4.6.1 (dietary non-occupational) and 4.6.2 (occupational) 

are a summary of the points of departure (PODs) selected for assessment of dietary, inhalation, 

and/or 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 combined based on the effects on the immune system organs seen at 

the lowest-observed adverse-effect level (LOAEL) in the selected studies. Short/intermediateterm oral, dermal, and inhalation exposures can be combined 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 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 proposed application scenarios. 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 

established. 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) piscivorus fish residue estimate for 

fish/shellfish. The resulting acute (1.6% aPAD; assessment only necessary for females 13-49 

years old) and chronic (≤7.2% 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 previously assessed to conform with the most recent policies 

and guidance. No risks of concern were identified for any scenario. 
Metaflumizone Human Health Risk Assessment D421321

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Aggregate-Risk Estimates: In accordance with the FQPA, HED aggregates pesticide exposures 

and risks from dietary (food and water) and residential (dermal, inhalation, and/or incidental 

oral) sources. Based on the proposed/registered uses and since inhalation, dermal, and incidental 

oral exposures can be combined, aggregate acute (dietary), short-term (dietary, incidental oral, 

and/or dermal), and chronic (dietary) assessments were conducted. All aggregate assessments 

resulted in risk estimates which are not of concern to HED. 

Occupational Exposure and Risk Assessment: Based on the proposed use patterns, types of 

equipment, and techniques that can potentially be used, short- and intermediate-term dermal and 

inhalation occupational handler exposure for the following scenarios are expected: (1) 

mixing/loading a granular formulation to support aerial applications, (2) applying granular 

formulations with aircraft, and (3) flagging to support aerial granular formulation applications. 

The calculated exposure and risks estimates for occupational handlers wearing the label 

prescribed personnel protective equipment (PPE; gloves plus baseline) and with engineering 

controls for aerial applications are not of concern (i.e., aggregate risk index (ARI) ≥ 1). 

The current proposed uses pertains to the application of a granular formulation via ground or 

aerial (fixed-wing aircraft) equipment for the control of fire ants. HED believes that, even when 

applied aerially, most granules will fall to the orchard or nursery floor and will therefore not 

present a dermal post-application exposure risk. Also, an occupational handler mixer/loader 

dermal exposure scenario was assessed and HED believes this to be protective of any postapplication dermal exposure. The non-cancer dermal risk estimate for a commercial aerial 

mixer/loader is not of concern (i.e., MOE > 100).

Environmental Justice Considerations: 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.”

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 Pesticide Handlers Exposure Database (PHED) 1.1, the 

Agricultural Handler Exposure Task Force (AHETF) database, and the Agricultural Reentry 

Task Force (ARTF) database 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 the following 

Agency websites: http://www.epa.gov/pesticides/science/handler-exposure-data.html and

http://www.epa.gov/pesticides/science/post-app-exposure-data.html. 
Metaflumizone Human Health Risk Assessment D421321

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2.0 HED Recommendations

Provided the petitioner submits revised Sections B and F, HED concludes that the toxicological and 

exposure databases are sufficient to support the establishment of permanent tolerances listed in 

Section 2.2.2. No additional data are required to support the establishment of these tolerances. 

2.1 Data Deficiencies/Data Needs

Toxicology/ORE: None

Residue Chemistry: Revised Sections B (see Section 2.3) and F (see Section 2.2.2). 

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

HED previously reviewed method validation and independent laboratory validation (ILV) studies 

for the BASF high-performance liquid chromatography (HPLC)/mass spectrometry (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 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). Based on the similarities of the proposed crops to that currently registered 

and since the grape, citrus, and tree nut residue samples 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. The limit of quantitation (LOQ) is 0.01 ppm for metaflumizone (E and Z 

isomers) and 0.018 ppm for M320I04 (expressed in parent equivalents). 

Analytical standards for metaflumizone (E and Z isomers; expiration date 1-June-2021) and 

M320I04 (expiration date 01-July-2017) are currently available at the EPA National Pesticide 

Standards Repository (communication from Theresa Cole, BEAD).
Metaflumizone Human Health Risk Assessment D421321

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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). With 

the establishment of the tolerances listed in Table 2.2.2.1, the fruit, citrus, group 10 and nut, tree, 

group 12 tolerances should be deleted.

Table 2.2.2.1: Tolerance Summary.

Commodity Proposed 

Tolerance (ppm)

HEDRecommended 

Tolerance (ppm)

Comments

Citrus (crop group 10-10) 0.04 0.04 commodity definition – fruit, citrus, group 10-10

Tree nut (crop group 14-12) 0.04 0.04 commodity definition – nut, tree, group 14-12

Pome fruit (crop group 11-10) 0.04 0.04 commodity definition – fruit, pome, group 11-10

Stone fruit (crop group 12-12) 0.04 0.04 commodity definition – fruit, stone, group 12-12

2.2.3 Revisions to Petitioned-For Tolerances

A revised Section F is requested which specifies the correct commodity definitions (see comments 

column of Table 2.2.2.1). 

2.2.4 International Harmonization

Canadian, Codex, and Mexican MRLs are not established in/on the relevant crops; therefore,

harmonization is not an issue for this petition.

2.3 Label Recommendations

A revised Section B is requested which indicates that only ground equipment may be used for 

application to bearing pome fruit and stone fruit.
Metaflumizone Human Health Risk Assessment D421321

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3.0 Ingredient Profile

3.1 Chemical Identify

The chemical structure and nomenclature of metaflumizone and its metabolites are presented in 

Tables 3.1.1. The physiochemical properties are summarized in Appendix C.

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

M320I28 (hydrolysis product of 

Metaflumizone)

N-[4-(trifluoromethoxy)phenyl]-acetamide

CN

N

N

H

N

H

O

O

F3C

CF3

CN

O

F3C

CN

N

F3C NH

N O

O

F3C

HO

H C3

N

H

O

O

CF3
Metaflumizone Human Health Risk Assessment D421321

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3.2 Proposed Use Pattern

The petitioner is proposing application of AltrevinTM Fire Ant Bait Insecticide (EPA Reg. No. 

7969-270) to pome fruit (CG 11-10) and stone fruit (CG 12-12); updating the crop group 

commodity definitions for citrus (CG 10-10) and tree nuts (CG 14-12); adding aerial application

to citrus, grape, and tree nut; and adding aerial application to nonbearing pome fruit and stone 

fruit. The proposed restricted-entry interval (REI) is 12 hours and the product labels direct 

mixers, loaders, applicators and other handlers to wear long-sleeved shirt and long pants, 

chemical resistant gloves, and shoes plus socks. Table 3.3.1 is a summary of the proposed enduse product and Table 3.3.2 is a summary of the proposed application scenarios. 

The crop group definitions for citrus, pome fruit, stone fruit, and tree nuts conform to the 

definitions specified in 40 CFR 180.41 for crop groups 10-10, 11-10, 12-12, and 14-12, 

respectively. Provided a revised Section B is submitted indicating that only ground equipment 

may be used for application to bearing pome fruit and stone fruit, the proposed use directions are 

adequate. For citrus, grape, and tree nuts, application using ground and aerial equipment is 

permitted (D421322, T. Bloem, 12-Aug-2014). 

Table 3.2.1: Summary of End-Use Products.

Trade Name Conc. Formulation Label Date Target Crops Target Pests

AltrevinTM Fire Ant Bait Insecticide 

(EPA Reg. No. 7969-270) 0.063% granular not indicated

stone fruit

imported and 

native fire ants

pome fruit

citrus

tree nut

Table 3.2.2: Summary of Proposed Directions for Metaflumizone.

Applic. Timing; 

Type; and Equip.

Formulation

[EPA Reg. No.] App. Rate Max. No. App. per Yr

Max. Yearly App. 

Rate

PHI

(days) Use Directions and Limitations

Citrus trees: Australian desert lime; Australian finger lime; Australian round lime; Brown River finger lime; Calamondin; Chironja; 

Citron; Citrus hybrids; Grapefruit; Japanese summer grapefruit; Kumquat; Lemon; Lime; Mediterranean mandarin; Mount White lime; 

New Guinea wild lime; Orange, sour; Orange, sweet; Pummelo; Russell River lime; Satsuma mandarin; Sweet lime; Tachibana orange; 

Tahiti lime; Tangelo; Tangerine (Mandarin); Tangor; Trifoliate orange; and Uniq fruit

Pome fruit trees: Apple; Azarole; Crabapple; Loquat; Mayhaw; Medlar; Pear, Pear, Asian; Quince, Quince, Chinese; Quince, 

Japanese; and Tejocote

Stone fruit trees: Apricot; Apricot, Japanese; Capulin; Cherry, black; Cherry, Nanking; Cherry, sweet; Cherry, tart; Jujube, Chinese; 

Nectarine; Peach; Plum; Plum, American; Plum, beach; Plum, Canada; Plum, cherry; Plum, Chickasaw; Plum, Damson; Plum, 

Japanese; Plum, Klamath; Plum, prune; Plumcot; and Sloe

Nut trees: African nut-tree; Almond; Beechnut; Brazil nut; Brazilian pine; Bunya; Bur oak; Butternut; Cajou nut; Candlenut; Cashew; 

Chestnut; Chinquapin; Coconut; Coquito nut; Dika nut; Ginkgo; Guiana chestnut; Hazelnut (Filbert); Heartnut; Hickory nut; Japanese 

horse-chestnut; Macadamia nut; Mongongo nut; Monkey-pot; Monkey puzzle nut; Okari nut; Pachira nut; Peach palm nut; Pecan; 

Pequi; Pili nut; Pine nut; Pistachio; Sapucaia nut; Tropical almond; Walnut, black; Walnut, English; and Yellowhorn 

Grape

Postemergence;

Broadcast; Ground

(also aerial for 

citrus, tree nuts, and 

grape)

0.063% G

[7969-270]

0.0007-0.001 

lb ai/acre 4 0.004 lb ai/acre 5

Broadcast applications are to be made 

in areas having a mound density of at 

least 1 mound per 2,000 square feet. 

Otherwise, individual mound spot 

treatments are to be made (see 

below). A minimum RTI of 4 weeks 

is proposed.

Postemergence;

Spot; Ground

0.063% G

[7969-270]

0.00004-

0.00008 

lb ai/mound

not indicated 0.004 lb ai/acre 5

Spot applications are to be made in 

areas having a mound density of less 

than 1 mound per 2,000 square feet. 

Otherwise, broadcast applications are 

to be made (see above). A minimum 

RTI of 4 weeks is proposed.
Metaflumizone Human Health Risk Assessment D421321

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3.3 Anticipated Exposure Pathways

Section 3 registrations for application of metaflumizone to citrus, tree nuts, and grape have been 

established (LOQ-level tolerances) and tolerances without a U.S. registration have been established 

in/on tomato, tomato paste, peppers, and eggplant. As a result of these uses and the proposed uses, 

dietary (food and water) exposure to metaflumizone is possible. Field trial data indicate that the 

major residue in/on the RACs is parent; however, the tomato processing study indicated that the 

major residue in/on the tomato processed commodities is M320I04. 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-Dec-2011). 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). 

3.4 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://epa.gov/compliance/ej/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 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.

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 aggregate exposure estimates were also less than HED’s LOC (see Appendix D). 
Metaflumizone Human Health Risk Assessment D421321

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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 (D410219, T. Bloem et al., 

21-Nov-2013), 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.

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. 
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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.

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 
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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

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. 
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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. 

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 Standard Operating Procedures (SOPs). 
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4.5 Toxicity Endpoint and Point of Departure (POD) Selections

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.

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, for both occupational and residential exposure, is 100 

based on a combined UF of 100 for interspecies (10x) and intraspecies (10x) extrapolation.
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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 of 0.03 mg/L 

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

(See Appendix B). The regional-deposited-dose ratio (RDDR), which accounts for the 

particulate diameter (mass median aerodynamic diameter [MMAD] and geometric standard 

deviation [g] 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 1.7m and g of 2.7. 

For this action with metaflumizone, residential and occupational handler scenarios are being 

assessed. For residential handler scenarios, 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 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. 

For occupational exposure, the HEC is 0.06323 mg/L. Three HEDs were subsequently 

calculated based upon the ventilation rates of 8.3, 16.7 and 29 L/min (3.6, 7.24 and 12.57

mg/kg/day for respectively). The safety factors, LOC is 300 similar to that for the residential 

inhalation exposure scenarios. For details regarding the calculation of the HECs and HEDs, see 

Appendix B. These HEDs are protective of the systemic effects observed through the inhalation 

route. This study is thus appropriate for the route and duration of exposure, and is protective of 

adults in occupational and residential settings.
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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 combined based on the immunotoxic effects seen at the LOAEL in 

the selected studies. Short/intermediate-term oral, dermal, and inhalation exposures can be 

combined 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. Tables 4.6.1 is a summary of the toxicological doses and endpoints selected for 

dietary and non-occupational risk assessment and Table 4.6.2 is a summary of the toxicological 

doses and endpoints selected for occupational risk assessment.

Table 4.6.1: Summary of Toxicological Doses and Endpoints for Metaflumizone for Use in Dietary and NonOccupational Human Health Risk Assessments .

1

Exposure Scenario Dose Used in Risk 

Assessment, UF

FQPA SF or LOC for Risk 

Assessment Study and Toxicological Effects

Acute 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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Table 4.6.2. Summary of Toxicological Doses and Endpoints for Metaflumizone for Use in Occupational Human 

Health Risk Assessments .

1

Exposure Scenario Dose Used in Risk Assessment, 

UF

FQPA SF or LOC for 

Risk Assessment Study and Toxicological Effects

Short- (1-30 days) and 

Intermediate-(1-6 

months) Term Dermal

NOAEL = 100 mg/kg/day LOC (occupational) = 

MOE < 100

90-day dermal (rat); LOAEL = 300 mg/kg/day 

based on decreased BW gain and food 

consumption (M&F); anogenital smearing, 

decreased BW, increased macrophages in the 

thymus, lymphocyte necrosis in the mesenteric 

lymph nodes, diffuse atrophy of the mandibular 

lymph node, and increased hemosiderin in the 

liver (F).

Short- (1-30 days) and 

Intermediate-

(1-6 months) Term 

Inhalation

LOAEL = 0.030 mg/L

NOAEL not observed

LOC (occupational) = 

MOE < 300

(includes 10x FQPA SF 

in form of UFL)

28-day inhalation (rat); LOAEL = 0.03 mg/L*

based lymphocyte necrosis in the mesenteric 

lymph node (F).

HEC = 0.06323 mg/L2

HEC (8.3 L/min) = POD of 3.6

HEC (16.7 L/min) = POD of 

7.24

HEC (29 L/min) = POD of 

12.57

Cancer (oral, dermal, 

inhalation) Classification: Not likely to be carcinogenic to humans.

1 UF = uncertainty factor, FQPA SF = FQPA Safety Factor, NOAEL = no-observed adverse-effect level, LOAEL = lowest-observed adverseeffect level, MOE = margin of exposure, LOC = level of concern, UFL = uncertainty factor for lack of a NOAEL

2 Human equivalent doses (HEDs) corresponding to the ventilation rates of 8.3, 16.7, and 29 L/min were calculated as 3.6, 7.24, and 12.57 

mg/kg/day, respectively, for occupational activities. Human Equivalent Concentration (HEC).The human concentration (for inhalation 

exposure) or dose (for other routes of exposure) of an agent that is believed to induce the same magnitude of toxic effect as the experimental 

animal species concentration or dose.
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5.0 Dietary Exposure and Risk Assessment

D421322, T. Bloem, 12-Aug-2014 (aerial application to citrus, grape, and tree nuts)

D425292, T. Bloem, 29-Sep-2015 (pome fruit and stone fruit)

D425293, T. Bloem, 29-Sep-2015 (dietary exposure analysis)

5.1 Metabolite/Degradate Residue Profile

HED has previously reviewed cabbage, cotton, tomato, ruminant, and poultry metabolism studies as 

well as a confined rotational crop study. Based on these data, HED concluded that the residues of 

concern are as defined in Table 4.0.1. The available data are adequate to support the proposed uses. 

HED notes that future petitions, depending on the proposed use pattern, may require additional 

metabolism data. 

Table 4.0.1: 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

1 D304496, R. Mitkus et al., 24-Jan-2006; D421320, T. Bloem, 6-Aug-2014

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

Pome Fruit and Stone Fruit: The petitioner is proposing application of AltrevinTM to pome fruit 

and stone fruit. No new residue data were submitted in conjunction with this request. Instead, 

the petitioner is proposing translation of the previously submitted/reviewed citrus 

(47235703.de1; 47235703.de2), grape (47235702.der), and tree nut (47235701.der) 

metaflumizone residue data to pome fruit and stone fruit. 

The HED Chemistry Science Advisory Council (ChemSAC) was consulted concerning the 

proposed residue translation. The ChemSAC concluded that provided the proposed pome fruit 

and stone fruit application scenarios were identical to that employed in the citrus, grape, and tree 

nut magnitude of the residue studies and based on the available field trial, processing, and 

rotational crop data, the proposed residue translation was acceptable (ChemSAC minutes 23-Oct2013). Since the proposed application scenarios are identical to that preformed in the referenced 

field trials and based on these data, HED is recommending for the establishment of a 0.04-ppm 

tolerance in/on pome fruit and stone fruit (tolerances in/on the processed commodities are

unnecessary). In addition, since the representative crops for the updated citrus and tree nut crop 

groups are identical to that for the old crop groups, HED concludes that the proposal to update 

the crop group commodity definitions is also acceptable. No additional data are required. 

Aerial Application to Citrus, Grape, and Tree Nuts: The petitioner is proposing a label amendment 

permitting aerial application of AltrevinTM to citrus, tree nut, and grape. The proposed application 

scenario is identical to the currently-registered with the exception that the label will permit aerial 

application. The ChemSAC was consulted concering the need for additional data and concluded that 

the currently available data and toelrances were adequate (ChemSAC minutes 29-Jan-2014). The 

ChemSAC did note that for crops where granules may get lodged in the edible portion of the plant 

(e.g., around an apple stem), this type of translation may not be appropriate. 
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5.3 Drinking Water Residue Profile

Table 5.3.1 is a summary of metaflumizone surface water and groundwater estimated drinking water 

concentrations (EDWCs) provided by EFED (D421741, M. Ruhman, 30-Mar-2015). The EDWCs were 

generated using the following models: Surface Water Concentration Calculator (SWCC) and the 

Pesticide Root Zone Model – Groundwater (PRZM-GW). The modeled application scenario yields the 

highest EDWCs and these estimates were incorporated into the current assessment. The water models 

and their description are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/. 

Table 5.3.1: Maximum Tier I Flutriafol EDWCs.1

Model Yearly Application Rate Concentration (ppb)

Groundwater (PRZM-GW) fly bait (26 x 0.0137 lb ai/acre) acute and chronic 1.09 x 10-12

Surface water (SWCC) fly bait (26 x 0.0137 lb ai/acre) acute 1.03

chronic 0.487

1

 Bolded estimates were incorporated into the current analyses. 

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 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 because a separate tolerance for this commodity is established. For the 

remaining relevant commodities, the DEEM (ver. 7.81) default processing factors were retained. 

Based on an assessment by the Environmental Fate and Effects Division (EFED) which concluded 

that metaflumizone has a high potential to bioaccumulate in aquatic food webs, the current analysis 

included the KABAM (ver. 1.0) piscivorus fish estimate for fish/shellfish. 

An acute endpoint of concern was not identified in the toxicological database for the general U.S. 

population including infants and children; however an acute toxicological endpoint was identified 

for females 13-49 years of age. The resulting acute (1.6% aPAD) and chronic (≤7.2% 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

0.001527 3.8

All Infants 0.000840 2.1

Children 1-2 years old 0.002864 7.2

Children 3-5 years old 0.002433 6.1

Children 6-12 years old 0.001663 4.2

Youth 13-19 years old 0.001095 2.7

Adults 20-49 years old 0.001466 3.7

Adults 50-99 years old 0.001498 3.7

Females 13-49 years old 0.33 0.005288 1.6 0.001264 3.2

1

 95th percentile (tier 1 analysis)
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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). 

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

 See D414616 (K. Lowe, 21-Nov-2013) for determination of the dose. Application rates = 0.001 lb ai/acre, 2.3 x 10-8lb 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 (LOC for MOEs < 100) and inhalation POD = 2.4

mg/kg/day (LOC for MOEs < 300).

3 ARI = 1 ÷ ((Dermal LOC ÷ Dermal MOE) + (Inhalation LOC ÷ Inhalation MOE)), where dermal LOC = 100 and inhalation LOC = 300. LOC 

for ARIs < 1.

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 (LOC for MOEs < 100) and incidental oral POD = 20

mg/kg/day (LOC for MOEs < 300).

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. LOC for ARIs < 1.
Metaflumizone Human Health Risk Assessment D421321

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Table 6.0.3: Recommendations for the Residential Exposures for Aggregate Assessment.1,2

Lifestage

(Scenario)

Dose (mg/kg/day) MOE

Dermal Inhalation Oral Dermal

(LOC < 100)

Inhalation

(LOC < 300)

Oral

(LOC < 300) Total3

Residential Handler

Adult Male

(Belly Grinder) 1.2E-04 1.3E-08 N/A 810,000 590,000,000 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 MOE = 

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 Listed are the highest are the highest handler and post-application dose/MOEs for each applicable lifestage of all residential scenarios assessed. 

3 ARI = 1÷ ((Dermal LOC ÷ Dermal MOE) + (Incidental oral LOC ÷ Incidental oral MOE)). LOC for ARI < 1.

6.1 Residential Bystander Post-Application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to individuals 

nearby pesticide applications. The agency sought expert advice and input on issues related to 

volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 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 has evaluated 

the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization 

Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). 

During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux 

studies, route-specific inhalation toxicological studies) or further analysis is required for

metaflumizone.

6.2 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential 

source of exposure from the ground application methods (e.g., groundboom and airblast) employed 

for metaflumizone. The agency has been working with the Spray Drift Task Force (a task force 

composed of various registrants which was developed as a result of a Data Call-In issued by EPA), 

EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop 

the best spray drift management practices (see the agency’s Spray Drift website for more 

information; http://www.epa.gov/opp00001/factsheets/spraydrift.htm). The agency has also 

developed a policy on how to appropriately consider spray drift as a potential source of exposure in 

risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for 

each pesticide during the Registration Review process which ensures that all uses for that pesticide 

will be considered concurrently. The approach is outlined in the revised (2012) Standard 

Operating Procedures For Residential Risk Assessment (SOPs) - Residential Exposure Assessment 

Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines 

the quantification of indirect non-occupational exposure to drift. 
Metaflumizone Human Health Risk Assessment D421321

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7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED aggregates pesticide exposures and risks from dietary (food 

and water) and residential (dermal, inhalation, and/or incidental oral) sources. Based on the 

proposed/registered uses and since inhalation, dermal, and incidental oral exposures can be 

combined, aggregate acute (dietary), short-term (dietary, incidental oral, and/or dermal), and 

chronic (dietary) 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

As indicated above, short-term dermal, incidental oral, and/or inhalation residential exposures are 

anticipated and exposure via these routes can be combined based on a common toxic effect (see 

Section 4.6). Since the LOC for the various routes of exposure differ, the aggregate risk estimates 

were calculated using the ARI approach (LOC for ARI < 1). 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. The aggregate ARIs are >1 and are, therefore, not of concern to HED (the 

populations assessed provide the worst-case short-term exposure estimates). It is noted that 

although only short-term residential exposure is anticipated, the short-term assessment is protective 

on intermediate-term exposure as the short and intermediate-term PODs/LOCs are identical. 

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

Adults 50-99 years old

300

0.001498 NA 13,000

100

0.0012 86,000 42

Children 1-2 years old 0.002864 0.000021 7,000 0.0023 44,000 22

1

 See Table 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 ÷ ((Oral LOC ÷ Oral MOE) + (Dermal LOC ÷ Dermal MOE)); 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 ≤7.2% 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. 
Metaflumizone Human Health Risk Assessment D421321

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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

D421322, J. Miller, 20-Nov-2014

9.1 Occupational Handler Exposure/Risk Assessment

Based on the proposed use patterns, types of equipment, and techniques that can potentially be 

used, short- and intermediate-term dermal and inhalation occupational handler exposure for the 

following scenarios are expected: (1) mixing/loading a granular formulation to support aerial 

applications, (2) applying granular formulations with aircraft, and (3) flagging to support aerial 

granular formulation applications.

The metaflumizone product label directs mixers, loaders, applicators and other handlers to wear 

chemical-resistant gloves and baseline PPE (long-sleeved shirt, long pants, shoes plus socks, and 

no respirator). A summary of the risk estimates representative of label-prescribed PPE for 

mixers and loaders and with engineering controls for aerial applicator are provided in Table 

9.1.1. The resulting exposure and risk estimates indicate that there is no risks of concern from

the proposed uses. 

Table 9.1.1: Occupational Handler Non-Cancer Exposure and Risk Estimates for Metaflumizone.

Exposure 

Scenario Crop or Target

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation 

Unit 

Exposure 

(μg/lb ai)1

Max. 

App.

Rate2

(lbs 

ai/acre)

Area Treated 

or Amount 

Handled 

Daily3

(acres)

Dermal

(LOC = 100)

Inhalation

(LOC = 300) Total

Dose 

(mg/kg/day)4,9 MOE5,9 Dose6,9(mg/kg/day) MOE7,9 ARI8,9

Mixer/Loader (Aerial-Fixed Winged)

Orchards Citrus, Tree Nuts, 

Stone/Pome fruit 

and Grapes

6.9

(BL/gloves)2

1.7

(No Resp.) 0.001

350 0.000031 3,200,000 0.0000077 1,600,000 4,600

Nurseries 60 0.0000053 19,000,000 0.0000013 9,600,000 27,000

Applicator (Aerial-Fixed Winged)

Orchards Citrus, Tree Nuts, 

Stone/Pome fruit 

and Grapes

1.7

(Eng control)

1.3

(Eng. 

control)

0.001

350 0.0000077 13,000,000 0.0000059 2,100,000 6,600

Nurseries 60 0.0000013 76,000,000 0.0000010 130,000 41,000
Metaflumizone Human Health Risk Assessment D421321

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Table 9.1.1: Occupational Handler Non-Cancer Exposure and Risk Estimates for Metaflumizone.

Exposure 

Scenario Crop or Target

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation 

Unit 

Exposure 

(μg/lb ai)1

Max. 

App.

Rate2

(lbs 

ai/acre)

Area Treated 

or Amount 

Handled 

Daily3

(acres)

Dermal

(LOC = 100)

Inhalation

(LOC = 300) Total

Dose 

(mg/kg/day)4,9 MOE5,9 Dose6,9(mg/kg/day) MOE7,9 ARI8,9

Flagger (Aerial-Fixed Winged)

Orchards Citrus, Tree Nuts, 

Stone/Pome fruit 

and Grapes

2.73

(BL/gloves)2

0.15

(No Resp.) 0.001

350 0.000012 8,100,000 0.00000068 19,000,000 36,000

Nurseries 60 0.0000021 47,000,000 0.00000012 110,000,000 21,0000

1

 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”; Level of mitigation: Baseline, PPE, Eng. Controls.

2 PPE and Maximum application rates are based on proposed label (Reg. No. 7969-270).

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or 

Amount Handled (A or gal/day) ÷ BW (80 kg).

5 Dermal MOE = Dermal POD (mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6

Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area 

Treated or Amount Handled (A or gal/day) ÷ BW (80 kg).

7

Inhalation MOE = Inhalation POD (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

8 ARI = Aggregate Risk Index = 1÷ [(Dermal LOC ÷ Dermal MOE) + (Inhalation LOC ÷ Inhalation MOE)]; LOC for ARIs < 1. 

9 Dermal and inhalation dose, MOE and ARI calculations for aerial application in orchards and nurseries are based on engineering control PPE.

9.2 Occupational Post-Application Exposure/Risk Assessment

The current proposes pertains to the application of a granular formulation via ground or aerial 

(fixed-wing aircraft) equipment for the control of fire ants. HED believes that, even when 

applied aerially, most granules will fall to the orchard or nursery floor and will therefore not 

present a dermal post-application exposure risk. Also, an occupational handler mixer/loader 

dermal exposure scenario was assessed and HED believes this to be protective of any postapplication dermal exposure. The non-cancer dermal risk estimate for commercial aerial 

mixer/loader application is not of concern (i.e., MOE > 100).

Restricted Entry Interval: The REI specified on the proposed label (12 hours) is based on the 

acute toxicity of metaflumizone. Metaflumizone is classified as Toxicity Category IV via the 

dermal route and Toxicity Category IV for skin irritation potential. It is not a skin sensitizer. 

Short- and intermediate-term post-application risk estimates were not a concern on day 0 (12 

hours following application) for all post-application activities. Under 40 CFR 156.208 (c) (2) 

(iii), ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irritation

are assigned a 12-hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim 

REI of 12 hours is adequate to protect agricultural workers from post-application exposures to 

metaflumizone. 

RDI: RAB1 (7-Apr-2015)

Appendix A. Toxicology Profile and Executive Summaries.

Appendix B. Methodologies for HEC Calculations.

Appendix C: Physiochemical Properties

Appendix D: Exposure to Metaflumizone in Fish/Shellfish at Consumption Levels Associated with 

Subsistence Fishing.
Metaflumizone Human Health Risk Assessment D421321

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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 D421321

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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 D421321

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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/Carcinogenicity 

rats (gavage)

46264240 (2003)

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

(high dose reduced to 200 

mg/kg/day in females after 2 weeks 

of treatment)

Acceptable (guideline)

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

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

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

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

No evidence of carcinogenicity.

870.5100

In Vitro bacterial reverse 

mutation (S. 

typhimurium/E. coli)

46264304 (2001)

15, 50, 150, 500, or 5000 g/plate 

(std. plate test) (-/+ activation)

Acceptable (guideline)

Negative.

870.5300

In Vitro mammalian 

gene mutation 

(CHO/HGPRT)

46264307 (2002)

0, 25.0, 50.0, 100.0, 156.3, 200.0, 

312.5, 400.0, 625.0, 800.0, 1250.0, 

2500.0 or 5000.0 μ g/mL (-

activation)

0, 50.0, 100.0, 156.3, 200.0, 312.5, 

400.0, 625.0, 800.0, 1200.0, 1250.0, 

2500.0 or 5000.0 μg/mL (+ 

activation)

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 D421321

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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.
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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

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.
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Appendix B. Methodologies for HEC Calculations.

The RfC methodology applies a dosimetric adjustment that takes into consideration not only the 

differences in ventilation rate (MV) but also the physicochemical properties of the inhaled 

compound, the type of toxicity observed (e.g., systemic vs. portal-of-entry) and the 

pharmacokinetic (PK) but not pharmacodynamic (PD) differences between animals and 

humans. Based on the EPA’s RfC guidance (1994), the methodology for RfCs derivation is an 

estimate of the quantitative dose-response assessment of chronic non-cancer toxicity for 

individual inhaled chemicals and includes dosimetric adjustment to account for the speciesspecific relationships of exposure concentration to deposited/delivered dose. This adjustment is 

influenced by the physicochemical properties of the inhaled compound as well as the type of 

toxicity observed (e.g., systemic vs. portal-of-entry), and takes into consideration the PK 

differences between animals and humans. Though the RfC methodology was developed to 

estimate toxicity of inhaled chemicals over a lifetime, it can be used for other inhalation 

exposures (e.g., acute and short-term exposures) since the dosimetric adjustment incorporates 

mechanistic determinants of disposition that can be applied to shorter duration of exposures 

provided the assumptions underlying the methodology are still valid. These assumptions, in turn, 

vary depending on the type of toxicity observed. Thus the derivation of a HEC for inhaled gases 

is described by the following equation:

Where:

PODstudy: Point of departure identified in the critical toxicology study

Danimal exposure: Duration of animal exposure (hrs/day; days/wk)

Danticipated exposure: Anticipated human duration of exposure (hrs/day; days/wk)

RGDR: Regional Gas Dose Ratio

Calculations used to estimate the inhalation risk to humans from aerosols are dependent not on 

the RGDR as for gases, but on the regional deposited dose ratio (RDDR). Inhalation studies 

using aerosols characterize particulate exposure by defining the particulate diameter (mass 

median aerodynamic diameter [MMAD]) and the geometric standard deviation (σg), which is 

then used to determine the RDDR. The RDDR is a multiplicative factor used to adjust an 

observed inhalation particulate exposure concentration of an animal (A) to the predicted 

inhalation particulate exposure concentration for a human (H) that would be associated with the 

same dose delivered to the rth region or target tissue.

RDDRr = (RDDr/Normalizing Factor)A

 (RDDr/Normalizing Factor)H 

As with calculations for gases, the r regions and potential target tissues are the three respiratory 

regions (ET, TB, PU). The RDDR is easily calculated by using a software program designed 

specifically for computing the RDDR from the MMAD and σg defined from an aerosol 

inhalation study. The values for the species-specific parameters used to calculate the RDDR are 

provided in the EPA document “Methods for Derivation of Inhalation Reference Concentrations 

and Application of Inhalation Dosimetry.”

HEC = POD * D 

D 

* W

W

study * RGDR animal exposure (hrs/ day)

human exposure (hrs/ day)

animal exposure (days / wk)

human exposure (days/ wk)
Metaflumizone Human Health Risk Assessment D421321

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Regional Deposited Dose Ratio (RDDR) for Metaflumizone

MMAD = 1.7

Sigma g = 2.7

 Body Minute 

SPECIES Weight (g) Ventilation (VE, ml) 

-----------------------------------------------------------------------------

 rat 156 122.1 

 human 70000 13800.0 

-----------------------------------------------------------------------------

 Extrarespiratory

SA (m^2) deposited fraction 

--------------------------------------------------------------------------------

 rat 156 0.453 

 human 7000 0.626 

--------------------------------------------------------------------------------

RATIO 0.002 0.723

RDDR = (VE/BW)animal/(VE/BW)human * deposited fractionanimal/deposited fractionhuman

= (122.1/156)animal/(13800/70000)human * 0.439/0.626

= 2.77

The magnitude of the UFs applied is dependent on the methodology used to calculate risk. The 

RfC methodology takes into consideration the PK differences but not the PD differences. 

Consequently, the UF for interspecies extrapolation may be reduced to 3X (to account for the PD 

differences) while the UF for intraspecies variation is retained at 10X. Thus, the UF when using 

the RfC methodology is customarily 30X.

B.1. HEC Calculations for Short- and Intermediate-term Residential Exposure:

Assume residents will be exposed for 24 hrs/day and 7 days/week:

HEC = NOAELstudy * (daily duration of exposureanimal/daily duration of exposurehuman) * 

(days/week of exposureanimal/days/week of exposurehuman) * RDDR

Residential Handler Outdoor HEC = 0.03 mg/L * 2.8 = 0.084 mg/L
Metaflumizone Human Health Risk Assessment D421321

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Table B.1. HEC Array for Residential Risk Assessment.

Relevant Study LOAEL

(mg/L)

NOAEL

(mg/L) Da Dh Wa Wh RDDR HEC (mg/L) inter intra UF

Short-& Intermediate-Term Exposure

Inhalation – Rat

(MRID 447839301) 

28-day

ER 0.03 -

See equations listed 

above table 2.8

Handler/Out

door 

Postapp.-

0.084 mg/L

3 10 10

Long-Term Exposure: Not appropriate for metaflumizone.

Key for Array Tables

LOAEL: Lowest-observed adverse-effect level

NOAEL: No-observed adverse-effect level

Da: Daily animal exposure (hrs/day)

Dh: Anticipated daily human exposure (hrs/day)

Wa: Weekly animal exposure (days/week)

Wh: Anticipated weekly human exposure (days/week)

RRDR: Regional Deposited Dose Ratio

HEC: Human-Equivalent Concentration

inter: Interspecies extrapolation UF

intra: Intraspecies variation UF

UF: Other UF(s)

ET: Extra-thoracic region

Route-to-Route Extrapolation

More information and details in: Memo, “Route-to-Route Extrapolations” J. Whalen and H. 

Pettigrew, 10/10/98.

HED’s route-to-route extrapolation converts human and animal values from mg/L concentrations 

to mg/kg oral equivalent doses. The equation uses a single conversion factor to account for 

default body weights and respiratory volumes. An activity factor is used to account for increased 

exposure resulting from increased respiration. 

Using the HEC calculated (based upon terminal airway inflammation in males), a conversion of 

the inhalation concentration to a dose (mg/L to mg/kg/day) was conducted as follows:

HED (mg/kg/day) = Dose (systemic HEC value, mg/L) x A x CF (L/hr/kg) x D (hours) x AF = 

mg/kg

Where: 

A = absorption: ratio of deposition and absorption in respiratory tract compared to 

absorption by the oral route.

CF = conversion factor; a L/hr/kg factor which accounts for respiratory volume and 

body weight for a given species and strain (Table 1 of J. Whalen and H. 

Pettigrew, 10/10/98).

D = duration; duration of daily animal or human exposure (hours).

AF = activity factor; animal default is 1. For humans with a ventilation rate of 16.7 

L/min, the value is 1.2.

Therefore, the residential HED for metaflumizone is calculated as follows:

Residential Handler and Outdoor Post-application HED: (0.08 mg/L) x 1.2 x 11.8 L/hr/kg x 
Metaflumizone Human Health Risk Assessment D421321

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2 hr x 1 = 2.413 mg/kg/day 

B.2. HEC Calculations for Short- and Intermediate-term Occupational Exposure:

Assume workers will be in the field for 8 hrs/day and 5 days/week:

HEC = NOAELstudy * (daily duration of exposureanimal/daily duration of exposurehuman) * 

(days/week of exposureanimal/days/week of exposurehuman) * RDDR

HEC = 0.03 mg/L * (6/8) * (5/5) * 2.8 = 0.6323 mg/L.

Table C.1. HEC Array for Occupational Risk Assessment.

Relevant Study LOAEL

(mg/L)

NOAEL

(mg/L) Da Dh Wa Wh RDDR HEC (mg/L) inter intra UF

Short-& Intermediate-Term Exposure

Inhalation – Rat

(MRID 47839301) 

28-day

ET 0.03 - 6 8 5 5 2.8 0.06 3 10 10

Long-Term Exposure: Not appropriate for metaflumizone.

Key for Array Tables

LOAEL: Lowest-observed adverse-effect level

NOAEL: No-observed adverse-effect level

Da: Daily animal exposure (hrs/day)

Dh: Anticipated daily human exposure (hrs/day)

Wa: Weekly animal exposure (days/week)

Wh: Anticipated weekly human exposure (days/week)

RRDR: Regional Deposited Dose Ratio

HEC: Human-Equivalent Concentration

inter: Interspecies extrapolation UF

intra: Intraspecies variation UF

UF: Other UF(s)

ET: Extra-thoracic region

Route-to-Route Extrapolation

More information and details in: Memo, “Route-to-Route Extrapolations” J. Whalen and H. 

Pettigrew, 10/10/98.

HED’s route-to-route extrapolation converts human and animal values from mg/L concentrations 

to mg/kg oral-equivalent doses. The equation uses a single conversion factor to account for 

default body weights and respiratory volumes. An activity factor is used to account for increased 

exposure resulting from increased respiration. 

Using the HEC calculated (based upon terminal airway inflammation in males), a conversion of 

the inhalation concentration to a dose (mg/L to mg/kg/day) was conducted as follows: 

HED (mg/kg/day) = Dose (systemic HEC value, mg/L) x A x CF (L/hr/kg) x D (hours) x AF = 

mg/kg

Where: 

A = absorption; ratio of deposition and absorption in respiratory tract compared to 

absorption by the oral route.
Metaflumizone Human Health Risk Assessment D421321

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CF = conversion factor; a L/hr/kg factor which accounts for respiratory volume and 

body weight for a given species and strain (Table 1 of J. Whalen and H. 

Pettigrew, 10/10/98).

D = duration; duration of daily animal or human exposure (hours).

AF = activity factor; animal default is 1. For humans, the value varies with ventilation 

rates determined by occupational/restidential scientists; 0.6 (8.3L/min), 1.2 (16.7 

L/min) and 2.1 (29 L/min)

Therefore, the occupational HED for metaflumizone is calculated as follows:

Occupational HED, Ventilation Rate, 8.3 L/min: (0.06323 mg/L) x 1 x 0.6 x 11.8 L/hr/kg x 8 

hr = 3.6 mg/kg/day 

Occupational HED, Ventilation Rate, 16.7 L/min: 0.0632 mg/L) x 1 x 1.2 x 11.8L/hr/kg x 8 

hr = 7.2 mg/kg/day

Occupational HED, Ventilation Rate, 29 L/min: (0.06323 mg/L) x 1 x 2.1 x 11.8 L/hr/kg x 8 

hr = 12.57 mg/kg/day

Based on the current metaflumizone label, HED believes exposures can be short- (1-30 days) or 

intermediate- (1 to 6 months) term in duration. Long-term exposures are not anticipated for 

metaflumizone based on proposed labeled uses. For the short- and intermediate-term scenarios, 

inhalation data from the 28-day inhalation rodent study was most appropriate for determining 

HECs. In the RfC methodology, different HECs may be calculated for the same experimental 

NOAEL due to the following:

1. Different algorithms are used to derive HECs for systemic versus portal-of-entry effects. 

Typically, HECs are calculated separately for systemic versus portal-of-entry effect. For 

metaflumizone, portal-of-entry irritation was observed and, therefore, only portal-of-entry 

HECs were derived. 

2. Time adjustments are traditionally needed for non-occupational (bystander) versus 

occupational exposure scenarios. Traditionally, HECs for non-occupational exposure are 

based on the number of hours an individual may be at home. Therefore, the most 

conservative estimate of hours spent at home would be 24 hours/day and 7 days/week. In 

comparison, the average workweek for an occupational worker is 8 hours/day and 5 

days/week. The HEC array table reflects the time adjustment in the calculations.
Metaflumizone Human Health Risk Assessment D421321

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Appendix C: Physiochemical 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 B.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
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Appendix D: 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) piscivorus 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) from the State of Washington Department of 

Ecology (https://fortress.wa.gov/ecy/publications/publications/1209058.pdf). 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) piscivorus fish 

residue estimate, exposure estimates were calculated and added to the DEEM-FCID estimates

(see Table C.1). The resulting aggregate exposure estimates are less than HED’s LOC (see 

Table C.2). 

HED notes that the exposure estimates presented in Table C.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 (highest registered/proposed rate assumed); this 

scenario is not typical for subsistence fishing; (2) the analysis assumes that all consumed 

fish/shellfish have the KABAM piscivorus fish metaflumizone residue estimate; and (3) the 

DEEM-FCIDTM 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 affect 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 used in the lindane analysis were not applicable to the 

current assessment. 
Metaflumizone Human Health Risk Assessment D421321

Page 38 of 38

Table C.1: Summary of Subsistence Dietary Inputs and Risks.

Population Fish/Shellfish Residue 

Estimate1(ppm)

Body 

Weight (kg)

Subsistence

DEEM-FCIDTM Exposure4combined %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

0.002864

acute 

assessment is 

unnecessary

29

Children 3-5 years old 20 25 0.004375 0.002433 17

Children 6-12 years old 30 113 0.013183 0.001663 37

Adults 70 214 0.010700 0.001498 30

Adult Females 60 797 214 0.046492 0.012483 0.005288 0.001264 16 34

1 As part of EFED’s ecological risk assessment associated with the registered fly bait application scenario, a residue estimate for piscivorus 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; https://fortress.wa.gov/ecy/publications/publications/1209058.pdf) 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-FCIDTM exposure) ÷ PAD (aPAD = 0.33 mg/kg/day; cPAD = 0.04 mg/kg/day).

Table C.2: Short- and Intermediate-Term Aggregate Risk

Population

Background Dietary + Incidental Oral Exposures Residential Exposures

ARI4

Oral LOC 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

Adults 50-99 years old

300

0.058975 NA 1,500

100

0.0012 86,000 4.8

Children 6-12 years old 0.014846 0.000021 1,300 0.0023 44,000 4.4

1

 See Table C.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 ÷ ((Oral LOC ÷ Oral MOE) + (Dermal LOC ÷ Dermal MOE)); ARI > 1 indicates an acceptable exposure.