Metaflumizone Human-Health Risk Assessment D393447

Page 1 of 39

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND

 POLLUTION PREVENTION

Date: December 21, 2011

Subject: Metaflumizone. Revised Human-Health Risk Assessment Associated with a Section 

3 Registration for a Fire Ant Bait for Application to Citrus, Tree Nuts, and Grape, and 

a new Section 3 Registration for a Fly Bait for Application around Industrial, 

Commercial, Agricultural and Recreational Facilities/Structures and Premises. 

PC Codes: 281250 (E Isomer); 281251 (Z isomer) DP Barcode: D393447

Decision No.: 384157 Registration No.: 7969-226

Petition No.: 7F7260 Regulatory Action: Section 3

Risk Assessment Type: single chemical aggregate Case No.: 7446

TXR No.: not available CAS No.: 139968-49-3

MRID No: none 40 CFR: 180.###

From: Kelly M. Lowe, Environmental Scientist

Tom Bloem, Chemist 

Chester E. Rodriguez, Ph.D., Toxicologist

Risk Assessment Branch 1 (RAB1)

Health Effects Division (HED, 7509P)

Through: Dana M. Vogel, Branch Chief

George F. Kramer, Ph.D., Senior Chemist

RAB1/HED (7509P)

To: Kable Davis (RM 07)

Registration Division (RD, 7505P)

Note: This document supersedes D345134 (T. Bloem et al., 26-Jan-10). An immunotoxicity 

study has been received and reviewed by the Agency and updates have been made to the Food 

Quality Protection Act (FQPA) Safety Factor (SF). In addition, an assessment for a new 

Section 3 Registration for a fly bait product has been included in this document.

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and 

exposure data and conduct dietary, occupational, residential, and aggregate exposure

assessments, as needed, to estimate the risk to human health that will result from all registered/ 

proposed metaflumizone uses. The hazard characterization was provided by Chester Rodriguez

(RAB1); the residue chemistry review and dietary exposure assessment were provided by Tom 

Bloem (RAB1); the occupational/residential exposure assessment and risk assessment was 

provided by Kelly Lowe (RAB1); and the drinking water assessment was provided by

Mohammed Ruhman of the Environmental Fate and Effects Division (EFED).
Metaflumizone Human-Health Risk Assessment D393447

Page 2 of 39

Table of Contents

2.1 Summary of Registered/Proposed Uses.....................................................................................8

2.2 Structure and Nomenclature ....................................................................................................10

3.1 Absorption, Distribution, Metabolism, Excretion (ADME) ....................................................11

3.2 Mammalian Toxicology...........................................................................................................11

3.3 Toxicity Endpoint Selection ....................................................................................................13

3.4 FQPA Safety Factor Considerations........................................................................................17

3.4.1 Completeness of the Toxicology Database..............................................................17

3.4.2 Evidence of Neurotoxicity .......................................................................................17

3.4.3 Evidence of Sensitivity/Susceptibility in Developing Animals...............................17

3.4.4 Residual Uncertainty in the Exposure Database......................................................18

4.1 Metabolism (Crops, Livestock, and Rotational Crops) and Environmental Degradation........18

4.2 Analytical Methodology ..........................................................................................................19

4.3 Comparative Metabolic Profile................................................................................................19

4.4 Drinking Water Residue Profile...............................................................................................20

4.5 Food Residue Profile................................................................................................................21

4.6 International Residue Limits and HED-Recommended Tolerances........................................22

4.7 Dietary Exposure and Risk ......................................................................................................22

5.1 Residential Handler Exposure..................................................................................................23

5.2 Residential Post-application Exposure.....................................................................................24

5.3 Combined Residential Exposure..............................................................................................24

6.1 Acute Aggregate Risk..............................................................................................................26

6.2 Short-/Intermediate- Term Aggregate Risk .............................................................................26

6.3 Chronic Aggregate Risk...........................................................................................................27

6.4 Cancer Aggregate Risk ............................................................................................................27

8.1 Occupational Handler Exposure ..............................................................................................27

8.2 Occupational Post-application Exposure .................................................................................31

8.3 Restricted Entry Interval..........................................................................................................31

9.1 Toxicology ...............................................................................................................................31

9.2 Residue Chemistry...................................................................................................................31

9.3 Occupational and Residential Exposure ..................................................................................32

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

2.0 Ingredient Profile ....................................................................................................................................8

3.0 Hazard Characterization/Assessment....................................................................................................10

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

5.0 Residential Exposure/Risk Characterization.........................................................................................23

6.0 Aggregate Risk Assessments and Risk Characterization......................................................................25

7.0 Cumulative Risk Characterization/Assessment ....................................................................................27

8.0 Occupational Exposure/Risk Characterization .....................................................................................27

9.0 Data Deficiencies..................................................................................................................................31

Appendix A. Toxicity Profile Tables.........................................................................................................33

Appendix B. Chemical Names and Structures...........................................................................................38
Metaflumizone Human-Health Risk Assessment D393447

Page 3 of 39

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 that blocks the sodium channels of the nervous system in susceptible insects leading 

to inhibited feeding and paralysis (Lepidoptera and Coleoptera). The E and Z isomers are 

typically present at an E:Z ratio of >9:1. HED previously reviewed a petition concerning the 

application of metaflumizone as a pet care product and fire ant bait for use on lawns, landscapes, 

golf courses, and other non-cropland (D304496, R. Mitkus et al., 24-Jan-2006). It should be 

noted that the pet use currently registered for metaflumizone is in the process of being cancelled; 

however, the use has been included in this risk assessment. Existing stock of the registered 

product will continue to be sold, but registration will not be maintained beyond 2012.

BASF Corporation is currently proposing the application of AltrevinTM Fire Ant Bait Insecticide 

(EPA File Symbol No. 7969-###) to citrus fruits, grapes, and tree nuts and proposed the 

establishment of the following permanent tolerances for residues of metaflumizone (E and Z 

isomers): Citrus Fruits, Group 10 - 0.01 ppm; Tree Nuts, Group 14 - 0.01 ppm; Grapes, table -

0.01 ppm; and Grapes, wine - 0.01 ppm. In addition, BASF Corporation is also proposing the 

application of Metaflumizone Fly Bait (EPA Reg #7969-xxx) for control of the adult common 

housefly around industrial buildings, commercial facilities, and agricultural structures and 

premises. It can also be used around recreational facilities and outdoor recreational areas.

A previous risk assessment (D345134, T. Bloem et.al, 26-Jan-10) assessed risks from the 

proposed new fire ant bait uses; however, the current risk assessment supersedes that document 

and reflects updates related to the FQPA SF and includes an assessment for the new Section 3 

registration as a fly bait product. 

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

concern following subchronic or chronic oral exposures to metaflumizone. Splenic 

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

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

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

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

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

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

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

hemoglobin. The postulated pesticidal mode of action of metaflumizone involves inhibition of 

sodium 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); however, there was no evidence of any functional 

deficits at the highest dose tested in a recently submitted and reviewed 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 was observed at the same 
Metaflumizone Human-Health Risk Assessment D393447

Page 4 of 39

dose as severe maternal toxicity, which included late-term abortions and other clinical signs of 

toxicity. There was no evidence (quantitative or qualitative) of increased susceptibility

following in utero exposures to rats or rabbit and following pre-and post natal exposures to rats. 

There was no evidence that metaflumizone is genotoxic and carcinogenicity studies with mice 

and rabbits were negative.

Dose-Response Assessment and FQPA SF Decision: The points of departures (PoDs) and 

toxicological endpoints of concern are the same as those described in the risk assessment 

document dated January 26, 2010 (D345134).

The metaflumizone risk assessment team recommends that the FQPA SF be (a) reduced from 

10x to 3x for all oral exposure scenarios, (b) retained at 10x for inhalation exposure scenarios, 

and (c) reduced from 10x to 1x for dermal exposure scenarios. The reasons are as follows (for a 

more detailed discussion see Section 3.4): 

1) Although metaflumizone shows evidence of potential immunotoxicity in the form of 

dose-related effects in the organs of the immune system across multiple studies with 

either the parent compound (composed of both E and Z isomers) or the Z-isomer of 

metaflumizone, evaluation of a recently submitted immunotoxicity study did not result in 

a point of departure lower than those from the last risk assessment and there were no 

immune system functional deficits (D345134, T. Bloem et al., 26-Jan-10).

2) Reducing the FQPA SF at 3x for a database uncertainty for all oral exposure scenarios is 

adequate to protect against any toxicity that might occur at 2-fold lower doses in dietary

exposures (absorption was noted to be 2-fold greater in dietary versus oral gavage 

studies).

3) The FQPA SF of 10x is being retained for inhalation exposure scenarios for the use of a 

lowest-observed adverse-effect level (LOAEL) instead of a NOAEL.

4) The FQPA SF for dermal exposure scenarios is being reduced from 10x to 1x since there 

is a route-specific study with a clear NOAEL and the concern for developmental toxicity

is low.

5) There are no residual concerns or uncertainties for pre- and/or postnatal toxicity.

6) There is no clear evidence that metaflumizone directly targets the nervous system in 

mammals.

7) 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 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).

8) The residential analysis is conservative in that health-protective assumptions were

assumed along with the use of the Residential SOPs. 

HED notes that route-specific toxicity studies were selected for assessment of short-

/intermediate-term dermal, inhalation, and oral exposures. Short/intermediate-term dermal and 

inhalation exposures can be aggregated based on the effects on the immune system organs seen 

at the LOAEL in the selected studies. Short/intermediate-term oral, dermal, and inhalation 

exposures can be aggregated based on the decreased body weight or decreased body-weight gain 

effects seen at the LOAEL in the selected oral and dermal studies and at doses above the LOAEL 
Metaflumizone Human-Health Risk Assessment D393447

Page 5 of 39

in the selected inhalation study. 

Dietary Exposure Assessment: Acute and chronic metaflumizone dietary risk assessments were 

conducted using the Dietary Exposure Evaluation Model - Food Consumption Intake Database 

(DEEM-FCID, ver. 2.03) model. DEEM-FCIDTM (ver. 2.03) incorporates consumption data 

from the United States Department of Agriculture (USDA) Continuing Surveys of Food Intakes 

by Individuals (CSFII; 1994-1996 and 1998). The acute and chronic dietary analyses assumed 

tolerance-level residues, 100% crop treated, and modeled drinking water estimates from the 

Pesticide Root Zone Model-Exposure Analysis Modeling System (PRZM-EXAMS). The 

drinking water estimates were based on the application of metaflumizone as a fly bait on use 

sites such as recreational facilities and outdoor recreational areas including parks, picnic 

grounds, and camp grounds, which are represented by the turf modeling scenario [this scenario 

resulted in the highest estimated drinking water concentration (EDWC)]. DEEMTM (ver. 7.81) 

default processing factors were assumed for all commodities excluding grape raisin, grape juice, 

and citrus juice, which were reduced to 1 based on empirical data. An acute dietary exposure 

estimate was generated for females 13-49 years old, but not for the remaining population 

subgroups since an endpoint attributed to a single dose was not identified for those populations. 

The acute dietary exposure estimate for females 13-49 years old was <1% of the acute 

population-adjusted dose (aPAD) and, therefore, does not exceed HED’s level of concern (LOC). 

The chronic dietary exposure estimates were <1% of the cPAD and, therefore, do not exceed 

HED’s LOC (children 1-2 years old were the most highly exposed population subgroup). 

Residential Risk: Residential exposure is not anticipated from the proposed fire ant bait 

applications to citrus fruits, grapes and tree nuts; however, residential post-application exposure 

is anticipated from the proposed fly bait application scenarios. The resulting dermal and 

incidental oral MOEs were greater than the LOCs of 100 and 300, respectively, and, therefore, 

were not of concern. 

There are already registered pet care and fire ant bait (for application to lawns, landscapes, golf 

courses, and other non-cropland) uses that may result in residential exposures. As was noted 

above, the pet care product is in the process of being cancelled; however, the use has been 

included in this risk assessment. The MOEs for the fire ant bait use (lawns, landscapes, golf 

courses, and other non-cropland) are >100 for dermal exposures, >300 for incidental oral 

exposures and >1000 for inhalation exposures and, therefore, do not exceed HED's LOCs. The 

MOEs for the pet care product are >100 for dermal exposures and >300 for incidental oral 

exposures and, therefore, do not exceed HEDs LOC. 

Aggregate Risk: In accordance with the FQPA, HED must consider and aggregate pesticide 

exposures and risks from dietary (food and water) and residential (dermal, inhalation, and 

incidental oral) sources. When aggregating exposures and risks from these sources, HED 

considers the route and duration of exposure as well as the toxicological effects for each route. 

Short-/intermediate-term dermal, oral, and inhalation exposures can be aggregated based on a 

common toxic effect (decreased body weight or decreased body-weight gain). Based on this and 

the proposed/registered uses, aggregate acute, short-/intermediate-term, and chronic assessments 

were conducted. An aggregate cancer risk assessment was not performed because 

metaflumizone is not considered to be a carcinogen. 

Acute/Chronic Aggregate Risk - Since there are no registered/proposed uses that result in acute 

or chronic residential exposure, the acute and chronic aggregate exposure assessment consists of 
Metaflumizone Human-Health Risk Assessment D393447

Page 6 of 39

exposure from food and water. The acute (<1% aPAD) and chronic (1% cPAD) dietary

exposure estimates do not exceed HED's LOC. 

Short-/Intermediate-Term Aggregate Risk – The short-term aggregate assessment combines food 

and drinking water exposure with the highest potential residential exposure. The pet care 

products result in the highest potential residential exposure estimates, with the fly bait products 

resulting in the second highest. Because the pet uses of metaflumizone are in the process of 

being cancelled, a short-term aggregate assessment was performed both for the pet care product 

and for the fly bait product. Intermediate-term exposures are possible for the pet care product; 

however, since the points of departure for the short- and intermediate-term durations are the 

same for metaflumizone, the short-term aggregate assessment is protective of longer-term 

exposures for the pet care product. For adults and the general U.S. population, the short- and 

intermediate-term aggregate assessment combines chronic dietary with residential postapplication dermal exposure. For young children, the short-and intermediate-term aggregate 

assessment combines chronic dietary exposure with incidental oral and dermal post-application 

exposures. Since the LOC is different for dermal and oral exposures (100 and 300, respectively), 

the aggregate risk index (ARI) method was used to determine aggregate risk (ARIs > 1 are not a 

risk of concern). The aggregate ARIs from food, water, and non-occupational exposures are >1 

for both the fly bait and pet care uses for adults and children. Therefore, short-/intermediate-term 

aggregate risk estimates do not exceed HED’s LOC.

Occupational Risk: The occupational handler assessment for the proposed uses (fire ant bait on 

citrus fruit, grapes and tree nuts, and fly bait around industrial buildings, commercial facilities, 

agricultural structures and premises, recreational facilities and outdoor recreational areas) was 

completed assuming the maximum label application rates. Broadcast applications were assumed 

to be made by tractor-drawn spreaders, belly grinders, and/or push-type spreaders. Placing bait 

in bait stations was assumed to be done using a cup/spoon or by hand. Based on the activity use 

pattern, the duration of exposure is expected to be short- and intermediate-term for occupational 

scenarios; long-term exposures (greater than 6 months) are not anticipated. The same points of 

departure are used for short- and intermediate-term exposures; therefore, risks are the same for 

all durations of exposure. The proposed labels require long-sleeved shirt and long pants and 

chemical-resistant gloves as dermal PPE for all applicators and other handlers. 

Occupational handler dermal and inhalation risk estimates were calculated. The dermal and 

inhalation exposure risks for mixer/loaders, applicators, and mixer/loader/applicators are not of 

concern (i.e., MOEs >100 for dermal exposures and >1000 for inhalation exposures) at baseline 

and with the addition of gloves as recommended by the label. Occupational dermal 

postapplication exposure was not assessed as it is not anticipated that workers will be exposed 

after application of the fly bait and/or the fire ant bait. HED believes the presence of commercial 

workers in treated areas (e.g., industrial and commercial buildings) is minimal after application

of the fly bait. In the case of the fire ant bait, all applications are directed towards the soil 

surface and workers are not expected to frequent areas infested with active fire ants. 

Restricted Entry Interval (REI): The proposed uses for the fly bait product are non-agricultural 

sites; therefore, a REI is not required. For the fire ant bait product (citrus fruits, grapes and tree 

nuts), since a quantitative post-application dermal risk assessment has not been conducted, the 

default Worker Protection Standard (WPS) REI applies and is based on the acute toxicity

category of the technical for dermal toxicity, skin irritation potential, and eye irritation potential. 

Metaflumizone has low acute toxicity (Category IV) via the dermal route, and is neither a dermal 
Metaflumizone Human-Health Risk Assessment D393447

Page 7 of 39

irritant (Category IV), eye irritant (Category IV), nor a dermal sensitizer. Therefore, the default 

REI of 12 hours would apply for metaflumizone. 

Environmental-Justice Considerations: Potential areas of environmental-justice concerns, to 

the extent possible, were considered in this human-health risk assessment, in accordance with 

U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority

Populations and Low-Income Populations," 

(http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.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 CSFII 

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.

HED Recommendation: Pending submission of a revised Section B, revised Section F, and 

analytical reference standards to the EPA National Pesticide Standards Repository; the 

toxicological, residue chemistry, and occupational/residential exposure databases support 

granting a conditional registration for the proposed metaflumizone uses. In conjunction with this 

registration, the tolerances listed below should be established with the tolerance expression, 

commodity definitions, and numerical tolerances described as follows: 

Tolerances are established for residues of the insecticide metaflumizone, including its 

metabolites and degradates, in or on the commodities listed below. Compliance with the 

tolerance levels specified below is to be determined by measuring only the sum of 

metaflumizone (E and Z isomers; 2-[2-(4-cyanophenyl)-1-[3-(trifluoromethyl)

phenyl]ethylidene]-N-[4-(trifluoromethoxy)phenyl] hydrazinecarboxamide) and its metabolite 4-

{2-oxo-2-[3-(trifluoromethyl) phenyl]ethyl}-benzonitrile, calculated as the stoichiometric 

equivalent of metaflumizone, in or on the following commodities: Fruit, citrus, group 10 - 0.04 

ppm; Nut, tree, group 14 - 0.04 ppm; Almond, hulls - 0.04 ppm; and Grape - 0.04 ppm. 

The conditional registration may be made unconditional pending resolution of the following 

issues: 

 Cabbage metabolism study (46264326.der.wpd) - Information pertaining to sample 

extraction and analysis dates is required; if the interval from harvest to analysis is greater 

than the currently validated interval, then additional storage stability data will also be 

necessary. 

 Cotton metabolism study (46264324.der.wpd) - Individual concentrations of the 

unknowns should be reported; if any unknown comprises >10% of the total radioactive 
Metaflumizone Human-Health Risk Assessment D393447

Page 8 of 39

residue (TRR), then further characterization/identification procedures may be required 

(based on these data additional residues may be included for risk assessment). 

 Storage stability data - To support the subject field trial and processing studies, the 

following storage stability data are required which demonstrate the stability of 

metaflumizone (E and Z isomers) and M320I04: grapes - 4.8 months; citrus fruit - 5.6 

months; almond hulls - 6.5 months; and almond nutmeat - 5.8 months. 

2.0 Ingredient Profile

2.1 Summary of Registered/Proposed Uses

Registered: HED previously reviewed a petition concerning the application of metaflumizone as 

a pet care product (maximum application rate of 0.002 lb ai/animal; 12 applications/year) and 

fire ant bait product for application to lawns, landscapes, golf courses, and other non-cropland 

(maximum application rate of 0.001 lb ai/acre; 4 applications/year; homeowner application 

permitted) (D304496, R. Mitkus et al., 24-Jan-2006). It should be noted that the pet use 

currently registered for metaflumizone is in the process of being cancelled; however, the use has 

been included in this risk assessment. Existing stock of the registered product will continue to be 

sold, but registration will not be maintained beyond 2012.

Proposed: The petitioner is proposing application of AltrevinTM Fire Ant Bait Insecticide (EPA 

Reg. No. 7969-###; granular (G); 0.063% active ingredient) to citrus fruits, grapes, and tree nuts 

(see Table 2.1.1). The label also includes directions for use in orchards and nurseries containing 

field- or container-grown nonbearing stone and pome fruit trees (application within a year of 

harvest is prohibited). The proposed label includes a 12-hour REI. On page 3 of the label, 

HED requests that the petitioner list the crops for each crop group as defined in 40 CFR 

180.41 and eliminate the "including but not limited to" phrase. A revised Section B is 

requested. 

In addition, the Registrant is proposing the use of metaflumizone as a granular fly bait for control 

of the adult common housefly around industrial buildings, commercial facilities, and agricultural 

structures and premises. It can also be used around recreational facilities and outdoor 

recreational areas. The end-use product is Metaflumizone Fly Bait (EPA Reg #7969-xxx; 

granular (G)), containing 0.063% active ingredient. The bait can be broadcast over large areas as 

a scatter bait or placed in bait stations/trays. The maximum application rate proposed for 

broadcast applications (scatter bait) is 0.014 lb ai/A, and for bait stations/trays is 2 oz bait/station 

hung or placed at a density of 8-10 stations/2000 square feet. 
Metaflumizone Human-Health Risk Assessment D393447

Page 9 of 39

Table 2.1.1: Summary of Proposed Directions for Metaflumizone.

Application

Timing; Type; 

and Equipment

Product; 

Formulation

[EPA Reg. No.]

Application

Rate

Max. No. 

App. per 

Season

Max. 

Seasonal 

App. Rate

PHI

(days) Use Directions and Limitations

Citrus trees (citrus and Fortunella spp.): including but not limited to orange (sweet, sour), lemon, lime, grapefruit, citrus 

hybrids (chironja, tangelo, tangor), kumquat, Mandarin (tangerine), pummelo, and Satsuma mandarin

Nut trees: including, but not limited to almond, beech nut, Brazil nut, butternut, cashew, chestnut, chinquapin, filbert, hickory 

nut, macadamia nut, pecan, and walnut

Grape vineyards; and orchards and nurseries containing field- or container-grown nonbearing stone and pome fruit trees

Postemergence;

Broadcast; 

Ground

AltrevinTM Fire 

Ant Bait 

Insecticide; 

0.063% G

[7969-###]

0.0006-0.001 

lb ai/acre

4 0.004 lb 

ai/acre

5

1 Broadcast applications are to be made in 

areas having a mound density of at least 1 

mound per 2,000 square feet. Otherwise, 

individual mound spot treatments are to be 

made (see below). A minimum 

retreatment interval (RTI) of 4 weeks is

proposed.

Postemergence;

Spot; Ground

AltrevinTM Fire 

Ant Bait 

Insecticide; 

0.063% G

[7969-###]

0.00004-

0.00008

lb ai/mound; 

not to exceed 

0.001 lb 

ai/acre

not 

indicated

0.004 lb 

ai/acre

5

1

Spot applications are to be made in areas 

having a mound density of less than 1 

mound per 2,000 square feet. Otherwise, 

broadcast applications are to be made (see 

above). A minimum RTI of 4 weeks is 

proposed.

Around industrial buildings, commercial facilities, agricultural structures and premises, recreational facilities and outdoor 

recreational areas.

Postemergence; 

Broadcast; 

Ground2

Metaflumizone 

Fly Bait; 

0.063% G

[7969-###]

0.014 lb 

ai/acre

not 

indicated

not indicated NA Do not apply in side homes. Apply in 

locations where children and pets cannot 

access or come into contact with bait 

granules.

Do not apply in are where livestock can 

ingest or contact bait.

Do not use (except for bait station use) in 

edible product areas where food is 

commercially prepared or process or in 

serving areas when food exposed.

Do not place bait in piles or in wet/moist 

areas.

Do not pile or heap bait in station or tray.

Reapply as bait is consumed to maintain 

control.

Postemergence; 

Spot; Ground3

Metaflumizone 

Fly Bait; 

0.063% G

[7969-###]

0.000079 lb 

ai/station and 

8-10 

stations/2000 

ft2

1. Application to non-bearing pome and stone fruit trees is permitted up to 1-year before first harvest.

2. Locations include: (1) Outside of food and beverage plants, meat and poultry processing plants, food handling establishments, 

restaurants, cafes, fast-food establishments, supermarkets, farm markets, bakeries, commissaries, warehouses, and the refuse 

dumpsters associated with these establishments. (2) Outside of livestock handling and feeding facilities including broiler and 

layer houses, swine production facilities, livestock barns, horse stables, milking parlors, dairy barns, feed lots, feed storage 

buildings, feed silos, and other animal handling and feeding facilities. (3) Indoors in livestock handling and feeding facilities. 

Only in areas where livestock cannot come in contact with or ingest bait granules; such as walkways or manure pits in caged 

layer houses, dairy barns, and swine facilities. (4) Outdoors around recreational facilities and outdoor recreational areas 

including parks, picnic grounds, campgrounds, and outdoor latrines.

3. Locations include: (1) In and around food and beverage processing plants, meat and poultry processing plants, food handling 

establishments, restaurants, cafes, fast-food establishments, supermarkets, farm markets, bakeries, commissaries and warehouses. 

(2) In and around livestock handling and feeding facilities including broiler and layer houses, swine production facilities, 

livestock barns, horse stables, milking parlors, dairy barns, feed lots, feed storage buildings, feed silos and other animal handling 

and feeding facilities. 
Metaflumizone Human-Health Risk Assessment D393447

Page 10 of 39

2.2 Structure and Nomenclature

The chemical structure and nomenclature of metaflumizone and the physicochemical properties 

of the technical grade of metaflumizone are presented in Tables 2.2.1 and 2.2.2, respectively.

Table 2.2.1: Metaflumizone 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

End-use product (EP) Altrevin Fire Ant Bait Insecticide (0.063% G formulation; EPA Reg. No. 7969-###)

Table 2.2.2: Physicochemical Properties of Metaflumizone.

Melting point Two melting points observed at approximately 127 oC and 186 oC. MRID 46264204

pH 6.48 at 25 oC (1% aqueous suspension) MRID 46264524

Density (20 oC) 1.461 g/cm3 MRID 46264204

Water solubility (20 oC)

D.I. water 1.79 μg/L

pH 5 1.35 μg/L

pH 7 1.81 μg/L

pH 9 1.73 μg/L

MRID 46264208

Solvent solubility (20 oC)

Acetone 142.7 mg/L

Acetonitrile 60.3 mg/L

DCM 92.7 mg/L

EtOAc 159.7 mg/L

Heptane 0.0084 mg/L

Methanol 13.95 mg/L

Toluene 3.96 mg/L

MRID 46264212

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

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

Octanol/water partition 

coefficient, Log(KOW)

Log POW = 5.1 (Z isomer)

Log POW = 4.4 (E isomer) MRID 46264213

UV/visible absorption spectrum Molar absorptivity: 3.81×104 L/Mcm at 234 nm; 1.93×104 L/Mcm at 

280 nm. MRID 46264207

3.0 Hazard Characterization/Assessment

The hazard characterization and toxicity profile tables (Appendix A) for metaflumizone have 

been updated since the last risk assessment (D345134, T. Bloem, 26-Jan-10) in order to include 

an immunotoxicity study recently submitted and reviewed by the Agency. This document 

includes information related to that study and updates to the FQPA SF. Oral gavage and dietary

exposures to metaflumizone are addressed when appropriate since an absorption study (MRID# 

47249001) demonstrated an approximately 2-fold greater absorption from dietary exposures as 

compared to oral gavage dosing. Because of this difference in absorption, toxicity via dietary

exposure has the potential to occur at doses 2-fold lower than those currently identified using 

CN

N

N

H

N

H

O

O

F3C

CF3
Metaflumizone Human-Health Risk Assessment D393447

Page 11 of 39

gavage dosing (for more details, see D345134, T. Bloem, 26-Jan-10).

3.1 Absorption, Distribution, Metabolism, Excretion (ADME)

Gavage Route: Metaflumizone was poorly absorbed from the gastrointestinal (GI) tract of rats 

following oral dosing via gavage at 30 and 1000 mg/kg with an apparent inverse dose-absorption 

relationship (up to 7% was absorbed following a 30 mg/kg dose; up to 2% after a 1000 mg/kg 

dose). Following a single dose (30 mg/kg/day) of radioactive metaflumizone by gavage, 

residues (up to 0.6% of the dose) were detected in the liver only. After two weeks of repeated 

daily dosing at 30 mg/kg/day, the tissue distribution of metaflumizone was increased, with up to 

1% of the administered dose measured in the liver, kidney, muscle, fat, and plasma. Average 

concentrations in fat did not decrease by 168 hrs following the last dose in a repeated dosing 

paradigm, a finding that is consistent with the lipophilic nature of metaflumizone (log KOW = 

5.1). These observations, as well as the relatively long elimination half-life of metaflumizone 

(up to 17 days, depending on which ring is labeled) and the very large volume of distribution of 

metaflumizone in rats (up to 156 L) indicate that the small fraction of metaflumizone absorbed 

from the GI tract following gavage dosing is slowly eliminated from the body. There were no 

major sex-related differences in excretion. Approximately 90% of the administered dose was 

excreted in the feces as untransformed metaflumizone seven days following a single dose, with 

1-2% excreted in urine. The absorbed fraction of metaflumizone was extensively

biotransformed, primarily by hydroxylation of the aniline or benzonitrile ring or hydrolysis of the 

central hydrazine carboxamide group, and all metabolites were excreted in either the urine or 

bile.

3.2 Mammalian Toxicology

A summary of the subchronic and chronic toxicity and genotoxicity databases for 

metaflumizone, its Z-isomer, and the goat/plant/soil metabolite M320I23 is found in Table A.2. 

Gavage Dosing with Metaflumizone

Metaflumizone technical (96% metaflumizone; mixture of ~90% E-isomer:10% Z-isomer) 

demonstrated low acute toxicity via the oral, dermal, and inhalation routes of exposure (Category

IV). It is neither a dermal irritant (Category IV), an eye irritant (Category IV), nor a dermal 

sensitizer. Acute toxicity testing of the Z-isomer and the goat/plant/soil metabolite M320I23 

yielded results similar to those for the technical product (Table A.1).

Metaflumizone caused both hematotoxicity (toxicity of the blood) and immunotoxicity as 

primary toxic effects following subchronic or chronic oral exposure. Metaflumizone induced 

slight anemia and/or a compensatory extramedullary hematopoiesis in the spleen in the 90-day

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

the chronic toxicity/carcinogenicity study in rats, however, a negative finding may have been due 

to an adaptive response to the anemia following long-term exposure in this species. In the 

chronic toxicity study in dog, anemia was observed in the form of slight decreases in mean 

corpuscular hemoglobin concentration and total hemoglobin leading to increased plasma 

bilirubin, increased urinary urobilinogen, and increased hemosiderin in the liver. In the 

chronic/carcinogenicity study in mice, anemia in the form of increased hemosiderin in the 

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

mean corpuscular hemoglobin were observed in both males and females. 
Metaflumizone Human-Health Risk Assessment D393447

Page 12 of 39

Hematotoxicity and/or immunotoxicity were also observed following dermal exposure to 

metaflumizone. In a rat 90-day dermal toxicity study, increased hemosiderin was 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. Lymphocyte 

necrosis in the mesenteric lymph node was also the critical effect (i.e., observed at the lowest 

dose) reported in a rat 28-day inhalation toxicity study, thereby supporting the conclusion that 

metaflumizone is immunotoxic across all routes of exposure tested.

The potential neurotoxicity of metaflumizone was assessed in both acute and subchronic 

neurotoxicity studies. There was no evidence of neurotoxicity in the acute neurotoxicity study in 

rats up to the highest dose tested (the limit dose). Piloerection and body temperature variations 

were noted in the subchronic neurotoxicity study in rats, and salivation and ataxia were observed 

at the high dose in a chronic study with dogs. However, reduced general condition and/or 

recumbency, indicators of general 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.

In the developmental toxicity study in rat, toxicity to the offspring was not observed at any dose, 

whereas mild maternal toxicity (decreased body-weight gain) was observed at the highest dose 

tested. In the developmental toxicity study in rabbits, the malformation absent subclavian artery

was observed at the same dose as severe maternal toxicity, which included late-term abortions 

and clinical signs of toxicity. In the 2-generation reproductive toxicity study in rats, perinatal 

mortality was 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 indicating that metaflumizone is genotoxic and carcinogenicity studies 

with mice and rats were negative. 

Oral Gavage Dosing with the Z-isomer of Metaflumizone: 

In a 3-month oral study with the Z-isomer alone (99.7%), groups of 10 Sprague-Dawley rats/sex 

were gavaged daily at doses of 0, 100, 300, or 1000 mg/kg/day for 90 days. Mortality, reduced 

general condition, piloerection, and decreased overall motor activity were observed in females at 

the LOAEL of 300 mg/kg/day (NOAEL = 100 mg/kg/day). In males, decreased overall motor 

activity was observed at the highest dose tested only (LOAEL = 1000 mg/kg/day; NOAEL = 300 

mg/kg/day). A comparison with the subchronic (90-day) neurotoxicity study in rats using 

metaflumizone technical (LOAEL = 150 mg/kg/day; NOAEL = 36 mg/kg/day), indicates that the 

Z-isomer is most likely less potent than metaflumizone technical (predominantly E-isomer), 

because it caused toxicity at doses that were 2-fold and 7-fold higher than the technical active in 

females and males, respectively. In addition, like metaflumizone technical, the Z-isomer of 

metaflumizone was negative for mutagenicity with and without metabolic activation in an in 

vitro bacterial reverse mutation (Ames) assay.

Oral Gavage Dosing with Metabolite M320I23: 

M320I23 is a metabolite of metaflumizone that is generated in soil, plants (cotton, tomato, white 
Metaflumizone Human-Health Risk Assessment D393447

Page 13 of 39

cabbage), and goats, but not in rats. No adverse effects were observed in a 3-month oral 

(gavage) study of M320I23 in rats. M320I23 was negative for mutagenicity in an in vitro 

bacterial reverse mutation (Ames) test with and without metabolic activation and an in vitro

mammalian gene mutation study at the 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 cytogenetics 

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 nonmutagenic like the parent compound.

Dietary Dosing with Metaflumizone

Five short-term toxicity studies, in which rats or mice were exposed to metaflumizone in the diet, 

were submitted to the Agency after the original data package submission. These studies were 

conducted early in the development of metaflumizone as an insecticide, and the results of these 

studies led to the (appropriate) decision by the registrant to conduct all of its guideline studies 

using gavage dosing. In every study, decreased body weight and body-weight gains were 

observed in the presence of decreased food consumption. Because the decreases in body weight 

were observed only in the presence of decreased food consumption at the doses tested in these 

studies (≥3.8 mg/kg bw/day), the effect on body weight could not be attributed to a direct effect 

of treatment, but rather was due to the decreased food consumption, which was most likely

caused by a lack of palatability of the test substance when administered in the diet. The results 

from these five studies were supported by two additional studies, also later submitted to the 

Agency, 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 (for example, on intermediary metabolism), they are not 

relevant for endpoint selection for risk assessment. However, it would be anticipated that 

humans, like rodents, might also smell and not eat food that contained residues of metaflumizone 

at the levels tested in these additional animal toxicity studies, thereby limiting ingestion of the 

compound.

3.3 Toxicity Endpoint Selection

A summary of the toxicological endpoints and doses chosen for the exposure scenarios relevant 

for the current human-health risk assessment are summarized below and in Tables 3.3.1 (for 

dietary and residential exposure) and 3.3.2 (for occupational exposure). Since the last risk 

assessment (D345134, T. Bloem, 26-Jan-10), an immunotoxicity study was submitted and 

reviewed by the Agency. The results of the study did not impact the toxicity endpoint selection 

from the last risk assessment; except for the FQPA factor, which was previously retained at 10x
Metaflumizone Human-Health Risk Assessment D393447

Page 14 of 39

due to the absence of an immunotoxicity study (see FQPA considerations below; Section 3.4). 

Since long-term dermal and inhalation exposures are not expected with the current use pattern, 

endpoints for these exposure scenarios are not presented. 

Dietary and Residential Exposure

Acute Dietary Endpoint (General population including infants and children): An acute dietary

endpoint was not established 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 uncertainty factor (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 

being retained for the higher absorption observed with dietary exposures to metaflumizone (see 

above). Thus, the cPAD is estimated to be 0.040 mg/kg bw/day.

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

maternal effects observed in the rat 2-generation reproductive toxicity study at the LOAEL of 50 

mg/kg bw/day metaflumizone (NOAEL = 20 mg/kg bw/day). 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 2-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 
Metaflumizone Human-Health Risk Assessment D393447

Page 15 of 39

males and females); anogenital smearing; increased macrophages in the thymus; lymphocyte 

necrosis in the mesenteric lymph nodes; diffuse atrophy of the mandibular lymph node; and 

increased hemosiderin in the liver (females only) were observed at the LOAEL of 300 mg/kg 

bw/day (NOAEL = 100 mg/kg bw/day). The LOC is 100 based on a combined UF of 100 for 

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

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

for both exposure durations. There was no NOAEL identified for female rats. At the LOAEL of 

0.10 mg/L metaflumizone (NOAEL = 0.03 mg/L), histopathology of the nasal tissues, lungs, 

thymus, prostate, and adrenal cortex was observed in males. The LOAEL identified in females 

resulted in lymphocyte necrosis in the mesenteric lymph node. The FQPA of 10x is being 

retained for lack of a NOAEL for females, in addition to the combined UF of 100 for interspecies 

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

HED notes that route-specific toxicity studies were selected for assessment of short-

/intermediate-term dermal, inhalation, and oral exposures. Short/intermediate-term dermal and 

inhalation exposures can be aggregated based on the immunotoxic effects seen at the LOAEL in 

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

aggregated based on the decreased body weight or decreased body-weight gain effects seen at the 

LOAEL in the selected oral and dermal studies and at doses above the LOAEL in the selected 

inhalation study. 

Table 3.3.1: Summary of Toxicological Doses and Endpoints for Metaflumizone Used in Residential HumanHealth Risk Assessments.1

Exposure Scenario Dose Used in Risk 

Assessment, UF

FQPA SF or LOC for Risk 

Assessment Study and Toxicological Effects

Acute Dietarygeneral population, 

including infants and 

children

N/A N/A

An endpoint of concern (effect) attributable to a 

single dose was not identified in the database. 

Quantification of acute risk to general 

population including infants and children is not 

required.

Acute Dietaryfemales 13-49 years 

old

NOAEL = 100 

mg/kg/day

UF = 100

FQPA SF = 3x 

aPAD =aRfD = 0.33 mg/kg/day

Developmental toxicity (rabbit; gavage dosing); 

Offspring LOAEL = 300 mg/kg/day based on 

absent subclavian artery.

Chronic Dietarygeneral population, 

including infants and 

children

NOAEL = 12 mg/kg/day

UF = 100

FQPA SF = 3x 

cPAD =cRfD = 0.04 mg/kg/day

Chronic toxicity (dog; capsule dosing); LOAEL 

= 30 mg/kg/day based on reduced general 

health condition, slight to severe ataxia, 

recumbency, and severe salivation, decreases in 

MCHC and total Hb and increased bilirubin, 

increased urobilinogen, and increased 

hemosiderin in the liver.

Short- (1-30 days) 

and Intermediate-

(1-6 months) Term 

Incidental Oral 

NOAEL = 20 mg/kg/day LOC (residential) = MOE < 300 2-generation reproduction (rat); Maternal 

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

health and decreased body weight.

Short- (1-30 days) 

and Intermediate-(1-

6 months) Term 

Dermal

NOAEL = 100 

mg/kg/day

LOC (residential) = MOE < 100

LOC (occupational) = MOE < 

100 

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

based on decreased BW gain and food 

consumption (M&F); anogenital smearing, 

decreased BW, increased macrophages in the 

thymus, lymphocyte necrosis in the mesenteric 

lymph nodes, diffuse atrophy of the mandibular 

lymph node, and increased hemosiderin in the 

liver (F).
Metaflumizone Human-Health Risk Assessment D393447

Page 16 of 39

Table 3.3.1: Summary of Toxicological Doses and Endpoints for Metaflumizone Used in Residential HumanHealth Risk Assessments.1

Exposure Scenario Dose Used in Risk 

Assessment, UF

FQPA SF or LOC for Risk 

Assessment Study and Toxicological Effects

Short- (1-30 days) 

and Intermediate-

(1-6 months) Term 

Inhalation

LOAEL = 0.03 mg/L*

NOAEL not observed

LOC (residential) = MOE < 1000 

(includes 10x FQPA SF in form 

of UFL)

LOC (occupational) = MOE < 

1000

(includes 10x UFL)

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

based lymphocyte necrosis in the mesenteric 

lymph node (F).

Cancer (oral, 

dermal, inhalation)

Classification: Not likely to be carcinogenic to humans.

1

 UF = uncertainty factor, FQPA SF = FQPA Safety Factor, NOAEL = no-observed adverse-effect level, LOAEL = 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.

*

 0.03 mg/L x 100% absorption x 45.2 L/hr/kg (conversion factor) x 6 hrs/day (exposure duration) x 1 (activity factor) = 8 mg/kg 

bw/day

Occupational Exposure

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

toxicity study in which deficits in body weight, body-weight gain and food consumption (in 

males and females); anogenital smearing; increased macrophages in the thymus; lymphocyte 

necrosis in the mesenteric lymph nodes; diffuse atrophy of the mandibular lymph node; and 

increased hemosiderin in the liver (females only) were observed at the LOAEL of 300 mg/kg 

bw/day (NOAEL = 100 mg/kg bw/day). The LOC is 100 based on a combined UF of 100 for 

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

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

for both exposure durations. There was no NOAEL identified for female rats. At the LOAEL of 

0.10 mg/L metaflumizone (NOAEL = 0.03 mg/L), histopathology of the nasal tissues, lungs, 

thymus, prostate, and adrenal cortex was observed in males. The LOAEL identified in females 

resulted in lymphocyte necrosis in the mesenteric lymph node. The FQPA of 10x is being 

retained for lack of a NOAEL for females, in addition to the combined UF of 100 for interspecies 

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

Table 3.3.2: Summary of Toxicological Doses and Endpoints for Metaflumizone Used 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 (residential) = MOE <100

LOC (occupational) = MOE <100 

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

based on decreased BW gain and food 

consumption (M&F); anogenital smearing, 

decreased BW, increased macrophages in the 

thymus, lymphocyte necrosis in the mesenteric 

lymph nodes, diffuse atrophy of the mandibular 

lymph node, and increased hemosiderin in the 

liver (F).

Short- (1-30 days) 

and Intermediate-

(1-6 months) Term 

Inhalation

LOAEL = 0.03 mg/L*

NOAEL not observed

LOC (residential) = MOE <1000 

(includes 10x FQPA SF in form 

of UFL)

LOC (occupational) = MOE 

<1000

(includes 10x UFL)

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

based on lymphocyte necrosis in the mesenteric 

lymph node (F).

1

 UF = uncertainty factor, FQPA SF = FQPA Safety Factor, NOAEL = no-observed adverse-effect level, LOAEL = lowestobserved adverse-effect level, RfD = reference dose (a = acute, c = chronic), PAD = population-adjusted dose, MOE = margin of 
Metaflumizone Human-Health Risk Assessment D393447

Page 17 of 39

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.

*

 0.03 mg/L x 100% absorption x 45.2 L/hr/kg (conversion factor) x 6 hrs/day (exposure duration) x 1 (activity factor) = 8 mg/kg 

bw/day

3.4 FQPA Safety Factor Considerations

The metaflumizone risk assessment team recommends that the FQPA SF be reduced from 10x to 

3x for all oral exposure scenarios, be retained at 10x for inhalation exposure scenarios, and be 

reduced to 1x for dermal exposures. 

3.4.1 Completeness of the Toxicology Database

The toxicology database for metaflumizone is adequate for registration. In the last risk 

assessment (D345134, T. Bloem, 26-Jan-10) the only database deficiency noted was an 

immunotoxicity study. Since then, an immunotoxicity study has been received and evaluated by 

the Agency. The results of the study did not result in a point of departure lower than those from 

the last risk assessment. 

A difference in absorption was 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 for all oral exposure scenarios to protect against any 

toxicity that might result via the dietary (oral) route.

In the case of inhalation exposure scenarios, the FQPA SF of 10x is being retained as an 

uncertainty factor for the use of a lowest-observed-adverse-effect level (LOAEL) in the absence 

of a 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.

3.4.2 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 2-generation reproduction studies. No 

adverse effects were reported on motor activity or in the functional observational battery in the 

chronic/carcinogenicity study in rats. There was no evidence of neurotoxicity in the acute 

neurotoxicity test in rat up to the limit dose. 

3.4.3 Evidence of Sensitivity/Susceptibility in Developing Animals

There are no residual concerns or uncertainties for increased sensitivity/susceptibility in 

developing animals resulting from pre- and/or postnatal exposure. 
Metaflumizone Human-Health Risk Assessment D393447

Page 18 of 39

3.4.4 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 

may conceivably result in adjustment of the maximum theoretical residue estimate, actual 

metaflumizone dietary exposure estimates will not be greater than those generated in the current 

risk assessment (i.e., incorporation of anticipated residues, percent crop treated estimates, and/or 

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

residue). The residential analysis is conservative in that health-protective assumptions were 

assumed along with the use of the Residential SOPs. 

4.0 Dietary Exposure/Risk Characterization

residue chemistry summary - D345540, T. Bloem, 26-Jan-10

dietary exposure - D393549, T. Bloem, 20-Sep-11

drinking water - D367556, J. Melendez, 3-Aug-2011

4.1 Metabolism (Crops, Livestock, and Rotational Crops) and Environmental Degradation

The petitioner previously submitted cotton, cabbage, tomato, goat, and hen metabolism studies 

and confined rotational crop studies conducted with metaflumizone uniformly ring-labeled in the 

[benzonitrile14C] metaflumizone (B-label) and [trifluoromethoxyphenyl14C] metaflumizone (Tlabel) rings. Based on these data and information concerning environmental degradation of 

metaflumizone, HED concluded that the residue of concern in plants, livestock, rotational crops, 

and drinking water are as defined in Table 4.1.1. For further information concerning these 

conclusions, see the HED risk assessment document D304496 (R. Mitkus et al., 24-Jan-06). 

HED notes that the residue of concern in ruminants is to be reevaluated if the ruminant dietary

burden increased significantly. Almond hulls (90% dry matter; dairy only) and dried citrus pulp 

(91% dry matter; beef and dairy) are the only feed commodities associated with the current 

petition (maximum of 10% of the diet). HED previously estimated beef and dairy cattle dietary

burdens at 2.53 ppm and 0.36 ppm, respectively (D308394, T. Bloem, 30-Nov-05). Based on the 

recommended almond hull and citrus tolerances (0.04 ppm), the maximum contribution of 

almond hulls and/or dried citrus pulp to the beef/dairy cattle diet is 0.008 ppm. Therefore, the 

previous conclusions concerning the residues of concern in ruminants remain appropriate. 

The metabolites M320I04, M320I23, and M320I28 are not considered to cause greater toxicity

than parent (metaflumizone) or toxicity other than the parent compound. M320I04 lacks the Tring, which is thought to drive the toxicity for metaflumizone. M320I23 and M320I28 contain 

the T-ring; however, they do not contain any additional functionalities that would enhance their

toxicity above that of parent. It is noted that the cotton (PHI = 21 days) and tomato (PHI = 0 and 

7 days) metabolism studies and the environmental degradation studies indicated that selective 

metabolism and/or isomerization resulted in E:Z metaflumizone isomer ratios of ~1:1 (cotton and 

tomato) and 1.7:1 (environmental degradation). However, as stated in Section 3.2, HED 

concludes that the Z-isomer, even when enriched to 100%, is of lesser toxicity than 

metaflumizone technical, and, therefore, the toxicological studies performed with the technical 

product (E:Z of >90%:10%) are protective of any potential enrichment of the Z-isomer.

HED notes the initial metaflumizone human-health risk assessment (D304496, R. Mitkus et al., 

24-Jan-2006) indicated that metaflumizone (E and Z isomers) and M320I23 were the residues of 
Metaflumizone Human-Health Risk Assessment D393447

Page 19 of 39

concern in drinking water and EFED provided estimated drinking water concentrations 

(EDWCs) for these compounds (D319414, M. Ruhman, 13-Mar-2006). Subsequent EDWC 

memorandum from EFED provided concentrations for parent only and noted that previously a 

conservative approach was taken by modeling parent plus M320I23. The environmental 

degradation section of the above referenced human-health risk assessment (Section 5.1.4) 

indicated the following: “...due to their low concentrations and slow formation, the 

environmental degradates of metaflumizone are not expected to be threats to surface water”. 

Based on this and since the groundwater EDWC for combined parent and M320I23 was orders 

of magnitude lower than that for surface water, HED concludes that EDWCs representing parent 

only are acceptable. 

Table 4.1.1: Residues of Concern for Tolerance Expression and Risk Assessment (see Appendix B.6 for 

structures).

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants1 metaflumizone (E and Z isomers) and 

M320I04

metaflumizone (E and Z isomers) and 

M320I04

Livestock (excluding ruminant 

liver)2 metaflumizone (E and Z isomers) metaflumizone (E and Z isomers)

Livestock ruminant liver2 metaflumizone (E and Z isomers) and 

M320I283 metaflumizone (E and Z isomers)

Rotational crops metaflumizone (E and Z isomers) and 

M320I04

metaflumizone (E and Z isomers) and 

M320I04

Drinking water metaflumizone (E and Z isomers) Not applicable

1 This decision is contingent on the petitioner submitting data which address the following: (1) cabbage metabolism study -

information pertaining to sample extraction and analysis dates; if the interval is > currently validated interval, then additional 

storage stability data are required; (2) cotton metabolism study - individual concentrations of the unknowns is needed; if any 

unknown comprises >10% of the TRR, then further characterization/identification procedures may be required (based on these 

data additional residues may be included for risk assessment).

2 For future petitions, these conclusions will be re-evaluated; see Section 5.1.6 of D304496 (R. Mitkus et al., 24-Jan-2006).

3 Acetonitrile and acetic acid microwave extraction of the methanol extracted liver residues results in the formation of M320I28 

(microwave assisted cleavage and/or derivatization; common moiety method).

4.2 Analytical Methodology

HED previously determined that the BASF liquid chromatography/mass spectrometer/mass 

spectrometer (LC/MS/MS) Method 531/0 is adequate for tolerance enforcement and forwarded 

this method to the Food and Drug Administration (FDA; D308394, T. Bloem, 30-Nov-05; 

D328915, T. Bloem, 17-May-06). Citrus, grape, and tree nut samples from the field trial and 

processing studies were analyzed for residues of metaflumizone (E and Z isomers; limit of 

quantitation (LOQ) = 0.01 ppm) and M320I04 (LOQ = 0.018 ppm) using BASF method 531/0. 

Based on the adequate validation data submitted with the field trial and processing studies, HED 

concludes that the current enforcement method is suitable for enforcement of the tolerances 

associated with the current petition. 

4.3 Comparative Metabolic Profile

M320I04 (all structures found in Appendix B) is the only metabolite that is common to plants, 

livestock (hen and goat), and the rat. In plants, it appears that metaflumizone is metabolized by

way of the following reactions: isomerization of the metaflumizone E isomer to the Z isomer

(cotton, tomato); ring closure to form metabolite M320I23 (circular parent; in cotton, tomato, 

and cabbage); cleavage of metaflumizone at the imine bridge, resulting in the formation of 

M320I04 and a metabolite containing the p-trifluoromethoxyaniline moiety (cotton, tomato, 

cabbage, and rotational crops); cleavage of M320I23 to form M320I05 (ptrifluoromethoxyaniline; cotton); and cleavage of M320I23 and/or M320I04 to form M320I06
Metaflumizone Human-Health Risk Assessment D393447

Page 20 of 39

(4-cyanobenzoic acid; cotton, tomato, and cabbage).

Metabolites M320I04/25/26/27 are common to both hen and goat. In hen, it appears that 

metaflumizone is metabolized via the following reactions: hydroxylation of metaflumizone at the 

3-trifluoromethylphenyl ring to form M320I27; formation of M320I04 and a metabolite 

containing the p-trifluoromethoxyaniline moiety (as in plants); and/or reduction of M320I04 to 

form M320I25, which is conjugated with glutamic acid to form M320I26. In goat, metabolism 

of metaflumizone appears to occur in the following manner: hydroxylation of metaflumizone at 

the trifluoromethoxyaniline ring forming M320I22 followed by conjugation to glucuronic acid to 

form M320I24; hydroxylation of metaflumizone at the benzyl position to form M320I07 

followed by oxidation and ring formation yielding M320I23; formation of M320I04 and a 

metabolite containing the p-trifluoromethoxyaniline moiety (as in plants and hen); cleavage of 

M320I04 to form M320I06, which is conjugated with glycine to form M320I13; and/or reduction 

of M320I04 to form M320I25, which is conjugated with glucuronic acid to form M320I10 or 

conjugated with glutamic acid to form M320I26. The petitioner isolated and identified M320I17

(trifluoromethoxyaniline derivative) as a major residue in urine (53% TRR), which indicates that 

free T-ring compounds are forming in significant concentrations.

In the rat, metaflumizone is thought to be metabolized by several pathways. M320I04 (plus the 

p-trifluoromethoxyaniline moiety) is formed in a similar manner as in plants and livestock. 

M320I04 is then further metabolized to M320I06 and then M320I13 and/or M320I10 (without 

M320I25 intermediate), as in goat. M320I05 is also formed from parent, as in cotton, but in one 

step (without cyclization). M320I23 (circular parent) is not formed in the rat as it is in certain 

plants and goat. Two metabolites were measured in the rat that were also found in goat 

(M320I07/17). Metabolites that were unique to the rat included M320I21

(trifluoromethoxyaniline derivative conjugated to glutathione and glucuronic acid), M320I12 

(product conjugated to glutathione and glucuronic acid after T-ring cleavage), and M320I16 

(trifluoromethoxyurea derivative).

4.4 Drinking Water Residue Profile

Metaflumizone has a low vapor pressure (9.30 x 10-11 torr) and very low solubility in water 

(solubility 1.79 ppb at 20oC). Metaflumizone was practically stable to aqueous hydrolysis in 

neutral and alkaline conditions and to photolysis on soil (predicted environmental soil photolysis 

half-life of 54 days). It has also shown the same stability to metabolism in the aerobic soil 

system (the 90th percentile half-life of 134 days), and the anaerobic aquatic water/sediment 

systems (half-life of >378 days). In field studies, metaflumizone has shown similar persistence 

in planted terrestrial field studies (half-life of 6-24 days in bare-ground plots and 174-618 days in 

plots planted with cotton and potatoes). In contrast, relatively low persistence was observed in 

highly acidic aqueous systems or in aqueous systems exposed to light energy (half-lives of 5-29 

days). For mobility, metaflumizone appears to have very high affinity to soil and sediment 

particles rendering it to be immobile in systems with varied textures and organic matter content 

(Koc of 16,534-51,031 L Kg-1). The chemical is not expected to partition into the air due to its 

very low vapor pressure.

EFED provided surface and ground estimated drinking water concentrations generated using the 

Screening Concentration in Groundwater (SCI-GROW) and Pesticide Root Zone Model -

Exposure Analysis Modeling System (PRZM-EXAMS) models, respectively ( D367556, J. 

Meléndez, 3-Aug-2011). The models were run using the fly bait application scenario to turf to 
Metaflumizone Human-Health Risk Assessment D393447

Page 21 of 39

represent application to use sites such as recreational facilities and outdoor recreational areas 

including parks, picnic grounds, and camp grounds (26 x 0.0137 lb ai/acre; yielded the highest 

EDWCs). The SCI-GROW model resulted in a point estimate of 2.14 x 10-3ppb and the PRZMEXAMS model resulted in peak residue of 1.14 ppb and a 1-in-10 year annual mean 

concentration of 0.597 ppb for residues of metaflumizone (E and Z isomers). Therefore, the 

acute and chronic dietary exposure analyses assumed a drinking water estimate of 1.14 ppb and 

0.597ppb, respectively. 

4.5 Food Residue Profile

Granular Fly Bait Application: The proposed granular fly bait application scenario does permit 

application in and around food handling establishments and agricultural structures and premises 

including inside livestock premises. However, the labels include the following restrictions: Do 

not apply in areas where livestock can ingest or contact the bait and do not use (except for bait 

station use) in edible product areas where food is commercially prepared or processed or in 

serving areas when food is exposed. Considering these restrictions and since metaflumizone has 

a low vapor pressure (1.24 x 10-8Pa at 20 oC), HED concludes that this use will not result in 

significant residues in/on food/feed. 

Citrus, Grape, Tree Nuts, and Non-Bearing Stone and Pome Fruit Trees: The submitted citrus 

fruit, grape, and tree nut magnitude of the residue studies are adequate pending submission of 

supporting storage stability data. Residues of metaflumizone (E and Z isomers) and M320I04 

were <LOQ (limit of quantitation) in/on all samples of citrus fruit, grape, tree nutmeat, and 

almond hulls harvested 5 days following a single soil application of the test formulation at 0.004 

lb ai/acre (4x/1x the maximum proposed single/seasonal application rate). The submitted data 

will support tolerances for the combined residues of metaflumizone (E and Z isomers) and the 

metabolite M320I04 (expressed as parent) in/on citrus fruit, grape, tree nuts, and almond hulls at 

the combined LOQ of 0.04 ppm. A revised Section F is requested.

The submitted grape and orange processing studies are adequate pending submission of 

supporting storage stability data. Residues of metaflumizone (E and Z isomers) and M320I04 

were <LOQ in/on the orange and grape raw agricultural commodity (RAC) and orange oil 

following application at 5x the proposed rate. Processing data for the grape processed 

commodities and the remaining orange processed commodities were not provided and are 

unnecessary since residues were <LOQ in/on the RAC following treatment at 5x. The data 

indicate that no tolerances are needed for the processed commodities of grape or citrus fruit. 

Based on the submitted residue data and low application rate, HED concludes that application to 

non-bearing stone and pome fruit trees may be considered a non-food use (application within 1 

year of harvest is prohibited).

Livestock: Considering the proposed/registered uses, the only feedstuffs are almond hulls and 

dried citrus pulp, which may be fed to cattle (no poultry or hog feed commodities). Using the 

revised OPPTS 860.1000 Table 1, the maximum reasonably balanced diet (MRBD) for beef and 

dairy cattle is 0.004 ppm; based on these dietary burdens and the previously reviewed cattle 

feeding study (D308394, T. Bloem, 30-Nov-05), HED concludes that livestock tolerances are 

unnecessary.
Metaflumizone Human-Health Risk Assessment D393447

Page 22 of 39

Rotational Crops: Citrus fruits, grapes, and tree nuts are typically not rotated; therefore, data 

pertaining to rotational crops are not required to support the proposed uses.

4.6 International Residue Limits and HED-Recommended Tolerances

There are no Canadian, Mexican, or Codex Maximum Residue Limits (MRLs) established for 

residues of metaflumizone; therefore, harmonization is not relevant. HED requests that the 

petitioner submit a revised Section F specifying the commodity definitions and numerical 

tolerances specified in Table 5.6.1 and the following tolerance definition: 

Tolerances are established for residues of the insecticide metaflumizone, including its metabolites and 

degradates, in or on the commodities in the table below. Compliance with the tolerance levels 

specified below is to be determined by measuring only the sum of metaflumizone (E and Z isomers; 

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

hydrazinecarboxamide) and its metabolite 4-{2-oxo-2-[3-(trifluoromethyl) phenyl]ethyl}-

benzonitrile, calculated as the stoichiometric equivalent of metaflumizone, in or on the following 

commodities: 

Table 4.6.1: Tolerance Summary for Metaflumizone.

Proposed HED-Recommended

Comments

Commodity Tolerance 

(ppm)

Commodity 

Definition Tolerance (ppm)

Citrus Fruits, Group 

10

0.01 Fruit, citrus, group 

10 0.04

Based on the field trial data, a higher tolerance 

Tree Nuts, Group 14 0.01 Nut, tree, group 14 0.04 is required.

Grapes, table 0.01 Grape 0.04

Grapes, wine 0.01 -- none

Based on the processing data, a separate 

tolerance for wine is not required.

Almond, hulls none Almond, hulls 0.04 Based on the field trial data, a tolerance is 

required.

4.7 Dietary Exposure and Risk

Acute and chronic metaflumizone dietary risk assessments were conducted using DEEM-FCID

(ver. 2.03) model. DEEM-FCIDTM (ver. 2.03) incorporates consumption data from the USDA 

CSFII (1994-1996 and 1998). The acute and chronic dietary analyses assumed tolerance-level 

residues, 100% crop treated, and modeled drinking water estimates from the Pesticide Root Zone 

Model-Exposure Analysis Modeling System (PRZM-EXAMS). The drinking water estimates 

were based on the application of metaflumizone as a fly bait on use sites such as recreational 

facilities and outdoor recreational areas including parks, picnic grounds, and camp grounds 

represented by the turf modeling scenario [this scenario resulted in the highest estimated 

drinking water concentration (EDWC)]. DEEMTM (ver. 7.81) default processing factors were 

assumed for all commodities excluding grape raisin, grape juice, and citrus juice, which were 

reduced to 1 based on empirical data. The acute dietary exposure estimate for females 13-49 

years old was <1% the aPAD and, therefore, does not exceed HED’s LOC. An endpoint 

attributable to a single dose was not identified for the remaining population subgroups. The 

chronic dietary exposure estimates were 1% the cPAD and, therefore, do not exceed HED’s 

LOC (children 1-2 years old were the most highly exposed population subgroup). Table 4.7.1 is 

a summary of the acute and chronic dietary exposure estimates for the various populations. 
Metaflumizone Human-Health Risk Assessment D393447

Page 23 of 39

Table 4.7.1. Summary of Acute and Chronic Dietary Exposure and Risk for Metaflumizone (drinking water 

included).

Population Subgroup

Acute Chronic

aPAD 

(mg/kg/day)

Exposure 

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

Exposure 

(mg/kg/day) %cPAD

General U.S. Population

no endpoint identified 0.04

0.000092 <1.0

All Infants (< 1 year old) 0.000102 <1.0

Children 1-2 years old 0.000323 <1.0

Children 3-5 years old 0.000239 <1.0

Children 6-12 years old 0.000132 <1.0

Youth 13-19 years old 0.000079 <1.0

Adults 20-49 years old 0.000066 <1.0

Adults 50+ years old 0.000071 <1.0

Females 13-49 years old 0.33 0.000329 <1.0 0.000071 <1.0

5.0 Residential Exposure/Risk Characterization

D393548, K. Lowe, 20-Sep-11

D393547, K. Lowe, 20-Sep-11

The proposed fire ant bait product (citrus fruit, grapes, and tree nuts) is not expected to result in 

residential exposure since the proposed use sites are agricultural sites. Note: The proposed use 

as an agricultural fire ant bait was previously assessed (D367561, M. Dow, 07-Dec-09), but 

revisions have been made to account for the revisions to the hazard assessment of metaflumizone

(D393547, K. Lowe, 20-Sep-11). 

The proposed fly bait product can be used in areas where children could be present and, 

therefore, a residential assessment was performed for this use. 

There are already registered fire ant bait uses (lawns, landscapes, golf courses, and other noncropland) and pet uses (spot-on product) that would result in residential exposure that have been 

previously assessed (D345154, T. Bloem et al., 26-Jan-2010; D315785, M. Dow, 19-Jan-2006). 

The pet use product is in the process of being cancelled; however, it has been included in this 

assessment. Existing product will continue to be sold; but the registration will not be maintained

past 2012.

 

5.1 Residential Handler Exposure

Fly Bait (proposed): The proposed product is not anticipated to result in non-occupational use as 

it is proposed for commercial/recreational areas such as campgrounds and picnic grounds. It is 

expected that commercial handlers would apply this product to areas such as these. Therefore, a 

residential handler assessment has not been performed for the proposed fly bait product.

Fire Ant Bait (registered on lawns, landscapes, golf courses, and other non-cropland): 

Residential handler exposure was expected for homeowners who may apply the registered fire 

ant bait product to home lawns. Since the residential and commercial fire ant products have 

identical application rates, HED used the commercial loader/applicator dermal (no gloves) and 

inhalation exposure assumptions to calculate exposure and risk estimates for the homeowner 

loader/applicator scenario (commercial push-type drop spreader; 5 acres/day; only short-term 

exposures anticipated). Risks were not a concern for residential handlers (i.e., MOEs > the LOC 

of 100 for dermal exposures and 1000 for inhalation exposures; see Table 4.4).

Pet Care (registered spot-on product): Residential handler exposure/risk from metaflumizone 

application to domestic pets was not assessed because handler contact is expected to be 
Metaflumizone Human-Health Risk Assessment D393447

Page 24 of 39

negligible. The spot-on product is designed to be self-contained as it is applied directly from the 

tube to the pet with the tip of the applicator used to part the pet’s hair. 

5.2 Residential Post-application Exposure

Fly Bait (proposed): The proposed fly bait product can be used in areas where adults and 

children could be present, such as campgrounds and picnic grounds. For adults, dermal exposure 

was assessed and for children (3 to <6 year olds), dermal and incidental oral exposure (e.g., 

hand-to-mouth exposure) was assessed for individuals contacting turf or soil treated with fly bait 

granules. Short-term dermal and incidental oral exposures/risks have been assessed here and 

since the short- and intermediate-term PODs are the same, the short-term assessment is 

protective of longer-term exposures. In addition, the fly bait product is a granular product and; 

therefore, ingestion of metaflumizone granules found in treated turf is also a potential source of 

exposure for children. This scenario is considered an episodic event by HED and, therefore, is 

assessed as an acute exposure (i.e., acute dietary endpoints are used). Since there is no acute 

dietary endpoint applicable to children, no quantitative assessment was needed. The resulting 

dermal and incidental oral MOEs were greater than the LOCs of 100 and 300, respectively, and, 

therefore, were not of concern (see Table 6.4.1). 

Fire Ant Bait (registered on lawns, landscapes, golf courses, and other non-cropland): Use of 

the fire ant bait products may result in short-term post-application exposure to children (3 to <6 

year olds; dermal and incidental oral), adults (dermal), and adolescents (dermal) contacting 

treated turf. As stated above, short-term exposures are expected; however, since the short- and 

intermediate-term PODs are the same, the short-term risk estimates are protective of any 

potential intermediate-term exposures. Ingestion of metaflumizone granules found in treated 

lawns is also a potential source of exposure for children. This scenario is considered an episodic 

event by HED and, therefore, is assessed as an acute exposure (i.e., acute dietary endpoints are 

used). Since there is no acute dietary endpoint applicable to children, no quantitative assessment 

was needed. The resulting dermal and incidental oral MOEs were greater than the LOCs of 100 

and 300, respectively, and, therefore, were not of concern (see Table 6.4.1). 

Pet Care (registered spot-on product): As mentioned above, the pet care products registered for 

metaflumizone are in the process of being cancelled; however, the uses have been included in 

this risk assessment. The pet care products may result in short- and intermediate-term postapplication dermal (all populations) and incidental oral [children (3 to<6 year olds)] exposures. 

The resulting MOEs are >100 for dermal exposure and >300 for incidental oral exposures and, 

therefore, exceed HED's LOC (see Table 6.4.1). HED notes that pet care product exposure 

calculations can be considered refined in that they are based on the assumptions that 0.78% of 

the application rate is available as dislodgeable residue rather than the default 20%; for further 

information see D315785 (M. Dow, 19-Jan-06).

5.3 Combined Residential Exposure

For residential handlers, dermal and inhalation exposures are combined since the endpoints are 

similar for these routes. For children (3 to <6 year olds), post-application hand-to-mouth and 

dermal exposures are combined. Dermal exposure could be combined with all the incidental oral 

exposure scenarios (e.g., hand-to-mouth, object-to-mouth, soil ingestion) since it is assumed that 

these exposures do not occur as single, isolated events, but rather as a series of concurrent events 

that may overlap. However, combining all of the incidental oral exposures with dermal exposure 
Metaflumizone Human-Health Risk Assessment D393447

Page 25 of 39

would be overly conservative because each of these scenarios, independently, incorporates highend, health protective inputs or assumptions. Combining post-application dermal exposure with 

only hand-to-mouth exposure is considered a protective estimate of children’s exposure to 

pesticides used in residential settings.

Since the LOCs for the dermal, inhalation and incidental oral routes are not the same (dermal 

LOC = 100, inhalation LOC = 1000, and incidental oral LOC = 300), these routes were 

combined using the ARI approach. All of the combined risk estimates are greater than the LOC 

and, therefore, are not of concern.

Table 5.3.1. Summary of Short-term Residential Handler and Post-application Exposures and Risks.

Population Route of Exposure Dose (mg/kg/day) MOE1

Fire Ant Bait (registered on lawns, landscapes, golf courses, and other non-cropland; D345154/D315785)

Adult -- Residential Handler

Dermal 0.00021 480,000

Inhalation 0.00000045 18,000,000

Combined dermal and inhalation -- ARI2 = 3,800

Adult – Residential Postapplication Dermal 0.000232 430,000

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

Adolescent – Golfer Postapplication Dermal 0.0000272 3,700,000

Children (3 to <6 year olds) –

Post-application

Incidental oral hand-to-mouth 0.000015 1,300,000

Incidental oral object-to-mouth 0.00000093 22,000,000

Dermal 0.00039 260,000

Combined incidental oral hand-tomouth and dermal -- ARI3 = 1,600

Pet Care (registered spot-on; D345154/D315785)

Adults – Post-application Dermal 0.29 340

Children (3 to <6 year olds) –

Post-application 

Incidental oral hand-to-mouth 0.035 570

Dermal 0.16 620

Combined incidental oral hand-tomouth and dermal -- ARI3 = 1.5

Fly Bait (proposed; D393548)

Adult –Post-application Dermal 0.0033 31,000

Children (3 to <6 year olds) –

Post-application

Incidental oral hand-to-mouth 0.00021 96,000

Incidental oral object-to-mouth 0.000052 380,000

Incidental soil ingestion 0.0000007 29,000,000

Dermal 0.0054 18,000

Combined incidental oral hand-tomouth and dermal -- ARI3 = 120

1. MOE = NOAEL (mg/kg/day) ÷ Dose (mg/kg/day). 

2. ARI = Aggregate Risk Index = 1 ÷ ((1 ÷ (MOEinhalation ÷ LOCinhalation)) + (1 ÷ (MOEdermal ÷ LOCdermal))); ARI > 1 indicates an acceptable 

exposure. 

3. ARI = Aggregate Risk Index = 1 ÷ ((1 ÷ (MOEincidental oral hand-to-mouth ÷ LOCincidental oral hand-to-mouth)) + (1 ÷ (MOEdermal ÷ LOCdermal))); ARI > 

1 indicates an acceptable exposure.

6.0 Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks 

from dietary (food and water) and residential (dermal, inhalation, incidental oral) sources. When 

aggregating exposures and risks from these sources, HED considers the route and duration of 

exposure as well as the toxicological effects for each route. As indicated above, short-

/intermediate-term dermal, oral, and inhalation exposures can be aggregated based on a common 

toxic effect (decreased body weight or decreased body-weight gain). Based on this and the 

proposed/registered uses, aggregate acute, short-/intermediate-term, and chronic assessments 
Metaflumizone Human-Health Risk Assessment D393447

Page 26 of 39

were conducted. 

6.1 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% the aPAD and, therefore, does not 

exceed HED’s LOC (see Section 5.2). 

6.2 Short-/Intermediate- Term Aggregate Risk

The short-term aggregate assessment combines food and drinking water exposure with the 

highest potential residential exposure. As seen in table 6.3.1, the pet care products result in the 

highest potential residential exposure estimates, with the fly bait products resulting in the second 

highest. Because the pet uses of metaflumizone are in the process of being cancelled, a shortterm aggregate assessment was performed both for the pet care product and for the fly bait 

product. Intermediate-term exposures are possible for the pet care product; however, since the 

points of departure for the short- and intermediate-term durations are the same for 

metaflumizone, the short-term aggregate assessment is protective of longer-term exposures for 

the pet care product. 

For adults and the general U.S. population, the short- and intermediate-term aggregate 

assessments combine chronic dietary with residential post-application dermal exposure. For 

young children, the short-and intermediate-term aggregate assessments combine chronic dietary

exposure with incidental oral and dermal post-application exposure. HED uses chronic dietary

exposure when conducting short- and intermediate-term aggregate assessments since it has been

determined that these will more accurately reflect exposure from food over the HED defined 

short- and intermediate-term interval than will acute exposure. 

Table 6.2.1 is a summary of the short-term and intermediate-term aggregate risk estimates

resulting from the fly bait product and the pet care product. Since the LOCs for the dermal and 

oral routes are not the same (dermal LOC = 100 and oral LOC = 300), these routes were 

combined using the ARI approach. The aggregate ARIs are >1; therefore, none of the calculated 

short- and intermediate-term aggregate risks are of concern. 

Table 6.2.1: Short- and Intermediate-Term Aggregate Risk

Population

Background Dietary + Incidental Oral Exposures Residential Exposures ARI 

(food, 

water, and 

residential)f

Oral 

LOC

Chronic Food 

and Water 

Exposure 

(mg/kg/day)a

Incidental 

Oral 

Exposure 

(mg/kg/day)b

Oral 

MOEc

Dermal 

LOC

Dermal 

Exposure 

(mg/kg/day)d

Dermal 

MOEe

Pet Care Product (Short and Intermediate-term)

General U.S. 

Population 300

0.00008 NA 250,000

100

0.29 340 3

Children 1-2 

years old 0.00031 0.035 570 0.16 620 2

Fly Bait Product (Short-term)

General U.S. 

Population 300

0.00008 NA 250,000

100

0.0033 31,000 230

Children 1-2 

years old 0.00031 0.00021 39,000 0.0054 18,000 75
Metaflumizone Human-Health Risk Assessment D393447

Page 27 of 39

a. See Table 5.7.1 for exposures.

b. See Table 6.3.1 for exposures. Incidental oral exposure only represents hand-to-mouth exposure for purposes of the aggregate assessment. 

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

d. See Table 6.3.1 for exposures.

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

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

exposure.

6.3 Chronic Aggregate Risk

Since there are no registered/proposed uses that result in chronic residential exposure, the 

chronic aggregate exposure assessment consists of exposure from food and water. The chronic 

dietary exposure estimate was ≤1% the cPAD and, therefore, does not exceed HED’s LOC (see 

Section 5.2). 

6.4 Cancer Aggregate Risk

An aggregate cancer risk assessment was not performed because metaflumizone is not 

considered to be a carcinogen. 

7.0 Cumulative Risk Characterization/Assessment

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

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

metaflumizone and any other substances; and metaflumizone does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has assumed that metaflumizone does not have a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

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

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

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

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

8.0 Occupational Exposure/Risk Characterization

D393547, K. Lowe, 20-Sep-11

D393548, K. Lowe, 20-Sep-11

There are two proposed products that may result in occupational handler and post-application 

exposure: (1) Metaflumizone Fly Bait for use around industrial buildings, commercial facilities, 

agricultural structures and premises, recreational facilities and outdoor recreational areas; and (2) 

Altrevin Fire Ant Bait Insecticide for use as a soil treatment in citrus orchards, tree nut orchards, 

grape vineyards, nonbearing stone and pome fruit orchards and in nurseries containing 

nonbearing container- or field-grown stone and pome fruit tree stock.

Note: The proposed use as an agricultural fire ant bait was previously assessed (D367561, M. 

Dow, 07-Dec-09), but revisions have been made to account for the revisions to the FQPA SF 

(D393547, K. Lowe, 20-Sep-11).

8.1 Occupational Handler Exposure

The proposed products are both solid bait formulations. Metaflumizone Fly Bait is to be used as 

a scatter bait for broadcast treatment or placed in bait stations/trays. Altrevin Fire Ant Bait 
Metaflumizone Human-Health Risk Assessment D393447

Page 28 of 39

Insecticide can be used for broadcast and individual mound applications. 

Dermal and inhalation exposures/risks were estimated for handlers involved in mixing/loading 

activities for granular formulations for tractor-drawn spreader equipment, applying granulars via 

tractor-drawn spreader or by hand, and mixing/loading/applying activities for handheld 

equipment, such as push-type spreaders, belly grinders and spoons. The metaflumizone product 

labels require long-sleeved shirt and long pants and chemical-resistant gloves as dermal PPE for 

all applicators and other handlers. 

No chemical-specific handler exposure data were submitted in support of this Section 3 

registration. To assess handler exposures for regulatory actions when chemical-specific 

monitoring data are not available, HED relies on the most scientifically reliable surrogate data 

currently available from various sources such as PHED, AHETF, and ORETF. Some of this 

data, such as the industry task force data, is compensatory, subject to the data protection 

provisions of FIFRA. HED policy on use of surrogate data is described in more detail on the 

Agency's website (http://www.epa.gov/pesticides/science/handler-exposure-data.html). 

Scenario-specific surrogate exposure data, including their sources, are presented in the 

“Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” 

(http://www.epa.gov/pesticides/science/handler-exposure-table.pdf). 

Typically, HED completes short- and intermediate-term assessments for occupational scenarios 

in all cases because these kinds of exposures are likely and acceptable use/usage data are not 

available to justify deleting intermediate-term scenarios. Based on use data and label 

instructions, HED believes that occupational exposures may occur over a single day or up to 

weeks at a time for many use-patterns and that intermittent exposure over several weeks may

also occur. Some applicators may apply these products over a period of weeks, because they are 

commercial applicators who are completing multiple applications for multiple clients. Longterm exposures are not expected, therefore, a long-term assessment was not conducted. 

Dermal and inhalation risks were combined in this assessment, since the toxicological effects for 

these exposure routes were similar. A total ARI was used since the LOCs for dermal exposure 

(100) and inhalation exposure (1000) are different. The target ARI is 1; therefore, ARIs of less 

than 1 are risks of concern. 

Table 8.1.1 presents the exposure/risks for short- and intermediate-term dermal and inhalation 

exposures at baseline and with gloves. The dermal and inhalation exposure risks for

mixer/loaders, applicators and mixer/loader/applicators are not of concern (i.e., MOEs >100 for 

dermal and >1000 for inhalation; ARIs >1) at baseline and with the addition of gloves. 
Metaflumizone Human-Health Risk Assessment D393447

Page 29 of 39

Table 8.1.1. Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Metaflumizone. 

Exposure Scenario Use Site Mitigation1

Dermal 

Unit 

Exposure

(ug/lb ai)2

Inhalation 

Unit 

Exposure

(ug/lb ai)2

Application 

Rate3

Amount 

Treated 

Daily4

Dermal Inhalation

ARI9

Dose

(mg/kg/day)5 MOE6 Dose(mg/kg/day)7 MOE8

MIXER/LOADER

Mixing / Loading 

Granules for Tractor 

Drawn Spreader 

Applications

Fire Ant 

Bait

Baseline 8.4 1.7 0.001 lb 

ai/acre 40 acres

0.0000048 21,000,000 9.70E-07 8,200,000 7,900

PPE-G 6.9 NA 0.0000039 25,000,000 NA NA 35,000

Fly Bait

Baseline 8.4 1.7 0.014 lb 

ai/acre 40 acres

0.000067 1,500,000 1.40E-05 590,000 570

PPE-G 6.9 NA 0.000055 1,800,000 NA NA 2,500

APPLICATOR

Applying Granules 

via Tractor Drawn 

Spreader

Fire Ant 

Bait

Baseline 9.9 1.2 0.001 lb 

ai/acre 40 acres

0.0000057 18,000,000 6.90E-07 12,000,000 11,000

PPE-G 7.2 NA 0.0000041 24,000,000 NA NA 47,000

Fly Bait

Baseline 9.9 1.2 0.014 lb 

ai/acre 40 acres

0.000079 1,300,000 9.60E-06 830,000 780

PPE-G 7.2 NA 0.000058 1,700,000 NA NA 3,400

Applying Granules 

by Hand

Fire Ant 

Bait

Baseline 104000 470 0.000078 lb 

ai/mound

5 

mounds

0.00058 170,000 2.60E-06 3,100,000 1,100

PPE-G 71000 NA 0.0004 250,000 NA NA 2,100

Fly Bait

Baseline 104000 470 0.017 lb 

ai/acre 0.5 acre

0.013 7,900 5.70E-05 140,000 51

PPE-G 71000 NA 0.0086 12,000 NA NA 100

MIXER/LOADER/APPLICATOR

Mixing / 

Loading/Applying 

Granulars via "Push 

Type" Rotary 

Spreader

Fire Ant 

Bait

Baseline 440 10 0.001 lb 

ai/acre 5 acres

0.000031 3,200,000 7.10E-07 11,000,000 8,200

PPE-G 240 NA 0.000017 5,800,000 NA NA 28,000

Fly Bait

Baseline 440 10 0.014 lb 

ai/acre 5 acres

0.00044 230,000 1.00E-05 800,000 590

PPE-G 240 NA 0.00024 420,000 NA NA 2,000

Applying Ready to 

Use Granular by 

Spoon (MRID 

#452507-01; 

Fipronil study)

Fire Ant 

Bait

Baseline No Data 45 0.000078 lb 

ai/mound

5 

mounds

No Data No Data 2.50E-07 32,000,000 No Data 

PPE-G 2000 NA 0.000011 9,000,000 NA NA 58,000

Fly Bait

Baseline No Data 45 0.017 lb 

ai/acre 0.5 acre

No Data No Data 5.50E-06 1,500,000 No Data

PPE-G 2000 NA 0.00024 410,000 NA NA 2,600

Mixing / Fire Ant Baseline 10000 62 0.001 lb 1 acre 0.00014 700,000 8.90E-07 9,000,000 3,900
Metaflumizone Human-Health Risk Assessment D393447

Page 30 of 39

Table 8.1.1. Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Metaflumizone. 

Exposure Scenario Use Site Mitigation1

Dermal 

Unit 

Exposure

(ug/lb ai)2

Inhalation 

Unit 

Exposure

(ug/lb ai)2

Application 

Rate3

Amount 

Treated 

Daily4

Dermal Inhalation

ARI9

Dose

(mg/kg/day)5 MOE6 Dose(mg/kg/day)7 MOE8

Loading/Applying 

Granulars via Belly 

Grinder

Bait PPE-G 9300 NA ai/acre 0.00013 750,000 NA NA 6,400

Fly Bait

Baseline 10000 62 0.014 lb 

ai/acre 1 acre

0.002 50,000 1.20E-05 650,000 280

PPE-G 9300 NA 0.0019 54,000 NA NA 460

1 Level of mitigation: Baseline and PPE-G (gloves). Gloves are recommended PPE on proposed label.

2 PHED/ORETF/AHETF 

3 Based on proposed label (Reg. No. #7969-xxx)

4 Exposure Science Advisory Council Policy #9.1

5 Dermal Dose = Dermal Unit Exposure (mg/kg) × Application Rate (lb ai/acre) × Amount Treated (acres/day) / BW (70 kg)

6 Dermal MOE = Dermal NOAEL (100 mg/kg/day) ÷ Dermal Dose (mg/kg/day). LOC = 100.

7 Inhalation Dose = Inhalation Unit Exposure (mg/kg) × Application Rate (lb ai/acre) × Amount Treated (acres/day) ÷ BW (70 kg)

8 Inhalation MOE = Inhalation NOAEL (8 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). LOC = 1000.

9 ARI (Aggregated Risk Index) = 1 / ((1 ÷ (Dermal MOE ÷ Dermal LOC)) + (1 ÷ (Inhalation MOE ÷ Inhalation LOC))). Baseline dermal and PPE-G Dermal combined with 

Baseline Inhalation.
Metaflumizone Human-Health Risk Assessment D393447

Page 31 of 39

8.2 Occupational Post-application Exposure

Occupational dermal postapplication exposure was not assessed. With regard to the fly bait use, 

it is not anticipated that workers will be exposed after application of the fly bait. HED believes 

the presence of commercial workers in treated areas is minimal after application. With regard to 

the fire ant bait use, dermal contact with treated surfaces is not expected; all applications are 

directed towards the soil surface. In addition, workers are not expected to frequent areas infested 

with active fire ants. For these reasons, a quantitative dermal post-application assessment has 

not been conducted. 

Based on the Agency's current practices, a quantitative occupational post-application inhalation 

exposure assessment was not performed for metaflumizone at this time. However, there are 

multiple potential sources of post-application inhalation exposure to individuals performing postapplication activities in previously treated fields. These potential sources include volatilization 

of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency

sought expert advice and input on issues related to volatilization of pesticides from its Federal 

Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in 

December 2009. The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for metaflumizone. 

8.3 Restricted Entry Interval

For the fly bait product, a REI is not required since the proposed use sites are non-agricultural 

sites. For the fire ant bait (citrus fruit, grapes, and tree nuts), a REI is required on the label and 

the draft label lists a 12-hour REI. Metaflumizone is classified in Acute Toxicity Category IV 

for acute dermal toxicity, acute inhalation toxicity, primary eye irritation, primary dermal 

irritation and it is not a dermal sensitizer. Therefore, the interim WPS REI of 12 hours is 

adequate to protect agricultural workers from post-application exposures. 

9.0 Data Deficiencies

9.1 Toxicology

 None.

9.2 Residue Chemistry

 A revised Section B is requested which list the crops for each crop group as defined in 40 

CFR 180.41 and eliminates the "including but not limited to" phrase.

 A revised Section F with the tolerance expression, commodity definitions, and numerical 

tolerances described as follows: Tolerances are established for residues of the insecticide 

metaflumizone, including its metabolites and degradates, in or on the commodities in the 

table below. Compliance with the tolerance levels specified below is to be determined by 
Metaflumizone Human-Health Risk Assessment D393447

Page 32 of 39

measuring only the sum of metaflumizone (E and Z isomers; 2-[2-(4-cyanophenyl)-1-[3-

(trifluoromethyl)phenyl]ethylidene]-N-[4-(trifluoromethoxy)phenyl] 

hydrazinecarboxamide) and its metabolite 4-{2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl}-

benzonitrile, calculated as the stoichiometric equivalent of metaflumizone, in or on the 

following commodities: Fruit, citrus, group 10 - 0.04 ppm; Nut, tree, group 14 - 0.04 

ppm; Almond, hulls - 0.04 ppm; and Grape - 0.04 ppm. 

 Standards of the metaflumizone (E and Z isomers) and 4-{2-oxo-2-[3-

(trifluoromethyl)phenyl] ethyl}-benzonitrile should be submitted to the EPA National 

Pesticide Standards Repository. 

 Cabbage metabolism study (46264326.der.wpd) - Information pertaining to sample 

extraction and analysis dates is required; if the interval from harvest to analysis is greater 

than the currently validated interval, then additional storage stability data will also be 

necessary. 

 Cotton metabolism study (46264324.der.wpd) - Individual concentrations of the 

unknowns should be reported; if any unknown comprises >10% TRR, then further 

characterization/ identification procedures may be required (based on these data 

additional residues may be included for risk assessment). 

 Storage stability data - To support the subject field trial and processing studies, the 

following storage stability data are required which demonstrate the stability of 

metaflumizone (E and Z isomers) and M320I04: grapes - 4.8 months; citrus fruit - 5.6 

months; almond hulls - 6.5 months; and almond nutmeat - 5.8 months. 

9.3 Occupational and Residential Exposure

 None.
Metaflumizone Human-Health Risk Assessment D393447

Page 33 of 39

Appendix A. Toxicity Profile Tables

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]

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 D393447

Page 34 of 39

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

Acceptable (non-guideline)

28-day oral mice 

(dietary)

47036905 (1999/2007)

0, 50, 200, or 800 ppm (equivalent 

to 0, 10, 42, or 101 mg/kg/day 

Acceptable (non-guideline)

NOAEL = 50 ppm (10 mg/kg/day)

LOAEL = 200 ppm (42 mg/kg/day) based on decreased food 

consumption, body-weight gains, and body 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)

8703465

28-day inhalation

rats 

47839301 (2004)

0, 0.03, 0.10, or 0.70 mg/L

Acceptable (non-guideline)

NOAEL= 0.03 mg/L (M) and not 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 

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 
Metaflumizone Human-Health Risk Assessment D393447

Page 35 of 39

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

group)

Acceptable (guideline)

increased bilirubin, increased urobilinogen, and increased 

hemosiderin in the liver

870.4200

Carcinogenicity

mice (gavage)

46264314 (2003)

0, 100, 250 or 1000 mg/kg/day

Acceptable (guideline)

NOAEL = 250 mg/kg/day

LOAEL = 1000 mg/kg/day (limit dose), based on incr. hemosiderin in 

the spleen, increased mean absolute reticulocyte count, and decreased 

mean corpuscular volume and mean corpuscular hemoglobin (M&F); 

and decreased BW gain (M).

No evidence of carcinogenicity.

870.4300

Chronic 

Toxicity/Carcinogeni

city rats (gavage)

46264240 (2003)

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

(high dose reduced to 200 

mg/kg/day in females after 2 weeks 

of treatment)

Acceptable (guideline)

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

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

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

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

No evidence of carcinogenicity.

870.5100

In Vitro bacterial 

reverse mutation (S. 

typhimurium/E. coli)

46264304 (2001)

15, 50, 150, 500, or 5000 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

Inconclusive with metabolic activation due to compound precipitation 

at all concentrations tested

870.5375

In Vitro mammalian 

chromosomal 

aberration (V79)

46264309 (2002)

0, 3.125, 6.25, 12.5, 25.0 or 50.0 μ

g/mL (- activation);

0, 25.0, 50.0 or 100.0 μ g/mL (+ 

activation)

Acceptable (guideline)

Positive without metabolic activation at soluble (12.5 μ g/mL) and 

insoluble (≥ 25 μ g/mL) concentrations. 

Negative with metabolic activation.

870.5395

In Vivo mammalian 

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 46264319 (2003) NOAEL = 36 mg/kg/day
Metaflumizone Human-Health Risk Assessment D393447

Page 36 of 39

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

Subchronic 

neurotoxicity rats 

(gavage)

0, 12, 36, 150 or 300 mg/kg/day

Acceptable (guideline)

LOAEL = 150 mg/kg/day, based on death, reduced general condition, 

and piloerection (M&F); hyperthermia (M); abnormal squatting 

posture, hypothermia, decreased BW, BW gain, and food 

consumption (F)

870.6300

Developmental 

Neurotoxicity

rats (gavage) (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 2 

doses were excreted in the feces. Biliary excretion accounted for <5% 

of the low dose and <2% of the high dose. Urinary excretion was also 

low at 1-2%. The absorbed doses were distributed quickly to the 

muscle, liver, kidney, and fat within 0.5-2 hours. Total radioactivity 

in muscle, liver, kidney, blood, and plasma reached maximal levels at 

or near the blood Tmaxirrespective 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, 

body weight gains, and food consumption.

Z-isomer

870.3100

3-month oral

rats - gavage

46264301 (2004)

0, 100, 300 or 1000 mg/kg/day

Acceptable (guideline)

NOAEL = 100 (F) and 300 (M) mg/kg/day 

LOAEL = 300 (F) and 1000 (M) mg/kg/day, based on mortality, 

clinical signs (reduced general condition and piloerection), and 

lymphocyte necrosis in the mesenteric lymph node (F) and decreased 

motor activity (M&F)

870.5100

In Vitro bacterial 

reverse mutation (S. 

46264305 (2002)

20-5000 μ g/plate (std. plate test) (-

Negative with and without metabolic activation.

Negative with and without metabolic activation.
Metaflumizone Human-Health Risk Assessment D393447

Page 37 of 39

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

typhimurium/E. coli) /+ activation)

4-2500 μ g/plate (preincubation 

assay) (-/+ activation)

Acceptable (guideline)

Metabolite M320I23

870.3100

3-month oral rats -

gavage

46264242 (2004)

0, 50, 200, or 1000 mg/kg/day

Acceptable (guideline)

NOAEL = 1000 mg/kg/day (HDT)

LOAEL > 1000 mg/kg/day

870.5100

In vitro bacterial 

reverse mutation (S. 

typhimurium, E. coli)

46264306 (2003)

20, 100, 500, 2500, or 5000 

μg/plate (std. plate test) (-/+ 

activation) 

62.5, 125, 250, 500, 1500 μg/plate 

(preincubation assay) (-/+ 

activation)

Acceptable (guideline)

Negative with and without metabolic activation.

Negative with and without metabolic activation.

870.5300

In Vitro mammalian 

gene mutation 

(CHO/HGPRT)

46264308 (2004)

0, 0.125, 0.25, 0.5, 1.0, 2.0, 2.5, 3.0, 

3.5, 4.0, 4.5, 5.0, or 6.0 μ g/mL (-

activation)

0, 1.25, 2.5, 3.125, 5, 6.25, 10, 12.5, 

15, 20, 25, 30, 40, 50, or 100 μ

g/mL (+ activation) 

Unacceptable (guideline)

Negative without metabolic activation.

Inconclusive with metabolic activation due to compound precipitation 

at all concentrations tested

870.5375

In Vitro mammalian 

chromosomal 

aberration (V79)

46264310 (2004)

0, 0.25, 0.5 or 1.0 μg/mL (-

activation)

0, 1.0, 5.0, 7.5, 10.0 or 12.5 μg/mL 

(+ activation)

Acceptable (guideline)

Negative without metabolic activation.

Positive with metabolic activation.

870.5395

In Vivo mammalian 

cytogenetics (mouse 

micronucleus)

46264312 (2004)

0, 500, 1000 or 2000 mg/kg 

Acceptable (guideline)

Negative.
Metaflumizone Human-Health Risk Assessment D393447

Page 38 of 39

Appendix B. Chemical Names and Structures

Common name/code Chemical name Chemical structure

Metaflumizone E isomer

4-{(2E)-2-({[4-(trifluoromethoxy)-

anilino]carbonyl}hydrazono)-2-[3-

(trifluoromethyl)phenyl]ethyl}-

benzonitrile

2-[2-(4-cyanophenyl)-1-[3-

trifluoromethyl)phenyl]ethylidene]-N-[4-

hydrazinecarboxamide (E)

Metaflumizone Z isomer

2-[2-(4-cyanophenyl)-1-[3-

trifluoromethyl)phenyl]ethylidene]-N-[4-

hydrazinecarboxamide (Z)

F3C

N

H

N OCF3

CN

O

HN

M320I04

4-{2-oxo-2-[3-

(trifluoromethyl)phenyl]ethyl}-

benzonitrile

M320I05

(CL 65504) p-trifluoromethoxyaniline

M320I06

(found in tomato and cattle 

urine)

4-cyanobenzoic acid

M320I07

2-[2-(4-cyanophenyl)-2-hydroxy-1-[3-

trifluoromethyl)phenyl]ethylidene]-N-[4-

hydrazinecarboxamide

M320I10

M320I13 {[(4_cyanophenyl)acetyl]amino}acetic 

acid

M320I17

(isolated and identified in goat 

urine)

oxo{[4_(trifluoromethoxy)phenyl]amino}

acetic acid

M320I22 (E and Z isomers) --

CN

N

N

H

N

H

O

O

F3C

CF3

H2N

O

CF3

CN

O

HO

O

OH

OH

HO

O

COOH

CN

F3C

N

H

O

O

CF3

HO

O

CN

N

N

H

N

H

O

O

F

3

C

CF3

OH
Metaflumizone Human-Health Risk Assessment D393447

Page 39 of 39

Common name/code Chemical name Chemical structure

M320I23

4-{5-hydroxy-3-oxo-4-[4-

(trifluoromethoxy)phenyl]-6-3-

(trifluoromethyl)phenyl]-2,3,4,5-

tetrahydro-1,2,4-triazin-5-yl}benzonitrile

M320I24 (E and Z isomers) --

M320I25

4-{2-hydroxy-2-[3-

(trifluoromethyl)phenyl]ethyl}-

benzonitrile

M320I26

4-amino-5-{2-(4-cyanophenyl)-1-[3-

(trifluoromethyl)phenyl]ethoxy}-5-

oxopentanoic acid

M320I28

(hydrolysis product of 

Metaflumizone)

N-[4-(trifluoromethoxy)phenyl]-

acetamide

CN

N

F3C NH

N O

O

F3C

HO

CN

N

N

H

N

H

O

O

F3C

CF3

O

O

OH

OH

OH

HOOC

CN

O

F3C

O

NH2

COOH

HC3 N

H

O

O

CF3