Problem Formulation for the 

Environmental Fate, Ecological Risk, Endangered 

Species, and Drinking Water Assessments 

in Support of the Registration Review of 

Hexaflumuron 

1-(3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl) -3-(2,6-difluorobenzoyl) urea. 

(Hexaflumuron CAS 86479-06-3) 

Prepared by:

Charles Peck, Fate Scientist 

Kristina Garber, Biologist

Reviewed by: 

Thomas Steeger, Senior Biologist 

Marietta Echeverria, Risk Assessment Process Leader 

Elizabeth Behl, Branch Chief

U. S. Environmental Protection Agency 

Office of Pesticide Programs 

Environmental Fate and Effects Division 

Environmental Risk Branch IV 

1200 Pennsylvania Ave., NW 

Mail Code 7507P 

Washington, DC 20460

August 12, 2009 

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Table of Contents 

1. Purpose 4 

2. Problem Formulation ..................................................................................................... 4 

2.1. Nature of Regulatory Action.................................................................................... 4 

2.2. Previous Risk Assessments...................................................................................... 4 

3. Stressor Source and Distribution .................................................................................... 5 

3.1. Mechanism of Action............................................................................................... 5 

3.2. Overview of Pesticide Usage................................................................................... 5 

3.3. Environmental Fate and Transport........................................................................... 6 

4. Receptors9 

4.1. Effects to Aquatic Organisms .................................................................................. 9 

4.2. Effects to Terrestrial Organisms ............................................................................ 10 

4.3. Effects of Degradates............................................................................................. 11 

4.4. Incident Database Review...................................................................................... 11 

4.5. Ecosystems Potentially at Risk .............................................................................. 12 

5. Assessment Endpoints .................................................................................................. 12 

6. Conceptual Model........................................................................................................ 12 

6.1. Risk Hypothesis ..................................................................................................... 12 

6.2. Conceptual Diagram .............................................................................................. 13 

7. Analysis Plan ............................................................................................................... 14 

7.1. Stressors of Concern .............................................................................................. 14 

7.2. Measures of Exposure............................................................................................ 14 

7.3. Measures of Effect ................................................................................................. 15 

7.4. Integration of Exposure and Effects ...................................................................... 16 

7.5. Deterministic and Probabilistic Assessment Methods........................................... 16 

7.6. Endangered Species Assessments.......................................................................... 16 

7.7. Drinking Water Assessment .................................................................................. 17 

7.8. Preliminary Identification of Data Gaps................................................................ 17 

7.8.1. Use Information .............................................................................................. 17 

7.8.2. Fate.................................................................................................................. 17 

7.8.3. Effects ............................................................................................................. 19 

8. References.................................................................................................................... 23 

Appendix A. Hexaflumuron and Degradates.................................................................... 26 

Appendix B. Fate Parameters For Hexaflumuron Degradates, Estimated Using EPISuite 

v. 4.0............................................................................................................. 28 

Appendix C. Data Call-In Tables...................................................................................... 29 

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1. Purpose 

The purpose of this problem formulation is to provide an understanding of what is known 

about the environmental fate and ecological effects of the registered uses of 

hexaflumuron. Hexaflumuron is a benzoylphenylurea compound used as termite bait; the 

compound is designed to regulate insect growth. This document will provide a plan for 

analyzing data on hexaflumuron and for conducting relevant environmental fate, 

ecological risk, endangered species and drinking water assessments for its registered 

uses. Additionally, this problem formulation is intended to identify data gaps, 

uncertainties, and potential assumptions used to address those uncertainties relative to 

characterizing the ecological risk associated with the registered uses of hexaflumuron. 

2. Problem Formulation 

2.1. Nature of Regulatory Action 

Under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), all pesticides 

distributed or sold in the United States generally must be registered by EPA. In 

determining whether a pesticide can be registered in the U.S., EPA evaluates its safety to 

non-target species based on a wide range of environmental and health effects studies. In 

1996, FIFRA was amended by the Food Quality Protection Act, and EPA was mandated 

to implement a new program for the periodic review of pesticides, i.e., registration review 

(http://www.epa.gov/oppsrrd1/registration_review/). The registration review program is 

intended to ensure that, as the ability to assess risk evolves and as policies and practices 

change, all registered pesticides continue to meet the statutory standard of no 

unreasonable adverse effects to human health and the environment. Changes in science, 

public policy, and pesticide use practices will occur over time. Through the new 

registration review program, the Agency periodically reevaluates pesticides to make sure 

that as change occurs, products in the marketplace can be used safely. 

As part of the implementation of the new Registration Review program pursuant to 

Section 3(g) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), the 

Agency is beginning its evaluation of hexaflumuron to determine whether it continues to 

meet the FIFRA standard for registration. This problem formulation for the 

environmental fate, ecological risk, endangered species, and drinking water assessment 

chapter in support of the registration review will be posted in the initial docket opening 

the public phase of the review process. 

2.2. Previous Risk Assessments 

Hexaflumuron is registered as an insecticide for controlling termites. Hexaflumuron is 

applied in above- and below-ground termite bait systems. Given this application method, 

it has historically been viewed as a “closed system” with minimal likelihood of 

environmental exposure. Therefore, there are no previous ecological risk assessments or 

drinking water exposure assessments for this chemical. 

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3. Stressor Source and Distribution 

3.1. Mechanism of Action 

Hexaflumuron, 1-(3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl)-3-(2,6-difluorobenzoyl) urea, is an insecticide used to control termites. Hexaflumuron is a chitin 

synthesis inhibitor, which disrupts the molting process of various insects, resulting in 

death of immature stages when they molt. The mode of action is slow and allows a large 

number of worker termites to feed on the bait. A decline in the number of workers is 

followed by a collapse of the colony, as there are insufficient workers to support 

dependent castes (MRID 45516725). 

3.2. Overview of Pesticide Usage 

Hexaflumuron was originally registered for use in the United States in March 1994, as a 

reduced risk pesticide. Hexaflumuron is used in conjunction with a monitoring system to 

control outbreaks of termites after a termite problem has been identified. Currently, 

hexaflumuron is registered for use in above- and below-ground termite bait systems. 

There are two active Section 3 products containing hexaflumuron (Recruit® AG, 

registration number 62719-270 and Shatter®, registration number 62719-272). 

In the Recruit® AG system, the bait station is a rectangular, rigid plastic housing 

containing 100-105 grams of the bait matrix (500-525 milligrams of hexaflumuron). The 

bait matrix takes the shape of "briquettes", roughly 5/8 inch long by 3/16 inch diameter. 

The remainder of the matrix contains a cellulose, inert carrier. After installation, if the 

bait matrix appears to be at least 1/3 to 1/2 consumed, a supplemental bait station can be 

stacked on top of the existing station. The bait station can be installed in food and 

nonfood areas, including, but not limited to, restaurants, grocery stores, bakeries, bottling 

plants, canneries, meat and poultry processing plants and grain mills. Treatment sites 

may include interior and exterior surfaces of buildings and crawl spaces, fences, utility 

poles, decking, landscape decorations, trees, and other features which could be damaged 

by termite foraging and feeding activity. 

In the Shatter® bait station, the 60-65 grams of bait matrix (300-325 milligrams of 

hexaflumuron) is contained within clear plastic tube with holes large enough to allow a 

worker termite to enter/exit. The bait matrix is the same formulation as that used in the 

above ground system. The sturdy plastic outer tube is put into the ground at various 

intervals and in likely places around susceptible wood structures so that the top plate rests 

on the soil surface. The tube containing the bait is placed into the underground bait 

station only after termites are detected. Once the population is suppressed or eradicated 

and no further feeding is observed, the clear plastic bait tubes are replaced with 

monitoring devices consisting of two strips of wood stapled loosely together along one 

edge of each piece. These devices are checked occasionally for the presence of termites. 

If there are termites feeding on the monitoring device, the monitoring device is replaced 

with the bait tube, with the termites being placed in the bait tube. 

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Hexaflumuron comprises 0.5% (w/w) of both products (approximately 0.5 g a.i. per 100 

g of product). Current labels for hexaflumuron products (Recruit® AG and Shatter®) do 

not specify the amount of product present in each bait station. In addition, labels do not 

specify the maximum number of bait stations that can be present on a designated area of 

land. Therefore, as the labels are now, application rates of hexaflumuron applied to a unit 

area (i.e., lbs a.i./A) cannot be determined. 

3.3. Environmental Fate and Transport 

Best-available data defining the physical, chemical, fate and transport characteristics 

associated with hexaflumuron are summarized in Table 1. 

Table 1. General chemical and environmental fate properties of hexaflumuron. 

Chemical/Fate parameter Value Source (MRID) Study 

Classification 

Molecular Weight (g/mol) 461 NA 

Vapor Pressure (torr) 4.43 x 10-11 426485-05 

Octanol-water Partition Coefficient 

(KOW) 

2.90 x 105 426485-05 

Water Solubility (mg/L; at 20°C) 0.027 426485-05 

Hydrolysis half-lives (days) Stable, pH=5 and 7 

22.5, pH=9 

426485-26 Acceptable 

Aerobic Soil Metabolism half-life 

(days) 

110 (Castle Rising sandy loam, UK) 

160 (Alconbury clay loam, UK) 

200 (Catlin silt loam, US) 

280 (Hanford sandy loam, US) 

426959-01 Supplemental 

Anaerobic Soil Metabolism halflife (days) 

54 (Hanford sandy loam, US) 

57 (Castle Rising sandy loam, UK) 

69 (Catlin silt loam, US) 

72 (Alconbury clay loam, UK) 

426959-01 Supplemental 

Leaching/Mobility Koc (L/kg) 6,092 – 7,272 

(range of 2 values) 

Estimated 

EPISuite v4.0 

NA 

NA = not applicable 

The primary route of dissipation for hexaflumuron, once in the soil, will be anaerobic and 

aerobic metabolism. Hexaflumuron is stable to hydrolysis at neutral to acidic pHs, but 

degrades with a half-life of 22.5 days in alkaline pHs. Given the methods of application 

(e.g., above- and below-ground bait stations), the material will not be subject to 

photodegradation when used as proposed. Koc estimates from EPISuite indicate that 

hexaflumuron is slightly to hardly mobile (Kashuba, 2006). Hexaflumuron's low 

solubility in water, high octanol-water partition coefficient, and predicted slight mobility 

in soil indicate that hexaflumuron will not dissolve in any moisture that may enter the 

bait stations, so that exposure from runoff from the bait stations should not be an issue. 

Any amount of hexaflumuron that leaches from the bait stations should bind readily to 

the soil. Additionally, current label restrictions prohibiting the use of the bait stations “in 

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depressions, low areas, near ponds, streams, springs, other water sources, or near 

downspout openings when the bait or its hexaflumuron contents could be washed out of 

the bait station into water at or near the surface of the ground”, reduce, if not eliminate, 

the chances for hexaflumuron to migrate to surface and ground water. Although the 

mobility of hexaflumuron’s degradates has not been adequately determined, it appears 

that the degradates, which are produced in small quantities, are not highly mobile. Given 

hexaflumuron’s low vapor pressure and application methods, volatilization of the active 

ingredient should not occur. 

Hexaflumuron’s persistence in aerobic and anaerobic environments has not adequately 

been determined, as the combined aerobic and anaerobic soil metabolism study (MRID 

426959-01) was classified as supplemental. Under aerobic soil conditions, anilinelabeled hexaflumuron degraded with a half-life of 110-260 days in U.S. and U.K. soils. 

The aerobic metabolism study does not fulfill the data requirements because: (1) one 

major degradate (M8 at 11% of the applied rate at 180 days) from the aniline-labeled 

study was not identified; and, (2) a low material balance (up to 55% of the applied 

radioactivity was not accounted for by the termination of the study) in the benzoyllabeled portion of the study prevented reliable interpretation of the data. Under anaerobic 

soil conditions using the same soils, aniline-labeled hexaflumuron degraded with a halflife of 40-72 days. As in the aerobic soil metabolism study, the benzoyl-labeled portion 

of the study was not acceptable because of low material balances (up to 60% of the 

applied radioactivity was not accounted for by the termination of the study). Given the 

current state of the data, hexaflumuron is not expected to be persistent in anaerobic 

environments while it is likely to be moderately persistent in aerobic environments. 

Table 2 depicts the major degradates identified in the hexaflumuron fate studies. One 

degradate, M8, was recovered in the aerobic soil metabolism study at a maximum of 11% 

of the amount applied in one soil sample; however, the degradate was not named nor was 

a structure provided, and it is unclear if it is a degradate separate from those already 

identified in other studies. A minor degradate, 2,6-difluorobenzamide, was recovered in 

the hydrolysis study, at 8% of the applied radioactivity. Remaining fate data pertaining 

to these degradates are not available. However, estimated vapor pressures, solubilities, 

and Kocs using EPISuite (see Appendix B) indicate that these major degradates are much 

more volatile, soluble, and mobile than there parent compound. 

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Table 2. Hexaflumuron Degradates 

Fate Study Soil Type Phenylamine1 Phenylurea2 DBA3 M8 MRID 

Hydrolysis NA 

10% 

(Day 33) 

59% 

(Day 37) 

55% 

(Day 33) 

ND 426485-26 

Hanford sandy loam 12% (Day 30) ND ND 3% (Day 365) 

Catlin silt loam 18% (Day 120) ND ND 5% (Day 365) 

Alconbury clay loam 18% (Day 60) ND ND 7% (Day 365) 

Aerobic 

Soil 

Metabolism 

Castle Rising sandy loam 20% (Day 120) ND ND 11% (Day 180) 

426959-01 

Hanford sandy loam 16% (Day 60) ND ND 4% (Day 90) 

Catlin silt loam 15% (Day 60) ND ND 5% (Day 90) 

Alconbury clay loam 17% (Day 60) ND ND 5% (Day 90) 

Anaerobic 

Soil 

Metabolism 

Castle Rising sandy loam 18% (Day 90) ND ND 2% (Day 90) 

426959-01 

1. 3,5-dichloro-4-(l,l,2,2-tetrafluoroethoxy) phenylamine 

2. 3,5-dichloro-4-(l,l,2,2-tetrafluoroethoxy)phenylurea 

3. 2,6-difluorobenzoic acid 

At this time, no empirical data are available to demonstrate the bioaccumulation potential 

of hexaflumuron or any of its environmental degradates. Bioconcentration and 

bioaccumulation factors (BCFs and BAFs, respectively) can be estimated for each of 

these chemicals using KABAM v1.0. BCFs and BAFs for hexaflumuron and its major 

environmental degradates estimated using Kow values (estimated from EPISuite v4.0) 

entered into KABAM v1.0 are depicted in Table 3. Based on these estimated BCFs and 

BAFs hexaflumuron has the potential to concentrate and accumulate in tissues of fish. By 

comparison, hexaflumuron’s major environmental degradates are expected to accumulate 

at levels that are at least 2 orders of magnitude less than the parent.

Table 3. Estimated Log Kow values for hexaflumuron and its major environmental degradates and 

corresponding BCF and BAF values representative of large fish.

Chemical Log Kow Estimated BCF 2,3 Estimated BAF2,3

Hexaflumuron 5.46 20,975 166,712 

3,5-Dichloro-4-(l,l,2,2-tetrafluoroethoxy)

phenylamine 

3.771

284 296 

3,5-Dichloro-4-(l,l,2,2-tetrafluoroethoxy)

phenylurea 

3.401

121 124 

2,6-Difluorobenzoic acid 1.591 2.6 2.6 

1

Estimated using EpiSuite v4.0. 

2

Representative of large fish. 

3

 BCFs and BAFs generated using default settings in KABAM. 

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4. Receptors 

Consistent with the process described in the Overview Document (U.S. EPA 2004), the 

risk assessment for hexaflumuron will rely on a surrogate species approach. 

Toxicological data generated from surrogate test species, which are intended to be 

representative of broad taxonomic groups, will be used to extrapolate to potential effects 

on a variety of species (receptors) included under these taxonomic groupings. 

Acute and chronic toxicity data from studies submitted by pesticide registrants along with 

the available open literature will be used to evaluate the potential direct and indirect 

effects of hexaflumuron to aquatic and terrestrial receptors. This includes toxicity on the 

technical grade active ingredient, degradates, and when available, formulated products 

(e.g., “Six-Pack” studies). The open literature studies will be identified through EPA’s 

ECOTOXicology (ECOTOX) database (USEPA 2007d), which employs a literature 

search engine for locating chemical toxicity data for aquatic life, terrestrial plants, and 

wildlife. The evaluation of both sources of data may also provide insight into the direct 

and indirect effects of hexaflumuron on biotic communities from loss of species that are 

sensitive to the chemical and from changes in structure and functional characteristics of 

the affected communities. 

A summary of the aquatic and terrestrial toxicity data is provided in Sections 4.1 and 4.2, 

respectively. In addition, a summary of ecological incidents associated with 

hexaflumuron and a description of ecosystems potentially at risk are provided in Sections 

4.3 and 4.4, respectively. 

4.1. Effects to Aquatic Organisms 

Data are available to define the toxicity of hexaflumuron to freshwater aquatic animals on 

an acute exposure basis. For both freshwater fish species tested, the median lethal 

concentration exceeded the highest concentration tested. Hexaflumuron is classified 

highly toxic to freshwater fish and very highly toxic to freshwater invertebrates (Table 

4). No data are available defining the toxicity of hexaflumuron to freshwater aquatic 

animals on a chronic exposure basis. In addition, no data are available to describe the 

toxicity of hexaflumuron to marine/estuarine animals or aquatic plants. 

9 of 34
Table 4. Summary of most sensitive endpoints from submitted aquatic toxicity studies for 

hexaflumuron. 

Species 

(common name) 

Taxa 

Represented 

Endpoint Duration 

(hours) 

Mean 

concentration 

(μg a.i./L) 

Citation 

MRID 

Study 

Classification

Lepomis 

macrochirus 

(bluegill sunfish) 

>255.6* 42648511 Supplemental 

Onchorynchus 

mykiss 

(rainbow trout)

Freshwater 

fish and 

aquatic-phase 

amphibians

LC50 96 

> 535.5* 42648512 Supplemental 

Daphnia magna 

(water flea) 

freshwater 

invertebrates LC50 48 0.111 42648513 Acceptable 

 *Exceeds the solubility limit (27 μg/L; MRID 426485-05). 

4.2. Effects to Terrestrial Organisms 

Hexaflumuron is classified as practically non-toxic to mammals and birds on an acute 

oral exposure basis. On a subacute dietary exposure basis, hexaflumuron is classified as 

slightly toxic to birds (Table 5). A 2-generation reproduction study with the rat has been 

submitted, but is currently under review by Health Effects Division. No data are available 

to describe the toxicity of hexaflumuron to birds resulting from chronic exposures. Also, 

data are not available to define the toxicity of hexaflumuron to honey bees. 

Table 5. Summary of most sensitive endpoints from submitted terrestrial toxicity studies for 

hexaflumuron. 

Species 

(common name)

Taxa 

Represented End-point Mean 

Concentration 

Citation 

MRID Study 

Classification 

Rattus norvegicus LD50 > 5,000 mg/kg 42648514 Acceptable 

(laboratory rat)

mammals 

NOAEL Not determined 44233003 Under review 

Anas LD50 > 2,000 mg/kg 42648508 Acceptable 

platyrhynchos

(mallard duck) LC50 > 5,200 ppm 42648510 Acceptable 

LD50 > 2,000 mg/kg 42648507 Acceptable Colinus 

virginianus 

(northern 

bobwhite quail)

birds, 

terrestrialphase 

amphibians 

and reptiles 

LC50 2,201 ppm 42648509 Acceptable 

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4.3. Effects of Degradates 

Based on the available environmental fate studies for hexaflumuron, 3 major degradates 

have been observed in laboratory studies. These include: 3,5-Dichloro-4-(l,l,2,2-

tetrafluoroethoxy)phenylamine, 3,5-Dichloro-4-(l,l,2,2-tetrafluoroethoxy)phenylurea and 

2,6-Difluorobenzoic acid (Section 3.3). 

At this time, no registrant submitted studies are available to characterize the effects of 

hexaflumuron’s major degradates to non-target organisms. In a literature study, midges 

(Chironomus plumosus), channel catfish (Ictalurus punctatus) bluegills (Lepomis 

macrochirus), rainbow trout (Oncorhynchus mykiss), and fathead minnows (Pimephales 

promelas) were exposed to 2,6-difluorobenzoic acid on an acute basis. The 48-h EC50 for 

midges was >100 mg/L. The 96-h LC50 for rainbow trout, channel catfish and bluegill 

was also >100 mg/L. The 96-h LC50 for fathead minnows was 69 mg/L (95% CI: 55-87) 

(Julin and Sanders 1978). These data indicate that 2,6-diflurobenzoid acid is less toxic to 

aquatic invertebrates than hexaflumuron on an acute exposure basis. In addition, these 

data do not indicate that 2,6-diflurobenzoid acid is more toxic to fish on an acute 

exposure basis when compared to hexaflumuron. 

No other data have been identified in the literature to characterize the toxicity of 

hexaflumuron’s major degradates to non-target organisms. One possible tool to estimate 

the toxicity of a chemical and its degradates to aquatic organisms is ECOSAR (v.1.0). 

When running this tool for hexaflumuron, predicted 48-h EC50 values (155-393 μg/L) are 

3 orders of magnitude greater than available empirical toxicity data for daphnids exposed 

to hexaflumuron on an acute exposure basis (EC50 = 0.111 μg/L; MRID 42648513). 

Therefore, ECOSAR was not used to determine the comparative toxicities of 

hexaflumuron and its known major environmental degradates to aquatic organisms. 

4.4. Incident Database Review 

A preliminary review of the Ecological Incident Information System (EIIS) maintained 

by the Agency’s Office of Pesticide Programs (OPP) indicates that there are no reported 

ecological incidents associated with the use of hexaflumuron (April 2009). The absence 

of reported incidents can not be used to confirm the absence of incidents. Incident 

reports for non-target animals typically provide information on mortality events only. 

Reports for other adverse effects, such as reduced growth or impaired reproduction, are 

rarely received. EPA’s changes in the registrant reporting requirements of incidents may 

also account for the reduced number of reported incidents even for mortality events. 

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4.5. Ecosystems Potentially at Risk 

Terrestrial ecosystems potentially at risk could include areas where bait stations 

containing hexaflumuron are placed and areas where exposed termite colonies are 

located. 

Given the chemical properties of hexaflumuron (i.e., low vapor pressure, low solubility, 

high organic carbon partition coefficient) in combination with its application method (i.e., 

enclosed bait box), it is assumed that transport of hexaflumuron via runoff, spray drift 

and long range atmospheric transport have a low likelihood of contributing to ecological 

risk in aquatic ecosystems. 

5. Assessment Endpoints 

Assessment endpoints represent the actual environmental value that is to be protected, 

defined by an ecological entity (species, community, or other entity) and its attribute or 

characteristics (USEPA 1998). 

6. Conceptual Model 

For a pesticide to pose an ecological risk, it must reach ecological receptors in 

biologically significant concentrations. An exposure pathway is the means by which a 

pesticide moves in the environment from a source to an ecological receptor. For an 

ecological pathway to be complete, it must have a source, a release mechanism, an 

environmental transport medium, a point of exposure for ecological receptors, and a 

feasible route of exposure. 

The conceptual model for hexaflumuron provides a written description and visual 

representation of the predicted relationships between hexaflumuron, potential routes of 

exposure, and the predicted effects for the assessment endpoint. A conceptual model 

consists of two major components: risk hypothesis and a conceptual diagram (USEPA 

1998).

6.1. Risk Hypothesis 

A risk hypothesis describes the predicted relationship among the stressor, exposure, and 

assessment endpoint response along with the rationale for their selection. For 

hexaflumuron, the following ecological risk hypothesis is being employed for this 

ecological risk assessment: 

Based on the application method, mode of action, fate and transport, and 

the sensitivity of non-target terrestrial species, hexaflumuron has the 

potential to reduce survival, reproduction, and/or growth in non-target 

terrestrial animals including birds, mammals, amphibians, reptiles and 

12 of 34
terrestrial insects when used in accordance with the current label. These 

non-target organisms include Federally listed threatened and endangered 

species as well as non-listed species. 

6.2. Conceptual Diagram 

Given the specificity of the use pattern for hexaflumuron, the transport mechanism(s) of 

interest include: transport of hexaflumuron by termites (the target pest). The transport 

mechanism (i.e., source) is depicted in the conceptual model below (Figure 1) along with 

the receptors of concern and the potential attribute changes in the receptors due to 

exposures of hexaflumuron. Given the application method of hexaflumuron (i.e. bait 

box) and its chemical properties, it is assumed that transport of hexaflumuron via runoff, 

spray drift and long range atmospheric transport have a low likelihood of contributing to 

ecological risk. Also, as hexaflumuron is odorless and the bait is a cellulose matrix, it is 

unlikely that other insects or mammals would be enticed to eat the bait containing 

hexaflumuron. 

Hexaflumuron in bait box 

Stressor 

Figure 1. Conceptual model for hexaflumuron effects on terrestrial organisms. Dotted lines indicate 

exposure pathways that have a low likelihood of contributing to ecological risk.

Source 

Receptors 

Attribute 

Change 

Direct 

application Movement 

via termites 

Birds / Terrestrialphase amphibians 

/ reptiles / 

mammals 

Terrestrial 

Insects* 

Individual organisms 

Reduced survival 

Reduced growth 

Reduced reproduction 

Food chain 

Reduction in prey 

Habitat integrity 

Reduction in primary productivity

Reduced cover 

Community change 

Terrestrial/riparian plants 

grasses/forbs, fruit, seeds 

(trees, shrubs) 

Runoff 

Mammals 

Exposure 

Media 

Soil 

Ingestion 

Ingestion

Ingestion

Ingestion

Dermal uptake/Ingestion 

Spray drift and 

Long range 

atmospheric 

transport 

Root uptake 

Wet/dry deposition 

Ingestion 

Birds / 

Amphibians 

*Including termites 

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7. Analysis Plan 

In order to address the risk hypothesis, the potential for adverse effects on the 

environment is estimated. The use, environmental fate, and ecological effects of 

hexaflumuron are characterized and integrated to assess the risks. This is accomplished 

using a risk quotient (ratio of exposure concentration to effects concentration) approach. 

Although risk is often defined as the likelihood and magnitude of adverse ecological 

effects, the risk quotient-based approach does not provide a quantitative estimate of 

likelihood and/or magnitude of an adverse effect. However, as outlined in the Overview 

Document (USEPA 2004), the likelihood of effects to individual organisms from 

particular uses of hexaflumuron is estimated using the probit dose-response slope and 

either the level of concern (discussed below) or the actual calculated risk quotient value. 

This analysis plan will be revisited and may be revised depending upon the data available 

in the open literature and the information submitted by the public in response to the 

opening of the Registration Review docket. 

7.1. Stressors of Concern 

Although limited environmental fate data are available for hexaflumuron, some 

environmental degradates have been identified (see Section 3.3). On a structural basis, 

these degradates are not similar to the parent (Appendix A). Available toxicity data do 

not suggest that hexaflumuron’s major degradates will be of greater or equal toxicity to 

non-target organisms when compared to hexaflumuron. As such, the focus of this 

assessment is expected to be the parent, hexaflumuron, with the assumption that it does 

not degrade appreciably. 

 

7.2. Measures of Exposure 

Considering the fate parameters for hexaflumuron and the method of application (i.e.,

bait stations), the only perceived means of hexaflumuron moving into the environment 

(e.g., soil and surface water) would be via termites eating the bait and then transporting it 

away from the bait station. Once in the termite, hexaflumuron could be transferred to 

termite predators. Based on the Kow and Koa of this chemical, it has the potential to 

bioaccumulate in termite predators. Therefore, future ecological risk assessments of 

hexaflumuron will involve assessing exposures of terrestrial animals to hexaflumuron 

through consumption of contaminated termites. 

This can be accomplished by estimating the mass of hexaflumuron per termite and 

deriving dietary-based and dose-based exposure concentrations for terrestrial animals 

through consumption of contaminated termites. 

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Empirical data may also be used to represent the mass of hexaflumuron per termite. For 

example, an available study (which is currently under review in EFED) measuring the 

uptake rate of 0.5% 14C labeled hexaflumuron in termites reported a steady state 

concentration of 320 ng (radioactive material)/termite (MRID 45516725). In this study, 

steady state was reached after 9-12 days. A representative termite body weight, such as 3 

mg (Zhou et al. 2008), can be used to translate the measured pesticide mass per termite to 

a concentration basis of 107 mg hexaflumuron/kg termite. This value can then be used to 

derive dose-based EECs for terrestrial animals potentially consuming termites using 

allometric equations intended to estimate food intake rates for mammals and birds 

(USEPA 1993). 

In addition, given that the labels recommend that an attractant be added (i.e., a sports 

drink), and the presence of ants observed in bait boxes during a field study (MRID 

455985-01), terrestrial invertebrates (other than termites) have the potential to be exposed 

to hexaflumuron through entry into the bait boxes and consumption of hexaflumuron. 

7.3. Measures of Effect 

 

Ecological effects data are used as measures of direct and indirect effects to biological 

receptors. Data are obtained from registrant-submitted studies or from literature studies 

identified by ECOTOX. The ECOTOX database (USEPA 2007d) provides more 

ecological effects data in an attempt to bridge existing data gaps. ECOTOX is a source 

for locating single chemical toxicity data and potential chemical mixture toxicity data for 

aquatic life, terrestrial plants, and wildlife. ECOTOX was created and is maintained by 

the USEPA, Office of Research and Development, and the National Health and 

Environmental Effects Research Laboratory's Mid-Continent Ecology Division. 

Where available, sublethal effects observed in both registrant-submitted and open 

literature studies will be evaluated qualitatively. Such effects may include behavioral 

changes (e.g., lethargy and changes in coloration). Quantitative assessments of risks, 

though, are limited to those endpoints that can be directly linked to the Agency’s 

assessment endpoints of impaired survival, growth and reproduction. 

The acute measures of effect used for animals in this assessment are the LD50, LC50 and 

EC50. LD stands for "Lethal Dose", and LD50 is the amount of a material, given all at 

once, that is estimated to cause the death of 50% of the test organisms. LC stands for 

“Lethal Concentration” and LC50 is the concentration of a chemical that is estimated to 

kill 50% of the test organisms. EC stands for “Effective Concentration” and the EC50 is 

the concentration of a chemical that is estimated to produce a specific effect in 50% of 

the test organisms. Endpoints for chronic measures of exposure for listed and non-listed 

animals are the NOAEL/NOAEC and NOEC. NOAEL stands for “No ObservedAdverse-Effect-Level” and refers to the highest tested dose of a substance that has been 

reported to have no harmful (adverse) effects on test organisms. The NOAEC (i.e., “NoObserved-Adverse-Effect-Concentration”) is the highest test concentration at which none 

of the observed effects were statistically different from the control. The NOEC is the NoObserved-Effects-Concentration. 

15 of 34
 

7.4. Integration of Exposure and Effects 

Risk characterization is the integration of exposure and ecological effects characterization 

to determine the potential ecological risk from the use of hexaflumuron in termite bait 

systems and the likelihood of direct and indirect effects to non-target organisms in 

terrestrial habitats. The exposure and toxicity effects data are integrated in order to 

evaluate the risks of adverse ecological effects on non-target species. For the assessment 

of hexaflumuron risks, the risk quotient (RQ) method is used to compare exposure and 

measured toxicity values. EECs are divided by acute and chronic toxicity values. The 

resulting RQs are then compared to the Agency’s Levels of Concern (LOCs) (USEPA 

2004). These criteria are used to indicate when hexaflumuron’s uses, as directed on the 

label, have the potential to cause adverse direct or indirect effects to non-target 

organisms. 

 

7.5. Deterministic and Probabilistic Assessment Methods 

The quantitative assessment of risk will primarily depend on the deterministic pointestimate based (RQ) approach described in the risk assessment. An effort will be made to 

further qualitatively describe risk using probabilistic tools that the Agency has developed. 

These tools have been reviewed by FIFRA Scientific Advisory Panels 

(http://www.epa.gov/scipoly/sap/index.htm) and have been deemed as appropriate means 

of refining assessments where deterministic approaches have identified risks. 

7.6. Endangered Species Assessments 

Consistent with the Agency’s responsibility under the Endangered Species Act (ESA), 

the Agency will evaluate risks to Federally-listed threatened and/or endangered (listed) 

species from registered uses of hexaflumuron. This assessment will be conducted in 

accordance with the Overview Document (USEPA 2004), provisions of the ESA, and the 

Services’ Endangered Species Consultation Handbook (USFWS/NMFS, 1998). 

The assessment of effects associated with the registration of hexaflumuron is based on an 

action area. The action area is considered to be the area directly or indirectly affected by 

the federal action, as indicated by the exceedance of Agency Levels of Concern (LOCs) 

used to evaluate direct or indirect effects. The Agency’s approach to defining the action 

area under the provisions of the Overview Document (USEPA 2004) considers the results 

of the risk assessment process to establish boundaries for that action area with the 

understanding that exposures below the Agency’s defined LOCs constitute a no-effect 

threshold. For the purposes of this assessment, attention will be focused on the footprint 

of the action (i.e., the area where hexaflumuron application occurs) that exceeds the 

Agency’s LOCs. Specific measures of ecological effect that define the action area for 

listed species include any direct and indirect effects and/or potential modification of its 

16 of 34
critical habitat, including reduction in survival, growth, and reproduction as well as the 

full suite of sublethal effects available in the effects literature. Therefore, the action area 

extends to a point where environmental exposures are below any measured lethal or 

sublethal effect threshold for any biological entity at the whole organism, organ, tissue, 

and cellular level of organization. 

7.7. Drinking Water Assessment 

Based on the application methods (e.g., above- and below-ground bait stations) and the 

fate properties (e.g., Kow = 2.90 x 105, Koc ≈ 6,500 L/kg) for hexaflumuron, the potential 

for hexaflumuron to migrate to the soil and to further migrate to surface water and/or 

groundwater sources is considered minimal. 

7.8. Preliminary Identification of Data Gaps 

Hexaflumuron use is defined as having terrestrial, non-food, domestic outdoor and indoor 

uses. According to Code of Federal Regulations 40 (CFR40 2007) Part 158 Subpart D 

(data requirements for pesticides) environmental fate and non-target organism effect data 

are required for hexaflumuron based on its terrestrial use. Available studies submitted to 

fulfill environmental fate and ecological effects guideline requirements, as well as 

outstanding data gaps for hexaflumuron are defined in Tables 6-9, below. 

Further information on data required to fulfill the Agency’s guideline requirements for 

hexaflumuron and its formulated products is presented as the Data Call-in (DCI) table in 

Appendix A. In addition to providing the guideline number and study title for required 

data, the DCI table provides a rationale for requiring the data, an explanation of how the 

data will be used, and a brief description of the how the data could impact the Agency’s 

future decision-making. 

7.8.1. Use Information

As indicated in Section 3.2, current labels for hexaflumuron products (Recruit AG and 

Shatter) do not specify the amount of product present in each bait station. In addition, 

labels do not specify the maximum number of bait stations that can be present on a 

designated area of land. EFED requests that hexaflumuron product labels be clarified to 

clarify the amount of product present in each bait station and the number of bait stations 

allowed per unit area of land (e.g., number bait boxes per acre). Absent this information, 

EFED will develop a conservative estimate based on label specifications. 

7.8.2. Fate 

The environmental fate data requirements for hexaflumuron are partially fulfilled with 

some data gaps still remaining (Table 6). Data gaps include: aerobic and anaerobic soil 

metabolism studies and adsorption/desorption data. The data gaps are discussed below. 

17 of 34
Table 6. Available environmental fate data for hexaflumuron and remaining data gaps. 

Guideline Description MRID Classification Data Gap? Comments 

835.2120 Hydrolysis 42648526 Acceptable No 

835.2240 Photodegradation in water NA No 

835.4100 Aerobic soil metabolism 42695901 Supplemental Yes 

835.4200 Anaerobic soil metabolism 42695901 Supplemental Yes 

835.4300 Aerobic Aquatic Metabolism NA Not applicable No 

835.4400 Anaerobic Aquatic 

Metabolism 

NA Not applicable No 

835.1230 

835.1240 

Leaching and adsorption/ 

desorption 

42648527 Supplemental Yes 

835.6100 Terrestrial Field Dissipation NA No 

850.1730 Bioaccumulation in Fish NA Not applicable No* 

*Although the Log Kow

of hexaflumuron (5.46) 

is >3, this is not 

considered a data gap, 

as the potential 

exposure to fish is 

negligible. 

NA = not available 

Aerobic Soil Metabolism 

An aerobic soil metabolism study (MRID 426959-01) provided supplemental data. 

Aniline-labeled hexaflumuron degraded with a half-life of 110-280 days (110 days, 

Castle Rising sandy loam; 160 days, Alconbury clay loam; 200 days, Catlin silt loam; and 

280 days, Hanford sandy loam). The aerobic metabolism study does not fulfill the data 

requirements because: (1) one major degradate (M8 at 11% of the applied rate at 180 

days) from the aniline-labeled study was not identified; and, (2) a low material balance 

(up to 55% of the applied radioactivity was not accounted for by the termination of the 

study) in the benzoyl-labeled portion of the study prevented reliable interpretation of the 

data. This study can be upgraded by identifying the degradate M8 and by providing 

quantitative evidence regarding the losses of 14C in the low material balances in the 

benzoyl-labeled study. Therefore, to fulfill the data gap for Guideline 835.4100, EFED is 

requesting additional information to upgrade this study. 

Anaerobic Soil Metabolism 

An anaerobic soil metabolism study (MRID 426959-01) provided supplemental data. In 

the anaerobic soil metabolism study, aniline-labeled hexaflumuron degraded with a halflife of 54-72 days (54 days, Hanford sandy loam; 57 days, Castle Rising sandy loam; 69 

days, Catlin silt loam; and, 72 days, Alconbury clay loam). As in the aerobic soil 

metabolism study, the benzoyl-labeled portion of the study was not acceptable because of 

low material balances as up to 60% of the applied radioactivity was not accounted for by 

the termination of the study. This study can be upgraded by providing quantitative 

evidence regarding the losses of 14C in the low material balances in the benzoyl-labeled 

study. Therefore, to fulfill the data gap for Guideline 835.4200, EFED is requesting 

additional information to upgrade this study. 

18 of 34
Leaching and Adsorption/Desorption 

The unaged leaching portion of the mobility/leaching study (MRID 42648527) partially 

satisfied the data requirements by providing mobility data for the unaged parent. 

Hexaflumuron was not considered mobile in silt loam, clay loam, and two sandy loam 

soils. The aerobically-aged mobility study was classified as not acceptable because of the 

experimental design and the data manipulation by the study authors. Acceptable data are 

needed for the mobility of hexaflumuron degradates and adsorption/desorption of 

hexaflumuron and its degradates. Therefore, to fulfill the data gap for Guideline 

835.1240, EFED is requesting a batch equilibrium study. A data call-in (DCI) table for 

this request is provided in Appendix C. 

Despite these data gaps, the available data suggest that hexaflumuron is relatively stable, 

i.e, persistent, and unlikely to be mobile. 

7.8.3. Effects 

 

The non-target organism effects data requirements for hexaflumuron are partially fulfilled 

with several data gaps still remaining (Tables 7-9). The data gaps are discussed below. 

 

Table 7. Available ecological effects data for terrestrial animals exposed to hexaflumuron and its 

formulated products and remaining data gaps. 

Guideline Description MRID Classification Data Gap? Comments 

850.2100 Avian oral toxicity 42648507 Acceptable 

42648508 Acceptable 

Yes* 

850.2200 Avian dietary toxicity 42648509 Acceptable 

42648510 Acceptable 

No 

850.2300 Avian reproduction NA Not applicable Yes 

850.3020 Honey bee acute 

contact toxicity 

NA Not applicable Yes 

850.3040 Field testing for 

pollinators 

NA Not applicable Yes 

*Avian acute oral toxicity data 

are not available for passerines, 

which are required under the new 

40 CFR Part 158. 

NA = not available 

19 of 34
Table 8. Available ecological effects data for aquatic animals exposed to hexaflumuron and 

remaining data gaps.

Guideline Description MRID/ 

Accession Classification Data Gap? comments 

42648511 Supplemental 850.1075 Freshwater fish – 

Acute toxicity 42648512 Supplemental 

Yes 

850.1075 Saltwater fish – 

Acute toxicity NA Not applicable Yes 

850.1010 

Freshwater 

invertebrates – 

Acute toxicity 

42648513 Acceptable No 

850.1025 

850.1035 

850.1045 

850.1055 

Saltwater invertebrates 

–Acute toxicity NA Not applicable Yes 

850.1300 

Freshwater 

invertebrate – 

life cycle test 

NA Not applicable Yes 

850.1400 Freshwater fish – 

early life stage test NA Not applicable Yes 

Given the application method 

of hexaflumuron (i.e. bait box) 

and its chemical properties, it 

is assumed that transport of 

hexaflumuron to aquatic 

systems is unlikely. Therefore, 

although several ecological 

effects guidelines for aquatic 

organisms remain as data 

gaps, EFED is not requesting 

additional studies to fulfill the 

guidelines at this time. 

NA = not available

Table 9. Available ecological effects data for plants exposed to hexaflumuron and remaining data 

gaps.

Guideline Description MRID Classification Data Gap? comments 

850.4100 Terrestrial Plant toxicity: 

Tier I seedling emergence 

NA Not applicable Yes 

850.4150 Terrestrial Plant toxicity: 

Tier I vegetative vigor 

NA Not applicable Yes 

850.5400 Aquatic Plant Growth: 

algae 

NA Not applicable Yes 

850.4400 Aquatic Plant Growth: 

vascular plants 

NA Not applicable Yes 

None 

NA = not available 

Avian acute oral toxicity 

Avian acute oral toxicity data are not available for passerines, which are required under 

the new 40 CFR Part 158. However, because on an acute oral exposure basis, 

hexaflumuron is practically non-toxic to mallards and northern bobwhite quail, EFED is 

not requesting an acute oral toxicity study with passerines. 

20 of 34
Avian reproduction 

At this time, no data are available to define the chronic toxicity of hexaflumuron to birds. 

As indicated in the conceptual model (Figure 1), transport of hexaflumuron by termites 

(the target pest) could potentially result in exposures of birds to hexaflumuron through 

consumption of contaminated termites. Although hexaflumuron is practically non-toxic to 

birds on an acute oral exposure basis, no data are available to characterize the toxicity of 

hexaflumuron to birds on a chronic exposure basis. Therefore, to fulfill the data gap for 

Guideline 850.2300, and to quantify the chronic toxicity of hexaflumuron to birds, EFED 

is requesting two avian reproduction studies; one with the mallard duck and one with the 

Northern bobwhite quail. A data call-in (DCI) table for this request is provided in 

Appendix C. 

Honey bee acute toxicity 

At this time, no data are available to define the toxicity of hexaflumuron to honey bees on 

an acute contact basis. Given that the labels recommend that an attractant be added (i.e., a 

sports drink), and the presence of ants observed in bait boxes during a field study (MRID 

455985-01), non-target insects have the potential to be exposed to hexaflumuron through 

entry into the bait boxes. It is expected that the major exposure route for non-target 

insects would be through consumption, not through contact. Therefore, EFED is 

requesting that the registrant submit an acute oral exposure study with honey bees (nonguideline). At this time, EFED is not requesting that an acute contact exposure study 

(Guideline 850.3020) be submitted. 

Field testing for pollinators 

According to 40 CFR Part 158, this study is required if any of the following are met: 1) 

data from other sources (Experimental Use Permit program, university research, 

registrant submittals, etc.) indicate potential adverse effects on colonies, especially 

effects other than acute mortality (reproductive, behavioral, etc.); 2) data from residual 

toxicity studies indicate extended residual toxicity; or 3) data derived from studies with 

terrestrial arthropods other than bees indicate potential chronic, reproductive or 

behavioral effects. Given the intended effect of hexaflumuron in causing collapse of 

termite colonies, submission of a field study of the effects of hexaflumuron on pollinators 

is required (Guideline 850.3040). These data will be used to characterize potential effects 

of hexaflumuron to terrestrial insects. A DCI table for this request is provided in 

Appendix C. Hexaflumuron registrants must submit a study protocol for review by 

the Agency prior to initiation of the field testing for pollinators study. 

21 of 34
Acute toxicity to freshwater fish 

Supplemental data are available to define the acute toxicity of hexaflumuron to 

freshwater fish. These supplemental data indicate that the 96-h LC50 exceeds the 

solubility limit of hexaflumuron. 

Given the application method of hexaflumuron (i.e. bait box) and its chemical properties, 

it is assumed that transport of hexaflumuron to aquatic systems is unlikely. Therefore, 

although guideline 850.1075 for freshwater fish remains a data gap since the existing 

studies failed to establish a definitive toxicity endpoint, EFED is not requesting 

additional studies to fulfill the guideline at this time. 

Acute toxicity to estuarine/marine animals 

At this time, no data are available to define the acute toxicity of hexaflumuron to 

estuarine/marine fish and invertebrates. Given the application method of hexaflumuron 

(i.e. bait box) and its chemical properties, it is assumed that transport of hexaflumuron to 

estuarine/marine systems is unlikely. Therefore, although guidelines 850.1025, 850.1035, 

850.1045, 850.1055 and 850.1075 for estuarine/marine animals remain a data gaps, 

EFED is not requesting additional studies to fulfill the guidelines at this time. 

Chronic toxicity to freshwater animals 

At this time, no data are available to define the chronic toxicity of hexaflumuron to 

freshwater fish and invertebrates. Given the application method of hexaflumuron (i.e. bait 

box) and its chemical properties, it is assumed that transport of hexaflumuron to 

freshwater aquatic systems is unlikely. Therefore, although guidelines 850.1300 and 

850.1400 for freshwater invertebrates and fish, respectively, remain data gaps, EFED is 

not requesting additional studies to fulfill the guidelines. 

Toxicity to aquatic plants 

At this time, no data are available to define the toxicity of hexaflumuron to non-vascular 

and vascular aquatic plants. Given the application method of hexaflumuron (i.e. bait box) 

and its chemical properties, it is assumed that transport of hexaflumuron to aquatic 

systems is unlikely. Therefore, although guidelines 850.4400 and 850.5400 for aquatic 

vascular and non-vascular plants, respectively, remain data gaps, EFED is not requesting 

additional studies to fulfill the guidelines. 

Toxicity to terrestrial plants 

At this time, no data are available to define the effects of hexaflumuron on terrestrial 

plants. Given the application method of hexaflumuron (i.e. bait box) and its chemical 

properties, it is assumed that transport of hexaflumuron via spray drift to non-target 

terrestrial plants is unlikely. Therefore, although guideline 850.4150 for effects to 

22 of 34
vegetative vigor of terrestrial plants remains a data gap, EFED is not requesting 

additional studies to fulfill this guideline, at this time. 

Because it is possible that plant roots could be exposed to hexaflumuron transported to 

terrestrial environments by termites, EFED is requesting that the registrant submit data to 

fulfill guideline 850.4100 for effects to seedling emergence of terrestrial plants. A DCI 

table for this request is provided in Appendix C. 

8. References 

CFR 40. 2007. Code of Federal Regulations 40 Parts 150 to 189. Protection of the Environment. U.S. 

Government Printing Office. 

Howard, P.H., Boethling, R.S., Stiteler, W.M., Meylan, W.M., Hueber, A.E., Beauman, J.A., and M.E. 

Larosche. 1992. Predictive model for aerobic biodegradability developed from a file of evaluated 

biodegradation data. Environ. Toxicol. Chem. 11: 593-603. 

Julin, A.M., and H.O. Sanders. 1978. Toxicity of the IGR, Diflubenzuron, to Freshwater Invertebrates and 

Fishes. Mosq.News 38(2):256-259 (Author Communication Used) (Publ in Part As 6797). (ECOTOX 

reference #939). 

Kashuba, R., Spatz, D. 2006 Memorandum to Steven Bradbury, Subject: Standard Soil Mobility 

Classification Guidance 

Maciorowski, A. 1993. Ecological Effects Review of Hexaflumuron for an Experimental Use Permit as a 

Termiticide in a “Safer Pesticide” Formulation. EPA File Symbol: 62719-EUP-EL, Chemical: 118202, DP 

Barcode D192759, Action: 700, EUP NC-non-food/feed. 

USEPA. 1993. Wildlife Exposure factors handbook. United States Environmental Protection Agency. 

Office of Research and Development. EPA/600/R-93/187. 

U.S. Environmental Protection Agency (USEPA). 1998. Guidelines for Ecological Risk Assessment. Risk 

Assessment Forum, Office of Research and Development, Washington, D.C. EPA/630/R-95/002F. April 

1998. http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=30759 

USEPA. 2004. Overview of the Ecological Risk Assessment Process in the Office of Pesticide Programs. 

U.S. Environmental Protection Agency, Office of Prevention, Pesticides and Toxic Substances, Office of 

Pesticide Programs, Washington DC. January 23, 2004. 

USEPA. 2007b. Ecological Incident Information System. http://www.epa.gov/espp/consultation/ecoriskoverview.pdf

USEPA. 2007c. 40 CFR Part 158. Pesticides; Data Requirements for Conventional Chemicals: Final Rule. 

72 FR 60934. October 26, 2007. 

USEPA. 2007d. ECOTOXicology Database. Office of Research and Development National Health and 

Environmental Effects Research Laboratory’s (NHEERL’s) Mid-Continent Ecology Division (MED). 

http://cfpub.epa.gov/ecotox/ 

U.S. Fish and Wildlife Service (USFWS) and National Marine Fisheries Service (NMFS). 1998. 

Endangered Species Consultation Handbook: Procedures for Conducting Consultation and Conference 

Activities Under Section 7 of the Endangered Species Act. Final Draft. March 1998. 

23 of 34
Zhou, X., Wheeler, M.M., Oi, F.M., and M.E. Scharf. 2008. RNA interference in the termite 

Reticulitermes flavipes through ingestion of double-stranded RNA. Insect Biochemistry and Molecular 

Biology, 38 (8): 805-815. 

SUBMITTED STUDIES:

MRID: 45516725 

Sheets, J. (1997) Uptake rate of (14C) Hexaflumuron Force-Fed to Groups of Reticulitermes flavipes: 

Report ID: DEI0376. Unpublished study prepared by Dow Agrosciences LLC. 

SUBMITTED FATE STUDIES:

MRID: 42648505 

Jones-Jefferson, T. (1992) Series 63: Physical and Chemical Characteristics of the Technical Grade of 

Active Ingredient, Hexaflumuron (DE-473): Lab Project Number: GHC 2927: FOR92076: FOR92100. 

Unpublished study prepared by DowElanco, Leeds University (UK) and Huntingdon Research Centre 

(UK). 

MRID: 42648526 

Jackson, R.; Yon, D. (1992) The Hydrolysis of Hexaflumuron in Buffered Distilled Water at pH 5, 7 and 9: 

Lab Project Number: GHE-P-2795. Unpublished study prepared by DowElanco, Letcombe (UK). 

MRID: 42695901 

Racke, K. (1993) Aerobic and Anaerobic Soil Metabolism of Hexaflumuron: Lab Project Number: GH-C 

2970. Unpublished study prepared by DowElanco North American Environmental Chemistry Lab. 

MRID: 42648527 

Racke, K. (1993) Leaching and Adsorption/Desorption of Hexaflumuron: Lab Project Number: GH-C 

2969. Unpublished study prepared by DowElanco. 

SUBMITTED EFFECTS STUDIES:

MRID: 42648507 

Mayes, M. (1992) Acute Oral Toxicity (LD50) of XRD 473 to the Bobwhite Quail: Summary Evaluation 

and Original Study (Appendix A): Lab Project Number: DWC 510/871169. Unpublished study prepared by 

DowElanco. 

MRID: 42648508 

Mayes, M. (1992) Acute Oral Toxicity (LD50) of XRD 473 to the Mallard Duck: Summary Evaluation and 

Original Study (Appendix A): Lab Project Number: DWC 494/86154. Unpublished study prepared by 

DowElanco. 

MRID: 42648509 

Mayes, M. (1992) The Dietary Toxicity of XRD 473 to the Bobwhite Quail: Summary Evaluation and 

Original Study (Appendix A): Lab Project Number: DWC 511/871193. Unpublished study prepared by 

DowElanco. 

MRID: 42648510 

Mayes, M. (1992) The Dietary Toxicity of XRD 473 to the Mallard Duck: Summary Evaluation and 

Original Study (Appendix A): Lab Project Number: DWC 512-871194. Unpublished study prepared by 

DowElanco. 

MRID: 42648511 

Mayes, M. (1992) The Acute Toxicity of XRD 473 to Bluegill Sunfish: Summary Evaluation and Original 

Study (Appendix A): Lab Project Number: 87/DCSO32/556. Unpublished study prepared by DowElanco. 

24 of 34
25 of 34

MRID: 42648512 

Mayes, M. (1992) The Acute Toxicity of XRD 473 to Rainbow Trout: Summary Evaluation and Original 

Study (Appendix A): Lab Project Number: 87/DCSO32/555. Unpublished study prepared by DowElanco. 

MRID: 42648513 

Mayes, M. (1992) The Acute Toxicity of XRD 473 to Daphnia magna: Summary Evaluation and Original 

Study (Appendix A): Lab Project Number: AFT/86/009. Unpublished study prepared by DowElanco. 

MRID: 42648514 

Cosse, P.; Sames, K.; Berdasco, N. (1993) DE-473: Acute Oral Toxicity Study in Fischer 344 Rats: Lab 

Project Number: DR-0210-2650-004A: DR-0210-2650-004A1. Unpublished study prepared by Dow 

Chemical Co. 28 p. 

MRID: 44233003 

Koeter, H.; van Marwijk, M.; Bruyntjes, J. (1988) Oral Multigeneration Reproduction Study with XRD-473 

in Rats: Lab Project Number: B86-0385: DET 1165: 857. Unpublished study prepared by TNO-CIVO 

Institutes. 500 p. 
Appendix A. Hexaflumuron and Degradates 

Chemical (CAS Number) MW Structure SMILES Hexaflumuron (86479-06-3) 

461.15 Fc1cccc(F)c1C(=O)NC(=O

2,6-Difluorobenzoic acid (385-00-2) 

158.11 OC(=O)c1c(F)cccc1F 

2,6-Difluorobenzamide (18063-03-1) 

157.12 NC(=O)c1c(F)cccc1F 

3,5-Dichloro-4-(l,l,2,2-tetrafluoroethoxy)phenylurea 

321.06 NC(=O)Nc1cc(Cl)c(O(C(F

26 of 34
Chemical 

(CAS Number) MW Structure SMILES 3,5-Dichloro-4-(l,l,2,2-tetrafluoroethoxy)phenylamine 

278.03 Nc1cc(Cl)c(O(C(F)(F)(C(F

27 of 34
28 of 34

Appendix B. Fate Parameters For Hexaflumuron Degradates, Estimated Using EPISuite v. 4.0 

Chemical/Fate parameter Hexaflumuron 2,6-Difluorobenzoic acid 2,6-Difluorobenzamide 

3,5-Dich

tetraflu

phe

Molecular Weight (g/mol) 461 158 157 Vapor Pressure (torr) 4.43 x 10-11 1.76 x 10-3 2.86 x 10-4 7.5Octanol-water Partition Coefficient (Log KOW) 5.64 1.59 0.25 Water Solubility (mg/L; at 25 °C) 2.07 x 10-2 3,063 43,140 Henry's Law Constant (atm-m3 mol-1) 9.96 x 10-10 1.20 x 10-7 1.37 x 10-9 2.7Leaching/Mobility Koc (L/kg) 6,092 – 7,272* 11 – 44* 7 – 46* 676 * Range of two values.
Appendix C. Data Call-In Tables 

Guideline Number: 835.4100 

Study Title: Aerobic Soil Metabolism Study 

Rationale for Requiring the Data 

The submitted aerobic soil metabolism study (MRID 426959-01) was classified as supplemental 

because: (1) one major degradate (M8 at 11% of the applied rate at 180 days) from the anilinelabeled study was not identified; and, (2) a low material balance (up to 55% of the applied 

radioactivity was not accounted for by the termination of the study) in the benzoyl-labeled portion 

of the study prevented reliable interpretation of the data. In order to fulfill the data gap for 

Guideline 835.4100 and upgrade this study, EFED is requesting the identification of the degradate 

M8 and quantitative evidence regarding the losses of 14C in the low material balances in the 

benzoyl-labeled study. 

Practical Utility of the Data 

How will the data be used and how could the data change the Agency’s decision, or impact 

the Agency’s future decision-making? 

Aerobic metabolism data is critical in assessing how long the active ingredient and its degradates 

will remain in the soil. The requested information will provide improved confidence in the results 

of the ecological risk assessment and the decisions made. 

How could the data impact the Agency’s future decision-making? 

If data indicate that hexaflumuron and/or its degradates degrade at a slower rate in aerobic soil, 

additional use precautions and/or restrictions may be necessary. 

Guideline Number: 835.4200 

Study Title: Anaerobic Soil Metabolism Study 

Rationale for Requiring the Data 

The submitted anaerobic soil metabolism study (MRID 426959-01) was classified as supplemental 

because of low material balances (up to 60% of the applied radioactivity was not accounted for by 

the termination of the study). In order to fulfill the data gap for Guideline 835.4200 and upgrade 

this study, EFED is requesting quantitative evidence regarding the losses of 14C in the low material 

balances in the benzoyl-labeled portion of the study. 

Practical Utility of the Data 

How will the data be used and how could the data change the Agency’s decision, or impact 

the Agency’s future decision-making? 

Anaerobic metabolism data is critical in assessing how long the active ingredient and its degradates 

will remain in the lower levels of soil and in sediment. The requested data will result in improved 

confidence in the results of the ecological risk assessment and the decisions made. 

How could the data impact the Agency’s future decision-making? 

If data indicate that hexaflumuron and/or its degradates degrade at a slower rate in anaerobic soil 

and sediment, additional use precautions and/or restrictions may be necessary. 

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Guideline Number: 835.1230/1240 

Study Title: Leachability/Mobility Study 

Rationale for Requiring the Data 

Mobility studies, which include leaching and adsorption/desorption, provide information on the 

mode of transport and eventual destination of the pesticide in the environment. The mobility 

portion of the submitted study (MRID 42648527) was deemed unacceptable by the Agency 

because the experimental design and data manipulation by the study authors are atypical and 

severely limit the interpretation of the results of the aged mobility study. In standard batch 

equilibrium experiments, pesticide-free soil is equilibrated with solutions containing individual 

degradates or parent to determine the amount of material adsorbed from the solution onto the soil. 

The soil containing the adsorbed compound of interest is then equilibrated with pesticide-free 

solution to determine the amount released from the soil to the solution (desorbed). In the aged 

mobility experiment described in this study, [14C] hexaflumuron was incubated in four soils under 

aerobic conditions for 30 days; the [14C] residues were then extracted from the soils by shaking 

three times with pesticide-free calcium chloride solution. The study authors assumed that during 

aging the hexaflumuron had adsorbed to the soil, and referred to all three equilibrations as 

"desorption." The soils were then further extracted with acetone and sodium hydroxide to 

determine the amount "adsorbed" to the soil. The registrant then calculated "Kd” values by dividing 

the amounts of hexaflumuron and each degradate remaining on the soils after the calcium chloride 

extractions by the amounts of hexaflumuron and each degradate found in the combined calcium 

chloride extracts. The reported "Kd” values can at best be considered to be qualitative estimates of 

Kdes for hexaflumuron and its degradates. No inferences can be made concerning Kads of the 

degradates, since adsorption of the degradates could not be separated from other processes 

occurring during metabolism in the soil. Including this study in a DCI ensures that all technical 

registrants satisfy data submission obligations equally for data used to make EPA’s RED finding. 

Practical Utility of the Data 

How will the data be used and how could the data change the Agency’s decision, or impact 

the Agency’s future decision-making? 

Adsorption/desorption data will facilitate a better understanding of the movement of hexaflumuron 

and its degradates through a soil column. A direct measurement of adsorption will provide higher 

confidence in simulation modeling for registration review and to better characterize the mobility of 

the compound. The study will result in improved confidence in the results of the ecological risk 

assessment. This is a critical input parameter for this assessment and the results are highly sensitive 

to the value. 

How could the data impact the Agency’s future decision-making? 

If data indicate that hexaflumuron and/or its degradates are mobile in soil and sediment, additional 

use precautions and/or restrictions may be necessary. 

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Guideline Number: 850.2300 

Study Title: Avian Reproduction Tests (with a waterfowl and upland game species) 

Rationale for Requiring the Data 

No acceptable avian reproduction effects data were submitted for hexaflumuron. The Part 158 data 

requirements [40 CFR Part 158 (CFR 40 2007)] specify that 2 avian reproduction studies be 

submitted a waterfowl and an upland game species in cases where the pesticide has a terrestrial use. 

Transport of hexaflumuron by termites (the target pest) could potentially result in exposures of 

birds to hexaflumuron through consumption of contaminated termites. Although hexaflumuron is 

practically non-toxic to birds on an acute oral exposure basis, no data are available to characterize 

the toxicity of hexaflumuron to birds on a chronic exposure basis. 

Practical Utility of the Data 

How will the data be used? 

Avian reproduction effects data will be used to identify potential risks to birds, terrestrial-phase 

amphibians and reptiles from chronic exposure to hexaflumuron. The data will reduce 

uncertainties associated with the current risk assessment for birds and will improve the Agency’s 

understanding of the potential effects of hexaflumuron on terrestrial species. If avian reproduction 

effects data are not submitted, than risk to birds, terrestrial-phase amphibians and reptiles from 

chronic exposure to hexaflumuron will be assumed. 

How could the data impact the Agency’s future decision-making? 

If future endangered species risk assessments are performed without these data, the Agency would 

have to assume that hexaflumuron “may affect” listed birds, terrestrial-phase amphibians and 

reptiles directly (and listed species from other taxa indirectly), and use of hexaflumuron and its 

formulated products may need to be restricted in areas where listed species could be exposed. The 

lack of these data will limit the flexibility the Agency and registrants have in coming into 

compliance with the Endangered Species Act and could result in use restrictions for hexaflumuron 

use that are unnecessarily severe. 

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Guideline Number: Non-guideline study 

Study Title: Acute oral toxicity to honey bees 

Rationale for Requiring the Data 

At this time, no data are available to define the toxicity of hexaflumuron to honey bees on an acute 

exposure basis. Given that the labels recommend that an attractant be added (i.e., a sports drink), 

and the presence of ants observed in bait boxes during a field study (MRID 455985-01), terrestrial 

invertebrates (other than termites) have the potential to be exposed to hexaflumuron through entry 

into the bait boxes and consumption of hexaflumuron. It is expected that the major exposure route 

for non-target insects would be through consumption, not through contact. Therefore, EFED is 

requesting that the registrant submit an acute oral exposure study with honey bees (non-guideline). 

Although this is not an EPA guideline study, guidelines are available. For example, OECD has an 

acute oral toxicity study with honey bees (# 213). 

Practical Utility of the Data 

How will the data be used? 

Acute effects data with honey bees will be used to identify potential risks to non-target, terrestrial 

invertebrates, including pollinators, from acute exposure to hexaflumuron. The data will reduce 

uncertainties associated with the current risk assessment for terrestrial insects and will improve the 

Agency’s understanding of the potential effects of hexaflumuron on terrestrial species. If acute 

oral effects data are not submitted, than risk to terrestrial insects from acute exposure to 

hexaflumuron will be assumed. 

How could the data impact the Agency’s future decision-making? 

If future endangered species risk assessments are performed without these data, the Agency would 

have to assume that hexaflumuron “may affect” listed terrestrial insects directly (and listed species 

from other taxa that rely upon terrestrial insects indirectly), and use of hexaflumuron and its 

formulated products may need to be restricted in areas where listed species could be exposed. The 

lack of these data will limit the flexibility the Agency and registrants have in coming into 

compliance with the Endangered Species Act and could result in use restrictions for hexaflumuron 

use that are unnecessarily severe. 

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Guideline Number: 850.3040 

Study Title: Field testing for pollinators 

Rationale for Requiring the Data 

Given that the labels recommend that an attractant be added (i.e., a sports drink), and the presence 

of ants observed in bait boxes during a field study (MRID 455985-01), terrestrial invertebrates 

(other than termites) have the potential to be exposed to hexaflumuron through entry into the bait 

boxes and consumption of hexaflumuron. According to 40 CFR Part 158, this study is required if 

any of the following are met: 1) data from other sources (Experimental Use Permit program, 

university research, registrant submittals, etc.) indicate potential adverse effects on colonies, 

especially effects other than acute mortality (reproductive, behavioral, etc.); 2) data from residual 

toxicity studies indicate extended residual toxicity; or 3) data derived from studies with terrestrial 

arthropods other than bees indicate potential chronic, reproductive or behavioral effects. Given the 

intended effect of hexaflumuron in causing collapse of termite colonies, submission of a field study 

of the effects of hexaflumuron on pollinators is required. 

There is some uncertainty as to the ability of non-target terrestrial invertebrates, such as native 

ground-dwelling pollinators, to enter the hexaflumuron bait stations. Data to fulfill guideline 

850.3040 may be unnecessary in the case that the registrant can adequately demonstrate that the 

hexaflumuron bait stations prevent non-target terrestrial invertebrates from being exposed to 

hexaflumuron. 

Practical Utility of the Data 

How will the data be used? 

Field testing data for pollinators (i.e., honey bees) will be used to identify potential risks to nontarget, terrestrial invertebrates, including native pollinators, from chronic exposure to 

hexaflumuron. In this case, hexaflumuron will be present in the field as it is intended to be applied 

according to labels (i.e., in bait boxes). The data will reduce uncertainties associated with the 

current risk assessment for terrestrial insects (in particular, native pollinators) and will improve the 

Agency’s understanding of the potential effects of hexaflumuron on terrestrial species. If field 

testing effects data are not submitted, than risk to terrestrial insects from chronic exposure to 

hexaflumuron will be assumed. 

How could the data impact the Agency’s future decision-making? 

If future endangered species risk assessments are performed without these data, the Agency would 

have to assume that hexaflumuron “may affect” listed terrestrial insects directly (and listed species 

from other taxa that rely upon terrestrial insects indirectly [ecological services] through 

pollination), and use of hexaflumuron and its formulated products may need to be restricted in 

areas where listed species could be affected. The lack of these data will limit the flexibility the 

Agency and registrants have in coming into compliance with the Endangered Species Act and 

could result in use restrictions for hexaflumuron use that are unnecessarily severe. 

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Guideline Number: 850.4100 

Study Title: Terrestrial Plant Toxicity Test, Tier I (Seedling Emergence) 

Rationale for Requiring the Data 

Toxicity data for terrestrial plants are not available for hexaflumuron. The current 40 CFR Part 

158 data requirements include Tier I level seedling emergence terrestrial plant effects data for all 

insecticides. In addition, it is possible that plant roots could be exposed to hexaflumuron 

transported to terrestrial environments by termites. Therefore, Tier I plant toxicity studies 

(seedling emergence) are required for terrestrial plants, as specified in 40 CFR Part 158. 

Practical Utility of the Data 

How will the data be used? 

Seedling emergence data for terrestrial plants will be used to determine the potential for 

hexaflumuron to affect non-target plant species in the terrestrial environment. The data will reduce 

uncertainties associated with the current risk assessment for terrestrial plants and will improve the 

Agency’s understanding of the potential effects of hexaflumuron on terrestrial plants. In the 

absence of data specific for these plants, risk to terrestrial plants will be assumed. 

How could the data impact the Agency’s future decision-making? 

Because terrestrial plants form the basis of the food chain in many terrestrial habitats, a solid 

understanding of the potential risks to terrestrial plants is essential for sound environmental risk 

management decision-making. Without terrestrial plant data for hexaflumuron, the Agency cannot 

determine if the current application rates for hexaflumuron may result in direct adverse effects to 

terrestrial plants and/or indirect effects resulting from reduction in the prey base and/or loss of 

habitat/cover. If future endangered species risk assessments are performed without these data, the 

Agency would have to presume risk to non-target terrestrial plants from use of hexaflumuron. 

Therefore, use of hexaflumuron and its formulated products may need to be restricted in areas 

where listed species could be exposed. The lack of these data will limit the flexibility the Agency 

and registrants have in coming into compliance with the Endangered Species Act and could result 

in use restrictions for hexaflumuron that are unnecessarily severe. 

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