# 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

2 of 34Table of Contents

1. Purpose 4

2. Problem Fo rmulation ..................................................................................................... 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 Hexaflum uron Degradates, Estimated Using EPISuite

v. 4.0............................................................................................................. 28 Appendix C. Data Call-In Tables...................................................................................... 29

3 of 341. Purpose

The purpose of this problem formulation is to provide an understanding of what is known about the environmental fate and ecologica l effects of the registered uses of hexaflumuron. Hexaflumuron is a benzoylphe nylurea compound used as termite bait; the compound is designed to regulate insect growt h. This document will provide a plan for analyzing data on hexaflumuron and for conducting relevant environmental fate, ecological risk, endangered species and dri nking water assessments for its registered uses. Additionally, this problem formulati on is intended to identify data gaps, uncertainties, and potential assumptions used to address those uncertainties relative to characterizing the ecological risk associated wi th the registered uses of hexaflumuron.

2. Problem Formulation

2.1. Nature of Regulatory Action

Under the Federal Insecticide, Fungicide, a nd 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 register ed in the U.S., EPA evaluates its safety to non-target species based on a wide range of envi ronmental and health e ffects studie s. 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/oppsrr d1/registration_review/ ). The registration review program is intended to ensure that, as the ability to assess risk evolve s 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 periodi cally reevaluates pesticides to make sure that as change occurs, products in th e marketplace can be used safely.

As part of the implementation of the ne w Registration Review program pursuant to Section 3(g) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), the Agency is beginning its evaluation of hexafl umuron to determine whether it continues to meet the FIFRA standard for registration. This problem formulation for the environmental fate, ecological risk, endange red species, and drinking water assessment chapter in support of the regi stration 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 “cl osed system” with mi nimal likelihood of environmental exposure. Therefore, there ar e no previous ecological risk assessments or drinking water exposure assessments for this chemical.

4 of 343. Stressor Source and Distribution

3.1. Mechanism of Action

Hexaflumuron, 1-(3,5-dich loro-4-(1,1,2,2-tetrafluoro ethoxy)phenyl)-3-(2,6-difluorobenzoyl) urea, is an insecticide used to control termites. Hexaflumuron is a chitin synthesis inhibitor, which disrupts the moltin g process of various insects, resulting in death of immature stages when they molt. Th e mode of action is slow and allows a large

number of worker termites to feed on the ba it. A decline in the number of workers is followed by a collapse of the colony, as th ere are insufficient workers to support dependent castes (MRID 45516725).

3.2. Overview of Pesticide Usage

Hexaflumuron was originally registered for us e in the United States in March 1994, as a reduced risk pesticide. Hexaflumuron is used in conjunc tion with a monitoring system to control outbreaks of termites after a termite problem has been identified. Currently, hexaflumuron is registered for use in a bove- 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 cellulo se, inert carrier. Afte r 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 in stalled in food and nonfood areas, including, but not limited to, restaurants, grocery stor es, 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, an d 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 w ithin 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 th e 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 termite s being placed in the bait tube.

5 of 34Hexaflumuron comprises 0.5% (w/w) of both products (approximately 0.5 g a.i. per 100 g of product). Current labels fo r hexaflumuron products (Recruit ® AG and Shatter ® ) do not specify the amount of product present in eac h bait station. In addi tion, 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, appli cation rates of hexaflumuron applied to a unit area (i.e., lbs a.i./A) ca nnot be determined.

3.3. Environmental Fate and Transport

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

associated with hexaflumuron are summarized in Table 1

.

Table 1. General chemical and environmen tal 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 (K OW ) 2.90 x 10 5 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 K

oc (L/kg) 6,092 – 7,272 (range of 2 values) Estimated

EPISuite v4.0 NA

NA = not applicable

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

aerobic metabolism. Hexaflumuron is stable to hydrolysis at neutra l to acidic pHs, but degrades with a half-life of 22.5 days in alkaline pHs. Give n the methods of application ( e.g ., above- and below-ground bait stations), the material will not be subject to photodegradation when used as proposed. K

oc estimates from EPISuite indicate that hexaflumuron is slightly to hardly m obile (Kashuba, 2006). Hexaflumuron's low solubility in water, high octa nol-water partition coefficient, and predicted slight mobility

in soil indicate that hexaflumuron will not di ssolve 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 restricti ons prohibiting the use of the bait stations “in

6 of 34depressions, low areas, near ponds, streams, springs, other water sources, or near downspout openings when the bait or its hexafl umuron contents could be washed out of

the bait station into wa ter at or near the su rface of the ground”, reduc e, if not eliminate, the chances for hexaflumuron to migrate to surface and ground water. Although the mobility of hexaflumuron’s degradates has no t been adequately determined, it appears that the degradates, which are produced in sma ll quantities, are not hi ghly mobile. Given hexaflumuron’s low vapor pressure and app lication methods, volati lization of the active ingredient should not occur.

Hexaflumuron’s persistence in aerobic and an aerobic environments has not adequately been determined, as the combined aerobic and anaerobic soil metabolism study (MRID426959-01) was classified as supplemental. Under aerobic soil conditions, anilinelabeled hexaflumuron degraded with a half-lif e of 110-260 days in U.S. and U.K. soils. The aerobic metabolism study does not fulfill th e data requirements because: (1) one major degradate (M8 at 11% of the applied ra te 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 te rmination 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 no t expected to be persistent in anaerobic

environments while it is like ly to be moderately persis tent in aerobic environments.

Table 2 depicts the major degradates identifi ed in the hexaflumuron fate studies. One degradate, M8, was recovered in the aerobic soil metabolis m 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 degradat e separate from those already identified in other studies. A minor degrad ate, 2,6-difluorobenzamide, was recovered in the hydrolysis study, at 8% of the applied radi oactivity. Remaining fate data pertaining to these degradates are not available. Howe ver, estimated vapor pressures, solubilities,

and K

oc s using EPISuite (see Appendix B) indicate that these major degradates are much more volatile, soluble, and mob ile than there parent compound.

7 of 34Table 2. Hexaflumuron Degradates

Fate Study Soil Type Phenylamine 1 Phenylurea 2 DBA 3 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% (D ay 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 availabl e to demonstrate the bioaccumulation potential of hexaflumuron or any of its environm ental degradates. Bioconcentration and bioaccumulation factors (BCFs and BAFs, resp ectively) can be estimated for each of these chemicals using KABAM v1.0. BCFs and BAFs for hexaflumuron and its major environmental degradates estimated using K

ow 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 concentr ate 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 BAF 2,3

Hexaflumuron 5.46 20,975 166,712

3,5-Dichloro-4-(l,l,2,2 -tetrafluoroethoxy) phenylamine 3.77 1 284 296

3,5-Dichloro-4-(l,l,2,2 -tetrafluoroethoxy) phenylurea 3.40 1 121 124

2,6-Difluorobenzoic acid 1.59 1 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.

8 of 344. 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 extr apolate to potential effects on a variety of species (receptors) incl uded 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 aqua tic 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 iden tified through EPA’s ECOTOXicology (ECOTOX) database (USEPA 2007 d ), which employs a literature search engine for locating chemical toxicity data for aquatic life, terrestrial plants, and

wildlife. The evaluation of both sources of da ta 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 functiona l characteristics of

the affected communities.

A summary of the aquatic and terrestrial toxici ty data is provided in Sections 4.1 and 4.2, respectively. In addition, a summary of ecological in cidents associated with hexaflumuron and a description of ecosystems pot entially 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 freshwat er 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 fi sh 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 addi tion, no data are available to describe the toxicity of hexaflumuron to marine/e stuarine animals or aquatic plants.

9 of 34Table 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 LC 50 96

> 535.5* 42648512 Supplemental

Daphnia magna (water flea) freshwater

invertebrates LC 50 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 sub acute dietary exposure basis, he xaflumuron 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 Heal th 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 sens itive endpoints from submitted terrestrial toxicity studies for

hexaflumuron.

Species

(common name) Taxa Represented End-point Mean

Concentration Citation

MRID Study

Classification

LD 50 > 5,000 mg/kg 4 2648514 Acceptable Rattus norvegicus

(laboratory rat) mammals

NOAEL Not determined 44233003 Under review

LD 50 > 2,000 mg/kg 4 2648508 Acceptable Anas platyrhynchos

(mallard duck) LC 50 > 5,200 ppm 42648510 Acceptable

LD 50 > 2,000 mg/kg 42648507 Acceptable Colinus virginianus

(northern bobwhite quail) birds,

terrestrialphase amphibians and reptiles

LC 50 2,201 ppm 42648509 Acceptable

10 of 344.3. Effects of Degradates

Based on the available environmental fate st udies 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 ar e 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 EC 50 for midges was >100 mg/L. The 96-h LC 50 for rainbow trout, channe l catfish and bluegill was also >100 mg/L. The 96-h LC 50 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 degradat es to aquatic organisms is ECOSAR (v.1.0). When running this tool for he xaflumuron, predicted 48-h EC 50 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 (EC 50 = 0.111 μg/L; MRID 42648513). Therefore, ECOSAR was not used to de termine the comparative toxicities of hexaflumuron and its known major environm ental degradates to aquatic organisms.

4.4. Incident Database Review

A preliminary review of the Ecological Inci dent Information System (EIIS) maintained by the Agency’s Office of Pesticide Programs (OPP) indicates that there are no reported ecological incidents associated with the us e of hexaflumuron (April 2009). The absence of reported incidents can not be used to confirm the absen ce of incidents. Incident reports for non-target animals typically prov ide information on mortality events only. Reports for other adverse effect s, such as reduced growth or impaired reproduction, are rarely received. EPA’s changes in the regist rant reporting requirements of incidents may also account for the reduced number of reported incidents even for mortality events.

11 of 344.5. 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 transp ort 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 th e actual environmental value that is to be protected, defined by an ecological entity (species, comm unity, or other entity) and its attribute or characteristics (USEPA 1998).

6. Conceptual Model

For a pesticide to pose an ecological ris k, it must reach ecological receptors in biologically significant concen trations. 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 pr ovides a written description and visual representation of the predicted relationships between hexaflumuron, potential routes of exposure, and the predicted effects for th e assessment endpoint. A conceptual model consists of two major components: risk hypo thesis and a conceptual diagram (USEPA 1998).

6.1. Risk Hypothesis

A risk hypothesis describes th e 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-ta rget terrestrial species , hexaflumuron has the potential to reduce survival, repro duction, and/or grow th in non-target terrestrial animals including birds, mammals, amphibians, reptiles and

12 of 34terrestrial 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 assume d that transport of hexaflumuron via runoff, spray drift and long range atmospheric transp ort have a low likelihood of contributing to ecological risk. Also, as hexaflumuron is odor less and the bait is a cellulose matrix, it is unlikely that other insects or mammals w ould be enticed to eat the bait containing

hexaflumuron.

Hexaflumuron in bait box 

### Stressor

Figure 1. Conceptual model for hexa flumuron 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 /

Am p hibians

*Includin g termites

13 of 347. 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 concentr ation to effects concentration) approach. Although risk is often defined as the like lihood and magnitude of adverse ecological effects, the risk quotient-based approach does not provide a quan titative estimate of likelihood and/or magnitude of an adverse eff ect. However, as outlined in the Overview Document (USEPA 2004), the likelihood of effects to individual organisms from particular uses of hexaflumuron is estimat ed using the probit dose-response slope and either the level of concern (dis cussed below) or the actual calcu lated 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, he xaflumuron, with the assu mption that it does not degrade appreciably.

7.2. Measures of Exposure

Considering the fate parameters for hexa flumuron 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 term ites eating the bait and then transporting it away from the bait station. Once in the te rmite, hexaflumuron coul d be transferred to termite predators. Based on the K

ow and K

oa of this chemical, it has the potential to bioaccumulate in termite predators. Therefor e, 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 dos e-based exposure concentrations for terrestrial animals through consumption of contaminated termites.

14 of 34Empirical data may also be used to repres ent the mass of hexaflumuron per termite. For example, an available study (w hich is curre ntly under review in EFED) measuring the uptake rate of 0.5% 14 C labeled hexaflumuron in termites reported a steady state concentration of 320 ng (radi oactive material)/termite (MRID 45516725). In this study, steady state was reached after 9-12 days. A re presentative 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 anim als potentially consuming termites using allometric equations intended to estimate food intake rates for mammals and birds (USEPA 1993).

In addition, given that the la bels recommend that an attrac tant 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 pot ential 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 2007 d) provides more ecological effects data in an attempt to bri dge existing data gaps. ECOTOX is a source for locating single chemical toxicity data and potential chemical mixtur e 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 Labora tory's Mid-Continent Ecology Division.

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

literature studies will be eval uated qualitatively. Such e ffects may include behavioral changes ( e.g. , lethargy and changes in coloration). Quantitative assessments of risks, though, are limited to those end points 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 LD 50 , LC 50 and

EC 50 . LD stands for "Lethal Dose", and LD 50 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 LC 50 is the concentration of a chemical that is estimated to kill 50% of the test organisms. EC sta nds for “Effective Concentration” and the EC 50 is

the concentration of a chemical that is esti mated to produce a specific effect in 50% of the test organisms. Endpoints for chronic meas ures 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) eff ects 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 diffe rent from the control. The NOEC is the NoObserved-Effects-Concentration.

15 of 347.4. Integration of Exposure and Effects

Risk characterization is the in tegration of exposure and ecolo gical effects characterization to determine the potential ecological risk fr om the use of hexaflumuron in termite bait systems and the likelihood of direct and indi rect effects to non-target organisms in terrestrial habitats. The expos ure and toxicity effects data are integrated in order to

evaluate the risks of advers e ecological effects on non-target species. For the assessment of hexaflumuron risks, the risk quotient (R Q) 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 Ag ency’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 i ndirect effects to non-target organisms.

7.5. Deterministic and Probabilistic Assessment Methods

The quantitative assessment of risk will pr imarily depend on the deterministic pointestimate based (RQ) approach described in the risk assessment. An effort will be made to further qualitatively describe risk using probabi listic tools that the Ag ency has developed. These tools have been reviewed by FIFRA Scientific Advisory Panels ( http://www.epa.gov/sc ipoly/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 (USE PA 2004), provisions of the ESA, and the

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

The assessment of effects associ ated 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 exceedan ce 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 Do cument (USEPA 2004) c onsiders the results of the risk assessment proce ss to establish boundaries fo r that action area with the understanding that exposures below the Agency’s defined LOCs constitute a no-effect threshold. For the purposes of this assessmen t, 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 ecologi cal effect that define the action area for listed species include any direct and indirect effects and/or potential modification of its

16 of 34critical habitat, incl uding reduction in surv ival, growth, and repr oduction as well as the

full suite of sublethal effects av ailable in the effects literature . Therefore, the action area extends to a point where environmental expos ures 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 ., K
ow = 2.90 x 10 5 , K
oc ≈ 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 terres trial, non-food, domestic outdoor and indoor uses. According to Code of Federal Re gulations 40 (CFR40 2007) Part 158 Subpart D (data requirements for pesticides) environmenta l fate and non-target organism effect data are required for hexaflumuron based on its terr estrial use. Available studies submitted to fulfill environmental fate and ecological effects guideline requirements, as well as outstanding data gaps for he xaflumuron are defined in Tables 6-9, below.

Further information on data required to fulf ill 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 re quiring the data, an explanation of how the data will be used, and a brie f description of the how the da ta 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 am ount of product present in each bait station. In addition, labels do not specify the maxi mum number of bait stations that can be present on a designated area of land. EFED requests that he xaflumuron 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 34Table 6. Available environmen tal 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 metabo lism 42695901 Supplemental Yes

835.4200 Anaerobic soil metabo lism 42695901 Supplemental Yes

835.4300 Aerobic Aquatic Metabo lism 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 Fiel d Dissipation NA No

850.1730 Bioaccumulation in Fi sh NA Not applicable No* *Although the Log K

ow 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 cl ay loam; 200 days, Ca tlin silt loam; and 280 days, Hanford sandy loam). The aerobic metabolism study does not fulfill the data requirements because: (1) one major degradat e (M8 at 11% of the applied rate at 180 days) from the aniline-labeled study was not id entified; and, (2) a low material balance (up to 55% of the applied radioactivity wa s not accounted for by th e termination of the study) in the benzoyl-labeled portion of the study prevented reliable interpretation of the data. This study can be upgraded by iden tifying the degradate M8 and by providing quantitative evidence regarding the losses of 14 C 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-la beled hexaflumuron degr aded with a halflife of 54-72 days (54 days, Hanford sandy lo am; 57 days, Castle Rising sandy loam; 69 days, Catlin silt loam; and, 72 days, Alconbur y 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 14 C in the low material balances in the benzoyl-labeled study. Therefore, to fulfill the data ga p for Guideline 835.4200, EFED is requesting

additional information to upgrade this study.

18 of 34Leaching and Adsorption/Desorption

The unaged leaching portion of the m obility/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 s uggest that hexaflumuron is relatively stable,

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

7.8.3. Effects

The non-target organism effects data requireme nts 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 t errestrial animals exposed to hexaflumuron and its formulated products and remaining data gaps.

Guideline Description MRID Classification Data Gap? Comments

42648507 Acceptable 850.2100 Avian oral toxicity

42648508 Acceptable Yes*

42648509 Acceptable 850.2200 Avian dietary toxicity

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 34Table 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 pl ants 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 availa ble for passerines, whic h are requir ed under the new 40 CFR Part 158. However, beca use on an acute oral exposure basis, hexaflumuron is practically non-toxic to ma llards and northern bobwhite quail, EFED is not requesting an acute oral t oxicity study with passerines.

20 of 34Avian 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. Alt hough hexaflumuron is practically non-toxic to birds on an acute oral exposure basis, no data are av ailable to characterize the toxicity of hexaflumuron to birds on a chronic exposure ba sis. Therefore, to fulfill the data gap for Guideline 850.2300, and to quantify the chronic t oxicity of hexaflumuron to birds, EFED is requesting two avian reproduc tion 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 labe ls recommend that an attractant be added ( i.e ., a sports drink), and the presence of ants obs erved in bait boxes dur ing a field study (MRID 455985-01), non-target insects have the potentia l 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 exposu re study with h oney bees (nonguideline). At this time, EFED is not re questing that an acute contact exposure study (Guideline 850.3020) be submitted.

Field testing for pollinators

According to 40 CFR Part 158, this study is re quired if any of the following are met: 1) data from other sources (Experimental Use Permit program, university research, registrant submittals, etc .) indicate potential adverse e ffects on colonies, especially

effects other than acute mort ality (reproductive, behavioral, etc .); 2) data from residual toxicity studies indicate exte nded residual toxicity; or 3) da ta derived from studies with terrestrial arthropods other than bees i ndicate potential chronic, reproductive or

behavioral effects. Given the intended e ffect 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). Th ese data will be used to ch aracterize 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 init iation of the field testing for pollinators study.

21 of 34Acute toxicity to freshwater fish

Supplemental data are availabl e to define the acute toxi city of hexaflumuron to freshwater fish. These supplementa l data indicate that the 96-h LC 50 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 defi ne the acute toxicity of hexaflumuron to

estuarine/marine fish and invertebrates. Given the application method of hexaflumuron ( i.e. bait box) and its chemical prope rties, it is assumed that tr ansport of hexaflumuron to estuarine/marine systems is unlikel y. 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. Give n the application method of hexaflumuron ( i.e. bait box) and its chemical properties, it is assu med that transport of hexaflumuron to freshwater aquatic systems is unlikely. Therefore, although guidelines 850.1300 and 850.1400 for freshwater invertebrates and fish, re spectively, remain da ta 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 hexafl umuron to non-vascular and vascular aquatic plants. Given th e 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, altho ugh guidelines 850.4400 and 850.5400 for aquatic vascular and non-vascular plants, respectively, remain data gaps, EFED is not requesting

additional studies to fu lfill the guidelines.

Toxicity to terrestrial plants

At this time, no data are available to defi ne 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. Therefor e, although guideline 850.4150 for effects to

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

additional studies to fulfill th is 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., Meyl an, 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 Pesticid e” 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 Environmen tal 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 Asse ssment Process in the Office of Pesticide Programs. U.S. Environmental Protection Agency, Office of Prev ention, 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. 2007 d . 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 34Zhou, X., Wheeler, M.M., Oi, F.M., and M.E. Sc harf. 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 ( 14 C) 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 Buff ered 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 An aerobic 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 3425 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) Or al 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 DegradatesChemical(CAS Number)MWStructureSMILESHexaflumuron(86479-06-3)461.15Fc1cccc(F)c1C(=O)NC(=O)Nc2cc(Cl)c(OC(F)(F)C(F)F)c(Cl)c22,6-Difluorobenzoic acid(385-00-2)158.11OC(=O)c1c(F)cccc1F2,6-Difluorobenzamide(18063-03-1)157.12NC(=O)c1c(F)cccc1F3,5-Dichloro-4-(l,l,2,2-tetrafluoroethoxy)phenylurea321.06NC(=O)Nc1cc(Cl)c(O(C(F)(F)(C(F)(F))))c(Cl)c126 of 34Chemical(CAS Number)MWStructureSMILES3,5-Dichloro-4-(l,l,2,2-tetrafluoroethoxy)phenylamine278.03Nc1cc(Cl)c(O(C(F)(F)(C(F)(F))))c(Cl)c127 of 3428 of 34Appendix B. Fate ParametersFor Hexaflumuron Degradates, Estimated Using EPISuite v. 4.0Chemical/Fate parameterHexaflumuron2,6-Difluorobenzoic acid2,6-Difluorobenzamide3,5-Dichloro-4-(l,l,2,2-tetrafluoroethoxy)phenylurea3,5-Dichloro-4-(l,l,2,2-tetrafluoroethoxy)phenylamineMolecular Weight (g/mol)461158157321278Vapor Pressure (torr)4.43 x 10-111.76 x 10-32.86 x 10-47.53 x 10-62.31 x 10-3Octanol-water PartitionCoefficient (Log KOW)5.641.590.253.403.77Water Solubility (mg/L; at 25 °C)2.07 x 10-23,06343,14011.529.92Henry's Law Constant(atm-m3mol-1)9.96 x 10-101.20 x 10-71.37 x 10-92.76 x 10-78.52 x 10-5Leaching/Mobility Koc(L/kg)6,092 – 7,272*11 – 44*7 – 46*676 – 783*1,108 – 1,482** 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 supplementalbecause: (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 termina tion of the study) in the benzoyl-labeled portion of the study prevented reliable interpretation of th e 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 14 C 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 da ta 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 informa tion 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 degr adates 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 (M RID 426959-01) was classified as supplemental because of low material balances (up to 60% of th e 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 14 C 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 da ta 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 sed iment. 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 degr adates degrade at a slower rate in anaerobic soil and sediment, additional use precautions a nd/or restrictions may be necessary.

29 of 34Guideline Number: 835.1230/1240 Study Title: Leachability/Mobility Study Rationale for Requiring the Data Mobility studies, which include leaching and adso rption/desorption, provi de 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 e quilibrated 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 inter est is then equilibrated with pesticide-free

solution to determine the amount released from th e soil to the solution (d esorbed). In the aged mobility experiment described in this study, [ 14 C] hexaflumuron was incubated in four soils under aerobic conditions for 30 days; the [ 14 C] residues were then extract ed 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 so il, and referred to all three equilibrations as "desorption." The soils were th en further extracted with acetone and sodium hydroxide to

determine the amount "adsorbed" to the soil. The registrant then calculated "K d ” 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 "K d ” values can at best be considered to be qualitative estimates of

K des for hexaflumuron and its degradates. No inferences can be made concerning K ads of the degradates, since adsorption of the degradat es 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 e qually for data used to make EPA’s RED finding. Practical Utility of the Data

How will the data be used and how could the da ta change the Agency’s decision, or impact the Agency’s future decision-making? Adsorption/desorption data will facilitate a bette r understanding of the move ment of hexaflumuron and its degradates through a soil column. A direct measurement of adsorption will provide higher confidence in simulation modeling for registration re view and to better characterize the mobility of the compound. The study will result in improved co nfidence 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 degr adates are mobile in soil and sediment, additional use precautions and/or restrictions may be necessary.

30 of 34Guideline 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 targ et pest) could potentially result in exposures of birds to hexaflumuron through consumption of cont aminated 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 hexaflum uron on terrestrial species. If avian reproduction effects data are not submitted, than risk to bi rds, 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 speci es 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 c ould result in use restrictions for hexaflumuron use that are unnecessarily severe.

31 of 34Guideline 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 labe ls 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 poten tial 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 consump tion, 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, guide lines 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 pollinat ors, from acute exposure to hexaflumuron. The data will reduce

uncertainties associated with the cu rrent risk assessment for terrest rial 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 insect s indirectly), and use of hexaflumuron and its formulated products may need to be restricted in areas where listed speci es 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 c ould result in use restrictions for hexaflumuron use that are unnecessarily severe.

32 of 34Guideline 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 e xposed 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 (reproduc tive, 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 chroni c, 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 pr esent in the field as it is intended to be applied according to labels (i.e., in bait boxes). The da ta will reduce uncertainti es 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 formul ated products may need to be restricted in areas where listed species could be affected. Th e 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 he xaflumuron use that are unnecessarily severe.

33 of 34Guideline 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 em ergence terrestrial plant effects data for all

insecticides. In addition, it is possible that plant ro ots 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 cu rrent 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 resu lting 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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