UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: 05-MAR-2014 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Hexa.flumuron. Human-Health Risk Assessment in Support of Registration 

Review 

PC Code: I 18202 

Decision No.: 471468 

DP Barcode: 0406546 

Registration Nos.: 62719-244,62719-270,62719-272,62719-

273, 9688-299 

Petition No.: NA Regulatory Action: Registration Review Risk Assessment 

Risl< Assessment Type: NA Case No.: 7413 

TXR No.: NA CAS No.: 86479-06-3 

MRID No.: NA 40 CFR: NA 

FROM: Sarah J. Levy, Chemist ;6c~ () 

Kelly M. Lowe, Environmental ScientiJ 

Monique M. Perron, S.D., Toxicologist 

Risk Assessment Branch 1 (RAB 1) 

Health Effects Division (HED, 7509P) 

THROUGH: Charles W. Smith III, Branch Ch' 

George F. Kramer, Ph.D., Senior --~ 

RAB 1/HED (7509P) 

TO: Ricardo Jones, Risk Manager Reviewer 

Neil Anderson, Branch Chief 

Risk Management and Implementation Branch 1 (RMIB 1) 

Pesticide Re-Evaluation Division (PRD/7508P) 

Page I of8 
Hexaflumuron Registration Review Human-Health Assessment Scoping Document 0406546 

1.0 

2.0 

2.1 

2.2 

2.3 

3.0 

3.1 

3.2 

3.3 

3.4 

4.0 

4. 1 

4.2 

5.0 

6.0 

7.0 

8.0 

9.0 

10.0 

11.0 

Table of Contents 

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

HED Recommendations .. ... .... ..................... .... .... ... ..... ....... .... .... .. .. ........... .... .... .... .... ......... .. 3 

Data Deficiencies ....... ....... .... .... .................. .... ... ........ ........ ... .... ............ .... .... ... .... ..... ....... 3 

Tolerance Considerations .. .............. ............ .... ........... ........ .............................. ................ 3 

Label Recommendations .......... ............................................................ .... .... .... ......... .... ... 4 

Introduction .. .... ... ....... ... .... ....... ........... .... ... .... .... ........ ... .... .... .... ... .... .... ..... ... .... ............ .... .... 4 

Chemical Identity ......... ........... ................................................. ....................... .... ............. 4 

Physical/Chemical Characteristics ................. .. ..... ...... .. .... ... ................... .... .... .... .... .... .... . 4 

Pesticide Use Pattern ........ ....... ....... .... ........... ........ .... ........... .... .... ............... ..................... 5 

Consideration of Environmental Justice ... .... .... ... ........ .... .... .... ............... .... ....... ......... ... .. 5 

Hazard Characterization and Dose-Response Assessment ............................................ .... .. 6 

Toxicology Analysis .... ... .... ... .... ........... ... ..... .... ...... ..... .... ....... ............... .......................... 6 

Consideration of Toxicity to Children ................. .... ............... ........... .... .... .... .... .... ........ .. 6 

Dietary Exposure and Risk Assessment.. .. ........ ................................................. .... .... .... .... .. 7 

Residential (Non-Occupational) Exposure/Risk Characterization ...................................... 7 

Aggregate Exposure/Risk Characterization ................................... .... .... .... ............ .... .......... 7 

Cumulative Exposure/Risk Characterization ... ....... ............ ... ............ ................................ .. 7 

Public Health and Pesticide Epidemiology Data ....................... ..... .... .............. ..... .... .... .... ... 7 

Occupational Exposure/Risk Characterization .... .... ........ ... ....... ..... ... ...... .......... ................... 8 

References .. ... .... ....... ... ...... ........ .... ..................................... .... .... .... ... .... .. .. .... .... .... ........ .... ... 8 

Page 2 of8 
Hexaflumuron Registration Review Human-Health Assessment Scoping Document D406546 

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1.0 Executive Summary

HED has prepared a qualitative human-health risk assessment to support registration review for 

the use of hexaflumuron (N-[[[3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl]amino] 

carbonyl]-2,6-difluorobenzamide). When writing this risk assessment, HED primarily 

considered the following three documents: (i) Hexaflumuron. Human-Health Assessment 

Scoping Document in Support of Registration Review (S. Levy et al., 12-AUG-2009; D362302); 

(ii) Hexaflumuron. Public Comments Regarding the Health Effects Division’s (HED’s) 

Human-Health Assessment Scoping Document in Support of Registration Review of 12-AUG2009. HED’s Response to Public Comments (S. Levy et al., 18-FEB-2010; D362321); and (iii) 

HED’s Hazard and Science Policy Council (HASPOC) recommendations (J. Leshin, 05-NOV2013, TXR #0056808). 

The only registered use for hexaflumuron is as a bait station/bait application delivery system for 

elimination of subterranean termite colonies. Three products are currently registered containing 

hexaflumuron, two of which are used in conjunction with services provided by pest-control 

operators licensed by the state to apply termiticides and a third that can be bought and used by 

homeowners. Hexaflumuron was the first successful candidate to be considered for registration 

under the Voluntary Reduced-Risk Pesticides Initiative (PR Notice 93-9) (Registration Action 

Decision (RAD) meeting, 27-SEP-1993). Hexaflumuron was first registered in 1994 and did not 

go through the reregistration process. Because of the low toxicity of hexaflumuron, and the 

negligible exposure expected from the currently-registered products, a quantitative human-health 

risk assessment has not been previously conducted. 

No data deficiencies were identified for the toxicology, residue chemistry, or occupational/ 

residential exposure databases. Dietary exposure is not expected and occupational/residential 

exposures are anticipated to be negligible from the currently registered uses of hexaflumuron. 

Based on the negligible exposure potential of the currently registered uses and the available 

hexaflumuron toxicity database, no toxicological points of departure have been established for 

hexaflumuron. As a result, quantitative risk assessments are not necessary to conclude with 

reasonable certainty that exposures to the currently registered uses of hexaflumuron do not pose 

a significant human health risk. 

2.0 HED Recommendations 

HED has no objection for continued registration of the current hexaflumuron pesticide products. 

2.1 Data Deficiencies 

o None. 

2.2 Tolerance Considerations 

Hexaflumuron is not a food-use chemical. There are no U.S. tolerances established for 

hexaflumuron. 

2.3 Label Recommendations 

HED has no label recommendations at this time. 
Hexaflumuron Registration Review Human-Health Assessment Scoping Document D406546 

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3.0 Introduction 

Hexaflumuron is an insecticide registered to control termites (Eastern and Formosan 

subterranean termites) and is a member of the benzoyl-phenylurea class of chemicals. The 

primary mode of action is as an insect-growth regulator, which inhibits chitin synthesis in the 

exoskeleton, disrupting the molting process. Hexaflumuron is active through ingestion and 

topical treatment; however, ingestion is the primary mode of lethal-dose accumulation. The 

structure, chemical names, and other identifiers are found in the chemical identity table below. 

3.1 Chemical Identity

Table 3.1. Test Compound Nomenclature.

Compound Chemical Structure

Common name Hexaflumuron

IUPAC name 1-[3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl]-3-(2,6-difluorobenzoyl)urea

CAS name N-[[[3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenyl]amino]carbonyl]-2,6-

difluorobenzamide

CAS # 86479-06-3

PC Code 118202

End-use product/(EP) 62719-270 (RecruitTM); 62719-272 (ShatterTM); Chemsico Insecticide Bait SR 

(9688-299)

3.2 Physical/Chemical Characteristics 

Table 3.2. Physicochemical Properties of Hexaflumuron. 

Parameter Value Reference

Melting range 202-205°C

EPA Pesticide Fact Sheet, 

10-MAR-1994; and 

American National 

Standard Institute (ANSI), 

1990.

pH 3.66 for 10% slurry in water

Specific gravity (at 20°C) 1.680

Water solubility (g/100 mL at 20°C) 2.7 x 10-6

Solvent solubility (at 18°C) Acetone: >100 ppb

Hexane: 7 ppm

Dichloromethane: 14.6 ppm

Toluene: 6.4 ppm

Xylene: 5.2 ppm

Propan-2-ol: 3 ppm

Vapor pressure (Pa at 25°C) 5.9 x 10-9

Octanol/water partition coefficient 

Log(KOW)

5.462 PAI

UV/visible absorption spectrum Not provided.

3.3 Pesticide Use Pattern 

Hexaflumuron is only registered for use as a bait station/bait application delivery system for 

elimination of subterranean termite colonies. Three products are currently registered containing 
Hexaflumuron Registration Review Human-Health Assessment Scoping Document D406546 

Page 5 of 8 

hexaflumuron, two of which are to be used only by professional applicators and a third that can 

be bought and used by homeowners. The product label for ShatterTM (EPA Registration Number 

62719-272) indicates it is for professional use only by individuals licensed by the state to apply 

termiticides, and the product label for RecruitTM AG (EPA Registration Number 62719-270) 

indicates that it is only sold in conjunction with services provided by a pest-control operators 

licensed by the state to apply termiticides. Chemsico Insecticide Bait SR (EPA Registration 

Number 9688-299) is sold as a do-it-yourself kit that can be used in residential areas by 

homeowners. 

ShatterTM and Chemsico Insecticide Bait SR are end-use bait products for in-ground stations, and 

RecruitTM AG is an end-use bait product for above-ground stations. All of the products can be 

used outdoors, potentially in residential settings (i.e., around the outside of non-agricultural 

buildings/structures, rights-of-way/fence rows/hedge rows, decking, uncultivated areas/soils, 

ornamentals and/or shade trees). ShatterTM and RecruitTM AG can also be used indoors (i.e., 

residential structures, eating establishments, food processing plant premises, stores/markets/ 

supermarkets premises). The ShatterTM label states “target sites for this system can include 

buildings...Shatter can be used on the inside or outside of foundation walls or crawl space areas 

or through concrete and asphalt.” The RecruitTM AG label states “target sites for use of this 

product include interior and exterior surfaces of buildings and crawl spaces.” The timing of the 

use of the bait station is on an “as needed” basis, and the bait station is kept in use until the 

termites are eliminated from the structure. 

Although the termite bait can be used in residential structures, the in-ground bait is confined in 

tamper-resistant termite stations, and these stations are rarely used in bath traps, through a slab, 

or in crawl spaces. Additionally, when used in above-ground bait stations, the bait formulation is 

confined inside tamper-resistant plastic bait housing. 

3.4 Consideration of Environmental Justice 

Potential areas of environmental justice concerns, to the extent possible, will be considered in 

future human health risk assessments for hexaflumuron, in accordance with U.S. Executive 

Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and 

Low-Income Populations," http://www.epa.gov/compliance/environmentaljustice/resources/ 

policy/exec_order_12898.pdf. As a part of every pesticide risk assessment, OPP considers a 

large variety of consumer subgroups according to well-established procedures. In line with OPP 

policy, HED estimates risks to population subgroups from pesticide exposures that are based on 

patterns of that subgroup’s food and water consumption, and activities in and around the home 

that involve pesticide use in a residential setting. Extensive data on food consumption patterns 

are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) 

and are used in pesticide risk assessments for all registered food uses of a pesticide. These data 

are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and 

region of the country. Additionally, OPP is able to assess dietary exposure to smaller, 

specialized subgroups and exposure assessments are performed when conditions or 

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

pesticide products and associated risks for adult applicators and for toddlers, youths, and adults 

entering or playing on treated areas post-application are evaluated. Further considerations are 

currently in development as OPP has committed resources and expertise to the development of 

specialized software and models that consider exposure to bystanders and farm workers as well 

as lifestyle and traditional dietary patterns among specific subgroups. 
Hexaflumuron Registration Review Human-Health Assessment Scoping Document D406546 

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4.0 Hazard Characterization and Dose-Response Assessment 

4.1 Toxicology Analysis

Since hexaflumuron was registered under the Voluntary Reduced Risk Pesticides Initiative, a 

limited toxicity database is considered adequate. In submitted studies, hexaflumuron was 

classified as having low acute toxicity (Toxicity Categories III and IV) and negative for 

mutagenicity. In developmental and reproduction toxicity studies, there was no indication that 

hexaflumuron had an adverse effect on fetal development, fertility, or reproductive performance. 

No developmental or maternal toxicity was observed up to the limit dose in developmental 

toxicity studies in rats and rabbits. In a rat reproduction toxicity study, the only effect observed 

was decreased pup weights at the highest dose tested (125 mg/kg/day); however this effect was 

not seen in other reproduction studies conducted at similar doses (see below). No adverse effects 

were observed for parental animals. As part of the revised 40 CFR Toxicology Data 

Requirements, acute neurotoxicity, subchronic neurotoxicity, and immunotoxicity studies are 

necessary for registration; however, the HED HASPOC concluded using a weight-of-evidence 

approach that these studies are not required at this time (J. Leshin, 05-NOV-2013, TXR 

#0056808).

Summaries of Organization for Economic Cooperation and Development (OECD) studies were 

also submitted (MRID 42648520) that further support the registration of hexaflumuron as a 

reduced-risk pesticide. In the rat metabolism study, the majority of hexaflumuron was absorbed 

at a dose of 5 mg/kg, while it was poorly absorbed at higher doses (250 mg/kg). Plasma halflives of hexaflumuron in rats, mice, and dogs were approximately the same (17-26 hours). 

Metabolites included 3,5-dichlorobenzoic acid (excreted in the urine) and 2,6-difluoro-1,1,2,2-

tetrafluoroethoxy aniline and the corresponding phenylurea. Hematological effects (Heinz-body 

formation and reversible increases in methemoglobin) were noted in the chronic dog study, but 

bone marrow and other hematological parameters were unaffected by treatment. No effects were 

observed in rat and rabbit developmental studies up to the limit dose (1,000 mg/kg/day). In a rat 

two-generation reproduction study, no effects were observed on fertility, reproductive 

performance, or fetal development up to the highest dose tested (125 mg/kg/day). In 

carcinogenicity studies, hexaflumuron was not found to be carcinogenic in rats or mice. 

Based on the negligible exposure potential of the currently registered uses and the available 

hexaflumuron toxicity database, no toxicological points of departure have been established for 

hexaflumuron. As a result, a quantitative risk assessment is not required for hexaflumuron to 

support the currently registered uses. 

4.2 Consideration of Toxicity to Children

Food Quality Protection Act (FQPA) considerations do not apply to hexaflumuron for the 

currently registered (non-food) use patterns described in this risk assessment. In addition, no 

toxicological points of departure where selected for hexaflumuron and thus, an additional safety 

factor to protect children is not needed. 
Hexaflumuron Registration Review Human-Health Assessment Scoping Document D406546 

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5.0 Dietary Exposure and Risk Assessment 

There are no food uses currently registered for hexaflumuron and thus no dietary exposure is 

expected. 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization 

Residential handler and post-application exposures from hexaflumuron are expected to be 

negligible because the registered products are packaged in an enclosed system. Even though 

termite bait is used in residential structures, the in-ground bait is confined in tamper-resistant 

termite stations, and these stations are rarely used in bath traps, through a slab, or in crawl 

spaces. Additionally, when used in above-ground bait stations, the bait formulation is confined 

inside tamper-resistant plastic bait housing. Additionally, no toxicological points of departure 

have been established for hexaflumuron. Therefore, quantitative residential handler and postapplication exposure assessments are not necessary to conclude with reasonable certainty that 

residential exposures to the currently registered uses of hexaflumuron do not pose a significant 

human health risk. 

7.0 Aggregate Exposure/Risk Characterization 

As quantitative dietary and residential exposure assessments are not required for hexaflumuron 

and no toxicological points of departure have been established for hexaflumuron, a quantitative 

aggregate assessment is not required either to conclude with reasonable certainty that aggregate 

exposures to the currently registered uses of hexaflumuron do not pose a significant human 

health risk. 

8.0 Cumulative Exposure/Risk Characterization 

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

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

to hexaflumuron and any other substances and hexaflumuron does not appear to produce a toxic 

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

assumed that hexaflumuron does not have a common mechanism of toxicity with other 

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

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

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

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

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

9.0 Public Health and Pesticide Epidemiology Data 

A summary report listing incidents for hexaflumuron reported to the OPP Incident Data System 

(IDS) has been previously conducted (Memo, M. Hawkins, 07-MAY-2009). The report 

represents incidents occurring in the U.S. from 2002 to 2009. The evaluation of incident data for 

hexaflumuron indicates only one reported incident. Symptoms appeared to be generic in nature 

and they were not confirmed to be related to exposure, and there is no clear evidence of a trend 

or exposure pattern. Therefore, at this time, there are no remarkable case reports that suggest a 

plausible association between a moderate or severe health outcome and exposure to 

hexaflumuron, nor can HED discern any suggestion of a trend or pattern regarding the health 
Hexaflumuron Registration Review Human-Health Assessment Scoping Document D406546 

Page 8 of 8 

effects due to the alleged exposure to hexaflumuron. The 2009 review of the incident data does 

not warrant further investigations at this time. 

10.0 Occupational Exposure/Risk Characterization

As mentioned in Section 3.3, hexaflumuron is registered for use in products to be used by 

professional applicators licensed to apply termiticides. Occupational handler and postapplication exposures are not anticipated since the products are packaged in an enclosed system. 

Additionally, no toxicological points of departure have been established for hexaflumuron. 

Therefore, quantitative occupational handler and post-application exposure assessments are not 

necessary to conclude with reasonable certainty that occupational exposures to the currently 

registered uses of hexaflumuron do not pose a significant human health risk. 

11.0 References 

Memo, M. Hawkins, 07-MAY-2009; No DP#. 

Memo, S. Levy et al., 12-AUG-2009; D362302. 

Memo, S. Levy et al., 18-FEB-2010; D362321. 

Memo, J. Leshin, 05-NOV-2013, TXR #0056808. 

cc: S. Levy (RAB1) 

RDI: RAB1 Branch (11/06/13)/D. Vogel (11/06/13) 

S.Levy:S10953:PY-S:(703)305-0783:7509P:RAB1