### 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< Assess m ent Type: N A 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 Mon iqu e M. Perron, S.D., Toxicologist Risk Assessment Branch 1 (RAB 1 ) Health Effects Division (HED, 7509P)

THROUGH: Charles W. Sm i th 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) Pe sticide Re-Evaluation Division (PRD/7508P)

Page I of8Hexaflumu r on R egistration Rev i ew Human-H ealt h Assessment Scop i ng 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 1 0

. 0 11.0 

### Tab l e of C ontent s

Executive Summa r y

.. .. . ... ..... . .. .. . .. ... . .. . ........... . ...... .. ............................................................. 3 HED Recommendat ions

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

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

.. . ............. .. ..... .. ... . ... . . ....... .. ..... ... . .................. ......... .. ........... . .... 3 Label Recommendations

........ .. ... . ..................................................... ... .. .. . ... .. .. .. .. .. ... . ... . .. 4 Introduct i on

.. . ... . .. . .. .. .. . .. .. .. . .. .. .. . ... . .. .. .. . ... . .. .. .. . ... . ....... . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. ... .. .. .. .. ..... ... .. .. .. .. 4 Chemical Identit y

......... . ........ .. . .. ..... . ........................................ . ...................... .. .. .. ........... 4 Physical/Chem i cal Characterist i cs

.............. ... .. . .. .. ... . .. .. . ... . .. . .................. . ... .. .. .. .. .. .. .. .. .. .. . 4 Pest i c id e Use Pattern

. . ...... . ...... . .. .. .. . ... . .......... .. ...... . ... . .......... . ... . ... ............ . .. . .. .................. 5 Consideration of Environment a l Justice

. .. .. .. . ... . .. .. .. .. .. .. .. . ... . ... .. . . ........... . ... . ... . .. .... . .. .. . .. .. 5 Hazard Characterization and Dose -R esponse Assessment

.......... .................................. .. .. .. 6 Tox i cology Ana l ysis

. ... . .. .. .. . .. .. .. . ... .. . .. .. . .. .. ... . ... . . .... . . ... .. .. .... ... ..... .......... .......................... 6 Consideration of To xicity to Children

............... .. . ... . .............. . .. .. .. .. .. .. .. .. .. .. .. . ... . ... ........ .. 6 Die ta ry Exposure and Ris k Assessment..

.. .. ...... ............................................... .. .. .. .. .. .. .. .. .. .. 7 Residential (Non

- Occupational) Exposure /Risk Charac t erization

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

............................. . .. ... .. .. .. .. . ... .. ..... .. ... .. .. .......... 7 Cumula tive Ex posure / Risk Characterization

... . ... . .. .. .. .. . ... .. . .. ... . ...... .. .......................... . ... .. .. 7 Pub li c Health and Pest i cide Epi demiolog y Data

.................. . .... . .. .. .. .. .............. . .. .. .. .. .. .. .. .. .. . 7 Occupational Exposure/Risk Characterization

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

.. . .. .. .. . ...... . .. . .. ... . .. . .. .. . ... ..................................... . . .. .. .. .. .. . .. .. .. .. .. . ... . ... . ... ...... .. . ... ... 8

Page 2 of8Hexaflumuron Registration Review Human-Health Assessment Scoping Document D406546

Page 3 of 8 

### 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 e t 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 (i ii ) HED’s Hazard and Science Policy Council (HASPOC) recommendations (J. Leshin, 05- NOV

2013, 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 he xaflumuron, two of which are used in conjunction with services provided by pest-control ope rators licensed by the state to apply termiticides and a third that can be bought and used by homeow ners. 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 a ssessment 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 he xaflumuron. 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

Page 4 of 8 

### 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 (Recruit TM ); 62719

- 272 ( Shatter TM ); 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(K OW ) 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 containingHexaflumuron 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 Shatter TM 

### (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 Recruit TM 

### AG (EPA Registration Number 62719-270) indicates that it is only sold in conjunction with services provided by a pest-control operators li censed 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.

Shatter TM 

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

### 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 buil dings/structures, rights-of-way/fence rows/hedge rows, decking, uncultivated areas/soils, ornamentals and/or shade trees). Shatter TM 

### and Recruit TM 

### AG can also be used indoors (i.e., residential structures, eating establishments, food processing plant premises, stores/markets/ supermarkets premises). The Shatter TM 

### 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 Recruit TM 

### 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 tampe r-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

c onfined 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/ poli cy/exec_order_12898.pdf. As a p art 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, spec ialized 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

c lassified 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

we re observed for parental animals. As part of the revised 40 CFR Toxicology Data R equirements, 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 absorbedat 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). Meta bolites included 3,5-dichlorobenzoic acid (excreted in the urine) and 2,6-difluo ro
- 1,1,2,2

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

B ased 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 he xaflumuron. 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 fa ctor to protect children is not needed.Hexaflumuron Registration Review Human-Health Assessment Scoping Document D406546

Page 7 of 8 

### 5.0 Dietary Exposure and Risk Assessment
There are no food uses currently registered for hexaflumuron and thus no dietary exposure is

e xpected.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization
Residential handler and post-application exposures from hexaflumuron are expected to be

ne gligible because the registered products are packaged in an enclosed system. Even though ter mite 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 insi de tamper-resistant plastic bait housing. Additionally, no toxicological points of departurehave 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

a ggregate 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 meta bolite 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

re presents incidents occurring in the U.S. from 2002 to 2009. The evaluation of incident data for he xaflumuron indicates only one reported incident. Symptoms appeared to be generic in nature

a nd 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 re ports that suggest a plausibl e 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 healthHexaflumuron 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 byprofessional 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. The refore, 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.

1 1 .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:S109 53 :PY-S:(703)305- 07 83 :7509P:RAB1