UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

Date: January 24, 2013 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

Subject: Metofluthrin. Occupational and Residential Exposure Assessment for a 

Proposed Use in an Outdoor Area Repellent 

PC Code: I 09709 

Decision No.: 462028 

Petition No.: NA 

Risk Assessment Type: Occupational/Residential Exposure Assessment 

TXR No.:NA 

MRIDNo.:NA 

From: 

Through: 

To: 

Introduction 

Matthew Lloyd, CIH 

Risk Assessment Branch VII 

Health Effects Division (7509P) 

Christina Swartz, Branch Chief 

Risk Assessment Branch II 

Health Effects Division (7509P) 

and 

Risk 

Alexandra 

Assessment 

LaMay 

Branch VII 

tJ ~~ P 

Health Effects Division (7509P) 

Kevin Sweeney I Richard Gebken (RMlO) 

Insecticides Branch 

Registration Division (7505P) 

DP Barcode: 0403191 

Registration No.: 4822-LIL-SGOL 

Regulatory Action: Section 3 

Registration 

Case No.: 4822 

CAS No.: 240494-70-6 

40CFR: NA 

The Registration Division (RD) requested that the Health Effects Division (HED) conduct an 

exposure and risk assessment for a proposed new product called FAN, which is a battery 

operated area repellent containing the insecticide metofluthrin. No risks of concern were 

identified in this assessment, and therefore HED has no objection to the registration of the 

proposed new product. 

Page I of23 
Page 2 of 23

Table of Contents

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

2.0 Risk Assessment Conclusions and Recommendations........................................................ 5

3.0 Hazard Characterization....................................................................................................... 5

3.1 Hazard Profile .................................................................................................................. 6

3.2 FQPA and Uncertainty Factor.......................................................................................... 7

4.0 Use Profile ......................................................................................................................... 10

5.0 Residential Exposure and Risk Estimates.......................................................................... 10

5.1 Residential Handler Exposure/Risk Estimates............................................................... 10

5.2 Residential Post-application Exposure/Risk Estimates.................................................. 11

5.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios) ......................... 14

5.4 Residential Risk Estimates for Use in Aggregate Assessment ...................................... 14

5.6 Residential Bystander Post-Application Inhalation Exposure ....................................... 15

6.0 Cumulative Exposure/Risk Characterization.......................................................................... 15

7.0 Occupational Exposure and Risk Estimates ...................................................................... 15

7.1 Occupational Handler Exposure/Risk Estimates............................................................ 15

7.2 Occupational Post-application Exposure/Risk Estimates .............................................. 16

Appendix A. Summary of Occupational and Residential Non-cancer Algorithms..................... 17

Appendix B. Metofluthrin - Calculations of RDDR, HEC and HED........................................... 23
Page 3 of 23

1.0 Executive Summary

The Registration Division (RD) requested that the Health Effects Division (HED) conduct an 

exposure and risk assessment for a proposed new product called FAN, a battery operated area 

repellent containing the pyrethroid insecticide metofluthrin. The solvent based formula will be 

packaged in a pressurized can and sold with a plastic shroud capable of releasing metered doses 

of repellent for preset time intervals up to 3 hours. 

Besides the proposed use, metofluthrin has a number of currently registered products including 

impregnated paper repellent strips, a personal outdoor insect repellent fan, and a recently 

registered candle product. There are no food/feed uses and no drinking water exposure is 

expected from the repellent uses (including the proposed use pattern). HED completed a human 

health risk assessment for a new use request to control bed bugs and to support registration 

review in September, 2012. That assessment also served as a preliminary risk assessment to 

support registration review in that HED prepared revised residential handler and post-application 

assessments for metofluthrin for the currently registered uses in mosquito repellent products 

(including a recently registered candle product) to reflect the Revised Residential SOPs (2012). 

No risks of concern were identified in this assessment; and the exposure scenarios assessed in 

this document result in lower risk estimates (i.e., higher calculated MOEs and ARIs) than the 

other scenarios assessed in the 2012 human health risk assessment.

Hazard Profile and Points of Departure (POD) 

Metofluthrin is a Type I pyrethroid, and like other pyrethroids, causes neurotoxicity from 

interaction with sodium channels leading to clinical signs of neurotoxicity. Following a single 

oral gavage dose, metofluthrin is absorbed quickly in rats. Neurotoxicity is observed within 6

hours, and rats recover within 24 hours without any persisting neurotoxic effects. This is 

generally consistent with the toxicity profiles for all the pyrethroids which are very similar and 

marked by rapid absorption, metabolism, and time-to-peak effect. The no-observed-adverseeffects-levels (NOAELs) and lowest-observed-adverse-effects-levels (LOAELs) established 

from metofluthrin single dose and repeat dosing studies show that repeat exposures do not result 

in lower NOAELs (i.e. increasing toxicity). Thus, for purpose of endpoint selection and 

exposure assessment, only single day risk assessments need to be conducted.

A 90-day dermal toxicity study in the rat was selected for use in assessment of short- and 

intermediate-term dermal exposures. The NOAEL was 300 mg/kg/day based on mortality and 

clinical signs of toxicity including tremors and salivation observed at the LOAEL of 1000 

mg/kg/day. The dermal study is protective of potential offspring effects since it adequately 

measured systemic toxicity in adult animals, and there were no developmental or offspring 

effects that were not evaluated in the dermal study. 

The maternal effects from the rat developmental toxicity study were selected for the assessment 

of short-term incidental oral exposure. The maternal NOAEL of 15 mg/kg/day, based on tremors 

at the high dose of 30 mg/kg/day, was the most sensitive endpoint for oral exposure for shortterm duration. The NOAEL and endpoint from the selected study are protective of potential 

developmental effects including offspring effects in the rat reproduction study which occurred at 

a higher dose (NOAEL/LOAEL = 97.6/183.6 mg/kg/day). 
Page 4 of 23

A 28-day inhalation toxicity study in the rat was selected for use in assessment of short- and 

intermediate-term inhalation exposures. The NOAEL was 0.099 mg/L (7.5 mg/kg/day for 

residential exposure) based on tremors, clinical signs and mortality, observed at the dose of 

0.196 mg/L. The inhalation study is protective of potential offspring effects since it adequately 

measured systemic toxicity in adult animals, and the developmental and reproduction studies did 

not identify effects that were not evaluated in the inhalation study. In order to assess exposure 

via the inhalation route, the reference concentration methodology developed by the Office or 

Research and Development (ORD) was used to determine human equivalent concentrations 

(HECs) and human equivalent doses (HEDs) for risk assessment.

In order to assess exposure and risk, HED used the default body weight of 11 kg for children and 

the average adult body weight of 80 kg, given that the endpoints chosen for risk assessment were 

not sex-specific. 

Metofluthrin is classified as ‘Not likely to be carcinogenic to humans at doses that do not result 

in a mitogenic response’. Genotoxicity studies were negative. The doses selected for risk 

assessment are protective of potential carcinogenic effects.

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

proposed and existing (non-food) use patterns. However, since metofluthrin is a pyrethroid and 

exposure to children under <6 years old is expected, the Agency has retained a 3X uncertainty 

factor (UF), based on the increased quantitative susceptibility seen in the scientific literature 

related to pyrethroid pharmacokinetics. 

For dermal residential and occupational scenarios involving adults, the level of concern (LOC) is 

a Margin of Exposure (MOE) of 100, based on the 10X uncertainty factors to account for 

interspecies extrapolation and intraspecies variability. For dermal and incidental oral exposure 

to children <6 years old, the additional 3X UF to account for potential sensitivity in the young 

results in LOCs of 300 for both the incidental oral and dermal exposure routes. Therefore, risk 

estimates (MOEs) above the respective LOCs for adults or children indicate risk estimates are 

not of concern.

For residential inhalation scenarios involving adults, the level of concern (LOC) is a Margin of 

Exposure (MOE) of 30, based on a 3X uncertainty factor to account for interspecies 

extrapolation (reduced from 10X because the HEC calculation accounts for pharmacokinetic 

differences between humans and rats) and a 10X uncertainty factor for intraspecies variability. 

For children <6 years old, the LOC is 100. Risk estimates (MOEs) above the respective 

inhalation LOCs for adults and children indicate risk estimates are not of concern.

Although the endpoints selected for incidental oral, dermal and inhalation routes of exposure are 

similar (i.e., tremors and clinical signs), the dermal and incidental oral routes have different 

LOCs than the inhalation route. Therefore, in order to combine exposure from the various routes 

the aggregate risk index (ARI) approach is used to estimate risk. ARIs ≥ 1 are not of concern.

Residential Handler Exposure and Risk
Page 5 of 23

FAN Area Repellent Use: The metofluthrin-based product FAN does not require a residential 

handler assessment as handler exposure is expected to be negligible.

Residential Post-application Exposure and Risk

There is the potential for post-application exposure for individuals exposed as a result of being in 

outdoors areas after the metofluthrin-based FAN product has been deployed. The ARI estimate 

for adult post-application exposure (inhalation and dermal) is 240 and the ARI estimate for 

children’s post-application exposure (inhalation, dermal, and incidental oral) is 27. Since the 

ARI’s for adults and children for the combined exposure routes are above 1, no risk estimates of 

concern have been identified in this assessment.

Human Studies Review

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include the Residential 

SOPs (Section 5: Outdoor Fogging and Misting Systems); are (1) subject to ethics review 

pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable 

ethics requirements. For certain studies, the ethics review may have included review by the 

Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, 

can be found at the Agency website1. 

2.0 Risk Assessment Conclusions and Recommendations

Short-term risk estimates for the residential post-application assessment exceed HED’s level of 

concern (i.e., MOEs > LOC for all lifestages assessed and the ARI>1) for the scenarios/exposure 

routes assessed. No quantitative assessment was conducted for the occupational exposure 

scenarios (handler or post-application) because this metofluthrin-based repellent is designed and 

intended to be marketed for the consumer market. 

The acute toxicity classification for primary eye irritation of metofluthrin is Category IV for 

primary eye and skin irritation. The acute toxicity classification for acute oral, dermal, and 

inhalation are all Category III. At this time, no additional information is needed to refine this 

assessment.

3.0 Hazard Characterization

HED completed a human health risk assessment for metofluthrin that evaluated a proposed use 

as well as the existing residential use patterns in September, 20122. Before completing this 

action, HED evaluated the toxicological database for metofluthrin and no new studies or 

information are available that would impact the hazard characterization and dose-response 

assessment identified in that risk assessment. 

 

1

http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html

2 Metofluthrin. Human Health Risk Assessment for the New Use to Control Bed Bugs and to Support Registration 

Review (D402777, D403390)
Page 6 of 23

3.1 Hazard Profile

Metofluthrin is a Type I pyrethroid, and like other pyrethroids, causes neurotoxicity from 

interaction with sodium channels leading to clinical signs of neurotoxicity. One of the key 

elements in risk assessment is the appropriate integration of temporality between the exposure 

and hazard assessments. Following a single oral gavage dose, metofluthrin is absorbed quickly 

in rats. Neurotoxicity is observed within 6 hours, and rats recover within 24 hours without any 

persisting neurotoxic effects. This is generally consistent with the toxicity profiles for all the 

pyrethroids which are very similar and marked by rapid absorption, metabolism, and time-topeak effect. The NOAELs and LOAELs established from metofluthrin single dose and repeat 

dosing studies show that repeat exposures do not result in lower NOAELs. Thus, for purposes of 

endpoint selection and exposure assessment, only single day risk assessments need to be 

conducted.

Technical metofluthrin has low acute oral, dermal, and inhalation toxicity (Toxicity Categories 

III). It is not a dermal or eye irritant (Toxicity Category IV) and is not a dermal sensitizer.

A 90-day dermal toxicity study in the rat was available and was selected for use in assessment of 

short- and intermediate-term dermal exposures. The NOAEL was 300 mg/kg/day. Significant 

findings at the LOAEL of 1000 mg/kg/day included tremors, which were also observed at the 

LOAEL of the critical study selected for incidental oral exposure assessment (rat developmental 

study). Mortality was also observed at 1000 mg/kg/day. The developmental toxicity and 

reproduction studies were also considered for dermal risk assessment. However, no 

developmental effects were noted in the developmental studies and the offspring effects in the 

reproduction study were seen in the presence of comparable maternal effects; therefore, there is 

no concern for increased susceptibility. The dermal study is protective of potential offspring 

effects since it adequately measured systemic toxicity in adult animals, and the developmental 

and reproduction studies did not identify effects that were not evaluated in the dermal study. 

Since the dermal endpoint was based on a dermal study, a separate dermal absorption factor was 

not required for estimating dermal exposure.

The maternal effects from the rat developmental toxicity study were selected for the assessment 

of short-term incidental oral exposure. The maternal NOAEL of 15 mg/kg/day, based on tremors 

observed at the high dose of 30 mg/kg/day, was the most sensitive endpoint for oral exposure for 

short-term duration. Comparable but slightly higher NOAELs were observed in the rat 90-day 

and six-month dietary studies (17-22 mg/kg/day), based on hepatotoxicity and body weight 

decreases at 54 -73 mg/kg/day. The NOAEL and endpoint from the selected study are protective 

of potential developmental effects including offspring effects in the rat reproduction study at a 

higher dose (NOAEL/LOAEL = 97.6/183.6 mg/kg/day). 

A 28-day inhalation toxicity study in the rat was selected for use in assessment of short- and 

intermediate-term inhalation exposures. The NOAEL was 0.099 mg/L (7.5 mg/kg/day) was 

based on tremors at the LOAEL of 0.196 mg/L. Tremors, which were also observed at the 

LOAEL of the critical study selected for incidental oral exposure assessment (rat developmental 

study), and other neurological clinical signs. A high rate of mortality was also observed. The 
Page 7 of 23

developmental toxicity and reproduction studies were also considered for inhalation risk 

assessment. However, no developmental effects were noted in the developmental studies and the 

offspring effects in the reproduction study were seen in the presence of comparable maternal 

effects; therefore, there is no concern for increased susceptibility. The inhalation study is 

protective of potential offspring effects since it adequately measured systemic toxicity in adult

animals, and the developmental and reproduction studies did not identify effects that were not 

evaluated in the inhalation study.

For purposes of estimating inhalation risk resulting from occupational and residential exposure, a 

human equivalent concentration (HEC) and human equivalent dose (HED) were derived in 

accordance with standard methodology that results in a reduction in the interspecies uncertainty 

factor (UF) from 10X to 3X. The HED determined for occupational inhalation risk assessment is 

7.4 mg/kg/day; for residential risk assessment, the HED is 7.5 mg/kg/day. 

For exposure and risk assessment, HED assumed a body weight of 11 kg for children; given that 

the endpoints chosen for risk assessment were not sex-specific, HED has used the average body 

weight of 80 kg for adults. 

Metofluthrin is classified as ‘Not likely to be carcinogenic to humans at doses that do not result 

in a mitogenic response’ (Metofluthrin: Second Report of the Cancer Assessment Review 

Committee, TXR No. 0054668, July 26, 2007). The classification was based on an increased 

incidence of liver adenomas and carcinomas in both sexes of Wistar rat with supporting 

mechanistic studies demonstrating a mitogenic mode of action based on induction of liver 

cytochrome p450, resulting in a proliferative (mitogenic) response and eventual tumor formation. 

Genotoxicity studies were negative. The doses selected for risk assessment are protective of 

potential carcinogenic effects.

3.2 FQPA and Uncertainty Factor

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

and proposed (non-food) use patterns described in this risk assessment. However, since 

metofluthrin is a pyrethroid and exposure to children under <6 years old is expected, 

metofluthrin must be considered in the greater context of the pyrethroids as a class. The Agency 

will retain a 3X uncertainty factor to protect for exposures to children <6 years of age based on 

the increased quantitative susceptibility seen in the scientific literature related to pyrethroid 

pharmacokinetics and the applicability of these findings to all pyrethroids. This is consistent 

with the Agency’s 2011 analysis and is supported by rat PBPK model predictions of a 3-fold 

increase of deltamethrin concentrations in the juvenile brain compared to adults. The PK of 

pyrethroids as a group is sufficiently similar that significant deviations from the 3-fold increase 

of deltamethrin concentrations are not expected for other pyrethroids. Juveniles are not more 

sensitive than adults with respect to pyrethroid pharmacodynamics and thus no uncertainty factor 

is needed for PD considerations.

Exposure from incidental oral, dermal and inhalation routes are based on different and routespecific studies, but similar endpoints all relevant to the sodium channel interaction of 

metofluthrin (i.e., clinical signs including tremors) were identified in each case. Occupational 
Page 8 of 23

and residential exposures from these routes may therefore be combined. Based on the traditional 

uncertainty factors of 10X for intraspecies variability and interspecies extrapolation, along with 

the additional 3X uncertainty factor to protect for exposures to children (<6 years of age), the 

level of concern (LOC) for children’s dermal and oral risk is an MOE of 300. The LOC for adult 

dermal risk is an MOE of 100, based on the traditional 10X UFs for intraspecies variability and 

interspecies extrapolation. However in the case of inhalation risk, the interspecies uncertainty 

factor was reduced from 10X to 3X because the HEC calculation accounts for pharmacokinetic 

(not pharmacodynamic) interspecies differences between animals and humans. Therefore, the 

inhalation LOC is an MOE of 30 for the adult population and is an MOE of 100 for children < 6 

years old. MOEs greater than the LOC are not of concern.

Although the incidental oral, dermal and inhalation routes of exposure have similar toxic effects 

(i.e., tremors), the dermal and incidental oral routes have different LOCs than the inhalation 

route. Therefore, in order to combine exposure from the various routes the aggregate risk index 

(ARI) approach was used to estimate risk. ARIs ≥ 1 are not of concern.

Acute Toxicity

The acute toxicity profile table for metofluthrin is below in Table 3.0.

Table 3.0 Acute Toxicity Profile – Metofluthrin Technical

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] 46406719 LD50 >2000 mg/kg III

870.1200 Acute dermal [rat] 46406721 LD50 >2000 mg/kg III

870.1300 Acute inhalation [rat] 46406723 LC50 >1.08 mg/L and 

<1.96 mg/L 

III

870.2400 Acute eye irritation [rabbit] 46406724 Not an eye irritant IV

870.2500 Acute dermal irritation [rabbit] 46406724 Mildly irritating (PDI = 

0.8)

IV

870.2600 Skin sensitization [Guinea pig] 46406726 Not a sensitizer -

Toxicological PODs Used for Risk Assessment

The endpoint table used for the metofluthrin assessment is below in Table 3.1 
Page 9 of 23

Table 3.1: Summary of Toxicological Endpoints and Doses for Metofluthrin Occupational and Residential 

Risk Assessments.

Exposure/

Scenario

Point of 

Departure

Uncertainty/ 

Safety Factors

Level of Concern for Risk 

Assessment

Study and Toxicological Effects

Incidental Oral 

Short-Term (1-30 

days)

NOAEL= 15 

mg/kg/day

UFA= 10x

UFH= 10x

UFDB = 3x, <6 

years of age

Residential LOC for 

children <6 years of age:

MOE = 300

Developmental toxicity in the rat 

(oral, gavage)

Maternal LOAEL = 30 mg/kg/day 

based on increased incidence of 

tremors in maternal animals.

Dermal Short-and 

IntermediateTerm (1-30 days

and 1-6 months, 

respectively)

NOAEL= 300

mg/kg/day

UFA= 10X

UFH=10X

UFDB = 3X, <6 

years of age

UFDB= 1X, ≥6 

years of age

Residential LOC for 

For children <6 years of 

age:

MOE = 300;

For individuals >6 years 

of age:

MOE = 100;

Occupational LOC

MOE = 100

90-day dermal toxicity in the rat

Systemic LOAEL = 1000 mg/kg/day 

based on mortality and clinical signs 

of toxicity including tremors and 

salivation.

Inhalation Shortand IntermediateTerm (1-30 days

and 1-6 months, 

respectively)

NOAEL =

0.099 mg/L

Residential 

HEC = 0.052 

mg/L

HED = 7.5 

mg/kg/day 

Occupational

HEC = 0.155 

mg/L

HED = 7.4 

mg/kg/day 

UFA= 3X

UFH=10X

UFDB = 3X, <6 

years of age

UFDB= 1X, ≥6 

years of age

Residential LOC for 

For children <6 years of 

age:

MOE = 100;

For individuals >6 years 

of age:

MOE = 30;

Occupational LOC:

MOE = 30

28-day inhalation in the rat

LOAEL = 0.196 mg/L based on 

mortality and clinical signs including 

tremors, hypersensitivity, abnormal 

gait, clonic convulsion and 

hypothermia.

HEC = 0.103 mg/L

HED = 14.8 mg/kg/day

Cancer (oral, 

dermal, 

inhalation)

Classification: Not likely to be carcinogenic to humans at doses that do not result in a mitogenic 

response, based on negative genotoxicity data and mechanistic data supporting a non-linear mode 

of action (induction of cytochrome p450 with proliferative response) for liver tumors in male and 

female rats. Doses selected for risk assessment are protective of carcinogenicity.

Absorption

Since the short- and intermediate-term dermal and inhalation PODs were based on route-specific 

toxicity studies, no absorption factors were necessary to estimate exposure.

Body Weight

The standard body weight for the general population (80 kg) for adults and 11 kg for children 

(1<2 years) was used for all exposure scenarios covered in this risk assessment since the 

endpoints selected were not developmental and/or fetal effects.
Page 10 of 23

4.0 Use Profile 

Table 4.0 (below) summarizes the proposed use pattern submitted on the product label by the 

registrant. The product is packaged in a 6.7 ounce container and consists of 0.23% active 

ingredient. It can be pre-set for 1, 2, or 3 hours of protection by the consumer; the battery 

operated device sprays at set intervals depending on the consumer settings.

Table 4.0. Summary of Directions for Use of Metofluthrin.

Applic. 

Timing, Type, 

and Equip.

Formulation 

[EPA Reg. 

No.]

Applic. Rate 

(lb ai/A) Use Directions and Limitations

Outdoor Residential Space

Product can be 

set for 1, 2 or 3 

hour intervals; 

spray interval is 

40ms of spray 

every 33 seconds 

regardless of 

selected interval

4822-LILSGOL

437 mg active 

ingredient per 6.7 

ounce can. 

Product designed 

to last for 30 

hours of area 

repellent

Product automatically shuts off after selected use duration (e.g., 

shutdown after 1, 2, or 3 hrs)

The proposed product label prohibits use of the product indoors, or in tents, enclosed areas, or 

near food or food preparation areas.

5.0 Residential Exposure and Risk Estimates

The proposed use for metofluthrin is intended for consumers – i.e., it is considered a residential 

use for purposes of this exposure assessment. HED conducted an occupational and residential 

exposure assessment to support a proposed bed bug use of metofluthrin in September, 2012 

(D397725). In that Section 3 assessment, the existing residential uses of metofluthrin were 

reassessed using the 2012 Residential SOPs and an up-to-date hazard database. There are 

currently no registered food uses for metofluthrin and drinking water exposure is not expected 

from the registered or the proposed bed bug control uses of metofluthrin; therefore, an aggregate 

risk assessment is not needed.

5.1 Residential Handler Exposure/Risk Estimates

HED uses the term “handlers” to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct tasks related to applications and that 

exposures can vary depending on the specifics of each task. Residential handlers are addressed 

somewhat differently by HED as homeowners are assumed to complete all elements of an 

application without use of any protective equipment.

The metofluthrin-based product FAN does not require a residential handler assessment as

handler exposure is expected to be negligible. The product is loaded with cartridges by the 

handler and the product is released by a timer mechanism without mixing, loading, or applying 

in the traditional sense. Adult and child post-application exposure (inhalation &dermal for adults

and children, and incidental oral for children only) are expected as the primary exposure routes.
Page 11 of 23

5.2 Residential Post-application Exposure/Risk Estimates

There is the potential for post-application exposure for individuals exposed as a result of being in 

an environment that has been previously treated with metofluthrin. The quantitative 

exposure/risk assessment for residential post-application exposures is based on the following 

scenarios: 

Post-application inhalation exposure (adults/children) from use of the battery operated 

area repellent

Post-application dermal exposure (adults/children) from contact surfaces where sprays 

have settled

Post-application incidental oral exposure (children) from contact with areas where sprays 

have settled

The lifestages selected for each post-application scenario are based on an analysis provided as an 

Appendix in the 2012 Residential SOPs3and the hazard profile table in section 3.0 of this 

document. These lifestages are not the only lifestages that could be potentially exposed for these 

post-application scenarios; however, the assessment of these lifestages is health protective for the 

exposures and risk estimates for any other potentially exposed lifestages.

Residential Post-application Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the residential 

post-application risk assessment. Each assumption and factor is detailed in the 2012 Residential 

SOPs3.

Residential Post-application Non-Cancer Exposure and Risk Equations

The algorithms used to estimate residential post-application exposure and dose can be found in 

Appendix A and/or the 2012 Residential SOPs3.

5.2.1 Post-application Inhalation Exposure and Risk Estimates

As identified above, post-application inhalation exposure is a likely exposure scenario for the 

metofluthrin-based FAN product for adults and children. This assessment follows the postapplication inhalation exposure for outdoor aerosol sprays outlined in the 2012 Residential SOPs 

with the following modifications:

The 43.7 mg ai/day exposure estimate is based on the use of the product for 3 hours.

The product label indicates that label claims will be made for a 12’ x 12’ treatment area 

and a 225 ft2treatment area. The discrepancy is a result of the results of the efficacy 

testing versus most simply explaining the treatment area on consumer packaging. The 

standard assumptions for treated area have been modified from the defaults to match the 

relevant treatment area. See Appendix A for more detail.

 

3 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
Page 12 of 23

Q = airflow through the treated space. 

Appendix A details the exposure calculations and the departure from defaults for the Q and Across inputs.

5.2.2 Post-application Dermal Exposure and Risk Estimates

As identified above, post-application dermal exposure is a likely exposure scenario for the 

metofluthrin-based FAN product for adults and children. This assessment follows the postapplication inhalation exposure for outdoor aerosol sprays outlined in the 2012 Residential SOPs

with the following modifications:

The calculated deposition of 6.7E-07 lb ai/ft2deposition represents a 3 hour use of the 

product settled onto turf surrounding the treated area.

See the explanation above in Section 5.2.1. regarding the product treatment area. The 

proposed product label indicates claims will be made for a 12’ x 12’ treatment area and a 

225 ft2treatment area, depending on specific product labels. The claims will not be mixed

on the end-use consumer labels. The area treated has been modified from the defaults to 

match the relevant treatment area (affecting the deposited residue calculation). See 

Appendix A for more detail.

Table 5.2.2 - Post-application Dermal Exposure and Risk Estimates for Metofluthrin

Lifestage Deposited Residue

(lb ai/ft2)

Fraction 

transferred

Transfer 

Coefficient

(cm2/hr) 

Exposure 

Time

(hr/day)

Exposure 

(mg/day)

Absorbed 

Dose 

(mg/kg/day) 

Dermal MOE 

(rounded)

Adults 4.28056E-07 0.01 180,000 1.5 0.9 0.01 27,000

Children (1 <2 

years) 4.28056E-07 0.01 49,000 1.5 0.2 0.02 14,000

Appendix A details the exposure calculations

The risk estimates calculated above in Table 5.2.2 involve conservative exposure calculations –

specifically, that the treatment area is a 12’ x 12’ area. The above calculations involve postapplication dermal exposure to a 12’ x 12’ treated area. The label claims for 225 ft2

treatment 

area would have correspondingly lower exposures (i.e., higher calculated MOEs). Either way the 

Table 5.2.1 - Post-application Inhalation Exposure and Risk Estimates for Metofluthrin

Lifestage

Application 

rate (mg 

ai/day)

Inhalation 

Rate

(m3/hr)

Q*

(m3/hr)

Exposure 

(mg/day)

Absorbed 

Dose 

(mg/kg/day) 

Inhalation MOE 

(rounded)

Adults 43.68735 0.64 3204 0.01 0.000109 69,000

Children (1 <2 

years) 43.68735 0.33 3204 0.00 0.000409 18,000
Page 13 of 23

dermal (or incidental oral) exposure is calculated, the risk estimates are significantly higher than 

the respective LOCs for adults or children.

5.2.3 Post-application Incidental Oral Exposure and Risk Estimates

As identified above, post-application incidental exposure is a likely exposure scenario for the 

metofluthrin-based FAN product for children. This assessment follows the post-application 

inhalation exposure for outdoor aerosol sprays outlined in the 2012 Residential SOPs with the 

following modifications:

The calculated deposition of 6.7E-07 lb ai/ft2deposition represents a 3 hour use of the 

product settled onto turf surrounding the treated area.

See the explanation above in Section 5.2.1. regarding the product treatment area. The 

proposed product label indicates claims will be made for a 12’ x 12’ treatment area and a 

225 ft2treatment area, depending on specific product labels. The claims will not be mixed

on the end-use consumer labels. The area treated has been modified from the defaults to 

match the relevant treatment area (affecting the deposited residue calculation). See 

Appendix A for more detail.

The rest of the exposure factors identified in Appendix A represent the default values to 

assess incidental oral (i.e., hand-to-mouth) exposure of children (the lifestage assessed 

represents children 1 < 2 years of age).

Table 5.2.2 - Post-application Incidental Oral Exposure and Risk Estimates for 

Metofluthrin

Lifestage Absorbed Dose (mg/kg/day) MOE (rounded) 

Children (1 <2 years) 0.0004 33,000

Appendix A details the exposure calculations

5.3 Combined Residential Exposure and Risk Estimates

Since dermal and incidental oral exposure routes share a common toxicological endpoint, risk 

estimates have been combined for those routes. The incidental oral scenarios (i.e., hand-tomouth and object-to-mouth) should be considered inter-related and it is likely that they occur 

interspersed amongst each other across time. Combining these scenarios with the dermal 

exposure scenario would be overly-conservative because of the conservative nature of each 

individual assessment. Therefore, the post-application exposure scenarios that were combined 

for children 1 < 2 years old are the dermal, inhalation, and hand-to-mouth scenarios. This 

combination should be considered a protective estimate of children’s exposure to pesticides used 

around the home.
Page 14 of 23

Summary of Residential Post-application Non-Cancer Exposure and Risk Estimates

Table 5.2.1. Residential Post-application Non-cancer Exposure and Risk Estimates for Metofluthrin.

Lifestage

Post-application Exposure 

Scenario Application 

Rate1

Dose 

(mg/kg/day)2 MOEs3

Combined Routes

(X indicates included 

in Combined MOE)

ARI4

Use Site Route of 

Exposure

Adult

Inhalation 3 hours of 

product use; 

43.7 mg ai

0.000109082 69,000 X

240 Dermal 0.01103 27,000 X

Child

Inhalation 3 hours of 

product use; 

43.7 mg ai

0.0004 18,000 X

Dermal 0.022 14,000 X 27

Incidental Oral 0.0004 33,000 X

1 Assessment is based on exposure to 3 hours of daily product use on proposed label (Reg. No. 4822-LIL-SGOL) for the 

duration of the short-term exposure duration.

2 Dose (mg/kg/day) equations: See Appendix A for the dose calculation equations for the inhalation, dermal, and incidental oral 

routes of exposure.

3 MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day). where Short-term Dermal PoD = NOAEL of 300 mg/kg/day and level of 

concern = 100 for adults and 300 for children < 6 years old).

4 Adult/Child Aggregate Risk Index = 

Adult = 1/ [(1/ARI Dermal) + (1/ARI inhalation)].

Child = 1/ [(1/ARI Dermal) + (1/ARI Inhalation) + (1/ARI Hand-to-Mouth)].

5.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios)

Metofluthrin does have multiple products with current registrations. However, HED does not 

believe that the proposed use pattern assessed in this document is likely to co-occur with the 

other registered metofluthrin use patterns (bed bug use, area mosquito repellent). The September 

2012 human health risk assessment (D402777, D403390) contains additional information. 

5.4 Residential Risk Estimates for Use in Aggregate Assessment

No aggregate assessment is required for metofluthrin as there are currently no registered food 

uses for metofluthrin and exposure to residues in drinking water is not expected from the 

registered or the proposed area repellent uses of metofluthrin; therefore, an aggregate risk 

assessment is not needed.

However, the residential exposure use pattern assessed in this document for metofluthrin as an 

area mosquito repellent did not identify risks of concern (ARI’s for adults and children are 240

and 27, respectively).
Page 15 of 23

5.6 Residential Bystander Post-Application Inhalation Exposure

In the case of metofluthrin, a residential post-application inhalation exposure assessment was 

performed. This exposure scenario is representative of a worse case inhalation exposure and 

should be considered protective of other individuals in the vicinity of the area repellent product.

6.0 Cumulative Exposure/Risk Characterization

The Agency is required to consider the cumulative risks of chemicals sharing a common 

mechanism of toxicity. The Agency has determined that the pyrethroids and pyrethrins, 

including metofluthrin, share a common mechanism of toxicity (http://www.regulations.gov; 

EPA-HQ-OPP-2008-0489-0006). The members of this group share the ability to interact with 

voltage-gated sodium channels ultimately leading to neurotoxicity. The cumulative risk 

assessment for the pyrethroids/pyrethrins was published on Nov. 9, 2011 (USEPA, 2011a) and is 

available at http://www.regulations.gov; EPA-HQ-OPP-2011-0746. Further information about 

the determination that pyrethroids and pyrethrins share a common mechanism of toxicity may be 

found in document ID: EPA-HQ- OPP-2008-0489-0006.

While metofluthrin has been included as an active ingredient in the pyrethroid cumulative

assessment, the exposure scenarios covered in this assessment (i.e., outdoor repellent uses) were 

not exposure scenarios addressed in the 2011 pyrethroid cumulative risk assessment. For that 

effort, the Agency focused on the four main (i.e., high potential exposure) pyrethroid residential 

use scenarios – turf, pets, gardens, and indoors (e.g., fogger and crack and crevice applications). 

Based on a qualitative review of the proposed use pattern and resulting risk estimates for 

metofluthrin, the Agency has c determined that it will not change the overall findings presented 

in the pyrethroid cumulative risk assessment. For information regarding EPA’s efforts to 

evaluate the risk of exposure to pyrethroids, refer to 

http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids-pyrethrins.html.

7.0 Occupational Exposure and Risk Estimates

7.1 Occupational Handler Exposure/Risk Estimates

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

Based on the anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, occupational handler exposure is not expected from the proposed 

uses. A recent (September, 2012) HED risk assessment (D402777, D403390) assessed both the 

existing and proposed new uses of metofluthrin to support registration review. The 
Page 16 of 23

accompanying ORE chapter further the details the quantitative assessment of metofluthrin for 

occupational and residential exposure. Besides the proposed action, there are no additional new 

uses of metofluthrin-based products. HED did not identify any occupational exposure concerns 

in the September 2012 risk assessment. In that assessment, all commercial handler scenarios 

resulted in ARIs greater than the LOC (i.e. ARI>1) with baseline attire (i.e., single layer of 

clothing, no respirator).

7.2 Occupational Post-application Exposure/Risk Estimates

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). HED did not conduct a quantitative post-application exposure assessment in the 

September 2012 risk assessment for metofluthrin because the presence of commercial handlers in 

treated residential or commercial areas is minimal after application, due to the lack of postapplication activities involved in treating structures. Therefore, a quantitative post-application 

exposure and risk assessment was not required for commercial handlers.
Page 17 of 23

Appendix A. Summary of Occupational and Residential Non-cancer Algorithms

Residential Non-cancer Handler Algorithms

Not applicable for metofluthrin

Residential Non-cancer Post-application Algorithms

The following algorithm is used to determine post-application inhalation exposure to outdoor 

aerosol space sprays:

Q

IR AR E*

where:

E = exposure (mg/day);

IR = inhalation rate (m3/hour);

AR = application rate (mg ai/day); and

Q = airflow through the treated area (m3/hour).

The airflow through the treated space can be calculated as follows:

Q = AV *CF1* CF2 * Across-section

where:

Q = airflow through treated space (m3/hr);

AV = air velocity (m/s);

CF1 = time unit conversion factor (60 seconds/1 minute);

CF2 = time unit conversion factor (60 minutes / hour); and

Across-section = cross-section of outdoor space treated (m2).

Application rate can be calculated as follows:

AR = A product * A.I. * CF1 * N

where:

AR = application rate (mg ai/ day);

A product = amount of product in 1 can (oz or g/can);

A.I. = percent active ingredient in product (% ai);

CF1 = weight conversion factor (28,350 mg/oz or 1,000 mg/g); and

N = number of cans applied per day in one application (cans/day).

Alternatively, if the aerosol can contents are expressed as a volume in milliliters, the application 

rate for use in the exposure assessment can be calculated as follows:
Page 18 of 23

AR = A.I. * Aproduct * CF * Dproduct * N

where:

AR = application rate (mg ai/day);

A.I. = percent active ingredient in product (% ai);

Aproduct = amount of product per can (mL/can);

CF = conversion factor to convert grams to milligrams (1,000 mg/1 g);

Dproduct = density of product (g/mL); and

N = number of cans applied per day in one application (cans/day).

Absorbed inhalation dose normalized to body weight is calculated as:

BW

E AF D*

where:

D = dose (mg/kg-day);

E = exposure (mg/day);

AF = absorption factor (inhalation); and

BW = body weight (kg).

Table A-1: Outdoor Aerosol Space Sprays –Inputs for Residential Post-application Inhalation Exposure 

Algorithm 

Notation

Exposure Factor

(units) Point Estimate(s)

AR Application rate

(mg ai/ day) 43.7 (based on use pattern)

Across-section

Cross sectional area of area treated

(m2)

8.9

AV Air velocity

(m/s) 0.1

Q

Airflow through treated area

(m3/hr) 3,204

N

Number of cans applied per day in one application

(cans/day) 1

D product

Density of product 

(g/mL) Product specific density 0.63 (product specific)

A.I. Percent ai in product

(%) 0.23

A product

Amount of product

(oz/can) 6.7

IR Inhalation rate

(m3/hour)

Adult 0.64

Children (1 < 2 years 

old) 0.33

BW Body Weight

(kg)

Adult 80

Children (1 < 2 years 

old) 11

Post-application Dermal Exposure Algorithm
Page 19 of 23

The following equation can be used to convert the application rate in pounds ai per square foot as 

is deposited on the turf:

TA

AR

Aproduct*A.I.*CF1 * N

where:

AR = application rate (lb ai/ft2 or lb ai/A);

Aproduct = amount of product per can (oz or g/can);

A.I. = percent active ingredient in product (% ai);

CF1 = weight conversion factor (1 lb/16 oz or 1 lb/454 g); 

N = number of cans applied per day in one application (cans); and

TA = treated area (ft2 or A).

Alternatively, if the aerosol can contents are expressed as a volume in milliliters, the application 

rate for use in the exposure assessment can be calculated as follows:

TA

AR

Aproduct*A.I.*CF *Dproduct* N

where:

AR = application rate (lb ai/ft2 or lb ai/A);

A.I. = percent active ingredient in product (% ai);

Aproduct = amount of product per can (mL/can);

CF = conversion factor (1 lb/454 g);

Dproduct = density of product (g/mL); 

N = number of cans per day in one application (cans); and

TA = treated area (ft2 or A).

The algorithm to calculate exposure is as follows:

E = TTRt * CF1 * TC * ET

where:

E = exposure (mg/day);

TTRt = turf transferable residue on day t (μg/cm2);

CF1 = weight unit conversion factor (0.001 mg/μg);

TC = transfer coefficient (cm2/hr); and

ET = exposure time (hr/day).

If chemical-specific TTR data are available, then surface residues from the day of application 

should be used (assume that individuals could be exposed to residues immediately after 

application). However, if data are not available, then TTRt can be calculated using the following 

formula:
Page 20 of 23

TTRt= AR * F * (1-FD)t * CF2 * CF3

where:

TTRt = turf transferable residue on day t (μg/cm2);

AR = application rate (lbs ai/ft2or lb ai/acre);

F = fraction of ai as transferable residue following application (unitless);

FD = fraction of residue that dissipates daily (unitless);

t = post-application day on which exposure is being assessed;

CF2 = weight unit conversion factor (4.54 x 108μg/lb); and

CF3 = area unit conversion factor (1.08 x 10-3ft2/cm2or 2.47 x 10-8acre/cm2).

Table A-3: Outdoor Aerosol Space Sprays -- Inputs for Residential Post-application Dermal Exposure

Algorithm Notation Exposure Factor

(units) Point Estimate(s)

A.I. Percent ai in product

(%) 0.23

A product

Amount of product

(oz/can) 6.7

N

Number of cans applied per day in one application

(cans/day) 1

D product Density of product (g/mL) Water-based products 0.63 (product 

Solvent-based products specific)

TA Treated area (ft2 or A)

12 ft. x 12 ft. [x 8 ft]

144 ft2

(although the product 

label can alternately 

claim 225 ft2) based 

on efficacy testing

AR Application rate

(mass active ingredient per unit area)

6.68E

-07

lb ai/ft2

(calculated based on 

treatment area of 

144ft2)

F

Fraction of AR as TTR following application (if 

chemical-specific data is unavailable) 0.01

FD

Daily residue dissipation (if chemical-specific data is 

unavailable)

(fraction)

0.1

TC Transfer Coefficient 

(cm2/hr)

Adults 180,000

Children 1 < 2 years old 49,000

ET Exposure Time

(hours per day)

Adults 1.5

Children 1 < 2 years old 1.5

BW Body Weight

(kg)

Adults 80

Children 1 < 2 years old 11

Post-application Hand-to-Mouth Exposure Algorithm

Exposure from hand-to-mouth activity is calculated as follows (based on the algorithm utilized in 

the SHEDS-Multimedia model):

E = [HR * (FM * SAH) * (ET * N_Replen) * (1- (1- SE)

(Freq_HtM/N-Replen))]
Page 21 of 23

where:

E = exposure (mg/day);

HR = hand residue loading (mg/cm2);

FM = fraction hand surface area mouthed / event (fraction/event);

SAH = typical surface area of one hand (cm2);

ET = exposure time (hr/day);

N_Replen = number of replenishment intervals per hour (intervals/hour);

SE = saliva extraction factor (i.e., mouthing removal efficiency); and

Freq_HtM = number of hand-to-mouth contacts events per hour (events/hour).

and

SA * 2

Fai *DE

HR

H

hands

where:

HR = hand residue loading (mg/cm2);

Faihands = fraction ai on hands compared to total surface residue from dermal transfer coefficient 

study (unitless);

DE = dermal exposure (mg); and

SAH = typical surface area of one hand (cm2).

Dose, normalized to body weight, is calculated as:

BW

E

D

where:

D = dose (mg/kg-day);

E = exposure (mg/day); and

BW = body weight (kg).

Table A-4: Outdoor Aerosol Space Sprays – Inputs for Residential Post-application Hand-to-Mouth 

Exposure 

Algorithm 

Notation

Exposure Factor

(units) Point Estimate(s)

Faihands

Fraction of ai on hands from dermal transfer 

coefficient study

(unitless)

0.06

DE Dermal exposure (mg) Calculated = 0.2

SAH

Typical surface area of one hand (cm2), children 1 < 

2 years old 150

AR Application rate

(mass active ingredient per unit area)

6.68E

-07

lb ai/ft2
Page 22 of 23

Table A-4: Outdoor Aerosol Space Sprays – Inputs for Residential Post-application Hand-to-Mouth 

Exposure 

Algorithm 

Notation

Exposure Factor

(units) Point Estimate(s)

(calculated based on treatment area of 

144ft2)

HR Residue available on the hands (mg/cm2) Calculated via (DE * Faihands)/SAH

FM

Fraction hand surface area mouthed

(fraction/event) 0.13

N_Replen Replenishment intervals per hour

(intervals/hr) 4

ET Exposure time 

(hrs/day) 1.5

SE Saliva extraction factor

(unitless) 0.48

Freq_HtM Hand-to-mouth events per hour

(events/hr) 13.9

BW Body Weight

(kg) Children 1 < 2 years old 11
Page 23 of 23

Appendix B. Metofluthrin - Calculations of RDDR, HEC and HED

Calculations were based on the US EPA “Methods for Derivation of Inhalation Reference Concentrations 

and Application of Inhalation Dosimetry,” October, 1994. Publication EPA/600/8-90/066F.

Study used: MRID 46406736, 28-week inhalation toxicity study in the rat

Exposure concentrations (aerosol) tested in the rat: 0, 0.01, 0.051, 0.099 or 0.196 mg/L. Animals 

exposed for 4 hours per day, 7 days per week for 28 consecutive days. 

 

1. RDDR (Regional Deposited Dose Ratio of particles for respiratory tract region): 3.14 calculated 

using the RfC (Reference Concentration) methodology computer program using the following 

inputs and the program’s default human inputs:

NOAEL (No Observed Adverse Effect Level): 0.099 mg/L 

MMAD (mass median aerodynamic diameter): 2.47 μm 

GSD (geometric standard deviation: 2.02 

Animal body weight: 185 g (rounded-up initial bw for males)

RDDR = RDDr/Normalizing Factor)A 

 RDDr/Normalizing Factor)H

Where RDD is the regional deposited dose of particles and r represents the extrathoracic, 

tracheobronchial and pulmonary respiratory tract regions

2. HEC (Human Equivalent Concentration, expressed as mg/L): NOAEL in mg/L x RDDR x 

[hours/day exposure, animals ÷ hours/day exposure, humans] x [exposure days/week, animals 

÷exposure days/week, humans]

Occupational HEC: 

 0.099 mg/L x 3.14 x [4 hours/day ÷ 8 hours/day] x [7 days ÷ 7 days]

 = 0.099 mg/L x 3.14 x 0.5 x 1

 = 0.155 mg/L 

Non-occupational HEC

0.099 mg/L x 3.14 x [4 hours/day ÷ 24 hours/day] x [7 days ÷ 7 days] 

= 0.099 mg/L x 3.14 x 0.167 x 1 

= 0.052 mg/L 

3. HED (Human Equivalent Dose, expressed as mg/kg/day): HEC (mg/L) x human conversion 

factor (6 L/hrs/kg) x duration of daily exposure (hrs)

Occupational HED:

0.155 mg/L x 6 L/hrs/kg x 8 hrs

= 7.4 mg/kg/day

Non-occupational HED:

0.052 mg/L x 6 L/hrs/kg x 24 hrs

= 7.5 mg/kg/day