UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

Date: January 24

, 20 1 3 OFFICE OF CHEMICA L SAFETY

AN D POLLUTION PREVENTION

Subject : Metofluthrin. Occupational and Reside n tia l 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)

Chr i stina Swartz, Branch Chief

Risk Assessment Branch II

Health Effects Divis i o n (7509P)

and

Alexandra LaMay 

# tJ**~~** Risk Assessment Branch 

### VII 

### P

Health Effects D iv i sion (7509P)

Kevin Sweeney I Richard Gebken (RMlO)

Insec t i c i des Branch Registration Division (7505P) DP Barcode: 0403191 Registration No.: 4822-LIL-SGOL Regulatory Action: Section 3 Reg i strat i on Case No. : 4822

CAS No.: 240494-70 -6

40CFR: NA

The Registration Division (RD) requeste d that t he Health Eff ec ts Div i s i on (HED) co ndu ct an

exposure and risk assessment for a proposed new product called FAN, w hich i s a battery operated area repellent containing the in secticide metofluthrin. No risks of concern were 

### identified in this assessment

, and the r efore HED has 

### no objection to the re gis tr ation of the proposed new pr oduct.

Page I of23Page 2 of 23 Table of Contents

1.0 Executi ve Summary

................................ ................................ ................................ ............. 3

2.0 Risk Assessment Conclusions and Recommendations

................................ ........................ 5

3.0 Hazard Characterization

................................ ................................ ................................ ....... 5

3.1 Ha zard 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 fo r 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 o f Occupational and Residential Non

- cancer Algorithms

..................... 17 Appendix B. Metofluthrin

- Calculations of RDDR, HEC and HED

................................ ........... 23Page 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 propo sed 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, m etofluthrin has a number of currently regi stered 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 revie w 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 asses sment; 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 asses sment.

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. F ollowing a single oral gavage d ose, meto fluthrin is absorbed quickly in rats. N eurotoxicity is observed within 6 hours, and rats recover within 24 hours without any persisting neurotoxic effects. This is generally consistent with the t oxicity profiles for all the pyrethroids which are very similar and marked by rapid absorption, metaboli sm, and time

- to

- peak effect. The no

- observed

- adverse

effects

- 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 selecte d 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 L OAEL of 1000 mg/kg/day. T he dermal study is protecti ve 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 short

term 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. T he inhala tion 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 a ssess 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) considerat ions do not apply to metofluthrin for the proposed and existing (non

- food) use patterns. However, s ince metofluthrin is a pyrethroid and exposure to children under <6 years old is expected, t he Agency has retain ed a 3X uncertainty factor (UF), based on th e 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 leve l 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 unc ertainty 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 in cidental 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

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

.

Residential Handler Exposure and Ri s kPage 5 of 23

FAN Area Repellent Use: The metofluthrin

- based product FAN does not require a residential

handler assessment as handler ex posure 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 t his 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 F ogging 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 Stu dies Review Board. Descriptions of data sources, as well as guidance on their use,

can be found at the Agency website 1

.

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 ir ritation of metofluthrin is Category I V 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 H azard 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, 2012 2 . Before completing this action, HED evaluated the toxicological databas e 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 pyre throids, 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. F ollowing a single oral gavage dose, meto fluthrin is absorbed quickly

in rats. N eurotoxicity is observed within 6 hours, and rats recover within 24 hours without any persisting neurotoxic effects. This is generally consistent with the t oxicity profiles fo r all the pyrethroids which are very similar and marked by rapid absorption, metaboli sm, and time

- to

peak effect. The NOAELs and LOAELs established from metofluthrin single dose and repeat dosing studies show that repeat exposures do not result in lower N OAELs. 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 toxicit y (Toxicity Categories

II I ). It is not a dermal or e ye 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 developme ntal 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 m aternal effects; therefore, there is no concern for increased susceptibility. T he 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 developmenta l 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 dura tion. 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 protect ive 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

interm ediate

- 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 develop mental study), and other neurological clinical signs. A high rate of mortality was also observed. ThePage 7 of 23

developmental toxicity and reproduction studies were also considered for inhalation risk

assessment. However, no developmental effects were noted in th e 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. T he inhalation study is protective of potential offspring ef fects 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 occup ational 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 d etermined 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 lik ely 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, s ince 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 cla ss. T he 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 th ese 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 gr oup 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 un certainty factor

is needed for PD considerations.

Exposure from incidental oral, dermal and inhalation routes are based on different and route

specific studies, but similar endpoints all relevant to the sodium channel interaction of metofluthrin (i.e., cl inical signs including tremors) were identified in each case. OccupationalPage 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 extrapolat ion, 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 trad itional 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 pharmacodynam ic) 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 in dex (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 LD 50 >2000 mg/kg III

870.1200 Acute dermal [rat] 46406721 LD 50 >2000 mg/kg III

870.1300 Acute inhalation [rat] 46406723 LC 50 >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 3.1Page 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 UF A = 10 x

UF H = 10 x UF DB = 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

Intermediate

Term (1

- 30 days

and 1

- 6 months, respectively ) NOAEL= 300

mg/kg/day UF A = 10X

UF H = 10X

UF DB = 3X, <6 years of age

UF DB = 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 Short

and Intermediate

Term (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

Occupat ional

HEC = 0.155 mg/L

HED = 7.4 mg/kg/day UF A = 3X

UF H = 10X

UF DB = 3X, <6 years of age

UF DB = 1X, ≥6 years of age Residential LOC for

For children <6 years of

age: MOE = 1 00 ; For individuals >6 years of age:

MOE = 3 0 ; Occupational LOC:

MOE = 3 0 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 0.2 3% 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

- LIL

SGOL 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 metof luthrin 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 witho ut 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 tradition al 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 (adult s /children) from use of the battery operated area repellent

Post

- application dermal exposure (adult s/ 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 an alysis provided as an Appendix in the 2012 Residential SOPs 3 and 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 as sessment 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 basi s for completing the residential
post

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

SOPs 3

.

Residen tial 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 SOPs 3

.

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 post

application 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 ft 2 treatment area. The discrepancy is a result of the results of the efficacy testing versus most simply explaining the treatment area on con sumer 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.htmlPage 12 of 23 Q = airflow through the treated space. Appendix A details the exposure calculations and the departure from defaults for the Q and A

cross 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 post

application inhalation exposure for outdoor aerosol sprays outlined in the 2012 Residential SOPs with the following modifications:

The calculated deposition of 6

. 7 E

- 07 lb ai/ft 2 deposition represent s 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 ft 2 treatment 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/ft 2 ) Fraction

transferred T ransfer

C oefficient (cm 2 /hr) E xposure

T ime (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 post

application dermal exposure to a 12’ x 12’ treated area. The label claims for 225 ft 2 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) I nhalation

R ate (m 3 /hr) Q *

(m 3 /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

, 000Page 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 .7 E

- 07 lb ai/ft 2 deposition represent s 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 fo r a 12’ x 12’ treatment area and a 225 ft 2 treatment 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 (affecti ng 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

repre sents 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) 0.000 4 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

- to

mo uth 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

Rate 1 Dose

(mg/kg/day) 2 MOEs 3 Combined Routes (X indicates included in Combined MOE) ARI 4

Use Site Route of

Exposure

Adult Inhalation 3 hours of product use; 43.7 mg ai 0.000109082 69,000 X

240 Dermal 0.0 1103 27 ,000 X

Child Inhalation 3 hours of product use; 43.7 mg ai 0.0004 18,000 X

27 Dermal 0.022 14,000 X

Incidental Oral 0.000 4 33 ,000 X

1 Assessment is b ased 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 = NO A EL 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 info rmation

.

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 vicinit y 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,

in cluding 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 ultima tely 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. Furt her 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 potentia l 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, t he 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 t ask. 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, D4 03390) assessed both the existing and proposed new uses of metofluthrin to support registration review. ThePage 16 of 23

accompanying ORE chapter further the details the quantitative assessment of metofluthrin for occupational and residential exposure. Besides the prop osed 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, a ll commercial handler scenarios

resulted in ARIs greater tha n 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 re

entry 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 post

application activities involved in treating structures . The refore, 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 a pplicable for metofluthrin

Residential Non

- cancer Post

- application Algorithms The following algorithm is used to determine post

- application inhalation exposure to outdoor aerosol space sprays:

where : E = exposure (mg/day);

IR = inhalation rate (m 3 /hour);

AR = application rate (mg ai/day); and Q = airflow through the treated area (m 3 /hour).

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

Q = AV *CF1* CF2 * A

cross

- section

where : Q = airflow through treated space (m 3 /hr);

AV = air velocity (m/s);

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

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

A
cross

- section = cross

- section of outdoor space treated (m 2 ).

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. * A

product * CF * D

product * N

where : AR = application rate (mg ai/day);

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

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

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

D product = 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:

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)

A

cross

- section Cross sectional area of area treated (m 2 ) 8.9

AV Air velocity (m/s) 0.1

Q Airflow through treated area (m 3 /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

(m 3 /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 AlgorithmPage 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:

where:

AR = application rate (lb ai/ft 2 or lb ai/A);

A product = 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 ap plication (cans); and

T A = treated area (ft 2 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:

where:

AR = application rate (lb ai/ft 2 or lb ai/A);

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

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

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

D product = density of product (g/mL);

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

T A = treated area (ft 2 or A).

The algorithm to calculate exposure is as follows:

E = TTRt * CF1 * TC * ET

where:

E = exposure (mg/day);

TTR t = turf transferable residue on day t (μg/cm2); CF1 = weight unit conversio n 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 TTR t can be calculated using the following

formula:Page 20 of 23 TTRt= AR * F * (1

- F D )t * CF2 * CF3

where:

TTR t = turf transferable residue on day t (μg/cm 2 ); AR = application rate (lb s ai/ft 2 or lb ai/acre); F = fraction of ai as transferable residue following application (unitless);

F D = fraction of residue that dissipates daily (unitless);
t = post

- application day on which exposure is being assessed; CF2 = weight unit conversion fact or (4.54 x 10 8 μg/lb); and CF3 = area unit conversion factor (1.08 x 10 - 3 ft 2 /cm 2 or 2.47 x 10 - 8 acre/cm 2 ).

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 (%) 0.2 3

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 specific) Solvent

- based products

T A Treated area (ft 2 or A) 12 ft. x 12 ft. [ x 8 ft ]

144 ft 2
( although the product label can alternately

claim 225 ft 2 ) based on efficacy testing

AR Application rate (mass active ingredient per unit area) 6.68 E - 07

lb ai/ft 2
(calculated based on

treatment area of

144ft 2 )

F Fraction of AR as TTR following application (if

chemical

- specific data is unavailable) 0.01

F D Daily residue dissipation (if chemical

- specific data is unavailable) (fraction) 0.1

TC Transfer Coefficient (cm 2 /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 * ( F

M * SA H ) * (ET * N_Replen) * (1

- (1

- SE ) (Freq_HtM/N

- Replen) )]Page 21 of 23

where:

E = exposure (mg/day);

HR = hand residue load ing (mg/cm 2 ); FM = fraction hand surface area mouthed / event (fraction/event); SAH = typical surface area of one hand (cm 2 ); 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

where:

HR = hand residue loading (mg/cm 2 );

Fai hands = fraction ai on hands compared to total surface resi due from dermal transfer coefficient study (unitless); DE = dermal exposure (mg); and

SA H = typical surface area of one hand (cm 2 ).

Dose, normalized to body weight, is calculated as:

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)

Fai hands Fraction of ai on hands from dermal transfer coefficient study (unitless) 0.06

DE Dermal exposure (mg) Calculated = 0.2

SA H Typical surface area of one hand (cm 2 ), children 1 < 2 years old 150

AR Application rate

(mass active ingredient per unit area) 6.68 E - 07

lb ai/ft 2Page 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

144ft 2 )

HR Residue available on the hands (mg/cm 2 ) Calculated via (DE * Fai hands )/SA H

F M Fraction hand surface area mouthed (fraction/event) 0.1 3

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 11Page 23 of 23

Appendix B. Metofluthrin

- C alculations 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 concent rations (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 = RDD

r

/Nor malizing Factor) A RDD

r /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