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 TABLE OF CONTENTS

1.0 Executive Summary .......................................................................................................... 5

2.0 HED Recommendations ................................................................................................... 8

2.1 Data Deficiencies/Conditions of Registration............................................................. 8

2.2 Tolerance Considerations............................................................................................. 8

2.3 Label Recommendations.............................................................................................. 8

3.0 Introduction....................................................................................................................... 8

3.1 Chemical Identity.......................................................................................................... 9

3.2 Physical/Chemical Characteristics.............................................................................. 9

3.3 Pesticide Use Pattern .................................................................................................... 9

3.4 Anticipated Exposure Pathways................................................................................ 10

3.5 Consideration of Environmental Justice .................................................................. 11

4.0 Hazard Characterization and Dose-Response Assessment......................................... 11

4.1 Toxicology Studies Available for Analysis................................................................ 12

4.2 Toxicological Profile of Metofluthrin........................................................................ 13

4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile................................. 14

4.3.1 Pharmacokinetics........................................................................................................ 14

4.3.2 Pharmacodynamics..................................................................................................... 16

4.3.3 Critical Duration of Exposure ................................................................................... 17

4.4 Consideration of Toxicity to Children ..................................................................... 20

4.4.1 Completeness of the Toxicology Database............................................................ 20

4.4.2 Evidence of Neurotoxicity ...................................................................................... 20

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ...... 21

4.4.4 Residual Uncertainty in the Exposure Database.................................................. 21

4.5 Toxicity Endpoint and Point of Departure Selections........................................... 212

4.5.1 Dose-Response Assessment .................................................................................. 222

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment. 233

4.5.3 Cancer Classification and Risk Assessment Recommendation .......................... 24

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment............................................................................................................................... 24

5.0 Dietary Exposure and Risk Assessment........................................................................ 25

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................ 26

6.1 Residential Handler (Bed Bug) Exposure................................................................. 26

6.2 Post-Application Exposure......................................................................................... 27

6.2.1 Post-Application Exposure and Risk Estimates Resulting from Bed Bug 

Treatment .............................................................................................................................. 267

6.2.2 Post-Application Exposure and Risk Estimates Resulting from Bed Bug 

Treatment ................................................................................................................................ 28

6.2.2.1 Bed Bug Use – Perimeter/Spot Application.............................................................. 28

6.2.2.2 Bed Bug Use – Mattress Application......................................................................... 29

6.2.3 Post-Application Incidental Oral Exposure and Risk Resulting from Bed Bug 

Treatment ................................................................................................................................ 30

6.2.3.1 Hand-to-Mouth ........................................................................................................... 30

6.2.3.2 Object-to-Mouth ......................................................................................................... 30

6.3 Combined Exposure.................................................................................................... 31
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6.3.1 Combined Residential Handler Risk Estimates from Proposed Bed Bug Use...... 31

6.3.2 Combined Residential Risk Estimates (Multiple Exposure Scenarios) ................. 32

6.4 Residential Bystander Post-Application Inhalation Exposure ............................... 32

6.5 Spray Drift................................................................................................................... 32

7.0 Aggregate Exposure/Risk Characterization................................................................. 33

8.0 Cumulative Exposure/Risk Characterization .............................................................. 33

9.0 Occupational Exposure/Risk Characterization ........................................................... 33

9.1 Short-/Intermediate-Term Handler Risk ................................................................. 33

9.2 Short-/Intermediate-Term Post-Application Risk................................................... 35

9.2.1 Inhalation/Dermal Postapplication Risk............................................................... 35

10.0 References........................................................................................................................ 36

Appendix A. Toxicology Profile and Executive Summaries .................................................. 39

A.1 Toxicology Data Requirements.................................................................................. 39

A.2 Toxicity Profiles .......................................................................................................... 40

A.3 Hazard Identification and Endpoint Selection......................................................... 47

A.4 Executive Summaries.................................................................................................. 49

A.5 Calculation of HEC/HED........................................................................................... 72

Appendix B. Physical/Chemical Properties........................................................................... 723

Appendix C. Review of Human Research.............................................................................. 734

Appendix D. Cumulative Exposure and Risk Issues................................................75

Appendix E. Registered Residential Exposure and Risk to Support Registration Review..80
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1.0 Executive Summary

Valent Corporation has requested registration of a proposed new combination product, Valent 

Bed Bug Combination (VBC3) Insecticide, to control bed bugs in residential homes and 

commercial buildings and structures. VBC3 is formulated as a liquid and contains three active 

ingredients, clothianidin, metofluthrin and piperonyl butoxide, packaged in a single unit dose. 

Directions indicate to mix the entire package contents (13 fl. oz.) in 1 gallon of water to treat 

1,000 square feet. The product includes instructions for perimeter/spot treatments, as well as 

treatment of entire mattresses. This document addresses only the potential human health risk 

from residential and occupational exposure to metofluthrin associated with use of this product. 

Exposure and risk associated with clothianidin and piperonyl butoxide are addressed in separate 

documents.

This risk assessment also supports registration review for metofluthrin’s currently registered 

repellent 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, so only residential and occupational 

exposure and risks have been assessed.

The toxicology database is largely complete and provides a robust hazard characterization. The 

only outstanding toxicology guideline requirement is an immunotoxicity study. Based on the 

lack of evidence of immunotoxicity in the metofluthrin database (and for pyrethroids as a 

chemical class), an additional database uncertainty factor (UFDB) was not included to account for 

the lack of this study. In addition to the submitted guideline studies on metofluthrin, numerous 

studies from the scientific literature that describe the pharmacodynamic and pharmacokinetic 

profile of the pyrethroids in general have been considered in this assessment. 

Metofluthrin is a Type I synthetic pyrethroid, which typically produce a distinct poisoning 

syndrome characterized by tremors and excessive salivation. Clinical signs observed in the 

metofluthrin database include tremors (all species), increased salivation (rats and dogs) and 

vomiting (dogs). In the acute neurotoxicity study, motor activity was increased. Rats were 

sensitive to inhalation exposure, showing mortality and clinical signs including ataxic gait, 

tremors, tip-toe gait, lateral position, clonic convulsions and hypothermia. Mortality also 

occurred from dermal exposure at the limit dose. Metofluthrin targeted the liver in rats and 

mice: increased absolute and relative liver weights, hepatocellular hypertrophy, enlarged or 

discolored liver, increased serum lipids, and/or hepatocellular degeneration/necrosis. No 

reproductive toxicity was observed at maternally toxic doses. Route-specific studies were 

available for oral, dermal and inhalation risk assessments. Since the route-specific endpoints 

were all based on the same neurotoxic effects (clinical signs including tremors), exposure via the 

oral, dermal and inhalation routes was combined when appropriate. 

Evidence of increased qualitative or quantitative susceptibility of offspring was not observed in 

studies with metofluthrin. However, the Agency will retain a 3X database uncertainty factor 

(UFDB) to protect for exposures to children <6 years of age based on the following: 1) agedependent pharmacokinetics, supported by rat Physiologically Based Pharmacokinetic (PBPK)

model predictions of a 3-fold increase of pyrethroid concentration in juvenile brain compared to 
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adults; 2) in vitro pharmacodynamic data and in vivo data indicating similar responses between 

adult and juvenile rats at low doses; and 3) data indicating that the rat is a conservative model 

compared to the human based on species-specific pharmacodynamics of homologous sodium 

channel isoforms.

One of the key elements in risk assessment is the appropriate integration of temporality between 

the exposure and hazard assessments. Following oral dosing, metofluthrin is absorbed quickly in 

rats. Neurotoxicity is observed within 6 hours and recovery is within 24 hours, consistent with 

the toxicity profiles for other pyrethroids, which are very similar and marked by rapid 

absorption, metabolism and time-to-peak effect. The no observed adverse effect levels 

(NOAELs) and lowest observed adverse effect levels (LOAELs) identified from metofluthrin 

single dose and repeat dosing studies show that repeat exposures do not result in lower NOAELs, 

i.e., toxicity does not increase with increased duration of dosing. Thus, for purposes of endpoint 

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

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

in a mitogenic response,” based on an increased incidence of liver adenomas and carcinomas in 

rats, with supporting mechanistic studies demonstrating a mitogenic mode of action following 

induction of liver cytochrome p450. Genotoxicity studies were negative. The doses selected for 

risk assessment are protective of liver effects, and are therefore protective of cancer risk.

Route-specific dermal and inhalation toxicity studies were available to select doses and 

endpoints for dermal and inhalation exposure and risk assessment. For the inhalation 

assessment, the results of the rat inhalation toxicity study were used, along with the reference 

concentration (RfC) methodology, to determine human equivalent concentrations (HECs) and 

human equivalent doses (HEDs) for use in risk assessment. The endpoints (tremors) and doses 

from the route-specific studies were selected to be protective of all effects in the database, 

including developmental effects. For the incidental oral exposure and risk assessment, the 

endpoint selected was maternal effects (tremors) observed in a rat developmental toxicity study; 

the endpoint and dose were considered protective of clinical signs and other effects observed at 

higher doses.

For residential scenarios involving dermal exposure to adults and children ≥6 years of age, and 

for occupational scenarios involving dermal exposure, HED’s level of concern (LOC) is a 

Margin of Exposure (MOE) of 100, based on the traditional 10X UFs to account for interspecies 

extrapolation and intraspecies variability. For residential and occupational scenarios involving 

inhalation exposure to adults and children ≥6 years of age, the LOC is 30X: the interspecies UF 

has been reduced to 3X because calculation of the HEC includes an adjustment for interspecies 

differences in pharmacokinetics. For children <6 years old, an additional 3X UFDB for 

pyrethroids results in an LOC of 100 for inhalation exposure and an LOC of 300 for dermal and 

incidental oral exposure. Risk estimates (MOEs) above the respective LOCs for adults or 

children are not of concern. For combined inhalation and dermal/oral exposures, the Aggregate 

Risk Index (ARI) approach was used to assess human health risk because different LOCs were 

used for dermal/oral and inhalation exposures.
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Although the proposed bed bug product is not intended for residential homeowner use, such 

exposures could occur if residential handlers obtained the product, and therefore HED has 

assessed short-term exposure and risk. For residential handlers who mix, load and apply the 

pesticide to indoor surfaces, the individual dermal and inhalation MOEs and the ARI for 

combined dermal and inhalation exposure are not of concern. Dermal and inhalation handler

exposures associated with existing outdoor repellent uses are expected to be negligible and were 

not quantitatively assessed.

Based on the proposed bed bug use pattern and surrogate pyrethroid data generated by the NonDietary Exposure Task Force (NDETF), HED does not have concerns for metofluthrin postapplication inhalation exposure, due to the very low indoor air concentrations expected following 

application. Post-application dermal exposure and risk estimates from the perimeter/spot/bed 

bug use and mattress treatment resulted in MOEs greater than the respective LOCs for adults and 

children and are not of concern. The lowest estimated dermal MOE was for children, at 25,000.

Children’s post-application incidental oral exposure resulting from hand-to-mouth and object-tomouth activities can occur following the indoor perimeter/spot/bed bug application and the bed 

bug/mattress use. Only incidental oral exposures resulting from the perimeter/spot/bed bug 

application were quantitatively assessed since they are considered to be protective of the 

exposure resulting from the mattress application. All hand-to-mouth and object-to-mouth postapplication exposure scenarios resulted in MOEs greater than 8,500 and are not of concern.

Post-application exposure and risk estimates for the registered repellent products including the 

personal device are not of concern. 

In order to determine the overall potential for residential exposure to a given pesticide, HED 

combines exposure and risk values resulting from separate residential exposure scenarios when it 

is likely they can occur simultaneously based on the use-pattern and the behavior associated with 

the exposed life stage. HED does not expect outdoor treatments with repellents to co-occur with 

indoor treatment for bed bugs. The residential handler exposure assessments resulting from bed 

bug use resulted in the worst case scenarios for adults, while the combined post-application 

exposure resulting from personal fans resulted in the worst case scenario for children. All 

scenarios resulted in ARIs > 1and are not of concern.

The Agency completed a cumulative risk assessment for pyrethroids in 2011. In conducting this 

risk assessment for metofluthrin, HED has completed a quantitative analysis of the proposed 

metofluthrin bed bug use and has determined that it will not contribute significantly or change 

the overall findings presented in the pyrethroid cumulative risk assessment. This analysis is 

summarized in Appendix D. 

Commercial handler exposure is expected for individuals applying VBC3 Insecticide in indoor 

residential, institutional and commercial settings. All scenarios associated with the proposed use 

pattern resulted in MOEs or ARIs that exceeded the respective LOCs, assuming baseline attire 

(i.e., single layer of clothing, no respirator), and using typical assumptions for each application 

method. HED does not anticipate post-application exposure for commercial handlers and 
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therefore a quantitative occupational post-application risk assessment was not performed for the 

bedbug use.

This assessment serves as the scoping document and human health risk assessment for 

Registration Review of metofluthrin. Both proposed and existing uses have been evaluated and 

no risks of concern were identified.

Review of Human Research: 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 studies 

(listed in Appendix C) have been determined to require a review of their ethical conduct and all 

of the studies utilized in this assessment have received the appropriate review.

2.0 HED Recommendations

HED has evaluated the toxicity and exposure databases for the active ingredient, metofluthrin, 

and has conducted a human health risk assessment in support of the proposed use for control of 

bed bugs. Based on this assessment, HED has determined that there are no potential risk 

estimates of concern for the proposed use of metofluthrin. HED recommends that the requested 

uses be granted.

HED’s conclusions regarding Registration Review are provided in Appendix E. There are no 

risks of concern, and HED is not recommending any label changes or mitigation in conjunction 

with registration review. Nonetheless, the Agency should continue to monitor the number of 

incidents associated with metofluthrin products, based on the 39 moderate severity incidents 

reported in the main incident data system (IDS) from 2007 through 2012.

2.1 Data Deficiencies/Conditions of Registration

An immunotoxicity study (§870.7800) is required for metofluthrin. An ongoing effort to 

conduct additional studies to evaluate the age-related sensitivity of pyrethroids is underway and 

eventually these studies will be considered in the assessment of metofluthrin.

2.2 Tolerance Considerations

There are no established or proposed tolerances for metofluthrin on or on any food or feed crops.

2.3 Label Recommendations

None.

3.0 Introduction

Metofluthrin is a synthetic Type I pyrethroid insecticide. It was first registered in 2006 for use in 

insect repellent strip and personal outdoor insect repellent clip-on products.
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3.1 Chemical Identity

TABLE 3.1. Test Compound Nomenclature

Chemical Structure

Empirical Formula C18H20F4O3

Common name Metofluthrin

Company experimental name S-1264

IUPAC name 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (EZ)-(1RS,3RS;1RS,3SR)-2,2-

dimethyl-3-prop-1-enylcyclopropanecarboxylate

CAS name [2,3,5,6-tetrafluoro-4-(methoxymethyl)phenyl]methyl 2,2-dimethyl-3-(1-

propenyl)cyclopropanecarboxylate

CAS Registry Number 240494-70-6

End-use products/EP VBC3, SumiOne , Eminence

Chemical Class Pyrethroid ester 

Known Impurities of Concern None of the impurities identified by the registrant are of toxicological concern.

3.2 Physical/Chemical Characteristics

The physical/chemical properties of metofluthrin are detailed in Appendix B. Metofluthrin is a 

type I pyrethroid ester and has a vapor pressure of 1.47 x 10-5 mmHg at 25°C. Based on existing 

and proposed use patterns, no exposure is expected through the environment. Although 

metofluthrin could potentially leach to groundwater, its solubility in water is so low that this is 

not a concern.

3.3 Pesticide Use Pattern

Valent BioScience Corporation is proposing a new use for metofluthrin. The new proposed 

product, “Valent Bed Bug Combination” (VBC3) Insecticide is intended to control bed bugs and 

their eggs for up to 4 weeks in indoor residential, institutional and commercial facilities. VBC3

is formulated as a liquid, and contains 0.1% of the active ingredient (a.i.) metofluthrin.

According to the proposed label, this product may be applied with a hand held or backpack 

sprayer or with a paintbrush for treatment of bed bugs in indoor residential and commercial 

buildings/structures. The proposed label indicates that VBC3 is to be applied as a pinstream, 
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coarse spray or low pressure spray for crack and crevice, carpet perimeter and direct spray 

applications on or around baseboards, floorboards, bed frames, wall hangings, headboards, 

furniture, door and window frames, mill work and walls, beneath floor coverings, luggage, shoes 

and backpacks. For bed bug infected mattresses and box springs, the label directs the applicator 

to use a pin stream, coarse or low pressure equipment to spray mattress surface paying special 

attention to tufts, seams, folds and edges until thoroughly damp. The label indicates that treated 

articles should not be used until after the spray has dried. VBC3 is packaged in a single unit 

dose. Directions indicate to mix the entire contents in the package (13 fl. oz.) in 1 gallon of 

water to treat 1,000 square feet. The personal protective equipment required for applicators and 

other handlers consists of baseline attire (i.e., long sleeved shirt, long pants, shoes and socks). 

The proposed use pattern for VBC3 is summarized in Table 3.3.

Table 3.3 Proposed Direction for Use of VBC3 Insecticide For Control of Bed Bugs.

Formulation

(EPA Reg. 

No.)

Method of 

Application

Application 

Rate 1

Max. No. 

Applications

per Season

Maximum

Seasonal 

Application

Rate

REI Use Directions and other 

Limitations

VBC3 

Insecticide 

EPA Reg. No.:

73049-UIE

Liquid

(1.022 g/ml)

0.1% 

metofluthrin

(0.00851 lb 

ai/gal product)

Hand held 

backpack 

sprayer, and 

paintbrush (as 

specified on the 

label)

0.000864 

lbs ai/1000ft2

or 

0.000864 lb 

ai/gal

NA NA NA Apply as an indoor crack and 

crevice, spot treatment or direct 

spray application to baseboards, 

floorboards, bed frames, 

headboards, wall hangings, 

furniture, door and window 

frames, walls ,closets, window 

treatments, under floor 

coverings, luggage, shoes and 

backpacks, and mattress surface, 

seams, folds, tufts and edges.

Do not allow adults, children or 

pets to enter treated area until 

sprays are dry.

Do not use treated articles until 

spray has dried.

Effective for up to 30 days post 

or after application.

1. Application Rate = 1.022 grams/ml x 0.001 ai x 0.0022 lb/1 gram x 3785 ml/gal = 0.00851 lb ai/gal product

 13 fl oz/1000ft2x 0.00851 lb ai/gal x 1 gal/128 fl oz = 0.000864 lb ai/1000ft2(0.000000864 lb ai/ft2) or 0.000864 lb ai/gal

There are currently three registered products for metofluthrin: DeckMateTM Mosquito Repellent 

Strip, NORM 1, a personal repellent device, and a candle, Charger OFF Patio Protector. 

Exposure assessments for DeckMate and NORM 1 have been revised to reflect the Revised 

Residential SOPs (2012) and updated body weight assumptions. The candle product has been 

assessed for the first time in conjunction with registration review [See Appendix E]. 

3.4 Anticipated Exposure Pathways

Humans will not be exposed to metofluthrin in food and drinking water, since there are no 
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agricultural uses on food or feed and no likelihood of contamination of surface and ground water 

sources of drinking water from the outdoor repellent uses. 

In a residential or non-occupational setting, exposure to humans may result from inhalation and 

dermal exposure while handling the pesticide prior to application, as well as during application. 

Post-application exposure is anticipated from the proposed use, including dermal exposure and 

children’s incidental oral exposure resulting from contact with treated indoor surfaces. Indoor 

post-application inhalation exposure resulting from the bed bug use is not of concern based on 

surrogate pyrethroid data showing air concentration values below the limit of quantitation. In an 

occupational setting, applicators may be exposed via dermal or inhalation routes while handling 

the pesticide prior to application, as well as during application. Occupational post-application 

exposure is not anticipated.

The existing repellent uses consist of outdoor products, and there is the potential for exposure via 

dermal and inhalation pathways; for children, incidental oral exposure can also occur.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary 

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas post-application are 

evaluated. Further considerations are currently in development as OPP has committed resources 

and expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

Metofluthrin is a member of the pyrethroid class of chemicals. Pyrethroids have historically 

been classified into two groups, Type I and Type II, based upon chemical structure and 

neurotoxicological effect. Type I pyrethroids, which lack an alpha-cyano moiety, induce in rats 

a syndrome consisting of aggressive sparring, altered sensitivity to external stimuli, and fine 

tremor progressing to whole-body tremor and prostration (T-syndrome). Type II pyrethroids, 
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which contain an alpha-cyano moiety, in rats produce a syndrome that includes pawing, 

burrowing, salivation, and coarse tremors leading to choreoathetosis (CS-syndrome) (Verschoyle 

and Aldridge 1980; Lawrence and Casida 1982). Metofluthrin is a Type I synthetic pyrethroid. 

The adverse outcome pathway (AOP) shared by pyrethroids involves the ability to interact with 

voltage-gated sodium channels (VGSCs) in the central and peripheral nervous system, leading to 

changes in neuron firing, and ultimately neurotoxicity (see Figure 1). 

Figure 1. Adverse outcome pathway for pyrethroids

4.1 Toxicology Studies Available for Analysis

The data base of experimental toxicology studies available for metofluthrin provides a robust 

characterization of the hazard potential for children 6 years old and older and for adults. An 

immunotoxicity study, according to Part 158 data requirements for a non-food use pesticide 

registration, has not been submitted. However, immunotoxicity was not observed in the 

available toxicity studies and is not typically a critical endpoint for pyrethroids. In addition, 

there are on-going efforts to develop data to inform the potential sensitivity of infants and 

younger children to pyrethroids as a class which is discussed further in Section 4.4. Despite 

these scientific efforts, HED is confident that it has chosen points of departure and uncertainty 

factors in this risk assessment which are health protective and have a strong scientific 

foundation.

Studies submitted include subchronic oral toxicity in the rat, mouse and dog; subchronic dermal 

(90-day) and inhalation (28-day) in the rat; chronic oral toxicity in the dog; oral carcinogenicity 

in the rat and mouse; oral developmental toxicity in the rat and rabbit; two-generation 

reproductive toxicity in the rat; acute and subchronic oral neurotoxicity in the rat; a genotoxicity 

assay battery; and rat general metabolism and dermal penetration. Several mechanistic studies 

were also submitted to characterize the mode of action of metofluthrin with respect to formation 

of liver tumors in the rat. More recently, bridging studies (28-day rat inhalation and bacterial 

reverse gene mutation assay) were submitted for a metofluthrin technical ingredient produced by 

a modification of the existing manufacturing process, which results in slight changes to the ratios 

of metofluthrin isomers. The submitted studies demonstrate that the modified metofluthrin 

technical ingredient is toxicologically equivalent to the original metofluthrin technical 

ingredient. 

In addition, numerous studies from the scientific literature conducted over several decades 

describe the pharmacodynamic and pharmacokinetic profile of the pyrethroids in general; this 

scientific literature has been recently reviewed by several groups (Wolansky and Harrill 2008; 

Weiner et. al. 2009). This literature provides little specific data on metofluthrin. However, 

because of the shared toxicological properties of the members of this class of pesticides, these 

studies are informative in the hazard characterization of metofluthrin.
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The current database is considered sufficient to characterize the hazard for current and proposed 

uses of metofluthrin. Residential and occupational dermal and inhalation short- and 

intermediate-term exposure are anticipated. 

4.2 Toxicological Profile of Metofluthrin

Metofluthrin demonstrated neurotoxicity consistent with Type I pyrethroids in numerous studies 

of varying duration in the rat and dog. As sodium channels are highly conserved across species 

and metofluthrin elicits neurotoxic effects in both species, it is likely that neurotoxic effects 

would be observed in humans. The most common finding was tremor, but twitching, 

convulsions, abnormal gait, respiratory changes, increased motor activity, excess salivation and 

vomiting were also reported. Neurological effects were seen regardless of the route of exposure 

(oral, dermal, inhalation). Neurohistopathology was not observed. In the rat acute neurotoxicity 

study, effects were observed at 2 hours after dosing but not at later times, and included tremors, 

twitches, tachypnea, convulsions, salivation, unusual behavior and increased motor activity. 

Of the available oral studies, the most sensitive NOAEL identified was from the rat 

developmental toxicity study, based on tremors in maternal animals. Two supplemental nonguideline developmental studies yielded similar NOAELs and LOAELs. In the rat subchronic 

neurotoxicity study, mortality, tremors and twitches in females, and soft/liquid/scant feces, 

decreased body weight gain and food consumption in males were observed, but there were no 

effects on motor activity. Increased motor activity was noted in the acute neurotoxicity study, 

along with abnormal respiration, twitches, and tremors. Tremors were also reported in two 

animals in a 6-month rat dietary study during Weeks 1 to 3, but not in the 3-month dietary study. 

In the 90-day rat dermal study, tremor, excess salivation and mortality were observed at the limit 

dose. Rats exposed via inhalation showed tremors, hypersensitivity, gait effects and convulsions 

during the first week of exposure and observed throughout the study. Significant mortality was 

seen at the highest concentration tested (7/10 males and 3/10 females). Tremors were observed 

in the subchronic and chronic dog study, along with occasional salivation, sporadic vomiting and 

repetitive jerking movements. 

The liver is also a target organ for metofluthrin. In rat and mouse subchronic and rat chronic 

toxicity/carcinogenicity studies, the following liver effects were observed: increased absolute 

and relative liver weight, increased serum cholesterol, phospholipids and triglycerides, increased 

incidence of enlarged and/or dark livers, fatty liver change, and hepatocellular hypertrophy, as 

well as necrosis. Liver hypertrophy was also reported in adult animals of the rat reproductive 

toxicity study. No liver effects were seen in the mouse carcinogenicity study, which tested at 

lower dose levels than the rat subchronic study, or in the dog.

An increased incidence of liver adenoma and carcinoma in both sexes was observed in the rat 

two-year dietary combined chronic toxicity/carcinogenicity study. Supplemental mechanistic 

studies evaluating the mode of action for liver tumor formation were submitted and the data 

supported a mitogenic mode of action, with cytochrome p450 induction leading to enhanced 

hepatocellular proliferation and eventual tumor formation. No treatment-related tumors were 

seen in the mouse. Genotoxicity studies were negative. 
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In the rat and rabbit developmental toxicity studies, no developmental toxicity was observed at 

doses causing maternal mortality, clinical signs and/or decreased maternal body weight gain. 

Tremors were seen in pregnant rats and salivation was occasionally reported. These effects were 

observed at a lower dose than in other studies, a finding that was reproducible in two 

supplemental non-guideline developmental studies. There was no evidence of reproductive 

toxicity in the rat two-generation reproduction study. Neurological signs (tremors, twitching) 

were observed at the two highest dose levels in lactating P and F1 females. However, effects on 

offspring were only observed at the highest dose tested. Findings included decreased F1 and F2 

pup weight (post-natal days 10 to weaning), delayed preputial separation/vaginal opening in high 

dose F1 pups (considered secondary to reduced body weight), tremors in F2 pups (lactation days 

24-25), and slightly decreased lactation index F1 pups. Therefore, there was no indication of 

increased qualitative or quantitative pre- and/or postnatal susceptibility in the metofluthrin 

database.

An immunotoxicity study is required but has not been submitted for metofluthrin. However, 

there was no evidence of immunogenic potential in the available database. As a class, 

pyrethroids do not typically show immunotoxicity as the most sensitive effect. 

Metofluthrin demonstrates relatively low toxicity (Category III) in acute lethality studies by all 

routes of exposure. It is not irritating to the eye or skin and is not a dermal sensitizer.

4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile

The pharmacokinetics of metofluthrin are similar to other pyrethroids, i.e., rapid absorption and 

clearance. Following a single oral dose, metofluthrin was extensively metabolized and excreted 

via both the urine (29-73% of the absorbed dose, or AD) and feces (22-66% AD), within 24 

hours. Biliary excretion was significant (27 to 55% of AD). Percentages excreted via urine and 

feces varied somewhat, depending upon the dose regimen, isomer evaluated and label location. 

The rapid absorption was also observed in a single-dose pharmacokinetic study where the 

maximum plasma levels of metofluthrin were found at 3.3 to 8 hours after administration. In a 

single-dose in vivo dermal absorption study in the rat, absorption of 17% was determined at 24 

hours post-exposure. 

The extensive body of scientific literature on the pyrethroids provides a unique insight into the 

contributions of pharmacokinetics (PK) and pharmacodynamics (PD) to the general toxicity 

profile of this class of chemicals. This information also provides valuable insight into the 

potential age-related differences in toxicity for the pyrethroids. The following sections discuss 

the specific issues related to pyrethroid pharmacokinetics, pyrethroid pharmacodynamics, and 

age-related differences in pyrethroid toxicity.

4.3.1 Pharmacokinetics

Pharmacokinetics can be defined as what the body does to the chemical; in this case, how 

pyrethroids are distributed and eliminated following exposure. Specific to pyrethroids, PK refers 

to the process(es) which determine the concentration of the pyrethroids reaching sodium 

channels. The underlying pharmacokinetics of pyrethroids is an important determinant of their 
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toxicity because the concentration of pyrethroid at the sodium channel relates to the extent of 

toxicity; greater pyrethroid concentration translates as increased neurotoxicity. Two 

physiological processes that significantly contribute to the PK include metabolism and 

partitioning. Carboxylesterases and P450 enzymes are the two major enzyme families 

responsible for metabolism of pyrethroids. It is the ontogeny of these enzymes that accounts for 

the age-related sensitivity observed after pyrethroid exposures. With respect to the partitioning 

of pyrethroids within the body, pyrethroids are highly lipophilic and preferentially deposit in 

fatty tissue such as adipose compared to leaner tissues such as muscle. Pyrethroid residues in 

fatty tissue are not available to interact with the VGSCs in vital tissues and therefore do not 

contribute to overall toxicity. 

Physiologically-based pharmacokinetic (PBPK) models, designed to predict pyrethroid 

concentration in tissues following in vivo exposure, have recently been developed by the 

Agency. The Agency has determined that the important PK properties relevant for the 

metabolism and distribution of pyrethroids in the body are sufficiently similar for members of 

this class such that using a ‘generic’ or family model structure for this class is scientifically 

appropriate. In other words, due to the similarities in the PK profiles of pyrethroids, a single 

model structure is able to predict the tissue dose based on the pharmacokinetics of every member 

of the class. The family modeling approach was presented to and supported by the FIFRA SAP 

(USEPA 2007).

In 2011 the Agency conducted an analysis of the toxicokinetic profile of pyrethroids as a class. 

Several studies in this analysis indicate that there are age-dependent pharmacokinetic differences

for the pyrethroids (i.e., there are differences in the ability of adults and juveniles to metabolize 

pyrethroids). The enzymes which metabolize and detoxify the pyrethroids are present in rats and 

humans at birth (Koukouritaki et al. 2004; Yang et al. 2009). As a result, both juveniles and 

adults are able to tolerate low doses of pyrethroids when the internal dose, or the amount of 

pyrethroid at the sodium channel, is low. However, the activity of these enzymes increases with 

age, conveying in adults a greater capacity to detoxify pyrethroids compared to juveniles (Anand 

et al. 2006; de Zwart et al. 2008; Yang et al. 2009). For example, the rate of in vitro metabolism 

of deltamethrin by plasma carboxyesterases, hepatic carboxyesterases, and hepatic microsomes 

are at least 6 times higher for PND 90 rats (mature adult) compared to PND 10 (approximately 

equivalent to a human age of 2 years) rats (Anand et al. 2006). As a consequence, higher 

internal doses (i.e., those associated with high doses in experimental toxicology studies) 

overwhelm the clearance mechanisms in juveniles but because adults have greater enzyme 

activity, they are able to tolerate higher doses prior to the onset of toxicity. As a matter of 

perspective, the anticipated exposures from typical dietary or residential activities are not 

expected to overwhelm the premature metabolic systems in juveniles. 

Predictive PBPK models have recently been developed to describe the PK of a few pyrethroids 

(Mirfazaelian et al. 2006; Godin et al. 2010). Among these is an age-dependent model 

developed by the Agency which is capable of predicting the concentration of deltamethrin in the 

brains of rats at multiple ages (Tornero-Velez et al., 2010). The brain is considered the primary 

target organ for pyrethroids and increased pyrethroid concentrations are correlated with 

increasing systemic toxicity. This model predicts that, compared to adult rats (i.e., 90-days old), 

equivalent brain concentrations of deltamethrin would be achieved with a 3.8X fold lower oral 
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dose in 10-day old rats and 2.5X lower dose in 21-day old rats, corresponding roughly to a 

human equivalent age of 2 and 5-6 years, respectively (Tornero-Velez et al., 2010). For 

example, a 1 mg/kg dose in the adult is equivalent to a 0.26 mg/kg dose (≈1 mg/kg÷3.8) in the 

10-day old rats and to a 0.4 mg/kg (≈1 mg/kg÷2.5) dose in a 21-day old rat. The difference 

between a 3.8- and a 2.5-fold dose is within background variability of the model. Based on these 

results, and the determination that data based on a single pyrethroid may be used to model the 

pharmacokinetics of pyrethroids in general, the Agency concludes that juvenile rats are 3X more 

sensitive than adults with respect to pyrethroid pharmacokinetics.

4.3.2 Pharmacodynamics

Pharmacodynamics (PD) can be defined as the changes that chemicals cause to the body, in this 

case, how pyrethroids interact with the sodium channels. Substantial evidence from in vitro and 

in vivo studies support the AOP illustrated in Figure 1 above as well as disruption of sodium 

channels by pyrethroids as an early key event in this AOP (Lund and Narahashi 1982; Salgado et

al. 1989; Song and Narahashi 1996; Tabarean and Narahashi 1998; Soderlund et al. 2002 

(review). No studies were identified for metofluthrin which provide information on its 

interaction with the sodium channels. However, there are several recent studies which provide 

information on a variety of other pyrethroids. Choi and Soderlund (2006) examined interactions 

of several pyrethroids with mammalian VGSCs expressed in Xenopus oocytes. With respect to 

altered neuronal excitability, Type I pyrethroids cause slight prolongations of the sodium current 

tails (e.g. ~20 ms), often resulting in long trains of action potentials. In contrast, Type II 

pyrethroids significantly prolong sodium current tails (e.g. 200ms to minutes) typically resulting 

in increased resting membrane potential and ultimately causing depolarization dependent action 

potential block. Cao et al. (2011a) measured Na influx in primary cultures of mammalian 

(mouse) neurons and demonstrated that pyrethroids caused increases in Na influx in this model; 

this confirms the ability of pyrethroids to interact with VGSC in intact mammalian neurons. An 

additional study by Cao et al. (2011b) demonstrated that the interaction of pyrethroids with 

VGSC caused changes in neuronal excitability that resulted in calcium influx into intact mouse 

neurons.

HED would prefer to use an early key event in the AOP for pyrethroids in selection of points of 

departure. However, in vivo techniques used to detect VGSC alteration and altered neuronal 

excitability are not practical for use in risk assessment at this time and approaches for 

extrapolating in vitro findings to in vivo measures are not yet developed. Therefore, the Agency 

is focusing its efforts for all pyrethroids in hazard characterization and identification on the 

apical endpoint (i.e., changes in neurobehavior in laboratory animals). Neurotoxicity resulting 

from pyrethroids is generally characterized by tremors, hyper- or hypothermia, altered response

to stimuli, salivation and convulsions (Nemec 2006; Wolansky and Harrill 2008; Breckenridge et 

al. 2009). 

In contrast to the age-related PK differences identified in the 2011 analysis, PD contributions to 

pyrethroid toxicity are not age-dependent even though there are several variations of sodium 

channels, called isoforms, which are differentially expressed by tissue and age. Due to the nature 

of the interaction of pyrethroids with sodium channels, it is difficult to obtain dynamic 

information in vivo. To date, a readily useable biomarker of in vivo pyrethroid interaction with 

sodium channels has not been identified, making it impractical to determine the isoform 
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combinations that are present and being modulated by pyrethroids. Therefore, much of the 

information available to the Agency to characterize the PD relationship between pyrethroids and 

sodium channels has been derived from in vitro studies using frog oocytes or cultured nerve

cells. While these in vitro techniques do not provide direct quantitative measure of in vivo

pyrethroid activity, they consistently and qualitatively demonstrate that channel isoforms 

expressed in juveniles are not more sensitive to pyrethroid perturbation compared to isoforms 

expressed in adults and that, pharmacodynamically, the rat is a conservative model for humans. 

For example, Meacham et al. (2008), compared the sensitivity of an adult and a juvenile isoform 

expressed in frog oocytes to deltamethrin. The isoforms had comparable responses at 

environmentally relevant concentrations (<500 nM) of deltamethrin, suggesting a lack of PD

difference between juveniles and adults at low exposure levels. In addition, in a direct 

comparison of a homologous rat and human VGSC isoform, NaV1.3, Tan and Soderlund (2009)

found the rat isoform was 4-fold more sensitive than the equivalent human sodium channel to the 

pyrethroid tefluthrin (Tan and Soderlund 2009), suggesting the rat is a highly sensitive model 

and extrapolations from the rat would be protective of human health. The occurrence and 

ontogeny of voltage-gated sodium channels in humans is not well characterized compared to the 

rat. However, based on the comparable function and distribution of sodium channels between 

the species, the rat is an appropriate surrogate for the evaluation of human PD (Goldin et al.

2000; Goldin 2002). As a result, the Agency concludes that juvenile rats are not more sensitive 

than adults with respect to pyrethroid pharmacodynamics.

4.3.3 Critical Duration of Exposure

One of the key elements in risk assessment is the appropriate integration of temporality between 

the exposure and hazard assessments. Table 4.3.3, below, summarizes the NOAELs and 

LOAELs from several toxicity studies on metofluthrin. Studies with clinical signs of 

neurotoxicity as endpoints at the LOAEL are shown in boldface. 

As a general rule, acute studies in pyrethroids have similar or lower PODs compared to longer 

duration studies. In other words, repeated dose studies do not typically result in lower NOAELs 

and LOAELs compared to acute studies. As indicated in section 4.2, pyrethroids are absorbed 

and metabolized relatively quickly following an oral dose. Acute studies result in a bolus dose 

and generally utilize a vehicle that enhances absorption from the gastrointestinal tract (e.g., corn 

oil). Repeated dose studies generally use dietary administration and therefore exposure occurs 

over a much longer time period, especially in rodents that tend to consume their food over 

several feedings and multiple hours. Therefore, acute studies result in a higher plasma 

concentration immediately after administration compared to dietary studies, and consequently 

result in clinical signs of neurotoxicity at lower doses compared to feeding studies. 

For metofluthrin, it is apparent that repeat exposures generally do not result in lower NOAELs 

for neurotoxic clinical signs. The lowest oral NOAEL/LOAEL for neurotoxicity was observed 

in the rat developmental toxicity study (i.e, bolus dose; MRID 46454111) and was supported by 

two supplemental non-guideline developmental studies (MRIDs 46454112, -13). The NOAELs 

and LOAELs for neurotoxicity in the rat dietary subchronic neurotoxicity study (MRID 

46406729) and rat 6-month subchronic (MRID 46406733) studies were greater. The NOAEL 

for the guideline acute neurotoxicity is relatively high compared to the other bolus dose studies. 
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The reason for this apparent discrepancy is unclear, however one possible explanation is the 

lower gavage dosing volume in these three studies (5 mL/kg bw) compared to the acute 

neurotoxicity study (10 mL/kg bw). Smaller gavage dosing volumes have been associated with 

increased pyrethroid toxicity (Wolansky et al. 2007). In a non-guideline acute oral study 

designed to specifically identify clinical signs of pyrethroid toxicity, only two doses (57 and 75 

mg/kg) were tested; neurological effects were seen at both doses and a NOAEL was not 

identified (WIL 2010, MRID 48333801). In the developmental gavage studies, toxicity was 

observed at 30 or 40 mg/kg/day, the highest doses tested, with no effects seen at 15 or 20 

mg/kg/day. In contrast, the acute neurotoxicity study identified a NOAEL of 50 mg/kg, with 

neurotoxicity observed at 100 mg/kg.

Furthermore, in the studies where metofluthrin was administered via gavage or capsule, clinical 

signs of toxicity were usually observed within a few hours after dosing but did not persist into 

the following day. This is consistent with toxicity profiles for pyrethroids, which are marked by 

rapid absorption, metabolism and time-to-peak effect. For example, following a single gavage 

dose in the rat (acute neurotoxicity study, MRID 46406728), tremors, body twitches, respiratory 

changes, and increased motor activity were observed by 2 hrs postdosing, the estimated time of 

peak effect, but the animals recovered within 24 hours with no persisting neurotoxicity. 

Pyrethroids typically cause a decrease in motor activity, as opposed to the increase in activity 

observed with metofluthrin. Although this single effect is not consistent with the established 

pyrethroids MOA (i.e., sodium channel disruption), the other clinical signs of neurotoxicity, and 

those observed in the non-guideline functional observational battery (FOB) study (WIL 2010, 

MRID 48333801), are consistent with the MOA.

Table 4.3.3. Experimental Toxicology Studies with Similar Results for Metofluthrin

Study Duration Study findings (doses in mg/kg/day)

RAT

Wolansky et al. (2006) Acute, single exposure Not evaluated

WIL (2010)

MRID 48333801

Acute, single exposure NOAEL-none LOAEL = 57

Acute neurotoxicity

MRID 46406728

Acute, single exposure NOAEL = 50 LOAEL = 100

Developmental toxicity, 

(guideline study)

MRID 46454111

14 days NOAEL = 15 LOAEL = 30

Developmental toxicity

(supplemental study)

MRID 46454113

41 days (GD 6-21 

through LD 20)

NOAEL = 15 LOAEL = 30

Developmental toxicity

(supplemental study)

MRID 46454112

Females up to 35 days (2 

weeks prior to premating, 

mating, through GD7) 

Males 57 days

NOAEL = 20 

mg/kg/day 

(females only)

LOAEL = 40 

mg/kg/day

(females only)

Subchronic neurotoxicity

MRID 46406729

90 days NOAEL = 60 LOAEL = 179

Subchronic

MRID 46454109

90 days NOAEL = 21 LOAEL = 70

Subchronic liver

MRID 46406733 tremors

6 months NOAEL = 16 

NOAEL = 54

LOAEL = 54

LOAEL = 165

Reproductive toxicity

MRID 48770701 

6 months Parental 

NOAEL = 19.5

Parental 

LOAEL = 97.6
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Table 4.3.3. Experimental Toxicology Studies with Similar Results for Metofluthrin

Study Duration Study findings (doses in mg/kg/day)

Offspring

NOAEL = 97.6

Offspring 

LOAEL = 183.6

Chronic-carcinogenicity

MRID 46611301

2-year NOAEL = 8 LOAEL = 38

DOG

Subchronic

MRID 46406734

90 days NOAEL = 30 LOAEL = 100

Chronic

MRID 46454110

1 year NOAEL = 10 LOAEL = 30

MOUSE

Subchronic

MRID 46454108

90 days NOAEL = 357 LOAEL = 487

Oncogenicity

MRID 46611302

78 weeks NOAEL = 116 LOAEL = 209

RABBIT

Developmental toxicity 

MRID 46454114

22 days NOAEL = 25 LOAEL = 125

Boldface indicates studies where neurotoxicity was observed.

Increased duration appears to result in a lower POD in the dog. In the chronic oral (capsule) 

dog study (46454110), tremors were observed at a lower dose (30 mg/kg/day) than in the 

subchronic dog study (100 mg/kg/day; MRID 46406734), although the first observed tremors at 

the LOAEL occurred earlier in the subchronic study (Day 10) than in the chronic (Day 96). 

However, examination of the methods and individual animal data for these studies suggests that 

this may be due, in part, to timing of clinical examinations and possibly dose selection. Dogs 

were examined prior to and immediately after capsule dosing in both the subchronic and 

chronic studies, but postdosing evaluations apparently were conducted more frequently in the 

chronic study (2, 4 and 6 hrs postdosing) than the subchronic study (between 2-6 hours 

postdosing). Comparison of tremor incidence at 100 mg/kg/day in the two studies showed 

sporadic occurrence in most animals, but a higher frequency in the chronic study. The dose of 

30 mg/kg/day may also be a borderline effect level in dogs. Observations of tremor at the 

LOAEL of 30 mg/kg/day in the chronic study were more sporadic than at 100 mg/kg/day: all 

males were affected at some point during the study, but tremors were not observed until Day 96

and incidence was infrequent in most animals (1-5 instances) except for one male that was 

affected on 46 days. Only a single female showed tremor on Day 289. 

Finally, the NOAELs for liver toxicity observed in the chronic and subchronic studies in the rat 

are lower or similar to those of the rat developmental studies, suggesting that liver toxicity may 

be as sensitive an endpoint as neurotoxicity. The chronic toxicity/carcinogenicity study showed a 

lower NOAEL/LOAEL (8/38 mg/kg/day) compared to the two subchronic studies (21/70 and 

16/54 mg/kg/day), but this difference may be due to dose spacing. The LOAELs for liver effects 

and for neurotoxicity in the dietary studies are similar to or higher than the maternal toxicity 

LOAELs (30 or 40 mg/kg/day based on tremors; NOAELs of 15 to 20 mg/kg/day) from the 

developmental studies. Neurotoxicity was reported in one subchronic study at 165 mg/kg/day. 

As previously noted, neurotoxicity in dietary studies on pyrethroids is often observed at higher 

dose levels than in studies using gavage dosing or other bolus dosing methods. The gavage 

developmental studies therefore provide an endpoint and dose that is protective of liver toxicity.
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The weight of evidence for the guideline and non-guideline studies support the information in 

Section 4.2 characterizing the toxicological profile of pyrethroids for neurotoxicity as being 

rapid. Thus, when taken together, the scientific information available supports the conclusion 

that neurotoxicity from pyrethroids is associated with acute, peak exposures. From a risk 

assessment perspective, only single day risk assessments need to be conducted for metofluthrin 

for current and proposed uses.

4.4 Consideration of Toxicity to Children

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

proposed and existing 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. This concept 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 (see Section 4.3.1). 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. As noted in Section 4.3.2, juveniles are not more sensitive than 

adults with respect to pyrethroid pharmacodynamics, and thus no uncertainty factor is needed for 

PD considerations. 

4.4.1 Completeness of the Toxicology Database

The toxicology database for metofluthrin is largely complete and there are no residual 

uncertainties with regard to assessment of pre- and/or postnatal susceptibility. An 

immunotoxicity study is required but has not been submitted. An additional UFDB is not required 

for lack of this study because there was no evidence of effects on the immune system in the 

available studies. Based on the observed lack of immunotoxicity and the toxicity profiles of 

pyrethroids as a class, an immunotoxicity study is unlikely to identify a lower point of departure 

than those selected for the current risk assessment. The requirement for a developmental 

neurotoxicity study was waived (2006, D332801) based on selection of protective endpoints, 

lack of developmental toxicity and lack of neurohistopathology; the waiver is further supported 

by the evaluation of DNT studies on pyrethroids (2011, D381210) which indicates the DNT is of 

limited value for pyrethroid risk assessments. The only other missing data are the studies being 

conducted to assess potential juvenile sensitivity for all pyrethroids.

4.4.2 Evidence of Neurotoxicity

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

interaction with sodium channels leading to clinical signs of neurotoxicity. Clinical signs 

observed for metofluthrin are generally consistent with typical Type I pyrethroid toxicity. There 

are no residual uncertainties with regard to evidence of neurotoxicity, which is observed in a 

dose-dependent manner in the majority of the available studies. Acute and subchronic 
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neurotoxicity studies in the rat are available for metofluthrin and neurotoxicity is wellcharacterized in the available database. 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

Based on the metofluthrin-specific data, there is no indication of increased juvenile sensitivity. 

However, after reviewing the extensive body of peer-reviewed literature on pyrethroids, the 

Agency has reached a number of conclusions regarding juvenile sensitivity for pyrethroids, 

including the following:

The Agency has no residual uncertainties regarding age related sensitivities for women 

of child bearing age as well as for all adult populations and children > 6 years of age, 

based on the absence of pre-natal sensitivity observed in 76 guideline studies for 24 

pyrethroids, the scientific literature, and the metofluthrin guideline toxicological studies.

The developmental and reproduction studies for metofluthrin did not demonstrate 

qualitative or quantitative susceptibility to the young or developing animal, consistent 

with other members of the pyrethroid class. The DNT study requirement for 

metofluthrin has been waived.

No evidence of increased quantitative or qualitative susceptibility was seen in the 

pyrethroid scientific literature related to pharmacodynamics.

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.

Additional in vitro and in vivo studies are currently being conducted that could potentially inform 

a number of issues related to pyrethroid toxicity as a class. In 2010, the Agency requested 

proposals for study protocols which could identify and quantify potential juvenile sensitivity and 

received a single, coordinated response from the Pyrethrin and Pyrethroids Working Group 

(PPTWG), a conglomerate of pyrethroid registrants. The PPTWG protocol was reviewed during 

a July 2010 FIFRA SAP meeting1. Based on comments from the SAP, the initial study proposal 

was refined. At present time, pesticide registrants and product formulators have come together 

as Council for the Advancement of Pyrethroid Human Risk Assessment (CAPHRA) and plan on 

doing the following: 1) conducting in vitro studies demonstrating the interaction of pyrethroids 

exogenously expressed rat and human VGSCs in Xenopus oocytes; 2) conducting in vitro studies 

demonstrating interaction of pyrethroids in rat neurolemma cells; 3) developing rat and human 

PBPK models, including additional pharmacokinetic data; and 4) conducting in vivo behavioral 

testing using auditory startle testing in rats. As these data become available, the Agency will 

determine whether re-evaluation of the age-related sensitivity of pyrethroids is appropriate. 

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties with regard to assessment of residential exposure. 

underestimate potential exposures to the proposed metofluthrin bed bug product or to the 

registered insect repellent products.

 

1

http://www.epa.gov/scipoly/sap/meetings/2010/072310meeting.html
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4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

The detailed rationales for selecting toxicity endpoints and points of departure (PODs) are 

presented in Appendix A2. Route-specific studies were available for all exposure scenarios 

(short- and intermediate-term incidental oral, dermal and inhalation) for the current and proposed 

use patterns of metofluthrin. There are currently no food/feed uses for metofluthrin and no risk 

of drinking water contamination; therefore, acute and chronic dietary assessments were not 

performed, and endpoints were not selected for these exposure scenarios. 

Incidental oral exposure: The rat developmental toxicity study was selected for the assessment 

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

tremors observed at the high dose (LOAEL) of 30 mg/kg/day between gestation days 10 to 19 

(dosing days 4 to 13), which was the most sensitive endpoint available for oral exposure. 

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 

postnatal toxicity, including offspring effects (tremors, decreased pup weight and lactation 

index) in the rat reproduction study at a higher dose (NOAEL/LOAEL = 97.6/183.6 mg/kg/day). 

Parental toxicity (tremors) was seen at 97.6 mg/kg/day (NOAEL = 19.5 mg/kg/day).

Dermal exposure (occupational and residential handler/applicator; residential postapplication): 

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), and mortality. The developmental toxicity and reproduction studies were also considered 

for dermal risk assessment. However, no developmental effects were noted in the developmental 

studies and 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 there were no developmental or reproductive effects seen in the relevant studies. 

Inhalation exposure (occupational and residential handler/applicator): A rat 28-day inhalation 

toxicity study was selected for use in assessment of short- and intermediate-term inhalation 

exposures. The NOAEL was 0.099 mg/L. Significant findings at the LOAEL of 0.196 mg/L 

included 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 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 there were no developmental or reproductive 

effects observed in the relevant studies. This study is supported by a second 28-day inhalation 
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study, a bridging study conducted on the technical active ingredient manufactured under a 

modified process. Essentially identical findings were observed in both studies.

In the 4-week inhalation study, rats were exposed to an aerosol containing both vapor and 

particulate forms of metofluthrin. This is the type of exposure expected to occur for handlers

making spray applications of the proposed bed bug product. However, post-application 

inhalation exposure is expected to be primarily to a vapor. Although toxicity from exposure to 

vapor and aerosol could differ, there is no study available to delineate toxicity observed from 

exposure to metofluthrin as a vapor. The use of the aerosol study for endpoint selection 

introduces some uncertainty into the risk assessment for repellent products, but the fact that test 

animals were also exposed to the vapor in the aerosol study reduces the uncertainty.

2

 Despite the 

limitations of using an aerosol study to assess vapor exposure, there is less uncertainty with this 

approach than there would be using an oral study and route-to-route extrapolation.

The results of the inhalation study were incorporated into the Agency’s Reference Concentration 

(RfC) methodology developed by the Office of Research and Development (ORD) to determine 

human equivalent concentrations (HECs) and human equivalent doses (HEDs) for risk 

assessment. The approach takes into account the differences between rat and human respiratory 

systems. The detailed calculations are presented in Appendix A.5.

For dermal residential and occupational scenarios involving adults and children ≥6 years of age, 

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 

juvenile sensitivity was utilized and results in incidental oral and dermal LOCs of 300. Risk 

estimates (MOEs) above the respective LOCs for adults or children are not of concern.

For residential and occupational inhalation scenarios involving adults and children ≥6 years of 

age, 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: the

additional 3X database uncertainty factor for potential juvenile sensitivity to pyrethroids was 

combined with the 3X interspecies factor and the 10X intraspecies factor. Risk estimates 

(MOEs) above the respective inhalation LOCs for adults and children are not of concern.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Exposure from incidental oral, dermal and inhalation routes are based on route-specific studies, 

but similar endpoints all relevant to the sodium channel interaction of metofluthrin (clinical signs 

including tremors) were identified in each case. Exposures from these routes may therefore be 

combined. There are currently no agricultural uses for metofluthrin and no anticipated exposure 

to metofluthrin via diet or drinking water (Moore, 2006, D313232).

 

2

http://www.epa.gov/scipoly/sap/meetings/2009/120109meeting.html
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4.5.3 Cancer Classification and Risk Assessment Recommendation

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.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Metofluthrin for Use in Non-Occupational 

Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(All 

Populations)

No risk is expected from this exposure scenario because there are currently no food uses for 

metofluthrin.

Chronic 

Dietary (All 

Populations)

No risk is expected from this exposure scenario because there are currently no food uses for 

metofluthrin.

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 = 

300

MRID 46454111

Developmental toxicity in the rat (oral, 

gavage)

Maternal LOAEL = 30 mg/kg/day based 

on increased incidence of tremors in 

maternal animals.

Dermal ShortTerm (1-30 

days)

NOAEL= 

300

mg/kg/day

UFA= 10X

UFH=10X

UFDB = 3X, <6 

years of age

UFDB= 1X, ≥6 years 

of age

Residential 

LOC for 

children <6 

years of age = 

300

For adults and 

children ≥6 

years of age = 

100

MRID 46556101

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- Term 

(1-30 days)

NOAEL =

0.099 mg/L

HEC = 

0.052 mg/L

HED = 7.5 

mg/kg/day

UFA= 3X

UFH=10X

UFDB = 3X, <6 

years of age

UFDB= 1X, ≥6 years 

of age

Residential 

LOC for 

children <6 

years of age = 

100

For adults and 

children ≥6 

years of age = 

30

MRID 46406736

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
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Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Metofluthrin for Use in Non-Occupational 

Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

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.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFDB = to account for the lack of definitive data 

on the quantitative susceptibility to pyrethroids of children <6 years of age. LOC = level of concern. N/A = not 

applicable. HEC = human equivalent concentration (mg/L). HED = human equivalent dose (mg/kg/day).

Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Metofluthrin for Use in Occupational 

Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal Shortand 

IntermediateTerm (1-30 

days and 1-6 

months, 

respectively)

NOAEL=

300

mg/kg/day

UFA=10X

UFH=10X

Occupational 

LOC for MOE = 

100

MRID 46556101

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 

IntermediateTerm (1-30 

days and 1-6 

months, 

respectively)

NOAEL = 

0.099 mg/L

HEC = 

0.155 mg/L

HED = 7.4

mg/kg/day

UFA=3X

UFH=10X

Occupational 

LOC for MOE = 

30

MRID 46406736

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 = 0.308 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.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of 

concern. N/A = not applicable. HEC = human equivalent concentration (mg/L). HED = human equivalent dose

(mg/kg/day).

5.0 Dietary Exposure and Risk Assessment 

There are no proposed or currently registered food uses for metofluthrin. Further, drinking water 

exposure is not expected based on the proposed indoor use and limited registered outdoor uses of 
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metofluthrin; a dietary assessment is not needed.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

SOURCE: Exposure Memo D397725, 9/5/12. M. Collantes

As indicated previously, there are currently three registered residential products for metofluthrin. 

Exposure assessments for these products have been updated to reflect the Revised Residential 

SOPs (2012) and updated body weight assumptions. A summary of the estimates exposure and 

risk resulting from these products in provided in Appendix E.

6.1 Residential Handler (Bed Bug) Exposure

According to the product label, VBC3 Insecticide is not a restricted use product when used for 

the control of bed bugs in homes, and could potentially be used by homeowners. Therefore, a 

residential handler exposure and risk assessment has been conducted. Residential handlers are 

expected to experience similar exposures to those of occupational handlers, except that the area 

treated, amount handled and frequency of exposure is reduced. Residential handlers are assumed 

to complete all elements of an application without the use of personal protective equipment

(PPE). Homeowner handler assessments are based on the assumption that individuals are 

wearing shorts, short-sleeved shirts, socks, and shoes.

Based on the proposed label, HED expects the following residential handler scenarios:

Mixing/loading/applying sprays with a manually-pressurized handwand (PHED), and

Applying with paintbrush.

Table 6.1 provides estimates of residential handler exposure and risk estimates resulting from use 

of metofluthrin to control bed bugs. The aggregate risk index (ARI) approach was used to 

combine exposures across pathways since the LOCs were different for dermal exposure (100) 

and inhalation exposure (30). The MOEs for individual dermal and inhalation routes of exposure 

are greater than 100 and are not of concern; risk estimates from combined dermal and inhalation 

exposure are also not of concern. The paint brush scenario provided the lowest ARI (ARI = 

400), largely driven by exposure via the dermal route.
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Table 6.1.: Residential Handler Exposure and Risk Estimates for Indoor Surface Bed Bug Treatment

Application 

Ratea

Amount 

Handledb

(lb ai/gal)

Unit Exposure

(mg/lb ai)c Dose (mg/kg/day) Short-Term MOE

ARIh

Dermal Inhalation DermaldInhalatione DermalfInhalationg

Mixing/Loading/Applying with Manually-pressurized Handwand (PHED)

0.000864

(lb ai/gal)

0.5 69 1.1 0.000378 0.0000059 810,000 1,300,000 2,500

Applying with Paintbrush

0.000864

(lb ai/gal)

0.5 450 0.2 0.00243 0.0000010 120,000 6,900,000 410

a. Application Rates based on proposed use on label for VBC3Insecticide label (EPA Reg. No. 73049-UIE).

b. Based on Revised Residential SOPs (2012).

c. Unit Exposures based on Revised Residential SOPs (2012).

d. Dermal Dose (mg/kg/day) = daily unit exposure (mg/lb ai) * application rate (lb ai/gallon) * amount handled (gallons) 

* dermal absorption factor (100%) / body weight (80 kg).

e. Inhalation Dose (mg/kg/day) = daily unit exposure (mg/lb ai) * application rate (lb ai/gallon) * amount handled

(gallons) * inhalation absorption factor (100%) / body weight (80 kg). 

f. Dermal MOE = NOAEL (300 mg/kg/day) / Daily dermal dose (mg/kg/day). LOC = 100

g. Inhalation MOE = HED (7.5 mg/kg/day) / Daily inhalation dose (mg/kg/day). LOC = 30

h. ARI = 1/[(1/ARIdermal) + (1/ARIinhal)] where, ARIdermal = MOEdermal/100 and ARIinhal = MOEinhal/30. ARIs greater than 

1 are not of concern.

6.2 Post-Application Exposure

6.2.1 Post-Application Inhalation Exposure and Risk Estimates Resulting from Bed Bug 

Treatment

Post-application inhalation exposure occurs for adults and children who occupy living spaces 

within a residence after a pesticide treatment has occurred. Post-application inhalation exposure 

to metofluthrin can result from the proposed bed bug use, from the volatilization of the pesticide 

after application. Volatilization of a pesticide indoors is dependent on many factors, including 

the vapor pressure of the chemical, the media on which it has been applied, and air temperature. 

No chemical specific post-application inhalation exposure data were submitted for the proposed 

use of metofluthrin for the control of bed bugs. However, HED has recently received an Office 

of Research and Development (ORD) exposure study that was performed in the U.S. EPA’s

Indoor Air Quality (IAQ) Research House. 

Although these data are not chemical-specific for metofluthrin, the Non-dietary Exposure Task 

Force (NDETF) has performed an analysis of all the pyrethroid surface deposition and hand 

press exposure data that they produced. The analysis shows the exposure data for one pyrethroid 

can generally be used to represent the entire chemical class. Based on this NDETF analysis, 

HED believes it is appropriate to use the air concentration data from the ORD study as a 

surrogate for metofluthrin when it is applied as described on the proposed label. HED does not 

have concerns for metofluthrin for the post-application inhalation exposure scenario given that 

all air concentration values were below the limit of quantitation in the ORD study.
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6.2.2 Post-Application Dermal Exposure and Risk Estimates Resulting from Bed Bug 

Treatment

Post-application dermal exposure can result from pesticide residue transfer to the skin of 

individuals who contact previously treated indoor surfaces (e.g., carpets, floors, furniture, and 

other surfaces). For the purpose of assessing dermal post-application exposure resulting from the 

use of metofluthrin to treat bed bugs, HED has performed 2 separate assessments – one for 

indoor surface (i.e., perimeter/spot/bedbug) treatment, and one for exposure to treated mattresses. 

The post-application dermal exposure following treatment of a mattress is considered worst-case 

and is protective of treatment other indoor treatments (such as furniture and empty luggage and 

back pack applications). Dermal post-application exposure to indoor surfaces is assumed to 

occur for both adults and small children.

 

HED has estimated dermal post-application exposure for indoor surface use based on the 

Revised Standard Operating Procedures for Residential Pesticide Exposure Assessment (2012): 

Indoor Environments, and pyrethroid-specific data provided by the Non-Dietary Exposure Task 

Force (NDETF) which can be used for the fraction of residue available for transfer for 

metofluthrin (Selim, 2004a; Selim, 2003b; Selim, 2003c; Selim, 2000; Selim, 2002b; Selim, 

2002c).

6.2.2.1 Bed Bug Use – Perimeter/Spot Application

Although the label indicates the product is to be applied as a “crack and crevice” and spot 

treatment, it is believed that the perimeter treatment use pattern would result in a higher residue 

available for exposure than a typical crack and crevice application. Therefore, it is assumed that 

the residue resulting from a perimeter treatment represents the most appropriate scenario to 

assess exposure following indoor treatments for bed bug control. Table 6.2.2.1 summarizes the 

dermal post-application exposure and risk estimates from the proposed perimeter/spot/bed bug 

use of metofluthrin. Dermal post-application exposure scenarios result in risk estimates (MOEs)

greater than the respective LOCs and are not of concern. 
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Table 6.2.2.1: Post-application Dermal Exposure and Risk Estimates for Adults and Children (1 to < 2 years 

old) Resulting from Perimeter/Spot/Bed Bug) Application.

Surface 

Type Lifestage DepRa (ug/cm2)

Fai

Fraction 

Transferredb

TC

Transfer 

Coefficient

(cm2/hr)

ET

Exposure 

time 

(hr/day)

E

Exposure 

(mg/day)

Dermal 

Dose b

(mg/kg/day)

Dermal MOE c

Carpet

Adult

0.9

0.02

6,800 8 1.0 0.012 25,000

Child (1 to 

< 2 years 

old)

1,800 4 0.1 0.011 25,000

Hard 

Surfaces

Adult

0.04

6,800

2

0.5 0.00612 49,000

Child (1 to 

< 2 years 

old)

1,800 0.1 0.011 25,000

a. Deposited residue is a surrogate value (0.9 ug/cm2) based on a pyrethroid-specific (esfenvalerate) study (Selim, 2008).

b. Fraction transferred is based on pyrethroid-specific data provided by the NDETF.

c. Dose (mg/kg/day) = Deposited residue (ug/cm2) * Fraction transferred * Transfer coefficient (cm2/hr) * Exposure time 

(hr/day) * Conversion factor (0.001 mg/ug) * / Body Weight (80 kg for adults and 11 kg for children 1 to < 2 years old).

d. 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).

6.2.2.2 Bed Bug Use – Mattress Application

All post-application dermal scenarios for the bed bug use on mattresses resulted in MOEs greater 

than 74,000 and are not of concern. Table 6.2.2.2 summarizes the dermal post-application 

exposure and risk from the bed bug use on mattresses.

Table 6.2.2.2. Post-application Dermal Exposure and Risk Estimates for Adults and Children (1 to < 2 years old) 

Resulting from Bed Bug Mattress Application. 

Surface 

Type Lifestage Residue (ug/cm2)

a

Surface 

area / 

Body 

Weight 

Ratio 

(cm2/kg)

Fraction of 

skin in 

contact 

with 

surface

Fai

Fraction 

transferred

Protection 

factor

Dermal Dose 

(mg/kg/day)b

Dermal MOE

Short/ Intermediateterm

Mattress

Adult

0.42

280

0.5 0.06 0.5

0.0017 170,000

Child (1 to 

2 years old)

640 0.0040 74,000

a. Residue value determined based on application rate (0.000864lb ai/gal) and assumptions for area treated and amount 

applied (see above text).

b. Dermal dose (mg/kg/day) = Surface residue (ug/cm2) * Surface area / Body weight ratio (cm2/kg) * Fraction of body that 

contacts residue (0.5) * Conversion factor (0.001 mg/ug) * Fraction transferred (0.06) * Protection factor (0.5) * Dermal 

Absorption Factor (100 %).

c. MOE = PoD (NOAEL = 300 mg/kg/day) / Dose (mg/kg/day), and level of concern = 100 for adults, and 300 for children 

<6 years old.
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6.2.3 Post-Application Incidental Oral Exposure and Risk Estimates Resulting from Bed 

Bug Treatment

Post-application incidental oral exposure resulting from hand-to-mouth and object-to-mouth 

activities can occur as a result of the indoor perimeter/spot/bed bug application and the bed 

bug/mattress use. Only incidental oral exposures resulting from the perimeter/spot/bed bug 

application have been assessed here since they are considered to be protective of the mattress 

application for the following reasons: (1) a protection factor of 0.5 is assumed for the mattress 

exposure due to the presence of a bed sheet over the mattress, and (2) the replenishment interval 

for hand-to-mouth activity is assumed to be less while a child is sleeping than while they are 

awake. Post-application incidental oral exposure following indoor applications is generally 

considered short-term in duration. All incidental oral exposure scenarios were assessed using the 

HED Standard Operating Procedures (SOP’s) for Residential Exposure Assessments (2012): 

Indoor Environments.

6.2.3.1 Hand-to-Mouth

Incidental oral (hand-to-mouth) exposure occurs when pesticide residues are transferred to the 

skin of children during post-application contact with treated indoor areas and are subsequently 

ingested as a result of hand-to-mouth transfer. Table 6.2.3.1 summarizes the MOEs for hand-tomouth transfer of metofluthrin residues from the indoor perimeter/spot/bed bug use. All hand-tomouth post-application exposure scenarios resulted in MOEs greater than 300 and are not of 

concern.

Table 6.2.3.1. Post-application Incidental Oral (Hand-to-Mouth) Exposure and Risk Estimates for Children Resulting from 

Perimeter/Spot/Bed Bug Application.

Dermal 

Exposurea

(mg/day)

Faihands SAH

(cm2)

Exposure 

Frequency 

(events/hr)

Fm SE ET 

(hours/day)

Replen_ 

Interval 

(min)

N_

Replenish 

HRb

(mg/cm2)

Oral Dose 

(mg/kg/day)c

Incidental 

Oral 

MOEd

Carpets

0.1 0.15 150 20 0.15 48% 4 15 4 0.0001 0.0017 8,500

Hard Surfaces

0.1 0.15 150 20 0.15 48% 2 15 4 0.0001 0.00088 17,000

a. Dermal Exposure value determined for perimeter scenario.

b. Hand Residue Loading (mg/cm2) = (Faihands * Dermal exposure) / (SAH * 2).

c. Oral Dose (mg/kg/day) = Exposure (mg/day)/ Body Weight (11 kg); where Exposure (mg/day) = HR * *FM * SAH) * 

(ET * N_Replen) * [1-(1-SE)(Freq_Replen / N_Replen)].

d. MOE = PoD (mg/kg/day) / Daily Dose (mg/kg/day); incidental oral PoD = NOAEL = 15 mg/kg/day and level of 

concern = 300.

6.2.3.2 Object-to-Mouth

Object-to-mouth exposure can occur when pesticide residues are transferred to a child’s toy and 

are subsequently ingested as a result of object-to-mouth transfer. Table 6.2.3.2 summarizes the 

MOEs for object-to-mouth exposure to pesticide residues from the indoor perimeter/spot/bed bug 
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use. All object-to-mouth post-application exposure scenarios resulted in risk estimates (MOEs)

greater than the LOC of 300 and are not of concern.

Table 6.2.3.2. Post-application Incidental Oral (Object-to-Mouth) Exposure and Risk Estimates Resulting from

Perimeter/Spot/Bed Bug Application.

DepRa

(ug/cm2)

Fo ORb

(μg/cm2)

SAMO

(cm2)

Freq_Replen

Exposure 

Frequency 

(events/hr)

SE ET 

(hours/day)

Replen_ 

Interval 

(min)

N_Replen

Exposure 

c

(mg/day)

Oral Dose 

(mg/kg/day)d

Incidental 

Oral 

MOEe

Carpets

0.9 0.02 0.018 10 14 48% 4 15 4 0.0026 0.000234 64,000

Hard Surfaces

0.9 0.04 0.036 10 14 48% 2 15 4 0.0026 0.000234 64,000

a. DepR = Deposited residue 

b. Chemical residue loading on the object = OR (μg/cm2) = Deposited residue (ug/cm2) * Fo. 

c. Exposure (mg/day) = 

d. Oral Dose (mg/kg/day) = Exposure (mg/day)/ Body Weight (11 kg); 

e. MOE = PoD (mg/kg/day) / Daily Dose (mg/kg/day); incidental oral PoD = NOAEL =15 mg/kg/day and level of 

concern = 300.

6.3 Combined Exposure

6.3.1 Combined Residential Post-Application Risk Estimates from Proposed Bed Bug Use

Risk estimates resulting from different exposure routes may be combined when it is likely that 

they can occur simultaneously based on the use pattern, and when the toxicological effects across 

different routes of exposure are the same. 

There is the potential for dermal and inhalation post-application exposure for children and adults, 

as well as oral exposure for children, resulting from use of metofluthrin as an indoor 

perimeter/spot/bed bug and bed bug/mattress use. However, as indicated previously, HED

believes post-application inhalation exposure is negligible. Therefore, since the dermal and oral

routes of exposure share common endpoints as well as LOCs, these routes of exposure were 

combined to estimate risk for children.

The incidental oral scenarios (i.e., hand-to-mouth 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, only hand-tomouth exposure was combined with the dermal post-application exposure scenarios for children

1 < 2 years old. Table 6.3.1 provides a summary of the combined post-application residential 

indoor perimeter/spot/bed bug (pin steam) and bed bug mattress exposures and risks. The adult 

combined dermal post-application exposure estimate resulted in an MOE of 22,000, while the 

combined child post-application exposure (dermal + incidental oral) estimate resulted in an MOE 

of 5,900. 
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Table 6.3.1. Combined Residential Post-Application Exposure and Risk Estimates from the 

Indoor Perimeter/Spot Bed Bug and Bed Bug Mattress Use.

Combined 

Scenario Lifestage Post-application 

Scenarios

Daily Dose

(mg/kg/day)a MOEb

Combined 

MOEscd

Bed Bug

Adult

Dermal -perimeter 0.012 25,000

22,000c Dermal – mattress 0.0017 170,000

Children 

1 < 2

years old 

Dermal - perimeter 0.012 25,000

5,900

Dermal d–mattress 0.0040 74,000

Hand-to-Mouth 0.0017 8,500

a. Dose = see Tables 6.2.2, 6.2.3.1, and 6.2.3.2.

b. MOE = see Tables 6.2.2, 6.2.3.1, and 6.2.3.2.

c Adult Combined MOE = 1/ [(1/MOE Dermal – perimeter) + (1/MOE Dermal –mattress)]. d Children < 6 years old Combined MOE 

= 1/ [(1/MOE Dermal – perimeter) + (1/MOE Dermal –mattress) + (1/MOE Hand-to-Mouth)].

6.3.2 Combined Residential Risk Estimates (Multiple Exposure Scenarios)

Two major residential use scenarios were considered in this assessment: outdoor repellent 

treatment (i.e., repellent strips, personal repellent and candle) and indoor treatment for bed bugs 

(i.e., perimeter/spot/bed bug, bed bug mattress). HED combines risk values resulting from 

separate residential exposure scenarios when it is likely they can occur simultaneously based on 

the use pattern and the behavior associated with the exposed lifestage. HED does not expect use 

of outdoor repellents to co-occur with indoor treatment for bed bugs. Therefore exposures from 

these scenarios were not combined. 

VBC3 is formulated as a liquid but can be applied using either a manually pressurized handwand 

or a paint brush, but HED doesn’t generally assume that both methods will be used 

simultaneously based on practical considerations. Furthermore, residential handler and postapplication scenarios should generally not be combined. Although there is potential for the same 

individual (i.e., adult) to apply a pesticide in and around the home and be exposed by reentering 

a treated area in the same day, HED considers combining these exposure scenarios to be too 

conservative, especially on a daily basis for up to 30 days. Therefore, HED selected the most 

conservative adult scenario, the handler dermal and inhalation exposure resulting from 

applications via paint brush (ARI = 410) as the contributing source of adult residential exposure.

6.4 Residential Bystander Post-Application Inhalation Exposure

This type of exposure is not applicable for the current or proposed uses of metofluthrin.

6.5 Spray Drift

Spray drift considerations are not applicable for the current or proposed uses of metofluthrin.
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7.0 Aggregate Exposure/Risk Characterization

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

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

risk assessment is not needed.

8.0 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 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. Metofluthrin was considered in this 

assessment, but was not included in the cumulative assessment group (CAG) based on the 

limited use and low exposure potential.

The Agency has conducted a quantitative analysis of the proposed metofluthrin bed bug use and 

has determined that it will not contribute significantly to residential exposure from pyrethroids or 

change the overall findings presented in the pyrethroid cumulative risk assessment. This analysis 

is summarized in Appendix D. Further, since there are no food uses and no exposure to 

metofluthrin through drinking water, the new use will not change the overall findings in the 

pyrethroid cumulative risk assessment with respect to dietary exposure. 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.

9.0 Occupational Exposure/Risk Characterization

SOURCE: Exposure Memo D397725, 9/5/12. M. Collantes

9.1 Short-/Intermediate-Term Handler Risk

Occupational exposure to metofluthrin is anticipated for handlers who apply the VBC3

Insecticide formulation in indoor residential, institutional and commercial facilities. Based on 

application rate and label information, dermal and inhalation exposure is expected to occur for 

short- and intermediate-term durations. Chronic exposure is not expected for the proposed use 

pattern. Based upon the proposed label, HED expects the following commercial pesticide 

handler scenarios:

Mixing/loading/applying sprays with manually-pressurized handwand;

Mixing/loading/applying sprays with backpack; and

Applying with paintbrush.

Chemical-specific data were not submitted to the Agency in support of this Section 3 application. 

Commercial handler risks were assessed for mixer/loader/applicator (MLA), using surrogate unit 
Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 34 of 84

exposures from the Pesticide Handlers Exposure Database (PHED) Version 1.11 and 

“Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” 

(http://www.epa.gov/pesticides/science/handler-exposure-table.pdf), dated March 2012. Unit 

exposure values for MLA were used to assess crack and crevice, spot and direct spray scenarios 

utilizing manually-pressurized handwand in warehouses, residential living spaces, childcare 

centers and schools, backpacks for industrial and commercial areas and application by 

paintbrush.

Table 9.1 presents a summary of the short- and intermediate-term occupational handler 

exposures and risks. All occupational handler scenarios resulted in risk estimates (ARIs) greater 

than the LOC of 1 assuming baseline attire (i.e., single layer of clothing, no respirator). The 

lowest ARI of 76 was associated with applying 20 gallons of the diluted product in commercial 

structures using a paintbrush, and was largely driven by dermal exposure. HED believes this is 

a conservative estimate of exposure, and the risk was not of concern.
Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

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Table 9.1: Commercial Handler Exposure and Risk Estimates.

Application 

Ratea 

(lb ai/gal)

Amount 

Treatedb 

(gals./day)

Baseline 

Dermal 

Unit 

Exposurec

(mg/lb ai)

Inhalation 

Unit 

Exposurec

(mg/lb ai)

Baseline 

Dermal 

Dosed

(mg/kg/day)

Inhalation 

Dosee

(mg/kg/day)

Baseline 

Dermal 

MOEf

Baseline

Inhalation 

MOEg

ARIh

Mixer/Loader/Applicator Using Manually-Pressurized Handwand

0.000864 

20

(hotels, 

motels)

29 1.1

Baseline 0.0062 0.00024 48,000 31,000 330

5 

(residential 

premises)

29 1.1

Baseline 0.00156 0.000059 190,000 120,000 1,300

Mixer/Loader/Applicator Using Backpack

0.000864 20 

(hotels, 

motels)

2.51 0.03 0.000542 0.0000065 550,000 1,100,000 4,800

5 

(residential 

premises) 

2.51 0.03 0.000136 0.0000016 2,200,000 4,500,000 19,000

Applicator Using Paintbrush

0.000864 20

(hotels, 

motels) 180 0.28

0.038 0.00006 7,700 120,000 76

0.5

(residential 

premises)

0.0097 0.000015 31,000 490,000 3,000

a. Application Rates based on proposed use on label for VBC3Insecticide (EPA Reg. No. 73049-UIE).

b. Science Advisory Council for Exposure Meeting Minutes (February 10, 2011). 

c. Unit Exposures based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (PHED)

(http://www.epa.gov/pesticides/science/handler-exposure-table.pdf), dated March 2012.

d. Dermal Dose (mg/kg/day) = daily unit exposure (mg/lb ai) * application rate (lb ai/gallon) * amount handled (gallons) 

* dermal absorption factor (100 %) / body weight (80 kg).

e. Inhalation Dose (mg/kg/day) = daily unit exposure (mg/lb ai) * application rate (lb ai/gallon) * amount handled 

(gallons) *inhalation absorption (100 %) / body weight (80 kg). 

f. Dermal MOE = NOAEL (300mg/kg/day) / dermal dose (mg/kg/day. LOC = 100.

g. Inhalation MOE = HED (7.4 mg/kg/day) / inhalation dose (mg/kg/day). LOC= 30.

h. ARI total = 1/[(1/ARIdermal) + (1/ARIinhal)] where, ARIdermal = MOEdermal/100 and ARIinhal = MOEinhal/30. ARIs greater 

than 1 are not of concern.

9.2 Short-/Intermediate-Term Post-Application Risk

9.2.1 Dermal and Inhalation Post-Application Risk

Based on the uses associated with the VBC3 Insecticide product, HED believes the presence of 

occupational handlers in treated commercial and residential areas is minimal after application of 

metofluthrin to control bed bugs. Therefore, a quantitative post-application exposure assessment 

for commercial handlers re-entering treated areas was not conducted for the proposed use.
Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 36 of 84

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Felts, P. A., S. Yokoyama, S. Dib-Hajj, J. A. Black and S. G. Waxman (1997). "Sodium channel 

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Godin, S. J., M. J. DeVito, M. F. Hughes, D. G. Ross, E. J. Scollon, J. M. Starr, R. W. Setzer, R. 

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Goldin, A., R. Barchi, J. Caldwell, F. Hofmann, J. Howe, J. Hunter, R. Kallen, G. Mandel, M. 

Meisler, YBNetter, M. Noda, M. Tamkun, S. Waxman, J. Wood and W. Catterall (2000). 

"Nomenclature of voltage-gated sodium channels." neuron 28(2): 365-368.

Goldin, A. L. (2002). "Evolution of voltage-gated Na+ channels." J Exp Biol 205(5): 575-584.

Harper, K. (2006) September 27, 2006. DP332801. “Metofluthrin: Human Health Risk 

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Herberth, M. T. (2010). "An Oral (Gavage) Acute Neurotoxicity Comparison Study in Rats.”

WIL Research Laboratories, LLC, 1407 George Road, Ashland, OH 44805-9281. 

Laboratory report number: WIL-118041, December 20, 2010. MRID 

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Hughes, M. F. and B. C. Edwards (2010). "In vitro dermal absorption of pyrethroid pesticides in 

human and rat skin." Toxicol Appl Pharmacol 246(1-2): 29-37.

Jaquith, D. (2006) September 22, 2006, D332693. “Metofluthrin: Exposure and Risk 

Assessment for Use as a Mosquito Repellent Strip and as a Personal Outdoor 

Insect Repellent.”

Kidwell, J. (2006) June 6, 2006, TXR No. 0054239. “Metofluthrin: Report of the Cancer 

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Kidwell, J. (2007) July 26, 2007, TXR No. 00054668. “Metofluthrin: Second Report of the 

Cancer Assessment Review Committee.”

Koukouritaki, S. B., J. R. Manro, S. A. Marsh, J. C. Stevens, A. E. Rettie, D. G. McCarver and 

R. N. Hines (2004). "Developmental Expression of Human Hepatic CYP2C9 and 

CYP2C19." Journal of Pharmacology and Experimental Therapeutics 308(3): 965-974.

Lawrence, L. and J. Casida (1982). "Pyrethroid toxicology: Mouse intracerebral sturcturetoxicity relationships." Pesticide Biochemistry and Physiology 18: 9-14.

Lund, A. and T. Narahashi (1982). "Dose-dependent interaction of the pyrethroid isomers with 

sodium channels of squid axon membranes." Neurotoxicology 3(1): 11-24.

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Mirfazaelian, A., K. Kim, S. Anand, H. Kim, R. Tornero-Velez, J. Bruckner and J. Fisher (2006). 

"Development of a physiologically based pharmacokinetic model for deltamethrin in the 

adult male Sprague-Dawley rat." Toxicol Sci 93(2): 432 - 442.

Moore, K. (2006) July 26, 2006, D313232. “Potential Drinking Water Exposure from 

Metofluthrin.”

Nemec, M. (2006). “An acute functional observational battery comparison study in rats.” WIL 

Research Laboratories study number 409002. 3: 867.

Recore, S. (2012). September 6, 2012, D404998. “Metofluthrin: Review of Human Incidents”

Ross, M. K., A. Borazjani, C. C. Edwards and P. M. Potter (2006). "Hydrolytic metabolism of 

pyrethroids by human and other mammalian carboxylesterases." Biochemical 

Pharmacology 71(5): 657-669.

Salgado, V., M. Herman and T. Narahashi (1989). "Interactions of the pyrethroid fenvalerate 

with nerve membrane sodium channels: Temperature dependence and mechanism of 

depolarization." Neurotoxicology 10(1): 1-14.

Scollon, E. J., J. M. Starr, S. J. Godin, M. J. DeVito and M. F. Hughes (2009). "In Vitro 

Metabolism of Pyrethroid Pesticides by Rat and Human Hepatic Microsomes and 

Cytochrome P450 Isoforms." Drug Metab Dispos 37(1): 221-228.

Soderlund, D., J. Clark, L. Sheets, L. Mullin, V. Piccirillo, D. Sargent, J. Stevens and M. Weiner 

(2002). "Mechanisms of pyrethroid neurotoxicity: implications for cumulative risk 

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maturing rat using a PBPK model." Toxicol Appl Pharmacol 244: 208-217.

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Pyrethroid Pesticides.”

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functional observational battery study of twelve commercial pyrethroid insecticides in 

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volume on the neurotoxicity of bifenthrin.” Neurotoxicology and Teratology 29(3):377-

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in adult animals: A critical review." Neurotoxicology and Teratology 30(2): 55-78.

Yang, D., R. E. Pearce, X. Wang, R. Gaedigk, Y.-J. Y. Wan and B. Yan (2009). "Human 

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Biochemical Pharmacology 77(2): 238-247.
Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for non-food uses for metofluthrin are in Table 1. Use of the new guideline 

numbers does not imply that the new (1998) guideline protocols were used.

Test Technical Metofluthrin

Required Satisfied

870.1100 Acute Oral Toxicity......................................................

870.1200 Acute Dermal Toxicity.................................................

870.1300 Acute Inhalation Toxicity.............................................

870.2400 Primary Eye Irritation...................................................

870.2500 Primary Dermal Irritation .............................................

870.2600 Dermal Sensitization ....................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)..............................................

870.3150 Oral Subchronic (nonrodent)........................................

870.3200 21-Day Dermal.............................................................

870.3250 90-Day Dermal.............................................................

870.3465 28-Day Inhalation.........................................................

yes

yes

no

yes

yes

yes

yes

-

yes

yes

870.3700a Developmental Toxicity (rodent) .................................

870.3700b Developmental Toxicity (nonrodent) ...........................

870.3800 Reproduction ................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent).............................................

870.4100b Chronic Toxicity (nonrodent).......................................

870.4200a Oncogenicity (rat).........................................................

870.4200b Carcinogenicity (mouse) ..............................................

870.4300 Chronic/Carcinogenicity (rat).......................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity Gene Mutation - bacterial.......................

870.5300 Mutagenicity Gene Mutation - mammalian..................

870.5xxx Mutagenicity Structural Chromosomal Aberrations.....

870.5xxx Mutagenicity Other Genotoxic Effects.........................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)..............................

870.6100b 90-Day Neurotoxicity (hen) .........................................

870.6200a Acute Neurotoxicity Screening Battery (rat)................

870.6200b 90 Day Neurotoxicity Screening Battery (rat)..............

870.6300 Developmental Neurotoxicity (rat)...............................

no

no

yes

yes

no

-

-

yes

yes

-

870.7485 General Metabolism .....................................................

870.7600 Dermal Penetration.......................................................

870.7600 Immunotoxicity ............................................................

yes

no 

yes

yes

yes 

no

Special Studies for Ocular Effects

Acute Oral (rat) ............................................................

Subchronic Oral (rat)....................................................

Six-month Oral (dog) ...................................................

no

no

no

-

-

-
Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

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A.2 Toxicity Profiles for Metofluthrin 

Table A.2.1 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 -

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Metofluthrin Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

870.3100 90-Day oral 

toxicity (Wistar 

rat)

46454109 (2003)

Acceptable/Guideline

0, 100, 300, 1000, or 

2500 ppm

M: 0, 6.8, 20.6, 70.4, or 

183.6 mg/kg/day

F: 0, 7.5, 21.6, 73.0, or 

185.6 mg/kg/day

NOAEL = 20.6/21.6 mg/kg/day

LOAEL = 70.4/73.0 mg/kg/day, based on 

increased absolute and relative liver weights in 

both sexes; increased serum total cholesterol 

and phospholipids levels in males, and 

increased incidences of enlarged livers, 

hepatocellular hypertrophy, and basophilia in 

males; and decreased body weight gain in 

females.

870.3100 6-Month oral 

toxicity (Sprague 

Dawley rat)

46406733 (2002)

Acceptable/Guideline

0, 100, 300, 1000, or 3000 

ppm

M: 0, 5.3, 16.0, 54.1, 

164.6 mg/kg/day

F: 0, 6.4, 19.0, 65.4, 

191.4 mg/kg/day

NOAEL = 16.0/19.0 mg/kg/day

LOAEL = 54.1/65.4 mg/kg/day, based on 

increased relative liver weights, serum 

phospholipids, and total cholesterol levels in 

males; increased incidences of dark, enlarged 

livers and hepatocellular hypertrophy in both 

sexes; and an increased incidence of slight 

focal hepatic necrosis in females. 

870.3100 90-Day oral 

toxicity (CD-1 

mouse)

46454108 (2004)

Acceptable/Guideline

0, 100, 1500, 2500, or 

3500 ppm

M: 0, 13.7, 209, 357, or 

487 mg/kg/day

F: 0, 17.2, 252, 439, or 

587 mg/kg/day

NOAEL = 357/439 mg/kg/day

LOAEL = 487/587 mg/kg/day, based on 

findings indicative of hepatotoxicity including 

increased absolute and relative liver weights in 

both sexes; increased serum total cholesterol, 

phospholipids, and triglycerides in females;

minimal degeneration/necrosis of the liver;

minimal to moderate hepatocellular 

hypertrophy in both sexes; and increased 

Kupffer cells in males.
Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Metofluthrin Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

870.3150 90-Day oral 

toxicity (Beagle 

dog)

46406734 (2002)

Acceptable/Guideline

0, 10, 30, or 100 

mg/kg/day

NOAEL = 30 mg/kg/day

LOAEL = 100 mg/kg/day, based on tremor, 

salivation, repetitive jerking movements and 

vomiting observed in both sexes

870.3200 21/28-Day 

dermal toxicity 

Not required

870.3250 90-Day dermal 

toxicity 

(Sprague-Dawley

rat)

46556101 (2004)

Acceptable/Guideline

0, 30, 100, 300, or 1000 

mg/kg/day

Systemic NOAEL = 300 mg/kg/day

Systemic LOAEL = 1000 mg/kg/day, based on 

mortality and clinical signs (tremor and 

salivation)

Dermal NOAEL = not determined

Dermal LOAEL = 30 mg/kg/day, based on 

hyperactivity and vocalization in the females 

during the daily exposure period only; not 

considered a systemic effect.

870.3465 90-Day 

inhalation 

toxicity (Sprague 

Dawley rat)

46406736 (2002)

Acceptable/Guideline

0, 10, 50, 100, or 200 

mg/m3

0, 0.01, 0.051, 0.099, or 

0.196 mg/L)

M: 4 hrs/day, 28 days

F: 4 hrs/day, 29 days

NOAEL = 0.099 mg/L

LOAEL = 0.196 mg/L, based on mortality and 

clinical signs including tremors, 

hypersensitivity, ataxic gait, tiptoe gait, lateral 

position, clonic convulsion, and hypothermia in 

both sexes. Clinical signs began on days 1-4 

and occurred consistently in the males and 

transiently in females thereafter.

870.3700a Prenatal 

developmental in 

(Sprague Dawley 

rat)

46454111 (2002)

Acceptable/Guideline

0, 5, 15, or 30 mg/kg/day 

from GD6 – GD19

Maternal NOAEL = 15 mg/kg/day

Maternal LOAEL = 30 based on increased 

incidence of tremor

Developmental NOAEL = 30 mg/kg/day

Developmental LOAEL = not observed

NonguidelinePrenatal 

developmental in 

(Sprague Dawley 

rat)

46454112 (2002)

Acceptable/Non-guideline

M: 0, 10 or 20 mg/kg/day 

beginning 2 weeks prior 

to mating through 

necropsy (57 days)

F: 0, 10, 20 or 40 

mg/kg/day beginning 2 

weeks prior to mating 

through GD7

Parental LOAEL = 40 mg/kg/day based on 

mortality and increased incidence of tremors 

and salivation in females (males not evaluated 

at this dose)

Parental NOAEL = 20 mg/kg/day (both sexes)

Reproductive NOAEL = 20/40 mg/kg/day

[M/F]

Reproductive LOAEL = not observed

Developmental NOAEL = 40 mg/kg/day

Developmental LOAEL = not observed
Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Metofluthrin Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

NonguidelinePrenatal 

developmental in 

(Sprague Dawley 

rat)

46454113 (2002)

Acceptable/Non-guideline

0, 5, 15 or 30 mg/kg/day 

from GD 6 through LD 20

Maternal NOAEL = 15 mg/kg/day

Maternal LOAEL = 30 based on increased 

incidence of tremors and salivation

Reproductive NOAEL = 30 mg/kg/day [M/F]

Reproductive LOAEL = not observed

Developmental NOAEL = 30 mg/kg/day

Developmental LOAEL = not observed

870.3700b Prenatal 

developmental in 

(New Zealand 

White rabbit)

46454114 (2002)

Acceptable/Guideline

0, 25, 125, or 250 

mg/kg/day from GD6 –

GD27

Maternal NOAEL = 25 mg/kg/day

Maternal LOAEL = 125 mg/kg/day, based on 

mortality (a non-pregnant female also showed 

convulsions prior to death).

Developmental NOAEL = 250 mg/kg/day

Developmental LOAEL = not observed

870.3800 Reproduction 

and fertility 

effects

(Sprague-Dawley 

rat)

48770701 (2005)

Acceptable/Guideline 

0, 50, 200, 1000 and 1800 

ppm

Premating P males 0, 3.5, 

14.6, 69.3, 126.4 

mg/kg/day; P females 0, 

3.9, 15.7, 76.8, 140.1 

mg/kg/day

Premating F1 males 0, 

4.4, 17.7, 88.7, 165.5 

mg/kg/day; F1 females 0, 

4.9, 19.5, 97.6, 183.6 

mg/kg/day

Parental NOAEL = 19.5 mg/kg/day (females)

Parental LOAEL = 97.6 mg/kg/day (females), 

based on increased incidences of tremors and 

salivation during lactation. 

Reproductive NOAEL ≥165.5/183.6

mg/kg/day [M/F]

Reproductive LOAEL = not observed

Offspring NOAEL = 97.6 mg/kg/day

Offspring LOAEL = 183.6 mg/kg/day, based 

on decreased lactation index (F1), tremors (F2, 

reduced pup weight (F1, F2) from lactation day 

10 to weaning (increased preputial separation, 

vaginal opening secondary to delayed growth). 

870.4100a Chronic toxicity

(rat)

See 870.4300

870.4100b Chronic toxicity 

(Beagle dog)

46454110 (2004)

Acceptable/Guideline

0, 10, 30, or 100 

mg/kg/day

NOAEL = 10 mg/kg/day

LOAEL = 30 mg/kg/day, based on increased 

incidence of tremor in males, salivation, 

vomiting, repetitive jerking movements.

870.4200 Carcinogenicity

(CD-1 mouse)

46611302 (2005)

Acceptable/Guideline

0, 100, 1000, or 

2500/1750 ppm

M: 0, 12, 116, or 209 

mg/kg/day

F: 0, 15, 155, or 277 

mg/kg/day

NOAEL = 116/155 mg/kg/day

LOAEL = 209/277 mg/kg/day, based on 

decreased body weight gain in both sexes.

There was no increased incidence of any tumor 

types in either sex at any dose.
Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Metofluthrin Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

870.4300 Chronic 

toxicity/Carcinog

enicity

(Wistar rat)

46611301 (2005)

Acceptable/Guideline

0, 20, 200, 900, or 1800 

ppm

M: 0, 0.8, 8.2, 38.1, or 

77.8 mg/kg/day

F: 0, 1.0, 10.1, 47.4, or 

96.1 mg/kg/day

NOAEL = 8.2/10.1 mg/kg/day

LOAEL – 38.1/47.4 mg/kg/day, based on 

decreased body weights and body weight gains 

in both sexes; increased incidence of hepatic 

clear cell foci in both sexes; increased fatty 

liver change, and kidney lesions (including 

interstitial fibrosis, lipofuscin, mononuclear 

foci, and glomerulosclerosis) in males; 

increased centrilobular hepatocellular 

hypertrophy in females

There was an increased incidence of adenoma, 

carcinomas, and combined tumor types in the 

livers of both male and female rats at or above 

900 ppm. However, mechanistic data were 

considered adequate to support a nonlinear 

mode of action (mitogenic stimulation 

secondary to p450 induction) for liver 

carcinogenicity. This chemical is classified as 

“not likely to be carcinogenic to humans at 

doses that do not result in a mitogenic 

response”.

870. 5100 Gene mutation -

Bacterial reverse 

gene mutation 

46406742 (2002)

Acceptable/Guideline

0, 156, 313, 625, 1250, 

2500, or 5000 g/plate +/-

S9 in S. typhimurium

TA98, TA100, TA1535 

and TA1537 and E. coli

WP2 uvrA

There was no evidence of induced mutant 

colonies over background levels.

870. 5100 Gene mutation -

Bacterial reverse 

gene mutation 

46454115 (2004)

Acceptable/Guideline

Trial 1 (-S9): 4.88, 9.77, 

19.5, 39.1, 78.1, or 156 

μg/plate strains TA100, 

TA1535

Trial 2 (+S9): 19.5, 39.1, 

78.1, 156, 313, or 625 

μg/plate strains TA100, 

TA1535, and TA1537 

Trial 3 (+/-S9): 156, 313, 

625, 1250, 2500, or 5000 

μg/plate strains TA98 and 

WP2uvrA

There was no evidence of induced mutant 

colonies over background levels.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Metofluthrin Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

870.5375 Cytogenetics - In 

vitro Mammalian 

Cytogenics 

(Chromosomal 

Aberration Assay 

in Chinese 

Hamster Lung 

Fibroblasts)

46406744 (2002)

Acceptable/Guideline

Trial 1 (-S9): 50, 70, 90, 

110, or 130 μg/mL 

Trial 1 (+S9): 50, 100, 

150, 200, or 250 μg/mL

Trial 2 (-S9) 20, 50, 80, or 

110 μg/mL Trial 2 (+S9): 

100, 150, 200, or 250 

μg/mL

There was no evidence of chromosome 

aberration induced over background in the 

presence or absence of S9-activation.

870.5395 Other Effects - In 

vivo Mammalian 

Cytogenetics –

Erythrocyte 

Micronucleus 

Assay in Mice

46406745 (2002)

Acceptable/Guideline

0, 12.5, 25, or 50 mg/kg

There was no significant increase in the 

frequency of micronucleated polychromatic 

erythrocytes in bone marrow compared to 

controls.

870.6200a Acute 

neurotoxicity 

screening battery 

(Sprague Dawley 

rat)

46406728 (2004)

Acceptable/Guideline

0, 20, 50, or 100 mg/kg

NOAEL = 50 mg/kg

LOAEL = 100 mg/kg, based on mortality

(within 24 hrs), adverse clinical signs, FOB 

(unusual behavior, limb twitches/tremors, and 

abnormal respiration) effects, and increased 

motor activity in both sexes. Clinical signs first 

reported at 2 hrs but not evident at 24 hrs.

870.6200b Subchronic 

neurotoxicity 

screening battery 

(Sprague Dawley 

rat)

46406729 (2004)

Acceptable/Guideline

0, 300, 1000, or 3000 ppm

M: 0, 18.3, 59.8, or 178.8 

mg/kg/day

F: 0, 20.9, 68.8, 206.0 

mg/kg/day

Systemic NOAEL = 59.8/68.8 mg/kg/day

Systemic LOAEL = 178.8/206.0 mg/kg/day, 

based on mortality (females only); clinical 

signs (soft/liquid feces and scant feces in the 

males and tremors and twitches in the females); 

decreased body weight, body weight gain, and 

absolute and relative food consumption in both 

sexes.

Neurotoxicity NOAEL = 59.8/68.8 mg/kg/day

Neurotoxicity LOAEL = 178.8/206.0 

mg/kg/day, based on the clinical signs of 

tremors and twitches in the females

870.6300 Developmental 

neurotoxicity Not required.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Metofluthrin Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

870.7485 Metabolism and 

pharmacokinetics

(Sprague Dawley 

rat)

46406746, 46406747, 

46406748, 46414002, and 

46414003 (2004)

Acceptable/Guideline

1 or 20 mg/kg for single 

dose studies

1 mg/kg for 21 day 

studies

Overall recoveries were 95-97% for both dose 

groups. Absorption was rapid (detectable 

plasma residues within 30 minutes, Tmax 3.3-8.0 

hours) and thorough (>80% absorption). 

Absorption was not dose limited. At 168 hours 

post dosing, urinary and fecal excretion 

accounted for 29-71% and 25-66% of the total 

administered dose, respectively. Radioactivity 

increased above plasma levels in both liver and 

kidney, but dissipated 12 hours post-dose. 46 

metabolites were identified, including all major 

metabolites.

870.7600 Dermal 

penetration 

(Sprague Dawley 

rat)

46406749 (2004)

Acceptable/Non-guideline

0.002 mg/5 L/cm2

At 6 hrs post dosing, 94.8% of the dose was 

recovered, 67.6% was recovered from the 

skin’s surface. At 24 hrs post dosing, 91.6% of 

the administered dose was recovered, 40.3% of 

the dose was recovered on the skin’s surface. 

The greatest concentration of absorbed dose 

was located in the skin at the application site. 

Dermal absorption was estimated to be 17.4%.

870.7800 Immunotoxicity Not available

Nonguideline

An evaluation of 

the human 

relevance of the 

metofluthrininduced liver 

tumors in rats 

based on mode of 

action

46756304 (2006)

Acceptable/Non-guideline

Summary of proposed MOA and weight of the 

evidence. The MOA for metofluthrin-induced 

liver tumors is postulated to involve liver 

cytochrome P450 enzyme induction leading to 

stimulation of increased cellular proliferation.

MOA accepted by CARC (second assessment).

Nonguideline

Study for the 

mode of action of 

S-1264 for liver 

tumor promotion 

in rats

(Wistar rats)

46581501 (2005)

Acceptable/Non-guideline

0, 900, 1800, or 3600 ppm 

in the diet for 7 days

Concurrent recovery 

group fed basal diet for 7 

days following treatment 

period

Liver morphology and enzyme induction were 

affected in at 900 ppm and above, as evidenced 

by increased liver weights, hepatocellular 

hypertrophy, replicative DNA synthesis in the 

hepatocytes, induction of CYP 2B and 3A 

mRNA, and increased expression of CYP 2B. 

All of these findings were reversible on 

cessation of treatment. 

NonguidelineThe 2nd study of 

mode of action of 

S-1264 for liver 

tumor promotion 

in Wistar rats

46756301 (2006)

Acceptable/Non-guideline

0, 200, 900, 1800, or 3600 

ppm in diet for 7 days

Metofluthrin inhibited gap junction interactions 

(as evidenced by decreased dye transfer) and 

induced oxidative stress (measured by lipid 

oxidation and GSH levels).
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Metofluthrin Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

NonguidelineStudy for mode 

of action of S1264 for liver 

tumor promotion 

in rats (in vitro

effects of S-1264 

on cytochrome 

P450 activity and 

mRNA levels)

46756302 (2006)

Acceptable/Non-guideline

Rat, mouse, and human 

hepatocytes were exposed 

to 50 M metofluthrin for 

3 days, and comparative 

metabolic profiles were 

examined.

Metofluthrin induced CYP 2B mRNA and 7-

pentoxyresorufin O-depentylase activity in rat 

and human hepatocytes, but not in mouse 

hepatocytes, but the induction level was less 

than that of phenobarbital induction in human 

hepatocytes.

Nonguideline

Gene expression 

profiling analysis 

of early phase 

treatment in the 

liver from S1264 treated 

Wistar rats

46756303 (2006)

Acceptable/Non-guideline

Wistar rats were exposed 

to 1800 ppm metofluthrin 

for 1 week. DNA 

microarray was used to 

evaluate gene expression.

The majority of genes upregulated by 

metofluthrin were GSTs, CYPs, and UDPGTs. 

In general, this resembled the upregulation of 

Phenobarbital, only to a lesser degree.

 Bridging Studies – Metofluthrin technical produced by new manufacturing process

870.3465 90-Day 

inhalation 

toxicity (Sprague 

Dawley rat)

48431213 (2006)

Acceptable/guideline

0, 10.50, 100 or 200 

mg/m

3

(0, 10.0, 49.6, 98.5 

and 189 mg/L) for 4 hour 

exposure periods per day, 

7 days/week for a total of 

4 weeks (28 days-male; 

29- days-female)

NOAEL = 0.099 mg/L

LOAEL = 0.189 mg/L based on mortality and 

clinical symptoms including tremors, tiptoe 

gait, lateral position, and clonic convulsions in 

both sexes.

870.5100 Gene mutation -

Bacterial reverse 

gene mutation

48431212 (2006)

Acceptable/guideline

0, 156, 313, 625, 1250, 

2500, and 5000 μg/plate 

(strains TA98, TA100, 

TA1535, and TA1537 and 

Escherichia coli strain 

WP2uvrA with and 

without S9 activation) in 

both the preliminary 

cytotoxicity and 

mutagenicity assays

There was no evidence of induced mutant 

colonies over background levels.
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A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) – All Populations

There are currently no food uses for metofluthrin. An aRfD was therefore not determined.

A.3.2 Chronic Reference Dose (cRfD)

There are currently no food uses for metofluthrin. A cRfD was therefore not determined.

A.3.3 Incidental Oral Exposure (Short-Term)

Study Selected: Developmental Rat Study (Oral)

MRID No.: 46454111

Executive Summary: See Appendix A, Guideline §870.3700

Dose and Endpoint for Risk Assessment: Maternal NOAEL = 15 mg/kg/day based on tremors 

seen at the maternal LOAEL = 30 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: This study was selected because it 

provided the most sensitive oral endpoint for an exposure of short-term duration. Tremors and 
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salivation, clinical signs typical of type I pyrethroids, were observed at the LOAEL of 30 

mg/kg/day. Selection of this NOAEL and endpoint is supported by two additional nonguideline 

rat developmental studies (maternal NOAELs of 15 and 20 mg/kg/day, based on mortality and 

tremors at 30 and 40 mg/kg/day). In general, the NOAELs for oral studies with metofluthrin 

range between 15-30 mg/kg/day in dogs, rats, and rabbits regardless of duration of exposure, 

consistent with the toxicokinetic profile of pyrethroids. Thus, selection of this study as the basis

for the point of departure would be protective for the effects seen throughout the database. A UF 

of 300 was utilized (10 each for UFH and UFA, plus a UFDB of 3 to account for pharmacokinetic 

differences between children in this age group and adults). 

A.3.4 Dermal Exposure (Short- and Intermediate-Term)

Study Selected: 90-Day Dermal Rat Study

MRID No.: 46406735

Executive Summary: See Appendix A, Guideline §870.3250

Dose and Endpoint for Risk Assessment: NOAEL = 300 mg/kg/day based on mortality (study 

Day 3), tremors and salivation at the LOAEL of 1000 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: 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. This study was selected because of the dermal route of exposure and because 

the onset of effects (mortality and clinical signs including tremors by Day 3) was appropriate for 

assessing both short- and intermediate-term dermal exposure. Since there were no 

developmental effects in the rat and rabbit developmental studies and the NOAEL for offspring 

toxicity in the rat reproduction study was higher than the NOAEL for the parental animals, 

selection of this study for the POD is appropriate for all lifestages. Vocalization and 

hyperactivity observed at the lowest dose of 30 mg/kg/day were considered to be linked to 

paresthesia rather than systemic effects because they were only observed during dosing on Days 

1-4. For adults and children ≥6 years of age, a UF of 100 was utilized (10 each for UFH and 

UFA). For children <6 years of age, a UF of 300 was utilized (10 each for UFH and UFA, plus a 

UFDB of 3 to account for pharmacokinetic differences between children in this age group and 

adults). 

A.3.5 Inhalation Exposure (Short- and Intermediate-Term) 

Study Selected: 28-Day Inhalation Rat Study

MRID No.: 46406736

Executive Summary: See Appendix A, Guideline [§ 870.3465] 

Dose and Endpoint for Risk Assessment: NOAEL = 0.099 mg/L based on mortality and 

clinical signs including tremors, hypersensitivity, abnormal gait, clonic convulsions and 
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hyperthermia seen at LOAEL = 0.196 mg/L. HEC (systemic effects) = 0.052 mg/L, residential 

exposure and 0.155 mg/L, occupational exposure. HED = 7.5 mg/kg/day, residential exposure 

and 7.4 mg/kg/day, occupational exposure.

Comments about Study/Endpoint/Uncertainty Factors: A 28-day inhalation toxicity study 

in the rat was selected for use in assessment of short- and intermediate-term inhalation 

exposures. This inhalation study was selected because it was of an appropriate route of exposure 

and duration for short or intermediate-term exposure. Essentially identical findings were also 

observed in a second 28-day inhalation study in the rat (MRID 48431212) that was conducted as 

a bridging study for metofluthrin (S-1264) produced by a new manufacturing process. The 

neurological clinical signs identified in the inhalation study were consistent with findings 

observed in the most sensitive oral and dermal studies. The 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 the developmental and reproduction studies did not identify effects that were not 

evaluated in the inhalation study. The selected inhalation study was conducted using aerosolized 

metofluthrin. Residential and occupational handler exposure to aerosolized metofluthrin is 

expected for the spray applications for the proposed bedbug product. However, exposure to 

metofluthrin as a vapor would be expected from paintbrush application and from post-application 

exposure to outdoor repellent products. Although toxicity could differ for vapor and aerosol 

exposure, it is anticipated that some vapor exposure would occur in an aerosol study: although 

there is some uncertainty in assessing exposure to metofluthrin as a vapor using the aerosol 

study, there is less uncertainty than there would be using route-to-route extrapolation from an 

oral study. For adults and children ≥6 years of age, a UF of 30X was utilized (10X for UFH and

3X for UFA , reduced from 10 based on the adjustment for PK in calculation of the HEC). For 

children <6 years of age, a UF of 100X (10X for UFH, 3X for UFA, plus a UFDB of 3X to account 

for uncertainties regarding sensitivities of the young to pyrethroids) was utilized. 

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity – Rat 

In a subchronic oral toxicity study (MRID 46454109), S-1264 (Metofluthrin; 94.9% 

a.i.; Lot # PK-010501 G) was administered to 12 Wistar rats/sex/dose in the diet at dose 

levels of 0, 100, 300, 1000, or 2500 ppm (equivalent to 0/0, 6.8/7.5, 20.6/21.6, 

70.4/73.0, and 183.6/185.6 mg/kg/day in males/females) for 13 weeks. 

No treatment-related effects were observed on mortality, clinical signs, neurological 

evaluation, food consumption, ophthalmoscopic examination, or hematology.

In the 1000 ppm females, cumulative body weight gains were often decreased (p 0.05) 

by 12-19% and overall (Days 1-91) body weight gains were decreased (not statistically 
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significant [NS]) by 13%. At 2500 ppm, minor decreases (p 0.05) were observed in 

body weight beginning at Day 22 in males ( 6-10%) and beginning at Day 64 in 

females ( 8-9%). Decreases (p 0.05) were also observed in cumulative body weight 

gain in males beginning at Day 57 ( 11-12%), and generally in the females beginning 

at Day 64 ( 13-14%). Overall (Days 1-91) body weight gain was decreased in the 

males ( 12%; 0.05) and females ( 13%, NS).

Slight hepatotoxicity was observed. At 1000 and 2500 ppm, serum total cholesterol 

and phospholipid levels were increased (p 0.05) in males by 21-38%. Increased 

(p 0.01) absolute and relative to body liver weights were observed in both sexes 

(excludes absolute weight in females) by 11-37%. Increased incidences of enlarged 

livers were observed (3-5/12) in males vs 0/12 in the controls and other groups. 

Hepatocellular hypertrophy (minimal to slight) and basophilia (minimal to moderate) 

were increased (p 0.001) in males (10-12/12 treated vs 0-1/12 controls). In the 2500 

ppm females, serum total cholesterol and phospholipid levels were increased (p 0.05) 

by 21-34%, and hepatocellular hypertrophy (minimal to slight) and basophilia 

(minimal) were also increased (4-5/12 treated vs 0/12 controls; p<=0.05). 

Nephrotoxicity was observed in males. Increased (p 0.01) numbers of leukocytes were 

noted at 1000 ( 167%) and 2500 ppm ( 354%). At 2500 ppm, relative to body kidney 

weights were slightly increased (p 0.01) by 13%. An increase in severity in hyaline 

droplets in the kidneys was observed. Moderate hyaline droplets were noted in 7/12 

treated animals vs 1/12 controls. The Sponsor stated that the increased incidence of 

hyaline droplets closely resembled the early stages of α2μ-globulin nephropathy, 

“which is generally accepted as a phenomenon found exclusively in male rats. 

Consequently, these findings in the kidney were considered of equivocal importance in 

humans. 

The LOAEL is 1000 ppm (equivalent to 70.4/73.0 mg/kg/day in males/females), based 

on increased absolute and relative to body liver weights in both sexes; increased serum 

total cholesterol and phospholipid levels in males, and increased incidences of enlarged 

livers, hepatocellular hypertrophy, and basophilia in males; and decreased body weight 

gain in females. The NOAEL is 300 ppm (equivalent to 20.6/21.6 mg/kg/day).

This study is classified as acceptable/guideline and satisfies the guideline requirements

(OPPTS 870.3100a; OECD 408) for a subchronic oral toxicity study in the rat.

870.3100 Subchronic Oral Toxicity – Rat (6 Months)

In a subchronic oral toxicity study (MRIDs 46406733 and 46406731), S-1264 

(Metofluthrin; 94.9% a.i.; Lot # PK-010501G) was administered to 12 Sprague Dawley 

rats/sex/dose in the diet at dose levels of 0, 100, 300, 1000, or 3000 ppm (equivalent to 

0/0, 5.3/6.4, 16.0/19.0, 54.1/65.4, or 164.6/191.4 mg/kg/day in males/females) for 6 

months. 
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No treatment-related, adverse effects were observed on mortality, body weights, body 

weight gains, food consumption, food efficiency, ophthalmology, hematology, or 

urinalysis.

In the 3000 ppm group, tremor was observed (p<=0.01) in all animals at Week 1. At 

Weeks 2 and 3, 0-2 rats/sex exhibited tremor, and tremor was observed in no animals 

after Week 3. 

Hepatotoxicity was observed. Increased (p<=0.01) relative to body liver weights were 

observed in the 1000 ppm males (incr 14%) and the 3000 ppm males (incr 25%) and 

females (incr 14%). Absolute liver weight was also increased (p<=0.01) in the 3000 

ppm males (incr 20%). An increased incidence (# affected/12) of dark, enlarged livers 

were observed at 1000 (2-5) and 3000 ppm (7-9) in both sexes vs 0/12 in the controls 

and other groups; and increases were significant (p<=0.05) in the 1000 ppm males 

(dark livers only) and the 3000 ppm group. Increased incidences (# affected/12 in 

treated vs controls) of the following slight to mild hepatic microscopic lesions were 

observed: (i) hepatocellular hypertrophy in both sexes at 1000 (4-9 vs 0; p<=0.05) and 

3000 ppm (10-12; p<=0.01); (ii) microvesicular steatosis in 3000 ppm males (9 vs 0; 

p<=0.01); and (iii) slight focal necrosis in >=1000 ppm females (2-3 vs 0; not 

statistically significant). A mild increase in smooth endoplasmic reticulum was 

observed by electron microscopy in both 3000 ppm male liver samples examined, and 

an increase in the number of lipid droplets was also noted. Additionally, increases 

(p<=0.01) were noted in the 1000 and 3000 ppm males in serum phospholipids (incr 

37-77%) and total cholesterol (incr 35-62%). 

The LOAEL is 1000 ppm (equivalent to 54.1/65.4 mg/kg/day in males/females), based 

on increased relative to body liver weight, serum phospholipids, and total cholesterol in 

males; increased incidences of dark, enlarged livers and hepatocellular hypertrophy in 

both sexes; and an increased incidence of slight focal hepatic necrosis in females. The 

NOAEL is 300 ppm (equivalent to 16.0/19.0 mg/kg/day).

This study is classified as acceptable/guideline and satisfies the guideline requirements 

(OPPTS 870.3100a; OECD 408) for a subchronic oral toxicity study in the rat.

870.3100 90-Day Oral Toxicity – Mouse

In a subchronic oral toxicity study (MRID 46454108), S-1264 (Metofluthrin, 94.9% 

a.i.; Lot #PK-010501 G) was administered to 12 CD-1 mice/sex/dose in the diet at dose 

levels of 1, 100, 1500, 2500 or 3500 ppm (equivalent to 0, 13.7/17.2, 209/252, 357/439 

or 487/587 mg/kg/day in males/females) for 13 weeks.

No treatment-related effects were observed on mortality, clinical signs, body weight, 

body weight gain, food consumption, hematology or gross pathology.

Mild hepatotoxicity was evident at 3500 ppm. In the females, serum total cholesterol 

and phospholipids were increased (p≤0.05; incr 46-53%), as well as triglycerides (not 
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statistically significant [NS]; incr 95%). Increased (p≤0.05) absolute and relative to 

body liver weights were observed in both sexes (incr 18-21%). Additionally, the 

following microscopic hepatic lesions were noted (# affected/12 in treated vs controls): 

minimal degeneration/necrosis in both sexes (3 each treated vs 0 controls; p≤0.01); 

minimal to moderate hepatocellular hypertrophy in both sexes (7-9 vs 0-1); and 

minimally increased Kupffer’s cells in the males (2 vs 0). The LOAEL is 3500 ppm 

(487/587 mg/kg/day), based on the findings indicative of hepatotoxicity 

summarized above. The NOAEL is 357/439 mg/kg/day.

This study is classified as acceptable/guideline and satisfies the guideline requirements 

(OPPTS 870.3100a; OECD 408) for a subchronic oral toxicity study in the mouse.

870.3150 90-Day Oral Toxicity – Dog

In a subchronic oral toxicity study (MRID 46406734), S-1264 (Metofluthrin; 94.9% 

a.i.; Lot No.: PK-010501G) was administered daily in gelatin capsules to 4 beagle 

dogs/sex/dose at doses of 0, 10, 30, or 100 mg/kg/day for 13 weeks. Additionally, 2 

dogs/sex were treated similarly at 0 and 100 mg/kg/day; after the treatment period, 

these animals were maintained untreated for an additional 42 days.

There were no adverse, treatment-related effects on mortality, body weight, body 

weight gain, food consumption, ophthalmology, hematology, clinical chemistry, 

urinalysis, or gross or histological pathology. 

In the 100 mg/kg/day males, tremor was sporadically observed 2-6 hours after dosing 

beginning on Day 25 in 5/6 animals on 1-7 days in the 90-day treatment period. In the 

100 mg/kg/day females, tremor was sporadically observed 2-10 hours after dosing 

beginning on Day 10 in 5/6 animals on 1-5 days (or 16 days for one animal) in the 90-

day treatment period. Tremor was also observed at 100 mg/kg/day during the detailed 

clinical observations. Mild repetitive symmetrical jerks or tremors of the head, limb, or 

body was noted in one male (#17) at Weeks 12 and 13 and in one female (#35) at 

Weeks 11 and 13 when the animals were in the cage and when they were on a table (vs 

0 in controls). Vomiting/vomitus was sporadically observed at 100 mg/kg/day (22 

[males] or 42 [females] animals days). Salivation was observed on 2 animal days in the 

100 mg/kg/day males. During the recovery period, one male and one female had 

vomitus in the cage on a single day. 

The LOAEL was 100 mg/kg/day, based on tremor and vomiting/vomitus observed in 

both sexes. The NOAEL is 30 mg/kg/day.

This study is classified acceptable/guideline and satisfies the guideline requirement 

(OPPTS 870.3150; OECD 409) for a 90-day oral toxicity study in dogs.

870.3200 90-Day Dermal Toxicity – Rat
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In a 90-day dermal toxicity study (MRIDs 46406735 and 46556101), S-1264 

(Metofluthrin; 96.6% a.i.; Lot #: PK-020301G) was applied (0.025-0.83 mL/kg) to the 

shaved intact skin of 12 Crj: CD (SD) rats/sex/dose at dose levels of 0, 30, 100, 300, or 

1000 mg/kg/day (limit dose) for 6 hours/day during a 90-day period. Dermal irritation 

was scored using the Draize method.

No treatment-related effects were observed in dermal effects, body weight, body weight 

gain, food consumption, ophthalmoscopy, hematology, clinical chemistry, organ 

weights, gross lesions, or microscopic pathology at any dose in either sex.

At 1000 mg/kg/day, two females were found dead on Day 3 of treatment (animal No. 

958 was found dead prior to dosing and animal No. 959 displayed tremor prior to 

dosing, salivation at 3-5 hours post-dosing, and was found dead at 5 hours post-dosing).

The systemic LOAEL is 1000 mg/kg/day (limit dose) based on mortality and clinical 

signs (tremor and salivation). The systemic NOAEL is 300 mg/kg/day.

Hyperactivity and vocalization were transiently observed in the >=30 mg/kg/day 

females and the >=100 mg/kg/day males during the daily application period on Days 1-

4; however, no treatment-related clinical signs were observed following the daily 

administration period at any dose in either sex. Although slight squamous cell 

hyperplasia of the treated skin was observed in the 1000 mg/kg/day females (5/10 

treated vs 0/12 controls), this finding was considered not to be adverse, as no dermal 

irritation (erythema or edema) was observed at any dose. Because clinical signs were 

observed at the lowest dose tested in the main study, two additional studies were 

provided to establish a dermal NOAEL. A dose-evaluation study (MRID 46556101; 

summarized and included as an Appendix to this DER) was performed to determine the 

dose at which no clinical signs were observed after a single dose. In this study, no 

hyperactivity or vocalizations were observed in female rats after a single exposure at 10 

or 30 mg/kg of S-1264. In a preliminary dose-finding study (Study No. S1090), 

hyperactivity and vocalizations were observed in female rats after a single exposure at 

30 mg/kg, but no clinical signs were observed at 10 mg/kg. Although no effects were 

seen in either study after a single dose of 10 mg/kg, this dose cannot be used as a 

NOAEL for a 90 day dermal study.

The dermal LOAEL is 30 mg/kg/day based on hyperactivity and vocalization in the 

females during the daily exposure period. The NOAEL was not observed.

This study is classified as acceptable/non-guideline and satisfies the guideline 

requirements (OPPTS 870.3250; OECD 411) for a 90-day dermal toxicity study in rats.

870.3465 28-Day Inhalation – Rat

In a subchronic inhalation toxicity study (MRID 46406736), Sprague-Dawley rats 

(10/sex/concentration) were exposed by nose-only inhalation to S-1264 (Metofluthrin) 

technical (94.9% a.i., Lot/Batch # PK-010501G) administered as a mist aerosol at 
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concentrations of 0, 10, 50, 100, or 200 mg/m3(equivalent to 0, 0.010, 0.051, 0.099, 

and 0.196 mg/L, respectively) for 4 hours/day, for 28 (males) or 29 (females) 

consecutive days.

There were no treatment-related effects on body weight, body weight gain, 

ophthalmology, hematology, clinical chemistry, urinalysis, organ weights, gross 

pathology, or histopathology.

At 200 mg/m3, 7/10 males and 3/10 females died. In the males in this group, 3 rats died 

on Day 4 and 1 rat/day died on Days 9, 19, 25, and 27. In the females at this 

concentration, 1 rat/day died on Days 3, 4, and 5. All other animals survived until 

scheduled sacrifice. Additionally at this concentration, tremor of the tail and tremor 

were observed in both sexes during exposure. After exposure, tremor, hypersensitivity, 

ataxic gait, tiptoe gait, lateral position, clonic convulsion, and hypothermia were 

observed. The day of onset for these clinical signs was Day 1 to Day 4, and they 

continued to be observed consistently in the males until Day 26 and less frequently in 

the females until Day 24. Food and water consumption were decreased ( 15-27%) in 

both sexes at 200 mg/m3on Day 3. However, because these decreases were transient 

and did not affect body weights, body weight gains, or urinalysis, they were not 

considered adverse.

The LOAEL is 200 mg/m3(equivalent to 0.196 mg/L) based on mortality and clinical 

signs indicating neurotoxicity in both sexes. The NOAEL is 100 mg/m3(equivalent to 

0.099 mg/L).

At the request of the Agency, this study was conducted for a duration of 28 days, 

instead of the 90 days required by Guideline OPPTS 870.3465. Aside from the 

different study duration, this study was conducted in accordance with Guideline OPPTS 

870.3465.

This 28-day study is classified as acceptable/guideline and satisfies the guideline 

requirement (OPPTS 870.3465; OECD 413) for a subchronic inhalation study in the rat.

A.4.2 Prenatal Developmental Toxicity

Guideline Prenatal Developmental Toxicity Study – Rat (1)

In a developmental toxicity study (MRID 46454111), S-1264 (Metofluthrin) technical 

(94.9-95.1% a.i.; Lot # PK-010501G) in corn oil was administered daily via oral gavage 

to 24 presumed pregnant Sprague-Dawley Crj:CD(SD) rats/group at a dose volume of 5 

mL/kg at dose levels of 0, 5, 15, or 30 mg/kg/day from gestation day (GD) 6 through 

19. All surviving dams were killed on GD 20; their fetuses were removed by cesarean 

section and examined.

There were no effects of treatment on maternal body weights, body weight gains, food 

consumption, or gross pathology. All dams survived until scheduled termination.
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At 30 mg/kg/day, tremor was observed in 5/24 dams for 1 to 3 days each during GD 

10-19. One dam (#308) exhibited tremor in the evening (from about 5 to 6 hours after 

dosing) on GD 12 and 14 and from about 2 to 3 hours after dosing on GD 18, with the 

tremor disappearing by the evening. Another dam (#317) exhibited tremor from 2-3 

hours after dosing on GD 10, with the tremor disappearing by the evening. On GD 19, 

three dams exhibited tremor (#313, 319, and 321); one dam exhibited tremor twice, 

about 2-3 hours after dosing and in the evening; and the other 2 dams exhibited it only 

in the evening. The tremor noted in the evening had ceased prior to dosing on the 

following day. There were no other clinical signs of toxicity.

The maternal LOAEL is 30 mg/kg/day based on incidences of tremor. The maternal 

NOAEL is 15 mg/kg/day.

There were no abortions, premature deliveries, complete litter resorptions, or dead 

fetuses, and there were no treatment-related effects on the numbers of litters, live 

fetuses, early resorptions, late resorptions, sex ratio, or post-implantation loss, 

indicating no effect of treatment on embryo-lethality. Furthermore, there were no 

treatment-related effects on fetal growth or development as indicated by fetal body 

weights, placental weights, and skeletal ossification. There were no treatment-related 

external, visceral, or skeletal malformations or variations.

The developmental LOAEL was not observed. The developmental NOAEL is 30 

mg/kg/day.

This study is classified acceptable/guideline (OPPTS 870.3700a) and satisfies the

guideline requirements for a developmental study in the rat.

Non-Guideline Prenatal Developmental Toxicity Study – Rat (2)

In a non-guideline developmental toxicity study (MRID 46454112), S-1264 

(Metofluthrin) technical (94.9-95.1% a.i.; Lot # PK-010501G) in corn oil was 

administered daily via oral gavage to 20 Sprague-Dawley Crj:CD(SD) rats/sex at a dose 

volume of 5 mL/kg. Male rats were administered dose levels of 0, 5, 10, or 20 

mg/kg/day from 2 weeks prior to mating and throughout the mating period until the day 

before necropsy (after 57 days of treatment). Female rats were administered dose 

levels of 0, 10, 20, and 40 mg/kg/day from 2 weeks prior to mating, throughout the 

mating period, and until gestation day (GD) 7. During the in-life period of the study, 

clinical signs, body weights, body weight gains, and food consumption were measured 

in both sexes. Additionally, estrous cycle length and periodicity were examined daily 

for the two weeks prior to mating. All surviving dams were killed on GD 20, subjected 

to gross necropsy, and their fetuses were removed by cesarean section and examined. 

After completion of the cesarean section in the females, males were euthanized, 

subjected to gross necropsy, and the testes and epididymides were weighed.
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There were no mortalities or clinical signs in the males, and there were no adverse 

effects of treatment on body weights, body weight gains, or food consumption in either 

sex. 

In the 40 mg/kg/day females, 5/20 rats were found dead in the morning; 2 died during 

the mating period (Days 20 or 22), and 3 dams died during gestation (GD 5 or 6). 

Among the 5 females that were found dead, pulmonary congestion was noted in 3 of 

these decedents. Of the 3 females that had pulmonary congestion, one also exhibited 

retention of foamy fluid in the bronchi, and another had scattered bleeding spots in the 

glandular stomach. There were no treatment-related macroscopic findings in the 

surviving females. Additionally at 40 mg/kg/day, tremor was observed in all of the 

females (20/20), beginning on Day 7 of administration and continuing throughout the 

treatment period (until GD 7). Tremor was usually noted in the post-dosing 

observations, 2-3 hours after dosing, although there were cases in which tremor was not 

observed until the evening observations. In all cases, tremor had disappeared prior to 

dosing on the following day. Additionally, salivation was noted in 3/20 females at this 

dose.

The maternal LOAEL is 40 mg/kg/day based on mortality and incidences of tremors 

and salivation in the females. The maternal NOAEL is 20 mg/kg/day for both sexes.

There were no effects of treatment on estrous cycle duration or periodicity, weights of 

the testes or epididymides, or on mating or fertility indices.

The reproductive LOAEL was not observed. The reproductive NOAEL is 20/40 

mg/kg/day in M/F.

There were no abortions, premature deliveries, complete litter resorptions, or dead 

fetuses, and there were no treatment-related effects on the numbers of corpora lutea, 

implantations, litters, live fetuses, early resorptions, late resorptions, or on the sex ratio, 

pre-implantation loss, or post-implantation loss. There were no treatment-related 

effects on fetal body weights, placental weights, or on skeletal ossification, indicating 

no effect on fetal growth or development. There were no treatment-related external, 

visceral, or skeletal malformations or variations.

The developmental LOAEL was not observed. The developmental NOAEL is 20/40 

mg/kg/day in M/F.

This study is classified as an acceptable/non-guideline developmental toxicity study in 

the rat.

Non-Guideline Prenatal Developmental Toxicity Study – Rat (3)

In a non-guideline developmental toxicity study (MRID 46454113), S-1264 

(Metofluthrin) technical (94.9-95.1% a.i.; Lot # PK-010501G) in corn oil was 

administered daily via oral gavage to 24 presumed pregnant Sprague-Dawley 
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Crj:CD(SD) rats/dose at 0, 5, 15, or 30 mg/kg at a dose volume of 5 mL/kg. The P 

dams were dosed from implantation on gestation day (GD) 6 through lactation day 

(LD) 20, the day prior to weaning. The F1 pups were examined for viability, body 

weight development, developmental landmarks, and early behavioral reflexes during 

lactation. On post-natal day (PND) 21, all surviving pups (except 2/sex/litter) were 

euthanized and examined grossly. One F1 pup/sex/litter was subjected to behavioral 

testing from PND 28-56 and sacrificed on PND 70. The remaining F1 pup/sex/litter 

was selected for reproductive performance; these animals were mated on PND 70, and 

the dams were subjected to a cesarean section on GD 14 to examine the uterine 

contents. 

There were no effects of treatment on maternal body weights, body weight gains, food 

consumption, or gross pathology in the P generation.

At 30 mg/kg/day, tremor was observed in a total of 20/24 dams during the treatment 

period (1-12 days each); 10 dams exhibited tremors during both gestation and lactation, 

while 5 dams each exhibited tremor only during gestation or lactation. Onset of tremor 

occurred approximately 2-3 hours after dosing and/or in the evening but had 

disappeared before dosing on the following day. There were no maternal mortalities 

during gestation. During lactation, one 30 mg/kg/day dam died on LD 3 following 

irregular respiration, decreased movement, prone position, and piloerection on LD 1 

and 2. Additionally at this dose, salivation was noted in another dam on LD 1. Several 

other clinical signs were noted but could not be attributed to treatment because the 

incidences of these findings in the treated groups were comparable to controls.

The maternal LOAEL is 30 mg/kg/day based on mortality and incidences of tremors 

and salivation in the P dams. The maternal NOAEL is 15 mg/kg/day.

There were no effects of treatment on the numbers of: P dams which delivered; P dams 

with live newborns; implantations; newborns; live newborns; stillbirths; F1 offspring 

deaths; cannibalism; or live newborns with external anomalies. Similarly, there were 

no treatment-related effects on gestation duration or on gestation, delivery, or birth 

indices in the P generation and no effects on mating or fertility indices in the F1

generation. 

The reproductive LOAEL was not observed. The reproductive NOAEL is 30 

mg/kg/day.

There were no treatment-related effects on viability, clinical signs, body weights, 

developmental landmarks, early behavioral reflexes, or gross pathology in the F1

offspring prior to weaning. There were no treatment-related effects on body weights, 

sensory reflexes, FOB parameters, learning ability, gross pathology, or sexual 

maturation in these animals after weaning.

The offspring LOAEL was not observed. The offspring NOAEL is 30 mg/kg/day.
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There were no treatment-related effects on the numbers of corpora lutea, implantations, 

litters, live embryos, early embryonic deaths, late embryonic deaths, pre-implantation 

loss, or post-implantation loss.

The developmental LOAEL was not observed. The developmental NOAEL is 30 

mg/kg/day.

This study is classified as an acceptable/non-guideline developmental toxicity study in 

the rat.

870.3700b Prenatal Developmental Toxicity Study – Rabbit

In a developmental toxicity study (MRID 46454114), S-1264 (Metofluthrin) technical 

(94.9-95.1% a.i.; Lot # PK-010501G) in corn oil was administered daily via oral gavage 

to 24 artificially inseminated New Zealand White Kbl:NZW SPF rabbits/group at a 

dose volume of 0.5 mL/kg at dose levels of 0, 25, 125, or 250 mg/kg/day from gestation 

day (GD) 6 through 27. All surviving does were killed on GD 28; their fetuses were 

removed by cesarean section and examined.

There were no effects of treatment on maternal body weights, body weight gains, food 

consumption, or gross pathology.

One non-pregnant female (#305) in the 125 mg/kg/day group exhibited sneezing and 

convulsions and died on GD 23. Furthermore, one 250 mg/kg/day doe (#421) was 

found dead prior to dosing on GD 14. Although no clinical signs of neurotoxicity were 

observed in this animal, its death is considered treatment-related because a 200 

mg/kg/day doe in the range-finding study (Study #D0172) was found dead, and clonic 

convulsions preceded its death. There were no other treatment-related mortalities or 

clinical signs.

The maternal LOAEL is 125 mg/kg/day based on mortality. The maternal NOAEL is 

25 mg/kg/day.

There were no treatment-related effects on the numbers of litters, fetuses (live or dead), 

resorptions (early, late, or complete litter) or on sex ratio or post-implantation loss. 

There were no treatment-related effects on fetal body weights or on skeletal 

ossification, indicating no effect on fetal growth or development. There were no 

treatment-related external, visceral, or skeletal malformations or variations.

The developmental LOAEL was not observed. The developmental NOAEL is 250 

mg/kg/day.

This study is classified acceptable/guideline (OPPTS 870.3700b) and satisfies the 

guideline requirements for a developmental study in the rabbit.

A.4.3 Reproductive Toxicity
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In a two generation reproductive toxicity study (MRID 48770701), S-1264 

(metofluthrin technical, 95.4% a.i., Lot No. PK-020301G) was administered 

continuously in the diet at concentrations of 0, 50, 200, 1000 or 1800 ppm to 30 

Crl:CD®(SD)IGS BR VAF Plus®rats/sex/dose, beginning at 10 weeks prior to mating. 

From control to high dose, respectively, average daily intakes for premating animals 

were 0, 3.5, 14.6, 69.3 or 126.4 mg/kg/day (P males); 0, 3.9, 15.7, 76.8 or 140.1 

mg/kg/day (P females); 0, 0, 4.4, 17.7, 88.7 or 165.5 mg/kg/day (F1 males); and 0, 4.9, 

19.5, 97.6 or 183.6 mg/kg/day (F1 females). Measurements of sperm parameters were 

included in the reproductive toxicity evaluation.

Parental toxicity: At 1000 ppm, tremors and twitches were observed in lactating 

females (in the P generation, 3-4 of 29 animals, total 8-10 occasions, LD 8 and later, 

ns; in the F1 generation, 13-14 of 26 animals, total 32-33 occasions, LD 4 and later, 

p<0.05). Increased absolute and relative liver weights (p<0.01) in premating P and F1 

males (16-18%) and F1 females (14%) were observed, along with an increased 

incidence of hepatocellular hypertrophy in P males (12/30) and F1 males (11/30), but 

no other microscopic changes. At 1800 ppm, P and F1 lactating females were affected 

at high incidence with tremors and/or twitches on numerous days (p<0.01), with the 

first recorded tremors seen on LD 6. In P females, decreased mean body weight (7-8% 

below controls, p<0.01) was observed from LD 7 to 17, with reduced weight gain 

between LD 0-14 (50% below controls, p<0.01). However, cumulative weight gain 

(LD 0-28) was not significantly reduced. Premating F1 males had significantly 

decreased mean body weight throughout, beginning from Day 1 (7 to 15% below 

controls, p<0.01 through Day 42 and generally p<0.05 through Day 99): the decrease 

was largely due to lower F1 postweaning weight, but gain was lower in the first two 

weeks (12%, p<0.01). Body weights of premating F1 females were lower than controls 

for all weekly measurements (11-15% below controls, p<0.01), due partly to the lower 

postweaning weights (15% below controls on premating Day 1) but cumulative weight 

gain in F1 premating females was also reduced (10%, p<0.01). During gestation and 

lactation, mean body weights in F1 females were also decreased by similar percentages 

at each weekly measurement (all p<0.01), but gains were not lower. There were no 

treatment-related effects on survival. The parental LOAEL is 1000 ppm (97.6 

mg/kg/day), based on tremors and twitches in lactating females. The parental 

toxicity NOAEL is 200 ppm (19.5 mg/kg/day). 

Reproductive toxicity: No reproductive toxicity was observed at the doses tested. The 

reproductive toxicity NOAEL is 1800 ppm (165.1 mg/kg/day, males and 183.6 

mg/kg/day, females). The reproductive toxicity LOAEL was not determined 

(>1800 ppm).

Offspring toxicity: At 1800 ppm in F1 pups, decreased pup weight after LD 10 (13% 

below controls at LD 28, p<0.01) and decreased lactation index (92.4%, vs. 98.4% 

controls) were observed. Survival indices calculated during lactation intervals for F1 

pups indicated that mortality at 1800 ppm was highest between LD 8-10 and 11-14. 

The cumulative mortality of 6.1% (p<0.01) between LD 8-14 was greater than controls 

and lower dose groups (0.6 to 1.5%). In F2 pups, tremors (9 pups from 5 litters) on LD 

24 and, in one pup, LD 25, were observed, along with decreased pup weight (12% 

below controls at LD 28, p<0.01). Based on the mid-to-late lactation onset of these 
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findings, affected pups may have been exposed to metofluthrin via direct consumption 

of treated diet, as well as via lactation. Significant increases in preputial 

separation/vaginal opening age (+4.1 day/+1.8 day) were related to delays in growth. 

The offspring LOAEL is 1800 ppm (183.6 mg/kg/day), based on decreased 

lactation index (F1 pups), tremors (F2 pups) and decreased pup weights (both 

generations). The offspring NOAEL is 1000 ppm (97.6 mg/kg/day).

This study is classified Acceptable/guideline and satisfies the guideline requirements 

for a two-generation reproductive toxicity study in the rat (OPPTS 870.3800).

A.4.4 Chronic Toxicity

870.4100b Chronic Toxicity – Dog

In a chronic toxicity study (MRID 46454110), S-1264 (Metofluthrin; 96.6% a.i.; Lot 

No.: PK-020301G) was administered to 4 beagle dogs/sex/dose in capsules for 52 

weeks at doses of 0, 10, 30, or 100 mg/kg/day. 

No treatment-related effects were observed on mortality, body weight, body weight 

gain, food consumption, ophthalmoscopic examination, hematology, clinical chemistry, 

urinalysis, organ weights, or gross or histological pathology.

At 30 mg/kg/day, tremor was observed beginning on Day 96 in all males: 46 days in 

Dog #10 and 1-5 days in each of the other males. Tremors in the head, limbs, and body 

were only observed in one female (only Day 289). Vomiting/vomitus was observed 

transiently in 3 males (#11 on 28 days and two other males on 2-6 days each) and in all 

females (2-8 days each). These changes were observed mainly at 2-6 hours after 

administration and disappeared by the time of observation on the next morning. 

Tremor was observed in the head, limbs, and body. In the controls, tremor was not 

observed, but vomiting/vomitus was observed in all males (1-5 days each), in female 

#23 (50 days) and female #22 (2 days). It is unclear why the incidence was so high in 

female #23. These signs were not observed during the detailed clinical observations 

(conducted weekly, 4 hours after administration), and an explanation was not provided.

At 100 mg/kg/day, tremor was observed in 7/8 dogs beginning as early as Day 1 during 

cage-side observations. These changes were observed mainly at 2-6 hours after 

administration and disappeared by the time of observation on the next morning. 

Tremor was observed in the head, limbs, and body. During the detailed clinical 

observations, the incidence of tremor inside the cage was the same as on the table. 

Repetitive symmetrical jerks in limbs or body were observed in both sexes (9-11 

occurrences in 2 treated dogs/sex vs 0 controls), as were body palindromic tremor (4-6 

occurrences in 2 treated dogs/sex vs 0 controls). In one female, a head tremor was 

observed once. During cage side observations, the incidence of vomiting/vomitus was 

increased at 100 mg/kg/day in males (62 treated vs 11 controls) and females (52 treated 

vs 2 controls, excluding the female control with an incidence of 51). 

The LOAEL is 30 mg/kg/day based on an increased incidence of tremor in males. The
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NOAEL is 10 mg/kg/day.

This study is classified as acceptable/guideline and satisfies the guideline requirement 

(OPPTS 870.4100b, OECD 452) for a chronic oral toxicity study in dogs.

A.4.5 Carcinogenicity

870.4300 Chronic/Carcinogenicity Study – Rat

In this combined chronic toxicity/carcinogenicity study (MRID 46611301), S-1264 

(Metofluthrin; 96.6% a.i.; Batch No.: PK-020301G) was administered in the diet to 

Wistar rats (70/sex/dose) at nominal concentrations of 0, 20, 200, 900, or 1800 ppm 

(equivalent to 0/0, 0.8/1.0, 8.2/10.1, 38.1/47.4, or 77.8/96.1 mg/kg/day in 

males/females) for up to 2 years. Twenty rats/sex/dose were sacrificed at Week 52, and 

the remaining animals were sacrificed at Week 104.

No adverse, treatment-related effect was observed on mortality, clinical signs, grip 

strength, locomotor activity, food consumption, ophthalmoscopic examination, or 

hematology, clinical chemistry or urinalysis parameters. 

At 900 and 1800 ppm, body weights were generally decreased by 3-12% beginning at 

Week 3 to 4 in the males. Body weights were decreased by 4-15% from Week 26 in 

the 1800 ppm females.

Body weight gains were decreased by 16-40% in females at Weeks 13-52 and in both 

sexes at Weeks 52-104. Overall (Weeks 1-104) body weight gains were decreased by 

10-21% in both sexes. 

Slight hepatotoxicity was evident along with neoplastic changes. Relative to body liver 

weights were increased in the >=900 ppm males and the 1800 ppm females at 1 year 

and in the females >= 900ppm and 1800 ppm males at 2 years. Increased incidences 

(% treated vs % controls; n=49-50) of the following hepatic lesions were observed at 2 

years at 900 and 1800 ppm: (i) minimal to marked clear cell foci in males (78-82% vs 

66%) and females (44-65% vs 33%); (ii) minimal to marked fatty change in the males 

(82-84% vs 72%); and (iii) minimal to marked centrilobular hepatocellular hypertrophy 

in females (18-24% vs 8%). Additionally, at 1800 ppm, increased incidences of the 

following liver lesions were observed: (i) nodules in both sexes; (ii) eosinophilic foci in 

males; (iii) mixed foci in the females; and (iv) centrilobular hepatocellular hypertrophy 

in males

Slight nephrotoxicity was evident at 900 and 1800 ppm. At 2 years, increased 

incidences (% treated vs % controls; n=49-50) in the following renal lesions were 

observed in males: (i) minimal to moderate interstitial fibrosis (40-48% vs 31%); (ii) 

minimal to moderate mononuclear foci (82-84% vs 71%); (iii) minimum to moderate 

glomerulosclerosis (58-66% vs 49%); and (iv) minimal lipofuscin in the males (16-24% 

vs 6%).
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Additional signs of nephrotoxicity were observed at 1800 ppm. In the females, relative 

to body kidney weights were increased at 1 and 2 years. At 1 year, increased 

incidences of renal tubular casts, tubular basophilia, and urothelial hyperplasia were 

observed in the females. At 2 years, increased incidences in the following renal lesions 

were observed: (i) tubular vacuolation in males; (ii) tubular casts in females; (iii) 

interstitial fibrosis in females; (iv) presence of cystic Bowman’s capsule in males; (v) 

pelvic mineralization in females; and (vi) lipofuscin in females.

The LOAEL is 900 ppm (equivalent to 38.1/47.4 mg/kg/day in males/females), based 

on decreased body weights and body weight gains in both sexes; increased incidence of 

hepatic clear cell foci in both sexes; increased fatty liver change, and kidney lesions 

(including interstitial fibrosis, lipofuscin, mononuclear foci, and glomerulosclerosis) in 

males; increased centrilobular hepatocellular hypertrophy in females. The NOAEL is 

200 ppm (equivalent to 8.2/10.1 mg/kg/day in males/females).

After 2 years, increased incidences in hepatic adenomas were observed in the >=900 

ppm males (10-12% treated vs 2% controls) and 1800 ppm females (14% treated vs 2% 

controls; p<=0.01). Increased incidences in hepatic carcinomas were noted in the 

>=900 ppm males (6-16% treated vs 0% controls; p<=0.01 at 1800 ppm) and 1800 ppm 

females (14% treated vs 0% controls). The Cochran-Armitage trend test was positive 

(p<=0.05) for both adenomas and carcinomas in both sexes. The increase in neoplasia 

corresponded to an increase in liver nodules grossly and eosinophilic, clear cell, and 

mixed foci microscopically.

This study is classified as acceptable/guideline and satisfies the guideline requirements 

(OPPTS 870.4300; OECD 453) for a combined chronic toxicity/carcinogenicity study 

in rats.

870.4200b Carcinogenicity (feeding) – Mouse

In this carcinogenicity study (MRID 46611302), S-1264 (Metofluthrin; 96.6% a.i.; 

Batch No.: PK-020301G) was administered in the diet to CD-1 mice (64/sex/dose) at 

nominal concentrations of 0, 100, 1000, or 2500/1750 ppm (equivalent to 0/0, 12/15, 

116/155, and 209/277 mg/kg/day in males/females) for up to 78 weeks. Mice in the 

high dose group were treated at 2500 ppm during the first week and at 1750 ppm 

thereafter due to mortality. Twelve mice/sex/dose were scheduled for sacrifice at Week 

52, and the remaining animals were scheduled for sacrifice at Week 78.

No adverse treatment-related effects were observed on clinical signs, food 

consumption, hematology, organ weights, or gross and microscopic pathology findings.

On Day 2, 12 males (4 of which were from the interim sacrifice group) and 4 females 

treated at 2500 ppm were found dead. After consultation with the EPA, the high dose 

was reduced to 1750 ppm after the first week. However, no further mortality was 

observed in the subsequent 5 days that the animals remained on the 2500 ppm diet. 
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Furthermore, there was no effect on mortality at doses up to 3500 ppm in the 

subchronic oral toxicity study in mice (MRID 46454108). In the subchronic study, one 

control male was sacrificed on Day 76 due to rolling spasms; one female each at 1500, 

2500, and 3500 ppm died shortly after blood withdrawal on Day 92. 

Even after the high dose was lowered, a marginal effect was observed on body weight 

gain in the 1750 ppm males. In the terminal sacrifice group, cumulative body weight 

gain (%) was decreased (p<=0.05) frequently throughout treatment (decr 14-67%). 

After 52 and 78 weeks, cumulative body weight gain was decreased by 13-14% (not 

statistically significant). Body weight gain decreases in females at 1000 and 1750 ppm 

transiently reached statistical significance. Overall body weight gain was decreased in 

the high dose females by 10%.

No treatment-related effect was observed on food consumption. Thus, marginal 

decreases in body weight gain in the 1750 ppm males without a concurrent effect on 

food consumption suggests that there may also be an impairment in food efficiency.

The LOAEL is 1750 ppm (equivalent to 209/277 mg/kg/day in males/females), based 

on decreased body weight gain in both sexes. The NOAEL is 1000 ppm (equivalent to 

116/155 mg/kg/day).

At the doses tested, there was not a treatment related increase in tumor incidence when 

compared to controls. Dosing was considered adequate based on decreased body 

weight gain.

This study is classified as acceptable/guideline and satisfies the guideline requirements 

(OPPTS 870.4200b; OECD 451) for a carcinogenicity study in mice.

A.4.6 Mutagenicity

Gene Mutation

870.5100, Bacterial Reverse Gene 

Mutation

MRID 46406742

Acceptable/Guideline

There was no evidence of induced mutant colonies over background levels up 

to the limit dose of 5000 g/plate in the presence or absence of S9 activation.

870.5100, In Vitro Bacterial Gene 

Mutation

MRID 46454115

Acceptable/Guideline

There was no evidence of induced mutant colonies over background.

Cytogenetics

870.5375, In Vitro Mammalian 

Cytogenetics (Chromosomal Aberration 

Assay)

MRID 46406744

Acceptable/Guideline

There was no evidence of chromosomal aberration induced over background 

in the presence or absence of S9 activation.

Other Genotoxicity
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870.5395, In Vivo Mammalian 

Cytogenetics – Erythrocyte 

Micronucleus Assay in Mice

MRID 46406745

Acceptable/Guideline

There was no significant increase in the frequency of micronucleated 

polychromatic erythrocytes in bone marrow compared to controls up to the 

highest dose tested (50 mg/kg).

A.4.7 Neurotoxicity

870.6200 Acute Neurotoxicity Screening Battery

In an acute oral neurotoxicity study (MRID 46406728), S-1264 (Metofluthrin; 96.6% 

a.i., Lot #: PK-020301G) in corn oil was administered in a single dose by gavage (5 

mL/kg) to non-fasted Sprague-Dawley rats (10/sex/dose) at doses of 0, 20, 50, or 100 

mg/kg. All animals were observed for up to 14 days post-dosing. Functional 

observational battery (FOB) and motor activity were evaluated pretreatment and on 

Days 2 (at the estimated time of peak effect, 2 hours post-dosing), 9, and 16. At 

termination, 5 rats/sex/group were perfused in situ for neurohistological examination. 

Positive control data were provided.

No compound-related effects on body weight, body weight gain, absolute or relative 

food consumption, or gross and neuropathology parameters were observed in either sex.

At 100 mg/kg, the following clinical signs (# affected/10 vs 0 controls) were observed 

on Day 2: (i) intermittent or continuous whole body tremors (8 males); (ii) intermittent 

and/or continuous whole body or limb tremors (8 females); (iii) intermittent whole 

body twitches (7 males and 4 females); and (iv) tachypnea (6 males). Additional 

clinical signs observed in the two males and five females found dead or sacrificed in 

extremis within 24 hours post-dosing included clonic convulsions, hyperpnea, 

prostration, lost righting reflex, soft or liquid feces, tonic extensor convulsions, 

salivation, chromorhinorrhea, and chromodacryorrhea. All tissues in these animals 

appeared normal at necropsy. The cause of death was not reported. Also at this dose, 

increased (p<=0.01) incidence (# affected/10 vs 0 controls) of the following FOB 

effects were noted at 2 hours post-dosing in the males: (i) unusual behavior in the home 

cage (5); (ii) limb twitches/tremor in the home cage (5); (iii) limb twitches/tremor in the 

open-field (5); and (iv) abnormal respiration (6). In both sexes at this dose, increases 

(p<=0.05) were observed in total session number of movements (incr 121-162%) and 

time spent in movement (incr 131-231%) on Day 2. Total session number of 

movements and time spent in movement were similar to controls at all doses in both 

sexes on Days 9 and 16. On Day 2, interval activity was also increased in the these 

animals compared to controls. In the males, the number of movements were increased 

(p<=0.05) by 359-2088% at Blocks 5-11, 13, and 15-18, and the time spent in 

movement was increased (p<=0.05) by 638-9283% at Blocks 5-11 and 18. In the 

females, the number of movements were increased (p<=0.05) by 185-795% at Blocks 

6-18, and the time spent in movement was increased (p<=0.05) by 72-1384% at Blocks 

3-18. Additionally, habituation was affected at 100 mg/kg in both sexes on Day 2. 

No treatment-related effects were observed at 20 or 50 mg/kg in either sex.
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The LOAEL is 100 mg/kg based on mortality, adverse clinical signs, FOB effects, and 

increased motor activity in both sexes. The NOAEL is 50 mg/kg.

Evidence of neurotoxicity was observed (clinical signs [twitches and tremors, and 

convulsions], FOB effects, and increased motor activity).

The submitted study is classified as acceptable/guideline and satisfies the guideline 

requirements (OPPTS 870.6200a; OECD 424) for an acute neurotoxicity screening 

battery in rats.

870.6200 Subchronic Neurotoxicity Screening Battery

In a subchronic neurotoxicity study (MRID 46406729), S-1264 (metofluthrin; 96.6% 

a.i., Batch #: PK-020301G) was administered in the diet to 12 CD rats/sex/group at 

doses of 0, 300, 1000, or 3000 ppm (equivalent to 0/0,18.3/20.9, 59.8/68.8, and 

178.8/206.0 mg/kg/day [M/F], respectively) for 13 weeks. All animals were subjected 

to a complete FOB and motor activity assessment during pretreatment and at Weeks 1 

(at least 24 hours after initiation of dosing), 4, 8, and 13. At termination, 6 

rats/sex/group were perfused in situ, and tissues from the control and 3000 ppm groups 

were examined microscopically. Positive control data were provided.

No compound-related effects on FOB, motor activity, absolute or relative brain weight, 

gross necropsy, or neuropathology parameters were observed.

At 3000 ppm, one female was found dead on Day 11, and displayed the following 

clinical signs from Days 7-11: red perioral substance, dehydration, chromorhinorrhea, 

cold to the touch, lacrimation, clear perinasal substance, pale extremities, ungroomed 

coat, tremors, chromodacryorrhea, twitches, and extreme excess salivation. Based on 

these clinical signs, this death was considered to be treatment-related. Additional 

treatment-related signs observed at this dose in the males included: soft or liquid feces 

and scant feces. Additionally at 3000 ppm, body weights were decreased (p<=0.05) by 

5-8% each in the males on Days 9 and 79-93, and in the females throughout the study. 

Body weight gains were also decreased (p<=0.05) in both sexes by 37-63% during 

Days 2-9 and by 15-26% overall (Days 2-93). Absolute food consumption was also 

sporadically decreased (p<=0.05) throughout the study in the males (decr 6-11%) and 

females (decr 8-18%), and overall (Days 2-93) absolute food consumption was 

decreased (p 0.05) by 6-8% in both sexes. Also at this dose, relative food consumption 

was decreased (p<=0.05) by 6-14% in both sexes during the first week of treatment 

(Days 2-9). These decreases in food consumption corresponded with the decreases 

noted in body weights and overall body weight gains in both sexes.

No treatment-related effects were observed at <=1000 ppm in either sex. 

There were no findings in either the FOB or locomotor activity tests which were 

considered treatment related. No evidence of neurohistopathology was reported.
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Tremors (4 females) and twitches (3 females) were observed in 3000 ppm rats versus 

none in controls.

The systemic LOAEL is 3000 ppm (equivalent to 178.8/206.0 mg/kg/day [M/F]) based 

on mortality (females only), clinical signs (soft/liquid feces and scant feces in the males 

and tremors and twitches in the females), decreased body weight, body weight gain, 

and absolute and relative food consumption. The systemic NOAEL is 1000 ppm 

(equivalent to 59.8/68.8 mg/kg/day [M/F]).

The neurotoxicity LOAEL is 3000 ppm (equivalent to 178.8/206.0 mg/kg/day [M/F]) 

based on clinical signs (tremors and twitches) in the females. The neurotoxicity 

NOAEL is 1000 ppm (equivalent to 59.8/68.8 mg/kg/day [M/F]).

The study is classified as acceptable/guideline and satisfies the guideline requirement 

(870.6200b) for a subchronic neurotoxicity study in the rat.

A.4.8 Metabolism

870.7485 Metabolism - Rat

In a series of metabolism studies (MRIDs 46406746, 46406747, 46406748, 46414002, 

and 46414003), [Carbonyl14C]-S-1264 R-trans-Z (Lot # RIS2000-019; radiochemical 

purity 98.4-99.7%), [Carbonyl14C]-S-1264 R-trans-E (Lot # RIS2000-020; 

radiochemical purity 98.1-99.4%), or [Methoxymethylbenzyl-α14C]-S-1264 R-trans-Z 

(Lot # RIS2001-003; radiochemical purity 98.6-99.6%) in corn oil was administered to 

Sprague-Dawley (Crj:CD[SD]IGS) rats as a single gavage dose at 1 or 20 mg/kg 

nominal in a mass balance study (four rats/sex/dose), a pharmacokinetics study (three 

rats/sex/dose), and a tissue distribution study (15 rats/sex/dose). In a biliary excretion 

study (four rats/sex/dose), [Carbonyl14C]-S-1264 RTZ or RTE was administered as a 

single gavage dose at 1 mg/kg nominal. Additionally, [Carbonyl14C]-S-1264 RTZ or 

[Methoxymethylbenzyl-α14C]-S-1264 RTZ was administered at 1 mg/kg nominal for 

21 consecutive days in a mass balance study (3 males) and a tissue distribution study 

(12 males). The distribution of radioactivity between the tissues and excreta were 

determined, and metabolites were identified in the urine, feces, and bile from the mass 

balance and biliary excretion studies, and in the plasma, liver, kidney, and hair in the 

tissue distribution studies.

Overall recoveries of the radioactive dose from all groups were 95-97% in the single 

dose and multiple dose mass-balance studies. Absorption was rapid, as radioactivity 

was detected in the plasma at 30 minutes post-dosing (first time point tested), with Tmax

of 3.3-8.0 h. Absorption was calculated to be 83-84% of the administered dose for 

[Carbonyl14C]-S-1264 RTZ, and 78-79% of the administered dose for [Carbonyl14C]-

S-1264 RTE, based on radioactivity in the urine and bile. Absorption also did not 

appear to be dose limited based on the proportional increase in AUC values from the 

low to high dose groups. The half-life of radioactivity in plasma was 50-163 h without 
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a clear relationship with sex, test compound, or dose. By 168 h post-dosing, total 

urinary excretion accounted for 29-71% of the administered dose and fecal excretion 

accounted for 25-66%. The levels of radioactivity in the urine were similar to that in 

the feces in the [Carbonyl14C]-S-1264-treated groups, but were slightly higher in the 

urine of the [Methoxymethylbenzyl-α14C]-S-1264-treated groups. Radioactivity found 

in the expired air and carcass was <=1.4% of the administered dose. The excretion 

profile was not affected by increasing dose level or number, nor was it related to sex 

(with the possible exception that [Carbonyl14C]-S-1264-treated females excreted 

slightly more radioactivity in the bile). Concentrations of radioactivity in each tissue 

decreased with time, and only 0.2% of the administered dose remained in the blood and 

tissues by 168 h post-dosing. Analysis of the tissues sampled during the multiple dose 

study indicated that bioaccumulation did not occur. 

The observed maximum tissue radioactivity levels occurred at 6 h. There was some 

association of radioactivity with the red blood cells, but the majority of the circulating 

radioactivity was associated with the plasma up to 12 h post-dosing at both dose levels. 

With the exception of the GI tract, the concentration of radioactivity was highest in the 

liver in both sexes at all time points. Kidney concentrations were also above plasma 

levels at all time points. Hair was found to have radioactivity levels above plasma at 

several time points, but the reviewers considered this to be due to urine contamination, 

and not toxicologically relevant. In other sampled tissues (excluding the GI tract), the 

concentrations of radioactivity were generally below the concentrations in plasma 

throughout the time course.

TLC analyses of excreta identified parent and a total of 46 metabolites accounting for 

72-92% of the administered dose in all groups. All metabolites accounting for at least 

5% of the administered dose were identified, except for one fecal (FUK1) and two bile 

(BUK1 and BUK2) fractions, which were isolated at 3-9% of the administered dose in 

at least one group and matrix. The Sponsor stated that FUK1 and BUK2 were 

considered to be mixtures of several polar metabolites, based on migration during TLC. 

Further efforts to characterize BUK1 were not carried out; however, BUK1 was not 

found in the feces of rats that had not been bile duct-cannulated. Parent was isolated in 

the feces from the bile duct-cannulated rats (16-52% of the administered dose) and the 

other treated groups (10-29%), but not in the urine or bile.

The primary urinary metabolites were X1 and X2, accounting for 14-35% of the 

administered dose in the [Methoxymethylbenzyl-α14C] S-1264-treated groups. The 

primary fecal metabolite was Ac16, accounting for 11-14% of the administered dose in 

the [Carbonyl14C] S-1264 RTE-treated groups. The metabolite profiles in plasma and 

liver were generally similar to those listed earlier, while the metabolite profile for 

kidney was generally the same as urine. Liver exhibited the highest total concentration 

of metabolites; however, the concentration of metabolites in all tissues was low. The 

profiles did not change with time, and tissue-specific metabolites were rarely observed.

Based on the results of identification of metabolites, the following major metabolic 

reactions were proposed: 1) cleavage of ester linkage; 2) oxidation of the methyl group 
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at the end of the acid moiety to yield alcohol, aldehyde, and carboxylic acid moieties; 

3) oxidation of the methyl group at the 2-position of the acid moiety to yield alcohol 

and carboxylic acid moieties; 4) epoxidation of the double bond of the acid moiety; 5) 

reduction of the double bond of the acid moiety; 6) hydroxylation of the epoxide 

formed in 4) to yield a diol; 7) glutathione conjugation of the epoxide formed from 4); 

8) formation of a mercapturic acid conjugate from the glutathione conjugate formed 

from 7) via cysteine conjugation; 9) formation of a lactone ring from the carboxylic 

acid formed from 1) and the alcohol formed from 3); 10) formation of an (E)-

carboxylic acid derivative formed by the isomerization of the aldehyde formed from 2); 

11) glucuronidation of the carboxylic acid formed from 1); 12) demethylation of the 

methyl group of the alcohol moiety; 13) formation of a mercapturic acid conjugate of 

benzyl alcohol formed from 12) via glutathione conjugation; 14) formation of a 

methylsulfinyl or methylsulfonyl compound via thiol from cleavage of the conjugate 

formed from 13); 15) formation of a methyl sulfinyl compound via an additive reaction 

of glutathione to the double bond; 16) cleavage by oxidation of the double bond; 17) 

cleavage of the cyclopropane ring; 18) hydration of the double bond; and 19) 

glucuronidation of the benzyl alcohol formed from 12). Observed reactions differed 

slightly, depending on stereoisomer and position of the radiocarbon label.

This metabolism study in the rat is classified acceptable/guideline and satisfies the 

guideline requirement for a Tier 1 metabolism study [OPPTS 870.7485, OPP 85-1] in 

rats.

870.7600 Dermal Absorption - Rat

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

Not available

A.4.10 Special/Other Studies 

Mechanistic Studies for Liver Tumor Formation

In a concurrently submitted two year chronic toxicity/carcinogenicity study in rats 

(MRID 46611301), dietary administration of S-1264 was observed to significantly 

increase the incidence of hepatocellular adenomas and/or carcinomas. However, a 

concurrently submitted 18-month mouse oncogenicity study (MRID 46611302) gave 

no indication of carcinogenic potential. Additionally, short term tests for genotoxic 

potential demonstrated that the test compound was not a genotoxic agent, suggesting 

that the mode of action of S-1264 for inducing liver tumors in rats was non-genotoxic. 

Therefore, the purpose of the present study was to investigate the mode of action of S1264 in the induction of hepatocellular adenomas and/or carcinomas in rats.

In a non-guideline study (MRID 46581501), five to seven 

BrlHan:WIST@Jcl(GALAS) rats/sex/dose were exposed to S-1264 (Metofluthrin; 
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96.6% a.i.; Lot #: PK-020301G) in the diet at concentrations of 0, 200, 900, 1800, or 

3600 ppm (equivalent to 0/0, 12.7/13.2, 63.5/57.6, 121.1/95.7, and 220.8/149.3 

mg/kg/day [M/F]) for up to seven days. In order to determine reversibility of 

treatment, five rats/sex/dose were exposed to S-1264 in the diet at concentrations of 0, 

1800, or 3600 ppm (equivalent to 0/0, 123.3/145.7, and 255.7/280.9 mg/kg/day [M/F]) 

for seven days, and then fed basal diet during a seven day recovery period. 

Additionally, treatment and recovery groups of five rats/sex were exposed to 

phenobarbital sodium (NaPB) in the diet at a concentration of 1000 ppm (equivalent to 

63.9/66.9 mg/kg/day [M/F] treatment; 67.3/78.0 mg/kg/day [M/F] recovery) as a 

positive control. On the day prior to scheduled termination, minipumps containing 5-

bromo-2'-deoxyuridine (BrdU) were subcutaneously implanted in all animals for 

determination of hepatocellular proliferation by BrdU incorportion into nuclear DNA. 

The animals were fasted and killed, and the liver was removed and weighed. Hepatic 

microsomes were prepared, and total hepatic microsomal P-450 levels and specific 

hepatic microsomal P-450 isoenzyme and mRNA levels were quantitated.

Systemic toxicity: At 3600 ppm, two treatment group females (one each on Day 4 and 

6), and one recovery group male (Day 7 of treatment) were found dead. Additionally 

at this dose, tremor was observed in both sexes generally on treatment Days 2-7. The 

1800 ppm treatment group females displayed decreased body weights and body weight 

gains on Day 4, resulting in decreased overall (Days 1-8) body weight gains. In the 

recovery group, body weight gains were decreased in the 1800 ppm males, and in the 

3600 ppm males and females on treatment Days 1-4. Food consumption was 

decreased in the 3600 ppm treatment group males and in the 900 ppm and above 

treatment group females on Day 4, but was similar to controls on Day 8 in both sexes. 

In the recovery group animals, food consumption in all treatment groups was similar 

to controls.

In the NaPB-treated rats, no deaths or clinical signs of toxicity were observed. Body 

weight gains were increased on Days 1-4 in the treatment group males. In the 

recovery group, body weight gains were decreased during the recovery period in both 

sexes; total body weight gains also were decreased in the males. Food consumption in 

all groups was similar to controls.

Liver effects: In the S-1264 treatment group, relative (to body) liver weights were 

increased in the 1800 ppm males and at 1800 ppm and above in the females. Dark 

liver and enlarged liver were observed at 1800 ppm and above in the males; in the 

females, enlarged liver was noted at 1800 ppm and above, and dark liver was observed 

at 3600 ppm. Slight to moderate decreased vacuolation of the hepatocytes was noted 

in both sexes at 3600 ppm. Slight centrilobular hepatocyte hypertrophy was observed 

at 1800 ppm and above in both sexes. Dilatation/proliferation of the smooth 

endoplasmic reticulum of the hepatocytes was reported in the livers at 3600 ppm; this 

finding was slight in the males and mild in the females. Additionally, it was stated 

that peroxisome proliferation was not observed in any group during this study. BrdU 

labeling indices were increased in the males at 900 and 1800 ppm compared to 

controls. No treatment-related changes were observed on hepatic microsomal protein 
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concentration or total microsomal P-450 levels. Relative levels of microsomal CYP 

2B were increased in both sexes at 3600 ppm. No treatment-related effects were 

observed on CYP 3A levels in any group. Relative levels of CYP 2B1/2 mRNA were 

increased in the 1800 ppm and above males and 900 ppm and above females compared 

to controls. Relative levels of CYP 3A1 mRNA were increased in the 3600 ppm 

males and 1800 ppm and above females compared to controls.

In the NaPB-treated rats, increased absolute and relative liver weights, dark liver and 

enlarged liver, mild to moderate centrilobular hepatocyte hypertrophy, and moderate 

dilatation/proliferation of the smooth endoplasmic reticulum of the hepatocytes were 

noted in both sexes. BrdU labeling indices were increased in both sexes compared to 

controls. Increased hepatic microsomal protein concentration was observed in the 

treatment group males. Total P-450, relative levels of CYP 2B protein, and relative 

levels of CYP 2B1/2, CYP 3A1 and CYP 3A2 mRNA were increased in both sexes 

compared to controls.

In animals allowed a seven-day recovery period, the above findings generally were 

reduced in incidence and/or severity, or were not observed, indicating the effects of 

both S-1264 and NaPB were reversible.

In summary, S-1264 affected liver morphology and/or enzyme induction at 900 ppm 

and above, as evidenced by increased liver weights, hepatocellular hypertrophy, 

replicative DNA synthesis in the hepatocytes, induction of CYP 2B and 3A mRNA, 

and increased expression of CYP 2B. All of these effects were reversible on cessation 

of treatment. The dose response relationships for these findings were consistent with 

an appearance of liver tumors observed in the two year chronic 

toxicity/carcinogenicity study in rats (MRID 46611301). The reviewers agree with the 

Sponsor that this study suggests that the mode of action of S-1264 on the induction of 

liver tumors is the promotion of spontaneously initiated preneoplastic hepatocytes 

through liver enzyme induction and subsequent cell proliferation. This is the same 

mode of action as phenobarbital, which reversibly induces hepatic CYP 2B1 in the rat, 

and induces tumors in rats, but not humans. Phenobarbital and similar acting 

chemicals exhibit clear dose-thresholds for tumor formation in the rat by nongenotoxic modes of action which are unlikely to occur in humans.

The submitted study is classified as acceptable/non-guideline.

Bridging Studies (Metofluthrin New Manufacturing Process)

870.3645 28-Day Inhalation 

In a subchronic inhalation toxicity study (MRID 48431212) Metofluthrin (96.2% a.i., Lot 

#5CMI222G) was administered to 10 SD strain rats/sex/concentration by dynamic noseonly exposure at nominal concentrations of 0, 10.50, 100 or 200 mg/m

3

for 4 hour 

exposure periods per day, 7 days/week for a total of 4 weeks (28 days-male; 29- daysfemale). The analytical concentrations were: 0, 10.0, 49.6, 98.5 and 189 mg/L.
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Four males and 4 females in the 200 mg/L group died during the study. Males and 

females in the 200 mg/L group also showed neurological signs of toxicity: tremor of the 

tail and general tremors during exposure. Tremor, tiptoe gait, lateral position or clonic 

convulsion was observed from first day to tenth day of exposure with relatively higher 

incidence. These clinical signs continued to be seen until Day 26 of exposure in males 

and Day 18 in females, although their incidence decreased with continued exposure.

The LOAEL is 200 mg/L/day, based on increased mortality and neurological signs

of toxicity (tremor, tiptoe gait, lateral position or clonic convulsions) in males and 

females. The NOAEL is 100 mg/L/day.

[Although exposures were for 4, not 6 hours/day, total exposure time was 112-116 hours. 

EPA requires 6hr daily exposures, 5 days/week, for 4 weeks. The total hours required by 

EPA would be 120 hours. The exposure times were comparable and thus deemed 

acceptable.]

This 28 day subchronic inhalation toxicity study in the rat is acceptable (guideline) and 

satisfies the guideline requirement for a subchronic inhalation study OPPTS 870.3465; 

OECD 413 in the rat.

870.5100 Bacterial Reverse Gene Mutation

In a reverse gene mutation assay in bacteria (appendix of MRID 48431213), Salmonella 

typhimurium strains TA98, TA100, TA1535, and TA1537 and Escherichia coli strain 

WP2uvrA were exposed to S-1264ZR (metabolite of Metofluthrin, 96.2%; Lot 

5CM1222G) in dimethyl sulfoxide (DMSO) at 0, 156, 313, 625, 1250, 2500, and 5000 

μg/plate (all strains with and without S9 activation) in both the preliminary cytotoxicity 

and mutagenicity assays. An additional study using the same dose levels and S9 

activation using strain TA1535 was conducted due to a technical error for this strain in 

the main study. The S9 fraction was derived from the livers of male Sprague-Dawley rats 

induced with phenobarbital and 5,6-benzoflavone. The standard plate incorporation 

method with a pre-incubation step was used both with and without S9-activation. 

Standard strain-specific mutagens served as positive controls. 

S-1264ZR was tested thru the limit of solubility (1250 μg/plate, +S9; 313 μg/plate, –S9) 

to 5000 μg /plate. Cytotoxicity (thinning of background lawn) was not observed in any 

strains at any dose levels with or without activation. There were no treatment-related 

increases in the mean number of revertants/plate in any strain +/- S9. The positive 

controls induced marked increases in revertant colonies compared to controls in all 

strains in the presence and absence of S9-activation. There was no evidence of induced 

mutant colonies over background.

The study is classified as acceptable/guideline and satisfies the guideline requirements 

(OPPTS 870.5100; OECD 471) for in vitro mutagenicity (bacterial reverse gene 

mutation) data.
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Appendix A.5 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
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Appendix B. Physical/Chemical Properties

TABLE C.1. Physicochemical Properties

Parameter Value Reference

Molecular Weight 360.34 Product Chemistry Review, S. 

Mathur, 1/24/04, D313236. Melting point/range NA

pH 5.24 at 25 C (1% aqueous solution)

Density 1.21 at 20 C

Water solubility (20°C) 0.67 mg/L (20 C) for (S-1264RTE)

0.50 mg/L (20 C) for (S-1264RTZ)

Solvent solubility (20°C to 25°C) (g/L) Acetone 303.4, methanol 312.2, 

ethyl acetate 307.6, toluene 326.9, 

n-hexanes 328.7, dichloromethane 

318.9, n-octanol 325.1, isopropyl 

alcohol 313.2

Vapor pressure (25°C) 1.47x10-5 Torr

Dissociation constant, pKa Could not be measured

Octanol/water partition coefficient, log 

POW (25°C)

5.03 (S-RTE)

4.97 (S-RTZ)

UV/visible absorption spectrum In 100% methanol: peak maximum 

= 273 nm, extinction coefficient = 

1670 M-1cm-1, band width 23 nm
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Appendix C. Review of Human Research

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, from the Pesticide Handlers 

Exposure Database Version 1.1 (PHED 1.1), and revised Residential SOP (2012) Indoor 

Environments and the Outdoor Fogging/Misting Systems, are subject to ethics review pursuant 

to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. 

For certain studies that 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 

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

http://www.epa.gov/pesticides/science/post-app-exposure-data.html
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Appendix D: Cumulative Exposure and Risk Issues

Since the bed bug (indoor) use of metofluthrin is a newly proposed use pattern and use site, it 

was not included in the 2011 pyrethroid CRA. Although metofluthrin was registered for use as 

an outdoor insect repellent it was not included quantitatively in the CRA due to the very low 

exposure expected under the use pattern. In order to determine if the proposed metofluthrin bed 

bug use significantly contributes to or changes the overall findings in the pyrethroid CRA, the 

Agency has performed a quantitative exposure and risk assessment. This assessment used the 

metofluthrin relative potency factor (RPF), discussed below, as well as the same exposure 

algorithms and inputs that were used in the 2011 pyrethroid CRA (see Appendix Table D). 

The pyrethroid CRA relies on the RPF approach, using administered dose as the metric for 

quantifying chemical potency. In the RPF approach, the toxic potency of each chemical in the 

common assessment group (CAG) is determined. One member of the CAG is selected as the 

index chemical for use as the point of reference for standardizing neurobehavioral potency of the 

other members of the CAG. In order to develop such potency estimates, EPA prefers to use a 

uniform measure of toxicity such as data from the same endpoint and same duration, and to the 

extent possible, any other factors which effect potency (e.g., time to peak effect, sex, etc). 

In the pyrethroid CRA, the Agency used the two special WIL Functional Observational Battery 

(FOB) studies for estimating relative potency. These data were selected because the studies 

examined the key behaviors for evaluating neurotoxicity specific to pyrethroids. The studies 

looked at a number of crucial parameters that are directly relevant to the Type I (e.g., 

hyperthermia tremors and clonus) and Type II (e.g., hypothermia, salivation, and mobility) 

syndromes. In addition to the WIL FOB studies, the Wolansky acute oral study also provided a 

high quality data set for estimating relative potency. Whereas the WIL FOB studies focus on 

endpoints specific to pyrethroid toxicity syndromes, the Wolansky study measured motor 

activity. Motor activity is considered an apical endpoint because it measures alterations in the 

activity level of an intact rat. Although the Wolansky study provides a potential data source for a 

uniform measure of potency, it was not used in the CRA because of the lack of specific relevance 

to the common mechanism of action for the pyrethroids. See Section 4 of the 2011 Pyrethroid 

CRA for a full description of the Agency’s RPF approach. 

In the CRA, deltamethrin was used as the index chemical. The RPFs used for the CAG in the 

pyrethroid screening level cumulative are shown below in Table D.1. They were determined by 

dividing the chemical-specific benchmark dose, or BMD20, by the BMD20 of the index chemical, 

deltamethrin. Calculations for the BMDs are described in Section 4.2 of the CRA. Twelve of 

the 15 pyrethroids result in relative potency estimates equal to or lower than deltamethrin. 

Bifenthrin, cyfluthrin, and tau-fluvalinate result in similar relative potency to deltamethrin, while 

lambda-cyhalothrin resulted in slightly greater potency than deltamethrin. An RPF of 0.48 was 

used to quantify comparative exposures from the proposed metofluthrin bed bug use.
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Table D.1. Relative Potency Estimates for Pyrethroids Included in the Screening 

Level Cumulative Risk Assessment

Pyrethroid Oral BMD20 Oral RPFb,d

Allethrinc135 0.11

Bifenthrin 14.3 1.01

Cyfluthrin 12.6 1.15

Lambda-Cyhalothrin 8.9 1.63

Cyphenothrin 100a0.15

Cypermethrin 76.3 0.19

Deltamethrin 14.5 1.0

Esfenvalerate 40.5 0.36

Fenpropathrin 29 0.50

Tau-Fluvalinate 14.5 1.0

Imiprothrin 750a0.02

Metofluthrin 30 0.48

Permethrin 156 0.09

Prallethrin 150a0.10

Pyrethrins 800a0.02

Resmethrin 291 0.05

a

Values estimated from studies; these values were not calculated using BMD. See Section 4.2 of the CRA.

bRPF = BMD20 of Index Chemical (e.g., deltamethrin)/Pyrethroid BMD20; For example: Metofluthrin 

RPF=14.5/30 = 0.48

c

Includes the isomeric enrichments S-Bioallethrin and D-Allethrin

dRPFs for Dermal and Inhalation exposures are based on oral BMD; 5% absorption values applied to 

dermal assessments and inhalation is considered equivalent to the oral route

Appendix Table D.2 summarizes a comparison of the MOEs currently driving indoor exposures 

and risks (as referenced from Table 6.4.7a of the 2011 pyrethroid CRA) to those estimated for 

the proposed metofluthrin bed bug use, which were assessed using the metofluthrin RPF and the 

same exposure algorithms and inputs used in the CRA. The routes of exposure include postapplication dermal for adults, and post-application dermal and incidental oral for children. 

Quantitative post-application inhalation exposures from the bed bug use are not included in the 

CRA assessment since this is not a significant route of exposure. The MOEs in the single 

chemical assessment are not of concern and, as was noted in the CRA, an Office of Research and 

Development exposure study that simulated crack and crevice applications of four pesticides, 

including two pyrethroids, showed that all air concentration values were below the limit of 

quantitation (D390098, C. Smith and S. Shelat, 9/15/2011). 

Adult indoor exposures and risks (dermal only) are currently driven by the cypermethrin indoor 

fogger use pattern with an MOE of 3,900, which is lower than the MOE estimated for adult 

dermal exposure from the proposed metofluthrin bed bug use, 32,000. The cypermethrin use 

also drives the CRA for children’s indoor exposure and risk, with an estimated combined MOE 

(dermal and incidental oral) of 720, which is lower than the combined MOE estimated for 

children’s indoor exposure and risk from the proposed metofluthrin use, 5,800. Based upon 

these outcomes, the Agency has determined that the proposed metofluthrin bed bug use will not 

contribute significantly to or change the findings for residential scenarios presented in the 

pyrethroid CRA. A summary of individual adult and child exposure scenarios assessed for the 

comparative evaluation are presented in Tables D.3 and D4. 
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D.2. Metofluthrin Screening Level “Cumulative” Combined Exposure and Risk from the Proposed Bed 

Bug Use

Chemical Exposure 

Scenario

Route of 

Exposure Population MOE Combined MOE

New Use Metofluthrin

Indoor Bed Bug -

Surface Directed 

Sprays

Handler Dermal -

handwand

Adult

1,100,000 NA

Handler Dermal -

paintbrush 160,000 NA

Post-Application 

Dermal 32,000 NA

Post-Application 

Dermal Children 

(1 < 2 years old)

27,000

5,800 Post-Application 

Incidental Oral 7,300

CRA Cypermethrin Indoor Fogger

Post-Application 

Dermal Adult 3,900 3,900

Post-Application 

Dermal Children 

(1 < 2 years old)

3,500

720 Post-Application 

Incidental Oral 900
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Appendix Table D.3: Metofluthrin Screening Level “Cumulative” MOEs – Handler Exposure

Handler Dermal Exposure

Exposure Scenario

Application 

Ratea

(lb ai/gal)

Amount 

Treatedb

(gals)

Baseline 

Dermal 

Unit 

Exposureb

(mg/lb ai)

Baseline 

Inhalation 

Unit 

Exposureb

(mg/lb/ai)

Baseline 

Dermal 

Dosec

(mg/kg/day)

Adjusted 

Baseline 

Dermal Dosed

(mg/kg/day)

Adjusted 

Baseline 

Dermale

MOE

Baseline 

Inhalation 

Dosef

(mg/kg/day)

Adjusted 

Baseline 

Inhalation 

Doseg

(mg/kg/day)

Adjusted 

Baseline 

Inhalation 

MOEh

Combined 

MOEi

Bed Bug - handwand 0.000864 0.5 69 1.1 0.00002 0.000010 1,100,000 0.00047 3.2E-6 3,300,000 800,000

Bed Bug - paintbrush 450 0.2 0.000135 0.000065 160,000 0.0000012 5.8E-7 18,000,000 160,000

a. Application Rate in accordance with proposed label

b. Indoor Environment Residential SOP 2012

c. Dermal Dose (mg/kg/day) = AR (lb ai/gal) x Amount Treated (gals) x Dermal Unit Exposure (mg/lb ai) x 5% DAF (based on deltamethrin)

d. Adjusted Dermal Dose (mg/kg/day) = Dermal Dose (mg/kg/day) x .48 (metofluthrin RPF)

e. Adjusted Dermal MOE = Deltamethrin BMDL (11)/Adjusted Dermal Dose (mg/kg/day)

f. Inhalation Dose (mg/kg/day) = AR (lb ai/gal) x Amount Treated (gals) x Inhalation Unit Exposure (mg/lb ai)

g. Adjusted Inhalation Dose (mg/kg/day) = Inhalation Dose (mg/kg/day) x .48 (metofluthrin RPF) 

h. Adjusted Inhalation MOE = Deltamethrin BMDL (11)/Adjusted Inhalation Dose (mg/kg/day) 

i. Combined MOE = Deltamethrin BMDL (11)/Adjusted Dermal Dose (mg/kg/day) + Adjusted Inhalation Dose (mg/kg/day)
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Appendix Table D.4: Metofluthrin Screening Level “Cumulative” MOEs – Post-application Exposure

Post-application Dermal Exposure

Exposure Scenario Surrogate 

Deposition 

(μg/cm2)

Fraction 

Transferred

Transfer 

Coefficient 

(cm2/hr)

Exposure 

Time (hours)

Conversion 

Factor (mg/μg)

Exposure 

(mg/day)

Body 

Weight 

(kg)

Absorbed Dermal 

Dose (mg/kg/day)

Adjusted 

Dose

(mg/kg/day)

a

Adjusted 

MOE b

Dermal Exposure from 

Carpet After Bed Bug 

Use 

(1 < 2 year olds) 0.9 0.02

2,000 5

0.0010

0.18 11.4 0.00079 0.00038 27,000

Dermal Exposure from 

Carpet after Bed Bug Use

(Adults)

6,800 8 0.98 71.8 0.00068 0.00032 32,000

Post-application Incidental Oral Exposure

Exposure Scenario Faihands

1-2 yr old 

Dermal 

Exposure

SAH

(cm2)

HRt

(mg/cm2)

FM

Exposure 

Time 

(hours/day)

N_Replen SE Freq_HtM

BW

Average Daily 

Dose

(mg/kg/day)

Adjusted Dose

(mg/kg/day) a

Adjusted 

MOE b

Fraction of Hand 

Surface Area 

Mouthed / Event

Number of 

replenishment 

intervals per hr 

(intervals/hr)

Extraction by 

Saliva

H-t-M 

events per 

hour

Incidental Oral Exposure 

from Bed Bug Use

(1 < 2 year olds)

0.15 0.18 150 8.9E-05 0.13 5 4 0.5 20 11.4 0.00290 0.0014 7,300

a. Doses were adjusted based on an estimated metofluthrin RPF of 0.48

b. MOEs were calculated by comparing the adjusted dose to the oral BMD20 from the WIL FOB data for the index chemical, deltamethrin (14.5 mg/kg/day)
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Appendix E: Registered Residential Exposure and Risk to Support Registration Review

SOURCE: Exposure Memo D397725, 9/5/12. M. Collantes;

Incident Data Review, D404998, 9/6/12, S. Recore

This assessment of the currently registered uses of metofluthrin, together with the updated hazard 

characterization and endpoint selection conducted for the proposed bed bug treatment use, serves 

as the preliminary risk assessment (PRA) document to support registration review of 

metofluthrin. There are currently no food/feed uses. The toxicology database has been reviewed 

and is largely complete, with the exception of an immunotoxicity study and additional data being 

conducted for all pyrethroids, to assess potential juvenile sensitivity. There are no risks of 

concern for metofluthrin, based on the updated risk assessment for the following registered 

products:

DeckMateTM Mosquito Repellent Strip (EPA Reg. No. 10308-31) is an impregnated 

paper strip containing 1.82% metofluthrin for use on patios, campsites, decks, cabanas, 

and other outdoor areas, and in barns/stables and kennels to protect companion non-food 

animals, such as horses, ponies, and dogs. Each strip contains approximately 200 mg of 

metofluthrin and can be effective for up to one week. The product also contains 

BitrexTM, a bittering agent, to discourage incidental oral exposure to children and 

animals. 

NORM 1 (EPA Reg No. 4822-542) is a personal outdoor insect repellent product 

consisting of a holder attached to the individual’s clothing. A replaceable cartridge 

coated with 15-20 mg metofluthrin is inserted into the holder. The holder uses a battery 

operated fan to draw air through the device, creating an approximately 6 foot zone of 

protection around the wearer. Each cartridge is effective for about 12 hours. 

Charger OFF Patio Protector (EPA Reg No. 4822-583) is a recently registered candle 

product which is sold in two sizes (0.01 or 0.30 oz). It contains a ring impregnated with 

31.68% metofluthrin that releases the active ingredient upon heating. It is intended for 

outdoor use only as a mosquito repellent. One candle is to be used to treat an area of up 

to 10 feet by 10 feet.

Recommendations from Incident Data Review

In order to evaluate the need for a more detailed incident review for metofluthrin, HED consulted 

the OPP Incident Data System (IDS). Within the IDS, less severe human incidents (minor, 

unknown, or no effects outcomes) are reported by registrants as aggregate summaries and are

recorded in a separate module called Aggregate IDS. In Aggregate IDS, from January 1, 2007 to 

February 22, 2012, there were 138 reported incidents involving metofluthrin. Incidents resulting 

in higher severity outcomes are captured in more detail in the Main IDS module. This system 

stores incident data for death, major and moderate incidents, and it includes more details about 

the location, date and nature of the incident. Main IDS incidents involving only one pesticide are 

considered to provide more certain information about the potential effects of exposure from the 

pesticide.
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For the Main IDS, from January 1, 2007 to February 22, 2012, there were 39 incidents with 

metofluthrin reported in the database. All of the incidents were classified as moderate severity. 

In addition, there were two more incidents reported that involved metofluthrin and other 

chemicals.

Overall the incident cases reported for metofluthrin were generally low frequency and low 

severity. However, because the personal repellent is a relatively new delivery method and there 

are 39 moderate incidents reported in IDS Main, these data indicate that the Agency should 

continue to monitor incidents with metofluthrin, through registration review and in conjunction 

with registration of any additional new uses.

Insect Repellent Handler Exposure and Risk Estimates

These products are typically marketed for outdoor residential use to repel flying insects and 

pests. Upon activation, these products emit small particles over the useful life of the product. 

Handler exposure does not need to be quantitatively assessed because the ignition or activation 

of these products is instantaneous and the quantitative post-application exposure assessment 

adequately addresses the exposure potential.

Post-Application Exposure and Risk Estimates Resulting from Registered Repellents

Insect Repellent Strips and Candles

The inhalation route of exposure is expected to be the primary post-application exposure route

for repellent products. As previously noted (Section 4.5.1), inhalation exposure to metofluthrin 

in repellent products is likely to be as a vapor. Although there is some uncertainty introduced by 

the use of an aerosol study to evaluate toxicity from vapor exposure, the uncertainty is less than 

expected using an oral study and route-to-route extrapolation. Residues deposited on patios or 

other surfaces are expected to be negligible after use of Candles, Coils, Torches and Mats 

(CCTM) products (e.g., repellent strip, candle). Due to the size fraction of particles released 

from the activation of CCTM products, particles are expected to remain airborne rather than be 

deposited on surfaces. Therefore, dermal and incidental oral post-application exposures to 

surface residues do not need to be quantitatively assessed. 

This assessment provides a post-application inhalation exposure assessment for CCTM products

using the Revised Residential SOP (2012) Outdoor Fogging/Misting Systems. 

All post-application inhalation scenarios resulted in MOEs greater than the respective LOCs and 

are not of concern. Table E.1 summarizes the post-application inhalation exposure and risk from 

repellent strips and candles.
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E.1: Inhalation Post-application Exposure and Risk Estimates for Repellent Strip.

Life 

Stage

Emission 

Rate

(mg ai/hr)

IR 

(m3/hr)

Airflow 

Q 

(m3/hr)

VE Exposure 

Time 

(hrs/day)

Volume 

treated 

(m3)

Exposure 

(mg/day)

Dose 

(mg/kg/day)

MOE1

Repellent Strip

Adult 50 0.64 4000 1 2.3 51 1.83E-2 0.000228 33,000

Children 50 0.33 4000 1 2.3 51 9.4E-3 0.00085 8,700

Candle

Adult 50 0.64 4000 1 2.3 51 2.4E-2 0.000309 24,000

Children 50 0.33 4000 1 2.3 51 1.27E-2 0.001158 6,500

1. Each strip contains 200 mg a.i. and candles contain 270 mg a.i. in accordance with the registered labels.

Personal Insect Repellent Device

The Revised Residential SOPs do not include a methodology for assessing personal repellents; 

therefore, previously assessed post-application exposure estimates for the personal repellent 

device were corrected for revised body weights and inhalation rates. Post-application oral 

exposure for children was assessed conservatively, assuming a child would “mouth” the product 

itself; chemical-specific data were used to simulate saliva extraction, including measurement of 

residues following washing of the product with isopropyl alcohol (IPA) or dioctyl sodium 

sulfosuccinate (DSS).

Post-application inhalation, dermal and incidental oral exposure estimates were greater than the 

respective LOCs and are not of concern. A summary of the post-application exposure estimates 

is provided in Tables E.2.a, b, and c.

Table E.2.a. Post-application Inhalation Exposure and Risk for Personal Insect Repellent.

Lifestage Mean 

Residue 

(ng)

Flow 

Rate 

(L/min)

Duration 

(min.)

Total 

Volume1

(m3)

Concentration2

(ug/m3)

Dose3

(mg/kg/day)

MOE4

Adult 21.4 2 180 0.36 0.059 5.6E-6 1,300,000

Child 2.1E-5 360,000

1. Volume = 2 L/min x 180 min x 10-3 m

3

/L = 0.36 m3.

2. Concentration = 21.4 ng / 0.36 m3= 59 ng/ m3= 0.059 μg/ m3= 0.000059 mg/ m3.

3. Adult Dose = 0.000059 mg/ m3x 15.36 m

3

/day × 0.5 days × 1/80 kg = 5.6 x 10-6 mg/kg/day.

 Child Dose = 0.000059 mg/ m3x 8m3/day × 0.5 days × 1/11 kg = 2.1 × 10-5 mg/kg/day.

4. MOE = Human Equivalent Dose (7.5 mg/kg/day)/ Dose (mg/kg/day).

Table E.2b. Post-application Dermal Exposure and Risk for Personal Insect Repellent.

Lifestage Total Dose (mg/kg/day) MOE1

Adult 0.0088 34,000a

Child 0.0436 6,900 b

1a. Dermal Adult MOE = NOAEL (300 mg/kg/day)/Dose (mg/kg/day).

1b. Dermal Child MOE = NOAEL (300 mg/kg/day)/Dose (mg/kg/day).
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Table E.2c. Children’s Post-application Incidental Oral Exposure and Risk for Personal Insect 

Repellent. 

Sampling 

Media*

Mean 

Residue 

(ug)

Mean 

(mg)

Cumulative 

Residue 1

(mg)

Oral Dose2

(mg/kg/day)

MOE3

DSS 0.54 0.00054 0.0010 2.9E-5 520,000

IPA 1.70 0.0017 0.0034 9.8E-5 150,000

1. Cumulative Residue (12 exposure events) = Mean Residue (6 hour) x 2.

2. Oral Dose = cumulative residue (mg) x 0.32 (Saliva Efficiency)/11 kg (BW).

3. MOE = NOAEL (15 mg/kg/day)/Dose (mg/kg/day).

DSS = dioctyl sodium sulfosuccinate

IPA = isopropyl alcohol

Combined Post-application Risk Estimates from Use of Metofluthrin in Repellents

Risk estimates resulting from different exposure routes may be combined when it is likely that 

they can occur simultaneously based on the use pattern and when the toxicological effects across 

different routes of exposure are the same. 

There is the potential for adult and child dermal and inhalation post-application exposure as well 

as oral exposure for children resulting from the use of metofluthrin formulated as CCTM 

products (i.e., repellent strips and candles). However, residues deposited on patios or other 

surfaces are expected to be negligible after use of a CCTM product. Therefore, dermal and 

incidental oral post-application exposures to surface residues are not quantitatively assessed. 

The only post-application route of exposure expected for CCTM products is inhalation (i.e., no 

routes of exposure were combined for these products).

However, there is the potential for post-application inhalation and dermal exposure to adults and 

children, as well as incidental oral exposure for children resulting from the use of the personal 

fan repellent. Since endpoints selected for the dermal, incidental oral and inhalation routes of 

exposure are the same toxicological effects (i.e., tremors), these routes of exposure were 

combined. Because the inhalation LOC is different than the dermal and incidental oral LOCs, 

the combined risk estimates must be calculated using the Aggregate Risk Index (ARI) approach. 

An ARI ≥ 1 is not of concern.

HED notes that while the individual incidental oral scenarios (i.e., hand-to-mouth and object-tomouth) could occur simultaneously, combining these scenarios with the dermal exposure 

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

assessment. Therefore, only hand-to-mouth exposure was combined with the dermal and 

inhalation post-application exposure scenarios for children 1 < 2 years old. 

The combined residential post-application risk estimate for adults resulting from use of personal 

fans was an ARI of 1,100; the risk estimate for children was an ARI of 22. These combined 

post-application risk estimates for repellents (summarized in Table E.3) were ARIs > 1, which 

are not of concern.
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Table E.3.: Combined Post-application Residential Exposure and Risk Estimates from 

Repellents.

Combined 

Scenario Lifestage Post-application 

Scenarios

Daily Dose

(mg/kg/day)a MOEb

ARIs

c

Repellents

Adults

Inhalation (Fan) 0.0000056 1,300,000

1100 Dermal (Fan) 0.0088 34,000

Children

Inhalation (Fan) 0.000021 360,000

22 Dermal (Fan) 0.0436 6,900

Hand-to-Mouth (Fan) 0.000098 150,000

a. See Tables E.2.a, E.2.b, and E.2.c. 

b. See Tables E.2.a; E.2.b; and E.2.c. 

c

1

. Adult ARI = total = 1/[(1/ARIdermal) + (1/ARIinhal)] where, ARIdermal = MOEdermal/100 and ARIinhal = 

MOEinhal/30. ARIs greater than 1 are not of concern.

c

2 Child ARI= 1/[(1/ARIdermal) + (1/ARIinhal) + (1/ARI oral)] where, ARIdermal and ARIoral = MOE/300 and 

ARIinhal = MOEinhal/100. ARIs greater than 1 are not of concern.