Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 3 of 84 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

................................ . 1 4
4.3.1 Pharmacokinetics

................................ ................................ ................................ ........ 1 4
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

................................ ........... 21 2
4.5.1 Dose

- Response Assessment

................................ ................................ .................. 2 2 2
4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

. 23 3
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

................................ ................................ ................................ .............................. 26 7
6.2.2 Post

- Application Exposure and Risk Estimates Resulting from Bed Bug
Treatment

................................ ................................ ................................ ................................ 2 8
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

................................ ................................ ................................ ........... 3 0
6.2. 3 .2 Object

- to

- Mouth

................................ ................................ ................................ ......... 3 0
6.3 Combined Exposure

................................ ................................ ................................ .... 31Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 4 of 84 6. 3.1 Combined Residential Handler Risk Estimates from Proposed Bed Bug Use

...... 3 1
6. 3. 2 Combined Residential Risk Estimates (Multiple Exposure Scenarios)

................. 3 2
6.4 Residential Bystander Post

- A pplication Inhalation Exposure

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

................................ ................................ ................................ ................... 32
7.0 Aggregate Ex posure/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. Tox icology Profile and Executive Summaries

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

................................ ................................ .................. 39
A.2 Toxicity Profiles

................................ ................................ ................................ .......... 4 0
A.3 Hazard Identification and Endpoint Selection

................................ ......................... 4 7
A.4 Executive Summaries

................................ ................................ ................................ .. 49
A. 5 Calculation of HEC/HED

................................ ................................ ........................... 7 2 Appendix B. Physical/Chemical Properties

................................ ................................ ........... 72 3 Appendix C. Review of Human Research

................................ ................................ .............. 73 4 Appendix D. Cumulative Exposure and Risk Issues................................................7 5 Appendix E. Registered Residential Exposure and Risk to Support Registration Review..8 0Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 5 of 84 1.0 Executive Summary

Valent Corporation has requested registration of a proposed new combination product, Valent Bed Bug Combination ( VB C 3 ) Insecticide , to control bed bugs in residential homes and commercial buildings and structures. VBC 3 is formulated as a liquid and contains three active ingredient s , 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 sq uare feet. The product includes instructions for perimeter/spot treatments, as well as
treatment of entire mattresses. This document address es 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 i mpregnated paper repellent strip s , 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

expo sure and risks have been assessed

.

The toxicology data base 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 immuno toxicity in the metofluthrin database ( and for pyrethroids as a
chemical class ) , an additional database uncertainty factor (UF DB ) was not included to account for the lack of this study. In addition to the submitted guideline studies on metofluthrin , numer ous studies from the scientific literature that describe the pharmacodynamic and pharmacokinetic profile of the pyrethroids in general have been considered in this assessment.

Metof luthrin is a Type I synthetic pyrethroid , which typically produce a dist inct 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, mot or activity was increased. Rats were sensitive to inhalation exposure , showing mortality and clinical signs includ ing ataxic gait, tremors, tip

- toe gait, lateral position, clonic convulsion s and hypothermia . Mortality also

o ccu rr ed from dermal exposure at the limit dose. Metofluthrin targe ted the liver in rats and
mice: increased absolute and relative liver weights, hepatocel lular hypertrophy, enlarged or discolored liver, increased serum lipids, and /or hepatocellular degeneration/necrosis. No reprodu ctive 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 tre mors) , exposure via the oral, dermal and inhalation routes w as combined when appropriate.

Evidence of increased qualitative or quantitative susceptibility of offspring was not o bserved in
studies with metofluthrin . However, t he Agency will retain a 3X database uncertainty factor ( UF DB ) to protect for exposures to children <6 years of age based on the following: 1) age

dependent pharmacokinetics, supported by rat Physiologically Based Pharmacokinetic (PBPK ) model predictions of a 3

- fold increase of pyre throid concentration in juvenile brain compared toMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 6 of 84 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. F ollowing oral dos ing

, meto fluthrin is absorbed quickly in

rats

. N eurotoxicity is observed within 6 hours a nd recovery is within 24 hours, consistent with
the t oxicity profiles for other pyrethroids

, which are very similar and marked by rapid absorption, metaboli sm 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 inhalati on 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 assessmen t, 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 adjustmen t for interspecies differences in pharmacokinetics. For children <6 years old, an additional 3X UF DB 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 t he 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 e xposures.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 7 of 84 Although the proposed bed bug product is not intended for residential homeowner use , such exposures could occur if residential handlers obtain ed 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 MOE s and the ARI for combined dermal and inhalation exposure are not of concern. D ermal and inhalation h andler

exposure s associated with existing outdoor repell ent uses are expected to be negligible and were

not quantitative ly assessed

.

Based on the proposed bed bug use pattern and surrogate pyrethroid data generated by the Non

Dietary Exposure Task Force (NDETF), HED does not have concerns for metofluthrin post

application inhalation exposure

, due to the very low indoor air concentrations expected following application

. Post

- application dermal exposure and risk estimates from the p erimeter/ sp ot/ b ed
b ug use and mattress treatment result ed in MOEs greater than the respective LOC s for adults and
children and are not of concern

. The lowest estimated dermal MOE was for children, at 25,000.

Children’s p ost

- application incidental oral exposure resulting from hand

- to

- mouth and object

- to

mouth activit ies can occur fo llowing the indoor p erimeter/ sp ot/ b ed b ug application and the bed bug/mattress use. Only incidental oral exposures resulting from the p erimeter/ sp ot/ b ed b ug application were quantitatively assessed since they are considered to be protective of the

exposur e resulting from the mattress application

. All hand

- to

- mouth and object

- to

- mouth post

application exposure scenarios resulted in MOEs greater than 8,500 and are not of concern.

P ost

- 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. T he residen tial handler exposure assessments resulting from bed bug use resulted in the worst case scenarios for adult s , while the combined post

- application exposure resulting from personal fans resulted in the worst case scenario for children. All
scenarios resulte d 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 ha s 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 VB C 3 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 LOC s , assuming baseline attire (i.e., single layer of clothing, no re spirator ) , and us ing typical assumptions for each application
method

. HED does not anticipate post

- application exposure for commercial handle rs andMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 8 of 84 t herefore a quantitative occupational post

- application risk assessment was not perform ed for the bedbug us e

.

T his 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 con clusions 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 Consid erations

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

2.3 Label Recommendations

None

.

3.0 In troduction

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.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 9 of 84 3.1 Chemical Identity

TABLE 3.1. Test Compound Nomenclature

Chemical Structure

Empirical Formula C 18 H 20 F 4 O 3
Common name Metofluthrin

Company experimental name S

- 1264

IUPAC name 2,3,5,6

- tetrafluoro

- 4

- (methoxymethyl)benzyl ( EZ )

- (1 RS ,3 RS ;1 RS ,3 SR )

- 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 product s /EP VBC 3 , 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 proposi ng a new use for metofluthrin. The new proposed product, “Valent Bed Bug Combination” (VBC 3 ) Insecticide is intended to control bed bugs and their eggs for up to 4 weeks in indoor residential, institutional and commercial facilities. VBC 3 is formulated a s 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 indicate s that VBC 3 is to be applied as a pinstream,Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 10 of 84 coarse spray or low pressure spray for crack and crevice, carpet perimeter and direct spray appli cations 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 afte r the spray has dried. VBC 3 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
oth er handlers consists of baseline attire (i.e., long sleeved shirt, long pants, shoes and socks).

The proposed use pattern for VBC 3 is summarized in Table 3 .3

.

Table 3. 3 Proposed Direction for Use of VBC 3 Insecticide For Control of Bed Bugs.

Formulation

(EPA Reg. No.) Method of

Application Application

Rate 1 Max. No.

Applic ations per Season Max imum

Seasonal Applic ation

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/1000ft 2

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 ad ults, 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 a i x 0.0022 lb/1 gram x 3785 ml/gal = 0. 00851 lb ai/gal product
13 f l oz/1000ft 2 x 0. 00851 lb ai/gal x 1 gal/128 fl oz = 0.0 00864 lb ai/1000ft 2 ( 0 .0000 00864 lb ai/ft 2 ) or 0.0 00864 lb ai/gal

There are currently t hree registered products for metofluthrin : DeckMateTM Mosquito Repellent Strip, NORM 1, a personal repellent device, and a can d le, 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 assum ptions

. 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 m etofluthrin in food and drinking water, since there are noMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 11 of 84 agric ultural 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
derma l 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

p ost

- 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, applic ators 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.

Th e 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 risk s 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 patt erns 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, seas on 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

- die tary 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 Characteri zation 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,Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 12 of 84 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 )

. Metof luthrin 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 metoflu thrin 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, immunotoxicit y was not observed in the available toxicity studies and is not typically a critical endpoint for pyrethroids. In addition,
there are o n

- 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 studie s 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 metofluth rin 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 toxic ologically 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 ; t his 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 toxicologi cal properties of the members of this class of pesticides, these
studies are informative in the hazard characterization of metofluthrin.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 13 of 84 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 var ying 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, bu t 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 avail able oral studies, the most sensitive NOAEL identified was from the rat developmental toxicity study, based on tremors in maternal animals. Two supplemental non

guideline developmental studies yielded similar NOAELs and LOAELs. In the rat subchronic

neur otoxicity 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, exces s 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 me tofluthrin. 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
inci dence 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 carcinogen icity 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. Sup plemental 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 forma tion. No treatment

- related tumors were seen in the mouse. Genotoxicity studies were negative.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 14 of 84 In the rat and rabbit developmental toxicity studies, no developmental toxicity was observed at doses causing maternal mortality, clinical signs and/or decrea sed 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 pup s (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 b ut 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 relativ ely 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 meto fluthrin are similar to other pyrethroids, i.e., rapid absorption and clearance. Following a single oral dose, meto f luthrin was extensively metabolized and excreted
via both the urine (29

- 73% of the absorbed dose, or AD) and feces (22

- 66% AD), within 24
h ours. 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 pharmacokin etic study where the maximum plasma levels of meto fluthrin 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 concentrati on of the pyrethroids reaching sodium channels. The underlying pharmacokinetics of pyrethroids is an important determina n t of theirMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 15 of 84 toxicity because the concentration of pyrethroid at the sodium channel relates to the extent of toxicity; greater pyrethroi d 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 majo r enzyme families responsible for metabolis m 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 preferentia lly deposit in fatty tissue such as adipose compared to leaner tissu es 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.

Physiologicall y

- based pharmacokinetic (PBPK) models, designed to predict pyrethroid concentration in tissues following in vivo exposure, have recently been developed by the Agency. T he Agency has determined that the important PK properties relevant for the
metabolism a nd 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 pyrethroid s as a class.
S everal studies in this analysis indicate that there are age

- dependent pharmacoki netic d ifferences for the pyrethroids (i.e., there are differences in the ability of adults and juven iles to metabolize pyrethroids). The enzymes which metabol ize and detoxify the pyrethroids are present in rats and
humans at birth ( Koukouritaki et al

. 2004 ; Yang et al

. 2009 )

. As a r esult, 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 capa city 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 bu t 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 pr emature 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 ( Torne ro

- 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),

eq uivalent brain concentrations of deltamethrin would be achieved with a 3.8X fold lower oralMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 16 of 84 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 juv enile 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 c hannels. 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 199 8 ; Soderlund et al. 2002 (review )

. No studies were identified for metoflu thrin w hich provide information on its
interact ion with the sodium channels. However, t here 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 neuro nal 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 minu tes) 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. A n 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

neur ons.

HED would prefer to use an early key event in the AOP for pyrethroids in selection of points of departure. However, i n 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 hypo thermia, altered response
to stimul i, salivation and convulsions ( N emec 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 t here are several variations of sodium
chann els, 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 p yrethroid interaction with sodium channels has not been identified, making it impractical to determine the isoformMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 17 of 84 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 nerv e

c ells . 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 conser vative model for humans. For example, Meacham et al. ( 2008 ) , compared the sensitivit y 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 ra t 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 func tion 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 mor e 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, b elow, summarizes the NOAELs and LOAELs from several toxicity studies on metofluthrin. Studies with clinical signs of neurotoxicity as endpoints at the L OAEL are shown in boldface.

As a general rule, acute studies in pyrethroids have similar or lower PO Ds 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 co nsequently 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 f or 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 diet ary 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

.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 18 of 84 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 as sociated 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 a t 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 neurotox icity 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 b ut did not persist into the following day. This is consistent with t oxicity 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 stu dy, 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 typ ically 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 = 5 7

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 t remors 6 months NOAEL = 16
NOAEL = 54 LOAEL = 54

LOAEL = 165 Reproductive toxicity
MRID 48770701 6 months Parental
NOAEL = 19.5 Parental

LOAEL = 97.6Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 19 of 84 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 ob served 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 exam inations 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 po stdosing) 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 a lso 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 o n 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.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 20 of 84 The weight of evidence for the guideline and non

- guideline studies support the inf ormation 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 wit h acute, peak exposures. F rom 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) consideration s do not apply to metofluthrin for the proposed and existing non

- food use patterns described in this risk assessment. However, s ince metofluthrin is a pyrethroid and exposure to children under < 6 years old is expected, metofluthrin must be considered in the greater context of the pyrethroids as a class. The Agency will retain a 3X uncertainty factor to protect for exposures to children < 6 years of age based on the increased quantitative suscept ibility 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 UF DB is not required for lack of this study because there wa s 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 fo r all pyrethroids.

4.4.2 Evidence of N eurotoxicity

Metofluthrin is a Type I pyrethroid and like other pyrethroids, causes neurotoxicity from interaction with sodium channels leading to clinical signs of neurotoxicity. C linical signs
observed for metoflut hrin 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 subchron icMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 21 of 84 neurotoxicity studies in the rat are available for metofluthrin and neurotoxicity is well

characterized in the available database.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

Based on the metoflu thrin

- 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 guidel ine studies for 24 pyrethroids, the scientific literature, and the metofluthrin guideline toxicological studies. The developmental and reproduction studies for meto f lu thrin 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 rela ted 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.

A ddit ional 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 pote ntial 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 meeting 1 . Based on com ments 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) c onducting 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 hum an 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 Datab ase

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.htmlMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 22 of 84 4.5 Toxicity Endpoint and Point of D eparture 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 th e 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 ava ilable 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 select ed 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 s een 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 i ntermediate

- 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 develo pmental 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. T he dermal study is protective of potential offspring effects since it adequately measured systemic toxicity in adult
animals , and the re were no developmental or reproducti ve 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 NOAE L 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 st udies and the offspring effects in the reproduction study were seen in the presence of comparable maternal effects; therefore, there is no concern for increased susceptibility. T he inhalation study is protective of potential offspring effects since it ade quately measured systemic toxicity in adult animals , and the re were no developmental or reproducti ve effects observed in the relevant studies. This study is supported by a second 28

- day inhalationMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 23 of 84 study, a bridging study conducted on the technical active ingredient manufactured under a modified process. Essentially identical findings were observed in both studies

.

In t he 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 f or handler s making spray appli cation s of the proposed bed bug product

. However, post

- application
inhalation exposure is expected to be primarily to a vapor. A lthough 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 uncert ainty into the risk assessment for repellent products, but the fact that test animals were also exposed to the v apor in the aerosol study r educ es the uncertainty

. 2 Despite the limitations of using an a erosol study to assess vapor exposure , there is less u ncertainty 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 a nd 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 prese nted 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 extrap olation 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 LOC s of 300. R isk
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 3 X uncertainty factor to account for interspecies extrapolation (reduced from 10 X because the HEC calculation accounts for pharmacokinetic differences between humans and rats) and a 10 X uncertainty factor for intraspecies variability. For children <6 years o ld, 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

. R isk estimates (MOEs) above the respective inhalation LOCs f or 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 t he 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

t o metofluthrin via diet or drinking water (Moore, 2006, D313232)

.

2 http://www.epa.gov/scipoly/sap/meetings/2009/120109meeting.htmlMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 24 of 84 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 ba sed 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) re sponse 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 Tox icological Effects

Acute Dietary ( All Population s ) 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 UF A = 10 x

UF H = 10 x UF DB = 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 Short

Term (1

- 30 days) NOAEL=

300 mg/kg/day UF A = 10 X

UF H = 10X
UF DB = 3 X , <6 years of age

UF DB = 1 X , ≥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 UF A = 3 X

UF H = 10 X
UF DB = 3 X , <6 years of age

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

LOC for
children <6 years of age = 1 00
For adults and
children ≥ 6 years of age =
3 0 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/dayMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 25 of 84 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 Tox icological 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 cytochro me 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. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF DB = 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 Occupat ional
Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk
Assessment Study and Toxicological Effects

Dermal Short

and
Intermediate

Term (1

- 30 days and 1

- 6 months, respectively ) NOAEL=

300 mg/kg/day UF A =10 X

UF H =10 X 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
Intermediate

Term (1

- 30 days and 1

- 6 months, respectively ) NOAEL =

0.099 mg/L
HEC =
0. 1 55 mg/L

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

UF H =10 X Occupational

LOC for MOE =
3 0 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 as sessment 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = 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, d rinking water exposure is not expected based on the proposed indoor use and limited registered outdoor uses ofMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 26 of 84 metofluthrin ; a dietary assessment is not needed

.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterizatio n

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

As indicated previously , there are currently t hree 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, VBC 3 Insecticide is not a restr icted use p roduct 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 expos ures to those of occupational handlers, except that the area treated, amount handled and frequency of exposure is reduced. R esidential 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 scenario s :

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 a nd 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

.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 27 of 84 Table 6.1

. : Residential Handler E xposure and Risk Estimates for Indoor Surface Bed Bug Treatment

Application
Rate a Amount

Handled b (lb ai/gal) Unit Exposure

(mg/lb ai) c Dose (mg/kg/day) Short

- Term MOE

ARI h

Dermal Inhalation Dermal d Inhalation e Dermal f Inhalation g

Mixing/Loading/Applying with Manually

- pressurized Handwand (PHED)

0.0 00864 (lb ai/gal ) 0.5 69 1.1 0.0 00378 0.000 0059 810 ,00 0 1,300

, 0 00 2,500

Applying with Paintbrush

0.0 00864 (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 VBC 3 Insecticide 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/ARI dermal ) + (1/ARI inhal )] where, ARI dermal = MOE dermal /100 and ARI inhal = MOE inhal /30. ARIs greater than
1 are not of concern.

6.2 Post

- Application Exposure

6 .2.1 Post

- A pplication 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

t o 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 ha s been applied, and air temperature. No chemical specific post

- application inhalation exposure data w ere 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 th ese 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. Th e 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 conc entration values were below the limit of quantitation in the ORD study.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 28 of 84 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

- applicat ion 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

- applicati o n dermal exposure f ollowing 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 pyreth roid

- specific d ata 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 summar izes the
dermal post

- application exposure and risk estimates from the proposed p erimeter/ sp ot/ b ed b ug

use of metofluthrin

. Dermal p ost

- application exposure scenarios result in risk estimates ( MOEs )
greater than the respective LOCs and are not of concern.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 29 of 84 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 DepR a

(ug/cm 2 ) F ai

Fraction
T ransferred b TC

Transfer
Coefficient (cm 2 /hr) ET

Exposure
time (hr/day) E

Exposure (mg/day) Dermal

Dose b (mg/kg/day) Dermal MOE c

Carpet Adult

0.9 0.0 2 6,800 8 1.0 0.0 12 25 ,000

Child ( 1 to < 2 years
old ) 1,800 4 0.1 0.0 11 25 ,000

Hard
Surfaces Adult

0.0 4 6,800

2 0.5 0.00 612 49 ,000

Child ( 1 to < 2 years
old ) 1,800 0.1 0.0 11 25 ,000

a. Deposited residue is a surrogate value ( 0. 9 ug/cm 2 ) 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/cm 2 ) * Fraction transferred * Transfer coefficient (cm 2 /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 D ermal PoD = N O A EL 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/cm 2 ) a Surface

area / Body Weight
Ratio (cm 2 /kg) Fraction of

skin in

contact with
surface F ai

Fraction
transferred Protection

factor Dermal Dose

(mg/kg/day) b Dermal MOE

Short/ Intermediate

term

Mattress Adult

0.42 2 8 0

0. 5 0.0 6 0.5 0.0017 170,000

Child (1 to
2 years old ) 6 4 0 0.00 40 74,000

a. Residue value determined based on application rate (0.0 00864 lb ai/gal) and assumptions for area treated and amount applied (see above text).
b. Dermal dose (mg/kg/day) = Surface residue (ug/cm 2 ) * Surface area / Body weight r atio (cm 2 /kg) * Fraction of body that contacts residue (0.5) * Conversion factor (0.001 mg/ug) * Fraction transferred (0.0 6 ) * 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.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 30 of 84 6 .2. 3 Post

- A pplication 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
activit ies can occur as a result of the indoor p erimeter/ sp ot/ b ed b ug application and the bed bug/mattress use. Only incidental oral exposures resulting from the p erimeter/ sp ot/ b ed b ug 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. Po st

- 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 Assessm ents (20 12 ) : 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

- to

mouth transfer of metofl uthrin residues from the indoor p erimeter/spot/bed bug use. All hand

- to

mouth post

- application exposure scenarios resulted in MOEs greater than 3 00 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 Exposure a (mg/day) F aihands SA H (cm 2 ) Exposure

Frequency (events/hr) F
m SE ET

(h ou rs/day) Replen_

Interval (min) N

_

Replen ish HR b

(mg/cm 2 ) Oral Dose

(mg/kg/day) c Incidental

Oral
MOE d

Carpets

0.1 0. 15 150 20 0.15 48% 4 15 4 0.0001 0.0 017 8,5 00

Hard Surfaces

0.1 0.1 5 150 20 0.15 48 % 2 15 4 0.0001 0.0 0088 1 7,0 00

a. Dermal Exposure value determined for perimeter scenario.
b. Hand Residue Loading (mg/cm 2 ) = (F aihands * Dermal exposure) / (SA H * 2).

c. Oral Dose (mg/kg/day) = Exposure (mg/day)/ Body Weight (11 kg); where Exposure (mg/day) = HR * *F M * SA H ) *

(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 p erimeter/spot/bed bugMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 31 of 84 use. All object

- to

- mouth post

- application exposure scenarios resulted in risk estimates ( MOEs )
greater than the LOC of 3 00 and are not of concern.

Table 6 .2. 3 .2. Post

- application Incidental Oral (Object

- to

- Mouth) Exposure and Risk Estimates Resulting f rom Perimeter/Spot/Bed Bug Application.

DepR a (ug/cm 2 ) F
o OR b

(μg/cm 2 ) SAM O

(cm 2 ) Freq_Replen

Exposure Frequency (events/hr) SE ET

(h ou rs/day) Replen_

Interval (min) N

_ Replen Exposure

c ( mg/day ) Oral Dose

(mg/kg/day) d Incidental

Oral
MOE e

Carpets

0.9 0. 02 0.018 10 14 48% 4 15 4 0.0026 0.000234 6 4,0 00

Hard Surfaces

0.9 0. 04 0.036 10 14 48 % 2 15 4 0.0026 0.000234 6 4 ,000

a. DepR = Deposited residue
b. Chemical residue loading on the object = OR (μg/cm 2 ) = Deposited residue (ug/cm 2 ) * 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/d ay); incidental oral PoD = NOAEL =15 mg/kg/d ay and level of
concern = 300.

6.3 Combined Exposure

6 .3.1 Combined Residential Post

- A pplication 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 toxicologica l effects across different routes of exposure are the same.

T here 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

p erime ter/spot/bed bug and bed bug/mattress use. However, as indicated previously, HED believes post

- application inhalation exposure is negligible . Therefore, since the d ermal and oral routes of exposure share common endpoints as well as LOCs, these routes of e xposure 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

- to

mouth 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 p erimeter/ s pot/

b ed b ug ( p in s team) 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.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 32 of 84 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 MOE b Combined
MOEs c d

Bed Bug Adult Dermal

- perimeter 0.012 2 5,000

22,000 c Dermal

– mattress 0.00 17 170 ,000

Children

1 < 2 years old Dermal

- perimeter 0. 012 25 ,000

5,900 d

Dermal

– mattress 0.00 40 74,000

Hand

- to

- Mouth 0.0 017 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 Scenario s)

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., p erimeter/ s p ot/

b ed b ug , b ed bug m attress ). 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 e xpect use of outdoor repellents to co

- occur with indoor treatment for bed bugs. Therefore exposures from
these scenarios were not combined.

VBC 3 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, r esidential handler and post

application 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

- A ppli cation Inhalation Exposure

This type of exposure is n ot 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

.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 33 of 84 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, a n 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 includ ed 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 resi dential 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 wat er , 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 VBC 3 Insecticide formulation in indoor residential, institutional and commercial facilities

. Based on application rate and label informa tion, 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 sce nario s :

Mixing/loading/applying sprays with m anually

- p ressurized h andwand ; 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.
Comm ercial handler risks were assessed for m ixer/loader/applicator (MLA)

, using surrogate unitMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 34 of 84 exposures from the Pesticide Handlers Exposure Database (PHED) Version 1.1 1 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 interm ediate

- term occupational handler exposures and risks. All occupational handler scenarios resulted in risk estimates ( ARI s ) greater tha n the LOC of 1 assuming baseline attire (i.e., single layer of clothing, no respirator)

. The
lowest ARI of 76 was assoc iated 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

Page 35 of 84 Table 9 .1: Commercial Handler Exposure and Risk Estimates.

Application

Rate a ( lb ai/gal) Amount

Treated b (gals./day) Baseline

Dermal
Unit Exposure c (mg/lb ai) Inhalation

Unit Exposure c (mg/lb ai) Baseline

Dermal

Dose d (mg/kg/day) Inhalation

Dose e (mg/kg/day) Baseline

Dermal
MOE f Baseline

Inhalation
MOE g ARI h

Mixer/Loader/Applicator Using Manually

- Pressurized Handwand

0.0 0086 4 20

(hotels, motels) 2 9 1.1
Baseline 0.0 062 0.0 0024 48

, 0 00 31,000 330

5 (residential premises) 29 1.1
Baseline 0.00 156 0.00 0059 190 ,000 120

, 0 00 1,300

Mixer/Loader/Applicator Using Backpack

0.0 0086 4 20

(hotels, motels) 2.51 0.03 0.000 542 0.000 0065 55 0,000 1,100 ,000 4,800

5 (residential premises) 2.51 0.03 0.000 136 0.0000 016 2,20 0,000 4,50 0,000 19,000

Applicator Using Paintbrush

0.000864 20

(hotels, motels) 180 0.28 0.0 38 0.000 06 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 VBC 3 Insecticide (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 Exposur e 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) *i nhalation absorption (100 %) / body weight (80 kg).
f. Dermal MOE = NOAEL (300 mg/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/ARI dermal ) + (1/ARI inhal )] where, ARI dermal = MOE dermal /100 and ARI inhal = MOE inhal /30. ARIs greater
than 1 are not of concern

.

9.2 Short

- /Intermediate

- Term Post

- Application Risk

9.2.1 Dermal and Inhalation Post

- A pplication Risk

Based on the uses associated with the VBC 3 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 comme rcial 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 10.0 References

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- 166.

Collantes, M. (2012), September 5 , 2012. D397725. “Metofluthrin: Occupational and Residential Exposure and Risk Assessment to Support the Proposed Bed Bug Treatment.”

de Zwart, L., M. Scholten, J. G. Monbaliu, P. P. Annaert, J. M. Van Houdt, I. Van den Wyngaert, L. M. De Schaepdrijver, G. P. Bailey, T. P. Coogan, W. C. Coussement and G. S. Mannens (2008). "The ontogeny of drug metabolizing enzymes and transporters in th e rat." Reproductive Toxicology 26(3

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Felts, P. A., S. Yokoyama, S. Dib

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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. B. Conolly and R. Tornero

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- Limited Model."
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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 (20 00). "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
Ass essment for the Proposed Section 3 Registrations of Metofluthrin.”

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 48333801.Unpublished. DP# 386418.".

Hughes, M. F. and B. C. Edwards (2010). " In vitro dermal absorption of pyrethroid p esticides 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.”

Kidw ell, J. (2006) June 6, 2006, TXR No. 0054239. “ Metofluthrin: Report of the Cancer

Assessment Review Committee

. ”Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 37 of 84 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.

Lawren ce, L. and J. Casida (1982). "Pyrethroid toxicology: Mouse intracerebral sturcture

toxicity 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.

Meacham, C. A., P. D. Brodfuehrer, J. A. Watkins and T. J. Shafer (2008). "Developmentally

regulated sodium channel subunits are differentially sensitive to [alpha]

- cyano containing pyrethroid s." Toxicology and Applied Pharmacology 231: 273

- 281.

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

- D awley 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 stu dy 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 carboxy lesterases." 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
assessment." Toxicology 171(1): 3

- 59.

Song, J. and T. Narahashi (1996). "Modulation of sodium channels of rat cerebellar Purkinje neurons by the pyrethroid tetramethrin." J Pharmacol Exp Ther 277(1): 445

- 453.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 38 of 84 Tabarean, I. V. and T. Narahashi (1998). "Potent Modulation of Tetrodotoxin

- Sensiti ve and
Tetrodotoxin

- Resistant Sodium Channels by the Type II Pyrethroid Deltamethrin." J Pharmacol Exp Ther 284(3): 958

- 965.

Tan, J. and D. M. Soderlund (2009). "Human and rat Nav1.3 voltage

- gated sodium channels differ in inactivation properties and sensi tivity to the pyrethroid insecticide tefluthrin." NeuroToxicology 30(1): 81

- 89.

Tornero

- Velez, R., A. Mirfazaelian, K.

- B. Kim, S. S. Anand, H. J. Kim, W. T. Haines, B. James V and J. W. Fisher (2010). "Evaluation of deltamethrin kinetics and dosimetry in t he maturing rat using a PBPK model." Toxicol Appl Pharmacol 244: 208

- 217.

USEPA (2007). "Meeting Minutes: FIFRA SAP Meeting on Assessing Approaches for the Development of PBPK Models of Pyrethroid Pesticides. Document ID: EPA

- HQ

- OPP

2007

- 0388

- 0049. www.regulations.gov. "

USEPA (2011a). September 4, 2011, D394567. "Pyrethroid Cumulative Ri sk Assessment ."

USEPA (2011b). June 27, 2011, D381210. “ Reevaluation of the FQPA Safety Factor for Pyrethr oid Pesticides

. ”

Verschoyle, R. D. and W. N. Aldridge (1980). "Structure

- activity relationships of some pyrethroids in rats." Arch Toxicol 45(4): 325

- 329.

Weiner, M. L., M. Nemec, L. Sheets, D. Sargent and C. Breckenridge (2009). "Comparative
functional observational batte ry study of twelve commercial pyrethroid insecticides in male rats following acute oral exposure." Neurotoxicology 30 Suppl 1: S1

- 16.

Wolansky, M.J., McDaniel, K.L., Moser, G.C. and Crofton, K.M. (2007) “Influence of dosing volume on the neurotoxicity of b ifenthrin.” Neurotoxicology and Teratology 29(3):377

- 384.

Wolansky, M. J. and J. A. Harrill (2008). "Neurobehavioral toxicology of pyrethroid insecticides
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 carboxylesterases HCE1 and HCE2: Ontogenic expression, inter

- individual variability and differential hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin."
Biochemical Pharmaco logy 77(2): 238

- 247.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 39 of 8 4 A ppendix 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

Page 40 of 84 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 LD 50 >2000 mg/kg III

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

870.1300 Acute inhalation [rat] 46406723 LC 50 >1.08 mg/L and <1.96 mg/L III

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

870.2500 Acute dermal irritation [rabbit] 46406724 Mildly irritating (PDI = 0.8) IV

870.2600 Skin sensitization [Guinea pig] 46406726 Not a sensitizer

-

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 li ver 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
increa sed 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 hep atocellular hypertrophy in both sexes ; and increased Kupffer cells in males.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 41 of 84 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 dail y 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/m 3
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

Non

guideline Prenatal

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 Parent al LOAEL = 40 mg/kg/day based on mortality and increased incidence of tremor s 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 = 4 0 mg/kg/day Developmental LOAEL = not observedMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 42 of 84 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Metofluthrin Technical

Guideline
No. Study Type MRID No. (year)/
Classification /Doses

Non

guideline Prenatal

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 tremor s 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 (increa sed 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

Page 43 of 84 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 glomerulosclerosi s) 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

co nsidered 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

respo nse ”

. 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. c oli
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
WP2 uvrA There was no evidence of induced mutant colonies over background levels.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 44 of 84 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

contro ls.

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 = 17 8.8/206.0 mg/kg/day, based on the clinical signs of
tremors and twitches in the females

870.6300 Developmental

neurotoxicity Not required.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 45 of 84 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, T

max 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 lev els 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/cm 2 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

Non

guideline An evaluation of

the human
relevance of the
metofluthrin

induced 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)

.

Non

guideline 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.

Non

guideline The 2 nd 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).Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 46 of 84 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Metofluthrin Technical

Guideline
No. Study Type MRID No. (year)/
Classification /Doses

Non

guideline Study for mode

of action of S

1264 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.

Non

guideline Gene expression

profiling analysis of early phase
treatment in the
liver from S

1264 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 convul sions 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
WP2 uvrA with and without S9 activation) in both the preliminary cytotoxicity and mutagenicity assays There was no evidence of induced mutant colonies over background levels.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 47 of 84 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 matern al 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 andMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 48 of 84 salivation, clinical signs typical of type I py rethroids, 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/da y). 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 3 00 was utilized (10 each for UF H and UF A

, plus a UF DB 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 a ll 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 UF H and
UF A ). For children <6 years of age, a UF of 300 was utilized (10 each for UF H and UF A, plus a
UF DB 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 m ortality and clinical signs including tremors, hypersensitivity, abnormal gait, clonic convulsions andMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 49 of 84 hyperthermia seen at LOAEL = 0.196 mg/L

. HEC (systemic effects) = 0.052 mg/L, residentia l exposure and 0.1 55 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 intermedi ate

- 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. T he inhalation study i s 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 a erosolized
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

exp osure 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 3 0 X was utili zed (10 X for UF H and
3 X for UF A

, reduced from 10 based on the adjustment for PK in calculation of the HEC ). For children <6 years of age, a UF of 1 00 X (10 X for UF H , 3 X for UF A, plus a UF DB of 3 X 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

- relat ed 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 statisticallyMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 50 of 84 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) w ere 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).

S light 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 abso lute 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 0.0 01) 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) b y 13%. An increase in severity in hyaline droplets in the kidneys w as 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 earl y 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 enlarg ed 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 ad ministered 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.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 51 of 84 No treatment

- related, adverse effects w ere 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 exhibit ed 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 gro ups; 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) hepat ocellular 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 chol esterol 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 (Me tofluthrin, 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 treatmen t

- 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 (notMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 52 of 84 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. T he 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 si milarly 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, h ematology, 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 o bservations. 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 control s). 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

– RatMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 53 of 84 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 meth od.

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 t ested 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 obse rved 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 obser ved 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 der mal 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 atMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 54 of 84 concentrations of 0, 10, 50, 100, or 200 mg/m 3 (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 w eights, gross pathology, or histopathology.

At 200 mg/m 3 , 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 posi tion, 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/m 3 on 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/m 3 (equiva lent to 0.196 mg/L) based on mortality and clinical signs indicating neurotoxicity in both sexes. The NOAEL is 100 mg/m 3 (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 87 0.3465; 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 f rom 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 patholog y. All dams survived until scheduled termination.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 55 of 84 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 abou t 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, an d 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 deve lopment 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 3 0 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 m ating, 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 periodi city 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, ma les were euthanized, subjected to gross necropsy, and the testes and epididymides were weighed.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 56 of 84 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 consumptio n 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 no ted 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 findin gs 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
ob servations, 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 a t 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
fetu ses, 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

- rel ated 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 develop mental 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

- DawleyMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 57 of 84 Crj:CD(SD) rats/dose at 0, 5, 15, or 30 mg/kg at a d ose 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 F 1 pups were examined for viability, body weight development, developmental landmarks, and early behaviora l reflexes during lactation. On post

- natal day (PND) 21, all surviving pups (except 2/sex/litter) were euthanized and examined grossly. One F 1 pup/sex/litter was subjected to behavioral testing from PND 28

- 56 and sacrificed on PND 70. The remaining F 1 p up/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 wei ght 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 ea ch 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 befor e dosing on the following day. There were no maternal mortalities during gestation. Durin g 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 m aternal 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; F 1 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 indice s in the F 1 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 p athology in the F 1 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.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 58 of 84 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 w eights, 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 G D 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. The re 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),

reso rptions (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

- r elated 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 ToxicityMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 59 of 84 In a two generation reproductive toxicity study (MRID 48770701), S

- 1264 (metofluthrin technical, 95.4% a.i., Lot No. PK

- 020301G) was administered

c ontinuously 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, to tal 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, decrease d 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 signific antly 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

- relate d 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 do ses 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 mo rtality 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 2 5, 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 theseMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 60 of 84 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 dec reased 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 fe male #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 pr ovided.

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.

Tre mor 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 1 00 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. TheMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 61 of 84 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 si gns, 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. Re lative 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 hepat ocellular 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%).Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 62 of 84 Additional signs of nephrotoxicity were observed at 1800 pp m. 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 ki dney 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, increa sed incidences in hepatic adenom a s 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 carcinoma s 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 in crease 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/carcinogenic ity 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

- r elated 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 de ad. 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.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 63 of 84 Furthermore, there was no effect on mort ality 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 wit hdrawal 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 w as 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 GenotoxicityMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 64 of 84 870.5395 , 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 batte ry (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 extens or 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 fo llowing 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 sex es 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

mo vement 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. Additionall y, 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.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 65 of 84 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 comple te 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 mi croscopically. 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 exc ess 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 weight s 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 co nsumption 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 c onsumption 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

- r elated 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.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 66 of 84 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 (870.62 00b) 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 ), [Carbonyl

14 C]

- S

- 1264 R

- trans

- Z (Lot # RIS2000

- 019; radioch emical purity 98.4

- 99.7%), [Carbonyl

14 C]

- S

- 1264 R

- trans

- E (Lot # RIS2000

- 020; radiochemical purity 98.1

- 99.4%), or [Methoxymethylbenzyl

- α

14 C]

- S

- 1264 R

- trans

- Z (Lot # RIS2001

- 003; radiochemical purity 98.6

- 99.6%) in corn oil was administered to Sprague

- Da wley (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), [Carbonyl

14 C]

- S

- 1264 RTZ or RTE was administered as a single gavage dose at 1 mg/kg nominal. Additionally, [Carbonyl

14 C]

- S

- 1264 RTZ or [Methoxymethylbenzyl

- α

14 C]

- 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 T
max of 3.3

- 8.0 h. Absorption was calculated to be 83

- 84% of the administered dose for [Carbonyl

14 C]

- S

- 1264 RTZ, and 78

- 79% of the administered dose for [Carbonyl

14 C]

- S

- 1264 RTE, based on radioactivity in the urine and bile. Absorption also did not

appe ar 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 withoutMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 67 of 84 a clear relationship with sex, test compound, or dose. By 168 h post

- dosing, total
urin ary 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 [Carbonyl

14 C]

- S

- 1264

- treated groups, but were slightly higher in the

u rine of the [Methoxymethylbenzyl

- α

14 C]

- 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 (w ith the possible exception that [Carbonyl

14 C]

- 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
ti ssues 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 toxi cologically 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 metabol ites 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 pri mary urinary metabolites were X1 and X2, accounting for 14

- 35% of the administered dose in the [Methoxymethylbenzyl

- α

14 C] S

- 1264

- treated groups. The primary fecal metabolite was Ac16, accounting for 11

- 14% of the administered dose in the [Carbonyl

14 C] 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 groupMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 68 of 84 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

a nd 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 ac id 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 alcoho l 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 stereois omer 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
concurrentl y 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 a ction 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 S

1264 in the induction of hepatocellular adenomas and/or carcinomas in rats.

In a non

- guideline stud y (MRID 46581501), five to seven BrlHan:WIST@Jcl(GALAS) rats/sex/dose were exposed to S

- 1264 (Metofluthrin;Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 69 of 84 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

- 4 50 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 bot h 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 decre ased 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 w as 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 treat ment 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 note d 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 sexe s. 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 obs erved 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 proteinMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 70 of 84 concentration or total microsomal P

- 450 levels. Re lative 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. Incre ased 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 anim als 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 enzy me 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 Sponso r 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 non

genotoxic modes of act ion 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
#5 CMI222G ) was administered to 10 SD strain rats /sex/concentration by dynamic nose

only 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

- days

female). The analytical concentrations were: 0, 10.0, 49.6, 98.5 and 189 mg/L.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 71 of 84 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 tremor s 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 co ntinued to be seen until Day 26 of exposure in males and Day 18 in females, although their inc idence decreased with continued exposure.

The LOAEL is 200 mg/L/day, based on in creased mortality and neurological signs of toxicity (tremor, tiptoe gait , latera l 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
WP2 uvr A were exposed to S

- 1264ZR (metabolite of Metofluthrin, 96.2%; Lot 5CM1222G) in dimethyl sulfoxide ( DMSO ) a t 0, 156, 313, 625, 1250, 2500, and 5000 μg/plate (all strains with and without S9 activation) in both the preliminary cytotoxicity
and m utagenici ty 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 p henobarbital 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 sol ubility (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 rev ertants/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.

Th e 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.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 72 of 84 Appendix A.5 METOFLUTHRIN

– CALCULATIONS OF RDDR, HEC AND HED

Calculation s 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 prog ram using the following inputs and the program’s default human inputs: NOAEL (No Observed Adverse Effect Level): 0.099 mg/L MMAD (mass median aerodynamic diameter): 2.47 μm GSD (geometric standard deviation: 2.02 Animal body weight: 185 g (rounded

- up initial bw for males)

RDDR = RDD

r

/Normalizing Factor) A RDD

r /Normalizing Factor) H

Where RDD is the regional deposited dose of particles and r represents the extrathoracic, tracheobronchial and pulmonary respiratory tract regions

2. HEC (Human Equivalent Concentration, expressed as mg/L) : NOAEL in mg/L x RDDR x [hours/day exposure, anim als ÷ 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/dayMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 73 of 84 A ppendix 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

P OW (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 - 1 cm - 1 , band width 23 nmMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 74 of 84 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 S OP (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

- d ata.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.htmlMetofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 75 of 84 Appendix D : Cumulative Exposure and Risk Issues

Since the bed bug (indoor) use of metofluthr in 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 expecte d under the use pattern . In order to determine if the proposed metofluthrin bed bug use significantly contributes to or change s the overall findings in the pyrethroid CRA

, the Agency has performed a quantitative exposure and risk assessment. This assessm ent 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 poss ible

, 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. Th ese data w ere selected beca use the studies
examined the key behaviors for evaluating neurotoxicity specific to pyrethroids

. T he 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., hypot hermia, 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 to xicity 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
unifo rm 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 CR A

, 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 BMD 20 , by the BMD 20 of the inde x 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 sim ilar relative potency to deltamethrin

, while
lambda

- cyhalothrin resulted in slightly greater potency than deltamethrin. An RPF of 0.48 was used to quantify comparative exposure s from the proposed metofluthrin bed bug use.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 76 of 84 Table D.1. Relative Potency Estimates for Pyrethroids Included in the Screening
Level Cumulative Risk Assessment

Pyrethroid Oral BMD 20 Oral RPF b,d

Allethrin c 135 0.11
Bifenthrin 14.3 1.01 Cyfluthrin 12.6 1.15
Lambda

- Cyhalothrin 8.9 1.63 Cyphenothrin 100 a 0.15 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 750 a 0.02

Metofluthrin 30 0.48
Permethrin 156 0.09
Prallethrin 150 a 0.10 Pyrethrins 800 a 0.02
Resmethrin 291 0.05

a Values estimated from studies; these values were not calculated using BMD. See Section 4.2 of the CRA.

b RPF = BMD 20 of Index Chemical (e.g., deltamethrin)/Pyrethroid BMD 20 ; For example: Metofluthrin
RPF=14.5/ 30 = 0.48

c Includes the isomeric enrichments S

- Bioall ethrin and D

- Allethrin

d RPFs 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 cur rently driving indoor exposures and risks (as referenced from Table 6.4.7a of the 2011 pyrethroid CRA ) to those estimated for the proposed metofluthri n 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 post

application 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 assessme nt 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 pe sticides, 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 indoo r fogger use pattern with an MOE of 3,9 00

, 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 estima ted 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 metoflu t hrin 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 presente d in Tables D.3 and D4.Metofluthrin Human Health Risk Assessment DP Nos. D402777, D403390

Page 77 of 84 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 900Metofluthrin Human Health Risk Assessment DP No s . D402777 , 403390

Page 78 of 84 Appendix Table D.3 : Metofluthrin Screening Level “Cumulative” MOEs

– Handler E xposure Handler Dermal Exposure

Exposure Scenario Application
Rate a (lb ai/gal) Amount

Treated b (gals) Baseline

Dermal
Unit Exposure b (mg/lb ai) Baseline

Inhalation
Unit Exposure b (mg/lb/ai) Baseline

Dermal
Dose c (mg/kg/day) Adjusted

Baseline
Dermal Dose d (mg/kg/day) Adjusted

Baseline
Dermal e
MOE Baseline

Inhalation
Dose f (mg/kg/day) Adjusted

Baseline
Inhalation
Dose g (mg/kg/day) Adjusted

Baseline
Inhalation
MOE h Combined

MOE i

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)/Adjuste d 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 = Delt amethrin 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)Metofluthrin Human Health Risk Assessment DP No s . D402777 , 403390

Page 79 of 84 Appendix Table D.4 : Metofluthrin Screening Level “Cumulative” MOEs

– Post

- application Exposure

Post

- application Dermal Exposure

Exposure Scenario Surrogate Deposition (μg/cm 2 ) 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 0.000 38 27,000

Dermal Exposure from Carpet after Bed Bug Use (A dults) 6,800 8 0.98 71.8 0.00068 0.000 32 32,000

Post

- application Incidental Oral Exposure

Exposure Scenario Fai hands 1

- 2 yr old
Dermal Exposure SA H

(cm2) HR t (mg/cm2) F M

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 8.9 E

- 0 5 0.13 5 4 0.5 20 11.4 0.0 0290 0.00 14 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 BMD 20 from the WIL FOB data for the index chemical, deltamethrin (14.5 mg/kg/day)Metofluthrin Human Health Risk Assessment DP No s . D402777 , 403390

Page 80 of 84 Appendix E: Registered Residential Exposure and Risk to Support Registration Review

SOURCE : Exp osure 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 propose d 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:

Dec kMateTM 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 contain s 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 ins ect 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 size s (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 f

eet.

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 effec ts outcomes) are reported by registrants as aggregate summaries and are recorded in a separate module called Aggregate IDS. In A ggregate IDS , from January 1, 200 7 to February 22, 2012, there were 138 reported incident s involving metofluthrin

. I ncidents r esulting
in high er 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

.Metofluthrin Human Health Risk Assessment DP No s . D402777 , 403390

Page 81 of 84 For the M ain IDS, from January 1, 200 7 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 met ofluthrin and other
chemicals.

Overall the incident cases reported for metofluthrin were generally low frequency and low severity. However, because th e personal repellent is a relatively new delivery method and there
are 39 moderate inciden ts reported in IDS Main, these data indicate that the Agency should
continue to monitor incidents with metofluthri n, 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. Upo n 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

- A pplication 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 us e of an aerosol stud y to evaluate toxicity fro m 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) product s (e. g. , repell e nt strip , candle ). Due to the size fraction of par t icles released from the activation of CCTM products, particles are expected to remain airborne rather than be deposited on surfaces. Therefore, dermal and incidental or al 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 Sys tems.

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

.Metofluthrin Human Health Risk Assessment DP No s . D402777 , 403390

Page 82 of 84 E .1: Inhalation Post

- application Exposure and Risk Estimates for Repell e nt Strip

. Life Stage Emission

Rate (mg ai/hr) IR

(m 3 /hr) Airflow

Q (m 3 /hr) VE Exposure

Time (hrs/day) Volume

treated (m 3 ) Exposure (mg/day) Dose

(mg/kg/day) MOE 1

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 Repell e nt Device

The Revised Residential SOPs do not include a methodology for assessing personal repellents; therefore, previously assessed post

- application expo sure estimates f or 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 esti mates 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

Volume 1
(m 3 ) Concentration 2

(ug/m 3 ) Dose 3

(mg/kg/day) MOE 4

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 m 3

. 2. Concentration = 21.4 ng / 0.36 m 3 = 59 ng/ m 3 = 0.059 μg/ m 3 = 0.000059 mg/ m 3

. 3. Adult Dose = 0.000059 mg/ m 3 x 15.36 m 3 /day × 0.5 days × 1/ 80 kg = 5.6 x 10 - 6 mg/kg/day. Child Dose = 0.000059 mg/ m 3 x 8m 3 /day × 0.5 days × 1/1 1 kg = 2.1 × 10 - 5 mg/kg/da y. 4. MOE = Human Equivalent Dose (7.5 mg/kg/day)/ Dose (mg/kg/day).

Table E

. 2 b. Post

- application Dermal Exposure and Risk f or Personal Insect Repellent. Lifestage Total Dose (mg/kg/day) MOE 1

Adult 0.0088 34, 000 a

Child 0.0436 6,9 00 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).Metofluthrin Human Health Risk Assessment DP No s . D402777 , 403390

Page 83 of 84 Table E .2c

. Children’s Post

- application Incidental Oral Exposure and Risk f or Personal Insect Repellent

. Sampling

Media * Mean

Residue (ug) Mean

(mg) Cumulative

Residue 1 (mg) Oral Dose 2

(mg/kg/day) MOE 3

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)/1 1 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 c an occur simultaneously based on the use pattern and when the toxicological effects across different routes of exposure are the same.

T here 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, r esidues deposited on patios or other surfaces are expected to be negligible after use of a CCTM product

. Therefore, dermal and
in cidental 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, th ere 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 ora l and inhalation routes of

exposure are the same toxicological effect s (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

- to

mouth) could occur simul taneously, c ombining 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.Metofluthrin Human Health Risk Assessment DP No s . D402777 , 403390

Page 84 of 84 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 MOE b ARI s 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/ARI dermal ) + (1/ARI inhal )] where, ARI dermal = MOE dermal /100 and ARI inhal = MOE inhal /30. ARIs greater than 1 are not of concern.

c 2 Child ARI= 1/[(1/ARI dermal ) + (1/ARI inhal ) + (1/ARI oral )] where, ARI dermal and ARI oral = MOE/300 and
ARI inhal = MOE inhal /100. ARIs greater than 1 are not of concern.