UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

MEMORANDUM

DATE: 8/27/2012

SUBJECT: Bifenthrin: Human Health Risk Assessment to Support Section 3 New Uses for a 

Bed Bug Treatment, Grass Grown for Seed, Tolerances for Imported Tea, and a Section 18 

Emergency Exemption Use on Apple, Nectarine, and Peach

PC Code: 128825 DP Barcode: D372550

MRID No.: Not Applicable Registration No.: 279-3313, 279-3108

Petition No.: 9E7652 Regulatory Action: Section 3 and 18 Registrations

Assessment Type: Single 

Chemical Aggregate

Reregistration Case No.: Not Applicable

TXR No.: Not Applicable CAS No.: 82657-04-3

FROM: Wade Britton, MPH, Risk Assessor

William Irwin, PhD, DABT, Toxicologist

Ana Rivera-Lupiáñez, Chemist

Pete Savoia, Chemist

Seyed Tadayon, Chemist

Risk Assessment Branch V

Health Effects Division (HED; 7509P)

THROUGH: Michael Metzger, Branch Chief

And 

Donna S. Davis, Chemist

William Donovan, Ph.D., Chemist

Risk Assessment Branch V/ VII

Health Effects Division (7509P)

TO: Laura Nollen, Biologist

And

Barbara Madden, Team Leader

Risk Integration Minor Use, and Emergency Response Branch

Registration Division (7505P)

Bewanda Alexander, Risk Manager

And 

Richard Gebken, PM 10

Insecticide Branch

Registration Branch (7505P)
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Jennifer Urbanksi, PhD, Biologist

And

Venus Eagle, PM 1

Insecticide-Rodenticide Branch

Registration Division (7505P)
Table of Contents

1.0 Executive Summary........................................................................................................... 6

2.0 HED Recommendations.................................................................................................. 10

2.1 Data Deficiencies .......................................................................................................... 10

2.2 Tolerance Considerations............................................................................................ 11

2.2.1 Enforcement Analytical Method................................................................................. 11

2.2.2 International Harmonization ...................................................................................... 11

2.2.3 Recommended Tolerances........................................................................................... 11

2.2.4 Revision to Petitioned-for Tolerances.......................................................................... 12

2.3 Label Recommendations.............................................................................................. 12

3.0 Introduction...................................................................................................................... 12

3.1 Chemical Identity ......................................................................................................... 12

3.2 Physical/Chemical Characteristics ............................................................................. 13

3.3 Pesticide Use Pattern.................................................................................................... 13

3.4 Anticipated Exposure Pathways................................................................................. 15

3.5 Consideration of Environmental Justice.................................................................... 15

4.0 Hazard Characterization and Dose-Response Assessment.......................................... 16

4.1 Toxicology Studies Available for Analysis................................................................. 17

4.2 Bifenthrin Toxicological Profile.................................................................................. 18

4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile.................................. 21

4.3.1 Pharmacokinetics......................................................................................................... 21

4.3.2 Pharmacodynamics...................................................................................................... 23

4.3.3 Critical Duration of Exposure..................................................................................... 25

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 26

4.4.1 Completeness of the Toxicology Database ................................................................. 27

4.4.2 Evidence of Neurotoxicity............................................................................................ 29

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ........... 29

4.4.4 Residual Uncertainty in the Exposure Database....................................................... 30

4.5 Toxicity Endpoint and Point of Departure Selections.............................................. 31

4.5.1 Dose-Response Assessment.......................................................................................... 31

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment.......... 33

4.5.3 Cancer Classification and Risk Assessment Recommendations.............................. 33

4.5.4 Points of Departure and Toxicity Endpoints Used in Human Risk Assessment.... 34
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5.0 Dietary Exposure and Risk Assessment......................................................................... 35

5.1 Metabolite/Degradate Residue Profile ....................................................................... 35

5.1.1 Plant and Livestock Metabolism Studies................................................................... 35

5.1.2 Summary of Environmental Degradation.................................................................. 35

5.1.3 Comparison of Metabolic Pathways........................................................................... 36

5.1.4 Residues of Concern Summary and Rationale.......................................................... 36

5.2 Food Residue Profile .................................................................................................... 37

5.3 Water Residue Profile.................................................................................................. 37

5.4 Dietary Risk Assessment.............................................................................................. 38

5.4.1 Description of Residue Data Used in Dietary Assessment........................................ 38

5.4.2 Percent Crop Treated Used in Dietary Assessment.................................................. 39

5.4.3 Acute Dietary Risk Assessment................................................................................... 40

5.4.5 Average Dietary Exposure........................................................................................... 41

5.4.6 Summary Table ............................................................................................................ 41

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 42

6.1 Residential Handler Exposure .................................................................................... 43

6.2 Residential Post-Application Exposure...................................................................... 44

6.3 Combined Exposure..................................................................................................... 44

6.4 Residential Bystander Post-application Inhalation Exposure ................................. 46

7.0 Aggregate Exposure/Risk Characterization.................................................................. 46

7.1 Acute Aggregate Risk................................................................................................... 47

7.2 Short-Term Aggregate Risk........................................................................................ 47

7.3 Intermediate-Term/Chronic Aggregate Risk ............................................................ 48

8.0 Cumulative Exposure/Risk Characterization ............................................................... 49

9.0 Occupational Exposure/Risk Characterization ............................................................ 49

9.1 Occupational Short -Term Handler Exposure/Risk ................................................. 49

9.2 Occupational Short-Term Post-Application Exposure/Risk.................................... 55

9.2.2 Inhalation Post-application Risk................................................................................. 56

10.0 References......................................................................................................................... 57

Appendix A. Toxicology Profile and Endpoint Selection....................................................... 62

A.1 Toxicology Data Requirements................................................................................... 62

A.2 Toxicity Profiles............................................................................................................ 63

A.3 Hazard Identification and Endpoint Selection............................................................. 71

A.3.1 Acute Reference Dose (aRfD, including General Population and Females 13-49), 

Acute Population Adjusted Dose, & Incidental Oral Exposure ......................................... 72
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A.3.2 Chronic Reference Dose (cRfD).................................................................................. 73

A.3.3 Dermal Exposure (Short-Term).................................................................................. 74

A.3.4 Inhalation Exposure (Short-Term)............................................................................. 74

Appendix B. Review of Human Research................................................................................ 75

Appendix C. Residential Exposure/Risk Summary Table ..................................................... 75

Appendix E: Bifenthrin BMD Analysis for the 21-Day Dermal Study................................. 82
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1.0 Executive Summary

Interregional Research Project No. 4 (IR-4) has requested a Section 3 registration of a new use 

on grass grown for seed and a tolerance (with no US registrations) for imported tea. In addition, 

a Section 18 emergency exemption for the control of Brown Marmorated Stink Bug in apple, 

nectarine, and peach crops was requested for use by the following seven eastern states: 

Delaware, Maryland, North Carolina, New Jersey, Pennsylvania, Virginia, and West Virginia. 

The Section 18 inquiry was communicated informally by the states to the Registration Division 

(RD) in an effort to identify an effective means to control the insect. HED has assessed the 

proposed uses and Section 18 inquiry and this document presents the findings and an assessment 

of human health risk.

Bifenthrin (2-methyl[1,1'-biphenyl]-3-yl)methyl-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-

dimethylcyclopropane-carboxylate) is an insecticide and miticide in the class of pyrethroids. 

The mode of action for bifenthrin and other pyrethroids is the delay of inactivation of affected 

voltage gated sodium channels (VGSCs), allowing for an increase in sodium ion influx and 

resulting in delayed repolarization and, ultimately, insect paralysis. Bifenthrin is registered for 

use on a wide variety of agricultural crops, as well as indoor and outdoor residential uses to 

control insect pests. 

Hazard Assessment: Pyrethroids have historically been classified into two groups, Type I and 

Type II, based upon chemical structure and toxicological effects. Bifenthrin is a Type I synthetic 

pyrethroid. Behavioral changes characteristic of Type I pyrethroids, such as muscle tremors, 

were seen in most of the bifenthrin experimental toxicology studies. The toxicity database for 

bifenthrin is not complete. The database of bifenthrin experimental toxicology studies provides a 

robust characterization of the hazard potential for children and adults. There are two outstanding 

Part 158 data requirements for bifenthrin. An immunotoxicity study is required due to recent 

changes to Part 158 which impose new data requirements for pesticide registration. An acute 

inhalation study with acute neurotoxicity (ACN) metrics is also required to substitute for the subchronic inhalation study. Numerous studies from the scientific literature that describe the 

pharmacodynamic and pharmacokinetic profile of the pyrethroids in general have been 

considered in this assessment. In addition, there are on-going efforts to develop methods to 

inform the possibility of increased sensitivity of juvenile rats to pyrethroids as a class at doses 

near the LOAEL values. 

Bifenthrin toxicity studies indicated muscle tremors, decreased locomotor activity and 

exaggerated hind-limb flexion. It does not cause developmental or reproductive effects. 

Bifenthrin has a low order of acute toxicity via the dermal and inhalation routes (Category III) of 

exposure and has moderate acute toxicity via the oral route (Category II). It is neither an eye nor 

skin irritant, nor is it a dermal sensitizer. 

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

the exposure and hazard assessments. Following a single oral gavage dose, bifenthrin is 

absorbed quickly in rats resulting in decreased motor activity and increased tremors. Toxicity is 

observed as quickly as 1 hour, peaks at 4 hours and motor activity started to return to normal at

7 hours, approximately following the blood pharmacokinetic (PK) profile (Wolansky, 2007). 
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This is generally consistent with the toxicity profiles for all the pyrethroids which are very

similar and marked by rapid absorption, metabolism, and time-to-peak effect. The NOAELs

and LOAELs established from bifenthrin single dose and repeat dosing studies show that repeat 

exposures do not result in lower NOAELs. Therefore, the endpoint from the acute study is 

protective of the endpoints from repeat dosing studies, which represent longer-term exposures. 

Thus, for purposes of endpoint selection and exposure assessment, only single-day risk 

assessments need to be conducted.

Given different levels of uncertainty for various risk assessment scenarios, EPA is applying 

different FQPA safety factors for the protection of fetuses, infants, and children depending on the 

route of exposure, data gaps and the population exposed. For non-inhalation exposure scenarios 

for adults (including women of child-bearing age) and children > 6 years of age, EPA is reducing 

the FQPA safety factor to 1X.

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

in any of the available animal testing guideline toxicity studies, including the developmental 

neurotoxicity study (DNT). However, the Agency is reducing the FQPA safety factor to 3X for 

non-inhalation exposure scenarios for infants and 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 pyrethroid concentration in 

juvenile brain compared to adults; 2) in vitro pharmacodynamic (PD) 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. 

EPA is requiring an inhalation toxicity study for bifenthrin because inhalation data for other 

pyrethroids show the potential for the inhalation route to be more potent than the oral route. Due 

to the inhalation study data gap, the Agency is retaining a 10X FQPA safety factor for all

inhalation exposure scenarios for all population groups. Once these data have been received, the 

Agency will determine how the results affect the toxicology endpoints and uncertainty factors. 

In the absence of specific immunotoxicity studies, the Agency has evaluated the bifenthrin 

toxicity database to determine whether an additional database uncertainty factor is needed. 

Because the 3X factor for infants and children < 6 years of age and the 10X factor for inhalation 

exposure scenarios are in response to different uncertainties, these safety factors have been 

combined for inhalation exposure scenarios for infants and children < 6 years of age resulting in 

an FQPA safety factor of 30X. 

The toxicology database for bifenthrin does not show any evidence of treatment-related effects 

on the immune system, and the overall weight-of-evidence suggests that this chemical does not 

directly target the immune system. Therefore, the Agency does not believe that conducting a 

functional immunotoxicity study will result in a lower POD than that currently in use for overall 

risk assessment, and additional safety factors are not needed to account for a lack of this study.
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For the acute dietary risk assessment, HED selected an endpoint from the most robust study for 

bifenthrin, the Wolansky acute oral study. The Wolansky study was considerably conservative, 

using the most sensitive rat strain, and gavage dosing using a vehicle and volume producing the 

most adverse responses. A benchmark dose (BMD) data analysis method was used to address 

any dose spacing effects. An acute reference dose (aRfD) of 0.010 mg/kg/day was selected for 

children < 6 years old (includes retention of the 3X FQPA SF) and 0.031 mg/kg/day was selected 

for assessment of all populations older than 6 years old, based on a BMDL1SD value of 3.1 mg/kg 

and a BMD1SD value of 4.1 mg/kg based on reductions in motor activity. The Wolansky acute 

oral study was also used for the assessment of short-term incidental oral and inhalation exposure 

scenarios. The BMDL1SD value of 3.1 mg/kg was selected for risk quantification. For short-term 

dermal exposure scenarios, risks were assessed using a 21-day dermal rat study with a BMDL10

of 96.3 mg/kg/day and a BMD10 of 187 mg/kg/day based on exaggerated hind limb flexion. 

Bifenthrin is classified as a “possible human carcinogen” based on an increased incidence of 

urinary bladder tumors in mice. However, EPA concluded that the bladder tumors may not be 

uncommon in mice and are not likely to be malignant. Additionally, these tumors were observed 

only in male mice at the highest dose tested and the incidence was of borderline significance. No 

evidence of carcinogenicity was observed in bifenthrin carcinogenicity studies in rats, and 

bifenthrin was negative in five different tests for mutagenicity but was marginally active in a 

forward mutation test in mouse lymphoma cells. Overall, based on the available information, 

there is a low concern for mutagenicity. Taking into account all of this information, the Agency

has determined that quantification of risk using a non-linear approach (i.e., an aPAD or aRfD) 

will adequately account for all chronic toxicity, including carcinogenicity that could result from 

exposure to bifenthrin. While the Agency would typically use a chronic population-adjusted dose 

(cPAD) to protect for cancer concerns, use of the aPAD is protective for bifenthrin because 

increasing toxicity with increasing duration of exposure is not seen for bifenthrin. 

Food Residue Profile: The residue chemistry database is considered complete for bifenthrin. 

For the purposes of the newly proposed uses, adequate metabolism data have been provided to 

demonstrate that the residue of concern in plants, livestock, and rotational crops is the parent 

compound only. Monitoring data available for bifenthrin shows residues in most crops are not 

found at, or above the limit of quantification of the analytical method. Field trial data supported 

by storage stability and method validation data have been submitted to support the proposed 

Section 3 and the tolerance proposed for dried tea (without U.S. registration actions). Adequate 

data are available by translation to support the Section 18 request. An analytical method is 

available to support the required tolerances. 

Dietary Exposure: A highly refined acute dietary assessment was conducted for all supported 

food uses and the newly proposed uses. High-end modeled drinking water estimates were 

directly incorporated into the assessment. The assessment incorporated the available monitoring 

data, percent crop treated (PCT) for the established uses, and processing factors as appropriate. 

For all registered and proposed uses, the acute dietary exposure estimates are below HED’s level 

of concern (<100% acute population adjusted dose (aPAD)) at the 99.9th percentile of exposure. 

At the 99.9th percentile of exposure from food and water to bifenthrin will occupy 5 % of the 
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aPAD for the general U.S. population and 29 % of the aPAD for children 1-2 years, the 

population group receiving the greatest exposures. 

Because there is no increase in hazard from repeat exposures to bifenthrin, the acute dietary

exposure assessment is protective for chronic dietary exposures; acute exposure levels are higher 

than chronic exposure levels. Accordingly, a dietary exposure assessment for the purpose of 

assessing chronic dietary risk was not conducted. However, in order to assess short-term 

aggregate risk to bifenthrin, it was necessary to calculate the average dietary (food and drinking 

water) exposure. The quantification of average dietary exposures required the use of average 

field trial residues, PDP data, and current tolerances as appropriate. The assessment also made 

use of PCT where available. Drinking water information was incorporated using the mean 

concentration (1-in-10-year annual mean) for surface water generated by the PRZM-EXAMS 

model.

Residential Exposure: Residential exposure is anticipated from the proposed Section 3 bed bug 

treatment use. In addition, residential exposures are anticipated from currently registered uses of 

the chemical: in indoor residential/household premises as a crack and crevice spray, paint 

additive and as a dust, in or on automobiles/recreational vehicles, and for termite treatments. 

HED has revised its Residential Standard Operating Procedures (SOPs) requiring the need for an 

update of bifenthrin residential risk estimates. Exposures are expected for adults who apply

bifenthrin-containing products and from post-application exposure to adults and children in 

residential areas previously treated with the chemical.

Residential uses of bifenthrin are many and vary widely. HED conducted a screen of the various 

indoor and outdoor residential uses of bifenthrin and identified those which would result in the 

greatest potential for exposure. The following uses are included in the residential risk 

assessment: the proposed indoor bed bug treatment use, including surface-directed application to 

indoor surfaces, and outdoor ornamental plant and turf uses. Residential indoor and outdoor uses 

are anticipated to be of short-term (i.e., 1 to 30 days) duration; however, bifenthrin does not 

increase in toxicity with repeated dosing. As such, only single day residential exposures were 

assessed. 

Residential handler dermal and inhalation risk estimates for bifenthrin are not of concern to HED 

(i.e., MOEs are ≥ 100 for dermal and ≥ 1,000 for inhalation, the levels of concern (LOC) for 

these assessments). The combined handler dermal and inhalation risk estimates calculated using 

the Aggregate Risk Index (ARI) are not of concern to HED (i.e., ARIs are ≥ 1). The ARI 

approach was required to combine the dermal and inhalation routes of exposure because of the 

different levels of concern (LOCs).

Adult residential post-application dermal exposures are not of concern to HED. For children 1 < 

2 years old, the most highly exposed children’s subgroup, the combined dermal and incidental 

oral risk estimates for the identified residential uses are not of concern to HED (i.e., MOEs are ≥ 

300, the LOC for these assessments). 

Aggregate Risk: The acute and short-term aggregate exposure assessments conducted for 

bifenthrin are not of concern to HED. 
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HED typically defines acute aggregate risk as including food and drinking water exposures only. 

As previously noted, acute dietary risk estimates are not of concern (<100% aPAD).

The short-term aggregate exposure assessment combines short-term residential (non-dietary) 

exposures with average dietary exposures (food and drinking water). As described previously, 

average dietary exposures were estimated and risk estimates (MOEs) were quantified using the 

short-term oral NOAEL for the purpose of characterizing short-term aggregate risk. It should be 

noted that although HED is classifying this as a short-term assessment (which typically reflect 

risks from longer duration hazard endpoints and exposure), bifenthrin risks reflect one-day

toxicity endpoints and maximum single-day exposures since bifenthrin does not increase in 

toxicity with increasing duration of exposure.

Short-term aggregate risk estimates (MOEs) for the most highly exposed population, children 1 <

2 years old, are not of concern to HED (i.e., MOEs are ≥ 300). 

Short-term aggregate risks estimated for the general U.S. population are not of concern to HED 

(i.e., ARIs are ≥ 1). An intermediate-term and/or chronic aggregate risk assessment was not 

conducted because bifenthrin does not increase in toxicity with repeated dosing. 

Occupational Exposure: Occupational assessments were conducted for the newly proposed 

uses of bifenthrin. Occupational exposures (dermal and inhalation) are anticipated for handlers 

who apply bifenthrin products and from dermal post-application exposure to workers who reenter treated fields. All occupational handler scenarios assessed resulted in risk estimates that 

were not of concern (i.e., ARIs are ≥ 1) with either baseline attire (i.e., single layer of clothing, 

no respirator) or the addition of a filtering face piece dust mask respirator. All post-application 

worker exposure scenarios assessed result in estimated risks that were not of concern [i.e., MOEs

are > 100 on Day 0 (12 hours)] for all potential post-application activities.

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, 

which comprise the Pesticide Handlers Exposure Database (PHED), the Agricultural Handler 

Exposure Task Force (AHETF), and the Outdoor Residential Exposure Task Force (ORETF)

have been determined to require a review of their ethical conduct, have received that review, and 

have been determined to be ethical.

2.0 HED Recommendations

2.1 Data Deficiencies

An acute inhalation study with additional neurotoxicity measurements and an immunotoxicity

study are required for bifenthrin. An additional uncertainty factor has been added to the human 

health risk assessment for all inhalation exposure scenarios to account for the required inhalation 

study. 
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Provided the end use product labels are revised as noted in Section 2.3.1, below, there are no

further data gaps with respect to toxicology, residue chemistry, or occupational exposure for 

bifenthrin. 

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate GC/ECD (gas chromatography/electron capture detection) analytical methods are 

available to enforce the proposed plant tolerances. The available methods for plant commodities 

involve extraction of bifenthrin residues with acetone, partitioning with hexane, purification 

using a Florisil column, and analysis of residues by GC/ECD.

2.2.2 International Harmonization

There are no Maximum Residue Limits (MRLs) established by Codex, Canada, or Mexico for 

any of the proposed commodities in the current registration actions (Section 3 and 18). 

However, Codex has proposed a 30 ppm MRL for Green and Black Tea (black, fermented and 

dried). In order to harmonize with the Codex MRL, a U.S. tolerance level of 30 ppm is 

recommended for dried tea. 

2.2.3 Recommended Tolerances

Table 2.2.3 summarizes the Section 3 and 18 proposed tolerances and the Agency’s final 

tolerance recommendations. 

Table 2.2.3. Tolerance Summary for Bifenthrin 

Commodity Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments

Correct Commodity Definition

Apple -- 0.5 Specified in (b) Section 18 emergency 

exemption; Apple

Grass, forage 2.5 4.0 Specified in (c) Tolerances with regional 

registrations; 

Grass, hay 4.5 15

Specified in (c) Tolerances with regional 

registrations; 

Nectarine -- 0.5 Specified in (b) Section 18 emergency 

exemption; Nectarine

Peach -- 0.5 Specified in (b) Section 18 emergency 

exemption; Peach

Tea 25 30 Specified in (a) General; Tea, dried

The tolerance on imported tea should be listed under §180.442(a) with a footnote that there are 

no U.S. registrations. The tolerance to support the use on grass grown for seed should be 

included in §180.442(c), tolerances with regional registrations. Lastly the tolerances on apples, 

nectarines, and peaches should be included in §180.442(b), Section 18 emergency exemptions.
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2.2.4 Revision to Petitioned-for Tolerances

A revision of the petitioned tolerance for dried tea was recommended, as described above in 

Section 2.2.2. 

A revision is also required for the grass grown for seed petitioned tolerance. Data submitted to 

determine the magnitude of bifenthrin residue in grass forage and hay was adjusted using 

Organization for Economic Cooperation and Development (OECD) calculation procedures. 

After correction for storage stability decline, HED recommends a revised tolerance level on 

grass, forage from 2.5 ppm to 4.0 ppm; grass, hay from 4.5 ppm to 15 ppm. 

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

HED recommends revision of the use directions for the proposed Section 3 and 18 bifenthrin 

labels. All field trials submitted for grass grown for seed were conducted in the Pacific 

Northwest states of Idaho, Oregon, and Washington. As such, an amended Section B is required 

for grass grown for seed by limiting this use to ID, OR, and WA on product labels 279-3108 and 

279-3313. If the registrant wishes to establish a nationwide registration and tolerance of the 

grass grown for seed use, three additional field trials from EPA Region 5 would be needed. 

For the proposed Section 18, application directions for treating apples, nectarines, and peaches as 

an emergency exemption in the states of Delaware, Maryland, New Jersey, North Carolina, 

Pennsylvania, Virginia, and West Virginia must be provided. Amended product labels are 

needed for the following bifenthrin products: EPA Reg. Nos. 279-3108, 70506-57, and 70506-

227.

2.3.2 Recommendations from Occupational Assessment

No label revisions are needed based on the occupational and/or residential exposure risk 

assessments. 

 

3.0 Introduction

3.1 Chemical Identity

Table 3.1. Nomenclature of Bifenthrin

Compound

Empirical Formula C23H22ClF3O2

Common name Bifenthrin

O

O

F Cl 3C

CH3

H3C CH3
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Table 3.1. Nomenclature of Bifenthrin

IUPAC name 2-methylbiphenyl-3-ylmethyl (1RS,3RS)-3-[(Z)-2-chloro-3,3,3-

trifluoroprop-1-enyl]-2,2-dimethylcyclopropanecarboxylate

or

2-methylbiphenyl-3-ylmethyl (1RS)-cis-3-[(Z)-2-chloro-3,3,3-

trifluoroprop-1-enyl]-2,2-dimethylcyclopropanecarboxylate

CAS name (2-methyl[1,1′-biphenyl]-3-yl)methyl (1R,3R)-rel-3-[(1Z)-2-chloro-3,3,3-

trifluoro-1-propenyl]-2,2-dimethylcyclopropanecarboxylate

CAS # 82657-04-03

3.2 Physical/Chemical Characteristics

Table 3.2. Physicochemical Properties of the Technical Grade Bifenthrin

Parameter Value Reference

Melting range 68-70.6°C

Product Chemistry Chapter of 

the Bifenthrin Tolerance 

Reassessment Eligibility 

Decision (TRED), (DP No. 

283808, 8/21/02, S. Levy)

pH NA1

Density at 24°C 1.26 g/mL

Water solubility <0.1 μg/L

Solvent solubility (g/100 mL) 8.9 in heptane and methanol

125 in acetone, chloroform, ether, 

methylene chloride, and toluene 

Vapor pressure (Pa) at 25°C 2.41 x 10-5

Dissociation constant (pKa) Not applicable

Octanol/water partition 

coefficient (Kow) >1 x 106

UV/visible absorption spectrum NA

1 NA = information not available.

3.3 Pesticide Use Pattern

Bifenthrin is currently registered for use on a variety of agricultural crops including nonfood/feed uses, as well as outdoor/indoor residential and indoor pet uses to control insect pests. 

Examples of registered bifenthrin uses which have been classified as “non-food/non-feed” 

include: 

 Outdoor premises: agricultural/farm; airports/landing fields; Christmas tree plantations; 

commercial and industrial lawns; forest trees; herbs; rights of way/fences/hedgerows; 

ornamental plants; and wide area treatments (public health, forest products); and 

 Indoor premises: automobiles/taxis; barns; warehouses; dairy/cheese processing plants; 

eating establishments; egg packing plants; greenhouses, and outdoor buildings. 
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Examples of registered bifenthrin food/feed uses include: beans; herbs; root vegetables; tree 

nuts; stone fruits; bushberries; leafy green vegetables; brassica; peas; leaf petiole vegetables; 

orchard crops; and cucurbits/melons/squashes. 

Rates of application for bifenthrin use vary: 0.10 to 0.20 lb ai/A for application by aircraft, 

ground, and chemigation; 0.30 to 0.50 lb ai/A for soil incorporation; 0.20 to 0.40 for dispersal of 

granular product with ground equipment; 0.0050 lb ai/1000 ft2 for crack and crevice and spot 

treatment applications; and 0.20 lb ai/A for spray and foam injection application. End-use 

products are formulated as ready-to-use-sprays (RTU), emulsified concentrate (EC), wettable 

powders (WP), granular (G), flowable concentrate (FIC), and pelletized tablets. A wide range of 

application methods may be used including aerial, ground boom, air blast, belly grinder, pushtype spreader, low/high pressure hand wand, paint roller, and foggers, etc.

The use patterns for the newly proposed uses of bifenthrin are summarized in Table 3.3. 

Table 3.3. Summary of Directions for Proposed Uses of Bifenthrin

Target/ 

Use Site

Formulation

(EPA Reg. No.)

Application Type, 

and Equipment

Application 

Rate 

(lb ai/A)

Max. No. 

Applic.

per 

Season

Max. 

Seasonal 

Applic. 

Rate

(lb ai/A)

PHI 

(days)

Use 

Directions1

Section 3

Grass, 

Grown for 

Seed 

(Forage 

and Hay)

Emulsifiable 

Concentrate -

Brigade® 2EC 

(279-3313) Aerial, 

Chemigation or 

Ground

0.033 - 0.10 Not 

Specified 0.20 30 

RTI: 

14 days

REI: 

12 hours

Water Soluble 

Bag -

Brigade® WSB 

(279-3108)

Bed Bug 

Treatment

Water Soluble 

Bag –

F4688 50 WSP 

(8033-96)

Surface-Directed 

Sprays, Bed (Box 

Spring, Frame, 

Headboard, 

Mattress), Closet, 

Dresser, Empty 

Luggage;

Manually 

Pressurized 

Handwand

0.0051

(lb ai/gallon)

Not 

Specified NA NA

Re-apply

every 7 to 

10 days if 

needed.

Section l8

Apple, 

Nectarine 

and Peach

Dry Flowable –

BifentureTM DF

(70506-227) Aerial, Airblast, 

Chemigation or 

Ground

0.040 - 0.20 Not 

Specified 0.50 14

RTI: 

30 days

REI: 

12 hours

Emulsifiable 

Concentrate -

BifentureTM EC -

(70506-57)
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Table 3.3. Summary of Directions for Proposed Uses of Bifenthrin

Target/ 

Use Site

Formulation

(EPA Reg. No.)

Application Type, 

and Equipment

Application 

Rate 

(lb ai/A)

Max. No. 

Applic.

per 

Season

Max. 

Seasonal 

Applic. 

Rate

(lb ai/A)

PHI 

(days)

Use 

Directions1

Water Soluble 

Bag -

Brigade® WSB 

(279-3108)

1. RTI: Re-treatement Interval; REI: Restricted Entry Interval

IR-4 submitted a petition to establish a tolerance for imported tea in the absence of a U.S. 

registration. Good Agricultural Practices (GAP) information was also provided for the products 

Talstar® 8SC and Brigade® 8SC for use on tea grown in India. Talstar® 8SC is an 80 g ai/L

soluble concentrate formulation of bifenthrin. One foliar application is made to tea using a spray

volume of 400 L/ha and a 7-day PHI. For Brigade® 8 SC, an 80 g ai/L SC formulation, one 

foliar application is made at 0.08 kg ai/ha (0.07 lb ai/A) using a spray volume of 400 L/ha which 

specifies a PHI of 7 days. 

3.4 Anticipated Exposure Pathways

RD has requested an assessment of human health risk to support proposed new use of bifenthrin 

on grass grown for seed, imported tea; apple, nectarine, and peach. Humans may be exposed to 

bifenthrin in their diet resulting from residues present on bifenthrin treated crops. Further, given 

the environmental fate parameters of bifenthrin and the proposed uses outdoors in agricultural 

settings, the potential exists for bifenthrin to reach water resources resulting in limited residues 

in drinking water. The potential exists for residential bifenthrin exposure from the proposed bed 

bug treatment, as well as from current use of the chemical. Residential bifenthrin exposures 

could occur from adults handling the pesticide and from post-application exposure of adults and 

children contacting previously treated areas. Adults could be exposed from the proposed uses of 

bifenthrin in an occupational setting. Occupational applicators may be exposed while handling 

the pesticide prior to, as well as during application. There is also the potential for exposure to 

workers who come into contact with the foliage of previously treated crops. 

This assessment will consider the dietary, residential, and occupational risks for all registered 

and newly proposed uses of bifenthrin. 

3.5 Consideration of Environmental Justice

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

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

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

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

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

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

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

and activities in and around the home that involve pesticide use in a residential setting. 
Bifenthrin Human Health Risk Assessment D372550

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

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

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

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

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

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

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

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

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

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

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

subgroups.

Bifenthrin may be stored and accumulated in aqueous sediment and, therefore, could be a 

potential dietary exposure source for individuals who eat fish (e.g., catfish) which dwell near the 

sediment. Subsistence fishers, or individuals who rely on fishing as the primary source of food, 

may be more highly exposed than the general population. HED conducted an acute screening 

level dietary exposure assessment to consider the intake of contaminated catfish by subsistence 

fishers. Because high-end bounding fish exposure assumptions were used to assess exposure to 

subsistence fishers, this potential dietary exposure source was not included in the acute or 

average dietary exposure and risk assessments conducted for the proposed Section 3 and 18 uses; 

rather, a stand-alone assessment was conducted. The dietary assessment of catfish intake 

resulted in a % aPAD value of < 1 % and, therefore, would not be anticipated to significantly

impact the dietary exposure assessments conducted for the proposed uses. See Section 5.4.1 for 

further detail.

4.0 Hazard Characterization and Dose-Response Assessment

Bifenthrin is a member of the pyrethroid class of insecticides. Pyrethroids have historically been 

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

effects. Type I pyrethroids, which lack an alpha-cyano moiety, induce in rats a syndrome 

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

tremor progressing to whole-body tremor and prostration (T-syndrome). Type II pyrethroids, 

which contain an alpha-cyano moiety, in rats produce a syndrome that includes pawing, 

burrowing, salivation, hypothermia, and coarse tremors leading to choreoathetosis (CSsyndrome) (Verschoyle and Aldridge 1980; Lawrence and Casida 1982). In general, Type II 

chemicals tend to be more potent than Type I pyrethroids and the cis forms tend to be more 

potent than the trans configurations. 

Bifenthrin is a Type I synthetic pyrethroid, unique to be the only member of the biphenyl-methyl 

ester class and it is enriched to 98% cis form. It has a relative potency factor of 0.60 with respect 

to the more potent Type II pyrethroid, deltamethrin, with a relative potency factor of 1.00. The 

adverse outcome pathway (AOP, based on the Bradford-Hill criteria) shared by pyrethroids 

involves the ability to interact with voltage-gated sodium channels (VGSCs) in the central and 

peripheral nervous systems, leading to changes in neuron firing, and ultimately neurotoxicity
Bifenthrin Human Health Risk Assessment

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(see Figure 4.0). The signs observed in the animal studies are consistent with the pesticidal mode 

of action. 

Figure 4.0. Adverse outcome pathway for pyrethroids

Dosing method, vehicle type and vehicle volume considerably influence the points of departure 

of the pyrethroids, including bifenthrin (Wolansky et al, 2007). For example, the ED

the effective dose for a 50% decrease) 

carboxymethylcellulose as the vehicle with gavage dosing, based on motor activity data (Crofton 

et al, 1995). The vehicle and volume used in gavage dosing vary considerably among 

pyrethroids thus making quantitative comparisons 

bifenthrin dosing volume affects toxicity, decreasing the corn oil volume from 5 mL/kg to 1

mL/kg lowers the ED50 value of motor activity by a factor of two (Wolansky 2007). 

Furthermore, bolus/gavage dosing results in increased potency of the pyrethroid relative to 

exposure in feed. In the bifenthrin rat developmental studies, the LOAEL was 1.

with corn oil gavage administration while a dietary administration had a LOAEL of 15.5 

mg/kg/day (8.8 times higher, with tremors as the common endpoint). The gavage ACN study 

which did not use a vehicle of any kind had a much higher LOAEL of 

changes in motor activity, clinical signs and mortality. The Wolansky acute study was 

particularly conservative in design and utilized a corn oil vehicle at 1 mL/kg with gavage dosing 

(point of departure was 3.1 mg/kg). In perspectiv

vegetable oil, such as corn oil. 

4.1 Toxicology Studies Available for Analysis

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

characterization of the hazard pote

are two outstanding Part 158 data requir

required due to recent changes to Part 158 which impose new data requirements for pesticide 

registration. An acute inhalation study with ACN metrics is also required to substitute for the 

sub-chronic inhalation study. In addition, 

inform the possibility of increased sensitivity to 

near the LOAEL values, which is discussed further in 

efforts, HED is confident that it has chosen points of departure and uncertainty factors in this risk 

assessment which are health protectiv

The data from the following studies were used to evaluate the hazard potential of bifenthrin:

-Wolansky Acute Oral Rat Study

-Nemec/WIL Acute Oral Rat Study

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). The signs observed in the animal studies are consistent with the pesticidal mode 

Adverse outcome pathway for pyrethroids

Dosing method, vehicle type and vehicle volume considerably influence the points of departure 

of the pyrethroids, including bifenthrin (Wolansky et al, 2007). For example, the ED

r a 50% decrease) for deltamethrin is 196 times lower using corn oil versus 

carboxymethylcellulose as the vehicle with gavage dosing, based on motor activity data (Crofton 

The vehicle and volume used in gavage dosing vary considerably among 

pyrethroids thus making quantitative comparisons among them difficult. In the specific case of 

bifenthrin dosing volume affects toxicity, decreasing the corn oil volume from 5 mL/kg to 1

value of motor activity by a factor of two (Wolansky 2007). 

Furthermore, bolus/gavage dosing results in increased potency of the pyrethroid relative to 

exposure in feed. In the bifenthrin rat developmental studies, the LOAEL was 1.

with corn oil gavage administration while a dietary administration had a LOAEL of 15.5 

mg/kg/day (8.8 times higher, with tremors as the common endpoint). The gavage ACN study 

which did not use a vehicle of any kind had a much higher LOAEL of 70.3 mg/kg, based on 

changes in motor activity, clinical signs and mortality. The Wolansky acute study was 

particularly conservative in design and utilized a corn oil vehicle at 1 mL/kg with gavage dosing 

(point of departure was 3.1 mg/kg). In perspective, rat feed often does contain some content of 

Toxicology Studies Available for Analysis

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

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

outstanding Part 158 data requirements for bifenthrin. An immunotoxicity study is 

due to recent changes to Part 158 which impose new data requirements for pesticide 

An acute inhalation study with ACN metrics is also required to substitute for the 

In addition, there are on-going efforts to develop methods

possibility of increased sensitivity to pyrethroids as a class in juvenile rats at 

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.

The data from the following studies were used to evaluate the hazard potential of bifenthrin:

Wolansky Acute Oral Rat Study

WIL Acute Oral Rat Study

D372550

______________________________________________________________________________

). The signs observed in the animal studies are consistent with the pesticidal mode 

Dosing method, vehicle type and vehicle volume considerably influence the points of departure 

of the pyrethroids, including bifenthrin (Wolansky et al, 2007). For example, the ED50 value (i.e. 

for deltamethrin is 196 times lower using corn oil versus 

carboxymethylcellulose as the vehicle with gavage dosing, based on motor activity data (Crofton 

The vehicle and volume used in gavage dosing vary considerably among 

In the specific case of 

bifenthrin dosing volume affects toxicity, decreasing the corn oil volume from 5 mL/kg to 1

value of motor activity by a factor of two (Wolansky 2007). 

Furthermore, bolus/gavage dosing results in increased potency of the pyrethroid relative to 

exposure in feed. In the bifenthrin rat developmental studies, the LOAEL was 1.77 mg/kg/day

with corn oil gavage administration while a dietary administration had a LOAEL of 15.5 

mg/kg/day (8.8 times higher, with tremors as the common endpoint). The gavage ACN study 

70.3 mg/kg, based on 

changes in motor activity, clinical signs and mortality. The Wolansky acute study was 

particularly conservative in design and utilized a corn oil vehicle at 1 mL/kg with gavage dosing 

e, rat feed often does contain some content of 

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

ntial for children 6 years old and older and for adults. There 

ements for bifenthrin. An immunotoxicity study is 

due to recent changes to Part 158 which impose new data requirements for pesticide 

An acute inhalation study with ACN metrics is also required to substitute for the 

methods to 

n juvenile rats at doses 

. Despite these scientific 

efforts, HED is confident that it has chosen points of departure and uncertainty factors in this risk 

The data from the following studies were used to evaluate the hazard potential of bifenthrin:
Bifenthrin Human Health Risk Assessment D372550

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Page 18 of 83

-ACN Rat Study

-SCN Rat Study

-DNT Rat Study

-21 Day Dermal Rat Study

-21 Day Dermal Rabbit Study

-90 Day Rat Study

-90 Day Dog Study

-Developmental Rat Studies (Gavage and Dietary)

-Developmental Rabbit Study

-Reproduction Rat Study

-1 Year Dog Study

-Chronic/Cancer Rat Study

-Chronic/Cancer Mouse Study

-Metabolism and Pharmacokinetic Studies

The studies available for consideration of bifenthrin toxicity provide a comprehensive database, 

with routes of administration which are consistent with potential exposure scenarios. In addition, 

numerous studies from the scientific literature conducted over several decades describe the 

pharmacodynamic and pharmacokinetic profile of the pyrethroids in general. This scientific 

literature has been recently reviewed by several groups (Wolansky and Harrill 2008; Weiner et. 

al. 2009). The non-guideline Wolansky acute oral study in rats measuring locomotor activity

provides the most robust data to evaluate the hazard potential of bifenthrin. 

4.2 Bifenthrin Toxicological Profile

Bifenthrin has been evaluated for a variety of toxic effects in guideline experimental toxicity

studies. Predominantly, behavioral changes characteristic of Type I pyrethroids such as muscle 

tremors were seen in most of the bifenthrin experimental toxicology studies, consistent with its 

MOA to activate sodium channels. This observation was noted in several bifenthrin toxicology

studies across various species at different durations, routes of exposure and life stages, including: 

the developmental toxicity studies in the rat and rabbit; 2-generation rat reproduction toxicity

study; developmental neurotoxicity study (DNT); sub-chronic toxicity studies in the rat and dog;

acute and sub-chronic neurotoxicity rat studies; a sub-chronic dermal toxicity study in rat; and 

chronic oral toxicity studies in the rat, mouse and dog. The most robust study for assessing 

bifenthrin toxicity was the acute Wolansky study measuring locomotor activity, due to the fact 

that it utilized nine dose groups and a benchmark dose (BMD) data analysis method to address 

dose spacing effects. 

The BMD analysis allows a constant threshold of change from the control group to be utilized so 

that all the pyrethroids are evaluated with the same toxicity metric, not possible with the standard 

LOAEL/NOAEL approach with variable dose spacings. For the Wolansky study with 

continuous data, the BMD-S software was set to calculate the dose at which the motor activity

change is equal to one standard deviation (SD) from the control value, or the BMD1SD. The 

BMD1SD value is used instead of the LOAEL value and the one SD magnitude is calculated from 

the control group data. The BMDL1SD is the lower 95% confidence limit of the BMD value and 

is used instead of the NOAEL value. For other studies with quantal data, a BMD10 value, or the 
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Page 19 of 83

dose which has a 10% toxicity change from the controls, has been calculated as the standard 

conservative approach for this type of data. For other data with higher variability and a 10% 

change is not statistically supportable; therefore, a BMD20 value has been calculated, or the dose 

at which a 20% toxicity change occurs relative to the control group.

The Wolansky study was considerably conservative, using the most sensitive rat strain, plus 

gavage dosing utilizing a vehicle and volume producing the most adverse responses (i.e. 1 ml/kg 

corn oil). Muscle tremors were observed in nearly all experimental studies in all species and 

durations, however, motor activity was not measured in most of these studies. The decreased 

locomotor activity observed in the acute Wolansky study was selected as the endpoint for risk 

assessment. In the acute Wolansky study, tremors were not observed at doses less than 8 mg/kg 

bifenthrin, while decreased motor activity was significant at doses of 4 mg/kg and above. 

Decreased motor activity was the most sensitive endpoint identified for bifenthrin and is 

protective of other endpoints recorded throughout the database, thus an acceptable literature 

study was utilized for risk assessment. Further, the Wolansky study monitored the toxicology at 

the time of peak effects, unlike most of the guideline studies. Additional effects seen in one or 

more studies included: muscle twitching; decreased grip strength; altered landing foot splay;

depressed respiration; increased grooming counts; loss of muscle coordination; staggered gait;

exaggerated hind limb flexion; and convulsions at high doses. Decreased body weight, body 

weight gains and food consumption were also noted in repeat-dosing dietary studies. There was 

no clear evidence in the database that either gender was more sensitive to bifenthrin. 

Bifenthrin has been evaluated for potential developmental effects in the rat (following gavage or 

dietary administration) and in the rabbit (gavage administration). Maternal toxicity included 

neurological effects (tremors in rats and rabbits; head and forelimb twitching in rabbits). There 

were no developmental effects of biological significance in either species. The registrant 

submitted a DNT study, which establishes a clear NOAEL for the adult and offspring toxicity. 

The NOAEL in adults and offspring is similar in magnitude and the LOAELs are based on the 

clinical signs of neurotoxicity (dams had tremors and convulsions, offspring had increased 

grooming counts). Based on targeted testing in the DNT study for common endpoints for 

bifenthrin, there was no increase in sensitivity in rat pups. However, the Agency has reviewed 

existing pyrethroid data and concludes that the DNT is not a particularly sensitive study for 

comparing the sensitivity of young and adult animals to pyrethroids (E. Scollon, D381210, 

6/27/11). Some literature studies did indicate susceptibility for other pyrethroids, but in context 

these studies were conducted at relatively high doses which may not reflect environmental 

exposures (Sheets et al, 1994). The reproductive toxicity of bifenthrin was examined in a twogeneration reproduction study in the rat. Tremors were noted only in females of both

generations, with one parental generation rat observed to have clonic convulsions and no 

observed effects in the offspring. Overall, there is no indication of increased juvenile sensitivity

specifically to bifenthrin.

Bifenthrin is classified as a Group C “Possible human carcinogen”, based on an increased 

incidence of urinary bladder tumors in mice. The classification was based on the following 

weight of evidence considerations: 
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 There was a statistically significant dose-related trend in bladder tumors at the high dose. 

HED concluded that the bladder tumors may not be uncommon in Swiss Webster mice and 

not likely to be malignant. Additionally, these tumors were observed in only one species 

(mice), in only one sex (male), at only the highest dose, and the incidence was of borderline 

significance. 

 There was a statistically significant dose-related trend for combined hepatocellular adenomas 

and carcinomas in male mice; however, there was no statistical significance in pairwise 

comparison. 

 There was a statistically significant increase in pairwise comparison for lung tumors, but 

there was no dose response. Additionally, there was no dose-related trend. There was also 

no indication that tumor formation occurred early in the mouse carcinogenicity study.

 Bifenthrin was negative in five different tests for mutagenicity, but it was marginally active 

in a forward mutation test in mouse lymphoma cells. Overall, based on the available 

information, there is a low concern for mutagenicity.

 No evidence of carcinogenicity was observed in carcinogenicity studies in rats with 

bifenthrin.

Taking into account all of this information, the Agency has determined that quantification of risk 

using a non-linear approach (i.e., an aPAD or aRfD) will adequately account for all chronic 

toxicity, including carcinogenicity that could result from exposure to bifenthrin. While the 

Agency would typically use a chronic population-adjusted dose (cPAD) to protect for cancer 

concerns, use of the aPAD is protective for bifenthrin because increasing toxicity with increasing 

duration of exposure is not seen for bifenthrin. The NOAEL observed in the mouse chronic 

study, in which tumors were observed, is 6.7 mg/kg/day, 2-fold higher than the POD used for 

acute risk assessment. The NOAEL in the study was based on tremors seen at the LOAEL 

of 25.6 mg/kg/day; however, the tumors were observed at 81.3 mg/kg/day, a dose that is 26-fold 

higher than the current acute POD.

The pharmacokinetics of bifenthrin is similar to other pyrethroids with rapid absorption and 

clearance. The rapid absorption was confirmed by the functional reduction in locomotor activity

at one hour post oral dosing (55% decrease at 12 mg/kg bifenthrin, Wolansky 2007). An oral 

absorption half-life of 1.5 hours (with a lag-time of a 0.5 hour following first order kinetics) has 

been calculated for bifenthrin at 4 mg/kg dosing. An oral absorption of approximately 50% was 

estimated. The half-life in blood is approximately 10 hours, supporting rapid clearance from this 

compartment. The major routes of bifenthrin metabolism are hydrolysis of the ester linkage with 

oxidation of the resulting alcohol to the acid form. Radio-labeled bifenthrin studies indicate that 

the parent had the highest radioactivity excreted in the feces, with 12 other metabolites 

identified. Approximately 70% of the total residues (bifenthrin and its hydroxylated metabolites) 

were excreted in the feces within 48 hours (range 66-88%). Approximately 13-25% of the 

administered doses were excreted in the urine, mostly as hydrolytic and hydrolytic/oxidative 

degradation products, with little parent detected. In a bioaccumulation study with rats orally

dosed with 0.5 mg/kg/day for up to 70 days, fat and skin tended to accumulate parent bifenthrin 

to a much greater extent than other tissues with half-lives of 51 and 50 days, respectively (JMPR 

Report, 2009). 
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With respect to acute lethality testing, bifenthrin has a low order of acute toxicity via the dermal 

route (Category III) of exposure and a moderate order of acute toxicity via the oral route 

(Category II). The combined male-female LC50 value for bifenthrin is 1.01 mg/L (Category III), 

based on an acute inhalation study. It is neither an eye nor skin irritant, nor is it a dermal 

sensitizer.

4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile

The extensive body of scientific literature on the pyrethroids provides 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 primary biological effects of 

bifenthrin and other pyrethroids on insects and vertebrates are stimulatory effects on voltagegated sodium channels coupled with secondary inhibition of the voltage-gated calcium channels 

and chloride channels. The following sections discuss the specific issues related to pyrethroid 

pharmacokinetics, pyrethroid pharmacodynamics, and age-related differences in pyrethroid 

toxicity.

4.3.1 Pharmacokinetics

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

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

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

channels in the peripheral nervous system (PNS) and central nervous system (CNS). The 

underlying pharmacokinetics of pyrethroids is an important determinant of their toxicity because 

the concentration of pyrethroid at the sodium channel relates to the extent of toxicity, with 

greater pyrethroid concentration translates as increased neurotoxicity. Physiological processes 

that significantly contribute to the PK include absorption, metabolism, protein binding and 

partitioning. The vehicle type and volume has been shown to affect the temporal and 

toxicological properties of the pyrethroids (Crofton 1995, Wolansky 2007). The blood brain 

barrier is less developed in the young and can also contribute to age-dependant neurotoxicity (US 

EPA Guidelines for Neurotoxicity Risk Assessment, Federal Register, 1998). Carboxylesterases 

(serum and intracellular) and cytochrome P450 enzymes in the endoplasmic reticulum are the 

two major enzyme families responsible for the metabolism of pyrethroids. The metabolism of 

bifenthrin in the liver is primarily by cytochrome P450 oxidation. It is the ontogeny of these 

enzymes that accounts for the age-related sensitivity observed after pyrethroid exposures. 

Pharmacokinetic changes may explain the disappearance of tremors in dogs after 29 weeks of 

bifenthrin dosing in the one-year study. Rats and rabbits also demonstrated tolerance to 

bifenthrin in repeated dosing studies. Bifenthrin has been demonstrated to transfer into milk in 

rat studies. For the pyrethroid index chemical deltamethrin with 2 mg/kg orally in PND40 rats at 

6 hours post-dosing, the tissue levels from lowest to highest were brain, liver, plasma, muscle 

and fat with levels of 20 ng/g, 50 ng/g, 70 ng/mL, 140 ng/g and 480 ng/g, respectively (Kim et 

al, 2010). However, pyrethroid residues in fatty tissue are not available to interact with the 

VGSCs in vital tissues and therefore do not contribute to overall toxicity. 
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Following a single oral dose of 4 mg/kg radio-labeled bifenthrin in corn oil, radioactivity in 

blood plasma peaked at 4 hours, which corresponds precisely with the peak time of effect on 

motor activity at this dose. In blood, bifenthrin residues have a half-life of approximately 10 

hours (see Figure 4.3.1) with 17% of the residues (compared to peak values) remained 24 hours 

post-dosing and only 8% of the peak radioactive residues remained in the serum at 72 hours. 

Similar kinetics were observed in rats given 35 mg/kg, although the peak plasma levels were 

slightly delayed to 6 hours (Selim 1986). As previously described, pyrethroids are susceptible to 

ester hydrolysis in the plasma and oxidative metabolism by intracellular cytochrome P450 

enzymes. Protein binding of radioactive parent and metabolites increased considerably with time 

(9% at 2 hours vs 34% at 10 hours). A radio-labeled bifenthrin guideline study reported that 

40% of the total residues in plasma is parent at 4 hours, following a 4 mg/kg oral dose (HPLC 

method, MRID 00163070). A literature study also revealed that the internal dose EC50 values for 

motor activity based on brain PK values were approximately three times higher than the EC50

value based on blood PK values (i.e. EC50 values of approximately 300 ng/cc and 90 ng/cc, 

respectively). Thus, bifenthrin effects on peripheral nerves/tissues cannot be excluded (Scollon 

et. al., 2011). 

Figure 4.3.1. Pharmacokinetic profile of radiolabeled-bifenthrin in rat plasma following a single oral dose 

of 4 mg/kg in corn oil. Bifenthrin blood concentration is based on radioactivity and, therefore, represents a 

total of parent and metabolic products (Selim 1986, MRID 00163069).

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

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

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

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

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

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

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

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70 Bifenthrin Blood PK Profile

C

14 Label on Alcohol Portion

4 mg/kg

Blo

o

d

C

o

n

c

e

ntratio

n (

g/m

L)

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

(US EPA 2007).

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

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

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

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

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

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

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

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

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

metabolism of deltamethrin by plasma carboxyesterases, plus hepatic carboxyesterases and 

cytochrome P450s (microsomes) are at least 6 times higher for PND 90 rats compared to PND 10 

rats. As a consequence, higher internal doses (i.e., those associated with high doses in 

experimental toxicology studies) can overwhelm the clearance mechanisms in juveniles; 

however, because adults have greater enzyme activity, they are able to tolerate higher doses prior 

to the onset of toxicity. As a matter of perspective, the anticipated exposures from typical 

dietary or residential activities are not expected to overwhelm the premature metabolic systems 

in juveniles. Bifenthrin has a melting point of 68oC and is, therefore, a solid at room 

temperature. Furthermore, pyrethroids are practically insoluble in water, minimizing risk from 

water exposure.

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

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

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

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

target organ for pyrethroids and increased pyrethroid concentrations are correlated with 

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

equivalent brain concentrations of deltamethrin would be achieved with a 3.8X fold lower oral 

dose in 10-day old rats and 2.5X lower dose in 21-day old rats (Tornero-Velez et. al. 2010). The 

10- and 21-day old rats encompass effects predicted in a human up to age six. For example, a 1 

mg/kg dose in the adult is equivalent to a 0.26 mg/kg dose (≈1 mg/kg÷3.8mg/kg) in the 10-day

old rats and to a 0.4 mg/kg (≈1 mg/kg÷2.5mg/kg) 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. As a result, the 

Agency concludes that juvenile rats are 3X more sensitive than adults with respect to pyrethroid 

pharmacokinetics.

4.3.2 Pharmacodynamics

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

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

in vivo studies support the AOP illustrated in Figure 4.0, as well as disruption of sodium 

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

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

Choi and Soderlund (2006) examined interactions of several pyrethroids with mammalian 
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VGSCs expressed in Xenopus oocytes. With respect to altered neuronal excitability, Type I 

pyrethroids cause slight prolongations of the sodium current tails (e.g. ~20 ms), often resulting in 

long trains of action potentials. In contrast, Type II pyrethroids significantly prolong sodium tail 

currents (e.g. 200ms to minutes) typically resulting in increased resting membrane potential and 

ultimately causing depolarization-dependent action potential block. Figure 4.3.2 confirms the 

effects of bifenthrin to increase sodium channel currents in rat NaV1.8 channels expressed in 

xenopus oocytes.

Figure 4.3.2. Resting modification of rat Nav1.8 sodium channels by bifenthrin, expressed in xenopus oocytes.

Channel current vs time traces from individual representative oocytes in the absence or presence (*) of 100 μM 

bifenthrin were obtained during and after 40-ms depolarizations from 100 mV to 10 mV. Calibration bars: 20 ms for 

the x-axis and 500 nAmp on the y-axis. Data extracted from Figure 3 in Choi and Soderlund (2006). 

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

departure, such as sodium channel modification. However, in vivo techniques used to detect 

VGSC alteration and altered neuronal excitability are not practical for use in risk assessment at 

this time and approaches for extrapolating in vitro findings to in vivo measures are not yet 

developed. As such, 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 are generally characterized by 

tremors, hyper- or hypothermia, altered response to stimuli, salivation, reduced locomotor 

activity or convulsions (Nemec 2006; Wolansky and Harrill 2008; Breckenridge et. al. 2009). 

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

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

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

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

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

sodium channels has not been identified, making it impractical to determine the isoform 

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 neuronal cells 
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cultured in defined media. These in vitro techniques do not provide direct quantitative measure 

of in vivo pyrethroid activity. However, these techniques consistently and qualitatively

demonstrate that channel isoforms expressed in juveniles are not more sensitive to pyrethroid 

perturbation compared to isoforms expressed in adults and that, pharmacodynamically, the rat is 

a conservative model for humans. For example, Meacham et al. (2008), compared the sensitivity

of an adult isoform 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, revealed that the rat isoform was 4-fold more sensitive than the equivalent human 

sodium channel to the pyrethroid tefluthrin (Tan and Soderlund 2009). This data suggests that 

the rat is a highly-sensitive model and extrapolations from the rat would be protective of human 

health. The occurrence and ontogeny of voltage-gated sodium channels in humans is not well 

characterized compared to the rat. However, based on the comparable function and distribution 

of sodium channels between the species, the rat is an appropriate surrogate for the evaluation of 

human PD (Goldin et. al. 2000; Goldin 2002). As a result, the Agency concludes that juvenile 

rats are not more sensitive than adults with respect to pyrethroid pharmacodynamics. Therefore, 

the pharmacodynamic contribution to the FQPA factor will be 1X.

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. Following a single oral gavage dose, bifenthrin is 

absorbed rapidly in rats and quickly displaying decreased motor activity and increased tremors. 

Toxicity is observed as quickly as 1 hour, peaks at 4 hours and motor activity started to increase 

at 7 hours, approximately following the blood PK profile (Wolansky, 2007). Tremors are absent 

at 12 hours and rats typically recover within 24 hours without any persisting neurotoxic effects,

at doses near the LOAEL value. In support, for deltamethrin the signs of salivation and tremors 

correlated very well with the internal dose, with r2=0.86-0.90 (i.e. blood AUC, Anand et. al. 

2006). The toxicity profiles for other pyrethroids are generally similar and marked by rapid 

absorption, metabolism, and time-to-peak effect. The NOAELs and LOAELs for tremors 

established from results of experimental toxicity studies with bifenthrin are remarkably 

consistent across durations of exposure, ranging from a single dose up to 2-years of dosing (see 

Table 4.3.3). The BMD values from the motor activity results from the Wolansky study are 

similar to the NOAEL/LOAEL values from the tremor endpoint.

Table 4.3.3. Bifenthrin NOAEL and LOAEL Values Versus Treatment Time

Study Duration Study findings

Wolansky et al (2006) rat Acute, single exposure BMDL=3.1 BMD=4.1

Developmental neurotoxicity rat 86 days NOAEL = 3.6 LOAEL = 7.2

Sub-chronic dog 90 days NOAEL = 2.21 LOAEL= 4.42

Sub-chronic rat 90 days NOAEL = 3.8 LOAEL = 7.5

Sub-chronic neurotoxicity rat 90 days NOAEL = 2.9 LOAEL = 6.0

Reproductive toxicity rat 120 days NOAEL = 3.0 LOAEL = 5.0

Chronic-carcinogenicity mouse 87 weeks NOAEL = 6.7 LOAEL = 25.6

Chronic-carcinogenicity rat 2-years NOAEL = 3.0 LOAEL = 6.1
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Comparing the NOAELs and LOAELs established from bifenthrin single dose and repeat 

dosing studies, it is apparent that repeat exposures do not result in lower NOAELs, within the 

variability of animal testing and body weight scaling corrections. The human equivalent doses 

(HED) for bifenthrin between the dog study and rat study are similar when normalized by body

weight. The human equivalent dose for the 90-day dog study NOAEL is 1.35 mg/kg and the 

value for the acute Wolansky rat study BMDL is similar at 0.90 mg/kg (see Appendix A.4). 

These data are consistent with the general kinetic profile for bifenthrin. The acute Wolansky 

study endpoint of decreased motor activity at 4.1 mg/kg (BMDL1SD value of 3.1 mg/kg) is 

slightly lower than the chronic two-year cancer study LOAEL= 6.1 mg/kg/day. Therefore, the 

endpoint from the acute study is protective of the endpoints from the repeat dosing studies. 

Thus, for purposes of endpoint selection and exposure assessment, only single-day risk 

assessments need to be conducted.

Appendix A.3 contains a graphical depiction and description of further NOAELs of other 

studies not listed in this table. While other studies did have lower NOAELs, they were 

inconsistent with the weight of evidence from the entire data base or were similar when the 

results were normalized to the human equivalent dose. The Nemec 2006 study (WIL) had a 

lower PoD, however, for bifenthrin the dose selection was sub-optimal, producing a poor dose 

response and atypical PoD results. Conversely, the ACN study did not utilize a dosing vehicle 

(which may not reflect exposure scenarios) and resulted in a non-conservative PoD an order of 

magnitude higher than the typical findings in Table 4.3.3. 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

Bifenthrin exposure to children under 6 years old is anticipated and must be considered in the 

context of the pyrethroids as a class. For non-inhalation exposure scenarios for infants and 

children < 6 years of age, EPA is reducing the FQPA safety factor to 3X based on the increased 

quantitative susceptibility seen in the scientific literature related to pyrethroid pharmacokinetics. 

This concept is consistent with the Agency’s 2011 analysis and is supported by rat PBPK model 

predictions of a 3-fold increase of deltamethrin concentrations in the juvenile brain compared to 

adults (see Section 4.3.1). The PK of pyrethroids as a group is sufficiently similar that 

significant deviations from the 3-fold increase of deltamethrin concentrations are not expected 

for other pyrethroids. As noted in Section 4.3.2, juveniles are not more sensitive than adults with 

respect to pyrethroid pharmacodynamics and thus no uncertainty factor is needed for PD 

considerations. 

There is no evidence that bifenthrin results in increased susceptibility in in utero rats or rabbits in 

the prenatal developmental studies or in young rats in the 2-generation reproduction study. This 

is consistent with the results of the guideline pre- and post-natal testing for other pyrethroid 

pesticides. There are, however, high-dose LD50 studies (studies assessing what dose results in 

lethality to 50 percent of the tested population) in the scientific literature indicating that 

pyrethroids can result in increased quantitative sensitivity in the young. Examination of 

pharmacokinetic and pharmacodynamic data indicates that the sensitivity observed at high doses 

is related to pyrethroid age-dependent pharmacokinetics - the activity of enzymes associated with 

the metabolism of pyrethroids. With otherwise equivalent administered doses for adults and 

juveniles, predictive pharmacokinetic models indicate that the differential adult-juvenile 
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pharmacokinetics will result in a 3X greater dose at the target organ in juveniles compared to 

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

pyrethroid scientific literature related to pharmacodynamics (the effect of pyrethroids at the 

target tissue) both with regard to inter-species differences between rats and humans and to 

differences between juveniles and adults. Specifically, there are in vitro pharmacodynamic data 

and in vivo data indicating similar responses between adult and juvenile rats at low doses and 

data indicating that the rat is a conservative model compared to the human based on speciesspecific pharmacodynamics of homologous sodium channel isoforms in rats and humans.

In light of the high-dose literature studies showing juvenile sensitivity to pyrethroids and the 

absence of the requested data on juvenile sensitivity to pyrethroids, EPA is retaining a 3X 

additional safety factor as estimated by pharmacokinetic modeling. For several reasons, EPA 

concludes there are reliable data showing that a 3X factor is protective of the safety of infants 

and children. First, the high doses that produced juvenile sensitivity in the literature studies are 

well above normal dietary or residential exposure levels of pyrethroids to juveniles and these 

lower levels of exposure are not expected to overwhelm the ability metabolize pyrethroids as 

occurred with the high doses used in the literature studies. This conclusion is confirmed by the 

lack of a finding of increased sensitivity in pre- and post-natal guideline studies in any

pyrethroid, including bifenthrin, despite the relatively high doses used in those studies. Second, 

the portions of the uncertainty factors that account for potential pharmacodynamic differences

are likely to overstate the risk of inter- and intraspecies pharmacodynamic differences, given the 

data showing similarities in pharmacodynamics between juveniles and adults and between 

humans and rats. For both the inter-species and intra-species uncertainty factors, the 

pharmacodynamic portions are generally considered to be 3X, however for pyrethroids it is 

reduced to 1X since no differences among the various groups are observed. Finally, as indicated, 

pharmacokinetic modeling only predicts a 3X difference between juveniles and adults.

In addition to 3X factor for infants and children < 6 years of age, a 10X FQPA safety factor is 

being retained for inhalation exposure scenarios for all population groups. This data gap is 

described in greater detail in the following Section (4.4.1). Because the 3X factor and the 10X 

factor for inhalation exposure scenarios are in response to different uncertainties, these safety 

factors have been combined for inhalation exposure scenarios for infants and children < 6 years 

of age resulting in a FQPA safety factor of 30X. 

This information described above is summarized in Re-Evaluation of the FQPA Safety Factor for 

pyrethroid pesticides (US EPA 2011c). 

4.4.1 Completeness of the Toxicology Database

The toxicology database for bifenthrin is not complete. Acceptable developmental toxicity

studies in rats and rabbits are available for bifenthrin, in addition to an acceptable reproduction 

study in rats. The main endpoint for bifenthrin is tremors, a common sign for a pyrethroid, 

which was detected in most toxicology studies, plus observed during targeted testing in the ACN, 

SCN and developmental neurotoxicity (DNT) studies. EPA lacks additional data on 

immunotoxicity, inhalation toxicity, and adult-juvenile sensitivity. Bifenthrin requires 

additional immunotoxicity testing (870.7800) and an inhalation study (870.3465) for pesticide 
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registration. However, a special acute inhalation study with more specific ACN study endpoints 

will replace the typical 28/90-day inhalation study due to the rapid clearance of bifenthrin and its 

signs of neurotoxicity. 

An oral NOAEL is used for assessing inhalation risk for short-term exposure scenarios. HED’s 

Hazard and Science Policy Council (HASPOC) met on January 12, 2012 to discuss the 

inhalation data requirements (D. Smegal; TXR 0056209; 2012). HASPOC concluded that a 

special acute inhalation study be required for bifenthrin based on a weight of evidence approach 

considering all the available hazard and exposure information. The following items were 

considered in this recommendation: (1) use patterns and MOEs from the most recent risk 

assessment, (2) the physical chemical properties of bifenthrin, (3) the toxicological profile of 

bifenthrin, and (4) inhalation data for other pyrethroids that show the potential for the inhalation 

route to be more potent than the oral route. The existing acute LC50 inhalation study for 

bifenthrin (870.1300) cannot substitute for this special study since it was not designed for 

neurotoxicity evaluations. There were deaths at the lowest dose in this study, thus it was not a 

sensitive data set for point of departure determinations. 

EPA is requiring an inhalation toxicity study for bifenthrin because inhalation data for other 

pyrethroids show the potential for the inhalation route to be more potent than the oral route. 

Currently, the POD for inhalation risk assessment scenarios is based on an oral toxicity study. 

Reliance on an oral study raises uncertainty as to whether the standard safety factors are 

protective of infants and children. For the inhalation study data gap, the Agency is retaining a 

10X database uncertainty factor for all inhalation exposure scenarios. Once these data have been 

received, the Agency will determine how the results will affect the toxicology endpoints and 

uncertainty factors. 

In the absence of specific immunotoxicity studies, the Agency has evaluated the available 

bifenthrin toxicity database to determine whether an additional database uncertainty factor is 

needed to account for potential immunotoxicity. The toxicology database for bifenthrin does not

show any evidence of treatment-related effects on the immune system, and the overall weight-ofevidence suggests that this chemical does not directly target the immune system. Therefore, the 

Agency does not believe that conducting a functional immunotoxicity study will result in a lower 

POD than that currently in use for overall risk assessment, and additional safety factors are not 

needed to account for a lack of this study. 

In light of the literature studies indicating a possibility of increased sensitivity to bifenthrin in 

juvenile rats at high doses, EPA has also the requested proposals for study protocols which could 

identify and quantify bifenthrin’s potential juvenile sensitivity. For the reasons discussed in 

Section 4.4, the uncertainty regarding the protectiveness of the intraspecies uncertainty factor 

raised by the literature studies and the absence of the requested data warrant application of an 

additional 3X for risk assessments for infants and children < 6 years of age.

Dermal exposures of greater than 21 days are possible for bifenthrin; however, the HASPOC 

concluded, based on a WOE approach, that a 90-day dermal toxicity study for bifenthrin is not 

required at this time (TXR No.: 0056209). This approach considered the following factors: 1) 

the established dermal absorption factor based on SAR considerations; 2) that there are no risk 
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estimates of concern for any scenario from using the oral PODs (i.e., MOEs are greater than 100

for adults, and 300 for children, respectively); 3) there are two 21-day day dermal toxicity

studies available for bifenthrin; and 4) the toxicity database for bifenthrin shows that in oral 

toxicity studies, NOAELs do not change considerably over longer exposure durations. 

4.4.2 Evidence of Neurotoxicity

There are no residual uncertainties with regard to evidence of neurotoxicity for bifenthrin. Like 

other pyrethroids, bifenthrin causes toxicity from interaction with sodium channels leading to 

clinical signs of neurotoxicity. These effects are adequately assessed by the available guideline 

and non-guideline studies. Bifenthrin is a Type I pyrethroid and tremors were consistently

observed throughout its toxicology database. Neurotoxicity was consistently observed 

throughout the database in a dose-dependent manner in most of the studies conducted. 

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

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

any of the available guideline toxicity studies for bifenthrin. 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 the 

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

24 pyrethroids, the scientific literature, and the bifenthrin guideline toxicological 

studies.

 The DNT, developmental and reproduction studies for bifenthrin did not demonstrate 

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

with other members of the pyrethroid class.

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

pyrethroid scientific literature related to pharmacodynamics.

 The Agency will retain a 3X uncertainty factor to protect for exposures to children < 6 

years of age based on the increased quantitative susceptibility seen in the scientific 

literature related to pyrethroid pharmacokinetics.

Bifenthrin is neither a developmental nor a reproductive toxicant. Bifenthrin has been 

evaluated for potential developmental effects in the rat (following gavage or dietary

administration) and in the rabbit (gavage administration). Maternal toxicity included 

neurological effects (tremors in rats and rabbits; head and forelimb twitching in rabbits). There 

were no developmental effects of biological significance in either species. The potential 

reproductive toxicity of bifenthrin was examined in a two-generation reproduction study in the 

rat. Tremors were noted only in females of both generations with one parental generation rat 

observed to have clonic convulsions. Furthermore, high-dose studies in the scientific literature 

indicated that younger animals were more susceptible to the toxicity of pyrethroids. For 

example, Sheets et al (1994) found increased brain deltamethrin levels in young rats (PND 11 

and 21) relative to adult rats (PND 72). These age-related differences in toxicity are principally 

due to age-dependent pharmacokinetics; the activity of enzymes associated with the metabolism 
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of pyrethroids increase with age (Anand et al, 2006). However in context, normal dietary or 

residential exposures to juveniles are not expected to overwhelm their ability metabolize 

pyrethroids. In support, at a dose of 4.0 mg/kg deltamethrin (near the Wolansky study LOAEL 

value of 3.0 mg/kg for deltamethrin), the change in the acoustic startle response was similar 

between adult and young rats (Sheets, 1994). In addition, ORD has recently developed an agedependent PBPK model for deltamethrin (Tornero-Velez et al, 2010) which predicts a 3–fold 

increase of pyrethroid in neuronal tissue in younger animals compared to adults. There are 

several studies (in vitro and in vivo) that indicate pharmacodynamic contributions to pyrethroid 

toxicity are not age-dependent. Examination of specific VGSCs have demonstrated that there is 

a lack of increased sensitivity in either juvenile specific isoforms (Meacham et al, 2008) or in 

human isoforms compared to rat variants (Tan and Soderlund, 2009). 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the bifenthrin database in regard to dietary (food and

drinking water), occupational, and residential exposures. Although the acute dietary exposure 

estimates are refined, HED does not believe that the exposure estimates under-estimate risk for

the established or proposed uses of bifenthrin. The reason is the residue levels used are based on 

either monitoring data reflecting actual residues found in the food supply, or on high-end 

residues from field trials which reflect the use patterns which would result in highest residues in 

foods. The residue data used for dietary exposure assessment are described in Section 5.4.1 of 

this document. Furthermore, processing factors used were either those measured in processing 

studies, or default high-end factors representing the maximum concentration of residue into a

processed commodity. EPA made conservative (protective) assumptions in the ground and 

surface water modeling used to assess exposure to bifenthrin in drinking water. Additionally, 

post-application exposure of children and incidental oral exposure of toddlers are based on 

conservative, health-protective assumptions that also ensure exposures are not underestimated. 

These assessments will not underestimate the exposure and risks posed by bifenthrin. 

 

1

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4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

The details for selecting toxicity endpoints and points of departure (PoDs) for various exposure 

scenarios are presented in Appendix A.2. Based on the proposed use patterns for bifenthrin, the 

expected exposure profile will be for dietary, dermal, inhalation and incidental oral exposures. 

Since acute PoDs are protective for chronic exposures, only acute endpoints have been selected 

for bifenthrin. 

As previously indicated, the toxicity endpoints in the bifenthrin database are consistently based 

on clinical signs of neurotoxicity, more specifically tremors. These studies include multiple 

species, study designs, and durations. Moreover, the acute exposure or bolus dosing studies 

generally result in lower NOAELs compared to longer-term dietary administration studies, 

consistent with other pyrethroids in this class. Because uncertainty associated with the PoD is 

propagated throughout the risk assessment, one of the key factors in POD selection is the 

robustness of the dose-response data. The guideline experimental toxicology studies available 

for bifenthrin are generally high quality and were considered in the POD selection process 

(Appendix A.2) and in the weight of the evidence evaluation. In addition to the typical guideline 

studies, data from two special studies (Wolansky study on locomotor activity and Nemec/WIL 

FOB study) evaluating neurobehavioral outcomes are available for bifenthrin (Nemec 2006; 

Wolansky et. al. 2006). Wolansky et al. (2006) individually measured locomotor activity at the 

time of peak effect after exposure to 11 pyrethroids, including bifenthrin. Dose-response 

relationships were determined using 6-11 doses per pyrethroid (9 doses used for bifenthrin) and 

3-18 rats per dose group (8-12 animals/group used for bifenthrin), minimizing variability and 

increasing the confidence in the benchmark dose (BMD) estimates determined from this study. 

The locomotor activity for bifenthrin had an excellent dose response. Locomotor activity is an 

objective toxicity metric, since it is recorded by photoelectric detectors. Moreover, each 

pyrethroid was evaluated by the same scientist thus decreasing some of the variability associated 

with neurobehavioral measures. In the Nemec/WIL study, 17 pyrethroids have been evaluated 

using a specially designed Functional Observational Battery (FOB) study focused on the 

outcomes associated with pyrethroid toxicity syndromes. The bifenthrin data from the 

Nemec/WIL study were not considered as part of PoD selection. The bifenthrin dose selection in 

the Nemec/WIL study was sub-optimal (i.e. only 2 doses and too close together), resulting in a 

poor dose response curve and low confidence of the calculated BMDL value (Nemec 2006). 

Observation of tremors is the most prominent findings in the guideline experimental toxicology

studies and was considered in the PoD determination. Unlike the Wolansky study, guideline 

studies typically have only three treatment groups and often do not evaluate clinical signs at the 

time of peak effect. Moreover, scoring metrics of tremors varies widely among guideline 

studies. 

The Wolansky study utilized a sensitive rat strain to neurotoxins (Long Evans), plus measured an 

objective apical endpoint of locomotor activity as the toxicity metric. The BMD1SD value was 

4.1 mg/kg at a 20% decrease in locomotor activity and the BMDL1SD value was 3.1 mg/kg. The 
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Wolansky study was considerably conservative, using gavage dosing with a vehicle and volume 

producing the most adverse responses (i.e. 1 ml/kg corn oil). The BMD data analysis was 

utilized as a standardized method to address concerns of dose selection and dose spacing. In 

support, the BMD1SD value for bifenthrin was verified in the study by Scollon et al (2011), with a 

20% decrease in motor activity at a dose of approximately 4 mg/kg (i.e. one SD for the 

Wolansky bifenthrin data corresponded to 20% of the control mean value). Furthermore, the 

PoD from the Wolansky study is supported by similar NOAEL values in multiple other guideline 

studies (see Table 4.3.3). Given the multiple strengths associated with study design of Wolansky 

et. al. (2006) and the resulting well-defined dose-response curve, this study provides the most 

robust data set for extrapolating risk from bifenthrin. The ACN is often considered for acute 

endpoints. However, this study for bifenthrin did not utilize a vehicle and had an atypical 

LOAEL value of 70.3 mg/kg. Thus, the Wolansky PoD is much more conservative. Further, 

there were deaths at the LOAEL value and, therefore, this is not a sensitive study for the 

selection of a point of departure. 

Acute Dietary (All Age Groups): Quantitation of the dietary risks were performed using the 

acute oral Wolansky study, with a BMDL value of 3.1 mg/kg and a BMD value of 4.1 mg/kg 

based on decreased locomotor activity. 

Short-term Dermal: Quantification of dermal risks were performed using a 21-day dermal rat 

study with a BMDL10 value of 96.3 mg/kg/day and a BMD10 value of 187.0 mg/kg/day based on 

exaggerated hind limb flexion (see Appendix G for the BMD analysis).

0.01 0.1 1 10

0

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125

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r=0.99 Wolansky 2006

Wolansky Study Bifenthrin Data +/- SD

T

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Bifenthrin (mg/kg)
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Short-term Incidental Oral: Quantitation of the incidental oral risks were performed using the 

acute oral Wolansky study, with a BMDL value of 3.1 mg/kg and a BMD value of 4.1 mg/kg 

based on decreased locomotor activity.

Short-term Inhalation: Quantitation of the inhalation risks were performed using the acute oral 

Wolansky study, with a BMDL value of 3.1 mg/kg and a BMD value of 4.1 mg/kg based on 

decreased locomotor activity. Equivalent inhalation and oral toxicity were assumed.

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

HED combines risk values resulting from separate routes of exposure when it is likely they can 

occur simultaneously based on the use pattern and the behavior associated with the exposed 

population, and if the hazard associated with the points of departure is similar across routes. A 

common toxicological endpoint, neurotoxicity, exists for dermal, incidental oral, and inhalation 

routes of exposure to bifenthrin. Therefore, these were combined for all residential exposure 

scenarios assessed. 

4.5.3 Cancer Classification and Risk Assessment Recommendations

Bifenthrin is classified as a “possible human carcinogen” based on an increased incidence of 

urinary bladder tumors in mice. However, EPA concluded that the bladder tumors may not be 

uncommon in mice and are not likely to be malignant. Additionally, these tumors were observed 

only in male mice at the highest dose tested and the incidence was of borderline significance. No 

evidence of carcinogenicity was observed in bifenthrin carcinogenicity studies in rats, and 

bifenthrin was negative in five different tests for mutagenicity but was marginally active in a 

forward mutation test in mouse lymphoma cells. Overall, based on the available information, 

there is a low concern for mutagenicity. 

Taking into account all of this information, the Agency has determined that quantification of risk 

using a non-linear approach (i.e., an aPAD or aRfD) will adequately account for all chronic 

toxicity, including carcinogenicity that could result from exposure to bifenthrin. While the 

Agency would typically use a chronic population-adjusted dose (cPAD) to protect for cancer 

concerns, use of the aPAD is protective for bifenthrin because increasing toxicity with increasing 

duration of exposure is not seen for bifenthrin. The NOAEL observed in the mouse chronic 

study, in which tumors were observed, is 6.7 mg/kg/day, 2-fold higher than the POD used for 

acute risk assessment. The NOAEL in the study was based on tremors seen at the LOAEL of

25.6 mg/kg/day; however, the tumors were observed at 81.3 mg/kg/day, a dose that is 26-fold 

higher than the current acute POD.
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4.5.4 Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

Table 4.5.4. Summary of Toxicological Doses and Endpoints for Bifenthrin

Exposure 

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD and 

LOC

Study and Toxicological 

Effects

Acute 

Dietary-

(< 6 years 

old)

BMDL1SD= 3.1 

mg/kg

Acute RfD = 

0.031 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 

3X

aPAD = acute RfD

 FQPA SF

= 0.010 

mg/kg/day

Wolansky et al (2006) 

BMD1SD = 4.1 mg/kg 

based on reductions in 

locomotor activity; 

Supported by multiple 

guideline studies

Acute 

Dietary-

(≥ 6 years 

old)

BMDL1SD = 3.1 

mg/kg

Acute RfD = 

0.031 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 

1X

aPAD = acute RfD

 FQPA SF

= 0.031 

mg/kg/day

Wolansky et al (2006) 

BMD1SD = 4.1 mg/kg 

based on reductions in 

locomotor activity; 

Supported by multiple 

guideline studies

Short-Term 

(1-30 days) 

Incidental 

Oral 

BMDL1SD = 3.1 

mg/kg

UFA = 10X

UFH = 10X

FQPA SF = 

3X

Residential:

< 6 years old

LOC is an MOE= 

300

≥ 6 years old, LOC 

is an MOE= 100

Wolansky et al (2006) 

BMD1SD = 4.1 mg/kg 

based on reductions in 

locomotor activity; 

Supported by multiple 

guideline studies

Short-Term 

(1-30 days) 

Dermal

BMDL10=96.3 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 

3X

Residential:

< 6 years old

LOC is an MOE= 

300

≥ 6 years old, LOC 

is an MOE= 100

Occupational:

Adults, LOC is an 

MOE=100

21-day dermal study in 

rats.

BMD10=187.0 mg/kg/day, 

based on exaggerated hind 

limb flexion

Short-Term 

(1-30 days)

Inhalation

BMDL1SD = 3.1 

mg/kg

UFA = 10X

UFH = 10X

FQPA SF = 

30X*

Residential:

< 6 years old, LOC 

is an MOE= 3,000

≥ 6 years old, LOC 

is an MOE= 1,000

Wolansky et al (2006) 

BMD1SD = 4.1 mg/kg 

based on reductions in 

locomotor activity; 

Supported by multiple 

guideline studies
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NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty 

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

members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not 

applicable.

* FQPA SF is composed of the 3X factor for increased quantitative susceptibility and the 10X factor for the 

inhalation study data gap. 

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Plant and Livestock Metabolism Studies

Plant Metabolism

The metabolism of bifenthrin was investigated in cotton, apples, corn and potatoes. Metabolism 

was generally similar in all plants. When directly applied to soil, most of the bifenthrin remains 

in the soil with very little uptake into the plants. When applied foliarly, the major residue in 

plants is the parent compound. Most residue stays on the surface where applied with only small 

amounts translocated throughout the plant. Bifenthrin in the major residue identified in all crops. 

4-hydroxy bifenthrin was the only residue identified at just over 10% of the TRR and was seen 

only in corn. 

Livestock Metabolism

The metabolism of bifenthrin was investigated in the goat and the hen. Ruminant and poultry

metabolism is similar. Most of the administered dose is excreted. The highest residues retained 

in the tissues are found in fat and liver. In ruminant milk, fat and muscle and poultry eggs, fat 

and muscle, unchanged parent is the major residue. In ruminants, the major metabolite in liver 

and kidney is 1-methyl-3-phenylbenzoic acid and in poultry, hydroxymethyl bifenthrin and fatty 

acid conjugates of hydroxymethyl bifenthrin were identified in fat and liver. 

5.1.2 Summary of Environmental Degradation

Drinking Water Memo, D372556, J. Melendez, 8/11/2010

Studies conducted on bifenthrin indicate that it is persistent under most conditions and 

bioaccumulative. It appears that a major route of degradation is aerobic metabolism. Bifenthrin 

is relatively stable to hydrolysis at all pH values. It is relatively stable to aqueous and soil 

photolysis and degrades slowly under both aerobic and anaerobic soil metabolism conditions 

(half-life range 97-250 days in 3 soils, and relatively stable, respectively). Bifenthrin is 

Occupational:

Adults MOE=1,000

Cancer 

(oral, 

dermal, 

inhalation)

Classification: Category C (possible human carcinogen). No Q1* has been derived. 

Anon-linear approach is recommended for cancer assessment.
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relatively immobile in four soils tested (KOC range 131,000 to 275,000). Field studies show a 

pattern consistent with the laboratory studies, with relatively high persistence (half-lives ranging 

from 78 to 345 days in 10 field trials) and low mobility of the chemical in soil. In aquatic 

environments, it appears that residues of bifenthrin persist in pond sediments for extended 

periods (at least 12 months of monitoring). No major metabolites were observed (> 10% of the 

applied) in any of the laboratory studies. The very low water solubility and hydrophobic nature 

of bifenthrin leads to strong soil adsorption and a tendency to partition to sediment in aquatic 

systems.

Bifenthrin has a vapor pressure of 1.8x10–7 mmHg, water solubility of 0.0140 ppb, and an 

estimated Henry’s law constant of 7.2x10-3 atm-m3/mol. Based upon its Henry’s law constant 

and vapor pressure, bifenthrin is expected to have a moderate to low potential for volatilization 

from soil and water surfaces. Bifenthrin’s potential for volatilization is reduced significantly 

because it adsorbs strongly to soils, suspended solids, sediment and organic matter in the water 

column. A laboratory volatility study showed a maximum volatility at 40°C of 5.07x10-4

μg/cm2 hr (average at 14 days), a relatively low value.

5.1.3 Comparison of Metabolic Pathways

The rat metabolism study is discussed in Section 4.2. Plant and animal metabolism studies are 

discussed in Section 5.1.1. 

The metabolic profile in plants is similar in cotton, apples, corn and potatoes. Further, the 

metabolism in ruminants, poultry, and the rat is also similar. In plants, the unchanged parent 

compound is the major residue and in animals, it is also the major residue in all animal matrices. 

Therefore, there are no residues of concern in plant studies that are not also present in the rat 

metabolism study. 

5.1.4 Residues of Concern Summary and Rationale

The residue of concern in plants, livestock and drinking water is the parent compound. 

Unchanged parent is the major residue in all plant matrices, drinking water and most animal 

matrices. In animals additional metabolites have been identified in liver, kidney and fat, 

however, these metabolites are likely present at fairly low levels and are considered to likely be 

of lesser toxicity than the parent and are therefore not of concern. 

Table 5.1.4. Summary of Metabolites and Degradates to be included in the Risk

Assessment and Tolerance Expression

Matrix Residues Included In 

Risk Assessment

Residues Included In 

Tolerance Expression

Plants Grass grown for seed 

(hay and forage) and Tea 

Bifenthrin parent only Bifenthrin parent only Rotational Crops

Livestock Ruminant
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Table 5.1.4. Summary of Metabolites and Degradates to be included in the Risk

Assessment and Tolerance Expression

Matrix Residues Included In 

Risk Assessment

Residues Included In 

Tolerance Expression

Poultry & Eggs

Drinking Water

5.2 Food Residue Profile

Bifenthrin is typically applied as a foliar application for later season uses. Applications directly 

to soil generally do not result in significant residues in plants due to bifenthrin’s affinity to bind 

to soil, its low soil mobility, and the low tendency of this pesticide to translocate within plants. 

Metabolism data shows that when applied foliarly, the vast majority of residue is likely to be 

surface residues at the site of application consisting primarily of unchanged parent compound. 

USDA’s Pesticide Data Program (PDP) has conducted extensive monitoring for residues of 

bifenthrin in a wide variety of crops. The data shows that bifenthrin residues in most crops are 

not found at or above the limit of quantification of the analytical method. A few quantifiable 

residues are found in the leafy vegetables, but even in these commodities, most monitoring 

samples have no residues above the method LOQ. Based on animal metabolism data and feeding 

studies, residues in livestock commodities resulting from feeding treated feedstuffs are likely to 

be very low, and given the low water solubility and high affinity to bind to soils, residues in 

water are also expected to be very low. 

5.3 Water Residue Profile

Drinking Water Memo, D372556, J. Melendez, 8/11/2010

The Tier I Estimated Surface Drinking Water Concentrations and Estimated Ground Water 

Concentrations (EDWCs) for bifenthrin were calculated using the Tier I aquatic models FQPA 

Index Reservoir Screening Tool (FIRST) and SCI-GROW, respectively. The very low water 

solubility and the tendency of bifenthrin to adsorb to soil indicate that drinking water is not a

major route of exposure; however, in the absence of acceptable monitoring data HED has used 

EDWCs which are anticipated to overestimate risk. 

The Estimated Drinking Water Concentrations (EDWCs) for bifenthrin were calculated based on 

a maximum application rate of 0.5 lb a.i./A/season. The acute drinking water concentration in 

surface water is 0.0140 ppb of bifenthrin, based on applications of the chemical to lettuce. The 

cancer/chronic drinking water concentration is 0.0140 ppb (based on applications of lettuce, with 

the highest application rate and PCA). The SCI-GROW generated EDWC is 0.014 ppb of 

bifenthrin, which is recommended for use, both for acute and chronic exposures. Because of the 

very low solubility of bifenthrin, the EDWCs did not exceed 0.0140 ppb (that is, the solubility of 

bifenthrin).

Table 5.2 provides a summary of the Tier I modeled drinking water concentrations for 

bifenthrin. 
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Table 5.2. Summary of Estimated Surface Water and Groundwater Concentrations for

Bifenthrin

Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b

Acute

0.0140 0.0030

Chronic (non-cancer)

a

From the Tier I FQPA Index Reservoir Screening Tool (FIRST). Input parameters are based on maximum 

application rate on lettuce (0.5 lb ai/A/season).

b

From the SCI-GROW model; lettuce scenario. 

Highest value for use in risk assessment is shown in bold.

5.4 Dietary Risk Assessment

Bifenthrin: Dietary Exposure Memo, D383085, S. Tadayon, 5/25/2012

A highly refined acute dietary exposure and risk assessment was conducted for bifenthrin. Highend modeled drinking water estimates were directly incorporated into the assessment. In order to 

assess short-term aggregate risk to bifenthrin, average dietary exposure estimates (i.e., food and

drinking water) were calculated. Because the endpoint from the acute study is protective of 

endpoints from repeat dosing studies, a chronic dietary risk assessment was not conducted. 

Bifenthrin may be stored and accumulated in aqueous sediment and, therefore, could be a 

potential dietary exposure source for people who eat fish (e.g., catfish) which dwell near the 

sediment. Subsistence fishers may be more highly exposed than the general population. HED 

conducted an acute screening level dietary exposure assessment to consider the intake of 

contaminated catfish by subsistence fishers. Because high-end bounding fish exposure 

assumptions were used to assess exposure to subsistence fishers, this potential dietary exposure 

source was not included in the acute or average dietary exposure and risk assessments conducted 

for the proposed Section 3 and 18 uses; rather, a stand-alone assessment was conducted.

5.4.1 Description of Residue Data Used in Dietary Assessment

The bifenthrin acute dietary exposure and risk assessment was conducted considering all 

supported food uses and drinking water. The assessment was conducted using DEEM-FCIDTM, 

Version 2.03, which incorporates consumption data from USDA’s CSFII, 1994-1996 and 1998. 

Anticipated residues (ARs) were developed based on the latest USDA’s Pesticide Data Program 

(PDP) monitoring data 1998-2010, Food and Drug Administration (FDA) data, and field trial 

data (FTD) for bifenthrin. 

The USDA’s PDP provides bifenthrin monitoring data from 1998-2010. The PDP sampling 

protocol calls for typical consumer practices such as rinsing vegetables, peeling and coring fruit 

prior to sample analysis. PDP data were used where available for both the Section 3 and 18 

proposed uses. For the acute dietary assessment the latest PDP data were used for the following

commodities: bell pepper; bean (succulent); blueberry; broccoli; cabbage; cauliflower; cilantro;

cranberry; cucumber; egg; eggplant; grape; grapefruit; orange; orange juice; lettuce; pear; 

cantaloupe; winter squash; spinach-canned; strawberry; sweet corn; sweet peas; tomato;

watermelon; and milk. For blackberry and raspberry, the 2002 FDA monitoring data were used.
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The chronic dietary assessment used PDP data for the following commodities: bean (succulent), 

beef, milk, pea and pork.

Field trial data (FTD) were submitted by IR-4 in support of the use of bifenthrin on grass grown 

for seed and the establishment of a tolerance on imported tea. The evaluation of the analytical 

chemistry and residue data for the submitted studies is described in a separate memorandum 

(D388604, P. Savoia, 5/25/2012).

No FTD was submitted by the states support of the Section 18 action request for use on apple, 

nectarine, and peach. However, these crops have use patterns that are similar to the registered 

use on pear. Therefore, the Agency relied on PDP data for pears, including for baby food and 

canned products, when assessing anticipated residues on peach, nectarine, and apple. EPA 

believes the use of PDP data for pears is appropriate, as bifenthrin residues are found mainly on 

the fruit surface and residues on peach, nectarine, and apple are expected to be similar to those 

found on pear. The evaluation of the analytical chemistry and residue data for the pear is 

described in a separate memorandum (D274839, S. Levy, 08/15/2002). 

The acute and chronic EDWCs for bifenthrin were calculated using the Tier I aquatic models 

FIRST and SCI-GROW and based on a maximum application rate of 0.5 lb ai/A/season. The 

acute and chronic EDWC in surface water was estimated is 0.014 ppb of bifenthrin, the solubility

of the chemical. 

The quantification of average dietary exposures was necessary to estimate short-term aggregate 

exposures. This required the use of anticipated residues (ARs) from average field trial residues 

for tree nuts, artichoke, beans, beet (roots and tops), cabbage, carrot, coriander, mustard greens 

and tea. ARs from PDP data were used for bean (succulent), beef, milk, pea, and pork. For all 

other commodities, the assessment used current tolerances. The assessment also made use of 

PCT information where available. Drinking water information was incorporated directly into the 

dietary assessment using the mean concentration (1-in-10-year annual mean) for surface water 

generated by the PRZM-EXAMS model.

The assessment of human exposure from contaminated catfish used the mean and maximum 

subsistence fish intake amounts (Exposure Factors Handbook, 2011), and 2010 PDP data for 

catfish. The mean fish intake for subsistence fishers is 81 g/day, and the maximum is 770 g/day. 

PDP sampled 384 fish (catfish) total, with 130 showing detectable bifenthrin residue. The 

highest residue was 0.06 ppb. 

5.4.2 Percent Crop Treated Used in Dietary Assessment

Percent Crop Treated (PCTn) Memo, D398265, J. Alsadek, 3/21/2012

A screening-level usage analysis (SLUA) was provided by the Biological Economic Analysis 

Division (BEAD), SLUA in Support of Registration for the Insecticide Bifenthrin, 10/31/2011. 

The estimated maximum percent crop treated (PCT) for each commodity was used for the acute 

dietary risk assessment. For proposed new uses and uses that have not been registered long 

enough for usage data, the Agency conservatively estimated that 100 % of the crops were treated

(see details below for the Section 18 uses). 
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BEAD also provided projected use information for the proposed Section 18 uses (i.e., apple, 

nectarine, and peach) in the memo, Estimates of the Percent Crop Treated for New Uses (PCTn) 

of Bifenthrin on Apples, Peaches, Nectarines, and Pears Considering Potential Emergency Use 

in DE, MD, NC, NJ, PA, VA, and WV. BEAD used data from 2010 USDA/NASS Agricultural 

Statistics for apples and peaches. Data on the most recent survey years, 2007-2009, were used to 

derive the needed PCT estimates. The sum of the utilized production in these states was divided 

by the total domestic utilized production and multiplied by 100 to determine the PCT for each of 

the crops for each of the named years. BEAD conservatively estimated that 100 percent of the 

crops in these states will be treated with bifenthrin and calculated the national PCT given the 

share of utilized production or grown acreage from the seven states likely to seek the use of 

bifenthrin.

The following maximum PCT estimates were used in the acute dietary risk assessment: alfalfa, 

1%; almonds, 25%; artichokes, 30%; beans, green, 50%; broccoli, 6 %; cabbage, 30%; 

caneberries, 45%; canola/rapeseed, 3%; cantaloupes, 60%; carrots, 10%; cauliflower, 10%; 

celery, 1%; corn, 5%,; cotton, 10 %; cucumbers, 15%; dry beans/peas, 1%; grapes, table, 1%; 

grapes, wine, 5%; honeydew, 75%; hazelnuts (filberts), 5%; lettuce, 15%; onions, 1%; lima 

beans, 35%; peanuts, 5%; peas, green, 25%; pears, 4%; pecans, 5%; peppers, 20%; pistachios, 

40%; potatoes, 5%; pumpkins, 40%; sorghum,1%; soybeans, 5%; squash, 20%; strawberries, 

55%; sweet corn, 50%; tomatoes, 20%; walnuts, 25%; watermelons, 15%; wheat, spring, 1%;

and wheat winter, 1%. In addition, the Agency estimated the PCT for the new uses with the time 

limited tolerances as follows: apples, 10%; peaches, 7%; nectarines, 3%; and pears 4%.

The following average PCT estimates were used to calculate average dietary exposures: alfalfa, 

1%; almonds, 12%; artichokes, 14%; beans, green, 40%; broccoli, 2%; cabbage, 20%;

caneberries, 35%; canola/rapeseed, 2%; cantaloupes, 40%; carrots, 2%; cauliflower, 5%; celery, 

1%; corn, 2%; cotton, 4%; cucumbers; 10%; dry beans/peas, 1%; grapes, table, 1%; grapes,wine, 

2%; honeydew, 70%; hazelnuts (filberts), 5%; lettuce, 5%; onions, 1%; lima beans, 10%; 

peanuts, 2%; peas, green, 5%; pears, 1%; pecans, 2%; peppers 10%, pistachios 35%, potatoes, 2

%; pumpkins, 20%; sorghum, 1%; soybeans, 1%; squash, 10%; strawberries, 30%; sweet corn,

30 %; tomatoes, 6 %; walnuts, 15%; watermelons, 10%; wheat, spring, 1%; and wheat, winter,

1%. In addition, the following PCT estimates were used to calculate average dietary exposures 

for the proposed Section 18 uses in DE, MD, NC, NJ, PA,VA, and WV: apples, 10%; peaches,

6%; nectarines, 3%; and pears, 4%.

5.4.3 Acute Dietary Risk Assessment

Highly-refined, acute probabilistic dietary exposure and risk assessments were conducted for all 

established food uses, as well as the petitioned for tolerances and the Section 18 time-limited 

tolerances. High-end modeled drinking water estimates were directly incorporated into the 

assessment. The acute dietary exposure estimates for food and drinking water are below HED’s 

level of concern (<100% aPAD) at the 99.9th percentile of exposure. 

Bifenthrin dietary exposure at the 99.9th percentile for food and drinking water is 5 % of the 

aPAD for the U.S. population and 29 % of the aPAD for children 1-2 years, the most highly
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exposed population subgroup. A summary of acute dietary exposures estimates for all 

populations is presented in Table 5.4.6, below.

For the acute assessment of bifenthrin exposure to subsistence fishers, the maximum intake level 

identified in the 2011 Exposure Factors Handbook, 770g/day, was used. The highest residue 

value from 2010 fish PDP data, 0.06 ng/g, was multiplied by the maximum fish intake resulting 

in a value of 46.2 ng/day of bifenthrin. This value was converted to mg/day and then divided the 

weight of an adult, 80 kg, resulting in an estimated daily dose of 5.8 x 10-7 mg/kg/day. This dose 

was then compared to the acute RfD to result in a highly conservative estimated % aPAD value 

of < 1 % and, therefore, would not be anticipated to significantly impact the dietary exposure 

assessments conducted for the proposed Section 3 and 18 uses.

5.4.4 Chronic/Cancer Dietary Risk Assessment

Chronic and cancer dietary risk assessments were not conducted for bifenthrin. Because there is 

no increase in hazard from repeat exposures to bifenthrin, the acute dietary exposure assessment 

is protective for chronic dietary exposures; acute exposure levels are higher than chronic 

exposure levels. Accordingly, a dietary exposure assessment for the purpose of assessing 

chronic dietary risk was not conducted.

5.4.5 Average Dietary Exposure

Average dietary exposures were quantified for the purpose of assessing short-term aggregate risk 

(i.e., food, drinking water, and residential exposures) of the proposed and established uses. A 

summary of average dietary exposures estimated for all population subgroups is presented in 

Table 5.4.6, below. 

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Bifenthrin

Population Subgroup

Acute Dietary

(99.9th Percentile) Average Dietary Exposure

(mg/kg/day) Dietary Exposure 

(mg/kg/day) % aPAD

General U.S. Population 0.0015 5.0 % 0.00074

All Infants (< 1 year old) 0.0013 13 % 0.0010

Children 1-2 years old 0.0030 29 % 0.0018

Children 3-5 years old 0.0022 22 % 0.0014

Children 6-12 years old 0.0014 4.6 % 0.00080

Youth 13-19 years old 0.0011 3.7 % 0.00060
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Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Bifenthrin

Population Subgroup

Acute Dietary

(99.9th Percentile) Average Dietary Exposure

(mg/kg/day) Dietary Exposure 

(mg/kg/day) % aPAD

Adults 20-49 years old 0.0015 4.8 % 0.00066

Adults 50+ years old 0.0016 5.1 % 0.00066

Females 13-49 years old 0.0012 3.8 % 0.00055

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

Residential exposure is anticipated from the proposed Section 3 bed bug treatment use. In 

addition, residential exposures are anticipated from currently registered uses of the chemical. 

Exposures are expected for individuals (adults) who apply bifenthrin-containing products and 

from post-application exposure in residential areas previously treated with the chemical. In 

accordance with FQPA, HED must consider and aggregate pesticide exposures and risks 

anticipated from food, drinking water, and residential exposures. A residential exposure 

assessment was conducted for the bed bug treatment use (D383326, A. Rivera-Lupiáñez, 

5/25/12) and considered for use in the aggregate assessment. An updated assessment of 

bifenthrin residential uses has also been conducted for the purpose of assessing bifenthrin 

aggregate risk because of the revision of the Residential SOPs. 

Residential uses of bifenthrin are many and vary widely. The chemical is used in indoor 

residential/household premises in the form of crack and crevice sprays, as a paint additive, dust, 

and automobiles/recreational vehicle and termite treatments. Outdoor residential uses of 

bifenthrin include broadcast and spot treatments to the following: residential lawns/turf; golf 

course turf and outdoor premises (fencerows/hedgerows, paths/patios) by means of liquid spray

and granular products; and ornamental (turf, shrubs, vines, trees, ground cover).

HED used the BEAD Label Use Information System (LUIS) in order to conduct a screen of the 

various indoor and outdoor residential uses of bifenthrin and determined those which would 

result in the greatest potential for exposure. The following high-end uses were selected for use 

in the bifenthrin short-term aggregate assessment: outdoor ornamental plant and turf uses. The 

bed bug treatment was proposed for surface-directed application to the following indoor use 

sites: baseboards, bed frames, box springs, closets, dressers, furniture, headboards, inside empty

luggage, mattresses, and moldings.

The Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide 

Exposure Assessment was used to assess exposure/risk anticipated from all bifenthrin uses 

considered. 
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The lifestages (i.e., adults, children 1< 2 years old, children 11 < 16 years old, and children 6 < 

11 years old) selected for each post-application scenario are based on an analysis provided as an 

Appendix in the 2012 Residential SOPs. These lifestages are not the only that could be 

potentially exposed for these post-application scenarios; however, the assessment of these are

health protective for the exposures and risks for any other potentially exposed lifestages.

Because of the rapid reversibility of the most sensitive neurotoxicity endpoint used for 

quantifying risks, there is no increase in hazard with increasing dosing duration. Therefore, the 

acute endpoint is protective of the endpoints from repeat dosing studies, including chronic 

exposures. Thus, for purposes of residential exposure assessment, only single-day risk 

assessments were conducted.

6.1 Residential Handler Exposure

The Agency uses the term “handlers” to describe those individuals who are involved in the 

pesticide application process. HED has determined that short-term dermal and inhalation 

exposure to residential handlers is likely during use of the following bifenthrin uses: the 

proposed indoor bed bug treatments; and registered outdoor ornamental, and turf uses. 

Residential handler dermal and inhalation risk estimates for bifenthrin are not of concern to HED 

(i.e., MOEs are ≥ 100 for dermal and ≥ 1,000 for inhalation, the levels of concern (LOC) for 

these assessments). 

HED’s level of concern for adult residential handlers is equal to an ARI of 1. The combined 

dermal and inhalation risk estimates (ARIs) to residential handlers for the identified residential

outdoor and proposed indoor bed bug uses are not of concern to HED (i.e., ARIs are ≥ 1). The 

lowest ARI is 2.1 from use of a backpack sprayer equipment to treat ornamentals. A summary of 

the results from the assessment of the proposed bed bug treatment is presented below in Table 

6.1. A summary of all other results is presented in Appendix C (Table C.1) of this document. 

Table 6.1. Residential Bifenthrin Handler Exposure and Risk Estimates for the Indoor Bed Bug 

Treatment

Application 

Rate 

(lb ai/gallon)a

Amount 

Handled 

(gallons)b

Unit Exposure (mg/lb ai)b Dose (mg/kg/day)d,e Short-Term MOEf

DermalcInhalationc Dermal Inhalation Dermal Inhalation

Mixing/Loading/Applying Wettable Powders with Manually-Pressurized Handwand 

0.0051 0.50 69 1.1 0.0021 0.000035 44,000 88,000

a. Application Rates based on proposed use on label for F4688 50 WSP Insecticide Termiticide label (EPA Reg. No. 

8033-96)

b. Based on 2011 Residential SOPs

c. Dermal: Short-sleeve shirt, shorts, and no gloves; Inhalation: no respirator.

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

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

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

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

f. Dermal MOE = PoD (BMDL10 of 96.3 (mg/kg/day) / Daily dermal dose (mg/kg/day); Inhalation MOE = PoD 

(BMDL1SD of 3.1 mg/kg/day) / Daily inhalation dose (mg/kg/day). Level of concern = 100 (Adult, dermal); 1000 (Adult, 

inhalation)
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6.2 Residential Post-Application Exposure

The Agency uses the term “post-application” to describe exposures to individuals that occur as a 

result of being in an environment that has been previously treated with a pesticide. Bifenthrin 

can be used in areas frequented by the general population, including indoor and outdoor 

residential areas. As a result, HED anticipates post-application exposures from the residential 

use of bifenthrin. The proposed indoor bed bug treatment and the same high-end outdoor uses 

considered for residential handlers were assessed for residential post-application exposure 

assessment. 

Adult residential post-application dermal exposures assessed for the registered outdoor and 

proposed indoor uses are not of concern to HED. The greatest estimated risk for adults 

corresponded to a dermal MOE of 270 for post-application exposure in ornamental gardens. For 

children 1 < 2 years old, the combined dermal and incidental oral risk estimates for the identified 

residential uses are not of concern to HED (i.e., MOEs are ≥ 300, the LOC for these 

assessments). The greatest estimated risk for children corresponds to a dermal MOE of 690 for 

children 1 < 2 years old contacting treated turf. A summary of these results is presented in 

Appendix C (Table C.2) of this document.

6.3 Combined Exposure

HED combines risk values resulting from separate routes of exposure when it is likely they can 

occur simultaneously based on the use pattern and the behavior associated with the exposed 

population, and if the hazard associated with the points of departure is similar across routes. A 

common toxicological endpoint, neurotoxicity, exists for dermal, incidental oral, and inhalation 

routes of exposure to bifenthrin. Therefore, these were combined for all residential exposure 

scenarios assessed. A summary of these results is presented in Appendix C (Table C.2) of this 

document.

Table 6.3.1 below presents the combined risk estimates for the uses resulting in the highest 

potential for residential handler and post-application exposure. These worst case estimates were 

used for the aggregate assessment. 

Combined adult handler exposure (dermal and inhalation) from applying bifenthrin to 

ornamentals with a backpack sprayer results in a risk estimate that is not of concern to HED (i.e., 

the ARI is > 1). The risk estimate for combined child 1 < 2 years old exposure (dermal and 

incidental oral) from contacting turf treated with a liquid formulated bifenthrin product is not of 

concern (i.e., the MOE is > 300). 
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Table 6.3.1 Combined Residential Bifenthrin Risk Estimates (High-End)

Lifestage Exposure 

Scenario App. Rate Route of Exposure Dose(mg/kg/day) MOE ARI

Handler

Adult

Ornamentals 

– Backpack 

Sprayer 

0.20 

lb ai/A

Dermal 0.34 270

2.1 Inhalation 0.00037 8,400

Lifestage Exposure 

Scenario App. Rate Route of Exposure Dose(mg/kg/day) MOE Combined MOE

Post-Application

Child 1 < 2 

Years Old Turf, Liquid 0.20lb ai/acre

Dermal 0.14 690 400 Incidental Oral 0.0029 1,000

Residential handler and post-application exposure scenarios are generally not combined. 

Although the potential exists for the same individual (i.e., adult) to apply a pesticide around the 

home and be exposed by re-entering a treated area in the same day, this is an unlikely exposure 

scenario. Combining these exposure scenarios would also be inappropriate because of the 

conservative nature of each individual assessment. 

Post-application residential exposure scenarios may be combined for purposes of an aggregate 

exposure assessment if they have a reasonable probability of occurring on a single day and the 

pest that an individual is attempting to control is the same. All residential exposure scenarios 

assessed in this document were considered and the proposed indoor bed bug treatment is the only

to meet this criteria. Post-application co-exposure could occur following the simultaneous 

treatment multiple use sites (e.g., baseboards, furniture and mattresses) due to a bed bug 

infestation. Therefore, combined risks for adults and children were estimated for the two postapplication exposure scenarios.

Combined adult post-application exposure assessed for surface-directed sprays (dermal and 

inhalation) and mattress (dermal) use sites is not of concern to HED (i.e., the ARI is > 1). For 

children 1 < 2 years old, combined post-application exposure assessed for surface-directed 

sprays (dermal, incidental oral, and inhalation), and mattress (dermal) are not of concern to HED 

(i.e., the ARI is > 1). Table 6.3.2 below presents the combined risk estimates for a residential 

bed bug treatment. 

Table 6.3.2. Combined Residential Post-Application Exposure Risk Estimates from Bed Bug 

Treatment

Lifestage Exposure 

Scenario

App. Rate

(lb 

ai/gallon)

Route of 

Exposure

Dose

(mg/kg/day) MOE ARI

Adult

Surface-directed 

Sprays

0.0051

Dermal 0.012 7,900

79 Inhalation 0.000016 190,000

Mattress Dermal 0.0014 140,000

Child 1 < 2 

Years Old

Surface-directed 

Sprays

Dermal 0.012 8,200 3.6 Inhalation 0.000066 45,000
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Table 6.3.2. Combined Residential Post-Application Exposure Risk Estimates from Bed Bug 

Treatment

Lifestage Exposure 

Scenario

App. Rate

(lb 

ai/gallon)

Route of 

Exposure

Dose

(mg/kg/day) MOE ARI

Incidental Oral 0.0018 1,800

Mattress Dermal 0.0032 61,000

6.4 Residential Bystander Post-application Inhalation Exposure

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for bifenthrin. The 

Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard air blast and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.

Although a quantitative residential post-application inhalation exposure assessment was not 

performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for flaggers. This exposure scenario, for which no risks of 

concern were identified, is representative of a worse case inhalation (drift) exposure and may be 

considered protective of most outdoor agricultural and commercial post-application inhalation 

exposure scenarios.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate bifenthrin pesticide exposures 

and risks from three major sources: food, drinking water, and residential exposures. In an 

aggregate assessment, exposures from relevant sources are added together and compared to 

quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be 

aggregated. When aggregating exposures and risks from various sources, HED considers both 

the route and duration of exposure.

Like other pyrethroids, bifenthrin causes clinical signs of neurotoxicity. Muscle tremors were 

consistently observed throughout the bifenthrin toxicology database, and hind-limb flexion was 

observed in the dermal study. Both effects are considered neurotoxic signs and, therefore, 

exposure estimates from multiple routes (i.e., dermal, incidental oral and inhalation) can be 

aggregated. 
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Residential exposure to bifenthrin is anticipated from the proposed Section 3 bed bug use 

treatment, as well as from currently registered uses of the chemical. As such, the short-term 

aggregate exposure and risk assessment of bifenthrin includes dietary (food and water) exposures 

anticipated from the proposed Section 3 and 18 uses and high-end, non-dietary exposures 

anticipated from the proposed bed bug use and currently registered residential uses. 

 

7.1 Acute Aggregate Risk

HED typically includes only food and water in the acute aggregate assessment, as one day

residential exposures are not routinely assessed. Please refer to Section 5.4.3 for a detailed 

discussion of the acute dietary risk assessment. 

7.2 Short-Term Aggregate Risk

The short-term aggregate exposure assessment includes exposures anticipated to occur from one 

to thirty days from dietary (food and water) and non-dietary, residential exposures from current 

and pending uses of bifenthrin. In order to aggregate short-term residential uses with dietary

exposure, it was necessary to calculate average dietary exposure. Risk estimates (MOEs) were 

calculated by comparison of the short-term oral NOAEL to average dietary exposures for all 

populations. It should be noted that although HED is classifying this as a short-term assessment 

(which typically reflect risks from longer duration hazard endpoints and exposure), bifenthrin 

risks reflect one-day toxicity endpoints and maximum single-day exposures since bifenthrin does 

not increase in toxicity with increasing duration of exposure.

Different methodologies were used for the presentation of short-term aggregate risk for adults 

and children. For adults, although the short-term dermal and inhalation risks were estimated 

using the same oral POD, these exposure estimates could not be directly combined for the adult 

short-term exposure assessment because the LOCs for dermal and inhalation routes of exposure 

are not the same (an MOE of <100 defines the LOC for dermal exposure, while inhalation risk is 

defined by an MOE of <1000). Accordingly an aggregate risk index (ARI) was required to 

estimate aggregate risk for adults. EPA identifies an ARI at or below 1 as a risk estimate of 

concern. The short-term aggregate ARI for adults is 2.0. 

Please refer to the residential assessment, Section 6.2, for a discussion regarding the exposures 

that are likely to be combined. 

Short-term aggregate risk estimates (ARIs) for the general U.S. population are not of concern to 

HED (i.e., ARIs are ≥ 1). Table 7.2.1, below, summarizes the results from the short-term 

aggregate for the general U.S. population. 

Short-term aggregate risk estimates (MOEs) for the most highly exposed population, children 1 <

2 years old, is also not of concern to HED (i.e, MOEs are ≥ 300). Table 7.2.2, below, 

summarizes the results from the short-term aggregate assessment of children 1 < 2 years old. 
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Table 7.2.1 Short-Term Adult Aggregate Risk Calculations1

Population

Short -Term Exposure Scenario

Dietary

Exposure2

Dermal Residential 

Exposure3

Inhalation Residential 

Exposure4

Aggregate ARI

(food, water, 

and 

residential)5 MOE ARI MOE ARI MOE ARI

Adult 

Female/Male 4,700 47 270 2.7 8,400 8.4 2.0

1. An ARI less than 1 is of concern to HED (ARI = Aggregate Risk Index.)

2. MOE dietary = [(short-term oral NOAEL)/(average dietary exposure)]. ARI dietary = [(MOE dietary)/(MOE 

target)]. Short-term oral NOAEL is 3.1 mg/kg/day. Average dietary exposure is 0.00066 mg/kg/day for Adults 20-

49 years old (See Table 5.4.6). The MOE target is 100. 

3. MOE dermal = [(short-term dermal NOAEL)/(high-end dermal residential exposure)]. ARI dermal = [(MOE 

dermal)/(MOE target)]. Short-term dermal NOAEL is 96.3 mg/kg/day. The target MOE is 100. See Table 6.3.1 for 

residential exposure values used in aggregate assessment.

4. MOE inhalation = [(short- term inhalation NOAEL)/(high-end inhalation residential exposure)]. ARI inhalation = 

[(MOE inhalation)/(MOE target)]. Short-term inhalation NOAEL is 3.1 mg/kg/day. The target MOE is 1,000. See 

Table 6.3.1 for residential exposure values used in aggregate assessment.

5. ARI Aggregate = 1/[(1/ARI dietary) + (1/ARI dermal) + (1/ARI inhalation)]

Table 7.2.2 Short-Term Child Aggregate Risk Calculations

Population

Short-Term Exposure Scenario

LOC for 

Aggregate 

Risk1

Dietary

MOE2

MOE Oral 

Residential 

Exposure3

MOE

Dermal 

Residential 

Exposure4

MOE

Inhalation 

Residential 

Exposure5

Aggregate 

MOE (food, 

water, and 

residential)6

Child 1 < 2

Years Old 300 1,700 1,000 690 NA 330

1. LOC is an MOE = 300 (10X inter- and intra- species uncertainty factors totaling 100, as well as additional 3X 

FQPA safety factor). 

2. MOE dietary = [(short-term oral NOAEL)/(average dietary exposure)]. Short-term oral NOAEL is 3.1 

mg/kg/day. Average dietary exposure is 0.0018 mg/kg/day for children 1-2 years old (See Table 5.4.6).

3. MOE oral = [(short- term incidental oral NOAEL)/(high-end residential incidental oral exposure)]. Short-term 

incidental oral NOAEL is 3.1 mg/kg/day. Residential incidental oral exposure is 0.0029 mg/kg/day. See Table 

6.3.1 for source of residential exposure values used in aggregate assessment.

4. MOE dermal = [(short-term dermal NOAEL)/(high-end dermal residential exposure)]. Short-term dermal 

NOAEL is 96.3 mg/kg/day. See Table 6.3.1 for source of residential exposure values used in aggregate assessment.

5. NA = Not applicable 

6. MOE Aggregate = 1/[(1/MOE dietary) + (1/MOE oral) + (1/MOE dermal)]

7.3 Intermediate-Term/Chronic Aggregate Risk

An intermediate-term and/or chronic aggregate risk assessment was not conducted because 

bifenthrin is acutely toxic and there is no increase in hazard with increasing dosing duration. 

Furthermore, chronic dietary exposures will be lower than acute exposures. Therefore, the acute 

aggregate assessment is protective of potential chronic aggregate exposures. For these same 

reasons, the acute aggregate assessment is also protective of potential cancer risk. 
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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, 

including bifenthrin, share a common mechanism of toxicity (http://www.regulations.gov; EPAHQ-OPP-2008-0489-0006). The members of this group share the ability to interact with voltagegated sodium channels ultimately leading to neurotoxicity. The cumulative risk assessment for 

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

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

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

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

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

determined that it will not contribute significantly or change the overall findings presented in the 

pyrethroid cumulative risk assessment. This analysis is summarized in Appendix D. Further, the 

proposed food uses of bifenthrin will not contribute significantly or change the overall findings 

in the pyrethroid cumulative risk assessment as the dietary risks are a minor component of total 

pyrethroid cumulative risk. For information regarding EPA’s efforts to evaluate the risk of 

exposure to pyrethroids, refer to http://www.epa.gov/oppsrrd1/reevaluation/pyrethroidspyrethrins.html.

9.0 Occupational Exposure/Risk Characterization

HED has determined that there is the potential for both occupational handler and post-application 

exposure to occur from the proposed Section 3 and 18 uses of bifenthrin. 

9.1 Occupational Short -Term Handler Exposure/Risk

Occupational exposure is expected for handlers who apply bifenthrin products for the proposed 

Section 3 and 18 uses. Handler exposure is expected to be short-and intermediate-term based on 

information provided on the proposed labels; however, bifenthrin does not increase in toxicity

with repeated dosing. As such, only single day residential exposures were assessed. 

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

or the 18 proposal. It is the policy of HED to use the best available data to assess handler 

exposure. Sources of generic handler data, used as surrogate data in the absence of chemicalspecific data, include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the 

Agricultural Handler Exposure Task Force (AHETF) database, or other registrant-submitted 

occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and 

subject to the data protection provisions of FIFRA. The standard values recommended for use in 

predicting handler exposure that are used in this assessment, known as “unit exposures”, are 

outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” 

(http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with 

additional information on HED policy on use of surrogate data, including descriptions of the 

various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposuredata.html.
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A quantitative exposure/risk assessment was developed for occupational handlers based on the 

following exposure scenarios:

Section 3 (Grass Grown for Seed Only)

 Mixing/loading liquids (open pour) and water soluble bags (WSB) in support of aerial, 

chemigation, and groundboom operations; 

 Aerial application (enclosed cockpit);

 Application using open-cab groundboom equipment; and

 Flagging in support of aerial applications.

Section 18

 Mixing/loading dry flowable, liquids (open pour), and WSB in support of aerial, 

chemigation, and groundboom operations;

 Aerial Application (enclosed cockpit);

 Application using open-cab groundboom equipment; 

 Application using airblast equipment; and

 Flagging in support of aerial applications.

All Section 3 and 18 occupational handler scenarios assessed are not of concern to HED (i.e., 

ARIs are ≥ 1) with baseline attire (i.e., single layer of clothing, no respirator) or the addition of a 

filtering face piece dust mask respirator. Tables 9.1.1 and 9.1.2 presents a summary of the shortterm occupational handler exposures and risks from the Section 3 and 18 proposed uses, 

respectively. 
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Table 9.1.1. Section 3: Short-Term Occupational Exposure and Risk Estimates for Bifenthrin

Exposure Scenario Crop or 

Target

Dermal 

Unit 

Exposure1

(mg/lb ai)

Inhalation 

Unit 

Exposure1

(mg/lb ai)

Maximum

Application 

Rate2

(lb ai/A)

Amount 

Treated 

Daily3

(Acres)

Dermal Inhalation

ARI8

Dose4

(mg/kg/day) MOE5 Dose6(mg/kg/day) MOE7

Mixer/Loader for Brigade®®2 EC

Mixing/Loading 

Liquid for Aerial 

Application

Grass 

Grown 

for Seed 

(Forage 

and Hay)

0.220

(baseline)

or

0.037 

(gloves)

0.00021 0.10

1,200

0.33 290

0.00032 9,800

2.2

0.056

(gloves) 1,700 17

Mixing/Loading 

Liquid for 

Groundboom 

Application 200

0.055 1,800

0.000053 59,000

14

0.0094

(gloves)

10,000 

(gloves) 37

Mixing/Loading 

Liquid for 

Chemigation 350

0.096 1,000

0.000092 34,000

7.7

0.017

(gloves)

5,900

(gloves) 22

Mixer/Loader for Brigade®® WSB

Mixing/Loading WP 

(WSB) for Aerial 

Application

Grass 

Grown 

for Seed 

(Forage 

and Hay)

0.0098 0.00024 0.10

1,200 0.015 6,600 0.00036 8,600 7.7

Mixing/Loading WP 

(WSB) for 

Groundboom 

Application

200 0.0025 39,000 0.000060 52,000 46

Mixing/Loading WP 

(WSB) for 

Chemigation

350 0.0043 22,000 0.00011 30,000 26

Applicator

Applying Sprays with 

Fixed-wing Aircraft 

(enclosed cockpit)

Grass 

Grown 

for Seed 

(Forage 

and Hay)

0.0050

(Eng.contro

l -no gloves 

needed )

0.000068

0.10

1,200 0.0075 13,000 0.00010 30,000 25

Applying Sprays with 

Open Cab 

Groundboom

Grass 

Grown 

for Seed 

0.0786 0.00034 200 0.020 4,900 0.000085 36,000 21
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Table 9.1.1. Section 3: Short-Term Occupational Exposure and Risk Estimates for Bifenthrin

Exposure Scenario Crop or 

Target

Dermal 

Unit 

Exposure1

(mg/lb ai)

Inhalation 

Unit 

Exposure1

(mg/lb ai)

Maximum

Application 

Rate2

(lb ai/A)

Amount 

Treated 

Daily3

(Acres)

Dermal Inhalation

ARI8

Dose4

(mg/kg/day) MOE5 Dose6(mg/kg/day) MOE7

(Forage 

and Hay)

Flagger

Flagging to Support 

Aerial Applications

Grass 

Grown 

for Seed 

(Forage 

and Hay)

0.011 0.00035 0.10 350 0.0048 20,000 0.00015 20,000 18

1 Unit Exposures based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (PHED)

(http://www.epa.gov/pesticides/science/handler-exposure-table.pdf), dated September 2011. 

All estimates are at Baseline PPE (Baseline Dermal: Long-sleeve shirt, long pants, and no gloves or respirator). 

2 Application Rates based on proposed supplemental labeling (Reg. No. #279-3313 and 279-3108)

3 Exposure Science Advisory Council Policy #9.1

4 Dermal Dose (mg/kg/day) = daily unit exposure (mg/lb ai) * application rate (lb ai/A) * area treated (A) * dermal absorption factor (100 %) / body weight (80 kg).

5 Dermal MOE = PoD (BMDL10 of 96.3 (mg/kg/day) / Daily dermal dose (mg/kg/day)

6

Inhalation Dose (mg/kg/day) = daily unit exposure (mg/lb ai) * application rate (lb ai/A) * area treated (A) * inhalation absorption (100 %) / body weight (80 kg). 

7

Inhalation MOE = PoD (BMDL1SD of 3.1 mg/kg/day) / Daily inhalation dose (mg/kg/day).

8 Aggregate Risk Index (ARI) = 1 / ((1/estimated MOE for adult dermal exposure/ LOC for adult dermal exposure ) + (1/estimated MOE for adult inhalation 

exposure/ LOC for adult inhalation oral exposure))
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Table 9.1.2. Section 18: Short-Term Occupational Exposure and Risk Estimates for Bifenthrin

Exposure Scenario Crop or 

Target

Dermal Unit 

Exposure 1

(mg/lb ai)

Inhalation Unit 

Exposure 1

(mg/lb ai)

Maximum

Application 

Rate 2

Amount 

Treated 

Daily 3

(Acres)

Dermal Inhalation

ARI8

Dose 4

(mg/kg/day) MOE 5 Dose 6(mg/kg/day) MOE 7

Mixer/Loader – Dry Flowable (BifentureTM DF)

Mixing/Loading DF for 

Aerial Application

Apple, 

Nectarine and 

Peach

0.23

0.0090 

0.20

350

0.20 480 0.0079 390 0.36

0.0018

(PF5 respirator) 0.046 2,100 0.0016 2,000 1.4

Mixing/Loading DF for 

Groundboom 

Application 0.0090

80 0.046 2,100 0.0018 1,700 1.6

Mixing/Loading DF for 

Airblast Application 40 0.023 4,200 0.00090 3,400 3.1

Mixer/Loader –Liquids (BifentureTM EC)

Mixing/Loading Liquid 

for Aerial Application

Apple, 

Nectarine and 

Peach

0.22 0.00021 0.20

350 0.19 500 0.00018 17,000 3.9

Mixing/Loading Liquid 

for Groundboom 

Application 

80 0.044 2,200 0.00004 74,000 17

Mixing/Loading Liquid 

for Airblast Application 40 0.022 4,400 0.00002 150,000 34

Mixer/Loader Water Soluble Bags- (Brigade® WSB)

Mixing/Loading WSB 

for Aerial Application

Apple, 

Nectarine and 

Peach

0.0098

0.00024

0.20

350 0.0086 11,000 0.00021 15,000 13

Mixing/Loading WSB 

for Groundboom 

Application 

0.00024 80 0.0020 49,000 0.000048 65,000 57

Mixing/Loading WSB 

for Airblast Application 0.00024 40 0.00098 99,000 0.000024 130,000 110

Applicator
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Table 9.1.2. Section 18: Short-Term Occupational Exposure and Risk Estimates for Bifenthrin

Exposure Scenario Crop or 

Target

Dermal Unit 

Exposure 1

(mg/lb ai)

Inhalation Unit 

Exposure 1

(mg/lb ai)

Maximum

Application 

Rate 2

Amount 

Treated 

Daily 3

(Acres)

Dermal Inhalation

ARI8

Dose 4

(mg/kg/day) MOE 5 Dose 6(mg/kg/day) MOE 7

Applying Sprays via 

Aerial Equipment 

(Enclosed Cockpit)

Apple, 

Nectarine and 

Peach

0.0050 0.00006 0.20 350 0.0044 22,000 0.00050 59,000 47

Applying Sprays via 

Groundboom

Equipment (Open Cab)

Apple, 

Nectarine and 

Peach

0.079 0.00034

0.20

80 0.016 6,100 0.000068 46,000 26

Applying Sprays via 

Groundboom Equipment 

(Enclosed Cab) 9

0.0051 0.00004 40 0.0010 94,000 0.0000080 390,000 280

Applying Sprays via 

Airblast Equipment 

(Open Cab)

1.8 0,00471 40 0.18 540 0.00047 6,600 3.0

Applying Sprays via 

Airblast Equipment 

(Enclosed Cab) 9

0.015 0.00006 40 0.0015 67,000 0.0000060 52,000 48

Flagger

Flagger for Support of 

Aerial Spray 

Applications

Apple, 

Nectarine and 

Peach

0.011 0.00035 0.20 350 0.0096 10,000 0.00030 10,000 9.1

1 Unit Exposures based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (PHED)

(http://www.epa.gov/pesticides/science/handler-exposure-table.pdf), dated September 2011. 

All estimates are at Baseline PPE (Baseline Dermal: Long-sleeve shirt, long pants, and no gloves; Baseline Inhalation: no respirator).

2 Application Rates based on registered labels (Reg. No. #279-3108, 70506-57, 70506-227) for use on pears.

3 Exposure Science Advisory Council Policy #9.1

4 Dermal Dose (mg/kg/day) = daily unit exposure (mg/lb ai) * application rate (lb ai/A) * area treated (A) *dermal absorption factor (100 %) / body weight (80 kg).

5 Dermal MOE = PoD (BMDL10 of 96.3 (mg/kg/day) / Daily dermal dose (mg/kg/day)

6

Inhalation Dose (mg/kg/day) = daily unit exposure (mg/lb ai) * application rate (lb ai/A) * area treated (A) * inhalation absorption (100 %) / body weight (80 kg). 

7

Inhalation MOE = PoD (BMDL1SD of 3.1 mg/kg/day) / Daily inhalation dose (mg/kg/day).

8 Aggregate Risk Index (ARI) = 1 / ((1/estimated MOE for adult dermal exposure/ LOC for adult dermal exposure ) + (1/estimated MOE for adult inhalation 

exposure/ LOC for adult inhalation oral exposure))
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9.2 Occupational Short-Term Post-Application Exposure/Risk

HED has determined that there is the potential for post-application dermal exposure to bifenthrin 

following application to the proposed Section 3 and 18 uses. Post-application exposure may

occur when workers enter previously treated areas to perform job functions. Re-entry workers

are expected to experience short-term exposure to bifenthrin while performing post-application 

activities such as scouting and irrigation. 

Chemical-specific dislodgeable foliar residue (DFR) studies for bifenthrin were identified for 

bifenthrin and were considered for use in the occupational post-application assessment. Because 

the use of this data has no effect on the risk outcome, HED used default DFR assumptions. 

Sources of generic post-application data, used as surrogate data in the absence of chemicalspecific data, are derived from Agricultural Reentry Task Force (ARTF) exposure monitoring 

studies, and, as proprietary data, are subject to the data protection provisions of FIFRA. The 

standard values recommended for use in predicting post-application exposure that are used in 

this assessment, known as “transfer coefficients”, are presented in the “Science Advisory

Council for Exposure (ExpoSAC) Policy 3” 

(http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along with additional 

information about the ARTF data, can be found at http://www.epa.gov/pesticides/science/postapp-exposure-data.html.

The results of the post-application exposure and risk assessment indicate that MOEs > 100 are 

achieved on Day 0 (12 hours) for all potential post-application activities and, therefore, are not of 

concern. The post-application activity scenarios along with respective TCs and risk estimates for 

short -term MOEs are summarized in Table 9.2. 

Table 9.2. Summary of Estimated Post-application MOEs for Proposed 

Bifenthrin Section 3 and 18 Uses

Crop

Maximum 

Application 

Rate1

DFR2 Activity TC3 MOE4 DAT5

Section 3

Grass 

Grown for 

Seed 

(Forage 

and Hay)

0.10 0.28

Scouting 1,100 3,100

0 (12 hours) Irrigation 1,900 1,800

Section 18

Apple, 

Nectarine 

and Peach

0.20 0.56

Orchard 

Maintenance, 

Propping

100 17,000

0 (12 hours) Hand Pruning,

Training,

Scouting

580 2,900

Hand 

Harvesting 1,400 1,200
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Table 9.2. Summary of Estimated Post-application MOEs for Proposed 

Bifenthrin Section 3 and 18 Uses

Crop

Maximum 

Application 

Rate1

DFR2 Activity TC3 MOE4 DAT5

Thinning Fruit 3,600 480

1. Maximum application rate (lb ai/A) indicated on proposed labels (See Table 3.3). 

2. DFR (μg/cm2) = Application rate (lb ai/A) x Conversion factor (11.2 ug/cm2) x Fraction of ai retained on foliage 

on day zero(25%)

3. TC (cm2/hr) = Transfer coefficients and associated activities from Science Advisory Council for Exposure Policy 

Number 3.2 “Agricultural Transfer Coefficients”, June 2011 

(http://www.epa.gov/pesticides/science/exposac_policy3.pdf

4. Daily Dose = [(DFR x TC x Exposure Time 8-hr)] / [(CF: 1000 μg/mg) x (Body Weight 80-kg)]

Short-term Dermal NOAEL = 96.3 mg/kg/day. The LOC is 100. 

MOE = NOAEL / Daily Dose. Dermal MOE= PoD (BMDL10 of 96.3 (mg/kg/day) / Daily dermal dose (mg/kg/day). 

Level of concern = 100 (Adult).

5. DAT = Days after treatment needed to reach the LOC of 100; DAT 0 = the day of treatment, after sprays have 

dried; assumed to be approximately 12 hours. 

9.2.2 Inhalation Post-application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for bifenthrin at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category III), low vapor pressure (1.8 x 10-7 mmHg at 25o C), and

the low proposed use rate (0.20 lb ai/A). However, there are multiple potential sources of postapplication inhalation exposure to individuals performing post-application activities in 

previously treated fields. These potential sources include volatilization of pesticides and 

resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert 

advice and input on issues related to volatilization of pesticides from its Federal Insecticide, 

Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and 

received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for bifenthrin.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.
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10.0 References

Toxicology

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Anand, S.S., Kim KB, Padilla S, Muralidhara S, Kim HJ, Fisher JW, Bruckner JV. "Ontogeny of 

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Choi, J.S., Soderlund, D.M. (2006). "Structure-activity relationships for the action of 11 

pyrethroid insecticides on rat Nav 1.8 sodium channels expressed in Xenopus oocytes". 

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489-95

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 the rat." Reproductive 

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Felts, P. A., S. Yokoyama, S. Dib-Hajj, J. A. Black and S. G. Waxman (1997). "Sodium channel 

[alpha]-subunit mRNAs I, II, III, NaG, Na6 and hNE (PN1): Different expression patterns in 

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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-Velez (2010). "Physiologically Based Pharmacokinetic Modeling of 

Deltamethrin: Development of a Rat and Human Diffusion-Limited Model." Toxicological

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Goldin, A., R. Barchi, J. Caldwell, F. Hofmann, J. Howe, J. Hunter, R. Kallen, G. Mandel, M. 

Meisler, YBNetter, M. Noda, M. Tamkun, S. Waxman, J. Wood and W. Catterall (2000). 

"Nomenclature of voltage-gated sodium channels." Neuron 28(2): 365-368.

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Herberth, M. T. (2010). "An Oral (Gavage) Acute Neurotoxicity Comparison Study in Rats. WIL 

Research Laboratories, LLC, 1407 George Road, Ashland, OH 44805-9281. Laboratory report 

number: WIL-118041, December 20, 2010. MRID 48333801.Unpublished. DP# 386418."

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human and rat skin." Toxicology and Applied Pharmacology 246(1-2): 29-37.
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Kiplinger, G. (2003) Acute Nose-Only Inhalation Toxicity, Study of Bifenthrin Technical in 

Albino Rats: Final Report. Project Number: A2003-5589, WIL-105015, 182TST02484. 

Unpublished study prepared by WIL Research Laboratories, Inc. 170 pp. MRID 46008101

Kim, K.-B., Anand, S.S., Kim, H.J., White, C.A., Fisher, J.W., Tornero-Velez, R., Bruckner, 

J.V., 2010. Age, dose, and time-dependency of plasma and tissue distribution of deltamethrin in 

immature rats. Toxicological Science 115, 354–368.

Koukouritaki, S. B., J. R. Manro, S. A. Marsh, J. C. Stevens, A. E. Rettie, D. G. McCarver and 

R. N. Hines (2004). "Developmental Expression of Human Hepatic CYP2C9 and CYP2C19." 

Journal of Pharmacology and Experimental Therapeutics 308(3): 965-974.

Lawrence, L. and J. Casida (1982). "Pyrethroid toxicology: Mouse intracerebral sturcturetoxicity relationships." Pesticide Biochemistry and Physiology 18: 9-14.

Lund, A. and T. Narahashi (1982). "Dose-dependent interaction of the pyrethroid isomers with 

sodium channels of squid axon membranes." Neurotoxicology 3(1): 11-24.

Meacham, C. A., P. D. Brodfuehrer, J. A. Watkins and T. J. Shafer (2008). "Developmentallyregulated sodium channel subunits are differentially sensitive to [alpha]-cyano containing 

pyrethroids." 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-Dawley rat." Toxicological Science 93(2): 432 - 442.

Nemec, M. (2006). An acute functional observational battery comparison study in rats, WIL 

Research Laboratories study number 409002. 3: 867.

Ross, M. K., A. Borazjani, C. C. Edwards and P. M. Potter (2006). "Hydrolytic metabolism of 

pyrethroids by human and other mammalian carboxylesterases." Biochemical Pharmacology

71(5): 657-669.

Salgado, V., M. Herman and T. Narahashi (1989). "Interactions of the pyrethroid fenvalerate 

with nerve membrane sodium channels: Temperature dependence and mechanism of 

depolarization." Neurotoxicology 10(1): 1-14.

Selim, S., "Kinetics of FMC 54800 in the Blood of Rats", FMC Corporation, Unpublished Study, 

MRID 00163069.

Sheets, L.P., et al., Age-Dependent Differences in the Susceptibility of Rats to Deltamethrin. 

Toxicology and Applied Pharmacology, 1994. 126(1): p. 186-190.

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 Metabolism and Disposition 37(1): 221-228.
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Scollon, E.J., Starr, J.M., Crofton, K.M., Wolansky, M.J., DeVito, M.J., Hughes, M.F. (2011) 

"Correlation of tissue concentrations of the pyrethroid bifenthrin with neurotoxicity in the rat". 

Toxicology 290 (2011) 1– 6.

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." Journal of Pharmacology and Experimental 

Therapeutics 277(1): 445 - 453.

Tabarean, I. V. and T. Narahashi (1998). "Potent Modulation of Tetrodotoxin-Sensitive and 

Tetrodotoxin-Resistant Sodium Channels by the Type II Pyrethroid Deltamethrin." Journal of

Pharmacology and Experimental Therapeutics 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 sensitivity 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 the maturing 

rat using a PBPK model." Toxicology and Applied Pharmacology 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."

US EPA (1998). Guidelines for Neurotoxicity Risk Assessment, Federal Register.

USEPA (2011a). "Pyrethroid Cumulative Risk Assessment,” D394567. 10/04/11.

USEPA (2011b). Reevaluation of the FQPA Safety Factor for Pyrethroid Pesticides, D381210, 

6/27/11.

US EPA (2011). Bifenthrin - ToxSAC Meeting Report (October 6, 2011)

US EPA (2012). Bifenthrin: Summary of Hazard and Science Policy Council (TXR# 0056209, 

HASPOC Report, Jan. 4, 2012)

Verschoyle, R. D. and W. N. Aldridge (1980). "Structure-activity relationships of some 

pyrethroids in rats." Archives of Toxicology 45(4): 325-329.

Weiner, M. L., M. Nemec, L. Sheets, D. Sargent and C. Breckenridge (2009). "Comparative 

functional observational battery study of twelve commercial pyrethroid insecticides in male rats 

following acute oral exposure." Neurotoxicology 30 Suppl 1: S1-16.
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Wolansky MJ, McDaniel KL, Moser VC, Crofton KM (2007), "Influence of dosing volume on 

the neurotoxicity of bifenthrin.” Neurotoxicology and Teratology 29(3):377-84

Wolansky, M.J, Gennings, C. , Crofton, K.M. (2006) “Relative Potencies for Acute Effects of 

Pyrethroids on Motor Function in Rats”. Office of Research and Development, US EPA, 

Research Triangle Park, NC, MRID 47885701. Toxicological Sciences 89(1):271-277

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 

Pharmacology 77(2): 238-247.

Dietary

S. Tadayon. “Bifenthrin: Acute Dietary (Food and Drinking Water) Exposure and Risk

Assessment for Sections 3 and 18 Registration of Bifenthrin on Grass, Forage, Hay, Imported 

Tea, Apple and Peach.” D383085. 5/25/2012

J. Luis Meléndez. “Tier 1 Estimated Environmental Concentrations of Bifenthrin for the Use in 

the Human Health Risk Assessment; IR-4 Petition for the Use of the Chemical on Vegetable 

Roots (except for sugar and garden beets), Beets, Radish, Pistachio, Peanuts, Soybean, Fruiting 

Vegetables and Mayhaw.” D372556. 8/11/2010

U.S. EPA. (2011). Exposure Factors Handbook 2011 Edition. U.S. Environmental Protection 

Agency, Washington, DC, EPA/600/R-09/052F.

Residue Chemistry

P. Savoia. “Bifenthrin. Section 3 Registration Adding Uses to Grass (Seed Crop) and Imported 

Tea along with a Section 18 Emergency Exemption for Treating Apples, Nectarines, and 

Peaches. Summary of Analytical Chemistry and Residue Data.” D388604. 5/25/2012.

S. Levy. “Bifenthrin on Pear and Nut, Tree, Group: Evaluation of Residue Data and Analytical 

Methods.” D274839. 8/15/2002.

Occupational and Residential Exposure 

A. Rivera-Lupiáñez. ” Bifenthrin: Occupational and Residential Risk Assessment to Support 

Request for Section 3 Registrations on Grass (Forage and Hay) and Imported Tea.” D401702. 

5/25/2011

A. Rivera-Lupiáñez. “Bifenthrin: Occupational and Residential Risk Assessment in Support of 

Proposed Section 18 Emergency Exemption for Use on Pome Fruits and Stone Fruits in Virginia, 
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New Jersey, Pennsylvania, Maryland, Delaware, West Virginia, and North Carolina to Control 

Stink Bugs.” D398490. 5/25/2012.

A. Rivera-Lupiáñez. “Bifenthrin: Occupational and Residential Risk Assessment for Proposed 

Bed Bug Treatment and Registered Crack and Crevice Use.” D383326. 5/25/2012

S. Tadayon. Bifenthrin: Revised Occupational and Residential Assessment for Turf Using the 

2012 Residential SOPs. D400326. 5/25/2012
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Appendix A. Toxicology Profile and Endpoint Selection

A.1 Toxicology Data Requirements

Table A. Toxicology Requirements for Bifenthrin 

Guideline Number and Toxicity Study 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 Sub-chronic (Rodent)...........................................

870.3150 Oral Sub-chronic (Non-Rodent)...................................

870.3200 21-Day Dermal.............................................................

870.3250 90-Day Dermal.............................................................

870.3465 90/28-Day Inhalation ...................................................

yes

yes

yes

no1

yes

yes

yes

yes

no1

no2

870.3700 Developmental Toxicity (Rodent)...............................

870.3700 Developmental Toxicity (Non-rodent).........................

870.3800 Reproduction................................................................

yes

yes

yes

yes

yes

yes

870.4100 Chronic Toxicity (Rodent) ...........................................

870.4100 Chronic Toxicity (Non-rodent) ....................................

870.4200 Oncogenicity (Rat).......................................................

870.4200 Oncogenicity (Mouse)..................................................

870.4300 Chronic/Oncogenicity ..................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity: Gene Mutation - bacterial .....................

870.5300 Mutagenicity: Gene Mutation - mammalian ................

870.5375 Mutagenicity: Structural Chromosomal Aberrations ...

870.5385 Mutagenicity: Structural Chromosomal Aberrations ...

870.5500 Mutagenicity: Other Genotoxic Effects .......................

870.5550 Mutagenicity: Other Genotoxic Effects .......................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.6100 Acute Delayed Neurotoxicity (Hen).............................

870.6100 90-Day Neurotoxicity (Hen) ........................................

870.6200 Acute Neurotoxicity Screening Battery (Rat) ..............

870.6200 90 Day Neurotoxicity. Screening Battery (Rat) ...........

870.6300 Developmental Neurotoxicity ......................................

no

no

yes

yes

yes

-

-

yes

yes

yes

870.7485 General Metabolism.....................................................

870.7600 Dermal Penetration.......................................................

870.7800 Immunotoxicity.......................................................................

yes

yes

yes

yes

yes

no

1. HASPOC decision, see memo cited in references (TXR# 0056209).

2. Study to be replaced by an acute study with targeted ACN metrics. 
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A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity Profile – Bifenthrin

Guideline No./Study Type MRID No. Results Toxicity 

Category

870.1100 Acute oral toxicity 0013519 LD50 = 70.1 mg/kg (♂); 53.8 mg/kg (♀) II

870.1200 Acute dermal 

toxicity 00132520

LD50 > 2,000 mg/kg III

870.1300 Acute inhalation 

toxicity

46008101

LC50=1.01 mg/L (combined value, Male is 

1.1 & Female is 0.8 mg/L)

Heated to 100° C for testing III

870.2400 Primary eye 

irritation 00132522

Non-irritant IV

870.2500 Primary dermal 

irritation 00132521

Non-irritant IV

870.2600 Dermal 

sensitization 00132523

Not a sensitizer N/A

Table A.2.2. Toxicity Profiles for Bifenthrin

Guideline 

Number

MRID No. Study Type Results

Acute and Sub-chronic Toxicity

Special Study 47885701

Wolansky Study (2006)

Acute Oral Toxicity in 

Long Evans Rats

BMDL1SD = 3.1 mg/kg

BMD1SD = 4.1 mg/kg based on decreased locomotor 

activity

0, 0.03, 0.1, 1.0, 4.0, 8.0, 12.0, 16.0, 24.0, 28.0 mg/kg

via gavage in corn oil (1 mL/kg)

Classification: Acceptable, Non-Guideline

Special Study

47050504,

47050505

Weiner/WIL Study 

(2009)

Acute Oral Toxicity in 

Rats

BMDL20 = 0.4 mg/kg

BMD20 = 14.3 mg/kg based on multiple FOB changes

0, 40, 55 mg/kg via gavage in corn oil (5 mL/kg)

Classification: Acceptable, Non-Guideline

870.3100 00141199 90-Day Oral Toxicity - NOAEL = 3.8 mg/kg/day (males); 4.3 mg/kg/day 
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Table A.2.2. Toxicity Profiles for Bifenthrin

Guideline 

Number

MRID No. Study Type Results

Rat (1984) (females)

LOAEL = 7.5 mg/kg/day (males), 8.5 mg/kg/day 

(females), based on increased incidence of tremors.

Classification: Acceptable-Guideline

870.3150 00141200 90-Day Oral Toxicity -

Dog (1984)

NOAEL = 2.21 mg/kg/day (males and females)

LOAEL = 4.42 mg/kg/day (males and females) based 

on increased incidence of tremors. 

Classification: Acceptable-Guideline

Prenatal Developmental Toxicity

870.3700 00154482

Developmental Toxicity 

(Gavage) - Rat

(1983)

Range-finding study

Maternal Toxicity

NOAEL = 0.88 mg/kg/day

LOAEL = 1.77 mg/kg/day based on tremors during 

gestation.

Developmental Toxicity

NOAEL = not determined (fetuses not examined)

LOAEL = not determined (fetuses not examined)

Classification: Acceptable-Guideline

870.3700 00141201

Developmental Toxicity 

(Gavage) - Rat

(1984)

Maternal Toxicity

NOAEL = 0.88 mg/kg/day

LOAEL = 1.77 mg/kg/day based on tremors during 

gestation.

Developmental Toxicity

NOAEL = 1.77 mg/kg/day

LOAEL = Not Observed

Classification: Acceptable-Guideline

870.3700 45352301

Developmental Toxicity 

(Dietary) - Rat

(2001)

Maternal Toxicity

NOAEL = 7.1 mg/kg/day

LOAEL = 15.5 mg/kg/day based clinical signs and 

decreased food consumption, body weight gains, and 

body weight gains adjusted for gravid uterine weight.

Developmental Toxicity

NOAEL = 15.5 mg/kg/day

LOAEL = not observed.

Classification: Acceptable-Guideline
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Table A.2.2. Toxicity Profiles for Bifenthrin

Guideline 

Number

MRID No. Study Type Results

870.3700 00145997

Developmental Toxicity -

Rabbit (1984)

Maternal Toxicity

NOAEL = 2.36 mg/kg/day

LOAEL = 3.5 mg/kg/day based on treatment-related 

head and forelimb twitching.

Developmental Toxicity

NOAEL = greater than 7 mg/kg/day

LOAEL = not observed

Classification: Acceptable-Guideline

Reproductive Toxicity

870.3800 00157225

Multigeneration 

Reproductive Toxicity -

Rat (1986)

Parental/Systemic Toxicity

NOAEL = 3.0 mg/kg/day for females and 5.0 

mg/kg/day for males

LOAEL = 5.0 mg/kg/day for females, based on 

tremors and decreased body weight; not observed for 

males.

Reproductive/offspring Toxicity

NOAEL =5.0 mg/kg/day.

LOAEL = not observed.

Classification: Acceptable-Guideline

Chronic Toxicity/Carcinogenicity

870.4100 00163065

Chronic Toxicity (1 Year) 

- Dog

(1985)

NOAEL = 1.3 mg/kg/day (males and females)

LOAEL = 2.7 mg/kg/day (males and females) based 

on increased incidence of tremors.

Classification: Acceptable-Guideline

870.4300 00157226

Combined Chronic 

Toxicity/Carcinogenicity 

- Rat (1986)

NOAEL = 3.0 mg/kg/day (females); 4.7 mg/kg/day 

(males)

LOAEL = 6.1 mg/kg/day (females), based on 

increased incidence of tremors; 9.7 mg/kg/day 

(males), based on increased incidence of tremors.

Carcinogenicity - No conclusive evidence of 

carcinogenic potential.

Classification: Acceptable-Guideline

870.4200 00157227 Carcinogenicity - Mice

(1986)

NOAEL = 6.7 mg/kg/day (males); 8.8 mg/kg/day 

(females)

LOAEL = 25.6 mg/kg/day (males) and 32.7 

mg/kg/day (females), based on increased incidence of 

tremors.

Carcinogenicity - carcinogenic potential was 

evidenced by a dose-related increase in the incidence 

of hemangiopericytoma in the urinary bladder, a 

significant dose-related trend for combined 
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Table A.2.2. Toxicity Profiles for Bifenthrin

Guideline 

Number

MRID No. Study Type Results

hepatocellular adenomas and carcinomas in males, 

and a significantly higher incidence of combined lung 

adenomas and carcinomas in females. 

 Classification: Acceptable-Guideline

Neurotoxicity

870.6200a 44862102 Acute Neurotoxicity - Rat

NOAEL = 35 mg/kg (32.8 mg ai/kg/day). 

LOAEL = 75 mg/kg (70.3 mg ai/kg/day) based on 

mortality (females only), clinical and FOB findings 

and differences in motor activity. No vehicle utilized 

and heated to 80° C to liquefy. 

Classification: Acceptable-Guideline

870.6200b 44862103 Sub-chronic 

Neurotoxicity - Rat

NOAEL = 50 ppm (equivalent to 2.9 mg/kg/day in 

males and 3.7 mg/kg/day in females). 

LOAEL =100 ppm (equivalent to 6.0 mg/kg/day in 

males and 7.2 mg/kg/day in females) based on 

neuromuscular findings (tremors, changes in grip 

strength and landing foot-splay). 

Classification: Acceptable-Guideline

870.6300 46750501 Developmental 

Neurotoxicity - Rat

Maternal NOAEL = 3.6 mg/kg/day during gestation 

and 8.3 mg/kg/day during lactation,

LOAEL = 7.2 mg/kg/day during gestation and 16.2 

mg/kg/day during lactation based on clinical signs of 

neurotoxicity (tremors, clonic convulsions, and 

increased grooming counts).

Developmental NOAEL =3.6 mg/kg/day during 

gestation and 8.3 mg/kg/day during lactation.

Developmental LOAEL = 7.2 mg/kg/day during 

gestation and 16.2 mg/kg/day during lactation based 

on clinical signs of neurotoxicity (increased grooming 

counts).

Dermal Toxicity

870.3200 00141198 Dermal Toxicity - Rabbit

NOAEL = 88 mg ai/kg/day (males and females)

LOAEL = 442 mg ai/kg/day (males and females), 

based on loss of muscle coordination and increased 

incidence of tremors.

870.3200 45280501 Dermal Toxicity - Rat NOAEL = 47 mg ai/kg/day (males and females)

BMDL10=96.3 mg/kg/day
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Table A.2.2. Toxicity Profiles for Bifenthrin

Guideline 

Number

MRID No. Study Type Results

LOAEL = 93 mg ai/kg/day (males and females), 

based on staggered gait (M) and exaggerated hind 

limb flexion (F)

BMD10=187.0 mg/kg/day, based on exaggerated hind 

limb flexion

Metabolism and Pharmacokinetics

870.7485 00163067 

40415102 Metabolism - Rat

Very little of the administered radioactive dose was 

expired as 14C-CO2 (0.028% for males and 0.053% for 

females). The majority (about 70%) of the 

administered radioactivity was found in the feces with 

about 20% in the urine. A complication of this study 

is that males were administered a radioactive dose 

with the label in the acid position, while females were 

administered a radioactive dose with the label in the 

alcohol position. This could make comparisons 

between males and females difficult. Despite the 

difference in 14C- labelling position in the bifenthrin 

administered to males and females, the study is 

acceptable. This conclusion is based on the fact that 

most (>90%) of the radioactivity was eliminated via 

the urine and feces, with no significant differences 

between the sexes in this respect. Further, there were 

no significant differences between dosage groups in 

percentages excreted. This suggests that most of the 

compound is excreted with little or no change, or in a 

form incorporating both of the labeled sites. The 

results also show that females retained slightly more 

radioactivity in their bodies (particularly in adipose 

tissue) than did males, particularly at the high-dose. 

Labeling of the material given to the females was in 

the biphenyl group, and, given a splitting of the 

molecule between the two labeling sites, this would 

have tended to give a more lipophilic radiolabeled 

residue. 

Classification: Acceptable-Guideline

870.7485 00163069 Metabolism - Rat

Plasma radioactivity in the low-dose (4 mg/kg) 

animals after dosing slowly rose, indicating a slow

rate of absorption from the gastrointestinal tract. The 

half-life of absorption was calculated to be about 1.5 

hours, with a lag-time of 0.5 hours following first 

order kinetics. Radioactivity peaked in plasma for 

low-dose animals in 4 hours. The elimination of 14Cbifenthrin from the plasma was equally slow, with 

significant radioactivity still remaining in blood at 72 

hours. Plasma radioactivity in the high-dose (35 

mg/kg) animals appeared to follow a similar course as 

seen in the low-dose animals. The peak radioactivity 

for the high-dose group appeared to be somewhat 

delayed, peaking at about 6 hours. Significant 

radioactivity still remained after 72 hours in the highdose animals. 
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Table A.2.2. Toxicity Profiles for Bifenthrin

Guideline 

Number

MRID No. Study Type Results

Classification: Acceptable-Guideline 

870.7485 00163070 Metabolism - Rat

The major metabolic route of radiolabeled bifenthrin 

appeared to be hydrolysis of the ester linkage with 

oxidation of the resulting alcohol to the acid. Protein 

binding of radioactive components or metabolites 

appears to increase with time. 

Classification: Acceptable-Guideline 

870.7485 00163071 Metabolism - Rat

Fat and skin half-lives were the longest with half-lives 

of 51 and 50 days, respectively. The half-lives for 

ovaries, liver, kidneys and sciatic nerve were 37.4, 

19.0, 28.5, and 42 days, respectively. Radioactive 

components were measured in fat at numerous time 

intervals, before and after daily dosing. The major 

component in fat is parent compound with a half-life 

of 47.5 days. Other unidentified components included 

a somewhat polar (Rf = 0.65) compound and two 

other relatively minor components. 

Classification: Acceptable-Guideline 

870.7485 00163066 Metabolism - Rat

Within 7 days, nearly all bifenthrin and/or metabolites 

were excreted in either urine or feces. The majority 

of radioactivity was excreted in the feces within 48 

hours. Tissues that retained bifenthrin and/or 

metabolites beyond 7 days included fat and skin in 

males and females, and gonads in females. 

Classification: Unacceptable-Guideline. Although 

the number of animals/group in this study was 3, and 

not 5/sex/group as recommended by guidelines, and a 

quality assurance statement was lacking, the results of 

this study provide useful information.

870.7485 40415100 Metabolism - Rat

Results showed minimal breakage of the ester linkage 

of the parent compound in the material eliminated via 

the feces in the period of 0-48 hours after dosage, 

when most of the administered radioactivity is 

identified as coming from unmodified parent 

compound. However, the material was subsequently 

eliminated, although a relatively small proportion of 

the administered dose appears to have undergone 

more modification. Since a greater proportion of the 

radioactivity was eliminated via the feces in the 

period of 48-168 hours in the form of 2-Methyl-3-

phenylbenzyl alcohol and 2-Methyl-3-phenylbenzoic 

acid than the parent compound, this is evidence that 

extensive breakage of the ester linkage does occur, 

either in the material retained in the intestines for 

more than 46 hours, or in the material absorbed and 

subsequently eliminated via the feces. 

Classification: Unacceptable-Guideline. While this 

study is limited, it does provide some insight into the 
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Table A.2.2. Toxicity Profiles for Bifenthrin

Guideline 

Number

MRID No. Study Type Results

incomplete absorption of bifenthrin from the intestine, 

and the lack of modification of most of the 

unabsorbed material, particularly that eliminated via 

the feces during the period of 0-48 hours. However, 

the metabolism of the absorbed compound 

(radioactivity primarily excreted via the urine, despite 

differences in labeling) is less clear.

870.7485 00163068 Metabolism - Rat

The results of the study demonstrated that the 

majority of radioactivity excreted in the feces was the 

parent compound and its intact hydroxylated 

metabolites. Much of the radioactivity excreted in 

urine was hydrolytic and hydrolytic/oxidative 

degradation products of the parent compound. 

Classification: Unacceptable-Guideline. 

Dermal Penetration

870.7600 41917503 Dermal Penetration - Rats

For animals in group A, means of 4.6, 14.2, 12.8 and 

14.7% total dose were recovered from the skin at 0, 4,

10 and 24 hours post-dose; corresponding percentages 

in the wash were 94.6, 80.8, 78.6 and 70%. For 

animals in group B, means of 20.0, 37.9, 42.0 and 

41.2% remained (and were recovered from) the skin 

at 0, 4, 10 and 24 hours post-dose; corresponding 

percentages in the wash were 73.9, 50.6, 41.3 and 

37.7% respectively.

This dermal absorption study is classified as 

acceptable. However, because only one dose was 

used, this study, by itself, does not satisfy the 

guideline requirement for a dermal penetration study 

(85-2) in the rat for technical bifenthrin (FMC 54800). 

However, it can be used, in conjunction with other 

dermal penetration studies, as supporting data for the 

purposes of registration and/or reregistration of 

products containing or consisting of bifenthrin.

870.7600 41917502 Dermal Penetration - Rats

Means of 96.83, 84.75, 76.86 and 72.88% of the 

radioactivity were recovered in the skin wash at 0, 4, 

10 and 24 hours post dosage, respectively. By the 

time the 4-hour post-dose and later skin samples were 

collected the emulsifying solvents had evaporated. 

Means of 4.04, 12.00, 16.55 and 19.44% total dose 

were recovered from the washed skin of the 

application site at 0, 4, 10 and 24 hours respectively; 

corresponding mean percentages recovered from the 

carcass were 0.09, 0.87, 0.85 and 1.67%. Mean 

percentages recovered in urine and feces were 0, 0.14, 

0.43 and 3.23%.

This dermal absorption study is classified as 

acceptable. However, because only one dose was 

used, this study, by itself, does not satisfy the 

guideline requirement for a dermal penetration study 

(85-2) in the rat for technical bifenthrin (FMC 54800). 
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Table A.2.2. Toxicity Profiles for Bifenthrin

Guideline 

Number

MRID No. Study Type Results

However, it can be used, in conjunction with other 

dermal penetration studies, as supporting data for the 

purposes of registration and/or reregistration of 

products containing or consisting of bifenthrin.

870.7600 00163072 Dermal Penetration - Rats

In general, only very small amounts of radioactivity 

were present in blood, excrement, and carcasses, with 

almost all (approximately 99%) of the absorbed 

radioactivity localized in skin at the application site, 

and in the skin adjacent to the application site. 

Average percentages of FMC 54800 dosages absorbed 

at 10 hours were 55.8%, 54.1%, and 37.5% for the 

49.2, 514 and 5253 μg/rat groups respectively. 

Corresponding percentages for the 3 groups at the 0.5 

hour sacrifice were 54.6%, 56.4%, and 52.5%, so the 

percentage absorption of FMC 54800 did not seem to 

depend on time-to-sacrifice. At 10 hours and the 

lowest dose level, the percentages present were as 

follows: excreta: <0.44%; carcass: <1.8%; skin at 

application site: 50.3%; skin adjacent to application 

site: 5.5%. At 10 hours and the highest dose level, the 

percentages of total dose present were as follows: 

excreta: 0.07%; carcass: 0.5%; skin at application site: 

34.6%; skin adjacent to application site: 2.7 %.

Classification: This dermal absorption study is 

classified as acceptable. However, by itself, does 

not satisfy the guideline requirement for a dermal 

penetration study (85-2) in the rat for technical 

bifenthrin (FMC 54800). However, it can be used, in 

conjunction with other dermal penetration studies, as 

supporting data for the purposes of registration and/or 

reregistration of products containing or consisting of 

bifenthrin.

870.7600 41284202 Dermal Penetration - Rats

The report states that at 24 hours post dose, 5.11% of 

the dose was absorbed (application-site skin + carcass 

+ urine + feces) in this second trial. However, it is 

noted that there was poor recovery (68% of the total 

dose) from one of the rats (C32545) sacrificed at 24 

hours in the second trial; disregarding the findings 

from this one animal then the mean value of the dose 

that was absorbed was 5.88%, and this can be taken as 

a reasonable estimate of the dermal absorption at this 

dose level.

This dermal absorption study is classified as 

acceptable. However, because only one dose was 

used, this study, by itself, does not satisfy the 

guideline requirement for a dermal penetration study 

(85-2) in the rat for technical bifenthrin (FMC 54800). 

However, it can be used, in conjunction with other 

dermal penetration studies, as supporting data for the 

purposes of registration and/or reregistration of 

products containing or consisting of bifenthrin.
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A.3 Hazard Identification and Endpoint Selection

1 10 100

0

1

2

3

4

5

6

7

8

9

10

DNT

S-C Dog

SCN Repro

Mice Chronic

Rat Chronic

Dog Chronic

Rabbit Gavage

Wolansky BMD-L

Rat Gavage

Rat Dietary

Mean=3.3 mg/kg, SD=2.0

Bifenthrin NOAEL vs Treatment Time

 Oral Studies Weight of Evidence

N

O

A

E

L (m

g

/

k

g

/

d

a

y)

Treatment Time (days)
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A.3.1 Acute Reference Dose (aRfD, including General Population and Females 13-49), 

Acute Population Adjusted Dose, & Incidental Oral Exposure

The following information was used in the PoD determination for acute oral endpoints. The 

previous figures provides a visual picture of this evaluation. 

1. The Wolansky acute rat study with a PoD of BMDL1SD = 3.1 mg/kg is selected for this 

endpoint due to the overall robust nature of the study with 9 doses, producing an

excellent dose response curve. The Wolansky study was considerably conservative, 

employing gavage dosing using 1 ml/kg corn oil vehicle and volume. This special study

had a uniform design for all of the pyrethroids tested. It also monitored the toxicology at 

the time of peak effects for each pyrethroid, thereby optimizing the responses, not always 

controlled in guideline studies. The BMD analysis provides a standardized metric of the 

study data which corrects for dose selection and dose spacing effects. The Wolansky

PoD is more consistent with the weight of evidence of the NOAELs in the bifenthrin data 

base listed in Table 4.3.3. 

2. The Nemec/WIL study (2006) also had a uniform study design with all pyrethroids 

tested. However, the study only had two doses with poor dose selection which resulted in 
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limited dose response information for bifenthrin. The Nemec/WIL study is not 

appropriate for endpoint selection for bifenthrin.

3. The Agency notes that a rat developmental study administered via gavage with corn oil 

provides a NOAEL of 0.88 mg/kg/day based on tremors at a dose of 1.77 mg/kg/day. 

However, a dietary rat developmental study had a NOAEL of 7.1 mg/kg/day also based 

on tremors. In the rat developmental gavage study, tremors at the highest dose tested of 

1.77 mg/kg/day were intermittent, lasting from as few as only one day up to 7 days of 

treatment. The hydroureter sign indicated in the rat gavage developmental study

(NOAEL=0.88 mg/kg/day) was not statistically significant, plus it was not reproduced in 

the rat dietary developmental study, suggesting to put less weight on this finding. 

Moreover, hydroureter is considered an artifact of the developmental process in rats, but 

not rabbits, and often resolves in rats. The rabbit developmental study, again by gavage 

dosing, also did not reproduce this developmental effect. The NOAEL of 0.88 mg/kg/day

is not consistent with other points of departure in the data base, including the DNT and 

reproduction study which also had signs of tremors and also dosed pregnant rats 

(NOAELs of 3.6 mg/kg/day and 3.0 mg/kg/day, respectively). In context, in the rat 

reproduction study only the females had tremors, the NOAEL was 5.0 mg/kg/day for 

males. The rabbit developmental study had a NOAEL of 2.36 mg/kg/day, however, 

bacterial infections in the animals may have sensitized them to chemical stress. Thus, by

a weight of evidence approach, the NOAEL of 0.88 mg/kg/day and the value of the 

hydroureter finding in determining points of departure is discounted.

4. The 1-year dog study resulted in a NOAEL of 1.3 mg/kg/day and LOAEL of 2.7 

mg/kg/day based on increased tremors in both sexes via capsule dosing. The tremors 

were also transient, existing in only in 1/4 male dogs and only 2/4 female dogs only 

during weeks 16-23 of treatment. With allometric scaling, the chronic dog Human 

Equivalent Dose (HED) is 0.78 mg/kg/day and the acute Wolansky rat study HED is a 

similar value of 0.72 mg/kg. Moreover, the HED for the 90-day dog study NOAEL is 

1.35 mg/kg, also similar to the HED value for the acute Wolansky rat study (see 

Appendix A.4). Thus, the points of departure between the two species are approximately

equivalent when normalized to the human reference dose. The Wolansky acute rat study 

utilizing nine dose groups with 8-12 animals/group with BMD analysis is a more reliable 

study than the studies using only 3 dose groups and 4-10 animals/group. 

5. While the ACN study is often considered for acute endpoints and used gavage dosing for 

bifenthrin, this study did not utilize a dosing vehicle (which is known to modulate 

pyrethroid toxicity), thus had an atypical LOAEL value of 70.3 mg/kg. Therefore, the 

Wolansky study PoD is much more conservative. Furthermore, there were deaths at the 

LOAEL for the ACN study, thus this data does not provide a sensitive endpoint for PoD 

selections.

A.3.2 Chronic Reference Dose (cRfD) 

Chronic endpoints have not been chosen for bifenthrin since the toxicology database indicates 

that the acute endpoints are protective of longer-term exposures.
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A.3.3 Dermal Exposure (Short-Term) 

The 21-day dermal study in rats with a BMDL10 of 96.3 mg/kg/day was selected for this 

endpoint. The BMD10 value of 187.0 mg/kg/day was based on observations of clinical signs of 

exaggerated hind limb flexion. The 10% threshold for the BMD analysis is the default limit for 

quantal data such as hind limb flexion. The BMD analysis can improve PoD selection when dose 

spacing is non-ideal. The rabbit dermal toxicity study had a very similar point of departure with a 

NOAEL of 88 mg/kg/day, with a LOAEL of 442 mg/kg/day based on the loss of muscle 

coordination and increased incidence of tremors. However, the dose spacing of the rat study was 

superior to the rabbit study. Also, based on the rat and rabbit gavage developmental studies, the 

rat is more sensitive than the rabbit to bifenthrin exposure (i.e. developmental NOAELs of 1.77 

and >7.0 mg/kg/day, respectively). Since a dermal toxicity study is selected for dermal risk 

assessment, a dermal-absorption factor is not required. The BMD analysis using the BMDS 

software is listed in Appendix E. 

A.3.4 Inhalation Exposure (Short-Term) 

In the absence of an inhalation study, an oral study is being used for this endpoint. A POD of 3.1 

mg/kg is selected from the Wolansky acute rat study for this endpoint due to the overall robust 

nature of the study. An inhalation-absorption factor of 100% (default value assuming equivalent 

inhalation and oral absorption) was used for route-to-route extrapolation. 

Appendix A.4. Human Equivalent Doses (dog study vs. acute rat motor activity study)

Table A.4. Human Equivalent Doses (dog study vs. acute rat motor activity study)

Rat Acute Data (Wolansky) Dog Data (Sub-chronic)

Chemical 

Rat Dose 

(mg/kg)

Human Dose

(mg/kg)

Dog Dose 

(mg/kg)

Human Dose 

(mg/kg)

BMD BMDL BMD BMDL NOAEL LOAEL NOAEL LOAEL

Beta-cyfluthrin 1.42 1.17 0.41 0.34 2.4 13.9 1.48 8.54

Bifenthrin 4.1 3.1 1.19 0.90 2.2 4.2 1.35 2.58

Bioallethrin 65.6 42.2 19.07 12.27 20 63 12.30 38.73

Cyhalothrin 0.92 0.64 0.27 0.19 1 2.5 0.61 1.54

Cyphenothrin - - - - 12.5 37.5 7.68 23.05

Cypermethrin 11.19 7.16 3.25 2.08 12.5 37.5 7.68 23.05

Deltamethrin 2.48 1.49 0.72 0.43 1 2.5 0.61 1.54

Esfenvalerate 1.19 0.65 0.34 0.19 5 7.5 3.07 4.61

Fenpropathrin 6.44 5.01 1.87 1.45 2.5 6.2 1.54 3.81

Permethrin 63.1 44.4 18.34 12.91 50 500 30.74 307.39

Resmethrin 162.32 75.89 47.19 22.06 300 - 184.4 -

Tefluthrin 3.67 2.8 1.067 0.81 0.5 1.5 0.31 0.92

Rat BW (kg) = 0.5, Dog BW (kg) = 10, Human BW (kg) = 70

Human Equivalent Dose (HED) = Animal Dose x (Animal BW/ 70)0.25 
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Appendix B. 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, which comprise the 

Pesticide Handlers Exposure Database (PHED), the Agricultural Handler Exposure Task Force 

(AHETF), the Outdoor Residential Exposure Task Force (ORETF) have been determined to 

require a review of their ethical conduct, have received that review, and have been determined to 

be ethical.

Appendix C. Residential Exposure/Risk Summary Table

A summary of bifenthrin residential handler exposure/risk is presented in Table D.1 below. 

Table C.1. Residential Bifenthrin Handler Short-Term Exposure and Risk

Use Site Equip. 

Types

App. 

Rate

(lbai/

gallon)1

Amount 

Handled 

(gallons)2

or Area 

Treated 

Route of 

Exposure

Dose 

(mg/kg/day)

3,4

MOE5 ARI6

Indoor

Indoor 

SurfaceDirected 

Sprays - Bed 

Bug 

Treatment

ManuallyPressurized 

Handwand

0.0051 0.5

Dermal 0.00211 44,000

73

Inhalation 0.000035 88,000

Outdoor

Ornamentals 

(Shade Tree, 

Herbaceous 

Plants, NonFlowering 

Plants, 

Woody

Shrubs and 

Vines)

Hose-End 

Sprayer 0.019 11

Dermal 0.15 630

6.3

Inhalation 0.0000037 840,000

Backpack 

Sprayer

0.20 

(lb ai/A)

5 gallons 

(0.023 A)

Dermal 0.34 270

2.1

Inhalation 0.00037 8,400

ManuallyPressurized 

Handwand,

Dermal 0.17 580

5.3

Inhalation 0.000048 65,000

Sprinkler Can

Dermal 0.15 630

6.2

Inhalation 0.0000037 840,000

Turf 

(Lawns, 

Ornamentals

, Outdoor 

Premises, 

Recreational 

Areas)

Belly Grinder

0.20 

(lb ai/A)

0.023 A

Dermal 0.021 4,600

45

Inhalation 0.0000023 1,400,000

Push-Type 

Spreader

0.5 A

Dermal 0.001 95,000

480

Inhalation 0.0000033 950,000

Hose-End 

Sprayer

Dermal 0.017 5,700

38

Inhalation 0.000028 110,000
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Table C.1. Residential Bifenthrin Handler Short-Term Exposure and Risk

Use Site Equip. 

Types

App. 

Rate

(lbai/

gallon)1

Amount 

Handled 

(gallons)2

or Area 

Treated 

Route of 

Exposure

Dose 

(mg/kg/day)

3,4

MOE5 ARI6

Indoor

Backpack 

Sprayer

Dermal 0.16 590

4.4

Inhalation 0.00018 18,000

1. Maximum application rates identified for residential uses of bifenthrin as referenced from Biological and

EconomicsAnalysis Division (BEAD) Label Data System.

2. Based on 2011 Residential SOPs

3. 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).

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

handled

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

5. Dermal MOE = PoD (BMDL10 of 96.3 (mg/kg/day) / Daily dermal dose (mg/kg/day); Inhalation MOE = 

PoD (BMDL1SD of 3.1 mg/kg/day) / Daily inhalation dose (mg/kg/day). Dermal Level of concern = 100, 

Inhalation Level of Concern = 1,000 (Adult)

6. Aggregate Risk Index (ARI) = 1 / ((1/estimated MOE for adult dermal exposure/ LOC for adult dermal 

exposure ) + (1/estimated MOE for adult inhalation exposure/ LOC for adult inhalation oral exposure))

Table C.2. Residential Post-application Exposure and Risk Estimates for High-end Bifenthrin

Uses

Exposure 

Scenario Lifestage App. Rate1 Route of 

Exposure

Exposure Source/

Activity

Dose2

(mg/kg/day) MOE3 ARI4

Indoor

SurfaceDirected 

Sprays/

Mattress for

Bed Bug 

Treatment

Adult

0.0051 

lb ai/gallon

Dermal

Surface-Directed 

Spray 0.0027 35,000

Mattress 0.0007 140,000 110

Inhalation Surface Directed 

Spray 0.000016 190,000

Child 1 < 2 

Years Old

Dermal

Surface Directed 

Spray 0.0025 37,000

2.5

Mattress 0.0032 61,000

Hand to 

Mouth Surface Directed 

Spray

0.00037 7,900

Inhalation 0.000066 45,000

Exposure 

Scenario Lifestage App. Rate1 Route of 

Exposure

Exposure Source/

Activity

Dose2

(mg/kg/day) MOE3 Comb.MOEs5

Outdoor

Turf - Liquid Adult 0.20

lb ai/A Dermal 

Physical Activities 

on Turf 0.076 1,300 NA

Mowing 0.0015 63,000
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1. Maximum application rates identified for residential uses of bifenthrin as referenced from Biological and

EconomicsAnalysis Division (BEAD) Label Data System

2. 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).

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

(gallons) * inhalation absorption (100%) / body weight (80 kg, adult; 32 kg, child 6 < 11; 11 kg, child 1 < 2). 

3. Dermal MOE = PoD (BMDL10 of 96.3 (mg/kg/day) / Daily dermal dose (mg/kg/day); Inhalation MOE = PoD 

(BMDL1SD of 3.1 mg/kg/day) / Daily inhalation dose (mg/kg/day). Level of concern = 100 (Adult)

4. Aggregate Risk Index (ARI) = 1 / ((1/estimated MOE for adult or child 1 < 2 dermal exposure/ LOC for adult 

or child 1 < 2 dermal exposure ) + (1/estimated MOE for adult or child 1 < 2 inhalation exposure/ LOC for adult 

Golfing 0.0059 16,000

Child 11 < 16 

Years Old Dermal Mowing 0.0018 55,000

Golfing 0.0069 14,000

Child 6 < 11 

Years Old Dermal Golfing 0.0081 12,000

Child 1 < 2 

Years Old

Dermal Physical Activities 

on Turf 0.14 690

400

Hand to Mouth 0.0030 1,000

Object to Mouth 0.000032 34,000

Short-term Incidental Soil Ingestion 0.000013 240,000

Turf -

Granular

Adult

0.50

lb ai/A

Dermal

Physical Activities 

on Turf 0.0419 2,300

NA

Mowing 0.00076 130,000

Golfing 0.0029 32,000

Child 11 < 16 

Years Old Dermal Mowing 0.00088 110,000

Golfing 0.0034 28,000

Child 6 < 11 

Years Old Dermal Golfing 0.0040 24,000

Child 1 < 2 

Years Old

Dermal Physical Activities 

on Turf 0.079 1,200

Hand to Mouth 0.00074 4,200 850

Object to Mouth 0.000228 14,000

Short-term Incidental Soil Ingestion 0.000033 35,000

Incidental ingestion of granules 0.05 59 NA

Ornamental 

Gardens - 

Liquid

Adult

0.21

lb ai/A

Dermal

Gardening

0.14 720

NA

Child 6 < 11 

Years Old 0.092 1,000

Ornamental 

Trees – Liquid

Adult

Picking Fruit

0.012 7,800

Child 6 < 11 

Years Old 0.0085 11,000

Ornamental 

Gardens –

Granular

Adult

0.40

lb ai/A

Gardening

0.26 370

Child 6 < 11 

Years Old 0.18 540

Ornamental 

Trees -

Granular

Adult

Picking Fruit

0.024 4,100

Child 6 < 11 

Years Old 0.016 5,900
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or child 1 < 2 inhalation oral exposure) + (1/estimated MOE for child 1 < 2 incidental oral exposure/ LOC for 

child 1 < 2 incidental oral exposure)

5. Combined MOEs = 1/ ((1/ Dermal MOE) + (1/Incidental Oral MOE))

Appendix D: Cumulative Exposure and Risk Issues

No bifenthrin indoor bed bug uses were included in the 2011 pyrethroid CRA, as there were no 

registered bed bug treatments at that time. However, indoor broadcast, crack and crevice, and 

fogger pyrethroid uses were included in the CRA. In order to determine if the proposed 

bifenthrin bed bug use significantly contributes to or changes the overall findings in the 

pyrethroid CRA, the Agency has performed a quantitative exposure and risk assessment. This 

assessment used the bifenthrin relative potency factor (RPF), discussed below, as well as the 

same exposure algorithms and inputs that were used in the 2011 pyrethroid CRA (see Appendix 

Table D). 

The pyrethroid CRA relies on the RPF approach, using administered dose as the metric for 

quantifying chemical potency. In the RPF approach, the toxic potency of each chemical in the 

common assessment group (CAG) is determined. One member of the CAG is selected as the 

index chemical for use as the point of reference for standardizing neurobehavioral potency of the 

other members of the CAG. In order to develop such potency estimates, EPA prefers to use a 

uniform measure of toxicity such as data from the same endpoint and same duration, and to the 

extent possible, any other factors which effect potency (e.g., time to peak effect, sex, etc). 

In the pyrethroid CRA, the Agency used the two special WIL Functional Observational Battery

(FOB) studies for estimating relative potency. This data was selected because these studies 

examined many behaviors, including key behaviors for evaluating neurotoxicity specific to 

pyrethroids. Specifically, the studies looked at a number of crucial parameters that are directly

relevant to the Type I (e.g., hyperthermia tremors and clonus) and Type II (e.g., hypothermia, 

salivation, and mobility) syndromes. In addition to the WIL FOB studies, the Wolansky acute 

oral study also provided a high quality data set for estimating relative potency. Whereas the 

WIL FOB studies focus on endpoints specific to pyrethroid toxicity syndromes, the Wolansky 

study measured motor activity. Motor activity is considered an apical endpoint because it 

measures alterations in the activity level of an intact rat. Although the Wolansky study provides 

a potential data source for a uniform measure of potency, it was not used in the CRA because of 

the lack of specific relevance to the common mechanism of action for the pyrethroids. Section 4 

of the CRA can be referenced for a full description of the Agency’s RPF approach. 

In the CRA, deltamethrin was used as the index chemical. The RPFs used for the CAG in the 

pyrethroid screening level cumulative are shown below in Table D.1. They were determined by

dividing the chemical-specific BMD20 by the BMD20 of the index chemical, deltamethrin. 

Calculations for the BMDs are described in Section 4.2 of the CRA. Twelve of the 15 

pyrethroids result in relative potency estimates equal to, or lower than deltamethrin. Bifenthrin, 

cyfluthrin, and tau-fluvalinate result in similar relative potency as deltamethrin, while lambdacyhalothrin resulted in slightly greater potency than deltamethrin. An RPF of 1.01 was used to

quantify comparative exposures from the proposed bifenthrin bed bug use.
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Table D.1. Relative Potency Estimates for Pyrethroids Included in the Screening 

Level Cumulative Risk Assessment

Pyrethroid Oral BMD20 Oral RPFb,d

Allethrinc135 0.11

Bifenthrin 14.3 1.01

Cyfluthrin 12.6 1.15

Lambda-Cyhalothrin 8.9 1.63

Cyphenothrin 100a0.15

Cypermethrin 76.3 0.19

Deltamethrin 14.5 1.0

Esfenvalerate 40.5 0.36

Fenpropathrin 29 0.50

Tau-Fluvalinate 14.5 1.0

Imiprothrin 750a0.02

Permethrin 156 0.09

Prallethrin 150a0.10

Pyrethrins 800a0.02

Resmethrin 291 0.05

a

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

bRPF = BMD20 of Index Chemical (e.g., deltamethrin)/Pyrethroid BMD20; For example: Bifenthrin 

RPF=14.5/14.3 = 1.01

c

Includes the isomeric enrichments S-Bioallethrin and D-Allethrin

dRPFs for Dermal and Inhalation exposures are based on oral BMD; 5% absorption values applied to 

dermal assessments and inhalation is considered equivalent to the oral route

Appendix Table D.2 summarizes a comparison of the MOEs currently driving indoor exposures 

and risks (as referenced from Table 6.4.7a of the 2011 pyrethroid CRA) to those estimated for 

the proposed bifenthrin bed bug use, which were assessed using the bifenthrin RPF and the same 

exposure algorithms and inputs used in the CRA. The routes of exposure include postapplication dermal for adults, and post-application dermal and incidental oral for children. 

Quantitative post-application inhalation exposures from the bed bug use are not included in the 

CRA assessment since this is not a significant route of exposure. The MOEs in the single 

chemical assessment are not of concern and, as was noted in the CRA, an Office of Research and 

Development exposure study that simulated crack and crevice applications of four pesticides, 

including two pyrethroids, showed that all air concentration values were below the limit of 

quantitation (D390098, C. Smith and S. Shelat, 9/15/2011). 

Adult indoor exposures and risks (dermal only) are currently driven by the cypermethrin indoor 

fogger use pattern with an MOE of 3,900, which is lower than the MOE estimated for adult 

dermal exposure from the proposed bifenthrin bed bug use, 15,000. The cypermethrin use also 

drives the CRA for child indoor exposures and risks with an estimated combined MOE (dermal 

and incidental oral) of 720, which is lower than the combined MOE estimated for child 

exposures and risk indoors from the proposed bifenthrin use, 2,700. Based upon these outcomes, 

the Agency has determined that the proposed bed bug use will not contribute significantly to or 

change the findings presented in the CRA. A summary of individual adult and child exposure 

scenarios assessed for the comparative evaluation are presented in Table D.3. 
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D.2. Bifenthrin 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 Bifenthrin

Indoor Bed Bug -

Surface Directed 

Sprays

Post-Application 

Dermal Adult 15,000 15,000

Post-Application 

Dermal Children 

(1 < 2 years old)

13,000

2,700 Post-Application 

Incidental Oral 3,500

CRA Cypermethrin Indoor Fogger

Post-Application 

Dermal Adult 3,900 3,900

Post-Application 

Dermal Children 

(1 < 2 years old)

3,500

720 Post-Application 

Incidental Oral 900
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Appendix Table D.3: Bifenthrin Screening Level “Cumulative” MOEs

Post-application Dermal Exposure

Exposure Scenario Surrogate 

Deposition 

(μg/cm2)

Fraction 

Transferred

Transfer 

Coefficient 

(cm2/hr)

Exposure Time 

(hours)

Conversion 

Factor 

(mg/μg)

Exposure 

(mg/day)

Body 

Weight 

(kg)

Absorbed Dermal 

Dose (mg/kg/day)

Adjusted 

Dose

(mg/kg/day)

a

Adjusted 

MOE b

Dermal Exposure from 

Carpet After Bed Bug 

Use 

(1 < 2 year olds)

0.9 0.02

2,000 5

0.0010

0.18 11.4 0.00079 0.00080 13,000

Dermal Exposure from

Carpet after Bed Bug 

Use

(Adults)

6,800 8 0.98 71.8 0.00068 0.00069 15,000

Post-application Incidental Oral Exposure

Exposure Scenario Faihands

1-2 yr old 

Dermal 

Exposure

SAH

(cm2)

HRt

(mg/cm2)

FM

Exposure 

Time 

(hours/day)

N_Replen SE Freq_HtM

BW

Average 

Daily Dose

(mg/kg/day)

Adjusted Dose

(mg/kg/day) a

Adjusted 

MOE b

Fraction of Hand 

Surface Area 

Mouthed / Event

Number of 

replenishment 

intervals per hr

(intervals/hr)

Extraction by 

Saliva

H-t-M 

events per 

hour

Incidental Oral 

Exposure from Bed 

Bug Use

(1 < 2 year olds)

0.15 0.18 150 8.9E-05 0.13 5 4 0.5 20 11.4 0.00290 0.0030 3,500

a Doses were adjusted based on an estimated bifenthrin RPF of 1.01

b MOEs were calculated by comparing the adjusted dose to the oral BMD20 from the WIL FOB data for the index chemical, deltamethrin (14.5 mg/kg/day)
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Appendix E: Bifenthrin BMD Analysis for the 21-Day Dermal Study

Bifenthrin BMD Analysis: 21-Day Rat Dermal Study – MRID 45280501

BMDS 2.1.1: Dichotomous – multistage. Extra Risk BMR at 10%

Endpoint: Exaggerated hind limb flexion in females

BMD Results:

 BMD = 187.052 mg/kg/day

 BMDL = 96.2927 mg/kg/day

Calculations:

==================================================================== 

 Multistage Model. (Version: 3.2; Date: 05/26/2010) 

 Input Data File: C:/Usepa/BMDS212/Data/mst_testrundichotomous_Opt.(d) 

 Gnuplot Plotting File: C:/Usepa/BMDS212/Data/mst_testrundichotomous_Opt.plt

Wed Apr 06 12:01:44 2011

==================================================================== 

BMDS_Model_Run 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

 The form of the probability function is: 

 P[response] = background + (1-background)*[1-EXP(

 -beta1*dose^1-beta2*dose^2)]

 The parameter betas are restricted to be positive

 Dependent variable = Effect

 Independent variable = Dose

Total number of observations = 5

Total number of records with missing values = 0

Total number of parameters in model = 3

Total number of specified parameters = 0

Degree of polynomial = 2

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

 Default Initial Parameter Values 

 Background = 0.0031824

 Beta(1) = 0.000548172

Beta(2) = 0

 Asymptotic Correlation Matrix of Parameter Estimates

 ( *** The model parameter(s) -Background -Beta(2) 

 have been estimated at a boundary point, or have been specified by 

the user,

 and do not appear in the correlation matrix )
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 Beta(1)

 Beta(1) 1

 Parameter Estimates

 95.0% Wald Confidence 

Interval

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. 

Limit

 Background 0 * * *

 Beta(1) 0.000563269 * * *

 Beta(2) 0 * * *

* - Indicates that this value is not calculated.

 Analysis of Deviance Table

 Model Log(likelihood) # Param's Deviance Test d.f. P-value

 Full model -9.98095 5

 Fitted model -10.5726 1 1.18324 4 0.8809

 Reduced model -16.2541 1 12.5464 4 0.01372

 AIC: 23.1451

 Goodness of Fit 

 Scaled

 Dose Est._Prob. Expected Observed Size Residual

 ------------------------------------------------------------------------

 0.0000 0.0000 0.000 0.000 10 0.000

 23.0000 0.0129 0.129 0.000 10 -0.361

 47.0000 0.0261 0.261 0.000 10 -0.518

 93.0000 0.0510 0.510 1.000 10 0.704

 932.0000 0.4084 4.084 4.000 10 -0.054

Chi^2 = 0.90 d.f. = 4 P-value = 0.9250

 Benchmark Dose Computation

Specified effect = 0.1

Risk Type = Extra risk 

Confidence level = 0.95

 BMD = 187.052

 BMDL = 96.2927

 BMDU = 598.842

Taken together, (96.2927, 598.842) is a 90 % two-sided confidence

interval for the BMD