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Chemical PC Code CAS No.

Allethrin 004001 584-79-2

Bioallethrin 004003 28057-48-9

S-Bioallethrin 004004 28434-00-6

D-Allethrin 004005 84030-86-4

Esbiothrin 004007 84030-86-4

Bifenthrin 128825 82657-04-3

Cyclethrin 004052 97-11-0

Cyfluthrin 128831 68359-37-5

Cyfluthrin, beta- 118831 68359-37-5

Cyhalothrin 128867 68085-85-8

Cyhalothin, lambda- 128897 91465-08-6

Cyhalothrin, gamma- 128807 76703-62-3

Cypermethrin 109702 52315-07-8

Cypermethrin, alpha- 209600 67375-30-8

Cypermethrin, beta- 109902 65731-84-2

Cypermethrin, zeta- 129064 52315-07-8

Cyphenothrin 129013 39515-40-7

Deltamethrin 097805 52918-63-5

Esfenvalerate 109303 66230-04-4

Fenvalerate 109301 51630-58-1

Fenfluthrin 109705 75867-00-4

Fenpropathrin 127901 39515-41-8

Imiprothrin 004006 72963-72-5

Metofluthrin 109709 240494-70-6

Permethrin 109701 52645-53-1

Prallethrin 128722 23031-36-9

Pyrethrins (not synthetic) 069001 8003-34-7

Resmethrin 097801 10453-86-8

Sumethrin (phenothrin) 069005 26002-80-2

Tau-fluvalinate 109302 102851-06-9

Tefluthrin 128912 79538-32-2

Tetramethrin 069003 7696-12-0

Tralomethrin 121501 66841-25-6
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Pyrethrins/Pyrethroid

Cumulative Risk Assessment

U.S. Environmental Protection Agency

Office of Pesticide Programs

October 4, 2011
Pyrethroid Cumulative Risk Assessment

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Table of Contents

1.0 Introduction .....................................................................................................................................5

2.0 Determining the Common Mechanism & Establishing the CMG ....................................................6

2.1 Pyrethroid Structure ...........................................................................................................7

2.2 Voltage Gated Sodium Channels ........................................................................................8

2.3 In vivo Toxicity...................................................................................................................11

2.4 CMG for CRA .....................................................................................................................11

3.0 Common Assessment Group .........................................................................................................12

4.0 Hazard Assessment/Characterization............................................................................................14

4.1 Endpoints and Toxicology Studies ....................................................................................14

4.1.1 Establishing a Uniform Measure of Toxicity ........................................................14

4.1.1.1 Common Mechanism Endpoint ..............................................................14

4.1.1.2 Experimental Laboratory Studies with Behavioral Measures.................16

4.1.1.3 Scientific Considerations in Evaluating Experimental Animal Studies....17

4.1.1.4 Selection of Critical Study for Estimating Relative Potency....................19

4.2 WIL FOB Study & Determining a Uniform Measure of Potency .......................................21

4.2.1 Introduction.........................................................................................................21

4.2.2 WIL Study Design .................................................................................................22

4.2.3 Severity Scoring ...................................................................................................22

4.2.4 Variable Coding....................................................................................................24

4.2.5 Dose-Response Modeling and Derivation of Benchmark Dose (BMD) Estimates 

for Dichotomous Data..........................................................................................25

4.2.5.1 Threshold Estimates for Pyrethroids Not Included in BMD Analysis......26

4.3 Routes and Duration of Exposure for Potency Determination.........................................28

4.3.1 Routes of Exposure..............................................................................................28

4.3.1.1 Oral .......................................................................................................29

4.3.1.2 Dermal and Inhalation..........................................................................29

4.4 Index Chemical..................................................................................................................30

4.4.1 Candidates for Index Chemical ............................................................................30

4.5 Relative Potency Estimates & Points of Departure for the Index Chemical.....................31

4.5.1 Relative Potency Factors.........................................................................................31

4.5.2 Points of Departure.................................................................................................32

4.6 FQPA Safety Factor for Protection of Infants & Children .................................................33

4.7 Incorporation of Uncertainty Factors/Extrapolation Factors and the Target MOE..........35

4.8 Dose Additivity ........................................................................................................................36

5.0 Dietary Cumulative Exposure and Risk Assessment/Characterization..........................................37

5.1 Food Exposure Pathway....................................................................................................37

5.1.1 Dietary Consumption Data ..................................................................................37

5.1.2 Pesticide Residue Data.........................................................................................38

5.1.3 Pyrethroid Pesticides Included in the Dietary Risk Assessment..........................38

5.1.4 Food Commodities Included in the Dietary Risk Assessment..............................40
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5.2 Drinking Water Pathway...................................................................................................40

5.3 Dietary (Food and Water) Assessment.............................................................................42

6.0 Residential Pyrethroid Cumulative Risk.........................................................................................45

6.1 Introduction ......................................................................................................................45

6.2 Residential Scenarios and Exposure Routes.....................................................................46

6.2.1 Lawn/Turf Use......................................................................................................46

6.2.2 Garden, Ornamental, and Tree Use.....................................................................47

6.2.3 Indoor Use............................................................................................................47

6.2.4 Pet Use.................................................................................................................48

6.3 Residential Handler Exposure and Risk.............................................................................48

6.3.1 Handler Algorithms..............................................................................................48

6.3.2 Handler Data and Assumptions...........................................................................49

6.3.2.1 Unit Exposure (UE)................................................................................49

6.3.2.2 Application Rate (AR)............................................................................53

6.3.2.3 Area Treated/Amount Handled (A) ......................................................53

6.3.3 Handler Risk Summary.........................................................................................54

6.4 Post-application Exposure and Risk..................................................................................54

6.4.1 Post-application Dermal Exposure.......................................................................54

6.4.1.1 Dermal Post-application Algorithm......................................................54

6.4.1.2 Dermal Post-application Data and Assumptions..................................55

6.4.1.2.1 Transferable Residue (TR) ....................................................55

6.4.1.2.2 Transfer Coefficient (TC).......................................................60

6.4.1.2.3 Exposure Time (ET)...............................................................61

6.4.2 Post-application Dermal Risk Summary...............................................................62

6.4.3 Post-application Inhalation Exposure..................................................................62

6.4.3.1 Post-application Inhalation Algorithms................................................63

6.4.3.2 Post-application Inhalation Data and Assumptions.............................64

6.4.3.2.1 Inhalation Rate (IR)...............................................................64

6.4.3.2.2 Mass of active ingredient applied (Mlabel).............................65

6.4.3.2.3 Air Changes per Hour (ACH) .................................................65

6.4.3.2.4 Volume of a Room (Vroom).....................................................65

6.4.3.2.5 First Order Decay Rate (k) ....................................................65

6.4.3.2.6 Exposure Time (ET)...............................................................65

6.4.4 Post-application Inhalation Risk Summary ..........................................................65

6.4.5 Post-application Incidental Oral Exposure and Risk ............................................66

6.4.5.1 Post-application Incidental Oral Algorithm..........................................66

6.4.5.2 Post-application Incidental Oral Data and Assumptions......................67

6.4.5.2.1 Hand Residue (HR)................................................................67

6.4.5.2.2 Fraction of Hand Mouthed per Event (FM) ...........................67

6.4.5.2.3 Hand Surface Area (SAH).......................................................68

6.4.5.2.4 Fraction of Pesticide Extracted by Saliva (SEH).....................68

6.4.5.2.5 Exposure Time (ET)...............................................................68

6.4.6 Post-application Incidental Oral Risks .................................................................68

6.4.7 Combined Exposure.............................................................................................68

7.0 Combined Screening Level Dietary + Residential Cumulative .......................................................70
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8.0 Characterizing the Screening-Level Pyrethroid Cumulative Risk Estimates..................................71

8.1 Hazard Characterization ...................................................................................................71

8.2 Dietary Exposure Assumptions and Characterization.......................................................75

8.2.1 Food Exposure Pathway.......................................................................................75

8.2.2 Drinking Water Exposure Pathway ......................................................................75

8.3 Non-Dietary Exposure Assumptions and Characterization ..............................................75

8.4 Aggregate Exposure (Dietary + Non-Dietary) Assumptions and Characterization...........77

9.0 Conclusion......................................................................................................................................78

References ..................................................................................................................................................80

Appendix 1 - Toxicity Data for the Screening Level Cumulative Risk Assessment.......................................A1

Appendix 2 - Herbeth Study DER...........................................................................................................................A2

Appendix 3 - Weiner Study DER............................................................................................................................A3

Appendix 4 - FOB Data for Weiner Study............................................................................................................A4

Appendix 5 - BMDs for T and CS from WIL FOB Study......................................................................................A5

Appendix 6 - Deltamethrin Studies......................................................................................................................A6

Appendix 7 - Residential Exposure Tables..................................................................................................A7
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1.0 Introduction

With the passage of the Food Quality Protection Act of 1996 (FQPA), EPA is required to consider 

available information concerning the cumulative effects on human health resulting from 

exposure to multiple chemicals that have a common mechanism of toxicity when making

decisions related to pesticide tolerances. Pyrethroids are a class of synthetic insecticides which 

are structurally based on the pyrethrins, botanical insecticides extracted from Chrysanthemum

cinerariaefolium (Soderlund et. al. 2002). Pyrethrins are potent insecticides with relatively low 

mammalian toxicity but are sensitive to air and light. Hence, the use of pyrethrins for crop 

protection and to control disease-carrying insects is limited. With an altered structure, the 

pyrethroids are more photostable, while retaining the insecticidal activity of the pyrethrins. 

Thus, pyrethroids are widely used today in agriculture and in medical and veterinary products. 

The Agency has determined that a growing class of pesticides, the naturally occurring 

pyrethrins and synthetic pyrethroids, has a common mechanism of toxicity and are thus subject 

to cumulative risk assessment under the FQPA. 

The cumulative risk assessment discussed in this document incorporates multiple high-end 

inputs and combines the highest exposures/risk estimates across all pathways in a deterministic 

fashion resulting in a screening level assessment which is highly conservative and health 

protective. This cumulative assessment considered all registered uses of pyrethrins/pyrethroids 

and included exposure from food, drinking water and residential settings from the oral, dermal 

and inhalation routes of exposure. Having completed this screening level assessment, the 

Agency concludes that cumulative estimated risks from existing pyrethrins/pyrethroid uses are 

not of concern. 

The Agency also concludes that there is sufficient room in the pyrethroid cumulative risk cup to 

support consideration of new pyrethroids (i.e., currently unregistered pyrethroid pesticides) 

and new uses of existing pyrethroids having similar toxicity profiles and use patterns to those in 

this assessment given the multiple conservative inputs into the assessment. Per Agency policy, 

all new uses/new pyrethroid registration actions submitted to the Agency will undergo a single 

chemical assessment and also an evaluation of their potential contributions to cumulative risk. 

But the Agency believes that most of these are unlikely to have a significant impact on this 

screening-level cumulative assessment, provided they meet the parameters outlined above.

Details of the cumulative risk assessment process can be found in the OPP guidance document 

entitled Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common 

Mechanism of Toxicity (USEPA 2002). Briefly summarized here, the cumulative risk assessment 

(CRA) is developed by a multi-step process. The first step is the identification of a group of 

pesticides, called a Common Mechanism Group (CMG), which induce a common toxic effect by 

a common mechanism of toxicity. Pesticides are determined to have a “common mechanism of 

toxicity” if they act the same way in the body – that is, the same toxic effect occurs in the same 

organ or tissue by essentially the same sequence of major biochemical events. Once a CMG is 

established, the next step is to evaluate registered and proposed uses for each CMG member in 

order to identify potential exposure pathways (food, drinking water, residential) and routes 
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(i.e., oral, inhalation, dermal). During the hazard characterization phase, the various endpoints 

associated with the common mechanism of toxicity are identified, as well as the test 

species/sex that might serve as a uniform basis for determining relative potencies among the 

chemicals of interest. The common effect is also evaluated to determine if it is expressed 

across all exposure routes and durations of interest for each CMG member. The temporal 

aspects (e.g., time to onset and peak effects, duration of effects, and time to recovery) of the 

common mechanism of toxicity are characterized to determine the exposure durations relevant 

for the common toxic effect. As part of the process, it is important to determine which 

chemicals from the CMG should be included in the quantification of cumulative risk. Therefore 

a subset of the CMG called the cumulative assessment group (CAG) is identified which excludes 

those CMG members which have a minimal toxic contribution to the cumulative hazard or are 

limited to minor exposure pathways, routes, or uses. A dose response analysis is performed for 

each CAG member to determine its toxic potency for the common toxic effect. When 

physiologically-based pharmacokinetic (PBPK) models are not available, EPA uses the relative 

potency factor (RPF) method to determine the combined estimated risk associated with 

exposure to the members of the CAG. Briefly, the RPF approach uses an index chemical as a 

point of reference for comparing the toxicity of the other members of the CAG. A point of 

departure is determined for the index chemical and relative potency factors are calculated (i.e., 

the ratio of the toxic potency of a given chemical relative to that of the index chemical). RPFs 

are used to convert exposures of all chemicals in the CAG to exposure equivalents of the index 

chemical. A quantitative cumulative risk assessment is conducted by comparing the exposure 

equivalents to the point of departure for the index chemical across all pertinent exposure 

routes and durations. The last step in the CRA process is to characterize risk (i.e., an appraisal 

of the science supporting the risk assessment including choices made about methods, strengths 

and limitations of the available data, and assumptions).

The Agency’s common mechanism grouping decision and screening level cumulative risk 

assessment for the pyrethrins and pyrethroid pesticides are presented in this document. 

Throughout the remainder of the document, references to the “pyrethroid CRA” include 

consideration of both the naturally occurring pyrethrins and the synthetic pyrethroid chemicals. 

2.0 Determining the Common Mechanism & Establishing the CMG 

As previously noted, the first step in conducting a cumulative risk assessment is the 

identification of a Common Mechanism Group (CMG), chemicals that induce a common toxic 

effect by a common mechanism of toxicity. Pesticides are determined to have a “common

mechanism of toxicity” if they act the same way in the body – that is, the same toxic effect 

occurs in the same organ or tissue by essentially the same sequence of major biochemical 

events. In 2009, the Agency developed the “Draft Science Policy Paper: Proposed Common 

Mechanism Grouping for the Pyrethrins and Synthetic Pyrethroids” which proposed the 

common mode of action for pyrethroids. This common mechanism grouping is based on 1) 

shared structural characteristics; and 2) shared ability to interact with voltage-gated sodium 

channels (VGSC), resulting in disruption of membrane excitability in the nervous system, and 3) 
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ultimately neurotoxicity characterized by two different toxicity syndromes (Figure 2.0). The 

steps involved in this common toxicity pathway are summarized below. (USEPA 2011a). This 

proposal was reviewed and supported by the FIFRA Scientific Advisory Panel (SAP)1. 

Figure 2.0. Common Toxicity Pathway of the Pyrethrins & Pyrethroids 

2.1 Pyrethroid Structure

Pyrethroids are composed of two basic structural moieties; an acid and an alcohol. For first 

generation pyrethroids, such as allethrin, tetramethrin, and resmethrin, the acid portion is 

based on chrysanthemic acid, a cyclopropane ring bonded to a carboxylic acid moiety and a 

variety of halogenated and non-halogenated substituents. More recently developed 

pyrethroids, such as fenvalerate, do not have a cyclopropane ring. The alcohol portion is either 

a primary or a secondary alcohol, which is bound to a variety of heterocyclic structures. In 

addition, several of the pyrethroids have a cyano substituent bound to the α-methylene of the 

alcohol, which results in enhanced toxicity of the compound. Pyrethroids lacking the α-cyano 

substituent are generally termed Type I compounds and the pyrethroids with the α-cyano 

substituent are generally termed Type II compounds. Figure 2.1, below, shows the structures of 

a Type I pyrethroid, permethrin, and a Type II pyrethroid, cypermethrin. 

 1 http://www.epa.gov/scipoly/sap/meetings/2007/august/pyrethroidpbpk_sap_2007_finalv1.pdf
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H3C CH3

O

Cl Cl

O

O

Permethrin

H3C CH3

Cl Cl

O

O

CN

O

Cypermethrin

Figure 2.1. The Structures of Permethrin (Type I) and Cypermethrin (Type II)

2.2 Voltage Gated Sodium Channels (VGSCs)

The naturally occurring pyrethrins and synthetic pyrethroids share the same mode of action, 

namely the interaction VGSCs (Narahashi 1996; Soderlund et. al. 2002; Shafer et. al. 2005; 

Weiner et. al. 2009). The effects of pyrethroid exposure on neuronal tissue (both insects and 

mammals) have been extensively reviewed (Soderlund and Bloomquist 1989; Vijverberg and 

Bercken 1990; Narahashi 1992; Bloomquist 1993; Clark 1995; Soderlund 1995; Bloomquist 

1996; Narahashi 1996). Pyrethroids delay the inactivation of affected VGSCs, allowing for an 

increase in sodium ion influx and resulting in delayed repolarization. The delay is more 

pronounced in cyano-containing (Type II) pyrethroids (>>200 ms) resulting in depolarizationdependent block of the neuronal action potentials and toxicity. The delay is considerably 

shorter for non-cyano (Type I) pyrethroids (20ms) and results in repetitive firing of action 

potentials and toxicity. Mixed-Type pyrethroids (e.g. esfenvalerate and fenpropathrin) produce 

delays intermediate between the characteristic Type I and Type II pyrethroids.

Figure 2.2 depicts generalized pyrethroid effects on individual channels, whole-cell sodium 

currents, and action potentials (extracted from Shafer et. al. 2005). Depolarization opens 

VGSCs (top left) allowing sodium to enter the cell. To limit sodium entry and depolarization 

length, VGSCs inactivate and must return to a “resting” state before reopening. Pyrethroids 

inhibit the function of two different “gates” that control sodium flux through VGSCs (top right), 

delaying inactivation (indicated by double arrows between states) of the channel and allowing 

continued sodium flux (Open*). If sodium current through an entire cell is measured,

depolarization leads to a rapidly inactivating current under normal circumstances (bottom left, 

Sodium Current). Pyrethroid-modified VGSCs remain open when depolarization ends (bottom 

right, Sodium Current), resulting in a “tail” current (the notch at the end of example currents). If 
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membrane voltage is examined, depolarization under normal circumstances generates a single 

action potential (bottom left). VGSCs modified by type I compounds (bottom right, Action 

Potential) depolarize the cell membrane above the threshold for action potential generation, 

resulting in a series of action potentials (repetitive firing). Type II compounds cause greater 

membrane depolarization, diminishing the sodium electrochemical gradient and subsequent 

action potential amplitude. Eventually, membrane potential becomes depolarized above the 

threshold for action potential generation (depolarization-dependent block) (Shafer et. al. 2005). 

While interaction with the VGSC has been established as a key event by the Agency, pyrethroids 

have been reported to inhibit other types of ion channels, including chloride-permeable ion 

channels, voltage-gated calcium channels and ligand-gated chloride channels (Vijverberg and 

Bercken 1990; Narahashi 1996; Narahashi et. al. 1998; Ray and Forshaw 2000; Ray 2001; 

Soderlund et. al. 2002; Burr and Ray 2004; Shafer and Meyer 2004). It has been suggested that 

pyrethroid actions at these separate target sites combine to prolong neuronal membrane 

depolarization, resulting in massive neurotransmitter release (Clark and Brooks 1989). While 

pyrethroid actions on VGSCs and neuronal excitability are well understood, information on the 

other channels were conducted using different experimental models and are often 

contradictory (Shafer and Meyer 2004; Clark and Symington 2008; Cao et. al. 2011b). Thus, 

relative to sodium channels, the level of evidence supporting modes of action via other 

channels is not compelling. 
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Figure 2.2. Effects of pyrethroids on Na channels, currents, and action potentials (From Shafer et al. (2005))
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2.3 In vivo Toxicity

High doses of pyrethroids in laboratory animals result in one of two syndromes; the Tsyndrome associated with Type I pyrethroids, and the CS-syndrome associated with Type II 

pyrethroids. The neurotoxic behaviors elicited by Type I pyrethroids are aggression, 

hyperexcitability, fine tremor, prostration with coarse whole body tremor, increased body 

temperature, coma and death. These neurobehavioral responses are termed the T-syndrome 

because of the fine tremors induced by the Type I pyrethroids. For Type II pyrethroids, the 

neurotoxic behaviors include pawing and burrowing, salivation, hyperexcitability, abnormal 

hind limb movements, coarse whole body tremor, sinuous writhing, coma and death. These 

neurobehavioral responses are termed the CS-syndrome for the choreoathetosis (i.e., whole 

body writhing) and salivation. Some pyrethroids such as fenpropathrin and esfenvalerate, are 

considered mixed (Type I/II) because they elicit mixed behaviors of both the T- and CSsyndromes. The T-and CS-syndromes are considered to be acute responses to pyrethroid 

exposure and are dose-dependent. In mammals, the onset of neurobehavioral effects occur 

within a few minutes to over an hour, depending on the route of exposure and chemical, but 

can take 2-8 hours to peak. Recovery from pyrethroid toxicity is rapid, typically within 24-48 

hours. Mammals, unlike insects, have extensive enzyme systems capable of metabolizing and 

detoxifying the pyrethroids. This difference in physiology makes pyrethroids an order of 

magnitude less toxic in mammals compared to insects.

2.4 CMG for CRA

At the present time, EPA has designated the naturally occurring pyrethrins and synthetic 

pyrethroids as a common mechanism grouping for purposes of conducting a cumulative risk 

assessment under the FQPA. Consistent with the screening-level nature of this cumulative 

assessment, the pyrethroid CRA includes an interim decision to evaluate the Type I and Type II 

pyrethroids in a single group (i.e., one risk cup) (USEPA 2011a). 

In the 2009 CMG proposal, EPA considered the science that supported separating the 

pyrethroid CMG into two subgroups representing Type I and II pyrethroids. This subgrouping is 

consistent with historical categorization of pyrethroids and is supported by in vitro and in vivo

studies from both older studies and new research. As described previously in Section 2.1, the 

designation of Type I and Type II pyrethroids is based upon differences in structure; the α-cyano 

moiety is absent in Type I pyrethroids (e.g., permethrin) and present in Type II (e.g., 

deltamethrin). The absence/presence of the α-cyano group is correlated with length of time 

the sodium channel is inactivated (-CN=shorter; +CN=longer) which in turn corresponds with 

the two distinct toxicity syndromes (-CN=T syndrome; +CN=CS syndrome). Two pyrethroids, 

esfenvalerate and fenpropathrin, though structurally similar to Type II pyrethroids, are 

considered mixed Type I/II because they demonstrate properties of both groups during in vitro

and in vivo evaluations. As noted above, this screening level assessment demonstrates that the 

cumulative estimated risk to pyrethrins and pyrethroids is not a concern. In the future, if the 
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Agency determines that a more refined cumulative assessment is appropriate, the Agency may 

consider evaluating the cumulative risk to the Type I and Type II pyrethroids separately.

3.0 Cumulative Assessment Group (CAG)

As part of the cumulative risk assessment process, it is important to determine which chemicals 

from the CMG should be included in the quantification of cumulative risk. Therefore, a subset 

of the CMG called the CAG is identified which excludes those CMG members with minimal toxic 

contribution to the cumulative hazard or those with limited uses or minor exposure pathways 

or routes. 

For the pyrethroid CAG, those chemicals which pose very low risk were considered unlikely 

contributors to cumulative risk and were precluded from the assessment. Criteria for not 

including CMG chemicals in the CAG include:

• Pyrethroids with low hazard potential for the common mechanism endpoint(s) were 

excluded. Specifically, tetramethrin and sumithrin were excluded due to no observed 

adverse effects at 5000 mg/kg in a specially designed functional observational battery 

for evaluating pyrethroid toxicity syndromes in the rat.

• For the dietary exposure assessment, pyrethroids without any residues in any crop in 

the Pesticide Data Program monitoring data were not included in the dietary 

assessment;

• For the residential exposure assessment, the Agency focused on only those residential 

uses that have potential for significant exposure (turf, pets, gardens, and indoor uses). 

Only pyrethroids with these residential uses were included in the CAG and assessed in 

the residential part of the CAG. In addition, those pyrethroids with residential uses that 

do not have a potential for significant exposure or have an insignificant amount of use 

(e.g., such as metofluthrin which is only registered for use in personal insect repellent 

systems) were considered minor contributors to the residential part of the CRA and 

therefore not included in the CAG.

A total of 15 synthetic pyrethroids and the naturally occurring pyrethrins (including pyrethrins I 

and pyrethrins II) are included in the CAG and are presented. Table 3.0 contains a list of 

pyrethroids registered with the Agency, highlighting those that were included in the CAG and 

offering brief explanations for those that were not. 
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Table 3.0. Pyrethroid Cumulative Assessment Group (CAG)

Chemical Name1 Type

Registrations PDP Data

Included in Screening Level 

Pyrethroid CRA/Comments Food Use 3

Registration

Non-food Use 

Registration 

(e.g. Residential 

Uses)?

PDP 

Data

PDP 

Detects

Allethrin I X X X X Included

Bifenthrin I X X X X Included

Cyfluthrin II X X X X Included

Cyhalothrin II X X X X Included

Cypermethrin II X X X X Included

Cyphenothrin I X X X Included

Deltamethrin II X X X X Included – index chemical

Fenpropathrin I/II X - X X Included

Fenvalerate2

/Esfenvalerate I/II X X X X Included

Flucythrinate II X X No PDP detects; not included 

in CAG

Fluvalinate II X X X X Included

Imiprothrin I - X X X Included

Metofluthrin I - X

No food use registrations and 

does not have major 

residential use registrations; 

not included in CAG

Permethrin I X X X X Included

Prallethrin I X X X X Included

Pyrethrins I X X X X Included

Resmethrin I X X X X Included

Sumithrin I X X X X

Did not elicit a toxic response 

consistent with the common 

mechanism at limit dose of 

2000 mg/kg; not included in 

CAG

Tefluthrin II X - X -

No PDP detects and no 

residential uses; not included 

in CAG

Tetramethrin II X X X X

Did not elicit a toxic response 

consistent with the common 

mechanism at limit dose of 

2000 mg/kg; not included in 

CAG

Tralomethrin4 II X X X - Included 1 Refers to all isomeric variations. 2 The registration for Fenvalerate has recently been cancelled and therefore future uses are not expected. 3 Pyrethroids that do not have registered uses were not included in the CAG (i.e., acrinathrin, barthrin, bioethanomethrin, 

cismethrin, cyclethrin, cycloprothrin, dimefluthrin, dimethrin, empenthrin, fenfluthrin, furethrin, profluthrin, 

pyresmethrin, terallethrin, and transfluthrin). 4 Due to recent cancellation of uses (http://www.federalregister.gov/articles/2010/11/17/2010-28823/tralomethrinnotice-of-receipt-of-request-to-voluntarily-cancel-pesticide-registrations), tralomethrin is included in the CAG, but will 

not be assessed as part of the cumulative risk assessment.
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4.0 Hazard Assessment/Characterization

As described above, the Agency has designated a CMG for the pyrethroids (USEPA 2011a) based 

on the shared structural similarities and their shared ability to alter VGSCs. Further, the Agency 

has determined which members of the CMG should be quantitatively included in the 

cumulative risk assessment by designating the CAG with an interim decision to include both 

Type I and Type IIs together in a single CAG. Because at this time PBPK models are only 

available for a small number of pyrethroids (Permethrin - Tornero-Velez et. al. 2007; 

Deltamethrin - Godin et. al. 2010), this screening level cumulative assessment 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 CAG is determined. One member of the 

CAG is selected as the index chemical which is used as the point of reference for standardizing 

neurobehavioral potency of the other members of the CAG. In the case of the screening level 

pyrethroid CRA, deltamethrin is being used as the index chemical.

The following discussion describes the Agency’s approach for: 

• Determination of the appropriate toxicity data for consideration in the CRA

• Determination of relative potency factors for each chemical in the CAG;

• Selection of the index chemical used as the point of reference to standardize the 

potency of each pyrethroid/pyrethrins;

• Establishment of a point of departure used to estimate potential risk for the oral, 

dermal, and inhalation routes of exposure; and

• Identification of the intra-species, inter-species, and FQPA safety factors

4.1 Endpoints and Toxicology Studies

As stated previously, relative potency for cumulative risk assessments should be based, 

whenever possible, on data from the same species and sex to provide a uniform measure of 

relative potency among the cumulative assessment group (USEPA 2002). The following section 

describes the studies evaluated and scientific factors considered in establishing a uniform 

measure of potency.

4.1.1 Establishing a Uniform Measure of Toxicity

4.1.1.1 Common Mechanism Endpoint

In cumulative risk assessment, the focus of the hazard characterization is on the common 

mechanism effect(s) and relevant duration of exposure. Use of in vivo data from a precursor 

event is preferred over apical endpoints. However, in the case of pyrethroids, practical 

methods for evaluating pyrethroid effects on VGSC in vivo are not currently available (Shafer et. 

al. 2005). Additionally, in vivo biomarkers of toxicity are not available for use in cumulative risk 

assessment. Data from in vitro microelectro array studies (Losa et. al. 2009; Cao et. al. 2011a)

using intact neuronal systems could potentially be used to consider relative potency. However, 
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using such in vitro studies in the absence of pharmacokinetic data and/or PBPK models to 

evaluate internal dosimetry of in vitro measures is problematic and would introduce significant 

uncertainty into the CRA. As such, the Agency has used these in vitro studies as qualitative 

characterization (See Hazard Characterization, Section 8.1) but not for quantitative relative 

potency calculations.

As recently reviewed (Wolansky and Harrill 2008) and discussed in OPP’s CMG science policy 

paper (USEPA 2011a), many studies have shown that behavioral responses, particularly 

measured in the rat, can be used as sensitive indicators of pyrethroid toxicity. Table 4.1.1.1 

provides a summary of several early behavioral studies with pyrethroids. 

Table 4.1.1.1. Behavioral Characterization of Pyrethroid Toxicity of Pyrethroids Included in the 

Proposed CMG from Peer-Reviewed Literature

Pyrethroid Verschoyle and 

Aldridge (1980)

Lawrence and 

Casida (1982)

Gammon et. al.

(1981)

Allethrin; S-Bioallethrin T I I

Permethrin T I I

Resmethrin T I I

Fenpropathrin CS/T I/II I/II

Esfenvalerate CS II II

Cypermethrin CS II II

Deltamethrin CS II II

More contemporary studies were designed to detect behavioral changes at a broad range of 

doses including both lower doses as well as high-doses. Some of these studies include 

evaluation of motor activity, coordination, neuromuscular response, tremors, acoustic startle 

response, learning and memory, somatosensory response, social/sexual interactions and 

behavior to handling, and the functional observational battery (FOB) (McDaniel and Moser 

1993; Sheets et. al. 1994; Soderlund et. al. 2002(review); Wolansky et. al. 2006; Raffaele et. al. 

2008; Wolansky and Harrill 2008(review); Breckenridge et. al. 2009). Given the lack of an in 

vivo biomarker for VGSC interaction, measures of behavior in laboratory animal studies are 

therefore considered appropriate endpoints for extrapolating risk to humans in the pyrethroid 

screening cumulative risk assessment.

The primary target organ of pyrethroids is the brain and therefore brain tissue concentration 

could potentially be a useful indicator of internal exposure. However, few studies have 

examined the brain concentration of pyrethroids and of these, only a small number of 

pyrethroids are represented (Deltamethrin (Anadón et. al. 1991; Sheets et. al. 1994; Kim et. al. 

2008); resmethrin (White et. al. 1976; Brodie 1983); and permethrin (Khanna et. al. 2002)). 

Similar limitations prevent the use of blood plasma concentrations as an indicator of toxicity. 

The Agency is aware of efforts by the Council for the Advancement of Pyrethroid Human Risk 

Assessment (CAPHRA), a group of pyrethroid registrants and product formulators which is

currently developing PBPK models for additional pyrethroids. As those research efforts 

progress, the Agency may, if appropriate, consider using such data in future revisions to the
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CRA. However, in this absence of measures of internal dose for a sufficient number of 

pyrethroids, the Agency will use administered dose as the metric for estimating relative 

potency. 

4.1.1.2 Experimental Laboratory Studies with Behavioral Measures

The Agency has evaluated multiple sources of data for potential endpoints, including guideline 

and non-guideline studies submitted for pesticide registration (Table 4.1.1.2), data developed 

by EPA’s Office of Research and Development (ORD), and other literature data. Under FIFRA, 

toxicology studies in various species (e.g., dog, mouse, rat and rabbit) are submitted to EPA. 

For the pyrethroids, toxicology studies in the rat provided the most extensive behavioral data 

for all routes and both sexes. Studies in the dog often provide sensitive endpoints (particularly 

through the observation of tremors) for use in single chemical, aggregate risk assessment. 

However, studies in the rat are the focus for cumulative risk assessment as rats are most often 

evaluated in neurotoxicity studies where a broad array of neurobehaviors are evaluated. 

Specifically, rat neurotoxicity studies may include measures of behavior or response to stimuli 

such as motor activity, auditory startle response, grip strength, righting ability, in-cage and 

handling observations and physiological parameters such as body temperature or catalepsy,

and, are therefore more likely to detect adverse responses to pyrethroids compared to other 

guideline studies. Appendix 1 (Toxicity Data for Screening Level Cumulative Risk Assessment)

provides a summary of guideline studies considered as sources of data for estimating relative 

potency the CRA. Noteworthy literature sources of behavioral studies with pyrethroids include 

an acute motor activity study (Wolansky et. al. (2006) and two special FOB studies (Herberth 

(2010) and Weiner et. al. (2009)), which are discussed in detail below.

Table 4.1.1.2. Guideline Studies Evaluated for Potential Cumulative Endpoints

Guideline # Type of Study

870.3100 90-day Toxicity Study in Rodents

870.3150 90-day Toxicity Study in Non-Rodents

870.3200 21/28 Dermal Toxicity 

870.3465 90-day Inhalation Toxicity

870.3700 Prenatal Developmental Toxicity Study

870.3800 Reproduction and Fertility Effects

870.4100 Chronic Toxicity

870.4200 Carcinogenicity

870.4300 Combined Toxicity/Carcinogenicity

870.6200 Neurotoxicity Screening Batter

870.6300 Developmental Neurotoxicity Study
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4.1.1.3 Scientific Considerations in Evaluating Experimental Animal Studies

As noted above, one of the most important components in cumulative hazard assessment is 

establishing a uniform measure of potency such that the relative rank of each pesticide can be 

confidently evaluated. There are properties of pyrethroids that must be taken into account 

when evaluating existing experimental laboratory studies. 

• Duration of Exposure: The toxicokinetic and toxicodynamic properties of pyrethroids 

create a narrow window for capturing peak neurotoxic effects; peak effects may last 

from only a few minutes to over an hour. Pyrethroids are acutely toxic and do not 

increase in potency with repeated dosing, as demonstrated in guideline studies. The 

rapid metabolism of pyrethroids is related to the acute nature of the neurotoxic effects. 

Oxidative and hydrolytic enzymes metabolize pyrethroids quickly rendering these 

pesticides inactive following in vivo exposure (Anand et. al. 2006). For example, plasma 

half-lives following neurotoxic doses are generally 9-15 hours; that is it takes 

approximately 9-15 hours for the plasma concentration of the pyrethroid to be reduced 

by 50%. Brain tissue half-lives may be slightly longer, depending on the pyrethroid 

(Anadón et. al. 1991; Anadón et. al. 1996; Anand et. al. 2006; Kim et. al. 2008). Plasma 

half-lives generally decrease in a dose-dependent manner such that lower doses 

generally have significantly shorter half-lives (< 6 hours) (Kim et. al. 2008). Therefore, 

human exposures which are expected to be orders of magnitude less than the 

experimental animal studies would be expected to be considerably shorter still. 

Because of the rapid clearance rates, pyrethroid concentrations do not accumulate in 

tissues following subsequent exposures. Thus, given the short temporal nature of 

pyrethroids, the CRA focuses on acute (24 hour), single dosing studies and involves 

exposure periods of only 24 hours.

• Timing of behavioral measures: The determination of the time-to-peak for behavioral 

effects and/or target tissue concentration is a critical component of study design for 

pyrethroids. As shown in Figure 4.1.1.3, levels of deltamethrin, a Type II pyrethroid, in 

brain tissue peaking 2-3 hours after a single oral bolus dose of 3 mg/kg (i.e., minimally

neurotoxic effects), followed by a rapid decrease in concentration (Godin et. al. 2010). 

In general, brain concentration time course typifies the progression of neurotoxic signs 

in mammalian species, which appear within 1 hour of oral exposure, peak within 4-8 

hours, and recover in 12–48 hours (Wolansky and Harrill 2008). If the animals are not 

examined near these peak tissue concentrations, the potency of the pyrethroid may be 

underestimated. As such, for purposes of determining relative potency, the Agency has 

focused on studies which measured effects at or near the peak time of effect.
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Figure 4.1.1.3. Model simulation and time course of brain concentration of deltamethrin 

after an oral dose. Dashed line represents the best-fit curve to the data points. Adapted 

from Godin, DeVito et al. (2010).

• Gavage dosing vs. Feeding: Longer term repetitive dosing studies are typically 

conducted using dietary administration whereas acute, single dose studies tend to use 

gavage dosing. The extended exposure period (i.e., over 12 hours during feeding) of 

dietary administration compared to the bolus dose in capsule and acute studies, results 

in much lower peak plasma/brain concentrations. As a result, neurotoxicity consistent 

with the pyrethroid mode of action (MOA) is more commonly observed in acute, gavage

studies in rats; thus, such gavage studies are being used in the CRA. 

• Vehicle & Volume in Gavage Dosing: Variations in laboratory protocols such as dosing 

vehicle and volume, lead to altered toxicokinetics and inconsistent results. For example, 

the Effective Dose (ED50) for deltamethrin in an acute oral motor activity study was 5.1 

mg/kg when administered with corn oil, but > 1000 mg/kg when carboxymethylcellulose 

was used as the vehicle (Crofton et. al. 1995). In another acute oral study, bifenthrin 

was administered at 1 ml/kg or 5 ml/kg in corn oil to rats. The higher dose volume 

decreased potency by 50% as determined by motor activity and other observational 

assays (Wolansky et. al. 2007). Many of the guideline studies and those available in the 

literature contain such variations making cross-study comparisons of pyrethroid potency 

difficult. This is shown in Table 4.1.1.3 where the vehicle and volume vary considerably 

across studies making quantitative comparisons challenging. In contrast to the guideline 

studies, two studies - Wolansky et al. (2006) and the special WIL FOB (Herberth 2010; 

Weiner et. al. 2009) - used a consistent (within study) vehicle and volume for each 

chemical evaluated. Specifically, Wolansky used 1 ml/kg corn oil for assessing motor 

activity in 11 pyrethroids and the WIL FOB study used 5 ml/kg corn oil in the evaluation 

of 17 pyrethroids; thus making the results across multiple pyrethroids comparable 

within each of these studies. 
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Table 4.1.1.3. Guideline Acute Oral Gavage Studies in the Rat. 

Pyrethroid1 MRID Vehicle; Volume

Allethrin; S-Bioallethrin 44517801 (1% CMC; 10 ml/kg)

Bifenthrin 44862102 No vehicle

Cyfluthrin, betacyfluthrin 00157802 2% aqueous cremophor EL

lambda-cyhalothrin 44861510 Corn oil; 10ml/kg

Cypermethrin; zetacypermethrin 

43152001 Corn Oil, 5% solution, total 

volume varied by dose group

44962201 No Vehicle

Deltamethrin 44557901 Corn Oil; 5 ml/kg

Esfenvalerate 45228301 (Corn Oil; 10 ml/kg)

Fenpropathrin 473745605 Corn oil, 5 mL/kg

Fluvalinate, tau 43433901 Corn oil, 10 ml/kg

Permethrin 43046301 Corn Oil, 1-30 ml/kg

Pyrethrins 42925801 Corn oil vehicle 5-10% pyrethrins,

total volume varied by dose group 1

This table captures all of the Guideline acute neurotoxicity studies available for the pyrethroids 

included in the CAG. Cyphenothrin, imiprothrin, and prallethrin, although included in the CAG, do 

not have acute neurotoxicity studies.

• Consistent evaluation of behavioral endpoints: There is considerable variability among 

laboratories in scoring procedures used in behavioral measures thus making across 

laboratory comparisons of behavioral findings challenging. Moreover, assessing rat 

behavior can be challenging and is often subjective. Therefore, it is important for 

individuals doing such measurements in the laboratory to be well-trained. Thus, given 

the inter-laboratory variability inherent in behavioral studies, it is desirable for relative 

potency to be based, to the extent possible, on data collected from a single laboratory. 

4.1.1.4 Selection of Critical Study for Estimating Relative Potency

Section 4.1.1.3 described desirable characteristics of experimental laboratory studies for use in 

establishing a uniform measure of potency for the pyrethroids. Based on a review of the 

available rat studies, the Agency has concluded that guideline studies submitted for pesticide 

registration do not provide sufficient data for establishing relative potency. As shown in table 

4.1.1.3, the vehicle and volume used in gavage dosing vary considerably among pyrethroids 

thus making quantitative comparisons difficult. Moreover, some of these studies do not 

measure behavioral endpoints at or near the time of peak effect and the behavioral scoring 

procedures used in these studies vary considerably among laboratories. Similarly, the 

differences in study design among many literature studies limits their usefulness for quantifying 

relative potency across a large number of pyrethroids. 

There are, however, two recently conducted large literature studies available which provide 

acute oral neurobehavioral data appropriate for establishing a uniform measure of potency.
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• Wolansky et. al. (2006) evaluated 11 pyrethroids after a single oral dose using a 

common vehicle (corn oil) and volume (1 mL/kg). The Wolansky study measured motor 

activity at the time of peak effect after exposure. All 12 chemicals were evaluated on 

the same instrument by the same scientist. Dose-response relationships were 

determined using 6-11 doses per pyrethroid and 3-18 rats per dose group, minimizing 

variability and increasing the confidence in the benchmark dose (BMD) estimates 

determined from this study. Increasing exposure to a pyrethroid generally decreased 

the rat’s ability to navigate through the maze and therefore reduced motor activity. 

Motor activity is considered an apical endpoint because it measures alterations in the 

activity level of an intact rat. However, altered movement patterns can result from any 

number of adverse outcome pathways resulting in general malaise or altered energy 

levels, and does not necessarily measure the targeted mechanism of action (i.e., 

interaction with the VGSC). Although the Wolansky study provides a potential data 

source for a uniform measure of potency, because of the lack of specific relevance to 

the common mechanism of action, this study is less desirable for the CRA. 

• Two special FOB studies conducted by the WIL laboratory and supported by pesticide 

registrants evaluated 17 pyrethroids in a comprehensive FOB. Twelve were evaluated in 

an initial study (Weiner et. al. 2009) and 5 more in a second study2 (Herberth 2010). 

The special FOB WIL study considered behavioral changes at the time of peak effect, 

using a common vehicle (corn oil) and volume (5 mL/kg). Each pyrethroid was evaluated 

by the same technicians who were specially trained to recognize pyrethroid toxicity. 

Therefore potency values generated in the Weiner et. al. (2009) and Herberth (2010) 

studies are directly comparable between studies since a conservative and uniform 

measure of toxicity was employed in the two special FOB WIL studies. These special 

studies examined many behaviors, including key ones for evaluating neurotoxicity 

specific to pyrethroids. Unlike motor activity which measures general behavior 

patterns, such as was measured in the Wolansky study, the FOB measures behaviors 

that are associated with the central and peripheral nervous system. For this reason, the 

specially designed FOB is more reflective of toxicity directly related to the pyrethroid 

mode of action and therefore, more appropriate for defining relative potencies related 

to pyrethroid cumulative risk. It is notable that the key parameters identified in the WIL 

FOB study are directly relevant to the Type I and Type II syndromes. Specifically, 

hyperthermia tremors, and clonus are important in Type I pyrethroids and hypothermia, 

salivation, and mobility are key for Type II pyrethroids (see Section 4.2 and 4.3 below). 

Given the strengths of the study design of the special FOB WIL study and the relevance of 

behavioral measures to pyrethroid toxicology, the Agency has determined that for the CRA, 

the special FOB WIL study provides the most robust source of data for the cumulative risk 

assessment. The Agency has used this study to derive RPFs and PoDs for the index chemical; 

the dose-response analysis is discussed in detail below.

 2 Throughout the remainder of this document, the Weiner et al (2009) and Herberth (2010) studies conducted at 

the WIL laboratories will be collectively referred to as the “WIL study.”
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4.2 WIL FOB Study & Determining a Uniform Measure of Potency

4.2.1 Introduction 

As described in the guidance document for cumulative risk assessment (USEPA 2002), doseresponse modeling is preferred over the use of NOAEL/LOAELs (i.e., no- or lowest-observedadverse-effect-levels) for determining relative toxicity potency. NOAELs and LOAELs can be 

greatly influenced by study dose selection and dose spacing and thus do not necessarily reflect 

the relationship between dose and response for a given chemical, nor do they reflect a uniform 

response across different chemicals. In the present analysis, benchmark dose (BMD) modeling 

has been used to determine the toxic potency of the pyrethroids, providing a constant 

threshold of toxicity for each pyrethroid and more uniform comparisons. EPA’s draft BMD 

guidance (USEPA 2000) suggests that the central estimate on the BMD provides an appropriate 

measure for comparing chemical potency (i.e., RPF) and that the lower limit on the central 

estimate (i.e., BMDL) provides an appropriate measure for extrapolating risk (i.e., PoD for the 

index chemical in a cumulative risk assessment). The point of comparison for four of the least 

potent pyrethroids (cyphenothrin, d-allethrin, imiprothrin, and prallethrin) was based on 

selecting a dose used in the WIL FOB study (see Section 4.2.5.1 below). 

The following sections provide a discussion of the WIL study and how the data from this study 

have been used by OPP to estimate relative potency for the oral route of exposure. 

The WIL study is the most appropriate study available for determination of the pyrethroid 

potency because it reflects acute toxicity at the level of the common mechanism (i.e. 

neurotoxicity), standardizes testing conditions for a large number of pyrethroids (i.e. strain, 

vehicle, dosing volume), and reflects the most relevant route (oral) and duration (acute) of 

exposure. Furthermore, the WIL dosing levels are appropriate for determination of PoDs for 

this cumulative risk assessment. As indicated in the previous section, pyrethroids are rapidly 

metabolized in vivo by oxidative and hydrolytic enzymes. Doses that are sufficiently high 

enough to cause neurotoxicity overwhelm these clearance mechanisms and interfere with the 

proper functioning of the sodium channels. Human exposures are expected to be much lower, 

significantly less likely to saturate the metabolic processes, and therefore less likely to result in 

neurotoxicity. 

As previously noted, the WIL study is a FOB study including numerous assays designed to 

quantify neurotoxicity caused by pyrethroids. The FOB is a series of evaluations to determine 

gross neurological function in the animal. In general, observations and short-duration tests are 

administered to determine effects on the autonomic, motor, and sensory systems. These 

simple tests take approximately 5-10 minutes after which rats are returned to their home cage. 

The FOB is a noninvasive procedure designed to detect gross functional deficits resulting from 

exposure to chemicals and to quantify neurotoxic effects. In the WIL study, observations 

included home cage handling, open field, sensory, neuromuscular, and physiological

parameters, conducted at the time of peak effect (2 to 8 hours post-dose). In many cases, the 
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FOB measures behaviors that are closely associated with toxicity related to the central and 

peripheral nervous system. Studies have demonstrated the ability of a FOB to describe and 

differentiate the known pyrethroid syndromes (McDaniel and Moser 1993; Weiner et. al. 2009). 

For this reason, the FOB is more reflective of a toxicity directly related to the pyrethroid mode 

of action and therefore, more appropriate for defining relative potencies related to pyrethroid 

cumulative risk.

4.2.2 WIL Study Design

Pyrethroids were administered as a single bolus dose via oral gavage using corn oil as the 

vehicle at 5 ml/kg. Ten adult male Crl:CD(SD)IGS BR rats were used per dose group. Numerous 

oral Guideline and literature studies conducted in both males and female rats indicate similar 

neurotoxic responses between the sexes, therefore the WIL study was restricted to a single sex.

FOB measurements were taken at the pyrethroids respective time to peak effect for adverse 

neurological behaviors (as determined in previous pilot studies). Table 4.2.2 provides a 

summary of pyrethroids examined in the WIL study.

Table 4.2.2. Pyrethroids Examined at the WIL Laboratory

Pyrethroid Doses (mg/kg) Time- to-peak-effect 

(hours)

D-Allethrinb 200, 320, 500 2

S-Bioallethrina 150, 200, 300 2

Bifenthrina 40, 55 8

Beta-cyfluthrina 12.5, 25, 45 2

Lambda-cyhalothrina 10, 20 4

Cyphenothrin b 60, 100, 160 2

Cypermethrina 65, 100, 150 4

Deltamethrina 12.5, 25, 35 4

Esfenvaleratea 15, 25, 50 8

Fenpropathrina 15, 30 2

Imiprothrin b 900, 1200, 1500 2

Permethrina 200, 250 4

Prallethrin b 150, 250, 400 2

Pyrethrins 400, 800 4

Resmethrina 350, 500, 750 4

Tefluthrina 10, 15 8 a

(Weiner et. al. 2009) b

(Herberth 2010)

4.2.3 Results from the WIL & Severity Scoring

The Agency has reviewed both Weiner et. al. (2009) and Herberth (2010); data evaluation 

records (DERs) for these studies can be found as Appendices 2 and 3, respectively. In brief, a

total of 46 neurobehavioral parameters were evaluated including home cage, handling, open 

field, sensory, neuromuscular and physiological observations. In the original (Weiner et al, 

2009) study, the FOB data for 11 pyrethroids in addition to pyrethrins were analyzed using 

principle component analysis to determine dissimilarity/similarity across endpoints and 
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treatments (Breckenridge et. al. 2009). These pyrethroids were segregated into two composite 

factors, T including the Type I pyrethroids, and CS including the Type II pyrethroids. This 

analysis revealed that three endpoints sufficiently described each factor: T was comprised of 

hyperthermia, tremors, and clonic convulsions, and CS included hypothermia, salivation, and 

mobility. These results agreed well with the substantial literature describing the differential 

toxicity of Types I and II pyrethroids (Verschoyle and Aldridge 1980; Lawrence and Casida 1982; 

Gray 1985; Vijverberg and Bercken 1990). Thus from the 46 endpoints measured, there were a 

total of five endpoints accounting for the majority of the dose-response relationships and were 

capable of differentiating Type I and Type II pyrethroids. This was especially true for the 

pesticides showing clear differential effects whereas mixed type pyrethroids (e.g.,

esfenvalerate) showed characteristics of both syndromes. 

For purposes of dose-response analysis for the CRA, the raw data from the WIL study for the 

five endpoints and 12 pesticides identified in the principle component analysis were converted

using a severity scoring approach. Moser and colleagues have developed a procedure for 

normalizing individual data for all measures to a single 1-to-4 scale, where ‘1’ reflects what was 

observed in control rats, and ‘4’ reflects a rare occurrence in control rats. This approach has 

been used successfully for delineating profiles of effects of different classes of chemicals 

including pyrethroids (Moser 1991; McDaniel and Moser 1993; Moser et. al. 1995; Moser et. al. 

1997). 

Of the endpoints examined, only body temperature was a continuous variable; a continuous 

variable is one where any value may be recorded, including fractions, with no clear cut or sharp 

breaks between possible values. Tremors and convulsions are ordinal variables; an ordinal 

variable is a variable whose values are not numerical but have an ordering (e.g. low, medium, 

and high). Body temperature was determined at the time-to-peak-effect. Muscle tremors and 

clonic convulsions were observed in both the home cage and open field; the observation with 

the most severe effect was used for this analysis. For example, if muscle tremors were 

observed in both home cage and open field scenarios, but were more severe in the home cage, 

the severity score for the home cage tremors was used for the calculation of the severity score. 

Clonic convulsions were scored in a similar fashion. Essentially, continuous data (body 

temperature) were converted on the basis of the control group mean ± multiples of standard 

deviation, and categorical data were converted based on severity of the original scoring criteria 

(Table 4.2.3). These scores were then summed for each animal to derive the T and CS

composite severity scores. 

Each animal was assigned a score from 3 to 12 for both T and CS. For example, if an animal did 

not demonstrate a dose-response in any of the 5 critical assays, it would have received a score 

of 3 for the T domain (1+1+1 = 3 for each T endpoint) and a 3 for the CS domain (1+1+1=3 for 

each CS endpoint). However, if it demonstrated a dose-response for hyperthermia, tremors,

and/or clonus, it would have received a score of up to 12 (depending on the severity of the 3 

endpoint responses) for T, and a score of 3 for CS (due to the lack of response in the 

hypothermia, salivation, and mobility assays). This example would be characteristic of a Type I 

pyrethroid. Conversely, an animal given a Type II pyrethroid would most likely have received a 
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score of 3 for T and up to 12 for CS. A mixed-type pyrethroid (e.g. fenpropathrin) would have 

demonstrated a dose response in tests for both the T and CS domains, resulting in T and CS 

scores between 4 and 12. 

Table 4.2.3. Conversion of Individual Data to Severity Scores to be Summed into the T or CS Domains.

Endpoint Severity conversion Score Domain

Body temperature; 

hyperthermia

Within X to X+SD

Between (X+SD) and (X+1.5SD)

Between (X+1.5SD) and (X+2SD)

>(X+2SD)

1

2

3

4

T

Tremors None

Slight

Moderately coarse

Markedly to extremely coarse

1

2

3

4

T

Clonic Convulsions Absent

Myoclonus 

1

4 T

Body temperature; 

hypothermia

Within X to X-SD

Between (X-SD) and (X-1.5SD)

Between (X-1.5SD) and (X-2SD)

>(X-2SD)

1

2

3

4

CS

Salivation None

Slight

Severe

Profuse

1

2

3

4

CS

Mobility Normal

Slightly impaired

Moderately impaired

Totally impaired

1

2

3

4

CS

4.2.4 Variable Coding

As described in section 4.2.3, the principal variables were utilized to calculate composite 

severity scores. These variables, T and CS, were defined as composites of five outputs measured 

in the WIL FOB study as follows:

• body temperature: T (hyperthermia) and CS (hypothermia)

• tremors: T

• clonic convulsions: T

• excessive salivation: CS

• impaired mobility: CS

Continuous data (body temperature) were converted on the basis of the control group mean ± 

multiples of standard deviation, and categorical data were converted based on severity of the 

original scoring criteria. Before the composite indices were constructed, body temperature was 

re-coded to 2 categorical variables, T and CS. Hyperthermia flags an increase, while 

hypothermia flags a decrease in body temperature. Each variable is based on the difference 
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between an observation and the concurrent control means. The data were analyzed in terms of 

pooled variance of all of the control groups, i.e. the overall control standard deviation. 

The resulting T and CS variables were dichotomized as 1 or 0; 1 if T > 4 or CS > 4, and 0 for 

individuals with scores of 3 or 4 (i.e., had little or no response to any of the 3 endpoints). The 

incidents of scores that were assigned a value of 1 were then plotted against administered dose 

to achieve a dose-response curve from which the BMDs were calculated. For example, if 4 out 

of 10 animals tested achieved scores > 4, the fraction affected for the given dose-group would 

be 0.4. FOB scores used in the determination of BMD estimates can be found in Appendix 4.

4.2.5 Dose-Response Modeling and Derivation of Benchmark Dose (BMD) 

Estimates for Dichotomous Data 

Before dose-response modeling of the 12 pesticides in Weiner et. al. (2009), each data set was 

tested for significant trend (e.g., Chi-Squared Test for Trend in Proportions; Tukey’s Trend Test). 

Only if a trend was statistically significant was a BMD computed. Statistical trends were limited 

to T for Type I pyrethroids and CS for Type II pyrethroids, that is, trends for T were not 

statistically significant for Type II pyrethroids and trends were for CS were not significant for 

Type I pyrethroids. While all pyrethroids could have resulted in significant trends for both the T 

and CS variables, this only occurred with the mixed type pyrethroid esfenvalerate. The Agency 

used the trend (T or CS) that resulted in the lowest BMD estimate (i.e. CS) for determining RPFs. 

The BMDs were modeled using a model averaging approach described in Wheeler and Bailer 

(2007). Model averaging is a statistical technique that allows for the incorporation of model 

uncertainty in quantitative risk estimation. The technique averages BMD dose estimates from 

several models using data derived from dichotomous dose-response experiments. This 

calculation is accomplished through a weighted average of multiple dose-response functions 

considered in the analysis, where the weights reflect the relation of the fitted function to the 

observed experimental data. The dose-response models utilized include the following: logistic, 

log-logistic, gamma, multi-stage, probit, log-probit, quantal-linear, quantal-quadratic and 

Weibull. Due to the limited doses and small samples sizes, this technique was considered more 

appropriate to account for model uncertainty compared to the Agency’s Benchmark Dose 

Software (BMDS) that is more commonly used to determine BMDs for risk assessment. This 

model averaging approach has been used in other studies (Benford et. al. 2010).

The BMD lower bound (BMDL) for the index chemical (deltamethrin) was computed through a 

parametric bootstrap technique. The BMDL and standard deviation of the natural logtransformed BMD were based on 4999 bootstrap samples. The confidence limits for the 

relative potency ratios were based on 500 random samples from the appropriate distributions. 

A 20% change from controls was selected as the BMD threshold (i.e., BMD20). Based on data 

variance and sample size, the BMD20 was the most conservative estimate able to predict a 

significant change from control values. Behavioral data, such as the WIL FOB data, tends to 

have a higher level of variability compared to other biomarkers of toxicity. The BMD20 used in 
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this analysis is consistent with threshold levels used in other pyrethroid behavior studies 

(Wolansky et. al. 2006; Raffaele et. al. 2008). 

The model algorithms along with detailed results of model outputs and graphs for each 

pyrethroid are presented in Appendix 5: BMDs for T and CS from WIL FOB Study, April 1, 2009.

Although severity scores were determined for the pyrethrins and the results analyzed by BMDS 

software, the lack of a dose-response precluded the model from fitting a curve for either T or 

CS variables (Table 4.2.5). Because of the flat response across the dose groups and effects 

which are comparable to the toxicity observed in the other pyrethroids at their BMD20s, the 

Agency is using 800 mg/kg (the highest dose tested) as the point of comparison for pyrethrins. 

4.2.5.1 Points of Comparisons for Pyrethroids Studied in Herberth (2010)

As mentioned in section 4.2.1, two FOB studies were conducted at the WIL laboratories; the 

first described in Weiner et. al., (2009) included 11 pyrethroids in addition to the pyrethrins, 

and the second described in Herberth (2010) included an additional 7 pyrethroids; 

cyphenothrin, imiprothrin, metofluthrin, prallethrin, sumithrin, tetramethrin, and d-allethrin. 

An essential part of any CRA is defining an endpoint for the purpose of a uniform measure of 

toxicity. Although 46 behaviors were observed in the FOB study, the Agency is using the five

parameters identified in the principle component analysis (Breckenridge et. al. 2009): body 

temperature, tremors, clonic convulsions, salivation, and mobility, to determine relative 

potency factors for purposes of the CRA. Furthermore, Type I and Type II pyrethroids can be 

separated based on the observation of hyperthermia, tremors, or clonus (Type I) or 

hypothermia, salivation, and mobility (Type II). Since the 7 pyrethroids in the Herbert (2010) 

study are all structurally Type I pyrethroids, alterations in body temperature, tremors and 

clonus can be expected at doses capable of inducing toxicity. Two pyrethroids from this study, 

tetramethrin and sumithrin, did not demonstrate toxicity at doses of 5,000 mg/kg and so were 

not included in the CAG. Due to minimal use and exposure, metofluthrin was also excluded 

from the CRA. The remaining four pyrethroids, cyphenothrin, imiprothrin, prallethrin, and dallethrin, were included in the CAG and required RPFs. These four pyrethroids are among the 

least potent members of this class. Because of that, and consistent with the screening nature 

of this assessment, the Agency has selected to use the defined doses instead of completing a 

refined BMD analysis. In the future, if appropriate, the Agency may determine BMD20s for 

these. The basis for OPP’s points of comparison is described below.

Imiprothrin: Rats were administered 900, 1200 or 1500 mg/kg. Moderate to severe tremors 

were observed in all three dose groups. Severe salivation was noted in one male in the highdose group that had tremors. No other clinical findings were noted at any dose. In the open 

field, 1 rat in the 1200 mg/kg group exhibited slightly impaired mobility, ataxia, moderately 

coarse tremors and considerable gait impairment. Clonic convulsions were noted for 1 rat in 

the 900 mg/kg group. In a pilot study, there were no adverse effects noted at any of the 

administered doses of 300, 500, or 800 mg/kg. Based on the observation of moderate tremors 

in a single rat, the Agency conservatively, selected a lower dose level, 750 mg/kg, for the point 

of comparison for imiprothrin in the CRA.
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Table 4.2.5.1a. FOB Effects Observed in Imiprothrin-Treated Rats in WIL Study (Herberth 2010)

Observations 900 mg/kg 1200 mg/kg 1500 mg/kg

Clinical a Tremors (#rats/#incidences) 1/1 3/3 3/3

Salivation 0 0 1/1

Convulsions 1 0 0

Open Field Mobility & Tremor 0 1 0 a

Clinical observations were made prior to FOB testing. Observations in all other scenarios were made at the time to peak effect

Prallethrin: Rats were administered 150, 250, or 400 mg/kg. Moderate tremors and body 

twitches were noted prior to the 2-hour FOB assessment for 1 male each in the 250 and 400 

mg/kg groups. Tremors were also observed in the low -and mid-dose groups and convulsions in 

the high dose group during home cage observations. Similar results were observed in the pilot 

study where five rats/group were given 120, 240, or 480 mg/kg. Mild tremors were observed in 

one animal in the 120 mg/kg group, and one animal in the 240 mg/kg group had an abnormal 

gait. Based on the mild tremors in 1 rat out of 10, the Agency selected 150 mg/kg as the point 

of comparison for prallethrin.

a

Clinical observations were made prior to FOB testing. Observations in all other scenarios were made at the time to peak effect

*Indicates a significant change from control group at P>0.05.

Cyphenothrin:

a

Clinical observations were made prior to FOB testing. Observations in all other scenarios were made at the time to peak effect

Rats were administered 60, 100, or 160 mg/kg. Two males in the 160 mg/kg 

group were found dead on study day 1. These deaths were considered to be test substancerelated as these males had multiple signs of overt toxicity during the 2-hour FOB evaluation. All 

other males in the 160 mg/kg group survived to the scheduled euthanasia. All males in the 60 

and 100 mg/kg cyphenothrin groups survived to the scheduled euthanasia. Similar to 

prallethrin, tremors were also observed in 1 rat in the low-dose group . The Agency selected 60 

mg/kg from the definitive study for a point of comparison based on mild tremors in 1 rat out of 

10.

*Indicates a significant change from control group at P>0.05.

Table 4.2.5.1b. FOB Effects Observed in Prallethrin-Treated Rats in WIL Study (Herberth 2010)

Observations 150 mg/kg 250 mg/kg 400 mg/kg

Clinical a Tremors (#rats/#incidences) 0 1/1 1/1

Home Cage Tremors 1 3 0

Convulsions 0 0 1

Physiological Body Temperature 38.4±0.63 37.8±0.48 37.2±0.61*

Table 4.2.5.1c. FOB Effects Observed in Cyphenothrin-Treated Rats in WIL Study (Herberth 2010)

Observations 60 mg/kg 100 mg/kg 160 mg/kg

Clinical a Tremors (#rats/#incidences) 0 1/1 2/2

Deaths 0 0 2

Home Cage Tremors 1 1 5*

Convulsions 0 0 2

Open Mobility 0 1 5*

Convulsions 0 1 1

Tremor 0 1 8*
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D-Allethrin: Rats were administered 200, 320, or 500 mg/kg. Four males were found dead 

between 2 hours and 3 hours following dose administration, or on study day 1 (1 in the midand 3 in the high-dose groups). Moderate tremors were noted for 1 male in the 500 mg/kg 

group at 1 hour 20 minutes following dose administration. Slight or moderately course tremors 

were noted in 2, 4, and 8 males in the low-, mid-, and high-dose groups, respectively, in the 

home cage. The most prevalent finding in the open field included slightly impaired mobility, 

convulsions, slight to moderate tremors and slight gait impairment.

D-allethrin and s-bioallethrin are both enrichments of the pyrethroid allethrin. As noted in 

section 4.5, a BMD20 of 135 mg/kg was calculated for s-bioallethrin. Although available as 

separate commercial products, d-allethrin and s-bioallethrin contain similar amounts of the dtrans isomer of the chrysanthemic acid, 80 and >90%, respectively. The greater concentration 

of the d-trans isomer in the s-bioallethrin resulted in slightly greater toxicity compared to dallethrin at a shared dose of 200 mg/kg. For example, in the open field, convulsions and 

tremors were observed in 5 and 6 rats out of 10 for s-bioallethrin but were limited to 2 and 2 

out of 10 for d-allethrin. Given the similarity of their compositions and in lieu of selecting a 

dose from Herbert (2010) for d-allethrin, the Agency is using 135 mg/kg (the BMD20 for sbioallethrin) for determination of the relative potency factor of d-allethrin. 

a

Clinical observations were made prior to FOB testing. Observations in all other scenarios were made at the time to peak effect

*Indicates a significant change from control group at P>0.05.

4.3 Routes and Duration of Exposure for Potency Determination

4.3.1 Routes of Exposure

Humans may be exposed to pyrethroids through their diet (food and drinking water) and in and 

around residences, schools, commercial buildings, etc. via the oral, dermal, and inhalation 

routes of exposure. Therefore, the potency of pyrethroids needs to be determined for all three 

routes of exposure3

 3 More detail related to exposure can be found in Sections 5.0 and 6.0

. Dermal and inhalation assessments are required for some pyrethroids; 

however, they generally do not significantly contribute to the overall risk picture. Oral 

exposure is the route of exposure of greatest concern with respect to pyrethroid toxicity for the 

screening level cumulative assessment.

Table 4.2.5.1d. FOB Effects Observed in D-Allethrin-Treated Rats in WIL Study (Herberth 2010)

Observations 200 mg/kg 320 mg/kg 500 mg/kg

Clinical a Tremors (#rats/#incidences) 0 1/1 1/1

Found Dead 0 1 3

Home Cage Tremors 2 4 8*

Convulsions 0 0 2

Open Field Mobility 0 1 4

Convulsions 2 4 7

Tremor 2 4 8
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4.3.1.1 Oral

Oral relative potency values were needed for all pyrethroid pesticides included in the CAG

because of potential dietary exposures from food and drinking water and hand to mouth 

exposures associated with residential/non-occupational uses. The Agency has determined that 

the WIL study is the most appropriate study available for determination of the pyrethroid BMDs

via the oral route because it reflects acute toxicity at the level of the common mechanism (i.e. 

neurotoxicity due to alterations of the VGSC), standardizes testing conditions for a large 

number of pyrethroids (i.e. strain, vehicle, dosing volume), and reflects the most relevant 

duration (acute).

4.3.1.2 Dermal and Inhalation 

Compared to the database for oral toxicity studies, the number of inhalation and dermal 

studies examining neurotoxic effects consistent with the pyrethroid common mechanism is 

much smaller. Several in vivo dermal studies are available to evaluate pyrethroid toxicity. 

However, these studies do not evaluate the full range of behavioral endpoints needed to assess 

pyrethroid toxicity, nor do they establish critical time-to peak-effect windows. There are even 

fewer inhalation studies available for the determination of pyrethroid toxicity compared to the 

dermal studies, and these too lack critical endpoint evaluation and appropriate time-to-peakeffect determination. Furthermore, the Agency’s limited ability to predict the impact of routespecific pharmacokinetics precludes the extrapolation of estimating RPFs from oral, dermal, 

and inhalation exposures. As PBPK models are further developed for this class of pesticides, 

limitations such as route-to-route extrapolation may be overcome. However, at the current 

time limitations in methodology and lack of coverage for all pyrethroids preclude the inclusion 

of dermal and inhalation studies in the calculation of the RPFs. As such, the Agency is assuming 

that the relative rank estimated for oral exposure applies to both the dermal and inhalation 

routes.

In lieu of determining BMDs for dermal and inhalation routes, the Agency is using the BMDs 

determined from oral studies and using a 5% dermal absorption factor and assuming inhalation

toxicity is equivalent to oral toxicity. Pyrethroid dermal absorption estimates used in single 

chemical risk assessment for the pyrethroids included in the CMG range from 0.2 to 33%. 

Dermal absorption estimates greater than 5% are either based on structural similarity which 

entails a high level of uncertainty and are therefore very conservative, or measurements of 

total skin absorption which is also highly conservative since pyrethroids bound to the upper 

dermis layers are not likely to be absorbed into the body. Furthermore, approximately half of 

these estimates are based on systemic toxicity, such as decreased body weights, decreased 

food consumption, or as a weight of evidence from the database, and therefore are not 

consistent with the pyrethroid common mechanism being used for the CRA. Those studies 

based on neurotoxic effects are not examined in a consistent manner and therefore such in vivo

dermal studies are not appropriate for the determination of BMDs for the purposes of the CRA. 

Estimates ≤ 5% are based on potency comparisons between oral and dermal studies within the 

same rat strain, direct measures of in vitro skin penetration (Hughes and Edwards 2010), or 
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penetration rates based on lower dermis levels of skin that are more likely to be absorbed by 

the body. Since these lower estimates are more robust and contain significantly less 

uncertainty, the Agency is confident that an estimate of 5% absorption is protective for human 

exposures. 

The Agency has guideline inhalation studies for 10 pyrethroids which are included in the CAG. 

Of these 10, the effects observed in the studies for five of these are either based on route of 

entry effects or other more generalized toxic effects such as decreased body weights. For the 

remaining five pyrethroids, s-bioallethrin, cyfluthrin, imiprothrin, lambda-cyhalothrin, and 

permethrin, the effect seen in the inhalation studies are based on adverse neurotoxic effects

including convulsions, tremors, and vocalizations during handling. Although these effects are 

consistent with the recognized pyrethroid common mechanism, these studies are lacking in 

consistent evaluation and scoring of neurotoxic behaviors, determination of the appropriate 

time-to-peak-exposure, and consistent exposure techniques, and thus are not appropriate for 

estimating relative potency. 

4.4 Index Chemical

The cumulative risk assessment guidance document (USEPA 2002) states that the index 

chemical should be selected based on the availability of high quality dose-response data

(preferably in each route of interest) for the common mechanism endpoint and that it acts 

toxicologically similar to other members of the common mechanism group. High quality doseresponse data allow the calculation of points of departures (PoD) with greater confidence, 

because the PoDs for the index chemical are used to extrapolate risk to the exposure levels 

anticipated in the human population and any error or uncertainty in an index chemical’s PoD 

value will be carried forward in the cumulative risk estimates. 

4.4.1 Candidates for Index Chemical

In previous cumulative assessments the Agency has typically evaluated those chemicals in the 

CAG with high quality data relevant for the CMG endpoint(s) for the oral, dermal, and 

inhalation routes of exposure. In the case of the pyrethroids, a complete database including 

dermal, oral, and inhalation studies measuring pyrethroid-specific neurotoxicity at the time-topeak-effect is not available for any single pyrethroid. Furthermore, although dermal and 

inhalation assessments are being conducted for some pyrethroids, they generally do not 

significantly contribute to the overall risk picture; therefore the focus of this CRA is the oral 

route of exposure. Oral exposure is the route of greatest concern with respect to pyrethroid 

toxicity for this screening level cumulative assessment and the source of the most robust dose 

response data for purposes of deriving PODs. The WIL study provides the most robust oral FOB 

data from which to compare the pyrethroid chemicals (See section 4.2). Therefore, for this 

screening level CRA the Agency is relying on the chemicals included in the oral WIL study for 

determination of candidates for the index chemical.
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In addition to considering the robustness of the toxicity database, the selection of the index 

chemical must also consider the pertinent duration of exposure. As previously discussed, the

CRA assesses exposures over a 24 hour period (i.e. acute exposures); therefore it is important 

that the index chemical have a robust database reflecting this exposure duration. 

Permethrin and deltamethrin stand out as having the most robust database of guideline and 

literature studies. For example, multiple studies on deltamethrin and/or permethrin have been 

identified examining in vivo neurotoxicity, in vitro sodium channel interaction, metabolism, 

pharmacokinetics following multiple routes of administration (oral, dermal, intravenous, 

intercerebral, etc.) and PBPK modeling. Thus, deltamethrin and permethrin are both strong 

candidates for selection as the index chemical. 

The deltamethrin PoD derived from the FOB data is of sufficiently high quality to minimize error 

or uncertainty in the cumulative risk estimates. In the WIL study, permethrin was only tested 

with two doses which are narrowly spaced whereas deltamethrin was tested with three doses 

well spaced to cover the low to high dose range. As such, there is greater variability around the 

BMD central estimate for permethrin compared to deltamethrin based on the distance of the 

BMDL (lower confidence limit) from the central estimate. Specifically, the BMD and BMDL 

estimates for permethrin are 155.5 and 73 mg/kg, compared to the deltamethrin BMD and 

BMDL estimates of 14.5 and 10.5 mg/kg. Therefore, the Agency has selected deltamethrin as 

the index chemical in the CRA.

4.5 Relative Potency Estimates & Points of Departure for the Index Chemical

 Several key literature studies supporting the use of deltamethrin 

as the index chemical are listed in Appendix 6. This list of literature is not exhaustive but it does

include the most salient studies covering a number of areas of deltamethrin research and it 

includes key seminal studies that are cited most often.

4.5.1 Relative Potency Factors

In this CRA, the Agency is quantifying cumulative risk to the pyrethroids using BMDs derived 

from the WIL study to calculate RPFs. Deltamethrin is being used as the index chemical. The 

RPFs for the CAG in this pyrethroid screening level cumulative are shown in Table 4.5.1. They 

are 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. Twelve of the 15

pyrethroids result in equal to or lower relative potency estimates compared to deltamethrin. 

Bifenthrin, cyfluthrin, and tau-fluvalinate result in similar relative potency as deltamethrin while 

lambda-cyhalothrin resulted in slightly greater potency than deltamethrin.
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Table 4.5.1. Relative Potency Estimates for Pyrethroids 

Included in the Screening Level Cumulative Risk Assessment

Pyrethroid Oral BMD20 Oral RPFb,d

Allethrinc 135 0.11

Bifenthrin 14.3 1.01

Cyfluthrin 12.6 1.15

Lambda-Cyhalothrin 8.9 1.63

Cyphenothrin 100a 0.15

Cypermethrin 76.3 0.19

Deltamethrin 14.5 1.0

Esfenvalerate 40.5 0.36

Fenpropathrin 29 0.50

Tau-Fluvalinate 14.5 1.0

Imiprothrin 750a 0.02

Permethrin 156 0.09

Prallethrin 150a 0.10

Pyrethrins 800a 0.02

Resmethrin 291 0.05 a

Values estimated from studies; these values were not calculated using BMD. See Section 4.2 b

RPF = BMD20 of Index Chemical (e.g., deltamethrin)/Pyrethroid BMD20; For example: Allethrin 

RPF=14.5/135=0.11

c

Includes the isomeric enrichments S-Bioallethrin and D-Allethrin d

RPFs for Dermal and Inhalation exposures are based on oral BMD; 5% absorption values applied to dermal 

assessments and inhalation is considered equivalent to the oral route

4.5.2 Points of Departure

The deltamethrin BMD20 is derived from oral data and is being applied to all three routes of 

exposure: oral, dermal, and inhalation. As with any risk assessment that relies on BMD analysis, 

the PoD is the lower confidence interval used to mark the beginning of extrapolation to

determine risk associated with human exposures. The 95% lower confidence interval for the 

BMD20, the BMDL20, of deltamethrin is 11 mg/kg (Figure 4.5.2). 
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Figure 4.5.2. BMD20 and , BMDL20, for FOB changes of Deltamethrin

4.6 FQPA Safety Factor for Protection of Infants & Children

The FQPA (1996) instructs EPA, in making its “reasonable certainty of no harm” finding, that in 

“the case of threshold effects, an additional tenfold margin of safety for the pesticide chemical 

residue and other sources of exposure shall be applied for infants and children, to take into 

account potential pre- and post-natal toxicity and completeness of data with respect to 

exposure and toxicity to infants and children.” Section 408 (b)(2)(C) further states that “the 

Administrator may use a different margin of safety for the pesticide chemical residue only if, on 

the basis of reliable data, such margin will be safe for infants and children.”

The Agency typically determines the appropriate FQPA safety factor on a chemical-by-chemical 

basis. However, there are a number of similarities between the pyrethroids (e.g., relative 

potency, structure, and pharmacokinetics) which support the conclusion that a single FQPA 

safety factor is appropriate for the entire class. Based on reliable data, EPA has concluded that 

a safety factor less than 10X is appropriate for the pyrethroid chemicals. The Agency is 

reducing the FQPA Safety Factor to 1X for adults, including pregnant females, and children 

greater than 6 years of age (USEPA 2011b). However, the Agency is retaining a 3X FQPA Safety 

Factor for children from birth to 6 years of age. This conclusion is based on a wide range of 

information on pyrethroids that includes the exposure profile for this class of pesticides, PBPK 

models, and in vitro and in vivo data. The scientific information that supports the reduction of 

the FQPA safety factor can be found in Re-Evaluation of the FQPA Safety Factor for Pyrethroid 

Pesticides (USEPA 2011b) and is summarized below: 

• Based on the available data and supporting evidence, the 10X FQPA safety factor will be 

reduced to 1X for all populations greater than 6 years of age, including women of child 

BMDL BMD
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bearing age. This is due to the absence of pre-natal sensitivity observed in 76 guideline 

studies for 24 pyrethroids and supporting scientific literature. 

• For exposures from birth to <6 years of age, the Agency will retain a 3X safety factor 

due to 1) age-dependent pharmacokinetics, supported by rat PBPK model predictions of 

a 3-fold increase of pyrethroid concentration in juvenile brain compared to adults; 2) in 

vitro pharmacodynamic data and in vivo data indicating similar responses between adult 

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

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

sodium channel isoforms. 

• Based on pharmacokinetic data, there is evidence that indicates an increase in 

sensitivity to pyrethroids of the young compared to adults. These differences are largely 

attributed to the ability of the adults and juveniles to metabolize pyrethroids. The 

available PK data is primarily based on experiments with deltamethrin, one of the more 

potent pyrethroids. Data has shown the rate of in vitro metabolism of deltamethrin by 

plasma carboxyesterases, hepatic carboxyesterases, and hepatic microsomes are at 

least 6 times higher for post-natal day (PND) 90 rats compared to PND 10 rats (Anand et. 

al. 2006). As a consequence, higher internal doses overwhelm the clearance 

mechanisms in juveniles but because adults have greater enzyme activity, they are able 

to tolerate higher doses prior to the onset of toxicity. PBPK models have predicted, 

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 difference between 

a 3.8- and a 2.5-fold dose is within background variability of the PBPK model and 

therefore the Agency approximates a 3-fold difference between adult and juvenile rats. 

Since there are no similar age-dependent PBPK models available for humans, the Agency 

cannot make any direct estimates of human infant brain concentrations following an 

exposure to pyrethroids. Therefore, the Agency has to rely on extrapolations from 

rodent studies. Comparisons between lifestages in the rat and human are difficult to 

make because the ontogeny of the brain development and metabolizing enzymes are 

not an exact match. However, 11-day old rats are considered to be equivalent in terms 

of development to newborn humans and 17-day old rats are believed to be 

developmentally equivalent to human toddlers 3 to 6 years of age (Davision and 

Dobbing 1966; Dobbing and Smart 1974; Benjamins and McKhann 1981). 

• In part, the Agency is reducing the FQPA factor because available data do not indicate 

any age-related differences in the pharmacodynamics through interaction with VGSCs. 

For example, in a direct comparison of a homologous rat and human sodium channel

isoform, NaV1.3, Tan and Soderlund (2009) found the rat isoform was 4-fold more 

sensitive than the equivalent human sodium channel to the pyrethroid tefluthrin, 

suggesting the rat is a highly sensitive model and extrapolations from the rat would be 

protective of human health. 
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• The population of greatest concern to the Agency for pyrethroid exposure is children 

from birth to <6 years of age. Pyrethroids have a wide variety of uses, including 

agricultural and residential scenarios. Despite the widespread use on food crops, 

residue levels in processed or whole foods, as determined by the USDA Pesticide Data 

Program, are generally low. Furthermore, pyrethroids are practically insoluble in water, 

minimizing water exposure. With respect to residential and occupational exposure 

scenarios, pyrethroids have low vapor pressure and are poorly absorbed dermally 

(Hughes and Edwards 2010). As such, the exposure assumptions made in this screening 

level assessment are conservative and protective of human health.

The Agency is expecting additional in vitro and in vivo data that will further inform the science 

behind the decision to reduce the FQPA factor. In 2010, the Agency requested proposals for 

study protocols which could identify and quantify potential juvenile sensitivity (USEPA 2010). 

There was a single 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 meeting4

4.7 Incorporation of Uncertainty Factors/Extrapolation Factors and the Target 

Margin of Exposure

. Based on comments from the SAP, the initial study proposal was refined. 

At present time, pesticide registrants and product formulators (Council for the Advancement of 

Pyrethroid Human Risk Assessment (CAPHRA) are i) conducting in vitro studies demonstrating 

the interaction of pyrethroids endogenously expressed rat and human VGSCs in Xenopus

oocytes; ii) conducting in vitro studies demonstrating interaction of pyrethroids in rat 

neurolemma cells; iii) developing rat and human PBPK models, including additional 

pharmacokinetic data; and iv) conducting in vivo behavioral testing using auditory startle 

testing in rats. As more data for individual pyrethroids become available, the Agency will 

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

In general, when performing a cumulative risk assessment using a RPF approach, as is being 

done with the pyrethroids, uncertainty and extrapolation factors can be incorporated into the 

risk assessment in two different ways: 1) adjustment of the chemical-specific RPF; or 2) 

incorporation into the target Margin of Exposure (MOE). For the pyrethroids, the inter-species, 

intra-species, and FQPA safety factor were all incorporated into the target MOE.

The magnitude of the uncertainty and extrapolation factors is the same for each member of the 

common mechanism group for the pyrethroid CRA. As described in detail earlier, the FQPA 

factor has been reduced to 3X for every pyrethroid for the subgroups of children six years old 

and younger and to 1X for all other subgroups. However, data are not available to reduce the 

10X inter-species or 10X intra-species factor. Therefore, the 10X is retained for both of these 

factors. As such, the target MOEs for the pyrethroid CRA are listed in Table 4.7. 

 4 http://www.epa.gov/scipoly/sap/meetings/2010/072310meeting.html
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As indicated in the previous section, the Agency is expecting additional data and PBPK models. 

PBPK models are able to address age- and species-specific pharmacokinetics that are key to 

extrapolating human health risks from rodent models. For example, Godin et. al. (2010)

predicted the concentrations of deltamethrin in the adult human brain based on studies in the 

rat and Tornero. et al. (2010) predicted deltamethrin concentrations in the brains of rats from 

PND 10 up to PND 90. These Agency models form the basis for newer models currently being 

developed by CAPHRA for several additional pyrethroids. As the models become available to 

the Agency, further adjustments to the FQPA and interspecies factors will be considered during 

future CRA revisions. 

Table 4.7 FQPA Safety Factors for Populations Relevant to Human Health Risk Assessments

Population FQPA Inter-species 

Factor

Intra-species 

Factor

Target MOE

Children 0 to 6 years 3 10 10 300

Children > 6 years 1 10 10 100

Females 13+ 1 10 10 100

Adults 1 10 10 100

4.8 Dose Additivity

A key assumption of the RPF method is dose-additivity. For pyrethroids, dose-additivity implies 

multiple pyrethroids can interact with the VGSC simultaneously, and the overall toxic response 

will be a summation of all the individual pyrethroids. For example, if deltamethrin and 

permethrin were administered at equipotent doses, the measured response would be double 

compared to the administration of either pyrethroid by itself. Dose-addition has recently been 

demonstrated in in vivo and in vitro studies. Wolanksy et. al. (2009) used a mixture of 11 

pyrethroids (both Type I and II) and the same testing paradigm used in single-compound assays 

to test the hypothesis that cumulative neurotoxic effects of pyrethroid mixtures can be 

predicted using the default dose-addition theory. When subthreshold doses of individual 

chemicals were combined in mixtures, significant dose-related decreases in motor activity were 

observed; there was no departure from the predicted dose-additive curve. This study presents 

the first in vivo evidence on pyrethroid cumulative effects supporting the default assumption of 

dose addition. Using the same mixture of 11 pyrethroids, Cao et. al. (2011a) measured Na+

influx in primary cultures of intact mammalian cerebrocortical neurons. When all 11 

pyrethroids were present at an equimolar mixing ratio, their actions on Na+ influx were 

consistent with a dose-additive model. While motor activity is an indirect measure of the 

common mechanism (i.e. interaction with VGSC), the measurement of Na+ influx at the 

neuronal level provides more definitive evidence of dose-addition at the level of the common 

mechanism. 

Furthermore, Scollon et. al. (2009) compared the rate of metabolism of the cis- and transisomers of permethrin in hepatic microsomal incubations separately and in a mixture. The 

metabolism of trans-permethrin was reduced when incubated with its diasteriomer, cispermethrin in both rat and human hepatic microsomes incubations. Since both isomers are 

metabolized by the same oxidative P450 enzymes, (CYP2C6 and CYP2C11), substrate 
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competition may have contributed to the difference in metabolic rate. While this potential 

interaction in metabolism does not necessarily result in dose-additivity, it may contribute and 

should be considered when modeling pyrethroid pharmacokinetics. OPP will continue to 

monitor and evaluate in vivo and in vitro studies evaluating dose-addition of pyrethroids as they 

become available.

In summary, given the current state of the science with respect to pyrethroid mixtures, the 

assumption of dose additivity is both reasonable and appropriate.

5.0 Dietary Cumulative Exposure and Risk Assessment/Characterization

This section discusses the cumulative estimated risk associated with the food and drinking 

water exposure pathways. An overview of the inputs and methodology for the dietary 

assessment is included here. Detailed information on conducting a cumulative dietary risk 

assessment is available in the Revised N-Methyl Carbamate Cumulative Risk Assessment, US 

EPA, September 24, 2007, pp. 58 – 82. 

It should be noted that while the methodology developed and implemented in the assessment 

of the cumulative risks for the organophosphate and N-methyl carbamates was closely followed 

for the pyrethroids, in light of the screening level nature of this assessment, some conservative 

assumptions were made. Inclusion of those conservative assumptions did not result in dietary 

risks of concern; therefore, additional refinements were not required at this time. 

5.1 Food Exposure Pathway

As with previous cumulative assessments released by the Agency, the data for this pathway are 

developed from two primary sources: dietary consumption data collected by USDA’s Continuing 

Survey of Food Intakes by Individuals (CSFII) and pesticide residue monitoring data collected by 

the USDA Pesticide Data Program (PDP). 

5.1.1 Dietary Consumption Data

The reliability of the food component of this assessment is supported by the use of the food 

consumption data from the USDA’s Continuing Survey of Food Intakes by Individuals (CSFII 

1994-1996/1998). The CSFII surveyed more than 20,000 individuals over two non-consecutive 

days and provides a detailed representation of the food consumption patterns of the U.S public 

across all age groups, during all times of the year, and across 50 states. Thus, the Agency has 

confidence that the consumption estimates for food are well established and consequently 

support reasonable risk estimates for the U.S. population. 
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5.1.2 Pesticide Residue Data

As with previous CRAs, the exposure estimates for food are based on residue monitoring data 

from the USDA’s Pesticide Data Program (PDP). PDP data collected from 2003 through the 

most recent data available in 2009 were incorporated in the pyrethroid screening level 

assessment. While additional years of data are available, prior to 2003, PDP did not analyze for 

all registered pyrethroids. The PDP data provide a reliable estimate of pesticide residues in the 

majority of foods, with care taken to sample foods with high consumption or foods which are 

likely to have the highest residues, including important children’s foods. The PDP data were 

either used directly or indirectly through the use of commodity surrogates. That is, for food not 

monitored in PDP, similar commodities that are measured by PDP served as surrogate data 

sources. This approach is consistent with the approach taken on previous CRAs and is 

considered to be reasonable given that it is based on the concept that families of commodities 

with similar cultural practices and insect pests are likely to have similar pesticide use patterns 

and residue levels. Additionally, PDP data provide direct measures of co-occurrence of the 

pyrethroid pesticides in the same samples. Consistent with prior practice for the 

organophosphate (OP) and N-methyl carbamate (NMC) pesticide cumulative assessments, PDP 

samples with non-detectable residues were treated in this assessment as “zero” values. 

Sensitivity analysis conducted for the OPs and NMC pesticides has determined that this 

approach for acute dietary assessments does not significantly underestimate exposures at the 

upper percentiles. 

5.1.3 Pyrethroid Pesticides Included in the Dietary Risk Assessment

The pyrethroids with registered agricultural uses on human feed items are summarized in Table 

5.1.3, below, along with their relative potency factors (RPFs). It is important to note that not all 

pyrethroids with registered food-uses were quantitatively included in this screening level 

assessment. As was previously noted and is captured in the CRA methodology, a pyrethroid 

with a relative potency that significantly lower than that of the index chemical was not included 

in the CAG since that specific chemical is unlikely to have an impact on the estimated 

cumulative risk. Further, food-use pesticides for which there are no detectable residues in the 

PDP monitoring data are not included in the assessment as there is not a likelihood of 

significant exposure. 
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1 Refers to all isomeric variations.

In contrast to prior CRAs, processing factors were not included in this screening level 

assessment, that is, the processing factor was set to “1” which indicates there is no 

concentration or reduction from processing. For processed commodities monitored directly by 

PDP, the residue values found in the monitored samples were directly used in the assessment. 

For those processed commodities which were not directly sampled, the monitored value from 

the raw agricultural commodity (RAC) or its commodity surrogate was used and the processing 

factor was set to “1”. This approach is considered reasonable and unlikely to underestimate 

risk since a review of tolerances (maximum allowed legal residues) for these commodities 

indicated that separate, higher tolerances were not required for the associated processed 

commodity. In other words, the tolerance for the RAC would also cover the residues found in 

the processed commodities supporting a lack of concentration of residues in the processed 

commodity. Further, no use of reduction factors was included in this assessment. Refining this 

assessment to include reduction factors (i.e., cooking factors, process reduction factors) for 

processed commodities for which RAC residue values were used, would only reduce the 

estimated exposure values. 

Table 5.1.3. Food Use Pyrethroids Considered in the Quantitative Screening Level CRA

Chemical 

Name1

Included Quantitatively in 

Screening Level 

Assessment/Comments RPF

Index 

Chemical 

POD UF

FQPA 

SF CRA Target MOE

Allethrin Included 0.11 100 3

100 adults

300 children

Bifenthrin Included 1.01 100 3

Cyfluthrin Included 1.15 100 3

Cyhalothrin Included 1.63 100 3

Cypermethrin Included 0.19 100 3

Cyphenothrin Included 0.15 100 3

Deltamethrin Included 1.0 11 

mg/kg/day 100 3

Fenpropathrin Included 0.5 100 3

Fenvalerate/

Esfenvalerate Included 0.36 100 3

Flucythrinate No detects in PDP; therefore not included quantitatively in the CRA

Fluvalinate Included 1 100 3

100 adults

300 children Imiprothrin Included 0.02 100 3

Permethrin Included 0.09 100 3

Prallethrin Included 0.1 100 3

100 adults

300 children Pyrethrins Included 0.02 100 3

Resmethrin Included 0.05 100 3

Sumithrin Did not produce any signs of toxicity; therefore not included quantitatively in the CRA

Tefluthrin No detects in PDP; therefore not included quantitatively in the CRA

Tetramethrin Did not produce any signs of toxicity; therefore not included quantitatively in the CRA

Tralomethrin No detects in PDP; therefore not included quantitatively in the CRA
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5.1.4 Food Commodities Included in the Dietary Risk Assessment 

The universe of foods included in the cumulative dietary exposure assessment is defined by the 

USDA CSFII 1994-96/1998. The CSFII food diary information is expressed in terms of food as 

consumed (e.g., pizza, apple pie, lasagna, etc.). These foods, as reported in CSFII diaries, are 

converted to food commodities (e.g., tomatoes, milk, wheat flour, beef, apples, etc.) using 

standard recipes. The recipe information used to break down the foods was developed jointly 

by EPA and USDA and is one module in the EPA’s Food Commodity Intake (FCID) database.

For this screening level assessment pesticide residue values were translated such that all major 

commodities contained in the Agency dietary exposure model, Dietary Exposure Evaluation 

Model-Food Commodity Index Database (DEEMFCIDTM), were assigned residue values. While 

monitoring data are not available for every commodity in DEEM, major foods are sampled by 

PDP and the residue values for those samples were translated to similar commodities. For 

example orange data was translated to limes. Translations were made based on the similarity 

of the commodities under the Agency’s crop grouping scheme codified in the 40CFR. 

Translations were made regardless of registered use patterns. For example, banana residue 

values were translated to plantains without verification that there is a pyrethroid registered on 

plantains. In a more refined CRA, those crops without pyrethroid registered uses would be 

assigned “zero” values; therefore, this approach would only be expected to result in an 

overestimate of risk. 

Despite the conservative assumptions with regard to processing factors and pyrethroid 

commodity registrations, by using the PDP monitoring data, the food component of the 

screening level pyrethroid CRA is considered to be refined and to provide reasonable estimates 

of the distribution of exposures across the U.S.

5.2 Drinking Water Pathway

As a class of chemicals, the pyrethroids have low solubility in water and a high affinity to bind to 

soils. Given these physical/chemical properties, it is unlikely that oral exposure from drinking 

water will be a major pathway of exposure. However, in the absence of a comprehensive set of 

monitoring data with sufficiently low detection limits which could be used to derive exposure 

values for drinking water, the Agency has incorporated modeled drinking water values into this 

screening level assessment. Estimated drinking water concentrations (EDWCs) were developed 

using FIRST, SCI-GROW and PRZM/EXAMS models. The models, including descriptions, are 

available at http://www.epa.gov/oppefed1/models/water/. 

The EDWC screening level assessments modeled the maximum application rate and the 

minimum interval between applications for each pyrethroid. Both surface water and ground 

water EDWCs were developed and are shown in Table 5.2, however, modeled surface water 

EDWCs were used as they are significantly higher and provide a conservative estimate for the 

screening level cumulative assessment. Where a modeled drinking water assessment would 
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predict a value greater than the limit of solubility for a pesticide, the output of the model will 

be the chemical’s limit of solubility.

The drinking water component of the screening level pyrethroid CRA is considered to be 

unrefined and highly conservative, both due to the use of the model and because of the level of 

refinement used in the modeling scenarios. The assessments are characterized as either Tier 1 

or Tier 2, which is an indicator of their level of refinement. For both of these tiers, significant 

refinements are available which are expected to significantly lower the predicted estimated 

drinking water concentrations. However, these refinements were not conducted as there were 

no risks of concern identified based on the unrefined assessments. 

Drinking water residues have to be expressed in terms of index chemical equivalents before 

they can be used in the cumulative risk assessment. Using the individual chemical relative 

potency factors (RPFs), the EDWCs for each pyrethroid were converted to deltamethrin 

equivalent exposure values. Since data are not available on the co-occurrence or relative 

amounts of individual pyrethroid in a single water sample, the Agency selected the EDWC from 

the pyrethroid which resulted in the highest residue value expressed as deltamethrin 

equivalents as surrogate for all drinking water exposure. The highest EDWC in terms of 

deltamethrin equivalents was derived from the lamda-cyhalothrin limit of solubility output 

from the model of 5 ppb. This value is included for all water in the assessment as a 

deltamethrin equivalent concentration of 8.15 ppb.

In summary, while the physical/chemical characteristics of the pyrethroids suggest that 

exposure to this class of compound through drinking water is not likely to be a major pathway 

of exposure; the Agency has incorporated unrefined, modeled estimated drinking water 

concentrations into this screening level cumulative assessment. Further, the single modeled 

value which represented the highest deltamethrin equivalent exposure was used to represent 

drinking water exposure for all pyrethroids; therefore, the drinking water inputs are considered 

to be highly conservative. Refinements to the modeled scenarios or availability of acceptable 

drinking water monitoring data is likely to significantly reduce the residue values used in a more 

refined cumulative assessment. The modeled EDWCs, chemical RPFs and corresponding 

exposures in deltamethrin equivalents are shown in Table 5.2.
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Table 5.2. Modeled EDWCs for the Pyrethroids

Chemical Name

Ground Water 

Acute EDWC 

(ppb)

Surface Water 

Acute EDWC 

(ppb)

RPF

Surface Water Acute 

EDWC in Deltamethrin 

Equivalents (ppb)

Allethrins Based on the use pattern, residues are not expected in drinking water. 

Bifenthrin 0.003 0.0141 1.01 0.014

Cyfluthrin 0.457 2

1 1.15 4.228

Cyhalothrin 0.00300 5

1 1.63 8.1502

Cypermethrin 0.0036 3.77 0.19 0.716

Deltamethrin 0.00269 0.21 1 0.200

Esfenvalerate3 0.009 7.54 0.36 2.714

Fenpropathrin 0.00480 10.3 0.5 5.150

Fluvalinate 0.0025 1.31 1.0 1.310

Permethrin 0.012 4.79 0.09 0.431

Prallethrin 0.00104 0.591 0.10 0.059

Pyrethrins 0.003 4.078 0.02 0.082

Resmethrin 0.065 0.20 0.05 0.010 1 The modeled value exceeded the solubility limit; therefore the actual model output is a concentration at the limit 

of solubility.

2 EDWC used in the pyrethroid cumulative risk assessment.

3

 Includes fenvalerate

5.3 Dietary (Food and Water) Assessment

As with previous cumulative risk assessments, the pyrethroid screening level cumulative 

dietary exposure was estimated using the Dietary Exposure Evaluation Model-Food 

Commodity Index Database (DEEMFCIDTM) software (Exponent, 2007). Estimation of dietary 

exposure was accomplished by combining distributions of pesticide concentrations on foods 

from USDA PDP with distributions of food consumption from USDA CSFII.

Consistent with OPP dietary exposure assessment guidance, separate assessments were 

conducted on the various sub-populations as represented in the CSFII 1994-96/1998. This 

screening level assessment reports on the U.S. general population and the following standard 

age groups: 

 Infants less than 1 year old 

 Children 1-2 years old 

 Children 3-5 years old 

 Children 6-12 years old 

 Youths 13-19 years old 

 Adults 20-49 years old

 Adults 50+ years old 

 Females 13-49 years old 
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The methodology and tools used for calculating cumulative food residues described in the 

revised NMC cumulative document are the same methodology and tools used to develop this 

screening level dietary assessment for the pyrethroids. This includes the generation of tables to 

hold the data on residue values, processing factors, relative potency factors and bridging 

information (translations between residue data and food forms), along with the use of forms in 

MS Access to perform the appropriate calculations to express all residues as deltamethrin 

equivalents and to combine residues on individual samples, creating a distribution of residues 

by commodity. The specific algorithms used to estimate exposure from dietary sources are 

detailed in the NMC cumulative document cited above.

The Agency conducted an acute probabilistic dietary risk assessment for food residues and food 

plus water. Cumulative dietary estimated risks for food alone and food plus drinking water, 

resulting from exposure to pyrethroids, significantly exceed the target MOE of 100 for adults 

and 300 for children and; therefore, estimated risks are not of concern for any population 

subgroup. The results of the dietary exposure and risk assessment are summarized below for 

food only (Table 5.3a) and food plus water (Table 5.3b). 

Table 5.3a. Summary of Food Only Dietary Exposure and Estimated Risk for the Pyrethroid CRA

Population Subgroup

Acute Dietary

95th Percentile

Acute Dietary

99th Percentile

Acute Dietary

99.9th Percentile

Dietary 

Exposure 

(mg/kg/day)

MOE

Dietary 

Exposure 

(mg/kg/day)

MOE

Dietary 

Exposure 

(mg/kg/day)

MOE

General U.S. Population 0.000111 99,000 0.000478 23,000 0.001852 5,900

All Infants (< 1 year old) 0.000104 110,000 0.000639 17,000 0.004739 2,300

Children 1-2 years old 0.000189 58,000 0.000793 14,000 0.003320 3,300

Children 3-5 years old 0.000168 65,000 0.000710 16,000 0.002817 3,900

Children 6-12 years old 0.000116 95,000 0.000483 23,000 0.001898 5,800

Youth 13-19 years old 0.000073 150,000 0.000361 30,000 0.001530 7,200

Adults 20-49 years old 0.000101 110,000 0.000438 25,000 0.001686 6,500

Adults 50+ years old 0.000120 91,000 0.000499 22,000 0.001712 6,400

Females 13-49 years old 0.000104 110,000 0.000455 24,000 0.001766 6,200

Most highly exposed subgroup highlighted.
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Table 5.3b. Summary of Food and Water Dietary Exposure and Estimated Risk for the Pyrethroid CRA

Population Subgroup

Acute Dietary

95th Percentile

Acute Dietary

99th Percentile

Acute Dietary

99.9th percentile

Dietary 

Exposure 

(mg/kg/day)

MOE

Dietary 

Exposure 

(mg/kg/day)

MOE

Dietary 

Exposure 

(mg/kg/day)

MOE

General U.S. Population 0.000521 21,000 0.001011 11,000 0.002321 4,700

All Infants (< 1 year old) 0.001722 6,400 0.002563 4,300 0.005544 2,000

Children 1-2 years old 0.000819 13,000 0.001434 7,700 0.003646 3,000

Children 3-5 years old 0.000731 15,000 0.001212 9,000 0.003157 3,500

Children 6-12 years old 0.000512 21,000 0.000864 13,000 0.002124 5,200

Youth 13-19 years old 0.000401 27,000 0.000763 14,000 0.002048 5,400

Adults 20-49 years old 0.000468 23,000 0.000872 13,000 0.001980 5,600

Adults 50+ years old 0.000431 26,000 0.000788 14,000 0.001926 5,700

Females 13-49 years old 0.000470 23,000 0.000870 13,000 0.002021 5,400

Most highly exposed subgroup highlighted.

For the U.S. population, lettuce, apples, and spinach are the food commodities which 

contribute the most significantly to dietary exposure from food. For “all infants”, the most 

highly exposed subgroup, spinach is the commodity which contributes most significantly to the 

dietary exposure from food. Based on residues seen in PDP, it appears that residues of 

permethrin on lettuce and spinach and fenpropathrin on apples are the residues most 

impacting the dietary exposure from food. However, it should be noted that MOEs for all foods 

combined are significantly above the target MOEs; therefore, while these residues are the 

highest contributors to exposure, they do not result in an estimated risk of concern. 

For the purpose of this screening level assessment, the Agency has included highly conservative 

modeled drinking water estimates of concentration in this assessment. However, as previously 

stated given the physical/chemical properties of the pyrethroids, drinking water is not likely to 

be a major pathway of dietary exposure; therefore actual dietary cumulative estimated risks 

are more likely to be closer to those reported for food only. 
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6.0 Residential Pyrethroid Cumulative Risk 

6.1 Introduction

In the past, the Office of Pesticide Programs (OPP) has employed calendar-based models to 

address the temporal aspects of the residential use of pesticides when performing a cumulative 

risk assessment (CRA). Considering the breadth of the pyrethroid residential uses, the use of a 

calendar-based model would involve significant analysis of available exposure and use data. 

With this in mind and seeking a less resource and time intensive resolution to the pyrethroid 

CRA, OPP performed a health protective, screening-level assessment to address the cumulative 

effects and risk of the pyrethroids.

A number of health protective assumptions were made in performing this assessment when 

compared to previous cumulative risk assessments performed by OPP. Further discussion of 

the implications of these assumptions is provided in Section 7. These assumptions include the 

following:

1) OPP limited this screening-level assessment to “users only” (i.e., only users of pyrethroid

pesticides were considered in this assessment). Since OPP aggregates both dietary and 

non-dietary exposures from multiple chemicals of the same class, cumulative risk 

assessments have typically been based on the entire U.S. population which includes 

individuals who don’t use pesticides and individuals that use non-pyrethroid pesticides.

2) OPP assumed no dissipation of chemicals and as such Day 0 (or day of application) 

residues were used in all cases.

3) OPP assumed all individuals are exposed (i.e., come in contact with treated surfaces) on 

the day of application. Typically, cumulative risk assessments have included an activity 

component that incorporates the potential for “no non-dietary exposure” days, where a 

pesticide application occurs but no one is exposed to the treated residues after the 

application (e.g., no one goes out on a treated lawn after an application).

4) OPP assumed that exposure for each scenario occurred as a result of use of the 

pyrethroid with the highest risk estimate registered for that scenario. Typically, 

cumulative risk assessments have included probabilities of pesticide use within an 

exposure scenario (i.e., probability of using pesticide A vs. using pesticide B for scenario 

X).

5) OPP assumed co-occurrence of certain residential scenarios as worst-case situations. 

Typically, cumulative risk assessments have included use data such as the Residential 

Exposure Joint Venture (REJV) survey to identify the likelihood of multiple scenario 

applications occurring on the same day.

In addition to these assumptions, information regarding residues, exposure, and standard (nonchemical-specific) exposure factors (such as breathing rates and activity duration) were 

incorporated in this assessment. In nearly all cases, the residential exposure scenarios in this 

assessment were developed using the best available residue and exposure data (some of which 

is proprietary in nature). Exposure factors such as breathing rates and durations of time spent 
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performing specific activities were taken from various sources including the U.S. EPA Exposure 

Factors Handbook (USEPA, 1997) and the U.S. EPA Child-Specific Exposure Factors Handbook 

(USEPA, 2008). Considering the screening-level nature of this assessment, point estimates were 

used to represent all the exposure inputs. While the dietary and drinking water assessments 

address only the oral exposure route, the residential assessment considers the dermal and 

inhalation exposure routes, as well as the oral route (i.e., hand-to-mouth behavior of young 

children).

6.2 Residential Scenarios and Exposure Routes 

There are a variety of pyrethroid pesticides currently registered for residential uses that have 

been considered as part of this screening-level assessment. The residential scenarios addressed 

in this document represent critical pyrethroid uses that have the potential for significant 

exposure when considered in a cumulative assessment. For this effort, the Agency focused on 

the four main pyrethroid residential use scenarios – turf, pets, gardens, and indoors (broadcast, 

fogger and crack and crevice applications). All other pyrethroid residential uses (e.g., 

pyrethroid impregnated clothing or personal insect repellent systems) are considered minor 

contributors to the pyrethroid CRA based on amount of use and exposure potential; therefore, 

those scenarios were not included in this screening-level assessment. The specific exposure 

routes and scenarios assessed in this screening level assessment are briefly described below, as 

well as summarized in Table 6.2.

Table 6.2. Specific Exposure Routes and Scenarios for the Pyrethroids

Scenario Lifestage Applicator Post-application

Dermal Inhalation Oral Dermal Inhalation

Lawn/Turf Adult X X X

1 < 2 yr old X X

Gardens, Ornamentals, and 

Trees

Adult X X X

6 < 11 yr old X

Indoors Adult X X X X

1 < 2 yr old X X X

Pets Adult X X X

1 < 2 yr old X X

6.2.1 Lawn/Turf Use

Based on an evaluation of risk assessments, reregistration eligibility documents (REDs), use 

reports, and labels; it was determined that a number of pyrethroids in the CAG currently have 

products registered for use on turf where residential exposure could occur (e.g., residential 

lawns, parks, recreational areas, etc.). These products include, liquid formulations for 

bifenthrin, cyhalothrin, cyfluthrin, cypermethrin, deltamethrin, permethrin, pyrethrins, and 

resmethrin; wettable powder formulations for cypermethrin; and granular formulations for 

cyhalothrin and permethrin.
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Potential dermal and inhalation exposure was assessed for individuals mixing, loading, and 

applying pyrethroids to residential lawns. This assessment also considers potential dermal 

post-application exposure for adults and young children (1 <2 year olds) contacting treated 

lawns. Additionally, oral non-dietary exposure (hand-to-mouth) was considered for young 

children (1 <2 year olds) potentially transferring treated-turf residues from their hands to their 

mouths.

6.2.2 Garden, Ornamental, and Tree Use

Based on an evaluation of risk assessments, reregistration eligibility documents (REDs), use 

reports, and labels; it was determined that a number of pyrethroids in the CAG currently have 

products registered for use on residential gardens, ornamentals, and trees. These products 

include, liquid formulations for bifenthrin, cyhalothrin, cyfluthrin, cypermethrin, deltamethrin, 

esfenvalerate, fluvalinate, permethrin, pyrethrins, and resmethrin.

Potential dermal and inhalation exposure was assessed for individuals mixing, loading, and 

applying pyrethroids to gardens, ornamentals, and trees. This assessment also considered 

potential dermal post-application exposure for adults and children (6 < 11 years old) contacting 

treated gardens, ornamentals, and trees.

6.2.3 Indoor Use

Based on an evaluation of risk assessments, reregistration eligibility documents (REDs), use 

reports, and labels; it was determined that a number of pyrethroids in the CAG currently have 

products registered for use indoors. These products include, liquid formulations for allethrin, 

bifenthrin, cyhalothrin, cyfluthrin, cypermethrin, deltamethrin, esfenvalerate, permethrin, 

prallethrin, pyrethrins, and resmethrin; ready-to-use aerosol can formulations for allethrin, 

cypermethrin, deltamethrin, esfenvalerate, permethrin, phenothrin, pyrethrins, and 

resmethrin; and ready-to-use fogger formulations for allethrin, cyfluthrin, cypermethrin, 

esfenvalerate, permethrin, prallethrin, pyrethrins, and resmethrin.

Potential dermal and inhalation exposure was assessed for individuals mixing, loading, and 

applying pyrethroids indoors. This assessment also considers potential dermal post-application 

exposure for adults and young children (1 <2 year olds) contacting treated indoor surfaces. 

Additionally, oral non-dietary exposure (hand-to-mouth) was considered for young children (1 

<2 year olds) potentially transferring treated-indoor surface residues from their hands to their 

mouths.
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6.2.4 Pet Use

Based on an evaluation of risk assessments, reregistration eligibility documents (REDs), use 

reports, and labels; it was determined that a number of pyrethroids in the CAG currently have 

products registered for use on pets. These products include, ready-to-use spot-on formulations 

for cyphenothrin and permethrin; ready-to-use aerosol can formulations for pyrethrins and 

prallethrin; ready-to-use shampoo formulations for permethrin; and ready-to-use trigger pump 

spray formulations for allethrin and resmethrin.

Potential dermal and inhalation exposure was assessed for individuals mixing, loading, and 

applying pyrethroids to pets. This assessment also considers potential dermal post-application 

exposure for adults and young children (1 <2 year olds) contacting treated pets. Additionally, 

oral non-dietary exposure (hand-to-mouth) was considered for young children (1 <2 year olds) 

potentially transferring treated-pet residues from their hands to their mouths.

6.3 Residential Handler Exposure and Risk 

Handler exposure refers to an exposure scenario in which an adult individual is exposed during 

mixing, loading, and applying a pesticide. Residential handler exposure assessments estimate 

dermal and inhalation exposures for individuals using pesticides in and around their homes. 

Dermal and inhalation handler exposure may occur from the residential use of pyrethroids. The 

algorithms used for estimating residential handler exposure and risk were the same for all of 

the residential handler scenarios. However, different assumptions and data sources were used 

depending on the scenario. The algorithms and assumptions are discussed in further detail 

below.

6.3.1 Handler Algorithms

Handler dermal and/or inhalation exposures are estimated by multiplying the application 

method-specific unit exposure by an estimate of the amount of active ingredient handled in a 

day, using the following algorithm:

E =UE * AR* A

where:

E = exposure (mg/day);

UE = unit exposure (mg/lb ai);

AR = application rate (e.g., lb ai/ft2

, lb ai/gal); and

A = area treated or amount handled (e.g., ft2

/day, gal/day).
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Dermal and/or inhalation doses are estimated using the following algorithm:

BW

E * AF D =

where:

D = dose rate (mg/kg-day);

AF = absorption factor (dermal and/or inhalation); and

BW = body weight (kg).

Finally, dermal and/or inhalation margins of exposure are estimated using the following 

algorithm:

D *RPF

IC POD MOE =

where:

MOE = margin of exposure;

D = dose rate (mg/kg-day);

RPF = relative potency factor of any pyrethroid compared to the index chemical, 

deltamethrin; and

IC POD = point of departure for the index chemical, deltamethrin.

6.3.2 Handler Data and Assumptions

The following sections describe the data and assumptions used to estimate dermal and 

inhalation residential handler risks for pyrethroid use on turf, on gardens, indoors, and on pets. 

6.3.2.1 Unit Exposure (UE)

Lawn/Turf Use

Dermal and inhalation exposure routes were considered in this assessment for all of the turf 

residential handler scenarios and application equipment. The unit exposures for each piece of 

application equipment and the studies from which these unit exposures were developed are 

presented below:

• Push-type spreader (granular) - The recommended dermal and inhalation unit exposures 

are 0.81 and 0.0026 mg/lb ai, respectively. The dermal unit exposure was developed 

based on an Outdoor Residential Exposure Task Force (ORETF) study that monitored 30 

applications of a granule formulation for approximately 20 minutes to approximately 

10,000 square feet of turf in North Carolina using a rotary spreader (Klonne, 1999). The 

inhalation unit exposure was developed based on two separate studies; the same ORETF 

study used in the dermal unit exposure (Klonne, 1999) and a proprietary study 
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(Rosenheck, 1993). The Rosenheck study monitored 15 applications of a granule 

formulation for approximately 30-40 minutes to turf in North Carolina using a push 

cyclone spreader.

• Hose-end Sprayer (liquids) - The recommended dermal and inhalation unit exposures 

are 15 and 0.024 mg/lb ai, respectively. Both the dermal and inhalation unit exposures 

were developed based on an ORETF study that monitored 30 applications of a liquid 

pesticide formulation for approximately 75 minutes to approximately 5000 ft2 of 

residential lawns using a dial-type hose-end sprayer (Klonne, 1999).

• Hose-end Sprayer (wettable powders) - No exposure data are available for this 

application scenario and, thus, data for applying liquids via hose-end sprayer were used 

as a surrogate.

• Low-Pressure Handwand Sprayer (liquids) - The recommended dermal and inhalation 

unit exposures are 65 and 0.0054 mg/lb ai, respectively. Both the dermal and inhalation 

unit exposures were developed based on two ORETF studies (Merricks, 1997 and 

Merricks, 1998). The 1997 Merricks study monitored 40 applications of a liquid 

pesticide formulation for approximately 20 minutes to tomato and cucumber gardens 

using a low-pressure handwand. The 1998 Merricks study monitored 20 applications of 

a liquid pesticide formulation for approximately 20 minutes to citrus trees and shrubs 

using a low-pressure handwand. 

• Low-Pressure Handwand Sprayer (wettable powders) - The recommended dermal and 

inhalation unit exposures are 69 and 1.1 mg/lb ai, respectively. The dermal unit 

exposure was developed based on two studies (Merricks, 1987 and Dean, 1988). The 

Merricks study monitored 18 applications of a wettable powder formulation in homes 

and commercial buildings with two 1-gallon “B&G stainless steel PCO sprayers”. The 

Dean study monitored 16 applications of a wettable powder formulation in homes for 

approximately 1.0-2.5 hours using a 1-gallon hand compression sprayer. The inhalation 

unit exposure was developed based only on the 1988 Dean study.

• Backpack Sprayer (liquids) - The recommended dermal and inhalation unit exposures are 

130 and 0.12 mg/lb ai, respectively. The dermal unit exposure was developed based on 

three studies (Merricks, 1988; Contardi et. al, 1993; and Beard, 1997). The Merricks 

study monitored 9 applications of three 2-gallon liquid pesticide solutions for 

approximately 47 minutes to poultry litter using a backpack sprayer. The Contardi study 

monitored 2 applications of a liquid pesticide formulation to greenhouse plants hanging 

overhead, on the floor, or on benches for approximately 1.5 hours using a backpack 

sprayer. The Beard study monitored 15 applications of a liquid pesticide formulation to 

approximately 6000 ft2 of Christmas tree farms in Michigan, Pennsylvania, and 

Connecticut for approximately 4 hours using a backpack sprayer. The inhalation unit 

exposure was developed based on one study (King and Prince, 1995) that monitored 16 

applications of a liquid pesticide formulation for approximately 63-94 minutes to 

greenhouse ornamentals in Florida, Maryland, and California.

• Backpack Sprayer (wettable powders) - No exposure data are available for this 

application scenario and, thus, data for applying wettable powders via low-pressure 

handwand were used as a surrogate.
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• Sprinkler Can (liquids) - No exposure data are available for this application scenario and, 

thus, data for applying liquids via hose-end sprayer were used as a surrogate.

• Sprinkler Can (wettable powders) - No exposure data are available for this application 

scenario and, thus, data for applying liquids via hose-end sprayer were used as a 

surrogate.

Garden, Ornamental, and Tree Use

Dermal and inhalation exposure routes were considered in this assessment for all the garden, 

ornamental, and tree residential handler scenarios and application equipment. The unit 

exposures for each piece of application equipment and the studies from which these unit 

exposures were developed are presented below:

• Hose-end Sprayer (liquids) - The recommended dermal and inhalation unit exposures 

are 15 and 0.024 mg/lb ai, respectively. Both the dermal and inhalation unit exposures 

were developed based on an ORETF study that monitored 30 applications of a liquid 

pesticide formulation for approximately 75 minutes to approximately 5000 ft2 of 

residential lawns using a dial-type hose-end sprayer (Klonne, 1999).

• Low-Pressure Handwand Sprayer (liquids) - The recommended dermal and inhalation 

unit exposures are 65 and 0.0054 mg/lb ai, respectively. Both the dermal and inhalation 

unit exposures were developed based on two ORETF studies (Merricks, 1997 and 

Merricks, 1998). The 1997 Merricks study monitored 40 applications of a liquid 

pesticide formulation for approximately 20 minutes to tomato and cucumber gardens 

using a low-pressure handwand. The 1998 Merricks study monitored 20 applications of 

a liquid pesticide formulation for approximately 20 minutes to citrus trees and shrubs 

using a low-pressure handwand. 

• Backpack Sprayer (liquids) - The recommended dermal and inhalation unit exposures are 

130 and 0.12 mg/lb ai, respectively. The dermal unit exposure was developed based on 

three studies (Merricks, 1988; Contardi 1993; and Beard, 1997). The Merricks study 

monitored 9 applications of three 2-gallon liquid pesticide solutions for approximately 

47 minutes to poultry litter using a backpack sprayer. The Contardi study monitored 2 

applications of a liquid pesticide formulation to greenhouse plants hanging overhead, on 

the floor, or on benches for approximately 1.5 hours using a backpack sprayer. The 

Beard study monitored 15 applications of a liquid pesticide formulation to 

approximately 6000 ft2 of Christmas tree farms in Michigan, Pennsylvania, and 

Connecticut for approximately 4 hours using a backpack sprayer. The inhalation unit 

exposure was developed based on one study (King and Prince; 1995) that monitored 16 

applications of a liquid pesticide formulation for approximately 63-94 minutes to 

greenhouse ornamentals in Florida, Maryland, and California.

• Sprinkler Can (liquids) - No exposure data are available for this application scenario and 

thus data for applying liquids via hose-end sprayer were used as a surrogate.

Indoor Use

Dermal and inhalation exposure routes were considered in this assessment for all of the indoor 

residential handler scenarios and application equipment. The unit exposures for each piece of 
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application equipment and the studies from which these unit exposures were developed are 

presented below:

• Low-Pressure Handwand Sprayer (liquids) - No exposure data are available for this 

application scenario and thus data for applying wettable powders via low-pressure 

handwand sprayer were used as a surrogate. 

• Low-Pressure Handwand Sprayer (wettable powders) - The recommended dermal and 

inhalation unit exposures are 69 and 1.1 mg/lb ai, respectively. The dermal unit 

exposure was developed based on two studies (Merricks, 1987 and Dean, 1988). The 

Merricks study monitored 18 applications of a wettable powder formulation in homes 

and commercial buildings with two 1-gallon “B&G stainless steel PCO sprayers”. The 

Dean study monitored 16 applications of a wettable powder formulation in homes for 

approximately 1.0-2.5 hours using a 1-gallon hand compression sprayer. The inhalation 

unit exposure was developed based only on the 1988 Dean study.

• RTU Aerosol can – The recommended dermal and inhalation unit exposures are 370 and 

3 mg/lb ai, respectively. The dermal and inhalation unit exposures were based on a 

study from Knarr (1991). The Knarr study monitored 15 applications to cracks, crevices, 

baseboards, under sinks, and behind appliances in 15 separate houses using an entire 16 

oz. aerosol can.

• Ready-to-Use (RTU) Total Release Fogger - Total release foggers are assumed to provide 

negligible exposure to the applicator since the label typically requires applicators to exit 

the treatment area immediately. 

Pet Use

Dermal and inhalation exposure routes were considered in this assessment for all of the pet 

residential handler scenarios and application equipment. The unit exposures for each piece of 

application equipment and the studies from which these unit exposures were developed are 

presented below:

• RTU Spot-on - The recommended dermal unit exposure is 220 mg/lb ai. Inhalation 

exposure data during application of spot-on treatments is unavailable; however,

exposure through this route is considered negligible. The dermal unit exposure was 

based on a study from Meo (1997). The Meo study monitored 16 applications by 

commercial pet groomers to 8 dogs for approximately 14-32 minutes using a read-touse (RTU), disposable, snap-top, plastic-backed pipette.

• RTU Shampoo - The recommended dermal and inhalation unit exposures are 2100 and 

0.28 mg/lb ai, respectively. The dermal unit exposure for shampoo applications of liquid 

pesticide formulations to pets, animals, or children is based on two studies (Mester, 

1998 and Selim, 2005). The Mester study monitored 16 applications by commercial pet 

groomers of shampoo to 8 dogs for approximately 149-295 minutes. The Selim study 

monitored 16 shampoo applications to one dog each for approximately 30 minutes. The 

inhalation unit exposure is based only on the Mester study.

• RTU Trigger-pump Sprayer - The recommended dermal and inhalation unit exposures 

are 820 and 3.3 mg/lb ai, respectively. The dermal and inhalation unit exposures for 

applications of liquid pesticide formulations using a trigger-pump sprayer to pets or 
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animals are based on a study from Meo (1997). This study monitored 16 applications by 

commercial pet groomers treating 8 dogs for approximately 38-72 minutes using a readto-use (RTU) trigger-spray bottle.

• RTU Aerosol Can - No exposure data are available for this application scenario and, thus, 

data for using a RTU Trigger-pump sprayer were used as a surrogate. 

6.3.2.2 Application Rate (AR)

In all cases, OPP used the maximum labeled application rate to assess dermal and inhalation 

handler risk estimates for all of the residential pyrethroid uses.

6.3.2.3 Area Treated/Amount Handled (A)

Lawn/Turf Use

OPP assumed two types of treatments could be performed by individuals treating turf: 

broadcast and spot treatments. For broadcast turf treatments using hose-end sprayers (liquids) 

and push-type spreaders (granular), OPP assumed 1⁄2 acre would be treated by a home-owner. 

For spot turf treatments using low-pressure handwand sprayers (liquids and wettable 

powders), backpack sprayers (liquids and wettable powders), and sprinkler cans (liquids and 

wettable powders), OPP assumed 1,000 ft2 would be treated by a home-owner. Determination 

of these values was based mainly on the Outdoor Residential Pesticide Use and Usage Survey 

and National Gardening Association Survey (Johnson, 1999), which showed that 73% of the 

people surveyed had lawns smaller than 1⁄2 acre.

Garden, Ornamental, and Tree Use

OPP assumed 1,200 ft2 would be treated by an individual when treating gardens, ornamentals, 

and trees. Determination of these values was based mainly on the Outdoor Residential 

Pesticide Use and Usage Survey and National Gardening Association Survey (Johnson, 1999), 

which showed that the average garden size was 1,200 ft2.

Indoor Use

OPP assumed broadcast and crack and crevice treatments could be performed by individuals 

treating indoor surfaces. Both of these types of treatments are surface-directed and could be 

applied with a low-pressure handwand or an aerosol can. The low-pressure handwand was 

assumed to be used for both broadcast and crack and crevice treatments. OPP assumed 0.5 

gallons would be used by a homeowner for both types of treatments. These values are 

supported by data from the Pesticide Handler Exposure Database (PHED), which indicate about 

0.5 gallons for a commercial applicator crack/crevice and limited surface treatment in 

residences. Based on the use pattern for the pyrethroids, aerosol cans are only registered for 

crack and crevice treatments. OPP assumed 1⁄2 of a 16-oz can would be used. This value is 

supported by data from the Pesticide Handler Exposure Database (PHED), in which studies were 

conducted with commercial applicators applying one 15-oz aerosol can to areas of residential 

homes, including cracks, crevices, baseboards, under sinks, behind appliances, etc.
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Pet Use

OPP assumed that residential handlers of pet treatment products will treat 2 animals per 

application. This estimate is based upon data from the American Pet Products Manufacturers 

Association (APPMA) 2007-2008 National Pet Owners Survey, which reports that pet owners 

have an average of 1.7 dogs and 2.3 cats.

6.3.3 Handler Risk Summary

For all scenarios, there are no residential handler risk estimates of concern associated with the 

registered uses of pyrethroids. All MOEs are greater than the target MOE of 100 for adult 

handlers (see Appendix 7 and Table 6.4.7a).

6.4 Post-application Exposure and Risk

Post-application exposure refers to an exposure scenario in which an individual is exposed 

through dermal, inhalation, and/or incidental oral (non-dietary ingestion) pathways as a result 

of being in an environment that has been previously treated with a pesticide. Post-application 

dermal exposure is dependent on surface residues after treatment and surface-to-skin transfer. 

Post-application inhalation exposure depends on concentrations in the air after treatment and 

inhalation rates. Post-application non-dietary oral exposures are based on the ingestion of 

residues that can result from transfer of residues from hand-to-mouth. Dermal, inhalation, and 

non-dietary oral (hand-to-mouth) post-application exposure may occur following the residential 

use of pyrethroids depending on the use site. The algorithms and assumptions used for 

estimating residential post-application dermal, inhalation, and non-dietary oral are discussed in 

further detail below.

6.4.1 Post-application Dermal Exposure

Post-application dermal exposure may occur following the residential uses of pyrethroids. 

6.4.1.1 Dermal Post-application Algorithm

The following general equation is used to calculate dermal exposures resulting from contact 

with treated residential surfaces. 
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E = TR * TC * ET

where:

E = exposure (mg/day);

TR = transferable residue (mg/cm2);

TC = transfer coefficient (cm2

/hr); 

ET = exposure time (hr/day).

Dermal doses are estimated using the following algorithm:

BW

E * AF D =

where:

D = dose rate (mg/kg-day);

AF = absorption factor (dermal); and

BW = body weight (kg).

Finally, dermal margins of exposure are estimated using the following algorithm:

D *RPF

IC POD MOE =

where:

MOE = margin of exposure;

D = dose rate (mg/kg-day);

RPF = relative potency factor of any pyrethroid compared to the index chemical, 

deltamethrin; and

IC POD = point of departure for the index chemical, deltamethrin.

6.4.1.2 Dermal Post-application Data and Assumptions

6.4.1.2.1 Transferable Residue (TR)

Following an application, pesticide residues, which are deposited and remain on surfaces, could 

be contacted and removed by an individual. The pesticide residue is then available for 

absorption through the skin or potential ingestion. The residue available for transfer is referred 

to as transferable residue (TR). If pyrethroid-specific transferable residue data were available 

for a specific chemical, they were used in the cumulative screen. If pyrethroid-specific data 

were not available, the TR was calculated based on a fraction of the pesticide applied.
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Lawn/Turf Use

For the lawn/turf use scenario, chemical-specific turf transferable residue (TTR) data collected 

with the Modified California Roller Method are available, and directly used, for four 

pyrethroids: cyfluthrin (liquid formulations), cypermethrin (liquid and wettable powder 

formulations), deltamethrin (liquid formulations), and permethrin (liquid formulations). 

Cyfluthrin resulted in the highest normalized turf transferable residues out of the available 

liquid formulation TTR data. For the liquid formulation pyrethroids that did not have TTR data 

available, cyfluthrin TTR data were used as a surrogate. In all cases, the cyfluthrin TTR data 

were adjusted to reflect the maximum individual pyrethroid application rates. Table 6.4.1.2.1a

summarizes the available pyrethroid TTR data.

Table 6.4.1.2.1a. Pyrethroid TTR Summary

Chemical Study Sites

Day 0 

TTR

(ug/cm2)

Average 

Day 0 TTR

(ug/cm2)

Average Day 0 

TTR Normalized 

to 0.1 lb ai/A

(ug/cm2)

Cyfluthrin

Determination of Transferable Turf 

Residues on Turf Treated With Cyfluthrin 

(MRID 45149001)

GA (L) 0.023

MS (L) 0.032 0.021 0.011

NY (L) 0.007

Cypermethrin Demon WP and Demon TC Transferable 

Turf Residue Study (MRID 45111501)

CA (WP) 0.081

MO (WP) 0.041 0.071 0.012

PA (WP) 0.090

CA (L) 0.035

MO (L) 0.009 0.023 0.0052

PA (L) 0.026

Deltamethrin

Determination of Transferable Turf 

Residues on Turf Treated with 

Deltamethrin (Deltagard GC or T&O) (MRID 

45251201)

NY (L) 0.008

CA (L) 0.020 0.014 0.010

GA (L) 0.013

Permethrin

Transferable Turf Residue Study: 

Permethrin Residues in Turf Following 

Application of Dragnet® SFR 

Insecticide/Miticide (MRID 44955501)

PA (L) 0.051

CA (L) 0.073 0.061 0.0070

GA (L) 0.058

Garden, Ornamental, and Tree Use

For the garden, ornamental, and tree use scenario, chemical-specific dislodgeable foliar residue 

(DFR) data are available for four pyrethroids: cyfluthrin, fluvalinate, esfenvalerate, and 

permethrin. Most of these DFR data were collected on orchard crops (i.e., stone fruits, apples, 

oranges) or in greenhouses. The esfenvalerate DFR data included analysis of foliar residues on 

corn and broccoli and are considered most representative of potential crops that could be 

found in a home garden. These data were combined and used as a surrogate for all of the 

pyrethroids. In all cases, the esfenvalerate DFR data were adjusted to reflect the maximum 

individual pyrethroid application rates. Table 6.4.1.2.1b summarizes the available pyrethroid 

DFR data.
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Table 6.4.1.2.1b. Pyrethroid DFR Summary

Chemical Study Sites Day 0 DFR

(ug/cm2)

Average Day 0 DFR

(ug/cm2)

Esfenvalerate

Dissipation of Dislodgeable Foliar 

Residues of Esfenvalerate from Broccoli 

Following Application of Asana® XL 

Insecticide in the USA - Season 1997

(MRID 44852402)

CA1 (L) 0.157

0.132

CA2 (L) 0.122

Dissipation of Dislodgeable Foliar 

Residues of Esfenvalerate from Sweet 

Corn Following Application of Asana® XL 

Insecticide in the USA - Season 1998 

(MRID 44852403)

FL (L) 0.072

PA (L) 0.177

Indoor Use

For the indoor uses scenarios, no chemical-specific transferable residue (TR) data are available 

for the pyrethroids; therefore, the TR was calculated using the following formula:

TR = DepR * Fai

where:

TR = indoor surface transferable residue (μg/cm2);

DepR = deposited residue (ug/cm2

), and

Fai = fraction of ai available for transfer from carpet or hard surface (unitless).

Deposited Residue (DepR)

Broadcast applications: For broadcast applications, the deposited residue was assumed to be 

equivalent to the application rate (a unit conversion was performed to achieve residue values in 

units of ug/cm2

). A formal evaluation was conducted for each pyrethroid with registered indoor 

broadcast uses to determine the maximum application rate currently registered. These rates

were used in the screening-level cumulative assessment. 

Fogger applications: For fogger applications, data from the Non-Dietary Exposure Task Force 

(NDETF) were used to estimate deposited residue for the pyrethroids with registered indoor 

fogger uses (Rogers, 2000; Selim, 2002a; Selim, 2003a). The NDETF conducted three studies 

measuring the deposited residue following application of a 0.2% deltamethrin fogger, a 0.5% 

permethrin fogger, and a 0.5% pyrethrins fogger. In each study, the fogger was discharged in 

an experimental room and the resulting deposited residues were measured using deposition 

coupons. The average residue value (adjusted to 0.5% active ingredient, if necessary) from 

each study was 5.6 ug/cm2 for deltamethrin, 4.8 ug/cm2 for permethrin, and 5.8 ug/cm2 for 

pyrethrins. The average residue value across the three studies was 5.4 ug/cm2 for a 0.5% 

fogger.

A formal evaluation of all the registered uses was conducted for each pyrethroid with 

registered indoor fogger uses to determine the maximum percent active ingredient in 

registered products. In the cumulative screen, the chemical-specific residue for deltamethrin, 
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permethrin, and pyrethrins was used, making an adjustment for the maximum percent active 

ingredient registered. For the pyrethroids without chemical-specific residue data, the average 

residue value from the three studies was used, making the same adjustment for maximum 

percent active ingredient registered. 

Crack and crevice applications: For crack and crevice applications, the Agency used a registrantsubmitted study (Selim, 2008) that provided an estimate of deposited residue from a crack and 

crevice application for esfenvalerate. In this study, a 0.1% esfenvalerate formulation was 

applied using an aerosol can with an injection tube. The test container was held 12 to 18 inches 

above the baseboard to achieve an approximate one inch spray band at the floor/wall interface. 

Residues were collected 30 minutes after application using deposition coupons. The residue 

value for the entire room was calculated as a weighted average of the “treated area” and the 

“untreated area” (10% of residue in treated area plus 90% of residue in untreated area). This 

resulted in a weighted residue value of 0.2 ug/cm2

. This value was used for all of the 

pyrethroids with registered crack and crevice uses. It was not adjusted for percent active 

ingredient because data available to the Agency do not seem to indicate a trend with respect to 

deposited residues and percent active ingredient (i.e., a higher percent active ingredient does 

not necessarily result in a higher deposited residue value for a room).

Fraction of Residue Available For Transfer (Fai)

Chemical-specific data provided by the Non-Dietary Exposure Task Force (NDETF) were used for 

the fraction of residue available for transfer (Selim, 2004a; Selim, 2003b; Selim, 2003c; Selim, 

2000; Selim, 2002b; Selim, 2002c). The NDETF studies examined the transferability of residues 

from bare hand-presses on carpets and hard surfaces for deltamethrin, permethrin, and 

pyrethrins. For carpets, the fraction transferred was 0.03, 0.02 and 0.01 for pyrethrins, 

permethrin and deltamethrin, respectively. For hard surfaces, the fraction transferred was 

0.04, 0.03, and 0.05 for pyrethrins, permethrin, and deltamethrin, respectively. Since the 

values were so similar across the three chemicals, the average fraction transferred was used for 

all the pyrethroids in the cumulative assessment: 0.02 for carpets and 0.04 for hard surfaces.

Pet Use

For the pet uses scenarios, no chemical-specific TR data are available; therefore, the TR was 

calculated using the following formula:

TR = (AR * FAR) / SA

 

where:

TR = transferable residue (mg/cm2);

AR = application rate or amount applied to animal (mg);

FAR = fraction of the application rate available as transferable residue; and

SA = surface area of the pet (cm2).
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Application Rate (AR)

A formal evaluation was conducted for each pyrethroid with registered pet uses to determine 

the maximum application rate currently registered. These rates were used in the screeninglevel cumulative assessment. 

Fraction Application Rate (FAR)

A default FAR was selected based on the review of 8 “petting” studies submitted to the Agency. 

Measurements of residue availability were derived by taking the ratio of the amount of active 

ingredient on a bare or gloved hand (on the day of highest observed transfer) to the amount of 

active ingredient applied. Studies were performed by means of volunteers “petting” or 

“stroking” animals treated with a known amount of active ingredient and determining the 

amount of residue transferred to the hands. FAR studies varied in the number, location and 

intensity of petting and stroking actions. Based on the available studies, the mean FAR is 

estimated to be 0.0096 (Hughes, 1997; Hughes, 1997b; McKeown, 2001; Brickel, et. al, 1997; 

Bach, 2002; Wrzesinski, 2009; Wrzesinski, 2010a; Wrzesinski, 2010b). Table 6.4.1.2.1c

summarizes the available FAR data.

 

Table 6.4.1.2.1c. Fraction Application Rate (FAR) Transferred

Study MRID N

Average 

Fraction of 

Application Rate 

Transferred

Dislodgeable Residues of Fipronil Following Application of 

Frontline® Spray Treatment to Dogs 44433306 30 0.0069

Dislodgeable Residues of Fipronil Following Application of 

Frontline® Spray Treatment to Cats 44433307 15 0.0039

Determination of the Dislodgeability of Tetrachlorvinphos (TCVP) 

from the Fur of Dogs Following the Application of an Insecticide 

Powder, Pump Spray or Aerosol

45485501 10 0.0030

Dislodgeable Residues of Fipronil Following Topical Application of 

Frontline® Spot-on Treatment to Dogs 44531203 18 0.0076

Stroking Test in Dogs After Topical Application of Imidacloprid 10% 

(w/v) + Permethrin 50% (w/v) Spot-On 46594103 18 0.0027

Dislodgeable Residue Study of SCH 783460 (Indoxacarb) from SpotOn Treated Beagle Dogs 47834502 20 0.0208

One-Month Dislodgeable Residue Study of SCH 783460 (Indoxacarb) 

from Spot-On Treated Cats 48010801 20 0.0100

One-Month Dislodgeable Residue Study of Indoxacarb from Spot-On 

Treated Beagle Dogs 48135326 20 0.0094

One-Month Dislodgeable Residue Study of Permethrin from SpotOn Treated Beagle Dogs 48135326 20 0.0176

Surface Area (SA)

Animal surface area (SA) is determined by inputting animal weight (lbs) into an algorithm 

(12.3*((animal body weight (lbs)*454)^0.65)) as referenced from U.S. EPA (1993) Wildlife 

Exposure Factors Handbook. For the purposes of the pyrethroid screen, the surface area of a 

medium dog was used in the calculations of exposure (7000 cm2). 
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6.4.1.2.2 Transfer Coefficient (TC)

The transfer coefficient (TC) provides a measure of surface-to-skin residue transfer and is 

derived from concurrent measurements of exposure and surface residue. Specifically, the TC is 

the ratio of exposure rate, measured in mass of chemical per time (i.e., ug/hr), to residue, 

measured in mass of chemical per surface area (i.e., ug/cm2). Table 6.4.1.2.2 summarizes the 

transfer coefficients for the different residential scenarios.

Lawn/Turf Use

The transfer coefficients used for assessing the lawn/turf dermal scenarios were derived from 

data gathered while adult human volunteers performed an approximate 2-hour composite 

routine consisting of 12 sequential activities which children and adults routinely engage on 

residential turf (Klonne and Johnson, MRID 47292001). These activities represent behaviors 

that are reported in the National Human Activity Pattern Survey (NHAPS) for children aged 1 to 

12 years (Klepeis, et. al., 2001). The two hour duration of the routine was chosen because 

NHAPS indicated that the upper-bound estimate of time children spend playing on turf is two 

hours per day. The potential dermal exposure to each study participant was measured by using 

whole-body dosimetry (inner and outer dosimeters), foot washes, hand washes, and face/neck 

wipes.

Garden, Ornamental, and Tree Use

The transfer coefficients used for assessing the garden, ornamental, and tree dermal scenarios 

were derived from data gathered while adult human volunteers performed various tasks such 

as weeding and picking flowers and vegetables. The data used to derive the transfer 

coefficients are from occupational reentry exposure studies conducted by the Agricultural 

Reentry Task Force (ARTF) because data to adequately characterize exposure for individuals 

who contact previously treated residential gardens, ornamentals, and trees are unavailable. 

Four separate exposure studies were used to develop the transfer coefficient: a study each for 

cabbage weeding (Klonne, 2000; MRID 45191701), tomato tying (Klonne, 2001; MRID 

45530103), squash harvesting (Klonne, 2001; MRID 45491902), and chrysanthemum pinching 

(Klonne, 2000; MRID 45344501). Therefore, transfer coefficients from occupational reentry 

exposure studies conducted by the Agricultural Reentry Task Force (ARTF), were used to 

establish composite transfer coefficients representing activities likely to occur in residential 

settings.

Indoor Use

The transfer coefficients used for indoor scenarios are derived from information provided in 

three different studies: (1) two studies which measured exposure and surface residues while 

subjects performed a JazzerciseTM routine (Krieger, 2000 and Selim, 2004) and (2) a study which 

measured biomonitoring doses while adults performed scripted activities for 4 hours on carpet 

(Vaccaro, 1991). In the Krieger and Selim studies, a JazzerciseTM routine was performed to 

achieve maximum contact of the entire body with a surface using low impact aerobic 

movements. The potential dermal exposure was measured by using whole-body dosimetry. 

The assumption is that the dosimeter represents the skin and that the dose retained by the 
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dosimeter is equivalent to dermal exposure. In the Vaccaro study, adult males, dressed in 

bathing suits only, performed different activities over a 4-hour activity period. These activities 

included: sitting-playing with blocks, on hands and knees crawling, walking on carpet, laying on 

back, and laying on abdomen. Using information from these studies on residue transfer, 

exposure and dose provides an estimated transfer coefficient for indoor activities. It is 

assumed that the shorter duration of high contact activity (i.e., JazzerciseTM) can be used to 

estimate exposure during longer durations of low contact activity.

Pet Use

The transfer coefficients used for pet exposure were derived from a study representing 

application and grooming activities with dogs using a carbaryl shampoo product (Mester, 1998). 

Data were gathered while human volunteers applied pet pesticide products to various dogs of 

differing sizes and fur lengths. 

Table 6.4.1.2.2. Transfer Coefficient Summary

Scenario Adults (cm2/hr) 6-11 year olds (cm2/hr) 1-2 year olds (cm2/hr)

Turf/Lawn Use 130,000 NA 37,000

Garden/Ornamental/Tree Use 8,400 5,000 NA

Indoor Use 6,800 NA 2,000

Pet Use 5,200 NA 1,500

6.4.1.2.3 Exposure Time (ET)

Table 5.4.1.2.3 summarizes the selected exposure times for the different residential scenarios.

Lawn/Turf Use

The exposure times used for assessing the lawn/turf dermal scenarios were selected from data 

presented in the Agency’s Exposure Factors Handbook Table 15-80 (USEPA, 1997). These data 

represent the amount of time spent outdoors rather than just on lawns. This adjustment allows 

for additional time that children may spend outdoors (such as parks and schools) where there is 

potential for additional contact with treated turf.

Garden, Ornamental, and Tree Use

The exposure times used for assessing the garden, ornamental, and tree dermal scenarios were 

derived using a residential survey (Johnson, 1999) and information from the U.S. EPA Exposure 

Factors Handbook (USEPA, 1997). The exposure time for gardening represents vegetable 

gardening and flower gardening in equal proportion (i.e., 50% each).

Indoor Use

A study which provides information specific to time spent on different types of surfaces indoors 

is not available. The Exposure Factors Handbook (U.S. EPA, 1997) and the Child Specific 

Exposure Factors Handbook (U.S. EPA, 2008) provide information on total time spent in a 

residence and time spent in various rooms within a residence. In order to develop inputs for 

exposure time on carpets and hard surfaces, two assumptions were made: (1) kitchens and 
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bathrooms would represent time spent on hard surfaces and (2) time spent in a residence, less 

time spent sleeping and napping, would represent time spent on carpets. 

Pet Use

The exposure time for adults and children were derived from the US EPA’s National Center for 

Environmental Assessment (NCEA) Exposure Factors Handbook (USEPA, 1997). The 

recommended data are included in Table 15-77, Statistics for 24-Hour Cumulative Number of 

Minutes Spent in Animal Care. Animal care is defined by NCEA as “care of household pets 

including activities with pets, playing with the dog, walking the dog and caring for pets of 

relatives, and friends.” The data identified the time spent with an animal while performing 

household activities as recorded in 24 hour diaries by study volunteers. While the activities 

defined do not necessarily represent the time volunteers were actively engaged in constant 

contact with the animal, as is implicit in the post-application dermal and incidental oral 

algorithms, they were used to derive the best data source available. 

Table 6.4.1.2.3. Exposure Time Summary

Scenario Adults (hrs) 6-11 year olds (hrs) 1-2 year olds (hrs)

Turf/Lawn Use 1.1 NA1 0.9

Garden/Ornamental/Tree Use 1.4 0.7 NA2

Indoor Use Carpets 8 NA1 5

Hard Surfaces 2 NA1 1

Pet Use 0.77 NA1 0.99

NA1 - not assessed because 1-2 yr olds are expected to be protective for 6-11 yr olds

NA2 - not assessed because 1-2 yr olds are not expected to be performing gardening activities

6.4.2 Post-application Dermal Risk Summary

For all scenarios, there are no residential post-application dermal risk estimates of concern 

associated with the registered uses of pyrethroids. All MOEs were greater than the Agency’s 

target MOE of 300 for children and 100 for adults (see Appendix 7 and Table 6.4.7a).

6.4.3 Post-application Inhalation Exposure

For turf and gardens, post-application inhalation exposure is generally not assessed. The 

combination of the generally low vapor pressure for pyrethroids and the substantial dilution of 

airborne concentrations outdoors is likely to result in minimal inhalation exposure.

For pet uses, post-application inhalation exposure is generally not assessed. The combination 

of the generally low vapor pressure for pyrethroids and the small amounts of pesticide applied 

to pets is likely to result in minimal inhalation exposure.

For indoor uses, post-application inhalation exposure is dependent on the type of application 

made: 
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Fogger applications: Post-application inhalation exposure due to the use of indoor foggers is 

expected to be negligible since most fogger product labels typically state a period of no-entry 

following application (usually up to 4 hours), as well as a ventilation period before occupants 

can return. 

Crack and crevice applications: For crack and crevice applications, there is the potential for 

post-application inhalation exposure to pesticide vapors emitting from the treated surfaces 

following application. For pyrethroids, this exposure is not expected to be significant primarily 

because of their low vapor pressure. HED has recently received an Office of Research and 

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

This study is currently unpublished but HED has reviewed the data (Smith, D390098, 2011). 

This study simulated crack and crevice applications of four pesticides; two emulsifiable 

concentrates products applied via a handheld sprayer (permethrin and cypermethrin), one 

aerosol can product (propoxur), and one gel bait product (fipronil). Permethrin and 

cypermethrin air concentrations were not found in any measurable quantities in any room in 

the research house. Although this study provides data for only two pyrethroids, the Nondietary Exposure Task Force (NDETF) has performed an analysis of all the pyrethroid exposure 

data that they produced (Osimitz and Holden, 2005; MRID 46493701). This analysis shows the 

exposure data for one pyrethroid can generally be used to represent the entire chemical class. 

Based on this NDETF analysis, the air concentration data from the ORD study can be considered 

representative of all pyrethroids. Given the negligible air concentration values that were 

reported from the ORD study, HED does not have concerns for post-application inhalation 

exposure from pyrethroid crack and crevice applications. 

Broadcast applications:

Similar to crack and crevice applications, there is the potential for post-application exposure to 

pesticide vapors emitting from treated indoor surfaces following indoor broadcast applications. 

For pyrethroids, this exposure is not expected to be significant primarily because of their low 

vapor pressure. Pyrethroid-specific air monitoring data following a broadcast application are 

not available; therefore, the approach discussed below was used to estimate potential postapplication exposure for the pyrethroids with broadcast uses (allethrin, esfenvalerate, 

permethrin, pyrethrins, and tetramethrin). 

6.4.3.1 Post-application Inhalation Algorithms 

Post-application inhalation exposure for adults/children resulting from surface-directed spray 

applications made indoors can be estimated using the following algorithm:
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( ) ( ) 



 





















−

− = −

− −

ACH k

ACH e k e

ACH V

IR M E

k ET ACH ET

room

label

* * * *

*1

*

*

Where:

E = exposure (mg/day);

IR = inhalation rate (m3

/hr);

Mlabel = mass of active ingredient applied, determined from product label (mg);

Vroom = volume of room (m3

);

ACH = air exchanges per hour (hour-1);

k = first order decay rate; and

ET = exposure time (hr).

Once the post-application inhalation exposure is calculated, the inhalation dose normalized to 

body weight is calculated as:

BW

E AF D * =

where:

D = dose (mg/kg-day);

E = exposure (mg/day);

AF = absorption factor (inhalation); and

BW = body weight (kg).

Finally, inhalation margins of exposure are estimated using the following algorithm:

D *RPF

IC POD MOE =

where:

MOE = margin of exposure;

D = dose rate (mg/kg-day);

RPF = relative potency factor of any pyrethroid compared to the index chemical, 

deltamethrin; and

IC POD = point of departure for the index chemical, deltamethrin.

6.4.3.2 Post-application Inhalation Data and Assumptions 

6.4.3.2.1 Inhalation Rate (IR)

For indoor post-application exposure, it is recommended that the inhalation rate for sedentary 

and passive activities be used in the exposure calculation. The values used in this assessment 

are 0.32 m3

/hr for adults and 0.28 m3/hr for 1 to <2 year olds (U.S. EPA, 2009).
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6.4.3.2.2 Mass of active ingredient applied (Mlabel)

The mass of active ingredient applied was calculated based on maximum application rates 

determined by a formal evaluation of all the registered pyrethroid indoor uses. The application 

rates were in units of lb ai/square feet and it was assumed for broadcast applications that the 

product was sprayed over an area of 144 square feet (12 ft by 12 ft room).

6.4.3.2.3 Air Changes per Hour (ACH)

Air changes per hour is the rate that air within an indoor environment is replaced by outdoor 

air. The value used in this assessment is 0.18 ACH, which represents the 10th percentile of the 

estimated national distribution for residential air exchange rates and is a conservative 

estimation of air exchange in residential settings (U.S. EPA, 1997). 

6.4.3.2.4 Volume of a Room (Vroom)

The volume of a room is based on typical dimensions of residential rooms from Exposure 

Factors Handbook (U.S. EPA, 1997). For a 12 foot by 12 foot room, with an 8 foot high ceiling, 

the typical volume is 33 m3

.

6.4.3.2.5 First Order Decay Rate (k)

The decay rate, k, defines the change in the emission rate from the treated surface. As 

proposed by Evans (1994), the decay rate constant is based on the 90% drying time. The 90% 

drying time, in turn, is calculated based on the evaporation time and volatility of the chemical 

using equations from Chinn (1981).

6.4.3.2.6 Exposure Time (ET)

For vapor emissions from surface-directed sprays, it is assumed that the vapors can continue to 

emit over time; therefore, exposure time is related to time spent in a residence. The value used 

in this assessment is 16 hours for both adults and 1 to <2 year olds (U.S. EPA, 1997 and U.S. 

EPA, 2008). 

6.4.4 Post-application Inhalation Risk Summary

For all scenarios, there are no residential post-application inhalation risk estimates of concern

associated with the registered uses of pyrethroids. All MOEs were greater than the Agency’s 

target MOE of 300 for children and 100 for adults (see Appendix 7 and Table 6.4.7a).
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6.4.5 Post-application Incidental Oral Exposure and Risk

Post-application incidental oral exposure may occur following the lawn/turf, indoor, and pet 

uses of pyrethroids. For gardens, post-application incidental oral exposure is not assessed as 

younger children are not expected to spend extended periods of time in contact with gardens, 

ornamentals, and trees.

6.4.5.1 Post-application Incidental Oral Algorithm

Post-application incidental oral exposure for children resulting can be estimated using the 

following algorithm:

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

(Freq_Replen/N-Replen))]

Where:

E = exposure (mg/day);

HR = hand residue loading (mg/cm2);

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

ET = exposure time (hr/day);

SAH = surface area of one hand (cm2);

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

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

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

Hand residues are estimated using the following algorithm.

HR = (Faihands * DE) / (SAH * 2)

Where:

HR = hand residue loading (mg/cm2

);

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

study (unitless);

DE = dermal exposure (mg); and

SAH = typical surface area of one hand (cm2

).

Non-dietary incidental oral doses are estimated using the following algorithm:

BW

E D =

where:

D = dose rate (mg/kg-day); and

BW = body weight (kg).
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Finally, non-dietary incidental oral margins of exposure are estimated using the following 

algorithm:

D *RPF

IC POD MOE =

where:

MOE = margin of exposure;

D = dose rate (mg/kg-day);

RPF = relative potency factor of any pyrethroid compared to the index chemical, 

deltamethrin; and

IC POD = point of departure for the index chemical, deltamethrin.

6.4.5.2 Post-application Incidental Oral Data and Assumptions

6.4.5.2.1 Hand Residue (HR)

The available residue on hands for non-dietary ingestion is linked to dermal exposure and is 

calculated as a fraction of the dermal exposure. The fraction of active ingredient available on 

the hands was based on data from the dermal transfer coefficient studies for turf, indoors, and 

pets. This value was estimated by taking the average fraction of active ingredient on the hands 

in each dermal study and comparing that value to the average fraction of active ingredient on 

the entire body assuming an individual is wearing a t-shirt and shorts. The fraction of active 

ingredient available on the hands (Faihands) for each scenario is provided in Table 6.4.5.2.1 

below. 

Table 6.4.5.2.1. Fraction of active ingredient available on hands

Scenario Faihands

Turf/Lawn Use 0.06

Indoor Use 0.15

Pet Use 0.039

6.4.5.2.2 Fraction of Hand Mouthed per Event (FM)

The fraction hand surface area mouthed value was taken from the Zartarian et al. (2005) 

analysis of data originally presented in Leckie et al. (2000). The Leckie et al. (2000) study 

consisted of a data set of 20 suburban children videotaped outdoors. Part of the videotape 

analysis performed by Leckie was to determine the amount of the hand that was mouthed by 

each child every time a mouthing event occurred. The analysis in Zartarian et al. (2005) 

consisted of assigning numerical values to each of five scenarios (outside mouth contact, partial 

finger, full finger, partial palm with fingers, and partial palm without fingers). It was assumed 

that each finger is 10% of the hand, and that the surface area of palm that can be mouthed is 
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25% of the hand. For 1 “partial finger” inserted into the mouth a value of 5% of the hand was 

selected, 2 partial fingers 10%, et cetera. The fraction of hand mouthed used for all non-dietary 

incidental oral ingestion scenarios in this assessment is 0.13.

6.4.5.2.3 Hand Surface Area (SAH)

The hand surface area for 1 to <2 year olds is 150 cm2 for one hand which is based on data from 

the Child-Specific Exposure Factors Handbook (U.S. EPA, 2008). This value was used for all nondietary incidental oral ingestion scenarios in this assessment.

6.4.5.2.4 Fraction of Pesticide Extracted by Saliva (SEH)

The value for fraction of pesticide extracted by saliva is based on analysis of data collected in a 

study by Camann et al. (1995). This study focused specifically on fraction of pesticide extracted 

by saliva from hands, not objects. The fraction of pesticide extracted by saliva value used for all 

non-dietary incidental oral ingestion scenarios in this assessment is 0.48.

6.4.5.2.5 Exposure Time (ET)

The exposure times used in the assessment of the non-dietary incidental oral ingestion 

scenarios is the same as described for 1 < 2 year olds above in Section 3.2.1.2.3 and Table X.

6.4.6 Post-application Incidental Oral Risks

For all scenarios, there are no residential post-application incidental oral risk estimates of 

concern associated with the registered uses of pyrethroids. All MOEs were greater than the 

Agency’s target MOE of 300 for children (see Appendix 7 and Table 6.4.7a).

6.4.7 Combined Exposure

The sections above describe the separate dermal (handler and post-application), inhalation 

(handler and post-application), and non-dietary oral ingestion (post-application) assessments 

that have been performed for the pyrethroids. In reality, exposures resulting from different 

routes do not occur as single, isolated events, but rather as a series of sequential or concurrent 

events that may overlap or be linked in time and space. Based on this, risk estimates resulting 

from different exposure routes are combined when it is likely that they can occur 

simultaneously based on the use pattern and when the toxicological effects across different 

routes of exposure are the same.

Table 6.4.7a presents the highest estimated risk (i.e., the lowest MOE) for each of the individual 

routes of exposure that could occur for a use scenario. It also presents the estimated risks for 

combining all of the individual routes of exposure within a use scenario. For children (1 to <2 

years), all MOEs were above the target MOE of 300 when all routes of exposure were combined 
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within a particular exposure scenario. For adults, all MOEs were above the target MOE of 100 

when all routes of exposure were combined within a particular exposure scenario.

Table 6.4.7a. Pyrethroid Screening Level Combined Residential Assessment Within Scenario Results

Lifestage Scenario

Handler Post-application Exposure Route Combined 

Within 

Scenario Dermal Inhalation Dermal Inhalation HtM

1 < 2 year 

olds

Turf NA NA 3,000 NA 21,000 2,600 (cyfluthrin)

Pet NA NA 4,200 NA 220003,500 (cyphenothrin)

Indoor 

Broadcast NA NA 15,000 110,000,000 3800

3,000 (esfenvalerate)

Indoor Fogger NA NA 3,500 NA 900720 (cypermethrin)

Indoor C&C NA NA 36,000 NA 9,700 7,600 (cyhalothrin)

Adults

Turf

9,200 280,000 4,500 NA NA

(cyfluthrin-hose-end 3,000

sprayer (cyfluthrin)

Garden 15,000 780,000 1,400 NA NA1,300 (fluvalinate-backpack) (fluvalinate)

Pet

27,000 10,000,000 9,800 NA NA

7,200 (permethrin-shampoo) (cyphenothrin)

Indoor 

Broadcast

240,000 760,000 17,000 610,000,000 NA

16,000 (allethrin-LPHW) (esfenvalerate)

Indoor Fogger NA NA 3,900 NA NA3,900 (cypermethrin)

Indoor C&C 43,000 140,000 43,000 NA NA19,000 (cyfluthrin-LPHW) (cyhalothrin)

Once the screening level values for residential exposure were combined within a use scenario, 

the next step was to combine scenarios that could potentially co-occur. For example, a child 

could be exposed in the same day by contacting a treated pet and a treated indoor surface. In 

all cases, the MOE representing the highest residential risk estimate (i.e., the lowest MOE) was 

chosen to represent each scenario for adults and children (1 to <2 years). For example, there 

are a number of pyrethroids registered for use on turf, but the combined turf cyfluthrin MOEs 

were used to represent all pyrethroid turf use because cyfluthrin resulted in the lowest 

combined turf MOEs for adults and 1 < 2 year olds. Although combining scenarios that use 

high-end, health protective inputs or assumptions is not typically appropriate due to 

compounding conservatisms, HED performed such a health protective, screening level 

combined residential exposure assessment for the pyrethroids. 

Table 6.4.7b presents an analysis of a number of scenario combinations. For children (1 to <2 

years), all MOEs were above the target MOE of 300 for all of the scenario combinations 
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considered. For adults, all MOEs were above the target MOE of 100 for all of the scenario 

combinations considered.

Table 6.4.7b. Pyrethroid Screening Level Combined Residential Assessment Across Scenario Results

Lifestage Scenario

Combined 

Within 

Scenario MOE

Routes of 

Exposure

Combined Across 

Scenarios

1 < 2 year olds

Turf 2,600 PD, PHtM

Pet 3,500 PD, PHtM 1,000

Indoor Broadcast 3,000 PD, PI, PHtM

Turf 2,600 PD, PHtM

Pet 3,500 PD, PHtM 490

Indoor Fogger 720 PD, PHtM

Turf 2,600 PD, PHtM

Pet 3,500 PD, PHtM 1,200

Indoor Crack & Crevice 7,600 PD, PHtM

Adults

Garden 1,300 HD, HI, PD 910 Turf 3,000 HD, HI, PD

Pet 7,200 HD, HI, PD 5,200 Indoor Crack & Crevice 19,000 HD, HI, PD

PD = post-application dermal exposure, PHtM = post-application hand-to-mouth exposure, PI = post-application inhalation exposure, HD = 

handler dermal exposure, HI = handler inhalation exposure. PD = post-application dermal exposure, PHtM = post-application hand-to-mouth 

exposure, PI = post-application inhalation exposure, HD = handler dermal exposure, HI = handler inhalation exposure 

7.0 Combined Screening Level Dietary + Residential Cumulative

Once the screening level risk estimates for exposure by the dietary and residential pathways 

were calculated, the next step was to combine them into a screening level pyrethroid 

cumulative assessment. In light of the complexity of the residential use patterns, the Agency 

elected to take a screening approach to the cumulative assessment, by combining the risk

estimates from the dietary pathway with the highest risk estimates from the appropriate 

residential pathways. This approach is considered highly conservative and health protective for 

reasons outlined in Section 8.0. The calculations for the screening level cumulative risk 

assessment combine the 99.9th percentile MOE from the dietary exposure values (see Table 

5.3b) for adults and children (1 to <2 years) with the combined residential scenarios (see Table 

6.4.7b).

Table 7.0 provides a summary of the combined estimated MOEs for adults and children (1 to <2 

years). For adults, all of the estimated MOEs are above the target MOE of 100. For children (1 

to <2 years), all of the estimated MOEs are above the target MOE of 300. 
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Table 7.0 Pyrethroid Screening Level Combined Dietary/Residential Assessment

Age Group

Exposure Route Screening 

Combined 

MOE

(Dietary + 

Residential)

Dietary Residential (non-dietary)

Scenario

MOE

(at 99.9th

percentile)

Combined Scenarios

(Routes of Exposure)

MOE

1 < 2 year 

olds

Food+ 

Water

3,000

Indoor C&C

(PD and PHtM) +

Pet

(PD and PHtM) +

Turf

(PD and 

PHtM)

1,200 860

Indoor Fogger

(PD and PHtM) +

Pet

(PD and PHtM) +

Turf

((PD and 

PHtM)

490 420

Indoor 

Broadcast

(PD, PI and 

PHtM)

+

Pet

PD and PHtM) +

Turf

PD and PHtM) 1,000 750

Adult 5,400

Turf

(HD, HI, and PD) +

Garden

(HD, HI, and PD) 950 810

Indoor C&C

(HD, HI, and PD) +

Pet

(HD, HI, and PD) 5,100 2,600

8.0 Characterizing the Screening-Level Pyrethroid Cumulative Risk Estimates

This screening-level pyrethroid cumulative risk assessment is considered to be a conservative 

and health protective assessment which likely greatly overestimates exposure and risk. The 

extent to which the characteristics and assumptions in this cumulative assessment are 

considered to be conservative is detailed below. The Agency believes that refinements to 

address the assumptions discussed below would further support this conclusion.

8.1 Hazard Characterization

The Agency has determined that the pyrethroids and pyrethrins share a common mechanism of 

toxicity through interaction with VGSCs and leading to neurotoxicity are generally characterized 

by two toxicity syndromes (i.e., T syndrome or Type I and CS syndrome or Type II). As discussed 

throughout this CRA, the current assessment is considered a screening level analysis. In the 

case of the cumulative hazard assessment, as discussed in Section 2.4, the Agency has elected 

to combine the Type I and Type II pyrethroids together. Type I and Type II pyrethroids differ in 

the duration and nature of VGSC interaction, with Type II pyrethroids causing an elongated 

open state of the sodium channel compared to the Type I pyrethroids. Behaviorally, the Type I 

pyrethroids produce hyperreactivity, fine to whole body tremors, and hyperthermia (T 

syndrome) whereas Type II pyrethroids cause salivation, and coarse tremors leading to sinuous 

writhing termed choreoathetosis (CS syndrome) (Verschoyle and Aldridge 1980). As such, there 

is scientific support for considering these pyrethroids in separate sub-groups if appropriate in 

the future.
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It would be preferred to use an in vivo endpoint related to VGSC interaction, but at this time 

current methods do not exist to practically measure such an in vivo biomarker. As such, the 

Agency must rely on apical endpoints related to neurobehaviors such as tremors, salivation, 

and changes in body temperature. An FOB study by the WIL laboratory provides the most 

complete and most relevant dataset from which to assess and compare pyrethroid toxicities for 

the purpose of developing the cumulative risk assessment. By incorporating several 

pyrethroids into a single study, using the same protocol and experimental design, 

interlaboratory differences (i.e., scoring criteria, vehicle, and vehicle volume) that complicate 

interpretation of behavioral responses and increase uncertainty when comparing relative 

potency were eliminated. This FOB study evaluated 46 measures using a standard protocol, 

with a few modifications to specifically describe behaviors relevant to the pyrethroid toxicity 

syndromes. Although the pyrethroids produced changes in numerous endpoints 

multidimensional analyses revealed that differential effects were arrayed across four principal 

components. Of these, differential syndromes could be defined by five FOB endpoints (T: 

hyperthermia, tremors, clonic convulsions, and CS: hypothermia, salivation, mobility); these 

findings agree well with earlier descriptions of the pyrethroid syndromes. 

The Agency has used a refined and novel approach to deriving BMDs for the 11 of the 15 

pyrethroids, including the eight most potent, for these neurobehavioral effects identified in the 

WIL FOB study. The approach used in the CRA to normalize the data based on relative severity 

of the effect (i.e., severity scores) is consistent with methods reported in the scientific literature 

used to differentiate profiles of effects for various neurotoxicants (Moser 1991; McDaniel and 

Moser 1993; Moser et. al. 1995). While the severity scoring approach combines individual 

effects on specific endpoints, and may thereby lose some resolution in individual differences, it 

provides more integrated data that may be compared across studies. In addition, the BMD 

analysis involved a model averaging procedure which was used to derive a 20% BMD estimate. 

Due to the limited doses and small samples sizes, this technique was considered more 

appropriate to account for model uncertainty compared to the Agency’s Benchmark Dose 

Software (BMDS) that is more commonly used to determine BMDs for risk assessment. The 

severity score and modeling average approaches used in this dose-response result in maximal 

use of the data from multiple endpoints collected in the WIL FOB study and thus strengthens 

the relative potency estimates and PoD used in this CRA. The Agency used a less refined 

approach for four pyrethroids (cyphenothrin, d-allethrin, imiprothrin, and prallethrin), selecting 

doses as a point of comparison. However, performing a BMD analysis is likely to increase the 

dose associated with the point of comparison, thereby reducing the RPFs and increasing MOEs.

Because neurobehavior is an apical endpoint, it is important to consider the extent to which 

these behavioral measures compare to in vitro endpoints measured using neurological tissue 

cultures and thus are early events in the adverse outcome pathway and biologically closer to 

VGSC interaction. For example, Losa et. al. (2009) measured spontaneous electrophysiological 

activity of glutamate networks in primary cultures of cortical neurons using microelectro array 

techniques; and Cao et. al. (2011a) determined sodium flux in primary cultures of 

cerebrocortical neurons using the Na+ sensitive dye SBFI. The results of these in vitro

techniques are similar to the Agency’s RPF estimates from the WIL study; Type II pyrethroids 
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are generally more potent than the Type I pyrethroids. There is a remarkable similarity in the 

relative rank of the in vitro measures to the RPFs based on FOB measures. These comparisons, 

thus, support the use of the behavioral measures for purposes of estimating cumulative risk.

a

Included in study but effective concentration estimates could were not determined due 

to minimal increase in Na+ influx

The Agency is using a single set of RPFs estimated for oral exposure for all relevant routes of 

exposure (oral, dermal, inhalation) and thus the Agency is assuming that the relative ranking of 

these oral RPFs applies to the other routes of exposure. The Agency has dermal and inhalation 

studies available for only a limited number of pyrethroids, and of those studies, neurological 

endpoints are not measured in a consistent manner nor are critical procedures, such as the 

determination of time-to-peak effect determined. Therefore, these dermal and inhalation 

studies are not appropriate for use in the determination of relative potency factors for the 

pyrethroids. However, the lack of these studies does not introduce significant uncertainty 

because pyrethroids are generally poorly absorbed through the skin and inhalation exposure is 

believed to be low. As described in Section 6.0 of this assessment, dermal and inhalation MOEs 

for the pyrethroids are large, ranging from 3,000 to 240,000 for dermal exposures and 130,000 

to 10, 000,000 for inhalation. Based on these values, the RPFs would have to be at least an 

order of magnitude greater than the index chemical to result in significant risk estimates. 

The selection of the index chemical is a key decision point in the cumulative risk assessment as 

any uncertainty in the index chemical’s dose-response data will be propagated through the 

entire risk assessment. For the CRA, deltamethrin was chosen as the index chemical because it 

provides robust dose-response data from which to estimate the PoD. Specifically deltamethrin 

was tested in the WIL FOB study with three well-spaced doses which include a dose near the 

BMD20 such that high confidence BMD20 and BMDL20 estimates can be estimated, as indicated 

Table 4.5.1. Relative Potency Estimates for Pyrethroids Included in the 

Screening Level Cumulative Risk Assessment

Pyrethroid WIL FOB Losa et. al. 

(2009)

Cao et. al. 

(2011a)

Allethrinc 0.11 0.11 0.68

Bifenthrin 1.01 0.40 -

a

Cyfluthrin 1.15 0.57 0.61

Lambda-Cyhalothrin 1.63 7 0.58

Cyphenothrin 0.15 Not Included Not Included

Cypermethrin 0.19 0.97 -

Deltamethrin 1.0 1.0 1.0

Esfenvalerate 0.36 0.22 0.49

Fenpropathrin 0.50 0.12 0.31

Tau-Fluvalinate 1.0 Not Included Not Included

Imiprothrin 0.02 Not Included Not Included

Permethrin 0.09 0.24 -

Prallethrin 0.10 Not Included Not Included

Pyrethrins 0.02 Not Included Not Included

Resmethrin 0.05 0.10 -
Pyrethroid Cumulative Risk Assessment

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by closely spaced BMD and BMDL estimates. Furthermore, deltamethrin was used as a 

laboratory method control in the second phase of the WIL study (Herberth 2010) and the 

findings were similar between studies. For example, at a given dose of 25 mg/kg, salivation was 

noted in six animals for each study, altered gait was observed in nine animals in the first and six 

in the second study, and finally low arousal or response was observed in four animals in the 

first study and in two animals in the second. In addition, deltamethrin is a commonly studied 

pyrethroid in research laboratories such that a large collection of literature studies is available, 

including a well-developed PBPK model. 

Dose-additivity is the foundation assumption when using a RPF approach. At this time, there is 

an 11-chemical mixture in vivo study evaluating motor activity and one in vitro study measuring 

sodium influx in cerebrocortical neurons for the same 11-pyrethroid mixture. Each study is 

consistent in finding no deviation from the dose-additive model and thus supports the use of 

the RPF approach. 

It is preferred to use a PBPK model to derive RPFs based on internal dosimetry instead of the 

administered dose metrics used in this CRA. The Agency has already developed PBPK models 

for permethrin and deltamethrin capable of extrapolating across species (Godin et. al. 2010) 

and age groups in rats (Tornero-Velez et. al. (2010). There is currently a large effort by CAPHRA 

to develop PBPK models relevant for assessing estimated risk to children 4-6 additional 

pyrethroids. These models have the potential to improve the CRA by refining the metric used 

to estimate RPFs and by better informing route to route extrapolation, high to low 

extrapolation, animal to human extrapolation, and potential for PK-driven age-dependant 

sensitivity.

The Agency has high confidence in this cumulative hazard assessment for the pyrethroids. The 

cumulative assessment is considered protective given that both Type I and Type II pyrethroids 

were included. Furthermore, there is a high level of confidence in the selection of the WIL FOB 

study for BMD determinations due to the high quality of the study, because it is supported by in 

vitro studies that measure effects at the level of the common mechanism, and the robust doseresponse analysis. Finally, the retention of the 3X FQPA safety factor for children < 6 years of 

age based on pharmacokinetic data, PBPK models, and established data (e.g., guideline and 

literature studies) is protective of the most susceptible population. As new data become 

available, particularly PBPK models, the Agency may, if appropriate, refine approaches or 

assumptions used in this assessment. 
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8.2 Dietary Exposure Assumptions and Characterization

8.2.1 Food Exposure Pathway

To provide risk estimates for the dietary portion of this cumulative risk assessment, the Agency 

conducted a refined, probabilistic dietary assessment and the food component of that 

assessment relied on PDP monitoring data. The food component of the assessment is 

considered a refined picture of potential acute food exposures for the U.S population and 

regulated subpopulations. However, two conservative assumptions were made in this 

assessment. The first assumption was that available residue data were translated to all food 

commodities in DEEM regardless of registered use pattern. The second assumption was that 

processing factors, which reflect potential reduction of pesticide residues, were not 

incorporated into the assessment. Incorporation of reduction factors and eliminating foods for 

which there are no registered use are expected to reduce dietary risk estimates. 

8.2.2 Drinking Water Exposure Pathway

The pyrethroids as a class have low water solubility and tend to bind to soil. As a result of these 

properties, exposure from the drinking water pathway is expected to be negligible. However, in 

the absence of a robust set of monitoring data or refined modeling to support this contention, 

the Agency has taken a highly conservative approach to address drinking water exposure in this 

screening level cumulative assessment. The single highest modeled drinking water exposure 

estimate in terms of index chemical equivalents was used in the assessment for all water 

consumption for an individual. The Agency believes that this a health protective approach to 

the screening level assessment and likely to overestimate dietary risks. It is more likely that if 

adequate monitoring data were available, actual concentrations of pyrethroids in water would 

be significantly lower than the modeled values and that risk estimates from water consumption 

would more closely follow the food only risk estimates reported in this document. 

8.3 Non-Dietary Exposure Assumptions and Characterization

Limiting the Assessment to Insecticide- and Pyrethroid-Users

In standard cumulative assessments, dietary plus non-dietary aggregate exposures reflect those 

individuals who use pesticide products and those who do not. That is, those with exposures via 

the dietary route may or may not have exposures from the non-dietary route, depending on 

whether they are users of pesticides (in this case pyrethroid insecticides, specifically). The 

current screening-level approach represents risk estimates for individuals (adults and children) 

exposed via dietary consumption of pyrethroid residues as well as contacting, and potentially 

ingesting, surface residues (i.e., non-dietary exposure). However, based on EPA’s recently 

released 2006-2007 market estimates for pesticide sales and usage 

(http://www.epa.gov/opp00001/pestsales/07pestsales/producers_users2007.htm#4_1), 

approximately 50% of U.S. households do not use insecticides. Furthermore, though likely a 

large portion of the residential use market, it is reasonable to assume that market share of 
Pyrethroid Cumulative Risk Assessment

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pyrethroids is less than 100%. Since the screening-level assessment aggregates dietary and 

non-dietary exposure, it does not reflect the substantial portion of the U.S. population with 

pyrethroid-related dietary exposure, but without pyrethroid-related non-dietary exposure. 

Thus, the current approach implicitly represents a population in which 100% experiences both 

dietary and non-dietary pyrethroid exposure. In a true population-based probabilistic 

assessment, approximately 50% of the modeled population would have only dietary exposure 

to pyrethroids, while the other 50% would experience both dietary and non-dietary pyrethroid 

exposure (per the estimate above). And, since those without non-dietary exposure would have 

correspondingly lower exposures and risk estimates, the overall distribution of exposure and 

risk estimates would be lower. Incorporating the likelihood of insecticide use, and, more 

specifically, pyrethroid use, would result in a lower estimate of risk than the current approach.

Limiting Non-Dietary Exposure to the “Day-of-application”

The screening-level approach estimates non-dietary exposure using surface residues 

immediately following pyrethroid applications. While it is certainly the case that individuals 

may be exposed in this fashion, this approach does not consider the likelihood of exposures 

resulting from surface residues that have dissipated over time. If applications are made every 

day or if there is no dissipation of pyrethroid residues in and around homes, estimates based on 

the “day-of-application” would be representative of non-dietary exposures. However, given 

available pesticide use data (e.g., REJV) and known pyrethroid dissipation rates, utilizing “dayof-application” exposures is a conservative approach. A refined assessment would utilize a 

calendar-based approach that specifies dates of application (based on use probabilities) and 

incorporates residue dissipation. EPA’s Stochastic Human Exposure and Dose Simulation 

(SHEDS) model, for example, utilizes diaries from the Consolidated Human Activities Database 

(CHAD) to more accurately reflect the coincidence of applications and individuals’ locations and 

activities. Utilizing this methodology would reflect exposure to residues that have dissipated 5, 

10 or 20 days after pyrethroid applications and result in a lower risk estimate than the current 

approach. 

Consideration of Pyrethroid-Specific Use Probabilities

The screening-level approach presents non-dietary risk estimates for only one pyrethroid for 

each of the major residential use scenarios. This should not be construed to imply that only 

one pyrethroid has uses for that scenario, or that this does not represent a cumulative 

methodology. Rather, the pyrethroid presented is the “highest potential risk” pyrethroid for 

each scenario, thus serves as a conservative benchmark to address each non-dietary scenario. 

For example, risk estimates for the pyrethroid cyfluthrin are presented for non-dietary 

exposures resulting from applications to home lawns since cyfluthrin results in the highest risk

estimate of the pyrethroids registered for use on turf. Similarly, cyphenothrin is used as the 

benchmark pyrethroid for those with registrations for household pets. In reality, however, 

there are many different pyrethroids registered for each residential use scenario, with each 

pyrethroid having a particular share of the consumer market for each use. It may be the case 

that though cyfluthrin presents the highest risk estimate for a pyrethroid with lawn uses, it is 
Pyrethroid Cumulative Risk Assessment

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the lawn-use pyrethroid used most infrequently. Thus, utilizing cyfluthrin as the benchmark 

pyrethroid for the lawn-use scenario is a conservative approach. A refined assessment that 

accurately assigns pyrethroid-specific residential scenario market-share probabilities would 

result in lower risk estimates than the current approach. 

Assuming Co-Occurrence of Non-Dietary Exposure Scenarios

The screening-level approach presents risk estimates separately for each individual residentialuse scenario, then presents an aggregate risk estimate that assumes an individual is exposed 

from all of the scenarios on the same day. For example, risk estimates are presented for 

children 1 < 2 years old exposed via contact with surfaces previously treated indoors (broadcast 

sprays, total release fogger, and “crack and crevice”) as well as contact with previously-treated 

lawns and pets. These separate risk estimates are then aggregated, which assumes a) each of 

those areas are treated on the same day, b) each is treated with the use-specific “highest 

potential risk” pyrethroid, and c) children contact those areas on the “day-of-application”. A 

refined approach would more accurately reflect the likelihood of experiencing pyrethroid 

exposure in this – likely improbable – co-occurrent fashion by incorporating its probability 

based on pesticide use surveys. The current approach conservatively assumes that these 

scenarios always co-occur (i.e., 100% co-occurrence probability). Any refinement which 

reduces co-occurrence would result in a lower risk estimate.

8.4 Aggregate Exposure (Dietary + Non-Dietary) Assumptions and 

Characterization

The Agency considers this screening-level cumulative risk assessment to be highly conservative. 

The screening-level approach utilizes a simple point-estimate aggregate methodology that adds 

a high-end dietary (food and water) exposure to a high-end residential exposure, assuming cooccurrence of dietary and non-dietary exposure. In other words, the non-dietary exposure 

patterns discussed in Section 6.0 would coincide with consumption of food and water 

(discussed in Section 5.0) with pyrethroid residues. While this is a possible exposure pattern, it 

is highly unlikely given the temporal aspects of residential insecticide use. Not only does this 

assessment assume and model co-occurrence, it utilizes high-end exposures from both the 

dietary and non-dietary pathways, making this outcome even less likely. A refined cumulative 

assessment would incorporate the appropriate temporal matching of exposures through these 

different pathways and reflect more realistic probabilities that pyrethroid exposure results from 

both dietary and non-dietary routes on the same day. Additionally, the use of distributions of 

both dietary and non-dietary exposures would mitigate the compounding effect of aggregating 

high-end point estimates. 
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9.0 Conclusion

The assessment combines a high-end dietary risk estimate from a probabilistically-derived 

realistic food exposure estimate and a high-end modeled drinking water exposure estimate 

with a high-end deterministic non-dietary residential risk estimate. The refinement of each 

pathway varies and has been described previously in each respective section. However, given 

the various assumptions outlined in Section 8.0, the overall methodology provides a reasonably 

conservative screening-level approach for determining cumulative and aggregate estimated risk

for pyrethroids. The current use of high-end exposure estimates, the general assumption of coexposure, and compounding conservative assumptions for each exposure route would likely 

represent an upper percentile exposure of a fully refined cumulative assessment (i.e., likely 

greater than the 99.9th percentile). That is, further refinements would result in MOEs 

significantly above those reported here. However, since risk estimates exceed the Agency’s 

target MOEs for adults and children, additional refinement is not required at this time.

This screening level CRA for pyrethroids uses deterministic residential and probabilistic dietary 

exposure models. There are alternative approaches that would be more refined, particularly 

the use of probabilistic estimates for all routes of exposure. OPP and ORD are working 

collaboratively to improve the Stochastic Human Exposure and Dose Simulator (SHEDS) model, 

specifically for use in such a refined risk assessment. Moreover, this collaborative effort 

involves linking PBPK models with the SHEDS model to estimate probabilistic population level 

risk. The linking of a PBPK model with a probabilistic exposure model may provide 

opportunities to calculate distributions of exposure to pesticides with effect levels across the 

U.S. population. In addition, this approach may allow estimation of data-derived uncertainty 

factors that consider use of toxicokinetic and toxicodynamic data to inform quantitative 

extrapolations for interspecies differences and human variability in dose response assessment. 

This research effort was reviewed by a FIFRA SAP in July, 20105

. In addition, the SAP also 

reviewed in February, 2011 Chlorpyrifos Physiologically Based Pharmacokinetic and 

Pharmacodynamic (PBPK/PD) Modeling Linked to Cumulative and Aggregate Risk Evaluation 

System (CARES) in which the CARES model was similarly linked to a PBPK/PD model in an effort 

made by Dow AgroScience6

Not only does the Agency believe that this screening level estimate indicates that there are no 

cumulative estimated risks of concern for the currently registered uses, the Agency also 

concludes that there is sufficient room in the pyrethroid cumulative risk cup to support 

consideration of new pyrethroids (i.e., currently unregistered pyrethroid pesticides) and new 

uses of existing pyrethroids having similar toxicity profiles and use patterns to those in this 

. OPP supports such research efforts as they advance the science of 

risk assessment. However, consistent with the screening approach of this cumulative 

assessment, such a highly refined and sophisticated approach is not needed at this time for 

pyrethroids. In the future, OPP may consider, if appropriate, similar research for pyrethroids or 

other classes of pesticides.

 5 http://www.epa.gov/scipoly/sap/meetings/2010/072010meeting.html

6 http://www.epa.gov/scipoly/sap/meetings/2011/021511meeting.html
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assessment. This is a screening level assessment which incorporated multiple high-end inputs 

and combined the highest exposures/risk estimates across all pathways in a deterministic 

fashion resulting in an assessment which is highly conservative and health protective. It is 

important to note that the pyrethroids are already registered on virtually all food crops and for 

all major residential use scenarios. The dietary component of the cumulative risk assessment 

included residues for all foods consumed – either based on monitored values or translation 

from monitoring data from crops in the same food group. The water exposure input was 

assumed to be the highest exposure value from conservative model outputs which was the limit 

of solubility for that specific chemical. Additionally, the residential scenarios used conservative 

inputs and combined in a deterministic fashion exposure from multiple residential pathways of 

exposure, assuming use of the most potent pyrethroid, to produce a highly conservative 

estimate of risk. 

For any new uses or new pyrethroids, the toxicity, proposed use sites, and potential exposure 

factors (e.g., application rate) would be compared with the inputs and assumptions utilized in 

this screening level assessment. However, if the pyrethroid is not significantly more toxic than 

those included in this assessment and has a similar use pattern to those registered uses 

considered in this assessment, its registration would likely be supported from a cumulative 

human health risk perspective because its inclusion within this assessment would not result in a 

higher estimate of risk than has been currently estimated. Per Agency policy, all new uses/new 

pyrethroid registration actions submitted to the Agency will undergo a single chemical 

assessment and also an evaluation of their potential contributions to cumulative risk estimates. 

But the Agency believes that most of these are unlikely to have a significant impact on this 

screening-level cumulative assessment, provided they meet the parameters outlined above.
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