Fenpropathrin Human Health Risk Assessment DP No. D368175

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

MEMORANDUM

Date: 8/30/2012

SUBJECT: Fenpropathrin. Human Health Risk Assessment for Section 3 Registration on 

Tropical Fruit and a Request for a Tolerance Without U.S. Registration on Tea 

PC Code: 127901 DP Barcode: D368175 

Decision No.: 417627 Registration No.: 59639-35

Petition No.: 9E7594 Regulatory Action: Section 3 Registration

Risk Assessment Type: Single Chemical

 Aggregate

Case No.: NA

TXR No.: NA CAS No.: 39515-41-8

MRID No.: NA 40 CFR: §180.466

FROM: Douglas A. Dotson, Ph.D., Chemist

Edward Scollon, Ph.D., Toxicologist

Suku Oonnithan, Ph.D., Biologist

Registration Action Branch II

Health Effects Division (7509P)

THROUGH: Karlyn Middleton, Toxicologist

Dennis McNeilly, Chemist

Zaida Figueroa, Industrial Hygienist

Christina Swartz, Branch Chief

Registration Action Branch II

and

Dana Vogel, Acting Associate Division Director

Deborah Smegal, MPH, Toxicologist

Health Effects Division

TO: Laura Nollen/Barbara Madden, RM Team 5 

RIMUERB

Registration Division (7505P)

The Registration Division (RD) requested that the Health Effects Division (HED) conduct a 

human health risk assessment for the proposed use of the insecticide fenpropathrin on tropical 
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fruit, and for a tolerance for residues in tea (without U.S. registration). This document contains 

the human health risk assessment associated with these actions and incorporates updated 

endpoints for risk assessment, updated residue monitoring data and percent crop treated 

assumptions, as well as the most recent data and assumptions for conducting occupational 

exposure assessments. No risks of concern were identified for the proposed registration action.
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1.0 Executive Summary.......................................................................................................... 5

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

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

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

2.2.1 Enforcement Analytical Method ............................................................................. 8

2.2.2 International Harmonization................................................................................... 8

2.2.3 Recommended Tolerances........................................................................................ 9

2.2.4 Revisions to Petitioned-For Tolerances .................................................................. 9

2.3 Label Recommendations........................................................................................ 10

3.0 Introduction..................................................................................................................... 10

3.1 Chemical Identity........................................................................................................ 10

3.2 Physical/Chemical Characteristics............................................................................ 10

3.3 Pesticide Use Pattern .................................................................................................. 10

3.4 Anticipated Exposure Pathways................................................................................ 11

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

4.0 Hazard Characterization and Dose-Response Assessment......................................... 12

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

4.2 Toxicological Profile ................................................................................................... 13

4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile................................. 15

4.3.1 Pharmacokinetics.................................................................................................... 15

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

4.3.3 Critical Duration of Exposure ............................................................................... 18

4.4 Safety Factor for Infants and Children (FQPA Safety Factor).............................. 19

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

4.4.2 Evidence of Neurotoxicity ...................................................................................... 21

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

4.4.4 Residual Uncertainty in the Exposure Database.................................................. 22

4.5 Toxicity Endpoint and Point of Departure Selections............................................. 22

4.5.1 Dose-Response Assessment .................................................................................... 22

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment..... 24

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

4.5.4 Summary of Points of Departure and Toxicity Endpoints ................................ 24

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

5.1 Metabolite/Degradate Residue Profile ...................................................................... 25

5.1.1 Summary of Plant and Animal Metabolism Studies ........................................... 25

5.1.2 Summary of Environmental Degradation ............................................................ 26

5.1.3 Comparison of Metabolic Pathways...................................................................... 26

5.1.4 Residues of Concern Summary and Rationale..................................................... 26

5.2 Food Residue Profile................................................................................................... 27

5.3 Water Residue Profile................................................................................................. 28

5.4 Dietary Risk Assessment ............................................................................................ 28

5.4.1 Description of Residue Data Used in Dietary Assessment .................................. 28

5.4.2 Percent Crop Treated Used in Dietary Assessment............................................. 29

5.4.3 Acute Dietary Risk Assessment ............................................................................. 29

5.4.4 Summary Table....................................................................................................... 30
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6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................ 30

6.1 Residential Handler and Post-Application Exposure and Risk Estimates............ 30

6.2 Spray Drift................................................................................................................... 31

7.0 Aggregate Exposure/Risk Characterization................................................................. 31

8.0 Cumulative Exposure/Risk Characterization .............................................................. 31

9.0 Occupational Exposure/Risk Characterization ........................................................... 32

9.1 Short-/Intermediate-Term Handler Risk ................................................................. 32

9.2 Occupational/Commercial Post-application............................................................. 34

10.0 References........................................................................................................................ 35

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

A.1 Toxicology Data Available for Penthiopyrad........................................................... 39

A.2 Toxicity Profile Tables................................................................................................ 40

A.3 Hazard Identification and Endpoint Selection......................................................... 46

A.4 Human Equivalent Analysis....................................................................................... 50

A.5 Pyrethroid Cumulative Screen .................................................................................. 50

Appendix B. Physical/Chemical Properties............................................................................. 51

Appendix C. Review of Human Research................................................................................ 52
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1.0 Executive Summary

Fenpropathrin (alpha-cyano-3-phenoxy-benzyl 2,2,3,3-tetramethylcyclopropanecarboxylate) is 

an ingestion and contact pyrethroid insecticide and acaricide currently registered for use on 

fruits, vegetables, field crops, and ornamental plants for the control of various insect pests and 

mites. 

Fenpropathrin is currently registered for use on a variety of tropical fruits. The Interregional 

Research Project Number 4 (IR-4) proposed tolerances for residues of fenpropathrin in/on 

numerous additional tropical fruits. IR-4 has also proposed a tolerance without U.S. registration 

on tea. The end use product proposed for use on the tropical fruits is Danitol®2.4 EC Spray

(EPA Registration Number 59639-35).

Pyrethroids have historically been classified into two groups, Type I and Type II, based on 

chemical structure and toxicological effects. Fenpropathrin is a mixed-type pyrethroid having 

intermediate effects between the Type I and Type II pyrethroids in in vitro and in vivo studies. 

Behavioral changes such as muscle tremors were observed in most of the fenpropathrin 

experimental toxicology studies. Although the database of fenpropathrin experimental 

toxicology studies is not complete, it provides a robust characterization of the hazard potential 

for children and adults. In addition to the standard guideline studies, numerous studies from the 

scientific literature that describe the pharmacodynamic and pharmacokinetic profile of the 

pyrethroids in general have been considered in this assessment. The only missing information is 

that needed to fully characterize sensitivity of juveniles following exposure to fenpropathrin. 

There are on-going efforts to develop methods to inform the possibility of increased sensitivity

of juvenile rats to pyrethroids as a class at doses near the LOAEL values. Pending receipt of the 

additional data, HED has conducted a conservative and health-protective assessment using the 

available guideline and literature studies.

Pyrethroids disrupt the voltage-gated sodium channels in the nervous system, resulting in 

neurotoxicity. In the fenpropathrin toxicity database, tremors were the most commonly observed 

effect and also the most sensitive relative to dose. Other neurotoxic effects observed included

ataxia, increased sensitivity (e.g., heightened response) to external stimuli, convulsions, and 

increased auditory startle response.

Fenpropathrin is rapidly absorbed following an oral dose. As a class, pyrethroids are also rapidly

metabolized in vivo and, therefore, effects are typically observed shortly after dosing. In 

addition, the severities of effects do not increase with duration. As the NOAELs for the acute 

and chronic studies are similar, the acute endpoint is protective of the endpoints from repeat 

dosing studies, which represent longer-term exposures. Thus, for purposes of endpoint selection 

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

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

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

neurotoxicity study (DNT). However, the Agency will retain a 3x uncertainty factor to protect 

for exposures to children < 6 years of age based on the following: 1) age-dependent 

pharmacokinetics, supported by rat Physiologically Based Pharmacokinetic (PBPK) model 
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predictions of a 3-fold increase of pyrethroid concentration in juvenile brain compared to adults; 

2) in vitro pharmacodynamic (PD) data and in vivo data indicating similar responses between 

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

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

channel isoforms. 

The dose and endpoint for acute dietary risk assessment were selected from the Wolansky et al.

(2006) acute oral study, in which decreased motor activity was observed. The dose used for risk 

assessment was determined using a benchmark dose (BMD) analysis conducted in accordance 

with standard Agency assumptions with respect to the benchmark response (BMR). The same 

study, endpoint, and dose were used for the inhalation risk assessment for workers, along with

standard assumptions for extrapolation from the oral route. Based on the available data for 

fenpropathrin, the use of the acute endpoint and dose for risk assessment is protective for 

repeated dose exposure and risk. A dermal risk assessment was not conducted based on the lack 

of effects in a 21-day dermal study and absence of qualitative or quantitative susceptibility in the 

toxicity database. As there are no existing or proposed uses that would result in non-dietary

exposure to children or adults in residential settings, these exposures were not considered for 

endpoint selection.

HED has characterized fenpropathrin as “not likely to be carcinogenic to humans” in accordance 

with the EPA Final Guidance for Carcinogen Risk Assessment (3/29/05).

Adequate residue data are available for the purpose of evaluating the proposed uses and 

associated tolerances, including adequate plant and livestock metabolism data, field residue and 

rotational crop studies, as well as appropriate supporting analytical methods and storage stability

data. The recommended tolerances are based on the potential for detectable residues in the 

treated commodities.

The acute dietary risk estimates for fenpropathrin are below HED’s level of concern for all 

population subgroups, including those comprised of infants and children. The acute risk estimate 

for the general U.S. population is 19% of the acute population adjusted dose (aPAD). The 

population subgroup with the highest acute dietary risk estimate is Children 3-5, which uses 97% 

of the aPAD. The assessment was refined by incorporating distributions of residues from field 

trial and monitoring data, and through use of estimated percent crop treated information. Both

empirical and default processing factors were used. For drinking water, a very conservative 

modeled surface water estimated drinking water concentration was used. As a result of the fact 

that many conservative assumptions were made for this assessment, in particular, the use of field 

trial data (as opposed to monitoring data) for many commodities, HED is confident that the acute 

dietary exposure assessment significantly overestimates risk to the general U.S. population and 

all population subgroups.

The acute aggregate risk estimates are equivalent to the corresponding dietary (food plus water) 

risk estimates, which are not of concern.

Fenpropathrin may be applied to fruit trees by ground equipment (airblast). In addition, aerial 

application may be used for avocado trees. Fenpropathrin is intended for use by commercial and 
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professional applicators. There is potential for short- and intermediate-term occupational handler 

and post-application exposure via the inhalation and dermal pathways. No long-term exposure 

(> 6 months) is expected. As fenpropathrin does not increase in potency with repeated dosing, 

only single-day occupational exposures are being assessed. As there is no dermal hazard 

associated with this chemical, inhalation risk only is being assessed quantitatively. 

It is HED policy to use the best available data to assess handler exposure. Sources of generic 

handler data, used as surrogate data in the absence of chemical-specific data, include the 

Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), and the Agricultural Handler 

Exposure Task Force (AHETF) database. Some of these data are proprietary (e.g., AHETF 

data), and subject to the data protection provisions of FIFRA. Default assumptions established 

by the HED’s Exposure Science Advisory Council (ExpoSAC) were used for parameters such as 

body weight and acres treated per day.

Occupational handler assessments are based on inhalation exposures only because a dermal 

endpoint and dose were not selected. As noted previously, an acute POD is considered to be 

protective of repeated inhalation exposures (i.e., short- and intermediate-term durations), and 

thus only a single POD was used to assess workers. The estimated short-term inhalation margins 

of exposure (MOEs) for occupational handlers are all above HED’s level of concern (LOC) of an 

MOE of 100 (the lowest MOE was 5,300), assuming the baseline level of personal protective 

equipment (PPE), and with the use of engineering controls (i.e., enclosed cockpit) for aerial 

applications.

There is a potential for post-application dermal and inhalation exposures to workers who enter 

fenpropathrin-treated fields to do irrigation, fruit thinning, scouting, and harvesting. However, 

HED did not quantitatively estimate post-application dermal exposure because of the lack of

toxicity via the dermal route of exposure. Based on the Agency’s current practices, a 

quantitative non-cancer occupational post-application inhalation exposure assessment is not 

being conducted at this time. If new policies or procedures are put into place, the Agency may

revisit the need for a quantitative occupational post-application inhalation exposure assessment 

for fenpropathrin. However, HED notes that inhalation exposure for aerial flaggers is considered 

to be protective of potential post-application inhalation exposure, and the associated inhalation 

risk estimates for flaggers are not of concern.

Fenpropathrin was included in a recent cumulative risk assessment for pyrethrins and 

pyrethroids. The proposed new uses will contribute minimal risk to the overall cumulative 

assessment. In the cumulative assessment, residential exposure was the greatest contributor to 

the total exposure. As there are no residential uses for fenpropathrin, the proposed new uses will 

have no impact on the residential component of the cumulative risk estimates. Dietary exposures 

make a minor contribution to total pyrethroid exposure in the 2011 cumulative risk assessment. 

The dietary exposure assessment performed in support of the pyrethroid cumulative was much 

more highly refined than that performed for the single chemical. In addition, for the 

fenpropathrin risk assessment, the most sensitive apical endpoint in the fenpropathrin database 

was selected to derive the POD. Additionally, the POD selected for fenpropathrin is specific to 

fenpropathrin, whereas the POD selected for the cumulative assessment was based on common 

mechanism of action data that are appropriate for all 20 pyrethroids included in the cumulative 

assessment.
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Review of Human Research: This risk assessment relies in part on data from studies in which 

adult human subjects were intentionally exposed to a pesticide or other chemical. These studies 

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

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

2.0 HED Recommendations

HED does not object to the granting of the requested registration or the recommended tolerances 

for fenpropathrin in/on the proposed new uses on tropical fruits. In addition, HED does not 

object to the granting of the recommended tolerance without U.S. registration for fenpropathrin 

in/on tea. 

2.1 Data Deficiencies/Conditions of Registration

None

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate method, Residue Method Number RM-22-4, is available for the enforcement of 

tolerances of fenpropathrin in plants. Residues in crops are extracted with acetone/hexane, 

partitioned into hexane, cleaned up by silica gel and C18 Sep Pak chromatography, and analyzed 

by GC/ECD. The LOD is 0.01 ppm.

There is also an adequate GC/ECD enforcement method for the determination of fenpropathrin 

residues in livestock commodities (RM-22A-1). The lowest limit of method validation was 0.05

ppm in milk and 0.5 ppm in fat and meat.

The FDA PESTDATA database (dated 6/2005) indicates that fenpropathrin is completely

recovered by multiresidue methods Section 302 (Protocol D). Recovery was variable using 

Section 303 (Protocol E; 43-71% recovery) and Section 304 (Protocol F; 58-114% recovery). 

2.2.2 International Harmonization

No Codex, Canadian, or Mexican MRLs are established for fenpropathrin on the proposed 

tropical fruits. As a result, harmonization of tolerances is not an issue for these commodities. A 

Codex MRL is established for residues of fenpropathrin in/on tea, green, black at 2 ppm. Using 

the Organization for Economic Cooperation and Development (OECD) MRL calculation 

procedures, the recommended tolerance for dried tea would be 3.0 ppm. For the purposes of 

harmonization of the U.S. tolerance with the established Codex MRL, HED is recommending in 

favor of a tolerance of 2.0 ppm for dried tea. HED considers this tolerance level to be adequate 

because the highest field trial value was 1.38 ppm. In the U.S., the residue definition is parent 

fenpropathrin. The Codex residue definition is fenpropathrin, the residue is fat soluble.
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2.2.3 Recommended Tolerances

HED recommends that 40CFR §180.466 be amended by establishing tolerances for the 

commodities listed in Table 2.2.3, below.

Currently, tolerances are established for residues of the pesticide chemical fenpropathrin (alphacyano-3-phenoxy-benzyl 2,2,3,3-tetramethylcyclopropanecarboxylate) in or on the commodities 

in 40CFR §180.466. This tolerance expression needs to be revised as follows: “Tolerances are 

established for residues of fenpropathrin including its metabolites and degradates, in or on the 

commodities in the table below. Compliance with the tolerance levels specified below is to be 

determined by measuring only fenpropathrin (alpha-cyano-3-phenoxy-benzyl 2,2,3,3-

tetramethylcyclopropanecarboxylate).”

Table 2.2.3. Tolerance Summary for Fenpropathrin

Commodity as Proposed 

by Registrant

Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Guava 1.5 3.0

Acerola 1.5 3.0

Feijoa 1.5 3.0

Jaboticaba 1.5 3.0

Passionfruit 1.5 3.0

Starfruit 1.5 3.0

Wax jambu 1.5 3.0

Lychee 3.0 7.0

Longan 3.0 7.0

Spanish lime 3.0 7.0

Pulasan 3.0 7.0

Rambutan 3.0 7.0

Sugar apple 1.0 1.5

Atemoya 1.0 1.5

Biriba 1.0 1.5

Cherimoya 1.0 1.5

Custard apple 1.0 1.5

Ilama 1.0 1.5

Soursop 1.0 1.5

Tea 2.0 2.0 Tea, dried

Tolerance should include a 

footnote stating “There is no U.S. 

registration on tea, dried, as of 

(date of FR notice).”

2.2.4 Revisions to Petitioned-For Tolerances

The proposed tolerances for residues in tropical fruits are different from the tolerances being 

recommended by HED. The reason for the differences is that the proposed tolerances were 
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determined using the NAFTA tolerance calculator, whereas HED used the OECD MRL

calculation procedures to determine the recommended tolerances. A revised Section F should be 

submitted to reflect the tolerances recommended by HED.

2.3 Label Recommendations

None

3.0 Introduction

3.1 Chemical Identity

Table 3.1. Fenpropathrin Nomenclature

Chemical structure

Common name Fenpropathrin

Company experimental 

name

WC-4741706 (Shell); S-5206 (Sumitomo)

IUPAC name (RS)-α-cyano-3-phenoxybenzyl 2,2,3,3-tetramethylcyclopropanecarboxylate

CAS name Cyano(3-phenoxyphenyl)methylester 2,2,3,3-tetramethyl-cyclopropanecarboxylic 

acid

CAS registry number 39515-41-8

End-use product (EP) 2.4 lb/gal EC formulation (Danitol®2.4 EC Spray; EPA Reg. No. 59639-35)

3.2 Physical/Chemical Characteristics

Fenpropathrin has very low water solubility (0.33 ppm at 25oC) and a relatively high 

octanol/water partition coefficient (log KOW = 5.1). These values account for the low surface and 

groundwater concentrations determined by EFED’s drinking water models. The chemical has a 

vapor pressure of 5.5 x 10-6 mm Hg at 25oC. See Appendix B for a listing of additional physical

and chemical properties. 

3.3 Pesticide Use Pattern

The petitioner submitted a draft label for the 2.4 lb/gal EC formulation of fenpropathrin 

(Danitol®2.4 EC Spray; EPA Reg. No. 59639-35). The label includes use directions for a 

number of fruit, vegetable, and field crops that are already registered. Danitol®is currently 

registered for use on avocado, canistel, mango, papaya, salal, sapodilla, black sapote, mamey

sapote, and star apple. The use directions for both the registered and proposed tropical and 

O

O

CN O

CH3

CH3

H3C CH3
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subtropical fruits are presented in Table 3.3. No directions were proposed for the domestic use 

of fenpropathrin on tea because only an import tolerance was proposed.

Table 3.3. Summary of Directions for Use of Fenpropathrin

Applic. Timing, 

Type, and Equip.

Formulation

[EPA Reg. No.]

Max. Single 

Applic. Rate 

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days) Use Directions and Limitations

Tropical and Subtropical Fruit: Acerola, Atemoya, Avocado, Biriba, Canistel, Cherimoya, Custard Apple, Feijoa, Guava, 

Ilama, Jaboticaba, Longan, Lychee, Mango, Papaya, Passion Fruit, Pulasan, Rambutan, Sapodilla, Sapote (Black, Mamey), 

Soursop, Spanish Lime, Star Apple, Star Fruit, Sugar Apple, and Wax Jambu

Foliar

Ground (all crops)

Aerial (avocado 

only)

2.4 lb/gal EC

[59639-35] 0.3-0.4

1 (avocado)

or

2 (all other 

crops)

0.8 1

Begin applications when first 

pest activity is noticed. A 14-

day retreatment interval is 

specified. Ground applications 

are to be made in ≥75 gal/A; 

aerial applications to avocado 

may be made in ≥50 gal/A.

PHI= Preharvest interval

The use directions for the proposed tropical and subtropical fruits are identical to those for the 

registered tropical and subtropical fruits except that the minimum spray volume for ground 

applications for all tropical fruits has been reduced from 100 gal/A to 75 gal/A. The personal 

protective equipment (PPE) on the proposed label includes a long-sleeved shirt, long pants, shoes 

with socks, chemical resistant gloves, and protective eyewear.

3.4 Anticipated Exposure Pathways

Humans could be exposed to fenpropathrin in food because fenpropathrin may be applied 

directly to growing crops. In addition, these applications can result in fenpropathrin reaching 

surface and groundwater, both of which can serve as sources of drinking water. However, the 

low water solubility of the chemical and its affinity to bind to soil organic matter would cause 

the chemical to be present at very low concentrations in drinking water sources. The domestic 

uses on tropical fruits result in the potential for occupational exposures. Because of the 

agricultural uses, applicators might be exposed while handling the pesticide prior to application, 

mixing/loading the pesticide, and during application. Also, there is a potential for postapplication exposure for workers re-entering treated fields. There are no registered or proposed 

residential uses for fenpropathrin; as a result, residential exposure is not an anticipated exposure 

pathway.

3.5 Consideration of Environmental Justice

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

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

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

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

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

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

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 
Fenpropathrin Human Health Risk Assessment

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

Extensive data on food consumption patterns are compi

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

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

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

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

performed when conditions or circumstances warrant. Whenever appropriate, non

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

for children, youths, and adults entering or playing on treated areas 

evaluated. Further considerations are currently in development as OPP has co

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

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

subgroups.

4.0 Hazard Characterization and Do

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

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

toxicological effects. Type I pyrethroids, which

syndrome consisting of aggressive sparring, altered sensitivity to external stimuli, hyperthermia, 

and fine tremor progressing to whole

pyrethroids, which contain an alpha

pawing, burrowing, salivation, hypothermia, and coarse tremors leading to choreoathetosis (CS

syndrome) (Verschoyle and Aldridge 1980

Mixed Type pyrethroid because the biochemical responses and resulting clinical signs of 

neurotoxicity are intermediate between 

outcome pathway (AOP, based on the Bradford

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

nervous systems, leading to changes in neuron firing and

Figure 4.0. Adverse outcome pathway for pyrethroids

4.1 Toxicology Studies Available for Analysis

The database of experimental toxicology studies available for fenpropathrin provides a robust 

characterization of the hazard potential for children 6 years old and 

90-day inhalation study is not available for consideration as required under the Part 158 

toxicology data requirements. However, HED has waived this study requirement for the current 

assessment (HASPOC memo, TXR# 0053978, 4/10/1

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

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

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

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

, ethnic group, and region of the country. Additionally, OPP is able to 

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

performed when conditions or circumstances warrant. Whenever appropriate, non

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

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

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

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

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

Hazard Characterization and Dose-Response Assessment

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

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

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

syndrome consisting of aggressive sparring, altered sensitivity to external stimuli, hyperthermia, 

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

ain an alpha-cyano moiety, in rats produce a syndrome that includes 

pawing, burrowing, salivation, hypothermia, and coarse tremors leading to choreoathetosis (CS

Verschoyle and Aldridge 1980; Lawrence and Casida 1982). Fenpropathrin is a 

Mixed Type pyrethroid because the biochemical responses and resulting clinical signs of 

neurotoxicity are intermediate between those of Type I and Type II pyrethroids. 

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

gated sodium channels (VGSCs) in the central and peripheral 

nervous systems, leading to changes in neuron firing and, ultimately, neurotoxicity (Figure 4.

Adverse outcome pathway for pyrethroids

Toxicology Studies Available for Analysis

The database of experimental toxicology studies available for fenpropathrin provides a robust 

characterization of the hazard potential for children 6 years old and older as well as

day inhalation study is not available for consideration as required under the Part 158 

toxicology data requirements. However, HED has waived this study requirement for the current 

TXR# 0053978, 4/10/12). In addition, there are ongoing efforts to 

DP No. D368175

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

led by the USDA under the Continuing 

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

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

, ethnic group, and region of the country. Additionally, OPP is able to 

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

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

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

application are 

mmitted resources 

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

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

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

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

cyano moiety, induce in rats a 

syndrome consisting of aggressive sparring, altered sensitivity to external stimuli, hyperthermia, 

syndrome). Type II 

cyano moiety, in rats produce a syndrome that includes 

pawing, burrowing, salivation, hypothermia, and coarse tremors leading to choreoathetosis (CS-

. Fenpropathrin is a 

Mixed Type pyrethroid because the biochemical responses and resulting clinical signs of 

Type I and Type II pyrethroids. The adverse 

eria) shared by pyrethroids involves the 

gated sodium channels (VGSCs) in the central and peripheral 

neurotoxicity (Figure 4.0). 

The database of experimental toxicology studies available for fenpropathrin provides a robust 

as well as for adults. A 

day inhalation study is not available for consideration as required under the Part 158 

toxicology data requirements. However, HED has waived this study requirement for the current 

In addition, there are ongoing efforts to 
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develop data in juvenile rats at doses near the LOAEL values (see Section 4.4) to inform the 

potential sensitivity of infants and young children to pyrethroids as a class. Despite these 

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

in this risk assessment that are health protective and have a strong scientific foundation.

Data from the following studies were used to evaluate the hazard potential of fenpropathrin:

-Wolansky Acute Oral Study in the Rat

-WIL Laboratory Acute Oral Study in the Rat

-21 Day Dermal Studies in the Rat and Rabbit

-90 Day Oral Studies in the Rat and Dog

-Chronic/Carcinogenicity Studies in the Rat, Mouse, and Dog

-Developmental Studies in the Rat and Rabbit

-Reproduction Study in the Rat 

-Acute, Subchronic, and Developmental Neurotoxicity (DNT) Studies in the Rat

- Immunotoxicity Study in the Rat

-Mutagenicity Battery of Studies

These studies are available for consideration of fenpropathrin toxicity and provide a 

comprehensive database. The Wolansky and WIL studies are acute oral non-guideline studies 

that measure locomotor and functional observational battery (FOB) activity, respectively, and 

provide robust data to evaluate the hazard potential of fenpropathrin.

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

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

scientific literature has recently been reviewed by several groups (Soderlund et. al. 2002; Shafer 

et. al. 2005; Wolansky and Harrill 2008). 

4.2 Toxicological Profile

Fenpropathrin has been evaluated for a variety of toxicological effects in guideline experimental 

toxicity studies. Behavioral changes characteristic of Type I pyrethroids such as muscle tremors 

were seen in most of the experimental toxicology studies including the acute, subchronic, and 

developmental neurotoxicity studies, subchronic studies in the rat and dog, the chronic 

carcinogenicity study in the rat, the developmental studies in the rat and rabbit, and in the 3-

generation reproduction study in the rat. Tremors were the most common indication of 

neurotoxicity; however, ataxia, increased sensitivity (e.g., heightened response) to external 

stimuli, convulsions, and increased auditory startle response were also observed.

Fenpropathrin has been evaluated for potential developmental effects in the rat and rabbit. 

Maternal toxicity included neurological effects such as ataxia, sensitivity to external stimuli, 

tremors in rat, and flicking of forepaws in the rabbit. Developmental effects were limited to 

incomplete or asymmetrical ossification of sternebrae at the maternally toxic dose in the rat. 

There were no developmental effects in the rabbit. Furthermore, there were no indications of 

immunotoxicity in any of the guideline studies, including the immunotoxicity study in rats. 
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The potential reproductive toxicity of fenpropathrin was examined in a 3-generation 

reproduction study in the rat. Maternal effects at the high dose included increased deaths and 

clinical signs of toxicity. Eighteen of the 24 dams in the high-dose group (32 mg/kg/day) died. 

Ten of these deaths occurred during lactation of the F1B dams (i.e., 2

nd litter of 2nd generation). 

Clinical signs including tremors, muscle twitches, and increased sensitivity were observed in all 

high-dose females in all generations and were most intense during the 2

nd or 3rd week of 

lactation. At the mid-dose, 10.1 mg/kg/day, clinical signs of toxicity were observed in a single 

dam. No treatment-related effects in the males at any dose were noted; however, it is not clear 

from the study if males were evaluated. It should be noted that the effects in the maternal rats 

occurred during lactation. During lactation, the dietary intake of nursing dams increases 

dramatically, resulting in a greater consumption of fenpropathrin. In the offspring, there was 

mortality at the high dose (32 mg/kg/day) in the F2A and F2B litters (3rd generation, 1st and 2nd

litters) although litter size was only significantly decreased at lactation day 21 in the F2B litters. 

At the mid-dose (10 mg/kg/day), tremors were observed in 3 pups from the F2B litter, 2 of which 

died. There were no reports of clinical signs of toxicity (i.e., tremors) in any other pups. 

Therefore, minimal signs of treatment-related effects were observed at the mid-dose for both 

adults and pups, reducing concern for quantitative or qualitative sensitivity.

The registrant submitted a DNT study which established a clear NOAEL for adult and offspring 

toxicity. Similar NOAELs and LOAELs were observed in adults and offspring. Effects in the 

dams were tremors and convulsions, while offspring effects consisted of decreased body weights. 

In the fenpropathrin DNT study there was no evidence of increased sensitivity in rat pups. 

However, the Agency has reviewed existing pyrethroid data, including a number of DNT studies, 

and has concluded that the DNT is not a particularly sensitive study for comparing the sensitivity

of young and adult animals to pyrethroids (E. Scollon, D381210, 6/27/11). Some literature 

studies did indicate susceptibility for other pyrethroids, but in context these studies were 

conducted at relatively high doses that might not reflect environmental exposures. Overall, there 

is no indication of increased juvenile sensitivity specifically to fenpropathrin.

There was no evidence of carcinogenicity in either the rat or mouse long-term dietary studies,

nor was there any mutagenic activity in bacteria or cultured mammalian cells. Fenpropathrin is 

classified as “not likely to be carcinogenic to humans” in accordance with the EPA Final 

Guidance for Carcinogen Risk Assessment (3/29/05). With respect to acute lethality studies, 

fenpropathrin exhibits high acute toxicity via the oral route and dermal route (Categories I and II, 

respectively). Conversely, toxicity via inhalation is Category IV. Fenpropathrin is a mild eye 

irritant (Category III), but does not cause dermal irritation in rabbits or skin sensitization in 

guinea pigs.

The resulting pharmacokinetics for fenpropathrin is similar to the pharmacokinetics of other 

pyrethroids, i.e., rapid absorption and clearance. Following a single oral dose of 2.5 or 25 mg/kg 

radiolabeled fenpropathrin in corn oil, 99% of the radioactivity was excreted via the urinary and 

fecal pathways by 7 days. A greater proportion was eliminated via the fecal route following a 

single dose (1:2 urine:feces) compared to repeated dosing (1:1 urine:feces). No differences were 

observed between sexes. By 168 hours, only minor traces of radioactivity remained in the 

carcass, primarily in the adipose tissue. As pyrethroid metabolites are not active, radiolabeled 

fenpropathrin studies that do not consider metabolism are likely to overestimate the amount of 
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active pesticide present in vivo. As previously described, pyrethroids are susceptible to ester 

hydrolysis in the plasma and oxidative metabolism by cytochrome P450 enzymes. Major 

biotransformation products from single and repeated dose rat metabolism studies included 

oxidation of the methyl group on the acid moiety, hydroxylation at the 4’-position of the alcohol 

moiety, cleavage of the ester linkage, and conjugation with sulfuric and glucuronic acid. 

4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile

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

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

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

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

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

age-related differences in pyrethroid toxicity.

4.3.1 Pharmacokinetics

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

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

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

channels. The underlying pharmacokinetics of pyrethroids is an important determinant of their 

toxicity because the concentration of pyrethroid at the sodium channel relates to the extent of 

toxicity. Greater pyrethroid concentration results in increased neurotoxicity. Physiological 

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

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

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

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

partitioning of pyrethroids within the body, pyrethroids are highly lipophilic and preferentially 

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

residues in fatty tissue are not available to interact with the voltage-gated sodium channels 

(VGSCs) in vital tissues and, therefore, do not contribute to overall toxicity. 

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

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

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

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

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

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

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

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

(USEPA 2007).

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

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

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

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

humans at birth (Koukouritaki et. al. 2004; Yang et. al. 2009). As a result, both juveniles and 
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adults are able to tolerate low doses of pyrethroids when the internal dose, or the amount of 

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

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

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

metabolism of deltamethrin by plasma carboxylesterases, plus hepatic carboxylesterases and 

cytochrome P450s (microsomes) are at least 6 times higher for post-natal day 90 (PND 90) rats 

compared to PND 10 rats (Anand et. al. 2006). As a consequence, higher internal doses (i.e., 

those associated with high doses in experimental toxicology studies) overwhelm the clearance 

mechanisms in juveniles, but because adults have greater enzyme activity, they are able to 

tolerate higher doses prior to the onset of toxicity. As a matter of perspective, the anticipated 

exposures from typical dietary or residential activities are not expected to overwhelm the 

premature metabolic systems in juveniles. 

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

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

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

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

primary target organ for pyrethroids, and increased pyrethroid concentrations are correlated with 

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

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

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

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

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

difference between a 3.8- and a 2.5-fold dose is within background variability of the model. As

these age groups bracket the developmental stage of greatest concern in humans (i.e., children ≤ 

6), the Agency concludes that juvenile rats are 3 times as sensitive as adults with respect to 

pyrethroid pharmacokinetics.

4.3.2 Pharmacodynamics

Pharmacodynamics can be defined as the changes that chemicals cause to the body, in this case, 

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

vivo studies support the adverse outcome pathway (AOP) illustrated in Figure 4.3 and the 

disruption of sodium channels by pyrethroids as an early key event (Lund and Narahashi 1982; 

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

2002). There are several recent studies that provide specific information for fenpropathrin. Choi 

and Soderlund (2006) examined interactions of several pyrethroids, including fenpropathrin, with 

mammalian VGSCs expressed in Xenopus oocytes (i.e., frog oocytes). Fenpropathrin produced 

modifications of sodium channel kinetics intermediate between Type I and Type II compounds 

(Figure 4.3). With respect to altered neuronal excitability, Type I pyrethroids cause slight 

prolongations of the sodium current tails (e.g. ~20 ms), often resulting in long trains of action 

potentials. In contrast, Type II pyrethroids significantly prolong sodium current tails (e.g. 200

ms to minutes) typically resulting in increased resting membrane potential and ultimately causing 

depolarization dependent action potential block. Cao et. al. (2011a) measured sodium influx in 

primary cultures of mammalian (mouse) neurons and demonstrated that fenpropathrin caused 

increases in sodium influx in this model; this confirms the ability of fenpropathrin to interact 

with VGSC in intact mammalian neurons. An additional study by Cao et. al. (2011b)
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demonstrated that the interaction of fenpropathrin with VGSC caused changes in neuronal 

excitability that resulted in calcium influx into intact mouse neurons. As this effect of 

fenpropathrin was entirely blocked by the VGSC blocker tetrodotoxin, it provides evidence that 

the changes in sodium channel function lead to changes in neuronal excitability, as illustrated in 

Figure 4.3.

Figure 4.3 Resting modification of rat Nav1.8 sodium channels by fenpropathrin expressed in Xenopus oocytes. 

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

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

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

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

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

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

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

developed. As such, the Agency is focusing its efforts for all pyrethroids in hazard 

characterization and identification on the apical endpoint (i.e., changes in neurobehavior in 

laboratory animals). Neurotoxicity resulting from pyrethroids is generally characterized by

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

activity or convulsions (Soderlund et. al. 2002; Wolansky and Harrill 2008; Weiner et. al. 2009). 

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

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

channels, called isoforms, which are differentially expressed by tissue and age. Because of the 

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

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

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

combinations that are present and being acted upon by pyrethroids. Therefore, much of the 

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

sodium channels has been derived from in vitro studies using frog oocytes or neuronal cells 

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

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

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

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

a conservative model for humans. For example, Meacham et al. (2008), expressed adult and 

juvenile isoforms of rat sodium channels in frog oocytes and compared their sensitivity

following exposure to deltamethrin. The isoforms had comparable responses at environmentally 

relevant concentrations (<500 nM) of deltamethrin, suggesting a lack of PD difference between 
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juveniles and adults at low exposure levels. In addition, in a direct comparison of a homologous 

rat and human VGSC isoform NaV1.3, the rat isoform was 4-fold more sensitive than the 

equivalent human sodium channel to the pyrethroid tefluthrin (Tan and Soderlund 2009). This 

observation suggests that the rat is a highly-sensitive model, and extrapolations from the rat 

would be protective of human health. The occurrence and ontogeny of voltage-gated sodium 

channels in humans is not well characterized compared to those of the rat. However, based on 

the comparable function and distribution of sodium channels between the species, the rat is an 

appropriate surrogate for the evaluation of human PD (Goldin et. al. 2000; Goldin 2002). As a 

result, the Agency concludes that juvenile rats are not more sensitive than adults with respect to 

pyrethroid pharmacodynamics. Therefore, the pharmacodynamic contribution to the FQPA 

factor will be 1x.

4.3.3 Critical Duration of Exposure

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

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

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

as tremors and ataxia were observed within 2 and 3 hours following dosing in the rat 

developmental and acute neurotoxicity studies, respectively. Rats typically recover within 24 

hours without any persisting neurotoxic effects at doses near the LOAEL value. This 

observation is consistent with the toxicity profiles for other pyrethroids which are marked by 

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

established from results of experimental toxicity studies with fenpropathrin are remarkably

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

(Table 4.3.3). 

Table 4.3.3. Fenpropathrin NOAEL and LOAEL Values versus Treatment Time

Study Duration Study findings

NOAEL

(mg/kg/day)

LOAEL 

(mg/kg/day)

Wolansky (2006) Acute, single exposure ABMDL1SD = 5.0 BMD1SD = 6.4

WIL Acute, single exposure BBMDL20 = 26.7 BMD20 = 28.9

Acute neurotoxicity Acute, single exposure 15 30

Developmental Rat 10 days 3 6

Developmental Rabbit210 days 4 12

Subchronic neurotoxicity 90 days 13 38

DNT 86 days 8 19

Sub-chronic dog 90 days <6.2 6.2

Sub-chronic rat 90 days 15 30

Reproductive toxicity 120 days 3.0 10.1

Chronic-carcinogenicity 2-years 7.2 19.5

A BMD1SD is the central estimate of the dose that results in decreased motor activity compared to control animals 

based upon a 1 standard deviation using Benchmark Dose Analysis. BMDL1SD is the 95% lower confidence limit of 

the central estimate. Data extrapolated for Wolansky (2006), MRID 47885701.

B BMD20 is the central estimate of the dose that results in a 20% difference in FOB scores compared to control 

animals using Benchmark Dose Analysis. BMDL is the 95% lower confidence limit of the central estimate. Data 

and analysis can be found in MRID 48714301.
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Comparing the NOAELs and LOAELs established from fenpropathrin single dose and repeat 

dosing studies, it is apparent that repeat exposures do not result in lower NOAELs. This 

observation is consistent with the general kinetic profile for pyrethroids. The BMDL1SD from 

the acute Wolansky study at 5.0 mg/kg is lower than that from the chronic two-year cancer 

study NOAEL= 7.2 mg/kg/day (LOAEL of 19.5 mg/kg/day). Therefore, the endpoint from the 

acute study is protective of the endpoints from the repeat dosing studies. Thus, for purposes of 

endpoint selection and exposure assessment, only single-day risk assessments need to be 

conducted.

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

Exposure of children under 6 years old to fenpropathrin is expected, and it must be considered in 

the context of the pyrethroids as a class. The Agency is retaining a 3x uncertainty factor to 

protect for exposures to children less than 6 years of age based on the increased quantitative 

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

decision is consistent with the Agency’s 2011 analysis, and is supported by rat PBPK model 

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

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

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

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

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

considerations.

There was no evidence of increased qualitative or quantitative susceptibility in developmental 

toxicity studies in the rat and rabbit, and a three-generation reproductive toxicity study in the rat. 

This lack of susceptibility is consistent with the results of the guideline pre- and post-natal 

testing for other pyrethroid pesticides. There are, however, high-dose LD50 studies (i.e., those 

that determine the dose that results in lethality to 50 percent of the tested population) in the 

scientific literature indicating that pyrethroids can result in increased quantitative sensitivity in 

the young. Examination of pharmacokinetic and pharmacodynamic data indicates that the 

sensitivity observed at high doses is related to pyrethroid age-dependent pharmacokinetics - the 

activity of enzymes associated with the metabolism of pyrethroids. With otherwise equivalent 

administered doses for adults and juveniles, predictive pharmacokinetic models indicate that the 

differential adult-juvenile pharmacokinetics will result in a 3x greater dose at the target organ in 

juveniles compared to adults. No evidence of increased quantitative or qualitative susceptibility

was seen in the pyrethroid scientific literature related to pharmacodynamics (the effect of 

pyrethroids at the target tissue) both with regard to inter-species differences between rats and 

humans and to differences between juveniles and adults. Specifically, there are in vitro

pharmacodynamic data and in vivo data indicating similar responses between adult and juvenile 

rats at low doses and data indicating that the rat is a conservative model compared to the human 

based on species-specific pharmacodynamics of homologous sodium channel isoforms in rats 

and humans.

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

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

factor as estimated by pharmacokinetic modeling. For several reasons, EPA concludes there are 
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reliable data showing that a 3x factor is protective for the safety of infants and children. First, 

the high doses that produced juvenile sensitivity in the literature studies are well above normal 

dietary or residential exposure levels of pyrethroids to juveniles, and these lower levels of 

exposure are not expected to overwhelm the ability to metabolize pyrethroids as occurred with 

the high doses used in the literature studies. This conclusion is confirmed by the lack of a 

finding of increased sensitivity in pre- and post-natal guideline studies in any pyrethroid, 

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

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

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

showing similarities in pharmacodynamics between juveniles and adults and between humans 

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

portions are generally considered to be 3x; however, for pyrethroids the factor is reduced to 1x

because no differences among the various groups are observed. Finally, as indicated, 

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

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

Pyrethroid Pesticides (D381210, E. Scollon, A. Lowit, 6/27/2011). 

4.4.1 Completeness of the Toxicology Database

The toxicology database for fenpropathrin is not complete. Acceptable fenpropathrin 

developmental toxicity studies in rats and rabbits are available, as well as an acceptable 

reproduction study in rats. The main toxic effect associated with dosing was tremors, a common 

sign for a pyrethroid. This effect was seen in most toxicology studies with fenpropathrin, and 

was observed during in the ACN, SCN and developmental neurotoxicity (DNT) studies. While 

the database is considered to be complete with respect to the guideline toxicity studies, EPA 

lacks additional data to address the potential for juvenile sensitivity to all pyrethroids, including 

fenpropathrin.

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

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

and quantify potential juvenile sensitivity associated with exposure to fenpropathrin. For the 

reasons discussed in Section 4.4, the uncertainty regarding the protectiveness of the intraspecies 

uncertainty factor raised by the literature studies and the absence of the requested data warrant 

application of an additional 3x for risk assessments for infants and children < 6 years of age.

Although a repeated dose inhalation toxicity study is not available, HED’s HASPOC discussed

the inhalation data requirements and concluded that an inhalation study is not required at this 

time (HASPOC memo, TXR 0053978, 4/10/2012). In making this determination, the HASPOC 

considered the following: (1) There are no residential uses; (2) the MOEs from the most recent 

risk assessment (occupational inhalation MOEs > 1,000), (3) the physical and chemical 

properties, and (4) the toxicological profile of fenpropathrin that shows neurotoxicity is the most 

sensitive effect and occurs at similar dose levels following both acute inhalation and oral 

exposures. 
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4.4.2 Evidence of Neurotoxicity

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

As with other pyrethroids, fenpropathrin causes neurotoxicity from interaction with sodium 

channels leading to clinical signs of neurotoxicity. These effects are well characterized and 

adequately assessed by the available guideline and non-guideline studies.

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

Based on the fenpropathrin-specific data from the guideline toxicity studies, there is no 

indication of increased juvenile sensitivity. Fenpropathrin is neither a developmental nor a 

reproductive toxicant. Fenpropathrin has been evaluated for potential developmental effects in 

the rat (following gavage or dietary administration) and in the rabbit (gavage administration). 

Maternal toxicity included neurological effects (i.e., tremors). There were no developmental 

effects of biological significance in either species. The potential reproductive toxicity of 

fenpropathrin was examined in a three-generation reproduction study in the rat. Tremors were 

noted only in females of both generations, while one parental generation rat had clonic 

convulsions. 

After reviewing the extensive body of peer-reviewed literature on pyrethroids, the Agency has 

reached a number of conclusions regarding juvenile sensitivity for pyrethroids including the 

following considerations: the Agency has no residual uncertainties regarding age-related 

sensitivity for women of child bearing age as well as for all adult populations and children > 6 

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

pyrethroids and the scientific literature. Additionally, no evidence of increased quantitative or 

qualitative susceptibility was seen in the pyrethroid scientific literature related to 

pharmacodynamics. The Agency is retaining a 3x uncertainty factor to protect for exposures of

children <6 years of age based on the increased quantitative susceptibility seen in the scientific 

literature related to pyrethroid pharmacokinetics.

Furthermore, high-dose studies in the scientific literature indicated that younger animals were 

more susceptible to the toxicity of pyrethroids. For example, Sheets et al (1994) found 

increased brain deltamethrin levels in young rats (PND 11 and 21) relative to adult rats (PND 

72). These age-related differences in toxicity are principally due to age-dependent 

pharmacokinetics; the activity of enzymes associated with the metabolism of pyrethroids 

increase with age (Anand et al, 2006). However, in context, normal dietary or residential 

exposures of juveniles are not expected to overwhelm their ability to metabolize pyrethroids. In 

support, at a dose of 4.0 mg/kg deltamethrin (near the Wolansky study LOAEL value of 3.0 

mg/kg for deltamethrin), the change in the acoustic startle response was similar between adult 

and young rats (Sheets, 1994). In addition, ORD has recently developed an age-dependent 

PBPK model for deltamethrin (Tornero-Velez et al, 2010) that predicts a 3–fold increase of 

pyrethroid in neuronal tissue in younger animals compared to adults. There are several studies 

(in vitro and in vivo) that indicate that pharmacodynamic contributions to pyrethroid toxicity are 

not age-dependent. Examination of specific VGSCs has demonstrated that there is a lack of 

increased sensitivity in either juvenile specific isoforms (Meacham et al, 2008) or in human 

isoforms compared to rat variants (Tan and Soderlund, 2009). 
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Additional in vitro and in vivo studies are currently being conducted that could potentially inform 

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

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

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

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

during a July 2010 FIFRA SAP meeting. Based on comments from the SAP, the initial study

proposal was refined. At the present time, pesticide registrants and product formulators have 

come together as the Council for the Advancement of Pyrethroid Human Risk Assessment 

(CAPHRA). The Council plans to: 1) conduct in vitro studies demonstrating the interaction of 

pyrethroids in rat and human VGSCs expressed in Xenopus oocytes, 2) conduct in vitro studies 

demonstrating interaction of pyrethroids in rat neurolemma cells, 3) develop rat and human 

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

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

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

4.4.4 Residual Uncertainty in the Exposure Database

There is no residual uncertainty in the exposure database because adequate residue data are 

available. Although the risk estimates for children under 6 years of age are high, many 

conservative assumptions were made in the dietary exposure assessment. Risk estimates are 

based on partially refined estimates of residues in foods and the percentage of the crop that will 

be treated. In addition, for drinking water, a very conservative surface water estimated drinking 

water concentration was used. 

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

The details for selecting toxicity endpoints and points of departure (PODs) are presented in 

Appendix A3. Based on the existing and proposed use patterns for fenpropathrin, the expected 

exposure profile will be for dietary, dermal, and inhalation exposures. 

As previously indicated, the toxicity endpoints in the fenpropathrin database are consistently

based on clinical signs of neurotoxicity and, more specifically, tremors. These studies include 

multiple species, study designs, and durations (Table 4.3.3). Moreover, the acute exposure or 

bolus dosing studies generally result in lower NOAELs compared to longer term dietary

administration studies, consistent with other pyrethroids in this class. Because uncertainty

associated with the POD is propagated throughout the risk assessment, one of the key factors in 

POD selection is the robustness of the dose-response data. The guideline experimental 

toxicology studies available for fenpropathrin are generally high quality and were considered in 

the POD selection process (Appendix A.2) and in the weight of the evidence evaluation. In 

addition to the typical guideline studies, data from two special studies (Wolansky study on motor 

activity and WIL FOB study) evaluating neurobehavioral outcomes are available for 

fenpropathrin (Wolansky et. al. 2006; Weiner et. al. 2009). Wolansky et al. (2006) measured 

motor activity at the time of peak effect after exposure to 11 pyrethroids, including 

fenpropathrin. Dose-response relationships were determined using 6-11 doses per pyrethroid (8 
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doses used for fenpropathrin) and 3-18 rats per dose group (7-12 animals/group used for 

fenpropathrin), minimizing variability and increasing the confidence in the BMD estimates 

determined from this study. Moreover, each pyrethroid was evaluated by the same scientist, thus 

decreasing some of the variability associated with neurobehavioral measures. In the WIL study, 

17 pyrethroids were evaluated using a specially designed FOB study focused on the outcomes 

associated with pyrethroid toxicity syndromes. The fenpropathrin data from the WIL study were 

not considered as part of POD selection. The fenpropathrin dose selection was poor (i.e., 2 doses 

out of the 3 administered resulted in no activity), resulting in low confidence of the calculated 

BMDL (MRID 48714301).

Observation of tremors is the most prominent finding in the guideline experimental toxicology

studies and was considered in the POD determination. Guideline studies typically have only 

three treatment groups and often do not evaluate clinical signs at the time of peak effect. 

Moreover, scoring metrics of tremors varies widely among guideline studies. Given the multiple 

strengths associated with study design of Wolansky, et al. (2006) and the resulting well-defined 

dose-response curve, Wolansky, et al. (2006) provides the most robust data set for extrapolating 

risk from fenpropathrin. 

A BMD analysis was conducted by the Agency for all the pyrethroids included in the Wolansky

study (MRID 48714301). Overall, because of the large number of doses and high quality 

measurements, the BMD analysis yielded high confidence results. In performing BMD analysis, 

a benchmark response (BMR) must be selected. As a general approach, it is preferred to use a 

combination of biological and statistical factors in the BMR selection. In the case of motor 

activity data, there is no specific level of change established by the scientific community as being 

considered adverse. Therefore, OPP has elected to use one standard deviation (1SD) from the 

control group, as suggested, for continuous endpoints in the Agency’s BMD guidance (USEPA 

2012) as the BMR. OPP has estimated both the BMD1SD and the BMDL1SD (where the 

BMDL1SD is the lower 95% confidence limit of the BMD1SD). The BMD1SD and the BMDL1SD

for fenpropathrin are 6.4 mg/kg and 5.0 mg/kg, respectively. As a matter of science policy, EPA 

uses the BMDL, not the BMD, for deriving PODs. Therefore, the BMDL1SD of 5.0 mg/kg is 

being used as the dose for acute dietary risk assessment. 

A route-specific inhalation study is not available for fenpropathrin; however, HED has waived 

the study. As a result, the oral BMDL1SD of 5.0 mg/kg is being used to extrapolate inhalation 

risk. Dermal toxicity studies are available for fenpropathrin in the rat and rabbit. However, no 

treatment-related findings were observed in either species at the limit dose and, therefore, a 

dermal assessment is not being conducted.

Acute Dietary (All Age Groups): Quantitation of the dietary risks was performed using the acute 

oral Wolansky study, with a BMDL1SD value of 5.0 mg/kg and a BMDL1SD value of 6.4 mg/kg 

based on decreased locomotor activity. 

Short-term Dermal: A dermal assessment was not conducted for fenpropathrin. Although the 

acute dermal toxicity of fenpropathrin is Category II, and a dermal penetration study indicates 

that up to 33% of a dermally applied dose is absorbed, HED’s residual concern for potential 

dermal toxicity is reduced because: 1) in the acute study there was no indication of toxicity
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below the 250 mg/kg dose (which is 50-fold greater than the proposed oral POD of 5 mg/kg),

and 2) the majority of residue in the dermal penetration study was bound to the upper dermal 

layers and was not available for systemic circulation.

Furthermore, there is no indication of increased susceptibility. As dermal studies do not assess 

developmental and reproductive parameters, there is the potential that such effects would be 

overlooked in a dermal study. As neurotoxicity is observed at the same or lower doses than

reproductive and developmental effects were observed and neurotoxicity would be apparent in a 

dermal study, there is reduced concern that developmental effects would be missed. 

Short-term Inhalation: In the absence of an inhalation study, an oral study is being used. A POD 

of 5.0 mg/kg is selected from the Wolansky acute rat study for this endpoint because of the 

overall robust nature of the study. Toxicity via the inhalation route is assumed to be equal to 

toxicity via the oral route.

See Appendix A.3 for a more detailed description of endpoint selection.

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

Only the acute dietary and inhalation routes of exposure are being assessed. There are no other 

routes of exposure to be combined.

4.5.3 Cancer Classification and Risk Assessment Recommendation

There was no evidence of carcinogenicity in either the rat or mouse long-term dietary studies nor 

was there any mutagenic activity in bacteria or cultured mammalian cells. Fenpropathrin is 

classified as “not likely to be carcinogenic to humans” in accordance with the EPA Final 

Guidance for Carcinogen Risk Assessment (3/29/2005). 

4.5.4 Summary of Points of Departure and Toxicity Endpoints

Table 4.5. Summary of Fenpropathrin Toxicological Doses and Endpoints for Use in Human Health Risk 

Assessment

Exposure 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors 

RfD, PAD, Level of 

Concern for Risk 

Assessment

Study and 

Toxicological Effects

Acute 

Dietary-

(≥ 6 years 

old)

Wolansky 

BMDL1SD = 5.0 

mg/kg

UFA = 10x

UFH = 10x

FQPA SF = 1x

Acute RfD = 0.05 

mg/kg

aPAD =0.05 mg/kg/day

Wolansky BMD1SD = 

6.4 mg/kg

based on decreased 

motor activity

Acute 

Dietary-

(< 6 years 

old)

Wolansky 

BMDL1SD = 5.0

mg/kg

UFA = 10x

UFH = 10x

FQPA SF = 3x

Acute RfD = 0.05 

mg/kg

aPAD =0.017

mg/kg/day

Wolansky BMD1SD = 

6.4 mg/kg

based on decreased 

motor activity

Short-Term

(1-30 days) 

Dermal

There was no systemic toxicity via the dermal route; therefore, no endpoint was selected.
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Table 4.5. Summary of Fenpropathrin Toxicological Doses and Endpoints for Use in Human Health Risk 

Assessment

Exposure 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors 

RfD, PAD, Level of 

Concern for Risk 

Assessment

Study and 

Toxicological Effects

Short-Term

(1-30 days)

Inhalation

Wolansky 

BMDL1SD = 5.0 

mg/kg1

UFA = 10x

UFH = 10x

FQPA SF = 1x

Occupational LOC for 

MOE = 100

Wolansky BMD1SD = 

6.4 mg/kg

based on decreased 

motor activity

Cancer (oral, 

dermal, 

inhalation)

Classification: “not likely to be carcinogenic to humans” in accordance with the EPA Final 

Guidance for Carcinogen Risk Assessment (3/29/05) 

1 Toxicity via the inhalation route is assumed to be equal to toxicity via the oral route.

Abbreviations: BMD1SD is the central estimate of the dose that results in decreased motor activity compared to 

control animals based upon a 1 standard deviation using Benchmark Dose Analysis; BMDL is the 95% lower 

confidence limit of the central estimate. Data extrapolated for Wolansky (2006), MRID 47885701; UF = 

uncertainty factor. Point of Departure (POD) = A data point or an estimated point that is derived from observed 

dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower 

environmentally relevant human exposures. UF = uncertainty factor. UFA = extrapolation from animal to human 

(interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). 

FQPA SF = FQPA Safety Factor. aPAD = acute population adjusted dose, RfD = reference dose. MOE = margin of 

exposure. LOC = level of concern.

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

HED has determined that the nature of the residue in primary crops is adequately understood. 

Metabolism studies were conducted on apples, cotton, pinto beans, and tomatoes. In these crops, 

parent fenpropathrin was the predominant residue identified. Conjugated metabolites were also 

present, but at very low levels. In the cotton metabolism study, there was extensive metabolism 

of the parent compound. HED determined that the residue of concern in primary crops is the 

parent compound.

The nature of the residue in rotational crops is also adequately understood. In a confined 

rotational crop study, the predominant residues in rotated crops were 2,2,3,3-tetramethylcyclopropanecarboxylic acid (TMPA) and 3-phenoxybenzoic acid (3-PBA). Fenpropathrin was also 

found in rotated crops, but at less than 10% of the total radioactive residues.

Metabolism studies with goats and poultry have been submitted and reviewed. The majority of 

the residue in muscle, fat, milk, and eggs was found to be the parent compound. The residues in 

kidney and liver consisted mainly of low levels of various metabolites. HED previously stated 

that the livestock metabolites, with the possible exception of TMPA lactone, have also been 

identified in rat metabolism studies and their contributions to the overall toxicity of 

fenpropathrin have been considered (Memo, J. Whalen, 9/16/1989).
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5.1.2 Summary of Environmental Degradation

Fenpropathrin appears to be resistant to degradation in biotic processes and is relatively stable to 

abiotic processes. The chemical is expected to have little mobility in soil surfaces, and leaching 

into groundwater is not expected to be an important transport process. Volatilization is not 

expected to be an important transport process. Fenpropathrin is stable to hydrolysis at both pH 5 

and 7, and shows moderate hydrolysis at pH 9 (half-lives on the order of 15 days). The chemical 

is light-stable under aqueous photolysis and soil photodegradation. Under both aerobic and 

anaerobic soil metabolism conditions, fenpropathrin degrades slowly, with half-lives of 152 and 

186 days, respectively. If released to water, fenpropathrin partitions with the sediment and 

organic matter, where it might persist. In the field, fenpropathrin shows a wide range of halflives (8-144 days). This variability might be due to the wide range of conditions observed in 

different parts of the U.S. Except for COOH-fenpropathrin (observed in the anaerobic soil 

metabolism study), other degradates observed in the laboratory result from the cleavage of the 

ester moiety of fenpropathrin. TMPA and 3-PBA were among the observed degradates in the 

hydrolysis study. CONH2-fenpropathrin, monitored in the field, was observed only in the upper 

layers of soil and appeared to be immobile.

5.1.3 Comparison of Metabolic Pathways

Adequate studies are available depicting the metabolism of fenpropathrin in rats, primary crops 

(apples, cotton, pinto beans, tomatoes), rotational crops (carrots, lettuce, wheat), and livestock 

(lactating goats, laying hens) (D222174, L. Cheng, 10/23/97). Fenpropathrin is susceptible to 

metabolism in plants and animals. In rats, the major biotransformation products from single and 

repeated dose rat metabolism studies included oxidation of the methyl group on the acid moiety, 

hydroxylation at the 4’-position of the alcohol moiety, cleavage of the ester linkage, and 

conjugation with sulfuric and glucuronic acid. Major metabolites (i.e., >10% of applied total 

radioactive residue (TRR)) were phenoxybenzoic acid and TMPA-glucuronic acid. Parent was 

the only major compound identified in the feces. The primary metabolites found in the confined 

rotational crop study were hydrolysis products of parent compound. Because of the similarity of 

the metabolites between the animal and plant studies, the rat toxicity studies account for the 

metabolites found in plants and livestock commodities.

5.1.4 Residues of Concern Summary and Rationale

The nature of the fenpropathrin residue is adequately understood in plants, rotational crops, 

livestock commodities, surface water, and groundwater. Parent fenpropathrin is the major 

residue in plant and livestock studies. Furthermore, the plant, animal, and environmental 

degradates identified are unlikely to be more toxic than the parent. Therefore, parent 

fenpropathrin is the residue of concern for both tolerance enforcement and risk assessment in 

plants, livestock commodities, and drinking water. 
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Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance 

Expression

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Plants

Primary Crop Fenpropathrin Fenpropathrin

Rotational Crop Not Applicable Not Applicable

Livestock

Ruminant Fenpropathrin Fenpropathrin

Poultry Fenpropathrin Fenpropathrin

Drinking Water Fenpropathrin Not Applicable

5.2 Food Residue Profile

The registrant submitted adequate use directions for the proposed tropical fruits. In addition, the 

registrant submitted adequate field trial data for guava, lychee, sugar apple, and atemoya to 

support the proposed uses on tropical fruits. HED’s Chemistry Science Advisory Council 

(ChemSAC) approved a revision of 40 CFR §180.1(g) to permit the extension of tolerances for 

guava, lychee, and sugar apple to tolerances for the other tropical fruits in this petition. The 

submitted crop field trial data for guava, lychee, and sugar apple may be translated to support the 

proposed uses on the corresponding specific commodities; however, a separate tolerance must be 

established for each commodity. ChemSAC approved the following revisions: (1) a tolerance 

for guava also applies to feijoa, jaboticaba, wax jambu, starfruit, passionfruit, and acerola; (2) a

tolerance for lychee also applies to longan, Spanish lime, rambutan, and pulasan; and (3) a

tolerance for sugar apple also applies to cherimoya, ilama, soursop, and biriba. A tolerance for 

sugar apple already applies to atemoya and custard apple. The submitted crop field trial data will 

support the proposed tolerances of 3.0 ppm for guava, acerola, feijoa, jaboticaba, passionfruit, 

starfruit, and wax jambu; 7.0 ppm for lychee, longan, Spanish lime, pulasan, and rambutan; and 

1.5 ppm for sugar apple, atemoya, biriba, cherimoya, custard apple, ilama, and soursop.

Table 5.2 provides a summary of the field trials that were performed for fenpropathrin.

Table 5.2. Summary of Residue Data from Crop Field Trials with Fenpropathrin.

Crop matrix Total Applic. 

Rate

(lb ai/A)

PHI 

(days)

Residue Levels (ppm)

n Min. Max. HAFT1 Median Mean Std. 

Dev.

TROPICAL AND SUBTROPICAL FRUITS

(proposed use = 0.8 lb ai/A total application rate, 1-day PHI)

Guava 0.78-0.82 1 6 0.48 1.1 1.0 0.59 0.71 0.25

Lychee 0.80-0.84 1 6 2.1 2.6 2.5 2.4 2.3 0.20

Sugar apple/atemoya 0.81-0.82 1 6 0.25 0.70 0.48 0.40 0.45 0.16

1

 HAFT = Highest average field trial result.

Adequate field trial data reflecting use of fenpropathrin on tea grown in India are available for 

establishing an import tolerance on dried tea. The OECD MRL calculation procedures 

recommend that the tolerance be established at 3.0 ppm. However, there is a Codex MRL of 2.0 
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ppm for dried tea. HED considers this tolerance level to be adequate because the highest field 

trial value was 1.38 ppm. As a result, HED recommends in favor of a tolerance of 2.0 ppm for 

tea, dried in order to harmonize with the Codex MRL. 

HED does not require residue data for any processed commodities associated with this tolerance 

petition. As a result, no processing studies were submitted and none are needed.

There are no livestock feedstuffs associated with the proposed use on tropical fruits or tea. As a 

result, the current tolerances for livestock commodities are adequate.

Information is available concerning the potential of fenpropathrin to bioconcentrate in fish. The 

chemical has a relatively high octanol/water partition coefficient and depurates from fish at a 

moderate rate. EFED’s registration review problem formulation (D371483, J. Melendez, 

6/16/2010) states that “...fenpropathrin appears to have a potential to bioconcentrate in aquatic 

organisms & biomagnify in aquatic and terrestrial organisms.” However, the moderate 

depuration rate reduces the concern for residues in fish for subsistence and recreational fishers.

5.3 Water Residue Profile

The Environmental Fate and Effects Division (EFED) provided the results of a drinking water 

assessment that was performed for fenpropathrin (D368174, Jose Melendez, 4/26/2010). In this 

memo, EFED stated that the results of a previous assessment (D313331, J. Melendez, 9/3/2008)

should be used in the current dietary exposure and risk assessment. Water numbers were based 

on parent only. The EFED memo of 9/3/2008 provided Tier 1 estimated environmental 

concentrations (EDWCs) for fenpropathrin that were calculated using the FIRST Model for 

surface water and the SCIGROW Model for groundwater. For surface water, the acute (peak) 

water concentration is 10.3 ppb. The groundwater screening concentration is 0.005 ppb. These 

values generally represent upper-bound estimates of the concentrations that might be found in 

surface water and groundwater resulting from the use of fenpropathrin on grapes, because this is 

the scenario that results in the highest EDWCs. For the acute dietary exposure assessment, the 

peak water concentration value of 10.3 ppb was used. The model and its description are 

available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/. 

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

An acute aggregate dietary (food and drinking water) exposure and risk assessment was

conducted using the Dietary Exposure Evaluation Model DEEM-FCIDTM, Version 2.03, which 

uses food consumption data from the U.S. Department of Agriculture’s Continuing Surveys of 

Food Intakes by Individuals (CSFII) from 1994-1996 and 1998.

A chronic dietary exposure assessment was not performed because repeated exposure to 

fenpropathrin does not result in a point of departure lower than that resulting from acute 

exposure, and a chronic dietary endpoint was not selected. The acute dietary risk assessment is 

considered to be protective of chronic dietary risk. An assessment for cancer was not performed 
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because fenpropathrin was classified as “not likely to be carcinogenic to humans.” As a result, 

an acute assessment was the only dietary exposure assessment performed for fenpropathrin. 

The acute assessment was based on tolerance level residues, distributions of field trial values,

and distributions of Pesticide Data Program (PDP) monitoring data. Residue distributions were 

used for the commodities that made the most significant contributions to the risk estimates (i.e., 

the “risk drivers”). Monitoring data were used for risk drivers when they were available; 

however, field trial data were used for the remaining risk drivers. Distributions of monitoring 

data values were used for broccoli, Chinese mustard cabbage, cauliflower, watermelon, squash, 

oranges, tangerines, apples, apple juice, pears, blueberries, huckleberries, grapes, grape juice, 

and strawberries. Monitoring data from the years 2007 through 2010, inclusive, were used. 

Broccoli PDP data were translated to Chinese mustard cabbage and cauliflower. Orange PDP 

data were translated to tangerines. Finally, blueberry PDP data were translated to huckleberries. 

Distributions of field trial data were used for cherries, peaches, plums, grapefruit, raspberries, 

blackberries, apricots, cabbage, papaya, olives, tomatoes, cucumbers, Brussels sprouts, and 

guava. For most processed commodities, DEEM default processing factors were used for those 

commodities for which they were available. In some cases, empirical processing factors were 

used. For drinking water, a very conservative surface water EDWC generated with the FIRST 

Model was used. As a result of the fact that many conservative assumptions were made for this 

assessment, in particular, the use of field trial data (as opposed to monitoring data) for many

commodities, HED is confident that the acute dietary exposure assessment significantly

overestimates risk to the general U.S. population and all population subgroups.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The Biological and Economic Analysis Division (BEAD) provided a Screening Level Usage 

Analysis (SLUA) for fenpropathrin (D402054, S. Haddad, 5/25/2012). The SLUA provided 

maximum percent crop treated estimates for commodities with established tolerances. Percent 

crop treated estimates were not used for any of the proposed commodities. 

The following maximum percent crop treated estimates were used in the acute dietary risk 

assessment for the following crops that are currently registered: apples (15%), apricots (2.5%),

blueberries (2.5%), broccoli (2.5%), Brussels sprouts (10%), cabbage (2.5%), cauliflower 

(2.5%), cherries (5%), cotton (2.5%), cucumbers (2.5%), grapefruit (35%), grapes (10%), 

nectarines (2.5%), oranges (35%), peaches (2.5%), pears (10%), plums (2.5%), prune plums 

(2.5%), squash (2.5%), strawberries (50%), tangerines (15%), tomatoes (10%), and watermelons 

(2.5%).

5.4.3 Acute Dietary Risk Assessment

The acute risk estimates are below HED’s level of concern for all population subgroups, 

including those comprised of infants and children. Generally, HED is concerned when risk 

estimates exceed 100% of the PAD. The acute risk estimate for the general U.S. population is 

19% of the aPAD. The population subgroup with the highest acute dietary risk estimate is 

Children 3-5, which uses 97% of the aPAD. As percent crop treated estimates were incorporated 

into the acute assessment, the risk estimates are being reported at the 99.9th percentile of 

exposure. The acute dietary risk estimates are given in Table 5.4.4.
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HED considers the acute assessment to be partially refined, but at the same time, very healthprotective. Refinements were made to the risk drivers in the assessment; however, for many of 

the risk drivers, these refinements consisted of the incorporation of field trial data (See Section 

5.4.1, above). For pyrethroids, monitoring data are almost always significantly lower than field 

trial data. Monitoring data more accurately represent the residue levels to which people will 

actually be exposed to pesticide residues in their diets. For many commodities, the assumption 

was made that 100% of the crop would be treated. For other commodities, maximum percent 

crop treated estimates were incorporated. These estimates are based on past usage data and are 

considered to be reliable. Percent crop treated estimates were not available for two of the risk 

drivers for children 1-6 years of age, raspberries and blackberries. As a result, 100% crop treated 

was used for these commodities. If usage estimates were available and had been used, the risk 

estimates for the population subgroups, Children 1-2 and Children 3-5, would have been lower. 

As all risk estimates are not of concern, it is not necessary to make any further refinements to the 

dietary exposure assessment at this time.

Residues in drinking water made a negligible contribution to the risk estimates. 

5.4.4 Summary Table

Table 5.4.4. Summary of the Acute Exposure and Risk Estimates for Fenpropathrin

Population 

Subgroup

Acute Assessment (99.9th Percentile) Chronic Assessment

aPAD, 

mg/day

Exposure Estimate, 

mg/day

% 

aPAD

cPAD, 

mg/day

Exposure Estimate, 

mg/day

% cPAD

U.S. Population 0.05 0.009489 19

NA NA NA

All infants 0.017 0.011457 67

Children 1-2 yrs 0.017 0.015343 90

Children 3-5 yrs* 0.017 0.016488 97

Children 6-12 yrs 0.05 0.013489 27

Youth 13-19 yrs 0.05 0.009290 19

Adults 20-49 yrs 0.05 0.007920 16

Adults 50+ yrs 0.05 0.008093 16

Females 13-49 yrs 0.05 0.008476 17

*Most highly exposed population subgroup

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

6.1 Residential Handler and Post-application Exposure and Risk Estimates

There are no registered or proposed residential uses for fenpropathrin. As a result, residential 

handler and post-application risk is not of concern. 
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6.2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby spraying operations. This 

is particularly the case with aerial application, but, to a lesser extent, could also be a potential 

source of exposure from the ground application method employed for fenpropathrin. The 

Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at: 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical-by-chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.

Although a quantitative post-application inhalation exposure assessment was not performed for 

fenpropathrin to address pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for flaggers who assist aerial applicators. This exposure 

scenario is representative of a worst-case inhalation (drift) exposure and may be considered 

protective of most outdoor agricultural and commercial post-application inhalation exposure 

scenarios.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risk estimates from three major sources: food, drinking water, and residential exposures. In an 

aggregate assessment, exposures from relevant sources are added together and compared to 

quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risk estimates themselves can 

be aggregated. When aggregating exposures and risks from various sources, HED considers 

both the route and duration of exposure. The only applicable aggregate scenario for 

fenpropathrin is acute aggregate risk which results from exposure to residues in food and 

drinking water alone. The acute dietary exposure analysis included both food and drinking 

water. Therefore, acute aggregate risk estimates are equivalent to the acute dietary risk

estimates, as discussed in Section 5.4.3, above. Acute aggregate risk is not of concern for the 

general U.S. population or any population subgroup. 

8.0 Cumulative Exposure/Risk Characterization

The Agency is required to consider the cumulative risks of chemicals sharing a common 

mechanism of toxicity. The Agency has determined that the pyrethroids and pyrethrins share a 

common mechanism of toxicity (http://www.regulations.gov; EPA-HQ-OPP-2008-0489-0006). 

The members of this group share the ability to interact with voltage-gated sodium channels 

ultimately leading to neurotoxicity. The cumulative risk assessment for the pyrethroids/ 

pyrethrins was published on 11/9/2011 and is available at http://www.regulations.gov; EPA-HQ-
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OPP-2011-0746. No cumulative risks of concern were identified, allowing the Agency to 

consider new uses for pyrethroids. For information regarding EPA’s efforts to evaluate the risk 

of exposure to this class of chemicals, refer to 

http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids-pyrethrins.html.

Fenpropathrin is included in the pyrethroid/pyrethrin cumulative risk assessment. The new uses 

that have been proposed have an insignificant impact on the cumulative risk assessment. No 

dietary, residential, or aggregate risk estimates of concern have been identified in the single 

chemical assessment. In the cumulative assessment, residential exposure was the greatest 

contributor to the total exposure. As there are no residential uses for fenpropathrin, the proposed 

new uses will have no impact on the residential component of the cumulative risk estimates.

Dietary exposures make a minor contribution to the total pyrethroid exposure. The dietary

exposure assessment performed in support of the pyrethroid cumulative was much more highly 

refined than that performed for the single chemical. In addition, for the fenpropathrin risk 

assessment, the most sensitive apical endpoint in the fenpropathrin database was selected to 

derive the POD. Additionally, the POD selected for fenpropathrin is specific to fenpropathrin, 

whereas the POD selected for the cumulative assessment was based on common mechanism of 

action data that are appropriate for all 20 pyrethroids included in the cumulative assessment. 

Dietary exposure to fenpropathrin residues in the proposed tropical fruits and tea will contribute 

very little to the dietary exposure to fenpropathrin alone. As a result, the proposed uses will 

make an insignificant contribution to dietary risk to the pyrethroids as a whole. 

9.0 Occupational Exposure/Risk Characterization

Fenpropathrin may be applied to fruit trees by ground equipment (airblast). In addition, aerial 

application may be used for avocado trees. Fenpropathrin is intended for use by commercial and 

professional applicators. Therefore, there is potential for short- and intermediate-term 

occupational handler and post-application exposure via the inhalation and dermal pathways. No 

long-term exposure (> 6 months) is expected. However, as noted previously, fenpropathrin does 

not increase in potency with repeated dosing, and therefore only single-day occupational

exposures are being assessed. These single-day risk estimates are protective for repeated 

exposures. As there is no dermal hazard associated with this chemical, only inhalation risk is 

being assessed quantitatively. 

9.1 Short-/Intermediate-Term Handler Risk

Exposure scenarios describe the handler activities (mixer, loader, applicator, and flagger) and 

type of application equipment. Based on the proposed use pattern, the following scenarios were 

identified for the application of fenpropathrin to tropical fruits: 

• Mixing/loading liquid formulation for aerial application,

• Mixing/ loading liquid formulation for airblast equipment,

• Applying the spray using air equipment (enclosed cockpit),

• Applying the spray using airblast equipment, and

• Flagging for aerial spray application
Fenpropathrin Human Health Risk Assessment DP No. D368175

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There are no chemical-specific exposure data for fenpropathrin to develop unit exposures 

required for estimating handler exposure. It is HED policy to use the best available data to 

assess handler exposure. Sources of generic handler data, used as surrogate data in the absence 

of chemical-specific data, include the PHED (Version 1.1) database, and the Agricultural 

Handler Exposure Task Force (AHETF) database. Some of these data are proprietary (e.g., 

AHETF data), and subject to the data protection provisions of FIFRA. The standard values 

recommended for use in predicting handler exposure that are used in this assessment, known as 

“unit exposures,” are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate 

Reference Table” (http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, 

along with additional information on HED policy on use of surrogate data, including descriptions 

of the various sources, can be found at: http://www.epa.gov/pesticides/science/handler-exposuredata.html.

The Danitol®label directs applicators and other handlers to wear long-sleeved shirt, long pants, 

chemical-resistant gloves, shoes, socks, and protective eyewear. 

Table 9.1 summarizes the short-term inhalation risk estimates for handlers resulting from the 

proposed use of fenpropathrin on tropical fruits, applied as a foliar treatment. There is no 

toxicity associated with dermal exposure to fenpropathrin and, therefore, there is no dermal risk 

for handlers. The acute inhalation endpoint and dose are protective of repeated exposures as 

discussed previously. The results of HED’s assessment indicate that the short-term inhalation 

risk estimates (MOE ≥ 5,300) are above HED’s LOC of an MOE of 100 at the baseline level of 

PPE (i.e., no respirator), and with the use of engineering controls for aerial applications. These 

risk estimates are not of concern.

Furthermore, the Agency has evaluated scenarios that might be limited in nature such as flagging 

during aerial applications because engineering controls (i.e., Global Positioning Satellite 

technology) are now predominantly used as indicated by the 1998 National Agricultural Aviation 

Association (NAAA) survey of their membership. It appears, however, flaggers are still used in 

approximately 10 to 15 percent of aerial application operations. In cases like these, the Agency

strongly encourages the use of the engineering control system but will continue to evaluate risks 

for flaggers and any other population where a clear exposure pathway exists until the potential 

for exposure is eliminated. The Agency is aware that NAAA is conducting another survey on 

exposure issues and will consider those results at such time as it is appropriate to do so.
Fenpropathrin Human Health Risk Assessment DP No. D368175

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Table 9.1. Fenpropathrin Occupational Handler Exposure and Risk Estimates 

Exposure

Scenario PPE 1

Max. Single

Appl. Rate

(lb ai/A)

Area

Treated

(Acres)

Inhalation Unit

Exposure & Source

(μg/lb ai)

Inhalation Dose

(mg/kg/

day) 2

Short-term

Inhalation MOE3

MIXER / LOADER

Liquids (EC) for 

aerial equipment

Baseline 

(no respirator) 0.4 350 0.219(AHETF) 0.00038 13,000

Liquids (EC) for 

airblast equipment 

Baseline

(no respirator)

0.4 40 0.219

(AHETF) 0.000044 110,000

APPLICATOR and FLAGGER

Spray for aerial 

equipment Closed cockpit 0.4 350 0.068(PHED) 0.00012 42,000

Spray for airblast

equipment

Baseline

(open cab and no 

respirator)

0.4 40 4.71

(AHETF) 0.00094 5,300

Flagger: Aerial 

Applications

Baseline 

(no respirator) 0.4 350 0.35(PHED) 0.00061 8,200

MOE = margin of exposure, AHETF=Agricultural Handler Exposure Task Force, PHED=Pesticide Handlers 

Exposure Database. 

1. Baseline PPE includes long-sleeved shirt, long pants and shoes with socks and engineering controls. The 

submitted label recommends baseline PPE plus chemical-resistant gloves and protective eyewear. 

2. Inhalation Dose (mg/kg/day) = [Appl. Rate (lb ai/A) * Acres Treated/Day * Inhalation Unit Exposure (μg/lb ai 

handled/day /1000)] / Body wt (80 kg).

3. Short-term Inhalation MOE = Short-term Inhalation POD (5.0 mg/kg/day) / Inhalation dose (mg/kg/day). 

9.2 Occupational/Commercial Post-application Exposure 

Post-application workers might be exposed to residues of fenpropathrin through dermal and 

inhalation routes when they enter treated tropical fruit orchards to perform post-application

activities, such as thinning, irrigation, scouting, harvesting, etc. Dermal post-application

exposure was not quantitatively estimated for use of fenpropathrin on tropical fruits because of

the absence of a dermal endpoint.

Based on the Agency’s current practices, a quantitative post-application inhalation exposure 

assessment is not being performed for fenpropathrin at this time primarily because of the low 

acute inhalation toxicity (Toxicity Category IV) and the low use rate (0.4 lb ai/A). However, 

there are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and re-suspension of dusts and/or particulates that contain 

pesticides. The Agency sought expert advice and input on issues related to volatilization of 

pesticides from its FIFRA Scientific Advisory Panel (SAP) in December 2009, and received the 

SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency’s risk assessments. If new policies or 
Fenpropathrin Human Health Risk Assessment DP No. D368175

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procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for fenpropathrin.

Although a quantitative post-application inhalation exposure assessment was not performed, 

HED has assessed inhalation exposure and risk for occupational/commercial flaggers for aerial 

applications of fenpropathrin on tropical fruits, and the risk estimates are not of concern. 

Inhalation exposure for flaggers is likely to be higher than inhalation exposure associated with 

post-application activities. Therefore, the flagger inhalation risk estimates are considered to be

protective of all potential post-application activities performed in treated tropical fruit orchards, 

and these risks are not of concern.

Restricted Entry Interval

The registered Danitol®2.4 EC Spray has a 24-hour restricted entry interval (REI) and is in 

compliance with the Worker Protection Standard because fenpropathrin is Toxicity Category II 

via the dermal route. It is not an eye or skin irritant, and it is not a skin sensitizer.

10.0 References

OPP Memoranda

D. Dotson, et al., 11/26/2008, D313330, Fenpropathrin. Human Health Risk Assessment for the 

Proposed Uses on Barley, Stone Fruit (Crop Group 12), Tree Nuts (Crop Group 14), Pistachio, 

Caneberries (Crop Subgroup 13-07A), Olive, Avocado, Black Sapote, Canistel, Mamey Sapote, 

Mango, Papaya, Sapodilla, and Star Apple 

D. Smegal, 4/10/2012, TXR# 0053978, Summary of Hazard and Science Policy Council 

(HASPOC) Meeting of January 19, 2012: Recommendations on waiver requests for a 90-day

inhalation study for fenpropathrin 

J. Kidwell, 7/24/2012, Fenpropathrin - Summary of Toxicology Science Advisory Council 

(ToxSAC) E-Meeting

E. Scollon, A. Lowit, 6/27/2011, D381210, Re-Evaluation of the FQPA Safety Factor for 

Pyrethroid Pesticides

D. Dotson, 7/24/2012, D368340, Fenpropathrin. Request for Tolerances in Support of New Uses 

on the Tropical Fruits Guava, Acerola, Feijoa, Jaboticaba, Passionfruit, Starfruit, Wax Jambu, 

Lychee, Longan, Spanish Lime, Pulasan, Rambutan, Sugar Apple, Atemoya, Biriba, Cherimoya, 

Custard Apple, Ilama, and Soursop. Request for a Tolerance Without U.S. Registration on Tea. 

Summary of Analytical Chemistry and Residue Data.

D. Dotson, 7/24/2012, D402246, Fenpropathrin. Acute Aggregate Dietary (Food and Drinking 

Water) Exposure and Risk Assessment for the Section 3 Registration Action on the Tropical 

Fruits Guava, Acerola, Feijoa, Jaboticaba, Passionfruit, Starfruit, Wax Jambu, Lychee, Longan, 
Fenpropathrin Human Health Risk Assessment DP No. D368175

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Spanish Lime, Pulasan, Rambutan, Sugar Apple, Atemoya, Biriba, Cherimoya, Custard Apple, 

Ilama, and Soursop, and a Tolerance Without U.S. Registration on Tea

Suku Oonnithan, 6/11/2012, D372847, Fenpropathrin: Occupational and Residential Exposure 

Assessment for the Proposed New Use on Additional Tropical Fruits.

M. Shamim, 7/6/1993, D180582, Review of Hydrolysis, Photolysis in Water, Photolysis on Soil, 

Anaerobic Soil Metabolism, Mobility and Adsorption/ Desorption, and Terrestrial Field 

Dissipation Studies; Proposed New Uses on Tomatoes and Strawberries; Label Amendment.

J. Melendez, 4/26/2010, D368174, Tier I Estimated Drinking Water Concentrations of 

Fenpropathrin: IR-4 Petition for the Use of Fenpropathrin on Additional Tropical and Sub 

Tropical Fruits and for Tolerance for Tea.

Toxicology References

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“Characterization of deltamethrin metabolism by rat plasma and liver microsomes.” Toxicology

and Applied Pharmacology 212(2): 156-166.

Cao, Z., T. J. Shafer, K. M. Crofton, C. Gennings and T. F. Murray (2011a). “Additivity of 

Pyrethroid Actions on Sodium Influx in Cerebrocortical Neurons in Primary Culture.” Environ 

Health Perspect.

Cao, Z., T. J. Shafer and T. F. Murry (2011b). “Mechanisms of Pyrethroid Insecticide-Induced 

Stimulation of Calcium Influx in Neocortical Neurons.” J Pharmacology and Experimental 

Therapy 336(1): 197-205.

Choi, J.-S. and D. M. Soderlund (2006). “Structure-activity relationships for the action of 11 

pyrethroid insecticides on rat Nav1.8 sodium channels expressed in Xenopus oocytes.”

Toxicology and Applied Pharmacology 211(3): 233-244.

de Zwart, L., M. Scholten, J. G. Monbaliu, P. P. Annaert, J. M. Van Houdt, I. Van den Wyngaert, 

L. M. De Schaepdrijver, G. P. Bailey, T. P. Coogan, W. C. Coussement and G. S. Mannens 

(2008). “The ontogeny of drug metabolizing enzymes and transporters in the rat.” Reproductive 

Toxicology 26(3-4): 220-230.

Godin, S. J., M. J. DeVito, M. F. Hughes, D. G. Ross, E. J. Scollon, J. M. Starr, R. W. Setzer, R. 

B. Conolly and R. Tornero-Velez (2010). “Physiologically Based Pharmacokinetic Modeling of 

Deltamethrin: Development of a Rat and Human Diffusion-Limited Model.” Toxicol. Sci. 

115(2): 330-343.

Goldin, A., R. Barchi, J. Caldwell, F. Hofmann, J. Howe, J. Hunter, R. Kallen, G. Mandel, M. 

Meisler, YBNetter, M. Noda, M. Tamkun, S. Waxman, J. Wood and W. Catterall (2000). 

“Nomenclature of voltage-gated sodium channels.” Neuron 28(2): 365-368.
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Koukouritaki, S. B., J. R. Manro, S. A. Marsh, J. C. Stevens, A. E. Rettie, D. G. McCarver and 

R. N. Hines (2004). “Developmental Expression of Human Hepatic CYP2C9 and CYP2C19.”

Journal of Pharmacology and Experimental Therapeutics 308(3): 965-974.

Lawrence, L. and J. Casida (1982). “Pyrethroid toxicology: Mouse intracerebral sturcturetoxicity relationships.” Pesticide Biochemistry and Physiology 18: 9-14.

Lund, A. and T. Narahashi (1982). “Dose-dependent interaction of the pyrethroid isomers with 

sodium channels of squid axon membranes.” Neurotoxicology 3(1): 11-24.

Meacham, C. A., P. D. Brodfuehrer, J. A. Watkins and T. J. Shafer (2008). “Developmentallyregulated sodium channel subunits are differentially sensitive to [alpha]-cyano containing 

pyrethroids.” Toxicology and Applied Pharmacology 231: 273-281.

Mirfazaelian, A., K. Kim, S. Anand, H. Kim, R. Tornero-Velez, J. Bruckner and J. Fisher (2006). 

“Development of a physiologically based pharmacokinetic model for deltamethrin in the adult 

male Sprague-Dawley rat.” Toxicol Sci 93(2): 432 - 442.

Salgado, V., M. Herman and T. Narahashi (1989). “Interactions of the pyrethroid fenvalerate 

with nerve membrane sodium channels: Temperature dependence and mechanism of 

depolarization.” Neurotoxicology 10(1): 1-14.

Shafer, T. J., D. Meyer and K. M. Crofton (2005). “Developmental neurotoxicity of pyrethroid 

insecticides: critical review and future needs.” Environmental Health Perspectives 113(2): 123-

136.

Soderlund, D., J. Clark, L. Sheets, L. Mullin, V. Piccirillo, D. Sargent, J. Stevens and M. Weiner 

(2002). “Mechanisms of pyrethroid neurotoxicity: implications for cumulative risk assessment.”

Toxicology 171(1): 3 - 59.

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Appendices

Appendix A: Toxicology Profile

Appendix A.1. Toxicology Data Requirements

Toxicology Requirements for Fenpropathrin 

Guideline Number and Toxicity Study Required Satisfied

870.1100 Acute Oral Toxicity ...............................................................

870.1200 Acute Dermal Toxicity ..........................................................

870.1300 Acute Inhalation Toxicity ......................................................

870.2400 Primary Eye Irritation ............................................................

870.2500 Primary Dermal Irritation ......................................................

870.2600 Dermal Sensitization..............................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Sub-chronic (Rodent).....................................................

870.3150 Oral Sub-chronic (Non-Rodent).............................................

870.3200 21-Day Dermal ......................................................................

870.3250 90-Day Dermal ......................................................................

870.3465 90/28-Day Inhalation .............................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes1

870.3700 Developmental Toxicity (Rodent).........................................

870.3700 Developmental Toxicity (Non-rodent)...................................

870.3800 Reproduction..........................................................................

yes

yes

yes

yes

yes

yes

870.4100 Chronic Toxicity (Rodent).....................................................

870.4100 Chronic Toxicity (Non-rodent)..............................................

870.4200 Oncogenicity (Rat).................................................................

870.4200 Oncogenicity (Mouse) ...........................................................

870.4300 Chronic/Oncogenicity............................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity: Gene Mutation - bacterial ...............................

870.5300 Mutagenicity: Gene Mutation - mammalian ..........................

870.5375 Mutagenicity: Structural Chromosomal Aberrations .............

870.5385 Mutagenicity: Structural Chromosomal Aberrations .............

870.5500 Mutagenicity: Other Genotoxic Effects .................................

870.5550 Mutagenicity: Other Genotoxic Effects .................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.6100 Acute Delayed Neurotoxicity (Hen) ......................................

870.6100 90-Day Neurotoxicity (Hen)..................................................

870.6200 Acute Neurotoxicity Screening Battery (Rat) ........................

870.6200 90 Day Neuro. Screening Battery (Rat).................................

870.6300 Developmental Neurotoxicity................................................

no

no

yes

yes

yes

-

-

yes

yes

yes

870.7485 General Metabolism...............................................................

870.7600 Dermal Penetration ................................................................

870.7800 Immunotoxicity.......................................................................

yes

yes

yes

yes

yes

yes

--Not Applicable

1The required 28-day inhalation study was waived by the HED HASPOC.
Fenpropathrin Human Health Risk Assessment DP No. D368175

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Appendix A2. Toxicity Profile Tables

Acute Toxicity of Fenpropathrin

Guideline No./Study Type MRID Results Toxicity 

Category

870.1100 Acute oral toxicity (rat) 00127343 LD50 =M:54 mg/kg

 F:48.5 mg/kg

I

870.1200 Acute dermal toxicity (rat) 00127352 LD50 = M:1600 mg/kg

 F:870 mg/kg

II

870.1200b Acute dermal toxicity (rabbit) 00127355 LD50 = M: >2000 mg/kg bw

 F: >2000 mg/kg bw

III

870.1300 Acute inhalation toxicity (rat) 00163812 LC50 = ND IV

870.2400 Acute eye irritation (rabbit) 00127357 Mild eye irritant III

870.2500 Acute dermal irritation (rabbit) 00127357 Not a dermal irritant IV

870.2600 Skin sensitization (guinea pig) 00127358 Not a dermal sensitizer NA

ND = Not Determined

Subchronic, Chronic, and Other Toxicity Studies for Fenpropathrin 

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

Subchronic Studies

870.3100

90-Day oral toxicity 

rats

(unreported strain)

00127363 (1979)

Acceptable/guideline

M&F: 0, 3, 30, 100, 300, 600 

ppm

(0, 0.15, 1.5, 5, 15, 30 

mg/kg/day), in diet

NOAEL = 15 mg/kg/day

LOAEL = 30 mg/kg/day based on clinical signs of 

tremors, body weight reductions, decreased blood 

clotting time in females, and possibly increased alkaline 

phosphatase levels (both sexes).

870.3150

90-Day oral toxicity

(Beagle dog)

00127364 (1980)

Acceptable/guideline

M&F: 0, 250, 500, 750 ppm

(0, 6.25, 12.5, 18.8 

mg/kg/day)

NOAEL = <6.2 mg/kg/day

LOAEL = 6.2 mg/kg/day based on effects on the 

gastrointestinal system, tremors, and body weight 

changes.

870.3200

21-Day dermal 

toxicity (SpragueDawley rat)

47325602 (2006)

Acceptable/guideline

0, 20, 200, or 1000 

mg/kg/day for 6 hrs/day, 21 

days

Systemic NOAEL = 1000 mg/kg/day

Systemic LOAEL = not observed

Dermal NOAEL = 1000 mg/kg/day

Dermal LOAEL = not observed
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Subchronic, Chronic, and Other Toxicity Studies for Fenpropathrin 

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.3200

21-Day dermal 

toxicity

(NZW rabbit)

00127366 (1982)

Acceptable/guideline

M&F: 0, 500, 1200, 3000 

mg/kg/day

NOAEL = >3000 mg/kg/day

Only local irritation was seen. There were no systemic 

effects, thus the LOAEL was not determined.

Developmental and Reproduction Studies

870.3700a

Prenatal 

developmental

[CDF® (F344)/CrLBR rats)

41525903 (1990)

Acceptable/guideline

0, 0.4, 1.5, 2.0, 3.0, 6.0, 10.0 

mg/kg/day (gavage)

LOAEL = 10 mg/kg/day 

based on increased incidence 

of asymmetrical ossification 

of sternebrae and incomplete 

ossification of the 5th and 6th

sternebrae

Maternal NOAEL = 3 mg/kg/day

LOAEL = 6 mg/kg/day based on decreased food 

consumption and body weight gains.

At 10 mg/kg/day, 6 dams died between days 7 and 13, 

and one dam was sacrificed moribund on day 8. The 

remaining 23 dams survived through the end of 

gestation.

Also in the high dose group, many clinical signs were 

observed in the dams including ataxia, sensitivity to 

external stimuli, spastic jumping, and tremors. These 

signs were most severe 2 hours post-dosing and during 

the first days of dosing. 

Developmental

NOAEL = 6 mg/kg/day 

LOAEL = 10 mg/kg/day based on increased incidence 

of asymmetrical ossification of sternebrae and 

incomplete ossification of the 5th and 6th sternebrae

870.3700b

Prenatal 

developmental

(NZW rabbit)

00163816 (1985)

Acceptable/guideline

0, 4, 12, 36 mg/kg/day 

(gavage)

Maternal NOAEL = 4 mg/kg/day

LOAEL = 12 mg/kg/day based on flicking of the 

forepaws.

Developmental NOAEL = >36 mg/kg/day

No dose related effects were seen, thus the LOAEL was 

not determined.

870.3800

Reproduction and 

fertility effects

(Sprague-Dawley rats)

00163817 (1986)

Acceptable/guideline

0, 40, 120, 360 ppm

(M: 0, 3.0, 8.9, 26.9 

mg/kg/day

F: 0, 3.4, 10.1, 32.0 

mg/kg/day), in diet, 

premating determinations

Parental/Systemic NOAEL = M:3.0; F: 3.0 mg/kg/day

LOAEL = M: 8.9; F: 10.1 mg/kg/day based on death 

and clinical signs of neurotoxicity in females.

Offspring NOAEL = M:3.0; F:3.4 mg/kg/day

LOAEL = M: 8.9; F: 10.1 mg/kg/day based on 

increased mortality and body tremors.

Chronic Toxicity Studies

870.4100b

Chronic toxicity 

(Beagle dog)

00143130 (1984)

Acceptable/guideline

0, 100, 250, 750 ppm

(0, 2.5, 6.25, 18.75 

mg/kg/day)

NOAEL = 2.5 mg/kg/day

LOAEL = 6.25 mg/kg/day based on tremors and ataxia 

in both sexes.
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Subchronic, Chronic, and Other Toxicity Studies for Fenpropathrin 

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

Chronic/Carcinogenicity Studies

870.4200b

Carcinogenicity (CD1 mouse)

00163814 (1985)

Acceptable/guideline

0, 40, 150, 600 ppm

(M: 0, 3.9, 13.7, 56.0 

mg/kg/day

F: 0, 4.2, 16.2, 65.2 

mg/kg/day), in diet

NOAEL = Not established

LOAEL = M: >56.0; F: >65.2 mg/kg/day

There was an overall lack of toxic response. However 

the aborted mouse carcinogenicity study (MRID No. 

00163815) demonstrated that at a slightly higher 

maximum tolerated dose (MTD) of 1000 ppm, the test 

article was lethal to 15% of the mice after only 13 

weeks. Thus the maximum dose used in this completed 

study (600 ppm) was very close to the MTD. A repeat 

study is not justified.

no evidence of carcinogenicity

870.4300

Chronic/

Carcinogenicity - (CD 

rat)

00163813 (1986)

Acceptable/guideline

0, 50, 150, 450, 600 ppm

(M: 0, 1.93, 5.71, 17.06, 22.8 

mg/kg/day

F: 0, 2.43, 7.23, 19.45, 23.98 

mg/kg/day), in diet

NOAEL = M:17.06; F: 7.23 mg/kg/day

LOAEL = 19.45 mg/kg/day based on increase mortality 

and body tremors in the females

no evidence of carcinogenicity

Mutagenicity Studies

Gene Mutation

870.5100

Bacterial Reverse 

Mutation Test

00163818 (1984)

Acceptable/guideline

0, 50, 10, 500, 100, or 5000 

μg/plate +/- S9

Negative in Salmonella typhimurium TA 1535, 

TA1537, TA1538, TA98, and TA100 and Escerichia 

coli Wp2 uvrA up to the limit concentration with 

evidence of compound insolubility.

Gene Mutation

870.5300

In vitro mammalian 

cell gene mutation test

00126832 (1982)

Acceptable/guideline

0, 50.3, 84.5 141.9, 238.2, 

400 μg/mL in the absence of

mammalian metabolic 

activation

0, 30, 47.5, 75.3, 119.4, 

189.2, 300 mg/mL in the 

presence of mammalian 

metabolic activation

There was no clear evidence (or a concentration related 

positive response) of induced mutant colonies over 

background.

870.5375

Cytogenetics 

In vitro mammalian 

cell chromosomal 

aberration assay

41281601 (1989)

Acceptable/guideline

10-30 μg/mL -S9 and 250-

1000 μg/mL +S9

Negative in Chinese hamster ovary (CHO) cells 

(cytotoxicity observed at ≥30 μg/mL -S9 and compound 

precipitation at 1000 μg/mL +S9).

870.5500 

Other Genotoxic 

Effects Bacterial 

DNA damage or 

repair test

00126831 (1980)

Acceptable/nonguideline

10-5000 μg/disc -S9 only 

Negative in Bacillus subtilis H17 (DNA repair 

proficient) and M45 (DNA repair deficient).
Fenpropathrin Human Health Risk Assessment DP No. D368175

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Subchronic, Chronic, and Other Toxicity Studies for Fenpropathrin 

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.5900 

Other Genotoxic 

Effects

In vitro sister 

chromatid exchange 

assay 

00163821 (1984)

Acceptable/guideline

3x10-6-1x10-4 M (solubility 

limit) +/-S9

Negative in CHO cells up to the solubility limit.

Neurotoxicity Studies

870.6200a Acute 

Neurotoxicity 

Screening Battery 

(Sprague-Dawley rats)

47345605 (2006)

Acceptable/guideline

0, 3, 6, 15, or 30 mg/kg

NOAEL = 15 mg/kg 

LOAEL = 30 mg/kg, based on slight tremors and clonic 

convulsions in both sexes at the time of peak effect

870.6200b Subchronic 

Neurotoxicity Study 

(Sprague-Dawley rats)

47345607 (2007)

Acceptable/guideline

0, 60, 190, or 570 ppm

M: 0, 4, 13, or 38 mg/kg/day

F: 0, 5, 15, or 50 mg/kg/day

NOAEL = 13/15 mg/kg/day

LOAEL = 38/50 mg/kg/day, based on tremors, 

convulsions, impaired gait, and related findings in the 

FOB predominantly in the females

870.6300 

Developmental 

Neurotoxicity Study 

(Sprague-Dawley rats)

47345609 (2008)

Acceptable/guideline

0, 40, 100, or 250 ppm

0/0, 3/7, 8/16, or 19/40 

mg/kg/day 

gestation/lactation, 

respectively

Maternal NOAEL = 8/16 mg/kg/day

Maternal LOAEL = 19/40 mg/kg/day, based on tremors 

during lactation

Offspring NOAEL = 8/16 mg/kg/day

Offspring LOAEL = 19/40 mg/kg/day, based on small 

pup size and decreased body weights and body weight 

gains during the pre-weaning period

Neurotoxicity NOAEL = 8/16 mg/kg/day

Neurotoxicity LOAEL = 19/40 mg/kg/day, based on 

increased mean overall maximum auditory startle 

response amplitude and average response amplitude in 

the females (PND60) and decreased absolute brain 

weights in the males

Other Studies
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Subchronic, Chronic, and Other Toxicity Studies for Fenpropathrin 

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.7485

Metabolism and 

pharmacokinetics 

(Sprague-Dawley rat)

43476801 (1994)

Acceptable/guideline

0, 2.5, 25 mg/kg/day

radiolabeled S-3206 on 

either the alcohol or acid 

portion of the molecule by 

gavage. In experiment I, rats 

received 14 daily doses of 

2.5 mg/kg followed on the 

15th day by radiolabeled S3206. In experiments II and 

III, rats received a single 

dose of radiolabeled S-3206 

at either 2.5 or 25 mg/kg.

Greater than 99% of the administered dose was excreted 

within 168 hours with 28%-56% excreted in the urine 

and the remainder in the fecs, following both a single 

and 14 day repeated doses. Major biotransformations of 

the absorbed compound included the oxidation of the 

methyl group of the acid moiety, hydroxylation at the 

4'-position of the alcohol moiety, cleavage of the ester 

linkage, and conjugation with sulfuric acid or 

glucuronic acid.

870.7600

Dermal penetration

43433801 (1991)

Acceptable/guideline

0, 0.03, 1.5, 30 mg/rat

(0, 0.0013, 0.0663, 1.26 

mg/cm2- radiolabeled) 

EC Formulation (31.9% a.i.)

Exposure times of 1.5, 1.2, 4, 

10, and 24 hours

Dermal absorption increased with dose but not 

proportionally. The percentage of the dose absorbed 

decreased with the increasing administered dose. The 

total body burden could be expected to rapidly decrease 

due to excretion via urine and feces. Mean dermal 

absorption for the 10-hour interval was 33.3, 20.1, and 

17.6% in the low, mid, and high dose groups, 

respectively.

870.7800

Immunotoxicity

(Sprague-Dawley rat)

48536804 (2011)

Acceptable/guideline

0, 150, 300, or 450 ppm

(0, 14, 26, or 42 mg/kg/day)

Humoral NOAEL = 42 mg/kg/day

Humoral LOAEL = not determined

Systemic NOAEL = 26 mg/kg/day

Systemic LOAEL = 42 mg/kg/day based on decreased 

body weights, body weight gain and clinical signs 

including hyperactivity, hyper-reactivity to touch, and 

twitching.

Non-Guideline Studies

Wolansky et. al. 

(2006)

47885701(Draft)

Acceptable-Non-Guideline

Acute Oral Toxicity in Rats -

Motor Activity

0, 0.01, 0.1, 1.0, 4.0, 8.0, 

12.0, 16.0, 24.0 mg/kg via 

gavage in corn oil (1 mL/kg)

BMDL1SD = 5.0 mg/kg

BMD = 6.4 mg/kg based on decreased locomotor 

activity
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Subchronic, Chronic, and Other Toxicity Studies for Fenpropathrin 

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

WIL Study 47050504 (2006) 

Acceptable-Non-Guideline

Acute Oral Toxicity in Rats

– FOB

0, 15, 30 mg/kg via gavage 

in corn oil (5 mL/kg)

BMDL20 = 26.7 mg/kg

BMD20 = 28.9 mg/kg based on multiple FOB changes
Fenpropathrin Human Health Risk Assessment

Appendix A3. Hazard Identification 

Figure A3. Decision tree for evaluating potential toxicity studies for endpoint selection

Acute Reference Dose (aRfD) and 

The information used in the POD determination for acute oral endpoints is listed here. 

A3 provides a visual picture of this evaluation.

1. The Wolansky acute rat study with a POD of 5.0 mg/kg is selected for this endpoint due 

to the overall robust nature of the study with 8 doses, producing an excellent dose 

response curve. The Wolansky study was considerably conservative, gavage dosing using 

1 ml/kg corn oil a vehicle and volume.

2. The WIL study also provided 

However, the WIL study evalutated FOB parameters based on the common mode of 

action (i.e., interaction with voltage gated sodium channels resulting in neurotoxicity). 

These FOB parameters provided a higher LOAEL than the Wolansky study and the

was not used for endpoint selection. 

3. The Agency notes that the lowest NOAELs were observed in bolus

including the subchronic and chronic dog studies

developmental studies in the rat and rabb

Fenpropathrin Human Health Risk Assessment DP No. D368175

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Hazard Identification and Endpoint Selection

Figure A3. Decision tree for evaluating potential toxicity studies for endpoint selection

and Acute Population Adjusted Dose

The information used in the POD determination for acute oral endpoints is listed here. 

provides a visual picture of this evaluation. 

The Wolansky acute rat study with a POD of 5.0 mg/kg is selected for this endpoint due 

nature of the study with 8 doses, producing an excellent dose 

response curve. The Wolansky study was considerably conservative, gavage dosing using 

1 ml/kg corn oil a vehicle and volume.

so provided a uniform study design with all pyrethroids tested. 

WIL study evalutated FOB parameters based on the common mode of 

action (i.e., interaction with voltage gated sodium channels resulting in neurotoxicity). 

These FOB parameters provided a higher LOAEL than the Wolansky study and the

was not used for endpoint selection. 

The Agency notes that the lowest NOAELs were observed in bolus/gavage 

subchronic and chronic dog studies (dietary administration)

developmental studies in the rat and rabbit (gavage dose). The dog studies are considered 

DP No. D368175

and Endpoint Selection

Figure A3. Decision tree for evaluating potential toxicity studies for endpoint selection

The information used in the POD determination for acute oral endpoints is listed here. Figure 

The Wolansky acute rat study with a POD of 5.0 mg/kg is selected for this endpoint due 

nature of the study with 8 doses, producing an excellent dose 

response curve. The Wolansky study was considerably conservative, gavage dosing using 

ids tested. 

WIL study evalutated FOB parameters based on the common mode of 

action (i.e., interaction with voltage gated sodium channels resulting in neurotoxicity). 

These FOB parameters provided a higher LOAEL than the Wolansky study and the refore 

/gavage studies, 

(dietary administration) and the prenatal 

The dog studies are considered 
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to be a bolus dose because dogs will typically consume their meals over a very short 

period, as opposed to rats which feed continuously over several hours. By consuming 

more fenpropathrin-treated food over a shorter period of time, the dog is more likely to 

have greater maximal plasma concentrations immediately after feeding compared to the 

rat.

 

As rats feed continuously, and fenpropathrin is metabolized and excreted from the system 

relatively quickly, the overall systemic concentration in the rat remains low. The higher 

plasma concentration in the dog will likely result in a more conservative LOAEL. The 

overall result of the dog’s feeding pattern is similar to gavage or capsule dosing as stated 

previously. The LOAELs for these studies were all based, at least in part, on 

neurotoxicity.

a. Dog Studies:

i. Subchronic dog – The 90-day dog study LOAEL was the lowest dose 

tested, 6.2 mg/kg, and was based on effects on the gastrointestinal system, 

tremors, and body weight changes.

ii. Chronic dog – The LOAEL for the chronic dog study was 6.25 mg/kg/day

and was based on tremors and ataxia. The NOAEL was 2.5 mg/kg/day.

iii. The dog studies were conducted by dietary administration. Although there 

was toxicity at doses slightly greater than the proposed POD of 5.0 mg/kg, 

the human equivalent dose based on allometric scaling indicates that the 

NOAELs from the Wolansky rat study and the dog studies are equivalent. 

Human equivalent Doses of Fenpropathrin 

Rat (Wolansky) Human Equiv. 

Dose *

Dog Human Equiv. 

Dose*

BMD BMDL1SD BMD BMDL1SD NOAEL LOAEL NOAEL LOAEL

6.4 5.0 1.87 1.46 2.5 6.2 1.54 3.81

*Human Equivalent based on allometric scaling: Scaling Factor 0.75; Default weights: rat = 0.5 kg, dog 

= 10 kg, Human = 70 kg; NOAELH=NOAELD (BWD/BWH)^1-0.75; Sample and Arenal, Bull Environ 

Contam Toxicol (1999) 62:653-63 

b. Developmental Studies

i. In the rat developmental study, effects including deaths (7/30) and 

neurotoxicity (ataxia, sensitivity to external stimuli, spastic jumping, and 

tremors) were observed at 10 mg/kg/day in dams. However, at the study 

LOAEL of 6 mg/kg/day, maternal toxicity was limited to decreased food 

consumption and body weight gains. The developmental LOAEL was 10 

mg/kg/day based on asymmetrical ossification of sternebrae and 

incomplete ossification of the 5th and 6th vertebrae. The developmental 
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NOAEL was 6 mg/kg/day and the maternal NOAEL is 3 mg/kg/day. The 

POD is lower, and therefore protective, of these effects.

The BMDL1SD from the Wolansky study is more appropriate for risk 

assessment based on the following:

1. The BMDL1SD is captured between the maternal NOAEL of 3 

mg/kg/day and LOAEL of 6 mg/kg/day and is below the 

developmental NOAEL of 6 mg/kg/day

2. The BMD is a more accurate estimate of toxicity compared to the 

NOAEL/LOAEL approach

3. The observed effects at the maternal LOAEL are not quantitatively

or qualitatively more severe compared to the decrease in motor 

activity observed in the Wolansky study

ii. In the rabbit developmental study, the maternal LOAEL was 12 

mg/kg/day based on flicking of the forepaws. The NOAEL was 4 

mg/kg/day. No developmental effects were observed. Although the 

NOAEL of 4 mg/kg/day is slightly lower than the proposed POD of 5.0 

mg/kg; 1) the effects observed in the rabbit study are not qualitatively 

more severe than the decreased motor activity observed in the Wolansky

study; and 2) the Wolansky is a more robust study containing more dose 

levels and is based on a BMD analysis which is a more estimate of toxicity

compared to NOAEL/LOAEL levels.

4. In the 3-generation study, the maternal LOAEL is 10 mg/kg/day based on increased 

mortality and tremors in females. The NOAEL is 3 mg/kg/day. Maternal effects at the 

high dose of 32 mg/kg/day included increased deaths and clinical signs of toxicity. 

Eighteen of the 24 high-dose dams died, 10 of which occurred during lactation of the F1B

dams (i.e., 2ndlitter of 2nd generation). Clinical signs including tremors, muscle twitches, 

and increased sensitivity were observed in all high-dose females in all generations and 

were most intense during the 2nd or 3rd week of lactation. At the maternal LOAEL of 10

mg/kg/day, clinical signs of toxicity were observed in a single dam. No treatment-related 

effects in the males at any dose, however, it is not clear from the study if males were 

observed. There was mortality in pups at the high dose (32 mg/kg/day) in the F2A and 

F2B litters (3rd generation, 1st and 2nd litters) although it appears there was an effect on 

litter size by lactation day 21 in the F2B litters. At the mid-dose (10 mg/kg/day), tremors 

were observed in 3 pups from the F2B litter, 2 of which died. There were no reports of 

clinical signs of toxicity (i.e., tremors) in any other pups. Therefore, minimal signs of 

treatment-related were observed at the mid-dose for both adults and pups, reducing any

concern for quantitative or qualitative sensitivity for this study. 

Although this study resulted in a lower NOAEL (3 mg/kg/day) compared to the proposed 

POD, the most severe maternal and offspring effects were limited to the high dose group 

(32 mg/kg/day). At the LOAEL (10 mg/kg/day), effects were limited to tremors in a 

single dam (in the 2nd generation) and 3 offspring from the 3rd generation (2 of which 

subsequently died). Because these effects occurred in subsequent generations, were only 
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observed in relatively few animals, were less severe compared to the high dose, and the 

BMD estimate is a more accurate estimate of toxicity compared to NOAELs and 

LOAELs (which are limited by dose-spacing, the proposed POD of 5.0 mg/kg is 

protective of the effects observed in this study.

5. The FQPA Factor for children <6 years of age is 3X based on evidence of juvenile 

sensitivity in the literature. This information described above is summarized in ReEvaluation of the FQPA Safety Factor for pyrethroid pesticides (D381210, E. Scollon, 

6/27/2011). 

Based on an evaluation of over 70 guideline toxicity studies submitted to the Agency, including 

prenatal developmental toxicity studies in rats and rabbits, and multi-generation reproduction 

toxicity studies and DNTs in rats in support of pyrethroid registrations, there is no evidence that 

pyrethroids directly impact developing fetuses (USEPA 2010; Table 1)). None of the studies 

show any indications of fetal/offspring toxicity at doses that do not cause maternal toxicity. 

Therefore the Agency is reducing the FQPA safety factor to 1X for women of child-bearing age.
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Appendix A4. Human Equivalent Analysis (Dog study vs. acute rat motor activity)

RAT Study (Wolansky) DOG Study (Sub-chronic)

chemical rat dose (mg/kg) human dose (mg/kg) dog dose (mg/kg) human dose (mg/kg)

BMD BMDL BMD BMDL NOAEL LOAEL LOAEL NOAEL

betacyfluthrin 1.42 1.17 0.41 0.34 2.4 13.9 8.54 1.48

bifenthrin 4.1 3.1 1.19 0.90 2.2 4.2 2.58 1.35

bioallethrin 65.6 42.2 19.07 12.27 20 63 38.73 12.30

cyhalothrin 0.92 0.64 0.27 0.19 1 2.5 1.54 0.61

cyphenothrin - - - - 12.5 37.5 23.05 7.68

cypermethrin 11.19 7.16 3.25 2.08 12.5 37.5 23.05 7.68

deltamethrin 2.48 1.49 0.72 0.43 1 2.5 1.54 0.61

esfenvalerate 1.19 0.65 0.34 0.19 5 7.5 4.61 3.07

fenpropathrin 6.44 5.01 1.87 1.46 2.5 6.2 3.81 1.54

permethrin 63.1 44.4 18.34 12.91 50 500 307.39 30.74

resmethrin 162.32 75.89 47.19 22.06 300 - - 184.4

tefluthrin 3.67 2.8 1.067 0.81 0.5 1.5 0.92 0.31

Appendix A5. Pyrethroid Cumulative Screen

The Agency is required to consider the cumulative risks of chemicals sharing a common 

mechanism of toxicity. The Agency has determined that the pyrethroids and pyrethrins share a 

common mechanism group (http://www.regulations.gov; EPA-HQ-OPP-2008-0489-0006). The 

members of this group share the ability to interact with voltage-gated sodium channels ultimately

leading to neurotoxicity. The cumulative risk assessment (CRA) for the pyrethroids/pyrethrins 

was published on Nov. 9, 2011 (USEPA, 2011a) and is available at http://www.regulations.gov; 

EPA-HQ-OPP-2011-0746. Fenpropathrin was included in this cumulative risk assessment. No 

cumulative risk estimates of concern were identified, allowing the Agency to consider new uses 

for pyrethroid actives. For information regarding EPA’s efforts to evaluate the risk of exposure 

to pyrethroids, refer to http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids-pyrethrins.html.
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Appendix B. Physical/Chemical Properties

Physicochemical Properties of Fenpropathrin

Parameter Value Reference

Melting point/range 45-50oC (113-122oF) DP# 315918, 9/20/05,

W. Cutchin pH 4-5 (1% emulsion)

Density g/cm31.103

Water solubility (25oC) 0.33 ppm

Solvent solubility (mg/L at 25oC) Xylene, cyclohexanone: 1,000

Methanol: 337

Vapor pressure at 25oC 5.5 x 10-6(0.730 mPa)

Dissociation constant, pKa NA

Octanol/water partition coefficient, 

Log(KOW)

5.1

UV/visible absorption spectrum Not available
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Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data are subject to ethics review 

pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics 

requirements. For certain studies that review may have included review by the Human Studies 

Review Board. Descriptions of data sources as well as guidance on their use can be found at 

http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html.