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

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

2.1 Data Deficiencies ................................................................................................................... 8

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

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

3.0 Ingredient Profile ....................................................................................................................... 8

3.1 Structure and Nomenclature................................................................................................... 9

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

3.3 Summary of Existing/Proposed Uses................................................................................... 10

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

3.5 Consideration of Environmental Justice .............................................................................. 10

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

4.1 Toxicology Studies Available for Analysis ......................................................................... 11

4.2 Toxicological Profile............................................................................................................ 12

4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile................................................ 13

4.3.1 Pharmacokinetics (PK) ................................................................................................ 13

4.3.2 Pharmacodynamics (PD) ............................................................................................. 15

4.3.3 Critical Duration of Exposure...................................................................................... 16

4.3.4 Dermal Absorption....................................................................................................... 17

4.4 Safety factor for Infants and Children (FQPA Safety Factor) ............................................. 17

4.4.1 Adequacy of the Toxicity Database............................................................................. 18

4.4.2 Evidence of Neurotoxicity ........................................................................................... 18

4.4.3 Evidence of Sensitivity in the Developing or Young Animal ..................................... 18

4.4.4 Residual Uncertainty in the Exposure Database.......................................................... 19

4.5 Toxicity Endpoint and Point of Departure Selections.......................................................... 19

4.5.1 Dose-Response Assessment......................................................................................... 19

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment .............. 21

4.5.3 Cancer Classification and Risk Assessment Recommendations ................................. 22

5.0 Dietary Exposure and Risk Assessment .................................................................................. 23

5.1 Food Residue Profile............................................................................................................ 23

5.2 Water Residue Profile .......................................................................................................... 24

5.3 Dietary Risk Assessment...................................................................................................... 25

5.3.1 Acute Dietary Risk Assessment................................................................................... 25

5.3.2 Chronic Dietary Risk Assessment ............................................................................... 25

5.3.3 Cancer Dietary Risk Assessment................................................................................. 25

5.4. Dietary Risk Assessment Summary Table ........................................................................... 25

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

7.0 Aggregate Exposure/Risk Characterization............................................................................. 26

8.0 Cumulative Exposure/Risk Characterization........................................................................... 26

9.0 Occupational Exposure/Risk Characterization ........................................................................ 26

9.1 Occupational Handler Exposure and Risk ........................................................................... 27

9.1.1 Handler Risk for the Existing At-plant Corn Uses ...................................................... 27

9.1.2 Handler Risk for the Proposed and Existing Seed Uses.............................................. 29

9.2 Occupational Post-Application Exposure and Risk ............................................................. 34

9.2.1 Occupational Post-Application Risk for the Existing At-plant Corn Uses.................. 34

9.2.2 Occupational Post-Application Risk for the Proposed and Existing Seed Uses.......... 34
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10.0 References................................................................................................................................ 35

Appendix A: Tefluthrin Toxicity Profiles....................................................................................... 37

Appendix B: Review of Human Research...................................................................................... 43
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1.0 Executive Summary

Syngenta Crop Protection, Inc. has submitted a Section 3 application to register a new end-use 

product formulation, Force®SB Insecticide (EPA File Symbol: 100-RGAR) containing tefluthrin 

as the sole active ingredient (ai) for use on sugar beet seeds. The Registration Division (RD) of 

OPP has requested that HED evaluate hazard and exposure data and conduct the necessary

exposure assessments, as needed, to estimate the risk to human health that will result from the 

proposed use of tefluthrin on sugar beet seeds. This document summarizes HED’s evaluation of 

the toxicity and exposure databases for tefluthrin as well as the human health risk assessment in 

support of the proposed sugar beet seed use.

Use Profile: Force® SB which is a microencapsulated suspension is being proposed for use on 

sugarbeet seeds only in commercial seed treatment facilities. The proposed label prohibits use of 

the product in hopper-box, planter-box, slurry-box, or any other on-farm applications. The 

application rate for sugar beet seed is 0.08 mg active ingredient (ai) per seed. Sugarbeet seeds 

are often treated with pesticides in conjunction with EPA approved polymers, pelleting materials,

and seed coating materials that are tested to be safe on sugarbeet seed. The pelleting process 

increases sugarbeet seed weight and therefore, decreases seed counts (i.e. number of seeds per 

pound seed). Seed counts will vary depending on the density of the seed pellet and the 

proprietary pelletizing process used by the seed treatment facility.

The currently registered formulations of tefluthrin include granules and a microencapsulated 

suspension applied at-planting for the control of soil insect pests of corn. There is also a 

microencapsulated suspension registered for treatment of corn seed in commercial seed 

treatment facilities.

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

Type II, based upon chemical structure and neurotoxicological effect. Tefluthrin is a Type I 

pyrethroid, which lack an alpha-cyano moiety and typically induce in rats a syndrome consisting 

of aggressive sparring, altered sensitivity to external stimuli, and fine tremor progressing to 

whole-body tremor and prostration (T-syndrome). The data base of experimental toxicology 

studies available for tefluthrin provides a robust characterization of the hazard. There are no 

outstanding studies according to Part 158 data requirements. In addition, numerous studies from 

the scientific literature that describe the pharmacodynamic and pharmacokinetic profile of 

tefluthrin and the pyrethroids in general have been considered in this assessment.

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

studies. As with other pyrethroids, tefluthrin targets the nervous system through interaction with 

sodium channels. Behavioral changes characteristic of Type I pyrethroids such as unsteadiness, 

tremors, and ataxia were observed in the guideline rat, dog, and rabbit studies. In addition, in 

dermal toxicity studies, experimental laboratory animals exhibited paresthesia and splayed gait. 

Other effects seen in multiple studies included liver (changes in liver weights and liver enzymes) 

and decreases in body weight and body weight gain.

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

the exposure and hazard assessments. Across the tefluthrin toxicological database, tefluthrin is 
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absorbed rapidly and neurotoxic effects including tremors and splayed gait are seen soon after 

exposure. Recovery typically occurs within 24 hours without any persisting neurotoxic effects. 

The NOAELs and LOAELs for neurotoxicity established from results of experimental toxicity 

studies with tefluthrin are remarkably consistent across durations of exposure, ranging from a 

single dose up to 2-years of dosing. This is consistent with the general toxicological profile 

described above for the pyrethroids (i.e. rapid metabolism, little to no accumulation, rapid time 

to peak and effect and recovery). 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. 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 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.

Quantification of acute dietary risks was performed using the chronic dog study with a NOAEL 

of 0.5 mg/kg/day based on tremors (LOAEL = 2.0 mg/kg/day). The acute PAD for Adults and 

Children ≥ 6 years old is 0.005 mg/kg/day using an uncertainty factor of 100 (10X interspecies 

extrapolation, 10X intraspecies variability). The acute PAD for Children < 6 years old is 0.0017 

mg/kg/day using an uncertainty factor of 300 (3X FQPA, 10X interspecies extrapolation, 10X 

intraspecies variability). Quantification of dermal risks for the microencapsulated formulations 

(Force CS, Force ST, and Force SB) was performed using the chronic dog study with a NOAEL 

of 0.5 mg/kg/day based on tremors (LOAEL = 2.0 mg/kg/day) with a formulation specific 

dermal absorption value of 0.79%. Quantification of dermal risks for the granular formulation 

(Force 3G) was performed using a 21-day dermal rat study (NOAEL of 0.1 mg/kg/day based on 

increased incidence of splayed gait (both sexes) with a LOAEL of 1.0 mg/kg/day) that utilized 

the technical formulation. Quantification of inhalation risks was performed using an acute 

inhalation rat study with a NOAEL of 7.7 mg/m3(HEC = 11 mg/m3, 0.54 mg/kg/day) based on 

central nervous system (CNS) effects including decreased activity, reduced foot withdrawal 

reflex, and reduced righting reflex (LOAEL = 14.9 mg/m3). An MOE of 100 is required for 

dermal exposure for adults which includes interspecies extrapolation (10X) and intraspecies 

variability (10X) and an MOE of 30 is required for inhalation exposure for adults which includes 

interspecies extrapolation (3X) and intraspecies variability (10X). 

Tefluthrin has been recently presented to the CARC (Kidwell; TXR 0056340; 2012) and was 

classified as “not likely to be a human carcinogen”. There are two adequate rodent 

carcinogenicity studies available for tefluthrin.

Food Residue Profile: Syngenta submitted a sugar beet metabolism study in support of the 

proposed sugar beet seed treatment use which HED has reviewed and deemed acceptable (W. 

Drew, D369668, 12/8/2009). Based on this study, the proposed use meets the requirements 

established by HED for classification of seed treatments as nonfood uses (ChemSAC memo 
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dated 28 October 1999). EFED has also provided information stating that the drinking water 

exposure for the proposed sugar beet seed treatment use is expected to be negligible. 

Dietary Exposure and Risk: Although no dietary exposure is expected from the proposed use, 

dietary exposure (food and drinking water) is expected from the currently registered uses. Since 

the last HED tefluthrin risk assessment, HED has updated the tefluthrin endpoints and points of 

departure as well as changed its policy regarding directly incorporating drinking water residues 

into the Dietary Evaluation Model (DEEM). As a result, a revised dietary assessment has been 

performed to reflect these changes.

The available toxicological data supports the conclusion that neurotoxicity from tefluthrin and 

pyrethroids in general is associated with acute, peak exposures. As such, only acute dietary risks 

were assessed. The acute dietary assessments include residue and drinking water values based 

on the currently registered preplant use on corn. The results of acute aggregate dietary (food + 

drinking water) analysis show that the acute dietary risks for the general U.S. population and all 

population subgroups are below HED’s level of concern. The acute dietary risk was < 1% of the 

aPAD for the general U.S. population and 28% of the aPAD for all-infants (< 1 year old), the 

most highly exposed population subgroup.

Residential Exposure: There are currently no registered residential uses associated with 

tefluthrin; therefore, a residential/non-occupational exposure assessment is not required.

Aggregate Risk: The acute aggregate risk estimates associated with exposure to tefluthrin are 

equivalent to the acute dietary risk estimates and do not exceed the Agency’s level of concern.

There are currently no registered residential uses associated with tefluthrin and therefore a shortterm aggregate risk assessment was not conducted.

Occupational Exposure/Risk: There is potential for occupational handler exposures from the 

proposed and existing uses of tefluthrin. Occupational post-application exposures from the 

proposed and existing uses of tefluthrin are expected to be negligible.

Existing At-plant Corn Uses: The aggregate risk index for occupational handlers for the 

microencapsulated suspension product do not exceed HED’s level of concern (i.e., ARIs are ≥ 1, 

the LOC for this assessment) with the use of gloves. The ARIs for occupational handlers for the 

granular product exceed HED’s level of concern (i.e., ARIs are < 1, the LOC for this assessment) 

unless engineering controls are utilized.

Proposed Sugar Beet Seed Use: The ARIs for the proposed sugar beet seed use for open and 

closed system primary handlers and secondary handlers do not exceed HED’s level of concern 

(i.e., ARIs are ≥ 1, the LOC for this assessment).

Existing Corn Seed Use: The ARIs for some of the assessed scenarios (e.g., loader/applicator, 

multiple activities, cleaing) for the existing corn seed use for open and closed system primary 

handlers exceed HED’s level of concern (i.e., ARIs are < 1, the LOC for this assessment). The 
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ARIs for the existing corn seed use for secondary handlers do not exceed HED’s level of concern 

(i.e., ARIs are ≥ 1, the LOC for this assessment)

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 B) have been determined to require a review of their ethical conduct and all 

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

2.0 HED Recommendations

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

has conducted a human health risk assessment in support of the proposed use. Based on this 

assessment, HED has determined that there are no potential risk estimates of concern for the 

proposed use of tefluthrin. HED recommends that the requested uses be granted.

2.1 Data Deficiencies

There are no outstanding data deficiencies for tefluthrin.

2.2 Tolerance Considerations

There are no proposed tolerances associated with this action. This assessment does include the 

existing tolerances which were previously established under 40 CFR §180.440 (a) for the 

combined residues of tefluthrin [(2,3,5,6 tetrafluoro-4-methylphenyl)methyl-(1 alpha, 3 alpha)-

(Z)-(±)-3(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate] and its 

metabolite PP 890 ((Z)-3-(2-chloro-3,3,3-trifluroro-1-propenyl)-2,2-dimethylcyclopropane 

carboxylic acid) in/on corn, field, fodder, and forage, and sweet corn, fresh (including sweet and 

K+CWHR; corn, field, grain; and pop), all at 0.06 ppm.

2.3 Label Recommendations

No label revisions are needed and no recommendations are being made by HED.

3.0 Ingredient Profile

Tefluthrin is a synthetic pyrethroid insecticide. 
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3.1 Structure and Nomenclature

TABLE 3.1: Tefluthrin Nomenclature

Compound

Common name Tefluthrin

Molecular formula C17H14ClF7O2

Molecular weight 418.74

IUPAC name 2,3,5,6-tetrafluoro-4-methylbenzyl (1RS)-cis-3-[(Z)-2-chloro-3,3,3-trifluoroprop1-enyl]-2,2-dimethylcyclopropanecarboxylate

CAS name (2,3,5,6-tetrafluoro-4-methylphenyl)methyl (1R,3R)-rel-3-[(1Z)-2-chloro-3,3,3-

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

CAS registry number 79538-32-2

End-use product (EP) Force® SB (EPA File Symbol 100-RGAR)

Chemical structure of 

regulated metabolite (PP890)

(Z)-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid

3.2 Physical/Chemical Characteristics

TABLE 2.3: Physicochemical Properties of the Technical Grade Tefluthrin

Parameter Value Reference*

Melting point/range 44.6°C MRID #47813007

Ph Not available

Density 1.48 g/cm3at 25oC MRID #40167301; P#7F3521

Water solubility (at 20°C) 2 x 10-2 mg/L at pH 5.0, 6.5, and 9.2 MRID #47813007

Solvent solubility (at 21°C) 263 g/L in methanol

>500 g/L in acetone, dichloromethane, 

ethyl acetate, hexane, and toluene. 

MRID #47813007

Vapor pressure 5 x 10-5kPa at 40°C

2 x 10-5kPa at 30°C

8 x 10-6kPa at 20°C

3 x 10-6kPa at 10°C

MRID #47813007

Dissociation constant, pKa Weak acid, pKa >9; hydrolysis prevents 

measurement. 

MRID #40167301; 

PP#7F3521

Octanol/water partition coefficient, Log (KOW) 6.5 at 20°C MRID #47813007

UV/visible absorption spectrum ε247 nm (minimum) 352 M-1cm-1

ε268 nm (maximum) 1190 M-1cm-1

MRID #40167301; 

PP#7F3521

* MRID #47813007 was submitted in association with the subject action (D369668). MRID #40167301 was 

submitted in conjunction with the initial petition, PP#7F3521 (J. Garbus; 21 December 1987). 

O

O

H3C CH3

Cl

CF3

F

F

F

F

CH2

OH

O

CH3 H3C

Cl

CF3
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3.3 Summary of Existing/Proposed Uses

The currently registered formulations of tefluthrin include granules and a microencapsulated 

suspension applied at-planting for the control of soil insect pests of corn. There is also a 

microencapsulated suspension registered for treatment of corn seed in commercial seed 

treatment facilities. The proposed use pattern for the Force® SB Insecticide on sugar beet seed 

is summarized in Table 3.3.

Table 3.3: Summary of the Proposed Use Pattern for Force® SB Insecticide on Sugar Beet Seed

Crop Product,

Formulation

Treatment 

Type

Timing of 

application

Application 

Equipment

Maximum 

Application 

Rate

(lb ai/lb seed)

Treatment 

Interval

Preharvest 

Interval

Sugar

beet

Force® SB

(Reg. No. 100-RGAR)

microencapsulated 

suspension 19.1% a.i.

Seed 

Treatment

Early season 

protection against 

injury from garden 

springtails, 

symphylids, 

wireworms, and 

white grub.

Commercial 

Seed 

Treatment 

Facility

0.0043 lb

ai/lb seed

(based on 

0.08 mg ai 

per seed and 

24,480 seeds 

per pound 1)

NA NA

1

 Sugarbeet seeds are often pelletized during the pesticide treatment process. The pelleting process increases sugarbeet seed 

weights and therefore, decreases seed counts (i.e. number of seeds per pound seed). Seed counts will vary depending on the 

density of the seed pellet and the proprietary pelletizing process used by the seed treatment facility.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the 

proposed new use of tefluthrin on sugar beet seed. Although no dietary exposure is expected 

from the proposed use, dietary exposure (food and drinking water) is expected from the currently 

registered uses. There is a potential for occupational handler exposure to the proposed use and 

the currently registered uses. Occupational post-application exposures from the proposed and 

existing uses of tefluthrin are expected to be negligible. There are currently no registered 

residential uses associated with tefluthrin and therefore residential exposures are not expected.

3.5 Consideration of Environmental Justice

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

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

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

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

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

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

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

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

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

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

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

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 
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assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

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

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

for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. 

Further considerations are currently in development as OPP has committed resources and 

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

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

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

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

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

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

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

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

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

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

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

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

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

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

Figure 1. Adverse outcome pathway for pyrethroids

4.1 Toxicology Studies Available for Analysis

The data base of experimental toxicology studies available for tefluthrin provides a 

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

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

and children younger than 6 years of age to pyrethroids as a class which is discussed further in 

Section 4.4. Despite these scientific efforts, HED is confident that it has chosen points of 

departure and uncertainty factors in this risk assessment which are health protective and have a 

strong scientific foundation.

The data from the following guideline studies in experimental toxicology animals were used to 

evaluate the hazard potential of tefluthrin:

-Developmental Rat Study

-Developmental Rabbit Studies

-Reproduction Rat Study
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-Cancer Mouse Study

-Chronic/Cancer Rat Study

-Sub-Chronic and chronic Dog Studies

-90-Day Rat and Mouse Study

-21-day Dermal Rat Studies

-Acute Inhalation Toxicity Study (with neurotoxicity measurements)

-Genotoxicity Studies (complete battery) 

-Triple pack dermal absorption studies

-Immunotoxicity study

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

describe the pharmacodynamic (PD) and pharmacokinetic (PK) profile of the pyrethroids in 

general; this scientific literature has been recently reviewed by several groups (Soderlund et. al. 

2002; Wolansky and Harrill 2008; Weiner et. al. 2009). Some of this literature provides specific 

toxicity data on tefluthrin, however much of the literature is general for the pyrethroids because 

of the shared toxicological properties of the members of this class of pesticides; these studies are 

informative in the hazard characterization of tefluthrin.

There are two outstanding studies according to Part 158 data requirements for a food use 

pesticide registration. These studies include an acute neurotoxicity (ACN) study and a 

subchronic neurotoxicity (SCN) study.

HED’s Hazard and Science Policy Council (HASPOC) met on April 26, 2012 to discuss the 

ACN and SCN data requirements (Rury; TXR 0056311; 05/31/2012). Two literature studies

(Wolansky et al., 2006 and Nemec, 2006) were discussed at the meeting both of which examine 

the acute neurotoxicity of a variety of pyrethroids, including tefluthrin. The current EPA 

required guideline study (870.6200) for the ACN has three major components: motor activity, 

FOB, and neuropathology. The Wolansky et al., 2006 study provides high quality motor activity 

data while the Nemec 2006 study provides specially designed FOB evaluation focused on 

pyrethroid toxicity. There are currently no concerns with regards to neuropathology for this 

class of pesticides as there have not been any major adverse findings associated in any ACN, 

SCN, nor developmental neurotoxicity (DNT) studies. As a result, HASPOC concluded that the 

Wolansky & Nemec literature studies together are sufficient to evaluate motor activity and FOB 

such that a guideline ACN study is not needed and will not provide additional information for 

tefluthrin. Furthermore, the acute duration is the focus of the tefluthrin risk assessment (see 

Section 4.2.1) and thus a guideline SCN study is not needed.

4.2 Toxicological Profile

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

studies. As with other pyrethroids, tefluthrin targets the nervous system through interaction with 

sodium channels. Behavioral changes characteristic of Type I pyrethroids such as unsteadiness, 

tremors, and ataxia were observed in the guideline rat, dog, and rabbit studies. In addition, in 

dermal toxicity studies, experimental laboratory animals exhibited paresthesia and splayed gait. 

Other effects seen in multiple studies included liver (changes in liver weights and liver enzymes) 

and decreases in body weight and body weight gain.
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Consistent with other pyrethroids, there was a lack of sensitivity to in utero exposure. In the 

prenatal developmental toxicity studies in rats and rabbits, the developmental NOAEL was 

greater than the maternal NOAEL. In rats, the maternal toxicity occurred at levels lower than the 

ossification reductions in the extremities of the fetuses. In the rabbit study, maternal toxicity was 

observed at all dose levels with no developmental toxicity observed. In the two-generation 

reproduction study in rats, slight offspring toxicity was observed only at the highest dose level 

tested, while evidence of neurotoxicity in parental animals was observed at significantly lower 

doses. The doses via gavage and feed were similar.

Tefluthrin has been recently presented to the CARC (Kidwell; TXR 0056340; 2012) and was 

classified as “not likely to be a human carcinogen. There are two adequate rodent 

carcinogenicity studies. The CARC did not consider the uterine tumors seen in the rat study or 

the pituitary gland tumors seen in the mouse study to be treatment-related.

Technical tefluthrin is acutely toxic (category I) via the oral, dermal, and inhalation routes of 

exposure. The primary dermal irritation study has a toxicity category of IV while the primary 

eye irritation study is classified as invalid although there are adequate studies with the 

formulation available. Tefluthrin is not a dermal sensitizer.

4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile

The PK of tefluthrin is similar to other pyrethroids, i.e., rapid absorption, metabolism, and 

clearance. Following a single oral dose to rats, tefluthrin was excreted mainly via the feces (54 

and 67% in females and males, respectively) and urine (33 and 20% in females and males, 

respectively) within 48 hours. Peak tefluthrin levels in feces and urine were seen after the first 

24 hours. Radiolabeled tefluthrin was readily detectable in the liver and kidneys with levels 

being typically less than 1.0 and 0.2%, respectively, of the administered dose. Following a 

single oral dose to dogs, tefluthrin was excreted mainly via the feces (61 and 65% in females and 

males, respectively) and urine (26 and 23% in females and males, respectively) within 48 hours. 

Peak tefluthrin levels in feces and urine were seen after the first 24 hours while peak blood levels 

were seen between 4 and 8 hours. Radiolabeled tefluthrin was readily detectable in the liver with 

levels being typically less than 1.6% of the administered dose. The major routes of tefluthrin 

metabolism are ester cleavage and oxidation at a variety of positions on the molecule.

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

contributions of PK and PD to the toxicity profile of this class of chemicals. This information 

also provides valuable information related to the endpoints used in pyrethroid risk assessment, 

the duration of exposure for pyrethroid risk assessment, and the potential age-related differences

in toxicity for the pyrethroids. The following sections discuss the specific issues related to 

pyrethroid PK, pyrethroid PD, and age-related differences in pyrethroid toxicity.

4.3.1 Pharmacokinetics (PK)

PK 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 
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process(es) which determine 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 translates as increased neurotoxicity. Two physiological processes that 

significantly contribute to the PK include metabolism and partitioning. Carboxylesterases and 

P450 enzymes are the two major enzyme families responsible for metabolism of pyrethroids. It 

is the ontogeny of these enzymes that accounts for the age-related sensitivity observed after 

pyrethroid exposures. With respect to the partitioning of pyrethroids within the body, 

pyrethroids are highly lipophilic and preferentially deposit in fatty tissue such as adipose 

compared to leaner tissues such as muscle. Pyrethroid residues in fatty tissue are not available to 

interact with the VGSCs in vital tissues and therefore do not contribute to overall toxicity. 

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

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

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

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

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

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

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

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

(USEPA 2007).

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

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

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

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

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

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

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

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

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

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

microsomes are at least 6 times higher for PND 90 rats 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 the primary 

target organ for pyrethroids and increased pyrethroid concentrations are correlated with 

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

equivalent brain concentrations of deltamethrin would be achieved with a 3.8X fold lower oral 
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dose in 10-day old rats and 2.5X lower dose in 21-day old rats, which represents children under 6 

years of age (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, which encompasses the younger than 6 year old age 

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

model. As a result, the Agency concludes that juvenile rats are 3x more sensitive than adults 

with respect to pyrethroid pharmacokinetics.

4.3.2 Pharmacodynamics (PD)

PD can be defined as the changes that chemicals cause to the body, in this case, how pyrethroids 

interact with the sodium channels. Tefluthrin was examined in several studies which provide 

specific information relevant to the AOP for pyrethroids. For example, Choi and Soderlund 

(2006) examined interactions of several pyrethroids with mammalian VGSCs expressed in 

Xenopus oocytes. With respect to altered neuronal excitability, Type I pyrethroids, like 

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

long trains of action potentials (Figure 1). In contrast, Type II pyrethroids significantly prolong 

sodium current tails (e.g. 200ms to minutes) typically resulting in increased resting membrane 

potential and ultimately causing depolarization dependent action potential block. 

Figure 1. Resting modification of rat Nav1.8 sodium channels by tefluthrin expressed in Xenopus oocytes. Channel 

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

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

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

Cao et. al. (2011a) measured Na influx in primary cultures of mammalian (mouse) neurons and 

demonstrated that tefluthrin, like other pyrethroids caused increases in Na influx in this model; 

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

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

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

As this effect of tefluthrin was entirely blocked by the VGSC blocker tetrodotoxin, it provides 

evidence that the changes in sodium channel function lead to changes in neuronal excitability.
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HED would prefer to use an early key event in the AOP for pyrethroids in selection of points of 

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

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

extrapolating in vitro findings to in vivo measures are not yet developed. As such, the Agency is 

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

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

pyrethroids are generally characterized by tremors, hyper- or hypothermia, heightened response

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

Breckenridge et. al. 2009). In the specific case of tefluthrin, tremors are the most common 

observation throughout the database of toxicology studies.

In contrast to the age-related PK differences discussed in Section 4.3.1, PD contributions to 

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

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

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

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

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

combinations that are present and being 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 nervous cells 

artificially grown in media. While these in vitro techniques do not provide direct quantitative 

measure of in vivo pyrethroid activity, they consistently and qualitatively demonstrate that 

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

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

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

of an adult isoform and a juvenile isoform expressed in frog oocytes to deltamethrin. The 

isoforms had comparable responses at environmentally relevant concentrations (<500 nM) of 

deltamethrin, suggesting a lack of PD difference between juveniles and adults at low exposure 

levels. In addition, in a direct comparison of a homologous rat and human VGSC isoform, 

NaV1.3, Tan and Soderlund, (2009) found the rat isoform was 4-fold more sensitive than the 

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

suggesting the rat is a highly sensitive model and extrapolations from the rat would be protective 

of human health. The occurrence and ontogeny of voltage-gated sodium channels in humans is 

not well characterized compared to the rat. However, based on the comparable function and 

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

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

that juvenile rats are not more sensitive than adults with respect to pyrethroid 

pharmacodynamics.

4.3.3 Critical Duration of Exposure

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

the exposure and hazard assessments.

Across the tefluthrin toxicological database, tefluthrin is absorbed rapidly and neurotoxic effects 

including tremors and splayed gait are seen soon after exposure. Recovery typically occurs 
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within 24 hours without any persisting neurotoxic effects. The NOAELs and LOAELs for 

neurotoxicity established from results of experimental toxicity studies with tefluthrin are 

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

dosing (see Table 4.3.3). This is consistent with the general toxicological profile described 

above for the pyrethroids (i.e. rapid metabolism, little to no accumulation, rapid time to peak and 

effect and recovery). Thus, for purposes of endpoint selection and exposure assessment, only 

single day risk assessments need to be conducted.

Table 4.3.3: Experimental Toxicology Studies with Similar Results for Neurotoxicity

Study Duration Study findings (mg/kg/day)

Wolansky and Harrill 2008

(acute rat) Acute, single exposure BMDL = 2.8 BMD = 3.67

Weiner et. al. 2009

(acute rat) Acute, single exposure BMDL = 4.4 BMD = 10.7

Developmental Rabbit 28-day NOAEL < 3 LAOEL ≤ 3

Sub-chronic dog 90-day NOAEL = 0.5 LOAEL = 1.5

Reproductive toxicity 120-day NOAEL = 2.5 LOAEL = 12.5

Chronic dog 1-year NOAEL = 0.5 LOAEL = 2.0

Chronic-carcinogenicity rat 2-year NOAEL = 1.1 LOAEL = 4.6

Dermal rat 21-day NOAEL = 0.1 LOAEL = 1

Inhalation rat Acute, single exposure NOAEL = 0.54 LOAEL = 1.1

4.3.4 Dermal Absorption

The registrant submitted an in vivo dermal penetration study in rats and two accompanying in 

vitro study dermal penetration studies using rat and human skin. In the in vivo dermal 

penetration study (MRID 47813014), [

14C]-tefluthrin (≥92.2% radiochemical purity, Batch 83-

19) in a microencapsulated suspension formulation containing 200 g/L tefluthrin was applied in a 

single dose to 16 male Wistar (Alpk:APfSD) rats on 10 cm2skin areas (two areas of 5 cm2) at a 

dose level of 10 mg/rat (1 mg/cm2). In the two accompanying in vitro dermal penetration 

studies, [14C]-tefluthrin (≥92.2% radiochemical purity, Batch 83-19) in a microencapsulated 

suspension formulation containing 200 g/L tefluthrin was applied in a single dose to either 

excised rat (MRID 47813015) or human epidermal (MRID 47813016) membranes at a nominal 

dose level of 2.54 mg/membrane (1 mg/cm2).

At 24 hours, dermal absorption for the in vivo study was 0.79% (stratum corneum + application 

site skin + absorbed); dermal absorption for the in vitro rat skin was 0.9%; and dermal absorption 

for the in vitro human skin was below the level of quantitation. It was concluded that although 

human epidermis exhibits significant resistance to dermal penetration that the 24 hour dermal 

absorption value from the rat in vivo study of 0.79% should be used in tefluthrin risk assessment 

(Smith; TXR 0055257; 05/31/2012).

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

Tefluthrin exposure to children under < 6 years old is expected and it must be considered in the 

context of the pyrethroids as a class. The Agency will retain a 3X uncertainty factor to protect 
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for exposures to children <6 years of age based on the increased quantitative susceptibility seen 

in the scientific literature related to pyrethroid pharmacokinetics. This is consistent with the 

Agency’s 2011 analysis and is supported by rat PBPK model predictions of a 3-fold increase of 

deltamethrin concentrations in the juvenile brain compared to adults (see Section 4.3.1). The PK 

of pyrethroids as a group is sufficiently similar that significant deviations from the 3-fold 

increase of deltamethrin concentrations are not expected for other pyrethroids. As noted in 

Section 4.3.2, juveniles are not more sensitive than adults with respect to pyrethroid 

pharmacodynamics and thus no uncertainty factor is needed for PD considerations.

4.4.1 Adequacy of the Toxicity Database

The toxicology data base is not complete for this food use chemical. There are two outstanding 

toxicological studies for tefluthrin according to revised 40 CFR Part 158 Toxicology Data 

Requirements. These studies include an ACN study and an SCN study.

HED’s HASPOC met on April 26, 2012 to discuss the ACN and SCN data requirements (Rury; 

TXR 0056311; 05/31/2012). HASPOC concluded that the available Wolansky & Nemec 

literature studies cover the neurobehavioral endpoints with high quality studies & a guideline 

ACN study is not needed and likely will not provide additional neurotoxicity information for 

tefluthrin. Furthermore, the acute duration is the focus of the tefluthrin risk assessment and thus 

a guideline SCN study is not needed.

4.4.2 Evidence of Neurotoxicity

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

Tefluthrin, like other pyrethroids, causes neurotoxicity from interaction with sodium channels 

leading to clinical signs of neurotoxicity. Neurotoxicity was consistently observed throughout 

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

neurotoxicity included tremors, ataxia, gait abnormalities, and spine curvature among others. 

Literature studies reporting similar results further support these findings.

4.4.3 Evidence of Sensitivity in the Developing or Young Animal

Based on the tefluthrin-specific data and the extensive body of peer-reviewed literature on 

pyrethroids available, the Agency reached a number of conclusions including the following:

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

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

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

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

The tefluthrin developmental and reproductive toxicity studies are consistent with other 

members of the pyrethroid class in that no evidence of increased quantitative or 

qualitative susceptibility was observed in these studies.

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

pyrethroid scientific literature related to pharmacodynamics.
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The Agency will retain a 3X uncertainty factor to protect for exposures to children <6 

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

literature related to pyrethroid pharmacokinetics.

More details regarding the Agency’s findings are outlined in Reevaluation of the FQPA Safety 

Factor for Pyrethroid Pesticides (D381210, 6/27/11).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties that impact the risk estimates presented in this assessment in 

the exposure database.

The acute dietary assessment conducted with DEEM-FCID was unrefined Tier 1 analysis. The 

assessment utilized tolerance level residues for all crops. In addition, default processing factors 

were assumed for all commodities. One hundred percent crop treated was assumed for all 

commodities. The DEEM analysis also assumed that all drinking water will contain tefluthrin at 

the highest acute estimated drinking water concentration (EDWC) levels modeled by EFED for 

ground water or surface water. For these reasons it can be concluded that the DEEM-FCID 

analysis does not underestimate risk from acute exposure to tefluthrin.

Similarly, HED does not believe that the non-dietary occupational exposures are underestimated 

because they are also based on conservative assumptions including maximum application rates, 

labeled PPE, and standard values for unit exposures, acreage treated/amount handled.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

The tefluthrin toxicity profile is presented in Table A.1.1 of Appendix A1.

 

1

http://www.epa.gov/scipoly/sap/meetings/2010/072310meeting.html
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Acute Dietary: HED considered the subchronic dog, the chronic dog and the acute rat Wolansky 

study for use in selection of the tefluthrin acute dietary endpoint. The subchronic dog study was 

not selected even though it had similar LOAELs and NOAELs as the chronic dog and Wolansky 

studies as the LOAEL in the study was not based on neurotoxicity (NOAEL = 0.5 mg/kg/day and 

LOAEL = 1.5 mg/kg/day based on thyroid changes, increased plasma triglycerides and aspartate 

transaminase). The LOAELs and NOAELs for the chronic dog and Wolansky studies are very 

similar (Wolansky BMDL is 2.8 mg/kg/day and BMD is 3.67 mg/kg/day while chronic dog 

LOAEL is 2.0 mg/kg/day and NOAEL is 0.5 mg/kg/day). Clinical signs of neurotoxicity were 

seen in both of these studies with decreased motor activity seen in the Wolansky study and 

tremors seen in the chronic dog study. Ultimately, HED selected the chronic dog study for 

selecting the acute dietary endpoint for tefluthrin based on the following reasons: 1) 

neurotoxicity (tremors) was identified in the chronic dog study throughout the first few weeks of 

treatment; 2) the chronic dog study has a slightly lower LOAEL than the Wolansky rat study; 3) 

the dog appears to be the most sensitive species in the tefluthrin toxicological database, 

particularly when allometric scaling is considered (see Appendix Table A.4); 4) the effects seen 

in the chronic dog study were consistent with the neurotoxic effects seen in other tefluthrin 

toxicity studies; and 5) the effects seen in the chronic dog study are consistent with effects seen 

for other Type I pyrethroids.

The acute PAD for Adults and Children ≥ 6 years old is 0.005 mg/kg/day using an uncertainty 

factor of 100 (10X interspecies extrapolation, 10X intraspecies variability).

The acute PAD for Children < 6 years old is 0.0017 mg/kg/day using an uncertainty factor of 300 

(3X FQPA, 10X interspecies extrapolation, 10X intraspecies variability).

Short-term Dermal: HED considered the two 21-day rat dermal studies, the chronic dog, and

the dermal absorption triple pack for use in selection of the tefluthrin dermal endpoint.

The two 21-day rat dermal toxicity studies available for tefluthrin (MRID 40141306 and 

41080002) were both performed with technical grade tefluthrin in polyethylene glycol 300. 

Downward curvature of the spine and tip toe gait were seen in both of these dermal studies. 

After discussions with the tefluthrin registrant (Syngenta) and Ginger Moser of EPA Office of 

Research and Development, it was determined that these effects are related to paraesthesia. 

Tefluthrin, along with other pyrethroids, is known to cause paraesthesia which is a sensation of 

tingling, burning, pricking, or numbness of a person's skin. Paraesthesia is a localized effect 

meaning it will only manifest in the area where contact was made to tefluthrin. Worker incidents 

occurring with tefluthrin clearly document that this effect lasts for a few hours with no apparent 

long-term physical effect. HED does not believe it is appropriate to regulate on paraesthesia.

In the first dermal study (MRID 40141306) a NOAEL was not determined but splayed gait was 

seen at the low dose in females (dosing 1, 5, and 50 mg/kg/day). The registrants subsequently 

performed a second dermal study (MRID 41080002) at lower doses (dosing 0.1, 1, and 50 

mg/kg/day). In this study, splayed gait was seen at the mid dose in both males and females 

(NOAEL of 0.1 mg/kg/day and LOAEL of 1 mg/kg/day).
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More recently, the registrants performed a “triple pack” for tefluthrin using one of the currently 

registered microencapsulated formulations Force CS (MRID 47813014, 47813015, 47813016, 

and 47813018). This study is discussed in more detail in Section 4.3.4. Based on an evaluation 

of the data presented in the in vivo study a conservative dermal absorption value of 0.79% was 

selected.

Quantification of dermal risks for the microencapsulated formulations (Force CS, Force ST, 

and Force SB) was performed using a chronic dog study (NOAEL of 0.5 mg/kg/day based on 

increased incidence of tremors in the dog (both sexes) with a LOAEL of 2.0 mg/kg/day) with a 

formulation specific dermal absorption value of 0.79%. This is the most appropriate study with 

regards to what occupational workers will be exposed to in the field for the microencapsulated 

formulations.

Quantification of dermal risks for the granular formulation (Force 3G) was performed using 

the second 21-day dermal rat study (NOAEL of 0.1 mg/kg/day based on increased incidence of 

splayed gait (both sexes) with a LOAEL of 1.0 mg/kg/day) that utilized the technical 

formulation. This study was selected in order to be protective of potential dermal contact to the 

granular formulation as using the chronic dog study with the microencapsulated specific dermal 

absorption factor is not appropriate. This is the most appropriate study with regards to what 

occupational workers will be exposed to in the field for granular applications.

An MOE of 100 is required for dermal exposure for adults which includes interspecies 

extrapolation (10X) and intraspecies variability (10X). There are no registered or proposed 

residential uses for tefluthrin and thus dermal exposures to children are not expected. It is noted 

that the dermal endpoints for tefluthrin will need to be revisisted if tefluthrin formulations are 

changed in the future.

Short-term Inhalation: A route specific inhalation study is available for tefluthrin. As a result, 

the Reference Concentration methodology (RfC) developed by the Office of Research and 

Development (ORD) was used to derive human equivalent concentrations (HECs) for tefluthrin. 

Quantification of inhalation risks was performed using an acute inhalation rat study with a 

NOAEL of 7.7 mg/m3(HEC = 11 mg/m3, 0.54 mg/kg/day) based on central nervous system 

(CNS) effects including decreased activity, reduced foot withdrawal reflex, and reduced righting 

reflex (LOAEL = 14.9 mg/m3).

Since the RfC methodology takes into consideration pharmacokinetic (PK) differences but not 

the pharmacodynamic (PD) differences, the UF for interspecies extrapolation may be reduced to 

3X (to account for the PD differences) while the UF for intraspecies variation is retained at 10X. 

Thus, an MOE of 30 is required for inhalation exposure for adults. There are no registered or 

proposed residential uses for tefluthrin and thus inhalation exposures to children are not 

expected.

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

HED combines risk values resulting from separate exposure pathways when it is likely they can 

occur simultaneously based on the use pattern, the behavior associated with the exposed 
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population, and the hazard associated with the points of departure. For tefluthrin, the points of 

departure for dermal and inhalation exposures are based on the same study and the same effects 

and thus it is appropriate to combine dermal and inhalation exposures for occupational workers 

to estimate an overall MOE.

4.5.3 Cancer Classification and Risk Assessment Recommendations

Tefluthrin has been recently presented to the CARC (Kidwell; TXR 0056340; 2012) and was 

classified as “not likely to be a human carcinogen”. There are two adequate rodent 

carcinogenicity studies available for tefluthrin.

The CARC did not consider the uterine tumors seen in female rats to be treatment-related. In 

female rats, there was a significant trend (p<0.05) for uterine adenocarcinomas. However, there 

were no significant pair-wise comparisons of the dosed groups with the controls. The incidences 

of this tumor at all dose groups were within the historical control range (0-15%) provided by the 

registrant. Additionally, there were no corroborative non-neoplastic lesions. There was no 

evidence of carcinogenicity in male rats. The dose levels tested were adequate to assess the 

carcinogenicity of tefluthrin in rats based on the clinical signs of neurotoxicity and changes in 

the body weight/body weight gains observed at the high dose in both sexes.

The CARC did not consider the pitutary gland tumors seen in both male and female mice to be 

treatment-related. Male mice had statistically significant trends in pituitary gland adenomas and 

combined adenomas and/or carcinomas, both at p < 0.05. However, there were no significant 

pair-wise comparisons of the dosed groups with the controls. Female mice had statistically 

significant trend in pituitary gland pars intermedia adenomas at p < 0.05 and a statistically

significant trend in pituitary gland pars intermedia combined adenomas and/or carcinomas at p < 

0.01. There was a statistically significant pair-wise comparison of the 400 ppm dose group with 

the controls for pituitary gland pars intermedia combined adenomas and/or carcinomas at p < 

0.05. The incidence of carcinomas at 400 ppm was low (a single carcinoma). Additionally, there 

were no corroborative non-neoplastic lesions. The dose levels tested were adequate to assess the 

carcinogenicity of tefluthrin in mice based on the decreased body weight and body weight gain

and non-neoplastic lesions in the uterus and liver observed at the high dose level in both sexes.
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4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.5.4: Summary of Toxicological Doses and Endpoints for Tefluthrin

Exposure/

Scenario Point of Departure Uncertainty/FQPA Safety Factors

PAD, Level of Concern 

for Risk Assessment

Study and Toxicological Effects

Acute 

Dietary

(General 

Population, 

including 

Infants and 

Children)

NOAEL = 0.5 

mg/kg/day

UFA= 10x

UFH =10x

FQPA= 3x (only 

individuals < 6 

years old)

aPAD for individuals < 

6 years old = 0.0017

mg/kg/day

aPAD for individuals ≥ 

6 years old = 0.005

mg/kg/day

Chronic Dietary – Dog

MRID 40141308

LOAEL = 2.0 mg/kg/day based on increased 

incidence of tremors in the dog (both sexes)

Dermal 

Short-Term

(1-30 days) 

NOAEL = 0.5 

mg/kg/day

(Microencapsulated 

formulations)

Dermal absorption 

factor = 0.79%

UFA =10x

UFH =10x

Occupational LOC for 

MOE = 100

Chronic Dietary – Dog

MRID 40141308

LOAEL = 2.0 mg/kg/day based on increased 

incidence of tremors in the dog (both sexes)

NOAEL = 0.1 

mg/kg/day

(Granular 

formulations)

UFA =10x

UFH =10x

Occupational LOC for 

MOE = 100

21-day Dermal – Rat

MRID 41080002

LOAEL = 1.0 mg/kg/day based on increased 

incidence of splayed gait (both sexes)

Inhalation 

Short-Term

(1-30 days)

NOAEL = 7.7 mg/m3

Occupational HEC= 

0.54 mg/kg; 11 

mg/m3

UFA = 3X

UFH = 10X

Occupational LOC for 

MOE = 30

Acute Inhalation toxicity study- Rat

MRID 40141302

LOAEL = 14.9 mg/m3based on CNS effects 

(decreased activity, reduced foot withdrawal 

reflex, and reduced righting reflex)

Cancer (oral, 

dermal, 

inhalation)

Tefluthrin is classified as “not likely to be a human carcinogen”

NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UFA = extrapolation from animal to 

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

FQPA Safety Factor. PAD = population adjusted dose (a = acute). MOE = margin of exposure. LOC = level of concern.

5.0 Dietary Exposure and Risk Assessment

5.1 Food Residue Profile

Qualitative nature of the residue of tefluthrin in plants is adequately understood. The residues 

of concern are the parent and the free acid PP 890. Metabolism studies in animals identified 

residues of the parent and metabolites in tissues, but at levels below the LOD by the 

enforcement method in force at that time (D208747, Garbus, J., 2/16/1995).

Syngenta submitted a sugar beet metabolism study in support of the proposed preplant seed 

treatment use. HED has reviewed the sugar beet metabolism study and deemed it acceptable (W. 

Drew, D369668, 12/8/2009). Total radioactive residues were <0.003 ppm in sugar beet roots and 

tops grown from seeds treated with [phenyl-U14C]tefluthrin or [cyclopropane14C]tefluthrin at 

0.08 or 0.15 mg ai/seed (roughly 1X and 2X the maximum proposed use rate). As a result, the 
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proposed use meets the requirements established by HED for classification of seed treatments as 

nonfood uses (ChemSAC memo dated 28 October 1999).

There are also a number of field trial studies that were conducted for examining the tefluthrin 

residues resulting from the existing preplant corn uses, which include a microencapsulated liquid 

product and a granular product (Force® CS Insecticide and Force®3G Insecticide). In all of the 

available trials for both products, residues of tefluthrin and its metabolite (PP 890) were <LOQ 

for both analytes in/on corn forage, K+CWHR, grain, and stover. Based on this data, an LOQ 

tolerance of 0.06 ppm (for tefluthrin + PP 890) was established for field corn (forage, grain and 

stover), pop corn (grain and stover), and sweet corn (forage, kernel plus cob with husks removed, 

and stover).

5.2 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by EFED in the 

following memorandum: “EFED Assessment for the Proposed New Use of Tefluthrin (Force® 

SB) as a Seed Treatment for Sugar Beets” (Melendez, J., Parker, R. D., DP#368327, May 2010). 

EFED used the Pesticide Root Zone Model/Exposure Analysis Modeling System

(PRZM/EXAMS) and Screening Concentrations in Ground Water (SCI-GROW) in estimating 

the residue of the tefluthrin in drinking water from the proposed sugar beet seed treatment use as 

well as the currently registered preplant corn uses. The EFED water assessment was performed 

for the parent compound only.

EFED found the drinking water exposure for the proposed sugar beet seed treatment use to be 

negligible. The PRZM-EXAMS surface water assessment predicted a concentration of ‘zero’ 

based on placement of all of the treated seed below the model’s runoff and erosion zone (below 

two centimeters). The SCI-GROW model predicted a concentration below 0.01 parts per trillion. 

These exposure values apply to both human health drinking water and ecological habitat water. 

A PRZM/EXAMS exposure assessment was also performed for the tefluthrin preplant corn use 

using the Pennsylvania corn (PA Corn) standard modeling scenario. The PA Corn scenario was 

chosen because the amount of soil erosion predicted in that scenario is most realistic for a 

pesticide like tefluthrin that moves to surface water bound to eroding soil. The percent cropped 

area (PCA) value for field corn (0.46) was applied to each of the concentration values predicted 

by the PRZM/EXAMS modeling system. The results of the EFED water modeling are presented 

in Table 5.2.

Table 5.2: Maximum Tier 2 Estimated Drinking Water Concentrations (EDWCs) for 

drinking water risk assessment based on ground application of tefluthrin on corn

USE (rate modeled) DRINKING WATER 

SOURCE (MODEL USED)

MAXIMUM ESTIMATED DRINKING WATER 

CONCENTRATION (EDWC) ( ppt)

Corn (0.165 lb. a.i./A,

one application at plant)

Groundwater

(SCI-GROW) Acute and Chronic 1.0

Surface Water

(PRZM/ EXAMS)

Acute 259

Non-cancer Chronic 8.74

Cancer Chronic 6.06
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5.3 Dietary Risk Assessment

5.3.1 Acute Dietary Risk Assessment

An unrefined acute dietary analysis was performed for tefluthrin that assumes 100% of the crops 

were treated and residues were at half the limit of quantitation (1/2 LOQ = 0.3 ppm) on all types 

of corn. The highest residues in drinking water, using the PRZM-EXAMS model for surface 

water sources (259 ppt from PA corn scenario) was used as the estimated residue in all direct or 

indirect drinking water. The results of acute aggregate dietary (food + drinking water) analysis 

show that the acute dietary risk for the general U.S. population and all population subgroups are

below HED’s level of concern (<100% acute Population Adjusted Dose (aPAD)) at the 95th

percentile of the exposure distribution. The acute dietary risk was <1% of the aPAD for the 

general U.S. population and 28% of the aPAD for all-infants (<1year old), the most highly 

exposed population subgroup. 

The acute dietary risk assessment for food only was estimated to be <1% of the aPAD for the 

general U.S. population and 27% of the aPAD for all infants <1 year old.

5.3.2 Chronic Dietary Risk Assessment

Chronic dietary risk assessments were not conducted for tefluthrin. The acute dietary assessment 

should be considered protective of chronic dietary exposures based on the lack of progression of 

effects in longer-term bifenthrin toxicity studies (see Section 4.3.3)

5.3.3 Cancer Dietary Risk Assessment

Cancer dietary risk assessments were not conducted for tefluthrin as tefluthrin has been classified 

as “not likely to be a human carcinogen” (see Section 4.5.3).

5.4. Dietary Risk Assessment Summary Table

Table 5.4: Summary of Dietary (Food and Drinking Water) Exposure and 

Risk for Tefluthrin

Population Subgroup

Acute Dietary

(95th Percentile)

Dietary Exposure 

(mg/kg/day) % aPAD

General U.S. Population 0.000206 0.41

All Infants (< 1 year old) 0.000471 281

Children 1-2 years old 0.000370 22

Children 3-5 years old 0.000372 22

Children 6-12 years old 0.000283 <1%

Youth 13-19 years old 0.000237 <1%

Adults 20-49 years old 0.000153 <1%

Adults 50+ years old 0.000095 <1%

Females 13-49 years old 0.000158 <1%
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6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are currently no registered residential uses associated with tefluthrin; therefore, a 

residential/non-occupational exposure assessment is not required.

7.0 Aggregate Exposure/Risk Characterization

The acute aggregate risk estimates associated with exposure to tefluthrin are equivalent to the 

acute dietary risk estimates and do not exceed the Agency’s level of concern (see Section 5.3.1).

There are currently no registered residential uses associated with tefluthrin and therefore a shortterm aggregate risk assessment was not conducted.

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 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 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. No cumulative risks 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.

9.0 Occupational Exposure/Risk Characterization

Based on the proposed tefluthrin sugar beet seed treatment use, there is potential for occupational 

handler exposure to occur. There is also potential for occupational handler and postapplication 

exposure to the currently registered uses of tefluthrin.
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9.1 Occupational Handler Exposure and Risk

9.1.1 Handler Risk for the Existing At-plant Corn Uses

Tefluthrin currently has a granular and a microencapsulated suspension registered for use as an 

at-plant soil application for corn. Based on the existing use pattern, HED expects the following

occupational pesticide handler scenarios:

1) mixing/loading liquids for ground applications;

2) mixing/loading granulars for ground applications;

3) applying sprays via groundboom equipment; and

4) applying granulars via tractor drawn spreader.

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

generic occupational 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. The 

standard values recommended for use in predicting occupational 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 specific unit exposures used in this assessment are presented in Appendix C 

(Appendix Table C1).

There is potential for short- or intermediate-term handler exposures for tefluthrin. However, the 

available toxicological data supports the conclusion that neurotoxicity from tefluthrin and 

pyrethroids in general is associated with acute, peak exposures (i.e., every day is a new day). 

As such, only single day dermal risks were assessed.

Table 9.1.1 presents the estimated aggregate risk index (ARIs) from the tefluthrin at-plant corn 

uses for occupational handlers. HED’s level of concern for combined dermal and inhalation 

occupational handler exposures is equal to an ARI of 1. The ARIs for occupational handlers for 

the microencapsulated suspension product do not exceed HED’s level of concern (i.e., ARIs are 

≥ 1, the LOC for this assessment) with the use of gloves. The ARIs for occupational handlers for 

the granular product exceed HED’s level of concern (i.e., ARIs are < 1, the LOC for this 

assessment) even if engineering controls are utilized for mixing/loading and unless engineering 

controls are utilized for application
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Table 9.1.1. Occupational Handler Exposures and Risks for Tefluthrin At-plant Corn Uses a

Exposure Scenario

Application 

Rate

Area 

Treated 

Daily

Dermal Dose (mg/kg/day)d Inhalation Dose 

(mg/kg/day)e Dermal MOEsf

Inhalation MOEsg ARIh

(lb ai/A)b(acres/day)c PPE-G, 

SL

PPE-G, 

DL

ENG 

CON Baseline ENG CON

PPE-G, 

SL

PPE-G, 

DL

ENG 

CON Baseline ENG CON

PPE-G + 

Baseline 

Inhalation

PPE G-DL + 

Baseline 

Inhalation

ENG 

CON

Mixing/Loading

Mixing/Loading 

Liquids

Groundboom 

Applications 

on At-plant 

Corn

0.164 200 0.00012 0.000094 0.000028 0.00009 0.000034 4,100 5,300 18,000 6,000 16,000 34 42 135

Loading 

Granulars

Tractor 

Drawn 

Spreader 

Applications 

on At-plant 

Corn

0.165 200 0.0028 0.0014 0.0035 0.0007 0.000035 34 69 27 750 15,000 0.34 0.67 0.27

Applying

Applying Liquid 

Sprays via 

Grounboom

At-plant 

Corn 0.164 200 0.000052 0.000041 0.000017 0.00014 0.0014 9,600 12,000 30,000 3,900 31,000 55 62 233

Appyling 

Granulars via 

Tractor Drawn 

Spreader

At-plant 

Corn 0.165 200 0.003 0.0017 0.00083 0.0005 0.000018 33 56 120 1,100 5,800 0.33 0.55 1.2

a. Unit Exposures taken from Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/handler-exposure-table.pdf)

b. Application rates = maximum application rates from labels.

c. Amount handled per day values are HED estimates of acres treated or gallons applied per day based on Exposure SAC SOP #9 “Standard Values for Daily Acres Treated in Agriculture,” industry 

sources, and HED estimates.

d. Dermal Dose (mg/kg/day) = Dermal Unit exposure (mg/lb ai) x App Rate x Area Treated x %Absorption / Body weight (80 kg). 

e. Inhalation Dose (mg/kg/day) = Inhalation Unit exposure (mg/lb ai) x App Rate x Area Treated x %Absorption (100% inhalation ) / Body weight (80 kg). 

f. Dermal MOE = NOAEL (10 mg/kg/day) / Dermal Dose (mg/kg/day) 

g. Inhalation MOE = NOAEL (10 mg/kg/day) / Inhalation Dose (mg/kg/day) 

h. Aggregate Risk Index (ARI) = 1 / (Dermal LOC/Dermal MOE) + (Inhalation LOC/Inhalation MOE)
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9.1.2 Handler Risk for the Proposed and Existing Seed Uses

Tefluthrin is being proposed for commercial seed treatment use on sugar beets (see Table 3.3) 

and is currently registered for commercial seed treatment use on corn. The tefluthrin labels do 

not permit on-farm seed treatment. Based on the existing seed treatment use pattern, there is 

potential for exposure to tefluthrin to primary handlers (i.e., activities related to treating the 

seed) and secondary handlers (i.e., planting treated seed). Primary and secondary handler 

exposure is expected to be short- or intermediate-term in duration based on information 

provided on the proposed label. However, the available toxicological data supports the 

conclusion that neurotoxicity from tefluthrin and pyrethroids in general is associated with acute, 

peak exposures (i.e., every day is a new day). As such, only single day dermal risks were 

assessed.

Primary Handler (Treating Seed)

Potential primary occupational handler exposure scenarios from the use of tefluthrin as a 

commercial seed treatment include:

Mixing, loading, applying liquid formulations;

Bagging treated seed;

Sewing bags; 

Cleaning equipment;

Forklift driving; and

Multiple activities.

Typically, for large-scale commercial seed treatments, workers perform only those specific 

individual tasks listed above; however, it is assumed that workers also may perform multiple 

activities throughout the day. As a result a “multiple activities” scenario (i.e. where one worker 

performs all seed treatment tasks such as loading/applying, sewing, bagging, cleaning, 

calibration, repair, forklift driver, etc.) was addressed. No assessment was performed for onfarm seed treatment as the tefluthrin labels do not permit on-farm seed treatment. 

Secondary Handler (Planting Treated Seed)

Potential secondary occupational handler exposure scenarios from the use of tefluthrin as a 

commercial seed treatment include planting treated seed.

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

generic handler data for seed treatment are incorporated in HED ExpoSAC Policy 14: SOPs for 

Seed Treatment. This tefluthrin seed treatment assessment also includes data from a Syngenta

proprietary seed treatment exposure study (MRID 45200002). The amount of active ingredient 

handled depends on the application rate (lb ai/lb seed or lb ai/seed), the pounds of seed treated in 

a day, and the pounds of seed that can be planted in a day, all of which vary depending upon the 

seed type. Values for the amount of seed treated and planted per day were obtained from a 

Biological and Economic Analysis Division memo entitled, “Acres Planted per Day and Seeding 

Rates of Crops Grown in the United States” (J. Becker and S. Ratnayake; 3/24/11).
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Summaries of the estimated aggregate risk index for primary (open and closed seed treatment 

systems) and secondary handlers are included in Tables 9.1.2a, 9.1.2b and 9.1.2c, respectively. 

HED’s level of concern for combined dermal and inhalation occupational handler exposures is 

equal to an ARI of 1. 

Proposed Sugar Beet Seed Use: The ARIs for the proposed sugar beet seed use for open and 

closed system primary handlers and secondary handlers do not exceed HED’s level of concern 

(i.e., ARIs are ≥ 1, the LOC for this assessment).

Existing Corn Seed Use: The ARIs for some of the assessed scenarios (e.g., loader/applicator, 

multiple activities, cleaning) for the existing corn seed use for open and closed system primary 

handlers exceed HED’s level of concern (i.e., ARIs are < 1, the LOC for this assessment). The 

ARIs for the existing corn seed use for secondary handlers do not exceed HED’s level of concern 

(i.e., ARIs are ≥ 1, the LOC for this assessment).
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Table 9.1.2a: Summary of Occupational Handler Exposure and Risk Estimates (Open System) for Tefluthrin Seed 

Treatment Uses

Seed Type lbs seed 

treated/day a, b

Application 

Rate c

(lb ai/lb seed)

Amount 

Handled per 

day

(lb ai/day)

Dermal Unit 

Exposure d

(mg/lb ai)

Inhalation Unit 

Exposure d

(ug/lb ai)

Dermal MOEs eInhalation MOEs f

ARI g

Base PPE-G

PPEG, DL Base 90%-R

Loader/Applicator

Sugar Beet Seed 5500 0.0043 24

Base: ND

PPE-G: 0.023

Base: 0.34

90%-R: 0.034 ND

9,300 1,200 5,400 54,000 PPE-G + Base = 61

Corn Seed 

(Field) 550,000 0.0053 2915 76 96 44 440 PPE-G,DL + 90%-R = 0.9

0.00078 429 510 660 300 3,000 PPE-G + Base = 3.4

Sewer

Sugar Beet Seed 5500 0.0043 24 Base: 0.0062

PPE-G: ND

Base: 0.23

90%-R: 0.023

34,000

ND ND

7,900 79,000 Base + Base = 150

Corn Seed 

(Field) 550,000 0.0053 2915 280 64 640 Base + 90%-R = 2.5

0.00078 429 1,900 440 4,400 Base + Base = 8.3

Bagger

Sugar Beet Seed 5500 0.0043 24 Base: 0.0091

PPE-G: ND

Base: 0.16

90%-R: 0.016

24,000

ND ND

11,000 110,000 Base + Base = 150

Corn Seed 

(Field) 550,000 0.0053 2915 190 93 930 Base + 90%-R = 1.8

0.00078 429 1,300 630 6,300 Base + Base = 8.0

Multiple Activities

Sugar Beet Seed 5500 0.0043 24

Base: ND

PPE-G: 0.042

Base: 1.6

90%-R: 0.16 ND

5,100

ND

1,100 11,000 PPE-G + Base = 21

Corn Seed 

(Field) 550,000 0.0053 2915 41 6.3 63 PPE-G + 90%-R = 0.34

0.00078 429 280 63 630 PPE-G + 90%-R = 2.5

a Value for lb sugar beet seed treated per day taken from information provided by Industry on treatment of vegetable seeds.

b HED default for lb corn seed treated per day from HED Exposure Science Advisory Council Policy 15.

c Application Rates based on tefluthrin labels. The two different corn rates reflect the two treatments described on the current corn seed treatment label.

d Unit Exposures from HED Exposure Science Advisory Council Policy 14.

e Dermal Dose (mg/kg/day) = dermal unit exposure (mg/lb ai) x application rate (lb ai/lb seed) x amount treated (lb seed/day) x absorption factor (0.79%) / body weight (80 kg 

adult). Dermal MOE = NOAEL (0.5 mg/kg/day for short- and intermediate-term exposure) / Dermal Dose (mg/kg/day). Level of concern = 100.

f Inhalation Dose (mg/kg/day) = inhalation unit exposure (mg/lb ai) x application rate (lb ai/lb seed) x amount treated (lb seed/day) x absorption factor (100%) / body weight (80 

kg adult). Inhalation MOE = NOAEL (0.54 mg/kg/day for short- and intermediate-term exposure) / Inhalation Dose (mg/kg/day). Level of concern = 30.

g Aggregate Risk Index (ARI) = 1 / (Dermal LOC/Dermal MOE) + (Inhalation LOC/Inhalation MOE)
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Table 9.1.2`b: Summary of Occupational Handler Exposure and Risk Estimates (Closed

System) for Tefluthrin Seed Treatment Uses

Seed Type

lbs seed 

treated or 

planted/day a, b

Application 

Rate (AR) (lb 

ai/100 lb) c

Amount 

Handled per 

day (lb 

ai/day)

Dermal Unit 

Exposure d

(mg/lb ai)

Inhalation 

Unit d

Exposure 

(ug/lb ai)

Dermal 

MOE e

Inhalation 

MOE f ARI g

Treater (loader/applicator)

Sugar Beet 5,500 0.43 24 0.0011 0.11

0.11

0.11

190000 17,000 436

Corn Seed (Field) 550,000 0.53 2915 0.0011 1600 130 3.4

550,000 0.078 429 0.0011 11000 920 24.0

Sewer/bagger/stacker (tyvek coveralls)

Sugar Beet 5,500 0.43 24 0.0042 0.064

0.064

0.064

51000 29,000 334

Corn Seed (Field)

550,000 0.53 2915 0.0042 410 230 2.7

550,000 0.078 429 0.0042 2800 1,600 18.4

Sewer/bagger/stacker (cotton coveralls)

Sugar Beet 5,500 0.43 24 0.00037 0.064

0.064

0.064

580000 29,000 829

Corn Seed (Field) 550,000 0.53 2915 0.00037 4700 230 7

550,000 0.078 429 0.00037 32000 1,600 46

Cleaner

Sugar Beet 5,500 0.43 24 0.00027 0.523

0.523

0.523

790000 3,500 115

Corn Seed (Field) 550,000 0.53 2915 0.00027 6400 28 0.92

550,000 0.078 429 0.00027 44000 190 6.24

Forklift

Sugar Beet 5,500 0.43 24 0.000145 0.010

0.010

0.010

1500000 180,000 4286

Corn Seed (Field) 550,000 0.53 2915 0.000145 12000 1,500 35

550,000 0.078 429 0.000145 81000 10,000 236

a Value for lb sugar beet seed treated per day taken from information provided by Industry on treatment of vegetable seeds.

b HED default for lb corn seed treated per day from HED Exposure Science Advisory Council Policy 15.

c Application Rates based on tefluthrin labels.

d Unit Exposures from MRID 45200002. This study represents the use of state of the art closed system seed treatment equipment and the use of chemical resistant coveralls over 

long-sleeved shirt, long pants; chemical resistant gloves. 

e Dermal Dose (mg/kg/day) = dermal unit exposure (mg/lb ai) x application rate (lb ai/lb seed) x amount treated (lb seed/day) x absorption factor (24.5%) / body weight (80 kg 

adult). Dermal MOE = NOAEL (10.0 mg/kg/day for short- and intermediate-term exposure) / Dermal Dose (mg/kg/day). Level of concern = 1000.

f Inhalation Dose (mg/kg/day) = inhalation unit exposure (mg/lb ai) x application rate (lb ai/lb seed) x amount treated (lb seed/day) x absorption factor (100%) / body weight (80 

kg adult). Inhalation MOE = NOAEL (10.0 mg/kg/day for short- and intermediate-term exposure) / Inhalation Dose (mg/kg/day). Level of concern = 1000.

g Aggregate Risk Index (ARI) = 1 / (Dermal LOC/Dermal MOE) + (Inhalation LOC/Inhalation MOE)
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Table 9.1.2c: Summary of Secondary Handler (Planter) Exposures and Risks for Tefluthrin

Crop

Application 

Rate a

(lb ai/lb seed)

Seeds/lb b seeds 

planted/acre b

lbs 

seed/acre

Amount 

Handled per 

day c

(lb ai/day)

PPE-G Dermal 

Unit Exposure 

(mg/lb ai) d

Baseline 

Inhalation Unit 

Exposure

(ug/lb ai) d

PPE-G 

Dermal 

MOE e

Baseline 

Inhalation 

MOE f

ARI g

PPE-G + Base

Sugar Beet 0.0043 22000 104544 4.8 1.6347 0.25 3.4 12000 7800 82

Corn Seed (Field)

0.0053 1361 40250 29.6 31.3483 0.25 3.4 650 410 4.4

0.00078 1361 40250 29.6 4.6135 0.25 3.4 4400 2800 30

a Application Rates based on tefluthrin labels.

b Taken from a Biological and Economic Analysis Division memo entitled, “Acres Planted per Day and Seeding Rates of Crops Grown in the United States” (J. Becker and S. 

Ratnayake; 3/24/11).

c Amount Handled per Day = Application Rate (lb ai/seed) * lbs seed/acre * 80 acres (sugar beet) or 200 acres (field corn).

d Unit Exposures from HED Exposure Science Advisory Council Policy 14. No data is available for baseline dermal exposure (i.e., no gloves).

e Dermal Dose (mg/kg/day) = dermal unit exposure (mg/lb ai) x application rate (lb ai/lb seed) x amount treated (lb seed/day) x absorption factor (0.79%) / body weight (80 kg 

adult). Dermal MOE = NOAEL (0.5 mg/kg/day for short- and intermediate-term exposure) / Dermal Dose (mg/kg/day). Level of concern = 100.

f Inhalation Dose (mg/kg/day) = inhalation unit exposure (mg/lb ai) x application rate (lb ai/lb seed) x amount treated (lb seed/day) x absorption factor (100%) / body weight (80 

kg adult). Inhalation MOE = NOAEL (0.54 mg/kg/day for short- and intermediate-term exposure) / Inhalation Dose (mg/kg/day). Level of concern = 30.

g Aggregate Risk Index (ARI) = 1 / (Dermal LOC/Dermal MOE) + (Inhalation LOC/Inhalation MOE)
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9.2 Occupational Post-Application Exposure and Risk

9.2.1 Occupational Post-Application Risk for the Existing At-plant Corn Uses

Significant occupational post-application exposure is not likely to occur from the existing atplant corn uses as the application is made to the soil during planting. As a result, no quantitative 

occupational post-application exposure and risk assessment has been performed for these uses.

9.2.2 Occupational Post-Application Risk for the Proposed and Existing Seed Uses

The potential for post-application exposures following the planting of tefluthrin-treated seeds is 

unlikely because sustained levels of contact with treated seed after it has been placed in the soil 

or other planting media would not be expected because no routine cultural practice required for 

the production of agricultural commodities involves such an activity as defined in the no/low 

contact criteria in the Worker Protection Standard (WPS). Therefore, no quantitative postapplication assessment is required for exposure to treated seeds that have already been planted.
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Appendix A: Tefluthrin Toxicity Profiles

A.1 Toxicology Data Requirements

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

no

yes

yes

yes

yes

no

yes

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..............

870.5395 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

no

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 ................................................

CR

CR

yes

yes

no

yes

--

yes 1

yes 1

no

870.7485 General Metabolism...............................................................

870.7600 Dermal Penetration.................................................................

870.7800 Immunotoxicity.......................................................................

yes

CR

yes

yes

yes

yes

--Not applicable

1 Rury; TXR 0056311; 05/31/2012
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Appendix A.2. Toxicity Profiles

Table A.1.1: Tefluthrin Toxicology Profile

Type of 

Study/Guideline Study Title MRID Results

870.1000 Acute oral LD50, Rat 

00156756

Acceptable

LD50 = 21.8 mg/kg (M)

 34.6 mg/kg (F)

Toxicity Category I

870.1200 Acute dermal LD50, Rat

00156756

Acceptable

LD50 = 316 mg/kg (M)

 177 mg/kg (F)

Toxicity Category I

870.1300 Acute inhalation toxicity, Rat 40141302

LC50 = 0.037 mg/L (M)

 0.049 mg/L (F)

Toxicity Category I

Inhalation NOAEL = 7.7 mg/m3(Occupational 

HEC= 0.54 mg/kg; 11 mg/m3)

Inhalation LOAEL = 14.9 mg/m3based on CNS 

effects (decreased activity, reduced foot 

withdrawal reflex, and reduced righting reflex)

870.2400 Primary eye irritation, Rabbit 00156757

Invalid study Studies with the formulations are available

870.2500 Primary dermal irritation, 

Rabbit 

00156757

Acceptable

Slightly irritating

Toxicity Category IV

870.2600 Dermal sensitization, Guinea 

Pig

00156758

Acceptable Not a sensitizer

870.6100

Acute Delayed Neurotoxicity 

- hen

40112402

Acceptable

Negative for delayed neurotoxicity

870.6200

Neurotoxicity screening 

battery – Acute Neurotoxicity 

- Rat

Not Available – Satisfied by Wolansky and 

Harrill (2008) and Weiner et. al. (2009)

870.6200

Subchronic Neurotoxicity 

(rat)

Not Available – Satisfied by Wolansky and 

Harrill (2008) and Weiner et. al. (2009)

870.3100

90-Day oral toxicity (rat)

Administered for 21 days

0, 25, 100 or 400 ppm

(calculated to be 0, 1.25, 5, 20 

mg/kg/day)

40180001

Unacceptable, needs 

additional data submitted 

to the Agency

Systemic Toxicity NOAEL = 5 mg/kg/day 

(Females), < 1.25 mg/kg/day (Males)

Systemic Toxicity LOAEL = 20 mg/kg/day 

(Females) based on decreased body weight gain, 

decreased platelet counts and increased WBC 

and lymphocytes (high dose); LOAEL <= 1.25 

mg/kg/day based on increased liver weights and 

changes in hematology and clinical chemistry 

parameters.

870.3100

90-Day oral toxicity (rat)

Administered for 90 days (13 

weeks)

0, 50, 150, or 350 ppm

(calculated to be 0, 2.5, 7.5, 

17.5 mg/kg/day)

40141304

Unacceptable/

Guideline, needs 

additional data submitted 

to the Agency

Systemic Toxicity NOAEL = 2.5 mg/kg/day 

(M/F)

Systemic Toxicity LOAEL = 7.5 mg/kg/day 

(M/F) based on changes in hemoglobin, 

cholesterol, and increased liver weights.

870.3100

28–Day oral toxicity (mouse)

0, 25, 75, 200 or 400 ppm

(calculated to be 0, 3.75, 11.3, 

30.0, 60.0 mg/kg/day)

40535701

Acceptable/

Nonguideline

Systemic Toxicity NOAEL = 30 mg/kg/day 

(M/F)

Systemic Toxicity LOAEL = 60 mg/kg/day 

based on decreased body weights (females) and 

body weight gains (both sexes)
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Table A.1.1: Tefluthrin Toxicology Profile

Type of 

Study/Guideline Study Title MRID Results

870.3100

90-Day oral toxicity (dog)

0, 0.1, 0.5 or 1.5 mg/kg/day in 

capsules

40141305

Acceptable/

Guideline

Systemic Toxicity NOAEL = 0.5 mg/kg/day 

(M/F) 

Systemic Toxicity LOAEL = 1.5 mg/kg based on 

thyroid changes, increased plasma triglycerides 

and aspartate transaminase.

870.3200

21-Day dermal toxicity (rat)

0, 1.0, 5.0 or 50.0 mg/kg/day

40141306 (1985)

Acceptable/

Guideline

Dermal Toxicity NOAEL = no NOAEL.

Dermal Toxicity LOAEL = 1.0 mg/kg/day based 

on splayed gait in females.

870.3200

21-Day dermal toxicity (rat)

0, 0.1, 1.0 or 50.0 mg/kg/day

41080002 (1989)

Acceptable/

Guideline

Dermal Toxicity NOAEL = 0.1 mg/kg/day.

Dermal Toxicity LOAEL = 1 mg/kg/day based 

on splayed gait in males and females.

870.3700

Prenatal developmental in 

(rat)

0, 1, 3 or 5 mg/kg in corn oil 

by gavage on gestation days 7 

through 16, inclusive.

A 7.5 mg/kg/day dose group 

was included; however 7/18 

dams died between gestation 

days 9-14.

40141309

Acceptable/

Guideline

Maternal Systemic Toxicity NOAEL = 3 

mg/kg/day

Maternal Systemic Toxicity LOAEL = 5 

mg/kg/day based on treatment related decrease in 

body weight gains.

Developmental Toxicity NOAEL = 3 mg/kg/day

Developmental Toxicity LOAEL = 5 mg/kg/day 

based on “inhibited” ossification.

870.3700

Prenatal developmental in 

(rabbit)

0, 3, 6 or 12 mg/kg in corn oil 

by gavage on gestation days 7 

through 19 inclusive

40141310

Acceptable/

Guideline

Maternal Systemic Toxicity NOAEL < 3 

mg/kg/day

Maternal Systemic Toxicity LOAEL <= 3 

mg/kg/day based on treatment related clinical 

sign of toxicity (tremors).

Developmental Toxicity NOAEL => 12 

mg/kg/day

Developmental Toxicity LOAEL > 12 

mg/kg/day.

870.3800

Reproduction and fertility 

effects (rat)

0, 1, 5 or 25 ppm

40141311

Acceptable/

Guideline

Parental Systemic Toxicity NOAEL = 2.5 

mg/kg/day.

Parental Systemic LOAEL = 12.5 mg/kg/day 

based on decreased body weight gains and 

abnormal, splayed, or high-stepping gait.

Reproductive Toxicity NOAEL => 25 

mg/kg/day. 

Reproductive Toxicity LOAEL > 25 mg/kg/day.

Offspring/Developmental Toxicity NOAEL = 

2.5 mg/kg/day. 

Offspring/Developmental Toxicity LOAEL 

=12.5 mg/kg/day based on lower pup body 

weight gains. 

870.4100 Chronic Toxicity (Rat) See guideline 870.4300 ( 83-5)

870.4100

Chronic Toxicity (Dog) – 1 

Year

0, 0.1, 0.5, or 2 mg/kg/day in 

corn oil by capsule

4011308

Acceptable/

Guideline

Systemic Toxicity NOAEL = 0.5 mg/kg 

Systemic Toxicity LOAEL = 2.0 mg/kg based on 

increased incidence of tremors
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Table A.1.1: Tefluthrin Toxicology Profile

Type of 

Study/Guideline Study Title MRID Results

870.4200

Carcinogenicity (mouse) -

18 Months

0, 25, 100 or 400 ppm

(calculated to be 0, 3.4, 13.5, 

54.4 mg/kg/day

40161106

Acceptable/

Guideline

Systemic Toxicity NOAEL = 3.4 mg/kg/day. 

Systemic Toxicity LOAEL = 13.5 mg/kg/day in 

females based on hemangiomatous changes of 

the uterus and liver necrosis

Neoplastic changes seen: significant positive 

trends along with Harderian (accessory) gland 

adenomas, pituitary gland adenomas in the males 

and adenomas and carcinomas in females.

870.4300

Combined Chronic 

Toxicity/Carcinogenicity (rat) 

– 2 Years

0, 25, 100 or 400 ppm 

(calculated to be 0, 1.1, 4.6, 

18.2 mg/kg/day)

40141307

Acceptable/

Guideline

Systemic Toxicity NOAEL = 1.1 mg/kg/day. 

Systemic Toxicity LOAEL = 4.6 (M/F) 

mg/kg/day based on decreased body weights and 

neurotoxicity and clinical chemistry changes. 

No evidence of carcinogenicity.

Open Lit

Neurotoxicity

six dose levels ranging from 

0.03 to 10 mg/kg in adult rats

Wolansky and Harrill 

(2008)

The BMDL and BMD were 2.8 mg/kg and 3.67

mg/kg, respectively, based on reduced motor 

activity in rats.

Open Lit

Neurotoxicity

Two dose levels 10 and 15 

mg/kg in adult rats

Weiner et. al. (2009)

The BMDL and BMD were 4.4 mg/kg and 10.7

mg/kg, respectively, based on FOB.

870.5100

Gene Mutation 

(Ames Assay)

40141312

Acceptable

Negative

870.5195 Mouse Lymphoma Assay

40141314

Acceptable

Negative

870.5300

Forward mutation assay in 

mammalian cells

40141315

Acceptable

Negative

870.5375 in vitro CHO Assay

41651027

Acceptable Negative

870.5385 in vivo chromosomal 

aberration test

40141316

Acceptable

Negative 

870.5450 Dominant lethal assay in mice

40141313

Acceptable

Negative

870.5550

Unscheduled DNA Synthesis 

in primary rat hepatocytes

40141317

Acceptable

Negative

870.7485

Metabolism and 

Pharmacokinetics (rat)

single oral gavage dose of 1 or 

10 mg/kg 14C-labeled 

technical

40161107 (rats)

Acceptable

40161110 (dogs)

Acceptable

Both rats and dogs eliminated the radioactivity in 

48 hours, 50-65% in the feces, 20-30% in the 

urine. Metabolites were identified.
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Table A.1.1: Tefluthrin Toxicology Profile

Type of 

Study/Guideline Study Title MRID Results

870.7600

Dermal absorption

20 CS formulation

47813014

in vivo - rat

47813015

in vitro - rat

47813016

in vitro - human

Registrant submitted a “triple pack” of studies.

The in vivo study is the most predictive with a 

value of 0.79% for a 24 hour period.

870.7800 Immunotoxicity

48756301

Acceptable/

Guideline

This study supported the overall weight of 

evidence which suggests that tefluthrin does not 

directly target the immune system.
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Appendix A.4. Pyrethroid Human Equivalent (dog study vs. acute rat motor activity)

RAT 

(Wolansky) DOG (Subchronic)

chemical rat dose (mg/kg) human dose (mg/kg) dog dose (mg/kg) human dose (mg/kg)

BMD BMDL BMD BMDL NOAEL LOAEL NOAEL LOAEL

beta-cyfluthrin 1.42 1.17 0.412816 0.340137 2.4 13.9 1.475491567 8.545555

bifenthrin 4.1 3.1 1.191933 0.9012176 2.2 4.2 1.352533936 2.58211

bioallethrin 65.6 42.2 19.07093 12.268189

cyhalothrin 0.92 0.64 0.267458 0.1860578 1 2.5 0.614788153 1.53697

cyphenothrin 12.5 37.5 7.684851912 23.05456

cypermethrin 11.19 7.16 3.253105 2.081522 12.5 37.5 7.684851912 23.05456

deltamethrin 2.48 1.49 0.720974 0.4331659 1 2.5 0.614788153 1.53697

esfenvalerate 1.19 0.65 0.345951 0.188965 5 7.5 3.073940765 4.610911

fenpropathrin 6.44 5.01 1.872207 1.456484

permethrin 63.1 44.4 18.34414 12.907762 50 500 30.73940765 307.3941

resmethrin 162.32 75.89 47.18892 22.062389

tefluthrin 3.67 2.8 1.066925 0.814003 0.5 1.5 0.31 0.92

Rat BW (kg) = 0.5

Dog BW (kg) = 10

Human BW (kg) = 70
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Appendix B: Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies, which comprise the Seed 

Treatment SOPs as well as a proprietary seed treatment exposure study (MRID 45200002) have

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

been determined to be ethical.