Tefluthrin Human Health Risk Assessment DP No. 368331

Page 3 of 43 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 Antici pated 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 fa ctor 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 Dietar y 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 Existin g Seed Uses

................................ .............. 29

9.2 Occupational Post

- Application Exposure and Risk

................................ ............................. 34

9.2.1 Occupational Post

- Application Risk for the Existing At

- pla nt Corn Uses

.................. 34

9.2.2 Occupational Post

- Application Risk for the Proposed and Existing Seed Uses

.......... 34Tefluthrin Human Health Risk Assessment DP No. 368331

Page 4 of 43 10.0 References

................................ ................................ ................................ ................................ 35 Appendix A: Tefluthrin Toxicity Profiles

................................ ................................ ....................... 37 Appendix B: Review of Human Research

................................ ................................ ...................... 43Tefluthrin Human Health Risk Assessment DP No. 368331

Page 5 of 43 1.0 Executive Summary

Syngent a 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 R egist ration 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

inc reases 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 cu rrently 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 comme rcial 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

- cya no 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 a vailable 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 pharmac okinetic 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 st udies, experimental laboratory animals exhibited paresthesia and splayed gait.

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

and de creases in body weight and body weight gain.

One of the key elements i n risk assessment is the appropriate integration of temporality between the exposure and hazard assessments. Across the tefluthrin toxicological database, tefluthrin isTefluthrin Human Health Risk Assessment DP No. 368331

Page 6 of 43 absorbed rapidly and neurotoxic effects including tremors and splayed gait are seen so on 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 dur ations 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 reco very). 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 ani mal testing guideline toxicity studies. However, t he 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

Pharmac okinetic ( 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 homol ogous 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 f or the microencapsulated formulations (Force CS, Force ST, and Force SB) was perf ormed 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 f or the granular formulation (Force 3G) was performed usi ng 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

inhalati on rat study with a NOAEL of 7.7 mg/m 3 (HEC = 11 mg/m 3 , 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/m 3 ) . An MOE of 100 is required for dermal exposure for adults which includes interspecies extrapolation (10X) and intraspecies variability (10X) and an MOE of 3 0 is required for inhalation exposure for adults which includes interspecies extrapolation ( 3 X) and intraspecies variability ( 10 X).

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 : S yngenta 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 memoTefluthrin Human Health Risk Assessment DP No. 368331

Page 7 of 43 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 teflu thrin endpoints and points of departure as well as changed its policy regarding directly incorporating d rinking 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 resi due and drinking water values based on the currently registered preplant use on corn. The results of acute aggregate dietary (food + drinking water ) analysi s show that the acute dietary risks for the general U.S. population and all population subgroups ar e below HE D’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 reg istered 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 dieta ry risk estimates and do not exceed the Agency’s level of concern.

T here are currently no registered residential uses associated with tefluthrin and therefore a short

term 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 Use s : The aggr egate 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 prod uct 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 secon dary 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 us e for open and closed system primary handlers exceed HED’s level of concern (i.e., ARIs are < 1, the LOC for this assessment). TheTefluthrin Human Health Risk Assessment DP No. 368331

Page 8 of 43 ARIs for the existing corn seed use for secondary handlers do not exceed HED’s level of concern (i.e., ARIs are ≥ 1, the LO C 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 determine d to require a r eview of their ethical conduct and a ll

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, a nd 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 pre viously 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 8 90 ( (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.Tefluthrin Human Health Risk Assessment DP No. 368331

Page 9 of 43 3.1 Structure and Nomenclature

TABLE 3.1 : Tefluthrin Nomenclature

Compound

Common name Tefluth rin

Molecular formula C 17 H 14 ClF 7 O 2 Molecular weight 418.74

IUPAC name 2,3,5,6

- tetrafluoro

- 4

- methylbenzyl (1 RS )

- cis

- 3

- [( Z )

- 2

- chloro

- 3,3,3

- trifluoroprop

1

- enyl]

- 2,2

- dimethylcyclopropanecarboxylate

CAS name (2,3,5,6

- tetrafluoro

- 4

- methylphenyl)methyl (1 R ,3 R )

- rel

- 3

- [(1 Z )

- 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

- t rifluoro

- 1

- propenyl)

- 2,2

- dimethyl

cyclopropanecarboxylic 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 a vailable Density 1.48 g / cm 3 at 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 - 5 kPa at 40°C

2 x 10 - 5 kPa at 30°C

8 x 10 - 6 kPa at 20°C

3 x 10 - 6 kPa at 10°C MRID # 47813007

Dissociation constant, pK

a Weak acid, pKa >9; hydrolysis prevents

measurement

. MRID # 40167301;

PP#7F3521

Oc tanol/water partition coefficient, Log ( K OW ) 6.5 at 20°C MRID # 47813007 UV/visible absorption spectrum ε247 nm (min imum ) 352 M - 1 cm - 1
ε268 nm (maximum ) 1190 M - 1 cm - 1 MRID # 40167301;

PP#7F3521

* MRID # 47813007 was submitted in association with the subject action (D 369668). MRID # 40167301 was submitted in conjunction with the initial petition

, PP#7F3521 (J. Garbus ; 21 December 19 87).Tefluthrin Human Health Risk Assessment DP No. 368331

Page 10 of 43 3.3 Summary of Existing/Proposed Uses

The currently registered formulations of tefluthrin include granules and a microe ncapsulated 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 ® S B 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

Ap plication

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, an d white grub. Commercial

Seed

Treatment Facility 0.0043 lb

a i/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 sugar beet 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 E xposure 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 drink ing water) is expected from the currently registered uses. T here 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 teflut hrin 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 c oncerns, 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 li ne 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.

E xtensive 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 categ orized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able toTefluthrin Human Health Risk Assessment DP No. 368331

Page 11 of 43 assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances w arrant. 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 consid erations 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 speci fic 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

neu rotoxicological 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

- syndrom e). 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 nervo us 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 to xicology studies available for tefluthrin provides a

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

. However, there are o n

- going efforts to develop data to inform the potent ial 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

stron g 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 StudyTefluthrin Human Health Risk Assessment DP No. 368331

Page 12 of 43 - Cancer M ouse 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 derm al 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 liter ature 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 mem bers 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 discus s 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 ac tivity, 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 in teraction 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 laborator y animals exhibited paresthesia and splayed gait.

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

and de creases in body weight and body weight gain.Tefluthrin Human Health Risk Assessment DP No. 368331

Page 13 of 43 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 i n 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

classif ied 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.

T echnic al 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 adequ ate 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. Foll owing 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 4 8 hours. Peak tefluthrin levels in feces and urine were seen a fter the first

24 hours. Radiolabeled t efluthrin 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 mai nly via the feces ( 61 and 65% in females and males, respectively ) and urine ( 26 and 23% in females and males, respectively ) within 4 8 hours. Peak tefluthrin levels in feces and urine were seen after the first 24 hours while peak blood levels

were seen bet ween 4 and 8 hours. Radiolabeled t efluthrin 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 t he 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 endpoi nts 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, pyreth roid 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, P K refers to theTefluthrin Human Health Risk Assessment DP No. 368331

Page 14 of 43 process(es) which determine the concentration of the pyrethroids reaching sodium channels. The underlying pharmacokinetics of pyrethroids is an important determina n t of their toxicity because the concentration of pyrethroid at the sodium c hannel 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 majo r 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 tissu es such as muscle. Pyrethroid residues in fatty tissue are not available to

interact with the VGSCs in vital tissues and therefo re 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. T he Agency has determined tha t 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 condu cted an analysis of the toxicokinetic profile of pyrethroids as a class.

S everal studies in this analysis indicate that there are age

- dependent pharmacoki netic d ifferences for the pyrethroids (i.e., there are differences in the ability of adults and juven iles to metabolize pyrethroids). The enzymes which 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 acti vity 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

micr osomes 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 d oses 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 ex posures 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 delt amethrin 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 oralTefluthrin Human Health Risk Assessment DP No. 368331

Page 15 of 43 dose in 10

- day old rats and 2.5X lower dose in 21

- day old rats , which r epresents 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

m g/kg÷2.5 mg/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 exami ned 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 t o 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 prol ong 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 tefl uthrin 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 m s for the x

- axis and 500 nAmp on the y

- axis

. Data e xtracted 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.Tefluthrin Human Health Risk Assessment DP No. 368331

Page 16 of 43 HED would prefer to use an early key event in the AOP for pyrethroids in selection of points of departure. However, i n vivo techniques used to detect VGSC alteration and altered neuronal excitability are not practical f or 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 apica l endpoint (i.e., changes in neurobehavior in laboratory animals). Neurotoxicity resulting from pyrethroids are generally characterized by tremors, hyper

- or hypo thermia, heightened response to stimuli, salivation, tremors and convulsions ( Nemec 2006 ; Wolansky and Harrill 2008 ; Breckenridge et. al. 2009 )

. In th e 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 e ven though t here 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 v ivo. 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, suggesti ng 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 c hannel 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 occursTefluthrin Human Health Risk Assessment DP No. 368331

Page 17 of 43 within 24 hours w ithout 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 select ion 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 = 1 2. 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 r egistrant submitted an in vivo dermal penetration study in rats and two accompanying in

vitro study dermal penetration studies using rat and human skin

. I n the in vivo dermal penetration study (MRID 47813014), [ 14 C]

- 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:AP f SD) rats on 10 cm 2 skin areas (two areas of 5 cm 2 ) at a

dose level of 10 mg/rat (1 mg/cm 2 )

. In the two accompanying in vitro dermal penetration studies, [ 14 C]

- 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 eit her excised rat (MRID 47813015) or human epidermal (MRID 47813016) membranes at a nominal dose level of 2.54 mg/membrane (1 mg/cm 2 ).

At 24 hours, dermal absorption for the in vivo study was 0.79% ( stratum corneum + application site skin + absorbed); derma l 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 d ermal 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 protectTefluthrin Human Health Risk Assessment DP No. 368331

Page 18 of 43 for exposures to children <6 years of age based on the increased quantitative susceptibility seen in the scientif

ic 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 concentration s in the juvenile brain compared to adults (see Secti on 4.3.1). T he PK of pyrethroids as a group is sufficiently similar that significant deviations from the 3

- fold

increase of deltamethrin concentration s are not expected for other pyrethroids. As noted in Section 4.3.2, juveniles are not more sensitive th an 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. T here 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 discus s the ACN and SCN data requirements ( Rury;

TXR 005631 1 ; 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 fo r 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 t efluthrin

. 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 o f the studies conducted. Signs of neurotoxicity included tremors, ataxia

, gait abnormalities, and spine curvature among others.

L iterature 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 r elated 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 te fluthrin guideline toxicological studies.

T he tefluthrin developmental and reproductive tox icity studies are consistent with other members of the pyrethroid class in that no evidence of increased quantitative or qualitative susceptibility was observed in t hese studies.

N o evidence of increased quantitative or qualitative susceptibility was seen in the pyrethroid scientific literature related to pharmacodynamics.Tefluthrin Human Health Risk Assessment DP No. 368331

Page 19 of 43 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 d etails regarding the Agency’s findings are outlined in Reevaluation of the FQPA Safety
Factor for Pyrethroid Pesticides (D381210, 6/27/11 )

.

A dditional 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 meeting 1 . 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 o n doing the following: 1 ) conducting in vitro studies demonstrating the interaction of pyrethroids

e x ogenously 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 t he 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 databa se.

The acute dietary as sessment conducted with DEEM

- FCID was u nrefined 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 a ll 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 conclu ded that the DEEM

- FCID analysis does not underestimate risk from acute exposure to tefluthrin.

Similarly, HED does not believe that the non

- dietary occupational exposure s are underestimated because they are also based on con servative 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 Tabl e A.1.1 of Appendix A1.

1 http://www.epa.gov/scipoly/sap/meetings/2010/072310meeting.htmlTefluthrin Human Health Risk Assessment DP No. 368331

Page 20 of 43 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 L OAELs 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)

ne urotoxicity (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 tefluthri n 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 se en in the chronic dog study are consistent with effects seen for other Type I pyrethroids.

The acute PA D 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 FQP A, 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 t wo 21

- day rat dermal toxicity studies a vailable for tefluthr in (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 stu dies.

After discussions with the tefluthrin registrant ( Syngenta ) and Ginger Moser of EPA O ffice of Research and Development , it was determined that these effects are related to paraesthesia

. Tefluthrin, along with other pyrethroids, is known to cause pa raesthesia 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 bo th males and females (NOAEL of 0.1 mg/kg/day and LOAEL of 1 mg/kg/day).Tefluthrin Human Health Risk Assessment DP No. 368331

Page 21 of 4 3 More recently, the registrants performed a “triple pack” for tefluthrin using o ne of the currently registered microencapsulated f ormulations Force CS (MRID 47813014, 47813015, 4781301 6, 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 f or the microencap sulated 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 absorp tion 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 f or 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 potent ial 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 t hus 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 R eference 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 perform ed using an acute inhalation rat study with a NOAEL of 7.7 mg/m 3 (HEC = 11 mg/m 3 , 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/m 3 )

.

Since the RfC metho dology 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 Co mbining 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 exposedTefluthrin Human Health Risk Assessment DP No. 368331

Page 22 of 43 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 d ermal and inhalation exposures for occupational w o rkers

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, the re were no significant pair

- wise comparisons of the dosed groups with the controls. The incidences of this tumor at all dose groups w ere 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 gai ns observed at the high dose in both sexes.

The CARC did not consider the pitu t ary 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 an d/or carcinomas, both at p < 0.05. However, t here 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 aden omas 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.Tefluthrin Human Health Risk Assessment DP No. 368331

Page 23 of 43 4.5.4 Summary of Points of Departure and Toxicity En dpoints Used in Human Risk

Asse ssment

T able 4.5.4 : Summary of Toxicological Doses and Endpoints for T efluthrin

Exposure/

Scenario Point of Departure Uncertainty/FQPA Safety Factors PAD, Level of Concern

for Risk Assessment Study and Toxicological Effects

Acute Dietary (General Population,

i ncluding

Infants and Children) NOAEL = 0.5

mg/kg/day UF A = 10x

UF H =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 4014 1308 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 % UF A =10x

UF H =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) UF A =10x

UF H =10x Occupational LOC for

MOE = 100 21

- day Dermal

– Rat

MRID 4108000 2
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/m 3

Occupational HEC= 0.54 mg/kg; 11 mg/m 3 UF A = 3X

UF H = 10X Occupational LOC for

MOE = 30 Acute Inhalation toxicity study

- Rat

MRID 40141302

LOAEL = 14.9 mg/m 3 based 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA = FQPA Safety Factor . PAD = popu lation 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., 2/1 6/1995).

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

- U

14 C]tefluthrin or [cyclopropane

14 C]tefluthrin at 0.08 or 0.15 mg ai/seed (roughly 1X and 2X the maximum proposed use rate). As a result, theTefluthrin Human Health Risk Assessment DP No. 368331

Page 24 of 43 proposed use meets the requirement s 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 a nalytes 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 co b 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 prop osed 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 t efluthrin preplant corn use usin g t he 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 t efluthrin that moves to surface water bound to eroding soil. T he 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 6.06Tefluthrin Human Health Risk Assessment DP No. 368331

Page 25 of 43 5. 3 Dietary Risk Assessment

5.3.1 Acute Dietary Risk Assessment

An u nrefined acut e dietary analysis was performed for tefluthrin that assumes 100% of the crops

were treated and residues were at half the l imit of q uanti t ation (1/2 LOQ = 0.3 ppm ) on all types

of corn. The h ighest residues in drinking water, using the PRZM

- EXAMS model fo r surface

water sources (259 ppt from PA corn scenario) was u sed as the estimated residue in all direct or indirect drinking water

. The results of acute aggregate dietary (food + drinking water ) analysi s show that the acute dietary risk for the general U. S. population and all population subgroups are below HE D’s level of concern (<100% acute Population Adjusted Dose (aPAD)) at the 95 th
percentile of the exposure distribution . The acute dietary risk was <1% of the aPAD for the general U.S. population and 2 8 % 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 exposure s based on the lack of progression of effects in longer

- t erm 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 28 1

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 0.000 095 <1%

Females 13

- 49 years old 0.000158 <1%Tefluthrin Human Health Risk Assessment DP No. 368331

Page 26 of 43 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 n ot 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).

T here are currently no registered residential uses associated with tefluthrin and therefore a short

term aggregate risk assessment was not conducted.

8.0 Cumulative Exposure/Risk Characterization

The Agency is required to consider the cumulative risks of chemical s sharing a common mechanism of toxicity. T he Agency has determined that the pyrethroid s and pyrethrin s 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 exposur e to pyrethroids, refer to http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids

- pyrethrins.html

.

9.0 Occupational Exposure/Risk Characterization

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

handler exposure to occur. T here is a lso potential for occupational handler and postapplication exposure to the currently registered uses of tefluthrin.Tefluthrin Human Health Risk Assessment DP No. 368331

Page 27 of 43 9.1 Occupational Handler Expo sure 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 s cenarios :

1) m ixing/ l oading l iquids for ground a pplications; 2) mixing/loading granulars for ground a pplications ; 3) a pplying s prays via g roundboom equipment ; and 4) applying granulars via tractor drawn spreader

.

It is the p olicy 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 D atabase Version 1.1 (PHED 1.1) and the Agricultural Handler Expos ure 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 ex posure 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

- exposure

data.htm l

. The specific unit exposures used in this assessment are presented in Appendix C (Appendix Table C1).

There is potential for short

- or intermediate

- term h andler exposure s for tefluthrin. However, the available toxicological data supports the conclusi on 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 eq ual to an ARI of 1. The ARIs for occupational handlers for the microencapsulated suspension pr oduct 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 en gineering controls are utilized for mixing/loading and unless engineering controls are utilized for applicationTefluthrin Human Health Risk Assessment DP No. 368331

Page 28 of 43 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 MOEs f Inhalation MOEs g ARI h

(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 Ap plications

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)Tefluthrin Human Health Risk Assessment DP No. 368331

Page 29 of 43 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, t here 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. Howev er, 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.

Prima ry 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 da y. 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 w as performed for on

farm seed treatment as the tef l uthrin 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 tefl uthrin seed treatment assessment also includes data from a Syngenta

p roprietar y 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 treate d 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).Tefluthrin Human Health Risk Assessment DP No. 368331

Page 30 of 43 Summaries of the estimated aggregate risk index for primary (open and closed seed treatment systems) and secondary handlers are included in Tabl es 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

eq ual to an ARI of 1.

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

clos ed system primary handlers and secondary ha ndlers 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, clea n ing) 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)

.Tefluthrin Human Health Risk Assessment DP No. 368331

Page 31 of 43 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 e Inhalation MOEs f

ARI g

Base PPE

- G PPE

G , 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 descri bed 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 applicati on 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 = 3 0.

g Agg regate Risk Index (ARI) = 1 / (Dermal LOC/Dermal MOE) + (Inhalation LOC/Inhalation MOE)Tefluthrin Human Health Risk Assessment DP No. 368331

Page 32 of 43 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 0.1 1

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

55 0,000 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 tre atment 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

. T his study represent s 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) = inhal ation 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)Tefluthrin Human Health Risk Assessment DP No. 368331

Page 33 of 43 Table 9 .1.2 c : Summary of Secondary Handler (Planter) Exposures and Risks for Tefluthrin

Crop Application

Rate a (lb ai/l b 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. 00 43 22000 104544 4.8 1.6347 0.25 3.4 12000 7800 82

Corn Seed (Field) 0. 00 53 1361 40250 29.6 31.3483 0.25 3.4 650 410 4.4

0.0 00 78 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 an d 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 bee t) 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 a i/lb seed) x amount treated (lb seed/day) x absorption factor ( 0.79 %) / body weight ( 8 0 kg adult). Dermal MOE = NOAEL ( 0.5 mg/kg/day for short

- and intermediate

- term exposure ) / Dermal Dose (mg/kg/day). Level of concern = 10 0

. f Inhalation Dose (mg/kg/d ay) = 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 ( 8 0 kg adult). Inhalation MOE = NOAEL ( 0.54 mg/kg/day for short

- and intermediate

- term exposure ) / Inhal ation Dose (m g/kg/day). Level of concern = 3 0

. g Aggregate Risk Index (ARI) = 1 / (Dermal LOC/Dermal MOE) + (Inhalation LOC/Inhalation MOE)Tefluthrin Human Health Risk Assessment DP No. 368331

Pa ge 34 of 43 9.2 Occupational Post

- Application Exposure and Risk

9.2.1 Occupational Post

- Application Risk for the Existing At

- p lant Corn Uses

Significant o ccupational post

- application exposure is not likely to occur from the existing at

plant 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 s ustai ned 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 post

application assessment is required for exposure to treated seeds that have already been planted

.Tefluthrin Human Health Risk Assessment DP No. 368331

Pa ge 35 of 43 10.0 References

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6/27/11.

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in adult animals: A critical review." Neurotoxicology and Teratology 30(2): 55

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- 247.Tefluthrin Human Health Risk Assessment DP No. 368331

Pa ge 37 of 43 Appendix A: Tef

luthrin Toxicity Profile s

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 Irri tation

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

y es

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 : Struct ural Chromosomal Aberrations

.............. 870.539 5 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 Delay ed Neurotox icity (Hen)

................................ ....... 87 0.6100 90

- Day Neurotoxicity (Hen)

................................ .................. 870.6200 Acute Neurotoxicity Screening Battery (Rat)

......................... 870.6200 90 Day Neuro. Screening Battery (Rat)

................................ .. 870.6300 Develop mental Neuro toxicity

................................ ................ CR
CR

yes
yes

no yes

-- yes 1

yes 1

no

870.7485 Gene ral Metabolism

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

................................ ................................ . 870.7800 Immunotoxicity....................................................................... yes CR

yes yes

yes

yes

-- Not applicable

1 Rury; TXR 0056311 ; 05/31/ 2012Tefluthrin Human Health Risk Assessment DP No. 368331

Pa ge 38 of 43 Appendix A.2. Toxicity Profiles

Table A.1.1: Tefluthrin Toxicology Profile

Type of Study/Guideline Study Title MRID Results

870.1000 Acute oral LD 50 , Rat 00156756 Acceptable LD 50 = 21.8 mg/kg (M) 34.6 mg/kg (F) Toxicity Category I

870.1200 Acute dermal LD 50 , Rat 00156 756 Acceptable LD 50 = 316 mg/kg (M)

177 mg/kg (F)

Toxicity Category I

870.1300 Acute inhalation toxicity, Rat 40141302 LC 50 = 0.037 mg/L (M)

0.049 mg/L (F)

Toxicity Category I

Inhalation NOAEL = 7.7 mg/m 3 (Occupational

HEC= 0.54 mg/kg; 11 mg/m 3 ) Inhalation LOAEL = 14.9 mg/m 3 based 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 a vailable

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

Acceptab le 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 he matology 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)Tefluthrin Human Health Risk Assessment DP No. 368331

Pa ge 39 of 43 Table A.1.1: Tefluthrin Toxicology Profile

Type of Study/Guideline Study Title MRID Results

870.3100 90

- Day ora l 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 c orn 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 Toxici ty 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 (t remors). 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.

Parent al 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

Yea r

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 tremorsTefluthrin Human Health Risk Assessment DP No. 368331

Pa ge 40 of 43 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 Neoplast ic 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 40 0 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

Accep table 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

8 70.7485 Metabolism and Pharmacokinetics (rat)
single oral gavage dose of 1 or 10 mg/kg 14 C

- 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 t he

urine. Metabolites were identified.Tefluthrin Human Health Risk Assessment DP No. 368331

Pa ge 41 of 43 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 0.7 9 % 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.Tefluthrin Human Health Risk Assessment DP No. 368331

Pa ge 42 of 43 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 7.68485 1912 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 1.87 2207 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) = 70Tefluthrin Human Health Risk Assessment DP No. 368331

Pa ge 43 of 43 Appe ndix 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 propri etary 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.