Revised Tefluthrin Human Health Risk Assessment DP No. 415796

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

MEMORANDUM



### Date: October 31, 2 013



### SUBJECT: Te flu thrin: Revised Human Health Risk Assessment. OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION



### PC Code: 128912


### Decision No.: 484390



### Petition No.: DP 

### Barcode: D415796 

### Registration No.: 1 00-RGAR



### Risk Assessment Type: Single

Chemical/ Aggregate 

### Regulatory Action: Section 3 Registration



### Case No.: N / A



### TXRNo.: N / A 

### CAS N o .: 79538-32-2

40 

### CFR: N/A MRID 

### No.: N/A

FROM: Christopher Schlosser, M.F.S.,**Toxicolog i~** **Y...-. ~~~~:_-----­**  Ri sk Assessment Branch VI

# ~~rles Smith, Branch Chi c__
Risk Assessment Branch I

Health Effects Division (7509P)



### THROUGH: Jeffery Dawson, Acting Branch Chief 

# err

.**~** 

# I**~** Risk Assessment Branch VI 

# r**j/ ~**  Health Effects Division (7509P)



### TO: Molly Clayton, Chemical Review Manager

Risk Management and Implementati on Branch 

### Ill

Pesticide Re-Evaluation Di vision (7508P)

Page I of 43Revised Tefluthr:in Human Health Risk Assessment DP No. 415796

In May 2012, the Health Effects Division (HED) of the Office of Pesticide Programs (OPP)

assessed a proposed use oftefluthrin on sugar beet seed (Smith; D368331; 5/31112). This proposed use was subsequently approved in June 2012. The May 2012 document also included

an assessment of all currently registered uses oftefluthrin as a comprehensive evaluation of the

tefluthr:in toxicological endpoints was performed. The 2012 assessment resulted in risks of

concern for some of the currently registered tefluthrin uses; particularly the granular at-plant

com uses. Since that time, HED has re-evaluated the dermal endpoint used to assess dermal

exposures to granular tefluthrin products. Additionally, HED has received both acute and

subchronic neurotoxicity studies. This revised tefluthrin assessment reflects the change in endpoints and provides a re-evaluation of the occupational exposures and risks for the registered

tefluthrin granular at-plant com uses. Based on the revised toxicological endpoints, HED has

determined that the occupational risks from the granular at-plant com uses are not of concern.
HED notes that the 2012 assessment also resulted in risks for some

. ofthe assessed scenarios · (e.g., loader/applicator, multiple activities, cleaning) for the existing com seed use. Since that

time the registrants have submitted revised labels that are currently being reviewed by the Registration Division (RD) that require use of closed systems for treating corn seed.

The HED team members contributing to this risk assessment include Charles Smith (occupational exposure and risk assessments), Christopher Schlosser (toxicologist), and Mohsen Sahafeyan (dietary exposure). Jose Melendez of the Environmental Fate and Effects Div i sion provided the drinking water exposure assessment.

Page 2 of43Revised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 3 of 43 1.0 Executive Summary

................................ ................................ ................................ ................... 5

2.0 HED Recommendations

................................ ................................ ................................ ............. 7

2.1 Data Deficiencies

................................ ................................ ................................ ................... 7

2.2 Tolerance Considerations

................................ ................................ ................................ ....... 8

3.0 Ingredient Profile

................................ ................................ ................................ ....................... 8

3.1 Structure and Nomenclature

................................ ................................ ................................ ... 8

3.2 Physical/Chemical Characteristics

................................ ................................ ......................... 8

3.3 Summary of Currently Registered Uses

................................ ................................ ................. 9

3.4 Anticipated Exposure Pathways

................................ ................................ ............................. 9

3.5 Consideration of Environmental Justice

................................ ................................ ................ 9

4.0 Hazard Characterizatio n and Dose

- Response Assessment

................................ ...................... 10

4.1 Toxicology Studies Available for Analysis

................................ ................................ ......... 10

4.2 Toxicological Profile

................................ ................................ ................................ ............ 11

4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile

................................ ................ 12

4.3.1 Pharmacokinetics (PK)

................................ ................................ ................................ 13

4.3.2 Pharmacodynamics (PD)

................................ ................................ ............................. 14

4.3.3 Critical Duration of Exposure

................................ ................................ ...................... 16

4.3.4 Dermal Absorption

................................ ................................ ................................ ....... 16

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

................................ ............. 17

4.4.1 Adequacy of the Toxicity Database

................................ ................................ ............. 17

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

- R esponse Assessment

................................ ................................ ......................... 19

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

.............. 20

4.5.3 Cancer Classification a nd Risk Assessment Recommendations

................................ . 21

5.0 Dietary Exposure and Risk Assessment

................................ ................................ .................. 22

5.1 Food Residue Profile

................................ ................................ ................................ ............ 22

5.2 Water Residue Profile

................................ ................................ ................................ .......... 23

5.3 Dietary Risk Assessment

................................ ................................ ................................ ...... 23

5.3.1 Acute Dietary Ri sk Assessment

................................ ................................ ................... 23

5.3.2 Chronic Dietary Risk Assessment

................................ ................................ ............... 24

5.3.3 Cancer Dietary Risk Assessment

................................ ................................ ................. 24

5.4. Dietary Risk Assessment Summary Table

................................ ................................ ........... 24

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ .......... 24

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ............. 24

8.0 Cumulative Exposure/Risk Characterization

................................ ................................ ........... 25

9.0 Occupa tional Exposure/Risk Characterization

................................ ................................ ........ 25

9.1 Occupational Handler Exposure and Risk

................................ ................................ ........... 26

9.1.1 Handler Risk for the Currently Regi stered At

- plant Corn Uses

................................ .. 26

9.1.2 Handler Risk for the Proposed and Existing Seed Uses

................................ .............. 28

9.2 Occupational Post

- Application Exp osure and Risk

................................ ............................. 33

9.2.1 Occupational Post

- Application Risk for the Existing At

- plant Corn Uses

.................. 33

9.2.2 Occupational Post

- Applic ation Risk for the Proposed and Existing Seed Uses

.......... 33Revised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 4 of 43 10.0 References

................................ ................................ ................................ ................................ 34 Appendix A: Tefluthrin Toxicity Profiles

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

................................ ................................ ...................... 43Revised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 5 of 43 1.0 Executive Summary

In May 2012, t he Health Effects Division (HED) of the Office of Pesticide Programs (OPP) assessed a propo sed use of tefluthrin on sugar beet seed (Smith; D368331; 5/31/12). This proposed use was subsequently approved in June 2012. The May 2012 document also included an assessment of all currently registered uses of tefluthrin as a comprehensive evaluation o f the tefluthrin toxicological endpoints was performed. Since that time, HED has re

- evaluated the dermal endpoint used to assess dermal exposures to granular tefluthrin products. Additionally, HED has received both acute and subchronic neurotoxicity stud ies. This revised tefluthrin assessment reflects the change in endpoints and provides a re

- evaluation of the occupational exposures and risks for the registered tefluthrin granular at

- plant corn uses.

Use Profile : The currently registered formulations of tefluthrin include granules and a microencapsulated suspension applied at

- planting for the control of soil insect pests of corn. There is also a microencapsulated suspension registered for treatment of corn and sugar beet seed in

commercial seed treat ment facilities.

Hazard Assessment : Pyrethroids have historically been classified into two groups, Type I and Type II, based upon chemical structure and neurotoxicological effect. Tefluthrin is a Type I pyrethroid, which lack an alpha

- cyano moiety and ty pically induce in rats a syndrome consisting of aggressive sparring, altered sensitivity to external stimuli, and fine tremor progressing to

whole

- body tremor and prostration (T

- syndrome). The data base of experimental toxicology

studies available for tef

luthrin provides a robust characterization of the hazard. There are no outstanding studies according to Part 158 data requirements. In addition, numerous studies from the scientific literature that describe the pharmacodynamic and pharmacokinetic profile of tefluthrin and the pyrethroids in general have been considered in this assessment.

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

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

sodium channels

. Behavioral changes characteristic of Type I pyrethroids such as unsteadiness, tremors, and ataxia were observed in the guideline rat, dog

, and rabbit studies. In addition, in dermal toxicity studies, experimen tal 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 in risk assessmen t 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

exposur e. Recovery typically occurs within 24 hours without any persisting neurotoxic effects. The NOAELs and LOAELs for neurotoxicity established from results of experimental toxicity

studies with tefluthrin are remarkably consistent across durations of exposu re, 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 timeRevised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 6 of 43 to peak and effect and recovery). Thus, fo r purposes of endpoint selection and exposure assessment, only single day risk assessments need to be conducted.

Evidence of increased qualitative or quantitative susceptibility of the offspring was not observed in any of the available animal testing guid eline 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 Pharmacokinetic ( PBPK ) model predictions of a 3

- fold increase of pyrethroid concentration in juvenile brain compared to adults; 2) in vitro pharmacodynamic ( PD ) data and in vivo data indicating similar responses between adult and juvenile rats at low doses; and 3) data indicati ng 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 b ased 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 FQP A, 10X interspecies extrapolation, 10X intraspecies variability). Quantification of dermal risks f or the microencapsulated and granular formulations was performed using the chronic dog study with a NOAEL of 0.5 mg/kg/day based

on tremors (LOAEL = 2.0 mg/k g/day)

. In addition

, a formulation specific dermal absorption

value of 0. 79 % was used for the microencapsulated formulations while a default pyrethroid dermal absorption value of 5.0% was for the granular formulations

. Quantification of

inhalation risk s was performed 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 ) . A MOE of 100 is required for dermal exposure for adults which includes interspecies extrapolation (10X) and intraspecies variability (10X) and a MOE of 3 0 is required for inhalation exposure for adults which includes interspecies extrapolatio n ( 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 : Qualitative nature of the residue of tefluthrin in plants is adequately understood. The residues of concern are the parent and the free acid PP 890. Metabolism studies in animals identified residues of the parent and metabolites in tissues, but at levels below the LOD by the enforcement method in force at that time (D208747, Garbus, J., 2/16/1995).

Dietary Exposure and Risk: D ietary exposure (food and drinking water) is expected from the currently registered uses of tefluthrin

. 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 for tefluthrin

. The acute dietar y assessments include residue and drinking water values based on the currently registered preplantRevised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 7 of 43 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 a ll population subgroups are 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 registered residential uses associated with tefluthrin; therefore, a residential/non

- occupational exposure assessment is not required.

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

equ ivalent to the acute dietary 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.

Occupationa l Exposure/Risk: There is potential for occupational handler exposures from the currently registered uses of tefluthrin. Occupational post

- application exposures from the currently registered uses of tefluthrin are expected to be negligible.

At

- plant Corn Use s : The aggregate risk index for occupational handlers for the microencapsulated suspension and granular product s do not exceed HED’s level of concern (i.e., ARIs are ≥ 1, the LOC for this assessment) with the use of gloves.

Seed Treatment Use s : The ARIs for the registered sugar beet seed treatment use for open and closed system primary handlers and secondary handl ers do not exceed HED’s level of concern (i.e., ARIs are ≥ 1, the LOC for this assessment). The ARIs for some of the assessed scenarios (e.g., loader/applicator, multiple activities, clea n ing) for the registered corn seed use for open and closed system pri mary handlers exceed HED’s level of concern (i.e., ARIs are < 1, the LOC for this assessment). The ARIs for the registered corn seed use for secondary handlers do not exceed HED’s level of concern (i.e., ARIs are ≥ 1, the LOC for this assessment)

Review of Human Research: This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies (listed in Appendix B ) have been determined to require a 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, and

has conducted a human health risk assessment in support of the proposed use. Based on this assessment, HED has determined that there are no potential risk estimates of concern for the currently registered use s of tefluthrin except for the corn seed treatment use ( labeled high rate

o nly)

.

2.1 Data Deficiencies

There are no outstanding data deficiencies for tefluthrin.Revised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 8 of 43 2.2 Tolerance Considerations

There are no tolerance considerations for associated with this assessment

. E xisting tefluthrin

tolerances are established under 40 CFR §180.440 (a) for the combined residues of tefluthrin [(2,3,5,6 tetrafluoro

- 4

- methylphenyl)methyl

- (1 alpha, 3 alpha)

- (Z)

- (±)

- 3(2

- chloro

- 3,3,3

- trifluoro

- 1

- propenyl)

- 2,2

- dimethylcyclopropanecarboxylate] and its metabolite PP 890 ( (Z)

- 3

- (2

- chloro

- 3,3,3

- trifl uroro

- 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.

3.0 Ingredient Profile

Tefluthrin is a synthetic pyrethr oid insecticide.

3.1 Structure and Nomenclature

TABLE 3.1 : Tefluthrin Nomenclature

Compound

Common name Tefluthrin

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

- trifluoro

- 1

- propenyl)

- 2,2

- dimethyl

cyclopropanecarboxylic acid

3.2 Physical/Chemical Characteristics

TABLE 2.3: Physicochemical Proper ties of the Technical Grade Tefluthrin

Parameter Value Reference* Melting point/range 44.6°C MRID # 47813007Revised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 9 of 43 TABLE 2.3: Physicochemical Proper ties of the Technical Grade Tefluthrin

Parameter Value Reference*

Ph Not available 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 # 4 7813007 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 # 4 7813007

Dissociation constant, pK

a Weak acid, pKa >9; hydrolysis prevents

measurement

. MRID # 40167301;

PP#7F3521 Octanol/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).

3.3 Summary of Currently Registered Uses

The currently registered formulations of tefluthrin include granules and a microencapsulated suspension applied at

- planting for the control of soil insect pests of corn. There are a lso microencapsulated suspension s registered for treatment of corn seed and sugar beet seed in

commercial seed treatment facilities.

3.4 Anticipated Exposure Pathways

D ietary exposure (food and drinking water) is expected from the currently registered u ses of

tefluthrin . T here is a lso potential for occupational handler exposure to the currently registered

uses. Occupational post

- application exposures from the currently registered uses of tefluthrin are expected to be negligible. There are currently no registered residential uses associated with tefluthrin and therefore residential exposures are not expected.

3.5 Consideration of Environmental Justice

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

hu man 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://w ww.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ) . As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subg roups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethn ic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments areRevised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 10 of 43 performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Respo nse Assessment

Tefluthrin is a member of the pyrethroid class of chemicals. Pyrethroids have historically been classified into two groups, Type I and Type II, based upon chemical structure and neurotoxicological effect. Type I pyrethroids, which lack an alpha

- cyano moiety, induce in rats a syndrome consisting of aggressive sparring, altered sensitivity to external stimuli, and fine tremor progressing to whole

- body tremor and prostration (T

- syndrome). Type II pyrethroids, which contain an alpha

- cyano moi ety, in rats produce a syndrome that includes pawing, burrowing, salivation, and coarse tremors leading to choreoathetosis (CS

- syndrome) ( Verschoyle and Aldridge 1980 ; Lawrence and Casida 1982 )

. Tefluthrin is a Type I synthetic pyrethroid

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

- gated sodium channels (VGSCs) in the central and peripheral nervous system, leading to changes in neuron firing, and ultima tely 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 i n Section 4.4. Despite these scientific efforts, HED is confident that it has chosen points of departure and uncertainty factors in this risk assessment which are health protective and have a strong scientific foundation.

The data from the following guid eline studies in experimental toxicology animals were used to evaluate the hazard potential of tefluthrin:

- Developmental Rat Study

- Developmental Rabbit Studies

- Reproduction Rat Study

- Cancer Mouse StudyRevised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 11 of 43 - Chronic/Cancer Rat Study

- Sub

- Chronic and C hro nic Dog Studies

- 90

- Day Rat and Mouse Study

- Acute and Subchronic Neurotoxicity Studies

- 21

- day Dermal Rat Studies

- Acute Inhalation Toxicity Study (with neurotoxicity measurements)

- Genotoxicity Studies (complete battery)

- Triple pack dermal absorption studies

- Immunotoxicity study

In addition, numerous studies from the scientific literature conducted over several decades describe the pharmacodynamic (PD) and pharmacokinetic (PK) profile of the pyrethroids in general ; this scientific literature has bee n recently reviewed by several groups ( Soderlund et. al.

2002 ; Wolansky and Harrill 2008 ; Weiner et. al. 2009 )

. Some of this literature provides specific toxicity data on tefluthrin, however much of the literature is general for the pyrethroids because of the shared toxicological properties of the members of this class of pesticides; these studies are

informative in the hazard characterization of tefluthrin.

There are no outstanding studies according to Part 158 data requirements for a food use pesticide registration. Since the May 2012 document, acute and subchro nic neurotoxicity studies have been submitted to the agency.

Prior to the submission of these studies

, 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. As a result, HASPOC concluded that the Wolansky & Nemec literatu re studies together were sufficient to evaluate motor activity and FOB such that a guideline ACN study was not needed and would not provide additional information for tefluthrin. Furthermore, the acute

duration is the focus of the tefluthrin risk assessme nt ( see Section 4.2.1) and thus a guideline SCN study was not needed.

T he toxicological database does not contain a dermal toxicity study that includes acceptable

clinical observations or FOB measurements which are important to the analysis of the pyrethr oid class. However, based on the toxicological data available for tefluthrin; the neurotoxic potential

of tefluthrin is well characterized and a n additional dermal toxicity study is not needed for tefluthrin at this time as such a study is unlikely to pro vide additional information for the

tefluthrin risk assessment.

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 nervou s 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. Other effects seenRevised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 12 of 43 in multiple studies inclu ded liver (changes in liver weights and liver enzymes) and de creases in body weight and body weight gain.

Consistent with other pyrethroids, there was a lack of sensitivity to in utero exposure

. In the prenatal developmental toxicity studies in rats and rabbits, the developmental NOAEL was greater than the maternal NOAEL . In rats, the maternal toxicity occurred at levels lower than the ossification reductions in the extremities of the fetuses. In the rabbit study, maternal toxicity was

observed at all d ose 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 signifi cantly lower doses. The doses via gavage and feed were similar.

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

classified as “not likely to be a human carcinogen

. There are two adequate rodent carcinogenicity stu dies. 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 echnical tefluthrin is acutely toxic (category I) via the oral, dermal, and inhalation routes of

expo sure . The primary dermal irritation study has a toxicity category of IV while the primary eye irritation study is classified as invalid although there are adequate studies with the

formulation available. Tefluthrin is not a dermal sensitizer

.

4.3 Pyret hroid Pharmacokinetic and Pharmacodynamic Profile

The PK of tefluthrin is similar to other pyrethroids, i.e., rapid absorption , metabolism, and clearance. Following a single oral dose to rats

, tefluthrin was excreted mainly via the feces ( 54

and 67% in f

emales 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 after the first

24 hours. Radiolabeled t efluthrin was readily detectable in the liver and kidne ys with levels being typically less than 1.0 and 0.2%, respectively, of the administered dose. Following a single oral dose to dogs

, tefluthrin was excreted mainly via the feces ( 61 and 65% in females and males, respectively ) and urine ( 26 and 23% in fema les 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 between 4 and 8 hours. Radiolabeled t efluthrin was readily detectable in the liver with

levels be ing typically less than 1.6% of the administered dose. The major routes of tefluthrin metabolism are ester cleavage and oxidation at a variety of positions on the molecule.

The extensive body of scientific literature on the pyrethroids provides insight i nto the

contributions of PK and PD to the toxicity profile of this class of chemicals . This information also provides valuable information related to the endpoints used in pyrethroid risk assessment, the duration of exposure for pyrethroid risk assessment , and the potential age

- related differences in toxicity for the pyrethroids. The following sections discuss the specific issues related to pyrethroid PK, pyrethroid PD, and age

- related differences in pyrethroid toxicity.Revised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 13 of 43 4. 3 .1 Pharmacokinetics (PK)

PK c an be defined as what the body does to the chemical; in this case, how pyrethroids are distributed and eliminated following exposure. Specific to pyrethroids, PK refers to the process(es) which determine the concentration of the pyrethroids reaching sodiu m channels. The underlying pharmacokinetics of pyrethroids is an important determina n t of their toxicity because the concentration of pyrethroid at the sodium channel relates to the extent of toxicity; greater pyrethroid concentration translates as increa sed 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 ontogen y 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 therefore do not contribute to overall toxicity.

Physiologically

- based pharmacokinetic (PBPK) model s, designed to predict pyrethroid concentration in tissues following in vivo exposure, have recently been developed by the Agency. T he Agency has determined that the important PK properties relevant for the metabolism and distribution of pyrethroids in th e 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 structu re is able to predict the tissue dose based on the pharmacokinetics of every member of the class. The family modeling approach was presented to and supported by the FIFRA SAP ( USEPA 2007 )

.

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

S everal studies in th is 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 juvenil es and adults are able to tolerate low doses of pyrethroids when the internal dose, or the amount of pyrethroid at the sodium channel, is low. However, the activity of these enzymes increases with age, conveying in adults a greater capacity to detoxify py rethroids compared to juveniles ( Anand

et. al. 2006 ; de Zwart et. al. 2008 ; Yang et. al. 2009 ) . For example, the rate of in vitro metabolism of deltamethrin by plasma carboxyesterases, hepatic carboxyesterases, and hepatic microsomes are at least 6 times higher for PND 90 rats compared to PND 10 rats ( Anand et. al.

2006 ) . As a consequence, higher internal doses (i.e., those associated with high doses in experimental toxicology studies) overwhelm the clearance mechanisms in juveniles but be cause adults have greater enzyme activity, they are able to tolerate higher doses prior to the onset of toxicity. As a matter of perspective, the anticipated exposures from typical dietary or residential activities are not expected to overwhelm the premat ure metabolic systems in juveniles.

Predictive PBPK models have recently been developed to describe the PK of a few pyrethroids ( Mirfazaelian et. al. 2006 ; Godin et. al. 2010 ) . Among these is an age

- dependent model developed by the Agency which is capable of predicting the concentration of deltamethrin in theRevised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 14 of 43 brains of rats at multiple ages ( Torner o

- 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), equi valent brain concentrations of deltamethrin would be achieved with a 3.8X fold lower oral

dose in 10

- day old rats and 2.5X lower dose in 21

- day old rats , which represents children under 6 years of age ( Tornero

- Velez et. al. 2010 ) . For example, a 1 mg/kg dose in the adult is equivalent to a 0.26 mg/kg dose (≈1 mg/kg÷3.8mg/kg) in the 10

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

- day old rat, which encompasses the younger than 6 year old age

group. The differe nce between a 3.8

- and a 2.5

- fold dose is within background variability of the

model . As a result, the Agency concludes that juvenile rats are 3x more sensitive than adults with respect to pyrethroid pharmacokinetics

.

4. 3

. 2 Pharmacodynamics (PD)

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

interact with the sodium channels. Tefluthrin was examined in several studies which provide specific information relevant to the AOP for pyrethroids

. For example, C hoi and Soderlund ( 2006 ) examined interactions of several pyrethroids with mammalian VGSCs expressed in Xenopus oocytes. With respect to altered neuronal excitability, Type I pyrethroids , like tefluthrin, cause slight prolongations of the sodium current tails (e.g. ~20 ms), often resulting in long trains of action potentials (Figure 1) . In contrast, Type II pyrethroids significantly prolong sodium current tails (e.g. 200ms to minutes) typically resulting in increased resting membrane potential a nd ultimately causing depolarization dependent action potential block.

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

current vs time traces from individual representative oocytes in the absence or presence (*) of 100 μM tefluthrin were obtained during and after 40

- ms depolarizations from 100 mV to 10 mV. Calibration bars: 20 ms for the x

- axis and 500 nAmp on the y

- axis

. Data 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 in teract with VGSC in intact mammalian neurons. An additional study by Cao et al (2011b) demonstrated that the interaction of bifenthrin with VGSCRevised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 15 of 43 caused changes in neuronal excitability that resulted in calcium influx into intact mouse neurons.

As this eff

ect 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.

HED would prefer to use an early key event in the AOP for pyrethroids in s election of points of departure. However, i n vivo techniques used to detect VGSC alteration and altered neuronal excitability are not practical for use in risk assessment at this time and approaches for extrapolating in vitro findings to in vivo measures are not yet developed. As such, the Agency is focusing its efforts for all pyrethroids in hazard characterization and identification on the apical endpoint (i.e., changes in neurobehavior in laboratory animals). Neurotoxicity resulting from pyrethroids a re 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 the specific case of tefluthrin, tremors are the most common observation throughout the database of toxicology s tudies.

In contrast to the age

- related PK differences discussed in Section 4.3.1, PD contributions to pyrethroid toxicity are not age

- dependent even though t here are several variations of sodium channels, called isoforms, which are differentially expresse d by tissue and age. Due to the nature of the interaction of pyrethroids with sodium channels, it is difficult to obtain dynamic

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

sodium channels has not been identified, making it impractical to determine the isoform combinations that are present and being acted upon by pyrethroids. Therefore, much of the information available to the Agency to characterize the PD relationship between pyrethroids and

sodium ch annels 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 d emonstrate 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 f rog oocytes to deltamethrin. The isoforms had comparable responses at environmentally relevant concentrations (<500 nM) of deltamethrin, suggesting a lack of PD difference between juveniles and adults at low exposure levels. In addition, in a direct comp arison of a homologous rat and human VGSC isoform, NaV1.3, Tan and Soderlund, ( 2009 ) found the rat isoform was 4

- fold more sensitive than the equivalent human sodium channel to the pyrethroid tefluthrin ( Tan and Soderlund 2009 )

, suggesting the rat is a highly sensitive model and extrapolations f rom 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 t he 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 pyrethroi d pharmacodynamics

.Revised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 16 of 43 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 abs orbed rapidly and neurotoxic effects including tremors and splayed gait are seen soon after exposure. Recovery typically occurs within 24 hours without any persisting neurotoxic effects. The NOAELs and LOAELs for neurotoxicity established from results of experimental toxicity studies with tefluthrin are remarkably consistent across durations of exposure, ranging from a single dose up to 2

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

above for the pyrethroids (i.e. rapid metabolism, little to no accumulation, rapid time to peak and effect and recovery). Thus, for purposes of endpoint selection and exposure assessment, only single day risk assessments need to be conducted.

Table 4.3.3 : Experiment al 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

Acute Neurotoxicity Acute, single exposure NOAEL = 5 LOAEL = 10

Sub

- chronic Neurotoxicity 90

- Day NOAEL = 13.6 LOAEL = 31.2

Inhalation rat Acu te, single exposure NOAEL = 0.54 LOAEL = 1.1

4.3

. 4 Dermal Absorption

Microencapsulated Formulations

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 s kin for the microencapsulated

formulation

. 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 si ngle 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 either 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, de rmal absorption for the in vivo study was 0.79% ( stratum corneum + application site skin + absorbed); dermal absorption for the in vitro rat skin was 0.9%; and dermal absorptionRevised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 17 of 43 for the in vitro human skin was below the level of quantitation

. It was concl uded that although human epidermis exhibits significant resistance to dermal penetration that the 24 hour dermal absorption value from the rat in vivo study of 0.79% should be used in tefluthrin risk assessment for the microencapsulated formulations (Smith ; TXR 0055257 ; 05/31/ 2012).

Granular Formulations Dermal absorption data are not available for technical tefluthrin or granular tefluthrin. For risk assessment of granular formulations, HED determined that a 5 .0 % dermal absorption factor

should be utiliz ed. This is consistent with the default pyrethroid dermal absorption factor utilized in the pyrethroid cumulative risk assessment (USEPA; 10/4/11)

. In general, pyrethroid dermal absorption e stimates based on potency comparisons between oral and dermal st udies within the same rat strain, direct measures of in vitro skin penetration ( Hughes and Edwards

2010 ) , or penetration rates based on lower dermis levels of skin that are more likely to be absorbed by the body are <5%

. HED is con fident that use of a 5 .0 % dermal absorption factor for granular tefluthrin formulations is health protective.

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

Tefluthrin exposure to children under < 6 years old is expected and it must be considered in the context of the pyrethroids as a class. The Agency will retain a 3X uncertainty factor to protect for exposures to children <6 years of age based on the increased quantitative susceptibility seen in the scientific literature related to pyrethroid pharmacokinetics. This is consistent with the Agency’s 2011 analysis and is supported by rat PBPK model predictions of a 3

- fold increase of

deltamethrin concentration s in the juvenile brain compared to adults (see Section 4.3.1). T he PK of py rethroids 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 than adults with respect t o 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 complete for this food use chemical. T here are no outstanding toxicological studies for tef luthrin according to revised 40 CFR Part 158 Toxicology Data Requirements. Since the May 2012 document, acute and subchronic neurotoxicity studies have been submitted to the agency.

Prior to the submission of these studies, HED’s HASPOC met on April 2 6, 2012 to discus s the

ACN and SCN data requirements ( Rury; TXR 0056311 ; 05/31/ 2012 ). HASPOC concluded that the available Wolansky & Nemec literature studies cover the neurobehavioral endpoints with high quality studies & a guideline ACN study was not nee ded and likely w ould not provide additional neurotoxicity information for tefluthrin. Furthermore, the acute duration is the focus of the tefluthrin risk assessment and thus a guideline SCN study was not needed.Revised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 18 of 43 4.4. 2 Evidence of Neurotoxicity

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

. Tefluthrin , like other pyrethroids, causes neurotoxicity from interaction with sodium channels leading to clinical signs of neurotoxicity. Neurotoxicity was consistently observed throughout

the database in a dose

- dependent manner in most all of the studies conducted. Signs of neurotoxicity included tremors, ataxia

, gait abnormalities, and spine curvature among others.

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 includin g the following: The Agency has no residual uncertainties regarding age related sensitivities for women of child bearing age as well as for all adult populations and children > 6 years of age, based on the absence of pre

- natal sensitivity observed in 76 gu ideline studies for 24 pyrethroids, the scientific literature, and the tefluthrin 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 these studies.

N o evidence of increased quantitative or qualitative susceptibility was seen in the pyrethroid scientific literature related to pharmacodynamics. The Agency will retain a 3X uncertainty factor to protect for exposures to children <6 years of age based on the increased quantitative susceptibility seen in the scientific literature related to pyrethroid pharmacokinetics.

More d etails regarding the Agency’s findings are outl ined 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 pyrethroi d 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 fo r the Advancement of Pyrethroid Human Risk Assessment (CAPHRA) and plan on 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 da ta become available, the Agency will

determine whether re

- evaluation of the age

- related sensitivity of pyrethroids is appropriate.

1 http://www.epa.gov/scipoly/sap/meetings/2010/072310meeting.htmlRevised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 19 of 43 4.4. 4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties that impact the risk estimates pre sented in this assessment in the exposure databa se.

The acute dietary assessment 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 all commodities. The DEEM analysis also assumed that all drinking water will contain tefluthrin at the highest acute estimated drinking water concentration (EDWC) levels modeled by EF ED for ground water or surface water. For these reasons it can be concluded that the DEEM

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

Similarly, HED does not believe that the non

- dietary occupational exposure s are underes timated 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 Table A.1.1 of Appendix A1.

Acute Dietary : HED considered the subchronic dog, the chronic dog , acute rat neurotoxicity,

and the acute rat Wolansky study for use in selection of the teflu thrin acute dietary endpoint. The subchronic dog study was not selected even though it had similar LOAELs and NOAELs as the chronic dog and Wolansky studies as the LOAEL in the study was not based on neurotoxicity ( NOAEL = 0.5 mg/kg/day and LOAEL = 1.5 mg /kg/day based on thyroid changes, increased plasma triglycerides and aspartate transaminase). The LOAELs and NOAELs for the chronic dog and Wolansky studies are very similar (Wolansky BMDL is 2.8 mg/kg/day and BMD is 3.67 mg/kg/day while chronic dog LOAEL is 2.0 mg/kg/day and NOAEL is 0.5 mg/kg/day). Clinical signs of neurotoxicity were seen in both of these studies with decreased motor activity seen in the Wolansky study and tremors seen in the chronic dog study. Ultimately, HED selected the chronic dog study for selecting the acute dietary endpoint for tefluthrin based on the following reasons: 1) neurotoxicity (tremors) was identified in the chronic dog study throughout the first

few weeks of treatment ; 2) the chronic dog study has a slightly lower LOA EL than the Wolansky rat study; 3) the dog appears to be the most sensitive species in the tefluthrin toxicological database, particularly when allometric scaling is considered (see Appendix Table A.4); 4) the effects seen in the chronic dog study were con sistent with the neurotoxic effects seen in other tefluthrin toxicity studies; and 5) the effects seen in the chronic dog study are consistent with effects seen for other Type I pyrethroids.

The acute 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).Revised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 20 of 43 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 : Although two route

- specific 21

- day rat dermal studies are available for tefluthrin; these studies were not used as the basis for the tefluthrin dermal endpoint as they d o not contain FOB measurements that are important to the pyrethroid class (see Section 4.1).

Quantification of dermal risks f or the microencapsulated formulations was performed using a chronic dog study (NOAEL of 0.5 mg/kg/day based on increased incidenc e of tremors in the dog (both sexes) with a LOAEL of 2.0 mg/kg/day) with a formulation specific dermal absorption

value of 0. 79 %. This is the most appropriate study with regards to what occupational workers will be exposed to in the field for the microenc apsulated formulations.

Quantification of dermal risks f or the granular formulation 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 defau lt pyrethroid dermal absorption value of 5.0 %.

This is the most appropriate study with regards to what occupational workers will be exposed to in the field for granular applications.

A MOE of 100 is required for dermal exposure for adults which includes interspecies extrapolation (10X) and intraspecies variability (10X). There are no registered or proposed residential uses for tefluthrin and thus dermal exposures to children are not expected.

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 w as performed 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 int raspecies 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 Recommendat ion for Combining Routes of Exposure for Risk Assessment

HED combines risk values resulting from separate exposure pathways when it is likely they can occur simultaneously based on the use pattern

, the behavior associated with the exposed 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 effects and thus it is appropriate to combine d ermal and inhalation exposures for occupational wo rkers to estimate an

overall MOE

.Revised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 21 of 43 4.5.3 Cancer Classification and Risk Assessment Recommendations

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

classified as “not likely to be a human carcinogen”

. There are two adequate rodent carcinogenicity studies available for tefluthrin

.

The CARC did not consider the uterine tumors seen in female rats to be treatment

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

were n o 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

- neoplast ic lesions. There was no evidence of carcinogenicity in male rats. The dose levels tested were adequate to assess the carcinogenicity of tefluthrin in rats based on the clinical signs of neurotoxicity and changes in the body weight/body weight gains observ ed at the high dose in both sexes.

The CARC did not consider the pitu it 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 and/or car cinomas, 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 signifi cant trend in pituitary gland pars intermedia combined adenomas and/or carcinomas at p < 0.01. There was a statistically significant pair

- wise comparison of the 400 ppm dose group with the controls for pituitary gland pars intermedia combined adenomas and /or carcinomas at p <

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

were no corroborative non

- neoplastic lesions. The dose levels tested were adequate to assess the carcinogenicity of tefluthrin in mice ba sed 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.Revised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 22 of 43 4.5.4 Summary of Points of Departure and Toxicity En dpoints Used in Human Risk

Asse ssment

Table 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, including

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 40141308

LOA EL = 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 : Microencapsulated

formulations = 0. 79 %

Granular

formulations = 5.0% 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)

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,

derm al, inhalation) Tefluthrin is classified as “not likely to be a human carcinogen”

NOAEL = no observed 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 P rofile

The q ualitative 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, b ut at levels below the LOD by the enforcement method in force at that time (D208747, Garbus, J., 2/16/1995).

There are a number of field trial studies that were conducted for examining the tefluthrin residues resulting from the currently registered prepl ant 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 itsRevised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 23 of 43 metabolite (PP 890) were <LOQ for bo th analytes in/on corn forage, K+CWHR, grain, and stover. Based on this data, an LOQ tolerance of 0.06 ppm (for tefluthrin + PP 890) was established for field corn (forage, grain and stover), pop corn (grain and stover), and sweet corn (forage, kernel plu s cob with husks removed, and stover).

A sugar beet metabolism study is also available for tefluthrin

. Total radioactive residues were <0.003 ppm in sugar beet roots and tops grown from seeds treated with tefluthrin at 0.08 or 0.15 mg ai/seed (roughly 1X and 2X the maximum proposed use rate). As a result, the sugar beet

seed was classified as a nonfood use.

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 Con centrations in Ground Water (SCI

- GROW) in estimating the residue of the tefluthrin in drinking water . The EFED water assessment was performed for the parent compound only.

A PRZM/EXAMS exposure assessment was performed for the t efluthrin preplant corn us e usin g the Pennsylvania corn (PA Corn) standard modeling scenario. The PA Corn scenario was chosen because the amount of soil erosion predicted in that scenario is most realistic for a pesticide like

t efluthrin that moves to surface water bound to eroding soil. The percent cropped area (PCA) value for field corn (0.46) was applied to each of the concentration values predicted by the

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

Table 5. 2

.

Table 5.2 : Maximum Tier 2 E stimated Drinking Water Concentrations (EDWCs) for drinking water risk assessment based on ground application of tefluthrin on corn

USE (rate modeled) DRINKING WATER SOURCE (MODEL USED) MAXIMUM ESTIMATED DRINKING WATER CONCENTRATION (EDWC) ( ppt)

Corn (0.165 lb. a.i./A, one application at plant) Groundwater (SCI

- GROW) Acute and Chronic 1.0

Surface Water (PRZM/ EXAMS) Acute 259

Non

- cancer Chronic 8.74

Cancer Chronic 6.06

5. 3 Dietary Risk Assessment

5.3.1 Acute Dietary Risk Assessment

An u nref ined acute 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 for 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 sRevised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 24 of 43 show that the acute dietary risk for the g eneral 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. populat ion and 28 % of the aPAD for all

- infants (<1year old), the most highly exposed population subgroup

.

The acute dietary risk assessment for food only was estimated to be <1% of the aPAD for the general U.S. population and 27% of the aPAD for all infants <1 year old.

5.3.2 Chronic Dietary Risk Assessment

Chronic dietary risk assessments were not conducted for tefluthrin. The acute dietary assessment should be considered protective of chronic dietary exposure s based on the lack of progression of

effects in longer

- term bifenthrin toxicity studies (see Section 4.3.3)

5.3.3 Cancer Dietary Risk Assessment

Cancer dietary risk assessments were not conducted for tefluthrin as tefluthrin has been classified as “not likely to be a human carcinogen” (see Section 4. 5.3).

5.4. Dietary Risk Assessment Summary Table

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

Risk for Tefluthrin

Population Subgroup Acute Dietary (95th Percentile) Dietary Exposure (mg/kg/day) % aPAD

General U.S. Population 0.000206 0.41
All Infants (< 1 year old) 0.000471 28

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 o ld 0.000095 <1%

Females 13

- 49 years old 0.000158 <1%

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

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

residential/non

- occupational exposure assessm ent is not required.

7.0 Aggregate Exposure/Risk Characterization

The acute aggregate risk estimates associated with exposure to tefluthrin are equivalent to the acute dietary risk estimates and do not exceed the Agency’s level of concern (see Section 5.3.1)

.Revised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 25 of 43 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 chemicals 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 exposure to pyrethroids, refer to http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids

- pyrethrins.html

.

9.0 Occupational Exposure/Risk Characterization

Based on the currently registered tefluthrin uses , 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.Revised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 26 of 43 9.1 Occupational Handler Exposure a nd Risk

9.1.1 Handler Risk for the Currently Registered 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 expect s 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 policy of HED to use the best available data to assess handler exposure. Sources of generic occupational handler data, used as surrogate data in the absence of chemical

- specific data, include the Pesticide Handlers Exposure 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 hand ler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf), which, along with

addit ional 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

da ta.html

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

There is potential for short

- or intermediate

- term h andler exposure s for tefluthrin. However, the available toxicological data supports the co nclusion 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 suspens ion and granular product s do not exceed HED’s level of concern (i.e., ARIs are ≥ 1, the LOC for this assessment) with the use of gloves.Revised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 27 of 43 Table 9 .1.1. Occupational Handler Exposures and Risks for Tefluthrin At

- plant Corn Uses a

Exposure Scenario Appl ication

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

I nhalation 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

Draw n Spreader Applications

on At

- plant

Corn 0.165 200 0.00 014 0.00 007 0.00 018 0.0007 0.000035 3500 7100 2800 7 7 0 1 6 ,000 15 19 27

Applying Applying Liquid Sprays via

Groun d boom 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 0.00 02 0.00 008 7 0.000 041 0.0005 0.000018 3 400 5800 120 00 1,100 6,000 17 22 75

a. Unit Exposures taken from Occupational Pesticide Handler Unit Exposure Sur rogate 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 o n 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 (0.79% or 5.0% depending on formul ation) / 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 ( 0.5 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)Revised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 28 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 i s 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 durati on based on information provided on the proposed label. However, the available toxicological data supports the conclusion that neurotoxicity from tefluthrin and pyrethroids in general is associated with acute, peak exposures (i.e., every day is a new day) . As such, only single day dermal risks were

assessed.

Primary Handler (Treating Seed )

Potential primary occupational handler exposure scenarios from the use of tefluthrin as a commercial seed treatment include: Mixing, loading, applying liquid formulat ions; Bagging treated seed; Sewing bags; Cleaning equipment; Forklift driving; and Multiple activities.

Typically, for large

- scale commercial seed treatments, workers perform only those specific individual tasks listed above; however, it is assumed that workers also may perform multiple activities throughout the day. As a result a “multiple activities” scenario (i.e. where one worker performs all seed treatment tasks such as loading/applying, sewing, bagging, cleaning, calibration, repair, forklift driver, etc.) was addressed. No assessment was performed for 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 expo sure scenarios from the use of tefluthrin as a commercial seed treatment include planting treated seed.

It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data for seed treatment are incorporated in HED ExpoSAC Policy 14: SOPs for

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

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 treated in a day, and the pounds of seed that can be planted in a day, all of which vary depending upon the seed type. Values for the amount of seed treated and planted per day were obtained from a

B iological 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).Revised Tefluthrin Human Health Risk Assessment DP No. 4 15796

Page 29 of 43 Summaries of the estimated aggregate risk index for primary (open and closed seed treatment systems) and secondary handlers are included in Tables 9 .1.2a , 9 .1.2b and 9.1.2c , respectively.

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

eq ual to an ARI of 1.

Proposed Sugar Beet Seed Use : T he ARIs for the proposed sugar beet seed use for open and closed system primary handlers and secondary handlers do not exceed HED’s level of concern (i.e., ARIs are ≥ 1, the LOC for this assessment).

Existing Corn Seed Use : The ARIs for some of the assess ed 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 cor n seed use for secondary handlers do not excee d HED’s level of concern (i.e., ARIs are ≥ 1, the LOC for this assessment)

. Since that time the registrants have submitted revised labels that are currently under review by the Registration Division (RD) that require use of closed systems for treating cor n seed.Tefluthrin Human Health Risk Assessment DP No. 415796

Page 30 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

Expos ure 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 54,00 0 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 7,90 0 79,000 Base + Base = 150

Corn Seed (Field) 550,000 0.0053 2915 280 64 640 Base + 90%

- R = 2.5

0.00078 429 1,900 440 4,400 Base + Base = 8.3
Bagger Sugar Beet Seed 5500 0.0043 24 Base: 0.0091

PPE

- G: ND Base: 0.16

90%

- R: 0.016 24,000

ND ND 11, 000 110,000 Base + Base = 150

Corn Seed (Field) 550,000 0.0053 2915 190 93 930 Base + 90%

- R = 1.8

0.00078 429 1,300 630 6,300 Base + Base = 8.0 Multiple Activities Sugar Beet Seed 5500 0.0043 24 Base: ND

PPE

- G: 0.042 Base: 1.6

90%

- R: 0.16 ND 5,100

ND 1,100 11,000 PPE

- G + Base = 21

Corn Seed (Field) 550,000 0.0053 2915 41 6.3 63 PPE

- G + 90%

- R = 0.34

0.00078 429 280 63 630 PPE

- G + 90%

- R = 2.5

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

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

c Application Rates based on tefluthrin labels

. The two different corn rates reflect the two treatments described on the current corn seed treatment label.

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

e Dermal Dose (mg/kg/day) = dermal unit exposure (mg/ lb ai) x application rate (lb ai/lb seed) x amount treated (lb seed/day) x absorption factor ( 0 .79 %) / body weight (80 kg adult). Dermal MOE = NOAEL ( 0.5 mg/kg/day for short

- and intermediate

- term exposure ) / Dermal Dose (mg/kg/day). Level of concern = 100.

f Inhalation Dose (mg/kg/day) = inhalation unit exposure (mg/ lb ai) x application rate (l b 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 Aggregate Ris k Index (ARI) = 1 / (Dermal LOC/Dermal MOE) + (Inhalation LOC/Inhalation MOE)Tefluthrin Human Health Risk Assessment DP No. 415796

Page 31 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 Ap plication

Rate (AR) (lb ai/100 lb) c Amount

Handled per day (lb ai/day) Dermal Unit

Exposure d
(mg/lb ai) Inhalation

Unit d

Exposure (ug/lb ai) Dermal

MOE e Inhalation

MOE f ARI g

Treater (loader/applicator) Sugar Beet 5,500 0.43 24 0.0011 0.11

0.11

0.11 190000 17,000 436

Corn Seed (Field) 550,000 0.53 2915 0.0011 1600 130 3.4
550,000 0.078 429 0.0011 11000 920 24.0

Sewer/bagger/stacker (tyvek coveralls) Sugar Beet 5,500 0.43 24 0.0042 0.064

0.064

0.064 51000 29,000 334

Corn Seed (Field) 550,000 0 .53 2915 0.0042 410 230 2.7
550,000 0.078 429 0.0042 2800 1,600 18.4

Sewer/bagger/stacker (cotton coveralls) Sugar Beet 5,500 0.43 24 0.00037 0.064

0.064

0.064 580000 29,000 829

Corn Seed (Field) 550,000 0.53 2915 0.00037 4700 230 7
550,000 0.078 429 0.00037 32000 1,600 46

Cleaner Sugar Beet 5,500 0.43 24 0.00027 0.523

0.523

0.523 790000 3,500 115

Corn Seed (Field) 550,000 0.53 2915 0.00027 6400 28 0.92
550,000 0.078 429 0.00027 44000 190 6.24

Forklift Sugar Beet 5,500 0.43 24 0.000145 0 .010

0.010

0.010 1500000 180,000 4286

Corn Seed (Field) 550,000 0.53 2915 0.000145 12000 1,500 35
550,000 0.078 429 0.000145 81000 10,000 236

a Value for lb sugar beet seed treated per day taken from information provided by Industry on treatment of v egetable 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 cl osed 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 trea ted (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 = 1000.

f Inhalation Dose (mg/kg/day) = inhalation unit e xposure (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. 415796

Page 32 of 43 Table 9 .1.2 c : Summary of Secondary Handler (Planter) Exposures and Risks for Tefluthrin

Crop Application

Rate a (lb ai/lb seed) Seed s/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 1 04544 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 and Economic A nalysis Division memo entitled, “ Acres Planted per Day and Seeding Rates of Crops Grown in the United States” ( J. Becker and S. Ratnayake; 3/24/11). c Amount Handled per Day = Application Rate (lb ai/seed) * lbs seed/acre * 80 acres (sugar beet) or 200 ac res (field corn)

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

e Dermal Dose (mg/kg/day) = dermal unit exposure (mg/ lb ai) x application rate (lb ai/lb seed) x amount treated (lb seed/day) x absorption factor ( 0.79 %) / body weight ( 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/day) = inhala tion 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 ) / Inhalation 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. 415796

Page 33 of 43 9.2 Occupational Post

- Application Exposure and Risk

9.2.1 Occupational Post

- Application Risk for the Existing At

- plant 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 assessmen t 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 ustained 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

con tact 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. 415796

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- gated sodium channels differ in inactivation properties and sensitivity to the pyrethroid insecticide tefluthrin." NeuroToxicology 30(1): 81

- 89.

Tornero

- Velez, R., A. Mirfazaelian, K.

- B. Kim, S. S. Ana nd, H. J. Kim, W. T. Haines, B. James V and J. W. Fisher (2010). "Evaluation of deltamethrin kinetics and dosimetry in the maturing rat using a PBPK model." Toxicol Appl Pharmacol 244: 208

- 217.

USEPA (2007). "Meeting Minutes: FIFRA SAP Meeting on Assessi ng Approaches for the Development of PBPK Models of Pyrethroid Pesticides. Document ID: EPA

- HQ

- OPP

2007

- 0388

- 0049. www.regulations.gov. "

USEPA (2011a). "Pyrethroid Cumulative Risk Assessment, D394567, 10/04/11."

USEPA (2011b). Reevaluation of the FQPA Safety Factor for Pyrethroid Pesticides, D381210,

6/27/11.

Verschoyle, R. D. and W. N. Aldridge (1980). "Structure

- activity relationships of some pyrethroids in rats." Arch Toxicol 45(4): 325

- 329.

Weiner, M. L., M. Nemec, L. Sheets, D. Sargent and C. Breckenridge (2009). "Comparative functional observational battery study of twelve commercial pyrethroid insecticides in male rats following acute oral exposure." Neurotoxicology 30 Suppl 1: S1

- 16.

Wolansky, M. J. an d J. A. Harrill (2008). "Neurobehavioral toxicology of pyrethroid insecticides

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

- 78.

Yang, D., R. E. Pearce, X. Wang, R. Gaedigk, Y.

- J. Y. Wan and B. Yan (2009). "Human carboxyle sterases HCE1 and HCE2: Ontogenic expression, inter

- individual variabilityTefluthrin Human Health Risk Assessment DP No. 415796

Page 36 of 43 and differential hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin." Biochemical Pharmacology 77(2): 238

- 247.Tefluthrin Human Health Risk Assessment DP No. 415796

Page 37 of 43 Appendix A: Tef

luthrin Toxicity Profiles

A.1 Toxicol ogy Data Requirements

Guideline Number and Toxicity Study Required Satisfied

870.1100 Acute Oral Toxicity

................................ ................................ 870.1200 Acute Dermal Toxicity

................................ ........................... 870.1300 Acute Inhalation Toxicity

................................ ....................... 870.2400 Primary Eye Irritation

................................ ............................. 870.2500 Primary Dermal Irritation

................................ ....................... 870.26 00 Dermal Sensitization

................................ .............................. yes
yes
yes
yes
yes
yes yes

yes
yes
yes
yes
yes

870.3100 Oral Sub

- chronic (Rodent)

................................ ..................... 870.3150 Oral Sub

- chronic (Non

- Rodent)

................................ ............. 870.3200 21

- Day Dermal

................................ ................................ ....... 870.3250 90

- Day Dermal

................................ ................................ ....... 870.3465 90 /28

- Day Inhalation

................................ .............................. yes

yes

yes

no

yes yes

yes
yes

no
yes

870.3700 Developmental Toxicity (Rodent)

................................ ......... 870.3700 Developmental Toxicity (Non

- rodent)

................................ ... 870.3800 Reproduction

................................ ................................ .......... yes
yes
yes yes

yes
yes

870.4100 Chronic Toxicity (Rodent)

................................ ..................... 870.4100 Chronic Toxicity (Non

- rodent)

................................ ............... 870.4200 Oncogenicity (Rat)

................................ ................................ . 870.4200 Oncogenicity (Mouse)

................................ ............................ 870.4300 Chronic/Oncogenicity

................................ ............................ yes

yes

yes

yes

yes yes

yes
yes
yes
yes

870.5100 Mutagenicity : Gene Mutation

- bacterial

................................ 870.5300 Mutagenicity : Gene Mutation

- mammalian

........................... 870.5375 Mutagenicity : Structural Chromosom al 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 Delayed Neurotox ici ty (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
yes

no

870.7485 General Metabolism

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

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

yes yes

yes

yes

-- Not applicableTefluthrin Human Health Risk Assessment DP No. 415796

Page 38 of 43 Appendix A.2. Toxicity Profiles

Table A.1.1: Tefluthrin Toxicology Profile

Typ e 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 00156756 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 available

870.2500 Primary dermal irritation,

Rab bit 00156757 Acceptable Slightly irritating
Toxicity Category IV

870.2600 Dermal sensitization, Guinea Pig 00156758

Acceptable Not a sensitizer

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,

decrease d platelet counts and increased WBC and lymphocytes (high dose); LOAEL <= 1.25 mg/kg/day based on increased liver weights and changes in hematology and clinical chemistry

parameters.

870.3100 90

- Day oral toxicity (rat) Administered for 90 days (13 weeks) 0, 50, 150, or 350 ppm (calculated to be 0, 2.5, 7.5, 17.5 mg/kg/day) 40141304 Unacceptable/ Guideline, needs

additional data submitted to the Agency Systemic Toxicity NOAEL = 2.5 mg/kg/day (M/F) Systemic Toxicity LOAEL = 7.5 mg/kg/day (M/F) based on chang es 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/

Non

- G uideline 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)

870.3100 90

- Day oral toxicity (dog)

0, 0.1, 0.5 or 1.5 mg/kg/day in capsules 40141305 Acceptable/

Guideline Systemic Toxicity NOAEL = 0.5 mg/kg/day (M/F) Systemic Toxicity LOAEL = 1.5 mg/kg based on thyroid changes, increased plasma triglycerides and aspartate transaminase.Tefluthrin Human Health Risk Assessment DP No. 415796

Page 39 of 43 Table A.1.1: Tefluthrin Toxicology Profile

Typ e of Study/Guideline Study Title MRID Results

870.3200 21

- Day dermal toxicity (rat)

0, 1.0, 5.0 or 50.0 mg/kg/day 40141306 (1985) Acceptable/

Non

- Guideline D ermal Toxicity NOAEL = 1 .0 mg/kg/day Dermal Toxicity LOAEL = 5 .0 mg/kg/day based decreased albumin, triglyceride, and total proteins.

Note: C linical observations were not considered

in the NOAEL and LOAEL statements as these measurements were not properly conducted and considered unacceptable for risk assessment use.

870.3200 21

- Day dermal toxicity (rat)

0, 0.1, 1.0 or 50.0 mg/kg/day 41080002 (1989) Acceptable/

Non

- Guideline Dermal Toxicity NOAEL = 1.0 mg/kg/day Dermal Toxicity LOAEL = 50 .0 mg/kg/day

ba sed on decreased triglycerides and creatinine,

Note: C linical observations were not considered

in the NOAEL and LOAEL statements as these measurements were not properly conducted and considered unacceptable for risk assessment use.

870.3700 Prenatal dev elopmental in (rat)

0, 1, 3 or 5 mg/kg in corn oil by gavage on gestation days 7 through 16, inclusive.

A 7.5 mg/kg/day dose group was included; however 7/18 dams died between gestation days 9

- 14. 40141309
Acceptable/

Guideline Maternal Systemic Toxicity N OAEL = 3 mg/kg/day Maternal Systemic Toxicity LOAEL = 5 mg/kg/day based on treatment related decrease in body weight gains. Developmental Toxicity NOAEL = 3 mg/kg/day Developmental Toxicity LOAEL = 5 mg/kg/day

based on “inhibited” ossification.

870.3700 Prenatal developmental in (rabbit)

0, 3, 6 or 12 mg/kg in corn oil by gavage on gestation days 7 through 19 inclusive 40141310 Acceptable/

Guideline Maternal Systemic Toxicity NOAEL < 3 mg/kg/day Maternal Systemic Toxicity LOAEL <= 3 mg/kg/day based on tre atment related clinical sign of toxicity (tremors). Developmental Toxicity NOAEL => 12 mg/kg/day Developmental Toxicity LOAEL > 12 mg/kg/day.

870.3800 Reproduction and fertility effects (rat)

0, 1, 5 or 25 ppm 40141311 Acceptable/

Guideline Parental Syst emic Toxicity NOAEL = 2.5 mg/kg/day. Parental Systemic LOAEL = 12.5 mg/kg/day based on decreased body weight gains and abnormal, splayed, or high

- stepping gait. Reproductive Toxicity NOAEL => 25 mg/kg/day. Reproductive Toxicity LOAEL > 25 mg/kg/day. Offsp ring/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)Tefluthrin Human Health Risk Assessment DP No. 415796

Page 40 of 43 Table A.1.1: Tefluthrin Toxicology Profile

Typ e of Study/Guideline Study Title MRID Results

870.4100 Chronic Toxicity (Dog)

– 1

Year

0, 0.1, 0.5, or 2 mg/kg/day in corn oil by capsule 4011308 Acceptable/

Guideline Systemic Toxicity NOAEL = 0.5 mg/kg

Systemic Toxicity LOAEL = 2.0 mg/kg based on

increased incidence of tremors

870.4200 Carcinogenicity (mouse)

- 18 Months

0, 25, 100 or 400 ppm (calculated to be 0, 3.4, 13.5, 54.4 mg/kg/day 40161106 Acceptable/

Guideline Systemic Toxicity NOAEL = 3.4 mg/kg/day. Systemic Toxicity LOAEL = 13.5 mg/kg/day in females based on hemangiomatous changes of

the uterus and liver necrosis Neoplastic ch anges seen: significant positive trends along with Harderian (accessory) gland adenomas, pituitary gland adenomas in the males

and adenomas and carcinomas in females.

870.4300 Combined Chronic Toxicity/Carcinogenicity (rat)

– 2 Years

0, 25, 100 or 400 ppm

(calculated to be 0, 1.1, 4.6, 18.2 mg/kg/day) 40141307 Acceptable/

Guideline Systemic Toxicity NOAEL = 1.1 mg/kg/day. Systemic Toxicity LOAEL = 4.6 (M/F) mg/kg/day based on decreased body weights and neurotoxicity and clinical chemistry changes. No evidence of carcinogenicity.

Open Lit Neurotoxicity

six dose levels ranging from 0.03 to 10 mg/kg in adult rats Wolansky and Harrill (2008 ) The BMDL and BMD were 2.8 mg/kg and 3.67 mg/kg, respectively, based on reduced motor activity in rats.

Open Lit Neurotoxicity

Two dose levels 10 and 15 mg/kg in adult rats Weiner et. al. (2009 ) The BMDL and BMD were 4.4 mg/kg and 10.7 mg/kg, respectively, based on F OB.

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

Accept able 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

87 0.6100 Acute Delayed Neurotoxicity

- hen 40112402

Acceptable Negative for delayed neurotoxicityTefluthrin Human Health Risk Assessment DP No. 415796

Page 41 of 43 Table A.1.1: Tefluthrin Toxicology Profile

Typ e of Study/Guideline Study Title MRID Results

870.6200a Acute Neurotoxicity 49037002

Acceptable/Guideline NOAEL = 5 mg/kg/day. LOAEL = 10 mg/kg/day based on significantly decreased landing foot splay in bo th sexes, tremors (2/10, males only), and ataxia (m: 4/10, F: 2/10).

870.6200b Subchronic Neurotoxicity 49037003

Acceptable/Guideline NOAEL = 13.6 mg/kg/day. LOAEL = 31.2 mg/kg/day based on reduced body weights, increased landing footsplay, and

clinical signs including: increased activity (10/12), increased breathing rates (5/12), slight to moderate reduced splay reflex (11/12), and slight to moderate upward curvature of the spine (10/12).

870.7485 Metabolism and Pharmacokinetics (rat)

single oral gavag e 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 the

urine. Metabolites were identified.

870.7600 Dermal absorp tion

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 4 8756301 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. 415796

Page 42 of 43 Appendix A.4. Pyrethroid Human Equivalent (dog study vs. acute rat motor activity)

RAT (Wolansk y) 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 1.19193 3 0.9012176 2.2 4.2 1.352533936 2.58211

bioallethrin 65.6 42.2 19.07093 12.268189

cyhalothrin 0.92 0.64 0.267458 0.1860578 1 2.5 0.614788153 1.53697

cyphenothrin 12.5 37.5 7.684851912 23.05456

cypermethrin 11.19 7.16 3.253105 2.081522 12.5 37. 5 7.684851912 23.05456

deltamethrin 2.48 1.49 0.720974 0.4331659 1 2.5 0.614788153 1.53697

esfenvalerate 1.19 0.65 0.345951 0.188965 5 7.5 3.073940765 4.610911

fenpropathrin 6.44 5.01 1.872207 1.456484

permethrin 63.1 44.4 18.34414 12.907762 50 50 0 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. 415796

Page 43 of 43 Appendix B: Review of Human Research

This risk assessment relies in p art on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies, which comprise the Seed

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

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

been determined to be ethical.