\* MERGEFORMAT
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460

                                                      OFFICE OF CHEMICAL SAFETY
                                                       AND POLLUTION PREVENTION

MEMORANDUM

DATE:  8/27/2012

SUBJECT:	Bifenthrin:  Human Health Risk Assessment to Support Section 3 New Uses for a Bed Bug Treatment, Grass Grown for Seed, Tolerances for Imported Tea, and a Section 18 Emergency Exemption Use on Apple, Nectarine, and Peach

PC Code:  128825
DP Barcode:  D372550
MRID No.:  Not Applicable
Registration No.:  279-3313, 279-3108
Petition No.:  9E7652
Regulatory Action:  Section 3 and 18 Registrations
Assessment Type:  Single Chemical Aggregate
Reregistration Case No.:  Not Applicable
TXR No.:  Not Applicable
CAS No.:  82657-04-3

FROM:	Wade Britton, MPH, Risk Assessor
		William Irwin, PhD, DABT, Toxicologist
		Ana Rivera-Lupiáñez, Chemist
		Pete Savoia, Chemist
		Seyed Tadayon, Chemist
		Risk Assessment Branch V
		Health Effects Division (HED; 7509P)

THROUGH:	Michael Metzger, Branch Chief
		And
		Donna S. Davis, Chemist
		William Donovan, Ph.D., Chemist
		Risk Assessment Branch V/ VII
		Health Effects Division (7509P)

TO:		Laura Nollen, Biologist
		And
		Barbara Madden, Team Leader
		Risk Integration Minor Use, and Emergency Response Branch
		Registration Division (7505P)

		Bewanda Alexander, Risk Manager
		And
		Richard Gebken, PM 10
		Insecticide Branch
		Registration Branch (7505P)

		Jennifer Urbanksi, PhD, Biologist
		And
		Venus Eagle, PM 1
		Insecticide-Rodenticide Branch
		Registration Division (7505P)

Table of Contents
1.0	Executive Summary	6
2.0	HED Recommendations	10
2.1	Data Deficiencies	10
2.2	Tolerance Considerations	11
2.2.1	Enforcement Analytical Method	11
2.2.2	International Harmonization	11
2.2.3	Recommended Tolerances	11
2.2.4 Revision to Petitioned-for Tolerances	12
2.3	Label Recommendations	12
3.0	Introduction	12
3.1	Chemical Identity	12
3.2	Physical/Chemical Characteristics	13
3.3	Pesticide Use Pattern	13
3.4	Anticipated Exposure Pathways	15
3.5	Consideration of Environmental Justice	15
4.0	Hazard Characterization and Dose-Response Assessment	16
4.1	Toxicology Studies Available for Analysis	17
4.2	Bifenthrin Toxicological Profile	18
4.3	Pyrethroid Pharmacokinetic and Pharmacodynamic Profile	21
4.3.1	Pharmacokinetics	21
4.3.2	Pharmacodynamics	23
4.3.3	Critical Duration of Exposure	25
4.4	Safety Factor for Infants and Children (FQPA Safety Factor)	26
4.4.1	Completeness of the Toxicology Database	27
4.4.2	Evidence of Neurotoxicity	29
4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	29
4.4.4	Residual Uncertainty in the Exposure Database	30
4.5	Toxicity Endpoint and Point of Departure Selections	31
4.5.1	Dose-Response Assessment	31
4.5.2	Recommendation for Combining Routes of Exposure for Risk Assessment	33
4.5.3	Cancer Classification and Risk Assessment Recommendations	33
4.5.4	Points of Departure and Toxicity Endpoints Used in Human Risk Assessment	34
5.0	Dietary Exposure and Risk Assessment	35
5.1	Metabolite/Degradate Residue Profile	35
5.1.1	Plant and Livestock Metabolism Studies	35
5.1.2	Summary of Environmental Degradation	35
5.1.3	Comparison of Metabolic Pathways	36
5.1.4	Residues of Concern Summary and Rationale	36
5.2	Food Residue Profile	37
5.3	Water Residue Profile	37
5.4	Dietary Risk Assessment	38
5.4.1	Description of Residue Data Used in Dietary Assessment	38
5.4.2	Percent Crop Treated Used in Dietary Assessment	39
5.4.3	Acute Dietary Risk Assessment	40
5.4.5	Average Dietary Exposure	41
5.4.6	Summary Table	41
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	42
6.1	Residential Handler Exposure	43
6.2	Residential Post-Application Exposure	44
6.3	Combined Exposure	44
6.4	Residential Bystander Post-application Inhalation Exposure	46
7.0	Aggregate Exposure/Risk Characterization	46
7.1	Acute Aggregate Risk	47
7.2	Short-Term Aggregate Risk	47
7.3	Intermediate-Term/Chronic Aggregate Risk	48
8.0	Cumulative Exposure/Risk Characterization	49
9.0	Occupational Exposure/Risk Characterization	49
9.1	Occupational Short -Term Handler Exposure/Risk	49
9.2	Occupational Short-Term Post-Application Exposure/Risk	55
9.2.2	Inhalation Post-application Risk	56
10.0	References	57
Appendix A.  Toxicology Profile and Endpoint Selection	62
A.1	Toxicology Data Requirements	62
A.2	Toxicity Profiles	63
A.3  Hazard Identification and Endpoint Selection	71
A.3.1	Acute Reference Dose (aRfD, including General Population and Females 13-49), Acute Population Adjusted Dose, & Incidental Oral Exposure	72
A.3.2	Chronic Reference Dose (cRfD)	73
A.3.3	Dermal Exposure (Short-Term)	74
A.3.4	Inhalation Exposure (Short-Term)	74
Appendix B.  Review of Human Research	75
Appendix C.  Residential Exposure/Risk Summary Table	75
Appendix E:  Bifenthrin BMD Analysis for the 21-Day Dermal Study	82

1.0	Executive Summary

Interregional Research Project No. 4 (IR-4) has requested a Section 3 registration of a new use on grass grown for seed and a tolerance (with no US registrations) for imported tea.  In addition, a Section 18 emergency exemption for the control of Brown Marmorated Stink Bug in apple, nectarine, and peach crops was requested for use by the following seven eastern states:  Delaware, Maryland, North Carolina, New Jersey, Pennsylvania, Virginia, and West Virginia.  The Section 18 inquiry was communicated informally by the states to the Registration Division (RD) in an effort to identify an effective means to control the insect.  HED has assessed the proposed uses and Section 18 inquiry and this document presents the findings and an assessment of human health risk.

Bifenthrin (2-methyl[1,1'-biphenyl]-3-yl)methyl-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropane-carboxylate) is an insecticide and miticide in the class of pyrethroids.  The mode of action for bifenthrin and other pyrethroids is the delay of inactivation of affected voltage gated sodium channels (VGSCs), allowing for an increase in sodium ion influx and resulting in delayed repolarization and, ultimately, insect paralysis.  Bifenthrin is registered for use on a wide variety of agricultural crops, as well as indoor and outdoor residential uses to control insect pests.

Hazard Assessment: Pyrethroids have historically been classified into two groups, Type I and Type II, based upon chemical structure and toxicological effects.  Bifenthrin is a Type I synthetic pyrethroid.  Behavioral changes characteristic of Type I pyrethroids, such as muscle tremors, were seen in most of the bifenthrin experimental toxicology studies.  The toxicity database for bifenthrin is not complete. The database of bifenthrin experimental toxicology studies provides a robust characterization of the hazard potential for children and adults.  There are two outstanding Part 158 data requirements for bifenthrin.  An immunotoxicity study is required due to recent changes to Part 158 which impose new data requirements for pesticide registration. An acute inhalation study with acute neurotoxicity (ACN) metrics is also required to substitute for the sub-chronic inhalation study.  Numerous studies from the scientific literature that describe the pharmacodynamic and pharmacokinetic profile of the pyrethroids in general have been considered in this assessment.  In addition, there are on-going efforts to develop methods to inform the possibility of increased sensitivity of juvenile rats to pyrethroids as a class at doses near the LOAEL values.

Bifenthrin toxicity studies indicated muscle tremors, decreased locomotor activity and exaggerated hind-limb flexion.  It does not cause developmental or reproductive effects.  Bifenthrin has a low order of acute toxicity via the dermal and inhalation routes (Category III) of exposure and has moderate acute toxicity via the oral route (Category II).  It is neither an eye nor skin irritant, nor is it a dermal sensitizer.

One of the key elements in risk assessment is the appropriate integration of temporality between the exposure and hazard assessments.  Following a single oral gavage dose, bifenthrin is absorbed quickly in rats resulting in decreased motor activity and increased tremors. Toxicity is observed as quickly as 1 hour, peaks at 4 hours and motor activity started to return to normal at 7 hours, approximately following the blood pharmacokinetic (PK) profile (Wolansky, 2007).  This is generally consistent with the toxicity profiles for all the pyrethroids which are very similar and marked by rapid absorption, metabolism, and time-to-peak effect.  The NOAELs and LOAELs established from bifenthrin single dose and repeat dosing studies show that repeat exposures do not result in lower NOAELs.  Therefore, the endpoint from the acute study is protective of the endpoints from repeat dosing studies, which represent longer-term exposures.  Thus, for purposes of endpoint selection and exposure assessment, only single-day risk assessments need to be conducted.

Given different levels of uncertainty for various risk assessment scenarios, EPA is applying different FQPA safety factors for the protection of fetuses, infants, and children depending on the route of exposure, data gaps and the population exposed.  For non-inhalation exposure scenarios for adults (including women of child-bearing age) and children > 6 years of age, EPA is reducing the FQPA safety factor to 1X.

Evidence of increased qualitative or quantitative susceptibility of the offspring was not observed in any of the available animal testing guideline toxicity studies, including the developmental neurotoxicity study (DNT).  However, the Agency is reducing the FQPA safety factor to 3X for non-inhalation exposure scenarios for infants and children < 6 years of age, based on the following:  1) age-dependent pharmacokinetics, supported by rat Physiologically Based Pharmacokinetic (PBPK) model predictions of a 3-fold increase of pyrethroid concentration in juvenile brain compared to adults; 2) in vitro pharmacodynamic (PD) data  and in vivo data indicating similar responses between adult and juvenile rats at low doses; and 3) data indicating that the rat is a conservative model compared to the human based on species-specific pharmacodynamics of homologous sodium channel isoforms.

EPA is requiring an inhalation toxicity study for bifenthrin because inhalation data for other pyrethroids show the potential for the inhalation route to be more potent than the oral route.  Due to the inhalation study data gap, the Agency is retaining a 10X FQPA safety factor for all inhalation exposure scenarios for all population groups.  Once these data have been received, the Agency will determine how the results affect the toxicology endpoints and uncertainty factors.  In the absence of specific immunotoxicity studies, the Agency has evaluated the bifenthrin toxicity database to determine whether an additional database uncertainty factor is needed.

Because the 3X factor for infants and children < 6 years of age and the 10X factor for inhalation exposure scenarios are in response to different uncertainties, these safety factors have been combined for inhalation exposure scenarios for infants and children < 6 years of age resulting in an FQPA safety factor of 30X.

The toxicology database for bifenthrin does not show any evidence of treatment-related effects on the immune system, and the overall weight-of-evidence suggests that this chemical does not directly target the immune system. Therefore, the Agency does not believe that conducting a functional immunotoxicity study will result in a lower POD than that currently in use for overall risk assessment, and additional safety factors are not needed to account for a lack of this study.

For the acute dietary risk assessment, HED selected an endpoint from the most robust study for bifenthrin, the Wolansky acute oral study.  The Wolansky study was considerably conservative, using the most sensitive rat strain, and gavage dosing using a vehicle and volume producing the most adverse responses.  A benchmark dose (BMD) data analysis method was used to address any dose spacing effects.  An acute reference dose (aRfD) of 0.010 mg/kg/day was selected for children < 6 years old (includes retention of the 3X FQPA SF) and 0.031 mg/kg/day was selected for assessment of all populations older than 6 years old, based on a BMDL1SD value of 3.1 mg/kg and a BMD1SD value of 4.1 mg/kg based on reductions in motor activity.   The Wolansky acute oral study was also used for the assessment of short-term incidental oral and inhalation exposure scenarios.  The BMDL1SD value of 3.1 mg/kg was selected for risk quantification.  For short-term dermal exposure scenarios, risks were assessed using a 21-day dermal rat study with a BMDL10 of 96.3 mg/kg/day and a BMD10 of 187 mg/kg/day based on exaggerated hind limb flexion.

Bifenthrin is classified as a "possible human carcinogen" based on an increased incidence of urinary bladder tumors in mice.  However, EPA concluded that the bladder tumors may not be uncommon in mice and are not likely to be malignant.  Additionally, these tumors were observed only in male mice at the highest dose tested and the incidence was of borderline significance.  No evidence of carcinogenicity was observed in bifenthrin carcinogenicity studies in rats, and bifenthrin was negative in five different tests for mutagenicity but was marginally active in a forward mutation test in mouse lymphoma cells.  Overall, based on the available information, there is a low concern for mutagenicity.  Taking into account all of this information, the Agency has determined that quantification of risk using a non-linear approach (i.e., an aPAD or aRfD) will adequately account for all chronic toxicity, including carcinogenicity that could result from exposure to bifenthrin. While the Agency would typically use a chronic population-adjusted dose (cPAD) to protect for cancer concerns, use of the aPAD is protective for bifenthrin because increasing toxicity with increasing duration of exposure is not seen for bifenthrin.

Food Residue Profile:  The residue chemistry database is considered complete for bifenthrin.  For the purposes of the newly proposed uses, adequate metabolism data have been provided to demonstrate that the residue of concern in plants, livestock, and rotational crops is the parent compound only.  Monitoring data available for bifenthrin shows residues in most crops are not found at, or above the limit of quantification of the analytical method.  Field trial data supported by storage stability and method validation data have been submitted to support the proposed Section 3 and the tolerance proposed for dried tea (without U.S. registration actions).  Adequate data are available by translation to support the Section 18 request.  An analytical method is available to support the required tolerances.

Dietary Exposure:  A highly refined acute dietary assessment was conducted for all supported food uses and the newly proposed uses.  High-end modeled drinking water estimates were directly incorporated into the assessment.  The assessment incorporated the available monitoring data, percent crop treated (PCT) for the established uses, and processing factors as appropriate.

For all registered and proposed uses, the acute dietary exposure estimates are below HED's level of concern (<100% acute population adjusted dose (aPAD)) at the 99.9th percentile of exposure.  At the 99.9th percentile of exposure from food and water to bifenthrin will occupy 5 % of the aPAD for the general U.S. population and 29 % of the aPAD for children 1-2 years, the population group receiving the greatest exposures.

Because there is no increase in hazard from repeat exposures to bifenthrin, the acute dietary exposure assessment is protective for chronic dietary exposures; acute exposure levels are higher than chronic exposure levels.  Accordingly, a dietary exposure assessment for the purpose of assessing chronic dietary risk was not conducted.  However, in order to assess short-term aggregate risk to bifenthrin, it was necessary to calculate the average dietary (food and drinking water) exposure.  The quantification of average dietary exposures required the use of average field trial residues, PDP data, and current tolerances as appropriate.  The assessment also made use of PCT where available.  Drinking water information was incorporated using the mean concentration (1-in-10-year annual mean) for surface water generated by the PRZM-EXAMS model.

Residential Exposure:  Residential exposure is anticipated from the proposed Section 3 bed bug treatment use.  In addition, residential exposures are anticipated from currently registered uses of the chemical: in indoor residential/household premises as a crack and crevice spray, paint additive and as a dust, in or on automobiles/recreational vehicles, and for termite treatments.  HED has revised its Residential Standard Operating Procedures (SOPs) requiring the need for an update of bifenthrin residential risk estimates.  Exposures are expected for adults who apply bifenthrin-containing products and from post-application exposure to adults and children in residential areas previously treated with the chemical.

Residential uses of bifenthrin are many and vary widely.  HED conducted a screen of the various indoor and outdoor residential uses of bifenthrin and identified those which would result in the greatest potential for exposure.  The following uses are included in the residential risk assessment:  the proposed indoor bed bug treatment use, including surface-directed application to indoor surfaces, and outdoor ornamental plant and turf uses.  Residential indoor and outdoor uses are anticipated to be of short-term (i.e., 1 to 30 days) duration; however, bifenthrin does not increase in toxicity with repeated dosing.  As such, only single day residential exposures were assessed.

Residential handler dermal and inhalation risk estimates for bifenthrin are not of concern to HED (i.e., MOEs are >= 100 for dermal and >= 1,000 for inhalation, the levels of concern (LOC) for these assessments).  The combined handler dermal and inhalation risk estimates calculated using the Aggregate Risk Index (ARI) are not of concern to HED (i.e., ARIs are >= 1).  The ARI approach was required to combine the dermal and inhalation routes of exposure because of the different levels of concern (LOCs).

Adult residential post-application dermal exposures are not of concern to HED.  For children 1 < 2 years old, the most highly exposed children's subgroup, the combined dermal and incidental oral risk estimates for the identified residential uses are not of concern to HED (i.e., MOEs are >= 300, the LOC for these assessments).

Aggregate Risk:  The acute and short-term aggregate exposure assessments conducted for bifenthrin are not of concern to HED.

HED typically defines acute aggregate risk as including food and drinking water exposures only.  As previously noted, acute dietary risk estimates are not of concern (<100% aPAD).

The short-term aggregate exposure assessment combines short-term residential (non-dietary) exposures with average dietary exposures (food and drinking water).  As described previously, average dietary exposures were estimated and risk estimates (MOEs) were quantified using the short-term oral NOAEL for the purpose of characterizing short-term aggregate risk.  It should be noted that although HED is classifying this as a short-term assessment (which typically reflect risks from longer duration hazard endpoints and exposure), bifenthrin risks reflect one-day toxicity endpoints and maximum single-day exposures since bifenthrin does not increase in toxicity  with increasing duration of exposure.

Short-term aggregate risk estimates (MOEs) for the most highly exposed population, children 1 < 2 years old, are not of concern to HED (i.e., MOEs are >= 300).

Short-term aggregate risks estimated for the general U.S. population are not of concern to HED (i.e., ARIs are >= 1).  An intermediate-term and/or chronic aggregate risk assessment was not conducted because bifenthrin does not increase in toxicity with repeated dosing.

Occupational Exposure:  Occupational assessments were conducted for the newly proposed uses of bifenthrin.  Occupational exposures (dermal and inhalation) are anticipated for handlers who apply bifenthrin products and from dermal post-application exposure to workers who re-enter treated fields.  All occupational handler scenarios assessed resulted in risk estimates that were not of concern (i.e., ARIs are >= 1) with either baseline attire (i.e., single layer of clothing, no respirator) or the addition of a filtering face piece dust mask respirator.  All post-application worker exposure scenarios assessed result in estimated risks that were not of concern [i.e., MOEs are > 100 on Day 0 (12 hours)] for all potential post-application activities.

Review of Human Research:  This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These studies, which comprise the Pesticide Handlers Exposure Database (PHED), the Agricultural Handler Exposure Task Force (AHETF), and the Outdoor Residential Exposure Task Force (ORETF) have been determined to require a review of their ethical conduct, have received that review, and have been determined to be ethical.

2.0	HED Recommendations

2.1	Data Deficiencies

An acute inhalation study with additional neurotoxicity measurements and an immunotoxicity study are required for bifenthrin.  An additional uncertainty factor has been added to the human health risk assessment for all inhalation exposure scenarios to account for the required inhalation study.

Provided the end use product labels are revised as noted in Section 2.3.1, below, there are no further data gaps with respect to toxicology, residue chemistry, or occupational exposure for bifenthrin.

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

Adequate GC/ECD (gas chromatography/electron capture detection) analytical methods are available to enforce the proposed plant tolerances.  The available methods for plant commodities involve extraction of bifenthrin residues with acetone, partitioning with hexane, purification using a Florisil column, and analysis of residues by GC/ECD.

2.2.2	International Harmonization

There are no Maximum Residue Limits (MRLs) established by Codex, Canada, or Mexico for any of the proposed commodities in the current registration actions (Section 3 and 18).  However, Codex has proposed a 30 ppm MRL for Green and Black Tea (black, fermented and dried).  In order to harmonize with the Codex MRL, a U.S. tolerance level of 30 ppm is recommended for dried tea.

2.2.3	Recommended Tolerances

Table 2.2.3 summarizes the Section 3 and 18 proposed tolerances and the Agency's final tolerance recommendations.

Table 2.2.3.  Tolerance Summary for Bifenthrin
                                   Commodity
                           Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
                                   Comments
                         Correct Commodity Definition
Apple
                                      --
                                      0.5
Specified in (b) Section 18 emergency exemption;  Apple
Grass, forage
                                      2.5
                                      4.0
Specified in (c) Tolerances with regional registrations;
Grass, hay
                                      4.5
                                      15
Specified in (c) Tolerances with regional registrations;
Nectarine
                                      --
                                      0.5
Specified in (b) Section 18 emergency exemption;  Nectarine
Peach
                                      --
                                      0.5
Specified in (b) Section 18 emergency exemption;  Peach
Tea
                                      25
                                      30
Specified in (a) General; Tea, dried

The tolerance on imported tea should be listed under §180.442(a) with a footnote that there are no U.S. registrations.  The tolerance to support the use on grass grown for seed should be included in §180.442(c), tolerances with regional registrations.  Lastly the tolerances on apples, nectarines, and peaches should be included in §180.442(b), Section 18 emergency exemptions.

2.2.4 Revision to Petitioned-for Tolerances

A revision of the petitioned tolerance for dried tea was recommended, as described above in Section 2.2.2.

A revision is also required for the grass grown for seed petitioned tolerance.  Data submitted to determine the magnitude of bifenthrin residue in grass forage and hay was adjusted using Organization for Economic Cooperation and Development (OECD) calculation procedures.  After correction for storage stability decline, HED recommends a revised tolerance level on grass, forage from 2.5 ppm to 4.0 ppm;  grass, hay from 4.5 ppm to 15 ppm.

2.3	Label Recommendations

2.3.1	Recommendations from Residue Reviews

HED recommends revision of the use directions for the proposed Section 3 and 18 bifenthrin labels.  All field trials submitted for grass grown for seed were conducted in the Pacific Northwest states of Idaho, Oregon, and Washington.  As such, an amended Section B is required for grass grown for seed by limiting this use to ID, OR, and WA on product labels 279-3108 and 279-3313.  If the registrant wishes to establish a nationwide registration and tolerance of the grass grown for seed use, three additional field trials from EPA Region 5 would be needed.

For the proposed Section 18, application directions for treating apples, nectarines, and peaches as an emergency exemption in the states of Delaware, Maryland, New Jersey, North Carolina, Pennsylvania, Virginia, and West Virginia must be provided.  Amended product labels are needed for the following bifenthrin products: EPA Reg. Nos. 279-3108, 70506-57, and 70506-227.

2.3.2	Recommendations from Occupational Assessment

No label revisions are needed based on the occupational and/or residential exposure risk assessments.

3.0	Introduction

3.1	Chemical Identity

Table 3.1.  Nomenclature of Bifenthrin
Compound

Empirical Formula
C23H22ClF3O2
Common name
Bifenthrin
IUPAC name
2-methylbiphenyl-3-ylmethyl (1RS,3RS)-3-[(Z)-2-chloro-3,3,3-trifluoroprop-1-enyl]-2,2-dimethylcyclopropanecarboxylate
or
2-methylbiphenyl-3-ylmethyl (1RS)-cis-3-[(Z)-2-chloro-3,3,3-trifluoroprop-1-enyl]-2,2-dimethylcyclopropanecarboxylate
CAS name
(2-methyl[1,1′-biphenyl]-3-yl)methyl (1R,3R)-rel-3-[(1Z)-2-chloro-3,3,3-trifluoro-1-propenyl]-2,2-dimethylcyclopropanecarboxylate
CAS #
82657-04-03

3.2	Physical/Chemical Characteristics

Table 3.2.  Physicochemical Properties of the Technical Grade Bifenthrin
                                   Parameter
                                     Value
                                   Reference
Melting range
                                  68-70.6°C
Product Chemistry Chapter of the Bifenthrin Tolerance Reassessment Eligibility Decision (TRED), (DP No. 283808, 8/21/02, S. Levy)
pH
                                     NA[1]

Density at 24°C
                                   1.26 g/mL

Water solubility
                                 <0.1 μg/L

Solvent solubility (g/100 mL)
                          8.9 in heptane and methanol
      125 in acetone, chloroform, ether, methylene chloride, and toluene

Vapor pressure (Pa) at 25°C
                                 2.41 x 10[-5]

Dissociation constant (pKa)
                                Not applicable

Octanol/water partition coefficient (Kow)
                                 >1 x 10[6]

UV/visible absorption spectrum
                                      NA

[1] NA = information not available.

3.3	Pesticide Use Pattern

Bifenthrin is currently registered for use on a variety of agricultural crops including non-food/feed uses, as well as outdoor/indoor residential and indoor pet uses to control insect pests.

Examples of registered bifenthrin uses which have been classified as "non-food/non-feed" include:

   * Outdoor premises: agricultural/farm; airports/landing fields; Christmas tree plantations; commercial and industrial lawns; forest trees; herbs; rights of way/fences/hedgerows; ornamental plants; and wide area treatments (public health, forest products); and
   * Indoor premises: automobiles/taxis; barns; warehouses; dairy/cheese processing plants; eating establishments; egg packing plants; greenhouses, and outdoor buildings.

Examples of registered bifenthrin food/feed uses include:  beans; herbs; root vegetables; tree nuts; stone fruits; bushberries; leafy green vegetables; brassica; peas; leaf petiole vegetables; orchard crops; and cucurbits/melons/squashes.

Rates of application for bifenthrin use vary:  0.10 to 0.20 lb ai/A for application by aircraft, ground, and chemigation; 0.30 to 0.50 lb ai/A for soil incorporation; 0.20 to 0.40 for dispersal of granular product with ground equipment; 0.0050 lb ai/1000 ft² for crack and crevice and spot treatment applications; and 0.20 lb ai/A for spray and foam injection application.  End-use products are formulated as ready-to-use-sprays (RTU), emulsified concentrate (EC), wettable powders (WP), granular (G), flowable concentrate (FIC), and pelletized tablets.  A wide range of application methods may be used including aerial, ground boom, air blast, belly grinder, push-type spreader, low/high pressure hand wand, paint roller, and foggers, etc.

The use patterns for the newly proposed uses of bifenthrin are summarized in Table 3.3.

Table 3.3.  Summary of Directions for Proposed Uses of Bifenthrin
                               Target/ Use Site
                                  Formulation
                                (EPA Reg. No.)
                       Application Type, and  Equipment
                               Application Rate
                                   (lb ai/A)
                          Max. No. Applic. per Season
                          Max. Seasonal Applic. Rate
                                   (lb ai/A)
                                  PHI (days)
                              Use Directions[1]
                                   Section 3
Grass, Grown for Seed (Forage and Hay)
Emulsifiable Concentrate -
Brigade(R) 2EC
(279-3313)
Aerial, Chemigation or Ground
                                 0.033 - 0.10
Not Specified
                                     0.20
                                      30
RTI:
14 days

REI:
12 hours

Water Soluble Bag -
Brigade(R) WSB
(279-3108)

Bed Bug Treatment
Water Soluble Bag  -
F4688 50 WSP
(8033-96)
Surface-Directed Sprays, Bed (Box Spring, Frame, Headboard, Mattress), Closet, Dresser, Empty Luggage;
Manually Pressurized Handwand
                                    0.0051
                                (lb ai/gallon)
Not Specified
                                      NA
                                      NA
Re-apply every 7 to 10 days if needed[.]
                                  Section l8
Apple,
Nectarine and Peach
Dry Flowable  -
Bifenture[TM] DF
(70506-227)
Aerial, Airblast, Chemigation or Ground
                                 0.040 - 0.20
Not Specified
                                     0.50
                                      14
RTI:
30 days

REI:
12 hours

Emulsifiable Concentrate -
Bifenture[TM] EC -
(70506-57)

Water Soluble Bag  -
Brigade(R) WSB
(279-3108)

1. RTI: Re-treatement Interval; REI: Restricted Entry Interval

IR-4 submitted a petition to establish a tolerance for imported tea in the absence of a U.S. registration.  Good Agricultural Practices (GAP) information was also provided for the products Talstar(R) 8SC and Brigade(R) 8SC for use on tea grown in India.  Talstar(R) 8SC is an 80 g ai/L soluble concentrate formulation of bifenthrin.  One foliar application is made to tea using a spray volume of 400 L/ha and a 7-day PHI.  For Brigade(R) 8 SC, an 80 g ai/L SC formulation, one foliar application is made at 0.08 kg ai/ha (0.07 lb ai/A) using a spray volume of 400 L/ha which specifies a PHI of 7 days.

3.4	Anticipated Exposure Pathways

RD has requested an assessment of human health risk to support proposed new use of bifenthrin on grass grown for seed, imported tea; apple, nectarine, and peach.  Humans may be exposed to bifenthrin in their diet resulting from residues present on bifenthrin treated crops.  Further, given the environmental fate parameters of bifenthrin and the proposed uses outdoors in agricultural settings, the potential exists for bifenthrin to reach water resources resulting in limited residues in drinking water.  The potential exists for residential bifenthrin exposure from the proposed bed bug treatment, as well as from current use of the chemical.  Residential bifenthrin exposures could occur from adults handling the pesticide and from post-application exposure of adults and children contacting previously treated areas.  Adults could be exposed from the proposed uses of bifenthrin in an occupational setting.  Occupational applicators may be exposed while handling the pesticide prior to, as well as during application.  There is also the potential for exposure to workers who come into contact with the foliage of previously treated crops.

This assessment will consider the dietary, residential, and occupational risks for all registered and newly proposed uses of bifenthrin.

3.5	Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application 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.

Bifenthrin may be stored and accumulated in aqueous sediment and, therefore, could be a potential dietary exposure source for individuals who eat fish (e.g., catfish) which dwell near the sediment.  Subsistence fishers, or individuals who rely on fishing as the primary source of food, may be more highly exposed than the general population.  HED conducted an acute screening level dietary exposure assessment to consider the intake of contaminated catfish by subsistence fishers.  Because high-end bounding fish exposure assumptions were used to assess exposure to subsistence fishers, this potential dietary exposure source was not included in the acute or average dietary exposure and risk assessments conducted for the proposed Section 3 and 18 uses; rather, a stand-alone assessment was conducted.  The dietary assessment of catfish intake resulted in a % aPAD value of < 1 % and, therefore, would not be anticipated to significantly impact the dietary exposure assessments conducted for the proposed uses.  See Section 5.4.1 for further detail.

4.0	Hazard Characterization and Dose-Response Assessment

Bifenthrin is a member of the pyrethroid class of insecticides.  Pyrethroids have historically been classified into two groups, Type I and Type II, based upon chemical structure and toxicological effects.  Type I pyrethroids, which lack an alpha-cyano moiety, induce in rats a syndrome consisting of aggressive sparring, altered sensitivity to external stimuli, hyperthermia, and fine tremor progressing to whole-body tremor and prostration (T-syndrome).  Type II pyrethroids, which contain an alpha-cyano moiety, in rats produce a syndrome that includes pawing, burrowing, salivation, hypothermia, and coarse tremors leading to choreoathetosis (CS-syndrome) (Verschoyle and Aldridge 1980; Lawrence and Casida 1982).  In general, Type II chemicals tend to be more potent than Type I pyrethroids and the cis forms tend to be more potent than the trans configurations.

Bifenthrin is a Type I synthetic pyrethroid, unique to be the only member of the biphenyl-methyl ester class and it is enriched to 98% cis form.  It has a relative potency factor of 0.60 with respect to the more potent Type II pyrethroid, deltamethrin, with a relative potency factor of 1.00.  The adverse outcome pathway (AOP, based on the Bradford-Hill criteria) shared by pyrethroids involves the ability to interact with voltage-gated sodium channels (VGSCs) in the central and peripheral nervous systems, leading to changes in neuron firing, and ultimately neurotoxicity (see Figure 4.0). The signs observed in the animal studies are consistent with the pesticidal mode of action.

Target Tissue DoseVGSC AlterationsIn Vivo Clinical SignsAltered NeuronalExcitability

             Figure 4.0.  Adverse outcome pathway for pyrethroids

Dosing method, vehicle type and vehicle volume considerably influence the points of departure of the pyrethroids, including bifenthrin (Wolansky et al, 2007).  For example, the ED50 value (i.e. the effective dose for a 50% decrease) for deltamethrin is 196 times lower using corn oil versus carboxymethylcellulose as the vehicle with gavage dosing, based on motor activity data (Crofton et al, 1995).  The vehicle and volume used in gavage dosing vary considerably among pyrethroids thus making quantitative comparisons among them difficult.  In the specific case of bifenthrin dosing volume affects toxicity, decreasing the corn oil volume from 5 mL/kg to 1 mL/kg lowers the ED50 value of motor activity by a factor of two (Wolansky 2007).  Furthermore, bolus/gavage dosing results in increased potency of the pyrethroid relative to exposure in feed.  In the bifenthrin rat developmental studies, the LOAEL was 1.77 mg/kg/day with corn oil gavage administration while a dietary administration had a LOAEL of 15.5 mg/kg/day (8.8 times higher, with tremors as the common endpoint).  The gavage ACN study which did not use a vehicle of any kind had a much higher LOAEL of 70.3 mg/kg, based on changes in motor activity, clinical signs and mortality.  The Wolansky acute study was particularly conservative in design and utilized a corn oil vehicle at 1 mL/kg with gavage dosing (point of departure was 3.1 mg/kg).  In perspective, rat feed often does contain some content of vegetable oil, such as corn oil.

4.1	Toxicology Studies Available for Analysis

The data base of experimental toxicology studies available for bifenthrin provides a robust characterization of the hazard potential for children 6 years old and older and for adults.  There are two outstanding Part 158 data requirements for bifenthrin.  An immunotoxicity study is required due to recent changes to Part 158 which impose new data requirements for pesticide registration.  An acute inhalation study with ACN metrics is also required to substitute for the sub-chronic inhalation study.  In addition, there are on-going efforts to develop methods to inform the possibility of increased sensitivity to pyrethroids as a class in juvenile rats at doses near the LOAEL values, which is discussed further in Section 4.4.  Despite these scientific efforts, HED is confident that it has chosen points of departure and uncertainty factors in this risk assessment which are health protective and have a strong scientific foundation.

The data from the following studies were used to evaluate the hazard potential of bifenthrin:

	-Wolansky Acute Oral Rat Study
      -Nemec/WIL Acute Oral Rat Study
      -ACN Rat Study
      -SCN Rat Study
      -DNT Rat Study
      -21 Day Dermal Rat Study
      -21 Day Dermal Rabbit Study
      -90 Day Rat Study
      -90 Day Dog Study
      -Developmental Rat Studies (Gavage and Dietary)
      -Developmental Rabbit Study
      -Reproduction Rat Study
      -1 Year Dog Study
      -Chronic/Cancer Rat Study
      -Chronic/Cancer Mouse Study
      -Metabolism and Pharmacokinetic Studies

The studies available for consideration of bifenthrin toxicity provide a comprehensive database, with routes of administration which are consistent with potential exposure scenarios. In addition, numerous studies from the scientific literature conducted over several decades describe the pharmacodynamic and pharmacokinetic profile of the pyrethroids in general.  This scientific literature has been recently reviewed by several groups (Wolansky and Harrill 2008; Weiner et. al. 2009).  The non-guideline Wolansky acute oral study in rats measuring locomotor activity provides the most robust data to evaluate the hazard potential of bifenthrin.

4.2	Bifenthrin Toxicological Profile

Bifenthrin has been evaluated for a variety of toxic effects in guideline experimental toxicity studies.  Predominantly, behavioral changes characteristic of Type I pyrethroids such as muscle tremors were seen in most of the bifenthrin experimental toxicology studies, consistent with its MOA to activate sodium channels.  This observation was noted in several bifenthrin toxicology studies across various species at different durations, routes of exposure and life stages, including: the developmental toxicity studies in the rat and rabbit; 2-generation rat reproduction toxicity study; developmental neurotoxicity study (DNT); sub-chronic toxicity studies in the rat and dog; acute and sub-chronic neurotoxicity rat studies; a sub-chronic dermal toxicity study in rat; and chronic oral toxicity studies in the rat, mouse and dog.  The most robust study for assessing bifenthrin toxicity was the acute Wolansky study measuring locomotor activity, due to the fact that it utilized nine dose groups and a benchmark dose (BMD) data analysis method to address dose spacing effects.

The BMD analysis allows a constant threshold of change from the control group to be utilized so that all the pyrethroids are evaluated with the same toxicity metric, not possible with the standard LOAEL/NOAEL approach with variable dose spacings.  For the Wolansky study with continuous data, the BMD-S software was set to calculate the dose at which the motor activity change is equal to one standard deviation (SD) from the control value, or the BMD1SD.  The BMD1SD value is used instead of the LOAEL value and the one SD magnitude is calculated from the control group data.  The BMDL1SD is the lower 95% confidence limit of the BMD value and is used instead of the NOAEL value.  For other studies with quantal data, a BMD10 value, or the dose which has a 10% toxicity change from the controls, has been calculated as the standard conservative approach for this type of data.  For other data with higher variability and a 10% change is not statistically supportable; therefore, a BMD20 value has been calculated, or the dose at which a 20% toxicity change occurs relative to the control group.

The Wolansky study was considerably conservative, using the most sensitive rat strain, plus gavage dosing utilizing a vehicle and volume producing the most adverse responses (i.e. 1 ml/kg corn oil).  Muscle tremors were observed in nearly all experimental studies in all species and durations, however, motor activity was not measured in most of these studies.  The decreased locomotor activity observed in the acute Wolansky study was selected as the endpoint for risk assessment.  In the acute Wolansky study, tremors were not observed at doses less than 8 mg/kg bifenthrin, while decreased motor activity was significant at doses of 4 mg/kg and above. Decreased motor activity was the most sensitive endpoint identified for bifenthrin and is protective of other endpoints recorded throughout the database, thus an acceptable literature study was utilized for risk assessment.  Further, the Wolansky study monitored the toxicology at the time of peak effects, unlike most of the guideline studies.  Additional effects seen in one or more studies included: muscle twitching; decreased grip strength; altered landing foot splay; depressed respiration; increased grooming counts; loss of muscle coordination; staggered gait; exaggerated hind limb flexion; and convulsions at high doses.  Decreased body weight, body weight gains and food consumption were also noted in repeat-dosing dietary studies.  There was no clear evidence in the database that either gender was more sensitive to bifenthrin.

Bifenthrin has been evaluated for potential developmental effects in the rat (following gavage or dietary administration) and in the rabbit (gavage administration).  Maternal toxicity included neurological effects (tremors in rats and rabbits; head and forelimb twitching in rabbits).  There were no developmental effects of biological significance in either species. The registrant submitted a DNT study, which establishes a clear NOAEL for the adult and offspring toxicity.  The NOAEL in adults and offspring is similar in magnitude and the LOAELs are based on the clinical signs of neurotoxicity (dams had tremors and convulsions, offspring had increased grooming counts).  Based on targeted testing in the DNT study for common endpoints for bifenthrin, there was no increase in sensitivity in rat pups.  However, the Agency has reviewed existing pyrethroid data and concludes that the DNT is not a particularly sensitive study for comparing the sensitivity of young and adult animals to pyrethroids (E. Scollon, D381210, 6/27/11).  Some literature studies did indicate susceptibility for other pyrethroids, but in context these studies were conducted at relatively high doses which may not reflect environmental exposures (Sheets et al, 1994).  The reproductive toxicity of bifenthrin was examined in a two-generation reproduction study in the rat.  Tremors were noted only in females of both generations, with one parental generation rat observed to have clonic convulsions and no observed effects in the offspring.  Overall, there is no indication of increased juvenile sensitivity specifically to bifenthrin.

Bifenthrin is classified as a Group C "Possible human carcinogen", based on an increased incidence of urinary bladder tumors in mice.  The classification was based on the following weight of evidence considerations:

 There was a statistically significant dose-related trend in bladder tumors at the high dose.  HED concluded that the bladder tumors may not be uncommon in Swiss Webster mice and not likely to be malignant.  Additionally, these tumors were observed in only one species (mice), in only one sex (male), at only the highest dose, and the incidence was of borderline significance.
 There was a statistically significant dose-related trend for combined hepatocellular adenomas and carcinomas in male mice; however, there was no statistical significance in pairwise comparison.
 There was a statistically significant increase in pairwise comparison for lung tumors, but there was no dose response.  Additionally, there was no dose-related trend.  There was also no indication that tumor formation occurred early in the mouse carcinogenicity study.
 Bifenthrin was negative in five different tests for mutagenicity, but it was marginally active in a forward mutation test in mouse lymphoma cells.  Overall, based on the available information, there is a low concern for mutagenicity.
  No evidence of carcinogenicity was observed in carcinogenicity studies in rats with bifenthrin.

Taking into account all of this information, the Agency has determined that quantification of risk using a non-linear approach (i.e., an aPAD or aRfD) will adequately account for all chronic toxicity, including carcinogenicity that could result from exposure to bifenthrin.  While the Agency would typically use a chronic population-adjusted dose (cPAD) to protect for cancer concerns, use of the aPAD is protective for bifenthrin because increasing toxicity with increasing duration of exposure is not seen for bifenthrin.  The NOAEL observed in the mouse chronic study, in which tumors were observed, is 6.7 mg/kg/day, 2-fold higher than the POD used for acute risk assessment.   The NOAEL in the study was based on tremors seen at the LOAEL of 25.6 mg/kg/day; however, the tumors were observed at 81.3 mg/kg/day, a dose that is 26-fold higher than the current acute POD.

The pharmacokinetics of bifenthrin is similar to other pyrethroids with rapid absorption and clearance. The rapid absorption was confirmed by the functional reduction in locomotor activity at one hour post oral dosing (55% decrease at 12 mg/kg bifenthrin, Wolansky 2007).  An oral absorption half-life of 1.5 hours (with a lag-time of a 0.5 hour following first order kinetics) has been calculated for bifenthrin at 4 mg/kg dosing.  An oral absorption of approximately 50% was estimated.  The half-life in blood is approximately 10 hours, supporting rapid clearance from this compartment.  The major routes of bifenthrin metabolism are hydrolysis of the ester linkage with oxidation of the resulting alcohol to the acid form.  Radio-labeled bifenthrin studies indicate that the parent had the highest radioactivity excreted in the feces, with 12 other metabolites identified.  Approximately 70% of the total residues (bifenthrin and its hydroxylated metabolites) were excreted in the feces within 48 hours (range 66-88%).  Approximately 13-25% of the administered doses were excreted in the urine, mostly as hydrolytic and hydrolytic/oxidative degradation products, with little parent detected. In a bioaccumulation study with rats orally dosed with 0.5 mg/kg/day for up to 70 days, fat and skin tended to accumulate parent bifenthrin to a much greater extent than other tissues with half-lives of 51 and 50 days, respectively (JMPR Report, 2009).

With respect to acute lethality testing, bifenthrin has a low order of acute toxicity via the dermal route (Category III) of exposure and a moderate order of acute toxicity via the oral route (Category II).  The combined male-female LC50 value for bifenthrin is 1.01 mg/L (Category III), based on an acute inhalation study.  It is neither an eye nor skin irritant, nor is it a dermal sensitizer.

4.3	Pyrethroid Pharmacokinetic and Pharmacodynamic Profile

The extensive body of scientific literature on the pyrethroids provides insight into the contributions of pharmacokinetics (PK) and pharmacodynamics (PD) to the general toxicity profile of this class of chemicals.  This information also provides valuable insight into the potential age-related differences in toxicity for the pyrethroids.  The primary biological effects of bifenthrin and other pyrethroids on insects and vertebrates are stimulatory effects on voltage-gated sodium channels coupled with secondary inhibition of the voltage-gated calcium channels and chloride channels.  The following sections discuss the specific issues related to pyrethroid pharmacokinetics, pyrethroid pharmacodynamics, and age-related differences in pyrethroid toxicity.

4.3.1	Pharmacokinetics

Pharmacokinetics can be defined as what the body does to the chemical; in this case, how pyrethroids are distributed and eliminated following exposure.  Specific to pyrethroids, PK refers to the process(es) which determine the concentration of the pyrethroids reaching sodium channels in the peripheral nervous system (PNS) and central nervous system (CNS).  The underlying pharmacokinetics of pyrethroids is an important determinant of their toxicity because the concentration of pyrethroid at the sodium channel relates to the extent of toxicity, with greater pyrethroid concentration translates as increased neurotoxicity.  Physiological processes that significantly contribute to the PK include absorption, metabolism, protein binding and partitioning.  The vehicle type and volume has been shown to affect the temporal and toxicological properties of the pyrethroids (Crofton 1995, Wolansky 2007).  The blood brain barrier is less developed in the young and can also contribute to age-dependant neurotoxicity (US EPA Guidelines for Neurotoxicity Risk Assessment, Federal Register, 1998).  Carboxylesterases (serum and intracellular) and cytochrome P450 enzymes in the endoplasmic reticulum are the two major enzyme families responsible for the metabolism of pyrethroids.  The metabolism of bifenthrin in the liver is primarily by cytochrome P450 oxidation.  It is the ontogeny of these enzymes that accounts for the age-related sensitivity observed after pyrethroid exposures.  Pharmacokinetic changes may explain the disappearance of tremors in dogs after 29 weeks of bifenthrin dosing in the one-year study.  Rats and rabbits also demonstrated tolerance to bifenthrin in repeated dosing studies.  Bifenthrin has been demonstrated to transfer into milk in rat studies.  For the pyrethroid index chemical deltamethrin with 2 mg/kg orally in PND40 rats at 6 hours post-dosing, the tissue levels from lowest to highest were brain, liver, plasma, muscle and fat with levels of  20 ng/g, 50 ng/g, 70 ng/mL, 140 ng/g and 480 ng/g, respectively (Kim et al, 2010).  However, pyrethroid residues in fatty tissue are not available to interact with the VGSCs in vital tissues and therefore do not contribute to overall toxicity.

Following a single oral dose of 4 mg/kg radio-labeled bifenthrin in corn oil, radioactivity in blood plasma peaked at 4 hours, which corresponds precisely with the peak time of effect on motor activity at this dose.  In blood, bifenthrin residues have a half-life of approximately 10 hours (see Figure 4.3.1) with 17% of the residues (compared to peak values) remained 24 hours post-dosing and only 8% of the peak radioactive residues remained in the serum at 72 hours.  Similar kinetics were observed in rats given 35 mg/kg, although the peak plasma levels were slightly delayed to 6 hours (Selim 1986).  As previously described, pyrethroids are susceptible to ester hydrolysis in the plasma and oxidative metabolism by intracellular cytochrome P450 enzymes.  Protein binding of radioactive parent and metabolites increased considerably with time (9% at 2 hours vs 34% at 10 hours).  A radio-labeled bifenthrin guideline study reported that 40% of the total residues in plasma is parent at 4 hours, following a 4 mg/kg oral dose (HPLC method, MRID 00163070).  A literature study also revealed that the internal dose EC50 values for motor activity based on brain PK values were approximately three times higher than the EC50 value based on blood PK values (i.e. EC50 values of approximately 300 ng/cc and 90 ng/cc, respectively).  Thus, bifenthrin effects on peripheral nerves/tissues cannot be excluded (Scollon et. al., 2011).

      Figure 4.3.1.  Pharmacokinetic profile of radiolabeled-bifenthrin in rat plasma following a single oral dose of 4 mg/kg in corn oil.  Bifenthrin blood concentration is based on radioactivity and, therefore, represents a total of parent and metabolic products (Selim 1986, MRID 00163069).

Physiologically-based pharmacokinetic (PBPK) models, designed to predict pyrethroid concentration in tissues following in vivo exposure, have recently been developed by the Agency.  The Agency has determined that the important PK properties relevant for the metabolism and distribution of pyrethroids in the body are sufficiently similar for members of this class such that using a `generic' or family model structure for this class is scientifically appropriate.  In other words, due to the similarities in the PK profiles of pyrethroids, a single model structure is able to predict the tissue dose based on the pharmacokinetics of every member of the class.  The family modeling approach was presented to and supported by the FIFRA SAP (US EPA 2007).

In 2011 the Agency conducted an analysis of the toxicokinetic profile of pyrethroids as a class.  Several studies in this analysis indicate that there are age-dependent pharmacokinetic differences for the pyrethroids (i.e., there are differences in the ability of adults and juveniles to metabolize pyrethroids).  The enzymes which metabolize and detoxify the pyrethroids are present in rats and humans at birth (Koukouritaki et. al. 2004; Yang et. al. 2009).  As a result, both juveniles and adults are able to tolerate low doses of pyrethroids when the internal dose, or the amount of pyrethroid at the sodium channel, is low.  However, the activity of these enzymes increases with age, conveying in adults a greater capacity to detoxify pyrethroids compared to juveniles (Anand et. al. 2006; de Zwart et. al. 2008; Yang et. al. 2009).  For example, the rate of in vitro metabolism of deltamethrin by plasma carboxyesterases, plus hepatic carboxyesterases and cytochrome P450s (microsomes) are at least 6 times higher for PND 90 rats compared to PND 10 rats.  As a consequence, higher internal doses (i.e., those associated with high doses in experimental toxicology studies) can overwhelm the clearance mechanisms in juveniles; however, because adults have greater enzyme activity, they are able to tolerate higher doses prior to the onset of toxicity.  As a matter of perspective, the anticipated exposures from typical dietary or residential activities are not expected to overwhelm the premature metabolic systems in juveniles.  Bifenthrin has a melting point of 68ºC and is, therefore, a solid at room temperature.  Furthermore, pyrethroids are practically insoluble in water, minimizing risk from water exposure.

Predictive PBPK models have recently been developed to describe the PK of a few pyrethroids (Mirfazaelian et. al. 2006; Godin et. al. 2010).  Among these is an age-dependent model developed by the Agency which is capable of predicting the concentration of deltamethrin in the brains of rats at multiple ages (Tornero-Velez et. al. 2010).  The brain is considered the primary target organ for pyrethroids and increased pyrethroid concentrations are correlated with increasing systemic toxicity.  This model predicts that, compared to adult rats (i.e., 90-days old), equivalent brain concentrations of deltamethrin would be achieved with a 3.8X fold lower oral dose in 10-day old rats and 2.5X lower dose in 21-day old rats (Tornero-Velez et. al. 2010).  The 10- and 21-day old rats encompass effects predicted in a human up to age six. For example, a 1 mg/kg dose in the adult is equivalent to a 0.26 mg/kg dose (≈1 mg/kg/3.8mg/kg) in the 10-day old rats and to a 0.4 mg/kg (≈1 mg/kg/2.5mg/kg) dose in a 21-day old rat.  The difference between a 3.8- and a 2.5-fold dose is within background variability of the model.  As a result, the Agency concludes that juvenile rats are 3X more sensitive than adults with respect to pyrethroid pharmacokinetics.

4.3.2	Pharmacodynamics

Pharmacodynamics (PD) can be defined as the changes that chemicals cause to the body, in this case, how pyrethroids interact with the sodium channels.  Substantial evidence from in vitro and in vivo studies support the AOP illustrated in Figure 4.0, as well as disruption of sodium channels by pyrethroids as an early key event in this AOP (Lund and Narahashi 1982; Salgado et. al. 1989; Song and Narahashi 1996; Tabarean and Narahashi 1998; Soderlund et. al. 2002 ).  Choi and Soderlund (2006) examined interactions of several pyrethroids with mammalian VGSCs expressed in Xenopus oocytes.  With respect to altered neuronal excitability, Type I pyrethroids cause slight prolongations of the sodium current tails (e.g. ~20 ms), often resulting in long trains of action potentials.  In contrast, Type II pyrethroids significantly prolong sodium tail currents (e.g. 200ms to minutes) typically resulting in increased resting membrane potential and ultimately causing depolarization-dependent action potential block.  Figure 4.3.2 confirms the effects of bifenthrin to increase sodium channel currents in rat NaV1.8 channels expressed in xenopus oocytes.

Figure 4.3.2.  Resting modification of rat Nav1.8 sodium channels by bifenthrin, expressed in xenopus oocytes. Channel current vs time traces from individual representative oocytes in the absence or presence (*) of 100 uM bifenthrin were obtained during and after 40-ms depolarizations from 100 mV to 10 mV. Calibration bars: 20 ms for the x-axis and 500 nAmp on the y-axis.  Data extracted from Figure 3 in Choi and Soderlund (2006).

HED would prefer to use an early key event in the AOP for pyrethroids in selection of points of departure, such as sodium channel modification.  However, in vivo techniques used to detect VGSC alteration and altered neuronal excitability are not practical for use in risk assessment at this time and approaches for extrapolating in vitro findings to in vivo measures are not yet developed.  As such, the Agency is focusing its efforts for all pyrethroids in hazard characterization and identification on the apical endpoint (i.e., changes in neurobehavior in laboratory animals).  Neurotoxicity resulting from pyrethroids are generally characterized by tremors, hyper- or hypothermia, altered response to stimuli, salivation, reduced locomotor activity or convulsions (Nemec 2006; Wolansky and Harrill 2008; Breckenridge et. al. 2009).

In contrast to the age-related PK differences identified in the 2011 analysis, PD contributions to pyrethroid toxicity are not age-dependent even though there are several variations of sodium channels, called isoforms, which are differentially expressed by tissue and age.  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 modulated by pyrethroids.  Therefore, much of the information available to the Agency to characterize the PD relationship between pyrethroids and sodium channels has been derived from in vitro studies using frog oocytes or neuronal cells cultured in defined media.  These in vitro techniques do not provide direct quantitative measure of in vivo pyrethroid activity.  However, these techniques consistently and qualitatively demonstrate that channel isoforms expressed in juveniles are not more sensitive to pyrethroid perturbation compared to isoforms expressed in adults and that, pharmacodynamically, the rat is a conservative model for humans.  For example, Meacham et al. (2008), compared the sensitivity of an adult isoform and a juvenile isoform expressed in frog oocytes to deltamethrin.  The isoforms had comparable responses at environmentally relevant concentrations (< 500 nM) of deltamethrin, suggesting a lack of PD difference between juveniles and adults at low exposure levels.  In addition, in a direct comparison of a homologous rat and human VGSC isoform, NaV1.3, revealed that the rat isoform was 4-fold more sensitive than the equivalent human sodium channel to the pyrethroid tefluthrin (Tan and Soderlund 2009).  This data suggests that the rat is a highly-sensitive model and extrapolations from the rat would be protective of human health.  The occurrence and ontogeny of voltage-gated sodium channels in humans is not well characterized compared to the rat.  However, based on the comparable function and distribution of sodium channels between the species, the rat is an appropriate surrogate for the evaluation of human PD (Goldin et. al. 2000; Goldin 2002).  As a result, the Agency concludes that juvenile rats are not more sensitive than adults with respect to pyrethroid pharmacodynamics.  Therefore, the pharmacodynamic contribution to the FQPA factor will be 1X.

4.3.3	Critical Duration of Exposure

One of the key elements in risk assessment is the appropriate integration of temporality between the exposure and hazard assessments.  Following a single oral gavage dose, bifenthrin is absorbed rapidly in rats and quickly displaying decreased motor activity and increased tremors. Toxicity is observed as quickly as 1 hour, peaks at 4 hours and motor activity started to increase at 7 hours, approximately following the blood PK profile (Wolansky, 2007). Tremors are absent at 12 hours and rats typically recover within 24 hours without any persisting neurotoxic effects, at doses near the LOAEL value.  In support, for deltamethrin the signs of salivation and tremors correlated very well with the internal dose, with r[2]=0.86-0.90 (i.e. blood AUC, Anand et. al. 2006).  The toxicity profiles for other pyrethroids are generally similar and marked by rapid absorption, metabolism, and time-to-peak effect.  The NOAELs and LOAELs for tremors established from results of experimental toxicity studies with bifenthrin are remarkably consistent across durations of exposure, ranging from a single dose up to 2-years of dosing (see Table 4.3.3).  The BMD values from the motor activity results from the Wolansky study are similar to the NOAEL/LOAEL values from the tremor endpoint.

Table 4.3.3. Bifenthrin NOAEL and LOAEL Values Versus Treatment Time
                                     Study
                                   Duration
                                Study findings
Wolansky et al (2006) rat
                            Acute, single exposure
                                   BMDL=3.1
                                    BMD=4.1
Developmental neurotoxicity rat
                                    86 days
                                  NOAEL = 3.6
                                  LOAEL = 7.2
Sub-chronic dog
                                    90 days
                                 NOAEL = 2.21
                                  LOAEL= 4.42
Sub-chronic rat
                                    90 days
                                  NOAEL = 3.8
                                  LOAEL = 7.5
Sub-chronic neurotoxicity rat
                                    90 days
                                  NOAEL = 2.9
                                  LOAEL = 6.0
Reproductive toxicity rat
                                   120 days
                                  NOAEL = 3.0
                                  LOAEL = 5.0
Chronic-carcinogenicity mouse
                                   87 weeks
                                  NOAEL = 6.7
                                 LOAEL = 25.6
Chronic-carcinogenicity rat
                                    2-years
                                  NOAEL = 3.0
                                  LOAEL = 6.1

Comparing the NOAELs and LOAELs established from bifenthrin single dose and repeat dosing studies, it is apparent that repeat exposures do not result in lower NOAELs, within the variability of animal testing and body weight scaling corrections.  The human equivalent doses (HED) for bifenthrin between the dog study and rat study are similar when normalized by body weight.  The human equivalent dose for the 90-day dog study NOAEL is 1.35 mg/kg and the value for the acute Wolansky rat study BMDL is similar at 0.90 mg/kg (see Appendix A.4). These data are consistent with the general kinetic profile for bifenthrin.  The acute Wolansky study endpoint of decreased motor activity at 4.1 mg/kg (BMDL1SD value of 3.1 mg/kg) is slightly lower than the chronic two-year cancer study LOAEL= 6.1 mg/kg/day.  Therefore, the endpoint from the acute study is protective of the endpoints from the repeat dosing studies.  Thus, for purposes of endpoint selection and exposure assessment, only single-day risk assessments need to be conducted.

Appendix A.3 contains a graphical depiction and description of further NOAELs of other studies not listed in this table. While other studies did have lower NOAELs, they were inconsistent with the weight of evidence from the entire data base or were similar when the results were normalized to the human equivalent dose.  The Nemec 2006 study (WIL) had a lower PoD, however, for bifenthrin the dose selection was sub-optimal, producing a poor dose response and atypical PoD results.  Conversely, the ACN study did not utilize a dosing vehicle (which may not reflect exposure scenarios) and resulted in a non-conservative PoD an order of magnitude higher than the typical findings in Table 4.3.3.

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

Bifenthrin exposure to children under 6 years old is anticipated and must be considered in the context of the pyrethroids as a class.  For non-inhalation exposure scenarios for infants and children < 6 years of age, EPA is reducing the FQPA safety factor to 3X based on the increased quantitative susceptibility seen in the scientific literature related to pyrethroid pharmacokinetics.  This concept is consistent with the Agency's 2011 analysis and is supported by rat PBPK model predictions of a 3-fold increase of deltamethrin concentrations in the juvenile brain compared to adults (see Section 4.3.1).  The PK of pyrethroids as a group is sufficiently similar that significant deviations from the 3-fold increase of deltamethrin concentrations are not expected for other pyrethroids.  As noted in Section 4.3.2, juveniles are not more sensitive than adults with respect to pyrethroid pharmacodynamics and thus no uncertainty factor is needed for PD considerations.

There is no evidence that bifenthrin results in increased susceptibility in in utero rats or rabbits in the prenatal developmental studies or in young rats in the 2-generation reproduction study.  This is consistent with the results of the guideline pre- and post-natal testing for other pyrethroid pesticides.  There are, however, high-dose LD50 studies (studies assessing what dose results in lethality to 50 percent of the tested population) in the scientific literature indicating that pyrethroids can result in increased quantitative sensitivity in the young.  Examination of pharmacokinetic and pharmacodynamic data indicates that the sensitivity observed at high doses is related to pyrethroid age-dependent pharmacokinetics - the activity of enzymes associated with the metabolism of pyrethroids.   With otherwise equivalent administered doses for adults and juveniles, predictive pharmacokinetic models indicate that the differential adult-juvenile pharmacokinetics will result in a 3X greater dose at the target organ in juveniles compared to adults.  No evidence of increased quantitative or qualitative susceptibility was seen in the pyrethroid scientific literature related to pharmacodynamics (the effect of pyrethroids at the target tissue) both with regard to inter-species differences between rats and humans and to differences between juveniles and adults.  Specifically, there are in vitro pharmacodynamic data and in vivo data indicating similar responses between adult and juvenile rats at low doses and data indicating that the rat is a conservative model compared to the human based on species-specific pharmacodynamics of homologous sodium channel isoforms in rats and humans.

In light of the high-dose literature studies showing juvenile sensitivity to pyrethroids and the absence of the requested data on juvenile sensitivity to pyrethroids, EPA is retaining a 3X additional safety factor as estimated by pharmacokinetic modeling.  For several reasons, EPA concludes there are reliable data showing that a 3X factor is protective of the safety of infants and children.  First, the high doses that produced juvenile sensitivity in the literature studies are well above normal dietary or residential exposure levels of pyrethroids to juveniles and these lower levels of exposure are not expected to overwhelm the ability metabolize pyrethroids as occurred with the high doses used in the literature studies.  This conclusion is confirmed by the lack of a finding of increased sensitivity in pre- and post-natal guideline studies in any pyrethroid, including bifenthrin, despite the relatively high doses used in those studies.  Second, the portions of the uncertainty factors that account for potential pharmacodynamic differences are likely to overstate the risk of inter- and intraspecies pharmacodynamic differences, given the data showing similarities in pharmacodynamics between juveniles and adults and between humans and rats.  For both the inter-species and intra-species uncertainty factors, the pharmacodynamic portions are generally considered to be 3X, however for pyrethroids it is reduced to 1X since no differences among the various groups are observed. Finally, as indicated, pharmacokinetic modeling only predicts a 3X difference between juveniles and adults.

In addition to 3X factor for infants and children < 6 years of age, a 10X FQPA safety factor is being retained for inhalation exposure scenarios for all population groups.  This data gap is described in greater detail in the following Section (4.4.1).  Because the 3X factor and the 10X factor for inhalation exposure scenarios are in response to different uncertainties, these safety factors have been combined for inhalation exposure scenarios for infants and children < 6 years of age resulting in a FQPA safety factor of 30X.

This information described above is summarized in Re-Evaluation of the FQPA Safety Factor for pyrethroid pesticides (US EPA 2011c).

4.4.1	Completeness of the Toxicology Database

The toxicology database for bifenthrin is not complete.  Acceptable developmental toxicity studies in rats and rabbits are available for bifenthrin, in addition to an acceptable reproduction study in rats.  The main endpoint for bifenthrin is tremors, a common sign for a pyrethroid, which was detected in most toxicology studies, plus observed during targeted testing in the ACN, SCN and developmental neurotoxicity (DNT) studies.  EPA lacks additional data on immunotoxicity, inhalation toxicity, and adult-juvenile sensitivity.   Bifenthrin requires additional immunotoxicity testing (870.7800) and an inhalation study (870.3465) for pesticide registration.  However, a special acute inhalation study with more specific ACN study endpoints will replace the typical 28/90-day inhalation study due to the rapid clearance of bifenthrin and its signs of neurotoxicity.

An oral NOAEL is used for assessing inhalation risk for short-term exposure scenarios.  HED's Hazard and Science Policy Council (HASPOC) met on January 12, 2012 to discuss the inhalation data requirements (D. Smegal; TXR 0056209; 2012).  HASPOC concluded that a special acute inhalation study be required for bifenthrin based on a weight of evidence approach considering all the available hazard and exposure information.  The following items were considered in this recommendation: (1) use patterns and MOEs from the most recent risk assessment, (2) the physical chemical properties of bifenthrin, (3) the toxicological profile of bifenthrin, and (4) inhalation data for other pyrethroids that show the potential for the inhalation route to be more potent than the oral route.  The existing acute LC50 inhalation study for bifenthrin (870.1300) cannot substitute for this special study since it was not designed for neurotoxicity evaluations. There were deaths at the lowest dose in this study, thus it was not a sensitive data set for point of departure determinations.

EPA is requiring an inhalation toxicity study for bifenthrin because inhalation data for other pyrethroids show the potential for the inhalation route to be more potent than the oral route.  Currently, the POD for inhalation risk assessment scenarios is based on an oral toxicity study.  Reliance on an oral study raises uncertainty as to whether the standard safety factors are protective of infants and children.  For the inhalation study data gap, the Agency is retaining a 10X database uncertainty factor for all inhalation exposure scenarios.  Once these data have been received, the Agency will determine how the results will affect the toxicology endpoints and uncertainty factors.

In the absence of specific immunotoxicity studies, the Agency has evaluated the available bifenthrin toxicity database to determine whether an additional database uncertainty factor is needed to account for potential immunotoxicity.  The toxicology database for bifenthrin does not show any evidence of treatment-related effects on the immune system, and the overall weight-of-evidence suggests that this chemical does not directly target the immune system.  Therefore, the Agency does not believe that conducting a functional immunotoxicity study will result in a lower POD than that currently in use for overall risk assessment, and additional safety factors are not needed to account for a lack of this study.

In light of the literature studies indicating a possibility of increased sensitivity to bifenthrin in juvenile rats at high doses, EPA has also the requested proposals for study protocols which could identify and quantify bifenthrin's potential juvenile sensitivity.  For the reasons discussed in Section 4.4, the uncertainty regarding the protectiveness of the intraspecies uncertainty factor raised by the literature studies and the absence of the requested data warrant application of an additional 3X for risk assessments for infants and children < 6 years of age.

Dermal exposures of greater than 21 days are possible for bifenthrin; however, the HASPOC concluded, based on a WOE approach, that a 90-day dermal toxicity study for bifenthrin is not required at this time (TXR No.: 0056209).  This approach considered the following factors:  1) the established dermal absorption factor based on SAR considerations;  2) that there are no risk estimates of concern for any scenario from using the oral PODs (i.e., MOEs are greater than 100 for adults, and 300 for children, respectively);  3) there are two 21-day day dermal toxicity studies available for bifenthrin; and  4) the toxicity database for bifenthrin shows that in oral toxicity studies, NOAELs do not change considerably over longer exposure durations.

4.4.2	Evidence of Neurotoxicity

There are no residual uncertainties with regard to evidence of neurotoxicity for bifenthrin.  Like other pyrethroids, bifenthrin causes toxicity from interaction with sodium channels leading to clinical signs of neurotoxicity.  These effects are adequately assessed by the available guideline and non-guideline studies.  Bifenthrin is a Type I pyrethroid and tremors were consistently observed throughout its toxicology database.  Neurotoxicity was consistently observed throughout the database in a dose-dependent manner in most of the studies conducted.

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

Evidence of increased qualitative or quantitative susceptibility of offspring was not observed in any of the available guideline toxicity studies for bifenthrin.  After reviewing the extensive body of peer-reviewed literature on pyrethroids, the Agency has reached a number of conclusions regarding juvenile sensitivity for pyrethroids, including the following:

   * The Agency has no residual uncertainties regarding age related sensitivities for the young, based on the absence of pre-natal sensitivity observed in 76 guideline studies for 24 pyrethroids, the scientific literature, and the bifenthrin guideline toxicological studies.
   * The DNT, developmental and reproduction studies for bifenthrin did not demonstrate qualitative or quantitative susceptibility to the young or developing animal, consistent with other members of the pyrethroid class.
   * No 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.

Bifenthrin is neither a developmental nor a reproductive toxicant.  Bifenthrin has been evaluated for potential developmental effects in the rat (following gavage or dietary administration) and in the rabbit (gavage administration).  Maternal toxicity included neurological effects (tremors in rats and rabbits; head and forelimb twitching in rabbits).  There were no developmental effects of biological significance in either species.  The potential reproductive toxicity of bifenthrin was examined in a two-generation reproduction study in the rat.  Tremors were noted only in females of both generations with one parental generation rat observed to have clonic convulsions.  Furthermore, high-dose studies in the scientific literature indicated that younger animals were more susceptible to the toxicity of pyrethroids.  For example, Sheets et al (1994) found increased brain deltamethrin levels in young rats (PND 11 and 21) relative to adult rats (PND 72).  These age-related differences in toxicity are principally due to age-dependent pharmacokinetics; the activity of enzymes associated with the metabolism of pyrethroids increase with age (Anand et al, 2006).  However in context, normal dietary or residential exposures to juveniles are not expected to overwhelm their ability metabolize pyrethroids.  In support, at a dose of 4.0 mg/kg deltamethrin (near the Wolansky study LOAEL value of 3.0 mg/kg for deltamethrin), the change in the acoustic startle response was similar between adult and young rats (Sheets, 1994).  In addition, ORD has recently developed an age-dependent PBPK model for deltamethrin (Tornero-Velez et al, 2010) which predicts a 3 - fold increase of pyrethroid in neuronal tissue in younger animals compared to adults.  There are several studies (in vitro and in vivo) that indicate pharmacodynamic contributions to pyrethroid toxicity are not age-dependent.  Examination of specific VGSCs have demonstrated that there is a lack of increased sensitivity in either juvenile specific isoforms (Meacham et al, 2008) or in human isoforms compared to rat variants (Tan and Soderlund, 2009).

Additional in vitro and in vivo studies are currently being conducted that could potentially inform a number of issues related to pyrethroid toxicity as a class.  In 2010, the Agency requested proposals for study protocols which could identify and quantify potential juvenile sensitivity and received a single, coordinated response from the Pyrethrin and Pyrethroids Working Group (PPTWG), a conglomerate of pyrethroid registrants.  The PPTWG protocol was reviewed during a July 2010 FIFRA SAP meeting.  Based on comments from the SAP, the initial study proposal was refined.  At present time, pesticide registrants and product formulators have come together as Council for the Advancement of Pyrethroid Human Risk Assessment (CAPHRA) and plan on doing the following: 1) conducting in vitro studies demonstrating the interaction of pyrethroids exogenously expressed rat and human VGSCs in Xenopus oocytes; 2) conducting in vitro studies demonstrating interaction of pyrethroids in rat neurolemma cells; 3) developing rat and human PBPK models, including additional pharmacokinetic data; and 4) conducting in vivo behavioral testing using auditory startle testing in rats.  As these data becomes available, the Agency will determine whether re-evaluation of the age-related sensitivity of pyrethroids is appropriate.

4.4.4	Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the bifenthrin database in regard to dietary (food and drinking water), occupational, and residential exposures.  Although the acute dietary exposure estimates are refined, HED does not believe that the exposure estimates under-estimate risk for the established or proposed uses of bifenthrin.  The reason is the residue levels used are based on either monitoring data reflecting actual residues found in the food supply, or on high-end residues from field trials which reflect the use patterns which would result in highest residues in foods.  The residue data used for dietary exposure assessment are described in Section 5.4.1 of this document.  Furthermore, processing factors used were either those measured in processing studies, or default high-end factors representing the maximum concentration of residue into a processed commodity.  EPA made conservative (protective) assumptions in the ground and surface water modeling used to assess exposure to bifenthrin in drinking water.  Additionally, post-application exposure of children and incidental oral exposure of toddlers are based on conservative, health-protective assumptions that also ensure exposures are not underestimated.  These assessments will not underestimate the exposure and risks posed by bifenthrin.

4.5	Toxicity Endpoint and Point of Departure Selections

4.5.1	Dose-Response Assessment

The details for selecting toxicity endpoints and points of departure (PoDs) for various exposure scenarios are presented in Appendix A.2.  Based on the proposed use patterns for bifenthrin, the expected exposure profile will be for dietary, dermal, inhalation and incidental oral exposures. Since acute PoDs are protective for chronic exposures, only acute endpoints have been selected for bifenthrin.

As previously indicated, the toxicity endpoints in the bifenthrin database are consistently based on clinical signs of neurotoxicity, more specifically tremors.  These studies include multiple species, study designs, and durations.  Moreover, the acute exposure or bolus dosing studies generally result in lower NOAELs compared to longer-term dietary administration studies, consistent with other pyrethroids in this class.  Because uncertainty associated with the PoD is propagated throughout the risk assessment, one of the key factors in POD selection is the robustness of the dose-response data.  The guideline experimental toxicology studies available for bifenthrin are generally high quality and were considered in the POD selection process (Appendix A.2) and in the weight of the evidence evaluation.  In addition to the typical guideline studies, data from two special studies (Wolansky study on locomotor activity and Nemec/WIL FOB study) evaluating neurobehavioral outcomes are available for bifenthrin (Nemec 2006; Wolansky et. al. 2006).  Wolansky et al. (2006) individually measured locomotor activity at the time of peak effect after exposure to 11 pyrethroids, including bifenthrin.  Dose-response relationships were determined using 6-11 doses per pyrethroid (9 doses used for bifenthrin) and 3-18 rats per dose group (8-12 animals/group used for bifenthrin), minimizing variability and increasing the confidence in the benchmark dose (BMD) estimates determined from this study.  The locomotor activity for bifenthrin had an excellent dose response.  Locomotor activity is an objective toxicity metric, since it is recorded by photoelectric detectors.  Moreover, each pyrethroid was evaluated by the same scientist thus decreasing some of the variability associated with neurobehavioral measures.  In the Nemec/WIL study, 17 pyrethroids have been evaluated using a specially designed Functional Observational Battery (FOB) study focused on the outcomes associated with pyrethroid toxicity syndromes.  The bifenthrin data from the Nemec/WIL study were not considered as part of PoD selection.  The bifenthrin dose selection in the Nemec/WIL study was sub-optimal (i.e. only 2 doses and too close together), resulting in a poor dose response curve and low confidence of the calculated BMDL value (Nemec 2006).

Observation of tremors is the most prominent findings in the guideline experimental toxicology studies and was considered in the PoD determination.  Unlike the Wolansky study, guideline studies typically have only three treatment groups and often do not evaluate clinical signs at the time of peak effect.  Moreover, scoring metrics of tremors varies widely among guideline studies.

The Wolansky study utilized a sensitive rat strain to neurotoxins (Long Evans), plus measured an objective apical endpoint of locomotor activity as the toxicity metric.  The BMD1SD value was 4.1 mg/kg at a 20% decrease in locomotor activity and the BMDL1SD value was 3.1 mg/kg. The Wolansky study was considerably conservative, using gavage dosing with a vehicle and volume producing the most adverse responses (i.e. 1 ml/kg corn oil).  The BMD data analysis was utilized as a standardized method to address concerns of dose selection and dose spacing. In support, the BMD1SD value for bifenthrin was verified in the study by Scollon et al (2011), with a 20% decrease in motor activity at a dose of approximately 4 mg/kg (i.e. one SD for the Wolansky bifenthrin data corresponded to 20% of the control mean value).  Furthermore, the PoD from the Wolansky study is supported by similar NOAEL values in multiple other guideline studies (see Table 4.3.3).  Given the multiple strengths associated with study design of Wolansky et. al. (2006) and the resulting well-defined dose-response curve, this study provides the most robust data set for extrapolating risk from bifenthrin.  The ACN is often considered for acute endpoints.  However, this study for bifenthrin did not utilize a vehicle and had an atypical LOAEL value of 70.3 mg/kg.  Thus, the Wolansky PoD is much more conservative.  Further, there were deaths at the LOAEL value and, therefore, this is not a sensitive study for the selection of a point of departure.

Acute Dietary (All Age Groups): Quantitation of the dietary risks were performed using the acute oral Wolansky study, with a BMDL value of 3.1 mg/kg and a BMD value of 4.1 mg/kg based on decreased locomotor activity.

Short-term Dermal: Quantification of dermal risks were performed using a 21-day dermal rat study with a BMDL10 value of 96.3 mg/kg/day and a BMD10 value of  187.0 mg/kg/day based on exaggerated hind limb flexion (see Appendix G for the BMD analysis).

Short-term Incidental Oral: Quantitation of the incidental oral risks were performed using the acute oral Wolansky study, with a BMDL value of 3.1 mg/kg and a BMD value of 4.1 mg/kg based on decreased locomotor activity.

Short-term Inhalation: Quantitation of the inhalation risks were performed using the acute oral Wolansky study, with a BMDL value of 3.1 mg/kg and a BMD value of 4.1 mg/kg based on decreased locomotor activity. Equivalent inhalation and oral toxicity were assumed.

4.5.2	Recommendation for Combining Routes of Exposure for Risk Assessment

HED combines risk values resulting from separate routes of exposure when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population, and if the hazard associated with the points of departure is similar across routes.  A common toxicological endpoint, neurotoxicity, exists for dermal, incidental oral, and inhalation routes of exposure to bifenthrin.  Therefore, these were combined for all residential exposure scenarios assessed.

4.5.3	Cancer Classification and Risk Assessment Recommendations

Bifenthrin is classified as a "possible human carcinogen" based on an increased incidence of urinary bladder tumors in mice.  However, EPA concluded that the bladder tumors may not be uncommon in mice and are not likely to be malignant.  Additionally, these tumors were observed only in male mice at the highest dose tested and the incidence was of borderline significance.  No evidence of carcinogenicity was observed in bifenthrin carcinogenicity studies in rats, and bifenthrin was negative in five different tests for mutagenicity but was marginally active in a forward mutation test in mouse lymphoma cells.  Overall, based on the available information, there is a low concern for mutagenicity.

Taking into account all of this information, the Agency has determined that quantification of risk using a non-linear approach (i.e., an aPAD or aRfD) will adequately account for all chronic toxicity, including carcinogenicity that could result from exposure to bifenthrin.  While the Agency would typically use a chronic population-adjusted dose (cPAD) to protect for cancer concerns, use of the aPAD is protective for bifenthrin because increasing toxicity with increasing duration of exposure is not seen for bifenthrin.  The NOAEL observed in the mouse chronic study, in which tumors were observed, is 6.7 mg/kg/day, 2-fold higher than the POD used for acute risk assessment.   The NOAEL in the study was based on tremors seen at the LOAEL of  25.6 mg/kg/day; however, the tumors were observed at 81.3 mg/kg/day, a dose that is 26-fold higher than the current acute POD.

4.5.4	Points of Departure and Toxicity Endpoints Used in Human Risk Assessment
Table 4.5.4.  Summary of Toxicological Doses and Endpoints for Bifenthrin

                               Exposure Scenario
                              Point of Departure
                                 Uncertainty/
                              FQPA Safety Factors
                               RfD, PAD and LOC
                        Study and Toxicological Effects
Acute Dietary-
(< 6 years old)
BMDL1SD= 3.1 mg/kg

Acute RfD =  0.031 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF = 3X

aPAD = acute RfD
               FQPA SF

=   0.010     mg/kg/day
Wolansky et al (2006) BMD1SD = 4.1 mg/kg based on reductions in locomotor activity; Supported by multiple guideline studies
Acute Dietary-
(>= 6 years old)
BMDL1SD = 3.1 mg/kg

Acute RfD =  0.031 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF = 1X

aPAD = acute RfD
               FQPA SF

=   0.031     mg/kg/day
Wolansky et al (2006) BMD1SD = 4.1 mg/kg based on reductions in locomotor activity; Supported by multiple guideline studies
Short-Term
(1-30 days)
Incidental Oral
BMDL1SD = 3.1 mg/kg
UFA = 10X
UFH = 10X
FQPA SF = 3X
Residential:
< 6 years old

LOC is an MOE= 300

>= 6 years old, LOC is an MOE= 100
Wolansky et al (2006) BMD1SD = 4.1 mg/kg based on reductions in locomotor activity; Supported by multiple guideline studies
Short-Term
(1-30 days)
Dermal
BMDL10=96.3 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF = 3X
Residential:
< 6 years old

LOC is an MOE= 300

>= 6 years old, LOC is an MOE= 100

Occupational:
Adults, LOC is an MOE=100
21-day dermal study in rats.
BMD10=187.0 mg/kg/day, based on exaggerated hind limb flexion
Short-Term
(1-30 days)
Inhalation
BMDL1SD = 3.1 mg/kg
UFA = 10X
UFH = 10X
FQPA SF = 30X*
Residential:
< 6 years old, LOC is an MOE= 3,000

>= 6 years old, LOC is an MOE= 1,000

Occupational:
Adults MOE=1,000
Wolansky et al (2006) BMD1SD = 4.1 mg/kg based on reductions in locomotor activity; Supported by multiple guideline studies
Cancer (oral, dermal, inhalation)
Classification:  Category C (possible human carcinogen).  No Q1* has been derived. Anon-linear approach is recommended for cancer assessment.
NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.
* FQPA SF is composed of the 3X factor for increased quantitative susceptibility and the 10X factor for the inhalation study data gap.

5.0	Dietary Exposure and Risk Assessment

5.1	Metabolite/Degradate Residue Profile

5.1.1	Plant and Livestock Metabolism Studies

Plant Metabolism

The metabolism of bifenthrin was investigated in cotton, apples, corn and potatoes.  Metabolism was generally similar in all plants.  When directly applied to soil, most of the bifenthrin remains in the soil with very little uptake into the plants.  When applied foliarly, the major residue in plants is the parent compound.  Most residue stays on the surface where applied with only small amounts translocated throughout the plant.  Bifenthrin in the major residue identified in all crops.  4-hydroxy bifenthrin was the only residue identified at just over 10% of the TRR and was seen only in corn.

Livestock Metabolism

The metabolism of bifenthrin was investigated in the goat and the hen.  Ruminant and poultry metabolism is similar.  Most of the administered dose is excreted.  The highest residues retained in the tissues are found in fat and liver.  In ruminant milk, fat and muscle and poultry eggs, fat and muscle, unchanged parent is the major residue.  In ruminants, the major metabolite in liver and kidney is 1-methyl-3-phenylbenzoic acid and in poultry, hydroxymethyl bifenthrin and fatty acid conjugates of hydroxymethyl bifenthrin were identified in fat and liver.

5.1.2	Summary of Environmental Degradation
Drinking Water Memo, D372556, J. Melendez, 8/11/2010

Studies conducted on bifenthrin indicate that it is persistent under most conditions and bioaccumulative.  It appears that a major route of degradation is aerobic metabolism.  Bifenthrin is relatively stable to hydrolysis at all pH values.  It is relatively stable to aqueous and soil photolysis and degrades slowly under both aerobic and anaerobic soil metabolism conditions (half-life range 97-250 days in 3 soils, and relatively stable, respectively).  Bifenthrin is relatively immobile in four soils tested (KOC range 131,000 to 275,000).  Field studies show a pattern consistent with the laboratory studies, with relatively high persistence (half-lives ranging from 78 to 345 days in 10 field trials) and  low mobility of the chemical in soil.  In aquatic environments, it appears that residues of bifenthrin persist in pond sediments for extended periods (at least 12 months of monitoring).  No major metabolites were observed (> 10% of the applied) in any of the laboratory studies.  The very low water solubility and hydrophobic nature of bifenthrin leads to strong soil adsorption and a tendency to partition to sediment in aquatic systems.

Bifenthrin has a vapor pressure of 1.8x10 - 7 mmHg, water solubility of 0.0140 ppb, and an estimated Henry's law constant of 7.2x10-3 atm-m3/mol.  Based upon its Henry's law constant and vapor pressure, bifenthrin is expected to have a moderate to low potential for volatilization from soil and water surfaces.  Bifenthrin's potential for volatilization is reduced significantly because it adsorbs strongly to soils, suspended solids, sediment and organic matter in the water column.  A laboratory volatility study showed a maximum volatility at 40°C of 5.07x10-4 μg/cm2 hr (average at 14 days), a relatively low value.

5.1.3	Comparison of Metabolic Pathways

The rat metabolism study is discussed in Section 4.2.  Plant and animal metabolism studies are discussed in Section 5.1.1.

The metabolic profile in plants is similar in cotton, apples, corn and potatoes.  Further, the metabolism in ruminants, poultry, and the rat is also similar.  In plants, the unchanged parent compound is the major residue and in animals, it is also the major residue in all animal matrices.  Therefore, there are no residues of concern in plant studies that are not also present in the rat metabolism study.

5.1.4	Residues of Concern Summary and Rationale

The residue of concern in plants, livestock and drinking water is the parent compound.  Unchanged parent is the major residue in all plant matrices, drinking water and most animal matrices.  In animals additional metabolites have been identified in liver, kidney and fat, however, these metabolites are likely present at fairly low levels and are considered to likely be of lesser toxicity than the parent and are therefore not of concern.

Table 5.1.4.    Summary of Metabolites and Degradates to be included in the Risk
Assessment and Tolerance Expression
                                    Matrix
                     Residues Included In Risk Assessment
                   Residues Included In Tolerance Expression
Plants

Grass grown for seed (hay and forage) and Tea
                            Bifenthrin parent only
                            Bifenthrin parent only

Rotational Crops

Livestock
Ruminant

Poultry & Eggs

Drinking Water

5.2	Food Residue Profile

Bifenthrin is typically applied as a foliar application for later season uses.  Applications directly to soil generally do not result in significant residues in plants due to bifenthrin's affinity to bind to soil, its low soil mobility, and the low tendency of this pesticide to translocate within plants.  Metabolism data shows that when applied foliarly, the vast majority of residue is likely to be surface residues at the site of application consisting primarily of unchanged parent compound.  USDA's Pesticide Data Program (PDP) has conducted extensive monitoring for residues of bifenthrin in a wide variety of crops.  The data shows that bifenthrin residues in most crops are not found at or above the limit of quantification of the analytical method.  A few quantifiable residues are found in the leafy vegetables, but even in these commodities, most monitoring samples have no residues above the method LOQ.  Based on animal metabolism data and feeding studies, residues in livestock commodities resulting from feeding treated feedstuffs are likely to be very low, and given the low water solubility and high affinity to bind to soils, residues in water are also expected to be very low.

5.3	Water Residue Profile
	Drinking Water Memo, D372556, J. Melendez, 8/11/2010

The Tier I Estimated Surface Drinking Water Concentrations and Estimated Ground Water Concentrations (EDWCs) for bifenthrin were calculated using the Tier I aquatic models FQPA Index Reservoir Screening Tool (FIRST) and SCI-GROW, respectively.  The very low water solubility and the tendency of bifenthrin to adsorb to soil indicate that drinking water is not a major route of exposure; however, in the absence of acceptable monitoring data HED has used EDWCs which are anticipated to overestimate risk.

The Estimated Drinking Water Concentrations (EDWCs) for bifenthrin were calculated based on a maximum application rate of 0.5 lb a.i./A/season.  The acute drinking water concentration in surface water is 0.0140 ppb of bifenthrin, based on applications of the chemical to lettuce.  The cancer/chronic drinking water concentration is 0.0140 ppb (based on applications of lettuce, with the highest application rate and PCA).  The SCI-GROW generated EDWC is 0.014 ppb of bifenthrin, which is recommended for use, both for acute and chronic exposures.  Because of the very low solubility of bifenthrin, the EDWCs did not exceed 0.0140 ppb (that is, the solubility of bifenthrin).

Table 5.2 provides a summary of the Tier I modeled drinking water concentrations for bifenthrin.

Table 5.2.  Summary of Estimated Surface Water and Groundwater Concentrations for
Bifenthrin
Scenario
                          Surface Water Conc., ppb a
                           Groundwater Conc., ppb b
Acute
                                    0.0140
                                    0.0030
Chronic (non-cancer)

[a] From the Tier I FQPA Index Reservoir Screening Tool (FIRST).  Input parameters are based on maximum application rate on lettuce (0.5 lb ai/A/season).
[b] From the SCI-GROW model; lettuce scenario.
Highest value for use in risk assessment is shown in bold.

5.4	Dietary Risk Assessment
	Bifenthrin: Dietary Exposure Memo, D383085, S. Tadayon, 5/25/2012

A highly refined acute dietary exposure and risk assessment was conducted for bifenthrin.  High-end modeled drinking water estimates were directly incorporated into the assessment.  In order to assess short-term aggregate risk to bifenthrin, average dietary exposure estimates (i.e., food and drinking water) were calculated.  Because the endpoint from the acute study is protective of endpoints from repeat dosing studies, a chronic dietary risk assessment was not conducted.

Bifenthrin may be stored and accumulated in aqueous sediment and, therefore, could be a potential dietary exposure source for people who eat fish (e.g., catfish) which dwell near the sediment.  Subsistence fishers may be more highly exposed than the general population.  HED conducted an acute screening level dietary exposure assessment to consider the intake of contaminated catfish by subsistence fishers.  Because high-end bounding fish exposure assumptions were used to assess exposure to subsistence fishers, this potential dietary exposure source was not included in the acute or average dietary exposure and risk assessments conducted for the proposed Section 3 and 18 uses; rather, a stand-alone assessment was conducted.

5.4.1	Description of Residue Data Used in Dietary Assessment

The bifenthrin acute dietary exposure and risk assessment was conducted considering all supported food uses and drinking water.  The assessment was conducted using DEEM-FCID(TM), Version 2.03, which incorporates consumption data from USDA's CSFII, 1994-1996 and 1998.  Anticipated residues (ARs) were developed based on the latest USDA's Pesticide Data Program (PDP) monitoring data 1998-2010, Food and Drug Administration (FDA) data, and field trial data (FTD) for bifenthrin.

The USDA's PDP provides bifenthrin monitoring data from 1998-2010.  The PDP sampling protocol calls for typical consumer practices such as rinsing vegetables, peeling and coring fruit prior to sample analysis.  PDP data were used where available for both the Section 3 and 18 proposed uses.  For the acute dietary assessment the latest PDP data were used for the following commodities: bell pepper; bean (succulent); blueberry; broccoli; cabbage; cauliflower; cilantro; cranberry; cucumber; egg; eggplant; grape; grapefruit; orange; orange juice; lettuce; pear; cantaloupe; winter squash; spinach-canned; strawberry; sweet corn; sweet peas; tomato; watermelon; and milk. For blackberry and raspberry, the 2002 FDA monitoring data were used. The chronic dietary assessment used PDP data for the following commodities: bean (succulent), beef, milk, pea and pork.

Field trial data (FTD) were submitted by IR-4 in support of the use of bifenthrin on grass grown for seed and the establishment of a tolerance on imported tea.  The evaluation of the analytical chemistry and residue data for the submitted studies is described in a separate memorandum (D388604, P. Savoia, 5/25/2012).

No FTD was submitted by the states support of the Section 18 action request for use on apple, nectarine, and peach.  However, these crops have use patterns that are similar to the registered use on pear.  Therefore, the Agency relied on PDP data for pears, including for baby food and canned products, when assessing anticipated residues on peach, nectarine, and apple.  EPA believes the use of PDP data for pears is appropriate, as bifenthrin residues are found mainly on the fruit surface and residues on peach, nectarine, and apple are expected to be similar to those found on pear.  The evaluation of the analytical chemistry and residue data for the pear is described in a separate memorandum (D274839, S. Levy, 08/15/2002).

The acute and chronic EDWCs for bifenthrin were calculated using the Tier I aquatic models FIRST and SCI-GROW and based on a maximum application rate of 0.5 lb ai/A/season.  The acute and chronic EDWC in surface water was estimated is 0.014 ppb of bifenthrin, the solubility of the chemical.

The quantification of average dietary exposures was necessary to estimate short-term aggregate exposures.  This required the use of anticipated residues (ARs) from average field trial residues for tree nuts, artichoke, beans, beet (roots and tops), cabbage, carrot, coriander, mustard greens and tea.  ARs from PDP data were used for bean (succulent), beef, milk, pea, and pork.  For all other commodities, the assessment used current tolerances.  The assessment also made use of PCT information where available.  Drinking water information was incorporated directly into the dietary assessment using the mean concentration (1-in-10-year annual mean) for surface water generated by the PRZM-EXAMS model.

The assessment of human exposure from contaminated catfish used the mean and maximum subsistence fish intake amounts (Exposure Factors Handbook, 2011), and 2010 PDP data for catfish.  The mean fish intake for subsistence fishers is 81 g/day, and the maximum is 770 g/day.  PDP sampled 384 fish (catfish) total, with 130 showing detectable bifenthrin residue.  The highest residue was 0.06 ppb.

5.4.2	Percent Crop Treated Used in Dietary Assessment
	Percent Crop Treated (PCTn) Memo, D398265, J. Alsadek, 3/21/2012

A screening-level usage analysis (SLUA) was provided by the Biological Economic Analysis Division (BEAD), SLUA in Support of Registration for the Insecticide Bifenthrin, 10/31/2011.  The estimated maximum percent crop treated (PCT) for each commodity was used for the acute dietary risk assessment. For proposed new uses and uses that have not been registered long enough for usage data, the Agency conservatively estimated that 100 % of the crops were treated (see details below for the Section 18 uses).

BEAD also provided projected use information for the proposed Section 18 uses (i.e., apple, nectarine, and peach) in the memo, Estimates of the Percent Crop Treated for New Uses (PCTn) of Bifenthrin on Apples, Peaches, Nectarines, and Pears Considering Potential Emergency Use in DE, MD, NC, NJ, PA, VA, and WV.  BEAD used data from 2010 USDA/NASS Agricultural Statistics for apples and peaches.  Data on the most recent survey years, 2007-2009, were used to derive the needed PCT estimates.  The sum of the utilized production in these states was divided by the total domestic utilized production and multiplied by 100 to determine the PCT for each of the crops for each of the named years. BEAD conservatively estimated that 100 percent of the crops in these states will be treated with bifenthrin and calculated the national PCT given the share of utilized production or grown acreage from the seven states likely to seek the use of bifenthrin.

The following maximum PCT estimates were used in the acute dietary risk assessment: alfalfa, 1%; almonds, 25%; artichokes, 30%; beans, green, 50%; broccoli, 6 %; cabbage, 30%; caneberries, 45%; canola/rapeseed, 3%; cantaloupes, 60%; carrots, 10%; cauliflower, 10%; celery, 1%; corn, 5%,; cotton, 10 %; cucumbers, 15%; dry beans/peas, 1%; grapes, table, 1%;  grapes, wine, 5%; honeydew, 75%; hazelnuts (filberts), 5%;  lettuce, 15%; onions, 1%; lima beans, 35%; peanuts, 5%; peas, green, 25%;  pears, 4%; pecans, 5%; peppers, 20%; pistachios, 40%;  potatoes, 5%; pumpkins, 40%; sorghum,1%; soybeans, 5%; squash, 20%; strawberries, 55%; sweet corn, 50%; tomatoes, 20%; walnuts, 25%; watermelons, 15%; wheat, spring, 1%; and wheat winter, 1%.  In addition, the Agency estimated the PCT for the new uses with the time limited tolerances as follows: apples, 10%; peaches, 7%; nectarines, 3%; and pears 4%.

The following average PCT estimates were used to calculate average dietary exposures:  alfalfa, 1%; almonds, 12%; artichokes, 14%; beans, green, 40%; broccoli, 2%; cabbage, 20%; caneberries, 35%; canola/rapeseed, 2%; cantaloupes, 40%; carrots, 2%; cauliflower, 5%; celery, 1%; corn, 2%; cotton, 4%; cucumbers; 10%; dry beans/peas, 1%; grapes, table, 1%; grapes,wine, 2%; honeydew, 70%; hazelnuts (filberts), 5%; lettuce, 5%; onions, 1%; lima beans, 10%; peanuts, 2%; peas, green, 5%; pears, 1%; pecans, 2%; peppers 10%, pistachios 35%, potatoes, 2 %; pumpkins, 20%; sorghum, 1%; soybeans, 1%; squash, 10%; strawberries, 30%; sweet corn, 30 %; tomatoes, 6 %; walnuts, 15%; watermelons, 10%; wheat, spring, 1%; and wheat, winter, 1%. In addition, the following PCT estimates were used to calculate average dietary exposures for the proposed Section 18 uses in DE, MD, NC, NJ, PA,VA, and WV: apples, 10%; peaches, 6%; nectarines, 3%; and pears, 4%.

5.4.3	Acute Dietary Risk Assessment

 Highly-refined, acute probabilistic dietary exposure and risk assessments were conducted for all established food uses, as well as the petitioned for tolerances and the Section 18 time-limited tolerances.  High-end modeled drinking water estimates were directly incorporated into the assessment.  The acute dietary exposure estimates for food and drinking water are below HED's level of concern (<100% aPAD) at the 99.9th percentile of exposure.

 Bifenthrin dietary exposure at the 99.9th percentile for food and drinking water is 5 % of the aPAD for the U.S. population and 29 % of the aPAD for children 1-2 years, the most highly exposed population subgroup.  A summary of acute dietary exposures estimates for all populations is presented in Table 5.4.6, below.

 For the acute assessment of bifenthrin exposure to subsistence fishers, the maximum intake level identified in the 2011 Exposure Factors Handbook, 770g/day, was used.  The highest residue value from 2010 fish PDP data, 0.06 ng/g, was multiplied by the maximum fish intake resulting in a value of 46.2 ng/day of bifenthrin.  This value was converted to mg/day and then divided the weight of an adult, 80 kg, resulting in an estimated daily dose of 5.8 x 10-7 mg/kg/day.  This dose was then compared to the acute RfD to result in a highly conservative estimated % aPAD value of < 1 % and, therefore, would not be anticipated to significantly impact the dietary exposure assessments conducted for the proposed Section 3 and 18 uses.

 5.4.4		Chronic/Cancer Dietary Risk Assessment

Chronic and cancer dietary risk assessments were not conducted for bifenthrin.  Because there is no increase in hazard from repeat exposures to bifenthrin, the acute dietary exposure assessment is protective for chronic dietary exposures; acute exposure levels are higher than chronic exposure levels.  Accordingly, a dietary exposure assessment for the purpose of assessing chronic dietary risk was not conducted.

5.4.5	Average Dietary Exposure

Average dietary exposures were quantified for the purpose of assessing short-term aggregate risk (i.e., food, drinking water, and residential exposures) of the proposed and established uses.  A summary of average dietary exposures estimated for all population subgroups is presented in Table 5.4.6, below.

5.4.6	Summary Table

 Table 5.4.6.  Summary of Dietary (Food and Drinking Water) Exposure and Risk for Bifenthrin
                              Population Subgroup
                                 Acute Dietary
                              (99.9th Percentile)
                            Average Dietary Exposure
                                   (mg/kg/day)

                          Dietary Exposure (mg/kg/day)
                                     % aPAD

 General U.S. Population
                                     0.0015
                                      5.0 %
                                    0.00074
 All Infants (< 1 year old)
                                     0.0013
                                      13 %
                                    0.0010
 Children 1-2 years old
                                     0.0030
                                      29 %
                                    0.0018
 Children 3-5 years old
                                     0.0022
                                      22 %
                                    0.0014
 Children 6-12 years old
                                     0.0014
                                     4.6 %
                                    0.00080
 Youth 13-19 years old
                                     0.0011
                                     3.7 %
                                    0.00060
 Adults 20-49 years old
                                     0.0015
                                     4.8 %
                                    0.00066
 Adults 50+ years old
                                     0.0016
                                     5.1 %
                                    0.00066
 Females 13-49 years old
                                     0.0012
                                     3.8 %
                                    0.00055

6.0	Residential (Non-Occupational) Exposure/Risk Characterization

Residential exposure is anticipated from the proposed Section 3 bed bug treatment use.  In addition, residential exposures are anticipated from currently registered uses of the chemical.  Exposures are expected for individuals (adults) who apply bifenthrin-containing products and from post-application exposure in residential areas previously treated with the chemical.  In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks anticipated from food, drinking water, and residential exposures.  A residential exposure assessment was conducted for the bed bug treatment use (D383326, A. Rivera-Lupiáñez, 5/25/12) and considered for use in the aggregate assessment.  An updated assessment of bifenthrin residential uses has also been conducted for the purpose of assessing bifenthrin aggregate risk because of the revision of the Residential SOPs.

Residential uses of bifenthrin are many and vary widely.  The chemical is used in indoor residential/household premises in the form of crack and crevice sprays, as a paint additive, dust, and automobiles/recreational vehicle and termite treatments.  Outdoor residential uses of bifenthrin include broadcast and spot treatments to the following:  residential lawns/turf; golf course turf and outdoor premises (fencerows/hedgerows, paths/patios) by means of liquid spray and granular products; and ornamental (turf, shrubs, vines, trees, ground cover).

HED used the BEAD Label Use Information System (LUIS) in order to conduct a screen of the various indoor and outdoor residential uses of bifenthrin and determined those which would result in the greatest potential for exposure.  The following high-end uses were selected for use in the bifenthrin short-term aggregate assessment:  outdoor ornamental plant and turf uses.  The bed bug treatment was proposed for surface-directed application to the following indoor use sites:  baseboards, bed frames, box springs, closets, dressers, furniture, headboards, inside empty luggage, mattresses, and moldings.

The Health Effects Division's 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment was used to assess exposure/risk anticipated from all bifenthrin uses considered.

The lifestages (i.e., adults, children 1< 2 years old, children 11 < 16 years old, and children 6 < 11 years old) selected for each post-application scenario are based on an analysis provided as an Appendix in the 2012 Residential SOPs.  These lifestages are not the only that could be potentially exposed for these post-application scenarios; however, the assessment of these are health protective for the exposures and risks for any other potentially exposed lifestages.

Because of the rapid reversibility of the most sensitive neurotoxicity endpoint used for quantifying risks, there is no increase in hazard with increasing dosing duration. Therefore, the acute endpoint is protective of the endpoints from repeat dosing studies, including chronic exposures.  Thus, for purposes of residential exposure assessment, only single-day risk assessments were conducted.

6.1	Residential Handler Exposure

The Agency uses the term "handlers" to describe those individuals who are involved in the pesticide application process.  HED has determined that short-term dermal and inhalation exposure to residential handlers is likely during use of the following bifenthrin uses:  the proposed indoor bed bug treatments; and registered outdoor ornamental, and turf uses.

Residential handler dermal and inhalation risk estimates for bifenthrin are not of concern to HED (i.e., MOEs are >= 100 for dermal and >= 1,000 for inhalation, the levels of concern (LOC) for these assessments).

HED's level of concern for adult residential handlers is equal to an ARI of 1.  The combined dermal and inhalation risk estimates (ARIs) to residential handlers for the identified residential outdoor and proposed indoor bed bug uses are not of concern to HED (i.e., ARIs are >= 1).  The lowest ARI is 2.1 from use of a backpack sprayer equipment to treat ornamentals.  A summary of the results from the assessment of the proposed bed bug treatment is presented below in Table 6.1.  A summary of all other results is presented in Appendix C (Table C.1) of this document.

Table 6.1.  Residential Bifenthrin Handler Exposure and Risk Estimates for the Indoor Bed Bug Treatment
                               Application Rate
                                (lb ai/gallon)a
                          Amount Handled (gallons)[b]
                           Unit Exposure (mg/lb ai)b
                             Dose (mg/kg/day)[d,e]
                               Short-Term MOE[f]

                                   Dermal[c]
                                 Inhalation[c]
                                    Dermal
                                  Inhalation
                                    Dermal
                                  Inhalation
 Mixing/Loading/Applying Wettable Powders with Manually-Pressurized Handwand
                                    0.0051
                                     0.50
                                      69
                                      1.1
                                    0.0021
                                   0.000035
                                    44,000
                                    88,000
a.	Application Rates based on proposed use on label for F4688 50 WSP Insecticide Termiticide label (EPA Reg. No. 8033-96)
b. 	Based on 2011 Residential SOPs
c. 	Dermal:  Short-sleeve shirt, shorts, and no gloves; Inhalation: no respirator.
d. 	Dermal Dose (mg/kg/day) = daily unit exposure (mg/ - lb ai) * application rate (lb ai/gallon) * amount handled (gallons) * dermal absorption factor (100 %) / -  body weight (80 kg).
e. 	Inhalation Dose (mg/kg/day) = daily unit exposure (mg/ - lb ai) * application rate (lb ai/gallon) * amount handled (gallons) * inhalation absorption (100%) /  - body weight (80 kg).
f. 	Dermal MOE = PoD (BMDL10 of 96.3 (mg/kg/day) / Daily dermal dose (mg/kg/day); Inhalation MOE = PoD (BMDL1SD of 3.1 mg/kg/day) / Daily inhalation dose (mg/kg/day). Level of concern = 100 (Adult, dermal); 1000 (Adult, inhalation)

6.2	Residential Post-Application Exposure

The Agency uses the term "post-application" to describe exposures to individuals that occur as a result of being in an environment that has been previously treated with a pesticide.  Bifenthrin can be used in areas frequented by the general population, including indoor and outdoor residential areas.  As a result, HED anticipates post-application exposures from the residential use of bifenthrin.  The proposed indoor bed bug treatment and the same high-end outdoor uses considered for residential handlers were assessed for residential post-application exposure assessment.

Adult residential post-application dermal exposures assessed for the registered outdoor and proposed indoor uses are not of concern to HED.  The greatest estimated risk for adults corresponded to a dermal MOE of 270 for post-application exposure in ornamental gardens.  For children 1 < 2 years old, the combined dermal and incidental oral risk estimates for the identified residential uses are not of concern to HED (i.e., MOEs are >= 300, the LOC for these assessments).  The greatest estimated risk for children corresponds to a dermal MOE of 690 for children 1 < 2 years old contacting treated turf.  A summary of these results is presented in Appendix C (Table C.2) of this document.

6.3	Combined Exposure

HED combines risk values resulting from separate routes of exposure when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population, and if the hazard associated with the points of departure is similar across routes.  A common toxicological endpoint, neurotoxicity, exists for dermal, incidental oral, and inhalation routes of exposure to bifenthrin.  Therefore, these were combined for all residential exposure scenarios assessed.  A summary of these results is presented in Appendix C (Table C.2) of this document.

Table 6.3.1 below presents the combined risk estimates for the uses resulting in the highest potential for residential handler and post-application exposure.  These worst case estimates were used for the aggregate assessment.

Combined adult handler exposure (dermal and inhalation) from applying bifenthrin to ornamentals with a backpack sprayer results in a risk estimate that is not of concern to HED (i.e., the ARI is > 1).  The risk estimate for combined child 1 < 2 years old exposure (dermal and incidental oral) from contacting turf treated with a liquid formulated bifenthrin product is not of concern (i.e., the MOE is > 300).

Table 6.3.1  Combined Residential Bifenthrin Risk Estimates (High-End)
                                   Lifestage