\* 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
                               Exposure Scenario
                                   App. Rate
                               Route of Exposure
                               Dose (mg/kg/day)
                                      MOE
                                      ARI
                                    Handler
                                     Adult
                       Ornamentals  -  Backpack Sprayer 
                                     0.20 
                                    lb ai/A
                                    Dermal 
                                     0.34
                                      270
                                      2.1
                                       
                                       
                                       
                                  Inhalation
                                    0.00037
                                     8,400
                                       
                                   Lifestage
                               Exposure Scenario
                                   App. Rate
                               Route of Exposure
                               Dose (mg/kg/day)
                                      MOE
                                 Combined MOE
                               Post-Application
                           Child 1 < 2 Years Old
                                 Turf, Liquid
                                     0.20
                                   lb ai/acre
                                    Dermal 
                                     0.14
                                      690
                                      400
                                       
                                       
                                       
                                Incidental Oral
                                    0.0029
                                     1,000
                                       


Residential handler and post-application exposure scenarios are generally not combined.  Although the potential exists for the same individual (i.e., adult) to apply a pesticide around the home and be exposed by re-entering a treated area in the same day, this is an unlikely exposure scenario.  Combining these exposure scenarios would also be inappropriate because of the conservative nature of each individual assessment. 

Post-application residential exposure scenarios may be combined for purposes of an aggregate exposure assessment if they have a reasonable probability of occurring on a single day and the pest that an individual is attempting to control is the same.  All residential exposure scenarios assessed in this document were considered and the proposed indoor bed bug treatment is the only to meet this criteria.  Post-application co-exposure could occur following the simultaneous treatment multiple use sites (e.g., baseboards, furniture and mattresses) due to a bed bug infestation.  Therefore, combined risks for adults and children were estimated for the two post-application exposure scenarios.

Combined adult post-application exposure assessed for surface-directed sprays (dermal and inhalation) and mattress (dermal) use sites is not of concern to HED (i.e., the ARI is > 1).  For children 1 < 2 years old, combined post-application exposure assessed for surface-directed sprays (dermal, incidental oral, and inhalation), and mattress (dermal) are not of concern to HED (i.e., the ARI is > 1).  Table 6.3.2 below presents the combined risk estimates for a residential bed bug treatment.  

Table 6.3.2.  Combined Residential Post-Application Exposure Risk Estimates from Bed Bug Treatment
                                   Lifestage
                               Exposure Scenario
                                   App. Rate
                                (lb ai/gallon)
                               Route of Exposure
                               Dose (mg/kg/day)
                                      MOE
                                      ARI
                                     Adult
                            Surface-directed Sprays
                                    0.0051
                                    Dermal 
                                     0.012
                                     7,900
                                      79
                                       
                                       
                                       
                                  Inhalation
                                   0.000016
                                    190,000
                                       
                                       
                                   Mattress
                                       
                                    Dermal
                                    0.0014
                                    140,000
                                       
                           Child 1 < 2 Years Old
                            Surface-directed Sprays
                                       
                                    Dermal 
                                     0.012
                                     8,200
                                      3.6
                                       
                                       
                                       
                                  Inhalation
                                   0.000066
                                    45,000
                                       
                                       
                                       
                                       
                                Incidental Oral
                                    0.0018
                                     1,800
                                       
                                       
                                   Mattress
                                       
                                    Dermal
                                    0.0032
                                    61,000
                                       

6.4	Residential Bystander Post-application Inhalation Exposure

Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for bifenthrin.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm).  On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling.  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard air blast and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant risks associated with drift.

Although a quantitative residential post-application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers.  This exposure scenario, for which no risks of concern were identified, is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post-application inhalation exposure scenarios. 

7.0	Aggregate Exposure/Risk Characterization
   
In accordance with the FQPA, HED must consider and aggregate bifenthrin pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

Like other pyrethroids, bifenthrin causes clinical signs of neurotoxicity.  Muscle tremors were consistently observed throughout the bifenthrin toxicology database, and hind-limb flexion was observed in the dermal study.  Both effects are considered neurotoxic signs and, therefore, exposure estimates from multiple routes (i.e., dermal, incidental oral and inhalation) can be aggregated.   

Residential exposure to bifenthrin is anticipated from the proposed Section 3 bed bug use treatment, as well as from currently registered uses of the chemical.  As such, the short-term aggregate exposure and risk assessment of bifenthrin includes dietary (food and water) exposures anticipated from the proposed Section 3 and 18 uses and high-end, non-dietary exposures anticipated from the proposed bed bug use and currently registered residential uses.    
  
7.1	Acute Aggregate Risk

HED typically includes only food and water in the acute aggregate assessment, as one day residential exposures are not routinely assessed.  Please refer to Section 5.4.3 for a detailed discussion of the acute dietary risk assessment. 

7.2	Short-Term Aggregate Risk

The short-term aggregate exposure assessment includes exposures anticipated to occur from one to thirty days from dietary (food and water) and non-dietary, residential exposures from current and pending uses of bifenthrin.  In order to aggregate short-term residential uses with dietary exposure, it was necessary to calculate average dietary exposure.  Risk estimates (MOEs) were calculated by comparison of the short-term oral NOAEL to average dietary exposures for all populations.  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.

Different methodologies were used for the presentation of short-term aggregate risk for adults and children.  For adults, although the short-term dermal and inhalation risks were estimated using the same oral POD, these exposure estimates could not be directly combined for the adult short-term exposure assessment because the LOCs for dermal and inhalation routes of exposure are not the same (an MOE of <100 defines the LOC for dermal exposure, while inhalation risk is defined by an MOE of <1000).  Accordingly an aggregate risk index (ARI) was required to estimate aggregate risk for adults.  EPA identifies an ARI at or below 1 as a risk estimate of concern.  The short-term aggregate ARI for adults is 2.0. 

Please refer to the residential assessment, Section 6.2, for a discussion regarding the exposures that are likely to be combined.  

Short-term aggregate risk estimates (ARIs) for the general U.S. population are not of concern to HED (i.e., ARIs are >= 1).  Table 7.2.1, below, summarizes the results from the short-term aggregate for the general U.S. population.  

Short-term aggregate risk estimates (MOEs) for the most highly exposed population, children 1 < 2 years old, is also not of concern to HED (i.e, MOEs are >= 300).  Table 7.2.2, below, summarizes the results from the short-term aggregate assessment of children 1 < 2 years old. 


Table 7.2.1  Short-Term Adult Aggregate Risk Calculations[1]
                                  Population
                         Short -Term Exposure Scenario
                                       
                             Dietary Exposure[2] 
                        Dermal Residential Exposure[3]
                      Inhalation Residential Exposure[4]
                Aggregate ARI (food, water, and residential)[5]
                                       
                                      MOE
                                      ARI
                                      MOE
                                      ARI
                                      MOE
                                      ARI
                                       
Adult Female/Male
                                     4,700
                                      47
                                      270
                                      2.7
                                     8,400
                                      8.4
                                      2.0
1. An ARI less than 1 is of concern to HED (ARI = Aggregate Risk Index.)
2. MOE dietary = [(short-term oral NOAEL)/(average dietary exposure)].  ARI dietary = [(MOE dietary)/(MOE target)].  Short-term oral NOAEL is 3.1 mg/kg/day.  Average dietary exposure is 0.00066 mg/kg/day for Adults 20-49 years old (See Table 5.4.6).  The MOE target is 100.  
3. MOE dermal = [(short-term dermal NOAEL)/(high-end dermal residential exposure)].  ARI dermal = [(MOE dermal)/(MOE target)].  Short-term dermal NOAEL is 96.3 mg/kg/day.  The target MOE is 100.  See Table 6.3.1 for residential exposure values used in aggregate assessment.
4. MOE inhalation = [(short- term inhalation NOAEL)/(high-end inhalation residential exposure)].  ARI inhalation = [(MOE inhalation)/(MOE target)].  Short-term inhalation NOAEL is 3.1 mg/kg/day.  The target MOE is 1,000.  See Table 6.3.1 for residential exposure values used in aggregate assessment.
5. ARI Aggregate = 1/[(1/ARI dietary) +  (1/ARI dermal) + (1/ARI inhalation)]


Table 7.2.2  Short-Term Child Aggregate Risk Calculations
                                  Population
                         Short-Term Exposure Scenario
                                       
                           LOC for Aggregate Risk[1]
                                    Dietary
                                    MOE[2] 
                       MOE Oral Residential Exposure[3] 
                      MOE Dermal Residential Exposure[4]
                    MOE Inhalation Residential Exposure[5]
                Aggregate MOE (food, water, and residential)[6]
Child 1 < 2 Years Old
                                      300
                                     1,700
                                     1,000
                                      690
                                      NA
                                      330
1.  LOC is an MOE = 300  (10X inter- and intra- species uncertainty factors totaling 100, as well as additional 3X FQPA safety factor). 
2.  MOE dietary = [(short-term oral NOAEL)/(average dietary exposure)].  Short-term oral NOAEL is 3.1 mg/kg/day.  Average dietary exposure is 0.0018 mg/kg/day for children 1-2 years old (See Table 5.4.6).
3.  MOE oral = [(short- term incidental oral NOAEL)/(high-end residential incidental oral exposure)].  Short-term incidental oral NOAEL is 3.1 mg/kg/day.  Residential incidental oral exposure is 0.0029 mg/kg/day.  See Table 6.3.1 for source of residential exposure values used in aggregate assessment.
4.  MOE dermal = [(short-term dermal NOAEL)/(high-end dermal residential exposure)].  Short-term dermal NOAEL is 96.3 mg/kg/day.  See Table 6.3.1 for source of residential exposure values used in aggregate assessment.
5.  NA = Not applicable 
6.  MOE Aggregate = 1/[(1/MOE dietary) + (1/MOE oral) + (1/MOE dermal)]

7.3	Intermediate-Term/Chronic Aggregate Risk

An intermediate-term and/or chronic aggregate risk assessment was not conducted because bifenthrin is acutely toxic and there is no increase in hazard with increasing dosing duration.  Furthermore, chronic dietary exposures will be lower than acute exposures.  Therefore, the acute aggregate assessment is protective of potential chronic aggregate exposures.  For these same reasons, the acute aggregate assessment is also protective of potential cancer risk. 



8.0	Cumulative Exposure/Risk Characterization

The Agency is required to consider the cumulative risks of chemicals sharing a common mechanism of toxicity.  The Agency has determined that the pyrethroids and pyrethrins, including bifenthrin, share a common mechanism of toxicity (http://www.regulations.gov; EPA-HQ-OPP-2008-0489-0006).  The members of this group share the ability to interact with voltage-gated sodium channels ultimately leading to neurotoxicity.  The cumulative risk assessment for the pyrethroids/pyrethrins was published on Nov. 9, 2011 (USEPA, 2011a) and is available at http://www.regulations.gov; EPA-HQ-OPP-2011-0746.  Further information about the determination that pyrethroids and pyrethrins share a common mechanism of toxicity may be found in document ID: EPA-HQ- OPP-2008-0489-0006.

The Agency has conducted a quantitative analysis of the proposed bifenthrin bed bug use and has determined that it will not contribute significantly or change the overall findings presented in the pyrethroid cumulative risk assessment.  This analysis is summarized in Appendix D.  Further, the proposed food uses of bifenthrin will not contribute significantly or change the overall findings in the pyrethroid cumulative risk assessment as the dietary risks are a minor component of total pyrethroid cumulative risk.  For information regarding EPA's efforts to evaluate the risk of exposure to pyrethroids, refer to http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids-pyrethrins.html.

9.0 	Occupational Exposure/Risk Characterization

HED has determined that there is the potential for both occupational handler and post-application exposure to occur from the proposed Section 3 and 18 uses of bifenthrin.   

9.1	Occupational Short -Term Handler Exposure/Risk

Occupational exposure is expected for handlers who apply bifenthrin products for the proposed Section 3 and 18 uses.  Handler exposure is expected to be short-and intermediate-term based on information provided on the proposed labels; however, bifenthrin does not increase in toxicity with repeated dosing.  As such, only single day residential exposures were assessed. 

Chemical-specific data were not submitted to the Agency in support of the Section 3 application or the 18 proposal.  It is the policy of HED to use the best available data to assess handler exposure.  Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, or other registrant-submitted occupational exposure studies.  Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA.  The standard values recommended for use in predicting handler exposure that are used in this assessment, known as "unit exposures", are outlined in the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html.

A quantitative exposure/risk assessment was developed for occupational handlers based on the following exposure scenarios:

Section 3 (Grass Grown for Seed Only)

   * Mixing/loading liquids (open pour) and water soluble bags (WSB) in support of aerial, chemigation, and groundboom operations; 
   * Aerial application (enclosed cockpit); 
   * Application using open-cab groundboom equipment; and
   * Flagging in support of aerial applications.

Section 18 

   *  Mixing/loading dry flowable, liquids (open pour), and WSB in support of aerial, chemigation, and groundboom operations;
   * Aerial Application (enclosed cockpit);
   * Application using open-cab groundboom equipment; 
   * Application using airblast equipment; and
   * Flagging in support of aerial applications.

All Section 3 and 18 occupational handler scenarios assessed are not of concern to HED (i.e., ARIs are >= 1) with baseline attire (i.e., single layer of clothing, no respirator) or the addition of a filtering face piece dust mask respirator.  Tables 9.1.1 and 9.1.2 presents a summary of the short- term occupational handler exposures and risks from the Section 3 and 18 proposed uses, respectively. 

Table 9.1.1.  Section 3:  Short-Term Occupational Exposure and Risk Estimates for Bifenthrin
                               Exposure Scenario
                                Crop or Target
                            Dermal Unit Exposure[1]
                                  (mg/lb ai)
                          Inhalation Unit Exposure[1]
                                  (mg/lb ai)
                                    Maximum
                              Application Rate[2]
                                   (lb ai/A)
                            Amount Treated Daily[3]
                                    (Acres)
                                    Dermal
                                  Inhalation
                                    ARI[8]
                                       
                                       
                                       
                                       
                                       
                                       
                                    Dose[4]
                                  (mg/kg/day)
                                    MOE[5]
                                    Dose[6]
                                  (mg/kg/day)
                                    MOE[7]
                                       
                      Mixer/Loader for Brigade(R)[(R)] 2 EC
Mixing/Loading Liquid for Aerial Application
                     Grass Grown for Seed (Forage and Hay)
                                     0.220
                                  (baseline)
                                       
                                      or
                                       
                                0.037 (gloves)
                                    0.00021
                                     0.10
                                       
                                     1,200
                                     0.33
                                      290
                                    0.00032
                                     9,800
                                      2.2

                                       
                                       
                                       
                                       
                                       
                                     0.056
                                   (gloves)
                                     1,700
                                       
                                       
                                      17
Mixing/Loading Liquid for Groundboom Application
                                       
                                       
                                       
                                       
                                       
                                       
                                      200
                                     0.055
                                     1,800
                                   0.000053
                                    59,000
                                      14

                                       
                                       
                                       
                                       
                                       
                                    0.0094
                                   (gloves)
                                10,000 (gloves)
                                       
                                       
                                      37
Mixing/Loading Liquid for Chemigation
                                       
                                       
                                       
                                       
                                       
                                      350
                                     0.096
                                     1,000
                                   0.000092
                                    34,000
                                      7.7

                                       
                                       
                                       
                                       
                                       
                                     0.017
                                   (gloves)
                                     5,900
                                   (gloves)
                                       
                                       
                                      22
                      Mixer/Loader for Brigade(R)[(R)] WSB
Mixing/Loading WP (WSB) for Aerial Application
                     Grass Grown for Seed (Forage and Hay)
                                    0.0098
                                    0.00024
                                     0.10
                                     1,200
                                     0.015
                                     6,600
                                    0.00036
                                     8,600
                                      7.7
Mixing/Loading WP (WSB) for Groundboom Application
                                       
                                       
                                       
                                       
                                      200
                                    0.0025
                                    39,000
                                   0.000060
                                    52,000
                                      46
Mixing/Loading WP (WSB) for Chemigation
                                       
                                       
                                       
                                       
                                      350
                                    0.0043
                                    22,000
                                    0.00011
                                    30,000
                                      26
                                  Applicator
Applying Sprays with Fixed-wing Aircraft (enclosed cockpit)
                     Grass Grown for Seed (Forage and Hay)
                                    0.0050
                       (Eng.control -no gloves needed )
                                   0.000068
                                       
                                       
                                     0.10
                                     1,200
                                    0.0075
                                    13,000
                                    0.00010
                                    30,000
                                      25
Applying Sprays with Open Cab Groundboom
                     Grass Grown for Seed (Forage and Hay)
                                    0.0786
                                    0.00034
                                       
                                      200
                                     0.020
                                     4,900
                                   0.000085
                                    36,000
                                      21
                                    Flagger
Flagging to Support Aerial Applications
                     Grass Grown for Seed (Forage and Hay)
                                     0.011
                                    0.00035
                                     0.10
                                      350
                                    0.0048
                                    20,000
                                    0.00015
                                    20,000
                                      18
1 Unit Exposures based on "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (PHED)
(http://www.epa.gov/pesticides/science/handler-exposure-table.pdf), dated September 2011. 
All estimates are at Baseline PPE (Baseline Dermal:  Long-sleeve shirt, long pants, and no gloves or respirator).  
2 Application Rates based on proposed supplemental labeling (Reg. No. #279-3313 and 279-3108) 
3 Exposure Science Advisory Council Policy #9.1
4 Dermal Dose (mg/kg/day) = daily unit exposure (mg/ - lb ai) * application rate (lb ai/A) * area treated (A) * dermal absorption factor (100 %) / -  body weight (80 kg).
5 Dermal MOE = PoD (BMDL10 of 96.3 (mg/kg/day) / Daily dermal dose (mg/kg/day)
[6]Inhalation Dose (mg/kg/day) = daily unit exposure (mg/ - lb ai) * application rate (lb ai/A) * area treated (A) * inhalation absorption (100 %) /  - body weight (80 kg).  
[7]Inhalation MOE = PoD (BMDL1SD of 3.1 mg/kg/day) / Daily inhalation dose (mg/kg/day).
[8] Aggregate Risk Index  (ARI)  =  1 /  ((1/estimated MOE for adult dermal exposure/ LOC for adult dermal exposure ) + (1/estimated MOE for adult inhalation exposure/ LOC for adult inhalation oral exposure))











Table 9.1.2.  Section 18:  Short-Term Occupational Exposure and Risk Estimates for Bifenthrin
                               Exposure Scenario
                                Crop or Target
                           Dermal Unit Exposure [1]
                                  (mg/lb ai)
                         Inhalation Unit Exposure [1]
                                  (mg/lb ai)
                                    Maximum
                             Application Rate [2]
                           Amount Treated Daily [3]
                                    (Acres)
                                    Dermal
                                  Inhalation
                                    ARI[8]
                                       
                                       
                                       
                                       
                                       
                                       
                                   Dose [4]
                                  (mg/kg/day)
                                    MOE [5]
                                   Dose [6]
                                  (mg/kg/day)
                                    MOE [7]
                                       
               Mixer/Loader  -  Dry Flowable (Bifenture[TM] DF) 
Mixing/Loading DF for Aerial Application
                          Apple, Nectarine and Peach
                                     0.23
                                    0.0090 
                                     0.20
                                      350
                                     0.20
                                      480
                                    0.0079
                                      390
                                     0.36

                                       
                                       
                                    0.0018
                               (PF5 respirator)
                                       
                                       
                                     0.046
                                     2,100
                                    0.0016
                                     2,000
                                      1.4
Mixing/Loading DF for Groundboom Application 


                                    0.0090

                                      80
                                     0.046
                                     2,100
                                    0.0018
                                     1,700
                                      1.6
Mixing/Loading DF for Airblast Application




                                      40
                                     0.023
                                     4,200
                                    0.00090
                                     3,400
                                      3.1
                  Mixer/Loader  - Liquids (Bifenture[TM] EC)
Mixing/Loading Liquid for Aerial Application
                          Apple, Nectarine and Peach
                                     0.22
                                    0.00021
                                     0.20
                                      350
                                     0.19
                                      500
                                    0.00018
                                    17,000
                                      3.9
Mixing/Loading Liquid for Groundboom Application 

                                       
                                       
                                       
                                      80
                                     0.044
                                     2,200
                                    0.00004
                                    74,000
                                      17
Mixing/Loading Liquid for Airblast Application

                                       
                                       
                                       
                                      40
                                     0.022
                                     4,400
                                    0.00002
                                    150,000
                                      34
               Mixer/Loader Water Soluble Bags- (Brigade(R) WSB)
Mixing/Loading WSB for Aerial Application
                          Apple, Nectarine and Peach
                                    0.0098
                                    0.00024
                                     0.20
                                      350
                                    0.0086
                                    11,000
                                    0.00021
                                    15,000
                                      13
Mixing/Loading WSB for Groundboom Application 
                                       
                                       
                                    0.00024
                                       
                                      80
                                    0.0020
                                    49,000
                                   0.000048
                                    65,000
                                      57
Mixing/Loading WSB for Airblast Application
                                       
                                       
                                    0.00024
                                       
                                      40
                                    0.00098
                                    99,000
                                   0.000024
                                    130,000
                                      110
                                  Applicator
Applying Sprays via Aerial Equipment (Enclosed Cockpit)
                          Apple, Nectarine and Peach
                                    0.0050
                                    0.00006
                                     0.20
                                      350
                                    0.0044
                                    22,000
                                    0.00050
                                    59,000
                                      47
Applying Sprays via Groundboom
Equipment (Open Cab)
                          Apple, Nectarine and Peach
                                     0.079
                                    0.00034
                                     0.20
                                      80
                                     0.016
                                     6,100
                                   0.000068
                                    46,000
                                      26
Applying Sprays via Groundboom Equipment 
(Enclosed Cab) [9]
                                       
                                    0.0051
                                    0.00004
                                       
                                      40
                                    0.0010
                                    94,000
                                   0.0000080
                                    390,000
                                      280
Applying Sprays via Airblast Equipment 
(Open Cab)
                                       
                                      1.8
                                    0,00471
                                       
                                      40
                                     0.18
                                      540
                                    0.00047
                                     6,600
                                      3.0
Applying Sprays via Airblast Equipment (Enclosed Cab) [9]
                                       
                                     0.015
                                    0.00006
                                       
                                      40
                                    0.0015
                                    67,000
                                   0.0000060
                                    52,000
                                      48
                                    Flagger
Flagger for Support of Aerial Spray Applications
                          Apple, Nectarine and Peach
                                       
                                     0.011
                                       
                                    0.00035
                                     0.20
                                      350
                                    0.0096
                                    10,000
                                    0.00030
                                    10,000
                                      9.1
1 Unit Exposures based on "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (PHED)
(http://www.epa.gov/pesticides/science/handler-exposure-table.pdf), dated September 2011. 
All estimates are at Baseline PPE (Baseline Dermal:  Long-sleeve shirt, long pants, and no gloves; Baseline Inhalation: no respirator).
2 Application Rates based on registered labels (Reg. No. #279-3108, 70506-57, 70506-227) for use on pears.
3 Exposure Science Advisory Council Policy #9.1
4 Dermal Dose (mg/kg/day) = daily unit exposure (mg/ - lb ai) * application rate (lb ai/A) * area treated (A) *dermal absorption factor (100 %) / -  body weight (80 kg).
5 Dermal MOE = PoD (BMDL10 of 96.3 (mg/kg/day) / Daily dermal dose (mg/kg/day)
[6]Inhalation Dose (mg/kg/day) = daily unit exposure (mg/ - lb ai) * application rate (lb ai/A) * area treated (A) * inhalation absorption (100 %) /  - body weight (80 kg).  
[7]Inhalation MOE = PoD (BMDL1SD of 3.1 mg/kg/day) / Daily inhalation dose (mg/kg/day).
[8] Aggregate Risk Index  (ARI)  =  1 /  ((1/estimated MOE for adult dermal exposure/ LOC for adult dermal exposure ) + (1/estimated MOE for adult inhalation exposure/ LOC for adult inhalation oral exposure))
9.2	Occupational Short-Term Post-Application Exposure/Risk

HED has determined that there is the potential for post-application dermal exposure to bifenthrin following application to the proposed Section 3 and 18 uses.  Post-application exposure may occur when workers enter previously treated areas to perform job functions.  Re-entry workers are expected to experience short-term exposure to bifenthrin while performing post-application activities such as scouting and irrigation. 

Chemical-specific dislodgeable foliar residue (DFR) studies for bifenthrin were identified for bifenthrin and were considered for use in the occupational post-application assessment.  Because the use of this data has no effect on the risk outcome, HED used default DFR assumptions.   Sources of generic post-application data, used as surrogate data in the absence of chemical-specific data, are derived from Agricultural Reentry Task Force (ARTF) exposure monitoring studies, and, as proprietary data, are subject to the data protection provisions of FIFRA.  The standard values recommended for use in predicting post-application exposure that are used in this assessment, known as "transfer coefficients",  are presented in the "Science Advisory Council for Exposure (ExpoSAC) Policy 3" (http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along with additional information about the ARTF data, can be found at http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

The results of the post-application exposure and risk assessment indicate that MOEs > 100 are achieved on Day 0 (12 hours) for all potential post-application activities and, therefore, are not of concern.  The post-application activity scenarios along with respective TCs and risk estimates for short -term MOEs are summarized in Table 9.2.  

Table 9.2.  Summary of Estimated Post-application MOEs for Proposed Bifenthrin Section 3 and 18 Uses
                                     Crop
                          Maximum Application Rate[1]
                                     DFR2 
                                   Activity
                                     TC[3]
                                    MOE[4]
                                    DAT[5]
                                   Section 3
Grass Grown for Seed (Forage and Hay)
                                     0.10
                                     0.28
                                   Scouting
                                     1,100
                                     3,100
                                 0 (12 hours)
                                       
                                       
                                       
                                  Irrigation
                                     1,900
                                     1,800
                                       
                                  Section 18
Apple, Nectarine and Peach
                                     0.20
                                     0.56
                         Orchard Maintenance, Propping
                                      100
                                    17,000
                                 0 (12 hours)

                                       
                                       
                                 Hand Pruning,
                                   Training,
                                   Scouting
                                      580
                                     2,900
                                       

                                       
                                       
                                Hand Harvesting
                                     1,400
                                     1,200
                                       

                                       
                                       
                                Thinning Fruit
                                     3,600
                                      480
                                       
1. Maximum application rate (lb ai/A) indicated on proposed labels (See Table 3.3). 
2.  DFR (ug/cm[2]) = Application rate (lb ai/A) x Conversion factor (11.2 ug/cm[2]) x Fraction of ai retained on foliage on day zero(25%)
3. TC (cm[2]/hr) = Transfer coefficients and associated activities from Science Advisory Council for Exposure Policy Number 3.2 "Agricultural Transfer Coefficients", June 2011 (http://www.epa.gov/pesticides/science/exposac_policy3.pdf
4. Daily Dose = [(DFR x  TC x  Exposure Time 8-hr)] / [(CF: 1000 ug/mg) x (Body Weight 80-kg)]
Short-term Dermal NOAEL = 96.3 mg/kg/day.  The LOC is 100.   
MOE = NOAEL / Daily Dose. Dermal MOE= PoD (BMDL10 of 96.3 (mg/kg/day) / Daily dermal dose (mg/kg/day). Level of concern = 100 (Adult).
5. DAT = Days after treatment needed to reach the LOC of 100; DAT 0 = the day of treatment, after sprays have dried; assumed to be approximately 12 hours.  

9.2.2	Inhalation Post-application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for bifenthrin at this time primarily because of the low acute inhalation toxicity (Toxicity Category III), low vapor pressure (1.8 x 10-7 mmHg at 25º C), and the low proposed use rate (0.20 lb ai/A).  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for bifenthrin.

Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers.  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.


10.0	References

Toxicology

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Anand, S.S., Kim KB, Padilla S, Muralidhara S, Kim HJ, Fisher JW, Bruckner JV. "Ontogeny of hepatic and plasma metabolism of deltamethrin in vitro: Role in age-dependent acute neurotoxicity". Drug Metabolism and Disposition. 2006 Mar;34(3): 389-97.

Choi, J.S., Soderlund, D.M. (2006). "Structure-activity relationships for the action of 11 pyrethroid insecticides on rat Nav 1.8 sodium channels expressed in Xenopus oocytes". Toxicology and Applied Pharmacology 211(3):233-44. 

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Lund, A. and T. Narahashi (1982). "Dose-dependent interaction of the pyrethroid isomers with sodium channels of squid axon membranes." Neurotoxicology 3(1): 11-24.

Meacham, C. A., P. D. Brodfuehrer, J. A. Watkins and T. J. Shafer (2008). "Developmentally-regulated sodium channel subunits are differentially sensitive to [alpha]-cyano containing pyrethroids." Toxicology and Applied Pharmacology 231: 273-281.

Mirfazaelian, A., K. Kim, S. Anand, H. Kim, R. Tornero-Velez, J. Bruckner and J. Fisher (2006). "Development of a physiologically based pharmacokinetic model for deltamethrin in the adult male Sprague-Dawley rat." Toxicological Science 93(2): 432 - 442.

Nemec, M. (2006). An acute functional observational battery comparison study in rats, WIL Research Laboratories study number 409002. 3: 867.

Ross, M. K., A. Borazjani, C. C. Edwards and P. M. Potter (2006). "Hydrolytic metabolism of pyrethroids by human and other mammalian carboxylesterases." Biochemical Pharmacology 71(5): 657-669.

Salgado, V., M. Herman and T. Narahashi (1989). "Interactions of the pyrethroid fenvalerate with nerve membrane sodium channels: Temperature dependence and mechanism of depolarization." Neurotoxicology 10(1): 1-14.

Selim, S., "Kinetics of FMC 54800 in the Blood of Rats", FMC Corporation, Unpublished Study, MRID 00163069.

Sheets, L.P., et al., Age-Dependent Differences in the Susceptibility of Rats to Deltamethrin. Toxicology and Applied Pharmacology, 1994. 126(1): p. 186-190.

Scollon, E. J., J. M. Starr, S. J. Godin, M. J. DeVito and M. F. Hughes (2009). "In Vitro Metabolism of Pyrethroid Pesticides by Rat and Human Hepatic Microsomes and Cytochrome P450 Isoforms." Drug Metabolism and Disposition 37(1): 221-228.

Scollon, E.J., Starr, J.M., Crofton, K.M., Wolansky, M.J., DeVito, M.J., Hughes, M.F. (2011) "Correlation of tissue concentrations of the pyrethroid bifenthrin with neurotoxicity in the rat".  Toxicology 290 (2011) 1 -  6.

Soderlund, D., J. Clark, L. Sheets, L. Mullin, V. Piccirillo, D. Sargent, J. Stevens and M. Weiner (2002). "Mechanisms of pyrethroid neurotoxicity: implications for cumulative risk assessment." Toxicology 171(1): 3 - 59.

Song, J. and T. Narahashi (1996). "Modulation of sodium channels of rat cerebellar Purkinje neurons by the pyrethroid tetramethrin." Journal of Pharmacology and Experimental Therapeutics 277(1): 445 - 453.
Tabarean, I. V. and T. Narahashi (1998). "Potent Modulation of Tetrodotoxin-Sensitive and Tetrodotoxin-Resistant Sodium Channels by the Type II Pyrethroid Deltamethrin." Journal of Pharmacology and Experimental Therapeutics 284(3): 958-965.

Tan, J. and D. M. Soderlund (2009). "Human and rat Nav1.3 voltage-gated sodium channels differ in inactivation properties and sensitivity to the pyrethroid insecticide tefluthrin." NeuroToxicology 30(1): 81-89.

Tornero-Velez, R., A. Mirfazaelian, K.-B. Kim, S. S. Anand, H. J. Kim, W. T. Haines, B. James V and J. W. Fisher (2010). "Evaluation of deltamethrin kinetics and dosimetry in the maturing rat using a PBPK model." Toxicology and Applied Pharmacology 244: 208-217.

USEPA (2007). "Meeting Minutes:  FIFRA SAP Meeting on Assessing Approaches for the Development of PBPK Models of Pyrethroid Pesticides. Document ID:  EPA-HQ-OPP-2007-0388-0049.  www.regulations.gov."

US EPA (1998). Guidelines for Neurotoxicity Risk Assessment, Federal Register.

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

USEPA (2011b). Reevaluation of the FQPA Safety Factor for Pyrethroid Pesticides, D381210, 6/27/11.

US EPA (2011). Bifenthrin - ToxSAC Meeting Report (October 6, 2011)

US EPA (2012). Bifenthrin: Summary of Hazard and Science Policy Council (TXR# 0056209, HASPOC Report, Jan. 4, 2012)

Verschoyle, R. D. and W. N. Aldridge (1980). "Structure-activity relationships of some pyrethroids in rats." Archives of Toxicology 45(4): 325-329.

Weiner, M. L., M. Nemec, L. Sheets, D. Sargent and C. Breckenridge (2009). "Comparative functional observational battery study of twelve commercial pyrethroid insecticides in male rats following acute oral exposure." Neurotoxicology 30 Suppl 1: S1-16.

Wolansky MJ, McDaniel KL, Moser VC, Crofton KM (2007), "Influence of dosing volume on the neurotoxicity of bifenthrin." Neurotoxicology and Teratology 29(3):377-84 

Wolansky, M.J, Gennings, C. , Crofton, K.M.  (2006) "Relative Potencies for Acute Effects of Pyrethroids on Motor Function in Rats". Office of Research and Development, US EPA, Research Triangle Park, NC, MRID 47885701. Toxicological Sciences 89(1):271-277

Wolansky, M. J. and J. A. Harrill (2008). "Neurobehavioral toxicology of pyrethroid insecticides in adult animals: A critical review." Neurotoxicology and Teratology 30(2): 55-78.

Yang, D., R. E. Pearce, X. Wang, R. Gaedigk, Y.-J. Y. Wan and B. Yan (2009). "Human carboxylesterases HCE1 and HCE2: Ontogenic expression, inter-individual variability and differential hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin." Biochemical Pharmacology 77(2): 238-247.

Dietary

S. Tadayon. "Bifenthrin:  Acute Dietary (Food and Drinking Water) Exposure and Risk Assessment for Sections 3 and 18 Registration of Bifenthrin on Grass, Forage, Hay, Imported Tea, Apple and Peach."  D383085.  5/25/2012

J. Luis Meléndez. "Tier 1 Estimated Environmental Concentrations of Bifenthrin for the Use in the Human Health Risk Assessment; IR-4 Petition for the Use of the Chemical on Vegetable Roots (except for sugar and garden beets), Beets, Radish, Pistachio, Peanuts, Soybean, Fruiting Vegetables and Mayhaw." D372556.  8/11/2010

U.S. EPA. (2011).  Exposure Factors Handbook 2011 Edition. U.S. Environmental Protection Agency, Washington, DC, EPA/600/R-09/052F.

Residue Chemistry

P. Savoia. "Bifenthrin.  Section 3 Registration Adding Uses to Grass (Seed Crop) and Imported Tea along with a Section 18 Emergency Exemption for Treating Apples, Nectarines, and Peaches.  Summary of Analytical Chemistry and Residue Data."  D388604.  5/25/2012.

S. Levy. "Bifenthrin on Pear and Nut, Tree, Group: Evaluation of Residue Data and Analytical Methods."  D274839.  8/15/2002.

Occupational and Residential Exposure 

A. Rivera-Lupiáñez. " Bifenthrin: Occupational and Residential Risk Assessment to Support Request for Section 3 Registrations on Grass (Forage and Hay) and Imported Tea." D401702.  5/25/2011

A. Rivera-Lupiáñez. "Bifenthrin: Occupational and Residential Risk Assessment in Support of Proposed Section 18 Emergency Exemption for Use on Pome Fruits and Stone Fruits in Virginia, New Jersey, Pennsylvania, Maryland, Delaware, West Virginia, and North Carolina to Control Stink Bugs."  D398490.  5/25/2012.

A. Rivera-Lupiáñez. "Bifenthrin: Occupational and Residential Risk Assessment for Proposed Bed Bug Treatment and Registered Crack and Crevice Use." D383326.  5/25/2012

S. Tadayon. Bifenthrin: Revised Occupational and Residential Assessment for Turf Using the 2012 Residential SOPs. D400326. 5/25/2012






































Appendix A.  Toxicology Profile and Endpoint Selection

A.1	Toxicology Data Requirements


Table A.     Toxicology Requirements for Bifenthrin  

Guideline Number and Toxicity Study

                                   Required

                                   Satisfied

870.1100	Acute Oral Toxicity	
870.1200	Acute Dermal Toxicity	
870.1300	Acute Inhalation Toxicity	
870.2400	Primary Eye Irritation	
870.2500	Primary Dermal Irritation	
870.2600	Dermal Sensitization	

                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

870.3100	Oral Sub-chronic (Rodent)	
870.3150	Oral Sub-chronic (Non-Rodent)	
870.3200	21-Day Dermal	
870.3250	90-Day Dermal	
870.3465	90/28-Day Inhalation	

                                      yes
                                      yes
                                      yes
                                     no[1]
                                      yes

                                      yes
                                      yes
                                      yes
                                     no[1]
                                     no[2]

870.3700	Developmental Toxicity  (Rodent)	
870.3700	Developmental Toxicity (Non-rodent)	
870.3800	Reproduction	

                                      yes
                                      yes
                                      yes

                                      yes
                                      yes
                                      yes

870.4100	Chronic Toxicity (Rodent)	
870.4100	Chronic Toxicity (Non-rodent)	
870.4200	Oncogenicity (Rat)	
870.4200	Oncogenicity (Mouse)	
870.4300	Chronic/Oncogenicity	

                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

870.5100	Mutagenicity: Gene Mutation - bacterial	
870.5300	Mutagenicity: Gene Mutation - mammalian	
870.5375	Mutagenicity: Structural Chromosomal Aberrations	
870.5385	Mutagenicity: Structural Chromosomal Aberrations	
870.5500	Mutagenicity: Other Genotoxic Effects	
870.5550	Mutagenicity: Other Genotoxic Effects	

                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

870.6100	Acute Delayed Neurotoxicity (Hen)	
870.6100	90-Day Neurotoxicity (Hen)	
870.6200	Acute Neurotoxicity Screening Battery (Rat)	
870.6200	90 Day Neurotoxicity. Screening Battery (Rat)	
870.6300	Developmental Neurotoxicity	

                                      no
                                      no
                                      yes
                                      yes
                                      yes

                                       -
                                       -
                                      yes
                                      yes
                                      yes

870.7485	General Metabolism	
870.7600	Dermal Penetration	
870.7800     Immunotoxicity.......................................................................

                                      yes
                                      yes
                                      yes

                                      yes
                                      yes
                                      no
1. HASPOC decision, see memo cited in references (TXR# 0056209).
2. Study to be replaced by an acute study with targeted ACN metrics.  








A.2	Toxicity Profiles

Table A.2.1.      Acute Toxicity Profile  -  Bifenthrin
                                       
                           Guideline No./Study Type
                                       
                                   MRID No.
                                       
                                    Results
                              Toxicity  Category
870.1100     Acute oral toxicity
0013519
LD50 = 70.1 mg/kg (♂); 53.8 mg/kg (♀) 
                                      II
870.1200     Acute dermal toxicity
00132520
LD50 > 2,000 mg/kg 
                                      III
870.1300     Acute inhalation toxicity
46008101
LC50=1.01 mg/L (combined value, Male is 1.1 & Female is 0.8 mg/L)
Heated to 100° C for testing
                                      III
870.2400     Primary eye irritation
00132522
Non-irritant
                                      IV
870.2500     Primary dermal irritation
00132521
Non-irritant
                                      IV
870.2600     Dermal sensitization
00132523
Not a sensitizer
                                      N/A



Table A.2.2.      Toxicity Profiles for Bifenthrin

                                  Guideline 
                                    Number

                                   MRID No.

                                  Study Type

                                    Results

                        Acute and Sub-chronic Toxicity
Special Study
47885701
Wolansky Study (2006)
Acute Oral Toxicity in Long Evans Rats
BMDL1SD = 3.1 mg/kg
BMD1SD = 4.1 mg/kg based on decreased locomotor activity
0, 0.03, 0.1, 1.0, 4.0, 8.0, 12.0, 16.0, 24.0, 28.0 mg/kg via gavage in corn oil (1 mL/kg)
Classification: Acceptable, Non-Guideline
Special Study
47050504,
47050505
Weiner/WIL Study (2009)
Acute Oral Toxicity in Rats
BMDL20 = 0.4 mg/kg
BMD20 = 14.3 mg/kg based on  multiple FOB changes
0, 40, 55 mg/kg via gavage in corn oil (5 mL/kg)
Classification: Acceptable, Non-Guideline
870.3100
00141199

90-Day Oral Toxicity - Rat (1984)

NOAEL = 3.8 mg/kg/day (males); 4.3 mg/kg/day (females)

LOAEL = 7.5 mg/kg/day (males), 8.5 mg/kg/day (females), based on increased incidence of tremors.

Classification: Acceptable-Guideline
870.3150
00141200

90-Day Oral Toxicity -
Dog (1984)

NOAEL = 2.21 mg/kg/day (males and females)

LOAEL = 4.42 mg/kg/day (males and females) based on increased incidence of tremors.  

Classification: Acceptable-Guideline

                        Prenatal Developmental Toxicity

870.3700

00154482

Developmental Toxicity (Gavage) - Rat
(1983)

Range-finding study

Maternal Toxicity 
NOAEL = 0.88 mg/kg/day
LOAEL = 1.77 mg/kg/day based on tremors during gestation.

Developmental Toxicity
NOAEL = not determined (fetuses not examined)
LOAEL = not determined (fetuses not examined)

Classification: Acceptable-Guideline

870.3700

00141201

Developmental Toxicity (Gavage) - Rat
(1984)

Maternal Toxicity 
NOAEL = 0.88 mg/kg/day
LOAEL = 1.77 mg/kg/day based on tremors during gestation.

Developmental Toxicity
NOAEL = 1.77 mg/kg/day
LOAEL = Not Observed

Classification: Acceptable-Guideline

870.3700

45352301

Developmental Toxicity (Dietary) - Rat
(2001)

Maternal Toxicity 
NOAEL = 7.1 mg/kg/day
LOAEL = 15.5 mg/kg/day based clinical signs and decreased food consumption, body weight gains, and body weight gains adjusted for gravid uterine weight.

Developmental Toxicity
NOAEL = 15.5 mg/kg/day
LOAEL = not observed.

Classification: Acceptable-Guideline

870.3700

00145997

Developmental Toxicity - Rabbit (1984)


Maternal Toxicity 
NOAEL = 2.36 mg/kg/day
LOAEL = 3.5 mg/kg/day based on treatment-related head and forelimb twitching.

Developmental Toxicity
NOAEL = greater than 7 mg/kg/day
LOAEL = not observed

Classification: Acceptable-Guideline

                             Reproductive Toxicity

870.3800

00157225

Multigeneration Reproductive Toxicity - Rat (1986)

Parental/Systemic Toxicity
NOAEL = 3.0 mg/kg/day for females and 5.0 mg/kg/day for males
LOAEL = 5.0 mg/kg/day for females, based on tremors and decreased body weight; not observed for males.

Reproductive/offspring Toxicity
NOAEL =5.0 mg/kg/day.
LOAEL = not observed.

Classification:  Acceptable-Guideline 

                       Chronic Toxicity/Carcinogenicity
870.4100
00163065
Chronic Toxicity (1 Year) - Dog
(1985)

NOAEL  = 1.3 mg/kg/day (males and females)
LOAEL = 2.7 mg/kg/day (males and females) based on increased incidence of tremors.

Classification:  Acceptable-Guideline 

870.4300

00157226

Combined Chronic Toxicity/Carcinogenicity - Rat (1986)

NOAEL  = 3.0 mg/kg/day (females); 4.7 mg/kg/day (males)
LOAEL = 6.1 mg/kg/day (females), based on increased incidence of tremors; 9.7 mg/kg/day (males), based on increased incidence of tremors.

Carcinogenicity - No conclusive evidence of carcinogenic potential.

Classification: Acceptable-Guideline

870.4200

00157227

Carcinogenicity - Mice
(1986)

NOAEL  = 6.7 mg/kg/day (males); 8.8 mg/kg/day (females)
LOAEL = 25.6 mg/kg/day (males) and 32.7 mg/kg/day (females), based on increased incidence of tremors.

Carcinogenicity - carcinogenic potential was evidenced by a dose-related increase in the incidence of hemangiopericytoma in the urinary bladder, a significant dose-related trend for combined hepatocellular adenomas and carcinomas in males, and a significantly higher incidence of combined lung adenomas and carcinomas in females.  

   Classification: Acceptable-Guideline

                                 Neurotoxicity

870.6200a

44862102

Acute Neurotoxicity - Rat

NOAEL = 35 mg/kg (32.8 mg ai/kg/day). 

LOAEL = 75 mg/kg (70.3 mg ai/kg/day) based on mortality (females only), clinical and FOB findings and differences in motor activity.  No vehicle utilized and heated to 80° C to liquefy. 

Classification: Acceptable-Guideline

870.6200b

44862103

Sub-chronic Neurotoxicity - Rat

NOAEL = 50 ppm (equivalent to 2.9 mg/kg/day in males and 3.7 mg/kg/day in females). 

LOAEL =100 ppm (equivalent to 6.0 mg/kg/day in males and 7.2 mg/kg/day in females) based on neuromuscular findings (tremors, changes in grip strength  and landing foot-splay).  

Classification: Acceptable-Guideline
870.6300
46750501 
Developmental 
Neurotoxicity - Rat
Maternal NOAEL = 3.6 mg/kg/day during gestation and 8.3 mg/kg/day during lactation,
LOAEL = 7.2 mg/kg/day during gestation and 16.2 mg/kg/day during lactation based on clinical signs of neurotoxicity (tremors, clonic convulsions, and increased grooming counts).

Developmental NOAEL =3.6 mg/kg/day during gestation and 8.3 mg/kg/day during lactation.
Developmental LOAEL = 7.2 mg/kg/day during gestation and 16.2 mg/kg/day during lactation based on clinical signs of neurotoxicity (increased grooming counts).

                                Dermal Toxicity

870.3200

00141198

Dermal Toxicity - Rabbit

NOAEL = 88 mg ai/kg/day (males and females)

LOAEL = 442 mg ai/kg/day (males and females), based on loss of muscle coordination and increased incidence of tremors.



870.3200

45280501

Dermal Toxicity - Rat 


NOAEL = 47 mg ai/kg/day (males and females)
BMDL10=96.3 mg/kg/day


LOAEL = 93 mg ai/kg/day (males and females), based on staggered gait (M) and exaggerated hind limb flexion (F)
BMD10=187.0 mg/kg/day, based on exaggerated hind limb flexion

                        Metabolism and Pharmacokinetics

870.7485

00163067 40415102

Metabolism - Rat

Very little of the administered radioactive dose was expired as [14]C-CO2 (0.028% for males and 0.053% for females).  The majority (about 70%) of the administered radioactivity was found in the feces with about 20% in the urine. A complication of this study is that males were administered a radioactive dose with the label in the acid position, while females were administered a radioactive dose with the label in the alcohol position.  This could make comparisons between males and females difficult.  Despite the difference in  [14]C- labelling position in the bifenthrin administered to males and females, the study is acceptable.  This conclusion is based on the fact that most (>90%) of the radioactivity was eliminated via the urine and feces, with no significant differences between the sexes in this respect.   Further, there were no significant differences between dosage groups in percentages excreted.  This suggests that most of the compound is excreted with little or no change, or in a form incorporating both of the labeled sites.  The results also show that females retained slightly more radioactivity in their bodies (particularly in adipose tissue) than did males, particularly at the high-dose.  Labeling of the material given to the females was in the biphenyl group, and, given a splitting of the molecule between the two labeling sites, this would have tended to give a more lipophilic radiolabeled residue.  

Classification:   Acceptable-Guideline

870.7485

00163069

Metabolism - Rat

Plasma radioactivity in the low-dose (4 mg/kg) animals after dosing slowly rose, indicating a slow rate of absorption from the gastrointestinal tract.  The half-life of absorption was calculated to be about 1.5 hours, with a lag-time of 0.5 hours following first order kinetics.  Radioactivity peaked in plasma for low-dose animals in 4 hours.  The elimination of  [14]C-bifenthrin from the plasma was equally slow, with significant radioactivity still remaining in blood at 72 hours.  Plasma radioactivity in the high-dose (35 mg/kg) animals appeared to follow a similar course as seen in the low-dose animals.  The peak radioactivity for the high-dose group appeared to be somewhat delayed, peaking at about 6 hours.  Significant radioactivity still remained after 72 hours in the high-dose animals. 

Classification:   Acceptable-Guideline  

870.7485

00163070

Metabolism - Rat

The major metabolic route of radiolabeled bifenthrin appeared to be hydrolysis of the ester linkage with oxidation of the resulting alcohol to the acid.  Protein binding of radioactive components or metabolites appears to increase with time.  
 
Classification:   Acceptable-Guideline  

870.7485

00163071

Metabolism - Rat

Fat and skin half-lives were the longest with half-lives of 51 and 50 days, respectively.  The half-lives for ovaries, liver, kidneys and sciatic nerve were 37.4, 19.0, 28.5, and 42 days, respectively.  Radioactive components were measured in fat at numerous time intervals, before and after daily dosing.  The major component in fat is parent compound with a half-life of 47.5 days.  Other unidentified components included a somewhat polar (Rf = 0.65) compound and two other relatively minor components.  

Classification:   Acceptable-Guideline  

870.7485

00163066

Metabolism - Rat

Within 7 days, nearly all bifenthrin and/or metabolites were excreted in either urine or feces.  The majority of radioactivity was excreted in the feces within 48 hours.  Tissues that retained bifenthrin and/or metabolites beyond 7 days included fat and skin in males and females, and gonads in females.   

Classification:  Unacceptable-Guideline. Although the number of animals/group in this study was 3, and not 5/sex/group as recommended by guidelines, and a quality assurance statement was lacking, the results of this study provide useful information.

870.7485

40415100

Metabolism - Rat

Results showed minimal breakage of the ester linkage of the parent compound in the material eliminated via the feces in the period of 0-48 hours after dosage, when most of the administered radioactivity is identified as coming from unmodified parent compound.  However, the material was subsequently eliminated, although a relatively small proportion of the administered dose appears to have undergone more modification.  Since a greater proportion of the radioactivity was eliminated via the feces in the period of 48-168 hours in the form of 2-Methyl-3-phenylbenzyl alcohol and 2-Methyl-3-phenylbenzoic acid than the parent compound, this is evidence that extensive breakage of the ester linkage does occur, either in the material retained in the intestines for more than 46 hours, or in the material absorbed and subsequently eliminated via the feces.  

Classification:  Unacceptable-Guideline. While this study is limited, it does provide some insight into the incomplete absorption of bifenthrin from the intestine, and the lack of modification of most of the unabsorbed material, particularly that eliminated via the feces during the period of 0-48 hours.  However, the metabolism of the absorbed compound (radioactivity primarily excreted via the urine, despite differences in labeling) is less clear.

870.7485

00163068

Metabolism - Rat

The results of the study demonstrated that the majority of radioactivity excreted in the feces was the parent compound and its intact hydroxylated metabolites.  Much of the radioactivity excreted in urine was hydrolytic and hydrolytic/oxidative degradation products of the parent compound.  

Classification:  Unacceptable-Guideline. 

                              Dermal Penetration

870.7600

41917503

Dermal Penetration - Rats

For animals in group A, means of 4.6, 14.2, 12.8 and 14.7% total dose were recovered from the skin at 0, 4, 10 and 24 hours post-dose; corresponding percentages in the wash were 94.6, 80.8, 78.6 and 70%.  For animals in group B, means of 20.0, 37.9, 42.0 and 41.2% remained (and were recovered from) the skin at 0, 4, 10 and 24 hours post-dose; corresponding percentages in the wash were 73.9, 50.6, 41.3 and 37.7% respectively.

This dermal absorption study is classified as acceptable.   However, because only one dose was used, this study, by itself, does not satisfy the guideline requirement for a dermal penetration study (85-2) in the rat for technical bifenthrin (FMC 54800). However, it can be used, in conjunction with other dermal penetration studies, as supporting data for the purposes of registration and/or reregistration of products containing or consisting of bifenthrin.

870.7600

41917502

Dermal Penetration - Rats

Means of 96.83, 84.75, 76.86 and 72.88% of the radioactivity were recovered in the skin wash at 0, 4, 10 and 24 hours post dosage, respectively.  By the time the 4-hour post-dose and later skin samples were collected the emulsifying solvents had evaporated.  Means of 4.04, 12.00, 16.55 and 19.44% total dose were recovered from the washed skin of the application site at 0, 4, 10 and 24 hours respectively; corresponding mean percentages recovered from the carcass were 0.09, 0.87, 0.85 and 1.67%.  Mean percentages recovered in urine and feces were 0, 0.14, 0.43 and 3.23%.

This dermal absorption study is classified as acceptable.   However, because only one dose was used, this study, by itself, does not satisfy the guideline requirement for a dermal penetration study (85-2) in the rat for technical bifenthrin (FMC 54800). However, it can be used, in conjunction with other dermal penetration studies, as supporting data for the purposes of registration and/or reregistration of products containing or consisting of bifenthrin.

870.7600

00163072

Dermal Penetration - Rats

In general, only very small amounts of radioactivity were present in blood, excrement, and carcasses, with almost all (approximately 99%) of the absorbed radioactivity localized in skin at the application site, and in the skin adjacent to the application site.  Average percentages of FMC 54800 dosages absorbed at 10 hours were 55.8%, 54.1%, and 37.5% for the 49.2, 514 and 5253 μg/rat groups respectively.  Corresponding percentages for the 3 groups at the 0.5 hour sacrifice were 54.6%, 56.4%, and 52.5%, so the percentage absorption of FMC 54800 did not seem to depend on time-to-sacrifice.  At 10 hours and the lowest dose level, the percentages present were as follows: excreta: <0.44%; carcass: <1.8%; skin at application site: 50.3%; skin adjacent to application site: 5.5%.  At 10 hours and the highest dose level, the percentages of total dose present were as follows: excreta: 0.07%; carcass: 0.5%; skin at application site: 34.6%; skin adjacent to application site: 2.7 %.

Classification:  This dermal absorption study is classified as acceptable.   However, by itself, does not satisfy the guideline requirement for a dermal penetration study (85-2) in the rat for technical bifenthrin (FMC 54800). However, it can be used, in conjunction with other dermal penetration studies, as supporting data for the purposes of registration and/or reregistration of products containing or consisting of bifenthrin.

870.7600

41284202

Dermal Penetration - Rats

The report states that at 24 hours post dose, 5.11% of the dose was absorbed (application-site skin + carcass + urine + feces) in this second trial.  However, it is noted that there was poor recovery (68% of the total dose) from one of the rats (C32545) sacrificed at 24 hours in the second trial; disregarding the findings from this one animal then the mean value of the dose that was absorbed was 5.88%, and this can be taken as a reasonable estimate of the dermal absorption at this dose level.

This dermal absorption study is classified as acceptable.   However, because only one dose was used, this study, by itself, does not satisfy the guideline requirement for a dermal penetration study (85-2) in the rat for technical bifenthrin (FMC 54800). However, it can be used, in conjunction with other dermal penetration studies, as supporting data for the purposes of registration and/or reregistration of products containing or consisting of bifenthrin.

A.3  Hazard Identification and Endpoint Selection




















                                       









A.3.1	Acute Reference Dose (aRfD, including General Population and Females 13-49), Acute Population Adjusted Dose, & Incidental Oral Exposure

The following information was used in the PoD determination for acute oral endpoints.  The previous figures provides a visual picture of this evaluation.  

   1. The Wolansky acute rat study with a PoD of BMDL1SD = 3.1 mg/kg is selected for this endpoint due to the overall robust nature of the study with 9 doses, producing an excellent dose response curve.  The Wolansky study was considerably conservative, employing gavage dosing using 1 ml/kg corn oil vehicle and volume.  This special study had a uniform design for all of the pyrethroids tested. It also monitored the toxicology at the time of peak effects for each pyrethroid, thereby optimizing the responses, not always controlled in guideline studies.  The BMD analysis provides a standardized metric of the study data which corrects for dose selection and dose spacing effects.  The Wolansky PoD is more consistent with the weight of evidence of the NOAELs in the bifenthrin data base listed in Table 4.3.3. 

   2. The Nemec/WIL study (2006) also had a uniform study design with all pyrethroids tested. However, the study only had two doses with poor dose selection which resulted in limited dose response information for bifenthrin. The Nemec/WIL study is not appropriate for endpoint selection for bifenthrin.
      
   3. The Agency notes that a rat developmental study administered via gavage with corn oil provides a NOAEL of 0.88 mg/kg/day based on tremors at a dose of 1.77 mg/kg/day. However, a dietary rat developmental study had a NOAEL of 7.1 mg/kg/day also based on tremors. In the rat developmental gavage study, tremors at the highest dose tested of 1.77 mg/kg/day were intermittent, lasting from as few as only one day up to 7 days of treatment. The hydroureter sign indicated in the rat gavage developmental study (NOAEL=0.88 mg/kg/day) was not statistically significant, plus it was not reproduced in the rat dietary developmental study, suggesting to put less weight on this finding. Moreover, hydroureter is considered an artifact of the developmental process in rats, but not rabbits, and often resolves in rats.  The rabbit developmental study, again by gavage dosing, also did not reproduce this developmental effect.  The NOAEL of 0.88 mg/kg/day is not consistent with other points of departure in the data base, including the DNT and reproduction study which also had signs of tremors and also dosed pregnant rats (NOAELs of 3.6 mg/kg/day and 3.0 mg/kg/day, respectively).  In context, in the rat reproduction study only the females had tremors, the NOAEL was 5.0 mg/kg/day for males. The rabbit developmental study had a NOAEL of 2.36 mg/kg/day, however,  bacterial infections in the animals may have sensitized them to chemical stress.  Thus, by a weight of evidence approach, the NOAEL of 0.88 mg/kg/day and the value of the hydroureter finding in determining points of departure is discounted.

   4. The 1-year dog study resulted in a NOAEL of 1.3 mg/kg/day and LOAEL of 2.7 mg/kg/day based on increased tremors in both sexes via capsule dosing.  The tremors were also transient, existing in only in 1/4 male dogs and only 2/4 female dogs only during weeks 16-23 of treatment.  With allometric scaling, the chronic dog Human Equivalent Dose (HED) is 0.78 mg/kg/day and the acute Wolansky rat study HED is a similar value of 0.72 mg/kg. Moreover, the HED for the 90-day dog study NOAEL is 1.35 mg/kg, also similar to the HED value for the acute Wolansky rat study (see Appendix A.4). Thus, the points of departure between the two species are approximately equivalent when normalized to the human reference dose. The Wolansky acute rat study utilizing nine dose groups with 8-12 animals/group with BMD analysis is a more reliable study than the studies using only 3 dose groups and 4-10 animals/group. 

   5. While the ACN study is often considered for acute endpoints and used gavage dosing for bifenthrin, this study did not utilize a dosing vehicle (which is known to modulate pyrethroid toxicity), thus had an atypical LOAEL value of 70.3 mg/kg.  Therefore, the Wolansky study PoD is much more conservative.  Furthermore, there were deaths at the LOAEL for the ACN study, thus this data does not provide a sensitive endpoint for PoD selections.

A.3.2	Chronic Reference Dose (cRfD) 

Chronic endpoints have not been chosen for bifenthrin since the toxicology database indicates that the acute endpoints are protective of longer-term exposures.

A.3.3	Dermal Exposure (Short-Term) 

The 21-day dermal study in rats with a BMDL10 of 96.3 mg/kg/day was selected for this endpoint.  The BMD10 value of 187.0 mg/kg/day was based on observations of clinical signs of exaggerated hind limb flexion.  The 10% threshold for the BMD analysis is the default limit for quantal data such as hind limb flexion. The BMD analysis can improve PoD selection when dose spacing is non-ideal. The rabbit dermal toxicity study had a very similar point of departure with a NOAEL of 88 mg/kg/day, with a LOAEL of 442 mg/kg/day based on the loss of muscle coordination and increased incidence of tremors.  However, the dose spacing of the rat study was superior to the rabbit study. Also, based on the rat and rabbit gavage developmental studies, the rat is more sensitive than the rabbit to bifenthrin exposure (i.e. developmental NOAELs of 1.77 and >7.0 mg/kg/day, respectively). Since a dermal toxicity study is selected for dermal risk assessment, a dermal-absorption factor is not required. The BMD analysis using the BMDS software is listed in Appendix E. 

A.3.4	Inhalation Exposure (Short-Term) 

In the absence of an inhalation study, an oral study is being used for this endpoint.  A POD of 3.1 mg/kg is selected from the Wolansky acute rat study for this endpoint due to the overall robust nature of the study. An inhalation-absorption factor of 100% (default value assuming equivalent inhalation and oral absorption) was used for route-to-route extrapolation.  

Appendix A.4.   Human Equivalent Doses (dog study vs. acute rat motor activity study)

Table A.4.  Human Equivalent Doses (dog study vs. acute rat motor activity study)

                           Rat Acute Data (Wolansky)
                            Dog Data (Sub-chronic)
Chemical 
 Rat Dose 
(mg/kg)
Human Dose
 (mg/kg)
Dog Dose 
(mg/kg)
Human Dose (mg/kg)

                                      BMD
                                     BMDL
                                      BMD
                                     BMDL
                                     NOAEL
                                     LOAEL
                                     NOAEL
                                     LOAEL
Beta-cyfluthrin
                                     1.42
                                     1.17
                                     0.41
                                     0.34
                                      2.4
                                     13.9
                                     1.48
                                     8.54
Bifenthrin
                                      4.1
                                      3.1
                                     1.19
                                     0.90
                                      2.2
                                      4.2
                                     1.35
                                     2.58
Bioallethrin
                                     65.6
                                     42.2
                                     19.07
                                     12.27
                                      20
                                      63
                                     12.30
                                     38.73
Cyhalothrin
                                     0.92
                                     0.64
                                     0.27
                                     0.19
                                       1
                                      2.5
                                     0.61
                                     1.54
Cyphenothrin
                                       -
                                       -
                                       -
                                       -
                                     12.5
                                     37.5
                                     7.68
                                     23.05
Cypermethrin
                                     11.19
                                     7.16
                                     3.25
                                     2.08
                                     12.5
                                     37.5
                                     7.68
                                     23.05
Deltamethrin
                                     2.48
                                     1.49
                                     0.72
                                     0.43
                                       1
                                      2.5
                                     0.61
                                     1.54
Esfenvalerate
                                     1.19
                                     0.65
                                     0.34
                                     0.19
                                       5
                                      7.5
                                     3.07
                                     4.61
Fenpropathrin
                                     6.44
                                     5.01
                                     1.87
                                     1.45
                                      2.5
                                      6.2
                                     1.54
                                     3.81
Permethrin
                                     63.1
                                     44.4
                                     18.34
                                     12.91
                                      50
                                      500
                                     30.74
                                    307.39
Resmethrin
                                    162.32
                                     75.89
                                     47.19
                                     22.06
                                      300
                                       -
                                     184.4
                                       -
Tefluthrin
                                     3.67
                                      2.8
                                     1.067
                                     0.81
                                      0.5
                                      1.5
                                     0.31
                                     0.92
Rat BW (kg) = 0.5, Dog BW (kg) = 10, Human BW (kg) = 70
Human Equivalent Dose (HED) = Animal Dose x (Animal BW/ 70)0.25    

Appendix B.  Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These studies, which comprise the Pesticide Handlers Exposure Database (PHED), the Agricultural Handler Exposure Task Force (AHETF), 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.

Appendix C.  Residential Exposure/Risk Summary Table

A summary of bifenthrin residential handler exposure/risk is presented in Table D.1 below.  

Table C.1.  Residential Bifenthrin Handler Short-Term Exposure and Risk
                                   Use Site
                                 Equip. Types
                                   App. Rate
                                     (lbai/
                                   gallon)1
                          Amount Handled (gallons)[2]
                               or Area Treated 
                               Route of Exposure
                             Dose (mg/kg/day)[3,4]
                                    MOE[5]
                                    ARI[6]
                                    Indoor
Indoor Surface-Directed Sprays - Bed Bug Treatment
Manually-Pressurized Handwand
                                    0.0051
                                      0.5
                                    Dermal
                                    0.00211
                                    44,000
                                      73


                                       
                                       
                                  Inhalation
                                   0.000035
                                    88,000
                                       
                                    Outdoor
Ornamentals (Shade Tree, Herbaceous Plants, Non-Flowering Plants, Woody Shrubs and Vines)
Hose-End Sprayer
                                     0.019
                                      11
                                    Dermal
                                     0.15
                                      630
                                      6.3


                                       
                                       
                                  Inhalation
                                   0.0000037
                                    840,000
                                       

Backpack Sprayer
                                     0.20 
                                   (lb ai/A)
                                  5 gallons 
                                       
                                   (0.023 A)
                                    Dermal
                                     0.34
                                      270
                                      2.1


                                       
                                       
                                  Inhalation
                                    0.00037
                                     8,400
                                       

Manually-Pressurized Handwand,
                                       
                                       
                                    Dermal
                                     0.17
                                      580
                                      5.3


                                       
                                       
                                  Inhalation
                                   0.000048
                                    65,000
                                       

Sprinkler Can
                                       
                                       
                                    Dermal
                                     0.15
                                      630
                                      6.2


                                       
                                       
                                  Inhalation
                                   0.0000037
                                    840,000
                                       
Turf (Lawns, Ornamentals, Outdoor Premises, Recreational Areas)
Belly Grinder
                                     0.20 
                                   (lb ai/A)
                                    0.023 A
                                    Dermal
                                     0.021
                                     4,600
                                      45


                                       
                                       
                                  Inhalation
                                   0.0000023
                                   1,400,000
                                       

Push-Type Spreader
                                       
                                       
                                     0.5 A
                                    Dermal
                                     0.001
                                    95,000
                                      480


                                       
                                       
                                  Inhalation
                                   0.0000033
                                    950,000
                                       

Hose-End Sprayer
                                       
                                       
                                    Dermal
                                     0.017
                                     5,700
                                      38


                                       
                                       
                                  Inhalation
                                   0.000028
                                    110,000
                                       

Backpack Sprayer
                                       
                                       
                                    Dermal
                                     0.16
                                      590
                                      4.4


                                       
                                       
                                  Inhalation
                                    0.00018
                                    18,000
                                       
   1. Maximum application rates identified for residential uses of bifenthrin as referenced from Biological and
EconomicsAnalysis Division (BEAD) Label Data System.
   2. Based on 2011 Residential SOPs
   3. 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).
   4. 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). 
   5. 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). Dermal Level of concern = 100, Inhalation Level of Concern = 1,000 (Adult)
   6. Aggregate Risk Index  (ARI)  =  1 /  ((1/estimated MOE for adult dermal exposure/ LOC for adult dermal 
	exposure ) + (1/estimated MOE for adult inhalation exposure/ LOC for adult inhalation oral exposure))


Table C.2.  Residential Post-application Exposure and Risk Estimates for High-end Bifenthrin Uses
                               Exposure Scenario
                                   Lifestage
                                 App. Rate[1]
                               Route of Exposure
                               Exposure Source/
                                   Activity
                              Dose[2] (mg/kg/day)
                                    MOE[3]
                                    ARI[4]
                                    Indoor
                           Surface-Directed Sprays/
                        Mattress for Bed Bug Treatment
                                     Adult
                                    0.0051 
                                 lb ai/gallon
                                    Dermal
                            Surface-Directed Spray
                                    0.0027
                                    35,000
                                      110
                                       
                                       
                                       
                                       
                                   Mattress
                                    0.0007
                                    140,000
                                       
                                       
                                       
                                       
                                  Inhalation
                            Surface Directed Spray
                                   0.000016
                                    190,000
                                       
                                       
                           Child 1 < 2 Years Old
                                       
                                    Dermal
                            Surface Directed Spray
                                    0.0025
                                    37,000
                                      2.5
                                       
                                       
                                       
                                       
                                   Mattress
                                    0.0032
                                    61,000
                                       
                                       
                                       
                                       
                                 Hand to Mouth
                            Surface Directed Spray
                                    0.00037
                                     7,900
                                       
                                       
                                       
                                       
                                  Inhalation
                                       
                                   0.000066
                                    45,000
                                       
                               Exposure Scenario
                                   Lifestage
                                 App. Rate[1]
                               Route of Exposure
                               Exposure Source/
                                   Activity
                              Dose[2] (mg/kg/day)
                                    MOE[3]
                                 Comb.MOEs[5]
                                    Outdoor
                                 Turf - Liquid
                                     Adult
                                     0.20
                                    lb ai/A
                                   Dermal  
                          Physical Activities on Turf
                                     0.076
                                     1,300
                                      NA
                                       
                                       
                                       
                                       
                                    Mowing
                                    0.0015
                                    63,000
                                       
                                       
                                       
                                       
                                       
                                    Golfing
                                    0.0059
                                    16,000
                                       
                                       
                          Child 11 < 16 Years Old
                                       
                                   Dermal  
                                    Mowing
                                    0.0018
                                    55,000
                                       
                                       
                                       
                                       
                                       
                                    Golfing
                                    0.0069
                                    14,000
                                       
                                       
                           Child 6 < 11 Years Old
                                       
                                   Dermal  
                                    Golfing
                                    0.0081
                                    12,000
                                       
                                       
                           Child 1 < 2 Years Old
                                       
                                   Dermal  
                          Physical Activities on Turf
                                     0.14
                                      690
                                      400
                                       
                                       
                                       
                                 Hand to Mouth
                                    0.0030
                                     1,000
                                       
                                       
                                       
                                       
                                Object to Mouth
                                   0.000032
                                    34,000
                                       
                                       
                                       
                                       
                     Short-term Incidental Soil Ingestion
                                   0.000013
                                    240,000
                                       
                                Turf - Granular
                                     Adult
                                     0.50
                                    lb ai/A
                                    Dermal
                          Physical Activities on Turf
                                    0.0419
                                     2,300
                                      NA
                                       
                                       
                                       
                                       
                                    Mowing
                                    0.00076
                                    130,000
                                       
                                       
                                       
                                       
                                       
                                    Golfing
                                    0.0029
                                    32,000
                                       
                                       
                          Child 11 < 16 Years Old
                                       
                                    Dermal
                                    Mowing
                                    0.00088
                                    110,000
                                       
                                       
                                       
                                       
                                       
                                    Golfing
                                    0.0034
                                    28,000
                                       
                                       
                           Child 6 < 11 Years Old
                                       
                                    Dermal
                                    Golfing
                                    0.0040
                                    24,000
                                       
                                       
                           Child 1 < 2 Years Old
                                       
                                    Dermal
                          Physical Activities on Turf
                                     0.079
                                     1,200
                                      850
                                       
                                       
                                       
                                 Hand to Mouth
                                    0.00074
                                     4,200
                                       
                                       
                                       
                                       
                                Object to Mouth
                                   0.000228
                                    14,000
                                       
                                       
                                       
                                       
                     Short-term Incidental Soil Ingestion
                                   0.000033
                                    35,000
                                       
                                       
                                       
                                       
                       Incidental ingestion of granules
                                     0.05
                                      59
                                      NA
                         Ornamental Gardens -  Liquid
                                     Adult
                                     0.21
                                    lb ai/A
                                    Dermal
                                   Gardening
                                     0.14
                                      720
                                      NA
                                       
                           Child 6 < 11 Years Old
                                       
                                       
                                       
                                     0.092
                                     1,000
                                       
                          Ornamental Trees  -  Liquid
                                     Adult
                                       
                                       
                                 Picking Fruit
                                     0.012
                                     7,800
                                       
                                       
                           Child 6 < 11 Years Old
                                       
                                       
                                       
                                    0.0085
                                    11,000
                                       
                       Ornamental Gardens   -  Granular
                                     Adult
                                     0.40
                                    lb ai/A
                                       
                                   Gardening
                                     0.26
                                      370
                                       
                                       
                           Child 6 < 11 Years Old
                                       
                                       
                                       
                                     0.18
                                      540
                                       
                         Ornamental  Trees - Granular
                                     Adult
                                       
                                       
                                 Picking Fruit
                                     0.024
                                     4,100
                                       
                                       
                           Child 6 < 11 Years Old
                                       
                                       
                                       
                                     0.016
                                     5,900
                                       
1. Maximum application rates identified for residential uses of bifenthrin as referenced from Biological and
   EconomicsAnalysis Division (BEAD) Label Data System
2. 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).
   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, adult; 32 kg, child 6 < 11; 11 kg, child 1 < 2). 
3. 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)
4. Aggregate Risk Index  (ARI)  =  1 /  ((1/estimated MOE for adult or child 1 < 2 dermal exposure/ LOC for adult or child 1 < 2 dermal exposure ) + (1/estimated MOE for adult or child 1 < 2 inhalation exposure/ LOC for adult or child 1 < 2 inhalation oral exposure) + (1/estimated MOE for child 1 < 2 incidental oral exposure/ LOC for child 1 < 2  incidental oral exposure)
5. Combined MOEs = 1/ ((1/ Dermal MOE) + (1/Incidental Oral MOE))

Appendix D:	Cumulative Exposure and Risk Issues

No bifenthrin indoor bed bug uses were included in the 2011 pyrethroid CRA, as there were no registered bed bug treatments at that time.  However, indoor broadcast, crack and crevice, and fogger pyrethroid uses were included in the CRA.  In order to determine if the proposed bifenthrin bed bug use significantly contributes to or changes the overall findings in the pyrethroid CRA, the Agency has performed a quantitative exposure and risk assessment.  This assessment used the bifenthrin relative potency factor (RPF), discussed below, as well as the same exposure algorithms and inputs that were used in the 2011 pyrethroid CRA (see Appendix Table D).  

The pyrethroid CRA relies on the RPF approach, using administered dose as the metric for quantifying chemical potency.  In the RPF approach, the toxic potency of each chemical in the common assessment group (CAG) is determined.  One member of the CAG is selected as the index chemical for use as the point of reference for standardizing neurobehavioral potency of the other members of the CAG.  In order to develop such potency estimates, EPA prefers to use a uniform measure of toxicity such as data from the same endpoint and same duration, and to the extent possible, any other factors which effect potency (e.g., time to peak effect, sex, etc).  

In the pyrethroid CRA, the Agency used the two special WIL Functional Observational Battery (FOB) studies for estimating relative potency.  This data was selected because these studies examined many behaviors, including key behaviors for evaluating neurotoxicity specific to pyrethroids.  Specifically, the studies looked at a number of crucial parameters that are directly relevant to the Type I (e.g., hyperthermia tremors and clonus) and Type II (e.g., hypothermia, salivation, and mobility) syndromes.  In addition to the WIL FOB studies, the Wolansky acute oral study also provided a high quality data set for estimating relative potency.  Whereas the WIL FOB studies focus on endpoints specific to pyrethroid toxicity syndromes, the Wolansky study measured motor activity.  Motor activity is considered an apical endpoint because it measures alterations in the activity level of an intact rat.  Although the Wolansky study provides a potential data source for a uniform measure of potency, it was not used in the CRA because of the lack of specific relevance to the common mechanism of action for the pyrethroids.  Section 4 of the CRA can be referenced for a full description of the Agency's RPF approach.    

In the CRA, deltamethrin was used as the index chemical.  The RPFs used for the CAG in the pyrethroid screening level cumulative are shown below in Table D.1.  They were determined by dividing the chemical-specific BMD20 by the BMD20 of the index chemical, deltamethrin.  Calculations for the BMDs are described in Section 4.2 of the CRA.  Twelve of the 15 pyrethroids result in relative potency estimates equal to, or lower than deltamethrin.  Bifenthrin, cyfluthrin, and tau-fluvalinate result in similar relative potency as deltamethrin, while lambda-cyhalothrin resulted in slightly greater potency than deltamethrin.  An RPF of 1.01 was used to quantify comparative exposures from the proposed bifenthrin bed bug use.




Table D.1.  Relative Potency Estimates for Pyrethroids Included in the Screening Level Cumulative Risk Assessment
                                  Pyrethroid
                                  Oral BMD20
                                 Oral RPF[b,d]
Allethrin[c]
                                      135
                                     0.11
Bifenthrin
                                     14.3
                                     1.01
Cyfluthrin
                                     12.6
                                     1.15
Lambda-Cyhalothrin
                                      8.9
                                     1.63
Cyphenothrin
                                    100[a]
                                     0.15
Cypermethrin
                                     76.3
                                     0.19
Deltamethrin
                                     14.5
                                      1.0
Esfenvalerate
                                     40.5
                                     0.36
Fenpropathrin
                                      29
                                     0.50
Tau-Fluvalinate
                                     14.5
                                      1.0
Imiprothrin
                                    750[a]
                                     0.02
Permethrin
                                      156
                                     0.09
Prallethrin
                                    150[a]
                                     0.10
Pyrethrins
                                    800[a]
                                     0.02
Resmethrin
                                      291
                                     0.05
      [a]Values estimated from studies; these values were not calculated using BMD.  See Section 4.2 of the CRA.
      [b]RPF = BMD20 of Index Chemical (e.g., deltamethrin)/Pyrethroid BMD20; For example: Bifenthrin RPF=14.5/14.3 = 1.01
      [c]Includes the isomeric enrichments S-Bioallethrin and D-Allethrin
      [d]RPFs for Dermal and Inhalation exposures are based on oral BMD; 5% absorption values applied to dermal assessments and inhalation is considered equivalent to the oral route

Appendix Table D.2 summarizes a comparison of the MOEs currently driving indoor exposures and risks (as referenced from Table 6.4.7a of the 2011 pyrethroid CRA) to those estimated for the proposed bifenthrin bed bug use, which were assessed using the bifenthrin RPF and the same exposure algorithms and inputs used in the CRA.  The routes of exposure include post-application dermal for adults, and post-application dermal and incidental oral for children.  Quantitative post-application inhalation exposures from the bed bug use are not included in the CRA assessment since this is not a significant route of exposure.  The MOEs in the single chemical assessment are not of concern and, as was noted in the CRA, an Office of Research and Development exposure study that simulated crack and crevice applications of four pesticides, including two pyrethroids, showed that all air concentration values were below the limit of quantitation (D390098, C. Smith and S. Shelat, 9/15/2011). 

Adult indoor exposures and risks (dermal only) are currently driven by the cypermethrin indoor fogger use pattern with an MOE of 3,900, which is lower than the MOE estimated for adult dermal exposure from the proposed bifenthrin bed bug use, 15,000.  The cypermethrin use also drives the CRA for child indoor exposures and risks with an estimated combined MOE (dermal and incidental oral) of 720, which is lower than the combined MOE estimated for child exposures and risk indoors from the proposed bifenthrin use, 2,700.  Based upon these outcomes, the Agency has determined that the proposed bed bug use will not contribute significantly to or change the findings presented in the CRA.  A summary of individual adult and child exposure scenarios assessed for the comparative evaluation are presented in Table D.3. 


D.2.  Bifenthrin Screening Level "Cumulative" Combined Exposure and Risk from the Proposed Bed Bug Use
                                   Chemical
                               Exposure Scenario
                               Route of Exposure
                                  Population
                                      MOE
                                 Combined MOE
                                    New Use
                                  Bifenthrin
                   Indoor Bed Bug - Surface Directed Sprays
                            Post-Application Dermal
                                     Adult
                                    15,000
                                    15,000
                                       
                                       
                                       
                           Post-Application Dermal 
                                   Children 
                             (1 < 2 years old)
                                    13,000
                                     2,700
                                       
                                       
                                       
                       Post-Application Incidental Oral
                                       
                                     3,500
                                       
                                      CRA
                                 Cypermethrin
                                 Indoor Fogger
                            Post-Application Dermal
                                     Adult
                                     3,900
                                     3,900
                                       
                                       
                                       
                           Post-Application Dermal 
                                   Children 
                             (1 < 2 years old)
                                     3,500
                                      720
                                       
                                       
                                       
                       Post-Application Incidental Oral
                                       
                                      900
                                       
                                       
Appendix Table D.3: Bifenthrin Screening Level "Cumulative" MOEs
                       Post-application Dermal Exposure
                               Exposure Scenario
                                       
                       Surrogate Deposition (ug/cm[2])
                             Fraction Transferred
                         Transfer Coefficient (cm2/hr)
                             Exposure Time (hours)
                          Conversion Factor (mg/ug)
                               Exposure (mg/day)
                               Body Weight (kg)
                       Absorbed Dermal Dose (mg/kg/day)
                         Adjusted Dose (mg/kg/day) [a]
                               Adjusted MOE [b]
                Dermal Exposure from Carpet After Bed Bug Use 
                             (1 < 2 year olds)
                                      0.9
                                     0.02
                                     2,000
                                       5
                                    0.0010
                                     0.18
                                     11.4
                                    0.00079
                                    0.00080
                                    13,000
                 Dermal Exposure from Carpet after Bed Bug Use
                                    (Adults)
                                       
                                       
                                     6,800
                                       8
                                       
                                     0.98
                                     71.8
                                    0.00068
                                    0.00069
                                    15,000
                   Post-application Incidental Oral Exposure
                               Exposure Scenario
                                   Faihands
                          1-2 yr old Dermal Exposure
                                   SAH (cm2)
                                 HRt (mg/cm2)
                                      FM
                           Exposure Time (hours/day)
                                   N_Replen
                                      SE
                                   Freq_HtM
                                      BW
                        Average Daily Dose
(mg/kg/day)
                         Adjusted Dose (mg/kg/day) [a]
                               Adjusted MOE [b]
                                       
                                       
                                       
                                       
                                       
                 Fraction of Hand Surface Area Mouthed / Event
                                       
            Number of replenishment intervals per hr (intervals/hr)
                             Extraction by Saliva
                             H-t-M events per hour
                                       
                                       
                                       
                                       
                   Incidental Oral Exposure from Bed Bug Use
                             (1 < 2 year olds)
                                     0.15
                                     0.18
                                      150
                                    8.9E-05
                                     0.13
                                       5
                                       4
                                      0.5
                                      20
                                     11.4
                                    0.00290
                                    0.0030
                                     3,500
a  Doses were adjusted based on an estimated bifenthrin RPF of 1.01
b  MOEs were calculated by comparing the adjusted dose to the oral BMD20 from the WIL FOB data for the index chemical, deltamethrin (14.5 mg/kg/day)

Appendix E:  Bifenthrin BMD Analysis for the 21-Day Dermal Study


Bifenthrin  BMD Analysis: 21-Day Rat Dermal Study  -  MRID  45280501

BMDS 2.1.1:  Dichotomous  -  multistage.  Extra Risk BMR at 10%
Endpoint:  Exaggerated hind limb flexion in females

BMD Results:
   	BMD =        187.052 mg/kg/day

       BMDL =        96.2927 mg/kg/day

Calculations:
 ==================================================================== 
   	  Multistage Model. (Version: 3.2;  Date: 05/26/2010) 
  	  Input Data File: C:/Usepa/BMDS212/Data/mst_testrundichotomous_Opt.(d)  
  	  Gnuplot Plotting File:  C:/Usepa/BMDS212/Data/mst_testrundichotomous_Opt.plt
 							Wed Apr 06 12:01:44 2011
 ==================================================================== 

 BMDS_Model_Run 
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
 
   The form of the probability function is: 

   P[response] = background + (1-background)*[1-EXP(
                 -beta1*dose^1-beta2*dose^2)]

   The parameter betas are restricted to be positive

   Dependent variable = Effect
   Independent variable = Dose

 Total number of observations = 5
 Total number of records with missing values = 0
 Total number of parameters in model = 3
 Total number of specified parameters = 0
 Degree of polynomial = 2


 Maximum number of iterations = 250
 Relative Function Convergence has been set to: 1e-008
 Parameter Convergence has been set to: 1e-008


                  Default Initial Parameter Values  
                     Background =    0.0031824
                        Beta(1) =  0.000548172
                        Beta(2) =            0


           Asymptotic Correlation Matrix of Parameter Estimates

           ( *** The model parameter(s)  -Background    -Beta(2)   
                 have been estimated at a boundary point, or have been specified by the user,
                 and do not appear in the correlation matrix )

                Beta(1)

   Beta(1)            1


                                 Parameter Estimates

                                                         95.0% Wald Confidence Interval
       Variable         Estimate        Std. Err.     Lower Conf. Limit   Upper Conf. Limit
     Background                0            *                *                  *
        Beta(1)      0.000563269            *                *                  *
        Beta(2)                0            *                *                  *

* - Indicates that this value is not calculated.

                        Analysis of Deviance Table

       Model      Log(likelihood)  # Param's  Deviance  Test d.f.   P-value
     Full model        -9.98095         5
   Fitted model        -10.5726         1       1.18324      4          0.8809
  Reduced model        -16.2541         1       12.5464      4         0.01372

           AIC:         23.1451

                                  Goodness  of  Fit 
                                                                 Scaled
     Dose     Est._Prob.    Expected    Observed     Size       Residual
  ------------------------------------------------------------------------
    0.0000     0.0000         0.000     0.000          10        0.000
   23.0000     0.0129         0.129     0.000          10       -0.361
   47.0000     0.0261         0.261     0.000          10       -0.518
   93.0000     0.0510         0.510     1.000          10        0.704
  932.0000     0.4084         4.084     4.000          10       -0.054

 Chi^2 = 0.90      d.f. = 4        P-value = 0.9250


   Benchmark Dose Computation

Specified effect =            0.1

Risk Type        =      Extra risk 

Confidence level =           0.95

             BMD =        187.052

            BMDL =        96.2927

            BMDU =        598.842

Taken together, (96.2927, 598.842) is a 90     % two-sided confidence
interval for the BMD

