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

Anand, S. S., J. V. Bruckner, W. T. Haines, S. Muralidhara, J. W. Fisher and S. Padilla (2006). "Characterization of deltamethrin metabolism by rat plasma and liver microsomes." Toxicology and Applied Pharmacology 212(2): 156-166.

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.

Crofton KM, Kehn LS, Gilbert ME (1995), "Vehicle and route dependent effects of a pyrethroid insecticide, deltamethrin, on motor function in the rat." Neurotoxicology and Teratology.17(4): 489-95

de Zwart, L., M. Scholten, J. G. Monbaliu, P. P. Annaert, J. M. Van Houdt, I. Van den Wyngaert, L. M. De Schaepdrijver, G. P. Bailey, T. P. Coogan, W. C. Coussement and G. S. Mannens (2008). "The ontogeny of drug metabolizing enzymes and transporters in the rat." Reproductive Toxicology 26(3-4): 220-230.

Felts, P. A., S. Yokoyama, S. Dib-Hajj, J. A. Black and S. G. Waxman (1997). "Sodium channel [alpha]-subunit mRNAs I, II, III, NaG, Na6 and hNE (PN1): Different expression patterns in developing rat nervous system." Molecular Brain Research 45(1): 71-82.

Godin, S. J., M. J. DeVito, M. F. Hughes, D. G. Ross, E. J. Scollon, J. M. Starr, R. W. Setzer, R. B. Conolly and R. Tornero-Velez (2010). "Physiologically Based Pharmacokinetic Modeling of Deltamethrin: Development of a Rat and Human Diffusion-Limited Model." Toxicological Science 115(2): 330-343.

Goldin, A., R. Barchi, J. Caldwell, F. Hofmann, J. Howe, J. Hunter, R. Kallen, G. Mandel, M. Meisler, YBNetter, M. Noda, M. Tamkun, S. Waxman, J. Wood and W. Catterall (2000). "Nomenclature of voltage-gated sodium channels." Neuron 28(2): 365-368.

Goldin, A. L. (2002). "Evolution of voltage-gated Na+ channels." J Exp Biol 205(5): 575-584.
Herberth, M. T. (2010). "An Oral (Gavage) Acute Neurotoxicity Comparison Study in Rats. WIL Research Laboratories, LLC, 1407 George Road, Ashland, OH 44805-9281. Laboratory report number: WIL-118041, December 20, 2010. MRID 48333801.Unpublished. DP# 386418."

Hughes, M. F. and B. C. Edwards (2010). "In vitro dermal absorption of pyrethroid pesticides in human and rat skin." Toxicology and Applied Pharmacology 246(1-2): 29-37.

Kiplinger, G. (2003) Acute Nose‐Only Inhalation Toxicity, Study of Bifenthrin Technical in Albino Rats: Final Report. Project Number: A2003‐5589, WIL‐105015, 182TST02484. Unpublished study prepared by WIL Research Laboratories, Inc. 170 pp. MRID 46008101

Kim, K.-B., Anand, S.S., Kim, H.J., White, C.A., Fisher, J.W., Tornero-Velez, R., Bruckner, J.V., 2010. Age, dose, and time-dependency of plasma and tissue distribution of deltamethrin in immature rats. Toxicological Science 115, 354 - 368.

Koukouritaki, S. B., J. R. Manro, S. A. Marsh, J. C. Stevens, A. E. Rettie, D. G. McCarver and R. N. Hines (2004). "Developmental Expression of Human Hepatic CYP2C9 and CYP2C19." Journal of Pharmacology and Experimental Therapeutics 308(3): 965-974.
Lawrence, L. and J. Casida (1982). "Pyrethroid toxicology: Mouse intracerebral sturcture-toxicity relationships." Pesticide Biochemistry and Physiology 18: 9-14.

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