**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460**  **OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION**  MEMORANDUM DATE: 8/2 7 /2012 SUBJECT: Bifenthrin: Human Health Risk As sessment to Support Section 3 New Us es for a Bed Bug Treatment, Grass Grown for Seed, Tolerances for Imported Tea, and a Section 18 Emergency

Exemption Use on Apple, Nectarine, and Peach PC Code: 128825 DP Barcode: D37255 0 MRID No.: Not Applicable Registration No. : 279 - 3313, 279 - 3108 Petition No.: 9E7652 Regulatory Action: Section 3 and 18 Registrations Assessment Ty

pe: Single Chemical Aggregate Reregistration Case No.: Not Applicable T XR No.: Not Applicable CAS No.: 82657 - 04 - 3 FROM: Wade Britton, MPH, Risk Assessor

William Irwin, PhD, DABT, Toxicologist Ana Rivera
- Lupiáñez, Chemist Pete Savoia, Chemist Seyed Tadayon, Chemist Risk Assessment Branch V Health Effects Division ( HED; 7509P) THROUGH: Michael Metzger, Branch Chief

And Donna S. Davis, Chemist William Donovan, Ph.D., Chemist Risk Assessment Branch V/ VII Health Effects Division (7509P) TO: Laura Nollen , Biologist

And Barbara Madden, Team Leader Ris k Integration Minor Use, and Emergency Response Branch Registration Division (7505 P) Bewanda Alexander , Risk Manager And Richard Gebken, PM 10 Insecticide Branch Registration Branch (7505P)Bifenthrin Human Health Risk Assessment D372550

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Page **2** of **83** Jennifer Urbanksi, PhD, Biologist And Venus Eagle, PM 1 Insecticide
- Rodenticide Branch Registration Division (7505P)

### Table of Contents

**1.0 Executive Summary**  **................................ ................................**  **................................ ...........**  **6 2.0**  **HED Recommendations ................................**  **................................ ................................**  **.. 10**  **2.1 Data**  **Deficiencies ................................**  **................................ ................................**  **.......... 10**  **2.2 Tolerance Considerations**  **................................ ................................**  **............................ 11**  **2.2. 1**  **Enforcement Analytical Method ................................**  **................................ .................**  **11 2.2.2**  **International Harmonization ................................**  **................................ ......................**  **11 2.2.3**  **Recommended Tolerances ................................**  **................................ ...........................**  **11 2.2.4 Revision to Petitioned**  **- for**  **Tolerances ................................**  **................................ ..........**  **12 2.3**  **Label Recommendations ................................**  **................................ ..............................**  **12 3.0**  **Introduction ................................**  **................................ ................................**  **...................... 12**  **3.1 Chemical Identity**  **................................ ................................**  **................................ .........**  **12 3.2**  **Physic al/Chemical Characteristics**  **................................ ................................**  **............. 13**  **3.3 Pesticide Use Pattern**  **................................ ................................**  **................................ ....**  **13 3.4**  **Anticipated Exposure Pathways ................................**  **................................ .................**  **15 3.5**  **Consideration of Environmental Justice ................................**  **................................ ....**  **15 4.0**  **Hazard Characterization and Dose -**  **Response Assessment ................................**  **.......... 16**  **4.1 Toxicology Studies Available for Analysis**  **................................ ................................**  **. 17**  **4.2 Bifenthrin Toxicological Profile**  **................................ ................................**  **.................. 18**  **4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile**  **................................ ..**  **21 4.3.1**  **Pharmacokinetics ................................**  **................................ ................................**  **......... 21**  **4.3.2 Pharmacodynamics**  **................................ ................................**  **................................ ......**  **23 4.3.3**  **Crit ical Duration of Exposure**  **................................ ................................**  **..................... 25**  **4.4 Safety Factor for Infants and Children (FQPA Safety Factor)**  **............................... 26**  **4.4.1 Completeness of the Toxicology Database**  **................................ ................................**  **. 27**  **4.4.2 Evidence of Neurotoxicity**  **................................ ................................**  **............................ 29**  **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  **........... 29**  **4.4.4 Residual Uncertainty in the Exposure Databas**  **e ................................**  **....................... 30**  **4.5 Toxicity Endpoint and Point of Departure Selections**  **................................ ..............**  **31 4.5.1**  **Dose -**  **Response Assessment ................................**  **................................ ..........................**  **31 4.**  **5.2 Recommendation for Combining Routes of Exposure for Risk Assessment**  **.......... 3**  **3 4.5.3**  **Cancer Classification and Risk Assessment Recommen dations**  **.............................. 33**  **4.5.4 Points of Departure and Toxicity Endpoints Used in Human Risk Assessment**  **.... 34** Bifenthrin Human Health Risk Assessment D372550

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Page **4** of **83 5.0**  **Dietary Exposure and Risk Assessment ................................**  **................................ .........**  **35 5.1**  **Metabolite/Degradate Residue Profile ................................**  **................................ .......**  **35 5.1.1**  **Plant and Livestock Metabolism Studies ................................**  **................................ ...**  **35 5.1.2**  **Summary of Environmental Degradation ................................**  **................................ ..**  **35 5.1.3**  **Comparison of Metabolic Pathways ................................**  **................................ ...........**  **36 5.1.4**  **Residues of Concern Summary and Rationale ................................**  **.......................... 36**  **5.2 Food Residue Profile**  **................................ ................................**  **................................ ....**  **37 5.3**  **Water Residue Profile ................................**  **................................ ................................**  **.. 37**  **5.4 Dietary Risk Assessment**  **................................ ................................**  **.............................. 38**  **5.4.1 Description of Residue Data Used in Dietary Assessment**  **................................ ........**  **38 5.4.2**  **Percent Crop Treated Used in Dietary Assessment ................................**  **.................. 39**  **5.4.3 Acute Dietary Risk Assessment**  **................................ ................................**  **................... 40**  **5.4.5 Average Dietary Exposure**  **................................ ................................**  **........................... 41**  **5.4.6 Summary Table**  **................................ ................................**  **................................ ............**  **41 6.0**  **Residential (Non -**  **Occupational) Exposure/Risk Characterization .............................**  **42 6.1**  **Residential Handler Exposure ................................**  **................................ ....................**  **43 6.2**  **Residential Post -**  **Application Exposure ................................**  **................................ ......**  **44 6.3**  **Combined Exposure ................................**  **................................ ................................**  **..... 44**  **6.4 Residential Bystander Post**  **- application Inhalation Exposure**  **................................ .**  **46 7.0**  **Aggregate Exposure/Risk Characterization ................................**  **................................ ..**  **46 7.1**  **Acute Aggregate Risk ................................**  **................................ ................................**  **... 47**  **7.2 Short**  **- Term Aggregate Risk**  **................................ ................................**  **........................ 47**  **7.3 Intermediate**  **- Term/Chronic Aggregate Risk**  **................................ ............................**  **48 8.0**  **Cumulative Exposure/Risk Characterization ................................**  **............................... 49**  **9.0 Occupational Exposure/Risk Characterization**  **................................ ............................**  **49 9.1**  **Occupational Short -**  **Term Handler Exposure/Risk ................................**  **................. 49**  **9.2 Occupational Short**  **- Term Post**  **- Application Exposure/Risk**  **................................ ....**  **55 9.2.2**  **Inhalation Post -**  **application Risk ................................**  **................................ .................**  **56 10.0**  **References ................................**  **................................ ................................**  **......................... 57**  **Appendix A. Toxicology Profile and Endpoint Selection ................................**  **....................... 62**  **A.1 Toxicology Data Requirements**  **................................ ................................**  **................... 62**  **A.2 Toxicity Profiles**  **................................ ................................**  **................................ ............**  **63 A.3 Hazard Identification and Endpoint Selection**  **................................ .............................**  **71 A.3.1**  **Acute Reference Dose (aRfD, including General Population and Females 13 -**  **49), Acute Population Adjusted Dose, & Incidental Oral Exposure**  **................................ .........**  **72**Bifenthrin Human Health Risk Assessment D372550

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Page **5** of **83 A.3.2**  **Chronic Reference Dose (cRfD) ................................**  **................................ ..................**  **73 A.3.3**  **Dermal Exposure (Short -**  **Term) ................................**  **................................ ..................**  **74 A.3.4**  **Inhalation Exposure (Short -**  **Term) ................................**  **................................ .............**  **74 Appendix B. Review of Human Research**  **................................ ................................**  **................ 75**  **Appendix C. Residential Exposure/Risk Summary Table ................................**  **..................... 75**  **Appendix E: Bifenthrin BMD Analysis for the 21 -**  **Day Dermal Study ................................**  **. 82** Bifenthrin Human Health Risk Assessment D372550

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Page **6** of **83 1.0**  **Executive Summary** Interregional Research Project No. 4 (IR
- 4) has requested a Section 3 registration of a new use on grass grown for seed and a tolerance (with no US registration s ) for imported tea. In addition, a Section 18 emergency

exemption for the control of Brown Marmorated Stink Bug in appl e, nectarine, and peach crops was request ed for use by the following seven eastern states: Delaware , Maryland, North Carolina, New Jersey , Pennsylvania, Virginia, and West Virginia. The Section 18 inquiry was communicated informally by the states to the Registration Division ( RD ) in an effort to identify an effective means to control the insect . HED h as assessed the proposed uses and Section 18 inquiry and this document presents the findings and an assessment of human health risk. Bifenthrin (2
- methyl[1,1'
- biphenyl]
- 3 - yl )meth yl
- 3 - (2
- chloro
- 3,3,3 - trifluoro
- 1 - propen yl )
- 2,2 - dimethylcyclopropane
- carbox yl ate) is an insecticide and miticide in the class of py rethroids. The mode of action for bifenthrin and other p yr ethroids is the delay of inactivation of affected voltage gated sodium channels (VGSCs), allowing for an increase in sodium ion influx and resulting in delayed repolarization and, ultimately , insect paral ys is. Bifenthrin is registere d for use on a wide variety of agricultural crops, as w ell as indoor and outdoor residential uses to control insect pests
. **Hazard Assessment:** Pyrethroids have historically been classified into two groups, Ty pe I and Ty pe II, based upon chemical structure and toxicological effects. Bifenthrin is a Ty pe I s y nthetic py rethroid. Behavioral changes characteristic of Ty pe I p yrethroids, such as muscle tremors, were seen in most of the bifenthrin experimental toxicology studies. The toxicity

database for bifenthrin is not complete
. The database of bifenthrin experimental toxicology studies provides a robust characterization of the hazard potential for children and adults. There are two outstanding Part 158 data requir ements for bifenthrin
. An immunotoxicity study is required due to recent changes to Part 158 which impose new data requirements for pesticide registration . An acute inhalation study

with acute neurotoxicity (ACN) metrics is also required to substitute for the sub
chronic inhalation study. Numerous studies from the scientific literature that desc ribe the pharmacodyn amic and pharmacokinetic profile of the py rethroids in general have been considered in this assessment. Inaddition, there are on
- going efforts to develop methods to inform the possibility

of increased sensitivity of juvenile rats to p yrethroids as a class at doses near the LOAEL values. Bifenthrin toxicity

studies indicated muscle tremors , decreased locomotor activity and exaggerated hind
- limb flexion. It does not cause developm ental or reproductive effects. Bifenthrin has a low order of acute toxicity via the dermal and inhalation routes (Category III) of exposure and has moderate acute toxic ity via the oral route (Category II). It is neither an eye nor skin irritant, nor is it a dermal sensitizer. One of the key elements in risk assessment is the appropriate integration of temporality between the exposure and hazard assessments. Following a single oral gavage dose, bifenthrin is absorbed quickl y in rats resulting in decreased motor activity and increased tremors. Toxici ty is observed as quickly

as 1 hour, peaks at 4 hours and motor activity started to return to normal at 7 hours, approximately

following the blood pharmacokinetic ( PK) profile (Wolansky , 2007)
.Bifenthrin Human Health Risk Assessment D372550

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Page **7** of **83** This is generall y consistent with the t oxicity profile s for all the py

rethroids which are very similar and marked b y rapid absorption, metaboli sm, and time
- to - peak effect. The NOAE Ls and LOAELs established from bifenthrin single dose and repeat dosing studies show that repeat exposures do not result in lower NOAE Ls . Therefore, the endpoint from the acute study is protective of the endpoints from repeat dosing studies , which represent longer
- term exposures . Thus, for purposes of endpoint selection and exposure assessment, onl y single
- day risk assessments nee d to be conducted. Given different levels of uncertainty for various risk assessment scenarios, EPA is applying different FQPA safety factors for the protection of fetuses, infants, and children depending on the route of exposure , data gaps and the population exposed. For non
- inhalation exposure scenarios for adults (including women of child
- bearing age) and children > 6 ye ars of age, EPA is reducing the FQPA safety factor to 1X. Evidence of increased qualitative or quantitative susceptibility of the off

spring was not observed in any of the available animal testing guideline toxicity studies , including the developmental neurotoxicity

study (DNT) . However, the Agency is reducing the FQPA safety factor to 3X for non - inhalation exposure scenarios for infant s and children < 6 ye ars of age, based on the following: 1) age
- dependent pharmacokinetics, supported by rat Ph ys iologically

Based Pharmacokinetic (PBPK) model predictions of a 3
- fold increase of p yr ethroid concentration in juvenile brain compared to adul ts; 2) in vitro pharmacodynamic (PD) data and in vivo data indicating similar responses between adult and juvenile rats at low doses; and 3) data indicating that the rat is a conservative model compared to the human based on species
- specific pharmacodyn am ics of homologous sodium channel isoforms. EPA is requiring an inhalation toxicity study for bifenthrin because inhalation data for other py rethroids show the potential for the inhalation route to be more potent than the oral route. Due to the inhalation study

data gap, the Agency

is retaining a 10X FQPA safety factor for all inhalation exposure scenarios for all population groups
. Once these data have been received, the Agency will determine how the results affect the toxicology end points and uncertainty factors. In the absence of specific immunotoxicity studies, the Agency

has evaluated the bifenthrin toxicity database to determine whether an additional database uncertainty factor is needed. Because the 3X factor for infants and children < 6 years of age and the 10X factor for inhalation exposure scenarios are in response to different uncertainties, these safety factors have been combined for inhalation exposure scenarios for infants and children < 6 years of age resulting in an FQPA safety factor of 30X. The toxicology

database for bifenthrin does not show any evidence of treatment
- related effects on the immune sy stem, and the overall weight
- of
- evidence suggests that this chemical does not directly target the immune sy stem. Th erefore, the Agency does not believe that conducting a functional immunotoxicity study will result in a lower POD than that currently in use for overall risk assessment, and additional safety factors are not needed to account for a lack of this study.Bifenthrin Human Health Risk Assessment D372550

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Page **8** of **83** Fo r the acute dietary

risk assessment, HED selected an endpoint from the most robust study for bifenthrin, the Wolansky

acute oral study
. The Wolansky study was considerabl y conservative, using the most sensitive rat strain, and gavage dosing using a vehicl e and volume producing the most adverse responses
. A benchmark dose ( BMD ) data anal ys is method was used to address any dose spacing effects. An acute reference dose (aRfD) of 0.010 mg/kg/day was selected for children < 6 years old (includes retention of the 3X FQPA SF) and 0.031 mg/kg/day was selected for assessment of all populations older than 6 years old , based on a BMD L 1 SD value of 3.1 mg/kg and a BMD 1 SD value of 4.1 mg/kg based on reductions in motor activity
. Th e Wolansky acute oral study was also used for the assessment of short
- term incident al oral and inhalation exposure scenarios . The BMD L 1 SD value of 3.1 mg/kg was selected for risk quantification. For short
- term dermal exposure scenarios, risks were assess ed using a 21
- day dermal rat study

with a BMDL 10 of 96.3 mg/kg/day

and a BMD 10 of 187 mg/kg/day based on exaggerated hind limb flexion. Bifenthrin is classified as a “possible human carcinogen” based on an increased incidence of urinary bladder tumors in mice. However, EPA concluded that the bladder tumors may not be uncommon in mice and are not likely to be malignant. Additionally , these tumors were observed only in male mice at the highest dose tested and the incidence was of borderline significance. No evidence of carcinogenicity was observed in bifenthrin carcinogenicity studies in rats, and bifenthrin was negative in five different tests for mutagenicity but was marginall y active in a forward mutation test in mouse ly mphoma cells. Overall, based o n the available information, there is a low concern for mutagenicity
. Taking into account all of this information, the Agency has determined that quantification of risk using a non
- linear approach (i.e., an aPAD or aRfD ) will adequatel y account for all chronic toxicity , including carcinogenicity that could result from exposure to bifenthrin. While the Agency would ty picall y use a chronic population
- adjusted dose (cPAD) to protect for cancer concerns, use of the aPAD is protective for bifenthrin because inc reasing toxicity

with increasing duration of exposure is not seen for bifenthrin. **Food Residue Profile:** The residue chemistry database is considered complete for bifenthrin. For the purposes of the newly proposed uses, adequate metabolism data have been provided to demonstrate that the residue of concern in plants, livestock, and rotational crops is the parent compound only
. Monitoring data available for bifenthrin shows resi dues in most crops are not found at, or above the limit of quantification of the anal yt ical method. Field trial data supported by storage stability

and method validation data have been submitted to support the proposed Section 3 and the tolerance proposed for dried tea (without U.S. registration actions ) . Adequate data are available b y translation to support the Section 18 request. An analytical method is available to support the required tolerances. **Dietary Exposure** : A highl y refined acute dietary assessment was conducted for all supported food uses and the newl y proposed uses
. High
- end modeled drinking water estimates were directly incorporated into the assessment. The assessment incorporated the available monitorin g data, percent crop treated (PCT) for the established uses , and processing factors as appropriate. For all registered and proposed uses , the acute dietary exposure estimates are below HED’s level of concern (<100% acute population adjusted dose ( aPAD ) ) at the 99.9th percentile of exposure. At the 99.9th percentile of exposure from food and water to bifenthrin will occupy 5 % of theBifenthrin Human Health Risk Assessment D372550

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Page **9** of **83** aP AD for the general U.S. population and 29 % of the aPAD for children 1 - 2 years, the population group receiving the greatest exposures . Because there is no increase in hazard from repeat exposures to bifenthrin, the acute dietary exposure assessment is protective for chronic dietary exposure s; acute exposure levels are higher than chronic exposure levels. Accordingl y, a dietary exposure assessment for the purpose of assessing chronic dietary risk was not conducted
. However, in order to assess short
- term aggregate risk to bifenthrin, it was necessary to calculate the average dietary (food and drinking water) exposure
. The quantification of average dietary exposures required the use of average field trial residues , PDP data , and current tolerances as appropriate . T he assessment also made use of P CT where available . Drinking water information was incorporated using the mean concentration (1
- in
- 10 - year annual mean) for surface water generated b y the PRZM
- EXAMS model. **Residential Exposure:** Residential exposure is anticipated from the proposed Section 3 bed bug treatment use. In addition , residential exposure s are anticipated from currently registered uses of the chemical : in indoor residential/household premises as a crack and crevice spray , paint additive and as a dust, in or on automobiles/recreational vehicles, and for termite treatments
. HED has revised its Re sidential Standard Operating Procedures (SOPs) requiring the need for an update of bifenthri n residential risk estimates. Exposures are expected for adults who apply bifenthrin
- containing products and from post
- application exposure to adults and children in residential areas previously treated with the chemical. Residential uses of bifenthrin are many and vary widely
. HED conducted a screen of the various indoor and outdoor residential uses of bifenthrin and identified those which would result in the greatest potential for exposure. The following uses are included in the residential risk assessment : the proposed indoor bed bug treatment use, including surface
- directed application to indoor surfaces, and outdoor ornamental plant and turf uses. Reside ntial indoor and outdoor uses are anticipated to be of short
- term (i.e., 1 to 30 day s) duration ; however, bifenthrin does not increase in toxicity with repeated dosing. As such, only single day

residential exposures were assessed. R esidential handler de rmal and inhalation risk estimates for bifenthrin are not of concern to HED (i.e., MOEs are ≥ 100 for dermal and ≥ 1,000 for inhalation, the levels of concern (LOC) for these assessments). The combined handler dermal and inhalation risk estimates calculated using the Aggregate Risk Index (ARI) are not of concern to HED (i.e., ARIs are ≥ 1 ). The ARI approach was required to combine the dermal and inhalation routes of exposure because of the different levels of concern (LOCs)
. Adult residential pos t - application dermal exposures are not of concern to HED . For c hildren 1 < 2 ye ars old , the most highly exposed children’s subgroup, the combined dermal and incidental oral risk estimates for the identified residential uses are not of concern to HED (i.e. , MOEs are ≥ 300 , the LOC for these assessments ). **Aggregate Risk:** The acute and short
- term aggregate exposure assessments conducted for bifenthrin are not of concern to HED.Bifenthrin Human Health Risk Assessment D372550

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Page **10** of **83** HED ty pically defines acute aggregate risk as including food and drinking w ater exposures onl y. As previously

noted, acute dietary

risk estimates are not of concern (<100% aPAD). The short
- ter

m aggregate exposure assessment combines short
- term residential (non
- dietary) exposures with average dietary exposures (food and drinking water). As described previousl y , average dietary

exposures w ere estimated and risk estimates (MOEs) were quantified using the short
- term oral NOAEL for the purpose of characterizing short
- term aggregate risk. It should be noted that although HED is classifying this as a short
- term assessment (which ty pically 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 toxic ity with increasing duration of exposure. Short
- term aggregate risk estimates (MOEs) for the most highly exposed populati on, children 1 < 2 years old, are not of concer n to HED (i.e., MOE s are ≥ 300). Short
- term aggregate risks estimated for the general U.S. population are not of concern to HED (i.e., ARIs are ≥ 1). An intermediate
- term and/or chronic aggregate risk assessment was not conducted because bifenthrin does not increase in toxicity with repe ated dosing. **Occupational Exposure:** Occupational assessments were conducted for the newl y proposed uses of bifenthrin. Occupational exposure s (dermal and inhalation) are anticipated for handlers who apply

bifenthrin products and from dermal post
- appli cation exposure to workers who re
enter treated fields
. All occupational handler scenarios assessed result ed in risk estimates that were not of concern (i.e., ARI s are ≥ 1 ) with either baseline attire ( i.e., single layer of clothing, no respirator) or the addition of a filtering face piece dust mask respirator
. All post
- application worker exposure scenarios assessed result in estimated risks that were not of concern [i.e., MOEs are > 1 00 on Day

0 (12 hours) ] for all potential post
- application activ ities
. **Review of Human Research:** This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies, which comprise the Pesticide Handlers Exposure Database ( PHED), the Agricultural Handler Exposure Task Force (AHETF), and the Outdoor Residential Exposure Task Force (ORETF) have been determined to require a review of their ethical conduct, have received that review, and have been determined to be ethical. **2.0 HED Recommendations**  **2.1 Data Deficiencies**  An acute inhalation study with additional neurotoxicity measurements and an immunotoxicity study are required for bifenthrin. An additional uncertainty factor has been added to the human health risk assessment f

or all inhalation exposure scenarios to account for the required inhalation study
.Bifenthrin Human Health Risk Assessment D372550

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Page **11** of **83** Provided the end use product labels are revised as noted in Section 2.3.1, below, there are no further data gaps with respect to toxicology , residue chemistry , or occup ational exposure for bifenthrin. **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  Adequate GC/ECD (gas chromatography /electron capture detection) anal yt ical methods are available to enforce the proposed plant tolerances. The available method s for plant commodities i nvol ve extraction of bifenthrin residues with acetone, partitioning with hexane, purification using a Florisil column, and anal ys is of residues by GC/ECD
. **2.2.2 International Harmonization**  There are no Maximum Residue L imits (MRL s) established by Codex, Canada, or Mexico for any of the proposed commodities in the current registration action s (Section 3 and 18). However, Codex has propos ed a 30 ppm MRLfor Green and Black Tea (black, fermented and dried). In order to harmonize with the Codex MRL, a U.S. tolerance level of 30 ppm is recommended for dried tea
. **2.2.3 Recommended Tolerances**  Table 2.2.3 summarizes the Section 3 and 18 proposed tolerances and the Agency ’s final tolerance recommendations. **Tab le 2.2.3. Tolerance Summary for Bifenthrin**  **Commodity Proposed Tolerance** 

**(ppm) Recommended** 

**Tolerance (ppm) Comments**  **Correct Commodity Definition** Apple
-- 0.5 Specified in (b) Section 18 emergency exemption; Apple Grass, forage 2.5 4.0 Specified in (c) Tolerances with regional registrations; Grass, hay 4.5 1 5 Specified in (c) Tolerances with regional registrations; Nectarine
-- 0.5 Specified in (b) Section 18 emergency exemption; Nectarine Peach
-- 0.5 Specified in (b) Section 18 emergency exemption; Peach Tea 25 30 Specified in (a) General; Tea, dried The tolerance on imported tea should be listed under §180.4 42 (a) with a footnote that there are no U.S. registrations. The tolerance to support the use on grass grown for seed should be included in §180.442(c), tolerances with regional registrations. Lastly the tolerances on apples, nectarines, and peaches should be included in §180.442(b), Section 18 emergency exemptions
.Bifenthrin Human Health Risk Assessment D372550

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Page **12** of **83 2.2.4 Revision to Petitioned**  **- for Tolerances**  A revision of the petitioned tolerance for dried tea was recommended , as described above in Section 2.2.2. A revision is also required for the grass grown for seed petitioned tolerance. Data submitted to determine the magnitude of bifenthrin residue in grass forage and hay was adjusted using Organization for Economic Cooperation and Development (OECD) calculation procedures. After correction for storage stability decline, HED recommends a revised tolerance level on grass , forage from 2.5 ppm to 4.0 ppm; grass , hay from 4.5 ppm to 15 ppm
. **2.3 Label Recommendations**  **2.3.1 Recommendations from Residue Reviews**  HED recommends revision of the use directions for the proposed Section 3 and 18 bifenthrin labels. All field trials submitted for grass grown for seed were conducted in the Pacific Northwest states of Idaho, Oregon, and Washington. As such, an amended Section B is required for grass grown for seed by limiting this use to ID, OR, and WA on product labels 279
- 3108 and 279 - 3313 . If the registrant wishes to establish a nationwide registration and tolerance of the grass grown for seed use, three additional field trials from EPA Reg ion 5 would be needed. For the proposed Section 18, application directions for treating apples, nectarines, and peaches as an emergency

exemption in the states of Delaware, Maryland, New Jersey , North Carolina, Pennsylvania, Virginia, and West Virginia must be provided. Amended product labels are needed for the following bifenthrin products: EPA Reg. Nos. 279 - 3108 , 70506 - 57 , and 70506
- 227. **2.3.2 Recommendations from**  **Occupational Assessment**  N o label revisions are needed based on the occupational and/or residential exposure risk assessments. **3.0 Introduction**  **3.1 Chemical Identity**  **Table 3.1. Nomenclature of Bifenthrin Compound** 

**Empirical Formula** C 23 H 22 ClF 3 O 2 **Common name** Bifenthrin O O Cl F 3 C C H 3

C H 3 C H 3Bifenthrin Human Health Risk Assessment D372550

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Page **13** of **83 Table 3.1. Nomenclature of Bifenthrin**  **IUPAC name** 2 - methylbiphenyl
- 3 - yl methyl (1 RS,3 RS )
- 3 - [(Z )
- 2 - chloro
- 3,3,3 - trifluoroprop
- 1 - enyl]
- 2,2 - dimethylcyclopropanecarboxylate or 2 - methylbiphenyl
- 3 - yl methyl (1 RS )
- cis - 3 - [(Z

)
- 2 - chloro
- 3,3,3 - trifluoroprop
- 1 - enyl]
- 2,2 - dimethylcyclopropanecarboxylate **CAS name** (2
- methyl[1,1 ′ -biphenyl]
- 3 - yl)methyl (1 R ,3 R )
- rel
- 3 - [(1 Z )
- 2 - chloro
- 3,3,3 - trifluoro
- 1 -propenyl]
- 2,2 - dimethylcyclopropanecarboxylate **CAS #** 82657 - 04 - 03 **3.2 Physical/Chemical Characteristics**  **Table 3.2. Physicochemical Properties of the Technical Grade Bifenthrin**

**Parameter Value**  **Reference** Melting range 68 - 70.6°C
Product Chemistry Chapter of the Bifenthrin Tolerance Reassessment Eligibility Decision (TRED), (DP No. 283808, 8/21/02, S. Levy) pH NA 1 Density at 24°C 1.26 g/mL Water solubility <0.1 μg/L Solvent solubility (g/100 mL) 8.9 in heptane and methanol 125 in acetone, chloroform, ether, methylene chloride, and toluene Vapor pressure (Pa) at 25°C 2.41 x 10 - 5 Dissociation constant (pK a) Not applicable Octanol/water partition coefficient (Kow) >1 x 10 6 UV/visible absorption spectrum NA 1 NA = information not available
. **3.3 Pesticide Use Pattern**  Bifenthrin is currentl y registered for use on a variety of agricultural crops including non
food/feed uses, as well as outdoor/indoor residential and indoor pet uses to control insect pests. Examples of registered bifenthrin uses which have been classified as “non
- food/non - feed ” include:

 Outdoor premises: agricultural/farm; airports/landing fields; Christmas tree plantations; commercial and industrial lawns; forest trees; herbs; rights of way/ fences/hedgerows; ornamental plants; and wide area treatments (public health, forest products); and  Indoor premises: automobiles/taxis; barns; warehouses; dairy /cheese processing plants; eating establishments; egg packing plants; greenhouses, and outdoo r buildings.Bifenthrin Human Health Risk Assessment D372550

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Page **14** of **83** Examples of registered bifenthrin food/feed uses include: beans; herbs; root vegetables; tree nuts; stone fruits; bushberries; leafy green vegetables; brassica; peas; leaf petiole vegetables; orchard crops; and cucurbits/melons/squashes. Rates of application for bifenthrin use vary : 0.1 0 to 0.2 0 lb ai/A for application by aircraft, ground, and chemigation; 0.3 0 to 0.5 0 lb ai/A for soil incorporation; 0.2 0 to 0.4 0 for dispersal of granular product with ground equipment; 0.005 0 lb ai/1000 ft2 for crack and crevice and spot treatment applications; and 0.2 0 lb ai/A for spray and foam injection application. End
- use products are formulated as ready- to - use - spray s (RTU), emulsified concentrate (EC), wettable po wders (WP), granular (G), flowable concentrate (FIC), and pelletized tablets. A wide range of application methods may be used including aerial, ground boom, air blast, belly grinder, push
ty pe spreader, low/high pressure hand wand, paint roller, and fogge rs, etc. The use pattern s for the newly proposed uses of bifenthrin are summarized in Table 3.3. **Table 3. 3. Summary of Directions for**  **Proposed Use**  **s of**  **Bifenthrin Target/**  **Use Site Form**  **ulation**

**(EPA Reg. No.) Application Type,** 

**and Equipment Application**  **Rate (lb ai/A)**  **Max. No.**

**Applic. per**  **Season Max.** 

**Seasonal Applic.**  **Rate (lb ai/A)**  **PHI**

**(days) Use** 

**Directions 1**  **Section 3** Grass, Grow n for Seed (Forage and Hay) Em

ulsifiable Concentrate - Brigade® 2EC (279
- 3313) Aerial,

Chemigation or Ground 0.0 33 - 0. 1 0 Not Specified 0. 2 0 30 RTI: 14 days REI: 12 hours Water Soluble Bag - Brigade® WSB (279
- 3108)
Bed Bug Treatment Water Soluble

Bag

– F4688 50 WSP (8033
- 96) Surface
- Directed

Sprays , Bed (Box Spring, Frame, Headboard, Mattress) , Closet, Dresser, Empty Luggage; Manually Pressurized Handwand 0.0051

(lb ai/gallon) Not

Specified NA NA Re - apply every 7 to 10 days if needed .
**Section l8** Apple, Nectarine and Peach Dry

Flowable

– Bifenture TM DF (70506
- 227) Aerial, Airblast,

Chemigation or Ground 0.040 - 0.20 Not Specified 0. 5 0 14 RTI: 30 days REI: 12 hours Em ulsifiable Concentrate - Bifenture TM EC - (70506
- 57)Bifenthrin Human Health Risk Assessment D372550

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Page **15** of **83 Table 3.**  **3. Summary of Directions for Proposed**  **Use s**  **of Bifenthrin**  **Target/ Use Site**  **Form ulation** 

**(EPA Reg. No.) Application Type,** 

**and Equipment Application**  **Rate (lb ai/A)**  **Max. No.**

**Applic. per**  **Season Max.** 

**Seasonal Applic.**  **Rate (lb ai/A)**  **PHI**

**(days) Use** 

**Directions 1**  Water Soluble Bag - Brigade® WSB (279
- 3108) 1. RTI: Re - treatement Interval; REI: Restricted Entry Interval IR - 4 submitted a petition to establish a tolerance for imported tea in the absence of a U.S. registration. Good Agricultural Practices (GAP) information was also provided for the products Talstar® 8SC and Brigade® 8SC for use on tea grown in India. Talstar® 8SC is an 80 g ai/L soluble concentr ate formulation of bifenthrin. One foliar application is made to tea using a spray volume of 400 L/ha and a 7
- day PHI. For Brigade® 8 SC, an 80 g ai/LSC formulation, one foliar application is made at 0.08 kg ai/ha (0.07 lb ai/A) using a spray volume of 400 L/ha which specifies a PHI of 7 day s. **3.4 Anticipated Exposure Pathways**  RD has requested an assessment of human health risk to support proposed new use of bifenthrin on grass grown for seed , imported tea; apple, nectarine, and peach. Humans may be exposed to bifenthrin in their diet resulting from residues present on bifenthrin treated crops. Further, given the environmental fate parameters of bifenthrin and the proposed uses outdoors in agricultural settings, the potential exists for bifenthrin to reach water resources resulting in limited residues in drinking water. The potential exists for residential bifenthrin exposure from the proposed bed bug treatment, as well as from current use o f the chemical. Residential bifenthrin exposures could occur from adults handling the pesticide and from post
- application exposure of adults and children contacting previously treated areas. Adults could be exposed from the proposed uses of bifenthrin in an occupational setting. Occupational applicators may be exposed while handling the pesticide prior to, as well as during application. There is also the potential for exposure to workers who come into contact with the foliage of previously treated crops
. This assessment will consider the dietary , residential, and occupational risks for all registered and newl y proposed uses of bifenthrin. **3.5 Consideration of Environmental Justice**  Potential areas of environmental justice concerns, to the extent po ssible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well
- established procedures. In line with OPP policy , HED e stimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.Bifenthrin Human Health Risk Assessment D372550

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Page **16** of **83** Extensive data on food con sumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . Additionally , OPP is able to assess dietary

exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non
- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post - application are evaluated. Further considerations are currentl y in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and tradition al dietary patterns among specific subgroups. Bifenthrin may

be stored and accumulated in aqueous sediment and, therefore, could be a potential dietary

exposure source for individuals who eat fish (e.g., catfish) which dwell near the sediment. Subsistenc e fishers , or individuals who rely on fishing as the primary source of food, may be more highl y exposed than the general population. HED conducted an acute screening level dietary

exposure assessment to consider the intake of contaminated catfish by subsi stence fisher s . Because high
- end bounding fish exposure assumptions were used to assess exposure to subsistence fish ers , this potential dietary exposure source was not included in the acute or average dietary

exposure and risk assessments conducted for th e proposed Section 3 and 18 uses ; rather, a stand
- alone assessment was conducted
. The dietary assessment of catfish intake resulted in a % aPAD value of < 1 % and, therefore, would not be anticipated to significantly impact the dietary

exposure assessment s c onducted for the proposed uses. See Section 5.4.1 for further detail. **4.0 Hazard Characterization and Dose**  **- Response Assessment**  Bifenthrin is a member of the py rethroid class of insecticides
. Py rethroids have historicall y been classified into two gro ups, Ty pe I and T yp e II, based upon chemical structure and toxicological effects. Ty

pe I p yr ethroids, which lack an alpha
- cyano moiety, induce in rats a syndrome consisting of aggressive sparring, altered sensitivity to external stimuli, hy

perthermia, and fine tremor progressing to whole
- body tremor and prostration (T
- sy ndrome). Ty

pe II py rethroids, which contain an alpha
- cyano moiety, in rats produce a s yndrome that includes pawing, burrowing, salivation, hypothermia, and coarse tremors leading to choreo athetosis (CS
sy ndrome) (Verscho yl e and Aldridge 1980 ; Lawrence and Casida 1982 )
. Ingeneral, T yp e II chemicals tend to be more potent than Ty pe I p yr ethroids and the cis fo rms tend to be more potent than the trans configurations. Bifenthrin is a Ty

pe I s ynthetic pyrethroid , unique to be the onl y member of the biphenyl
- methyl ester class and it is enriched to 98% cis form
. It has a relative potency factor of 0.60 with resp ect to the more potent Ty

pe II p yr ethroid, deltamethrin, with a relative potency factor of 1.00. The adverse outcome pathway (AOP, based on the Bradford
- Hill criteria) shared by py rethroids involves the ability

to interact with voltage
- gated sodium channe ls (VGSCs) in the central and peripheral nervous s ys tems, leading to changes in neuron firing, and ultimately neurotoxicityBifenthrin Human Health Risk Assessment

______________________________________________________________________________ (see Figure 4.0 ). The signs observed in the animal studies are consistent with the pesticidal mode of action.

**Figure 4.0**  **. Adverse outcome pathway for pyrethroids**  Dosing method, vehicle type and vehicle volume considerably influence the points of departure of the py rethroids, including bifenthrin (Wolansk y et al, 2007). For example, the ED the effective dose fo r a 50% decrease) carbox ym eth yl cellulose as the vehicle with gavage dosing, based on motor activity data (Crofton et al, 1995). The vehicle and volume used in gavage dosing vary considerably

among py rethroids thus making quantitative comparisons bifenthrin dosing volume affects toxicity , decreasing the corn oil volume from 5 mL /kg to 1 mL/kg lowers the ED 50 value of motor activity b y a factor of two (Wolansky 2007). Furthermore, bolus/gavage dosing results in increased potency of the pyrethroid relative to exposure in feed. In the bifenthrin rat developmental studies, the L OAEL was 1. with corn oil gavage administration while a dietary administration had a LOAEL of 15.5 mg/kg/day

(8.8 times higher, with tremors as the common endpoint). The gavage ACN stud y which did not use a vehicle of any kind had a much higher LOAEL of changes in motor activity, clinical signs and mortality. The Wolansky acute study

was particularl y conservative in design and utilized a corn oil vehicle at 1 mL /kg with gavage dosing (point of departure was 3.1 mg/kg). In perspectiv vegetable oil, such as corn oil. **4.1 Toxicology Studies Available for Analysis**  The data base of experimental toxicology studies available for bifenthrin provides a robust characterization of the hazard pote are two outstanding Part 158 data requir required due to recent changes to Part 158 which impose new data requirements for pesticide registrat ion. An acute inhalation study with ACN metrics is also required to substitute for the sub
- chronic inhalation study
. In addition, inform the possibility

of increased sensitivity

to near the LOAEL values, which is discussed further in efforts, HED is confident that it has chosen points of departure and uncertainty factors in this risk assessment which are health protectiv The data from the following studies were used to evaluate the hazard potential of bifenthrin:

- Wolansky

Acute Oral Rat Study

-Nemec/WI L Acute Oral Rat Study Bifenthrin Human Health Risk Assessment

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Page **17** of **83** ). The signs observed in the animal studies are consistent with the pesticidal mode

**Adverse outcome pathway for pyrethroids** Dosing method, vehicle type and vehicle volume considerably influence the points of departure of the py rethroids, including bifenthrin (Wolansk y et al, 2007). For example, the ED r a 50% decrease) for deltamethrin is 196 times lower using corn oil versus carbox ym eth yl cellulose as the vehicle with gavage dosing, based on motor activity data (Crofton The vehicle and volume used in gavage dosing vary considerably

among py rethroids thus making quantitative comparisons among them difficult. In the specific case of bifenthrin dosing volume affects toxicity , decreasing the corn oil volume from 5 mL /kg to 1 value of motor activity b y a factor of two (Wolansky 2007). Furthermore, bolus/gavage dosing results in increased potency of the pyrethroid relative to exposure in feed. In the bifenthrin rat developmental studies, the L OAEL was 1. with corn oil gavage administration while a dietary administration had a LOAEL of 15.5 mg/kg/day

(8.8 times higher, with tremors as the common endpoint). The gavage ACN stud y which did not use a vehicle of any kind had a much higher LOAEL of 70.3 mg/kg, based on changes in motor activity, clinical signs and mortality. The Wolansky acute study

was particularl y conservative in design and utilized a corn oil vehicle at 1 mL /kg with gavage dosing (point of departure was 3.1 mg/kg). In perspectiv e, rat feed often does contain some content of **Toxicology Studies Available for Analysis** The data base of experimental toxicology studies available for bifenthrin provides a robust characterization of the hazard pote ntial for children 6 years old and older and for adults. outstanding Part 158 data requir ements for bifenthrin. An immunotoxicity study is due to recent changes to Part 158 which impose new data requirements for pesticide An acute inhalation study with ACN metrics is also required to substitute for the In addition, there are on
- going efforts to develop methods possibility

of increased sensitivity

to pyrethroids as a class i n juvenile rats at which is discussed further in Section 4.4 . Despite these scientific efforts, HED is confident that it has chosen points of departure and uncertainty factors in this risk assessment which are health protectiv e and have a strong scientific foundation. The data from the following studies were used to evaluate the hazard potential of bifenthrin: Wolansky

Acute Oral Rat Study WI L Acute Oral Rat Study D372550

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). The signs observed in the animal studies are consistent with the pesticidal mode

Dosing method, vehicle type and vehicle volume considerably influence the points of departure of the py rethroids, including bifenthrin (Wolansk y et al, 2007). For example, the ED 50 value (i.e. for deltamethrin is 196 times lower using corn oil versus carbox ym eth yl cellulose as the vehicle with gavage dosing, based on motor activity data (Crofton The vehicle and volume used in gavage dosing vary considerably

among In the specific case of bifenthrin dosing volume affects toxicity , decreasing the corn oil volume from 5 mL /kg to 1 value of motor activity b y a factor of two (Wolansky 2007). Furthermore, bolus/gavage dosing results in increased potency of the pyrethroid relative to exposure in feed. In the bifenthrin rat developmental studies, the L OAEL was 1. 77 mg/kg/day with corn oil gavage administration while a dietary administration had a LOAEL of 15.5 mg/kg/day

(8.8 times higher, with tremors as the common endpoint). The gavage ACN stud y 70.3 mg/kg, based on changes in motor activity, clinical signs and mortality. The Wolansky acute study

was particularl y conservative in design and utilized a corn oil vehicle at 1 mL /kg with gavage dosing e, rat feed often does contain some content of
The data base of experimental toxicology studies available for bifenthrin provides a robust ntial for children 6 years old and older and for adults. There ements for bifenthrin. An immunotoxicity study is due to recent changes to Part 158 which impose new data requirements for pesticide An acute inhalation study with ACN metrics is also required to substitute for the methods to n juvenile rats at doses . Despite these scientific efforts, HED is confident that it has chosen points of departure and uncertainty factors in this risk The data from the following studies were used to evaluate the hazard potential of bifenthrin:Bifenthrin Human Health Risk Assessment D372550

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Page **18** of **83** - ACN Rat Study

- SCN Rat Study

- DNT Rat Study

- 21 Day Dermal Rat Study

- 21 Day Dermal Rabbit Study

- 90 Day Rat Study

- 90 Day Dog Study

- Developmental Rat Studies (Gavage and Dietary)

- Developmental Rabbit Study

- Reproduction Rat Study

- 1 Year Dog Study

- Chronic/Cancer Rat Study

- Chronic/Cancer Mouse Study

- Metabolism and Pharmacokinetic Studies The studies available for consideration of bifenthrin toxicity provide a comprehensive database , with routes of administration which are consistent with potential exposure scenarios
. In addition, numerous studies f

rom the scientific literature conducted over several decades describe the pharmacodyn amic and pharmacokinetic profile of the py rethroids in general. This scientific literature has been recently reviewed b y s everal groups ( Wolansky and Harrill 2008 ; Weiner et. al. 2009 )
. The non
- guideline Wolansky acute oral study

in rats measuring locomotor activity provides the most robust data to evaluate the hazard potential of bifenthrin. **4.2 Bifenthr**  **in Toxicological Profile** Bifenthrin has been evaluated for a variety of toxic effects in guideline experi mental toxicity studies. Predominantly , b ehavioral changes characteristic of Ty pe I p yrethroids such as muscle tremors were seen in most of the bifenthrin experimental toxicology studies, consistent with its MOA to activate sodium channels. This observation was noted in several bifenthrin toxicology studies across various species at different durations, routes of exposure and life stages, including: the dev elopmental toxicity studies in the rat and rabbit ; 2 - generation rat reproduction toxicity study ; developmental neurotoxicity study (DNT) ; sub
- chronic toxicity studies in the rat and dog ; acute and sub
- chronic neurotoxicity rat studies ; a sub
- chronic dermal toxicity study in rat ; and chronic oral toxicity

studies in the rat, mouse and dog. The most robust study for assessing bifenthrin toxicity

was the acute Wolansky study measuring locomotor activity , due to the fact that it utilized nine dose groups and a benchmark dose ( BMD ) data anal ys is method to address dose spacing effects. The BMD anal ys is allows a constant threshold of change from the control group to be utilized so that all the py

rethroids are evaluated with the same toxicity metric, not possible with the standard LOAEL/NOAEL approach with variable dose spacings. For the Wolansky study with continuous data, the BMD
- S software was set to calculate the dose at which the motor activity change is equal to one standard deviation (SD) from the control value, or the BMD 1SD . The BMD 1SD value is used instead of the LOAEL value and the one SD magnitude is calculated from the control group data. The BMDL 1SD is the lower 95% confidence limit of the BMD value and is used instead of the NOAELvalue. For othe r studies with quantal data, a BMD 10 value, or theBifenthrin Human Health Risk Assessment D372550

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Page **19** of **83** dose which has a 10% toxicity change from the controls, has been calculated as the standard conservative approach for this ty pe of data. For other data with higher variability and a 10% change is not statistically supportable; therefore, a BMD 20 value has been calculated, or the dose at which a 20% toxicity

change occurs relative to the control group. The Wolansky

study was considerabl y conservative, using the most sensitive rat strain, plus gavage dosing utilizing a vehicle and volume producing the most adverse responses (i.e. 1 ml/kg corn oil). Muscle tremors were observed in nearl y all experimental studies in all species and durations, however, motor activity was not measured in most of these studies. T he decreased loco motor activity

observed in the acute Wolansky study was selected as the endpoint for risk assessment. In the acute Wolansky study , tremors were not observed at doses less than 8 mg/kg bifenthrin, while decreased motor activity was signi ficant at doses of 4 mg/kg and above. D ecreased motor activity was the most sensitive endpoint identified for bifenthrin and is protective of other endpoints recorded throughout the database, thus an acceptable literature study wa s utilized for risk assessment. Further , the Wolansky study monitored the toxicology at the time of peak effects, unlike most of the guideline studies. Additional effects seen in one or more studies included : muscle twitching ; decreased grip strength ; al tered landing foot splay ; depressed respiration ; increased grooming counts ; loss of muscle coordination ; staggered gait ; exaggerated hind limb flexion ; and convulsions at high doses
. Decreased body weight, body weight gains and food consumption were also noted in repeat
- dosing dietary studies. There was no clear evidence in the database that either gender was more sensitive to bifenthrin. Bifenthrin has been evaluated for potential developmental effects in the rat (following gavage or dietary administration) and in the rabbit (gavage administration). Maternal toxicity included neurological effects (tremors in rats and rabbits; head and forelimb twitching in rabbits). There were no developmental effects of biological significance in either species. The registrant submitted a DNT study , which establishes a clear NOAEL for the adult and offspring toxicity
. The NOAEL in adults and offspring is similar in magnitude and the LOAEL s are based on the clinical signs of neurotoxicity (dams had tremors and convuls ions, offspring had increased grooming counts). Based on targeted testing in the DNT study for common endpoints for bifenthrin, there was no increase in sensitivity in rat pups. However, the Agency has reviewed existing py

rethroid data and concludes that the DNT is not a particularl y sensitive study for comparing the sensitivity of young and adult animals to py rethroids ( E. Scollon, D381210, 6/27/11 ). Some literature studies did indicate susceptibility for other p yrethroids, but in context these studies were conducted at relatively high doses which may

not reflect environmental exposures (Sheets et al, 1994). The reproductive toxicity of bifenthrin was examined in a two
generation reproduction study in the rat. Tremors were noted onl y in females of both generations , with one parental generation rat observe d to have clonic convulsions and no observed effects in the offspring. Overall, there is no indication of increased juvenile sensitivity specificall y to bifenthrin. Bifenthrin is classified as a Group C “Possible human carcinogen”, based on an increased incidence of urinary

bladder tumors in mice. The classification was based on the following weight of evidence considerations:Bifenthrin Human Health Risk Assessment D372550

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Page **20** of **83**  There was a statisticall y significant dose
- related trend in bladder tumors at the high dose. HED concluded that the bladder tumors may not be uncommon in Swiss Webster mice and not likely to be malignant. Additionally, these tumors were observed in only one species (mice), in onl y one sex (m ale), at onl y the highest dose, and the incidence was of borderline significance.  There was a statisticall y significant dose
- related trend for combined hepatocellular adenomas and carcinomas in male mice; however, there was no statistical significance in pairwise comparison.  There was a statisticall y significant increase in pairwise comparison for lung tumors, but there was no dose response. Additionally , there was no dose
- related trend. There was also no indication that tumor formation occurred earl y i n the mouse carcinogenicity study
.  Bifenthrin was negative in five different tests for mutagenicity , but it was marginally active in a forward mutation test in mouse ly mphoma cells. Overall, based on the available information, there is a low concern for mutagenicity
.  No evidence of carcinogenicity was observed in carcinogenicity studies in rats with bifenthrin. Taking into account all of this information, the Agency has determined that quantification of risk using a non
- linear approach (i.e., an aPAD or aRfD) will adequatel y account for all chronic toxicity, including carcinogenicity that could result from exposure to bifenthrin. While the Agency would typicall y use a chronic population
- adjusted dose (cPAD) to protect for cancer concerns, use of the aPAD is protective for bifenthrin because increasing toxicity with increasing duration of exposure is not seen for bifenthrin. The NOAEL observed in the mouse chronic study , in which tumors were observed, is 6.7 mg/kg/day , 2 - fold higher than the POD used for acute risk assessment. The NOAEL in the study was based on tremors seen at the LOAEL of 25.6 mg/kg/day ; however, the tumors were observed at 81.3 mg/kg/day , a dose that is 26
- fold higher than the current acute POD. The pharmacokinetics of bifenthrin is similar to other p yrethroids with rapid absorption and clearance
. The rapid absorption was confirmed b y the functional reduction in loco motor activity at one hour post oral dosing (55% decrease at 12 mg/kg bifenthrin, Wolansky 2007). An oral absorption half

- life of 1.5 hours (with a lag
- time of a 0.5 hour following first order kinetics) has been calculated for bifenthrin at 4 mg/kg dosing. An oral absorption of approximately 50% was estimated. The half

- life in blood is approximately 10 hours, supporti ng rapid clearance from this compartment. The major routes of bifenthrin metabolism are hydroly sis of the ester linkage with oxidation of the resulting alcohol to the acid form. Radio
- labeled bifenthrin studies indicate that the parent had the highest ra dioactivity excreted in the feces, with 12 other metabolites identified. Approximately 70% of the total residues (bifenthrin and its hydroxylated metabolites) were excreted in the feces within 48 hours (range 66
- 88% ) . Approximately 13 - 25% of the administ ered doses were ex creted in the urine, mostly as hydrol yt ic and h ydrolytic/oxidative degradation products, with little parent detected. In a bioaccumulation study with rats orally dosed with 0.5 mg/kg/day for up to 70 day s, fat and skin tended to accumulat e parent bifenthrin to a much greater extent than other tissues with half
- lives of 51 and 50 day s, respectivel y (JMPR Report, 2009).Bifenthrin Human Health Risk Assessment D372550

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Page **21** of **83** With respect to acute lethality testing, b ifenthrin has a low order of acute toxicity via the dermal route (Category III) of exposure and a moderate order of acute toxicity via the oral route (Category II)
. The combined male
- female LC 50 value for bifenthrin is 1.01 mg/L (Cate gory III), based on an acute inhalation study
. It is neither an eye nor skin irritant, nor is i t a dermal sensitizer. **4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile**  The extensive body

of scientific literature on the py rethroids provides insight into the contributions of pharmacokinetics (PK) and pharmacodynamics (PD) to the general tox icity profile of this class of chemicals. This information also provides valuable insight into the potential age
- related differences in toxicity for the py

rethroids. The primary

biological effects of bifenthrin and other p yr ethroids on insects and verteb rates are stimulatory effects on voltage
gated sodium channels coupled with secondary inhibition of the voltage
- gated calcium channels and chloride channels. The following sections discuss the specific issues related to py rethroid pharmacokinetics, p yr ethroid pharmacodyn amics, and age
- related differences in py rethroid toxicity
. **4.3.1 Pharmacokinetics**  Pharmacokinetics can be defined as what the body does to the chemical; in this case, how py rethroids are distributed and eliminated following exposure. Spe cific to py rethroids, PK refers to the process(es) which determine the concentration of the p yrethroids reaching sodium channels in the peripheral nervous sy stem ( PNS ) and central nervous s ys tem ( CNS ) . The underlying pharmacokinetics of py rethroids is an important determinant of their toxicity because the concentration of p yrethroid at the sodium channel relates to the extent of toxicity, with greater p yrethroid concentration translates as increased neurotoxicity . P hy siological processes that significantl y contribute to the PK include absorption, metabolism , protein binding and partitioning. The vehicle ty pe and volume has been shown to affect the temporal and toxicological properties of the py rethroids (Crofton 1995, Wolansky 2007). The blood brain barrier is less developed in the young and can also contribute to age - dependant neurotoxicity (US EPA Guidelines for Neurotoxicity Risk Assessment, Federal Register, 1998). Carbox yl esterases (serum and intracellular) and cy tochrome P450 enzy

mes in the endopla smic reticulum are the two major enzy

me families responsible for the metabolism of py rethroids. The metabolism of bifenthrin in the liver is primarily by cy tochrome P450 oxidation. Itis the ontogeny of these enzy mes that accounts for the age
- related sen sitivity observed after p yr ethroid exposures. Pharmacokinetic changes may explain the disappearance of tremors in dogs after 29 weeks of bifenthrin dosing in the one
- year study. Rats and rabbits also demonstrated tolerance to bifenthrin in repeated dosin g studies. Bifenthrin has been demonstrated to transfer into milk in rat studies. For the p yr ethroid index chemical deltamethrin with 2 mg/kg orally in PND40 rats at 6 hours post
- dosing, the tissue levels from lowest to highest were brain, liver, plasma, muscle and fat with level s of 20 ng/g, 50 ng/g, 70 ng/mL , 140 ng/g and 480 ng/g , respectivel y (Kim et al, 2010). However, p yr ethroid residues in fatty t issue are not available to interact with the VGSCs in vital tissues and therefore do not contribute t o overall toxicity
.Bifenthrin Human Health Risk Assessment D372550

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Page **22** of **83** Following a single oral dose of 4 mg/kg radio
- labeled bifenthrin in corn oil, radioactivity in blood plasma peaked at 4 hours, which corresponds precisel y with the peak time of effect on motor activity

at this dose. In blood, bifenthrin residues have a half
- life of approximately

10 hours (see Figure 4.3.1 ) with 17% of the residues (compared to peak values) remained 24 hours post - dosing and onl y 8% of the peak radioactive residues remained in the serum at 72 hours. Similar kinetics w ere observed in rats given 35 mg/kg, although the peak plasma level s were slightly delayed to 6 hours (Selim 1986)
. As previously described, p yr ethroids are susceptible to ester h ydrol ys is in the plasma and oxidative metabolism by intracellular cy tochrome P450 enzy mes. Protein binding of radioactive parent and metabolites increased considerabl y with time (9% at 2 hours vs 34% at 10 hours). A radio
- labeled bif enthrin guideline study

reported that 4 0% of the total residues in plasma is parent at 4 hours, following a 4 mg/kg oral dose (HPLC method, MRID 00163070). A literature study also revealed that the internal dose EC 50 value s for motor activity

based on brain PK values were approximately three times higher than the EC 50 value based on blood P K values (i.e. EC 50 value s of approximately 300 ng/cc and 90 ng/cc, respectivel y). Thus, bifenthrin effects on peripheral nerves/tissues cannot be excluded (Scollon et. al., 2011).

**Figure 4.3.1 .**  Pharmacokinetic profile of radiolabeled
- bifenthrin in rat plasma following a single oral dose of 4 mg/kg in corn oil. Bifenthrin blood concentratio n is based on radioactivity and, therefore , represents a total of parent and metabolic products (Selim 1986, MRID 00163069). Phy siologically
- based pharmacokinetic (PBPK) models, designed to predict py rethroid concentration in tissues following in vivo exposure, have recently been developed by

the Agency . The Agency

has determined that the important PK properties relevant for the metabolism and distribution of py rethroids in the body

are sufficientl y similar for members of this class such that using a ‘generic’ or famil y model structure for this cl ass is scientifically appropriate. In other words, due to the similarities in the PK profiles of p yrethroids, a single model structure is able to predict the tissue dose based on the pharmacokinetics of every member **0 5**  **10 15**  **20 25**  **30 35**  **40 45**  **50 55**  **60 65**  **70 75**  **0.00 0.05**  **0.10 0.15**  **0.20 0.25**  **0.30 0.35**  **0.40 0.45**  **0.50 0.55**  **0.60 0.65**  **0.70 Bifenthrin Blood PK Profile** 

C 14Label on Alcohol Portion **4 mg/kg B** **l o** **o d** **C o** **n c** **e n** **t r** **a t** **i o** **n (** **g /** **m L** **)**



### Time (Hours)Bifenthrin Human Health Risk Assessment D372550

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Page **23** of **83** of the class. The family

modeling approach was presented to and supported by the FIFRA SAP (US EPA 2007 )
. In 2011 the Agency

conducted an anal ys is of the toxicokinetic profile of pyrethroids as a class. Several studies in this analy sis indicate that there are age
- dependent pharmacokinetic differences for the p yrethroids (i.e., there are differences in the ability of adults and juveniles to metabolize py rethroids). The enzy

mes which metabolize and detoxify the p yr ethroids are present in rats and humans at birth ( Koukouritaki et. al. 2004 ; Yang et. al. 2009 )
. As a result, both juveniles and adults are able to tolerate low doses of p yrethroids when the internal dose, or the amount of py rethroid at the sodium channel, is low. However, the activity of these enzy

mes increases with age, conveying in adults a greate r capacity to detoxify

py rethroids compared to juveniles (Anand et. al. 2006 ; de Zwart et. al. 2008 ; Yang et. al. 2009 )
. For example, the rate of in vitro m etabolism of deltamethrin by plasma carbox ye sterases, plus hepatic carboxyesterases and cy tochrome P450s (microsomes ) are at least 6 times higher for PND 90 rats compared to PND 10 rats . As a consequence, higher internal doses (i.e., those associated with high doses in experimental toxicology

studies) can overwhelm the cle arance mechanisms in juveniles; however, b ecause adults have greater enzy me activity , they

are able to tolerate higher doses prior to the onset of toxicity . As a matter of perspective, the anticipated exposures from typical dietary or residential activities are not expected to overwhelm the premature metabolic s ys tems in juveniles. Bifenthrin has a melting point of 68oC and is, therefore, a solid at room temperature. Furthermore, py rethroids are practically

insoluble in water, minimizing risk from water exposure. Predictive PBPK models have recentl y been developed to describe the PK of a few p yrethroids ( Mirfazaelian et. al. 2006 ; Godin et. al. 2010 ) . Among these is an age
- dependent model developed b y the Agency which is capable of predicting the concentration of deltamethrin in the brains of rats at multiple ages ( Tornero - Velez et. al. 2010 )
. The brain is considered the primary target organ for p yr ethroids and increased p yr ethroid concentrations are correlated with increasing s ys temic toxicity . This model predicts that, compared to adult rats (i.e., 90
- day s old), equivalent brain concentration s of deltamethrin would be achieved with a 3.8X fold lower oral dose in 10
- day

old rats and 2.5X lower dose in 21
- day old rats ( Tornero - Velez et. al. 2010 )
. The 10 - and 21
- day

old rats encompass effects predicted in a human up to age six. For example, a 1 mg/kg dose in the adult is equivalent to a 0.26 mg/kg dose ( ≈1 mg/kg÷3.8mg/kg) in the 10
- day old rats and to a 0.4 mg/kg ( ≈1 mg/kg÷2.5mg/kg) dose in a 21
- day old rat. The difference between a 3.8
- and a 2.5
- fold dose is within background variability of the model. As a result, the Agency con cludes that juvenile rats are 3X more sensitive than adults with respect to p yr ethroid pharmacokinetics. **4.3.2 Pharmacodynamics**  Pharmacodynamics (PD) can be defined as the ch anges that chemicals cause to the body , in this case, how p yr ethroids interact with the sodium channels. Substantial evidence from in vitro and in vivo studies support the AOP illustrated in Figure 4. 0 , as well as disruption of sodium channels b y p yr ethro ids as an earl y ke y event in this AOP ( Lund and Narahashi 1982 ; Salgado et. al. 1989 ; Song and Narahashi 1996 ; Tabarean and Narahashi 1998 ; Soderlund et. al. 2002 )
. Choi and Soderlund ( 2006 ) examined interactions of several py rethroids with mammalianBifenthrin Human Health Risk Assessment D372550

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Page **24** of **83** VGSCs expressed in Xenopus oocy tes. With respect to altered neuronal excitability , Ty pe I py rethroids cause slight prolongations of the sodium current tails (e.g. ~20 ms), often resulting in long trains of action potentials. In contrast, Ty pe II py rethro ids significantly

prolong sodium tail currents (e.g. 200ms to minutes) ty pically resulting in increased resting membrane potential and ultimately

causing depolarization
- dependent action potential block. Figure 4.3 .2 confirms the effects of bifenthrin to i ncrease sodium channel currents in rat NaV 1.8 channels expressed in xenopus oocy

tes.

**Figure 4.3 .2.**  Resting modification of rat Nav1.8 sodium channels by bifenthrin, expressed in xenopus oocytes. Channel current vs time traces from individual representative oocytes in the absence or presence (*) of 100 μM bifenthrin were obtained during and after 40
- ms depolarizations from 100 mV to 10 mV. Calibration bars: 20 ms for the x
- axis and 500 nAmp on the y
- axis
. Data e xtracted from Figure 3 in Choi and Soderlund ( 2006 )
. HED would prefer to use an earl y key event in the AOP for p yrethroids in selection of points of departure, such as sodium channel modification. However, i n vivo techniques used to detect VG SC alteration and altered neuronal excitability are not practical for use in risk assessment at this time and approaches for extrapolating in vitro findings to in vivo measures are not yet developed. As such, the Agency is focusing its efforts for all p yr ethroids in hazard characterization and identification on the apical endpoint (i.e., changes in neurobehavior in laboratory

animals). Neurotoxicity resulting from py

rethroids are generall y characterized b y tremors, h yper - or h ypothermia, altered response to stimuli, salivation, reduced locomotor activity or convulsions (Nemec 2006 ; Wolansky and Harrill 2008 ; Breckenridge et. al. 2009 )
. In contrast to the age
- related PK differences identified in the 2011 anal ys is, PD contributions to py rethroid tox icity

are not age - dependent even though there are several variations of sodium channels, called isoforms, which are differentiall y expressed by tissue and age. Due to the nature of the interaction of py

rethroids with sodium channels, it is difficult to ob tain dy namic information in vivo. To date, a readil y useable biomarker of in vivo py rethroid interaction with sodium channels has not been identified, making it impractical to determine the isoform combinations that are present and being modulated by py re throids. Therefore, much of the information available to the Agency to characterize the PD relationship between py rethroids and sodium channels has been derived from in vitro studies using frog oocy tes or neuronal cellsBifenthrin Human Health Risk Assessment D372550

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Page **25** of **83** cultured in defined media. These in vitro techniques do not provide direct quantitative measure of in vivo py

rethroid activity
. However, these techniques consistently and qualitatively demonstrate that channel isoforms expressed in juveniles are not more sensitive to py rethroid perturbati on compared to isoforms expressed in adults and that, pharmacody namically , the rat is a conservative model for humans. For example, Meacham et al. ( 2008 ) , compared the sensitivity of an adult isoform and a juvenile isoform expressed in frog oocy tes to deltamethrin. The isoforms had comparable responses at environmentally relevant concentrations (< 500 nM) of deltamethrin, suggesting a lack of PD difference between juveniles and adults at low exposure levels. In addition, in a direct comparison of a homologous rat and human VGSC isoform, NaV 1.3 , revealed that the rat isoform was 4
- fold mo re sensitive than the equivalent human sodium channel to the pyrethroid tefluthrin ( Tan and Soderlund 2009 )
. This data suggests that the rat is a highly
- sensitive model and extrapolations from the rat would be protective of human health. The occurrence and ontogeny of volt age - gated sodium channels in humans is not well characterized compared to the rat. However, based on the comparable function and distribution of sodium channels between the species, the rat is an appropriate surrogate for the evaluation of human PD ( Goldin et. al. 2000 ; Goldin 2002 ) . As a result, the Agency concludes that juvenile rats are not more sensitive than adults with respect to py rethroid pharmacody

namics. Therefore, the pharmacodyn amic contribution to the FQPA f actor will be 1X. **4. 3.3**  **Critical Duration of Exposure** One of the key

elements in risk assessment is the appropriate integration of temporality between the exposure and hazard assessments. Following a single oral gavage dose, bifenthrin is absorbed rapidly in rats and quickly displaying decreased motor activity and increased tremors. Toxici ty is observed as quickly

as 1 hour, peaks at 4 hours and motor activity started to increase at 7 hours, approximately following the blood PK profile (Wolansky , 2007)
. Tremors are absent at 12 hours and r ats ty

pically recover within 24 hours without any persisting neurotoxic effects , at doses near the LOAEL value. In support, for deltamethrin the signs of salivation and tremors correlated very

well with the internal dos e, with r2 =0.86 - 0.90 ( i.e. blood AUC, Anand et. al. 2006 )
. The toxicity

profiles for other py

rethroids are generally similar and marked by rapid absorption, metabolism, and time
- to - peak effect. The NOAELs and LOAELs for tremors established from results of experimental toxicity studies with bifenthrin are remarkabl y consistent across durations of exposure, ranging from a single dose up to 2 - ye ars of dosing (see Table 4.3.3 ). The BMD values from the motor activity results from the Wolansky study are similar to the NOAEL/LOAEL values from the tremor endpoint. **Table 4. 3.3.**  **Bifenthrin NOAEL and LOAEL Values Versus Treatment Time**

**Study Duration**  **Study findings** Wolansky et al (2006) rat Acute, single exposure BMDL=3.1 BMD=4.1 Developmental neurotoxicity rat 86 days NOAEL = 3.6 LOAEL = 7.2 Sub
- chronic dog 90 days NOAEL = 2.21 LOAEL= 4.42 Sub
- chronic rat 90 days NOAEL = 3.8 LOAEL = 7.5 Sub
- chronic neurotoxicity rat 90 days NOAEL = 2.9 LOAEL = 6.0 Reproductive toxicity rat 120 days NOAEL = 3.0 LOAEL = 5.0 Chronic
- carcinogenicity mouse 87 weeks NOAEL = 6.7 LOAEL = 25.6 Chronic
- carcinogenicity rat 2 - years NOAEL = 3.0 LOAEL = 6.1Bifenthrin Human Health Risk Assessment D372550

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Page **26** of **83** Comparing the NOAELs and LOAELs established from bifenthrin single dose and repeat dosing studies , it is apparent that repeat exposures do not result in lower NOAELs , within the variability

of animal testing and body weight scaling corrections
. The human equivalent doses (HED) for bifenthrin between the dog study and rat study

are similar when normalized by body weight. The human equivalent dose for the 90
- day dog study

NOAE L is 1.35 mg/kg and the value for the acute Wolansky rat study BMDL is similar at 0.90 mg/kg (see Appendix A.4). These data are consistent with the general kinetic profile for bifenthrin. The acute Wolansky study endpoint of decreased motor activity at 4.1 mg/kg (BMDL 1SD value of 3.1 mg/kg) is slightly lower than the chronic two
- ye ar cancer study L OAEL= 6.1 mg/kg/day . Therefore , the endpoint from the acute study is protective of the endpoints from the repeat dosing studies. Thus, for purposes of endpoint selection and exposure assessment, onl y single
- day risk assessments need to be conducted. Appendix A.3 contains a graphical depiction and description of further NOAEL s of other studies not listed in this table. While other studies did have lower NOAELs, they were inconsistent with the weight of evidence from the entire data base or were similar when the results were normalize d to the human equivalent dose. The Nemec 2006 study (WIL) had a lower PoD, however, for bifenthrin the dose selection was sub
- optimal, producing a poor dose response and atypical PoD results. Conversel y, the ACN study did not utilize a dosing vehicle (which may

not reflect exposure scenarios) and resulted in a non
- conservative PoD an order of magnitude higher than the ty pical findings in Table 4.3.3. **4.4 Safety Factor for Infants and Children (FQPA Safety Factor)**  Bifenthrin exposure to children under 6 ye ars old is anticipated and must be considered in the context of the py

rethroids as a class. For non - inhalation exposure scenarios for infants and children < 6 ye ars of age, EPA is reducing the FQPA safety factor t o 3X based on the increased quantitative susceptibility seen in the scientific literature related to py rethroid pharmacokinetics. This concept is consistent with the Agency ’s 2011 anal ys is and is supported by rat PBPK model predictions of a 3
- fold increas e of deltamethrin concentrations in the juvenile brain compared to adults (see Section 4.3.1). The PK of p yrethroids as a group is sufficiently similar that significant deviations from the 3
- fold increase of deltamethrin concentrations are not expected fo r other p yr ethroids. As noted in Section 4.3.2, juveniles are not more sensitive than adults with respect to p yr ethroid pharmacodynamics and thus no uncertainty factor is needed for PD considerations. There is no evidence that bifenthrin results in inc reased susceptibility in in utero rats or rabbits in the prenatal developmental studies or in young rats in the 2
- generation reproduction study . This is consistent with the results of the guideline pre
- and post
- natal testing for other py rethroid pesticid es. There are, however, high
- dose LD 50 studies (studies assessing what dose results in lethality to 50 percent of the tested population) in the scientific literature indicating that py rethroids can result in increased quantitative sensitivity in the young . Examination of pharmacokinetic and pharmacodynamic data indicates that the sensitivity observed at high doses is related to p yrethroid age
- dependent pharmacokinetics
- the activity of enzy mes associated with the metabolism of py

rethroids. With otherwi se equivalent administered doses for adults and juveniles, p redictive pharmacokinetic models indicate that the differential adult
- juvenileBifenthrin Human Health Risk Assessment D372550

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Page **27** of **83** pharmacokinetics will result in a 3X greater dose at the target organ in juveniles compared to adults. No evidence o f increased quantitative or qualitative susceptibility was seen in the py rethroid scientific literature related to pharmacody namics (the effect of py

rethroids at the target tissue) both with regard to inter
- species differences between rats and humans and t o differences between juveniles and adults. Specifically , there are in vitro pharmacodyn amic data and in vivo data indicating similar responses between adult and juvenile rats at low doses and data indicating that the rat is a conservative model compared to the human based on species
specific pharmacodyn amics of homologous sodium channel isoforms in rats and humans. In light of the high
- dose literature studies showing juvenile sensitivity to pyrethroids and the absence of the requested data on juvenile sensitivity to py rethroids, EPA is retaining a 3X additional safety factor as estimated by pharmacokinetic modeling. For several reasons, EPA concludes there are reliable data showing that a 3X factor is protective of the safety of infants and children. Fi rst, the high doses that produced juvenile sensitivity in the literature studies are well above normal dietary or residential exposure levels of py rethroids to juveniles and these lower levels of exposure are not expected to overwhelm the ability metaboliz e py

rethroids as occurred with the high doses used in the literature studies. This conclusion is confirmed b y the lack of a finding of increased sensitivity in pre
- and post
- natal guideline studies in any py rethroid, including bifenthrin, despite the relatively high doses used in those studies. Second, the portions of the uncertainty factors that account for potential pharmacody namic differences are likel y to overstate the risk of inter
- and intraspecies pharmacodyn amic differences , given the data showing similarities in pharmacodynamics between juveniles and adults and between humans and rats. For both the inter
- species and intra
- species uncertainty factors, the pharmacodyn amic portions are generall y considered to be 3X, however fo r py rethroids it is reduced to 1X since no differences among the various groups are observed. Finally , as indicated, pharmacokinetic modeling onl y predicts a 3X difference between juveniles and adults. In addition to 3X factor for infants and children < 6 ye ars of age, a 10X FQPA safety factor is being retained for inhalation exposure scenarios for all population groups. This data gap is described in greater detail in the following Section ( 4.4.1 ) . Because the 3X factor and the 10X factor for inhalation exposure scenarios are in response to different uncertainties, these safety factors have been combined for inhalation exposure scenarios for infants and children < 6 ye ars of age resulting in a FQPA safety factor of 30X. This information described above is summarized in Re
- Evaluation of the FQPA Safety Factor for py rethroid pesticides (US EPA 2011c). **4.4.1 Completeness of the Toxicology Database**  The toxicology

database for bifenthrin is not complete
. Acceptable developmental toxicity studies in rats and rabbits are available for bifenthrin, in addition to an acceptable reproduction study in rats. The main endpoint for bifenthrin is tremors, a common sign for a py rethroid, which was detected in most toxicology studies, plus observed during targeted t esting in the ACN, SCN and developmental neurotoxicity (DN T) studies. EPA lacks additional data on immunotoxicity, inhalation toxicity, and adult
- juvenile sensitivity
. Bifenthrin requires additional immunotoxicity testing (870.7800) and an inhalation study (870.3465) for pesticideBifenthrin Human Health Risk Assessment D372550

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Page **28** of **83** registration
. However, a special acute inhalation study with more specific ACN study endpoints will replace the typical 28/90
- day inhalation study due to the rapid clearance of bifenthrin and its signs of neurotoxicity
. An oral NOAE L is used for assessing inhalation risk for short
- term exposure scenarios. HED’s Hazard and Science Policy Council ( HASPOC ) met on January 12, 2012 to discuss the inhalation data requirements ( D. Smegal ; TXR 0056209; 2012). HASPOC concluded that a special acute inhalation study be required for bifenthrin based on a weight of evidence approach considering all the available hazard and exposure information. The following items were considered in this recommendation: (1) use patterns and MOEs from the most recent risk assessment, (2) the ph ys ical chemical properties of bifenthrin, (3) the toxicological profile of bifenthrin, and (4) inhalation data for other p yr ethroids that show the potential for the inhalation route to be more potent than the o ral route. The existing acute LC 50 inhalation study for bifenthrin (870.1300) cannot substitute for this special study since it was not designed for neurotoxicity

evaluations. There were deaths at the lowest dose in this study , thus it was not a s ensitive data set for point of departure determinations. EPA is requiring an inhalation toxicity study for bifenthrin because inhalation data for other py rethroids show the potential for the inhalation route to be more potent than the oral route. Currently , the POD for inhalation risk assessment scenarios is based on an oral toxicity study
. Reliance on an oral study raises uncertainty as to whether the standard safety factors are protective of infants and children. For the inhalation study data gap, the Agency is retaining a 10X database uncertainty factor for all inhalation exposure scenarios. Once these data have been received, the Agency

will determine how the results will affect the toxicology endpoints and uncertainty factors. In the absence of specifi c immunotoxicity studies, the Agency

has evaluated the available bifenthrin toxicity

database to determine whether an additional database uncertainty factor is needed to account for po tential immunotoxicity
. The toxicology database for bifenthrin does not show an y evidence of treatment
- related effects on the immune sy stem, and the overall weight
- of
evidence suggests that this chemical does not directly target the immune system. Therefore, the Agency does not believe that conducting a functional immunotoxi city study will result in a lower POD than that currently

in use for overall risk assessment, and additional safety factors are not needed to account for a lack of this study
. In light of the literature studies indicating a possibility of increased sens itivity

to bifenthrin in juvenile rats at high doses, EPA has also the requested proposals for study protocols which could identify and quantify

bifenthrin’s potential juvenile sensitivity . For the reasons discussed in Section 4.4, the uncertainty regardi ng the protectiveness of the intraspecies uncertainty factor raised b y the literature studies and the absence of the requested data warrant application of an additional 3X for risk assessments for infants and children < 6 ye ars of age. Dermal exposures of greater than 21 day s are possible for bifenthrin; however, the HASPOC concluded, based on a WOE approach, that a 90
- day dermal toxicity

study for bifenthrin is not required at this time ( T XR No.: 0056209 )
. This approach considered the following factors: 1) the established dermal absorption factor based on SAR considerations; 2) that there are no riskBifenthrin Human Health Risk Assessment D372550

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Page **29** of **83** estimates of concern for any scenario from using the oral PODs (i.e., MOEs are greater than 100 for adults, and 300 for children, respectively); 3) there are two 21 - day day dermal toxicity studies available for bifenthrin; and 4 ) the toxicity database for bifenthrin shows that in oral toxicity studies, NOAELs do not change considerably over longer exposure durations. **4.4.2 Evidence of Neurotoxicity**  The re are no residual uncertainties with regard to evidence o f neurotoxicity for bifenthrin. Like other py rethroids, bifenthrin causes toxicity from interaction with sodium channels leading to cli nical signs of neurotoxicity
. These effects are adequatel y as sessed by the available guideline and non
- guideline studies. Bifenthrin is a Ty pe I py rethroid and tremors were consistently observed throughout its toxicology database. Neurotoxicity

was consistently

observed throughout the database in a dose
- dependent manner in most of the studies conducted. **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  Evidence of increased qualitative or quantitative susceptibility of offspring was not observed in any of the available guideline toxicity studies for bifenthrin
. A fter reviewing the extensive body of peer
- reviewed literature on py rethroids, the Agency

has reached a number of conclusions regarding juvenile sensitivity for p yr ethroids, including the following:

 The Agency

has no resi dual uncertainties regarding age related sensitivities for the yo ung , based on the absence of pre
- natal sensitivity observed in 76 guideline studies for 24 py rethroids, the scientific literature, and the bifenthrin guideline toxicological studies.  The DNT, developmental and reproduction studies for bifenthrin did not demonstrate qualitative or quantitative susceptibility to the young or developing animal , consistent with other members of the py rethroid class
.  No evidence of increased quantitative or qualitative susceptibility was seen in the py rethroid scientific literature related to pharmacody namics.  The Agency

will retain a 3X uncertainty factor to protect for exposures to children < 6 ye ars of age based on the increased quantitative susceptibility seen i n the scientific literature related to p yrethroid pharmacokinetics. Bifenthrin is neither a developmental nor a reproductive toxicant. Bifenthrin has been evaluated for potential developmental effects in the rat (following gavage or dietary administratio n) and in the rabbit (gavage administration). Maternal toxicity included neurological effects (tremors in rats and rabbits; head and forelimb twitching in rabbits). There were no developmental effects of biological significance in either species. The po tential reproductive toxicity

of bifenthrin was examined in a two
- generation reproduction study in the rat . Tremors were noted only in females of both generations with one parental generation rat observed to have clonic convulsions. Furthermore, high
- dos e studies in the scientific literature indicated that younger animals were more susceptible to the toxicity of p yr ethroids. For example, Sheets et al (1994) found increased brain deltamethrin levels in young rats (PND 11 and 21) relative to adult rats (PND 72). These age
- related differences in toxicity are principall y due to age
- dependent pharmacokinetics; the activity of enz ym es associated with the metabolismBifenthrin Human Health Risk Assessment D372550

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Page **30** of **83** of py rethroids increase with age (Anand et al, 2006). However in context, normal dietary or res idential exposures to juveniles are not expected to overwhelm their ability metabolize py rethroids
. In support, at a dose of 4.0 mg/kg deltamethrin (near the Wolansky study L OAEL value of 3.0 mg/kg for deltamethrin), the change in the acoustic startle response was similar between adult and young rats (Sheets, 1994). In addition, ORD has recently developed an age
dependent PBPK model for deltamethrin (Tornero
- Velez et al, 2010) which predicts a 3

– fold increase of p yr ethroid in neuronal tissue in younger an imals compared to adults. There are several studies (in vitro and in vivo) that indicate pharmacodyn amic contributions to py rethroid to xicity are not age - dependent. Examination of specific VGSCs have demonstrated that there is a lack of increased sensitivity in either juvenile specific isoforms (Meacham et al, 2008) or in human isoforms compared to rat variants (Tan and Soderlund, 2009). A dditional in vitro and in vivo studies are currently being conducted that could potentially inform a number of issues related to py rethroid toxicity

as a class. In 2010, the Agency requested proposals for study protocols which could identify and quantify potential juvenile sensiti vity and received a single, coordinated response from the Py rethrin and Py

rethroids Working Group (PPTWG), a conglomerate of py rethroid registrants. The PPTWG protocol was reviewed during a July 2010 FIFRA SAP meeting 1 . Based on comments from the SAP, th e initial study proposal was refined. At present time, pesticide registrants and product formulators have come together as Council for the Advancement of P yrethroid Human Risk Assessment (CAPHRA) and plan on doing the following: 1) conducting in vitro stu dies demonstrating the interaction of py rethroids exogenousl y expressed rat and human VGSCs in Xenopus oocy tes; 2) conducting in vitro studies demonstrating interaction of py rethroids in rat neurolemma cells; 3) developing rat and human PBPK models, including additional pharmacokinetic data; and 4) conducting in vivo behavioral testing using auditory

startle testing in rats. As these data becomes available, the Agency will determine whether re
- evaluation of the age
- related sensitivity of p yr ethroids is app ropriate. **4.4.4 Residual Uncertainty in the Exposure Database**  There are no residual uncertainties in the bifenthrin database in regard to dietary (food and drinking water), occupational, and residential exposures. Although the acute dietary exposure estimates are refined, HED does not believe that the exposure estimates under
- estimate risk for the established or proposed uses of bifenthrin
. The reason is the residue levels used are based on either monitoring data reflecting actual residues found in the food supply , or on high
- end residues from field trials which reflect the use patterns which would result in highest residues in foods. The residue data us ed for dietary exposure assessment are described in Section 5.4.1 of this document. Furthermore, processing factors used were either those measured in processing studies, or default high
- end factors representing the maximum concentration of residue into a processed commodity
. EPA made conservative (protective) assumptions in the ground and surface water modeling used to assess exposure to bifenthrin in drinking water. Additionally , post - application exposure of children and incidental oral exposure of toddlers are based on conservative, health
- protective assumptions that also ensure exposures are not underestimated. These assessments will not underestimate the exposure and risks posed b y bifenthrin.

1 http://www.epa.gov/scipoly/sap/meetings/2010/ 072310meeting.htmlBifenthrin Human Health Risk Assessment D372550

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Page **31** of **83 4.5**  **Toxicity Endpoint and Point of Departure Selection s**  **4.5.1 Dose**  **- Response Assessment**  The details for selecting toxicity endpo ints and points of departure (Po Ds) for various exposure scenarios are presented in Appendix A
. 2. Based on the proposed use pattern s for bifenthrin, the expected exposure profile w ill be for dietary , dermal, inhalation and incidental oral exposures. Since acute PoDs are protective for chronic exposures, only acute endpoints have been selected for bifenthrin. As previously

indicated, the toxicity

endpoints in the bifenthrin databas e are consistently based on clinical signs of neurotoxicity, more specifically tremors. These studies include multiple species, study designs, and durations. Moreover, the acute exposure or bolus dosing studies generall y result in lower NOAELs compared t o longer
- term dietary administration studies, consistent with other py

re throids in this class. Because un certainty associated with the Po D is propagated throughout the risk assessment, one of the key factors in POD selection is the robustness of the dose
- response data. The guideline experimental toxicology studies available for bifenthrin are generally high quality

and were considered in the POD selection process (Appendix A
. 2) and in the weight of the evidence evaluation. In addition to the typical guid eline studies, data from two special studies (Wolansky study on loco motor activity

and Nemec/WI L FOB study) evaluating neurobehavioral outcomes are available for bifenthrin (Nemec 2006 ; Wolansky

et. al. 2006 ) . Wolansky

et al. ( 2006 ) indivi d

ually measured loco mot or activity at the time of peak effect after exposure to 11 py rethroids, including bifenthrin. Dose
- response relationships were determined using 6
- 11 doses per py rethroid (9 doses used for bifenthrin) and 3 - 18 rats per dose group ( 8 - 12 animals/group used for bifenthrin) , minimizing variability and increasing the confidence in the benchmark dose (BMD) estimates determined from this study
. The locomotor activity

for bifenthrin had an excellent dose response. Locomotor activity is an objective toxicity

metric, since it is recorded by photoelectric detectors. Moreover, each py rethroid was evaluated by the same scientist thus decreasing some of the variability associated w ith neurobehavioral measures. In the Nemec/WI L study, 17 p yr ethroids have been evaluate d using a speciall y designed Functional Observational Battery (FOB) study

focused on the outcomes associated with py rethroid toxicity

s yndromes. The bifenthrin data from the Nemec/WIL study

w ere not considered as part of Po D selection. The bifenthrin dos e selection in the Nemec/WIL study

was sub
- optimal (i.e. only 2 doses and too close together), resulting in a poor dose response curve and low confidence of the calculated BMDL value (Nemec 2006 )
. Observation of tremors is the most prominent findings in th e guideline experimental toxicology studies and was considered in the Po D determination. Unlike the Wolansky study , guideline studies ty picall y have only three treatment groups and often do not evaluate clinical signs at the time of peak effect. Moreover , scoring metrics of tremors varies widely among guideline studies. The Wolansky

study utilized a sensitive rat strain to neurotoxins (L ong Evans), plus measured an objective apical endpoint of locomotor activity as the toxicity

metric. The BMD 1SD value was 4.1 mg/kg at a 20% decrease in locomotor activity and the BMDL 1SD value was 3.1 mg/kg. TheBifenthrin Human Health Risk Assessment D372550

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Page **32** of **83** Wolansky

study was considerabl y conservative, using gavage dosing with a vehicle and volume producing the most adverse responses (i.e. 1 ml/kg corn oil). The BMD data anal ys is was utilized as a standardized method to address concerns of dose selection and dose spacing. In support, the BMD 1SD value for bifenthrin was verified in the study by Scollon et al (2011), with a 20% decrease in motor activity at a d ose of approximately 4 mg/kg (i.e. one SD for the Wolansky

bifenthrin data corresponded to 20% of the control mean value). Furthermore, the PoD from the Wolansky

study is supported b y similar NOAEL values in multiple other guideline studies (see Table 4.3 .3). Given the multiple strengths associated with study design of Wolansky et. al. ( 2006 ) and the resulting well
- defined dose
- response curve, this study provides the most robust data set for extrapolating risk from bifenthrin. The ACN is often considered for acute endpoints
. However, this study for bifenthrin did not utilize a vehicle and had an atypical LOAEL value of 70.3 mg/kg
. Thus, the Wolansky PoD is much more conservative. Further, there were deaths at the LOAEL value and, therefore, this is not a sensitive study for the selection of a point of departure.

Acute Dietary (All Age Groups) : Quantitation of the dietary risks were performed using the acute oral Wolansky

study , with a BMDL value of 3.1 mg/kg and a BMD value of 4.1 mg/kg based on decreased loco motor activity
. Short
- term Dermal: Quantification of dermal risks were performed using a 21
- day dermal rat study with a BMD L 10 value of 96.3 mg/kg/day and a BMD 10 value of 187.0 mg/kg/day based on exaggerated hind limb flexion (see Appendix G for the BMD anal ys is). **0.01 0.1**  **1 10**  **0 25**  **50 75**  **100 125**  **150 175**  **200 225**  **250 275**  **300 325**  **350 375**  **400** Control

r=0.99 Wolansky 2006 

### Wolansky Study Bifenthrin Data +/- SD**T o** **t a** **l L** **o c** **o m** **o t** **o r** **A c** **t i** **v i** **t y** 



## Bifenthrin (mg/kg)Bifenthrin Human Health Risk Assessment D372550

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Page **33** of **83** Short
- term Incidental Oral: Quantitation of the incidental oral risks were performed using the acute oral Wolansky

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

study , with a BMDL value of 3.1 mg/kg and a BMD value of 4.1 mg/kg based on decreased loco motor activity
. Equivalent inhalation and oral toxicity were assumed. **4.5.2 Recommendation for Combining Routes of Expo**  **sure for Risk Assessment** HED combines risk values resulting from separate routes of exposure when it is likely they can occur simultaneousl y based on the use pattern and the behavior associated with the exposed population, and if the hazard associated with the points of departure is similar across routes. A common toxicological endpoint, neurotoxicity , exists for dermal, incidental oral, and inhalation routes of exposure to bifenthrin. Therefore, these were combined for all residential exposure scenarios assessed. **4.5.3 Cancer Classification and Risk Assessment Recommendations**  Bifenthrin is classified as a “possible human carcinogen” based on an increased incidence of urinary bladder tumors in mice. However, EPA concluded that the bladder tumors may not be uncommon in mice and are not likely to be malignant. Additionally , these tumors were observed only in male mice at the highest dose tested and the incidence was of borderline significance. No evidence of carcinogenicity was observed in bifenthrin carcinogenicity studies in rats, and bifenthrin was negative in five different tests for mutagenicity but was marginall y active in a forward mutation test in mouse ly mphoma cells. Overall, based on the available information, there is a low concern for mut agenicity
. Taking into account all of this information, the Agency has determined that quantification of risk using a non
- linear approach (i.e., an aPAD or aRfD) will adequatel y account for all chronic toxicity, including carcinogenicity that could resu lt from exposure to bifenthrin. While the Agency would typicall y use a chronic population
- adjusted dose (cPAD) to protect for cancer concerns, use of the aPAD is protective for bifenthrin because increasing toxicity with increasing duration of exposure is not seen for bifenthrin. The NOAEL observed in the mouse chronic study , in which tumors were observed, is 6.7 mg/kg/day , 2 - fold higher than the POD used for acute risk assessment. The NOAEL in the study was based on tremors seen at the LOAEL of 25.6 m g/kg/day ; however, the tumors were observed at 81.3 mg/kg/day , a dose that is 26
- fold higher than the current acute POD.Bifenthrin Human Health Risk Assessment D372550

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Page **34** of **83 4.5.4**  **Points of Departure and Toxicity Endpoints Used in Human Risk Assessment Table 4.5.4. Summary of Toxicological Doses and**  **Endpoints for Bifenthrin Exposure**  **Scenario Point of** 

**Departure Uncertainty/** 

**FQ PA Safety**  **Factors RfD, PAD and** 

**LOC Study and Toxicological**  **Effects** Acute Dietary
- (< 6 years old) BMDL 1SD = 3.1

mg/kg Acute RfD = 0.031 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 3X aPAD = acute RfD FQPA SF
= 0.010 mg/kg/day Wolansky et al (2006) BMD 1SD = 4.1 mg/kg based on reductions in locomotor activity ; Supported by

multiple guideline studies Acute Dietary
- ( ≥ 6 years old) BMDL 1SD = 3.1

mg/kg Acute RfD = 0.031 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X aPAD = acute RfD FQPA SF
= 0.031 mg/kg/day Wolansky et al (2006) BMD 1SD = 4.1 mg/kg based on reductions in locomotor activity ; Supported by

multiple guideline studies
Short
- Term (1
- 30 day s) In cidental Oral BMDL 1SD = 3.1

mg/kg UF A = 10X

UF H = 10X FQPA SF = 3 X Residential:

< 6 years old LOC is an MOE = 300 ≥ 6 years old , LOC is an MOE= 100 Wolansky et al (2006) BMD 1SD = 4.1 mg/kg based on reductions in locomotor activity ; Supported by

multiple guideline studies

Short
- Term (1
- 30 day s) Dermal BMDL 10 =96.3

mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 3 X Residential:

< 6 years o ld LOC is an MOE = 300 ≥ 6 years old , LOC is an MOE= 100 Occupational: Adults , L OC is an MOE=100 21 - day dermal study

in rats. BMD 10 =187.0 mg/kg/day, based on exaggerated hind limb flexion

Short
- Term (1
- 30 day s) Inhalation BMDL 1SD = 3.1

mg/kg UF A = 10X

UF H = 10X FQPA SF = 3 0 X * Residential:

< 6 years old , LOC is an MOE = 3 , 000 ≥ 6 years old , LOC is an MOE= 1 , 000 Wolansky et al (2006) BMD 1SD = 4.1 mg/kg based on reductions in locomotor activity ; Supported by

multiple guideline studiesBifenthrin Human Health Risk Assessment D372550

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Page **35** of **83** NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable. * FQPA SF is composed of the 3X factor for increased quantitative susceptibility and the 10X factor for the inhalation study data gap. **5.0 Dietary Exposure and Risk Assessment**  **5.1 Metabolite/Degradate Residue Profile**  **5.1.1 Plant**  **and Livestock Metabolism Studi**  **es** Plant Metabolism The metabolism of bifenthrin was investigated in cotton, apples, corn and potatoes. Metabolism was generall y similar in all plants. When directly applied to soil, most of the bifenthrin remains in the soil with very

little uptake into the plants. When a pplied foliarl y, the major residue in plants is the parent compound. Most residue stays on the surface where applied with only small amounts translocated throughout the plant. Bifenthrin in the major residue identified in all crops. 4 - hydroxy

bifenthrin was the only

residue identified at just over 10% of the TRR and was seen only in corn. Livestock Metabolism The metabolism of bifenthrin was investigated in the goat and the hen. Ruminant and poultry metabolism is similar. Most of the administered d ose is excreted. The highest residues retained in the tissues are found in fat and liver. In ruminant milk, fat and muscle and poultry eggs, fat and muscle, unchanged parent is the major residue. In ruminants, the major metabolite in liver and kidney

is 1 - methyl
- 3 - phen ylbenzoic acid and in poultry , hydrox ym ethyl bifenthrin and fatty acid conjugates of h ydrox ym eth ylbifenthrin were identified in fat and liver. **5.1.2 Summary of Environmental Degradation**  Drinking Water Memo, D372556, J. Melendez, 8/11/201 0 Studies conducted on bifenthrin indicate that it is persistent under most conditions and bioaccumulative. It appears that a major route of degradation is aerobic metabolism. Bifenthrin is relatively stable to hydroly sis at all pH values . It is relati vely stable to aqueous and soil photoly sis and degrades slowly under both aerobic and anaerobic soil metabolism conditions (half
- life range 97
- 250 day s in 3 soils, and relatively stable, respectivel y). Bifenthrin is Occupational: Adults MOE=1 , 000 Cancer (oral, dermal, inhalation) **Classification: Category C**  (possible human carcinogen). No Q 1 * has been derived.

Anon - lin ear approach is recommended for cancer assessment.Bifenthrin Human Health Risk Assessment D372550

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Page **36** of **83** relativel y immobile in four soils teste d (KOC range 131,000 to 275,000 ). Field studies show a pattern consistent with the laboratory studies, with relativel y high persistence (half
- lives ranging from 78 to 345 day s in 10 field trials) and low mobility of the chemical in soil. In aquatic envi ronments, it appears that residues of bifenthrin persist in pond sediments for extended periods (at least 12 months of monitoring). No major metabolites were observed (> 10% of the applied) in any

of the laboratory

studies. The very

low water solubility and hydrophobic nature of bifenthrin leads to strong soil adsorption and a tendency to partition to sediment in aquatic sy stems. Bifenthrin has a vapor pressure of 1.8x10

–7 mmHg, water solubility of 0. 0 1 40 ppb, and an estimated Henry ’s law constant of 7.2 x10 - 3 atm - m 3 /mol. Based upon its Henry ’s law constant and vapor pressure, bifenthrin is expected to have a moderate to low potential for volatilizatio n from soil and water surfaces. Bifenthrin’s potential for volatilization is reduced significantl y becau se it adsorbs strongly to soils, suspended solids, sediment and organic matter in the water column. A laboratory

volatility study showed a maximum volatility at 40 ° C of 5.07x10
- 4 μg/cm2 hr (average at 14 day s), a relativel y low value. **5.1.3 Comparison of**  **Metabolic Pathways** The rat metabolism study is discussed in Section 4.2. Plant and animal metabolism studies are discussed in Section 5.1.1. The metabolic profile in plants is similar in cotton, apples, corn and potatoes. Further, the metabolism in ruminants, poultry , and the rat is also similar. In plants, the unchanged parent compound is the major residue and in animals, it is also the major residue in all animal matrices. Therefore, there are no residues of concern in plant studies that are not also present in the rat metabolism study
. **5.1.4 Residues of Concern Summary and Rationale**  The residue of concern in plants, livestock and drinking water is the parent compound. Unchanged parent is the major residue in all plant matrices, drinkin g water and most animal matrices. In animals additional metabolites have been identified in liver, kidney and fat, however, these metabolites are likel y present at fairly low levels and are considered to likely be of lesser toxicity

than the parent and are therefore not of concern. **Table 5.1.4. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression** 

**Matrix Residues Included In**  **Risk Assessment Residues Included In** 

**Tolerance Expression** Plants Grass grown for seed

(hay and forage) and Tea Bifenthrin parent only Bifenthrin parent only Rotational Crops Livestock RuminantBifenthrin Human Health Risk Assessment D372550

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Page **37** of **83 Table 5.1.4. Summary of Metabolites and Degradates to be included in the Risk**  **Assessment and Tolerance Expression**

**Matrix Residues Included In**  **Risk Assessment Residues Included In** 

**Tolerance Expression** Poultry & Eggs Drinking Water **5.2 Food Residue Profile**  Bifenthrin is typicall y applied as a foliar application for later season uses. Applications directl y to soil generally

do not result in significant residues in plants due to bifenthrin’s affinity to bind to soil, its low soil mobility , and the low tendenc y of this pesticide to translocate within plants. Metabolism data shows that when applied foliarl y, the vast majority of residue is likely to be surface residues at the site of application consisting primarily of unchanged parent compound. USDA’s Pestici de Data Program (PDP) has conducted extensive monitoring for residues of bifenthrin in a wide variety of crops. The data shows that bifenthrin residues in most crops are not found at or above the limit of quantification of the anal yt ical method. A few qu antifiable residues are found in the leafy vegetables, but even in these commodities, most monitoring samples have no residues above the method LOQ. Based on animal metabolism data and feeding studies, residues in livestock commodities resulting from feeding treated feedstuffs are likely to be very low, and given the low water solubility and high affinity

to bind to soils, residues in water are also expected to be very low. **5.3 Water Residue Profile**  Drinking Water Memo, D372556, J. Melendez, 8/11/2010 The Tier I Estimated Surface Drinking Water Concentrations and Estimated Ground Water Concentrations (EDWCs) for bifenthrin were calculated using the Tier I aquatic models FQPA Index Reservoir Screening Tool ( FIRST ) and SCI
- GROW , respectivel y. The very l ow water solubility and the tendency

o f bifenthrin to adsorb to soil indicate that drinking water is not a major route of exposure; however, in the absence of acceptable monitoring data HED has used EDWCs which are anticipated to overestimate risk. The E stimated Drinking Water Concentrations (EDWCs) for bifenthrin were calculated based on a maximum application rate of 0.5 lb a.i ./A/season. The acute drinking water concentration in surface water is 0.0140 ppb of bifenthrin, based on applicatio ns of the ch emical to lettuce. The cancer/chronic drinking water concentration is 0.0140 ppb (based on applications of lettuce, with the highest application rate and PCA). The SCI
- GROW generated EDWC is 0. 014 ppb of bifenthrin, which is recommended for use, both for acute and chronic exposures. Because of the very low solubility

of bifenthrin, the EDWCs did not exceed 0.0140 ppb ( that is, the solubility of bifenthrin). **Table 5.2** provides a summary of the Tier I modeled drinking water concentrations for bifenthrin
.Bifenthrin Human Health Risk Assessment D372550

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Page **38** of **83 Table 5.**  **2. Summary of Estimated Surface Water and Groundwater Concentrations fo**  **r Bifenthrin**  Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b Ac ute **0.0140** 0.0030 Chronic (non
- cancer) a From the Tier I FQPA Index Reservoir Screening Tool (FIRST)
. Input parameters are based on maximum application rate on lettuce (0.5 lb ai/A/season). b From the SCI
- GROW model; lettuce scenario. Highest value for use in risk assessment is shown in **bold. 5.4**  **Dietary Risk Assessment** Bifenthrin: Dietary Exposure Memo, D383085, S. Tadayon, 5/25 /2012 A highl y refined acute dietary exposure and risk assessment was conducted for bifenthrin. High
end modeled drinking water estimates were directly incorporated into the assessment. Inorder to assess short
- term aggregate risk to bifenthrin, average dietary exposure estimates (i.e., food and drinking water) were calculated
. Because the endpoint from the acute study is protective of endpoints from repeat dosing studies, a chronic diet ary risk assessment was not conducted. Bifenthrin may be stored and accumulated in aqueous sediment and, therefore, could be a potential dietary

exposure source for people who eat fish (e.g., catfish) which dwell near the sediment
. Subsistence fishers may be more highly

exposed than the general population. HED conducted an acute screening level dietary exposure assessment to consider the intake of contaminated catfish by

subsistence fishers
. Because high
- end bounding fish exposure assumptions were use d to assess exposure to subsistence fishers, this potential dietary exposure source was not included in the acute or average dietary exposure and risk assessments conducted for the proposed Section 3 and 18 uses; rather, a stand
- alone assessment was conduc ted. **5.4.1 Description of Residue Data Used in Dietary Assessment**  The b ifenthrin ac ute dietary exposure and risk assessment was conducted considering all supported food uses and drinking water. The assessment was conducted using DEEM - FCIDTM, Version 2.03 , which incorporates consumption data from USDA’s CS FII, 1994 - 1996 and 1998. Anticipated residues (ARs) were developed based on the latest USDA’s Pesticide Data Program (PDP) monitoring data 1998
- 20 10 , Food and Drug Administration (FDA) data, and field trial data (FTD) for bifenthrin. The USDA’s PDP provides bifenthrin monitoring data from 1998
- 20 10 . The PDP sampling protocol calls for typical consumer practices such as rinsing vegetables, peeling and coring fruit prior to sample anal ys is. PDP data were used where available for both the Section 3 and 18 proposed uses. For the acute dietary assessment the latest PDP data were used for the following commodities : bell pepper; bean (succulent); blueberry ; broccoli; cabbage; cauliflower; cilantro; cranberry ; cucumber; egg; eggplant; grape; grapefruit; orange; orange juice; lettuce; pear; cantaloupe; winter squash; spinach
- canned; strawberry ; sweet corn; sweet peas; tomato; watermelon ; and milk. For b lackberry and raspberry , the 2002 FDA monito rin g data were used
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Page **39** of **83** The chronic dietary

assessment used PDP data for the following commodities: bean (succulent), beef, milk, pea and pork. Field trial data (FTD) were submitted by IR - 4 in support of the use of bifenthrin on grass grown for seed and the establishment of a tolerance on imported tea. The evaluation of the anal yt ical chemistry and residue data for the submitted studies is described in a separate memorandum (D388604, P. Savoia, 5/25 /2012). No FTD was submitted by the states support of the Section 18 action request for use on apple, nectarine, and peach
. However, these crops have use patterns that are similar to the registered use on pear. Therefore, the Agency relied on PDP data for pears, including for baby food and canned products, when assessing anticipated residues on peach, nectarine, and apple. EPA believes the use of PDP data for pears is appropriate, as bifenthrin res idues are found mainly on the fruit surface and residues on peach, nectarine, and apple are expected to be similar to those found on pear. The evaluation of the anal yt ical chemistry and residue data for the pear is described in a separate memorandum (D274 839, S. L ev y, 08/15/2002). The acute and chronic EDWCs for bifenthrin were calculated using the Tier I aquatic models FIRST and SCI
- GROW and based on a maximum application rate of 0.5 lb ai/A/season . The acute and chronic EDWC in surface water was esti mated is 0.014 ppb of bifenthrin , the solubility of the chemical
. The quantification of average dietary exposures was necessary to estimate short
- term aggregate exposures . This required the use of anticipated residues (ARs) from average field trial res idues for tree nuts, artichoke, beans, beet (roots and tops), cabbage, carrot, coriander, mustard greens and tea. ARs from PDP data were used for bean (succulent), beef, milk, pea, and pork. For all other commodities, the assessment used current toleranc es. T he assessment also made use of P CT information where available. Drinking water information was incorporated directly into the dietary assessment using the mean concentration (1
- in
- 10 - year annual mean) for surface water generated b y the PRZM
- EXAMS model. The assessment of human exposure from contaminated catfish used the mean and maximum s ubsistence fish intake amounts (Exposure Factors Handbook, 2011), and 2010 PDP data for catfish
. The mean fish intake for subsistence fishers is 81 g/day , and th e maximum is 770 g/day
. PDP sampled 384 fish (catfish) total, with 130 showing detectable bifenthrin residue. The highest residue was 0.06 ppb. **5.4.2 Percent Crop Treated Used in Dietary Assessment**  Percent Crop Treated (PCTn) Memo, D398265, J. Alsadek , 3/21/2012 A screening
- level usage anal ys is (SLUA) was provided by the Biological Economic Anal ys is Division (BEAD), SLUA in Support of Registration for the Insecticide Bifenthrin , 10/31/2011. The estimated maximum percent crop treated (PCT) for each co mmodity was used for the acute dietary risk assessment. For proposed new uses and uses that have not been registered long enough for usage data, the Agency conservativel y estimated that 100 % of the crops were treated (see details below for the Section 18 uses)
.Bifenthrin Human Health Risk Assessment D372550

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Page **40** of **83** BEAD also provided projected use information for the proposed Section 18 uses (i.e., apple, nectarine, and peach) in the memo, Es timates of the Percent Crop Treated for New Uses (PCTn) of Bifenthrin on Apples, Peaches, Nectarines, and Pears Considering Potential Emergency Use in DE, MD, NC, NJ, PA, VA, and WV
. BEAD used data from 2010 USDA/NASS Agricultural Statistics for apples and peaches. Data on the most recent survey years, 2007 - 2009, were used to derive the needed PCT estimates. The sum o f the utilized production in these states was divided by the total domestic utilized production and multiplied by 100 to determine the PCT for each of the crops for each of the named years. BEAD conservativel y estimated that 100 percent of the crops in the se states will be treated with bifenthrin and calculated the national PCT given the share of utilized production or grown acreage from the seven states likel y to seek the use of bifenthrin. The following maximum PCT estimates were used in the acute dietary risk assessment: alfalfa, 1%; almonds, 25%; artichokes, 30%; beans, green, 50%; broccoli, 6 %; cabbage, 30%; caneberries, 45%; canola/rapeseed, 3%; cantaloupes, 60%; carrots, 10%; cauliflower, 10%; celery , 1%; corn, 5%,; cotton, 10 %; cucumbers, 15%; dry beans/peas, 1%; grapes, table, 1%; grapes, wine, 5%; honeydew, 75%; hazelnuts (filberts), 5%; lettuce, 15%; onions, 1%; lima beans, 35%; peanuts, 5%; peas, green, 25%; pears, 4%; pecans, 5%; peppers, 20%; pistachios, 40%; potatoes, 5%; pumpkins , 40%; sorghum ,1%; soy beans , 5%; squash , 20%; strawberries , 55%; sweet corn , 50% ; tomatoes , 20% ; walnuts , 25%; watermelons , 15%; wheat, spring , 1%; and wheat winter , 1%. In addition , the Agency estimated the PCT for the new uses with the time limited tolerances as follows : a pples , 10% ; p eaches , 7% ; n ectarines , 3%; and p ears 4%. The following average PCT estimates were used to calculate average dietary exposures : alfalfa, 1%; almonds, 12%; artichokes , 14%; beans, green , 40 %; broccoli , 2%; cabbage , 20 %; caneberri es , 35%; canola/rapeseed , 2%; cantaloupes , 40 %; carrots , 2%; cauliflower , 5%; celery , 1%; corn , 2%; cotton, 4%; cucumbers ; 10%; dry beans/peas , 1%; grapes, table , 1%; grapes,wine , 2%; honeydew , 70%; hazelnuts (filberts) , 5%; lettuce , 5%; onions , 1%; lima b eans , 10%; peanuts , 2%; peas, green , 5%; pears , 1%; pecans , 2%; peppers 10 %, pistachios 35%, potatoes, 2 %; pumpkins , 20%; sorghum , 1%; soy beans , 1%; squash , 10%; strawberries , 30%; sweet corn , 30 %; tomatoes , 6 %; walnuts , 15% ; watermelons, 10%; wheat, spring, 1%; and wheat , winter , 1%. In addition , the following PCT estimates were used to calculate average dietary exposures for the proposed Section 18 uses in DE, MD, NC, NJ, PA, VA, and WV : a pples , 10% ; p eaches , 6% ; n ectarines , 3% ; and p ears , 4% . **5.4.3 Acute Dietary Risk Assessment**  Highl y- refined , acute probabilistic dietary exposure and risk assessments were conducted for all established food uses, as well as the petitioned for tolerances and the Section 18 time
- limited tolerances. High
- end modeled drinking water estimates were directl y incorporated into the assessment. The acute dietary exposure estimates for food and drinking water are below HED’s level of concern (<100% aPAD) at the 99.9th percentile of exposure. Bifenthrin dietary

exposure at the 99.9th percentile for food and drinking water is 5 % of the aPAD for the U.S. population and 29 % of the aPAD for children 1
- 2 years, the most highlyBifenthrin Human Health Risk Assessment D372550

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Page **41** of **83** exposed population subgroup. A summary of acute dietary

exposures estimates for all populations is presented in Table 5.4.6, below. For the acute assessment of bifenthrin e xposure to subsistence fishers , the maximum intake level identified in the 2011 Exposure Factors Handboo k, 770g/day , was used. The highest residue value from 2010 fish PDP data, 0.06 ng/g, was multiplied by the maximum fish intake resulting in a value of 4 6.2 ng/day

of bifenthrin. Th is value was converted to mg/day and then divided the w eight of an adult, 80 kg, resulting in an estimated daily dose of 5.8 x 10 - 7 mg/kg/day . This dose was then compared to the acute RfD to result in a highl y conservative estimated % aPAD value of < 1 % and, therefore, would not be anticipated to significantl y impact the dietary exposure assessme nts conducted for the proposed Section 3 and 18 uses. **5.4.4 Chronic** **/Cancer Dietary Risk Assessment**  Chronic and cancer dietary risk assessment s were not conducted for bifenthrin. Because there is no increase in hazard from repeat exposures to bifenthrin , the acute dietary exposure assessment is protective for chronic dietary exposures; acute exposure levels are higher than chronic exposure levels. Accordingl y, a dietary exposure assessment for the purpose of assessing chronic dietary

risk was not conducted
. **5.4. 5**  **Average Dietary**  **Exposure** Average dietary

exposure s were quantified for the purpose of assessing short
- term aggregate risk (i.e., food, drinking water, and residential exposures) of the proposed and established uses. A summary of average dietary

exposures estimated for all population subgroups is presented in Table 5.4.6, below. **5.4.6 Summary Table**  **Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Bifenthrin Population Subgroup**  **Acute Dietary (99.9**  **th Percentile)**  **Average Dietary**  **Exposure (mg/kg/day)**  **Dietary Exposure (mg/kg/day)**  **% aPA D**  General U.S. Population 0.0015 5.0 % 0.000 74 All Infants (< 1 year old) 0.0013 13 % 0.001 0 Children 1
- 2 years old 0.0030 29 % 0.00 18 Children 3
- 5 years old 0.0022 22 % 0.00 14 Children 6
- 12 years old 0.0014 4.6 % 0.00 080 Youth 13
- 19 years old 0.0011 3.7 % 0.000 60Bifenthrin Human Health Risk Assessment D372550

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Page **42** of **83 Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Bifenthrin**  **Population Subgroup Acute Dietary**  **(99.9 th**  **Percentile) Average**  **Dietary Exposure**  **(mg/kg/day) Dietary Exposure**  **(mg/kg/day) % aPA** **D** Adults 20
- 49 years old 0.0015 4.8 % 0.000 66 Adults 50+ years old 0.0016 5.1 % 0.000 66 Females 13
- 49 years old 0.0012 3.8 % 0.000 55 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  Residential exposure is anticipated from the proposed Section 3 bed bug treatment use. In addition , residential exposure s are anticipated from currentl y registered uses of the chemical. Expos ures are expected for i ndividuals (adults) who apply bifenthrin
- containing products and from post
- application exposure in residential areas previously treated with the chemical. In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks anticipated from food, drinking water, and residenti al exposures. A residential exposure assessment was conducted for the bed bug treatment use ( D 383326, A. Rivera
- Lupiáñez , 5/25 /12) and considered for use in the aggregate assessment . An updated assessment of bifenthrin residential uses has also been conducted for the purpose of asses sing bifenthrin aggregate risk because of the revision of the Residential SOPs. Residential uses of bifenthrin are many and vary widely
. The chemical is us ed in indoor residential/household premises in the form of crack and crevice spray s, as a paint additive, dust, and automobiles/recreational vehicle and termite treatment s . Outdoor residential uses of bifenthrin include broadcast and spot treatments to th e following: res idential lawns/turf; golf course turf and outdoor premises (fencerows/hedgerows, paths/patios) b y means of liq uid spray and granular products; and ornamental (turf, shru bs, vines, trees, ground cover). HED used the BEAD Label Use Inform ation Sy stem (LUIS) in order to conduct a screen of the various indoor and outdoor residential uses of bifenthrin and determined those which would result in the greatest potential for exposure. The following high
- end uses were selected for use in the bifenthrin short
- term aggregate assessment : outdoor ornamental plant and turf uses. The bed bug treatment was proposed for surface
- directed application to the following indoor use sites: ba seboards, bed frames, box springs, closets, dressers, furniture, headboards, inside empty luggage, mattresses, and moldings. The Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment was used to assess exposure/risk anticipated from all bifenthrin uses considered.Bifenthrin Human Health Risk Assessment D372550

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Page **43** of **83** The lifestages (i.e., adults, children 1< 2 years old, children 11 < 16 years old, and children 6 < 11 years old) selected for each post
- application scenario are based on an analy sis provided as an Appendix in the 2012 Residential SOPs. These lifestages are not the onl y that could be potentially exposed for these post
- application scenarios; however, the assessment of these are health protective for the exposures and risks for any other potentially

exposed lifestages. Because of the rapid reversibility of the most sensitive neurotoxicity endpoint used for quantifying risks, there is no increase in hazard with increasing dosing duration. Therefore, the acute endpoint is protective of the endpoints from repeat dosing studies, including chronic exposures. Thus, for purposes of residential exposure assessment, onl y single
- day risk assessments were conducted. **6.1 Residential Handler Exposure**  The Agency

uses the term “handlers” to describe those individuals who are involved in the pesti cide application process. HED has determined that short
- term dermal and inhalation exposure to residential handlers is likely during use of the following bifenthrin uses : the proposed indoor bed bug treatments ; and registered outdoor ornamental , and turf uses. Residential handler dermal and inhalation risk estimates for bifenthrin are not of concern to HED (i.e., MOEs are ≥ 100 for dermal and ≥ 1,000 for inhalation, the levels of concern (LOC) for these assessments). HED’s level of conc ern for adult residential handlers is eq ual to an ARI of 1
. The combined dermal and inhalation risk estimates (ARI s) to residential handlers for the identified residential outdoor and proposed indoor bed bug uses are not of concern to HED (i.e., ARI s are ≥ 1 ). The lowest ARIis 2.1 from use of a backpack sprayer equipment to treat ornamentals. A summary of the results from the assessment of the proposed bed bug treatment is presented below in Table 6.1. A summary

of all other results is presented in Appendix C (Table C .1) of this document. **Table 6.1. Residential Bifenthrin**  **Handler Exposure and Risk Estimates**  **fo r**  **the Indoor Bed Bug**  **Treatment Application**  **Rate (lb ai/gallon)**  **a Am**  **ount**

**Handled (gallons)**  **b Unit Exposure**  **(m g/lb**  **ai) b**  **Dose (m g/kg/day)**  **d,e Short**  **- Term**  **MOE f** 

**Derm al**  **c Inhalation**  **c Derm**  **al Inhalation**  **Derm al**  **Inhalatio n**  **Mixing/Loading/Applying Wettable Powders with Manually** **- P**  **ressurized Handwand** 0.0051 0.50 69 1.1 0.0021 0.000035 44,000 88,000
a. Application Rates based on proposed use on label for F4688 50 WSP Insecticide Termiticide label (EPA Reg. No.

8033 - 96) b. Based on 2011 Residential SOPs c . Dermal: Short
- sleeve shirt, shorts, and no gloves; Inhalation: no respirator. d
. Dermal Dose (mg/kg/day) = daily unit exposure (mg/ lb ai) * application rate (lb ai/gallon) * amount handled (gallons)

* dermal absorption factor (100 %) / body weight ( 80 kg). e . Inhalation Dose (mg/kg/day) = daily unit exposure (mg/ lb ai) * application rate (lb ai/gallon) * amount handled

(gallons) * inhalation absorption (100%) / body weight ( 80 kg). f
. Dermal MOE = PoD ( BMDL 10 of 96.3 ( mg/kg/day) / Daily dermal dose (mg/kg/day); Inhalation MOE = PoD (BMDL 1SD of 3.1 mg/kg/day) / Daily inhalation dose (mg/kg/day). Level of concern = 100 (Adult , dermal ) ; 1000 (Adult, inhalation)Bifenthrin Human Health Risk Assessment D372550

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Page **44** of **83 6.2**  **Residential Post -**  **Application Exposure** The Agency

uses the term “post
- application” to describe exposures to individuals that occur as a result of being in an environment that has been previ ously treated with a pesticide. Bifenthrin can be used in areas frequented b y the general population, including indoor and outdoor residential areas. As a result, HED anticipates post
- application exposures from the residential use of bifenthrin. The pr oposed indoor bed bu g treatment and the same high
- end outdoor uses considered for residential handlers were assessed for residential post
- application exposure assessment. Adult residential post
- application dermal exposures assessed for the registered outdoor and proposed indoor uses are not of concern to HED. The greatest estimated risk for adults corresponded to a dermal MOE of 2 70 for post
- application exposure in ornamental gardens. For children 1 < 2 ye ars old, the comb ined dermal and incidental oral risk estimates for the identified residential uses are not of concern to HED (i.e., MOEs are ≥ 300, the LOC for these assessments). The greatest estimated ris k for children corresponds to a dermal MOE of 690 for children 1 < 2 years old contacting treated turf. A summary of these results is presented in Appendix C (Table C .2) of this document. **6.3 Combined Exposure**  HED combines risk values resulting from separate routes of exposure when it is likely they can occur simultaneousl y based on the use pattern and the behavior associated with the exposed population, and if the hazard associated with the points of departure is similar across routes. A common toxicological endpoint, neurotoxicity , exists for dermal, incidental oral, and inhalation routes of exposure to bifenthrin. Therefore, these were combined for all residential exposure scenarios assessed. A summary of these re sults is presented in Appendix C (Table C .2) of this document. Table 6.3.1 below presents the combin ed risk estimates for the uses resulting in the highest potential for residential handler an d post
- application exposure. These worst case estimates were used for the aggregate assessment. Combined adult handler exposure (dermal and inhalation) from appl yi ng bifenthrin to ornamentals with a backpack sprayer results in a risk estimate that is not of concern to HED (i.e., the ARIis > 1). The risk estimate for combined child 1 < 2 years old exposure (dermal and incidental oral) from contacting tur f treated with a liquid formulated bifenthrin product is not of concern (i.e., the MOE is > 300).Bifenthrin Human Health Risk Assessment D372550

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Page **45** of **83 Table 6.3.1 Combined Residential Bifenthrin Risk Estimates (High**  **- End)**  **Lifestage Exposure** 

**Scenario App. Rate**  **Route of Exposure Dose**  **(mg/kg/day) MOE**  **ARI Handler**  Adult Ornamentals

– Backpack Sprayer 0.20

lb ai/A Dermal 0.34 270 2.1

Inhalation 0.00037 8,400 **Lifestage Exposure** 

**Scenario App. Rate**  **Route of Exposure Dose**  **(mg/kg/day) MOE**  **Combined MOE**  **Post -**  **Application** Child 1 < 2 Years Old Turf, Liquid 0.20 lb ai/acre Dermal 0.1 4 690 400

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 appl y a pesticide around the home and be exposed b y 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. P ost - 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 pro posed indoor bed bug treatment is the only to meet th is criteria. P ost - application co - exposure could occur following the simultaneous treatment multiple use sites (e.g., baseboards, furniture and mattresses) due to a bed bug infestation. T herefore, combi ned risks for adults and children were estimated for the two post
application exposure scenarios
. Combined adult post - application exposure assessed for surface
- directed spray s (dermal and inhalation) and mattress ( dermal ) use sites is not of concern to HE D (i.e., the ARI is > 1). For children 1 < 2 ye ars old, combined post
- application exposure assessed for surface
- directed spray s (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 45,000Bifenthrin Human Health Risk Assessment D372550

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Page **46** of **83 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** Incidental Oral 0.0018 1,8 00 Mattress Dermal 0.0032 61,000 **6.4 Residential Bystander**  **Post -**  **application Inhalation Exposure**  Spray drift is alway s 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 metho d 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 appropriatel y apply the data and the AgDRIFT computer model to its risk ass essments for pesticides applied b y 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 w as 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 i nhalation 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. Inan 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, H ED considers both the route and duration of exposure. Like other p yrethroids, bifenthrin causes clinical signs of neurotoxicity . Muscle tremors were con sistently observed throughout the bifenthrin toxicology database, and h ind
- limb flexion was observed i n 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.Bifenthrin Human Health Risk Assessment D372550

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Page **47** of **83** R esidenti al exposure to bifenthrin is anticipated from the propo sed Section 3 bed bug use treatment, as well as from currentl y 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 ty pically 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 day s from dietary

(food and water) and non
- dietary , residential exposures from current and pending uses of bifenthrin. In order to aggregate short
- term re sidential uses with dietary exposure , it was necessary to calculate average dietary exposure . Risk estimates (MOEs) were calculated b y comparison of the short
- term oral NOAEL to average dietary exposures for all populations
. Itshould be noted that altho ugh HED is classifying this as a short
- term assessment (which ty picall y 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 increa se 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 directl y 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 b y an MOE of <1000). Accordingl y 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 likel y to be combined. Short
- term aggregate risk estimates (ARIs ) for the general U.S. population are not of concern to HED (i.e., ARI s 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 e xposed population, children 1 < 2 years old, is also not of concern to HED (i.e, MOE s are ≥ 300). Table 7.2.2, below, summarizes the results from the short
- term aggregate assessment of children 1 < 2 years old.Bifenthrin Human Health Risk Assessment D372550

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Page **48** of **83 Table 7.2**  **.1 Short**  **- Term Adult Aggregate R** **isk 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 di etary = [( 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**  **M OE**  **Oral**

**Residential Exposure**  **3 M**  **OE**

**Dermal Residential**  **Exposure 4**  **M OE** 

**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 Ris**  **k** An intermediate
- term and/or chronic aggregate risk assessment was not conducted because bifenthrin is acutel y 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.Bifenthrin Human Health Risk Assessment D372550

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Page **49** of **83 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 py rethroids and py

rethrins , 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 ultim ately leading to neurotoxicity
. The cumulative risk assessment for the py rethroids/py

rethrins 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 py

rethroids and py

rethrins share a common mechanism of toxicity may be found in document ID: EPA
- HQ - OPP - 2008 - 0489 - 0006. The Agency

has conducted a quantitative analy sis of the proposed bifenthrin bed bug use and has determined that it will not contribute significantly or change the overall findings presented in the py rethroid cumulative risk assessment. This anal ysis is summarized in Appendix D
. Further, the proposed food uses of bifenthrin will not contribut e significantly or change the overall findings in the py rethroid cumulative risk assessment as the dietary risks are a minor component of total py rethroid cumulative risk. For information regarding EPA’s efforts to evaluate the risk of exposure to py

rethroids, refer to http://www.epa.gov/oppsrrd1/reevaluation/py rethroids
py rethrins.html
. **9.0 Occ**  **upational 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 Ex**  **posure/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 label s ; 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 Agricul tural 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 recommende d 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.p df), 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/pesticide s/science/handler
- exposure data.html
.Bifenthrin Human Health Risk Assessment D372550

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Page **50** of **83** A quantitative exposure/risk assessment was developed for occupational handlers based on the following exposure scenarios: Section 3 ( Grass Grown for Seed Onl y)

 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 ground boom equipment; and  Flagging in support of aerial applications. Section 18

 M ixing/loading dry

flowable, liquids (open pour) , and WSB in support of aerial, chemigation , and groundboom operations;  A erial Application (enclosed cockpit);  Application using open
- cab groundboom equipment;  Application using airblast equipment; and  Flaggi ng in support of aerial applications. All Section 3 and 18 occupational handler scenarios assessed are not of concern to HED (i.e., ARI s are ≥ 1 ) with baseline attire ( i.e ., single layer of clothing, no respirator) or the addition of a filtering face piec e dust mask respirator
. Table s 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, respectivel y.Bifenthrin Human Health Risk Assessment D372550

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Page **51** of **83 Table**  **9.1.1 .**  **Section 3: Short -**  **Term Occupational Exposure and**  **Risk Estimates for Bifenthrin Exposure Scenario**  **Crop or Target**  **Derm al** 

**Unit Exposure**  **1 (m**  **g/lb ai) Inhalation** 

**Unit Exposure**  **1 (m**  **g/lb ai) Maximum** 

**Application Rate**  **2 (lb ai/** **A )**  **Am ount** 

**Trea ted**  **Daily 3**  **(Acres) Derm**  **al Inhalation**  **ARI 8** 

**Dose 4**  **(m g/kg/day)**  **MOE 5**  **Dose 6**  **(m g/kg/day)**  **MOE 7**  **Mixer/Loader for Brigade®**  **® 2 EC**  Mixing/Loading Liquid for Aerial A pplication Grass Grow n 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 A pplication 200 0. 055 1,800 0.000053 59,000 14 0.0094 (gloves) 10,0 00

(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®**  **® WSB**  Mixing/Loading WP (WSB) for Aerial A pplication Grass Grow n for Seed (Forage and Hay) 0.0098 0.00024 0.10 1 , 200 0.015 6,600 0.00036 8,6 00 7.7 Mixing/Loading WP (WSB) for Groundboom A pplication 200 0.0025 39,000 0.000060 52,0 00 46 Mixing/Loading WP (WSB) for Chemigation 350 0.0043 22,000 0.00011 30,0 00 26 **Applicator** Applying Sprays with Fixed
- wing Aircraft (enclosed cockpit) Grass Grow n for Seed (Forage and Hay) 0.0050

(Eng.contro l
- no gloves needed ) 0.000068 0.1 0 1 , 200 0.0075 13,00 0 0.0001 0 30,0 00 25 Applying Sprays with Open Cab Groundboom Grass Grow n for Seed 0.0786 0.00034 200 0.020 4,900 0.000085 36 , 0 00 21Bifenthrin Human Health Risk Assessment D372550

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Page **52** of **83 Table**  **9.1.1 .**  **Section 3: Short -**  **Term Occupational Exposure and**  **Risk Estimates for Bifenthrin Exposure Scenario**  **Crop or Target**  **Derm al** 

**Unit Exposure**  **1 (m**  **g/lb ai) Inhalation** 

**Unit Exposure**  **1 (m**  **g/lb ai) Maximum** 

**Application Rate**  **2 (lb ai/** **A )**  **Am ount** 

**Trea ted**  **Daily 3**  **(Acres) Derm**  **al Inhalation**  **ARI 8** 

**Dose 4**  **(m g/kg/day)**  **MOE 5**  **Dose 6**  **(m g/kg/day)**  **MOE 7**  (Forage and Hay) **Flagger** Flagging to Support Aerial Applications Grass Grow n for Seed (Forage and Hay) 0.011 0.00035 0. 1 0 350 0.0048 20 ,000 0.00015 20,0 00 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 n o 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 ( BMDL 10 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 (BMDL 1S D of 3.1 mg/kg/day) / Daily inhalation dose (mg/kg/day). 8 Aggregate Risk Index (ARI) = 1 / ((1/estimated MOE for adult de rmal exposure/ LOC for adult dermal exposure ) + (1/estimated MOE for adult inhalation exposure/ LOC for adult inhalation oral exposure) )Bifenthrin Human Health Risk Assessment D372550

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Page **53** of **83 Table**  **9.1. 2**  **. Section**  **18 :**  **Short -**  **Term Occupational Exposure and Risk Estimates for**  **Bifenthrin Exposure**  **Scenario Crop or**  **Target Derm**  **al Unit**

**Exposure 1**  **(m g/lb ai)**  **Inhalation Unit**

**Exposure 1**  **(m g/lb ai)**  **Maximum**

**Application Rate**  **2 Am**  **ount**

**Treated Daily**  **3 (Acres)**  **Derm al**  **Inhalation ARI**  **8**

**Dose 4**  **(m g/kg/day)**  **MOE 5**  **Dose 6**  **(m g/kg/day)**  **MOE 7**  **Mixer/Loader**
**– Dry Flowable**  **( Bifenture**  **TM DF**  **)** M ixing/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 )**  M ixing/Loading Liquid for Aerial Application Apple, Nectarine and Peach 0.22 0.00021 0.2 0 350 0.19 500 0.00018 1 7,000 3.9 Mixing/Loading Liquid for Groundboom Application 80 0.044 2 ,200 0.00004 7 4,000 17 Mixing/Loading Liquid for Airblast Application 40 0.022 4 ,400 0.00002 1 50,000 34 **Mixer/Loader Water Soluble Bags**  **- (** **Brigade® WSB)**  Mixing/Loading WSB for Aerial Application Apple, Nectarine and Peach 0.0098 0.00024 0.2 0 350 0.0086 11 ,000 0.00021 1 5,000 13 Mixing/Loading WSB for Groundboom Application 0.00024 80 0.0020 49 ,000 0.000048 6 5,000 57 Mixing/Loading WSB for Airblast Application 0.00024 40 0.00098 9 9,000 0.000024 1 30,000 110 **Applicator**Bifenthrin Human Health Risk Assessment D372550

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Page **54** of **83 Table**  **9.1. 2**  **. Section**  **18 :**  **Short -**  **Term Occupational Exposure and Risk Estimates for**  **Bifenthrin Exposure**  **Scenario Crop or**  **Target Derm**  **al Unit**

**Exposure 1**  **(m g/lb ai)**  **Inhalation Unit**

**Exposure 1**  **(m g/lb ai)**  **Maximum**

**Application Rate**  **2 Am**  **ount**

**Treated Daily**  **3 (Acres)**  **Derm al**  **Inhalation ARI**  **8**

**Dose 4**  **(m g/kg/day)**  **MOE 5**  **Dose 6**  **(m g/kg/day)**  **MOE 7**  Applying Sprays via Aerial Equipment (Enclosed Cockpit) Apple, Nectarine and Peach 0.0050 0.00006 0.2 0 350 0.0044 22 ,000 0.0005 0 5 9,000 47 Applying Sprays via Groundboom Equipment (Open Cab) Apple, Nectarine and Peach 0.07 9 0.00034

0.2 0 80 0.016 6 ,100 0.000068 4 6,000 26 Applying Sprays via Groundboom Equipment (Enclosed Cab) 9 0.0051 0.00004 40 0.0010 94 ,000 0.000008 0 3 90,000 280 Applying Sprays via Airblast Equipment (Open Cab) 1. 8 0,00471 40 0.18 54 0 0.00047 6 ,600 3.0 Applying Sprays via Airblast Equipment (Enclosed Cab) 9 0.01 5 0.00006 40 0.0015 6 7,000 0.000006 0 5 2,000 48 **Flagger** Flagger for Support of Aerial Spray Applications Apple, Nectarine and Peach 0.011 0.00035 0.2 0 350 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 n o gloves; Baseline Inhalation: no respirator)
. 2 Application Rates based on registered label s (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 ( BMDL 10 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 (BMDL 1S D of 3.1 mg/kg/day) / Daily inhalation dose (mg/kg/day). 8 Aggregate Risk Index (ARI) = 1 / ((1/estimated MOE for adult de rmal exposure/ LOC for adult dermal exposure ) + (1/estimated MOE for adult inhalation exposure/ LOC for adult inhalation oral exposure) )Bifenthrin Human Health Risk Assessment D372550

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Page 55 of 83 **9.2 Occupational**  **Short -**  **Term Post**  **- Application**  **Exposure/ Risk**  HED has determined that the re 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 previousl y treated areas to perform job functions. R e - entry workers are expected to experience short
- term exposure to bifenthrin while performing post
- application activities such as s couting 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
- applicat ion 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 DFR** **2 Activity**  **TC 3**  **MOE 4**  **DAT 5** 

**Section 3** Grass Grown for Seed ( Forage and Hay) 0.1 0 0. 28 Scouting 1,100 3,100 0 (12 hours) Irrigation 1,900 1,80 0 **Section 18** Apple, Nectarine and Peach 0.20 0. 56 Orchard Maintenance, Propping 100 17 , 000 0 (12 hours) Hand Pruning, Training, Scouting 580 2,9 00 Hand Harvesting 1,400 1 , 2 00Bifenthrin Human Health Risk Assessment D372550

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Page 56 of 83 **Table 9.2.**  **Summary of Estimated Post -**  **application MOEs for Proposed**  **Bifenthrin Section 3 and 18**  **Uses Crop**  **Maximum**

**Application Rate**  **1 DFR** **2 Activity**  **TC 3**  **MOE 4**  **DAT 5** 

Thinning Fruit 3,600 480 1. Maximum application rate (lb ai/A) indicated on proposed labels (See Table 3.3 ). 2 . DFR (μg/cm2 ) = Application rate (lb ai/A) x Conversion factor (11.2 ug/cm 2 ) x Fraction of ai re tained 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 μg/mg) x (Body Weight 8 0 - kg)] Short
- term Dermal NOAEL = 96.3 mg/kg/day. The LOC is 100. MOE = NOAEL / Daily Dose. Dermal MOE= PoD ( BMDL 10 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 inhalatio n 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 advi ce 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 b y the A gricultural 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 polici es 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 n ot 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.Bifenthrin Human Health Risk Assessment D372550

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Page 57 of 83 **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 Metab olism and Dispos ition . 2006 Mar;34(3): 389
- 97. Choi, J.S ., Soderlund, D.M . (2006). "Structure
- activity relationships for the action of 11 py rethroid insecticides on rat Nav 1.8 sodium channels expressed in Xenopus oocy tes". Toxicology

and Applied Pharmacology 211(3):233
- 44. Crofton KM , Kehn LS , Gilbert ME (1995), "Vehicle and route dependent effects of a p yr ethroid 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 W yn gaert, 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). "Ph ys iologically Based Pharmacokinetic Modeling of Deltamethrin: Development of a Rat and Human Di ffusion
- Limited Mod el." Toxicological Sci ence 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. L aboratory report number: WIL
- 118041, December 20, 2010. MRID 483 33801.Unpublished. DP# 386418." Hughes, M. F. and B. C. Edwards (2010). "In vitro dermal absorption of py rethroid pesticides in human and rat skin." Toxi cology and Applied Pharmacology 246(1
- 2): 29
- 37.Bifenthrin Human Health Risk Assessment D372550

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Page 58 of 83 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

prepare d by

WI L Research Laboratories, In c. 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 Sci ence 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). "Py rethroid toxicology : Mouse intracerebral sturcture
toxicity relationships." Pesticide Biochemistry and Phy siology

18: 9 - 14. Lund, A. and T. Narahashi (1982). "Dose
- dependent interaction of the p yr ethroid 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). "Developmentall yregulated sodium channel subunits are differentially sensitive to [alpha]
- cyano containing py rethroids." 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 ph ys iologicall y based pharmacokinetic m odel for deltamethrin in the adult male Sprague
- Dawley

rat." Toxicological Sci ence 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). "Hydroly tic metabolism of py rethroids by

human and other mammalian carboxylesterases." Biochemical Pharmacology 71(5): 657
- 669. Salgado, V., M. Herman and T. Narahashi (1989). "Interactions of the p yr e throid 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 . Shee ts, 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 Py

rethroid Pesticides by

Rat and Human Hepatic Microsomes and Cy tochrome P450 I soforms." Drug Metab olism and Dispos ition 37(1): 221
- 228.Bifenthrin Human Health Risk Assessment D372550

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Page 59 of 83 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 p yr ethroid 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 py rethroid neurotoxicity : i mplications for cumulative risk assessment." Toxicology

171(1): 3
- 59. Song, J. and T. Narahashi (1996). "Modulation of sodium channels of rat cerebellar Purkinje neurons b y the p yr ethroid tetramethrin." J ournal of Pharmacol ogy and Experimental Therapeut ics 277(1): 445
- 453. Tabarean, I. V. and T. Narahashi (1998). "Potent Modulation of Tetrodotoxin
- Sensitive and Tetrodotoxin
- Resistant Sodium Channels by the Ty pe II P yrethroid Deltamethrin." J ournal of Pharmacol ogy

and Exp erimental Therapeutics 284(3): 9 58 - 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 py rethroid 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 Py rethroid Pesticides. Document ID: EPA
- HQ - OPP - 2007 - 0388 - 0049. www.regulations.gov. " US EPA (1998)
. Guidelines for Neurotoxicity Risk Assessment, Federal Register
. USEPA (2011a). "Py

rethroid Cumulative Risk Assessment,” D394567. 10/04/11. USEPA (2011b). Reevaluation of the FQPA Safety Factor for P yrethroid 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) Verscho yl e, R. D. and W. N. Aldridge (1980). "Structure
- activity relationships of s ome py rethroids in rats." Arch ives of Toxicol ogy 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 py rethroid insecticides in male rats following acute oral exposure." Neurotoxicology 30 Suppl 1: S1
- 16.Bifenthrin Human Health Risk Assessment D372550

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Page 60 of 83 Wol ansky

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. , Croft on, K.M. (2006) “Relative Potencies for Acute Effects of Py rethroids 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 py rethroid 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 carbox yl esterases HCE1 and HCE2: Ontogenic expression, inter
- individual variability and differential h ydroly sis 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 Section s 3 and 18 Registration of Bifenthrin on Grass, Forage, Hay , Imported Tea , Apple and Peach.” D383085. 5/25 /2012 J. Lu is 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, Soy bean, Fruiting Vegetables and May

haw .” 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 Emergenc y Exemption for Treating Apples, Nectarines, and Peaches. Summary

of Analy tical Chemistry

and Residue Data.” D388604. 5/25 /2012. S. Lev y . “ Bifenthrin on Pear and Nut, Tree, Group : Evaluation of Residue Data and Anal yt ical 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 (F orage and Hay) and Imported T ea .” D 401702 . 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,Bifenthrin Human Health Risk Assessment D372550

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Page 61 of 83 New Jersey , Penns yl vania, Maryland, Delaware, West Virginia, and North Carolina to Control S tink 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 /20 12 S. Tadayon . Bifenthrin : Revised Occupational and Residential Assessment for Turf Using the 2012 Residential SOPs
. D400326. 5/25 /2012Bifenthrin Human Health Risk Assessment D372550

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Page 62 of 83 **A ppendix**  **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 Ac ute Oral Toxicity
................................ ...................... 870.1200 Ac ute Dermal Toxicity
................................ ................. 870.1300 Ac ute 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 Ac ute Delayed Neurotoxicity (Hen)
............................. 870.6100 90 - Day

Neurotoxicity (Hen)
................................ ........ 870.6200 Ac ute Neurotoxicity Screening Battery (Rat)
.............. 870.6200 90 Day Neuro toxicity . 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.Bifenthrin Human Health Risk Assessment D372550

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Page 63 of 83 **A.2 Toxicity Profiles**  **Table A**  **. 2.1**  **. Acut**  **e Toxicity Profile**
**– Bifenthrin**  **Guideline No./Study Type MRID No.**  **Results Toxicity**  **Category** 870.1100 Acute oral toxicity 0013519 LD 50 = 70.1 mg/kg ( ♂); 53.8 mg/kg (♀) II 870.1200 Acute dermal toxicity 00132520 LD 50 > 2,000 mg/kg III 870.1300 Acute inhalation toxicity 46008101 LC 50 =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) Ac ute Oral Toxicity in Long Evans Rats BMD L 1S D = 3.1 mg/kg BMD 1SD = 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,

4705050 5 Weiner/WIL Study

(2009) Ac ute Oral Toxicity in Rats BMDL 20 = 0.4 mg/kg BMD 20 = 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
- NOAEL = 3.8 mg/kg/day (males); 4.3 mg/kg/dayBifenthrin Human Health Risk Assessment D372550

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Page 64 of 83 **Table A**  **. 2.2**  **. Toxicity Profiles for Bifenthrin**  **Guideline Number**  **MRID No.**  **Study Type Results**  Rat (1984) (females) LOAEL = 7.5 mg/kg/day (males), 8.5 mg/kg/day (females), based on increased incidence of tremor s. **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 Developm**  **ental 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**Bifenthrin Human Health Risk Assessment D372550

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Page 65 of 83 **Table A**  **. 2.2**  **. Toxicity Profiles for Bifenthrin**  **Guideline Number**  **MRID No.**  **Study Type Results** 

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 Com bined 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 combinedBifenthrin Human Health Risk Assessment D372550

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Page 66 of 83 **Table A**  **. 2.2**  **. Toxicity Profiles for Bifenthrin**  **Guideline Number**  **MRID No.**  **Study Type Results**  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 Ac ute Neurotoxicity
- Rat NOAEL = 35 mg/kg (32.8 mg ai/kg/day). LOAEL = 75 mg/kg (70.3 mg ai/kg/day) based on mo rtality (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 lactatio n based on clinical signs of neurotoxicity (tremors, clonic convulsions, and in creased grooming counts )
. **Developm ental**  NOAEL = 3.6 mg/kg/day during gestation and 8.3 mg/kg/day during lactation
. **Developm ental**  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)
. **Derm al 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) BMDL 10 =96.3 mg/kg/dayBifenthrin Human Health Risk Assessment D372550

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Page 67 of 83 **Table A**  **. 2.2**  **. Toxicity Profiles for Bifenthrin**  **Guideline Number**  **MRID No.**  **Study Type Results**  LOAEL = 93 mg ai/kg/day (males and females), based on staggered gait (M) and exaggerated hind limb flexion (F) BMD 10 =187.0 mg/kg/day, based on exaggerated hind limb flexion **Me tabolism** **and Pharm acokinetics** 

870.7485 00163067

40415102 Metabolism
- Rat Very little of the administered radioactive dose was expired as 14 C - CO 2 (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 th e 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 mo st (>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 slightl y 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 mo lecule between the two labeling s ites, 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 some what delayed, peaking at about 6 hours. Significant radioactivity still remained after 72 hours in the high
dose animals.Bifenthrin Human Health Risk Assessment D372550

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Page 68 of 83 **Table A**  **. 2.2**  **. Toxicity Profiles for Bifenthrin**  **Guideline Number**  **MRID No.**  **Study Type Results**  **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. **Classifica tion: 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 pol ar (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 mo re 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 mo re 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 theBifenthrin Human Health Risk Assessment D372550

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Page 69 of 83 **Table A**  **. 2.2**  **. Toxicity Profiles for Bifenthrin**  **Guideline Number**  **MRID No.**  **Study Type Results**  incomplete absorption of bifenthrin from the intestine, an d 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 difference s 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** . **Derm al 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 perc entages 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 penetrati on 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 o f 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).Bifenthrin Human Health Risk Assessment D372550

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Page 70 of 83 **Table A**  **. 2.2**  **. Toxicity Profiles for Bifenthrin**  **Guideline Number**  **MRID No.**  **Study Type Results**  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 perce ntages 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%; carca ss: 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 r at 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.Bifenthrin Human Health Risk Assessment D372550

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Page 71 of 83 **A.3 Hazard Identification and Endpoint Selection** 

**1 10**  **100 0**  **1 2**  **3 4**  **5 6**  **7 8**  **9 10** 

DNT

S- C Dog SCN Repr o

Mi ce C hr oni c

Rat C hr oni c Dog Chr oni c Rabbi t G avage Wo la nsky BM D- L

Rat G avage Rat D ie ta ry

Me an=3. 3 mg /k g, S D=2. 0 **Bi fe**  **nt hri**  **n NOAEL**  **vs Treatm**  **ent T**  **im e**  O ra l S tu di es We ig ht o f E vi dence**N O** **A E** **L (** **m g** **/ k** **g /** **d a** **y )** 



## Tr **eat me**  **nt T**  **im e**  **(d ays)** Bifenthrin Human Health Risk Assessment D372550

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Page 72 of 83 **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 BMDL 1SD = 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 considerabl y conservative, employing gavage dosing using 1 ml/kg corn oil vehicle and volume. This special study had a uniform design for all of the py rethroids te sted. It also monitored the toxicology at the time of peak effects for each p yr ethroid, thereby optimizing the responses, not alway s controlled in guideline studies. The BMD anal ys is 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/WI L study (2006) also had a uniform study design with all py

rethroids tested. However, the study only had two doses with poor dose selection which resulted inBifenthrin Human Health Risk Assessment D372550

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Page 73 of 83 limited dose response information for bifenthrin. The Nemec/WI L 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 onl y one day up to 7 day s of treatment. The h ydroureter sign indicated in the rat gavage developmental study (NOAEL=0.88 mg/kg/day) was not statistically sign ificant, plus it was not reproduced in the rat dietary

developmental study , suggesting to put less weight on this finding. Moreover, h ydroureter is considered an artifact of the developmental process in rats, but not rabbi ts, and often resolves in rats. T he rabbit developmental study , again by gavage dosing, also did not repro duce 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 an d 3.0 mg/kg/day , respectivel y). 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 N OAELof 2.36 mg/kg/day , however, bacterial infections in the animals may have sens itized 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
- ye ar 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 onl y in 1/4 male dogs and onl y 2/4 female do gs onl y 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 utilizin g nine dose groups with 8
- 12 animals/group with BMD anal ys is is a more reliable study than the studies using onl y 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, thi s study

did not utilize a dosing vehicle (which is known to modulate py rethroid toxicity

), thus had an atyp ical 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 o f longer
- term exposures.Bifenthrin Human Health Risk Assessment D372550

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Page 74 of 83 **A.3.3 Dermal Exposure (Short**  **- Term)**  The 21
- day

dermal study in rats with a BMDL 10 of 96.3 mg/kg/day was selected for this endpoint. The BMD 10 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 anal ys is is the default limit for quantal data such as hind limb flexion. The BMD anal ys is 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 s pacing 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 , respectivel y). Since a dermal toxicity study is selected for dermal risk assessment, a dermal
- absorption factor is not required. The BMD anal ys is 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) 0.25Bifenthrin Human Health Risk Assessment D372550

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Page 75 of 83 **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 Exp osure 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. **A ppendix C**  **. Residential**  **Exposure/Risk Summ ary Table**  A summary

of bifenthrin residential handler exposure/risk is presented in Table D.1 below. **Table C .1.**  **Residential Bifenthrin**  **Handler Short**  **- T**  **erm Exposure and Risk**  **Use Site Equip.** 

**Types App**  **.**

**Rate (lb**  **ai/ gallon)**  **1 Am**  **ount**

**Handled (gallons)**  **2 or Area**  **Treated Route of** 

**Exposure Dose** 

**(m g/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 44,0 00 73 Inhalation 0.000035 88,0 00 **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
- Ty pe 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 110,000Bifenthrin Human Health Risk Assessment D372550

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Page 76 of 83 **Table C .1.**  **Residential Bifenthrin**  **Handler Short**  **- T**  **erm Exposure and Risk**  **Use Site Equip.** 

**Types App**  **.**

**Rate (lb**  **ai/ gallon)**  **1 Am**  **ount**

**Handled (gallons)**  **2 or Area**  **Treated Route of** 

**Exposure Dose** 

**(m g/kg/day)**  **3,4 MOE**  **5 ARI**  **6 Indoor**  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 D ivision (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 r ate (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 de rmal 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 0.2 0 lb ai/A Dermal Physical Activities on Turf 0.07 6 1,300 NA Mowing 0.0015 63,000Bifenthrin Human Health Risk Assessment D372550

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Page 77 of 83 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 Golfing 0.0059 16,000 Child 11 < 16 Years O ld Dermal Mowing 0.001 8 55,000 Golfing 0.0069 14,000 Child 6 < 11 Years O ld Dermal Golfing 0.0081 12,000
Child 1 < 2 Years Old Dermal Physical Activities on Turf 0.14 6 9 0 400 Hand to Mouth 0.00 30 1, 000 Object to Mouth 0.00003 2 34,000 Short
- term Incidental Soil Ingestion 0.00001 3 240,000

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 O ld Dermal Mowing 0.00088 110,000 Golfing 0.0034 28,000 Child 6 < 11 Years O ld 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 5,900Bifenthrin Human Health Risk Assessment D372550

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Page 78 of 83 or child 1 < 2 inhalation oral exposure) + (1/estimat ed MOE for child 1 < 2 incidental oral exposure/ LOC for child 1 < 2 incidental oral exposure) 5. Com bined MOEs = 1/ ((1/ Dermal MOE) + (1/In cidental Oral MOE)) **Appendix D :**  **Cumulative Exposure and Risk Issues** No bifenthrin indoor bed bug uses were included in the 2011 py rethroid CRA, as there were no registered bed bug treatments at that time . However, indoor broadcast, crack and crevice, and fogger p yr ethroid uses were included in the CRA. In order to determine if the proposed bifenthrin bed bug use significantly contributes to or change s the overall findings in the py rethroid CRA , the Agency has performed a quantitative exposure and risk assessment. This assessment used the bifenthrin relative potency factor (RPF) , disc ussed below, as well as the same exposure algorithms and inputs that were used in the 2011 py rethroid CRA (see Appendix Table D). The py rethroid 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 effec t, sex, etc). In the p yr ethroid 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 e valuating neurotoxicity specific to py rethroids
. Specifically, the studies looked at a number of crucial parameters that are directly relevant to the Ty

pe I (e.g., hy

perthermia tremors and clonus) and Ty pe II (e.g., hy

pothermia, salivation, and mobility

) sy ndromes. 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 WI L FOB studies focus on endpoints specific to py rethroid toxicity

s yndromes, the Wolansky stu dy 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 py rethroids. 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 py rethroid screening level cumulative are shown below in Table D.1. They were determined by dividing the chemical
- specific BMD 20 by the BMD 20 of the index chemical, deltamethrin. Calculations for the BMDs are described in Section 4.2 of the CRA. Twelve of the 15 py rethroids 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
cy halothrin resulted in slightl y greater potency than deltamethrin. An RPF of 1.01 was used to quantify comparative exposure s from the proposed bifenthrin bed bug use.Bifenthrin Human Health Risk Assessment D372550

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Page 79 of 83 **Table D.1. Relative Potency Estimates for Pyrethroids Included in the Screening**  **Level Cumulative Risk Assessment**

**Pyrethroid Oral BMD**  **20 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 aValues estimated from studies; these values were not calculated using BMD. See Section 4.2 of the CRA. b RPF = BMD 20 of Index Chemical (e.g., deltamethrin)/Pyrethroid BMD 20 ; For example: Bifenthrin RPF=14.5/14.3 = 1.01 c Includes the isomeric enrichments S
- Bioallethrin and D
- Allethrin dRPFs for Dermal an d 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 py rethroid 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 inclu de 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 p yrethroids, showed th at 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 onl y) are currently driven by

the cy permethrin indoor fogger use pattern with an MOE of 3,9 00 , whi ch is lower than the MOE estimated for adult dermal exposure from the proposed bifenthrin bed bug use, 15,000. The cy permethrin 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 chang e 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.Bifenthrin Human Health Risk Assessment D372550

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Page 80 of 83 **D.2. Bifenthrin Screening Level “Cumulative” Combined Exposure and Risk from the Propos ed 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 900Bifenthrin Human Health Risk Assessment D372550

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Page 81 of 83 **Appendix Table D.3 :**  **Bifenthrin Screening Level “Cumulative” MOEs**  **Post -**  **application Dermal**  **Exposure** Exposure Scenario Surrogate Deposition (μg/cm2 ) Fraction

Transferred Transfer

Coefficient (cm2/hr) Exposure Time

(hours) Conversion

Factor (mg/μg) 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 0.000 80 13,000 Dermal Exposure from Carpet after Bed Bug Use (Adults) 6,800 8 0.98 71.8 0.00068 0.000 69 15,000 **Post -**  **application Incidental Oral Exposure** 
Exposure Scenario Fai hands 1 - 2 yr old Dermal Exposure SAH

(cm2) HR

t (mg/cm2) F M 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 8.9 E - 0 5 0.13 5 4 0.5 20 11.4 0.0 0290 0.00 30 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 BMD 20 from the WIL FOB data for the index chemical, deltamethrin (14.5 mg/kg/day)Bifenthrin Human Health Risk Assessment D372550

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Page 82 of 83 **A ppendix E:**  **Bifenthrin BMD Analysis for the 21 -**  **Day Dermal Study** Bifenthrin BMD Analy sis: 21
- Day Rat Dermal Study

– MRID 45280501 BMDS 2.1.1: D i chotomous

– multistage. Extra Risk BMR at 10% Endpoint: Exaggerated hind limb flexion in females BMD Results:

BMD = 187.052 mg/kg/day BMDL = 96.2927 mg/kg/day Calculations: ====================================================================

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

======== ============================================================ BMDS_Model_Run

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The form of the probability function is: P[response] = background + (1 - background)*[1 - EXP(

- beta1*dose^1 - beta2*dose^2)] The parameter betas are restricted to be positive Dependent variable = Effect Independent variable = Dose Total number of observations = 5 Total number of records with missing values = 0 Total number of parameters in model = 3 Total number of specified parameters = 0 Degree of polynomial = 2 Maximum number of iterations = 250 Relative Function Convergence has been set to: 1e - 008 Parameter Convergence has been set to: 1e - 008 Default Initial Parameter Values Background = 0.0031824 Beta(1) = 0.000548172 Beta(2) = 0 Asymptotic Correlation Matrix of Parameter Estimates ( *** The model parameter(s) - Background - Beta(2) have been estimated at a boundary point, or have been specified by the user, and do not appear in the correlation matrix )Bifenthrin Human Health Risk Assessment D372550

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Page 83 of 83 Beta(1) Be ta(1) 1 Parameter Estimates 95.0% Wald Confidence Interval

Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit Background 0 * * *

Beta(1) 0.000563269 * * * Beta(2) 0 * * * * - Indic ates that this value is not calculated. Analysis of Deviance Table Model Log(likelihood) # Param's Deviance Test d.f. P
- value Full model - 9.98095 5 Fitted model - 10.5726 1 1.18324 4 0.8809 Reduced model - 16.2541 1 12.5464 4 0.01372

AIC: 23.1451 Goodness of Fit Scaled Dose Est._Prob. Expected Observed Size Residual

------------------------------------------------------------------------ 0.0000 0.0000 0.000 0.000 10 0.000 23.0000 0.0129 0.129 0.000 10 - 0.361 47.0000 0.0261 0.261 0.000 10 - 0.518 93.0000 0.0510 0.510 1.000 10 0.704 932.0000 0.4084 4.084 4.000 10 - 0.054 Chi^2 = 0.90 d.f. = 4 P - value = 0.9250 Benchmark Dose Computation Specified effect = 0.1 Risk Type = Extra risk Confidence level = 0.95

BMD = 187.052 BMDL = 96.2927 BMDU = 598.842 Taken together, (96.2927, 598.842) is a 90 % two - sided confidence interval for the BMD