Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 1 of 52 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460
**OFFICE OF CHEMICA**  **L SA FETY**  **AN D**  **POLLUTION PREVENTION MEMORANDUM**  **Date :**  **8 /** **30 /201**  **2 SUBJECT:**  **Fenpropathrin** . Human Health Risk Assessment for Section 3 Registration on

Tropical Fruit and a Request for a Tolerance Without U.S. Registration on Tea
**PC Code: 127901**  **DP Barcode: D3**  **68175 Decision No.:**  **4 17627**  **Registration No. :**  **59639 -**  **35 Petition No.:**  **9 E**  **7 594**  **Regulatory Action: Section 3 Registration**  **Risk A**  **ss essment Type:**  **Single Chemical Aggregate**  **Case No.: NA**  **T XR No.:**  **NA CAS No.:**  **39515 -**  **41 -**  **8 MRID No.:**  **NA 40 CFR:**  **§ 180.466**  **FROM:** Douglas A. Dotson, Ph.D., Chemist

Edward Scollon, Ph.D. , Toxicologist Suku Oonnithan, Ph.D. , Biologist Registration Action Branch II Health Effects Division (7509P) **THROUGH:** Karl yn Middleton , Toxicologist

Dennis McNeill y , Chemist Zaida Figueroa , Industrial Hygienist Christina Swartz, Branch Chief Registration Action Branch II and Dana Vogel, Acting Associate Division Director Deborah Smegal, MPH, Toxicologist Health Effects Division **TO:** Laura Nollen/Barbara Madden, RM Team 5

RIMUERB R egistration Division (7505P) The Registration Division (RD) requested that the Health Effects Division (HED) conduct a human health risk assessment for the proposed use of the insecticide fenpropathrin on tropicalFenpropathrin Human Health Risk Assessment DP No. D368175

Page 2 of 52 frui t, and for a tolerance for residues in tea (without U
. S
. registration) . This document contains the human health risk assessment associated with these actions and incorporates updated endpoints for risk assessment, updated residue monitoring data and percent crop treated assumptions, as well as the most recent data and assumptions for conducting occupational exposure assessments. N o risks of concern were identified for the proposed registration action
.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 3 of 52 **1.0 Executive Summary** 
................................ ................................ ................................ .......... 5 **2.0 HED Recommendations** 
................................ ................................ ................................ ... 8 **2.1 Data Deficiencies/Conditions of Registration** 
................................ ............................. 8 **2.2 Tolerance Considerations** 
................................ ................................ ............................. 8 **2.2.1 Enforcement Analytical Method** 
................................ ................................ ............. 8 **2.2.2 International Harmonization** 
................................ ................................ ................... 8 **2.2.3 Recommended Tolerances** 
................................ ................................ ........................ 9 **2.2. 4**  **Revisions to Petitioned -**  **For Tolerances**
................................ ................................ .. 9 **2.3 Label Recommendations** 
................................ ................................ ........................ 10 **3.0 Introduction** 
................................ ................................ ................................ ..................... 10 **3.1 Chemical Ide**  **ntity**
................................ ................................ ................................ ........ 10 **3.2 Physical/Chemical Characteristics** 
................................ ................................ ............ 10 **3.3 Pesticide Use Pattern** 
................................ ................................ ................................ .. 10 **3.4 Anticipated Exposure Pathways** 
................................ ................................ ................ 11 **3.5 Consideration of Environmental Justice** 
................................ ................................ .. 11 **4.0 Hazard Characterization and Dose**  **- Response Assessment** 
................................ ......... 12 **4.1 Toxicology Studies Availab**  **le for Analysis**
................................ ................................ 1 2 **4.2 Toxicological Profile** 
................................ ................................ ................................ ... 1 3 **4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile** 
................................ . 1 5 **4. 3**  **.1 Pharmacokinetics** 
................................ ................................ ................................ .... 15 **4. 3**  **.2 Pharmacodynamic**  **s** ................................ ................................ ................................ . 16 **4. 3**  **.3 Critical Duration of Exposure** 
................................ ................................ ............... 18 **4.4 Safety**  **F actor for Infants and Children (FQPA Safety Factor)** 
.............................. 19 **4.4.1 Completeness of the Toxicology Database** 
................................ ............................ 20 **4.4.2 Evidence of Neurotoxicity** 
................................ ................................ ...................... 21 **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal** 
...... 2 1 **4.4.4 Residual Uncertainty in the Exposure Database** 
................................ .................. 2 2 **4.5 Toxicity Endpoint and Point of Departure Selections** 
................................ ............. 2 2 **4.5.1 Dose**  **- Response Assessment** 
................................ ................................ .................... 2 2 **4.5.2 Recommendation for Combining Rout**  **es of Exposure for Risk Assessment** 
..... 2 4 **4.5.3 Cancer Classification and Risk Assessment Recommendation** 
.......................... 2 4 **4.5.4 Summary of Points of Departure and Toxicity Endpoints** 
................................ 2 4 **5.0 Dietary Exposure and Risk Assessment** 
................................ ................................ ........ 25 **5.1 Metabolite/Degradate Residue Profile** 
................................ ................................ ...... 25 **5.1.1 Summary of Plant and Animal Metabolism Studies** 
................................ ........... 25 **5.1.2 Summary of Environmental Degradation** 
................................ ............................ 26 **5.1.3 Comparison of Metabolic Pathways** 
................................ ................................ ...... 26 **5.1.4 Residues of Concern Summary and Rationale** 
................................ ..................... 26 **5.2 Food Residue Profile** 
................................ ................................ ................................ ... 27 **5.3 Water Residue Profile** 
................................ ................................ ................................ . 28 **5.4 Dietary Risk Assessment** 
................................ ................................ ............................ 28 **5.4.1 Description of Residue Data Used in Dietary Assessment** 
................................ .. 28 **5.4.2 Percent Crop Treated Used in Dietary Assessment** 
................................ ............. 29 **5.4.3 Acute Dietary Risk Assessment** 
................................ ................................ ............. 29 **5.4.4 Summary Table** 
................................ ................................ ................................ ....... 30Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 4 of 52 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization** 
............................ 30 **6.1 Residential Handler**  **and Post -** **Application Exposure**  **and Risk Estimates** 
............ 30 **6.2 Spray Drift** 
................................ ................................ ................................ ................... 31 **7.0 Aggregate Exposure/Risk Characterization** 
................................ ................................ . 31 **8.0 Cumulative Exposure/Risk Characterization** 
................................ .............................. 31 **9.0 Occupational Exposure/Risk Characterization** 
................................ ........................... 32 **9.1 Short**  **- /** **Intermediate -**  **Term Handler Risk**
................................ ................................ . 32 **9.2 Occupational/Commercial**  **Post -**  **application**
................................ ............................. 3 4 **10.0 References** 
................................ ................................ ................................ ........................ 35 **Appendix A. Toxicology Profile and Executive Summaries**
................................ .................. 3 9 **A.1 Toxicology Data**  **Available for Penthiopyrad**
................................ ........................... 3 9 **A.2 Toxicity Profile**  **Table s**  ................................ ................................ ................................ 40 **A.3 Hazard Identification and**  **Endpoint Selection**
................................ ......................... 4 6 **A.4 Human Equivalent Analysis** 
................................ ................................ ....................... 50 **A. 5**  **Pyrethroid Cumulative Screen**
................................ ................................ .................. 50 **Appendix B**  **. Physical/Chemical Properties**
................................ ................................ ............. 51 **Appendix C**  **. Review of Human Research**
................................ ................................ ................ 52Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 5 of 52 **1.0 Executive Summary**  Fenpropathrin (alpha
- cyano - 3
- phenox y- benzyl 2,2,3,3
- tetrameth yl cyclopropanecarboxylate) is an ingestion and contact py rethroid insecticide and acaricide currentl y registered for use on fruits, vegetables, field crops, and ornamental plants for the control of various insect pests and mites. Fenpropathrin is currently registered for use on a variety of tropical fruits . T he Interregional Research Project Number 4 (IR
- 4) propos ed tolerances for residues of fenpropathrin in/on numerous additional tropical fr uits. IR
- 4 has also proposed a tolerance without U.S. registration on tea. The end use product proposed for use on the tropical fruits is Danitol ® 2.4 EC Spray (EPA Registration Number 59639
- 35 ). Py rethroids have historically been classified into two groups, Ty pe I and Ty

pe II, based on chemical structure and toxicological effects. Fenpropathrin is a mixed
- ty pe py rethroid having intermediate effects between the Ty pe I and T yp e II py

rethroids in in vitro and in vivo studies. Behavioral changes such as muscle tremors were observed in most of the fenpropathrin experimental toxicology

studies. Although the database of fenpropathrin experimental toxicology

studies is not complete , it provides a robust characterization of the hazard potential for children and adults. In addition to the standard guideline studies, n umerous studies from the scientific literature that describe the pharmacodyn amic and pharmacokinetic profile of the py rethroids in general have been considere d in this assessment. The onl y missing information is that needed to full y characterize sensitivity of juveniles following exposure to fenpropathrin. There are on - going efforts to develop methods to inform the possibility of increased sensitivity of juve nile rats to p yrethroids as a class at doses near the LOAEL values. Pending receipt of the additional data, HED has conducted a conservative and health
- protective assessment using the available guideline and literature studies. Py rethroids disrupt the vo ltage
- gated sodium channels in the nervous s ys tem, resulting in neurotoxicity . In the fenpropathrin toxicity database, tremors were the most commonly observed effect and also the most sensitive relative to dose. Other neurotoxic effects observed included ataxia, increased sensitivity (e.g., heightened response) to external stimuli, convulsions , and increased auditory

startle response. Fenpropathrin is rapidl y absorbed following an oral dose. As a class, py rethroids are also rapidly metabolized in vivo and , therefore , effects are typi cally observed shortly

after dosing. In addition, the severities of effects do not increase with duration. As the NOAEL s for the acute and chronic studies are similar, the acute endpoint is protective of the endpoints from repeat dosing studies, which represent longer
- term exposures. Thus, for purposes of endpoint selection and exposure assessment, only single
- day

risk assessments need to be conducted. Evidence of increased qualitative or quantitative susceptibility of the offspring was not observed in any of the available animal testing guideline toxicity studies, including the developmental neurotoxicity

study (DNT). However, the Agency will retain a 3 x uncertainty factor to protect for exposures to children < 6 years of age based on the following: 1) age
- dependent pharmacokinetics, supported by rat Phy siologically

Based Pharmacokinetic (PBPK) modelFenpropathrin Human Health Risk Assessment DP No. D368175

Page 6 of 52 predictions of a 3
- fold increase of p yr ethroid concentration in juvenile brain compared to adults; 2) in vitro pharmacodyn amic (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 amics of homologous sodium channel isoforms. The dose and endpoint f

or acute dietary

risk assessment were selected from the Wolansky et al
. (2006) acute oral study , in which decrease d motor activity was observed. The dose used for risk assessment was determined using a benchmark dose (BMD) analy sis conducted in accordance with standard Agency

assumptions with respect to the benchmark response (BMR). The same study , endpoint , and dose were used for the inhalation risk assessment for workers, along with standard assumptions for extrapolation from the oral route. Based on the available data for fenpropathrin, the use of the acute endpoint and dose for risk assessment is protective for repeated dose exposure and risk. A dermal risk assessment was not con ducted based on the lack of effects in a 21
- day

dermal study

and absence of qualitative or quantitative susceptibility in the toxicity database. As there are no existing or proposed uses that would result in non
- dietary exposure to children or adults in residential settings, these exposure s were not considered for endpoint selection. HED has characterized fenpropathrin as “not likely to be carcinogenic to humans” in accordance with the EPA Final Guidance for Carcinogen Risk Assessment (3/29/05). Adequate residue data are available for the purpose of evaluating the proposed uses and associated tolerances, including adequate plant and livestock metabolism data, field residue and rotational crop studies, as well as appropriate supporting analy tical methods and storage stability data. The recommended tolerances are based on the potential for detectable residues in the treated commodities. The acute dietary risk estimates for fenpropathrin are below HED’s level of concern for all population subgroups, includi ng those comprised of infants and children. The acute risk estimate for the general U.S. population is 19 % of the acute population adjusted dose ( aPAD ) . The population subgroup with the highest acute dietary risk estimate is Children 3
- 5, which uses 9 7 % of the aPAD. T he assessment was refined by incorporating distributions of residues from field trial and monitoring data, and through use of estimate d percent crop treated information
. Both empirical and default processing factors were used. For drinking water, a very conservative modeled surface water estimated drinking water concentration was used. As a result of the fact that many conservative assumptions were made for this assessment , in particular, the use of field trial data (as opposed to monitoring data) for many commodities , HED is confident that the acute dietary exposure assessment significantly ov erestimate s risk to the general U.S. population and all population subgroup s . The acute aggregate risk es timate s are equivalent to the corresponding dietary (food plus water) risk estimate s, which are not of concern. Fenpropathrin may

be applied to fruit trees b y ground equipment ( airblast)
. Inaddition, aerial application may

be used for avocado trees. F enpropathrin is intended for use by commercial andFenpropathrin Human Health Risk Assessment DP No. D368175

Page 7 of 52 professional applicators. T here is potential for short
- and intermediate
- term occupational handler and post - application exposure via the inhalation and dermal pathway s. No long
- term exposure (> 6 months) is expected. As fenpropathrin does not increase in potency with repeated dosing, only single
- day occupation al exposures are being assessed. As there is no dermal hazard associated with this chemical, inhalation risk only i s being assessed quantitatively
. It is HED policy

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) , and the Agricultural Handler Exposure Task Force (AHETF) database. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. Default assumptions established by the HED ’s Exposure Science Advisory Council ( ExpoSAC ) were used for parameters such as body weight and acres treated per day
. Occupational handler assessments are based on inhalation exposures only because a dermal endpoint and dose w ere not selected
. As noted previously , an acute POD is considered to be protective of repeated inhalation exposures (i.e., short
- and intermediate
- term durations), and thus only a single POD was used to assess workers. The estimated short
- term inhalation margins of exposure ( MOEs ) for occupational handlers are all above HED’s level of concern (LOC) of an MOE of 100 (the lowest MOE was 5,300 ), assuming the baseline level of personal protective equipment ( PPE ) , and with the use of engineering controls ( i.e., en closed cockpit) for aerial applications. There is a potential for post - application dermal and inhalation exposures to workers who enter fenpropathrin
- treated fields to do irrigation, fruit thinning, scouting , and harvesting. However, HED did not quantitatively estimate post - application dermal exposure because of the lack of toxicity via the dermal route of exposure
. Based on the Agency ’ s current practices, a quantitative non
- cancer occupational post - application inhalation exposure assessment i s not being conducted at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for fenpropathrin. However, HED notes that inhalation exposure for aerial flaggers is considered to be protective of potential post
- application inhalation exposure, and the associated inhalation risk estimates for flaggers are not of concern. Fenpropathrin was included in a recent cumulative risk assessment for p yr ethrins and py rethroids. The proposed new uses will contribute minimal risk to the overall cumulative assessment. In the cumulative assessment, residential exposure was the greatest contributor to the total exposure. As there are no residential uses for fenpropathrin, the proposed new uses will have no impact on the residential component of the cumulative risk estimates. D ietary exposures make a minor contribution to total py rethroid exposure in the 2011 cumulative risk assessment. The dietary

exposure assessment performed in support of th e p yrethroid cumulative was much more highl y refined than that performed for the single chemical. In addition, f or the fenpropathrin risk assessment, the most sensitive apical endpoint in the fenpropathrin database was selected to derive the POD
. Additio nally , the POD selected for fenpropathrin is specific to fenpropathrin, whereas the POD selected for the cumulative assessment was based on common mechanism of action data that are appropriate for all 20 py rethroids included in the cumulative assessment.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 8 of 52 **R eview of Human Research:**  This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies (listed in Appendix C ) have been determined to require a review of their ethical conduct , and all of the studies utilized in this assessment have received the appropriate review. **2.0 HED**  **Recommendations** HED does not object to the granting of the requested registration or the recommended tolerances for fenpropathrin in/ o n the proposed new uses on tropical fruits . In addition, HED does not object to the granting of the recommended tolerance without U.S. registration for fenpropathrin in/on tea . **2.1 Data Deficiencies/Conditions of Registration**  None **2.2 Tolerance Cons**  **iderations 2.2.1**  **Enforcement Analytical Method** An adequate method, Residue Method Number RM
- 22
- 4 , is available for the enforcement of tolerances of fenpropathrin in plants. Residues in crops are extracted with acetone/hexane, partitioned into hexane, cleaned up b y silica gel and C 18 Sep Pak chromatograph y, and anal yz ed by GC/ECD. The LOD is 0.01 ppm. There is also an adequate GC/ECD enforcement method for the determination of fenpropathrin residues in livestock commodities (RM
- 22A
- 1). The lowest l imit of method validation w as 0.05 ppm in milk and 0.5 ppm in fat and meat. The FDA PESTDATA database (dated 6/20 05) indicates that fenpropathrin is completely recovered b y multiresidue methods Section 302 (Protocol D). Recovery was variable using Section 303 (Protocol E; 43
- 71% recovery) and Section 304 (Protocol F; 58
- 114% recovery). **2.2.2 International Harmonization**  No Codex, Canadian , or Mexican MRL s are established for fenpropathrin on the proposed tropical fruits. As a result, harmonization of tolerances is not an issue for the se commodities
. A Codex MRLis established for residues of fenpropathrin in/on tea, green, black at 2 ppm. Using the Organization for Economic Cooperation and Development ( OECD ) MRLcalculati o n procedures , the recommended tolerance for dried tea would be 3.0 ppm. For the purposes of harmonization of the U.S. tolerance with the established Codex MRL , HED is recommending in favor of a tolerance of 2.0 ppm for dried tea. HED considers this tolerance level to be adequate because the highest field trial valu e was 1.38 ppm. Inthe U.S., the residue definition is parent fenpropathrin. The Codex residue definition is fenpropathrin, the residue is fat soluble.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 9 of 52 **2.2.3 Recommended Tolerances**  HED recommends that 40CFR §180.466 be amended by establishing toleranc es for the commodities listed in T able 2.2.3 , below
. Currently , t olerances are established for residues of the pesticide chemical fenprop athrin (alpha
cyano - 3
- phenoxy
- benzyl 2,2,3,3
- tetrameth yl cyclopropanecarbox yl ate) in or on the commodities in 40CFR §18 0.466. This tolerance expression needs to be revised as follows: “T olerances are established for residues of fenprop athrin including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels speci fied below is to be determined b y measuring only fenprop athrin (alpha
- cyano - 3
- phenox y- benzyl 2,2,3,3
- tetrameth yl cyclopropanecarbox yl ate)
. ” **Table 2.2.3**  **. Tolerance Summary for Fenpropathrin**  Commodity as Proposed by Registrant Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition Guava 1.5 3.0 Acerola 1.5 3.0 Feijoa 1.5 3.0 Jaboticaba 1.5 3.0 Passionfruit 1.5 3.0 Starfruit 1.5 3.0 Wax jambu 1.5 3.0 Lychee 3.0 7.0 Longan 3.0 7.0 Spanish lime 3.0 7.0 Pulasan 3.0 7.0 Rambutan 3.0 7.0 Sugar apple 1.0 1.5 Atemoya 1.0 1.5 Biriba 1.0 1.5 Cherimoya 1.0 1.5 Custard apple 1.0 1.5 Ilama 1.0 1.5 Soursop 1.0 1.5 Tea 2.0 2 .0 Tea, dried Tolerance should include a footnote stating “There is no U.S. registration on tea, dried, as of ( date of FR notice ) .” **2.2.4 Revisions to Petitioned**  **- For Tolerances**  T he proposed tolerances for residues in tropical fruits are different from the tolerances being recommended b y HED. The reason for the differences is that the proposed tolerances wereFenpropathrin Human Health Risk Assessment DP No. D368175

Page 10 of 52 determined using the NAFTA tolerance calculator , whereas HED used the OECD MRL calculation procedures to determine the recommen ded tolerance s . A revised Section F should be submitted to reflect the tolerances recommended by HED. **2.3 Label Recommendations**  None **3.0 In**  **troduction 3.1**  **Chemical Identity Table**  **3.1 . Fenpropathrin Nom**  **enclature** Chemical structure

Common name Fenpropathrin Com pany experimental name WC
- 4741706 (Shell); S
- 5206 (Sumitomo) IUPAC name (RS )
- α - cyano - 3
- phenoxybenzyl 2,2,3,3
- tetramethylcyclopropanecarboxylate CAS name Cyano(3
- phenoxyphenyl)methylester 2,2,3,3
- tetramethyl
- cyclopropanecarboxylic acid CAS registry number 39515
- 41
- 8 End
- use product (EP) 2.4 lb/gal EC formulation (Danitol ® 2.4 EC Spray; EPA Reg. No. 59639
- 35) **3.2 Physical/Chemical Characteristics**  Fenpropathrin has very

low water solubility (0.33 ppm at 25oC) and a relatively high octanol/water partition coefficient ( l og K OW = 5
. 1 )
. These values account for the low surface and groundwater concentrations determined b y EFED’s drinking water models. The chemical has a vap or pressure of 5.5 x 10 - 6 mm Hg at 2 5 oC
. See Appendix B for a listing of additional p hy sical and c hemical properties. **3.3 Pesticide Use Pattern**  The petitioner submitted a draft label for the 2.4 lb/gal EC formulation of fenpropathrin (Danitol ® 2.4 EC Spray ; EPA Reg. No. 59639
- 35). The label includes us e directions for a number of fruit, vegetable, and field crops that are already register ed. Danitol ® is currentl y registered for use on avocado, canistel, mango, papaya, salal, sapodilla, black sapote, mamey sapote, and star apple. The use directions for both the registered and proposed tropical and O O

CN O C H 3

C H 3 C H 3 C H 3Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 11 of 52 subtropical fruits are presented in Table 3.3 . No directions were proposed for the domestic use of fenpropathrin on tea because onl y an import tolerance was proposed. **Table 3.3**  **. Summ**  **ary of Directions for Use of Fenpropathrin**  Applic. Timing, Ty pe, and Equip. Form ulation [EPA Reg. No.] Max. Single

Applic. Rate (lb ai/A) Max. No.

Applic. per Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Use Directions and Limitations Tropical and Subtropical Fruit: Acerola, Atemoya, Avocado, Biriba, Canistel, Cherimoya, Custard Apple, Feijoa, Guava, Ilama, Jaboticaba, Longan, Lychee, Mango, Papaya, Passion Fruit, Pulasan, Rambutan, Sapodilla, Sapote (Black, Mamey),

Soursop, Spanish Lime, Star Apple, Star Frui t, Sugar Apple, and Wax Jambu Foliar Ground (all crops) A erial (avocado only) 2.4 lb/gal EC

[59639
- 35] 0.3
- 0.4 1 (avocado)
or 2 (all other crops) 0.8 1 Begin applications when first pest activity is noticed. A 14
- day retreatment interval is specified. Ground applications are to be made in ≥75 gal/A; aerial applications to avocado may be made in ≥50 gal/A. PHI= Preharvest interval T he use directions for the proposed tropical and subtropical fruit s are identical to those for the registered tropical and subtropical fruit s except that the minimum spray volume for ground applications for all tropical fruits has been reduced from 100 gal/A to 75 gal/A
. The personal protective equipment (PPE) on the proposed label include s a long
- sleeved shirt, long pant s, shoes with socks, chemical resistant gloves , and protective eyewear. **3.4 Anticipated Exposure Pathways**  Humans could be exposed to fenpropathrin i n food because fenpropathrin may be applied directly to growing crops . In addition, these applications can result in fenpropathrin reaching surface and groundwater , both of which can serve as sources of drinking water. However, the low water solubility

of the chemical and its affinity to bind to soil organic matter would cause the chemical to be present at very low concentrations in drinking water sources. T he domestic uses on tropical fruits result in the potential for occupational exposures. B ecause of the agricultural uses, applicators might be exposed while handling the pesticide prior to application, mixing/loading the pesticide, and during application. Also, there is a potential for post
application exposure for workers re
- entering treated fields. There are no registered or proposed residential uses for fenpropathrin ; a s a result, residential exposure is not an anticipated exposure pathway
. **3.5 Consideration of Environmental Justice**  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “ Federal Actions to Address Environmental Justice in Minority Populations and 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 estimates risks to populatio n subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption,Fenpropathrin Human Health Risk Assessment

and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compi Survey of Food Intake b y Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyz 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 exposures based on home use of pesticide products and associated risks for adult applicators and for children , youths, and adults entering or play ing on treated areas evaluated. Further considerations are currently in development as OPP has co and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifesty le and traditional dietary

patterns among specific subgroups. **4.0 Hazard Characterization and Do**  Fenpropathrin is a member of the p yr ethroid class of insecticides. Py rethroids have historicall y been classified into two groups, Type I and Ty pe II, based on chemical structure and toxicological effects. Type I p yrethroids, which sy ndrome consisting of aggressive sparring, altered sensitivity to external stimuli, hy

perthermia, and fine tremor progressing to whole py rethroids, which cont ain an alpha pawing, burrowing, salivation, hy pothermia, and coarse tremors leading to choreoathetosis (CS sy ndrome) (Verscho yl e and Aldridge 1980 Mixed Ty pe py rethroid because the biochemical responses and resulting clinical signs of neurotoxicity

are intermediate between outcome pathway

(AOP, based on the Bradford ability to interact with voltage
- gated sodium channels (VGSCs) in the central and peripheral nervous s ys tems, leading to changes in neuron firing and

**Figure 4. 0**  **. Adverse outcome pathway for pyrethroids**  **4.1 Toxicology Studies Available for Analysis**  The database of experimental toxicology studies available for fenpropathrin provides a robust characterization of the hazard potential for children 6 years old and 90
- day inhalation study

is not available for consideration as required under the Part 158 toxicology

data requirements. However, HED has waived this study requirement for the current assessment ( HASPOC memo, TXR# 0053978, 4/10/1

Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 12 of 52 and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compi led by the USDA under the Continuing Survey of Food Intake b y Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyz ed and categorized by subgroups based , 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

based on home use of pesticide products and associated risks for adult applicators and , youths, and adults entering or play ing on treated areas post - application evaluated. Further considerations are currently in development as OPP has co mmitted resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifesty le and traditional dietary

patterns among specific

**Hazard Characterization and Do se**  **- Response Assessment**  Fenpropathrin is a member of the p yr ethroid class of insecticides. Py rethroids have historicall y been classified into two groups, Type I and Ty pe II, based on chemical structure and toxicological effects. Type I p yrethroids, which lack an alpha
- cyano moiety , induce in rats a sy ndrome 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 ain an alpha
- cyano moiety, in rats produce a s yndrome that includes pawing, burrowing, salivation, hy pothermia, and coarse tremors leading to choreoathetosis (CS Verscho yl e and Aldridge 1980 ; Lawrence and Casida 1982 ) . Fenpropathrin is a Mixed Ty pe py rethroid because the biochemical responses and resulting clinical signs of neurotoxicity

are intermediate between those of Ty pe Iand T yp e II p yr ethroids. outcome pathway

(AOP, based on the Bradford
- Hill crit eria) shared b y p yr ethroids involves the

gated sodium channels (VGSCs) in the central and peripheral nervous s ys tems, leading to changes in neuron firing and , ultimatel y , neurotoxicity (Figure 4.

**Adverse outcome pathway for pyrethroids Toxicology Studies Available for Analysis**  The database of experimental toxicology studies available for fenpropathrin provides a robust characterization of the hazard potential for children 6 years old and older as well as day inhalation study

is not available for consideration as required under the Part 158 toxicology

data requirements. However, HED has waived this study requirement for the current TXR# 0053978, 4/10/1 2). Inaddition, there are ongoing efforts to DP No. D368175 and activities in and around the home that involve pesticide use in a residential setting. led by the USDA under the Continuing Survey of Food Intake b y Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyz ed and categorized by subgroups based , 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

based on home use of pesticide products and associated risks for adult applicators and application are mmitted resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifesty le and traditional dietary

patterns among specific

Fenpropathrin is a member of the p yr ethroid class of insecticides. Py rethroids have historicall y been classified into two groups, Type I and Ty pe II, based on chemical structure and

cyano moiety , induce in rats a sy ndrome consisting of aggressive sparring, altered sensitivity to external stimuli, hy

perthermia, sy ndrome). Ty

pe II cyano moiety, in rats produce a s yndrome that includes pawing, burrowing, salivation, hy pothermia, and coarse tremors leading to choreoathetosis (CS
- . Fenpropathrin is a Mixed Ty pe py rethroid because the biochemical responses and resulting clinical signs of Ty pe Iand T yp e II p yr ethroids. The adverse eria) shared b y p yr ethroids involves the gated sodium channels (VGSCs) in the central and peripheral neurotoxicity

(Figure 4. 0 ).

The database of experimental toxicology studies available for fenpropathrin provides a robust as well as for adults. A day inhalation study

is not available for consideration as required under the Part 158 toxicology

data requirements. However, HED has waived this study requirement for the current Inaddition, there are ongoing efforts toFenpropathrin Human Health Risk Assessment DP No. D368175

Page 13 of 52 develop data in juvenile rats at doses near the LOAELvalues (see Section 4.4) to inform the potential sensitivity

of infants and young children to py rethroids as a class. Despite these scientific efforts, HE D is confident that it has chosen points of departure and uncertainty factors in this risk assessment that are health protective and have a strong scientific foundation. D ata from the following studies were used to evaluate the hazard potential of fenpropathrin:

- Wolansky

Acute Oral Study in the Rat

- WI L Laboratory Acute Oral Study in the Rat

- 21 Day Dermal Studies in the Rat and Rabbit

- 90 Day Oral Studies in the Rat and Dog

- Chronic/Carcinogenicity Studies in the Rat, Mouse , and Dog

- Developmental Studies in the Rat and Rabbit

- Reproduction Study

in the Rat

- A cute, Subchronic, and Developmental Neurotoxicity (DNT) Studies in the Rat

- Immunotoxicity

Study in the Rat

- Mutagenicity Battery of Studies These studies are available for c onsideration of fenpropathrin toxicity and provide a comprehensive database. The Wolansky and WIL studies are acute oral non
- guideline studies that measure locomotor and functional observational battery ( FOB ) activity , respectivel y, and provide robust dat a to evaluate the hazard potential of fenpropathrin. In addition, numerous studies from the scientific literature conducted over several decades describe the pharmacodynamic and pharmacokinetic profile of the p yr ethroids in general. This scientific literature has recently been reviewed by several groups ( Soderlund et. al. 2002 ; Shafer et. al. 2005 ; Wolansky

and Harrill 2008 )
. **4.2 Toxicological Profile**  Fenpropathrin has been evaluated for a variety of toxic ological effects in guideline experimental toxicity studies. Behavioral changes characteristic of Ty pe I py rethroids such as muscle tremors were seen in most of the experimental toxicology studies including the acute, subchronic, and developmental neurotoxicity s tudies, subchronic studies in the rat and dog, the chronic carcinogenicity

study in the rat, the developmental studies in the rat and rabbit, and in the 3
- generation reproduction study in the rat. Tremors w ere the most common indication of neurotoxicity ; however , ataxia, increased sensitivity (e.g., heightened response) to external stimuli, convulsions , and increased auditory startle response were also observed. Fenpropathrin has been evaluated for potential developmental effects in the rat and rabbit. Maternal toxicity

included neurological effects such as ataxia, sensitivity to external stimuli, tremors in rat , and flicking of forepaws in the rabbit. Developmental effects were limited to incomplete or as ymmetrical ossification of sternebrae at the mat ernall y toxic dose in the rat. There were no developmental effects in the rabbit. Furthermore, there were no indications of immunotoxicity

in an y of the guideline studies, including the immunotoxicity study in rats.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 14 of 52 The potential reproductive toxicity of fenpropathrin was examined in a 3
- generation reproduction study in the rat. Maternal effects at the high dose included increased deaths and clinical signs of toxicity . Eighteen of the 24 dams in the high
- dose group (32 mg/kg/day) died
. Ten of these deaths occurred during lactation of the F1 B dams ( i.e., 2 nd litter of 2 nd generation). Clinical signs including tremors, muscle twitches, and increased sensitivity were observed in all high
- dose females in all generations and were most intense during the 2 nd or 3 rd week of lactation. At the mid
- dose, 10.1 mg/kg/day , clinical signs of toxicity were observed in a single dam. No treatment
- related effects in the males at any dose were noted; however, it is not clear from the study

if males were evaluated. It should be noted that the effects in the maternal rats occurred during lactation. During lactation, the dietary intake of nursing dams increases dramaticall y, resulting in a greater consumption of fenpropathrin. In the offspring, there was mortality at the high dose (32 mg/kg/day) in the F2 A and F2 B litters (3 rd generation, 1 st and 2 nd litters) although litter size was onl y significantl y decreased at lactation day 21 in the F2 B litters. At the mid
- dose (10 mg/kg/day) , tremors were observed in 3 pups fro m the F2 B litter, 2 of which died. There were no reports of clinical signs of toxicity (i.e., tremors) in any

other pups. Therefore, minimal signs of treatment
- related effects were observed at the mid
- dose for both adults and pups, reducing concern for q uantitative or qualitative sensitivity
. The registrant submitted a DNT study which establishe d a clear NOAEL for adult and offspring toxicity
. Similar NOAELs and LOAELs were observed in adults and offspring . E ffects in the dams were tremors and convuls ions, while offspring effects consisted of d ecreased body weights
. In the fenpropathrin DNT study there was no evidence of increase d sensitivity in rat pups. However, the Agency

has reviewed existing py rethroid data , including a number of DNT studies, and has conclude d that the DNT is not a particularly 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 yr ethroids, but in context these studies were conducted at relativel y high doses that might not reflect environmental exposures
. Overall, there is no indication of increased juvenile sensitivity specificall y to fenpropathrin
. There was no evidence of carcinogenicity in either the rat or mouse long
- term dietary studies , nor was there any mutagenic activity in bacteria or cultured mammalian cells. Fenpropathrin is classified as “not likel y t o be carcinogenic to humans” in accordance with the EPA Final Guidance for Carcinogen Risk Assessment (3/29/05)
. With respect to acute lethality studies , fenpropathrin exhibits high acute toxicity via the oral route and dermal route (Categories I and II, respectivel y). Conversely , toxicity via inhalation is Category IV. Fenpropathrin is a mild eye irritant (Category

III), but does not cause dermal irritation in rabbits or skin sensitization in guinea pigs. The resulting pharmacokinetics for fenpropathrin is similar to the pharmacokinetics of other py rethroids, i.e., rapid absorption and clearance. Following a single oral dose of 2.5 or 2 5 mg/kg radiolabeled fenpropathrin in corn oil, 99% of the radioactivity was excreted via the urinary and fecal pathway s by

7 day s . A greater proportion was eliminated via the fecal route following a si ngle dose (1:2 urine:feces) compared to repeated dosing (1:1 urine:feces). No differences were observed between sexes. By 168 hours, onl y minor traces of radioactivity remained in the carcass, primaril y in the adipose tissue. As py rethroid metabolites are not active, radiolabeled fenpropathrin studies that do not consider metabolism are likel y to overestimate the amount ofFenpropathrin Human Health Risk Assessment DP No. D368175

Page 15 of 52 active pesticide present in vivo . As previousl y described, p yrethroids are susceptible to ester hydrol ys is in the plasma and oxidative metabolism by cy tochrome P450 enzy

mes. Major biotransformation products from single and repeated dose rat metabolism studies included oxidation of the methyl group on the acid moiety, hydrox yl ation at the 4’
- position of the alc ohol moiety , cleavage of the ester linkage, and conjugation with sulfuric and glucuronic acid. **4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile**  The extensive body

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

rethroids. The following sec tions discuss the specific issues related to py rethroid pharmacokinetics, py rethroid pharmacody

namics, 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 thi s case, how py rethroids are distributed and eliminated following exposure. Specific to py rethroids, PK refers to the process(es) th at determine (s) the concentration of the py rethroids reaching sodium channels. The underl yi ng pharmacokinetics of pyrethroi ds is an important determinant of their toxicity because the concentration of p yrethroid at the sodium channel relates to the extent of toxicity . Greater p yr ethroid concentration results in increased neurotoxicity . Phy siological processes that significantly contribute to the PK include metabolism, protein binding, and partitioning. Carbox yl esterase s and cy tochrome P450 enzy

mes are the two major enzy me families responsible for the metabolism of py rethroids. It is the ontogeny of these enz ym es that accounts for the age
- related sensitivity observed after py

rethroid exposures. With respect to the partitioning of p yr ethroids within the body , py rethroids are highl y lipophilic and preferentially deposit in fatty

tissue such as adipose compared to leaner tissue s such as muscle. Py rethroid residues in fatty tissue are not available to interact with the voltage
- gated sodium channels (VGSCs ) in vital tissues and , therefore , do not contribute to overall toxicity
. Phy siologically
- based pharmacokinetic (PBPK) mode ls, 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 class is scientifically appropriate. In other words, because of the similarities in the PK profiles of py rethroids, a single model structure is able to predict the tissue dose based on the pharmacokinetics of every member of the class. The family

modeling approach was presented to and supported by the FIFRA SAP (USEPA 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 that 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 andFenpropathrin Human Health Risk Assessment DP No. D368175

Page 16 of 52 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 greater capacity to detoxify

py rethroids compared to juveniles (Anand et. al. 2006 ; de Zwart et. al. 2008 ; Yang et. al. 2009 )
. For example, the rate of in vitro metabolism of deltamethrin by plasma carbox yl esterase s, plus hepatic carboxylesterase s and cy tochrome P450s (microsomes) are at least 6 times higher for post - natal day 90 ( PND 90 ) rats compared to PND 10 rats (Anand et. al. 2006 ) . As a consequence, higher internal doses (i.e., those associated with high doses in experimental toxicology studies) overwhelm the clearance mechanisms in juveniles , but becaus e 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 ty

pical dietary

or residential activities are not expected to overwhelm the premature metabolic s ys tems in juveniles. 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 to be the primary target organ for py

rethroids , and increased py rethroid 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 concentrations of deltamethrin would be achieved with a 3.8 x fold lower oral dose in 10
- day

old rats and 2.5 x lower dose in 21
- day old rats ( Tornero
- Velez et. al. 2010 ) . For example, a 1 mg/kg dose in the adult is equivalent to a 0.26 mg/kg dose (≈1 mg/kg÷3.8mg/kg) in the 10
- day

old rats and to a 0.4 mg/kg ( ≈1 mg/kg÷2.5mg/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 these age groups bracket the developmental stage of greatest concern in humans (i.e., children ≤ 6), the Agency

concludes that juvenile rats are 3 times as sensitive as adults with respect to py rethroid pharmacokinetics. **4.3.2 Pharmacodynamics**  Pharmacodynamics can be defined as the changes that chemicals cause to the body, in this case, how py rethroids interact with the sodium channels. Substantial evidence from in vitro and in vivo studies support the adverse outcome pathway (AOP ) illustrated in Figure 4. 3 and the disruption of sodium channels by py rethroids as an earl y ke y event ( Lund and Narahashi 1982 ; Salgado et. al. 1989 ; Song and Narahashi 1996 ; Tabarean and Narahashi 1998 ; Soderlund et. al. 2002 ) . There are several recent studies that provide specific information for fenpropathrin. Choi and Soderlund ( 2006 ) examined interactions of several py rethro ids, including fenpropathrin, with mammalian VGSCs expressed in Xenopus oocy tes (i.e., frog oocy

tes) . Fenpropathrin produced modifications of sodium channel kinetics intermediate between Ty pe I and Ty

pe II compounds (Figure 4.3). 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 rethroids significantly

prolong sodium current tails (e.g. 200 ms t o minutes) ty

pically resulting in increased resting membrane potential and ultimately causing depolarization dependent action potential block. Cao et. al. ( 2011a) measured sodium influx in primary cultures of mammalian (mouse) neurons and dem onstrated that fenpropathrin caused increases in sodium influx in this model; this confirms the ability of fenpropathrin to interact with VGSC in intact mammalian neurons. An additional study by Cao et. al. ( 2011b )Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 17 of 52 demonstrated that the interaction of fenpropathrin with VGSC caused changes in neuronal excitability

that resulted in calcium influx i nto intact mouse neurons. As this effect of fenpropathrin was entirely blocked b y the VGSC blocker tetrodotoxin, it provides evidence that the changes in sodium channel function lead to changes in neuronal excitability , as illustrated in Figure 4. 3
.

F igure 4.3 Resting modification of rat Nav1.8 sodium channels by fenpropathrin expressed in X enopus oocytes. Channel current vs time traces from individual representative oocytes in the absence or presence (*) of 100 μM fenpropathrin 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. Figure 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, in vivo techniques used to detect VGSC alteration and altered neuronal excitability are not practical for use in risk assessment at this time , and approaches for extrapolating in vitro findings to in vivo measures are not yet developed. As such, the Agency is f ocusing 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 is generally

characterized by tremors, h yper - or hy

pothermia, heightened response to stimuli, salivation, reduced locomotor activity or convulsions ( Soderlund et. al. 2002 ; Wolansky and Harrill 2008 ; Weiner et. al. 2009 )
. In contrast to the age
- related PK differences identified in the 2011 anal ys is, PD contributions to py rethroid toxicity

are not age - dependent , even though there are several variations of sodium channels, called isoforms, which are differentiall y expressed by tissue and age. Because of the nature of the interaction of py rethroids with sodium channels, it is difficult to obtai n 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 acted upon by py rethroids. 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 cells 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 perturbation compared to isoforms expressed in adults and that, pharmacody namically , the rat is a conservative model for humans. For example, Meacham et al. ( 2008 ) , expressed adult and juvenile isoforms of rat sodium channels in frog oocy tes and compared their sensit ivity following exposure to deltamethrin . The isoforms had comparable responses at environmentall y relevant concentrations (<500 nM) of deltamethrin, suggesting a lack of PD difference betweenFenpropathrin Human Health Risk Assessment DP No. D368175

Page 18 of 52 juveniles and adults at low exposure levels. In addition, in a direct comparison of a homologous rat and human VGSC isoform NaV 1.3 , the rat isoform was 4
- fold more sensitive than the equivalent human sodium channel to the p yrethroid tefluthrin ( Tan and Soderlund 2009 )
. This observation suggests that the rat is a highly
- sensitive mode l , and extrapolations from the rat would be protective of human health. The occurrence and ontogeny of voltage
- gated sodium channels in humans is not well characterized compared to those of the rat. However, based on the comparable function and distribut ion 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 factor will be 1 x . **4.3.3 Critical Duration of Exposure**  One of the key

elements in risk assessment is the appropriate integration of temporality b etween the exposure and hazard assessments. Following a single oral gavage dose, fenpropathrin is absorbed quickl y in rats displaying decreased motor activity and increased tremors. Effects such as tremors and ataxia were observed within 2 and 3 hours fo llowing dosing in the rat developmental and acute neurotoxicity studies, respectivel y. Rats typically recover within 24 hours without any

persisting neurotoxic effects at doses near the LOAEL value. This observation is consistent with the toxicity profil es for other p yr ethroids which are marked b y rapid absorption, metabolism, and time
- to - peak effect. The NOAELs and LOAELs for tremors established from results of experimental toxicity studies with fenpropathrin are remarkably consistent across durations o f exposure, ranging from a single dose up to 2
- ye ars of dosing (Table 4. 3.3 ). **Table 4.3.3. Fenpropathrin NOAEL and LOAEL Values versus Treatm ent Time** 

**Study Duration**  **Study findings** NOAEL (mg/kg/day) LOAEL

(mg/kg/day) Wolansky (2006) Acute, single exposure ABMDL 1SD = 5.0 BMD 1SD = 6.4 WIL Acute, single exposure B BMDL 20 = 26.7 BMD 20 = 28.9 Acute neurotoxicity Acute, single exposure 15 30 Developmental Rat 10 days 3 6 Developmental Rabbit2 10 days 4 12 Subchronic neurotoxicity 90 days 13 38 DNT 86 days 8 19 Sub
- chronic dog 90 days <6.2 6.2 Sub
- chronic rat 90 days 15 30 Reproductive toxicity 120 days 3.0 10.1 Chronic
- carcinogenicity 2
- years 7.2 19.5 A BMD 1S D is the central estimate of the dose that results in decreased motor activity compared to control animals based upon a 1 standard deviation using Benchm ark Dose Analysis. BMD L 1S D is the 95% lower confidence limit of the central estimate. Data extrapolat ed for Wolansky (2006), MRID 47885701. B BMD 20 is the central estimate of the dose that results in a 20% difference in FOB scores compared to control animals using Benchmark Dose Analysis. BMD L is the 95% lower confidence limit of the central estimate. Data and analysis can be found in MRID 48714301
.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 19 of 52 Comparing the NOAELs and LOAELs established from fenpropathrin single dose and repeat dosing studies, it is apparent that repeat exposures do no t result in lower NOAELs. This observation is consistent with the general kinetic profile for p yr ethroids. The BMDL 1SD from the acute Wolansky study at 5.0 mg/kg is lower than that from the chronic two
- ye ar cancer study N OAE L= 7.2 mg/kg/day (L OAEL of 19. 5 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. **4.4 Safety**  **Factor for Infants and Children (FQPA Safety Factor)** E xposure of children under 6 years old to f enpropathrin is expected , and it must be considered in the context of the py

rethroids as a class. The Agency is retain ing a 3 x uncertainty factor to protect f or exposures to children less than 6 years of age based on the increased quantitative susceptibility

seen in the scientific literature related to py rethroid pharmacokinetics. This decision is consistent with the Agency ’s 2011 analy sis , and is supported b y rat PBPK model predictions of a 3
- fold increase of deltamethrin concentrations in the juvenile brain compared to adult brains (see Section 4.3.1). The PK of p yr ethroids as a group is sufficiently similar that significant deviations from the 3
- fold increa se of deltamethrin concentrations are not expected for 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 was no evidence of increased qualitative or quantitative susceptibility in developmental toxicity studies in the rat and rabbit , and a three
- generation reproductive toxicity study in the rat
. This lack of susceptibility is consistent with the resu lts of the guideline pre
- and post
- natal testing for other p yrethroid pesticides. There are, however, high
- dose LD 50 studies ( i.e., those that determine the dose that 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 pharmacodyn amic data indicates that the sensitivity

observed at high doses is related to py rethroid age
- dependent pharmacokinetics
- the activity of enzy mes associated with the metabolism of py rethroids. With otherwise equivalent administered doses for adults and juveniles, predictive pharmacokinetic models indicate that the differential adult
-

juvenile pharmacokinetics will resul t in a 3 x greater dose at the target organ in juveniles compared to adults. No evidence of increased quantitative or qualitative susceptibility was seen in the p yr ethroid scientific literature related to pharmacodyn amics (the effect of py rethroids at the target tissue) both with regard to inter
- species differences between rats and humans and to differences between juveniles and adults. Specifically , there are in vitro pharmacodyn amic data and in vivo data indicating similar responses between adult and juv enile 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 showin g juvenile sensitivity to pyrethroids , and the absence of the requested data on juvenile sensitivity to py rethroids, EPA is retaining a 3 x safety factor as estimated b y pharmacokinetic modeling. For several reasons, EPA concludes there areFenpropathrin Human Health Risk Assessment DP No. D368175

Page 20 of 52 reliable data s howing that a 3 x factor is protective f or the safety of infants and children. First, the high doses that produced juvenile sensitivity in the literature studies are well above normal dietary or residential exposure levels of p yr ethroids to juveniles , and these lower levels of exposure are not expected to overwhelm the ability to metabolize py rethroids as occurred with the high doses used in the literature studies. This conclusion is confirmed by the lack of a finding of increased sensitivity in pre
- and p ost - natal guideline studies in any py rethroid, including fenpropathrin , despite the relativel y high doses used in those studies. Second, the portions of the uncertainty factors that account for potential pharmacody namic differences are likely to overstat e the risk of inter
- and intraspecies pharmacody namic differences, given the data showing similarities in pharmacodyn amics between juveniles and adults and between humans and rats. For both the inter
- species and intra
- species uncertainty factors, the phar

macody namic portions are generall y considered to be 3 x; however , for p yr ethroids the factor is reduced to 1 x because no differences among the various groups are observed. Finally , as indicated, pharmacokinetic modeling onl y predicts a 3 x difference between juveniles and adults. Th e information described above is summarized in Re
- Evaluation of the FQPA Safety Factor for P yrethroid P esticides ( D381210, E. Scollon, A. Lowit, 6/27/2011 ). **4.4.1 Completeness of the Toxicology Database**  The toxicology

database for fenpropathrin is not complete . Acceptable fenpropathrin developmental toxicity

studies in rats and rabbits are available , as well as an acceptable reproduction study in rats. The main toxic effect associated with dosing w as tre mors, a common sign for a p yrethroid . T his effect was seen in most toxicology studies with fenpropathrin, and was observed during in the ACN, SCN and developmental neurotoxicity (DNT) studies. While the database is considered to be complete with respect to the guideline toxicity studies, EPA lacks additional data to address the potential for juvenile sensitivity to all py rethroids, including fenpropathrin
. In light of the literature studies indicating a possibility of increased sensitivity

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

potential juvenile sensitivity associated with exposure to fenpropathrin . For the reasons discussed in Section 4.4, the uncertainty regarding the protectiveness of the intraspecies uncertainty factor raised by the literature studies and the absence of the requested data warrant application of an additional 3 x for risk assessments for infants and children < 6 years of age. Although a repeate d dose inhalation toxicity study is not available, HED’s HASPOC discuss ed the inhalation data requirements and concluded that an inhalation study is not required at this time (HASPOC memo, TXR 0053978, 4/10/2012). Inmaking this determination, the HASPOC considered the following: (1) There are no residential uses; (2) the MOEs from the most recent risk assessment (occupational inhalation MOEs > 1,000), ( 3 ) the ph ys ical and chemical properties , and ( 4 ) the toxicological profile of fenpropathrin that shows neurotoxicity is the most sensitive effect and occurs at similar dose levels following both acute inhalation and oral exposures.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 21 of 52 **4.4.2 Evidence of Neurotoxicity**  There are no residual uncertainties with regard to evidence of neurotoxicity for fenpropathrin. As with other py

rethroids, fenpropathrin causes neurotoxicity from interaction with sodium channels leading to clinical signs of neurotoxicity . These effects are well characterized and adequatel y assessed b y the available guideline and non
- guideline studies. **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  Based on the fenpropathrin
- specific data from the guideline toxicity studies , there is no indication of increased juvenile sensitivity
. Fenpropathrin is neither a developmental nor a reproductive toxicant. Fenpropathrin has been evaluated for potential developmental effects in the rat (followi ng gavage or dietary administration) and in the rabbit (gavage administration). Maternal toxicity

included neurological effects (i.e., tremors). There were no developmental effects of biological significance in either species. The potential reproductive toxicity of fenpropathrin was examined in a three
- generation reproduction study in the rat. Tremors were noted only

in females of both generations , while o ne parental generation rat ha d clonic convulsions. A fter reviewing the extensive body of peer
- re viewed literature on py rethroids, the Agency

has reached a number of conclusions regarding juvenile sensitivity for py rethroids including the following considerations: the Agency has no residual uncertainties regarding age
- related sensitivity for women of child bearing age as well as for all adult populations and children > 6 ye ars of age, based on the absence of pre
- natal sensitivity observed in 76 guideline studies for 24 py rethroids and the scientific literature . Additionally , no evidence of increased quantitative or qualitative susceptibility

was seen in the p yr ethroid scientific literature related to pharmacodyn amics. The Agency is retain ing a 3 x uncertainty factor to protect for exposures of children <6 ye ars of age based on the increased quantitati ve susceptibility seen in the scientific literature related to p yrethroid pharmacokinetics. Furthermore, high
- dose studies in the scientific literature indicated that younger animals were more susceptible to the toxicity of p yr ethroids. For example, Shee ts et al (1994) found increased brain deltamethrin levels in young rats (PND 11 and 21) relative to adult rats (PND 72). These age
- related differences in toxicity are principally

due to age
- dependent pharmacokinetics; the activity of enzy mes associated wi th the metabolism of py rethroids increase with age (Anand et al, 2006). However , in context, normal dietary or residential exposures of juveniles are not expected to overwhelm their ability to metabolize py rethroids. In support, at a dose of 4.0 mg/kg de ltamethrin (near the Wolansky study L OAELvalue 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 de ltamethrin (Tornero
- Velez et al, 2010) that predicts a 3

– fold increase of py rethroid in neuronal tissue in younger animals compared to adults. There are several studies ( in vitro and in vivo ) that indicate that pharmacodynamic contributions to pyrethroid toxicity are not age - dependent. Examination of specific VGSCs ha s 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)
.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 22 of 52 Additional 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 sensitivity
. The Agency received a single, coordinated response from the P yrethrin and Pyrethroids Working Group (PPTWG), a conglomerate of p yr ethroid registrants. The PPTWG protocol was reviewed during a July

2010 FIFRA SAP m eeting. Based on comments from the SAP, the initial study proposal was refined. At the present time, pesticide registrants and product formulators have come together as the Council for the Advancement of Py rethroid Human Risk Assessment (CAPHRA) . The Co uncil plan s to : 1) conduct in vitro studies demonstrating the interaction of py rethroids in rat and human VGSCs expressed in Xenopus oocy tes , 2) conduct in vitro studies demonstrating interaction of py rethroids in rat neurolemma cells , 3) develop rat and human PBPK models, including additional pharmacokinetic data , and 4) conduct in vivo behavioral testing using auditory

startle testing in rats. As these data become available, the Agency will determine whether re
- evaluation of the age
- related sensitivity of p yr ethroids is appropriate. **4.4.4 Residual Uncertainty in the Exposure Database**  There is no residual uncertainty in the exposure database because adequate residue data are available. Although the risk estimates for children under 6 years of age are high, man y conservative assumptions were made in the dietary exposure assessment. Ris k estimates are based on partiall y refined estimates of residues in foods and the percentage of the crop that will be treated. In addition, f

or drinking water, a very

conservative surface water estimated drinking water concentration was used. **4.5 Toxicity Endpoint and Point of Departure Selections**  **4.5.1 Dose**  **- Response Assessment**  The details for selecting toxicity endpoints and points of departure (PODs) are presented in Appendix A3. Based on the existing and proposed use patterns for fenpropathri n, the expected exposure profile will be for dietary , dermal , and inhalation exposures. As previously

indicated, the toxicity

endpoints in the fenpropathrin database are consistently based on clinical signs of neurotoxicity and , more specificall y , tremor s. These studies include multiple species, study

designs, and durations (Table 4.3.3 ). Moreover, the acute exposure or bolus dosing studies generall y result in lower NOAEL s compared to longer term dietary administration studies, consistent with other py r ethroids in this class. Because uncertainty associated with the POD is propagated throughout the risk assessment, one of the key factors in POD selection is the robustness of the dose
- response data. The guideline experimental toxicology

studies available for fenpropathrin are generall y 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 ty

pical guideline studies, data from two special studies (Wolansky study on moto r activity and WIL FOB study) evaluating neurobehavioral outcomes are available for fenpropathrin ( Wolansky et. al. 2006 ; Weiner et. al. 2009 ) . Wol ansky et al. ( 2006 ) measured motor activity

at the time of peak effect after exposure to 11 py rethroids, including fenpropathrin. Dose
- response relationships were determined using 6
- 11 doses per py rethroid (8Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 23 of 52 doses used for fenp ropathrin) and 3
- 18 rats per dose group ( 7
- 12 animals/group used for fenpropathrin) , minimizing variability and increasing the confidence in the BMD estimates determined from this study . Moreover, each py rethroid was evaluated b y the same scientist , thus decreasing some of the variability associated with neurobehavioral measures. In the WIL study , 17 py rethroids were evaluated using a specially designed FOB study

focused on the outcomes associated with p yrethroid toxicity sy ndromes. The fenpropathrin dat a from the WIL study were not considered as part of POD selection. The fenpropathrin dose selection was poor (i.e., 2 doses out of the 3 administered resulted in no activity), resulting in low confidence of the calculated BMDL (MRID 48714301). Observatio n of tremors is the most prominent finding in the guideline experimental toxicology studies and was considered in the POD determination. Guideline studies typically have onl y three treatment groups and often do not evaluate clinical signs at the time of p eak effect. Moreover, scoring metrics of tremors varies widely among guideline studies. Given the multiple strengths associated with study design of Wolansky , et al. ( 2006 ) and the resulting well
- defined dose
- response curve, Wo lansky , et al. ( 2006 ) provides the most robust data set for extrapolating risk from fenpropathrin. A BMD anal ys is was conducted by the Agency

for all the py

rethroids included in the Wolansky study (MRID 48714301) . Overall, because of the large number of doses and high quality measurements, the BMD anal ys is yielded high confidence results. In performing BMD anal ys is, a benchmark response (BMR) must be selected. As a general approach, it is preferred to use a combination of biological and statistical factors in the BMR selection. In the case of motor activity data, there is no specific level of change established by the scientific community as being considered adverse. Therefore, OPP has elected to use one standard deviatio n (1SD) from the control group , as suggested , for continuous endpoints in the Agency ’s BMD guidance ( USEPA 20 12 ) as the BMR. OPP has estimated both the BMD 1SD and the BMDL 1SD (where the BMDL 1SD is the lower 95% confidence limit of the BMD 1SD ). The BMD 1SD and the BMDL 1SD for fenpropathrin are 6.4 m g/kg and 5.0 mg/kg, respectivel y. As a matter of science policy, EPA uses the BMDL, not the BMD, for deriving PODs. Therefore , the BMDL 1SD of 5.0 mg/kg is being used as the dose for acute dietary risk assessment
. A route
- specific inhalation study is n ot available for fenpropathrin ; however , HED has waived the study . As a result, the oral BMDL 1SD of 5.0 mg/kg is being used to extrapolate inhalation risk. Dermal toxicity

studies are available for fenpropathrin in the rat and rabbit. However, no treatm ent - related findings were observed in either species at the limit dose and , therefore , a dermal assessment is not being conducted. Acute Dietary

(All Age Groups) : Quantitation of the dietary risks w as performed using the acute oral Wolansky

study , with a BMDL 1SD value of 5.0 mg/kg and a BMDL 1SD value of 6.4 mg/kg based on decreased locomotor activity
. Short
- term Dermal : A dermal assessment was not conducted for fenpropathrin. Although the acute der mal toxicity

of fenpropathrin is Category II, and a dermal penetration study indicates that up to 33% of a dermally applied dose is absorbed, HED’s residual concern for potential dermal toxicity

is reduced because: 1) in the acute study there was no indic ation of toxicityFenpropathrin Human Health Risk Assessment DP No. D368175

Page 24 of 52 below the 250 mg/kg dose (which is 5 0
- fold greater than the proposed oral POD of 5 mg/kg ) , and 2) the majority of residue in the dermal penetration study was bound to the upper dermal layers and was not available for s ys temic circulation. Furthermore, there is no indication of increased susceptibility
. As dermal studies do not assess developmental and reproductive parameters, there is the potential that such effects would be overlooked in a dermal study
. As neurotoxicity is observed at the same or lower doses than reproductive and developmental effects were observed and neurotoxicity would be apparent in a dermal study , there is reduced concern that developmental effects would be missed. Short
- term Inhalation : In the absence of an inhalation study , an oral study is being used. A POD of 5.0 mg/kg is selected from the Wolansky acute rat study

for this endpoint because of the overall robust nature of the study
. Toxicity via the inhalation route is assumed to be equal to t oxicity via the oral route. See Appendix A.3 for a more detailed description of endpoint selection. **4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment**  Only the acute dietary

and inhalation routes of exposure are being assessed. There are no other routes of exposure to be combined. **4.5.3 Cancer Classification and Risk Assessment Recommendation**  There was no evidence of carcinogenicity in either the rat or mouse long
- term dietary studies nor was there any mutagenic activity in bacteria or cult ured mammalian cells. Fenpropathrin is classified as “not likel y t o be carcinogenic to humans” in accordance with the EPA Final Guidance for Carcinogen Risk Assessment (3/29/20 05). **4.5.4 Summary of**  **Points of Departure and Toxicity Endpoints Table 4.5.**  **Summ ary of**  **Fenpropathrin Toxicological Doses and Endpoints for**  **Use in Hum an Health Risk**  **Assessment Exposure**  **Scenario Point of** 

**Departure Uncertainty/** **FQPA**

**S afety Factors**  **RfD, PAD, Level of Concern for Risk**  **Assessment Study and** 

**Toxicological Effects** Ac ute Dietary
- ( ≥ 6 years old) Wolansky

BMDL 1S D = 5.0 mg/kg UF A = 10 x

UF H = 10 x FQPA SF = 1 x Ac ute RfD = 0.05 mg/kg aPAD =0.05 mg/kg/day Wolansky BMD 1S D = 6.4 mg/kg based on decreased mo tor activity Ac ute Dietary
- (< 6 years old) Wolansky

BMDL 1S D = 5.0 mg/kg UF A = 10 x

UF H = 10 x FQPA SF = 3 x Ac ute RfD = 0.05 mg/kg aPAD =0.017 mg/kg/day Wolansky BMD 1S D = 6.4 mg/kg based on decreased mo tor activity Short
- Term (1
- 30 days) Dermal There was n o systemic toxicity via the dermal route; therefore, no endpoint was selected.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 25 of 52 **Table 4.5. Summ**  **ary of Fenpropathrin**  **Toxicological Doses and Endpoints for Use in Hum**  **an Health Risk Assessment**  **Exposure Scenario**  **Point of**

**Departure Uncertainty/** **FQPA**

**S afety Factors**  **RfD, PAD, Level of Concern for Risk**  **Assessment Study and** 

**Toxicological Effects** Short
- Term (1
- 30 days) Inhalation Wolansky

BMDL 1S D = 5.0 mg/kg 1 UF A = 10 x

UF H = 10 x FQPA SF = 1 x Occupational LOC for MOE = 100 Wolansky BMD 1S D = 6.4 mg/kg based on decreased mo tor activity Cancer (oral, dermal, inhalation) Classification: “not likely to be carcinogenic to humans” in accordance with the EPA Final

Guidance for Carcinogen Risk Assessment (3/29/05)
1 Toxicity via the inhalation route is assumed to be equal to toxicity via the oral route. Abbreviations: BMD 1S D is the central estimate of the dose that results in decreased motor activity compared to control animals based upon a 1 standard deviation using Benchmark Dose Analysis; BMD L is the 95% lower confidence limit of the central estimate. Data extrapolated for Wolansky (2006), MRID 47885701 ; UF = uncertainty factor. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose
- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity amo ng members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. aPAD = acute population adjusted dose , RfD = reference dose. MOE = margin of exposure. LOC = level of concern. **5.0 Dietary Exposure and Risk Assessment**  **5.1 Metabolite/** **Degradate Residue Profile 5.1.1**  **Summary of Plant and Animal Metabolism Studies** HED has determined that the nature of the residue in primary crops is adequately

understood. M etabolism studies were conducted on apple s , cotton, pinto beans, and tomatoes. In these crops, parent fenpropathrin was the predominant residue identified. C onjugated metabolites were also present, but at very

low levels. In the cotton metabolism study, there was extensive metabolism of the parent compound. HED determined that the residue of concern in primary crops is the parent compound. The nature of the residue in rotational crops is also adequatel y understood. In a confined rotational crop study, the predominant residues in rotated crops were 2,2,3,3
- tetrameth yl cyclo
propanecarbox yl ic acid (TMPA) and 3
- phenox yb enzoic acid (3
- PBA). Fenpropathrin was also found in rotated crops, but at less than 10% of the total radioactive residues. Metabolism studies with goats and poultry have been submitted and reviewed. The majority of the residue in muscle, fat, milk, and eggs was found to be the parent compound. The residues in kidney and liver consisted mainly of low levels of various metabolites. HED previously stated that the livestock metabolites, with the possible exception of TMPA lactone, have also been identified in rat metabolism studies and their contributions to the overall toxicity of fenpropathrin have been considered ( M emo, J. Whalen, 9/16/ 19 89)
.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 26 of 52 **5.1.2 Summary of Environmental Degradation**  Fenpropathrin appears to be resistant to degradation in biotic processes and is relatively stable to abiotic processes. The chemical is expected to have little mobility in soil surfaces, and leaching into groundwater is not expected to be an important transport process. Volatilization is not expected to be an important transport process
. Fenpropathrin is stable to hydroly sis at both pH 5 and 7, and shows moderate hydrol ys is at pH 9 (half
- lives on the order of 15 day s). The chemical is light
- stable unde r aqueous photolysis and soil photodegradation. Under both aerobic and anaerobic soil metabolism conditions, fenpropathrin degrades slowly , with half
- lives of 152 and 186 day s, respectively . If released to water, fenpropathrin partition s with the sediment and organic matter , where it might persist. In the field, fenpropathrin shows a wide range of half
lives (8
- 144 day s). This variability might be due to the wide range of conditions observed in different parts of the U.S. Except for COOH
- fenpropathrin (observed in the anaerobic soil metabolism study), other degradates observed in the laboratory result from the cleavage of the ester moiety of fenpropathrin. TMPA and 3
- PBA were among the observed degradates in the hydrol ys is study . CONH 2 - fenpropathrin, monitored in the field, was observed only in the upper layers of soil and appeared to be immobile. **5.1.3 Comparison of Metabolic Pathways**  Adequate studies are available depicting the metabolism of fenpropathrin in rats, primary crops (apples, cotton, pinto beans, tomatoes), rotational crops (carrots, lettuce, wheat), and livestock (lactating goats, laying hens) (D222174, L. Cheng, 10/23/ 97). Fenpropathrin is susceptible to metabolism in plants and animals. In rats, the m ajor biotransformation products f rom single and repeated dose rat metabolism studies included oxidation of the methyl group on the acid moiety, hydrox yl ation at the 4’
- position of the alcohol moiety , cleavage of the ester linkage, and conjugation with sulfuric and glucuronic acid. Major metabolites (i.e., >10% of applied total radioactive residue (TRR)) were phenox yb enzoic acid and TMPA
- glucuronic acid. Parent was the only major compound identified in the feces. The primary metabolites found in the confined rotational crop study were hydroly sis products of parent compound. Because of the similarity of the metabolites between the animal and plant studies, the rat toxicity studies account for the metabolites found in plants and livestock commodities. **5.1.4 Residues of Concern Summary and**  **Rationale** The nature of the f

enpropathrin residue is adequately understood in plants, rotational crops, livestock commodities, surface water , and groundwater. Parent fenpropathrin is the major residue in plant and livestock studies. Furthermore, the pl ant, animal, and environmental degradates identified are unlikely to be more toxic than the parent. Therefore, parent fenpropathrin is the residue of concern for both tolerance enforcement and risk assessment in plants, livestock commodities, and drinking water.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 27 of 52 **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 Primary Crop Fenpropathrin Fenpropathrin

Rotational Crop Not Applicable Not Applicable Livestock Ruminant Fenpropathrin Fenpropathrin

Poultry Fenpropathrin Fenpropathrin Drinking Water Fenpropathrin Not Applicable **5 .2**  **Food Residue**  **Profile** T he registrant submitted adequate use directions for the proposed tropical fruits. Inaddition, the registrant submitted adequate field trial data for guava, l ychee, sugar apple, and atemo ya to support the proposed uses on tropical fruits. HED’s Chemistry Science Advisory Council (ChemSAC) approved a revision of 40 CFR §180.1(g) to permit the extension of tolerances for guava, l ychee, and sugar apple to tolerances for the other tropical fruits in this petition. T he submitted crop field trial data for guav a, l ych ee, and sugar apple may be translated to support the proposed uses on the corresponding specific commodities; however, a separate tolerance must be established for each commodity
. ChemSAC approved the following revisions: (1) a tolerance for guava also applies to f eijoa, jaboticaba, wax jambu, starfruit, passionfruit, and acerola; (2) a tolerance for l ych ee also applies to longan, Spanish lime, rambutan, and pulasan; and (3) a tolerance for sugar apple also applies to cherimo ya , ilama, soursop, and biriba . A tolerance for sugar apple already applies to atemoya and custard apple. The submitted crop field trial data will support the proposed tolerances of 3.0 ppm for guava, acerola, feijoa, jaboticaba, passionfruit, starfruit, and wax jambu; 7 .0 ppm for lychee, longan, Spanish lime, pulasan, and rambutan; and 1. 5 ppm for sugar apple, atemoya, biriba, cherimoya, custard apple, ilama, and soursop. Table 5.2 provides a summary of the field trials that were performed for fenpropathrin. **Table 5.2**  **. Summ**  **ary of Residue Data from Crop Field Trials with Fenpropathrin.**  Crop matrix Total Applic. Rate (lb ai/A) PHI

(days) Residue Levels (ppm) n Min. Max. HAFT 1 Median Mean Std. Dev. **TROPICAL AND SUBTROPICAL FRUITS (proposed use = 0.8 lb ai/A total**  **application rate, 1 -**  **day PHI)** Guava 0.78
- 0.82 1 6 0.48 1. 1 1.0 0.59 0.71 0.2 5 Lychee 0.80
- 0.84 1 6 2.1 2.6 2.5 2.4 2.3 0.20 Sugar apple/atemoya 0.81
- 0.8 2 1 6 0.2 5 0.70 0.48 0.40 0.45 0.16 1 HAFT = Highest average field trial result. A dequate field trial data reflecting use of fenpropathrin on tea grown in India are available for establishing an import tolerance on dried tea. Th e OECD MRLcalculation procedures recommend that the tolerance be established at 3.0 ppm. However, there is a Codex MRLof 2.0Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 28 of 52 ppm for dried tea. HED considers this tolerance level to be adequate because the highest field trial value was 1.38 ppm. As a result, HED recommends in favor of a tolerance of 2.0 ppm for tea, dried in order to harmonize with the Codex MRL
. HED does not require residue data for any processed commodities associated with th is tolerance petition
. As a result, no processing studies were submitted and none are needed. There are no livestock feedstuffs associated with the proposed use on tropical fruits or tea. As a result, the current tolerances for livestock commodities are adequate. In formation is available concerning the potential of fenpropathrin to bioconcentrate in fish. The chemical has a relativel y high octanol/water partition coefficient and depurates from fish at a moderate rate. EFED’s registration review problem formulation (D371483, J. Melendez, 6/16/2010) states that “...fenpropathrin appears to have a po tential to bioconcentrate in aquatic organisms & biomagnify in aquatic and terrestrial organisms.” However, the moderate depuration rate reduces the concern for residues in fish for subsistence and recreational fishers. **5.3 Water Residue Profile**  The Environmental Fate and Effects Division (EFED) p rovided the results of a drinking water assessment that was performed for fenpropathrin ( D368174, Jose Melendez, 4/26/2010). In this memo, EFED stated that the results of a previous assessment (D313331, J. Mel endez, 9/3/2008) should be used in the current dietary exposure and risk assessment
. Water numbers were based on parent onl y . The EFED memo of 9/3/2008 provided Tier 1 estimated environmental concentrations (EDWCs) for fenpropathrin that were calculated using the FIRST Model for surface water and the SCIGROW Model for groundwater. For surface water, the acute (peak) water concentration is 10.3 ppb. The groundwater screening concentration is 0.005 ppb. These values generall y represent upper - bound estimates of the concentrations that might be found in surface water and groundwater resulting from the use of fenpropathrin on grapes, because this is the scenario that results in the highest EDWCs. For the acute dietary exposure assessment, the peak water con centration value of 10.3 ppb was used. The model and its description are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/
. **5.4 Dietary Risk Assessment**  **5.4.1 Description of Residue Data Used in Dietary Assessment**  An a cute aggregate dietary (food and drinking water) exposure and risk assessment w as conducted using the Dietary Exposure Evaluation Model DEEM
- FCIDTM, Version 2.03 , which uses food consumption data f rom the U.S. Department of Agriculture’s Continuing Survey s of Food Intakes by

Individuals (CSFII) from 1994
- 1996 and 1998. A chronic dietary

exposure assessment was not performed because repeated exposure to fenpropathrin does not result in a point of departure lower than that resulting from acute exposure , and a chronic dietary endpoint was not selected
. T he acute dietary risk assessment is considered to be protective of chronic dietary risk. An assessment for cancer was not performedFenpropathrin Human Health Risk Assessment DP No. D368175

Page 29 of 52 because fenpropathrin was classified as “not likely to be carcinogenic to humans.” As a result, an acute assessment was the only dietary exposure assessment performed for fenpropathrin. T he acute assessment was based on tolerance level residues, distributions of field trial values, and distributions of Pesticide Data Program (PDP) monitoring data. Residue distributions were used for the commodities that made the most significant contributions to the risk estimates (i.e., the “risk drivers”). Monitoring data were used for risk drivers when they were available; however, field trial data were used for the remaining risk drivers. Distributions of monitoring data values were used for broccoli, Chinese mustard cabbage, cauliflower, watermelon, squash, oranges, tangerines, apples, apple juice, pears, blueberries, huckleberries, grapes, grape juice, and strawberries. Monitoring data from the ye ars 2007 through 2010, inclusive, were used. Broccoli PDP data were translated to Chinese mustard cabbage and cauliflower. Orange P DP data were translated to tangerines. Finally , blueberry PDP data were translated to huckleberries. Distributions of field trial data were used for cherries, peaches, plums, grapefruit, raspberries, blackberries, apricots, cabbage, papaya, olives, tomat oes, cucumbers, Brussels sprouts, and guava. For most processed commodities, DEEM default processing factors were used for those commodities for which they were available. In some cases, empirical processing factors were used. For drinking water, a very conservative surface water EDWC generated with the FIRST Model was used. As a result of the fact that many conservative assumptions were made for this assessment , in particular, the use of field trial data (as opposed to monitoring data) for many commodi ties , HED is confident that the acute dietary exposure assessment significantl y overestimate s risk to the general U.S. population and all population subgroup s . **5.4.2 Percent Crop Treated Used in Dietary Assessment**  The Biological and Economic Analy sis Div ision (BEAD) provided a Screening Level Usage Analy sis (SLUA) for fenpropathrin (D402054, S. Haddad, 5/25/2012). The SLUA provided maximum percent crop treated estimates for commodities with established tolerances. Percent crop treated estimates were not used for any of the proposed commodities. The following maximum percent crop treated estimates were used in the acute dietary risk assessment for the following crops that are currently registered: apples ( 15% ), apricots (2. 5% ), blueberries ( 2.5 %), broccoli (2.5%), Brussels sprouts (10%), cabbage (2.5%), cauliflower (2.5%), cherries (5%), cotton (2.5%), cucumbers (2.5%), grapefruit (35%), grapes (10%), nectarines (2.5%), oranges (35%), peaches (2.5%), pears (10%), plums (2.5%), prune plums (2.5%), squash (2.5%), strawberries (50%), tangerines (15%), tomatoes (10%), and watermelons (2.5%). **5.4.3 Acute Dietary Risk Assessment**  The acute risk estimates are below HED’s level of concern for all population subgroups, including those comprised of infants an d children. Generally , HED is concerned when risk estimates exceed 100% of the PAD. The acute risk estimate for the general U.S. population is 19 % of the aP AD. The population subgroup with the highest acute dietary risk estimate is Children 3
- 5 , which u ses 97 % of the aPAD. As percent crop treated estimates were incorporated into the acute assessment, the risk estimates are being reported at the 9 9.9 th percentile of exposure. The acute dietary risk es timates are given in Table 5.4.4
.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 30 of 52 HED considers the acute assessment to be partially refined, but at the same time, very health
protective. Refinements were made to the risk drivers in the assessment; however, for many of the risk drivers , these refinements consisted of the incorporation of field trial data (See Section 5.4.1, above)
. For p yr ethroids, m onitoring data are almost alway s significantly lower than field trial data. Monitoring data more accurately represent the residue levels to which people will actuall y be exposed to pestici de residues in their diets. For many commodities, the assumption was made that 100% of the crop would be treated. For other commodities, maximum percent crop treated estimates were incorporated. These estimates are based on past usage data and are consi dered to be reliable. Percent crop treated estimates were not available for two of the risk drivers for children 1
- 6 years of age, raspberries and blackberries. As a result, 100% crop treated was used for these commodities. I f usage estimates were avail able and had been used, the risk estimates for the population subgroups, Children 1
- 2 and Children 3
- 5 , would have been lower. A s all risk estimates are not of concern, it is not necessary to make any further refinements to the dietary exposure assessment at this time. Residues in drinking water made a negligible contribution to the risk estimates. **5.4. 4**  **Summary Table**
**Table 5**  **. 4.**  **4 .**  Summary of the Acute Exposure and Risk Estimates for Fenpropathrin Population Subgroup Ac ute Assessment (99.9 th Percentile) Chronic Assessment

aPAD, mg/day Exposure Estimate,

mg/day %

aPAD cPAD,

mg/day Exposure Estimate,

mg/day % cPAD U.S. Population 0.05 0.009489 19 NA NA NA All infants 0.017 0.011457 67 Children 1
- 2 y

rs 0.017 0.0153 43 90 **Children 3 -**  **5 yrs** ***** 0.017 **0.016 488**  **9 7**  Children 6
- 12 y

rs 0.05 0.013489 27 Youth 13
- 19 y

rs 0.05 0.009290 19 Adults 20
- 49 y

rs 0.05 0.007920 16 Adults 50+ yrs 0.05 0.008093 16 Females 13
- 49 y

rs 0.05 0.0 08476 17 *Most highly exposed population subgroup
**6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  **6.1 Residential Handler**  **and Post**  **- application**  **Exposure and Risk Estimates**  There are no registered or proposed residential uses for fenpropathrin. As a result, residential handler and post - application risk is not of concern.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 31 of 52 **6.2 Spray Drift**  Spray drift is alway s a potential source of exposure to residents nearby sprayingoperations. This is particularl y the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for fenpropathrin. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and othe r 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 miti gation 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 po licy

on how to appropriatel y apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y air, orchard airblast and ground hydraulic methods. After the policy

is in place, the Agency

may impose further refinements in s pray drift management practices to reduce off
- target drift with specific products with significant risks associated with drift. Although a quantitative post - application inhalation exposure assessment was not performed for fenpropathrin to address pesticid e drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers who assist aerial applicators. This exposure scenario is representative of a worst
- case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post - application inhalation exposure scenarios. **7.0 Aggregate Exposure/Risk Characterization**  In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risk estimate s from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risk estimate s themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. The only applicable aggregate scenario for fenpropathrin is acute aggregate risk which result s from exposure to residues in food and drinking water alone. The acute dietary exposure anal ys is included both food and drinking water . Therefore, acute aggregate risk estimates are equivalent to the acute dietary risk estimates , as discussed in Section 5.4.3, above. Acute aggreg ate risk is not of concern for the general U.S. population or any population subgroup
. **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 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
- gate d sodium channels ultimately

leading to neurotoxicity . The cumulative risk assessment for the py rethroids/ py rethrins was published on 11/9/2011 and is available at http://www.regulations.gov ; EPA
- HQ
-Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 32 of 52 OPP
- 2011
- 0746
. No cumulative risks of concern were identified , allowing the Agency to consider new uses for p yrethroid s . For information regarding EPA’s efforts to evaluate the risk of exposure to this class of chemicals , refer to http://www.epa.gov/oppsrrd1/reevaluation/py rethroids
- py

rethrins.html
. Fenpropathrin is included in the py rethroid/py

rethrin cumulative risk assessment. The new uses that have been proposed have an insignific ant impact on the cumulative risk assessment. No dietary , residential, or aggregate risk estimates of concern have been identified in the single chemical assessment. In the cumulative assessment, residential exposure was the greatest contributor to the total exposure. As there are no residential uses for fenpropathrin, the proposed new uses will have no impact on the residential component of the cumulative risk estimates. D ietary exposures make a minor contribution to the total py rethroid exposure. The dietary exposure assessment performed in support of the pyrethroid cumulative was much more highl y refined than that performed for the single chemical. In addition, f or the fenpropathrin risk assessment, the most sensitive apical endpoint in the fenpropathrin database was selected to derive the POD. Additionally , the POD selected for fenpropathrin is specific to fenpropathrin, whereas the POD selected for the cumulative assessment was based on common mechanism of action data that are appropriate for all 20 py rethroids included in the cumulative assessment. Dietary exposure to fenpropathrin residues in the pro posed tropical fruits and tea will contribute very little to the dietary

exposure to fenpropathrin alone. As a result, the proposed uses will make an insignificant contribution to dietary risk to the py

rethroids as a whole. **9.0 Occupational Exposure/Risk**  **Characterization** Fenpropathrin may

be applied to fruit trees b y ground equipment ( airblast)
. Inaddition, aerial application may

be used for avocado trees. Fenpropathrin is intended for use by commercial and professional applicators. Therefore, there i s potential for short
- and intermediate
- term occupational handler and post - application exposure via the inhalation and dermal pathway s . No long
- term exposure (> 6 months) is expected. However, as noted previously , fenpropathrin does not increase in potency

with repeated dosing , and therefore onl y single
- day occupational exposures are being assessed. These single
- day risk estimates are protective for repeated exposures. As there is no dermal hazard associated with this chemical, only inhalation risk i s being assessed quantitatively
. **9.1 Short**  **- /Intermediate**  **- Term**  **Handler Risk** E xposure scenarios describe the handler activities (mixer, loader, applicator, and flagger) and ty pe of application equipment. Based on the proposed use pattern, the followin g scenarios were identified for the appl ication of fenpropathrin t o tropical fruits:

• Mixing/loading liquid formulation for aerial application,
• Mixing/ loading liquid formulation for airblast equipment,
• Applying the spray using ai r equipment (enclo sed cockpit) , • Applying the spray using airblast equipment, and
• Flagging for aerial spray applicationFenpropathrin Human Health Risk Assessment DP No. D368175

Page 33 of 52 The re are no chemical
- specific exposure data for fenpropathrin to develop unit exposures required for estimating handler exposure. It is HED policy 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 PHED (Version 1.1) database, and the Agricultural Handler Exposure Task Force (AHETF ) database. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures , ” are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/handler
- exposure - table.pdf ), which, along with additional information on HED policy on use of surrogate data, including descripti ons of the various sources, can be found at: http://www.epa.gov/pesticides/science/handler
- exposure data.html. The Danitol ® label directs applicators and other handlers to wear long
- sleeved shirt, long pants, chemical
- resistant gloves, shoes, socks, and p rotective eyewear. Table 9.1 summarizes the short
- term inhalation risk estimates for handlers resulting from the proposed use of fenpropathrin on tropical fruits, applied as a foliar treatment. There is no toxicity associated with dermal exposure to fenpropathrin and , therefore , the re is no dermal risk for handlers. The acute inhalation endpoint and dose are protective of repeated exposures as discussed previousl y. The results of HED’s assessment indicate that the short
- term inhalation risk estimates (MOE ≥ 5,300) are above HED’s L OC of an MOE of 100 at the baseline level of PPE (i.e., no respirator) , and with the use of engineering controls for aerial applications . T hese risk estimates are not of concern. Furthermore, the Agency has evaluated scenarios that m ight be limited in nature such as flagging during aerial applications because engineering controls (i.e., Global Positioning Satellite technology) are now predominantly used as indicated b y the 1998 National Agricultural Aviation Association (NAAA) survey of their membership. Itappears, however, flaggers are still used in approximately

10 to 15 percent of aerial application operations. In cases like these, the Agency strongl y encourages the use of the engineering control system but will continue to evaluate risks for flagger s and any

other population where a clear exposure pathway exists until the potential for exposure is eliminated. The Agency is aware that NAAA is conducting another survey on exposure issues and will consider those results at such time as it is appropriat e to do so
.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 34 of 52 **Table 9.1**  **. Fenpropathrin**  **Occupational Handler**  **Exposure and Risk Estimates Exposure**  **Scenario PPE**  **1 Max. Single**  **Appl. Rate (lb ai/A)**  **Area**

**Treated (Acres)**  **Inhalation Unit**

**Exposure & Source (μg/lb ai)**  **Inhalation Dose**

**(m g/kg/**  **day) 2**  **Short -**  **term**

**Inhalation MOE 3**  MIXER / LOADER Liquids ( EC ) for aerial equipment Baseline

(no respirator) 0.4 350 0.219 (AHETF) 0.00038 13,000 Liquids ( EC ) for airblast equipment Baseline

(no respirator) 0.4 40 0.219 (AHETF) 0.000044 110,000 APPLICATOR and FLAGGER S pray for a erial equipment Closed cockpit 0.4 350 0.068 (PHED) 0.00012 42,000 S pray for a i rb l ast equipment Baseline

(open cab and no respirator) 0.4 40 4.71 (AHETF) 0.00094 5,300 Flagger : Aerial Applications Baseline

(no respirator) 0.4 350 0.35 (PHED) 0.00061 8,200 MOE = margin of exposure , AHETF=Agricultural Handler Exposure Task Force, PHED=Pesticide Handlers Exposure Database
. 1. Baseline PPE includes long
- sleeved shirt, long pants and shoes with socks and engineering controls. The submitted label recommends baseline PPE plus chemical
- resistant gloves and protective eyewear. 2. Inhalation Dose (mg/kg/day) = [Appl. Rate (lb ai/A) * Acres Treated/Day * Inhalation Unit Exposure (μg/lb ai handled/day /1000)] / Body wt ( 80 kg). 3. Short
- term

Inhalation MOE = Short
- term Inhalation POD (5.0 mg/kg/day) / Inhalation dose (mg/kg/day). **9 .2**  **Occupational/Commercial Post**  **- application**  **Exposure** Post
- application workers m ight be exposed to residues of fenpropathrin through dermal and inhalation routes when they enter treated tropical fruit orchards to perform post - application activities, such as thinning, irrigation, scouting, harvesting, etc. Dermal post - application exposure was not quantitatively estimated for use of fenpropathrin on tropical fruits because of the absence of a dermal endpoint. Based on the Agency ’ s current practices, a quantitative post - application inhalation exposure assessment i s not being performed for fenpropathrin at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV) and the low use rate (0.4 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 re
- suspension of dusts and/or particulates that contain pesticides. The Agency

sought expert advice and input on issues related to volatilization of pesticides from its FIFRA 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 ). Th e Agency is in the process of evaluating the SAP report as well as available post
- application inhalation exposure data generated b y the Agricultural Reentry Task Force and may , as appropriate, develop policies and procedures to identify the need for and, s ubsequently , the way to incorporate occupational post - application inhalation exposure into the Agency ’ s risk assessments. If new policies orFenpropathrin Human Health Risk Assessment DP No. D368175

Page 35 of 52 procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for fenpropathrin. Although a quantitative post
- application inhalation exposure assessment was not performed, HED has assessed inhalation exposure and risk for occupational/commercial flaggers for aerial applications of fenpro pathrin on tropical fruits , and the risk estimates are not of concern. Inhalation exposure for flaggers is likely to be higher than inhalation exposure associated with post - application activities. Therefore, the flagger inhalation risk estimates are cons idered to be protective of all potential post
- application activities performed in treated tropical fruit orchards, and these risks are not of concern. Restricted Entry

Interval The registered Danitol ® 2.4 EC Spray has a 24
- hour restricted entry interval ( REI) and is in compliance with the Worker Protection Standard because fenpropathrin is Toxicity Category I I via the dermal route . It is not an eye or skin irritant, and it is not a skin sensitizer. **10.0 References**  OPP Memoranda D. Dotson, et al., 11/26/2008, D313330, Fenpropathrin. Human Health Risk Assessment for the Proposed Uses on Barley, Stone Fruit (Crop Group 12), Tree Nuts (Crop Group 14), Pistachio, Caneberries (Crop Subgroup 13
- 07A), Olive, Avocado, Black Sapote, Canistel, Mamey Sapote, Man go, Papaya, Sapodilla, and Star Apple D. Smegal, 4/10/2012, TXR# 0053978, Summary of Hazard and Science Policy Council (HASPOC) Meeting of January 19, 2012: Recommendations on waiver requests for a 90
- day inhalation study

for fenpropathrin J. Kidwell, 7 /24 /2012 , Fenpropathrin
- Summary of Toxicology

Science Advisory

Council (ToxSAC) E
- Meeting E. Scollon, A. L owit, 6/27/2011, D381210, Re
- Evaluation of the FQPA Safety Factor for Py rethroid Pesticides D. Dotson, 7 /24 /2012 , D368340 , Fenpropathrin. Request for Tolerances in Support of New Uses on the Tropical Fruits Guava, Acerola, Feijoa, Jaboticaba, Passionfruit, Starfruit, Wax Jambu, Lychee, Longan, Spanish L ime, Pulasan, Rambutan, Sugar Apple, Atemoya, Biriba, Cherimo ya, Custard Apple, Ilama, and Soursop. Request for a Tolerance Without U.S. Registration on Tea. Summary of Anal yt ical Chemistry

and Residue Data. D. Dotson, 7 /24 /2012 , D 402246, Fenpropathrin **.** Acute Aggregate Dietary (Food and Drinking Water) Exposure and Risk Asse ssment for the Section 3 Registration Action on the Tropical Fruits Guava, Acerola, Feijoa, Jaboticaba, Passionfruit, Starfruit, Wax Jambu, Lychee, Longan,Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 36 of 52 Spanish L ime, Pulasan, Rambutan, Sugar Apple, Atemoya, Biriba, Cherimoya, Custard Apple, Ilama, and Soursop, and a Tolerance Without U.S. Registration on Tea Suku Oonnithan, 6/11/2012, D 372847 , Fenpropathrin: Occupational and Residential Exposure Assessment for the Proposed New Use on Additional Tropical Fruits. M. Shamim, 7/6/1993, D180582, Review of Hydroly sis, Photoly sis in Water, Photoly sis on Soil, Anaerobic Soil Metabolism, Mobility and Adsorption/ Desorption, and Terrestrial Field Dissipation Studies; Proposed New Uses on Tomatoes and Strawberries; Label Amendment
. J. Melendez, 4/26/2010, D36817 4, Tier I Estimated Drinking Water Concentrations of Fenpropathrin: IR
- 4 Petition for the Use of Fenpropathrin on Additional Tropical and Sub Tropical Fruits and for Tolerance for Tea. Toxicology

References 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. Cao, Z., T. J. Shafer, K . M. Crofton, C. Gennings and T. F. Murray (2011a). “ Additivity

of Py rethroid Actions on Sodium Influx in Cerebrocortical Neurons in Primary Culture. ” Environ Health Perspect. Cao, Z., T. J. S hafer and T. F. Murry (2011b). “ Mechanisms of P yrethroid Insecticide
- Induced Stimulation of Calcium Influx in Neocortical Neurons. ” J Pharmacology and Experimental Therap y 336(1): 197
- 205. Choi, J.
- S. and D. M. Soderlund (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
- 244. 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. 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). “ Phy siologically Based Pharmacokinetic Modeling of Deltamethrin: Development of a Rat and Human Diffusion
- Limited Model. ” Toxicol. Sci. 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. ” N euron 28(2): 365
- 368.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 37 of 52 Goldin, A. L . (2002). “ Evolution of V oltage
- G ated Na+ C hannels. ” J Exp Biol 205(5): 575
- 584. 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 Therap eutics 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 py re throid isomers with sodium channels of squid axon membranes. ” Neurotoxicology 3(1): 11
- 24. Meacham, C. A., P. D. Brodfuehrer, J. A. Watkins and T. J. Shafer (2008). “ Developmentally
regulated sodium channel subunits are differentially sensitive to [alpha]
- cyano containing 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 model for deltam ethrin in the adult male Sprague
- Dawley

rat. ” Toxicol Sci 93(2): 432
- 442. Salgado, V., M. Herman and T. Narahashi (1989). “ Interactions of the p yr ethroid fenvalerate with nerve membrane sodium channels: Temperature dependence and mechanism of depolarization. ” Neurotoxicology 10(1): 1
- 14. Shafer, T. J., D. M eyer and K. M. Crofton (2005). “ Developmental neurotoxicity of p yr ethroid insecticides: critical review and future needs. ” Environmental Health Perspectives 113(2): 123
- 136. Soderlund, D., J. Clark, L. Sheets, L. Mullin, V. Piccirillo, D. Sargent, J. Stevens and M. Weiner (2002). “ Mechanisms of py rethroid neurotoxicity : implications for cumulative risk assessment. ” Toxicology

171(1): 3
- 59. Song, J. H. and T. Narahashi (1996). “ Modulation of sodium channels of rat cerebellar purkinje neurons b y the p yr ethroid tetramethrin. ” Journal of Pharmacology and Experimental Therapeutics 277: 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 Pharmacol Exp Ther 284(3): 958
- 965. Tan, J. and D. M. Soderlund (2009). “ Human and rat Nav1.3 voltage
- gated sodium channels differ in inactivation properties and sensitivity to the py rethroid insecticide tefluthrin. ” NeuroToxicology

30(1): 81
- 89.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 38 of 52 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. ” Toxicol Appl Pharmacol 244: 208
- 217. USEPA ( 20 12 ). “ Benchmark Dose Technical Guidance. Risk Assessment Forum, Office of Research and Development, U.S. Environmental Protection Agency . Washington, DC. EPA/ 10 0 /R
- 12 /001. ” 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
. USEPA (2010). “ Py

rethroids: E valuation of Data from Developmental Neurotoxicity Studies and Consideration of Comparative Sensitivity, ” D31723 Jan 20, 2010. Document ID: E PA
- HQ
OPP
- 2008
- 0331
- 0028 Verscho yl e, R. D. and W. N. Aldridge (1980). “ Structure
- activity relationships of some py rethroids in rats. ” Arch Toxicol 45(4): 325
- 329. Weiner, M. L ., M. Nemec, L . Sheets, D. Sargent and C. Breckenridge (2009). “ Comparative functional observational battery study of twelve commercial py rethroid insecticides in male rats following acute oral exposure. ” Neurotoxicology 30 Suppl 1: S1
- 16. Wolansky , M., C. Gennings and K. Crofton (2006). “ Relative potencies for acute effects of py rethroids on motor function in rats. ” Toxicol Sci 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: O ntogenic expression, inter
- individual variability and differential h ydroly sis of oseltamivir, aspirin, deltamethrin and permethrin. ” Biochemical Pharmacology

77(2): 238
- 247.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 39 of 52 **Appendices Appendix A: Toxicology**  **Profile Appendix**  **A.1. Toxicology Data Requirements**  **Toxicology Requirements for Fenpropathrin Guideline Number and Toxicity Study**  **Required Satisfied**  870.1100 Acute Oral Toxicity
................................ ............................... 870.1200 Acute Dermal Toxicity
................................ .......................... 870.1300 Acute Inhalation Toxicity
................................ ...................... 870.2400 Primary Eye Irritation
................................ ............................ 870.2500 Primary Dermal Irritation
................................ ...................... 870.2600 Dermal Sensitization
................................ .............................. yes yes yes yes yes yes yes

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

yes yes yes yes 1 870.3700 Developmental Toxicity (Rodent)
................................ ......... 870.3700 Developmental Toxicity (Non
- rodent)
................................ ... 870.3800 Reproduction
................................ ................................ .......... yes yes yes yes

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

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

yes yes yes yes yes 870.6100 Acute Delayed Neurotoxicity (Hen)
................................ ...... 870.6100 90
- Day Neurotoxicity (Hen)
................................ .................. 870.6200 Acute Neurotoxicity Screening Battery (Rat)
........................ 870.6200 90 Day Neuro. 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 yes

--Not Applicable 1 The required 28
- day inhalation study was waived by the HED HASPOC.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 40 of 52 **Appendix A2 .**  **Toxicity Profile Table**  **s Acute Toxicity**  **of Fenpropathrin Guideline No./Study Type**  **MRID Results**  **Toxicity Category**  **870.1100 Acute oral toxicity (rat) 00127343**  **LD 50**  **=M:54 m g/kg**  **F:48.5 m g/kg**  **I 870.1200 Acute derm**  **al toxicity (rat) 00127352**  **LD 50**  = **M** : **1600 m g/kg**  **F:870 m g/kg**  **II 870.1200b Acute derm**  **al toxicity (rabbit) 00127355**  **LD50 = M: >2000**  **mg /k** **g bw F: >2000 m**  **g/kg bw III**  **870.1300 Acute inhalation toxicity (rat) 00163812**  **LC 50**  **= ND IV**  **870.2400 Acute eye irritation (rabbit)**  **00127357 Mild eye irritant**  **III 870.2500 Acute derm**  **al irritation (rabbit) 00127357**  **Not a derm al irritant**  **IV 870.2600 Skin sensitization (guinea pig)**  **00127358 Not a derm**  **al sensitizer NA**  ND = Not Determined **Subchronic, Chronic, and Other Toxicity Studies for Fenpropathrin Guideline No./ Study**  **Type MRID No. (year)/** 

**Classification /Doses Results**  **Subchronic Studies** 870.3100 90
- Day oral toxicity rats (unreported strain) 00127363 (1979)

Acceptable/guideline M&F: 0, 3, 30, 100, 300, 600 ppm (0, 0.15, 1.5, 5, 15, 30 mg/kg/day), in diet NOAEL = 15 mg/kg/day LOAEL = 30 mg/kg/day based on clinical signs of tremors, body weight reductions, decreased blood clotting time in females, and possibly increased alkaline ph osphatase levels (both sexes).

870.3150 90
- Day oral toxicity (Beagle dog) 00127364 (1980)

Acceptable/guideline M&F: 0, 250, 500, 750 ppm (0, 6.25, 12.5, 18.8 mg/kg/day) NOAEL = <6.2 mg/kg/day LOAEL = 6.2 mg/kg/day based on effects on the gastrointestinal system, tremors, and body weight changes. 870.3200 21
- Day dermal toxicity (Sprague
Dawley rat) 47325602 (2006)

Acceptable/guideline 0, 20, 200, or 1000 mg/kg/day for 6 hrs/day, 21 days Sy stemic NOAEL = 1000 mg/kg/day Sy stemic LOAEL = not observed Dermal NOAEL = 1000 mg/kg/day Dermal LOAEL = not observedFenpropathrin Human Health Risk Assessment DP No. D368175

Page 41 of 52 **Subchronic, Chronic, and Other Toxicity Studies for Fenpropathrin Guideline No./ Study**  **Type MRID No. (year)/** 

**Classification /Doses Results**  870.3200 21
- Day dermal toxicity (NZW rabbit) 00127366 (1982)

Acceptable/guideline M&F: 0, 500, 1200, 3000 mg/kg/day NOAEL = >3000 mg/kg/day Only local irritation was seen. There were no systemic effects, thus the LOAEL was not determined. **Developm ental and Reproduction Studies**  870.3700a Prenatal developmental [CDF® (F
344)/CrLBR rats) 41525903 (1990)

Acceptable/guideline 0, 0.4, 1.5, 2.0, 3.0, 6.0, 10.0 mg/kg/day (gavage) LOAEL = 10 mg/kg/day based on increased incidence of asymmetrical ossification of sternebrae and incomplete ossification of the 5 th and 6 th sternebrae **Maternal** NOAEL = 3 mg/kg/day LOAEL = 6 mg/kg/day based on decreased food consumption and body weight gains. At 10 mg/kg/day, 6 dams died between days 7 and 13, and one dam was sacrificed moribund on day 8. The remaining 23 dams survived through the end of gestation. Also in the high dose group, many clinical signs were observed in the dams including ataxia, sensitivity to exte rnal stimuli, spastic jumping, and tremors. These signs were most severe 2 hours post
- dosing and during the first days of dosing. **Developm ental**  NOAEL = 6 mg/kg/day LOAEL = 10 mg/kg/day based on increased incidence of asymmetrical ossification of stern ebrae and incomplete ossification of the 5 th and 6 th sternebrae 870.3700b Prenatal developmental (NZW rabbit) 00163816 (1985)

Acceptable/guideline 0, 4, 12, 36 mg/kg/day (gavage) **Materna** l NOAEL = 4 mg/kg/day LOAEL = 12 mg/kg/day based on flicking of the forepaw s. **Developm enta**  l NOAEL = >36 mg/kg/day No dose related effects were seen, thus the LOAEL was not determined. 870.3800 Reproduction and fertility effects (Sprague
- Dawley rats) 00163817 (1986)

Acceptable/guideline 0, 40, 120, 360 ppm (M: 0, 3.0, 8.9, 26.9 mg/kg/day F: 0, 3.4, 10.1, 32.0 mg/kg/day), in diet, premating determinations **Parental/System ic**  NOAEL = M:3.0; F: 3.0 mg/kg/day LOAEL = M: 8.9; F: 10.1 mg/kg/day based on death and clinical signs of neurotoxicity in females. **Offspring** NOAEL = M:3.0; F:3.4 mg/kg/day LOAEL = M: 8.9; F: 10.1 mg/kg/day based on increased mortality and body tremors. **Chronic Toxicity Studies** 870.4100b Chronic toxicity (Beagle dog) 00143130 (1984)

Acceptable/guideline 0, 100, 250, 750 ppm (0, 2.5, 6.25, 18.75 mg/kg/day) NOAEL = 2.5 mg/kg/day LOAEL = 6.25 mg/kg/day based on tremors and ataxia in both sexes.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 42 of 52 **Subchronic, Chronic, and Other Toxicity Studies for Fenpropathrin Guideline No./ Study**  **Type MRID No. (year)/** 

**Classification /Doses Results**  **Chronic/Carcinogenicity Studies** 870.4200b Carcinogenicity (CD
1 mouse) 00163814 (1985)

Acceptable/guideline 0, 40, 150, 600 ppm (M: 0, 3.9, 13.7, 56.0 mg/kg/day F: 0, 4.2, 16.2, 65.2 mg/kg/day), in diet NOAEL = Not established LOAEL = M: >56.0; F: >65.2 mg/kg/day There was an overall lack of toxic response. However the aborted mouse carcinogenicity study (MRID No. 00163815) demonstrated that at a slightly higher max imum tolerated dose (MTD) of 1000 ppm, the test article was lethal to 15% of the mice after only 13 weeks. Thus the maximum dose used in this completed study (600 ppm) was very close to the MTD. A repeat study is not justified. **no evidence of carcinogeni city**  870.4300 Chronic/ Carcinogenicity
- (CD rat) 00163813 (1986)

Acceptable/guideline 0, 50, 150, 450, 600 ppm (M: 0, 1.93, 5.71, 17.06, 22.8 mg/kg/day F: 0, 2.43, 7.23, 19.45, 23.98 mg/kg/day), in diet NOAEL = M:17.06; F: 7.23 mg/kg/day LOAEL = 19.45 mg/kg/day based on increase mortality and body tremors in the females **no evidence of carcinogenicity Mutagenicity Studies**  Gene Mutation 870.5100 Bacterial Reverse Mutation Test 00163818 (1984)

Acceptable/guideline 0, 50, 10, 500, 100, or 5000 μ g/plate +/
- S9 Negative in Salmonella typhimurium TA 1535, TA 1537, TA1538, TA98, and TA100 and Escerichia coli Wp2 uvrA up to the limit concentration with evidence of compound insolubility. Gene Mutation 870.5300 In vitro mammalian cell gene mutation test 00126832 (1982)

Acceptable/guideline 0, 50.3, 84.5 141.9, 238.2, 400 μ g/mL in the absence of mammalian metabolic activation 0, 30, 47.5, 75.3, 119.4, 189.2, 300 mg/mL in the presence of mammalian metabolic activation There was no clear evidence (or a conce ntration related positive response) of induced mutant colonies over background.

870.5375 Cy togenetics In vitro mammalian cell chromosomal aberration assay 41281601 (1989)

Acceptable/guideline 10
- 30 μg/mL
- S9 and 250
- 1000 μg/mL +S9 Negative in Chinese hamster ovary (CHO) cells (cytotoxicity observed at ≥30 μg/mL
- S9 and compound precipitation at 1000 μg/mL +S9).

870.5500 Other Genotoxic Effects Bacterial DNA damage or repair test 00126831 (1980)

Acceptable/nonguideline 10
- 5000 μg/disc
- S9 only Negative in Bacillus subtilis H17 (DNA repair proficient) and M45 (DNA repair deficient).Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 43 of 52 **Subchronic, Chronic, and Other Toxicity Studies for Fenpropathrin Guideline No./ Study**  **Type MRID No. (year)/** 

**Classification /Doses Results**  870.5900 Other Genotoxic Effects In vitro sister chromatid exchange assay 00163821 (1984)

Acceptable/guideline 3x10 - 6

- 1x10 - 4 M (solubility limit) +/
- S9 Negative in CHO cells up to the solubility limit.

**Neurotoxicity Studies** 870.6200a Acute Neurotoxicity Screening Battery (Sprague
- Dawley rats) 47345605 (2006)

Acceptable/guideline 0, 3, 6, 15, or 30 mg/kg NOAEL = 15 mg/kg LOAEL = 30 mg/kg, based on slight tremors and clonic convulsions in both sexes at the time of peak effect 870.6200b Subchronic Neurotoxicity Study (Sprague
- Dawley rats) 47345607 (2007)

Acceptable/guideline 0, 60, 190, or 570 ppm M: 0, 4, 13, or 38 mg/kg/day F: 0, 5, 15, or 50 mg/kg/day NOAEL = 13/15 mg/kg/day LOAEL = 38/50 mg/kg/day, based on tremors, convulsions, impaired gait, and related findings in the FOB predominantly in the females 870.6300 Developmental Neurotoxicity Study (Sprague
- Dawley rats) 47345609 (2008)

Acceptable/guideline 0, 40, 100, or 250 ppm 0/0, 3/7, 8/16, or 19/40 mg/kg/day gestation/lactation, respectively Maternal NOAEL = 8/16 mg/kg/day Maternal LOAEL = 19/40 mg/kg/day, based on tremors during lactation Offspring NOAEL = 8/16 mg/kg/day Offspring LOAEL = 19/40 mg/kg/day, based on small pup size and decreased body weights and body weight gains during the pre
- weaning period Neurotoxicity NOAEL = 8/16 mg/kg/day Neurotoxicity LOAEL = 19/40 mg/kg/day, based on increased mean overall maximum auditory startle response amplitude and average response amplitude in the females (PND60) and decreased absolute brain weights in the males **Other Studies**Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 44 of 52 **Subchronic, Chronic, and Other Toxicity Studies for Fenpropathrin Guideline No./ Study**  **Type MRID No. (year)/** 

**Classification /Doses Results**  870.7485 Metabolism and pharmacokinetics (Sprague
- Dawley rat) 43476801 (1994)

Acceptable/guideline 0, 2.5, 25 mg/kg/day radiolabeled S
- 3206 on either the alcohol or acid portion of the molecule by gavage. In experiment I, rats received 14 daily doses of 2.5 mg/kg followed on the 15 th day by radiolabeled S
3206. In experiments II and III, rats received a singl e dose of radiolabeled S
- 3206 at either 2.5 or 25 mg/kg. Greater than 99% of the administered dose was excreted within 168 hours with 28%
- 56% excreted in the urine and the remainder in the fec s, following both a single and 14 day repeated dose s. Major bi otransformations of the absorbed compound included the oxidation of the methyl group of the acid moiety, hydroxylation at the 4'
- position of the alcohol moiety, cleavage of the ester linkage, and conjugation with sulfuric acid or glucuronic acid.

870.7600 Dermal penetration 43433801 (1991)

Acceptable/guideline 0, 0.03, 1.5, 30 mg/rat (0, 0.0013, 0.0663, 1.26 mg/cm2

- radiolabeled) EC Formulation (31.9% a.i.) Exposure times of 1.5, 1.2, 4, 10, and 24 hours Dermal absorption increased with dose but not proportionally. The percentage of the dose absorbed decreased with the increasing administered dose. The total body burden could be expected to rapidly decrease due to excretion via urine and feces. Mean dermal absorption for the 10
- hour interval was 33 .3, 20.1, and 17.6% in the low , mid, and high dose groups, respectively. 870.7800 Immunotoxicity (Sprague
- Dawley rat) 48536804 (2011)

Acceptable/guideline 0, 150, 300, or 450 ppm (0, 14, 26, or 42 mg/kg/day) Humoral NOAEL = 42 mg/kg/day Humoral LOAEL = not determined Sy stemic NOAEL = 26 mg/kg/day Sy stemic LOAEL = 42 mg/kg/day based on decreased body weights, body weight gain and clinical signs including hyperactivity, hyper
- reactivity to touch, and twitching. Non
- Guideline Studies Wolansky et. al. (2006) 47885701 (Draft)

Acceptable
-Non
- Guideline Ac ute Oral Toxicity in Rats
- Motor Activity 0, 0.01, 0.1, 1.0, 4.0, 8.0, 12.0, 16.0, 24.0 mg/kg via gavage in corn oil (1 mL/kg) BMDL 1S D = 5.0 mg/kg BMD = 6.4 mg/kg based on decreased locomotor activityFenpropathrin Human Health Risk Assessment DP No. D368175

Page 45 of 52 **Subchronic, Chronic, and Other Toxicity Studies for Fenpropathrin Guideline No./ Study**  **Type MRID No. (year)/** 

**Classification /Doses Results**  WIL Study 47050504 (2006)

Acceptable
-Non
- Guideline Ac ute Oral Toxicity in Rats

– FOB 0, 15, 30 mg/kg via gavage in corn oil (5 mL/kg) BMDL 20 = 26.7 mg/kg BMD 20 = 28.9 mg/kg based on multiple FOB changesFenpropathrin Human Health Risk Assessment **A ppendix A**  **3 .**  **Hazard Identification Figure A3. Decision tree for evaluating potential toxicity studies for endpoint selection** 

**Acute Reference Dose (aRfD) and**  The information used in the POD determination for acute oral endpoints is listed here. A3 provides a visual picture of this evaluation. 1. The Wolansky

acute rat study

with a POD of 5.0 mg/kg is selected for this endpoint due to the overall robust nature of the study with 8 doses, producing an excellent dose response curve. The Wolansky study was considerably

conservative, gavage dosing using 1 ml/kg corn oil a vehicle and volume. 2. The WIL study a l so provided However, the WI L study

evalutated FOB parameters based on the common mode of action (i.e., interaction with voltage gated sodium channels resulting in neurotoxicity ). These FOB parameters provided a higher LOAEL than the Wolansky study and the was not used for endpoint selection. 3. The Agency

notes that the lowest NOAELs were observed in bolus including the subchronic and chronic dog studies developmental studies in the rat and rabb

Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 46 of 52 **Hazard Identification and Endpoint Selection**  **Figure A3. Decision tree for evaluating potential toxicity studies for endpoint selection**

**and Acute Population Adjusted Dose**  The information used in the POD determination for acute oral endpoints is listed here. provides a visual picture of this evaluation. The Wolansky

acute rat study

with a POD of 5.0 mg/kg is selected for this endpoint due nature of the study with 8 doses, producing an excellent dose response curve. The Wolansky study was considerably

conservative, gavage dosing using 1 ml/kg corn oil a vehicle and volume.

so provided a uniform study design with all py

rethro ids tested. WI L study

evalutated FOB parameters based on the common mode of action (i.e., interaction with voltage gated sodium channels resulting in neurotoxicity ). These FOB parameters provided a higher LOAEL than the Wolansky study and the was not used for endpoint selection. The Agency

notes that the lowest NOAELs were observed in bolus /gavage subchronic and chronic dog studies (dietary administration) developmental studies in the rat and rabb it (gavage dose)
. The dog studies are considered DP No. D368175 **and Endpoint Selection Figure A3. Decision tree for evaluating potential toxicity studies for endpoint selection** 

The information used in the POD determination for acute oral endpoints is listed here. Figure The Wolansky

acute rat study

with a POD of 5.0 mg/kg is selected for this endpoint due nature of the study with 8 doses, producing an excellent dose response curve. The Wolansky study was considerably

conservative, gavage dosing using

ids tested. WI L study

evalutated FOB parameters based on the common mode of action (i.e., interaction with voltage gated sodium channels resulting in neurotoxicity ). These FOB parameters provided a higher LOAEL than the Wolansky study and the refore /gavage studies, (dietary administration) and the prenatal The dog studies are consideredFenpropathrin Human Health Risk Assessment DP No. D368175

Page 47 of 52 to be a bolus dose because dogs will ty picall y consume their meals over a very short period, as opposed to rats which feed continuously over several hours. By consuming more fenpropathrin
- treated food over a shorter period of time, the dog is more likely to have greater maximal plasma concentrations immediately after feeding compared to the rat. As rats feed continuously , and fenpropathrin is metabolized and excreted from the sy stem relativel y quickl y, the overall s ys temic concentration in the rat remains low. The higher plasma concentration in the dog will likely result in a more conservative LOAEL. The overall result o f the dog’s feeding pattern is similar to gavage or capsule dosing as stated previously
. The LOAELs for these studies were all based, at least in part, on neurotoxicity
. a. Dog Studies: i. Subchronic dog

– The 90
- day dog study

L OAEL was the lowest dose tested , 6.2 mg/kg, and was based on effects on the gastrointestinal sy stem, tremors, and body weight changes. ii. Chro nic dog

– The LOAELfor the chro nic dog study was 6.25 mg/kg/day and was based on tremors and ataxia. The NOAEL was 2.5 mg/kg/day
. iii. The dog studies were conducted b y dietary administration
. Although there was toxicity

at doses slightly

greater than the proposed POD of 5.0 mg/kg, the human equivalent dose based on allometric scaling indicates that the NOAELs from the Wolansky rat study and the dog stu dies are equivalent. Human equivalent Doses of Fenpropathrin Rat (Wolansky) Human Equiv.

Dose * Dog Human Equiv. Dose* BMD BMDL 1SD BMD BMDL 1SD NOAEL LOAEL NOAEL LOAEL 6.4 5.0 1.87 **1.46** 2.5 6.2 **1.54** 3.81 *Human Equivalent based on allometric scaling: Scaling Factor 0.75; Default weights: rat = 0.5 kg, dog = 10 kg, Human = 70 kg ; NOAEL H =NOAEL D (BW D/BW H )^1
- 0.75; Sample and Arenal, Bull Environ Contam Toxicol (1999) 62:653
- 63 b. Developmental Studies i. Inthe rat developmental study , effects including deaths (7/30) and neurotoxicity

(ataxia, sensitivity

to external stimuli, spastic jumping, and tremors) were observed at 10 mg/kg/day in dams . However, at the study LOAEL of 6 mg/kg/day , maternal toxicity was limited to decreased food consumption and body

weight gains. The developmental L OAEL was 10 mg/kg/day

based on as ymmetrical ossification of sternebrae and incomplete ossification of the 5 th and 6 th vertebrae. The developmentalFenpropathrin Human Health Risk Assessment DP No. D368175

Page 48 of 52 NOAEL was 6 mg/kg/day and the maternal NOAELis 3 mg/kg/day . The POD is lower, and therefore protective, of these effects. The BMDL 1SD from the Wolansky study is more appropriate for risk assessment based on the following: 1. The BMDL 1SD is captured between the maternal N O AEL of 3 mg/kg/day and LOAEL of 6 mg/kg/day and is below the developmental NOAEL of 6 mg/kg/day 2. The BMD is a more accurate estimate of toxicity compared to the N OAEL/L OAEL approach 3. The observed effects at the maternal LOAEL are not quantitatively or qualitativel y more severe compared to the decrease in motor activity observed in the Wolansky study ii. In the rabbit developmental study , the maternal LOAEL was 12 mg/kg/day

based on flicking of the forepaws. The NOAEL was 4 mg/kg/day . No developmental effects were ob served. Although the NOAEL of 4 mg/kg/day

is slightly

lower than the proposed POD of 5.0 mg/kg; 1) the effects observed in the rabbit study are not qualitativel y more severe than the decreased motor activity observed in the Wolansky study ; and 2) the Wolansky is a more robust study containing more dose levels and is based on a BMD analy sis which is a more estimate of toxicity compared to NOAEL/LOAELlevels. 4. In the 3
- generation study, the maternal LOAEL is 10 mg/kg/day based on increased mortality and trem ors in females. The NOAEL is 3 mg/kg/day . Maternal effects at the high dose of 32 mg/kg/day included increased deaths and clinical signs of toxicity
. Eighteen of the 24 high
- dose dams died, 10 of which occurred during lactation of the F1 B dams (i.e., 2 n d litter of 2 nd generation). Clinical signs including tremors, muscle twitches, and increased sensitivity

were observed in all high
- dose females in all generations and were most intense during the 2 nd or 3 rd week of lactation. At the maternal LOAEL of 10 mg/kg/day , clinical signs of toxicity were observed in a **single** dam. No treatment
- related effects in the males at any dose, however, it is not clear from the study if males were observed. There was mortality in pups at the high dose (32 mg/kg/day) in th e F2 A and F2 B litters (3 rd generation, 1 st and 2 nd litters) although it appears there was an effect on litter size by

lactation day

21 in the F2 B litters. At the mid
- dose (10 mg/kg/day) , tremors were observed in 3 pups from the F2 B litter, 2 of which died. There were no reports of clinical signs of toxicity

(i.e., tremors) in any other pups. Therefore, minimal signs of treatment - related were observed at the mid
- dose for both adults and pups, reducing any concern for quantitative o r qualitative sensitivity for this study
. Although this study

resulted in a lower NOAEL (3 mg/kg/day) compared to the proposed POD, the most severe maternal and offspring effects were limited to the high dose group (32 mg/kg/day). At the LOAEL (10 mg/k g/day), effects were limited to tremors in a single dam (in the 2 nd generation) and 3 offspring from the 3 rd generation (2 of which subsequently

died). Because these effects occurred in subsequent generations, were onl yFenpropathrin Human Health Risk Assessment DP No. D368175

Page 49 of 52 observed in relatively

few animals, were less severe compared to the high dose, and the BMD estimate is a more accurate estimate of toxicity compared to NOAELs and LOAELs (which are limited by dose
- spacing, the proposed POD of 5.0 mg/kg is protective of the effects observed in this study
. 5. The FQPA Factor for children <6 ye ars of age is 3X based on evidence of juvenile sensitivity

in the literature. This information described above is summarized in Re
Evaluation of the FQPA Safety Factor for pyrethroid pesticides ( D381210, E. Scollon, 6/27/2011 )
. Based on an evaluation of over 70 guideline toxicity studies submitted to the Agency, including prenatal developmental toxicity studies in rats and rabbi ts, and multi
- generation reproduction toxicity studies and DNTs in rats in support of pyrethroid registrations, there is no evidence that pyrethroids directly impact developing fetuses ( USEPA 2010; Table 1 ) ). None of the studies show any indications of fetal/offspring toxicity at doses that do not cause maternal toxicity. Therefore the Agency is reducing the FQPA safety factor to 1X for women of child
-bearing age.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 50 of 52 **Appendix A4 .**  **Human Equivalent A**  **nalysis (Dog study vs**  **. acute rat motor activity)**  **RAT Study (Wolansky) DOG Study (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**  **LOAEL NOAEL**  **beta**   ** cyfluthrin** 1.42 1.17 0.41 0.34 2.4 13.9 8.54 1.48 **bifenthrin** 4.1 3.1 1.19 0.90 2.2 4.2 2.58 1.35 **bioallethrin** 65.6 42.2 19.07 12.27 20 63 38.73 12.30 **cyhalothrin** 0.92 0.64 0.27 0.19 1 2.5 1.54 0.61 **cyphenothrin**
- - - - 12.5 37.5 23.05 7.68 **cypermethrin** 11.19 7.16 3.25 2.08 12.5 37.5 23.05 7.68 **deltamethrin** 2.48 1.49 0.72 0.43 1 2.5 1.54 0.61 **esfenvalerate** 1.19 0.65 0.34 0.19 5 7.5 4.61 3.07 **fenpropathrin** 6.44 5.01 1.87 1.4 6 2.5 6.2 3.81 1.54 **permethrin** 63.1 44.4 18.34 12.91 50 500 307.39 30.74 **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 0.92 0.31

**Appendix A5. Pyrethroid Cumulative Screen**  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 share a common mechanism group (http://www.regulations.gov ; EPA
- HQ
- OPP
- 2008
- 0489
- 0006). The members of this group share the ability to interact with voltage
- gated sodium channels ultimately leading to neurotoxicity
. The cumulative risk assessment (CRA) for the p yr ethroids/py rethrins was published on Nov. 9, 2011 (USEPA, 2011a) and is available at http://www.regulations.gov ; EPA
- HQ
- OPP
- 2011
- 0746. Fenpropathrin was included in this cumulative risk assessment. No cumulative risk estimates of concern were identified , allowing the Agency to consider new uses for p yrethroid actives. 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
.Fenpropathrin Human Health Risk Assessment DP No. D368175

Page 51 of 52 **Appendix B**  **. Physical/Chemical Properties**  **Physicochemical Properties of Fenpropathrin**

Parameter Value Reference Melting point/range 45
- 50oC (113
- 122oF) DP# 315918, 9/20/05, W. Cutchin pH 4
- 5 (1% emulsion) Density g/cm 3 1.103 Water solubility (25oC) 0.33 ppm Solvent solubility (mg/L at 25oC) Xylene, cyclohexanone: 1 , 000 Methanol: 337 Vapor pressure at 25oC 5.5 x 10 - 6 ( 0.730 mPa) Dissociation constant, pKa NA Octanol/water partition coefficient, Log(KOW) 5.1 UV/visible absorption spectrum Not availableFenpropathrin Human Health Risk Assessment DP No. D368175

Page 52 of 52 **Appendix C**  **. 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 data are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain studies that review may have included review b y the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler
- exposure - data.html and http://www.epa.gov/pesticides/science/post
- app - exposure - data.html
.