Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **1** of **60** UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA**  **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM Date**  **: August 6**  **, 2013 SUBJECT:**  **Methoxyfenozide .**  Human Health Risk Assessment to Support Proposed New

Use s on Herbs, Caneberries, Dates and Sorghum; to Establish Rotational Crop Tolerances in the Rapeseed and Sunflower Oilseed Subgroups; as well as to extend and update Crop Group Tolerances on Multiple Commodities. **PC Code:** 1 21027 **DP Barcode:** D 407285 **Decision No.:** 4 72142 **Registration No. :**  6 2719 - 442 ; 13 - CA - 09 **Petition No .:**  2E8118 **Regulatory Action:** Section 3 Registration ; Section 18 Registration (Date s only) **Risk A**  **ss essment Typ**  **e :**  Single Chemical Aggregate **Case No.:** 7431 **T XR No.:**  NA **CAS No.:** 161050 - 58 - 4 **MRID No.:** NA **40 CFR:** 180. 5 44 **FROM:** Elizabeth Holman, Physical Scientist/Risk Assessor

Margarita Collantes, Biologist William Drew, Chemist Linnea J. Hansen, Ph.D., Biologist Risk Assessment Branch II (RABII) Health Effects Division (7509P) **THROUGH:** Christina Swartz, Branch Chief

Risk Assessment Branch II (RABII) Health Effects Division (7509P) **TO:** Laura Nollen/Barbara Madden , RM Team 05

Risk Integration Minor Use, and Emergency Response Branch (RIMUERB) R egistration Division (7505P) The Registration Division (RD) requested that the Health Effects Divis i on (HED) conduct a risk assessment for the active ingredient methoxyfenozide to estimate the risk to human health that will result from proposed new uses on herbs (subgroup 19A ) except chives , caneberry (subgroup 13 - 07A) , date, and sorghum . Inaddition, this assessment also updates existing tolerances for multiple commodities; specificall y, t olerances in the updated crop groups 8 - 10 and 11 - 10, and in the updated subgroups 13 - 07F and 13 - 07G we re request ed. Tolerances in sugar apple s , cherimo ya s , atemoya s , custard apple s , ilama s , soursop s , and biriba s we re also requested , basedMethoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **2** of **60** on translation of avocado residues. Additionally , indi rect or inadvertent tolerances in the rapeseed subgroup ( 20A ) and the s unflower subgroup ( 20B ) were requested . While the proposed Section 3 use on dates was undergoi ng review in the Agency , the state of California submitted a Section 18 Specific Emergency Exemption request for use of methox yf enozide on dates to control carob moth. The proposed use pattern in CA is the same as the use pattern proposed for Section 3 re gistration, and therefore this risk assessment addressed the proposed S18 use. The attached human health risk assessment addresses exposure and risk associated with the proposed uses , revisions to existing tolerances, as well as the existing use on ornamentals . The exposures assessed include dietary (food and water), inhalation for occupational workers and residential handlers, and aggregate exposure and risk for residential handlers resulting from use on ornamentals . There were no risks of concern identified for any route or duration of exposure.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **3** of **60** 

### Table of **Contents 1.0**  **Executive Summary** ................................ ................................ ................................ ........... 5 **2.0 HED Recommendations**  ................................ ................................ ................................ .... 7 **2.1 Data Deficiencies/Conditions of Registration**  ................................ .............................. 7 **2.2 Tolerance Considerations**  ................................ ................................ .............................. 7 2.2.1 Enforcement Anal yt ical Method ................................ ................................ ............... 7 2.2.2 International Harmonization ................................ ................................ ..................... 8 2.2.3 Recommended Tolerances ................................ ................................ ........................ 8 2.2.4 Revisions to Petitioned - For Tolerances ................................ ................................ .. 10 **2.3 Label Recommendations From Residue Review**  ................................ ....................... 10 **3.0 Introduction**  ................................ ................................ ................................ ...................... 11 **3.1 Chemical Identity**  ................................ ................................ ................................ ......... 12 **3.2 Ph**  **ysical/Chemical Characteristics** ................................ ................................ ............. 12 **3.3 Pesticide Use Pattern**  ................................ ................................ ................................ .... 12 **3.4 Anticipated Exposure Pathways**  ................................ ................................ ................. 14 **3.5 Consideration of Environmental Justice**  ................................ ................................ .... 14 **4.0 Hazard Characterization and Dose**  **- Response Assessment**  ................................ .......... 15 **4.1 Toxicology Studies Available for Analysis**  ................................ ................................ . 15 **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  ............................. 15 4.2.1 Dermal Absorption ................................ ................................ ................................ .. 16 **4.3 Toxicological Effects**  ................................ ................................ ................................ .... 16 **4.4 Safety Factor for Infants and Children (FQPA Safety Factor)**  ............................... 18 4.4.2 Evidence of Neurotoxicity ................................ ................................ ...................... 18 4.4.3 Evidence of Sensitivity /Susceptibility

in the Develo ping or Young Animal ......... 18 **4.5 Toxicity Endpoint and Point of Departure Selections**  ................................ .............. 19 4.5.1 Dose - Response Assessment ................................ ................................ .................... 19 4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment ........ 20 4.5.3 Cancer Classification and Risk Assessment Recommendation .............................. 21 **5.0 Dietary Exposure and Risk Assessment**  ................................ ................................ ......... 23 **5.1 Metabolite/Degradate Residue Profile**  ................................ ................................ ....... 23 5.1.1 Summary

of Plant and Animal Metabolism Studies ................................ ............... 23 5.1.2 Summary

of Environmental Degradation ................................ ............................... 24 5.1.3 Comparison of Metabolic Pathway s ................................ ................................ ....... 24 5.1.4 Residues of Concern Summary and Rationale ................................ ........................ 24 **5.2 Food Residue Profile**  ................................ ................................ ................................ .... 26 **5.3 Water Residue Profile**  ................................ ................................ ................................ .. 27 **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 ................................ ................................ .............. 29Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **4** of **60** 5.4.4 Chronic Dietary

Risk Assessment ................................ ................................ .......... 29 5.4.5 Cancer Dietary

Risk Assessment ................................ ................................ ............ 30 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  ............................. 30 **6.1 Residential Handler Exposure**  ................................ ................................ .................... 30 **6.2 Dermal Post**  **- application Exposure**  ................................ ................................ ............. 31 **6.5 Spray Drift**  ................................ ................................ ................................ .................... 32 **7.0 Aggregate Exposure/Risk Characterization**  ................................ ................................ .. 32 **7.1 Acute Aggregate Risk**  ................................ ................................ ................................ ... 32 **7.2 Short**  **- Term Aggregate Risk**  ................................ ................................ ........................ 32 **7.3 Chronic Aggregate Risk**  ................................ ................................ .............................. 33 **8.0 Cumulative Exposure/Risk Characterization**  ................................ ............................... 33 **9.0 Occupational Exposure/Risk Characterization**  ................................ ............................ 33 **9.1 Occupational Handlers**  ................................ ................................ ................................ 34 **9. 2**  **Post -**  **application Risk** ................................ ................................ ................................ ... 36 9.2.1 Post - application Dermal Exposure ................................ ................................ ......... 36 9.2.2. Post - application Inhalation Exposure ................................ ................................ ..... 36 **10.0 References**  ................................ ................................ ................................ ......................... 37 **Appendix A. Toxicology Profile and Executive Summaries** ................................ .................. 38 **Appendix B. Physical/Chemical Properties.**  ................................ ................................ .......... 60 **Appendix C. Review of Human Research** ................................ ................................ ................ 60Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **5** of **60 1.0**  **Executive Summary**  The Interregional Research Project Number 4 (IR - 4) has submitted a petition requesting the establishment of permanent tolerances for residues of methoxyfenozide in or on dates; caneberries (subgroup 13 - 07A); grain sorghum forage; grain sorghum sto ver; grain sorghum grain; sweet sorghum forage; sweet sorghum stover; sweet sorghum grain; sweet sorghum stalk; aspirated grain fractions (AGF), based on sorghum data; dried shelled peas and beans, except soy bean (subgroup 6C), except blackeyed pea and southern pea; fresh herbs (subgroup 19A), except chives; and dried herbs (subgroup 19A), except chives. Tolerances in the updated crop groups 8 - 10 and 11 - 10, and in the updated subgroups 13 - 07F and 13 - 07G were requested. Tolerances in sugar apples, cherimo yas, atemoyas, custard apples, ilamas, soursops, and biribas were also requested, based on translation of avocado residues. Additionally , indirect or inadvertent tolerances in the rapeseed subgroup (20A) and the sunflower subgroup (20B) were requested. The proposed new uses in dates, caneberries, sorghum and herbs are supported b y magnitude of residue data generated b y IR - 4. Other changes are supported b y data previousl y reviewed by the Agency in 2009. The requested changes for rapeseed and sunflower group are based on 2012 recommendations by EPA. The petition proposes the deletion of the (expired) temporary tolerances in sorghum commodities, and their replacement with permanent tolerances in those commodities. The tolerance in AGF would be increased from 2.0 to 120 ppm. The tolerance of 0.5 ppm in dried shelled peas and beans, except so ybean (subgroup 6C) was proposed at the Agency's request to better harmonize with existing Codex MRLs , with no changes in the existing use pattern for these commoditie s . The existing tolerances in dried beans and dried peas would be deleted concurrentl y with the establishment of tolerances in subgroup 6C. The tolerance in coriander leaves would be deleted concurrently

with the establishment of the tolerance in sub grou p 19A. Finally , California is requesting a Section 18 for use of Intrepid 2F on dates/palm only . The proposed use pattern for this Section 18 use is identical to that for the Section 3 IR - 4 petition, with the same submitted residue data being used in sup port of both petitions. In developing this human health risk assessment, HED has examined the available hazard and exposure information regarding methox yfenozide as it re l ates to its registered and requested uses. The existing use on ornamentals was previously reassessed in accordance with current policies, based on the potential for residential handlers to use products in and around home gardens. The toxicology

database is considered complete for the purpose of characterizing the hazard associated w ith methoxyfenozide and for conducting a human health risk assessment. The main target organs in the rat and dog were the liver, thy roid and red blood cells (RBC s ). The most consistent findings across species and studies were decreased red blood cell p arameters and increased liver, th yro id, adrenal and spleen weights. Many of the available short - term or subchronic toxicity

studies showed little or no toxicity . Increases in thy roid and adrenal weights were observed in the rat chronic oral study . Th yr o id weights were also increased in the dog following chronic exposure, but no accompanyi ng histopathology was observed. Toxicological testing indicates that methox yfenoz ide is not neurotoxi c or immunotoxi c; it has been categorized as “not likely” to be carcinogenic to humans. There is no evidence ofMethoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **6** of **60** qualitative or quantitative susceptibility of the developing fetus or offspring, based on the developmental and reproductive toxicity study results. Therefore, b ased on the completeness of the database , the l ack of susceptibility , the lack of neurotoxicity and the conservative nature of the exposure assessment, HED has reduced the 10X Food Quality Protection Act ( FQPA ) Safety Factor to 1X. Based on the submitted toxicology data and the current and proposed us e patterns, HED selected endpoints for chronic dietary risk assessment, as well as for inhalation risk assessment for residential and occupational handlers. Acute dietary risk was not evaluated because there were no toxic effects associated with a single dose, and therefore an appropriate endpoint was not identified. There was no toxicity observed in the dermal toxicity study , and no concern for potential developmental effects ; therefore , a dermal endpoint was not selected, and no dermal exposure and risk assessments were conducted (i.e., there is no hazard via the dermal route) . F urth e rmore , HED did not select an endpoint for incidental oral risk assessment, since the potential for post - applicati o n oral exposure to children resulting from the existing us e of methoxyfenozide on ornamentals is extremely low . Inhalation risks were assessed using the endpoint and dose from an oral study , with the assumption that inhalation toxicity would be equivalent to oral toxicity for the purpose of route - to - route extrapolation. The endpoint selected for chronic dietary

risk assessment was based on liver and thy roid effects observed in the chronic/ carcinogenicity s tudy in the rat; the blood effects seen in the dog study were considered co - critical. For inhalation risk assessment, the endpoint selected was based on blood effects seen in a range - finding study i n the dog. HED used modeling to assess chronic dietary exposure to methoxyfenozide. In combination with an extensive database of food consumption patterns fo r the U.S. population and population subgroups, th is modeling used conservative upper - bound assumptions regarding residues of methoxyfenozide and its breakdown products in food and drinking water . Specificall y, the dietary assessment included tolerance - le vel residues from the existing and proposed use s , the assumption of 100% crop treated (CT) for all crops, and drinking water residues derived from modeling the maximum application rate in vulnerable areas . The highest potential drinking water exposure is from ground water sources. The chronic dietary exposure and risk estimates are below HED’s level of concern (LOC) of 100% of the chronic population adjusted dose (cPAD) for the general U . S . populati on and all population subgroups, including those of infants and children. The highest exposed population subgroup was children 1 - 2 years old, with a dietary risk estimate of 84 % c PAD; all other population subgroups had lower risk estimates, including the general U . S . population at 31 % c PAD. Residential exposures are those that may occur as a result of activities in and around the home, schools and recreational areas. Prior to 2012, a residential exposure assessment was not performed in conjunction with registration of the use of methoxyfenoz ide on ornamentals. Since then an inhalation endpoint was selected and the OPP HED Residential SOPs were finalized and approved for risk assessment purposes. Therefore, in the most recent 2012 new use risk assessment, HED assessed potential inhalation exposure for residential handlers treating ornamentals in and around home gardens (D388978, M. Collantes et al, 05/23/2012) . The resulting risk estimates are margins of exposure ( MOEs ) ranging from 76,000 to more than 3 million, which are not of concern.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **7** of **60** In accordance with the FQPA, i n evaluating human health risks from exposure to pesticides, HED aggregate s exposure from various routes, i.e., residential exposure is added to dietary exposure from food and drinking water . The residential handler exposure resulting from applying methoxyfenozide to ornamentals using a backpack sprayer was combined with the chronic dietary

exposure from the most highl y exposed adult population subgroup ( general US adult population) to determine aggregate exposure and risk. Th e calculated exposure resulted in an aggregate MOE of 530 ; this risk estimate is not of concern, since it is significantly higher than the L OC of 100. An occupational exposure assessment was also performed for handler and post - application activities , based on standard assumptions with respect to body weight and area treated , in accordance with HED’s standard procedures. There were no chemical specific data available to assess handlers’ inhalation exposure, so HED relied on surrogate data generated b y various task forces. The resulting inhalation risk estimates were MOEs ranging from 2 0 ,000 to more than 3 million and were not of concern. A quantitative post - application e xposure assessment was not completed due to the lack of dermal toxicity , and because the handlers’ MOEs are expected to be protective of post - application exposure via the inhalation route. Th e risk assess ment is based, in part, on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These studies are compliant with applicable ethic al requirements (refer to Appendix C ) . **2.0 HED**  **Recommendations** HED recommends in favor of the proposed registration of the new uses of methoxyfenozide on dates , sorghum, caneberries (subgroup 13 - 07A), and herbs (subgroup 19A ) except chives, as well a s updates to multiple existing tolerances supported by the existing database (with no changes in the use pattern), and establishment of the associated permanent tolerances as summarized in **Table 2.2.3** . **2.1 Data Deficiencies/Conditions of Registration**  None **2.2 Tolerance Considerations**  **2.2.1 Enforcement An**  **alytical Method** The FDA multiresidue methods are not suitable for anal ys is of methoxyfenozide or its regulated metabolites. However , a dequate single methods are available for enforcing the current tolerances for methox yf

enozide in primary

crops and animal commodities. Depending on the plant commodity , the limits of quantitation (L OQs) for methox yf enozide in primary

crop commodities are 0.010 - 0.050 ppm. T he tolerance enforc ement methods include u se of high performance liquid chromatography (HP LC) , with e ither tandem mass spectrometric detection (L C/MS/MS), or ultraviolet detection (HPL C /UV) .Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **8** of **60 2.2.2**  **International Harmonization** Codex has not established MRL s in any of the proposed new uses. As such, there are no harmonization issues associated with Codex for the proposed new uses in the current action. Canada’s PMRA has established MRL s in fresh Chinese chive leaves and fresh chive leaves at 5 mg/kg. There are no Canadian MRL s in dates, caneberries or sorghum commodities. However, for basil and caneberries, this action is being performed as a joint review with Canada’s PMRA , and the recommended tolerances have been harmonized with the recommended PMRA tolerances as appropriate. HED’s recommended tolerances for the new uses were determined using the Organization for Economic Cooperation and Development ( OECD) tolerance calculation procedures. Codex has established MRL s in grapes at 1 mg/kg, in strawberries and pome fruits at 2 mg/kg, in avocadoes at 0.7 mg/kg, and in papayas at 1 mg/kg. The recommended tolerance of 2.0 ppm in the updated pome fruits group (11 - 10), increased from the current tolerance of 1.5 ppm in group 11, would be harmonized with the Codex MRL . It is noted that this recommended revise d tolerance in pome fruit will not be harmonized with the existing PMRA tolerance of 1.5 ppm. HED has made PMRA aware of this issue, but has determined that Codex harmonization is beneficial at this time. The recommended tolerance of 1.0 ppm in small vine - climbing fruit, except fuzzy kiwifruit (subgroup 13 - 07F), translated from grape data, would be harmonized with the Codex MRLin grapes. The recommended tolerance of 2.0 ppm in low - growing berries (subgrou p 13 - 07G), translated from strawberry data, and increased from the current tolerance of 1.5 ppm in strawberries, would be harmonized with the Codex MRLin strawberries. The recommended tolerance of 0.50 ppm in dried shelled peas and beans, except soy beans (subgroup 6C) was proposed at the Agency's request to better harmonize with the existing Codex MRLof 0.5 mg/kg in dried beans. This tolerance would replace the current tolerances of 0.24 ppm in dried beans, and 2.5 ppm in dried peas, which would both be removed. The recommended tolerance of 0.60 ppm i n various tropical tree fruits is translated from avocado data , where there is an existing USEPA tolerance of 0.6 ppm. There is also an existing USEPA tolerance of 0.6 ppm on papaya. With the existing avocado and papaya tolerances not being harmonized, these new tropical tree fruit tolerances would also not be harmonized with the Cod ex MRL s as well . During registration review, to the extent possible USEPA will consider opportunities for harmonizing tropical tree fruit tolerances with Codex. **2.2.3 Recommended Tolerances** Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **9** of **60 TABLE**  **2.2.3. Tolerance Summary for**  **Methoxyfenozide .** 

**Comm odity**  **Tolerance (ppm) Correct Commodity**  **Definition .**  **Rationale Existing**  **Proposed Recommended**  **180.544[a][1]** Herb subgroup 19A, fresh, except chives None 70 400 Herb subgroup 19A, except chive . Based on submitted dried basil field trial data. Herb subgroup 19A, dried, except chives None 400 Date None 7.0 8 .0 Based on submitted crop field trial data. Caneberry subgroup 13 - 07A None 6.0 6.0 Sorghum, grain, forage None 9.0 15 Sorghum, grain, stover None 15 20 Sorghum, grain, grain None 4.0 6.0 Sorghum, sweet, forage None 9.0 15 Sorghum, sweet, stover None 15 20 Sorghum, sweet, grain None 4.0 6.0 Sorghum, sweet, stalk None 9.0 15 Grain, aspirated grain fractions 2.0 80 120 Based on sorghum field trial and processing study data. Pea and bean, dried shelled, except soybean, subgroup 6C, except pea, blackeyed, seed and pea, southern, seed None 0.5 0.5 0 To harmonize with Codex MRLs. Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13 - 07F None 1.0 1.0 Translated from grape data. Berry, low

growing, subgroup 13 - 07G, except cranberry None 1.5 2.0 Translated from straw berry data , and raised to harmonize with Codex MRL in straw berries . Fruit, pome, group 11 - 10 None 1.5 2.0 Update of group 11 , and raised to harmonize with Codex MRL in appl es . Vegetable, fruiting, group 8 - 10 None 2.0 2.0 Update of group 8 . Sugar apple None 0.6 0.6 0 Translated from avocado data. Cherimoya None 0.6 0.6 0 Atemoya None 0.6 0.6 0 Custard apple None 0.6 0.6 0 llama None 0.6 0.6 0 Soursop None 0.6 0.6 0 Biriba None 0.6 0.6 0 Pea, blackeyed, seed 4.0 4.0 4.0 Keep as exception s to subgroup 6C . Pea, southern, seed 4.0 4.0 4.0 Coriander, leaves 30 Remove Remove Covered under subgroup 19A tolerance. Grape 1.0 Remove Remove Covered under subgroup 1 3 - 07F tolerance.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **10** of **60 TABLE**  **2.2.3. Tolerance Summary for**  **Methoxyfenozide .** 

**Comm odity**  **Tolerance (ppm) Correct Commodity**  **Definition .**  **Rationale Existing**  **Proposed Recommended**  Straw berry 1.5 Remove Remove Covered under subgroup 13 - 07 G tolerance. Okra 2.0 None Remove Covered under group 8 - 10 tolerance. Pea, dry seed 2.5 Remove Remove C overed under subgroup 6C tolerance . Bean, dry, seed 0.24 Remove Remove **180.544[ b**  **]** Sorghum, grain, forage 30 None Remove Expired time - limited tolerances. Sorghum, grain, stover 60 None Remove Sorghum, grain, grain 0.05 None Remove **180.544[ d**  **][ 2**  **]** Herb and spice, group 19, except coriander, leaves 4.5 None Remove Replaced by primary tolerance in subgroup 19A, except chive , and rotational tolerances in chive and subgroup 19B . Spice subgroup 19B None None 4.5 These replace the rotational crop tolerance in group 19, except coriander leaves . Chive None None 4.5 Rapeseed subgroup 20A None 1.0 1.0 Based on existing rotational crop data , and HED’s previous recommendation . Sunflower subgroup 20B None 1.0 1.0

**2.2.4 Revisions to Petitioned**  **- For Tolerances**  In fresh herbs, subgroup 19A ( except chives ), the petitioner proposed a tolerance of 70 ppm, based on the Organization of Economic Development and Cooperation’s (OECD’s) tolerance calculation procedure. However, the petitioner entered all 10 sample residues into the MRL calculator. When the avera ge residues from each of the 5 basil field trials were entered, as the OECD guidance stipulates, the resulting recommended tolerance would be 80 ppm. However, USEPA has determined that setting separate subgroup 19A tolerances for fresh and dried commoditi es is not feasible from a regulatory perspective. Therefore, HED recommends setting the entire subgroup 19A tolerance, except chives, for both fresh and dried commodities at the higher 400 ppm level. This 400 ppm level is derived using the submitted drie d basil field trial data in the OECD calculation procedure. The primary

crop tolerance in coriander leaves , along with the rotational crop tolerance in h erb s and spices ( group 19 ), except coriander leaves , would be remove d concurrently with the establis hment of the primary crop tolerance in subgroup 19A , except chives . Although not proposed in the petition, rotational crop tolerances would necessarily be established in chives andMethoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **11** of **60** in spices (subgroup 19B) upon establishment of the primary crop tolerance in subgroup 19A, except chives. In dates , the petitioner proposed a tolerance of 7 . 0 ppm, based on 4 date field trials and OECD’ s tolerance calculation procedure. However, HED determined that onl y 3 of the trials were truly independent. The 4 sample residues from the 2 trials deemed to be non - independent were averaged together as one input into the MRLcalculator. In addition , the total application rate at one of the other trials was only half the proposed maximum seasonal use rate, a difference of >25%. Therefore, the residue values from this trial were doubled, per OECD’s preliminary guidance on proportionality of sample residues to application rate [EPA Chemistry Science Advisory Council ( ChemSAC ), minutes , 3/28/2012 ] . When the average of these residues , along with the average residues from each of the other 2 field trials were entered into the MRL calculator , the resulting recommended tolerance wa s 8 . 0 ppm. In sorghum commodities , the petitioner proposed t olerance s of 9.0, 15 and 4.0 ppm in the forage, stover and grain, respectively , of both grain and sweet sorghum, and 9.0 ppm in sweet sorghum stalks, based on OECD’s tolerance calculation procedure . A tolerance of 80 ppm in sorghum AGF was proposed , based on the sorghum processi ng study. However, with the use of the correction for proportionality , the resulting recommended tolerance s were 15, 20 and 6.0 ppm in the forage, stover and grain, respectivel y, of both grain and sweet sorghum , and 15 ppm in sweet sorghum stalks. The in crease in the proposed tolerance of 80 to 120 ppm for residues in AGF was also based on the adjustment for proportionality . Although not proposed by the registrant, HED recommends that existing time - limited sorghum tolerances (established under 180.544[b] ), be removed for forage, stover, and grain, as these tolerances have now expired. Instead of the proposed tolerance s in the various tropical tree fruits (0. 6 ppm), HED recommends establishing the tolerance s at 0. 6 0 ppm, in order to avoid the situation where a field sample containing residues significantly above the tolerance (0. 6 4 ppm, for example) would be considered non - violative. For the same reason, HED recommends that the proposed tolerance of 0. 5 ppm in subgroup 6C (except blackeyed and southern peas ) be revised to 0. 5 0 ppm. A s previously

discussed, HED recommends the tolerance of 2 .0 ppm in the updated pome fruits group ( 1 1 - 1 0), increas ed from the proposed tolerance of 1.5 ppm, in order to be harmonized with the Codex MRL . The recommend ed tol erance of 2.0 ppm in low - growing b erries ( subgroup 13 - 07G), translated from strawberry data , was increased from the proposed tolerance of 1.5 ppm , in order to be harmonized with the Codex MRLin strawberries. **2.3 Label Recommendations**  **From Residue Review**  Methox yf enozide is a candidate for a 4 - hour restricted entry interval ( REI ) which appears on the proposed supplemental and master lab els . However, the Registration Division should confirm that methoxyfenozide is a reduced risk chemical and that the correc t REI is on the final registered label. **3.0 In**  **troduction**Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **12** of **60 3.1**  **Chemical Identity TABLE**  **3. 1**  **Me thoxyfenozide Nom**  **enclature.** Chemical structure

Common name Methoxyfenozide Com pany experimental name RH - 2485 Molecular formula C 22 H 28N 2 O 3 Molecular we ight 368.47 IUPAC name N - tert- butyl - N ′ - (3 - methoxy - o - toluoyl) - 3,5 - xylohydrazide CAS name 3 - methoxy - 2 - methylbenzoic acid 2 - (3,5 - dimethylbenzoyl) - 2 - (1,1 - dimethylethyl)hydrazide CAS registry number 161050 - 58 - 4 End - use product (EP) 2 lb ai/gal F (Intrepid 2F, EPA Registration #62719 - 442) **3.2 Physical/Chemical Characteristics**  The information regarding p hy sical chemical characteristics of methoxyfenozide do es not indicate that there are any special concerns in terms of bioaccumulation, exposure or other risk assessment considerations . A table of ph ys ical and chemical properties for methoxyfenozide is included in Appendix B . Methox yfenozide has a low dermal absorption factor. Dermal absorption is the process b y which chemicals are transported from the outer surface of the skin into both the inner layers of the skin and into the body . The dermal absorption factor is a numerical estimate of the percentage of the topical external dose that traverses the skin layers to the sy stemic circulation (e.g. the perc entage of the topical external dose that is bioavailable). An in vivo dermal absorption study on an 80% wettable powder (WP) formulation of methoxyfenozide was conducted in the rat. Cumulative absorption of approximately 2% of the applied dermal dose was observed after a 10 or 24 hour dermal exposure duration . Consistent with the low level of absorption, a 28 - day dermal study

in the rat showed no toxicity up to the limit dose (1000 mg/kg/day). Furthermore, methoxyfenozide has a large octanol - water parti tion coefficient (Kow) of 10 3.72 which further supports that methoxyfenozide is not easily absorbed by

the skin and thus would result in lower dermal exposure. Although m ethox yfenozide is very persistent (t 1/2 = 1 to 3 years in soil and water), it is not significantl y volatile, and has a vapor pressure of 1.0 x 10 - 7 mm Hg at 25  ̊ C. Therefore, significant inhalation exposure to methoxyfenozide is not expected . **3.3 Pesticide Use Pattern**  C H 3 O N H N O C H 3

C H 3 C H 3 C H 3

O C H 3 C H 3Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **13** of **60** Methox yf enozide is currently

registered for use on ornamentals and a wide variety of agricultural crops . Dow AgroSciences LLC is requesting new proposed uses of the insecticide methoxyfenozide be added to the Intrepid 2F (Reg. No. 62719 - 442) label. The proposed Section 3 registration includes use on herbs (subgroup 19A) except chives, dates, sorghum and caneberries (subgroup 13 - 07A). In addition, California is requesting a Section 18 for use of Intrepid 2F on dates/palm only . Intrepid 2F is formulated as a flowable concentrate containing 22.6% active ingredient (ai) or 2 lb ai per gallon. Intrepid 2F may be applied by

air, groundboom, airblast and hand held equipment. The master label specifies that the product is not to be applied by chemigation un less specified in crop - specific directions on the label or supplemental labeling. Therefore, since the supplemental labels did not specify use of chemigation for the proposed crops, it was not assessed as a potential method of application. The Personal P rotective Equipment (PPE ) statement on the propo sed label requires applicators and other handlers to wear long - sleeved shirt and long pants, socks, shoes, and chemical - resistant gloves. **Table 3 .3**  provides a summary of the proposed uses **. TABLE**  **3.3 Summary of Directions for Use of Methoxyfenozide.**  **Application Type; Equipment**  **Use Rate** 

**(lb ai/A) Max. Uses** 

**Per Season Max. Seasonal** 

**Use Rate (lb ai/A)**  **1 PHI**  **1**

**(Days) Use Directions,**  **Application Timing,**

**and Limitations Herbs (Subgroup 19A), Except Chives**  Foliar; Ground and Aerial 0.12 NS **2** 1.0 1 Minimum RTI **3** of 10 days. Ground application: Apply in a minimum of 10 GPA**4** to young crop or small plants. Apply in a minimum of 20 GPA to densely foliated or difficult - to - cover crops to ensure thorough coverage. Aerial application: Apply in a minimum of 10 GPA. **Dates** Ground (Airblast) 0.31 NS 1.0 7 Begin applications before eggs hatch. Minimum RTI of 10 days. Alternate or intersperse with other insecticides. Apply in a minimum of 100 GPA. **Sorghum** Foliar; Ground and Aerial 0.16 NS 0.75 3, 21 **5** Apply at first sign of egg hatch or when infestations reach threshold levels . Ground application: Apply in a minimum of 15 GPA. Aerial application: Apply in a minimum of 10 GPA.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **14** of **60 TABLE**  **3.3 Summary of Directions for Use of Methoxyfenozide.**  **Application Type; Equipment**  **Use Rate** 

**(lb ai/A) Max. Uses** 

**Per Season Max. Seasonal** 

**Use Rate (lb ai/A)**  **1 PHI**  **1**

**(Days) Use Directions,**  **Application Timing,**

**and Limitations Caneberries**  **(Subgroup 13 -**  **07A)** Foliar; Ground and Aerial 0.25 3 0.75 3 Apply at initiation of egg - laying. Make second application at 100% petal fall. A third application may be required under high pest pressure. Minimum RTI of 7 days. Ground application: Apply in a minimum of 30 GPA. Aerial: Apply in a minimum of 10 GPA. 1. PHI = Pre - Harvest Interval. 2. NS = Not Specified. 3. RTI = Re - T reatment I nterval . 4. GPA = G allons Per A cre . 5. Minimum PHI of 3 days for forage and sweet sorghum stalks, and 21 days for grain and stover . **3.4 Anticipated Exposure Pathways**  As a result of the registered and proposed uses of the insecticide methoxyfenozide , humans may be exposed through food and drinking water, since the chemical may be applied directly

to growing crops and may

reach surface and ground water sources of drinking water. In an occupational setting, applicators may be exposed while handling the pesticide prior to application (i.e., mixing/loading), as well as during application. There is also potential for post application exposure for workers re - entering treated fields. Since methox yf

enozide is also registered for use on ornamentals there is likely to be exposure in resid ential and non - occupational settings as well . While the product does not appear to be intended for homeowner use, there is the potential for homeowners to purchase and appl y the product to their own ornamentals . Although there is also potential for dermal exposure , there is no expectation of dermal risk , based on the lack of dermal toxicity for methoxyfenozide. Furthermore , the potential for post - application oral exposure to children is not expected since the extent to which young children engage in ac tivities associated with areas where residential ornamentals are grown or u se these areas for prolonged periods of play is low. This risk assessment considers all of the relevant exposure pathway s , combining them as appropriate, to estimate overall expos ure and risk. **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 population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water co nsumption, and activities in and around the home that involve pesticide use in a residential setting.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **15** of **60** Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture under the National Health and Nutrition Examination Survey, What We E at in America, (NHANES/WWEIA). These food consumption patterns are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country . Additionally , OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non - dietary

exposures based on h ome use of pesticide products and associated risks for adult applicators and for children , youths, and adults entering or playing on treated areas post - application are evaluated. Further considerations are currentl y in development as OPP has committed res ources and expertise to the development of specialized software and models that consider exposure to b ys tanders and farm workers as well as lifestyl e and traditional dietary patterns among specific subgroups. **4.0 Hazard Characterization and Dose**  **- Response**  **Assessment 4.1**  **Toxicology Studies Available for Analysis** The toxicological database is considered complete for methox yf enozide. The following studies, which utilize exposure routes (oral and dermal) consistent with potential human exposure scenarios, h ave been submitted: primary acute toxicity, irritation and dermal sensitization; subchronic oral toxicity

in the rat, mouse and dog; rat 28 - day dermal toxicity ; rat chronic oral toxicity /carcinogenicity; dog chronic oral toxicity ; mouse oral carcinogenici ty ; rat and rabbit oral toxicity ; rat oral two - generation reproductive toxicity ; genotoxicity battery ; rat acute and subchronic neurotoxicity ; rat general metabolism; rat dermal penetration (on formulation); and rat immunotoxicity . Although a 28 - day inh alation toxicity

study has not been submitted, HED has determined that this study is not needed (i.e., the study has been waived) for methoxyfenozide , based on a weight of evidence (WOE) approach that considered all of the available hazard and exposure inf ormation, including the use of a conservative oral point of departure (POD) that results in MOEs ranging from 2 0 ,000 to 3 ,100,000 for risk via the inhalation route due to residential and occupational exposures (TXR # 0053782 , 4/17/12) . **4.2 Absorption,**  **Distribution, Metabolism, & Elimination (ADME)** In the rat, 14 C - radiolabeled methox yf enozide was rapidly

absorbed following gavage administration, with maximum peak plasma concentrations observed within 15 minutes of dosing. Peak plasma concentrations at 10 mg/kg ranged from 0.70 to 1.09 ppm in males and 0.5 to 0.59 ppm in females, depending on the ring location of the radiolabel; at 1000 mg/kg, peak levels were 26.11 - 35.52 ppm in males and 21.92 to 29.74 ppm in females. Plasma elimination was biphasic, with an α - phase T 1/2 of 0.2 to 0.6 hr and a β - phase T 1/2 of 15.2 - 35.6 hr and showed some variation with radiolabel location. The total plasma elimination rate was longer for the high dose compared to the low dose animals, suggesting metabolic pathway saturation, and the effect was more prominent in female rats. Radioactivity was extensivel y distributed among tissues, with the highest concentrations at C max (0.25 hr) observed in the intestinal tract, stomach, liver and residual carcass. Enterohepatic circulation was observed. Methoxyfenozide did not show a potential for bioaccumulation: by 5 days’ post - treatment, the highest levels wereMethoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **16** of **60** observed in the liver and carcass, but tissue radioactivity in all tissues was insignificant b y that time. Excretion o f radiolabel was essentially complete by

48 hrs postdosing. Based on the minimal level of radioactivity in tissues at 72 hours, absorption was estimated to be at least 62 to 70% of the administered dose (biliary plus urinary excretion). The major route o f excretion was in the feces (86 - 97% of the administered dose), with 5 - 13% of the dose excreted in the urine. Significant dose - or sex - dependent differences in metabolic disposition were not observed. Methox yf enozide was extensively

metabolized. The maj or routes of metabolism involved O

– demethylation and oxidative hydrox yl ation of the A - ring phenyland/or B - ring meth ylgroups, followed b y glucuronic acid or sulfate conjugation. In addition to the parent compound, seven major metabolites were identified in excreta. These included RH - 131,157, RH - 141,581 and RH 117,236, metabolites also identified in residues in crops or livestock. Up to 25 metabolites were isolated from urine, but the majority represented <1 - 2% of the radioactive dose. Up to 16 metaboli tes were identified in the feces, including the parent compound, with only six containing ≥5% of the administered radiolabel. The major fecal metabolites in all groups were products of Phase I O - demethylation and oxidative hydrox yl ation on the A - ring and, to a lesser extent, the B ring. Levels of excreted parent compound in the feces were greater in animals receiving 1000 mg/kg test material (30 to 39% of dose) when compared to the 10 mg/kg groups (14 - 26% of dose), consistent with saturation of absorption . In the bile, up to 24 metabolites were detected, with the primary

metabolite (13 - 18% of dose) being derived b y glucuronide conjugation at the 0 - demethylated alpha ring. **4.2.1 Dermal Absorption**  An in vivo dermal absorption study on an 80% wettable pow der (WP) formulation of methoxyfenozide was conducted in the rat. Cumulative absorption of approximately 2% of the applied dermal dose was observed after 10 or 24 hour s of dermal exposure. Consistent with this low level of absorption, a 28 - day dermal stu dy

in the rat showed no toxicity up to the limit dose (1000 mg/kg/day). **4.3 Toxicological Effects**  Methox yf enozide is a diacylhydrazine insecticide active against lepidopterous insects (moths and butterflies) b y competitively binding to receptors of the m olting hormone in larvae. Many of the available short - term or subchronic toxicity studies on methoxyfenozide showed little or no toxicity . The main target organs were the liver, thy roid and red blood cells. In the rat metabolism study, liver contained 2 - 9% of the administered radioactivity at C max , but levels decreased and bioaccumulation was not observed. L evels in the blood were negligible. The effects of methox yfenozide on the blood in mammals (methemoglobinemia, decreased red blood cell parameters, Heinz body formation) are consistent with those of other hydrazine compounds. Hematologic parameters in the rat and dog were affected b y exposure to methoxyfenozide. Mild anemia (decreases in RBC count, hematocrit and hemoglobin) w as observed in both sp ecies following chronic dietary exposure, along with methemoglobinemia and RBC structural abnormalities. Increased platelets were also observed. An increase in the cellularity of rib and sternum bone marrow, along with macrophage pigmentation in the liver and spleen, wereMethoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **17** of **60** reported in the dog. No significant hematological changes were seen in the dog or rat subchronic studies, or the rat two week range - finding studies ; however, hematological effects were observed in the dog two week range - finding study , along with increased spleen weight. The data suggest that a compensatory

mechanism for the RBC effects may occur over time, based on the effects observed at two weeks in the dog range - finding studies that were not observed in the subchronic study , and on m ore pronounced changes in hematological parameters at Week 14 in the rat and dog chronic studies than were observed at evaluations conducted at later times in those studies. No hematological effects were reported in the mouse. In creased liver weight an d periportal h ypertroph y were observed in the rat and dog. These findings were observed in the rat following two - week, subchronic or chronic dietary exposure, and in the dietary

reproductive toxicity

study , and in the dog following chronic exposure. In the rat two - week study , increased adrenal gland weight and minimal hy pertrophy of the zone fasciculata, and increased thy roid follicular cell hy

pertrophy /hy perplasia were also observed; however, these findings were not seen with subchronic exposure. Thy roi d hy pertrophy and altered colloid and increased adrenal weights were observed in the rat chronic oral study, and the incidence and severity

of chronic progressive glomerulonephropathy was increased. Th yroid weights were increased in the dog following chro nic exposure, but there was no accompanyi ng histopathology . In the mouse, effects were limited to decreased body weights and weight gain in the subchronic study ; however, no effects were seen in the carcinogenicity study at dietary concentrations exceedin g the limit dose. No body weight effects were observed in the rat or dog. Acute and subchronic oral neurotoxicity studies in the rat did not show evidence of potential neurotoxicity . In the acute study , decreased hindlimb grip strength on Day 0 was repo rted in males. This finding was only observed at the limit dose in males and was not observed in the subchronic neurotoxicity

study and was therefore not considered evidence of neurotoxicity . No clinical signs of toxicity

or neurohistopathology

were obse rved in other guideline studies. No maternal or developmental effects were observed in either the rat or rabbit oral developmental toxicity

studies. In the rat two - generation reproductive toxicity study , parental effects were limited to increased liver w eight and microscopic periportal hy pertrophy . No offspring or reproductive toxicity was observed. In a 28 - day dietary immunotoxicity

study in the rat, no immunotoxicity

was observed. The onl y observed effect was increased liver weight. Dermal effects w ere not observed in the rat following a 28 - day exposure period (5 exposure day s per week for a total of 20 exposures). This finding is consistent with the relatively low dermal absorption of 2% of the applied dose, observed in an in vivo dermal absorption study in rats treated with an 80% WP formulation product. There was no evidence of carcinogenicity in the rat dietary 24 - month chronic toxicity /carcinogenicity s tudy

or the mouse dietary 18 - month carcinogenicity study. No mutagenic or clastogenic potent ial was observed in the battery of genotoxicity

studies on methoxyfenozide. Based on these findings, methoxyfenozide is classified as “not likely to be carcinogenic to humans” (2005 Agency revised carcinogenicity assessment guidelines).Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **18** of **60 4.4**  **Safety F**  **actor for Infants and Children (FQPA Safety Factor)**  The required 10X FQPA safety factor for methoxyfenozide was reduced to 1X , based on the following considerations: 1) the toxicity database for methoxyfenozide is complete, including studies addressing potenti al pre - and post - natal susceptibility ; 2) there is no evidence that methoxyfenozide is neurotoxic, and a developmental neurotoxicity study is not required; 3) there is no residual uncertainty, and no evidence of increased quantitative or qualitative susceptibility in the developing or young animal ; and 4) the dietary exposure assessments do not underestimate potential exposure from food and drinking water, and the use pattern indicates a low potential for residential exposure. **4.4.1 Completeness**  **o f**  **the T**  **oxicology Database** The database is considered complete with respect to evaluation of potential susceptibility

/sensitivity

of infants and children. Acceptable developmental toxicity studies in two species (rat and rabbit) and a rat two - generation reproduc tion study have been submitted, as well as rat acute and subchronic neurotoxicity and immunotoxicity

studies. A developmental neurotoxicity

study is not required, based on the lack of evidence of neurotoxicity in the adult animal and lack of increased sen sitivity /susceptibility

in the developing or young animal. **4.4.2 Evidence of Neurotoxicity**  The available toxicity

data, which include acute and subchronic neurotoxicity studies in the rat, d o not demonstrate neurotoxic potential. A decrease in hindlimb grip strength, observed in male rats on Day

0 of the acute neurotoxicity study , was not considered to be evidence of neurotoxicity

because it was an isolated finding in males, not observed in females and seen onl y at the limit dose of 2000 mg/kg. Additionally , no evidence of neurotoxicity was observed in the rat subchronic neurotoxicity or other studies. A developmental neurotoxicity study is therefore not required. **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  There was n o evidence of increased qualitative or quantitative susceptibility in the developing or yo ung animal. No developmental toxicity was observed in either the rat or rabbit developmental toxicity studies, and there was no evidence of offspring or reproductive toxicity in the rat two generation reproductive toxicity study . Dosing in all studies achieved the limit dose ( ≥1000 mg/kg/day). **4.4.4 Residual Uncertainty in the Exposure Database**  There is no residual uncertainty with respect to the exposure assessme nts conducted for methoxyfenozide. The dietary exposure estimates incorporate conservative estimates of all residues of concern from the food exposure pathway s. There remains an outstanding data requirement for monitoring of surface water and sediment in a representative sample of high use areas in proximity

to surface water. Thus, the Environmental Fate and Effects Division ( EFED ) continues to have concerns about the persistence of methoxyfenozide and potential uncertaintiesMethoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **19** of **60** regarding the long - term drinking water exposure associated with the use of methox yfenozide , and has used a highl y conservative approach in deriving modeled drinking water values for the purpose of risk assessment . The aggregate assessment including exposure from the proposed use on ornamentals also used high - end default assumptions; there is a very low potential for children’s exposure to residues resulting from treatment of ornamentals. **4.5 Toxicity Endpoint and Point of**  **D eparture Selections**  **4.5.1 Dose**  **- Response Assessment**  A to xicity

profile table, endpoint selection rationales and detailed summaries of the toxicity studies considered in the selection of toxicity endpoints for exposure assessment are provided in Appendix A of this document. For acute dietary

exposure assessment , the rat acute oral neurotoxicity study was considered for selection of a dose and endpoint. This study was not selected because the only finding was decreased grip strength in males on Day 0 (day of dosing) at the limit dose of 2000 mg/kg; no toxicity w as observed at 1000 mg/kg in males or in females up to 2000 mg/kg. The developmental oral toxicity studies in the rat and rabbit were also considered but not selected because no maternal or developmental toxicity was observed at doses up to the limit dose (1000 mg/kg/day). There were also no clinical effects on the initial day of dosing in any

other oral toxicity study . For selection of a chronic dietary exposure assessment dose and endpoint, the dietary rat chronic toxicity /carcinogenicity, dog chronic (1 ye ar) and rat reproductive toxicity studies were considered. The mouse carcinogenicity study showed no effects at dietary concentrations administering methox yf

enozide slightly

above the limit dose of 1000 mg/kg/day . Increased liver weight at doses exc eeding the limit dose was the only effect observed in parental animals in the rat reproductive toxicity

study , and there were no offspring or reproductive effects. The rat chronic toxicity

/carcinogenicity

study with a NOAELof 10.2 mg/kg/day was selected for determination of the cRfD. The chronic dog study was selected as the co - critical study because these were the most sensitive studies available and the similar NOAELs (10.2 and 9.8 mg/kg/day for the rat and dog, respectively) yi elded the same cRfD of 0 .10 mg/kg/day. Hematological effects were observed in both studies at the L OAELs of 106 mg/kg/day in the dog and 411 mg/kg/day

in the rat. In the rat, periportal liver h ypertroph y, th yroid h ypertrophy and altered colloid and increased adrenal weight were also observed at the LOAEL. The selected dose and endpoint is protective for potential developmental effects and toxicity to the young, based on lack of developmental effects (rat and rabbit developmental studies) or toxicity to offspring (rat reproducti ve toxicity

study) and lack of evidence of neurotoxicity . It is also protective of hematological and other effects observed in the dog and rat two - week range - finding studies (see below). The NOAELs/LOAELs from all other available studies were observed at higher dose levels. Endpoints were not selected for incidental oral exposure because , based on current and proposed use patterns which specify use on ornamentals and not turf, there are no residential uses for methoxyfenozide where significant post - application exposure to young children is anticipated.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **20** of **60** For dermal exposure (all durations, residential and occupational exposure), an endpoint was not selected. The rat 28 - day

dermal toxicity

study demonstrated no toxicity up to the limit dose (1000 mg/kg/day). Several oral toxicity studies with observed LOAEL s were also considered, including the subchronic dietary studies in the rat, mouse and dog, two - week range - finding studies in the rat and dog, and the rat reproductive toxicity study . However, the e ffects observed in the oral studies, which included liver hypertrophy and hematologic parameters, were evaluated in the 28 - day

dermal study

but showed no effect of treatment. The developmental oral toxicity studies in the rat and rabbit showed no maternal or developmental toxicity and the rat subchronic dietary neurotoxicity

showed no toxicity at doses up to the limit dose (1000 mg/kg/day). The rat 28 - day dermal toxicity

study was therefore considered protective of sensitive populations, including potenti al developmental effects. In past risk assessments, HED did not quantitatively assess inhalation exposure and risk, and there is no route - specific repeated - dose inhalation toxicity study available for this purpose; however, in accordance with the current policy for conducting inhalation assessments, the risk assessment team selected a dose and endpoint from the available oral studies. The studies considered included two - week oral range - finding studies in the rat and dog, subchronic oral toxicity studies in the rat and mouse, and the reproductive toxicity study in the rat. The subchronic oral dog study, rat and rabbit oral developmental toxicity and the rat 90 - day neurotoxicity

and immuno toxicity studies were not considered because no toxicity was observ ed. The two week dietary

study in the dog was selected for both short - and intermediate - term inhalation exposure because it provided the most sensitive dose and endpoint available (NOAEL = 16.8 mg/kg/day , based on hematological effects at the LOAEL of 9 0.8 mg/kg/day) and was of an appropriate duration. The NOAEL and LOAEL were selected from the highest individual animal NOAEL and lowest L OAEL because onl y two animals/sex/dose were tested. Effects observed at the LOAEL included mild anemia, methemoglobinemia and abnormal RBC structure, and were consistently observed in individual animals. Although these effects were not identified in the dog 90 - day dietary study at dose levels up to about 200 mg/kg/day , mild anemia and methemoglobinemia were observed at Week 14 and later in the chronic dog study at doses of 106 mg/kg/day . Additionally , in the rat two week range - finding study there were effects observed on the th yroid and adrenal gland at a comparable dose (69.3 mg/kg/day), with a NOAEL of 17 mg/kg/day ( effects not observed in the subchronic rat study). These findings were not seen in the subchronic studies, suggesting a compensatory mechanism for the toxicity of methoxyfenozide with prolonged exposure. This dose and endpoint are therefore considered to be very conservative, but protective of all populations that may be exposed. In light of the conservative endpoint, low acute inhalation toxicity of methoxyfenozide, low vapor pressure and low application rates for current use patterns, this oral study i s considered to be protective for potential inhalation toxicity . **4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment**  Dermal exposure was not assessed due to a lack of toxicity via the dermal route. Since adults were assessed for po tential inhalation exposure while applying methoxyfenozide to ornamentals , this exposure should be combined with background levels in food and water to determine aggregate exposure. For children’s residential exposure, oral post - application exposure was n otMethoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **21** of **60** assessed; only

exposure from background levels of food and drinking water were assessed. For occupational workers, only inhalation exposure and risk were assessed. **4.5.3 Cancer Classification and Risk Assessment Recommendation**  Methox yf enozide is class ified as “not likel y to be carcinogenic to humans,” according to the revised 2005 Agency

Guidelines for Carcinogen Risk Assessment. The classification is based on lack of evidence of carcinogenicity in long - term dietary

studies in the rat and the mouse, and lack of evidence of genotoxicity in the battery

of mutagenicity

studies. **4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk**  **Assessment Tables 4.5.4.1**  and **4.5.4.2** , below, summarize the dose and endpoint selection for dietary /non occupational and occupational exposure: **Table 4 .5.**  **4. 1**  **Summary of Toxicological Doses and Endpoints for Methoxyfenozide**  **for Use in Dietary and Non**  **- Occupational Hum**  **an Health Risk Assessments Exposure/**  **Scenario Point of** 

**Departure Uncertainty/FQPA** 

**Safety Factors RfD, PAD,** 

**Level of Concern for**  **Risk Assessment**  **Study and Toxicological Effects** Ac ute Dietary ( All Population s , including Infants and Children and Females 13 - 49 years of age) No hazard was identified for a single oral exposure.

Chronic Dietary (All Populations) NOAEL=

10.2 mg/kg/day UF A= 10X

UF H = 10X FQPA SF= 1 Chronic RfD

= 0.10 mg/kg/day cPAD = 0.10 mg/kg/day Co - critical studies:

Com bined oral chronic toxicity/carcinogenicity - rat LOAEL = 411/491 mg/kg/day [M/F] , based on hematological changes (decreased RBC parameters), periportal liver hypertrophy, thyroid hypertrophy and altered colloid; possibly increased adrenal weight. Chronic oral toxicity - dog NOAEL = 9.8/12.6 mg/kg/day[M/F] LOAEL = 106.1/110.6 mg/kg/day , based on hematological changes (decreased RBC parameters, slight methemoglobinemia) and increased serum bilirubin. Incidental Oral Short - Term (1 - 30 days) There are no residential uses for methoxyfenozide that would result in significant post - application

incidental oral exposure to children.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **22** of **60 Table 4**  **.5. 4.**  **1 Summary of Toxicological Doses and Endpoints for**  **Methoxyfenozide for Use in Dietary and**  **Non -**  **Occupational Hum an Health Risk Assessments**  **Exposure/ Scenario**  **Point of**

**Departure Uncertainty/FQPA** 

**Safety Factors RfD, PAD,** 

**Level of Concern for**  **Risk Assessment**  **Study and Toxicological Effects** Dermal Short Term (1 - 30 days) or Intermediate term (1 - 6 mo nths) No toxicity, i.e., no hazard , was identified for dermal exposure. Inhalation Short - Term (1 - 30 days) and Intermediate Term (1 - 6 mo nths) NOAEL =

16.8 mg/kg/day UF A= 10X

UF H = 10X Residential

LOC for MOE ≤ 100 Two - week oral range - finding study - dog

LOAEL = 90.8 mg/kg/day , based on hematological changes (decreased RBC parameters, increased Heinz body count, reticulocyte counts, erythrocyte mo rp hology and methemoglobinemia) and increased spleen weights. Cancer (oral, dermal, inhalation) Classification: not likely to be carcinogenic to humans . 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. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (c = chronic). RfD = referen ce dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. **Table 4.5. 4**  **.2 Summary of Toxicological Doses and Endpoints for Methoxyfenozide**  **for Use in Occupational Hum**  **an Health Risk Assessments Exposure/**  **Scenario Point of** 

**Departure Uncertainty** 

**Factors Level of Concern** 

**for Risk Assessment**  **Study and Toxicological Effects** Dermal Short Term (1 - 30 days) or Intermediate Term (1 - 6 mo nths) No toxicity, i.e., no hazard , was identified for dermal exposure

Inhalation Short - Term (1 - 30 days) and Intermediate T erm (1 - 6 mo nths) NOAEL =

16.8 mg/kg/day UF A= 10X

UF H = 10X Occupational

LOC for MOE ≤ 100 Two - week oral range - finding study - dog

LOAEL = 90.8 mg/kg/day , based on hematological changes (decreased RBC parameters, increased Heinz body count, reticulocyte counts, erythrocyte mo rphology and methemoglobinemia) and increased spleen weights.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **23** of **60 Table 4.5.**  **4 .2 Summary of Toxicological Doses and Endpoints for**  **Methoxyfenozide for Use in Occupational**  **Hum an Health Risk Assessments**  **Exposure/ Scenario**  **Point of**

**Departure Uncertainty** 

**Factors Level of Concern** 

**for Risk Assessment**  **Study and Toxicological Effects** Cancer (oral, dermal, inhalation) Classification : not likely to be carcinogenic to humans . 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. N OAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applic able **5.0 Dietary Exposure and Risk Assessment**  **5.1 Metabolite/Degradate Residue Profile**  **5.1.1 Summary of Plant and Animal Metabolism Studies**  A cceptable studies are available depicting the metabolic fate of methoxyfenozide in target crops, rotational crops and livestock. The main distinction between study results was that although methoxyfenozide does not undergo extensive metabolism in primary crops, it is highl y metabolized in livestock and rotational crops. The nature of methox yfenozide residues in primary crops is adequately understood, based on acceptable metabolism studies in cotton, apples, grapes and rice. Methox yfenozide does not undergo extensive metab olism in primary crops. HED has determined that the residue of concern for both the tolerance expression and risk assessment in primary crops is the parent compound only , methoxyfenozide. However, in rotational crops and livestock, additional metabolit es are included in both the tolerance expression and the risk assessment. The residue of concern in milk and ruminant tissues (other than liver and kidney) is parent compound; in ruminant liver and kidney methoxyfenozide and its RH - 141,518 metabolite are of concern . The residue of concern in poultry meat (muscle) and fat is parent methoxyfenozide; however, in eggs, poultry liver, and poultry meat b yp roducts, residues of concern include methoxyfenozide and its metabolite, RH 141,518. In rotational crops, m ethoxyfenozide was highly metabolized by

oxidation, demethylation and hydrox yl ation to non - conjugated metabolites, which were then conjugated with biomolecules, yi elding bound residues and precursors in the sugar s ynthesis pathway. The metabolites identi fied in the rotational crops were not similar to those found in the primary crop metabolism study . T he residues of concern in rotational crops include methoxyfenozide, its free phenol metabolite (RH - 117,236), conjugated forms of the phenol metabolite (RH - 151,055 and RH 152,072), and the metabolites RH - 152,067, RH - 131,157 and RH - 152,071. For enforcement purposes, the tolerance definition for rotated crops includes parent onl y in high - moisture crops,Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **24** of **60** and the combined residues of parent and metabolites RH - 15 1,055, RH - 152,072 and RH - 117,236 in low - moisture crops. **5.1.2 Summary of Environmental Degradation**  Memo, K. Milians, Ph.D . , Chemist, 8/17/2011, D388876 Methox yf enozide is very persistent (t 1/2 = 1 to 3 years in soil and water) and moderatel y mobile (Koc = 219

– 922 L/kg oc in various soils). It is stable to photolysis and hydroly sis, is not significantl y volatile, and degrades onl y very slowly by microbial activity . Degradates are predominantly

RH - 117236 ( 3,5 - dimethylbenzoic acid N - tert- butyl -N’ - (3 - hydroxy- 2 - m ethylbenzoyl)hydrazide) and RH - 131154 ( 3 - [N - tert- butyl -N’ - (3 - methoxy- 2 - methylbenzoyl) - hydrazinocarbonyl] - 5 - methylbenz o ic a cid), but these are onl y present at low concentrations. Because of its resistance to degradation and its mobility , meth oxyfenozide has the potential to accumulate and to move off the site of application by leaching and erosion/runoff resulting in ground - and surface - water contamination . **5.1.3 Comparison of Metabolic Pathways**  Methox yf enozide is rapidly

absorbed, distribute d, metabolized and almost completely excreted within 48 hours in rats. The major route of excretion was feces (86 - 97%) with lesser amounts in the urine (5 - 13%). An enterohepatic circulation was observed. The test material was metabolized principally

by O - demeth yl ation of the A - ring methox y group and oxidative hydrox yl ation of the B - ring meth ylgroups followed by conjugation with glucuronic acid. No significant sex - related or dose - dependent differences in metabolic disposition were noted. Seven metaboli tes and the parent accounted for 74 - 90% of the administered dose in all groups. These metabolites included RH - 131,157, RH - 141,5 1 8 and RH - 117,236, metabolites also identified in residues in crops or livestock. Metabolism of methoxyfenozide in other animal s (poultry and ruminants) appears to be similar to its metabolism in rats. Although m ethox yfenoz ide does not undergo extensive metabolism in primary crops , it is highly

metabolized in rotational crops. Methox yf enozide is metabolized by oxidation, demethylation and hydroxylation to non - conjugated metabolites, which were then conjugated with biomolecules, yielding bound residues and precursors in the sugar s ynthesis pathway . This is the same basic pathway as observed in the rat. The major drinking water d egradates are also formed by ring hydrox yl ation and oxidation of methyl groups. These degradates were also found in the rat. Therefore, there were no significant residues in food or drinking water that were not seen in the rat. **5.1.4 Residues of Concern**  **Summary and Rationale** The methox yfenozide glucuronide conjugates are considered to be less toxic than the parent compound because glucuronide conjugation is well known to be a commonly occurring detoxification mechanism in mammalian species since it results in the formation of more polar, more water - soluble metabolites which are readil y and easil y excreted from the body (in this case, in the bile and urine). Further, based on similarities of chemical structure, the non - conjugated metabolite s would be expected to be no more toxic than the parent compound. The metabolites were included in risk assessment and the tolerance expression , based on the potential for toxicityMethoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **25** of **60** similar to that of the parent, as well as the potential for significant levels in crops and livest ock, as well as the metabolites determined b y the enforcement methods. Primary Crops : B ased on acceptable metabolism studies in cotton, apples, grapes and rice , the nature of methox yf

enozide residues in primary crops is adequatel y understood . HED concluded that the residue of concern for both the tolerance expression and the risk assessment in prim ary crops is methox yfenozide. Livestock: The qualitative nature of methoxyfenozide residues in livestock is also adequatel y understo od , based on available ruminant and poultry metabolism studies. HED determined that the residue of concern is the parent compound in milk and ruminant tissues (except meat by products), and in poultry

meat and fat. The residues of concern in meat by produc ts and eggs are methoxyfenozide and its m etabolite , RH - 141,518. Rotational Crops: The nature of methox yf enozide residues in rotational crops is a dequatel y understood, based on the adequate confined accumulation study . For enforcement purposes, the tolerance definition for rotated crops includes parent only in high - moisture crops, and the combined residues of parent and metabolites RH - 151,055, RH - 152,072 and RH - 117,236 in low moisture crops. Metabolites RH - 152,067, RH - 1 31,157 and RH - 152,071 are also to be taken into account in risk assessments. Drinking W

ater: The residues of concern in drinking water are the parent methoxyfenozide and the following d egradates : RH - 117236 ( 3,5 - dimethylbenzoic acid N - tert- butyl -N’ - (3 - hydrox y- 2 - m ethylbenzoyl)hydrazide) and RH - 131154 ( 3 - [N - tert- butyl -N’ - (3 - methoxy- 2 - methylbenzoyl) - hydrazinocarbonyl] - 5 - methylbenzoic a cid), but these are onl y present at low concentrations. The toxicological and residue chemistry databases for methoxyfenoz ide have been examined to determine residue definitions for the purposes of setting tolerance s and risk assessment s . The residue definitions are summarized in **Table 5.1.4** . **Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance**  **Expression .**  **1** Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Parent methoxyfenozide Parent methoxyfenozide

Rotational Crop Parent methoxyfenozide and

metabolites , RH 117,236; RH 151,055; RH 152,072; RH - 152,067 ; RH - 131,157 ; and RH - 152,071 Parent methoxyfenozide, and metabolites RH - 151,055 ; RH - 152,072 ; and RH 117,236 Livestock Ruminant Parent methoxyfenozide and metabolite RH - 141,518 Parent methoxyfenozide and metabolite RH - 141,518 Poultry Parent methoxyfenozide and

metabolite 141,518 Parent methoxyfenozide and metabolite 141,518Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **26** of **60 Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk**  **Assessment and Tolerance Expression**  **. 1**  Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Drinking Water Parent methoxyfenozide and degradates RH - 117236 and RH 131154 Not Applicable 1 Chemical s tructures for the residues of concern for tolerance enforcement purposes are provided in HED’s Metabolism Committee memo randum of 7/23/99 (D258034, W. Wassell) . **5 .2**  **Food Residue**  **Profile** Memo, W. Drew , Chemist, 7 / 16 /2013, D407758 A cceptable crop field trial data are avai lable to support uses on herbs (subgroup 19A ) except chives , dates, sorghum, and caneberry (subgroup 13 - 07A), and to establish tolerances for residues in the associated commodities . Quantifiable residues were observed in/on all crop commodities. Residue decline data indicate that residues generally declined for caneberries and sorghum . The available data are adequate for risk assessment and tolerance assessment. The results from these field trials are summarized in **Table 5.2** . Because there are no proce ssed commodities for caneberries or dates, processing studies were not required for these raw agricultural commodities (RACs). The processed commodity for basil is dried basil, samples of which were produced at the field trial sites, and subsequently anal yz ed along with the fresh basil samples. The submitted sorghum processing study data are adequate, and support a tolerance of 120 ppm in sorghum AGF. This will be reflected in an increase of the currentl y established tolerance in AGF, from 2.0 to 120 ppm . A tolerance in sweet sorghum sy rup is not required. The available storage stability data are adequate, and support the storage conditions and durations for samples from the submitted caneberry, date, sorghum, and basil field trials, and the sorghum p rocessing study . Adequate livestock feeding studies are available for methox yfenozide. No livestock feeding studies were submitted with this petition. Although the proposed tolerances for this action include an increase of the tolerance in sorghum gra in, the revised estimated dietary burdens result ed in anticipated residues that do not exceed the tolerances currentl y established in livestock commodities. Therefore, revisions to the currently established livestock tolerances are not needed as a result of the new uses .Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **27** of **60 TABLE**  **5. 2**  **Summary of Residue Data from Crop**  **Field Trials with Methoxyfenozide. Crop Matrix**  **Total Use**

**Rate (**  **lb ai/A)**  **[g ai/ha] PHI** 

**(Days) Residue Levels**  **( ppm** **)**

**n Min.**  **Max. LAFT**  **HAFT Median**  **Me an**  **Std. Dev.**

**Basil** Fresh leaves and stems 0.988 - 1.032

[1107 - 1157] 1 10 9.26 47.2 -- -- 19.2 21.7 12. 3 5 -- -- 9.88 43.4 19.2 21.7 12.8 Dried leaves and stems 10 56.3 194 -- -- 10 0 110 44.8 5 -- -- 60.5 188 102 110 47.0 **Caneberries** Caneb erries 0.744 - 0.778

[834 - 872] 3 12 0.62 2.5 -- -- 1. 90 1.70 0.6 5 6 -- -- 0.68 2. 5 1.90 1.73 0.67

**Dates** Dried fruit 0.501 - 0.933 7 8 1.5 3.3 1.6 2.3 2.0 2. 0 0. 7 0 **Grain Sorghum** Forage 0.478 - 0.494 2 - 4 12 0.70 5.6 0.77 5.0 2.15 2.76 1.45 Grain 11; 21 - 23 12 0.15 2.6 0.15 2.3 0.40 0.72 0.72 Stover 21 - 23 12 0.29 9.7 0.45 7.6 2.95 3.18 2.39 **Sweet Sorghum** Stalks 0.481 3 1 0.045 0.18 0.11 0.11 0.11 0.11 NA A dequate residue data are available to support proposed updates to crop group tolerances , and to establish indirect or inadvertent tolerances. Specifically , t olerances in the updated crop groups 8 - 10 and 11 - 10, and in the updated subgroups 13 - 07F and 13 - 07G we re request ed. Tolerances in sugar apple s , cherimoya s , atemoya s , custard apple s , ilama s , soursop s , and biriba s we re also requested , based o n translation of avocado residues. Additionally, indi rect or inadvertent tolerances in the rapeseed subgroup ( 20A ) and the s unflower subgroup ( 20B ) were requested . T he requested changes for the rapeseed and sunflower sub group s are based on 2012 recommendations b y EP A. Other changes are supported by data previously

reviewed by

the Agency in 2009. **5.3 Water Residue Profile**  Memo, K. Milians, Ph.D . , Chemist, 4/23 /2013 , D 407566 The estimated drinking water concentrations (EDWCs) are based on all current methoxyfenozide uses as well as the new proposed uses. Surface water residues were modeled with the Pesticide Root Zone Model and Exposure Anal ys is Modeling S ys tem (PRZM - EXAMS), using EFED's standard index reservoir which incorporates flow into and out of the reservoir. Groundwater residues were estimated using the Pesticide Root Zone Model

– Ground Water (PRZM - GW) model , which accounts for pesticide fate in the crop root zone and multiple years of application. The surface water values are based on the existing globe artichoke use represented by the CA lettuce scenario with an application rate of 0.25 lbs. a.i./acre/application and a total of 1.0 lb a.i./acre/season . The estimated drinking water concentrations (EDWCs) are listed in Table 2. The EDWC used in this assessment is bolded in the table below, with the value of 251 ppb coming from the groundwater residues estimated by the PRZM - GW model.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **28** of **60** There remains an outstanding d ata requirement for monitoring of surface water and sediment in a representative sample of high use areas in proximity to surface water. Additionally , EFED continues to have concerns about the persistence of methoxyfenozide. This persistence makes it plau sible that methoxyfenozide may pose a greater long - term drinking water exposure concern than what is suggested by the screening - level assessment. In particular, once introduced into the environment, this compound could travel to key aquatic environmental compartments, such as aquatic sediment, and persist for extended periods of time. Thus, there are significant uncertainties regarding the potential long - term drinking water exposure associated with the use of methox yfenozide. Therefore EFED has used a co nservative approach to modeling potential residues in ground water sources of drinking water. **Table 5.3. Tier II estimated drinking water concentrations (EDWCs) resulting from**  **applications of m ethoxyfenozide (PRZ** **M -**  **EXAMS) Drinking water source**  **Use (m**  **odeled rate) 1**  **- in**  **- 10 year acute**  **(ppb) 1**  **- in**  **- 10 year** 

**chronic (ppb) 30**  **- year average**  **(ppb)** Surface water (aerial application) Globe Artichoke (0.25 lb a.i./A x 4 applic.; total of 1.0 lb/A/yr) 77.7 51.6 37.4 Surface water (ground application) Globe Artichoke (0.25 lb a.i./A x 4 applic.; total of 1.0 lb/A/yr) 77.4 50.4 35.8 **Tier I EDWCs for Groundwater (PRZ M**  **- GW)**  **Crop/Scenario Highest Daily value**  **(μg/L) Post Breakthrough** 

**Average (μg/L) Average Sim**  **ulation**

**Breakthrough Time (days)** Fruiting Vegetable/WI corn **251** 214 8684.63 **5.4 Dietary Risk Assessment**  Memo, E. Holman, 7 / 16 /201 3 , D 412460 **5.4.1 Description of Residue Data Used in Dietary Assessment**  For this anal ys is existing and recommended tolerance levels were used, as well as 100% CT assumptions for all commodities. DEEM (Version 7.81) default processing factors were used for most processed commodities that do not have individual tolerances; the only exception was an Alternative Risk Integration Assessment Team (ARIA) determined proce ssing factor of 0.2 X for orange juice (D 358341, D. Rate, 6/10/2009) from a reviewed processing study . The existing tolerances for livestock commodities were considered adequate ( D 407758, W. Drew , 7/16/13 ). Drinking water was incorporated directly into the dietary

assessment using the maximum chronic concentration for groundwater generated b y the Pesticide Root Zone Model

– Ground Water (PRZM - GW) at 251 ppb.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **29** of **60 5.4.2**  **Percent Crop Treated Used in Dietary Assessm ent**  The chronic dietary

exposure assessment , based on food and drinking water , includes the assumption of 100% CT for all existing and proposed uses. **5.4.3 Acute Dietary Risk Assessment**  There was no appropriate endpoint identified for assessing acute dietary exposure; therefore, no acute dietary

risk assessment was performed. **5.4.4 Chronic Dietary Risk Assessment**  An unrefined chronic dietary anal ys is for methox yfenozide was conducted using tolerance level residues and 100% CT for all existing and prop osed primary crop uses, and additional residues of concern in livestock commodities. Methoxyfenozide chronic dietary (food + drinking water) exposure estimates using the DEEM - FCIDTM software are below HED’s level of concern for the U.S. population and each of the population subgroups. Chronic dietary exposure was 31 % of the cPAD for the U.S. population. The chronic dietary exposure for the highest reported exposed population subgroup, children 1 - 2 years old, was 84 % of the cPAD. The results of the anal ys is indicate that chronic risk from the dietary (food + drinking water) exposure to methoxyfenozide will not exceed HED’s LOC for the general U.S. population, nor any other population subgroups. Based on the very

conservative assumptions used, actual dietary exposure to methoxyfenozide form food and drinking water is expected to be significantly lower than the exposures presented in Table 5.4.4. The results of the chronic dietary exposure anal ys is are reported in the Summary **Table 5.4.4** . **Table 5.4.4. Sum mary of Dietary Exposure and Risk for Methoxyfenozide.**  **Population Subgroup 1**  **DEEM Acute Dietary Analysis, 95**  **th Percentile**  **DEEM Chronic Dietary Analysis Exposure**  **(m g/kg/day)**  **% aPAD Exposure**  **(m g/kg/day)**  **% cPAD** General U.S. Population

NA **2** 0.031520 31 All Infants (< 1 year old) 0.047975 4 7 Children 1 - 2 years old **0.085207 84**  Children 3 - 5 years old 0.065025 64 Children 6 - 12 years old 0.036288 3 6 Youth 13 - 19 years old 0.023942 2 4 Adults 20 - 49 years old 0.027714 2 7 Adults 50+ years old 0.027499 2 7 Females 13 - 49 years old 0.028308 2 8 1 Values for the population with the highest risk for each type of risk assessment are **bolded** . 2 NA = Not Applicable; no acute dietary endpoint was identified for these population subgroups.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **30** of **60 5.4.5**  **Cancer Dietary Risk Assessment**  HED classified methox yf enozide as “not likely

to be carcinogenetic to humans” and, therefore, cancer risk is not of concern for methox yf enozide . **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  Memo, M. Collantes 2 /27 /2012; D 389739 Memo, M. Collantes 6/07/2013; D411612 There are no new proposed residential uses at this time; however, there are existing residential ornamental uses that were previousl y reassessed to reflect updates to HED’s 2012 Residential SOPs 1 alon g with policy

changes for body

weight assumptions (M. Collantes, D389739, 02/27/12) . Inorder to incorporate residential exposure into the short - term aggregate risk assessment, a summary

of the residential exposure and risk estimates resulting from the us e of methoxyfenozide on ornamentals is provided below . **6.1 Residential Handler Exposure**  The Intrepid 2F label indicates that it is to be used on trees, shrubs, foliage plants and flowers grown in commercial nurseries and greenhouses, Christmas tree farms, outdoor landsc a pes areas, parks, recreational areas, institutional groun d s and “residential property ” . Si nce the label does not identify

this product as a restricted use, a residential handler exposure assessment was performed to be protective of p otential home owner exposure. The following use scenarios and sources of unit exposures were used to assess residential handler exposures:  Mixing/L oading/Applying for Spray s Using Manually Pressurized Handwand  Mixing/L oading/Applying for Spray s with Back - Pack Sprayer  Mixing/L oading/Applying for Spray s with H ose - end Sprayer HED’s LOC is a MOE greater than or equal to 100 for residential exposure. A quantitative dermal ass essment for residential handlers was not conducted since there is no sy stemic toxicity associated with dermal exposure to methoxyfenozide . Handler inhalation exposure scenarios resulted in MOEs greater than 100 , ranging from 76,000 to greater than 3 million, and these risk estimates are not of concern . Although a point of departure from an oral study was used to assess the handler inhalation risks, the calculated MOEs are all > 76,000, thus providing an ample margin of safety

to account for any

uncertainties in the route - to - route extrapolation. Handler exposure and risk estimates are summarized in **Table 6**  **.1. Table**  **6.1. :**  **Residential Handler Exposure and Risk Estimates**  **for Methoxyfenozide**  **Exposure Scenario**  **Application**

**Rate a**  **(lb ai/gal) Am**  **ount**

**Treated b**  **(gallons) Inhalation** 

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

**Dose c**  **(m g/kg/day)**  **Inhalation**

**MOE d**  Liquid with Manually Pressurized 0.025 5 0.018 0.0000283 590,000

1 Available: http://www.epa.gov/pesticides/science/residential - exposure - sop.htmlMethoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **31** of **60 Table**  **6.1. :**  **Residential Handler Exposure and Risk Estimates**  **for Methoxyfenozide**  **Exposure Scenario**  **Application**

**Rate a**  **(lb ai/gal) Am**  **ount**

**Treated b**  **(gallons) Inhalation** 

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

**Dose c**  **(m g/kg/day)**  **Inhalation**

**MOE d**  Handwand Liquid with Back Pack 5 0.14 0.00022 76,000 Liquid with Hose - end Sprayer 11 0.0014 0.00000484 3,500,000

a. In accordance with Intrepid® 2F (Reg. No.: 62719 - 442) label : 0.025 lb ai per gallon for treatment of ornamentals (0.25 lb ai/A ÷ 10 gallons/A for mist blowers and air blast sprayers) b. In accordance with revised Residential (Garden and Trees) SOP c. Inhalation dose (mg/kg/day) = inhalation unit exposure (mg/lb ai) * application rate * acres treated / body weight ( 80 kg) d. Inhalation MOE = NOAE L (16.8 mg/kg/day)/ Inhalation Dose (mg/kg/day) **6.2 Dermal**  **Post -**  **a pplication Exposure**  Although there is potential for post - application der mal exposure as a result of th e use on ornamentals , there’s no dermal toxicity associated with this exposure, and a dermal post application exposure assessment was not conducted. Furthermore, post - application oral exposure to children is not expected since the extent to which young children engage in activities associated with areas where residential ornamentals are grown or utilize these areas for prolonged periods of play is low. Therefore an incidental oral endpoint was not selected and an incidental oral post - application exposure assessment was not conducted . **6.3 Inhalation Post**  **- application Exposure**  Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for methoxyfenozide at this time primarily because of the low acute inhalation toxicity

(Toxicity Category III and IV), vapor pressure (1 x 10 - 7 mm Hg at 25oC), and the low proposed use rate (0.31 lb ai/A). However, volatilization of pesticides may be a sourc e of post - application inhalation exposure to individuals nearb y pesticide applications. The Agency

sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Adv isory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 2 . The Agency is in the process of evaluating the SAP report and may , as appropriate, develop policies and procedures to identify the need for and, subsequently , the w ay to incorporate post - application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post - application inhalation exposure assessment for methox yfenozide.

2 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlMethoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **32** of **60 6.5**  **Spray Drift** Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for methoxyfenozide. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray

drift management practic es (see the Agency ’s Spray Drift website for more information 3 . The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriatel y apply the data and the AgDRIFT computer model to its risk 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 spray drift management prac tices to reduce off - target drift with specific products with significant risk estimates associated with drift. Although a quantitative residential post - application inhalation exposure assessment was not performed as a result of pesticide drift from neighb oring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. This exposure scenario is representative of a wors t case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commerc ial 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 risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. In the case of methoxyfenozide , chronic aggregate risks result from exposure through food and water onl y. For short - term risk, adult residential handlers’ inhalation exposure w as combined with background exposure from food and water. As previously discussed (see Section 6.2), there are no residential uses for methox yfenozide that would result in significant post - application exposure to children, based on ornamental use only

. T h erefore, aggregate exposure and risk for children are equivalent to those from food and water (see Section 5.4). **7.1 Acute Aggregate Risk**  There are no single dose effects associated with methox yf enozide, and therefore no acute aggregate risk. **7.2 Short**  **- Term Aggregate Risk** 

3 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmMethoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **33** of **60** The residential handler exposure from applying methoxyfenozide using a backpack ( **Table 6.1** ) w as combined with the chronic dietary exposure from the mostly highl y exposed adult ( General U.S. Population) sub - population , to determin e aggregate exposure and ris k as shown in **Table 7.2**  . T he aggregate MOEs are above the LOC of 100, and therefore the aggregate risk estimate is not o f concern. **Table 7.2 .**  **Short -**  **Term Aggregate Risk Calculations**  **for Me**  **thoxyfenozide .**  **Population NOAEL** 

**mg/kg/day LOC**  **1 Max** 

**Allowable Exposure**  **2 mg/kg/day**  **Average**

**Food and Water**  **Exposure mg/kg/day**  **Residential**

**Exposure mg/kg/day**  **3 Total** 

**Exposure mg/kg/day**  **4 Aggregate** 

**MOE (food, water, and**  **residential) 5**  Adult (Handler) 1 6.8 100 0. 1 68 0.031520 0.00 022 0. 0 3174 5 3 0 1 The LOC is based on the standard inter - and intra - species uncertainty factors totaling 100 . The FQPA Safety Factor has been reduced to 1X. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC 3 Residential Exposure (Adult Handler) = Inhalation Exposure (Table 6.1) . 4 Total Exposure = ( Avg . Food & Water Exposure + Residential Exposure) 5 Aggregate MOE = [NOAEL 16.8 mg/kg/day /Total Exposure mg/kg/day] **7. 3**  **Chronic Aggregate Risk** Chronic aggregate risk is equivalent to chronic dietary exposure and risk, which is not of concern. Refer to Section 5.4.4. **8.0 Cumulative Exposure/Risk Characterization**  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to methoxyfenozide and any other substances and methoxyfenozide does not appear to produce a toxic metabolite produced by other substances. For the purposes of this action, therefore, EPA has not assumed that methoxyfenozide has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determin e which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulatin g effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. **9.0 Occupational Exposure/Risk Characterization**  Memo, M. Collantes 6/07/2013; D411612 Methox yf enozide is intended for use b y commercial and professional applicators for the control of lepidopterous pests on herbs (subgroup 19A ) except chives, dates, sorghum, and caneberries (subgroup 13 - 07A). In addition, California is requesting a Section 18 for use of Intrepid 2F on dates/palm only . Methoxyfenozide is an insecticide currently registered for use on ornamentals and on numerous agricultural crops, such as dried peas and beans (subgroup 6C;Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **34** of **60** except soy

bean), pomegranate, popcorn, citrus fruits (group 10 - 10), and root vegetables, except s ugar beet (subgroup 1B). It may be applied through a variety of application methods including: aerial, ground equipment (airblast and groundboom), hand held equipment (backpack sprayer, manually- pressurized h andwand and hand gun), and hose end sprayer. Therefore, there is potential for short - and intermediate - term occupational handler and post - application exposure ; long - term exposures are not expected . **9.1 Occupational Handlers**  Based upon the proposed use pattern , HED expects the most highly exposed occupational pesticide handler s cenarios to be :  Mixing/loading liquid for aerial application to orchards (i.e., caneberries) and high acreage field crops (i.e.,herbs and sorghum)  Mixing/loading liquid for airblast to orchards (i.e., caneberries and dates)  Mixing/loading liquid for groundboom to high acreage field crops (i.e., herbs and sorghum)  Mixing/loading liquid for groundboom to low acreage field crops (i.e, caneberries)  Applying spray s via aerial application to orchards (i.e., caneberries) and high acreage field crops (i.e., herbs and sorghum)  Applying spray s via airblast to orchards (i.e., caneberries and dates)  Applying spray s via groundboom to high acreage field crops (i.e.,herbs and sorghum)  Flagger for aerial application to orchards (i.e., caneberries) and high acreage field crops (i.e.,herbs and sorghum)  Mixing/loading/appl yi ng liquid via backpack (ground/soil directed) to orchards (i.e., caneberries and dates)  Mixing/loading/appl yi ng liquid via mechanically pressurized handwand (broadcast foliar and drench) to orchards (i.e., caneberries and dates) Handler exposure is expected to be short - or intermediate - term in duration , based on information provided on proposed labels. However, since the short - and intermediate - term toxicological endpoints are the same; only short - term dermal exposures have be en assessed. HED estimates exposure based on day- 0 residues. Using day- 0 residues to assess intermediate - term exposure does not take into account dissipation of residues over time and thus results in a conservative estimat e . Therefore, the short - term exposure assessment represents the worst case scenario and is protective of intermediate - term exposure. Lo ng - term exposures are not expected , based on the existing and proposed use pattern . No chemical - specific handler exposure data were submitted in support of th e proposed use s , and therefore HED relied on the best available surrogate data to complete the occupational handler assessment . The proposed product label involved in this assessment directs applicators and other handlers to wear long sleeved shirt and long pants, shoes plus socks, and chemical - resistant gloves. HEDMethoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **35** of **60** ty picall y assesses handler exposure using “baseline” clothing ass umptions, and if risks of concern are identified, the use of personal protective equipment (PPE) may be incorporated into the exposure assessment. In the case of methoxyfenozide , there is no toxicity via the dermal route, and onl y inhalation exposures were assessed . **Table 9**  **.1** presents the estimated risks for workers , based on short - term inhalation exposures at baseline (i.e. single layer clothing and no respirator) , and in some situations the use of gloves or engineering controls for aerial applications. Short - term risks for handlers are not of concern (i.e., MOEs were equal to or greater than 100) with inhalation MOEs rang ing from 2 0 , 0 00 to 3,100,000 . No additi onal PPE (i.e., respirators) were needed to achieve MOEs above the LOC of 100. **Table 9**  **.1. Occupational Handler Non -**  **Cancer Exposure and Risk Estimates for Methoxyfenozide**  **. Exposure Scenario**  **Crop or Target Inhalation Unit**  **Exposure (**  **μ g/lb ai)**  **1 Ma** **xim um** 

**Application Rate**  **2 Area** 

**Treated or Am**  **ount Handled**  **Daily 3**  **Inhalation Mitigation Level**  **Dose (m**  **g/k g/day)**  **4 MOE**  **5 Mi** **xer/Loader** Aerial Orchard

(caneberries) 0.219

(no respirator) 0.25 lb ai/A 350 A 0.00024 70,000 High acreage field crop (herbs and sorghum) 1200 A 0.00082 20,000 Groundboom High acreage field

crop (herbs and sorghum) 0.25 lb ai/A 200 A 0.000138 120,000 Airblast Orchard (caneberries

and dates) 0.31 lb ai/A 40 A 0.0027 490,000 **Applicator** Aerial Orchard

(caneberries) 0.0049 0.25 lb ai/A 350 A 0.0000053 3,100,000 High acreage field crop (herbs and sorghum) 1200 A 0.000018 910,000 Groundboom High acreage field

crop (herbs and sorghum) 0.34

(no respirator) 0.25 lb ai/A 200 A 0.000213 79,000 Airblast Orchard (caneberries

and dates) 4.71

(no respirator) 0.31 lb ai/A 40 A 0.00073 23,000

**Flagger** Aerial Orchard and High

acreage field crop (caneberries, herbs and sorghum) 0.35

(no respirator) 0.25 lb ai/A 350 A 0.00038 44,000 **Mi xer/Loader/Applicator**  Back Pack Orchard ( caneberries

and dates) 2.58

(no respirator) 0.0083 lb ai/gal 40 gals 0.000010 1,600,000 Mechanically Pressurized Handgun 3.9 (no respirator) 1000 gals 0.00040 41,000Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **36** of **60** 1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( **[DATE]** ); L evel of mitigation: Baseline, PPE, Eng. Controls. 2 Based on registered or proposed label (Reg. No. 62719 - 442 ). 3 Exposure Science Advisory Council Policy #9.1. 6 Inhalation Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW ( 80 kg). 7 Inhalation MOE = I

nhalation NOAEL ( 16.8 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). **9.2 Post**  **- a**  **pplication Risk**  **9.2. 1**  **Post -**  **application Dermal Exposure** Since there’s no dermal toxicity associated with methoxyfenozide, a dermal post - application exposure and risk assessment was not conducted. **9.2.2. Post**  **- application Inhalation Exposure**  Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for methoxyfenozide at this time primarily because of the low acute inhalation toxicity

(Toxicity Category III and IV), vapor pressure ( 1 x 10 - 7 mm Hg ), and the low proposed use rate (0. 31 lb ai/A). However, there are multiple potential sources of post application inhalatio n exposure to individuals performing post - application activities in previously

treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 4 . The Agency is in the proc ess of evaluating the SAP report as well as available post - application inhalation exposure data generated b y the ARTF and may , as appropriate, develop policies and procedures, to identify the need for and, subsequently , the way

to incorporate occupational post - application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for methoxfenozide . Although a quantitative occupational post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoo rs is likely to result in higher exposure than post - application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post - application inhalation exposure scenarios. Restricted Entry Interval The REI specified on the proposed label is based on the acute toxicity of methoxyfenozide . Methox yf enozide is classified as Toxicity Category III vi a the dermal route and Toxicity Category IV for skin irritation potential. It is not a skin sens itizer. Since a dermal endpoint was not selected a post - application risk estimates were not required for post - application activities. Under 40 CFR 156.208 (c) (2) (iii) , ai’s classified as Acute III or IV for acute dermal, eye 4 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlMethoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **37** of **60** irritation and primary

ski n irrigati on are assigned a 12 - hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim REIof 12 hours is adequate to protect agricultural workers from post - application exposures to methoxyfenozide . However, methox yfenozide is no t classified as a carcinogen or a neurotoxicant, nor is it associated with known reproductive or developmental effects. Therefore , methoxyfenozide is a candidate for a 4 - hour REIwhich appears on the proposed supplemental and master label . **10.0 References**  D 407758 . Methox yfenozide. Petition to Establish Permanent Tolerances (and Section 3 Registration) for Residues Resulting from Food/Feed Uses of the Insecticide on Herbs (Subgroup 19A) Except Chives, Caneberries (Subgroup 13 - 07A), Dates and So rghum; to Update Pome Fruits from Group 11 to 11 - 10, and Fruiting Vegetables from Group 8 to 8 - 10; to Extend the Tolerance in Grapes to Small Vine Climbing Fruits Except Fuzzy Kiwifruit (S ubgroup 13 - 07F), the Tolerance in Strawberries to Low Growing Berrie s (Subgroup 13 - 07G) Except Cranberry , and the Tolerance in Avocadoes to Various Tropical Tree Fruits; to Delete the Tolerances in Dried Shelled Peas and Beans and Add a Tolerance in Subgroup 6C; and to Establish Rotational Crop Tolerances in the Rapeseed ( Subgroup 20A) and Sunflower (Subgroup 20B) Oilseed Subgroups. Summary

of Analy tical Chemistry

and Residue Data. W. Drew , 7/16 /1 3 D 407566 . Drinking Water Assessment for the IR - 4 New Use Petitions for the Use of Methox yf enozide on Herb Subgroup 19A (except chives), Dates, Sorghum, Fruiting Vegetable Group 8 - 10, Pome Fruit Group 11 - 10, Berry Subgroup s 13 - 07 A, F & G and Tropical Tree Fruits . K. Milians , 4 /23/13 . D 412460 . Methox yfenozide. Chronic Aggregate Dietary ( Food and Drinki ng Water) Exposure and Risk Assess ment for the Section 3 Registration on Herbs (Subgroup 19A) Except Chives, Caneberries (Subgroup 13 - 07A), Dates and Sorghum; to Establish Rotational Crop Tolerances in the Rapeseed (Subgroup 20A) and Sunflower (Subgroup 20B) Oilseed Subgrou ps; as well as to extend and update Crop Group Tolerances on Multiple Commodities. E. Holman , 7 / 16 /201 3 . D394924. Methox yfenozide . Occupational and Residential Exposure Assessment for New Uses on Root Vegetables and Citrus . M. Collantes , 2 /27 /1 2 . D394924. Methox yfenozide **.** Occupational and Residential Exposure Assessment for a Proposed Use on Dates, Sorghum, Herbs (subgroup 19A except chives) and Caneberries (subgroup 13 - 07A). M. Collantes, 6 /7/1 3 . D258034. PP#8F5004 & PP#8F5006: Methoxyfenozi de. Conclusions of the 7/13/99 Meeting of the Metabolism Assessment Review Committee. W. Wassell, 7/13/99 . M ethox yf enozide: Summary

of Hazard and Science Policy Council (HASPOC) Meeting of March 29, 2012: Recommendation on the need for a 28 - day inhalation study . K. Rury and J. Van Alstine, 03/23/12 .Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **38** of **60** 

### A **ppendix A**  **. Toxicology	Profile	and	Executive	Summaries**  **A.1 Toxicology Data Requirements**  The requirements (40 CFR 158.340) for food use for me thoxyfenozide are in Table 1. Use of the ne w guideline numbers does not imply that the new (1998) guideline protocols were used. **Study Technical**  **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 Subchronic (rodent) ................................ ............... 870.3150 Oral Subchronic (nonrodent) ................................ ......... 870.3200 21 - Day

Dermal ................................ .............................. 870.3250 90 - Day

Dermal ................................ .............................. 870.3465 28 - or 90 - Day Inhalation ................................ ................ yes yes yes no no* yes

yes yes

- no 870.3700a Developmental Toxicity (rodent) ................................ ... 870.3700b Developmental Toxicity (nonrodent) ............................. 870.3800 Reproduction ................................ ................................ . yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) ................................ .............. 870.4100b Chronic Toxicity (nonrodent) ................................ ........ 870.4200a Oncogenicity (rat) ................................ .......................... 870.4200b 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 ................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations ... 870.5xxx Mutagenicity

—Other Genotoxic Effects ....................... yes yes yes yes yes

yes yes yes 870.6100a Acute Delayed Neurotoxicity (hen) ............................... 870.6100b 90 - Day

Neurotoxicity (hen) ................................ ........... 870.6200a Acute Neurotoxicity Screening Battery (rat) ................. 870.6200b 90 - Day

Neurotoxicity Screening Battery (rat) ............... 870.6300 Develop. Neurotoxicity ................................ ................. no no yes yes no -

- yes yes

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

yes yes Special Studies for Ocular Effects

Ac ute Oral (rat) ................................ ........................... Subchronic Oral (rat) ................................ .................. Six - mo nth Oral (dog) ................................ .................. no no no -

-

- * The required repeated dose inhalation toxicity study has been waived.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **39** of **60 A.2**  **Toxicity Profiles Table A.2.1**  **Acute Toxicity Profile –**  **Methoxyfenozide technical Guideline No.**  **Study Type MRID(s)**  **Results Toxicity Category**  870.1100 Ac ute oral [rat] 44144415 LD 50 > 5000 mg/kg, both sexes IV 870.1100 Ac ute oral [mouse] 44144416 LD 50 >5000 mg/kg, both sexes IV 870.1200 Ac ute dermal [rat] 44144418 LD 50 >2000 mg/kg, both sexes III 870.1300 Ac ute inhalation [rat] 44144420 LC 50 >4.3 mg/L, both sexes IV 870.2400 Ac ute eye irritation [rabbit] 44144422 Very mild irritant IV 870.2500 Ac ute dermal irritation [rabbit] 44144424 Not an irritant IV 870.2600 Skin sensitization [Guinea pig] 44144426 Not a sensitizer N/A **Table A.2.2 Subchronic, Chronic and Other Toxicity**  **Profile Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** Nonguideline 2 - week oral

range - finding (rat) 44617722 (1995)

Acceptable/nonguideline 0, 5 0, 25 0, 10 00 , 5000, 20,000 ppm in the diet [note: mg/kg/day equivalents not calculated; see 90 - day

oral rat for mg/kg/day] NOAEL = 250 ppm (approximately 17.0/19.1 mg/kg/day M/F based on main study doses) LOAEL = 1000 ppm (approximately 69.3/72.4 mg/kg/day M/F based on main study doses), based on thyroid gland hypertrophy/hyperpla sia in males and females, and increased adrenal hypertrophy of zona fasciculata in females. At ≥5000 ppm , increased abs/rel liver and adrenal weights, hepatocellular hypertrophy 870.3100 90 - Day

oral toxicity (rat) 44617722 (1995)

Acceptable/guideline 0, 5 0, 25 0, 10 00 , 5000, 20,000 ppm in the diet M: 0, 3.4 , 17.0 , 69.3, 353.4, 1368.8 mg/kg/d ay F: 0, 3.7 , 19.1 , 72.4, 379.3, 1531.2 mg/kg/d ay NOAEL = 69.3/72.4 mg/kg/day [M/F] LOAEL = 353.4 mg/kg/day [M/F] based on periportal hepatocellular hypertrophy and increased liver weight. At 1368.8/1531.2 mg/kg/day: decreased RBC and Hg in females.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **40** of **60 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile**  **Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results**  870.3100 90 - Day

oral toxicity (mouse) 44617723 (1995)

Acceptable/guideline 0, 70, 700, 2500, 7000 ppm in the diet M: 0, 11.9, 112.5, 428.2, 1149.3 mg/kg/day; F: 0, 17.4, 165.1, 589.4, 1742.1 mg/kg/day NOAEL = 428.2/589.4 mg/kg/day [M/F] LOAEL = 1149.3/1742.1 mg/kg/day [M/F] based on decreased body weight gain.

Nonguideline 2 - week range finding (dog) 44617724 (1995)

Acceptable/nonguideline 0, 300, 3500, 15,000 or 30,000 ppm in the diet (2 animals/sex/dose) M: 0, 11.7 - 14.7, 141.6 - 167.6, 264.7 - 370.4, 571.4 - 631.7, 1113.7 - 1337.0 mg/kg/day; F: 0, 13.3 - 16.8, 90.8 - 184.8, 285.9 - 336.8, 582.3 - 630.9, 1092.6 - 1169.1 mg/kg/day NOAEL = 11.7 - 14.7/13.3 - 16.8 mg/kg/day [M/F] LOAEL = 141.6 - 167.6/90.8 - 184.8 mg/kg/day [M/F], based on hematological changes (decreased RBC parameters, increased Heinz body count, reticulocyte counts, erythrocyte mo rphology and methemoglobinemia) and increased spleen wei ghts. At ≥264.7 mg/kg/day, bilirubinemia

870.3150 90 - Day

oral toxicity (dog) 44617724 (1995)

Acceptable/guideline 0, 15, 50, 500 or 5000 ppm in the diet M: 0, 0.6, 2.0, 21.4, 197.5 mg/kg/day; F: 0, 0.6, 1.9, 20.4, 208.8 mg/kg/day NOAEL = 197.5/208.8 mg/kg/day [M/F] LOAEL >197.5/208.8 mg/kg/day [M/F](HDT).

870.3200 28 - Day

dermal toxicity (rat) 44517725 (1998)

Acceptable/guideline 0, 75, 300, 1000 mg/kg/day Sy stemic NOAEL = 1000 mg/kg/day Sy stemic LOAEL > 1000 mg/kg/day (HDT) Local dermal NOAEL = 1000 mg/kg/day Local dermal LOAEL > 1000 mg/kg/day (HDT) 870.3700a Prenatal

developmental in (rat) 44638201 (1994)

Acceptable/guideline 0, 100, 300, 1000 mg/kg/day (gavage) **Maternal** NOAEL = 1000 mg/kg/day LOAEL >1000 mg/kg/day (HDT) **Developm ental**  NOAEL = 1000 mg/kg/day LOAEL >1000 mg/kg/day (HDT)Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **41** of **60 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile**  **Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results**  870.3700b Prenatal

developmental in (rabbit) 44617726 (1997)

Acceptable/guideline 0, 100, 300, 1000 mg/kg/day (gavage) **Materna** l NOAEL = 1000 mg/kg/day LOAEL > 1000 mg/kg/day (HDT) **Developm enta**  l NOAEL = 1000 mg/kg/day LOAEL > 1000 mg/kg/day (HDT) 870.3800 Reproduction

and fertility effects (rat) 44617727 (1997)

Acceptable/guideline 0, 200, 2000 or 20,000 ppm in diet P1 males: 0, 15.4, 153.4 or 1551.9 mg/kg/day; P1 females: 0, 17.9, 180.7, 1820.7 mg/kg/day **Parental/System ic**  NOAEL = 153.4/180.7 mg/kg/day [M/F]; LOAEL = 1551.9/1820.7 mg/kg/day [M/F] based on increased absolute and relative liver weights and microscopic midzonal to periportal hepatocellular hypertrophy. **Reproductive** NOAEL = 1551.9/182 0.7 mg/kg/day [M/F]; LOAEL > 1551.9/1820.7 mg/kg/day [M/F](HDT) **Offspring** NOAEL = mg/kg/day LOAEL > 1551.9/1820.7 mg/kg/day [M/F](HDT) 870.4100a Chronic toxicity

(rat) See 870.4300 870.4100b Chronic toxicity

(dog) 44617728 (1997)

Acceptable/guideline 0, 60, 300, 3000 or 30,000 ppm in diet M: 0, 2.2, 9.8, 106.1, 1152.4 mg/kg/day F: 0, 2.2, 12.6, 110.6, 1199.2 mg/kg/day NOAEL = 9.8/12.6 mg/kg/day [M/F] LOAEL = 106.1/110.6 mg/kg/day [M/F] based on mild hematological changes (decreased RBC parameters, slight methemoglobinemia) and increased serum bilirubin. Hematological effects first observed at week 14. At 1152.4/1199.2 mg/kg/day: bilirubinemia in male s, increased abs/rel liver and thyroid weights, increased cellularity of sternum and rib marrow , increased pigmented macrophages in liver and spleen. 870.4200 Carcinogenicity

(rat) 44617731 (1998)

Acceptable/guideline 0, 200, 8000 or 20,000 ppm in diet M: 0, 10.2, 411 or 1045 mg/kg/day F: 0, 11.9, 491 or 1248 mg/kg/day NOAEL = 10.2/11.9 mg/kg/day [M/F] LOAEL = 411/491 mg/kg/day [M/F] based on hematological changes (decreased RBC parameters), periportal liver hypertrophy, thyroid hypertrophy and altered colloid; possibly increased adrenal weight. At 1045/1248 mg/kg/day: decreased survival in males, decreased body weight in females, increased abs/rel liver weight, chronic progressive glomerulonephropathy, tissue mineralization. **no evidence of carcinogenicity**Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **42** of **60 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile**  **Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results**  870.4300 Carcinogenicity

(mouse) 44617729 (1998)

Acceptable/guideline 0, 70, 2800, 7000 ppm M: 0, 10.0, 40.5 or 1020 mg/kg/day F: 0, 12.8, 529 or 1354 mg/kg/day NOAEL = 1020/1354 mg/kg/day [M/F] LOAEL >1020/1354 mg/kg/day [M/F](HDT) **no evidence of carcinogenicity**

Gene Mutation 870. 5100 Bacterial reverse

gene mutation - Salmonella 44144428 (1995)

Acceptable/guideline 0, 50, 200, 500, 2000, 5000 μg/plate, initial assay; 0, 160, 300, 500, 900, 1600 μg/plate, repeat assay No evidence of mutagenicity with or without S9 activation up to solubility limit (precipitation observed at ≥900 μg/plate).

Gene Mutation 870.5100 Bacterial reverse

gene mutation - Salmonella 44617733 (1998)

Acceptable/guideline 0, 50, 200, 500, 2000, 5000 μg/plate, test material: RH - 117,236 (Metabolite M - B) No evidence of mutagenicity with or without S9 activation up to solubility limit (precipitation observed at 2000 and 5000 μg/plate)

In Vitro Mammalian Gene Mutation 870.5300 HGPRT forward

gene mutation assay (Chinese hamster ovary, or CHO, cells) 44617734 (1994)

Acceptable/guideline 0, 0.1, 0.5, 1.0, 5.0, 10, 50, 100, 500, 1000, 1250 μg/mL (range - finding study); 0.5, 1.0, 5.0, 10, 50, 100 μg/mL (definitive study) No evidence of mutagenicity with or without S9 activation up to solubility limit (precipitation observed at ≥100 μg/mL) .

In Vitro Cy togenetics 870.5375 Chromosomal

aberration, CHO cells 44617735 (1994)

Acceptable/guideline 0, 0.21, 0.63, 2.1, 6.3, 21, 63, 108, 625, 1250 μg/mL (range - finding study); 0, 13, 125, 100, 150 μg/mL (definitive study) No evidence of increased frequency of chromosomal aberration in the presence or absence of S9 activation up doses causing reduced mitotic indices ( ≥50 μg/mL ).

Other Effects 870.5395 In vivo mo use

micronucleus assay 44617801 (1995)

Acceptable/nonguideline 0, 500, 2500, 5000 mg/kg single IP dose No evidence of increased frequency of micronucleus formation in treated CD - 1mice in bone marrow

at 24 or 48 hrs postdosing; tested up to the limit dose for this assay.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **43** of **60 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile**  **Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results**  870.6200a Ac ute

neurotoxicity screening battery (rat) 44617802 (1996)

Acceptable/guideline 0, 1000, 2000 mg/kg by gavage NOAEL = 1000 mg/kg (males); 2000 mg/kg (females; HDT) LOAEL = 2000 mg/kg (males) based on decreased hindlimb grip strength on Day 0; >2000 mg/kg females (HDT) 870.6200b Subchronic

neurotoxicity screening battery (rat) 44617803 (1996)

Acceptable/guideline 0, 200, 2000 or 20,000 ppm in diet Males 0, 13, 130, 1318 mg/kg/day Females 0, 16, 159, 1577 mg/kg/day NOAEL = 1318/1577 mg/kg/day [M/F]; LOAEL > 1318/1577 mg/kg/day [M/F] (HDT)

870.7485 Metabolism and

pharmacokinetics (rat) 44617804 (1998)

Acceptable/guideline Single gavage doses of 10 mg/kg and 1000 mg/kg; 5 - day repeated gavage doses of 10 mg/kg Absorption and excretion were rapid (<48 hrs postdosing ). Tissue distribution was extensive but bioaccumulation was not observed. Major route of excretion was via feces (86 - 97%) and to a lesser extent, the urine (5 - 13%). Enterohepatic circulation was observed. The primary routes of metabolism were O demethylation and oxidative hydroxylation followed by conjugation with glucuronic acid. 870.7600 Dermal

penetration (rat) 44638202 (1998)

Acceptable/guideline Mean dermal absorption at 10 and 24 hrs was 2% using an 80WP formulation. 870.7800 Immunotoxicity

(female rat) 48592601 (2011)

Acceptable/guideline 0, 76.9, 324 or 1076 mg/kg/day in the diet (ppm not indicated) Immunotoxicity NOAEL = 1076 mg/kg/day

Immunotoxicity LOAEL = not established Sy stemic toxicity NOAEL = = 76.9 mg/kg/day Sy stemic toxicity LOAEL = 324 mg/kg/day, based on increased liver weights.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **44** of **60 A.3**  **Hazard Identification and Endpoint Selection A.3.1**  **Acute Reference Dose (aRfD) –**  **All Populations including Infants and Children and Females age 13**  **- 49**  An acute reference dose for methoxyfenozide was not selected. An appropriate toxicity dose and endpoint were not identified that could be attributed to a single exposure. D ecreased hindlimb grip strength in male rats in the acute neurotoxicity s tudy w as only o bserved at the limit d ose of 2000 mg/kg on the day

of dosing. **A.3.2 Chronic Reference Dose (cRfD**  **) Study Selected:**  Chronic Feeding - Rat and Dog (co - critical studies) **MRID Nos.:** 44617731 (rat) and 44617728 (dog) **Executive Summar**  **ies :**  See Appendix A, Guideline [§ 870.3150 (dog study) and 870.3500 (rat study) ] **Dose and**  **Endpoint for**  **Risk Assessment:**  NOAEL = 10.2 mg/kg/day (rat study) , based on hematological changes (decreased RBC counts, hemoglobin concentrations, and/or hematocrit in males and females), liver effects (incre ased liver weights in males; periportal hepatocellular hy pertrophy i n males and females), histopathological changes in the thy roid (increased follicular cell hy pertrophy , altered colloid in males) and possible adrenal toxicity ( increased adrenal weights in males and females) seen at the LOAEL= 411 mg/kg/day . Supported by the co critical chronic dog NOAEL=9 .8 mg/kg/day , based on mild hematological changes (decreased RBC counts, hemoglobin concentrations and/or hematocrit in males and females; slight meth emoglobinemia in males and females; increased platelets in males) and clinical chemistry changes (increased total serum bilirubin in males and females; slightl y increased severity o f bilirubinemia in males) seen at the LOAEL = 106 mg/kg/day . **Comments abo**  **ut Study/Endpoint/Uncertainty**  **Factors:** These studies were selected because they w ere of the appropriate duration (chronic) and route of exposure (dietary) and provided the most sensitive doses and endpoints. T hey w ere selected as co - critical because of their similar NOAELs, both of which provide a cRfD of 0.10 mg/kg/day . T he selected dose is protective of potential hematological, hepatic and thy roid effects identified in two - week dietary s tudies in the rat and dog, which identified slightly h igher NOAEL s (see A.3.5, below), as well as potential developmental effects. Ac ombined UF of 100x was utilized ( 10X each to account for inter - and intra - species variability). **A.3.3 Incidental Oral Exposure (Short** **- and Intermediate**  **- Term)**  An incidental oral expos ure dose and endpoint were not selected. Methox yfenozide may be used on ornamental plants in a residential setting. However, post - application incidental oral exposure is not expected since the extent to which young children engage in prolonged play or other activities involving such areas is low, and this assessment was not performed.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **45** of **60 A.3.4**  **Dermal Exposure (Short -**  **and Intermediate -**  **Term )**  A dose and endpoint for dermal exposure were not selected, based on the lack of toxicity in the rat dermal exposure study and a dermal absorption study demonstrating low (about 2%) absorption of methox yfenozide in the 80WP formulation. An oral study was not selected because the appropriate studies either showed no toxicity at any dose tested, or the parameters affected in oral studies (e.g., hematologic changes) were examined but showed no treatment related changes in the dermal study . **A.3.5 Inhalation Exposure (Short**  **- and Intermediate**  **- Term)**  **Study Selected:** T wo - week range - finding study for the subchronic dietary study in the dog **MRID No. :**  44617722 **Executive Summary :**  See Appendix A, Guideline [§ 870.3150] **Dose and**  **Endpoint for**  **Risk Assessment:**  NOAEL=1 6.8 mg/kg/day , based on hematological changes seen at LOAEL = 90.8 mg/kg/day . **Comments about**  **Study/Endpoint/Uncertainty Fa**  **ctors:** No short - term or subchronic inhalation toxicity

s tudies were available; an oral study w as therefore selected for route - to - route extrapolation. T he dog 2 - week dietary range - finding study

w as selected b ecause it is of an appropriate duration and it identified the most sensitive dose and endpoint for this exposure scenario. Findings included hematological effects (including decreased RBC counts, decreased hemoglobin concentrations, Heinz bodies and change s in RBC morphology , increased reticulocy te counts and methemoglobinemia). T he range - finding study w as selected in lieu of the 90 - day

s ubchronic dog study

b ecause no effects were reported at doses up to about 200 mg/kg/day . H owever, in the chronic dog study , mild hematological changes were reported at 14 weeks at the LOAEL of 106 mg/kg/day , with a NOAEL of 9.8 mg/kg/day . T he reason for the earl y effects is unclear, but it may reflect adaptation of the animals to the test material. A similar circumstance was observed with the rat two - week and 90 - day dietary studies: thy

roid and adrenal effects were observed at lower dose levels in the two - week study ( 1000 ppm, or estimated 69 mg/kg/day

w ith a NOAELo f 250 ppm or 17 mg/kg/day) whereas the subchronic NOAEL was 1000 ppm with a LOAEL of 5000 ppm or 353 mg/kg/day) , based on liver weight increases and hy

pertrophy . D ecreased body w eight was observed in the subchronic mouse dietary study , but no effects were seen in the 18 - month carcinogenicity study . Because o nl y two animals/sex/dose were in each dose group, the NOAEL and LOAEL for this risk assessment were selected from the highest NOAEL and lowest LOAELf rom individual animals’ average daily

c ompound intake. T he selected dose and endpoint are considered to b e conservative endpoints that provide protection from potential hematological effects, which may be transient at the selected study L OAEL, based on the lack of effects in the subchronic dog study . T he study

i s protective of potential developmental effects , because no developmental or offspring toxicity

w as observed in any

o f the available developmental and reproductive toxicity studies. A lthough a repeated - dose inhalation toxicity s tudy i s not available, the oral study i s considered adequatel y protective, based on the conservative endpoint selected, low vapor pressure of methoxyfenozide, low application rate for current use patterns, and low acute inhalation toxicity ; a 10X UF DB is therefore not required. A combined UF of 100x was utilized ( 10X each to ac count for inter - and intra - species variability).Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **46** of **60 A.4**  **Executive Summaries A.4.1**  **Subchronic Toxicity 870.3100**  **90 -**  **Day Oral Toxicity -**  **Rat** In a subchronic oral toxicity study (M RID No. 44617722), methoxyfenozide technical (99.2% purity , Lot No. WS - 10395, TD No. 92 - 014 ) was administered by dietary admix to Charles River Crl:CD BR rats (10/sex/group) at doses of 0 , 50, 250, 1000, 5000 or 20,000 (limit dose) ppm ( equivalent to average daily intakes of 0, 3.4, 17.0, 69.3, 353.4 or 1368.8 mg/kg/day i n males and 0,3.7, 19.1, 72.4, 379.3 and 1,531.2 mg/kg/day in females ) for 13 weeks. The following parameters were examined: mortality , clinical signs, body weights, food consumption, ophthalmology , hematology , clinical chemistry , urinaly sis, organ weight s, macroscopic pathology and microscopic pathology . The following effects were observed: a statistically significant reduction in red blood cells and hemoglobin in 20,000 ppm females (7 - 8% less than controls) and slight or moderate periportal hepatocellul ar h yp ertrophy in all 5000 and 20,000 ppm males and females compared with none observed in controls or lower dose rats. There were statistically significant increases in relative to - body weight liver weights in 5000 and 20,000 ppm males as well as in 20,00 0 ppm females (11 - 16% above controls) . There were increases in absolute liver weights in both sexes at 5000 and 20,000 ppm when compared to controls (+7 to 13% in mal es and +9 to 10% in females), however these increases were not statisticall y significant. [ It is n oted that in the 2 - week range - finding study, which tested at 0, 50, 250, 1000, 5000 and 20,000 ppm, some effects were observed which were not observed in the 13 - week study , and these findings were seen at a lower dose than the LOAEL for the subchronic study . At 1000 ppm, follicular cell thy

roid follicular cell hy

pertrophy /hy perplasia in 3/5 males and 2/5 females, and minimal hy

pertrophy of the adrenal gland zona fasciculata in 1/5 female (all vs. 0/5 controls) were observed; these effects were also seen at higher doses. At ≥5000 ppm, liver absolute and relative weights in males, adrenal absolute and relative weights in females, and hepatocellular hy pertrophy in females were also increased. Necrosis of hepatocy tes was observed in males at 20,000 ppm.] **The LOAEL (subchronic study only)**  **is 5000 ppm (353.4/379.3 mg/kg/day, males/females) ,**  **based on effects on the liver (increased absolu te and relative weights, and**  **periportal hepatocellular hypertrophy in both sexes).**  **The NOAEL is 1000 ppm (69.3/7**  **2.4 mg/kg/day in males/females).**  Th is study

is classified A cceptable/guideline and satisfies the data requirement for OPPTS §870.3100 for a three - month oral toxicity study in rats. **870.3100 90**  **- Day Oral Toxicity**  **- Mouse**  In a. subchronic toxicity

study (M RID No. 44617723), methoxyfenozide technical (99.2% purity , Lot No. WS - 10395, TD No. 92 - 014 ) was administered b y dietary admix to Charles RiverMethoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **47** of **60** Crl:CD - 1 (I CR) BR VAF/+ mice (10/sex/group) at doses of 0, 70, 700, 2500 or 7000 ppm ( equivalent to average da ily intakes of 0, 11.9, 112.5, 428.2 or 1149.3 mg/kg/day in males and 0, 17.4, 165.1, 589.4 and 1742.1 mg/kg/day in females ) for 13 weeks. The following parameters were examined: mortality, clinical signs, body weights, feed consumption, hematology, clinic al chemistry , organ weights, macroscopic pathology and microscopic pathology . There were no clinical signs and all mice survived until scheduled sacrifice. Body weight gains in the 7,000 ppm group were less than respective controls for males (18%) and fem ales (15%) for the 13 - week period. Food consumption did not appear to be altered. There were no apparent effects on the following parameters: hematology , clinical chemistry , organ weights, macroscopic pathology or microscopic pathology . **The LOAEL is 7000 ppm (**  **1149.3/1742.1 mg/kg/day**  **in males**  **/ females**  **; lim**  **it dose) ,**  **based on a decrease in body weight gain in males and females.**  **The NOAEL is 2500 ppm (428.2**  **/589.4 mg/kg/day**  **in males/f emales**  **) .**  This study

is classified acceptable/ guideline and satisfies the data requirement for a subchronic oral toxicity

study in the mouse ( OPPTS §870.3100 ) . **870.3150 90**  **- Day Oral Toxicity**  **- Dog**  In a subchronic toxicity

study (MRID No.44617724), methoxyfenozide technical (99.8% purity , Lot No. WS - 10395, TD No. 92 - 014 ) was admi nistered b y dietary admix to Hazleton Research Products beagle dogs (4/sex/group) at doses of 0, 15, 50, 500 or 5000 ppm ( equivalent to average daily intakes of 0, 0.6, 2.0, 21.4 or 197.5 mg/kg/day in males and 0, 0.6, 1.9, 20.4 or 208.8 mg/kg/day

in femal es ) for 13 weeks. The 15 ppm group was then dosed for an additional 2 weeks at 15 ppm , followed by an increase in dose to 15,000 ppm for another 6 weeks. The doses in mg/kg/day

for the additional 6 weeks were 422.0 mg/kg/day for males and 460.4 mg/kg/day for females. No control animals were kept beyond the original 13 weeks for comparison with these higher dose levels. The following parameters were examined : mortality , clinical signs, ophthalmology , body

weights, feed consumption, hematology , clinical ch emistry , urinal ys is, organ weights, macroscopic pathology and microscopic pathology . There was the suggestion (no statistical significance) that 5000 ppm caused a decrease in body weight gain in both sexes over the 13 - week period (males: controls = 3.7 kg , 5000 ppm 3.3 kg; females: controls = 3.0 kg, 5000 ppm = 2.4 kg). However, these differences were not considered sufficient to establish an adverse effect. All dogs treated with 15,000 ppm for the 6 additional weeks gained weight. However, there was no additional control group with which to compare the results. No other parameters were affected by test article administration. [Results of a two week range - finding study were also provided in this report, which dosed 2 dogs/sex/group at 0, 300, 3500, 7000 , 15,000 or 30,000 ppm (equivalent to individual animal intakes of 0, 11.7 - 14.7, 141.6 - 167.6, 264.7 - 370.4, 571.4 - 631.7 or 1113.7 - 1337.0 mg/kg/day for males and 0, 13.3 - 16.8, 90.8 - 184.8, 285.9 - 336.8, 582.3 - 630.9 or 1092.6 - 1169.1 mg/kg/day for females). Although there were no clear - cut definitive effects on any hematology parameters in th e 13 - week study, in the 2 - week range - finding study , there were decreases for all animals ofMethoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **48** of **60** both sexes in RBC count (13 - 20%), hemoglobin (9 - 18%) and hematoc rit (8 - 16%) for all animals of both sexes at ≥ 3500 ppm after two weeks when compared with the pre - dose values. Methemoglobinemia and abnormal RBC morphology (Heinz bodies, Howell - Jolly bodies, polychromasia) were reported as well. Increased spleen weights were also observed at ≥ 3500 ppm . Bilirubinemia was observed at ≥7000 ppm in males. No effects were identified in the range - finding study at 300 ppm. **The NOAEL (subchronic study only) is 5000 ppm (197.5/208.8 mg/kg/day, males/females; HDT). A LOAEL was not determine**  **d (>5000 ppm).** This study

is classified acceptable/ guideline and satisfies the data requirement for a three - month toxicity study in dogs ( OPPTS §870.3150 ) . Although a LOAEL was not achieved, toxicity was observed in a two - week range - finding study and an acceptable chronic dog toxicity study is available (MRID 44617728). **870.3200 28**  **- Day Dermal Toxicity**  **– Rat**  In a 28 - day

repeated dose dermal toxicity study (MRID 44617725), groups of 10 male and 10 female Crl:CD®BR rats were treated with RH - 2485 Technical (98%, Lot No. 1) , by dermal application to shaved skin moistened with tap water and held in place by dermal occlusion , at doses of 0, 75, 300, or 1000 mg/kg/day for 6 hours/day , 5 day s/week. No mortality

was reco rded, and there were no clinical signs indicative of s ystemic toxicity at any treatment level. No treatment - related dermal irritation was produced. Additionally, there were no treatment - related effects on body weight, food consumption, absolute or relative organ weight, hematology , or clinical chemistry in either sex of rats. No gross or microscopic changes in either sex were found to be caused by the treatments. **The systemic NOAEL is 1000 mg/kg/day (HDT). The systemic LOAEL was not determined for either**  **male or female rats (>1000 mg/kg/day). The dermal NOAEL was 1000 mg/kg/day. The dermal LOAEL was not established (>1000 mg/kg/day).**  This study

is classified as Acceptable/guideline and satisfies the guideline requirement for a 28 - day dermal study

in rats ( OPPTS § 870.3200 ). Although a LOAEL was not established, the highest dose tested (1000 mg/kg) is the limit dose. **870.3465 90**  **- Day Inhalation**  **– Rat**  Not required and not submitted **A.4.2 Prenatal Developmental Toxicity**  **870.3700a Prenatal Developmental T oxicity Study**  **- Rat**  In a developmental toxicity study (MRID No. 44638201), methoxyfenozide technical (99.2% purity) was administered by gavage to Charles River Crl:CD BR VAF/Plus (Sprague - Dawley)Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **49** of **60** rats (25/group) at doses of 0 (0.5% aqueous methylcellulose vehicle), 100, 300 or 1,000 mg/kg/day

on gestation day s 6 through 15. The following parameters were examined: maternal (clinical signs, morbidity, mortality , body weights, food consumption, corpo ra lutea, implantation sites, resorption sites, abdominal/thoracic cavities and the position of live/dead fetuses) and fetuses (weights, external changes, Bouin’s soft tissue examination and skeletal changes). **Maternal toxicity**  **:** T here were no deaths or c linical signs, nor where there any effects on body weights or food consumption. No changes were noted in any of the reproductive parameters. **The maternal NOAEL is 1,000 mg/kg/day (HDT, limit dose). A maternal LOAEL was not determined (>1,000 mg/kg/day).**  **Developmental toxicity :**  Fetal examinations did not reveal any affects on body weight or gross/visceral/skeletal aspects. **The developmental NOAEL is 1,000 mg/kg/day. A developmental LOAEL was not determined (>1,000 mg/kg/day).**  This study

is classified Acceptable/guideline and satisfies the guideline criteria for a developmental toxicity

study in the rat (OPPTS §870.3700a). **870.3700b Prenatal Developmental Toxicity Study -**  **Rabbit** In a developmental toxicity study (MRID No. 44617726), methoxyfenozide technical (98.0% purity) was administered by gavage to Hazleton Research Products New Zealand White rabbits (16/group) at doses of 0 (0.5% aqueous methyl cellulose vehicle), 100, 300 or 1,000 mg/kg/day on gestation day s 7 through 19. The following paramete rs were examined: maternal (clinical signs, morbidity , mortality , body weights, food consumption, corpora lutea, implantation sites, resorption sites, abdominal/thoracic cavities and the position of live/dead fetuses) and fetuses (weights, external changes , soft tissue examination, brain, eyes and skeletal changes). **Maternal toxicity**  **:** T here were no deaths or clinical signs, nor where there any effects on body weights or food consumption. No changes were noted in any of the reproductive parameters. **The m aternal NOAEL is 1,000 mg/kg/day (HDT, limit dose). A maternal LOAEL was not**  **determined (>1,000 mg/kg/day). Developmental toxicity**  **:** Fetal examinations did not reveal any affects on body weight or gross/visceral/skeletal aspects. **The developmental NOAEL is 1,000 mg/kg/day. A**  **developmental LOAEL was not determined (>1,000 mg/kg/day).** This study

is classified Acceptable/guideline and satisfies the guideline criteria for a developmental toxicity

study in the rabbit (OPPTS §870.3700b). **A.4.3 Reproductive**  **Toxicity 870.3800 Reproduction and Fertility Effects**  **- Rat** Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **50** of **60** In a two - generation reproduction study (MRID 44617727), RH - 2485 Technical (98.0% a.i.) was administered to 30 Crl:CD®BR rats/sex/dose in the diet at concentrations of 0, 200, 2000, or 20,000 pp m (equivalent to average dail y intake for P 1 males of 0, 15.4, 153.4, or 1551.9 mg/kg/day , respectivel y; for P 1 females of 0, 17.9, 180.7, or 1820.7 mg/kg/day , respectivel y; for P 2 males of 0, 19.1, 193.1, or 1956.0 mg/kg/day , respectivel y; and for P 2 females of 0, 20.4, 202.7, or 2036.5 mg/kg/day , respectivel y). Treatment was continuous throughout the study. The two parental generations, P 1 and P 2 , produced one litter of pups each (F 1 and F 2 , respectivel y). The parental animals received the test di et for 10 weeks before mating and throughout mating, pregnancy , and lactation of their litters. Pups were selected from the F 1 litters to parent the F 2 generation. The P 1 generation produced 22 to 27 litters/group consisting of liveborn pups, the P 2 generation produced 24 to 28 liveborn litters/group. Parental toxicity : In this study , the target organ for the sy stemic toxicity of RH - 2485 Technical to adult rats was the liver. For the P 1 and P 2 males and females exposed to 20,000 ppm, the absolute and relative terminal liver weights were significantl y increased by 13 to 27% (p<0.05), in comparison to control values. Microscopic changes in the liver included midzonal to periportal hepatocellular hy pertrophy in all of the animals of both generations at 20,000 ppm, and in females, onl y, at 2000 ppm. The incidence rates for hepatocellular hypertrophy at 0, 200, 2,000 and 20,000 ppm were as follows: 0/30, 0/30, 0/30, and 30/30 (100%), respectivel y, for the P 1 and P 2 males: 0/30, 0/30, 4/30 (13.3%) and 30/30 (100%), respectivel y, for the P 1 females; and 0/30, 0/30, 1/30 (3.3%), and 30/30 (100%), respectively, for the P 2 females. Statistically

significant reductions (p<0.05) in body weights and cumu lative body weight gains were observed among the high - dose P 1 males during the last 12 weeks of the study ; however, the reductions were never more than 7% ( p<0.05), in comparison to control values; the overall body weight gain (weeks 0 - 20) for this group was depressed by 10% (p<0.05). Body

weights, food consumption, and body- weight gains were comparable to, or significantl y higher than, control values for the P 2 males throughout the study and for the P 1 and P 2 females during premating, gestation, and lact ation. Therefore, the biological significance of the reduced body weights of the P 1 males is questionable. The following parameters of sy stemic toxicity were comparable for RH - 2485 Technical - treated and control P 1 and P 2 males and females: mortality, cli nical signs, gross pathology , relative and absolute terminal weights of the reproductive organs, and microscopic pathology of the reproductive organs. **The LOAEL for parental toxicity is 20,000 ppm (1551.9 mg/kg/day), based on increased absolute and relati** **ve liver weights in males and females and on hepatocellular hypertrophy in males and females. The NOAEL for parental toxicity is**  **2000 ppm (153.4 mg/kg/day).** Offspring toxicity : Treated F 1 and F 2 litters were comparable to control litters with regard to macroscopic abnormalities, malformations, or variations; number of liveborn pups (total and per litter); number of live pups/litter on day s 4, 7, 14, or 21 of lactation; the number of stillborn pups (total and per litter); body weights on days 0, 4, 7, 14, and 21 of lactation; sexual maturity ; sex ratios; anogenital distance; and indices of survival. **The NOAEL for offspring toxicity is 20,000 ppm (**  **1551.9 mg/kg/day; HDT ). A LOAEL for offspring toxicity was not established**  **(>20,000 ppm).**Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **51** of **60** Reproductive toxic ity : There were no treatment - related reproductive effects on the P 1 and P 2 males and females or their F 1 and F 2 offspring. The endpoints of reproductive function and performance for P 1 and P 2 parental generations were comparable for RH - 2485 Technical - treated and control animals with regard to the following: length and periodicity of the estrous cycle; copulatory

interval; number of females inseminated and/or pregnant; length of gestation; sperm motility, morphology , and concentration; and indices of mating, fertility , and gestation. **The NOAEL for reproductive toxicity is >20,000 ppm (1551.9 mg/kg/day). The LOAEL for**  **reproductive toxicity was not identified (>20,000 ppm).** This study

is class ified Acceptable/guideline and satisfies the guideline criteria for a reproductive toxicity study in the rat (OPPTS §870.3800). **A.4.4 Chronic Toxicity**  **870.4100a (870.4300) Chronic Toxicity –**  **Rat** See 870.4300, below **870.4100b Chronic Toxicity -**  **Dog** In a chronic oral toxicity

study (MRID 44617728), RH - 2486 technical (methox yf enozide, 98.9% a.i., L ot No. 1, TD94 - 134) was administered in the diet to 4 beagle dogs/sex/dose at dietary concentrations of 0, 60, 300, 3000 or 30,000 ppm for 52 weeks (equivalent to average dail y intakes of 0, 2.2, 9.8, 106.1 or 1152.4 mg/kg/day in males and 0, 2.2, 12.6, 110.6 or 1199.2 mg/kg/day

in females). The most notable compound - related hematologic effects consisted of methemoglobinemia, nucleated red blood cells (RBCs) an d mild hemolysis, particularl y in females. At 3000 ppm, mild hematological effects were observed b y 14 weeks of treatment. Methemoglobinemia was observed in males (increased to 157 - 167% of controls) and females (153 - 183% of controls) at most or all time points. In males, platelets were significantly increased (156 - 163%) at all time points and RBCs were significantly decreased at week 14. Hct, Hg and RBCs were generall y decreased in females throughout the study (13 - 18%), but only occasionall y achieved st atistical significance. No overt clinical signs of treatment - related toxicity were observed, and survival, body weights, body weight gains and food consumption were also unaffected by compound administration. At 30,000 ppm, hematological effects were more pronounced and increased cellularity of the rib and sternum marrow were observed in 1 - 2 males and females. Absolute and relative liver weight were slightly

increased (10 - 24%), but onl y absolute weight in male s was statistically significant (24% above controls). An increase in pigmented macrophages was observed in the liver and spleen in 1 - 3 animals in both sexes. Absolute and relative thyroid weights were increased (144%/163%), but there was no corresponding histopathology . Bilirubinemia in males was also observed. **The LOAEL is 3000 ppm (106.1/110.6 mg/kg/day in males/females), based on hematological**Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **52** of **60 effects including mild anemia and methemoglobinemia. The NOAEL is 300 ppm (9.8/12.6**  **mg/kg/day in males/fema les).**  This study

is classified Acceptable/guideline and satisfies the guideline criteria for a chronic oral toxicity study in the dog (OPPTS §870.4100b). **A.4.5 Carcinogenicity**  **870.4200a Carcinogenicity Study -**  **rat** See 870.4300, below **870.4200b Carcinogenicity (feeding)**  **– Mouse**  In a carcinogenicity

feeding study

(MRID 44617729), RH - 2485 (98.0% a.i.; Sample No. 94 - 134, Lot No. 1) was administered to 60 Crl:CD - 1 (ICR) BR (VAF/+) mice/sex/dose in the diet at concentrations of 0, 70, 2800 or 7000 pp m for 18 months (intake for males: 0, 10.0, 405, or 1020 mg/kg/day ; for females: 0, 12.8, 529, or 1354 mg/kg/day). No toxicologically

significant differences were found between the treated and control animals of either sex. Clinical signs, survival, body weight, and food consumption were comparable in treated and control animals. The lower l ymphocy te count and alterations in kidney and testes weights in males were small in magnitude (  16%, p < 0.05), not dose - related, and/or lacked histopathological cor

relates. There were no treatment - related gross or microscopic lesions. **The NOAEL is 7000 ppm (1020/1354 mg/kg/day for males/females)(HDT). A LOAEL was not established in this study (> 7000 ppm).**  **There was no evidence of carcinogenicity in male or female mice. The incidence of**  **neoplasms found in numerous organs and tissues was comparable in treated and control groups. The animals were dosed adequately since their intake exceeded the limit dose of**  **1000 mg/kg/day.** Discussion of Tumor Data: **There was no evidence of carcinogenicity in this study.**  Adequacy

of the Dose Levels Tested: In this study, methox yf enozide was administered at adequate dose levels for carcinogenicity testing since it was tested at the limit dose of 7000 ppm (1020 mg/kg/day

in male s and 1354 mg/kg/day in females). This study

is classified Acceptable/guideline and satisfies the guideline requirement for a dietary carcinogenicity

study in the mouse (OPPTS §870.4200b) **870.4300 Chronic toxicity/carcinogenicity (feeding) –**  **Rat** In a combined chronic toxicity /carcinogenicity study

(MRID 44617731), RH - 2485 technical (methox yfenozide 98% a.i.; L ot Number 1, TD94 - 134) was administered in the diet to 70 maleMethoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **53** of **60** and 70 female Crl:CD ® BR rats per group at concentrations of 0, 200, 8000, or 20,000 ppm (0, 10.2, 411, or 1045 mg/kg/day for males and 0, 11.9, 491, or 1248 mg/kg/day for females) for up to 99 weeks in males (only 89 weeks in the 20,000 - ppm group) and 95 weeks in females except for 10 animals per sex per dose that were sacrificed at 52 weeks for interim evaluation. Survival was adversel y affected in males at the 20,000 - ppm dose level. Survival rates to week 89 in the 0 and 20,000 - ppm groups in the main experiment on males were 28/60 (53% dead) and 17/60 (72% dead), respectively , with this difference being significant, p<0.05 as calculated by reviewer. The onl y significant (p<0.05) effects on absolute body weight, body- weight gain, and food efficiency

were in the 20,000 - ppm females. In approximately the last year of the experi ment, reductions in absolute body weight were often to a level of slightly less than 90% that of the control. At the end of the experiment, absolute body weight was reduced 17% in females. Reductions in body- weight gain were often to a level of about 80% of the control. Reductions in food efficiency

were about 11% and 49% in the first and second years, respectivel y. Treatment - related and significant (p<0.05) hematology changes at the two higher doses consisted of small reductions (less than 10% compared to control) in RBC counts, hemoglobin concentrations, and/or hematocrit, and these effects were seen in both sexes. At the highest dose, there were significant (p<0.05) increases in methemoglobin over the control in both sexes, and there was a significant (p<0.05) increase in platelet counts over control in females. Clinical chemistry evaluations in both sexes at the two higher doses showed significant (p<0.05) and probably treatment - related increases in serum levels of gamma glutamyltranspeptidase (GGT ) and reductions in total bilirubin in the serum. These two effects on clinical chemistry are of uncertain, and probabl y unlikely , biological significance. The liver, kidney s and thy roid were identified as targets for RH - 2485 Technical toxicity . Signifi cant increases (p<0.05) were found in absolute and relative liver weights compared to control in both sexes at the 20,000 ppm dose. These ranged up to 23% increase in males and 24% increase in females at the terminal sacrifice. At the 8000 ppm dose in males at 52 weeks, a significant increase (p<0.05) was found in relative liver weight (19%) and a non - significant increase was found in absolute liver weight (21%). These changes are consistent with the finding of much increased and significant (p<0.01) inc idences of periportal hepatocellular hy pertrophy in both sexes at both the 8000 - and 20,000 - ppm doses. At the terminal sacrifice, the incidences of this lesion in control males and females were 2% and 3%, respectivel y. [Here and below in this paragraph, percents refer to all animals in the main study .] In contrast, in males of the 8000 - and 20,000 - ppm groups, the incidences were 35% and 53%, respectivel y. In females of these same groups at the terminal sacrifice, the incidences were 40% and 70%, respec tively . An increase in the incidence of the more serious manifestations of chronic progressive glomerulonephropath y is thought to have increased the mortality rate of males fed 20,000 - ppm of the test substance. Microscopic anal ys is demonstrated two treatment - related lesions in the thy roid at the terminal sacrifice: 1) follicular cell hy pertrophy in 8000 - ppm males (25%, not significant) and 20,000 - ppm males (31%, p<0.05) compared with 13% in controls; 2) altered colloid in 8000 ppm males (22%, not signifi cant) and 20,000 ppm males (24%, not significant) compared with 12% in controls as well as in 20,000 - ppm females (38%, p<0.01) compared with 17% in controls. Increases were found at the terminal sacrifice for absolute and relative weights of adrenal gland s compared to controls in 20,000 - ppm males (up to 25%, not significant) and inMethoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **54** of **60** 20,000 ppm females (up to 100%, p<0.05 for relative weight). Similar increases were found at the terminal sacrifice for absolute and relative weights of adrenal glands compared to controls in 8000 - ppm males (up to 55%, not significant) and in 8000 ppm females (up to 31%, not significant). Numerous other treatment - related microscopic lesions were identified only in 20,000 - ppm females (mainly mineralizations of tissues found in f rom 7-13% of the animals); these were considered secondary changes attributable to uremia that resulted from the chronic progressive glomerulonephropathy. No effects attributable to the test material were observed at 200 ppm. **The LOAEL is 8000 ppm (411 m g/kg/day for males and 491 mg/kg/day for**  **females) ,**  **based on hematological changes (decreased RBC counts, hemoglobin concentrations, and/or hematocrit in males and females), liver toxicity (increased liver**  **weights in males and periportal hepatocellular hype rtrophy in males and females),**  **histopathological changes in the thyroid (increased follicular hypertrophy and altered colloid in males) and possible adrenal toxicity (increased adrenal weights in males and**  **females). The absence of treatment -**  **related effect s identifies a NOAEL of 200 ppm (10.2**  **mg/kg/day for males and 11.9 mg/kg/day for females). No evidence of carcinogenicity was observed in rats fed RH**  **- 2485 Technical at dietary**  **concentrations of 200, 8000, or 20,000 ppm for up to 99 weeks. Dosing was con sidered**  **adequate because of the decreases in body weights, body -** **weight gain, and food efficiency in female rats fed the 20,000**  **- ppm diet and because of the decrease in survival in male rats fed**  **the 20,000 -**  **ppm diet. The highest dose tested for both males an d females is also higher than**  **the limit dose of 1000 mg/kg/day.** This study

is classified Acceptable/guideline and satisfies the guideline requirement for a dietary carcinogenicity

study in the rat (OPPTS §870.4200a) A.4.6 Mutagenicity **Gene Mutation** 870.5100 Bacterial reverse gene mutation assay

(S. typhimurium strains TA 98, TA100, TA1535, TA1537 MRID 44617728 Acceptable/guideline Dose range Negative for gene mutation up to insoluble concentrations (precipitation observed at ≥2000 μg/plate) in the presence or absence of S9 metabolic activation 870.5100 Bacterial reverse gene mutation assay

(S. typhimurium strains TA 98, TA100, TA1535, TA1537 MRID 44617733 Acceptable/guideline Dose range 50 to 5000 μg/plate, test material RH - 117,236 (metabolite of methoxyfenozide) Negative for gene mutation up to insoluble concentrations (precipitation observed at 5000 μg/plate) in the presence or absence of S9 metabolic activation. 870.5300 Mammalian in vitro cell forward gene mutation assay (CHO cells) MRID 44617734 Acceptable/guideline Dose range 0.1 to 1250 μg/mL. Negative for gene mutation up to insoluble concentrations (precipitation observed at ≥100 μg/mL) in the presence or absence of S9 metabolic activation.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **55** of **60 Cytogenetics**  870. 5375 , Mammalian in vitro chromosomal aberration assay (CHO cells) MRID 44617735 Acceptable/guideline Dose range 0.21 to 1250 μg/mL. Negative for increased frequency of chromosomal aberration, up to concentrations ( ≥50 μg/mL ) at which the mitotic indices were decreased, in the presence or absence of S9 metabolic activation. **Other Genotoxicity** 870.5395, Mouse micronucleus assay MRID 44617801 Acceptable/guideline Dose range 500 to 5000 mg/kg (single IP dose). Negative for increased frequency of micronucleus formation in CD - 1 mice at 24 or 48 hrs postdosing up to the limit dose for this assay . A.4.7 Neurotoxicity **870.6100 Delayed Neurotoxicity Study -**  **Hen** Not required and not submitted **870.6200 Acute Neurotoxicity Screening Battery**  In an acute oral neurotoxicity study (MRID 44617802), groups of 10 Crl:CD®BR rats/sex/group were administered single gavage doses of RH - 2485 technical (Toxicology Department Sample Number 94 - 134; Lot No. 1; 98 % active in gredient) at 0 (control), 500, 1000, or 2000 mg a.i./kg. The active ingredient was suspended in 0.5% aqueous methylcellulose and administered at a constant volume of 20 ml/kg. Functional observational battery (FOB) and motor activity (MA) testing were perf

ormed prior to administration and within 3 hours (time of peak effect) of dosing (day 0), and on day s 7 and 14 post - dose. Body weights were recorded pre - test, weekl y during the study period and on FOB assessment day s. Clinical signs were recorded daily . At necrops y all rats were perfused in situ and given a limited gross necrops y; six rats/sex/dose (high - dose and control) were further processed for neuropathological evaluation at study termination. All animals survived to scheduled termination. Daily cag e - side observations revealed no overt signs of treatment - related effects in males or females at any exposure concentration. No treatment - related effects on body weight were observed during the study. There were no observable signs of a neurotoxic effect even at the highest concentration in females. FOB assessment on Day 0 (3 hours after dosing) revealed a decrease in hindlimb grip strength (% below controls) for males in the 2000 mg/kg group. MA assessment remained comparable to controls throughout the s tudy for males and females in all exposure groups. No neuropathological endpoints were observed during the histological examinations of the peripheral or central nervous sy stems of these animals at any exposure concentration. **Based on the absence of any substance**  **- related effects on body weight or body weight gain**  **and any clinical signs of toxicity, the NOAEL for systemic toxicity is a concentration of**Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **56** of **60 2000 mg/kg for males and females. The NOAEL for neurotoxic effects is 2000 mg/kg for**  **females. Based on a decrease in hindlimb grip strength on day 0 in the 2000 mg/kg male**  **group, the NOAEL for males is 1000 mg/kg and the LOAEL for males is 2000 mg/kg. No LOAEL was established for systemic effects in males or females or for neurotoxic effects in**  **females.** This study

is classified as Acceptable/guideline and satisfies the guideline requirement for an acute oral neurotoxicity

screening study

in the rat (OPPTS § 870.6200a). **870.6200 Subchronic Neurotoxicity Screening Battery** In a subchronic oral neurotoxicity study (MRID 44617803), groups of Crl:CD®BR rats (10 rats/sex/group) were administered concentrations of 0, 200, 2000 or 20,000 ppm of RH - 2485 technical (Toxicology

Department Sample Number 94 - 0134; Lot No. 1; 98 % active ingredient) in the diet for 3 months. These doses resulted in average daily intake values of 0, 13, 130, and 1318 mg/kg/day

for males and 0, 16, 159, and 1577 mg/kg/day in females for 0, 200, 2000, and 20,000 ppm, respectivel y. Functional observational battery (FOB) and motor activity (MA ) testing were performed prior to administration and in the 4 th , 8 th , and 13 th week of the administration period. Body weights were recorded pre - test, weekl y during the study period and on FOB assessment day s. Food consumption was determined weekl y for ea ch animal. All rats surviving to necrops y were perfused in situ and given a limited gross necropsy . Six/rats/sex/dose (high - dose and control) were further processed for neuropathological evaluation at study termination. One male in the 20,000 ppm group wa s found dead during week 5 of the study ; this death was attributed to a urethral obstruction and was not considered to be treatment - related. All animals in all other exposure groups survived to scheduled termination. Daily cage - side observations and weekl y ph ys ical examinations revealed no overt signs of treatment - related effects in males or females at any exposure concentration. No treatment - related effects on body weight, body weight gain, or food consumption were observed during the study. There were no observable signs of a neurotoxic effect even at the highest concentration in males or females. FOB and MA remained comparable to controls throughout the study and no neuropathological endpoints were observed during the histological examinations of thes e animals at any exposure concentration. **Based on the absence of any substance -**  **related effects on body weight or body weight gain and any clinical signs of toxicity, the NOAEL for systemic toxicity is 20,000 ppm for males**  **(1318 mg/kg/day) and females (157 7 mg/kg/day). The NOAEL for neurotoxic effects is**  **20,000 ppm (1318/1577 mg/kg/day in males/females). A LOAEL was not established for either systemic or neurotoxic effects (>20,000 ppm).**  This study

is classified as Acceptable/guideline and satisfies the guideline requirement for a subchronic oral neurobehavioral screening study in the rat ( § 870.6200b).Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **57** of **60 870.6300 Developmental Neurotoxicity Study**  Not required and not submitted **A.4.8 Metabolism**  **870.7485 Metabolism**  **– Rat**  In an oral metabolism study (MRID 44617804), groups of five Crl:CD®BR rats/sex/dose group received methox yfenozide (technical grade, several lots labeled at different positions with radiochemical purity

ranging from 96.4 to 99.0%) according to the following schedules: a single low dose (10 mg/kg labeled with 14 C at the t - butyl, A - ring or B - ring); high dose (1000 mg/kg labeled at the t - butylor A - ring); or diets containing 10 mg/kg unlabeled test material for two weeks, followed b y a single 10 mg/kg gavage dose of test material labeled on the A - ring. Other groups of 3 - 6 male and 3 - 6 female rats received five daily doses of 10 mg/kg test material labeled on the A - ring or a single low - or high - dose of test material labeled at the t - butyl or A ring to determine pharmacokinetics and tissue distribution. One additional group of 4 male and 4 female cannulated rats received a single low - dose of test material labeled on the A - ring to determine biliary

excretion. In a preliminary study , expired air was collected from male and female rats that rec eived 1000 mg/kg test material labeled at the t - butyl , A - ring, or B - ring positions. It was found that < 0.1% of the administered dose was removed in this manner and no further expired air studies were done. No test material - related deaths occurred and mas s balance, ranging from 93 - 104%, was acceptable. The total plasma elimination rate for male and female rats was longer for high dose relative to low dose animals; suggestive of metabolic pathway saturation. This particular effect was more prominent with fe male rats, regardless of label position. Following absorption, the test material was rapidly

metabolized and excreted. The highest radiolabel tissue concentrations at C max (0.25 hours post - treatment) w ere found in the intestinal tract, stomach, and liver, respectivel y, although at C max the liver contained <9% of the administere d dose. By 1/2 C max , (1 - 2 hours post - treatment), radiolabel concentrations in the stomach and liver had decreased to <3% of the dose but remained relativel y constant in the intestinal tract. Male and female cannulated rats excreted 62 - 70% of the administered dose into the bile and urine, indicating that absorption would at least be equivalent. By five day s after treatment, the highest concentrations of radioactivity

were found in the l iver (<0.2% of dose) and carcass (<0.1% of dose) with <0.01% of the dose in other tissues and organs. No apparent effects attributable to label position or sex were noted. The test material was excreted primaril y into the feces with approximately 86 - 97% of a 10 mg/kg or 1000 mg/kg dose eliminated by this route. Urinary

excretion was relativel y minor and accounted for 5 - 13% of the administered dose. No substantial quantitative differences in the urine and fecal excretion profiles for the different radiolab el positions were observed. Elimination of the radiolabel b y all treatment groups and both sexes was essentially complete within 48 hours of treatment.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **58** of **60** Before excretion, the test material was metabolized principally by O - demethylation and oxidative hydroxylation on the A - ring phenyland/or B - ring meth ylgroups followed by glucuronic acid or sulfate conjugation. Cleavage of the amide linkage from either the A - ring or B - ring side and conjugation with gl ycine to form the corresponding substituted hippuric acid metabolite was a minor route. No significant sex - related differences in the metabolic disposition of the test material were noted, although there were some minor sex - related differences. No significant dose - dependent differences in metabolic dispositio n were found. This metabolism study

in the rat is classified as Acceptable/guideline and satisfies the guideline requirement for a general metabolism study ( OPPTS § 870.7485 ) in the rat. **870.7600 Dermal Absorption**  **- Rat**  In an in vivo dermal penetration study (MRID 44638202), f

our male rats per experimental group were dosed by

dermal application to shaved skin of methoxyfenozide as either the a - ring labeled 14 C - RH - 1 12,48 5 80WP (80% a.i.) or the 2F formulation (2% a.i.) at 0.25, 0.025 or 0.0025 mg/cm 2 a.i. for 1, 10 or 24 hours. Percent absorption of the 80WP formulation at 24 hours was 0.64, 1.02 and 1.83 for the respective high to low doses. After washing, 8.90, 9.53 and 7.35 percent of the dose remained in the washed skin. Percent absorption of the 2F formulation at 24 ho urs was 0.44, 0.83 and 3.20 for the respective high to low doses. After washing, 6.40, 8.85 and 10.64 percent of the dose remained in the washed skin. Because of the combination effects of the low doses used and the low rates of absorption, the sample assay values tended to be scattered. The absorption pattern s of the two formulations overlapped with no apparent differences. Because of the absorption pattern, the quantity remaining in the skin is not expected to add significantly to the total absorbed and should not be used for risk assessment. This study

is classified as Acceptable/guideline and satisfies the guideline requirement for a dermal absorption study in the rat (OPPTS §870.7600). **A.4.9 Immunotoxicity**  **870.7800 Immunotoxicity**  In an immunotoxicity

study (MRID 48592601 ), Methoxyfenozide (98.0% a.i., L ot # 6329B01) was administered to female Crl:CD(SD) rats (10/dose) in the diet targeted to deliver nominal doses of 0, 75, 300, or 1000 mg/kg bw/day (actual doses of 0, 76.9, 324, or 1076 mg/kg bw/day , respectivel y) for 28 day s. On Day 25, animals in all groups were immunized with a suspension of sheep red blood cells (SRBC) by intravenous injection (2x10 8 SRBC/animal, 0.5 mL/animal dose volume). Animals in the positive control group received an intraperitoneal injection of cyclophosphamide at a dose of 20 mg/kg bw (1 mL/kg bw dose volume) on Day s 24 - 28. All animals were evaluated for mortality , clinical si gns, body w eight changes, and gross pathology . The vehicle control and test substance treatment groups also were evaluated for food consumption and hematologic parameters. Immunotoxicity was assessed for all animals by an Enzy me - linked Immunosorbent Assay (ELISA). Spleen and th ymus weights were measured atMethoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **59** of **60** necrops y (Day

29) for all animals; liver weights were measured for the vehicle control and test substance treatment groups. There were no test substance treatment - related effects on mortality , clinical signs, body weight changes, food consumption, or hematologic parameters. A statistically significant increase in relative but not absolute liver weight was found in the 300 and 1 000 mg/kg bw/day groups; one animal in the 1000 mg/kg bw/day group also had a grossly

observable enlarged liver. These increases in liver weights were treatment - related and are consistent with previously reported results . **The systemic toxicity LOAEL for M ethoxyfenozide in female rats is 300 mg/kg bw/day**  **(actual dose of 324 mg/kg bw/day) ,**  **based on increased relative liver weight which was**  **consistent with previously reported results . The NOAEL for systemic toxicity is 75 mg/kg**  **bw/day (actual dose of 76.9 mg/ kg bw/day).**  For immunotoxicity, there were no test substance treatment - related effects on thy mus and spleen weights or serum anti - SRBC IgM antibody levels as measured b y an ELISA. A high inter individual variability

of anti - SRBC antibody

level was noted i n all the treatment groups as well as in the control group. Evaluation of individual animal data of this study did not show any

trend or distribution that would demonstrate significant suppression of anti - SRBC antibody response. Animals in the positive control group showed marked decreases of anti - SRBC abtibody response. The positive control group confirmed the ability of the test sy stem to detect immuno suppressive effects and confirmed the validity of the study

design. The Natural Killer (NK) cells acti vity was not evaluated in this study . The toxicology database for Methox yfenozide does not reveal any evidence of treatment - related effects on the immune sy stem. The onl y potential evidence of immunotoxicity in the submitted studies was anemia and other re lated blood effects observed in rats and dogs; however, additional parameters indicated these effects were compensatory response to the anemia, which was observed primaril y after chronic dosing. The overall weight of evidence suggests that this chemical do es not dire ctl y target the immune s ys tem. Under HED guidance, a NK cells activity assay is not required at this time. **Under conditions of this study, the immunotoxicity NOAEL is 1000 mg/kg/day (actual dose of 1076 mg/kg/day); the LOAEL was not establish**  **ed.** This immunotoxicity

study is classified **acceptable/guideline** and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in rats.Methoxyfenozide Human Health Risk Assessment DP Barcode 407285

Page **60** of **60 Appendix B.**  **Physical/Chemical Properties .**  **TABLE 2**  **Physicochemical Properties of Methoxyfenozide.**

**Param eter**  **Value Reference**  Molecular Weight 368.47 D231303; H. Podall; 19 M ay 1997 Melting point/range ( oC ) 206.1 - 208 pH 7.0 Density (g/ cm 3 ) 0.740 ± 0.0081 Water solubility (mg/L at 20oC) 3.3 Solvent solubility (g/L at 20oC) N - heptane 1.87 Xylene 3.38 1,2 - dichloroethane 36.72 Methanol 192.92 2 - Propanol 50.22 Vapor pressure ( 25oC ) 1.33 x 10 - 5 Pa (1 x 10 - 7 mm Hg) Dissociation constant, pKa None Octan ol/water partition coefficient ( Log [ KOW ] ) 3.72 ± 0.04 UV/visible absorption (max) ε 55313 at 203 nm European Commission; SANCO/10384/202

– rev. 4 ; 7 October 2004 **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, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; and the Outdoor Residential Exp osure Task Force (ORETF) database; 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 by the Human Studies Review B oard. Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handlerexposure - data.html and http://www.epa.gov/pesticides/science/post - app - exposure - data.html.