Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **1** of **73** UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA** **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM Date**  **:** 14 January 2014 **Subject :**  **Cyflumetofen .**  Revised New Active In gredient Human Health Risk Assessment

to Support Uses on Citrus (Crop Group 10 - 10), Pome Fruits (Crop Group 11 - 10), Tree Nuts (Crop Gr oup 14 - 12), Grape, Strawberry, and Tomato. **PC Code:** 138831 **DP Barcode :**  D398246 **Decision No.:** 459424 **Registration No. :**  7969 - GGA, 7959 - GGT, 7969 - GGL **Petition No .:**  2F7973 **Regulatory Action:** Section 3 Registration **Risk A**  **ss essment Typ**  **e :**  Single Chemical / Aggregate **Case No.:** NA **T XR No.:**  NA **CAS No.:** 400882 - 07 - 7 **MRID No.:** NA **40 CFR:** TBD **From :**  Donald Wilbur, Chemist/Risk Assessor

Shalu Shelat, I

ndustrial Hygienist Yung Yang, Ph.D., Toxicologist Risk Assessment Branch VI Health Effects Division (7509P) **Through :**  Anna Lowit, Senior Toxicologist

Dana Vogel, Deputy Division Director Risk Assessment Review Committee (RARC) Health Effects Division (7509P) Donna Davis , Acting Chief Risk Assessment Branch VI Health Effects Division (7509P) **T o**  **:** Driss Benmhend/Richard Gebken, PM10

Insecticide Branch Registration Division (7505P)Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **2** of **73** The Health Effects Division (HED) of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. BASF has requested registration of the new miticide cyflumetofen for foliar use on citrus fruit, grapes, pome fruit, strawberry , tomato, tree nuts, and ornamentals . The Registration Division (RD) of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, residential, occupational, and aggregate exposure assessments, as needed , to estimate the risk to human health that will result from the se proposed uses of cy flumetofen. HED has evaluated the toxicity and exposure databases for cyflumetofen and has conducted a human health risk assessment which is provided in this document . Based on this assessment, HED has determined that there are no potential risk estimates of concern for the proposed uses of cyflumetofen . The HED team members contributing to this risk assessment include Donald Wilbur (residue chemistry , dietary exposure assessment , and risk assessment), Shalu Shelat (occupational and residential exposure assessment s ), and Yung Yang (hazard assessment) . Stephen Wente of the Environmental Fate and Effects Division (EFED) performed the drinking water assessment .Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **3** of **73 Table of Contents**  1.0 Executive Summary ................................ ................................ ................................ ............. 5 2.0 HED Recommendations ................................ ................................ ................................ ....... 7 2.1 Data Deficiencies ................................ ................................ ................................ ............. 8 2.2 Tolerance Considerations ................................ ................................ ................................ . 8 2.2.1 Enforcement Anal yt ical Method ................................ ................................ ............... 8 2.2.2 Recommended Tolerances ................................ ................................ ........................ 8 2.2.3 Revisions to Petitioned - For Tolerances ................................ ................................ .... 9 2.2.4 International Harmonization ................................ ................................ ..................... 9 2.3 Label Recommendations ................................ ................................ ................................ .... 10 3.0 Introduction ................................ ................................ ................................ ........................ 10 3.1 Chemical Identity ................................ ................................ ................................ ........... 10 3.2 Phy sical/Chemical Characteristics ................................ ................................ ................. 10 3.3 Pesticide Use Pattern ................................ ................................ ................................ ...... 10 3.4 Anticipated Exposure Pathway s ................................ ................................ ..................... 11 3.5 Consideration of Environmental Justice ................................ ................................ ........ 11 4.0 Hazard Characterization and Dose - Response Assessment ................................ ................ 12 4.1 Toxicology

Studies Available for Analy sis ................................ ................................ ... 12 4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) ................................ ... 12 4.2.1 Dermal Absorption ................................ ................................ ................................ .. 13 4.3 Toxicological Effects ................................ ................................ ................................ ..... 13 4.4 Safety

Factor for Infants and Children (FQPA Safety Factor) ................................ ....... 14 4.4.1 Completeness of the Toxicology Database ................................ ............................. 14 4.4.2 Evidence of Neurotoxicity ................................ ................................ ...................... 14 4.4.3 Evidence of Sensitivity /Susceptibility

in the Developing or Young Animal ......... 14 4.4.4 Residual Uncertaint y in the Exposure Database ................................ ..................... 15 4.5 Toxicity

Endpoint and Point of Departure Selections ................................ .................... 15 4.5.1 Dose - Response Assessment ................................ ................................ .................... 15 4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment ........ 16 4.5.3 Cancer Classification and Risk Assessment Recommendation .............................. 17 4.5.4 Summary

of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment ................................ ................................ ................................ ............................ 18 5.0 Dietary

Exposure and Risk Assessment ................................ ................................ ............ 20 5.1 Metabolite/Degradate Residue Profile ................................ ................................ ........... 20 5.1.1 Summary

of Plant and Animal Metabolism Studies ................................ ............... 20 5.1.2 Summ ary

of Environmental Degradation ................................ ............................... 21 5.1.3 Comparison of Metabolic Pathway s ................................ ................................ ....... 22 5.1.4 Residues of Concern Summary and Rationale ................................ ........................ 22 5.2 Food Residue Profile ................................ ................................ ................................ ...... 24 5.3 Water Residue Profile ................................ ................................ ................................ .... 25 5.4 Dietary

Risk Assessment ................................ ................................ ................................ 25 5.4.1 Description of Residue Data Used in Dietary Assessment ................................ ..... 26 5.4.2 Percent Crop Treated Used in Dietary Assessment ................................ ................ 26 5.4.3 Acute Dietary

Risk Assessment ................................ ................................ .............. 26 5.4.4 Chronic Dietary

Risk Assessment ................................ ................................ .......... 26 5.4.5 Cancer Dietary

Risk Assessment ................................ ................................ ............ 26Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **4** of **73** 5.4.6 Summary

Table ................................ ................................ ................................ ....... 27 6.0 Residential (Non - Occupational) Exposure/Risk Characterization ................................ .... 27 6.1 Residential Handler Exposure ................................ ................................ ........................ 27 6.2 Post - Application Exposure ................................ ................................ ............................. 28 6.3 Residential Risk Estimates for Use in Aggregate Assessment ................................ ...... 28 6.4 Residential By stander Post - application Inhalation Exposure ................................ ........ 29 6.5 Spray

Drift ................................ ................................ ................................ ...................... 29 7.0 Aggregate Exposure/Risk Characterization ................................ ................................ ....... 30 7.1 Acute Aggregate Risk ................................ ................................ ................................ .... 30 7.2 Short - Term Aggregate Risk ................................ ................................ ........................... 30 7.3 Chronic Aggregate Risk ................................ ................................ ................................ . 31 7.4 Cancer Aggregate Risk ................................ ................................ ................................ ... 31 8.0 Cumulative Exposure/Risk Characterization ................................ ................................ ..... 31 9.0 Occupational Exposure/Risk Characterization ................................ ................................ .. 32 9.1 Short - /Intermediate - Term Handler Risk ................................ ................................ ....... 32 9.2 Short - /Intermediate - Term Post - Application Risk ................................ ......................... 35 9.2.1 Dermal Post - application Risk ................................ ................................ ................. 35 9.2.2 Inhalation Post - application Risk ................................ ................................ ............. 35 10.0 References ................................ ................................ ................................ .......................... 37 Appendix A. Toxicology Profile and Executive Summaries ................................ ....................... 38 A.1 Toxicology

Data Requirements ................................ ................................ ...................... 38 A.2 Toxicity

Profiles ................................ ................................ ................................ ............. 39 A.3 Hazard Identification and Endpoint Selection ................................ ............................... 42 A.4 Executive Summaries ................................ ................................ ................................ ..... 45 A.5 Summary

of Toxicological Doses and Endpoints for Cy flumetofen ............................. 64 Appendix B. Metabolism Summary Table ................................ ................................ ................... 65 B.1 Structures of C yflumetofen Metabolites ................................ ................................ ........ 65 B.2 Tabular Summary

of Metabolites and Degradates ................................ ......................... 68 Appendix C. Phy sical/Chemical Properties ................................ ................................ ................. 71 Appendix D. Review of Human Research ................................ ................................ ................... 72 Appendix E. Residue Summary Table ................................ ................................ ......................... 73Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **5** of **73 1.0**  **Executive Summary**  Cyflumetofen (2 - methoxyethyl α - cyano - α - [4 - (1,1 - dimethylethyl)phenyl] - β - oxo - 2 - (trifluorometh yl )benzenepropanoate) is a new active ingredient from BASF that belongs to the acryl onitrile class of chemicals with a novel insecticidal mode of action

– mitochondria complex II electron transport inhibition. It is a selective contact miticide that is effective on all mite life stages. Itis currently

proposed only

for foliar applications via ground or aerial equipment. Cyflumetofen is formulated as a 20% suspension concentrate (SC). BASF is proposing uses/tolerances on tree nuts (crop group 14 - 12), pome fruits (crop group 11 - 10), citrus (crop group 10 - 10), grapes, strawberries, tomatoes, and ornamentals. The present action was conducted as a joint revie w with Health Canada’s Pesticide Management Regulatory Authorit y (PMRA) and Mexico’s Federal Commission for the Protection against Sanitary Risk (COFEPRI S) . The toxicology

database is considered complete for cyflumetofen. A subchronic inhalation study wa s not available; however, the HASPOC determined that the requirement for this study is not needed at this time. The major target organ in rats, mice, and dogs following short - term and long - term oral administration of cy flumetofen is the adrenal glands char acterized by increased organ weight and histopathology (vacuolation and hy

pertrophy of the adrenal cortical cells). Cyflumetofen has low acute toxicity by oral, dermal, and inhalation routes of exposure. It is minimally

irritating to the eyes but not to the skin. It is a skin sensitizer. Decreased serum hormone concentrations (FSH, progesterone, and 17 β - estradiol) were observed in the mid - and high - dose F 1 females in a rat reproduction study while no hormonal effect was observed in the F 1 male rats at any

dose level. However, there were no corresponding changes in reproductive performance at an y dose level. In the developmental toxicity study in rats, an increased incidence of wav y ribs was noted at the high - dose (1000 mg/kg/day), while an increased i ncidence of incompletely ossified sternal centra was observed at the mid - and high - dose levels. These incidences occurred in the presence of maternal toxicity . In the developmental toxicity study in rabbits, a downward flexion of the forepaws and/or hind paws was observed in the high dose (1000 mg/kg/day) group pups and delay s in skeletal ossification were observed in pups at the mid - and high - doses. Maternal toxicity (adrenal effects) was also observed at the mid - and high - doses. No evidence of neuro toxicity or immunotoxicity

was observed in any

of the submitted studies for cyflumetofen. No acute reference dose (aRfD) was established to assess acute dietary risks since there was no evidence of toxicity

attributable to a single dose for the general U.S. population, infants and children, or females 13 - 49 years of age in an y studies. For the chronic dietary risk assessment, a chronic reference dose (cRfD) of 0.17 mg/kg/day was established for assessments of all populations, with a no observed adverse effect level (NOAEL) of 16.5 mg/kg/day and a lowest observed adverse effect level (LOAEL) of 30.6 mg/kg/day based on effects on the adrenals (increased organ weight and histop athology), which is the target organ. Three rat studies (90 - day subchronic, chronic toxicity /carcinogenicit y, and reproduction studies) were selected as co critical studies for the chronic dietary endpoint. These studies are appropriate for the duration and populations of concern since there is no progression of toxicity over time. No dermal hazard was identified for cy flumetofen. For short - and intermediate - term inhalation exposure, theCyflumetofen Human Health Risk Assessment DP No. D398246

Page **6** of **73** NOAEL of 16.5 mg/kg/day with a LOAEL of 30.6 mg/kg/day based on effe cts on the adrenals was selected from the same co - critical studies chosen for the chronic reference dose. The risk assessments conducted for cy flumetofen were based on the most sensitive endpoints in the toxicity

database, and the NOAELs selected for risk assessment are considered protective of potential developmental, neurotoxic, and immunotoxic eff ects for infants and children. There is no evidence of increased qualitative or quantitative susceptibility in the rat 2 - generation reproduction study; ho wever, the rat and rabbit developmental studies indicate susceptibility in the pups. There is evidence of increased quantitative susceptibility in the rabbit developmental toxicity study , since developmental effects at the limit dose were observed where n o maternal toxicity was present. There is evidence of increased qualitative susceptibility in the rat developmental toxicity

study as developmental effects were seen at the same dose that caused an increase in adrenal weights and organ - to - body weight rati o in the maternal animals. Notwithstanding, the degree of concern for these effects in infants and children is low because the rat and rabbit developmental effects have clearly defined NOAE L/ LOAEL s and the dose selected for chronic risk assessment is prot ective of these effects . There is no evidence of neurotoxicity

in an y of the submitted studies for cyflumetofen. Further, highly conservative exposure estimates were incorporated into the risk assessment; therefore, reduction of the 10X FQPA safety

factor to 1X is considered appropriate. Cyflumetofen has been classified as having “Suggestive Evidence of Carcinogenic Potential” in accordance with the EPA's Final Guidelines for Carcinogen Risk Assessment (March, 2005). This classification is based on the pr esence of a single tumor t ype (thyroid c - cell) in one sex (male) and one species (rat), and the lack of concern for mutagenicity. When there is suggestive evidence of carcinogenicity , the Agency does not attempt a dose - response assessment as the nature of the data generally would not support one. Therefore, the Agency has determined that quantification of risk using a non - linear approach (i.e. the chronic reference dose) will adequatel y protect for all chronic toxicity , including carcinogenicity , likel y to result from exposure to cy flumetofen. The residue chemistry

database is considered complete for cyflumetofen for the purposes of this petition . The nature and magnitude of the residue in plants has been adequately delineated. The residue of concern in plants is the parent compound only . No cy flumetofen residues are expected in livestock commodities based on the submitted ruminant metabolism study and the calculated dietary

burden. Adequate storage stability , method validation data and processing studi es have been submitted. An adequate LC/MS/MS (liquid chromatography /tandem mass spectrometry) anal yt ical method is available to enforce the proposed tolerances. As part of the joint review process, harmonization of recommended tolerance levels was achiev ed. Environmentally , the cyflumetofen molecule has very low water solubility and is expected to degrade quickly

through multiple fate processes (with half - lives of hours to several day s) under environmental conditions. As this is a new active ingredi ent , there are no monitoring data available, thus drinking water concentrations were estimated using models. An acute reference dose was not selected for cy flumetofen; therefore, the Agency conducted only a chronic dietary

(food and drinking water) expo sure and risk assessment. This assessment was conducted using tolerance level residues, empirical processing factors where available ,Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **7** of **73** 100% crop treated and modeled surface water exposure estimates . Using assumptions considered to be highl y conservative , the chronic dietary risk estimates are below HED’s level of concern (<100% of the chronic population adjusted dose (cPAD)) , and range from <1% of the cPAD for the general U.S. population to 2.3% of the cPAD for the highest exposed population subgroup of ch ildren 1 - 2 years old. The proposed uses of cy flumetofen on ornamentals may result in adult residential handler and post - application exposure. This exposure is expected to be onl y short - term in duration ( i.e., 1 to 30 day s) as intermediate - or long - term exposures are not likely based on the intermittent nature of applications b y homeowners. Since no dermal hazard was identified for cyflumetofen in the toxicological database, only inhalation exposure assessments were conducted. These assessments were co nducted according to HED’s 2012 Residential Standard Operating Procedures (SOPs) and the resulting inhalation margins of exposure (MOEs) for all scenarios are not of concern since they are above the level of concern (LOC) of 100 (MOEs ≥ 100). Since there are no acute points of departure identified , an acute aggregate risk assessment was not conducted. HED has conducted short - term and long - term (chronic) aggregate risk assessments for cyflumetofen . Short - term aggregate MOEs are above the LOC of 100 and ar e not of concern (MOEs ≥ 100) . The long - term (chronic) aggregate assessment includes only dietary (food and water) exposure as long - term residential exposure is not expected . Chronic dietary risk is not of concern. No dermal hazard has been identified for cyflumetofen ; therefore occupational handler and post application risks were assessed for the inhalation route of exposure onl y. All estimated short and intermediate - term handler inhalation risk estimates are above the Agency ’s level of concern (MOE s ≥ 100) . Based on the Agency 's current practices, a quantitative post - application inhalation exposure assessment was not performed for cyflumetofen . This risk assessment relies, in part, on data from studies in which adult human subjects were intentiona lly

exposed to a pesticide or other chemical. These data, which include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) dat abase; the Agricultural Re - entry

Task Force (ARTF) database; and the Residential SOPs (Residential Handler) are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain s tudies that review may have included review b y the Human Studies Review Board. **2.0 HED**  **Recommendations** Provided a revised Section F to amend the proposed tolerances is submitted as noted in Section 2.2 below, there are no hazard, exposure, or risk considerations that would preclude granting the requested uses of cy flumetofen or establishing the tolerances required to support those uses.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **8** of **73 2.1**  **Data Deficiencies** There are no data deficiencies relating to toxicology , residue chemistry , or occupationa l/residential exposure assessment associated with this action. **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  An adequate anal yt ical method is available to enforce the HED recommended tolerances for cyflumetofen in plant commodities. The high - performance liquid chromatography with tandem mass spectrometry

(HPLC - MS/MS) method, BASF D1003, has been adequately validated, has undergone a successful ILV (independent laboratory validation), is considered adequatel y radio validated and has b een reviewed b y the Agency for appropriateness as an enforcement method. BASF method D1003 has a limit of quantitation (LOQ) of 0.01 ppm for residues of cy flumetofen in all matrix ty

pes. The method limit of detection (LOD) for residues of cyflumetofen i n all matrices, except orange oil, has been set at 0.002 ppm, or approximately 20% of the LOQ. Orange oil has an LOD of 0.0035 ppm. BASF method D1003 is described briefl y as follows. Residues of cy flumetofen are extracted from crop matrices b y shaking w ith acetonitrile followed by acetonitrile - water (hexane is also added for extractions from oil) . An aliquot of the extract is concentrated to remove the acetonitrile (the hexane phase is also removed from oil extractions) and acidified with formic acid. The residues are then partitioned with a mixture of eth ylacetate - cyclohexane. An aliquot of the organic phase is concentrated in the presence of 0.1% formic acid in water, and re dissolved in 0.1% formic acid in acetonitrile for HPL C - MS/MS determination. Cyflumetofen has also been subjected to analy sis by the Food and Drug Administration (FDA) multi - residue method (MRM) protocols. Cy flumetofen is not adequatel y recovered through an y of the FDA multi - residue protocols. **2.2. 2**  **Recommended Tolerances** HED recommends that 40 CFR be amended b y establishing tolerances for residues of cyflumetofen in plant commodities as listed in Table 2.2.2. For the purposes of this petition, tolerances for residues of cy flumetofen were derived using the Organization for Ec onomic Cooperation and Development Maximum Residue Level (OECD MRL) Calculation Procedures. Based on the HED Interim Guidance on Tolerance Expressions (S. Knizner, 05/27/2009), the following tolerance expression is recommended. Tolerances are established for residues of the insecticide cy flumetofen, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels for cyflumetofen is to be determined by measuring only cyflumetofen, 2 - methoxyethyl α - cyano - α - [4 - (1,1 - dimethylethyl)phen yl ] - β - oxo - 2 - (trifluorometh yl )benzenepropanoate, in or on the commodity .Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **9** of **73 Table**  **2.2.2 . Tolerance Summary for**  **Cyflum etofen**  **Comm odity**  **P roposed**  **Tolerance (ppm)**  **HED -**  **Recommended**

**Tolerance (ppm) Comments**  Almond, hulls 4.0 4.0 Citrus, oil 16.0 16 Fruit, citrus, group 10 - 10 0.3 0.30 Fruit, pome, group 11 - 10 0.3 0.30 Grape 0.6 0.60 Grape, raisin 0.9 N/A Not required, raisin is covered by RAC grape tolerance Nut, tree, group 14 - 12 0.01 0.01 Straw berry 0.6 0.60 Tomato 0.2 0.40 **2.2. 3**  **Revisions to Petitioned -**  **For Tolerances** HED is recommending that tolerances be set for the commodities requested by the registrant at the levels requested, with the changes noted below. Additionally , minor modifications to some co mmodity

definitions are recommended. The petition er had requested toleranc es on Fruit, citrus, group 10 ; Fruit, pome, group 11; and Nut, tree, group 14. To be consistent with updated Agency naming - conventions for crop groups, these have been changed to F ruit, citrus, group 10 - 10; Fruit, pome, group 11 - 10; and Nut, tree, group 14 - 12. The requested changes to tolerance levels are shown above in Table 2.2.2. The proposed tolerance level of 0.2 ppm for tomato should be increased to 0.40 ppm to fully account for residue loss from the field trial samples during freezer storage from the time of harvest to the time of analy sis. The proposed tolerance for grape, raisin of 0.9 ppm is not required since the tolerance for the raw agricultural commodity grape at 0.6 0 ppm is adequate to account for an y residue concentration shown in the processed commodity. **2.2.4 International Harmonization**  The present action was conducted as a joint review with Health Canada’s Pesticide Management Regulatory

Authority

(PMRA) and Mexico’s Federal Commission for the Protection against Sanitary Risk (COFEPRIS). Harmonization of tolerance expression and levels for plant commodities was achieved during the review process. Based on the submitted ruminant metabolism data and the limite d livestock feedstuffs associated with this petition, HED concludes the proposed uses can be classified as 40 CFR 180.6 (a)(3), no reasonable expectation of finite residues in ruminant livestock commodities; therefore, the U.S. will not need to set toleran ces for ruminant livestock commodities. However, since PMRA is not legall y able to waive the requirement for a tolerance based on no reasonable expectation of finite residues, tolerances at the LOQ of the enforcement analy tical method will be established in Canada for ruminant livestock commodities. No Codex MRLs have be en established for cy flumetofen.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **10** of **73 2.3**  **Label Recommendations** There are no label recommendations relating to toxicology , residue chemistry , or occupational/residential exposure assessment associated with this action. **3.0 In**  **troduction 3.1**  **Chemical Identity Table 3.1. Cyflum**  **etofen Nomenclature** Com pound Chemical Structure

Common name Cyflumetofen Com pany experimental name BAS 9210 I, OK 5101 IUPAC name 2 - methoxyethyl (RS) - 2 - (4 - tert - butylphenyl) - 2 - cyano - 3 - oxo - 3 - (α , α ,α - trifluoro o - tolyl) propionate CAS name 2 - methoxyethyl α - cyano - α - [4 - (1,1 - dimethylethyl)phenyl] - β - oxo - 2 - (trifluoromethyl)benzenepropanoate CAS # 400882 - 07 - 7 End - use product/EP Nealta TM , Sultan TM **3.2 Physical/Chemical Characteristics**  Cyflumetofen has low water solubility . Its octanol/water partition coefficient suggests that it is a hydrophobic compound that is more fat soluble than water soluble, exhibiting a tendency to dissolve in fats, oils, lipids, and non - polar solvents more rea dil y than in water. Further, cyflumetofen has a low vapor pressure. The phys iochemical properties for this active ingredient are shown in Appendix C, Table C . 1. **3.3 Pesticide Use Pattern**  Cyflumetofen end - use products Nealta TM and Sultan TM are both fo rmulated as a 20% suspension concentrate (SC). Two applications may be made per season at a maximum single application rate of 0.2 lbs ai/acre with retreatment intervals of 14 to 21 days as stated on the proposed product labels. The maximum seasonal appl ication rate is 0.4 lbs ai/A/season for all use sites. Applications may

be made using open - cab ground - boom sprayers, airblast sprayers, and aerial equipment for the proposed occupational use s, while handheld equipment is allowed for both occupational and as well as residential uses. Aerial application is allowed only on tomatoes. Chemigation is prohibited on all proposed use sites. The proposed preharvest interval (PHI) ranges from 1 to 14 day s depending on the use.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **11** of **73 Table 3.3. Summ**  **ary of Directions f or Use of Cyflum**  **etofen Proposed**  **Use Application** 

**Equipment Form**  **ulation**

**[EPA Reg. No.]**  **Applic.**

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

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

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

**(days) Use Directions and** 

**Limitations** Citrus Fruit Airblast,

Groundboom Nealta

[EPA Reg . No . 7969 - GGA] 0.2 2 0.4 7 Do not apply by air to citrus fruit, pome fruit, straw berries, or tree nuts. Aerial only allowed on tomatoes. Do not apply through an irrigation system . Retreatment interval: 14 days Grapes 14 Pome Fruit 7 Tree Nut Group 7 Straw berry Groundboom 1 Tomato Groundboom,

Aerial 3

Ornamentals Groundboom

and handheld equipment Sultan

[EPA Reg . No . 7969 - GGT] 0.2

(0.002 lbs ai/gallon) 2 0.4 n/s DO NOT apply by chemigation or air. DO NOT use on vegetables grown in greenhouses for crop production or in vegetable production of transplant for outdoor use. Retreatment interval: 14 - 21 days **3.4 Anticipated Exposure Pathways**  The Registration Division has requested an assessment of human health risk to support the proposed new use s of cyflumetofen on citrus fruit, grapes, pome fruit, strawberry , tomato, tree nuts, and ornamentals . Humans may be exposed to cyflumetofen in food and drinking water, since cyflumetofen may

be applied directly to growing crops and application may result in cyflumetofen reaching surface and ground water sources of drinking water. Cyflumetofen is being proposed for use on ornamentals ( i.e., residential landscape areas) and may be applied in residential settings; therefore there is a potential for exposure in residential or non - occupational settings. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is also a potential fo r post - application exposure for workers re - entering treated fields. **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 variet y of consumer subgroups according to well - established procedures. In line with OPP policy , HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department ofCyflumetofen Human Health Risk Assessment DP No. D398246

Page **12** of **73** Agricu lture’s (USDA’s) National Health and Nutrition Examination Survey , What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized b y subgroups based on age, season of the year, ethnic group, and region of the country . Additionall y, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate , non - dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post - application are evaluated. Further considerations are currently in de velopment as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifest yle and traditional dietary patterns among specific subgroups. **4.0 Hazard C**  **haracterization and Dose -**  **Response Assessment 4.1**  **Toxicology Studies Available for Analysis** The toxicology

database is complete and the toxicity profile can be characterized for a wide range of effects, including potential developmental, reproductive, neurotoxic, mutagenic, carcinogenic, and immunotoxic effects. The HASPOC determined that a subchronic inhalation study is not needed for cyflumetofen (TXR# 0056691, July 3, 2013) based on a weight of evidence (WOE) approach that considered all of the availabl e hazard and exposure information for cyflumetofen, including: 1) the phy sical/chemical properties of cyflumetofen including its low volatility

(4.43 x 10 - 8 mm Hg at 25 oC); (2) its low acute inhalation toxicity (Toxicity Category IV); and (3) the use of an oral POD results in MOEs that are ≥5,500, and above the Agency ’s level of concern. The available toxicity studies for cyflumetofen are listed in Table A.1 in Appendix A. **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  There were a series of metabolism studies conducted for cy flumetofen. Detailed information is provided in the Appendix A.4 .8 . 14 C - cyflumetofen was rapidl y absorbed following administration of the low dose, with plasma levels of radioactivity peaking at 1 hour post - do sing. Absorption was slightl y s lower following administration of the high dose, with peak plasma levels attained at 2 - 4 hours post - dosing indicating saturation of absorption. At the high dose, females demonstrated higher C max and area under the curve (AU C) values than males. At 72 hours post - dosing, the gastr ointestinal tract, carcass, liver and kidney contained the highe st proportions of radioactivity . Most of the radioactivity excreted in urine from low dose rats (90 - 96%) was eliminated within 24 ho urs after dosing, whereas at the high dose, excretion was slower with only

74 - 88% eliminated with in 24 hours of dosing. At both low and high doses, 60 - 89% of the radioactivity

excreted in feces was eliminated within 24 hours of dosing. The unchanged pare nt was not detected in the urine of an y test group. Metabolite AB - 3 was identified as a major metabolite in the urine of female rats but was a minor urinary metabolite in males. Metabolite AB - 2 was a minor metabolite in urine of all test groups except fema les from the low dose group, in which residues for this metabolite reached 4% of the administered dose.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **13** of **73** The major metabolites detected in the bile from all test groups were the glucuronic acid conjugate s of metabolites AB - 1 and AB - 3. Metabolite AB - 2 was also detected at lower levels in the bile from all test groups. Unique metabolites identified in the bile of rats administered the A ring or B - ring label included the glucuronic acid conjugate of A - 6 and the glutathione conjugate of B - 1, respectively . 14 C - cyflumetofen was metabolized in the rat primarily by hydrol yt ic cleavage of the trifluoromethylbenzoyl moiety resulting in metabolite B - 1 (trifluoromethylbenzoic acid) and A 18. Another minor pathway included successive hydrox yl ation of the tert - butyl side chain. **4.2.1 Dermal Absorption**  A dermal absorption study was submitted which supports an estimated dermal absorption of 11%. However, since no dermal hazard has been identified for cy flumetofen, no dermal endpoint was selected for use in risk assessment. **4.3 Toxicological Effects**  The major target organ in rats, mice, and dogs following short - term and long - term oral exposure is the adrenal glands characterized with increased organ weight and histopathology (vacuolation and hy pertrophy of the adrenal cortical cells). The adrenal effects are the most sensitive and protective endpoint for all lifestages and populations of concern since there is no progression of toxicity over time. Cyflumetofen has low acute toxicity by oral, dermal, and inhalation routes of exposure. Itis minimally

irritating to the eyes but not to the skin. It is a skin sensitizer. There is no evidence of neurotoxicity

or immunotoxicity

in an y of the submitted studies for cyflumetofen. In the developmental toxicity

study in rats, an increased incidence of wav y ribs was noted at the high dose (1000 mg/kg/day), while an increased incidence of incompletel y ossified sternal centra was observed at the mid - and high - dose levels. These incidences occurred in the presence of materna l toxicity . In the developmental toxicity study in rabbits, delay s in skeletal ossification were observed at the mid - and high - doses where the maternal toxicity was observed. T he onl y adverse external alteration observed was a downward flexion of the forepaws (2 fetuses from one litter) or hind paws (1 fetus from one litter) in the high - dose (1000 mg/kg/day) group with observed maternal toxicity . The incidences were slightl y above historical controls and were considered a treatment - related adver se effect. In the rat reproduction study , adrenal effects (increased weight and histopathology) were observed in the parental and offspring animals at the mid - and high - doses. S erum hormone concentrations were measured in the F 1 parental rats. The FSH, p rogesterone, and 17 β - estradiol levels in the mid - and high - dose female groups were significantl y lower than the corresponding values in the control groups. No hormonal effect was observed in the F 1 male rats at an y dose level. Overall reproductive perform ance showed that there were no corresponding changes in reproductive performance at an y dose level. In accordance with the EPA's Final Guidelines for Carcinogen Risk Assessment (March, 2005) , the Cancer Assessment Review Committee (CARC) classified cyflumetofen as “SuggestiveCyflumetofen Human Health Risk Assessment DP No. D398246

Page **14** of **73** Evide nce of Carcinogenic Potential”. This classification is based on the presence of a single tumor ty pe (th yroid c - cell) in one sex (male) and one species (rat), and the lack of concern for mutagenicity . When there is suggestive ev idence of carcinogenicit y, the Agency does not attempt a dose - response assessment as the nature of the data generall y would not support one. Therefore, the Agency

has determined that quantification of risk using a non - linear approach (i.e. the chronic refe rence dose) will adequatel y protect for all chronic toxicity , including carcinogenicity , likely to result from exposure to cyflumetofen . **4.4 Safety F**  **actor for Infants and Children (FQPA Safety Factor)** HED recommends that the 10X FQPA Safety Factor (for the protection of infants and children) be reduced to 1X. An FQPA Safet y Factor of 1X is appropriate for the following reasons: The toxicity

database is complete and adequate to assess safet y for infants and children. There is no evidence of increased qualitative or quantitative susceptibility in the rat 2 - generation reproduction study. While there is evidence of increased susceptibility in the rabbit and rat developmental studies, these studies have clearly defined NOAEL/LOAEL s. There is no evidence of neurotoxicity in the acute and subchronic neurotoxicity studies for cyflumetofen, and a developmental neurotoxicity study is not required. Based on the use of conservative assumptions with respect to potential exposure from foo d, water and residential uses, the assessment will not underestimate children’s exposure to cy flumetofen. Further details may be found in the following sections. **4.4 .1**  **Completeness of the Toxicology Database** The database is complete and adequate to characterize potential pre - and/or post - natal risk for infants and children . **4.4.2 Evidence of Neurotoxicity**  There are acute and subchronic neurotoxicity studies available. No evidence of neurotoxicity was observed in an y of the subm itted studies fo r cyflumetofen. A developmental neurotoxicity study is not required. **4.4.3 Evidence of Sensitivity/Su**  **sceptibility in the Developing or Young Animal**  There is no evidence of increased qualitative or quantitative susceptibility in the rat 2 - generation reproduction study ; however, the rat and rabbit developmental studies indicate susceptibility in the pups. There is evidence of increased quantitative susceptibility in the rabbit developmental toxicity study , since developmental effects (changes in ossicific ation, paw flexion, and decreased fetal body weights) at the limit dose were observed where no maternal toxicity was present. There is evidence of increased qualitative susceptibility in the rat developmental toxicity study as developmental effects (incre ased incidence of incompletely ossified sternal centra) were seen at the same dose that caused an increase in adrenal weights and organ - to - body weight ratio in the maternal animals. Notwithstanding, the degree of concern for these effects in infants and c hildren is low because the rat and rabbit developmental effects have clearly definedCyflumetofen Human Health Risk Assessment DP No. D398246

Page **15** of **73** NOAEL/LOAELs and the dose selected for chronic risk assessment is protective of these effects. Therefore, the PODs based on adrenal effects in rat are health protective of all lifestages. **4.4.4 Residual Uncertainty in the Exposure Database**  There are no residual uncertainties in the exposure database. Since the dietary and residential exposure estimates were based on conservative assumptions, HED is confident that this assessment does not underestimate dietary (food and water) or residential exposure. The c hronic dietary exposure assessment used tolerance level residues for all commodities, 100% crop treated (% CT) , and empirical proc essing esti mates when available or DEEMTM default processing factors. The drinking water assessment utilized water concentration values generated b y models and associated modeling parameters which are designed to produce conservative, health protective, high - end esti mates of water concentrations which are not likel y to be exceeded. For these reasons it can be concluded that the chronic dietary exposure anal ys is does not underestimate risk from chronic exposure to cyflumetofen . Similarly , HED does not believe that th e residential exposure estimates are underestimated because they

are also based on conservative assumptions inclu ding maximum application rates and standard values for unit exposures, acreage treated/amount handled. **4.5 Toxicity Endpoint and Point of**  **Departure Selections 4.5.1**  **Dose -**  **Response Assessment** The detailed description of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in Appendix A .3 . No appropriate endpoint attributable to a single exposure (dose) was identified from studies including an acute neurotoxicity study and developmental toxicity studies in rats and rabbits. An acute RfD was not established for the general population including infants, children, and fem ales age 13 - 49. In the developmental toxicity study in rabbits, increased incidence of paw flexion was observed at 1000 mg/kg/day and was slightl y above historical controls. Maternal toxicity , decreased fetal body weight, and incomplete ossification were also observed at this dose. Paw flexion was considered to be associated with ossification effects ( i.e., all three pups that exhibited paw flexions also had incomplete ossification). Delay s in ossification and developmental delay s are not ty picall y consid ered to occur as a result of exposure to a single dose and therefore are not appropriate as endp oints for acute risk assessment . For the chronic dietary , three studies were selected as co - critical studies for endpoint selection. These studies are approp riate for the duration and populations of concern since there is no progression of toxicity

over time. The NOAEL and L OAEL selected were based on the weight of evidence from the three studies which had similar target organ toxicities. The point of departur e of 16.5 mg/kg/day

(NOAEL) was selected from the 90 - day and the chronic toxicity

/ carcinogenicity

rat studies, which have similar NOAEL s and LOAELs based on effects on the adrenals. In the 2 - generation reproduction study , a lower NOAEL of 9.2 mg/kg/day w asCyflumetofen Human Health Risk Assessment DP No. D398246

Page **16** of **73** identified with a LOAEL of 30.6 mg/kg/day based on effects on the adrenals; however, this NOAEL of 9.2 mg/kg/day was not selected as the POD for risk assessment since it is considered to be a function of calculated compound intake (based on food consumption) rather than a lower NOAEL/LOAEL per se. The POD of 16.5 mg/kg/day selected is still protective of similar effects seen at 30.6 mg/kg/day in the 2 - generation reproduction toxicity study , the 28 day

rat study at LOAEL of 75 mg/k g/day , the chronic mouse study at LOAEL of 537/483 mg/kg/day (M/F), and the chronic dog study at LOAEL of 300 mg/kg/day. There is no incidental oral exposure expected based on the current use pattern; however, an endpoint was selected during the full revi ew of the database. Similar to the chronic endpoint selection, three studies were selected as co - critical studies for short - and intermediate - term incidental oral exposure . These studies are appropriate for the duration since there is no progression of to xicity

over time. The point of departure of 16.5 mg/kg/day (NOAEL) was selected from the 90 - day

and the chronic toxicity

/carcinogenicit y rat studies. The LOAEL of 30.6 mg/kg/day

was selected based on effects on the adrenals from the 2 - generation reproduct ion study . For short - and intermediate - term dermal exposure, no appropriate endpoint was identified for risk assessment. A 28 - day dermal toxicity

study in rats is available; however, no adverse effects were seen at the highest dose tested of 1000 mg/kg/d ay , including the endpoints of concern (adrenal effects). Although developmental/reproductive effects (not assessed in the dermal study) were observed in the developmental and reproductive toxicity studies, the effects occurred at dermal equivalent doses above the limit dose or in the presence of parental toxicity . Therefore, since no effects were observed in adults at the limit dose, no developmental or reproductive effects would be expected to occur due to parental dermal exposure. A route - specific subchronic inhalation toxicity study is not available for cyflumetofen. For short - and intermediate - term inhalation risk assessments, an oral NOAEL was selected from three studies as described in the chronic dietary . These studies are appropriate for the duration since there is no progression of toxicity over time. The point of departure of 16.5 mg/kg/day (NOAEL) was selected from the 90 - day and the chronic toxicity

/carcinogenicity

rat studies, which have similar NOAELs and LOAEL s. The LOAEL of 30.6 mg/kg/ day was selected from the 2 - generation reproduction study . Since an oral study was selected, absorption via inhalation is presumed to be equivalent to oral absorption. There is no proposed long - term use; therefore, risk assessment for long - term inhalati on exposure is not required. A 100X uncertainty

factor is applied (interspecies factor of 10X and intraspecies factor of 10X) for chronic dietary

risk assessments. For inhalation risk assessment, the level of concern (LOC) is a margin of exposure (MOE) of 100, based on the combined i nterspecies (10X) and intraspecies (10X) uncertainty factors. **4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment**  When there are potential occupational and residential exposures to a pesticide, the risk assessment must address exp osures from three major sources ( oral, dermal, and inhalation ) and then determine whether the individual exposures can be combined if they have the sameCyflumetofen Human Health Risk Assessment DP No. D398246

Page **17** of **73** toxicological effects. Since no dermal hazard has been identified for cyflumetofen, a dermal assessment was not conducted. However , inhalation and oral routes can be combined since the points of departure are based on the same studies and the toxicological effects are the same. **4.5.3 Cancer Classification and Risk Assessment Recommendation**  The carcinogenic potential of cyflumetofen was evaluated following dietary administration to male and female Fischer 344 rats and male and female CD - 1 mice. Two separate studies were conduct ed in both species. In2004, the Registrant conducted a carcinogenicity study in Fischer 344 rats and a carcinogenicity study in CD - 1 mice. Since there was no evidence of carcinogenicity

in either species, and to address concern regarding the adequacy of the doses tested in the above studies, the Registrant elected to conduct supplemental studies to evaluate higher doses in mice and rats. Cyflumetofen was administered in the diet to groups of 50 rats/sex/dose for 104 weeks. One study was conducted at doses of 0, 150, 500 and 1500 ppm (0, 4.9, 16.5, and 49.5 mg/kg/day in males and 6.14, 20.3, and 61.9 mg/kg/day in females) while a second high dose study was conducted at 0 and 6000 ppm (0 and 220 mg/kg/day in males and 0 and 287 mg/kg/day in females). There w as limited evidence of carcinogenicity characterized by

the presence of th yr oid c - cell tumors and interstitial cell tumors of the testes in male rats onl y at the highest dose tested (HDT). There was no evidence of carcinogenicity in female rats at an y dos e level. The doses tested in the rat study

were considered to be adequate to assess the carcinogenic potential of cyflumetofen. The thy roid c - cell tumors were determined to be treatment - related based on the following considerations: a statistically signi ficant trend and a pair - wise significance (both at p < 0.05) for thy roid c - cell adenocarcinomas when compared to controls; a statistically significant trend (p < 0.05) and a pair - wise significance (p<0.01) for thy roid c - cell adenomas and/or adenocarcinomas combined; and the incidences of the adenocarcinomas (31%) and the combined tumors (57%) exceeded the historical control range from the testing laboratory (c - cell adenocarcinoma, 6 - 18%, and combined c - cell adenoma/carcinomas, 26 - 50%). The testicular inte rstitial cell tumors, although exacerbated by treatment were not considered to be biologically

relevant since this tumor (Leydig cell, L CT) is extremel y common in the F344 rat, with a reported background incidence of 56 - 100% in 2 - ye ar cancer studies. The r easons for the different background incidence rate for L CT among species stem from both quantitative and qualitative differences in the Leydig cell response to hormonal stimuli. The rat Leydig cell is extremely sensitive to slight changes in circulating luteinizing hormone (LH) levels. Among rat strains, the F344 rat is particularl y susceptible to this process and is not considered a relevant model for studying LCT. By contrast, the incidence rate in humans of LC T is very low (i.e., 0.00004%). Similarly , rats are known to have approximately 13 - times more LH receptors per cell than humans (Hutaniemi, 1983). Because of the differences present between the human and the rat Leydig cells, non - genotoxic compounds that cause L CTs in rats have little relevance to humans. The data with cyflumetofen supports this species and strain - specific effect on the Le ydi g cells.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **18** of **73** Additionally , the carcinogenic potential of cy flumetofen was evaluated following dietary administration to male and female CD - 1 mice. Two studies were c onducted in the mice . Cyflumetofen was administered to groups of 52 mice/sex/dose for 78 weeks. One study was conducted at doses of 0, 150, 500, 1500 and 5000 ppm (0, 15.5, 54.3, 156 and 537mg/kg/day in males and 14.3, 48.1, 144 and 483 mg/kg/day in female s) while a second high dose study was conducted at 0 and 10,000 ppm (0 and 1143 mg/kg/day in males and 1132 mg/kg/day in females. There was no evidence of carcinogenicity in male or female mice at an y dose level. The doses tested in the mouse were consider ed adequate to assess the carcinogenic potential of cyflumetofen. The mutagenic potential of cyflumetofen, its metabolites, and an impurity was tested in in vitro and in vivo studies. There was no concern for mutagenicit y for the parent, the metabolites or the impurity . Consequently , mutagenicity can be ruled out as a possible mode of action for tumor formation. In accordance with the EPA's Final Guidelines for Carcinogen Ri sk Assessment (March, 2005) , the Cancer Assessment Review Committee (CARC) classified cyflumetofen as “Suggestive Evidence of Carcinogenic Potential”. This classification is based on the presence of a single tumor ty pe (th yroid c - cell) in one sex (male) an d one species (rat), and the lack of concern for mutagenicity . When there is suggestive evidence of carcinogenicit y, the Agency does not attempt a dose - response assessment as the nature of the data generall y would not support one. Therefore, the Agency

has determined that quantification of risk using a non - linear approach (i.e. the chronic reference dose) will adequatel y protect for all chronic toxicity , including carcinogenicity , likely to result from exposure to cyflumetofen (TXR# 0056862) . **4. 5**  **. 4**  **Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment**  **Table 4.5.4. Summary of Toxicological Doses and Endpoints for Cyflum etofen for Use in Dietary, Non**  **** **Occupational and 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 populations) An acute reference dose has not been established for either the general population or for Females

13 - 49 years of age since there were no appropriate studies that demonstrated evidence of toxicity attributable to a single dose for these populations.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **19** of **73 Table 4.5.4. Summary of Toxicological Doses and Endpoints for Cyflum**  **etofen for Use in Dietary, Non**   ** Occupational and 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**

Chronic Dietary (All Populations) NOAEL =

16.5 mg/kg/day UF A= 10x

UF H = 10x FQPA SF= 1x Chronic RfD =

0.17 mg/kg/day cPAD = 0.17 mg/kg/day **Three co -**  **critical studies :** 

90 - day feeding study in rats LOAEL = 1000 ppm (54.5/62.8 mg/kg/day in M/F) based on hematology and organ weight changes in the liver, adrenal, kidney and ovaries; and histopathology effects in the adrenals and the ovaries . NOAEL=300 ppm (16.5/19 mg/kg/day in males/females) Chronic toxicity/carcinogenicity study in rats LOAEL = 1500 ppm (49.5/61.9 mg/kg/day in M/F) based on increased adrenal weights and histopathology. NOAEL=500 ppm (16.5/20.3 mg/kg/day in males/females) Two generation reproduction study in rats Parental: LOAEL = 500 ppm (30.6/46.6 mg/kg/day in M/F) based on increased o rgan weight and histopathology in adrenals. NOAEL=150 ppm (9.2/13.8 mg/kg/day in males/females) Dermal (Short - , Intermediate and Long Term) No dermal hazard was identified. No appropriate endpoint was selected for risk assessment. Inhalation (Short - , Intermediate and Long Term) NOAEL =

16.5 mg/kg/day UF A= 10x

UF H = 10x FQPA SF= 1x Occupational

and Residential LOC for MOE = 100 **Same as chronic dietary endpoint** Cancer (oral, dermal, inhalation) CARC Classification: Suggestive Evidence of Carcinogenic Potential. * The complete summary of toxicological doses and endpoints for cyflumetofen can be found in Appendix A.5. 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 = e xtrapolation 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 (a = acute, c = chronic). RfD = reference dose . MOE = margin of exposure. LOC = level of concern. N/A = not applicable.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **20** of **73 5.0**  **Dietary Exposure and Risk Assessment 5.1**  **Metabolite/Degradate Residue Profile** A tabular summary

of the major metabolites and degradates for cyflumetofen are shown in Appendix B, Tables B.1 and B.2. **5.1.1 Summary of Plant and Animal Metabolism Studies**  Plants Metabolism studies on fruit crops (mandarin, apple, and eggplant) were submitted/reviewed and found to be scientificall y acceptable. The studies were conducted w ith a single foliar application of 14 C - cyflumetofen, either labeled on the butylphenyl ring (label A) or the benzoyl ring (label B) at a rate of 600 g ai/ha (~1.5x the maximum seasonal label application rate of 0.4 lbs ai/acre). The metabolism was seen to be limited in the three studies . The major part of the total radioactive residue (TRR) remained on the surface of fruits and leaves (56% to 97% TRR) and was easil y removed b y s olvent rinses. The parent cyflumetofen was identified as the major component, accounting for 67% to 87% TRR on fruits and leaves 7 day s after application, and 44% to 81% TRR after 30 day s. Degradation compounds were recovered at a level lower than 10% TRR, except for the metabolite B - 1 ( 2 - trifluoromethylbenzoic acid) resulting from the cleavage of the parent molecule and representing up to 11% TRR in mandarin (0.06 ppm) and 15% TRR in eggplant (0.06 ppm). In addition B - 1 conju gates (metabolites U1 and U2) were detected up to 16% TRR in eggplant fruits at a PHI of 14 day s. The nature of the residue for cy flumetofen in the proposed crops is considered to be adequately understood. Metabolism in these three crops shared a commo n metabolic pathway with cyflumetofen as the primary component. However, in the absence of data on small grains, leafy vegetables, and root/tuber crops, this data set is not considered adequate to define the nature of the residue in all plants. Therefore , if new uses on small grains, leafy vegetables, bulb vegetables, head/stem brassica, oilseeds, and/or root/tuber crops are proposed in the future, then additional metabolism studies may be required to reconsider the residues of concern in plants. The ava ilable metabolism data are onl y considered adequate to support uses on fruits, cucurbit vegetables, and fruiting vegetables. Rotational Crops Confined rotational crop data were submitted, reviewed and found to be scientifically acceptable. Cyflumetofen w as applied to bare sandy loam soil in plastic containers at an application rate of 1 x 400 g ai/ha (approximately 0.357 lb/A, ~ 0.9x the proposed maximum single application rate). The nature and the quantities of the radioactive residues were investigated in lettuce (immature and mature), white radish (top and root) and spring wheat (forage, hay , straw, chaff and grain) after plantback intervals (PBIs) of 30, 120 and 365 day s. Although the metabolic profile was similar across the rotational crop matrices, significant differences were shown between the two different radiolabels (benzoyl or butylphen yl ) , and the metabolic pathway in rotational crops is significantl y different than that in primary crops.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **21** of **73** Following application to bare soil, the degradation of cyflumetofen in rotational crops appears to follow four major pathway s: hydrol yt ic cleavage of the parent molecule results in the formation of the metabolite B - 1 ( trifluoromethyl benzoic acid) - which is onl y detectable with the benzoyl label - and one or several butylphen yllabel - specific intermediates which were not identified. The predominant metabolite in the case of the benzoyl label, trifluoroacetic acid (TFA), can be derived from cy flumetofen or the metabolite B - 1. The butylphen yllabel - specific c leavage products (such as the goat metabolite A - 2) which is formed b y h ydrol ys is of the formic acid ester, decarbox yl ation and hydrol yt ic detachment of the trifluoromethyl benzoyl moiet y) are further transformed to a series of minor (<0.01 ppm), mainly uni dentified medium - polar metabolites. Livestock The metabolism of cyflumetofen was investigated in lactating goats following repeated oral administration of 14 C - cyflumetofen , labeled either in the benzoyl ring (benzoyl label) or in the tert - butylphenyl rin g (butylphenyl label) . Cyflumetofen was administered by gavage (two animals per label) for twelve (b enzoyl l abel) or ten (butylphen ylL abel) consecutive day s at a nominal dose of 12 ppm feed (~171x the maximum reasonabl y balanced diet (MRBD)) . There are n o poultry

feedstuffs associated with the proposed uses; therefore a poultry metabolism study is not required and was not submitted. Cyflumetofen and its metabolites were rapidl y excreted b y lactating goats, mainly via feces and urine. For both labels, only low portions of the administered dose were retained in edible tissues and organs. In edible tissues, parent cyflumetofen was only identified in fat of the benzoyl label. Metabolite B - 1 was identified in all matrices of the benzoyl label as the sole benzoyl label specific metabolite. The major metabolic pathway of cyflumetofen in lactating goats comprises hydrol yt ic cleava ge of the trifluoromethylbenzoyl moiety resulting in metabolite B - 1. The submitted goat metabolism studies adequately address the requirement to elucidate the nature of the residue for cyflumetofen in ruminants . Based on the ruminant metabolism data and the limited livestock feedstuffs associated with this petition, the proposed uses can be classified as 40 CFR 180.6 (a)(3), no reasonable expectation of finite residues in ruminant livestock commodities. However, this decision may be reconsidered if the use pattern changes and/or additional livestock feedstuffs are proposed in the future. Additionally , if additional uses are proposed that contain poultry feedstuffs, a poultry metabolism study will be required. **5.1.2 Summary of Environmental Degradation**  Cyflumetofen has limited solubility in water (28 ug/L) and is quite lipophilic; therefore, it is expected to absorb to foliage surfaces and soil (Koc of 131,826) at the site of application. Once deposited, either at the site of application or farther afi eld through spray drift (or through erosion of cy flumetofen bearing soil particles), the parent molecule is expected to degrade quickly through multiple fate processes (half - lives of hours to several day s) under environmental conditions. Cyflumetofen form s man y degradates with a wide range of fate properties ( e.g. , from highl y soluble to less soluble than the parent). The two bonds on either side of the cyano group readil y break in all of the fate studies involving water other than photolysis (hydrolysis, aerobic and anaerobic soil and aquatic metabolism, and terrestrial field dissipation studies), which meansCyflumetofen Human Health Risk Assessment DP No. D398246

Page **22** of **73** that cyflumetofen is not persistent in the environment (Hydroly sis DT50 = 9.75 hours at pH 7) and rapidl y converts to degradates via biotic and abio tic hydrol ys is reactions. Many degradates are much more persistent than the parent. **5.1.3 Comparison of Metabolic Pathways**  Metabolism in plants was similar, with parent cyflumetofen being the primary component in most matrices. Other identified metabo lites were B - 1, A - 12, AB - 6 and AB - 7. The major metabolic pathway

in plants consisted of the hydroly tic cleavage of the benzoyl moiet y leading to metabolite B - 1 followed by conjugation. Metabolites AB - 6 and AB - 7 were primarily photochemical metabolites fo und as surface residue in crop matrices. Residues in plants tend to be surface residues. Metabolism in rotational crops was seen to be very different from that in primary crops. Depending on the position of the radiolabel, either trifluoroacetic acid (TF A) or a series of medium - polar metabolites in minor concentrations were detected. Metabolism studies performed in rat and goat showed a common metabolic pathway in animals. In both goat and rat, cy flumetofen is rapidl y absorbed and excreted. C yflumetofen is metabolized in goat and rat primarily by hydroly tic cleavage of the trifluoromethylbenzoyl moiety resulting in metabolite B1 (trifluoromethylbenzoic acid) (goat and rat) and A - 18 (rat) as primary metabolites. Another minor pathway includes hydroxylatio n and oxidation of the tert butyl side chain. The metabolic pathway s in both rat and goat were qualitatively similar. **5.1.4 Residues of Concern Summary and Rationale**  The HED Residues of Concern Knowledgebase Sub - committee (ROCKS) considered the availabl e data on the nature and magnitude of residues of cyflumetofen and concluded that for the subject crops, the parent compound only be included for tolerance enforcement and dietary risk assessment. At this time, there is no reasonable expectation of finite residues in livestock so the committee had no recommendation on residues of concern in livestock. For drinking water, the ROCKS recommended including the parent cyflumetofen and all of the AB degradates. The reasoning behind these recommendations is as follows: Primary Crops : Parent cyflumetofen was detected as a main residue in the primary crop metabolism studies and crop field trials. It is considered an appropriate marker of misuse on primary crops and is recommended as the residue of concern for tolerance enforcement. The metabolite B - 1 was also a major residue in some commodities. The ROCKS recommended inclusion of parent onl y for risk assessment purposes based on the following weight of evidence anal ys is:  The structure of metabolite B - 1 is unlike the parent ( i.e. , it is a carbox yl ate and its molecular weight is 2 times lower);  The octanol:water partition coefficient of parent cyflumetofen is much higher than that of B - 1 (Log P = 4.3 versus 2.5, respectivel y), indicating that B1 is much mor e water soluble. As a carbox yl ate, B - 1is also likely to be charged (predicted pKa = 3.12) in the body (pHCyflumetofen Human Health Risk Assessment DP No. D398246

Page **23** of **73** 7.4) and readily

excretable by

renal anion transporters, decreasing the likelihood of re absorption;  Rat metabolism studies show that B - 1 is likel y a detoxification product of parent cyflumetofen. Once formed, B - 1 undergoes conjugation with glutathione (phase II metabolism) resulting in a higher excretion potential;  The structure of metabolite B - 1 resembles benzoic acid (the trifluoromethyl group i n B - 1 is unlikely to change reactivity), which exhibits very low single - and repeated - dose toxicity (NOAEL  800 mg/kg/day ; http://toxnet.nlm.nih.gov , accessed 02/25/2013). If new uses are requested in the future, additional metabolism studies may be required to reconsider the residues of concern in plants. Rotational Crops : The major residue found in rotational crops was trifluoroacetic acid (TFA). The ROCKS recommended excluding it from risk assessment conside ration for the following reasons: 1) TFA is a polar, low molecular weight organic acid with no structural resemblance to the parent molecule, 2) the toxicity of TFA is due to its strong acidity (pKa<1) and at phy siological pH, TFA would exist as an anion and not the acid and would therefore not exhibit acid toxicity

(http://www.afeas.org/environ.html), and 3) it is not likely to contribute to toxic effects found for cy flumetofen. Since there were no major residues of toxicological concern in the rotationa l crop studies, no residues of concern for tolerance enforcement or risk assessment were identified. Livestock: Based on the submitted ruminant metabolism data and the limited feedstuffs associated with this petition, the ROCKS concurred with the team th at the proposed uses can be classified as 40 CFR 180.6 (a)(3), no reasonable expectation of finite residues in livestock commodities. The residues of concern may be reconsidered if the use pattern changes and/or additional livestock feedstuffs are proposed in the future. Drinking W

ater: The ROCKS recommended inclusion of parent cyflumetofen, the degradates AB - 1, AB - 7, AB - 11, AB - 15, and three dimers of AB - 1 (AB - 1 dimer, AU16 and AU17 ) as residues of concern in the drinking water risk assessment. Estimated drinking water concentrations would be based on total residues of parent and the degradates listed above , expressed as parent cy flumetofen. Since the degradates are structurall y simil ar to the parent cyflumetofen, similar toxicity is assumed. The degradate B - 1 is not recommended based on the rationale explained above and B - 3 is excluded as well based on its structure being significantl y distinct from the parent. The octanol:water parti tion coefficient of parent cy flumetofen is much higher than B - 3, and no alerts were reported in DEREK while the parent show alerts that may be correlated to effects observed in the toxicity studies. The other degradates containing the t butylphen ylmoiet y, A - 1, A - 2, A - 12, and A - 18, are excluded based on structural differences to parent, significantl y lower octanol:water partition coefficients than parent cyflumetofen, or presence in the rat metabolism study (i.e. A - 12 and A - 18).Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **24** of **73** The residues of concern for cyflumetofen are summarized below in Table 5.1.4. **Table 5.1.4. Summary of Metabolites and Degradates Recommended for inclusion in the Risk Assessment and Tolerance Expression**  **Matrix Residues Included In Risk**  **Assessment Residues Included In**  **Tolerance Expression** Plants 1 Cyflumetofen Cyflumetofen Rotational crops NA NA Livestock (ruminants and poultry) NA NA Drinking Water Cyflumetofen + AB Degradates 2 NA NA

– Not applicable. 1 If new uses on small grains, leafy vegetables and root/tuber crops are proposed in the future, then additional metabolism studies may be required to reconsider the residues of concern. 2 AB degrad ates include AB - 1, AB - 7, AB - 11 , AB - 15, and three dimers of AB - 1 (AB - 1 dimer, AU16 and AU17) . Refer to Appendix B for the names and/or chemical structures of the AB degradates. **5 .2**  **Food Residue**  **Profile** The results from plant metabolism studies in mandarin, eggplants, and apples conducted following a foliar treatment of formulated cyflumetofen indicate that the major component of the extractable residue was unchanged parent cyflumetofen in both fruit and leaves, and that residues are generally

low. The only

major metabolite found in/on fruits was metabolite B - 1 (f ree and conjugate), with residues exceeding 10% of the TRR in mandarin and eggplants only . The highest residues are generally found in the foliage (leaves) of plants, and not in the fruit itself. The residue is expected to be a surface residue consisting of primaril y parent compound and minor photoly

tic degradates, as the majority of the radioactivity

was removed by

acetonitrile surface rinses. The available metabolism data in plants shows that cyflumetofen undergoes limited translocation or degradation. Adequate residue chemistry data have been provided for cy flumetofen. Field trials are of adequate number and geographic representation and showed levels of cyflumetofen residues found in the edible portions of target crops ranging from <0.01 ppm (almond s and pecan nutmeat) to 0.5 ppm (citrus, pome fruit, tomato, strawberry and grapes). Residues decline with increasing pre - harvest intervals (PHIs). Levels of cyflumetofen residues in livestock feedstuffs were higher and ranged from 0.3 - 2.0 ppm (see Append ix E Table E .1 for a summary of the residue data for cyflumetofen). The data were generated using a validated data collection method and are adequately supported b y frozen storage stability data, with the exception of tomato which was corrected for residue loss during freezer storage. Sufficient processing studies were sub mitted for apple, citrus, tomato, and grape to elucidate the fate of cy flumetofen in processed commodities derived from these crops, with concentration onl y s een in citrus oil and raisins. HED determined that the proposed uses of cyflumetofen are classifi ed as 180.6 (a) (3), no reasonable expectation of finite residues with respect to residues in livestock commodities. Metabolism in rotational crops was seen to be very different from that in primary crops. Depending on the position of the radiolabel, either trifluoroacetic acid (TFA) or a series of medium - polar metabolites in minor concentrations were detected.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **25** of **73 5.3**  **Water Residue Profile** Cyflumetofen is a new active ingredient; therefore, there are no monitoring data currentl y available for the parent molecule or its residues of concern in drinking water. E stimated drinking water concentrations (EDWCs) were generated using OPP’s standard suite of models. The EDWCs from surface water sources were calcul ated using Tier II models Pesticide Root Zone Mode l (PRZM) and Exposure Anal ys is Modeling Sy stem (EXAMS) . Estimated groundwater EDWCs were calculated using the model Screening Concentrations in Ground Water (SCI GROW, version 2.3, 07/29/03) as well as Pesticide Root Zone Model - Groundwater (PRZM - GW , versi on 1.0, December 11, 2012) . Maximum application rates for cyflumetofen as a high - end estimate of exposure in drinking water were modeled based on the proposed labels. In accord with recommendations of the ROCKS, a total toxic residues approach was used f or the modeling that included cyflumetofen, the degradates AB - 1, AB - 7, AB - 11, AB - 15, and three dimers of AB - 1 (AB - 1 dimer, AU16 and AU17) . Surface water EDWCs were corrected for a percent cropped area (PCA) of 0.91. The PRZM/EXAMS surface water simulatio ns of a NY grapes scenario produced the highest surface water EDWCs of 4.7 μg/L for acute exposure, 0.33 μg/L for chronic exposure, and 0.28 μg/L for long - term cancer exposure. The SCI - GROW groundwater simulation produced the highest groundwater EDWC of 2 .4 × 10 - 3 μg/Lfor both acute and chronic exposure s . The maximum surface and ground water EDWCs for use in the human health risk assessment for cyflumetofen are shown in Table 5.3. **Table 5.3 .**  **Summary of Estimated Surface Water and Groundwater Concentrations for Cyflum**  **etofen** Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b Ac ute **4.7** 0.0024 Chronic (non - cancer) **0.33** 0.0024 Chronic (cancer) **0.2 8**  Not Determined a From the Tier II PRZM - EXAMS (NY grape scenario) b From the SCI - GROW model Highest value for use in risk assessment is in **bold ed**  **5.4 Dietary Risk Assessment**  A chronic aggregate dietary food and drinking water exposure and risk assessment was conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM - FCID) Version 3.16. This software uses 2003 - 2008 food consumption data from the U .S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey , What We Eat in America, (NHANES/WWEIA). No acute dietary

exposure and risk analy sis was performed since there were no appropriate studies identified in the toxico logy database that demonstrated evidence of toxicity attributable to a single dose.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **26** of **73 5.4.1**  **Description of Residue Data Used in Dietary Assessment** The chronic dietary

exposure and risk anal ys is was based on tolerance - level residues, 100% crop treated assumptions, and both empirical and default processing factors. Empirical processing factors derived from apple, orange, grape, and tomato processing studies were incorporated into the assessment for all processed commodities with the exception of dried t omato, where the DEEM default processing factor was used. Estimates of residues in drinking water were directly incorporated in the assessments (see Section 5.3). **5.4.2 Percent Crop Treated Used in Dietary Assessment**  The chronic dietary

exposure and risk assessment assumed 100% crop treated for all commodities included in the assessment. **5.4.3 Acute Dietary Risk Assessment**  As previously

stated, no acute dietary

exposure and risk anal ys is was performed since there were no appropriate studies identifie d in the toxicology database that demonstrated evidence of toxicity attributable to a single dose. **5.4.4 Chronic Dietary Risk Assessment**  A partially

refined chronic anal ys is was conducted that was based on tolerance - level residues, 100% crop treated (%CT ) assumptions, and both empirically derived and default processing factors. Using assumptions considered to be highly protective of human health, the chronic dietary risk estimates are below HED’s level of concern (<100% of the chronic population adjusted dose (cPAD)) and range from <1% of the cPAD for the general U.S. population to 2.3% of the cPAD for the highest exposed population subgroup of children 1 - 2 years old. **5.4.5 Cancer Dietary Risk Assessment**  Cyflumetofen has been classified as having “Sugge stive Evidence of Carcinogenic Potential” based on the presence of a single tumor t ype (thyr oid c - cell) in one sex (male) and one species (rat), and the lack of concern for mutagenicity. T he Agency has determined that quantification of risk using a non - lin ear approach (i.e., reference dose (RfD) will adequatel y account for all chronic toxicity , including carcinogenicity , that could result from exposure to cy flumetofen (see Section 4. 5. 3). The results of the chronic dietary risk assessment are discussed in Section 5.4.4.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **27** of **73 5.4.6**  **Summary Table Table 5.4.6. Summary of**  **Chronic Dietary (Food + Drinking Water) Exposures and Risk for Cyflumetofen**  **Population Subgroup cPAD,**  **mg/kg/day Exposure, mg/kg/day**  **Risk, % cPAD**  U.S. Population

0.17 0.000829 <1 All infants (< 1 year) 0.002493 1.5 **Children 1 -**  **2 yrs 0.003842**  **2.3** Children 3 - 5 y

rs 0.002562 1.5 Children 6 - 12 y

rs 0.001275 <1 Youth 13 - 19 y

rs 0.000573 <1 Adults 20 - 49 y

rs 0.000527 <1 Adults 50 - 99 y

rs 0.000596 <1 Females 13 - 49 y

rs 0.000548 <1 *The subpopulation with the highest risk estimates is **bolded 6.0**  **Residential (Non -**  **Occupational) Exposure/Risk Characterizatio n**  Cyflumetofen is being proposed for use on ornamentals ( i.e., residential landscape areas) and may be applied in residential settings (Sultan TM EPA Reg . No. 7969 - GGT). Therefore, residential handler and residential post - application exposure assessments have been conducted according to HED’s 2012 Residential Standard Operating Procedure s (SOPs) 1

. **6.1 Residential Handler Expo**  **sure** The proposed uses of cy flumetofen on ornamentals may result in residential hand l er exposure. Residential handler exposure is expected to be short - term in duration as i ntermediate - or long term exposures are not likely because of the intermittent nature of applications by homeowners . Residential handlers are assumed to be wearing short - sleeved shirts, short pants, shoes and socks during application of cy flumetofen ( i.e., no protective equipment). The assessments were conducted assuming the maximum a pplication rate (0.2 lbs ai/acre , 0.002 lbs ai/gallon ) and used unit exposure values and estimates for area treated or amount handled along with algorithms taken from HED’s 2012 Residential SOPs. The quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios:  Mixing/L oading/Applying Liquid to ornamentals with Hose - End Sprayer  Mixing/L oading/Applying Liquid to ornamentals with Manually - pressurized handwand  Mixing/L oading/Applying Liquid to ornamentals w ith Backpack  Mixing/L oading/Applying Liquid to ornamentals with a Sprinkler Can Since no dermal hazard was identified for cy flumetofen in the toxicological database, onl y inhalation exposure assessments were conducted for residential handlers. Inhalation margins of exposure (MOEs) are above the LOC of 100 for all scenarios assessed and are not of concern

1 Available: http://www.epa.gov/pesticides/science/residential - exposure - sop.htmlCyflumetofen Human Health Risk Assessment DP No. D398246

Page **28** of **73** (MOEs ≥ 100) . Short - term inhalation r esidential handler estimated exposure and risk estimates are shown in Table 6. 1 below . **Table 6.1 .**  **Short -**  **T erm**  **Residential Handler Non -**  **cancer Exposure and Risk Estimates for Cyflum etofen**  **Exposure Scenario Level of** 

**Concern Inhalation** 

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

**Application Rate**  **1 (lbs ai/gallon)**  **Area Treated**

**or Am ount**  **Handled Daily 2**  **(gallons) Inhalation** 

**Dose (m**  **g/kg/day) 3**  **MOE 4**  Mixer/Loader/Applicator Manually - pressurized handwand 100 0.018 0.002 5 0.0000023 7,300,000 Hose - end Sprayer 0.0014 0.002 11 0.00000039 43,000,000 Backpack 0.14 0.002 5 0.000018 940,000 Sprinkler can 0.0014 0.002 5 0.00000018 94,000,000 1 Based on registered or proposed label (EPA Reg. No. 7969 - GGT ) 2 Based on HED’s 2012 Residential SOPs 3 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A/day or gallons/day) ÷ BW (80 kg) 4 Inhalation MOE = Inhalation NOAEL (16.5 mg/kg/day) ÷ Inhalation Dose (mg/kg/day) **6.2 Post**  **- Application Exposure**  There is the potential for post - application exposure to individuals (adults and children 6 < 11 ye ars old) as a result of being in an environment that has been previously treated with cyflumetofen. However, since no dermal hazard was identified in the toxicity database for cyflumetofen, a quantitative residential post - application dermal risk assessment is not required and was not completed. Post - application inhalation exposure while performing activities i n previously

treated gardens was not assessed due to the low vapor pressure (4.43 x 10 - 8 mm Hg @ 25 oC) and the expected dilution in outdoor air after an application has occurred. F or the residential ornamental/landscape use scenario, post - application non - dietary ingestion exposure is not assessed for children (1 < 2 years old). T he potential for exposure via non dietary ingestion for young children is greatl y diminished since young children are not expected to engage in the t ypes of activities associated with these areas (e. g., gardening) or utilize these areas for prolonged periods of play . **6. 3**  **Residential Risk Estimates for Use in Aggregate Assessment** Table 6.3 reflects the residential risk estimates that are recommended for use in the aggregate assessment for cy flumetofe n.  The recommended residential exposure for use in the adult (male and female) aggregate assessment reflects inhalation exposure from mixing/loading/appl yi ng the liquid cyflumetofen formulation with a backpack sprayer (0.002 lbs ai/gallon).  There is no rec ommended residential contribution to the children aggregate assessment.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **29** of **73 Table 6.3**  **. Recommendation for the Short**  **- Term** **Residential Exposures for the Cyflumetofen Aggregate**  **Assessment 1**  **Lifestage Residential Handler**  **Dose (m g/kg/day)**  **2 MOE**  **3 Derm**  **al Inhalation**  **Total Derm**  **al Inhalation**  **Total**

**Short -**  **Term** Adult Handler N/A **0.000018 0.000018**  N/A **940,000 940,000**  1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment. 2 Residential Handler Dose = the highest handler dose for each applicable lifestage of all scenarios assessed from Table 6.1 . Total = dermal + inhalation. 3 Residential Handler MOE = the MOEs associated with the highest doses identified in Table 6.1. Total = 1 ÷ (1/Dermal MOE) + (1/I nhalation MOE). **6. 4**  **Residential Bystander Post**  **- application**  **Inhalation Exposure** Based on the Agency 's current practices, a quantitative post - application inhalation exposure assessment was not performed for cy flumetofen at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV), low vapor pressure (4.43 x 10 - 8 mm Hg @ 25 oC), and the low proposed use rate (0.2 lb ai/A). However, volatilization of pesticides may be a source of post - application inha lation exposure to individuals nearby 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 Advisory 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 way to incorporate post - app lication 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 cyflumetofen. **6. 5**  **Spray Drift** Spray drif t 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 cyflumetofen. The Agency

has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency ’s Spray Drift webs ite 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 practices to reduce off - target drift with specific products with significant risk estimates associated with drift.

2 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html 3 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmCyflumetofen Human Health Risk Assessment DP No. D398246

Page **30** of **73 7.0**  **Aggregate Exposure/Risk Characterization** In accordance with the FQPA, HED must consider and aggregate 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. For cyflumetofen , potential exposures from food , drinking water, and residential scenarios were aggregated. This assessment is based on the changes in the new Residenti al SOPs implemented in January of 2012. **7.1 Acute Aggregate Risk**  Acute aggregate risk estimates include exposure to residues in food and water alone; therefore, the acute aggregate risk estimates are equivalent to the acute dietary risk assessment. However, for cyflumetofen, no toxic effects attributable to a single dose were observed in the toxicology database. A s a result, an acute aggregate risk assessment is not required for this chemical. **7.2 Short**  **- Term Aggregate Risk**  T here is a potential for short - term exposure to cyflumetofen via dietary and residential exposure pathway s . To estimate short - term aggregat e risk, HED therefore combined chronic diet ary (food and water) exposures ( as a measure of aver age background dietary exposure) with short - term residential exposures. T hese pathway s lead to exposure via oral (background) and inhalation (primary) routes on ly , since no dermal hazard has been identified fo r cyflumetofen . The most conservative residential exposure scenario was chosen for the adult population which reflects inhalation exposure from mixing/loading/applying the liquid cyflumetofen formulation wi th a backpack sprayer (refer to S ection 6.3). For background dietary exposure, the adult sub population with the highest exposure (adults 50 - 99) was chosen since this is protective for all other adult sub - populations. There are no residential exposures expected for children (refer to Section 6.2) ; therefore a short - term aggregate risk assessment for children is not required and was not performed. Short - term aggregate margins of exposure for adults (all adult sub - populations) are above the LOC of 100 and are not of concern (MOEs ≥ 100). Short - term estimated exposures and risks are shown below in Table 7.2.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **31** of **73 Table 7.2**  **. Short**  **- Term** **Aggregate Risk Calculations Population**  **Short -**  **or Interm ediate**  **- Term Scenario** 

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

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

**Food and Water**  **Exposure 3**  **mg/kg/day Residential** 

**Exposure 4**  **mg/kg/day Total** 

**Exposure 5**  **mg/kg/day Aggregate** 

**MOE (food, water, and**  **residential) 6**  Adult s 50 - 99 16.5 100 0.165 0.000596 0.000018 0.000614 27,000 1 Intraspecies factor= 10x; Interspecies factor = 10x 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL (16.5 mg/kg/day) /LOC (100) 3 Average food and water exposure for adults = chronic dietary exposure for adults 50 - 99 (the highest exposed adult sub population) 4 Residential Exposur e = [Inhalation Exposure] 5 Total Exposure = Avg Food & Water Exposure + Residential Exposure) - Refer to Table 6.3 6 Aggregate MOE = [NOAEL / ( Av g F o o d & W at e r E xp o s ur e + R e s i d e nt i a l E xp o sur e ) ] **7. 3**  **Chronic Aggregate Risk** As there are no uses that are expected to result in long - term residential exposure, long - term (chronic) aggregate risk includes only chronic dietary (food and water) exposure. As noted in Section 5.4.4, there are no chronic dietary risks of concern for cyflumetofen . **7. 4**  **Cancer Aggregate Risk** Cancer aggregate risk estimates for the general U.S. population include chronic exposure to residues in food and water as well as residential sources. Cyflumetofen has been classified as having “Suggestive Evidence of Carcinogenic Potential” based on the presence of a single tumor ty pe (th yr oid c - cell) in one sex (male) and one species (rat), and the lack of concern for mutagenicity . The Agency has determined that quantification of risk using a non - linear approach (i .e., reference dose (RfD) will adequatel y account for all chronic toxicity, including carcinogenicity , that could result from exposure to cy flumetofen (see Section 4.5.3). Based on this , s ince the chronic dietary risk assessment (refer to S ection 5.4.4) i s considered to be protective of an y cancer effects , a separate quantitative cancer aggregate risk assessment is not required . **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 cyflumetofen and any

other substances and cyflumetofen does not appear to p roduce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that cyflumetofen has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determi ne 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 cumulati ng effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **32** of **73 9.0**  **Occupational Exposure/Risk Characterization** An occupation al exposure and risk assessment was conducted to support the proposed uses of cyflumetofen . Full details of that assessment are included in the occupational and residential memorandum listed in the reference section and the results are briefl y summarized here. **9.1 Short**  **- /Intermediate**  **- Term**  **Handler Risk** Cyflumetofen is a s elective contact miticide that is effective on all mite life stages. Application methods, maximum application rates and use sites were summarized previously in Table 3.3. The occupational exposure and risk assessment generall y addresses risks to workers exposed in an occupational setting via the dermal and inhalation routes of exposure. However, since no dermal hazard was identified in the toxicity database for cyflumetofen, a quantitative dermal assessment is not required and risks were quantitatively a ssessed for inhalation exposure only . Based on the proposed use pattern of cy flumetofen , short - and intermediate - term exposures are anticipated for handlers for the following reasons: (1) the product can be applied twice per season (2) the product can be applied to multiple application sites, (3) there may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks, and (4) repeated use of miticides with similar modes of action can lead to build up therefore rotati ng miticides with different modes of action reduces the potential for developing mite resistance. Long - term exposure is not expected for the proposed use pattern s. Estimates of inhalation exposure were calculated for various levels of personal protecti ve equipment (PPE). Results are presented for “baseline” level of attire defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline attire with various levels of PPE as necessary (e.g., gloves, respirator, etc . ). The cy flumetofen product labels direct mixers, loaders, applicators and other handlers to wear long - sleeved shirts, long pants, protective eyewear, chemical - resistant gloves, and shoes p lus socks. All occupational handler scenarios assessed for the proposed uses of cyflumetofen resulted in estimated inhalation margins of exposure (MOEs) above the LOC of 100 for all scenarios assessed and , therefore, are not of concern (MOEs ≥100) . Occup ational handler risk estimates are shown in Table 9.1. **Table 9.1. Occupational Handler Non -**  **Cancer Exposure and Risk Estimates for Cyflumetofen Exposure**  **Scenario Crop or Target**  **Inhalation Unit Exposure**  **(μg/lb ai) 1**  **Maximum**

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

**Treated or**  **Am ount**  **Handled Daily**  **3 Inhalation**  **Baseline Dose**  **(m g/kg/day)**  **4 MOE**  **5** Mixer/Loader Aerial Tomato 0.219 0.2 lb ai/acre 350 0.000191 86,000 Airblast Nursery

(ornamentals, container stock) 0.219 20 0.000011 1,500,000 Citrus Fruit, Grapes, 0.219 40 0.0000219 750,000Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **33** of **73 Table 9.1. Occupational Handler Non**  **- Cancer Exposure and Risk Estimates for Cyflumetofen**  **Exposure Scenario**  **Crop or Target Inhalation Unit**  **Exposure (μg/lb ai)**  **1 Maximum** 

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

**Treated or**  **Am ount**  **Handled Daily**  **3 Inhalation**  **Baseline Dose**  **(m g/kg/day)**  **4 MOE**  **5** Pome Fruit, Tree Nut Group

Groundboom Field - grown

ornamental crops 0.219 40 0.000022 750,000 Nursery (ornamentals, container stock) 0.219 60 0.000033 500,000 Greenhouse (ornamentals, roses, cut flowers, container stock) 0.219 60 0.000033 500,000 Citrus Fruit, Grapes, Pome Fruit, Straw berry , Tomato, Tree Nut Group 0.219 80 0.000044 380,000 Applicator Aerial Tomato 0.068

0.2 lb ai/acre 350 0.0000595 280,000 Airblast Nursery

(ornamentals, container stock) 4.71 20 0.000235 70,000 Citrus Fruit, Grapes, Pome Fruit, Tree Nut Group 4.71 40 0.000471 35,000

Groundboom Field - grown

ornamental crops 0.34 40 0.000034 490,000 Nursery (ornamentals, container stock) 0.34 60 0.000051 320,000 Greenhouse (ornamentals, roses, cut flowers, container stock) 0.34 60 0.000051 320,000 Citrus Fruit, Grapes, Pome Fruit, Straw berry , Tomato, Tree Nut Group 0.34 80 0.000068 240,000 Flagger Flagger Tomato 0.35 0.2 lb ai/acre 350 0.000306 54,000 Mixer/Loader/Applicator Backpack (broadcast foliar) Greenhouse

(ornamentals, roses, cut flowers, container stock) 140 0.002 lb ai/gal 40 0.0001 4 1 2 0,000 Forestry 2.58 40 0.00000258 6,400,000 Nursery (ornamentals, 140 40 0.00014 120,000Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **34** of **73 Table 9.1. Occupational Handler Non**  **- Cancer Exposure and Risk Estimates for Cyflumetofen**  **Exposure Scenario**  **Crop or Target Inhalation Unit**  **Exposure (μg/lb ai)**  **1 Maximum** 

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

**Treated or**  **Am ount**  **Handled Daily**  **3 Inhalation**  **Baseline Dose**  **(m g/kg/day)**  **4 MOE**  **5** container stock) Landscaping, trees/shrubs/bushes 140 40 0.00014 120,000 Landscaping, plants/flowers 140 40 0.00014 120,000

Manually pressurized Handwand (broadcast foliar) Greenhouse

(ornamentals, roses, cut flowers, container stock) 30 40 0.00003 550,000 Nursery (ornamentals, container stock) Landscaping, trees/shrubs/bushes Landscaping, plants/flowers Interior landscaping Mechanically pressurized Handgun (broadcast foliar) Citrus Fruit, Tree

Nut Group 3.9 0.002 lb ai/gal 1000 0.0000975 170,000 Greenhouse (ornamentals, roses, cut flowers, container stock) 120 1000 0.003 5,500 Nursery (ornamentals, container stock) 3.9 0.002 lb ai/gal 1000 0.0000975 170,000 Landscaping, trees/shrubs/bushes 3.9 1000 0.0000975 170,000 1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September 2012); Level of mitigation: Baseline . 2 Based on registered or proposed label (Reg. No. 7969 - GGT; 7969 - GGA). 3 Exposure Science Advisory Council Policy #9.1. 4 Inhalation Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/ μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (kg). 5 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **35** of **73 9.2**  **Short -** **/Intermediate -**  **Term Post**  **- Application Risk**  **9.2.1 Dermal**  **Post -**  **application Risk**  There is the potential for post - application exposure to workers as a result of proposed uses of cyflumetofen. However, since no dermal hazard was identified in the toxicity database for cyflumetofen, a quantitative occupational post - application dermal risk assessment is not required and was not completed. **9.2.2 Inhalation**  **Post -**  **application Risk**  Based on the Agency 's current practices, a quantitativ e post - application inhalation exposure assessment was not performed for cy flumetofen at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV), low vapor pressure (4.43 x 10 - 8 mm Hg @ 25 oC), and the low proposed use rate ( 0.2 lb ai/A). However, there are multiple potential sources of post - application inhalation exposure to individuals performing post - application activities in previously

treated fields. These potential sources include volatilization of pesticides and resus pension 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 process 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 cyflumetofen. Furthermore, inhalation exposure during dusty mechanical activities such as shaking and mechanical harvesting tree nuts is another potential source of post - applicatio n inhalation exposure. However, the airblast applicator scenario is believed to represent a reasonable worst case surrogate estimate of post - application inhalation exposure during these dusty mechanical harvesting activities. The non - cancer inhalation ri sk estimate for commercial airblast application is not of concern (i.e., MOE > 100). Although a quantitative occupational post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/c ommercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post - application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective o f most occupational post - application inhalation exposure scenarios. Additionally , the Worker Protection Standard (WPS) for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applicat ions through the use of ventilation requirements [40 CFR 170.110, (3) (Restrictions 4 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlCyflumetofen Human Health Risk Assessment DP No. D398246

Page **36** of **73** associated with pesticide applications)]. Itis assumed that the user will have met the ventilation requirement within the 12 hour REI(unless there is no ventilation capa bility , then the user must wait 24 hours). It is reasonable to assume that based on the WPS ventilation requirements, postapplication inhalation exposure will be negligible.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **37** of **73 10.0**  **References** I. Negrón - Encarnación, 26 - March - 2013, D408530, Cyflumetofen. Report of the Residues of Concern Knowledgebase Subcommittee (ROCKS). S. Shelat, 07 - January - 2014 , D408532, Cy flumetofen. Occupational and Residential Exposure Assessment for a Proposed Use on Citrus Fruit, Grapes, Pome Fruit, Strawberry, Tomato, Tree Nut Group, and Ornamentals. J. Van Alstine, 03 - July - 2013, TXR No. 0056691, Cy flumetofen: Summary of the Hazard and Science Policy

Council (HASPOC) Meeting of June 6, 2013: Recommendations on the Need for an Inhalation Study . S. Wente , 12 - June - 2013, D410981, Drinking Water Exposure for Cy flumetofen Section 3 New Use on Citrus, Pome Fruits, Grapes, Strawberries, Tomatoes, Tree Nuts, and Ornamentals. D. Wilbur, 26 - June - 2013, D408533, Cyflumetofen. Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action on Grape, Strawberry , and Tomato. D. Wilbur, 09 - July- 2013, D408531, Cy flumetofen. Petition for the Establishment of Permanent Tolerances and Registration for Use on Ci trus (Crop Group 10 - 10), Pome Fruits (Crop Group 11 - 10), Tree Nuts (Crop Group 14 - 12), Grape, Strawberry , and Tomato. Summary of Anal yt ical Chemistry

and Residue Data.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **38** of **73 A**  **ppendix A**  **. Toxicology Profile and Executive Summaries**  **A.1 Toxicology Data**  **Requirements** The requirements (40CFR §158.340) for the food use of cy flumetofen are in Table A.1. **T able**  **A.1. Toxicology Data Requirements for Cyflumetofen**  **Test 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 (non - rodent) 870.3200 21/28 - Day Dermal 870.3250 90 - Day

Dermal 870.3465 90 - Day

Inhalation yes yes yes no yes yes

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

yes yes 870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (non - rodent) 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) 870.5375 Mutagenicity

— Structural Chromosomal Aberrations 870.5395 Mutagenicity

— Other Genotoxic Effects 870.5500 Mutagenicity

— Other Genoto xic Effects yes yes 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 Developmental Neurotoxicity no no yes yes no no

no yes yes no 870.7485 General Metabolism 870.7600 Dermal Penetration 870.7800 Immunotoxicity yes no yes yes

yes yes aInhalation study was waived by the HASPOC.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **39** of **73 A.2**  **Toxicity Profile s**  **Table A.2 -**  **1. Acute Toxicity Profile**  **- Test Substance**  **Guideline No. Study Type**  **MRID(s) Results**  **Toxicity Category** 870.1100 Ac ute oral [Rat] 48542669 >2000 mg/kg III 870.1200 Ac ute dermal [Rat] 48542671 >5000 mg/kg IV 870.1300 Ac ute inhalation [Rat] 48542672 - 3 >2.65 mg/L IV 870.2400 Ac ute eye irritation [Rabbit] 48542675 Minimal irritant II 870.2500 Ac ute dermal irritation [Rabbit] 48542674 Not an irritant IV 870.2600 Skin sensitization [Guinea pig] 48542676 Skin sensitizer NA **Table A.2 -**  **2. Subchronic, Chronic and Other Toxicity Profile**  **Guideline Number/ Study Type**  **MRID(s) (year)/**

**Classification/Doses Results**  870.3200 28 - day dermal toxicity [rat] 48542686 (2010) 0, 100, 300, 1000 mg/kg/day (mkd), 6 hours/day for 5 days/week Acceptable/Guideline The NOAEL is 1000 mg/kg/day. The LOAEL was not determined. 28 - day feeding study (rat) 48542678 (2004) 0, 100, 500, 1000, 5000 ppm M: 0, 7.5, 37.6, 75.1, 384 m/k/d F: 0, 8.05, 40.8, 79.8, 409 m/k/d Acceptable/nonguideline The NOAEL is 500 ppm (37.6/40.8 mg/kg/day in males/females). The LOAEL is 1000 ppm (75.1/79.8 mg/kg/day in males/females) based on increased adrenal weight and histopathology. 870.3100 90 - Day feeding study [rat] 48542682 (2004) 0, 100, 300, 1000, 3000 ppm M:0, 5.4, 16.5, 54.5 167 m/k/d, F: 0, 6.28, 19.0, 62.8,193 m/k/d Acceptable/guideline The NOAEL is 300 ppm (16.5/19.0 mg/kg/day in males/females). The LOAEL is 1000 ppm (54.5/62.8 mg/kg/day in males/females) based on the hemat ology and organ weight changes in the liver, adrenal, kidney and ovaries; and histopathology effects in the adrenals and the ovaries. 28 - day feeding study (mouse) 48542679 (2004) 0, 100, 500, 1000, 5000 ppm M: 0, 13.1, 67.2,135,663 m/k/d; F: 0, 14.5, 7 4.9, 150, 763 m/k/d Acceptable/nonguideline The NOAEL is 1000 ppm (135/150 mg/kg/day in males/females). The LOAEL is 5000 ppm (663/763 mg/kg/day in males/females) based on increased adrenal weights and adrenal vacuolation. 870.3100 90 - Day feeding study [mouse] 48542683 (2004) 0, 300, 1000, 3000, 10000 ppm M: 0, 35.4, 117, 348, 1200 m/k/d F: 0, 45.0, 150, 447, 1509 m/k/d Acceptable/guideline The NOAEL is 1000 ppm (117/150 mg/kg/day in males/females). The LOAEL is 3000 ppm (348/447 mg/kg/day in males/femal es), based on decreased body weights in females, and diffuse hypertrophy and vacuolation of cortical cells in the adrenals in both sexes. 870.3150 90 - Day oral (capsule) study [dog] 48542684 (2003) 0, 30, 300, 1000 mkd (M/F) (capsule) Acceptable/guideline The NOAEL is 300 mg/kg/day. The LOAEL is 1000 mg/kg/day, based on decreased body weight and body weight gain, increased adrenal weights (males only) and vacuolation of the adrenals. 870.3700 Prenatal developmental [rabbit] 48542706 (2003) 0, 50, 250, 10 00 mkd Gavage GD 6 - 28 Acceptable/guideline The maternal NOAEL is 1000 mg/kg/day (the highest dose tested). The developmental NOAEL is 250 mg/kg/day. The developmental LOAEL is 1000 mg/kg/day based on changes in ossification, paw flexion and decreased fetal body weights . 870.3700 Prenatal developmental [rats] 48542704 (2001) 0, 50, 250, 1000 mkd Gavage, GD 6 - 19 Acceptable/guideline The maternal NOAEL is 50 mg/kg/day. The maternal LOAEL is 250 mg/kg/day, based on an increase in adrenal weights and organ to body weight ratio. The developmental NOAEL is 50 mg/kg/day.The developmental LOAEL is 250 mg/kg/day, based on an increased incide nce of incompletely ossified sternal centra .Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **40** of **73 Table A.2**  **- 2.**  **Subchronic, Chronic and Other Toxicity Profile Guideline Number/**  **Study Type MRID(s) (year)/** 

**Classification/Doses Results**  870.3800 Reproduction and fertility effects [rat] 48542702 (2004) 0, 150, 500, 1500 ppm (0,9.2, 30.6, 89.4/0, 13.8, 46.6, 141.1 mkd, M/F) Acceptable/guideline The parental NOAEL is 150 ppm (9.2/13.8 mg/kg/day in males/females). Parental LOAEL is 500 ppm (30.6/46.6 mg/kg/day in males/females) based on effects on the adrenals (increased organ weights and histopathology). The reproductive NOAEL in females is 150 ppm (13.8 mg/kg/day). Reproductive LOAEL in females is 500 ppm (46.6 mg/kg/day) based on hormone changes (significantly decreased FSH, progesterone, and 17 β - estradiol). The reproductive the NOAEL in males is 1500 ppm (89.4 mg/kg/day); the LOAEL in males is not determined, The offspring NOAEL is 150 ppm (9.2/13.8 mg/kg/day in males/females).Offspring LOAEL is 500 ppm (30.6/46.6 mg/kg/day in males/females) based on effects on the adrenals (increased organ weights and histopathology) in both sexes. 870.4100a Chronic toxicity [rat] 48542696 (2004) 0, 50, 150, 500,1500 ppm (0, 4.9, 16.5, 49.5/0, 6.1, 20.3, 61.9 mkd, M/F) Acceptable/guideline The NOAEL is 500 ppm (16.5/20.3 mg/kg/day in males/females ). The LOAEL is 1500 ppm (49.5/61.9 mg/kg/day in males/females ) based on increased adrenal weights, hyperplasia and hypertrophy of the adrenal cortex in both sexes, and luminal dilatation of the gland in the uterine horn in females. 8 70.4100a Chronic toxicity [rat] 49029701 (2013) 0, 60 00 ppm (0, 250/319 mkd, M/F) Acceptable/guideline In this supplemental study, the LOAEL was 600 0 ppm (250/319 mg/kg bw/day in males/females) based on increased adrenal weights accompanied by gross pathology and histopathology lesions noted in both sexes, vacuolation of the interstitia l gland cell of the ovary and hyperplasia of the interstitial cell of the testes. Only one dose was tested. 870.4100b Chronic toxicity [dog] 48542685 (2008) 0,30, 300, 1000 mkd (capsule) Acceptable/guideline The NOAEL is 30 mg/kg/day. The LOAEL is 300 mg/kg/day, based on vacuolation and histopathology findings in the adrenals. 8 70.4 2 00 a Carcinogenicity [rat] 46542697 (2004) 0, 50, 150, 500,1500 ppm (0, 4.9, 16.5, 49.5/0, 6.1, 20.3, 61.9 mkd, M/F) Acceptable/guideline The NOAEL is 500 ppm (16.5/20.3 mg/kgkday for males and females). The LOAEL is 1500 ppm (49.5/61.9 mg/kg/day in males/ females) based on increased adrenal weights, hyperplasia and hypertrophy of the adrenal cortex in both sexes, and luminal dilatation of the gland in t he uterine horn in females. There was no treatment related increase in tumor incidence when compared to controls. 870.42 00 a Carcinogenicity [rat] 49226601 (2013) 0 or 6000 ppm (0, 220/287 m

kd, M/F) Acceptable/guideline The LOAEL for this supplementary study is 6000 ppm, based on effects on clinical signs of toxicity (females), decreased body weight (both sexes) and body weight gain (males), changes in hematological parameters (males), organ weights (both sexes), and hist opathology findings (both sexes). Only one dose was tested. I ncrease d incidence was observed in thyroid C - cell tumours (carcinomas, as well as adenomas and carcinomas combined) in males only as well as an increase in the incidence of testicular interstiti al cell tumours. There was no treatment related increase in tumor incidence in females when compared to controls. 870.4 2 00 b Carcinogenicity [mouse] 48542698 (2004) 0,150,500,1500,5000 ppm (0,15.5/14.3, 54.3/48.1,156/144, 537/483 mkd, M/F) Acceptable/guideline The NOAEL is 1500 ppm (156/144 mg/kg/day in males/females ); the LOAEL is 5000 ppm (537/483 mg/kg/day in males/females ) based on increased incidence of diffuse adrenal cortical cell vacuolation and increased adrenal wt in males. There was no treatment related increase in tumor incidence when compared to controls . 870.4 2 00 b Carcinogenicity [mouse] 49209101 (2013) 0, 6000 ppm (0,1143/1132 mkd, M/F) Acceptable/guideline The LOAEL for this confirmatory study is 10,000 ppm (1143/1132 mg/kg/day, in males/ females) , based on clinical signs of toxicity, increased adrenal weights, enlarged spleen and an increased incidence of extramedullary hematopoiesis in the spleen of treated females and an increased incidence of diffuseCyflumetofen Human Health Risk Assessment DP No. D398246

Page **41** of **73 Table A.2**  **- 2.**  **Subchronic, Chronic and Other Toxicity Profile Guideline Number/**  **Study Type MRID(s) (year)/** 

**Classification/Doses Results**  adrenal cortica l cell vacuolation and deposition of brown pigment in the cortico - medullary junction of the adrenals in both sexes. . At the dose tested, there was no treatment - related increase in tumor incidence when compared to controls. 870.5100 Gene Mutation (TA98, TA 100, TA1535, TA1537 of S. typhimurium and WP2 uvrA E.coli) 48542687 (2001) Acceptable/guideline Negative

870.5300 In vitro mammalian cell gene mutation test (Mouse lymphoma cell) 48542692 (2007) Acceptable/guideline Positive (+/ - S9) 870.5375 In vitro mammalian chromosome aberration test (CHL) 48542691 (2011) 48542689 (2003) Acceptable/guideline Negative 870.5395 Mammalian bone morrow micronucleus test 48542694 (2003) Acceptable/guideline Negative 870.5550 In vivo, Unscheduled DNA synthesis (UDS) 48542695 (2007) Acceptable/guideline Negative 870.7485 Metabolism and pharmacokinetics [rat] 48542662,48542661,48542667, 48542663, 48542665, 48542664, 48542666, 48542668, 48542825 (2004 - 2011) Acceptable/guideline 14 C - cyflumetofen is fairly rapidly absorbed and eliminated. The test material was fairly well absorbed at the low dose (approximately 68 - 78% of the administered dose), but less so at the high dose (approximately 35 - 46% of the administered dose). Saturation o f absorption was evident at the high dose, and was more pronounced in males than in females. Only low levels of radioactivity were retained in tissues up to 72 hours post - dosing, with the highest levels observed in the gastrointestinal tract, liver and ki dneys. The parent compound was extensively metabolized following administration of a low dose of 14 C - cyflumetofen, but poorly metabolized following administration of a high dose. It appears as though the parent molecule is metabolized via cleavage of the t olyl and phenyl ring structures. 870.7600 Dermal penetration [rat] 48542724 (2011) Single dose: 2, 20, 2000 μg/cm2 Acceptable/guideline Dermal absorption factor (11%) 870.6200 Acute Neurotoxicity - Rats 48542702 (2010) 0, 125, 500, 2000 mg/kg (gavage) Acceptable/guideline The NOAEL is 2000 mg/kg, the highest dose tested. No LOAEL was established. No evidence of neurotoxicity. 870.6200 Subchronic neurotoxicity [rat] 48542708 (2012) 0, 500, 1500, 5000 ppm (0, 30/41, 89/99, 293/353 mkd, M/F) Acceptable/guideline The systemic NOAEL is 500 ppm (30/41 mg/kg/day in males/females ). The systemic LOAEL is 1500 ppm (89/99 mg/kg/day in males/females ) based on the increased adrenal weights in females and the altered adrenal histopathology of both sexes. No evidence of neurotoxicity at 5000 ppm (HDT). 870.7800 Immunotoxicity [rat] 48542726 (2011) 0, 500, 1500, or 5000 ppm (0, 33, 107, 349 mkd, females only) Acceptable/Guideline The NOAEL for systemic toxicity is 500 ppm (33 mg/kg/day) in female rats. The systemic toxicity LOAEL was 1500 ppm (107 mg/kg/day) based upon increased adrenal weights and correlating histopathology. The NOAEL for immunotoxicity is 5000 ppm (349 mg/kg/day).The immunotoxicity LOAEL was not observed.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **42** of **73 A.3**  **Hazard Identification and Endpoint Selection A.3.1**  **Acute Reference Dose (aRfD) -**  **General Population and Females A ge 13**  **- 49**  **Study Selected:** None **Comments:** No appropriate endpoint attributable to a single exposure (dose) was identified from studies including acute neurotoxicity study and developmental toxicity studies in rats and rabbits. An acute reference dose was not established for the general population including infants, children, and females age 13 - 49. In the developmental toxicity study in rabbits, increased incidence of paw flexion was observed at 1000 mg/kg/day and was slightl y above historical controls. Maternal toxicity , decreased fetal body weight, and incomplete ossification were also observed at this dose. Paw flexion was considered to be associated with ossification effects (i.e., all three pups that exhibited paw flexions also had incomplete ossification). Delay s in ossification and developm ental delay s are not ty pically used to set acute reference doses, therefore, paw flexion would not be used as an acute endpoint. **A.3. 2**  **Chronic Reference Dose (cRfD) Study Selected:**  Three co - critical studies selected **:** Combined Chronic Toxicity /Carcinogeni city Study in Rats, 90 - Day

Feeding Study

in Rats and Two - generation Reproduction Study in Rats. **MRID No:** 48542696, 48542697 (chronic toxicity /carcinogenicity

rat); 48542682 (90 day feeding rat); 48542702 (2 - generation reproduction study) **Executive Summa ry:**  See Appendix A.4. **Dose and Endpoint for Risk Assessment:** NOAEL= 16.5 mg/kg/day from both the 90 - day

and chronic toxicity

/carcinogenicity

toxicity studies in rats. The LOAEL = 30.6 mg/kg/day from the 2 - generation reproduction toxicity study . This parental LOAEL is based on effects on the adrenals (increased organ weights and histopathology), which is the target organ. **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x intraspecies variability , 1x FQPA Safety Factor) **Comments on Study/Endpoint/Uncertainty Factors:**  Three studies were selected as co critical studies for the chronic dietary endpoint. These studies are appropriate for the duration and populations of concern since there is no progression of toxicity over time. The NOA ELand LOAEL selected were based on the weight of evidence from the three studies which had similar target organ toxicities. The point of departure of 16.5 mg/kg/day (NOAEL) was selected from the 90 - day

and the chronic toxicity

/carcinogenicity rat studies, which have similar NOAELs and LOAELs. The LOAEL of 30.6 mg/kg/day was selected from the 2 - generation reproduction study . Although a lower NOAEL of 9.2 mg/kg/day was identified in the reproduction study (LOAEL = 30.6 mg/kg/day) this NOAEL was not selected as the POD for risk assessment since it is considered to be a function of calculated compound intake (based on food consumption) rather than a lower NOAEL/L OAEL per se. The higher POD of 16.5 mg/kg/day selected is still protective of the effects seen at 30.6 mg/kg/day in the 2 - generation reproduction toxicity study . The POD is also protective of similar effects seen in the 28 day rat study at L OAEL of 75 mg/kg/day , the chronic mouse study at LOAEL of 537/483 mg/kg/day (M/F), and the chronic dog study at LOAEL of 300 mg/kg/day. **Chronic RfD** = ) ( 100 mg/kg/day 5 . 16 UF = **0.17 m g/kg/day** Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **43** of **73 A.3.3**  **Incidental Oral Exposure (Short -**  **and Intermediate -**  **Term) Study Selected:**  Three co - c ritical studies selected: Combined Chronic/Carcinogenicity Study in Rats, 90 - Day

Feeding Study

in Rats and Two - generation Reproduction Study in Rats **MRID No.:** 48542696, 48542697 (chronic/carcinogenicity rat); 48542682 (90 day

feeding rat); 48542702 (2 - gen eration reproduction study) **Executive Summary:** See Appendix A.4. **Dose and Endpoint for Risk Assessment:** NOAEL= 16.5 mg/kg/day from both the 90 - day

and chronic toxicity

/carcinogenicity

toxicity studies in rats. The LOAEL = 30.6 mg/kg/day from the 2 - generat ion reproduction toxicity study . This parental LOAEL is based on effects on the adrenals (increased organ weights and histopathology), which is the target organ. **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x intraspecies variability , 1x FQPA Safety Factor) **Comments on Study/Endpoint/Uncertainty Factors:** There is no incidental oral exposure expected based on the current use pattern; however, an endpoint was selected during the full review of the database. **A.3.4 Dermal Exposure (Short**  **- , Intermediate**  **- and Long**  **- Term)**  **Study Selected:** None **Comments:** For short and intermediate - term dermal exposure, no appropriate endpoint was identified for risk assessment. A 28 - day dermal toxicity

study in rats is available; howeve r, no adverse effects were seen at the highest dose tested of 1000 mg/kg/day . The endpoints of concern (adrenal effects) were also looked at in this study . Although developmental/reproductive effects (not assessed in the dermal study) were observed in the developmental and reproductive toxicity studies, the effects occurred in the presence of parental toxicity . Therefore, since no effects were observed in adults at the limit dose, no developmental or reproductive effects would be expected to occur due to parental dermal exposure. Risk assessment for short - and intermediate, and long term dermal exposure is not necessary . **A.3. 5**  **Inhalation Exposure (Short -**  **, Intermediate -**  **and Long -**  **Term) Study Selected:**  Three co - critical studies selected: Combined Chronic/Carcinogenicity Study in Rats, 90 - Day

Feeding Study

in Rats and Two - generation Reproduction Study in Rats **MRID No.:** 48542696, 48542697 (chronic/carcinogenicity rat); 48542682 (90 day

feeding rat); 48542702 (2 - generation reproduction study) **Executive Summary:** See Appendix A.4. **Dose and Endpoint for Risk Assessment:** NOAEL= 16.5 mg/kg/day from both the 90 - day

and chronic toxicity

/carcinogenicity

toxicity studies in rats. The LOAEL = 30.6 mg/kg/day from the 2 - generation reproduction toxicity study . This parental LOAEL is based on effects on the adrenals (increased organ weights and histopathology), which is the target organ. **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x intraspecies variability) **Inhalation Absorption Factor:** Equivalent to oral absorption. **Comments on Study/Endpoint/Uncertainty Factors:** The HASPOC, based on a WOE approach, determined that a subchronic inhalation toxicity study is not needed for cyflumetofen at this time (TXR# 0056691). This approach considere d all of the available hazard and exposure information for cyflumetofen, including: 1) the phy sical/chemical properties of cyflumetofen including its low volatility (4.43 x 10 - 8 mm Hg at 25 oC); (2) its low acute inhalation toxicity ; and (3) the use of an oral POD results in MOEs that are ≥5,500, and above the Agency ’s level ofCyflumetofen Human Health Risk Assessment DP No. D398246

Page **44** of **73** concern. A route - specific inhalation toxicity study is not available for cyflumetofen, except for the a cute inhalation toxicity study . Therefore, the oral toxicity study was selected for inhalation risk assessments. Three co - critical studies selected: Combined Chronic/Carcinogenicity Study in Rats, 90 - Day

Feeding Study

in Rats and Two - generation Reproductio n Study in Rats. Since an oral NOAEL was selected, the inhalation exposure component (μg ai/day) using 100% absorption rate should be converted to an equivalent oral dose (mg/kg/day) in calculating the risk for inhalation exposure.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **45** of **73 A.4**  **Executive Summaries**  **A.4.1 Subchronic Toxicity**  **870.3100 28**  **- Day Oral Toxicity**  **- Rat**  In a 28 - day

feeding study (MRID 48542678), OK - 5101 (99.3% a.i.) was administered to 6 Fischer rats/sex/dose in the diet at dose levels of 0, 100, 500, 1000 or 5000 ppm (0, 7.5, 37. 6, 75.1 or 384 mg/kg bw/day in males, 0, 8.05, 40.8, 79.8 or 409 mg/kg bw/day in females) for 28 day s. Indications of liver dys function were exhibited by animals of both sexes in the 5000 ppm group and males in the 1000 ppm group with statistically signif icant decreases in total cholesterol and trigl yceride, and statistically significant increases in absolute and relative liver weights with diffuse h ypertroph y of hepatocy tes. Absolute and relative kidney weights were statistically increased in both male s and females of the 5000 ppm group. An increase in blood urea nitrogen and potassium observed in the males and a decrease in sodium levels in the females further indicate possible kidney dy sfunction. Gross pathology

examinations revealed hy pertrophy and white color of the adrenals in all males and females in the 5000 ppm group. Absolute and relative adrenal weights were statisticall y increased in these animals. In addition, females in the 1000 ppm group exhibited a statistical increase in relative a drenal weight. Histopathological examinations revealed diffuse vacuolation of cortical cells in the adrenals in all 1000 and 5000 ppm animals. The vacuolation was demonstrated to be lipid deposition. All females in the 1000 and 5000 ppm groups also disp layed diffuse h ypertrophy of cortical cells in the adrenals. In creases were detected in absolute and relative ovary weights in the 5000 ppm females. Histopathological examinations revealed vacuolation of interstitial cells in the ovaries of these animals and the same lesions were observed in two 1000 ppm females. Through lipid staining, the vacuolation was demonstrated to also be lipid deposition. **The LOAEL is 1000 ppm (75.1 mg/kg bw/day in males, 79.8 mg/kg bw/day in females), based on increased adrena**  **l weight and histopathology. The NOAEL is 500 ppm (37.6 mg/kg bw/day in males, 40.8 mg/kg bw/day in females).**  This 28 - day

toxicity study in the rat is acceptable/nonguideline for a repeat - dose oral study in rats. **870.3100 90 -**  **Day Oral Toxicity -**  **Rat** In a subchronic toxicity

study (MRID 48542682), OK - 5101 (97.6% a.i.) was administered to 10 Fischer rats/sex/dose in the diet at dose levels of 0, 100, 300, 1000 or 3000 ppm (0, 5.4, 16.5, 54.5 or 167 mg/kg bw/day in males, 0, 6.28, 19.0, 62.8 or 193 mg/kg bw/day in females) for 90 day s. Indications of liver effects were seen. OK - 5101 caused an increase in prothrombin time in highCyflumetofen Human Health Risk Assessment DP No. D398246

Page **4 6**  of **73** dose males. In females, increases observed in albumin/globulin ratio in the 1000 and 3000 ppm groups were correlated to the dec reases in observed globulin levels. Organ examination revealed that liver weights were increased in both males and females at the high dose and in the 1000 ppm males. At necrops y, all females in the 3000 ppm group had white and enlarged adrenals. In ad dition, adrenal weights were increased in the 1000 and 3000 ppm females. Histopathology examinations found an increase of diffuse vacuolation and diffuse hy pertrophy of cortical cells in the adrenals of all 1000 and 3000 ppm animals. Relative kidney

weights were increased in high dose males and females. Eight of ten high dose females were observed to have vacuolation of interstitial gland cells in their ovaries. **The LOAEL is 1000 ppm (54.5 mg/kg bw/day in males, 62.8 mg/kg bw/day in females) based on th**  **e hematology and organ weight changes in the liver, organ weight and histopathology effects in the adrenals, kidneys and ovaries. The NOAEL is 300 ppm (16.5**  **mg/kg bw/day in males, 19.0 mg/kg bw/day in females).** This subchronic toxicity

study in the rat is acceptable/guideline and satisfies the guideline requirement for a subchronic oral study (OPPTS 870.3100; OECD 408) in the rat. **870.3100 90**  **- Day Oral Toxicity**  **- Mouse**  In a subchronic toxicity

study (MRID 48542683), OK - 5101 (97.7% a.i.) was administered to 10 SPR I CR mice/sex/dose in diet at dose levels of 0, 300, 1000, 3000 or 10000 ppm (0, 35.4, 117, 348 or 1200 mg/kg bw/day in males; 0, 45.0, 150, 447 or 1509 mg/kg bw/day in females) for 90 day s. Body weight and food consumption were decr eased at ≥ 3000 ppm in females. Organ weight examinations revealed increased adrenal weights in high dose males. During necrops y, 9 of 10 male mice in the 10000 ppm exhibited enlarged adrenals. Histopathological findings showed an increased incidence of diffuse hy pertrophy of cortical cells in males at the 3000 and 10000 ppm doses. Two and seven females exhibited diffuse vacuolation of cortical cells in the adrenals at 3000 and 10000 ppm, respectivel y. The degree of severit y and incidence of the lesion appeared in a dose - related manner, indicating a treatment - related effect. **The LOAEL is 3000 ppm (348 mg/kg bw/day in males; 447 mg/kg bw/day in females), based on decreased body weights in females, and diffuse hypertrophy and vacuolation of**  **cortical cell s in the adrenals in both sexes. The NOAEL is 1000 ppm (117 mg/kg bw/day in**  **males; 150 mg/kg bw/day in females).** This subchronic toxicity

study in the mouse is acceptable/guideline and satisfies the guideline requirement for a subchronic oral study (OPPTS 870.3100; OECD 408) in the mouse. **870.3150 90**  **- Day Oral Toxicity**  **- Dog** Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **47** of **73** In a 90 - day

dog study

(MRID 48542684), OK - 5101 (98.4% a.i.) was administered to 4 beagle dogs/sex/dose by

capsule at dose levels of 0, 30, 300, or 1000 mg/kg bw/day). All animals survived until study termination. There were no adverse compound related effects on clinical signs, hematology , clinical chemistry , urinaly sis, or gross pathology . Feces containing test substance - like material was observed in mid - and high - dose males and fe males. High - dose males and females exhibited decreased body weights and body weight gains when compared to controls. In addition, high dose males had decreased food efficiency and high dose females had slightly

reduced food consumption. A treatment - related increase in adrenal weights was observed in high - dose males. Animals of both sex exhibited vacuolation of the adrenals associated with treatment. **The LOAEL is 1000 mg/kg bw/day, based on decreased body weight and body weight gain, increased adrenal**  **weights (males only) and vacuolation of the adrenals. The NOAEL is 300 mg/kg bw/day.**  This study

in dogs is acceptable/guideline and satisfies the guideline requirement for a subchronic oral toxicity

study in dogs (OPPTS 870.4100; OECD 452). **870.3200 2**  **1/28 -**  **Day Dermal Toxicity –**  **Rat** In a repeat - dose dermal toxicity study (MRID 48542686), BAS 9210 I (98.4% a.i.) was applied to the shaved skin of 10 Wistar rats/sex/dose at dose levels of 0, 100, 300 or 1000 mg/kg bw/day , 6 hours/day

for 5 day s/week during a 28 - day period. There were no treatment related adverse effects noted for an y parameter examined in this study . **The LOAEL was not determined. The NOAEL is 1000 mg/kg bw/day.** This dermal toxicity

study in the rat is acceptable/guideline and satisfies the guideline requirement for a repeat - dose dermal toxicity study (OPPTS 870.3200, OECD 410) in the rat. **870.3465 90**  **- Day Inhalation**  **– Rat**  No study was conducted. **A.4.2 Prenatal Developmental Toxicity**  **870.3700a Prenatal Developmental Toxicity Study -**  **Rat** In a developmental toxicity study (MRID 48542704), OK - 5101 Technical (97.67 % a.i.) was administered to 25 female Wistar rats/dose via gavage at dose levels of 0, 50, 250 or 1000 mg/kg bw/day from day s 6 through 19 of gestation. All animals survived to scheduled termination. Slight decreases in body weight gain and food consumption throughout the treatment period were associated with a decrease in correctedCyflumetofen Human Health Risk Assessment DP No. D398246

Page **48** of **73** overall body weight gain (GD 6 - 20 and GD 0 - 20) at 1000 mg/kg bw/day . Abs olute left adrenal gland weight and organ to body weight ratio were increased in the mid (p ≤ 0.05) and high (p ≤0.01) doses, while the absolute right adrenal gland weight and organ to body weight ratio were increased in the high dose only (p ≤0.01). An in crease in the incidence of slight diffuse hy pertrophy of the cortical cells of both adrenal glands was noted in the high dose group. The incidence of slight or moderate bilateral diffuse cytoplasmic vacuolation of the cortical cells was also increased in the high dose group when compared to controls. **The maternal LOAEL is 250 mg/kg bw/day, based on an increase in adrenal weights and organ to body weight ratio. The maternal NOAEL is 50 mg/kg bw/day**  . An increased incidence of wav y ribs was noted at 1000 mg/kg/day , while an increased incidence of incompletely

ossified sternal centra was observed at the 250 and 1000 mg/kg bw/day dose levels. There were no additional treatment related effects on developmental parameters. **The developmental LOAEL is 250 m g/kg bw/day, based on**  **an increased incidence of incompletely ossified sternal centra**  **. The developmental NOAEL is 50 mg/kg bw/day.** The developmental toxicity study in the rat is classified acceptable/guideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat. **870.3700b Prenatal Developmental Toxicity Study -**  **Rabbit** In a developmental toxicity study (MRID 48542706) , OK - 5101 Technical (97.67 % a.i.) was administered to 25 female New Zealand White rabbits/dose by gavage at dose levels of 0, 50, 250, or 1000 mg/kg bw/day from day s 6 through 28 of gestation. There were no deaths attributed to the test substance. Body weight gains were generally slightly reduced at 250 and 1000 mg/kg bw/day , w ith a resulting decrease in overall body weight gain and corrected body weight gain when compared to controls. Food consumption was generally decreased at 1000 mg/kg bw/day , resulting in decreased overall food consumption in this group during the treatment period. Absolute liver weights were decreased in the mid - and high - dose groups and absolute weights of the left and right adrenals were decreased in the high dose group only . In the absence of body weight decrements, decreases in body weight gain (35 - 53 %), food consumption and liver weights (marginal decrease of 8%) at the limit dose are not considered adverse effects. As a result, no treatment related maternal adverse effects were observed. This is consistent with the range finding study where no mater nal toxicity

was observed. **The maternal LOAEL is not established. The maternal NOAEL is 1000 mg/kg bw/day.** There were no abortions or premature deliveries. No effects of treatment were noted on numbers of litters, live or dead fetuses, corpora lutea, earl y or late resorptions, sex ratio, or pre - or post implantation loss. Male, female and combined fetal body weights and combined placental weights were significantly reduced in the 1000 mg/kg bw/day dose group. The 250 and 1000 mg/kg bw/day

dose groups exhibited increased incidences in the average number of ossifiedCyflumetofen Human Health Risk Assessment DP No. D398246

Page **49** of **73** pairs of ribs and thoracic vertebrae, with a concomitant decrease in the average number of ossified lumbar vertebrae when compared to controls. The numbers of ossified xiphoid were also significantl y decreased in these dose groups. Litter and fetal incidences of angulated h yoid and incompletel y oss ified sternal centra were increased in the 1000 mg/kg bw/day dose group. Low incidence of ossification effects at 250 mg/kg/day were not considered an adverse effect. The only malformation attributable to treatment was a downward flexion of the forepaws (2 fetuses in one litter) and hind paws (1 fetus in one litter) in the high dose group. The incidence of downward paw flexion (litter incidence: 8%; fetal incidence: 1.4%) in the 1000 mg/kg/day group was slightl y above historical controls (litter incidence: 0 - 5.3%; fetal incidence: 0 - 0.6%) and was considered treatment - related adverse effect. **The developmental NOAEL is 250 mg/kg/day; and the LOAEL is 1000 mg/kg/day based on**  **increased incidences of ossification**  **and paw flexion**  **; and decreased fetal body weight.**  The developmental toxicity study in the rabbit is classified acceptable/guideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rabbit. **A.4.3 Reproductive**  **Toxicity 870.3800 Reproduction and Fertility Effects**  **- Rat**  In a 2 - generation reproduction study , OK - 5101 (97.67% a.i.) was administered to 24 Wistar rats/sex/dose in the diet at dose levels of 0, 150, 500 or 1500 ppm (0, 9.21/13.8, 30.6/46.6, or 89.4/141.1 mg/kg bw/day in males/females). P and F 1 male and female parental animals were administered test or control diet for 10 weeks prior to mating, throughout mating, gestation and lactation, and until necropsy . A single litter was produced b y each generation. Serum LH, FSH, testosterone (males onl y) , progesterone (females only) and 17 ß - estradiol (females only) hormone assay s were conducted using blood samples collected from 10 surviving F 1 adult animals/sex/dose at necropsy . There were no treatm ent - related effects on parental animals of either generation for clinical signs of toxicity , mortality

or food consumption. There were no changes in body weight/body weight gain observed in an y m ale parental animal. At 1500 ppm, parental females exhibite d a decrease in body weight gain during pre - mating weeks 1 - 2 (F 1 generation) or 6 - 8 (P generation). Absolute and relative adrenal weights were increased in P and F 1 parental females at 500 ppm and above. In parental males at 1500 ppm, absolute and relat ive adrenal weights were increased in the P and F 1 generations. In addition, absolute and relative ovary weights were increased in P generation females at 1500 ppm only . Following macroscopic examination, male and female parental animals of both generatio ns exhibited white and/or enlarged adrenals at 1500 ppm. Histopathological examination of the adrenals revealed an increased incidence of hypertroph y of the zona glomerulosa cells at 500 ppm and above in P generation females and F 1 generation males and fe males and in P males at 1500 ppm. Additionally in the adrenals, an increased incidence of vacuolation of the zona fasciculata cells was observed at 1500 ppm in P generation females and in both sexes of the F 1 generation. An increased incidence of vacuolation of the interstitial cells of the ovary was also noted at 1500 ppm in F 1 females.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **50** of **73 The parental LOAEL is 500 ppm (30.6/46.6 mg/kg bw/day in males/females) based on**  **effects on the adrenals (increased organ weights and histopathology). The parental NOA EL**  **is 150 ppm (9.21/13.8 mg/kg bw/day in males/females).** There were no treatment - related effects observed on ovarian follicle counts, sperm measurements or reproductive performance. An increase in estrous cycle length was noted at 1500 ppm. However, the estrous cycle length is within the range of the historical controls and would not be considered an adverse effect. In addition, decreased FSH levels were noted at 500 and 1500 ppm and decreased progesterone was noted at 150 ppm and above in F 1 females. Ho rmone changes are considered a reproductive effect. A dose response was observed with three hormones affected at the highest dose (1500 ppm) and two hormones affected at 500 ppm. **The reproductive NOAEL in females is 150 ppm (13.8 mg/kg/day); and the LOAE L in**  **females is 500 ppm (46.6 mg/kg/day) based on hormone changes (significantly decreased FSH and progesterone levels). The reproductive LOAEL is not determined in males. The**  **reproductive NOAEL in males is ≥1500 ppm (89.4 mg/kg bw/day).**  In the offspring, there were no treatment - related effects on clinical signs of toxicity , viability and measured anogenital distances. At 1500 ppm, body weights were decreased in male and female pups of the F 2 generation during LD 7 - 21. Absolute and relative adrenal w eights were increased at 500 ppm and above in both sexes of both generations of offspring. An increased incidence of adrenals that were white in color was observed in both sexes of F 2 pups at 1500 ppm. Microscopic examination of the adrenals revealed an increased incidence of hy pertrophy of the zona glomerulosa cells in both generations of males at 500 ppm and above and in both generations of females at 1500 ppm. Additionally in the adrenals, an increased incidence of hy pertrophy of the zona fasciculata cells was noted at 500 ppm and above in F 1 males and females and F 2 males, and at 1500 ppm in F 2 females. Delayed sexual maturation was observed in females (increased time to vaginal opening) at 500 ppm and above, and in males (increased time to preputia l separation) at 1500 ppm. However, slight delay of sexual maturation at 500 ppm (approximately

1 day relative to the control group) would not be considered an adverse effect **The offspring LOAEL is 500 ppm (30.6/46.6 mg/kg bw/day in males/females) based o n**  **effects on the adrenals (increased organ weights and histopathology) in both sexes. The offspring NOAEL is 150 ppm (9.21/13.8 mg/kg bw/day in males/females).**  This study

is acceptable/guideline and satisfies the guideline requirement for a 2 - generation reproductive study (OPPTS 870.3800); OECD 416 in the rat. **A.4.4 Chronic Toxicity**  **870.4100a (870.4300) Chronic Toxicity –**  **Rat** In a chronic toxicity

study (MRID 48542696), OK - 5101 (97.67% cy flumetofen) was administered to Fischer (F344/DuCrj) rats (50/sex/dose) in the diet at dose levels of 0, 50, 150,Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **51** of **73** 500 or 1500 ppm (equivalent to 0/0, 1.90/2.31, 5.63/6.92, 18.8/23.3 or 56.8/69. 2 mg/kg bw/day in males/females, respectively) for one ye ar. Interim sacrifices (10/sex/dose) were performed at 4, 13 and 26 weeks. All remaining animals were sacrificed at 52 weeks. There were no adverse treatment - related effects on mortality , clinical signs, body weight, food consumption, hematology , clinical chemistry and urinaly sis parameters. Treatment related effects were noted in the adrenals of both sexes at the high dose. In females, absolute and relative adrenal weights were increased at all scheduled sacrifices, along with diffuse hy pertrophy of adrenal cortical cells. Effects in males were slightl y different with diffuse vacuolation of the cortical cells recorded at all interim and terminal sacrifices. An increased incidence of vacuolation of ovarian interstitial gland cells was observed in high dose females from week 13 on, along with increased ovarian weights at terminal sacrifice. An increased incidence of atroph y of the seminal vesicles and coagulating gland were recorded in high dose m ales at terminal sacrifice only . There were no corresponding effects observed during histopathological examination. **The LOAEL for chronic administration of cyflumetofen in rats is 1500 ppm (equivalent to 56.8/69.2 in males/females, respectively) based**  **on diffuse vacuolation of adrenal cortical cells and increased incidence of atrophy of the seminal vesicles and coagulating glands in**  **males and increased adrenal weights and ovarian weights, diffuse hypertrophy of adrenal cortical cells and vacuolation of**  **the ovarian interstitial gland cells in females. The NOAEL is 500 ppm (equivalent to 18.8/23.3 mg/kg bw/day in males/females, respectively).**  This chronic study

in the rat is acceptable/guideline and satisfies the guideline requirement for a chronic ora l study

(OPPTS 870.4100), OECD 452 in the rat. **870.4100a (870.4300) Chronic Toxicity –**  **Rat** In a supplemental chronic toxicity study (MRID 49029701) , OK - 5101 (cy flumetofen, 97.82 % a.i.) was administered to SPF/VAF Fischer rats (F344/DuCrj) (50/sex/dose) in the diet at dose levels of 0 or 6000 ppm (0 or 250/319 mg/kg bw/day in males/females ) for 52 weeks. Interim sacrifices (10/sex/dose) were performed at 4, 13, 26 weeks. All remaining animals were sacrificed at 52 weeks. There were no treatment - relate d deaths or effects on food consumption, food efficiency , or in the ophthalmologic assessment. In treated females, an increased incidence of soiled fur around the external genital area and a consistent decrease in body weight and body

weight gain when compared to the control group were observed throughout most of the study . Males of the 6000 ppm group had reduced body weight gain throughout the study . In treated animals of both sexes, affected hematological parameters included decreased platelet count and fibrinogen concentration and elongated prothrombin time and activated partial thromboplastin time (APTT). Blood urea nitrogen (BUN) was elevated from 26 and 52 week in males and at all sampling points in females and was slightly outside of the submitted hi storical control data range for the females. This observation was considered treatment - related in conjunction with increased kidney weights for the treated animals. In both sexes at 6000 ppm, absolute and relative liver, kidney and adrenal weights were inc reased at all sacrifice time points. Gross necropsy revealed anCyflumetofen Human Health Risk Assessment DP No. D398246

Page **52** of **73** increase in the incidence of white colour in the adrenal gland in both sexes at 6000 ppm as well as adrenal enlargement in females. Treatment - related histological observations included effects noted in the adrenal gland such as diffuse h yp ertrophy of the cortical cell in treated females and diffuse cortical cell vacuolation in treated males and focal vacuolation of the cortical cell in treated females with higher incidence of these lesions by the end of the study . In treated males, gross lesions in the testis such as atroph y, softening, and spots were observed as well as an increased incidence of interstitial cell hy perplasia. Atrophy

of the acinar cell of the pancreas was also noted in the treated males. In treated females, vacuolation of the interstitial gland cell of the ovary was observed. **In this supplemental study, the LOAEL was 6000 ppm (250/319 mg/kg bw/day in**  **males/females )**  **based on increased adrenal weights accompanied by gross pathology and**  **histopathology lesions noted in both sexes, vacuolation of the interstitial gland cell of the ovary and hyperplasia of the interstitial cell of the testes. A NOAEL was not set.**  This chronic study

in the rat is supplemental; however, when co nsidered in conjunction with the previous study

( MRID 48542696), it satisfies the guideline requirement for a chronic toxicity study (OPPTS 870.4100), OECD 452 in rats. **870.4100b Chronic Toxicity -**  **Dog** In a 1 - ye ar dog study (MRID 48542685), OK - 5101 ( c yflumetofen, 98.4% a.i.) was administered to 4 beagle dogs/sex/dose by capsule at dose levels of 0, 30, 300, or 1000 mg/kg bw/day for one ye ar. There were no compound related effects on mortality , body weight, body

weight gain, food consumption, urinaly si s, hematology , clinical chemistry , or ophthalmoscopy . Feces containing test substance - like material was observed in both sexes at the mid - and high - dose levels. High dose males exhibited a treatment related increase in vomiting and soft/mucous/watery fece s. High - dose animals of both sexes exhibited decreased trigl yc erides. Increased absolute and relative adrenal weights were noted in both sexes at the high dose. In the adrenals, treatment related vacuolation, cortical degeneration, fibrosis, cell infiltration and pigmented macrophages (males only) were observed to some extent in mid - and high - dose males and females. In addition, high - dose females exhibited enlarged adrenals. **The LOAEL is 300 mg/kg bw/day, based on adrenal cortical cell vacuolation and additional**  **adrenal histopathology findings. The NOAEL is 30 mg/kg bw/day.** This study

in dogs is acceptable/guideline and satisfies the guideline requirement for a 1 - year oral toxicity

study in dogs (OPPTS 870.4100; OECD 452). **A.4.5 Carcinogenicity**  **870 .4200a Carcinogenicity**  **- Rat**  In a carcinogenicity

study (MRID 48542697), OK - 5101( cyflumetofen, 97.67 % a.i.) wasCyflumetofen Human Health Risk Assessment DP No. D398246

Page **53** of **73** administered to 50 Fischer rats/sex/dose in the diet at dose levels of 0, 150, 500, or 1500 ppm (0, 4.92/6.14, 16.5/20.3, 49.5/61.9 mg/kg bw/d ay in males/females) for 104 weeks. There were no compound related effects on mortality , clinical signs, body weight, food consumption, hematology or gross necropsy

observations. Diffuse h ypertrophy of the adrenal cortex was noted in high dose males and females in conjunction with increased adrenal weights. In addition, luminal dilatation of the gland of the uterine horn was observed in high dose females. At the doses tested, there was no treatment related increase in tumor incidence when compared to controls. **The LOAEL is 1500 ppm (49.5/61.9 mg/kg/day for males and females) based on increased adrenal weights, hyperplasia and hypertrophy of the adrenal cortex in both sexes, and**  **luminal dilatation of the gland in the uterine horn in females. The NOAEL i s 500ppm**  **(16.5/20.3 mg/kgkday for males and females). There was no treatment related increase in tumor incidence when compared to controls.**  This carcinogenicity

study in the rat is considered acceptable/guideline and satisfies the guideline requirement fo r a carcinogenicity study (OPPTS 870.4200); OECD 451 in the rat. **870.4200a Carcinogenicity (Supplementary)**  **- Rat**  In a supplemental carcinogenicity study , BAS 9210 I(cyflumetofen, 97.82 % a.i.) was administered to 50 Fischer rats (F344/DuCrlCrlj)/sex/dose in the diet at dose levels of 0 or 6000 ppm (0, 220/287 mg/kg bw/day in males/females) for 104 weeks. There was no treatment - related effect on mortality and food consumption. Treated females exhibited an increased incidence of t actile hair loss and soiled fur. Males showed no clinical signs of toxicity . Treated males exhibited decreased final body weight and overall body weight gain, while treated females exhibited decreased body weight intermittentl y throughout the study period . Decreased differential leukocy te count was observed in treated males but was unaffected in females. Absolute and/or relative weights of the kidneys, liver, and adrenals in both sexes as well as testis weights in treated males and ovary weights in treat ed females were affected b y treatment. Although clinical chemistry and hematological parameters were not assessed in the current study, effects were noted on these parameters in the confirmatory 1 - ye ar rat chronic toxicity study (MRID# 49029701) and were c onsidered as corroborating findings in support of the organ weight changes in the current study. Incidences of diffuse h ypertrophy and focal vacuolation (both sexes) and diffuse vacuolation (females onl y) were increased in the adrenal cortical gland cells . An increased incidence of focal atroph y of the pancreatic acinar cells was noted in treated males of the current study and was also observed in treated males in the confirmatory

1 - ye ar rat chronic toxicity study . At necrops y, increased incidences of atroph y of the epididy

mis and masses in the testis were observed in treated males. There was a treatment related increase in the incidence of Leydigcell tumours in male rats when compared to controls. Corresponding decreased incidences of softening of the testis, seminiferous tubule atrophy , and testicular interstitial cell hy perplasia were considered to be secondary to the development of testicular interstitial cell tumours in treated male rats. In addition, treated males exhibited an increase in the inci dence of thy roid C - cell tumours (combined adenomas and carcinomas).Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **54** of **73 The LOAEL for this**  **supplementary study is 6000 ppm ( 220/287 mg/kg bw/day in**  **males/females) , based on effects on clinical signs of toxicity (females), decreased body**  **weight (both sexes) an d body weight gain (males), changes in hematological parameters**  **(males), organ wei ghts (both sexes), and histopathology findings (both sexes). A NOAEL**  **was not identified for this study. Treatment with cyflumetofen was associated with an increase in thy**  **roid C -**  **cell tumours (carcinomas, as well as adenomas and carcinomas combined) in males as well as an**  **increase in the incidence of testicular interstitial cell tumours. There was no treatment**  **related increase in tumor incidence in females when compared to controls.**  This carcinogenicity

study in the rat is supplemental; however, when considered in conjunction with the previous study

(MRID# 48542697), it satisfies the guideline requirement for a carcinogenicity

study (OPPTS 870.4200); OECD 451 in rats. **870 .4200b Carcinogenicity**  **- Mouse**  In a carcinogenicity

study (MRID 48542698), OK - 5101( cyflumetofen, 97.67 % a.i.) was administered to 52 CD - 1 mice/sex/dose in the diet at dose levels of 0, 150, 500, 1500 or 5000 ppm (0, 15.5/14.3, 54.3/48.1, 156/144, 537/483 mg/kg bw/day in males/females) for 78 weeks. There were no compound - related effects on mortality , clinical signs, body weight, food consumption, hematology or gross necropsy

observations at any

dose level. Diffuse adrenal cortical cell vacuolation was noted in 5000 ppm males and females, with a corr esponding increase in adrenal weight in males. At the doses tested, there h as no treatment related increase in tumor incidence when compared to controls. **The LOAEL is 5000 ppm, based on an increased incidence of diffuse adrenal cortical cell vacuolation**  **in males and females, and an increase in adrenal weight in males. The NOAEL is 1500 ppm.**  **There w**  **as no treatment related increase in tumor incidences**  **when compared to controls.**  This carcinogenicity

study in the mouse is acceptable/guideline and satisfies the guideline requirement for a carcinogenicity study (OPPTS 870.4200); OECD 451 in mice. **870.4200b Carcinogenicity (Supplementary)**  **- Mouse**  In a supplemental carcinogenicity study (MRID 49209101), BAS 9210 I (cy flumetofen, 97.82 % a.i.) was administered to SPF I CR (Crj:CD1) mice (52/ sex/dose) in the diet at dose levels of 0 or 10,000 ppm (0, 1143/1132 mg/kg bw/day in males/females) for 78 weeks. There were no compound - related effects on mortality , body weight, food consumption, or hematology

parameters at the dose tested. Diffuse adrenal cortical cell vacuolation and deposition of brown pigment in the cortico - medullary junction of the adrenals was observed in treated animals of both sexes. Treated females exhibited a significant increase in the incidenc e of pale - colored skin and pale - colored eye/eyelid, increased adrenal weights, enlarged spleen andCyflumetofen Human Health Risk Assessment DP No. D398246

Page **55** of **73** an increased incidence of extramedullary hematopoiesis in the spleen. **The LOAEL for this confirmatory study is 10,000 ppm, based on clinical signs of toxi city,**  **increased adrenal weights, enlarged spleen and an increased incidence of extramedullary hematopoiesis in the spleen of treated females and an increased incidence of diffuse adrenal**  **cortical cell vacuolation and deposition of brown pigment in the cort ico**  **- medullary junction**  **of the adrenals in both sexes. A NOAEL was not identified for this study. At the dose tested, there was no treatment**  **- related increase in tumor incidence when**  **compared to controls. Dosing was considered adequate as animals were dose d above the**  **limit dose of 1000 mg/kg bw/day.** This carcinogenicity

study in the mouse is supplemental; however, when considered in conjunction with the previous study (MRID 48542698), it satisfies the guideline requirement for a carcinogenicity study (OPPT S 870.4200); OECD 451 in mice. **A.4.6 Mutagenicity**  Cyflumetofen, two metabolites (B - 1 and B - 3) and one impurity (AB - 13) were evaluated in a comprehensive battery

of Genetic Toxicology

assay s. The data indicate that neither the parent compound nor metabolite B - 1 were mutagenic in bacteria. However, metabo lite B - 3 induced a weak but reproducible and concentration - related mutagenic response (1.7 - 2.2 fold increases at 3330 and 5000 μg/plate) in Salmonella typhimurium TA100; the effect was, nevertheless, abolished in the presence of exogenous metabolic activation. There was also evidence of a mutagenic response in the L 5178Y mouse l ymphoma assay that was induced by

the parent and the two metabolites. The response was the strongest in the parent compound (90 μg/mL

– S9 vs. the limit concentration for the two me tabolites). However, for both the parent and metabolite B 1, mutagenic activity

was only seen at severel y c yt otoxic concentration (i.e., ≈10% survival); consequentl y, these results are not considered sufficient evidence of a mutagenic response in this tes t sy stem. For metabolite B - 3, the 4.3 - fold increase in the mutation frequency at 1891 μg/mL (equivalent to the limit concentration of 10 mM) was confined to this level and not observed in the S9 - activated portion of the assay . For the remaining genetic endpoints, the parent and the two metabolites were not clastogenic in Chinese hamster lung cells (parent in two studies performed b y independent laboratories) or peripheral human ly

mphocy tes (metabolites B - 1 and B - 3). Similarl y, c yflumetofen was not clast ogenic or aneugenic in mouse bone marrow cells up to the limit dose. Finally , neither the parent nor the two metabolites induced a genotoxic response in hepatocy tes harvest from male rats orall y exposed up to the limit dose (parent and metabolite B - 1) or an overtly toxic level for the test animals (metabolite B - 3). Studies performed on an impurity of cy flumetofen (AB - 13) showed negative results for reverse gene mutations in bacteria (S. typhimurium TA 1535, TA 1537, TA 98 or TA 100 or Escherichia coli W P2 uvr A), forward gene mutations in mammalian cells (L5178Y mouse ly mphoma cells), and chromosome aberrations in mammalian cells (human peripheral lymphocytes).Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **56** of **73** Overall, the data indicate that while there was some evidence of a mutagenic response from in v itro assay s, the responses were confined to severely cy totoxic concentrations, abolished in the presence of exogenous metabolic activation, or were not expressed in whole animal studies. **Based on these considerations, there is no concern for mutagenicity for the parent or the**  **metabolites** . Similarly , the impurity was uniformly

negative; hence, there is also no concern for mutagenicity . All assay s were well - conducted, acceptable and satisfy FIFRA test guidelines for mutagenicity

testing. Consequently , mut agenicity can be ruled out as a possible mode of action for tumor formation. Results from these assay s are summarized below: **Parent** Cyflumetofen was negative in bacteria in two independent trials using the pre - incubation method at concentrations of 2 0.6 to 5000 μg/plate +/ - S9 (MRID 48542687). In the mouse ly

mphoma forward gene mutation assay , concentrations of 20 to 90 μg/mL

– S9 or 10 to 140 μg/mL+S9 for 3 hours. Although increases in the total mutation frequencies (MF) occurred at 90 μg/mL

– S9 (3. 2 - fold) and at 140 μg/mL +S9 (6.1 - fold), these concentrations were insoluble and severel y cytotoxic (relative suspension growth (RSG) was 10% at 90 μg/mL

– S9 and 12% at 140 μg/mL+S9). These results are, therefore, not considered sufficient evidence of a mutagenic response in this test sy stem (MRID 48542692). In an in vitro chromosome aberration study , Chinese hamster lung fibroblasts (V79) cells were exposed to 6.25 to 50 μg/mL

– S9 and 25 to 200 μg/mL +S9 for 6 hours and allowed an 18 - hour recovery perio d. Cells were also continuously treated with 3.75 to 30 μg/mL

– S9 for 24 or 48 hours and harvested at the end of treatment. Compound precipitation was seen at ≥200 μg/mL +S9. Less than 50% of the cells were available for anal ys is at the highest dose t ested with or without S9 activation. There were however, and no significant increases in cells with structural or numerical chromosome aberrations (MRID 48542689). In a second in vitro chromosome aberration study, Chinese hamster lung fibroblasts (V79) c ells were exposed to 2.5 to 80 μg/mL

– S9 and 10 to 160 μg/mL+S9 for 4 hours and allowed a 14 - hour recovery

period. Due to severe cy totoxicity , the assay

was repeated with 3.1 to 10 μg/mL

– S9. Cells were also continuously treated with 3.1 to 40 μg/mL

– S9 for 18 hours and harvested or allowed an additional 10 hour recovery . With S9, cells were dosed with 20 - 320 μg/mLfor 4 hours and harvested after a 24 - hour recovery period. Compound precipitation was seen at ≥120 μg/mL . Less than 50% of the cells were available for anal ys is at ≥160 μg/mL+S9, ≥20 μg/mL S9 (18 - hour exposure), or 40 μg/mL - S9 (18 - hour exposure with 10 - hour recovery). There were however, and no significant increases in cells with structural or numerical chromosome aberrations (MRID 48542691 ). In the mouse bone marrow micronucleus assay , levels up to the limit dose were not overtly toxic to the test animals, cy

totoxic to the target cells or induce an aneugenic or a clastogenic response (MRID 48542694).Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **57** of **73** In an in vivo unscheduled DNA s ynth esis (UDS) assay in male Wistar rats, metabolite B - 1 was not overtly

toxic to the test animals or genotoxic in the hepatocy tes harvested 2 - 4 or 12 - 16 hours after oral administration of levels up to the limit dose of 2000 mg/kg (MRID 48542695). **Metabolite B**  **- 1**  Metabolite B - 1 was negative in bacteria in two independent trials using the plate incorporation method at concentrations of 3 to 5000 μg/plate +/ - S9 (MRID 48542710). In the mouse ly

mphoma forward gene mutation assay , concentrations of 1 to 1901 μg/mL +/

– S9 (1901 μg/mL is equivalent to the limit concentration of 10 mM) were tested using a 3 - hour exposure. A second assay was performed with comparable nonactivated concentrations and a 24 - hour exposure and S9 - activated levels of 3 - 1910 μg/mLwith a 3 - hour exposure. The nonactivated assay

was repeated for the 24 - hour exposure with 3 - 1910 μg/mL . The 3 - hour exposure with or without S9 activation was negative up to the highest dose tested (HDT). Although marked increases in the total MF occurred at the HD T without S9 activation after the 24 - hour treatment in both the initial (8.2 - fold) and repeat trials (7 - fold), these concentrations were severely

cy totoxic (RSG was 13 or 9%, respectivel y). Consequentl y, these results are not considered sufficient evidenc e of a mutagenic response in this test system (MRID 48542712). In an in vitro chromosome aberration study , peripheral human l ymphocy tes were exposed to 333 to 1901 μg/mL+/

– S9 (1901 μg/mLis equivalent to the limit concentration of 10 mM) for 3 hours and allowed a 21 - hour recovery period. Cells were also continuously treated with 100 to 1000 μg/mL

– S9 for 24 or 48 hours and harvested at the end of exposure. With S9, cells were dosed with 333 - 1901 μg/mLfor 3 hours and harvested after 48 hours. There wer e no significant increases in cells with structural chromosome aberrations without S9 activation up to concentrations that caused a ≥50% decrease in relative suspension growth (≥ 750 μg/mL , prolonged 24 - hour exposure or ( ≥ 560 μg/mL, prolonged 48 - hour expo sure). Similarly , no evidence of a clastogenic response was seen after exposure for 3 hours with or with S9 up to the limit dose (MRID 48542711). In an in vivo unscheduled DNA s ynthesis (UDS) assay in male Wistar rats, metabolite B - 1 was not overtly

toxic to the test animals or genotoxic in the hepatocy tes harvested 2 - 4 or 12 - 16 hours after oral administration of levels up to the limit dose of 2000 mg/kg (MRID 4 8542713). **Metabolite B -**  **3 [2 -**  **(trifluoromethyl)benzamide]** Metabolite - 3 induced a reproducible and dose - related increase in mutant colonies of Salmonella typhimurium TA100. Fold increases were 1.7 and 1.9 - fold at 3330 and 5000 μg/plate

– S9 in Trial 1 and 1 .7 and 2.2 - fold at 3330 and 5000 μg/plate

– S9 in Trial 2. The response was, however, abolished in the presence of S9 activation and was not seen in any other Salmonella strain or in Escherichia coli WP2 uvrA (MRID 48542715). In the mouse ly

mphoma forward gene mutation assay , concentrations of 1 to 1891 μg/mL+/

– S9 (1891 μg/mL is equivalent to the limit concentration of 10 mM) were tested using a 3 - hour exposure. A second assay was performed with comparable nonactivated concentrations and aCyflumetofen Human Health Risk Assessment DP No. D398246

Page **58** of **73** 24 - hour exposure and comparable S9 - activated concentrations with a 3 - hour exposure. The 3 - hour exposure with or without S9 activation was negative up to the highest dose tested (HDT). A marked increase in the total MF occurred at the HDT without S9 activation (4.3 - fol d) following the prolonged and in the absence of severe cy totoxicity . However, the response was confined to this concentration and not observed when S9 activation was incorporated into the reaction mixture (MRID 48542717). In an in vitro chromosome abe rration study , peripheral human l ymphocy tes were exposed to 333 to 1891 μg/mL+/

– S9 (1891 μg/mLis equivalent to the limit concentration of 10 mM) for 3 hours and allowed a 21 - hour recovery period. Cells were also continuously treated with 100 to 1891 μg/mL

– S9 for 24 hours or 33 to 1891 μg/mL

– S9 for 48 hours. Cells were harvested at the end of the prolonged exposures. With S9, cells were dosed with 333 - 1891 μg/mLfor 3 hours and harvested after 48 hours. There were no significant increases in cells with structural chromosome aberrations with or without S9 up to the limit concentrations (MRID 48542716). In an in vivo unscheduled DNA s ynthesis (UDS) assay in male Wistar rats, metabolite B - 3 was toxic to the test animals at 350 mg/kg but was not genotoxic in the hepatocy tes harvested 2 - 4 or 12 - 16 hours after oral administration of 0, 175 or 350 mg/kg (MRID 48542718). **Impurity AB -**  **13** Impurit y AB - 13 was negative in bacteria in two independent trials using the plate incorporation method up to insoluble conce ntrations ( ≥333 μg/plate +/ - S9) (MRID 48542688). In the mouse ly

mphoma forward gene mutation assay , concentrations of 0.03 to 100 μg/mL+/

– S9 were tested using a 3 - hour exposure. A second assay was performed with similar concentrations and a 24 - hour expo sure for the nonactivated phase of testing and with a 3 - hour exposure for the S9 - activated concentrations. The 3 - hour exposure with or without S9 activation was negative up to the highest dose tested. Compound precipitation was seen at 100 μg/mL +/

– S9. R SG was generall y s imilar to the control at all concentrations and exposure intervals. There was no appreciable increase in the MF at an y nonactivated or S9 - activated concentration (MRID 48849413). In an in vitro chromosome aberration study , peripheral human l ymphocy tes were exposed continuously

to 10 to 333 μg/mL

– S9 for 24 or 48 hours and harvested at the end of the prolonged exposures. With S9, cells were dosed with 10 to 333 μg/mLfor 3 hours and harvested after 48 hours. Compound precipitation was n oted at ≥100 μg/mL . There were no adverse effects on the mitotic indices or significant increases in cells with structural chromosome aberrations with or without S9 up to insoluble levels (MRID 48542716690). **A.4.7 Neurotoxicity**  **870.6200 Acute Neurotoxicity Screening Battery -**  **Rat** In an acute neurotoxicity

study (MRID 48542707), groups of young adult Wistar rats (10/sex) were given a single gavage dose of BAS 9210 I (97.08% a.i.) in 1% carboxy methylcellulose at doses of 0, 125, 5 00, 2000 mg/kg bw. Rats were observed for 14 day s.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **59** of **73** Neurobehavioral assessments (functional observation battery and motor activity

testing) were performed in 10 animals/sex/group 7 day s before dosing, the day of dosing, and 7 and 14 day s post - dosing. At s tudy

termination, 5 animals/sex/group were euthanized and perfused for neuropathological examination. Of the perfused animals, 5/sex from the control and high dose groups were subjected to histopathological evaluation of brain and peripheral nervous s ys tem tissues. Brains weights were taken for 5 animals/sex/group. No treatment - related effects were noted on mortality , clinical signs, body weight, brain weight, gross pathology

or histologic neuropathology . FOB and motor activity testing revealed no treatment - related effects. **The NOAEL is 2000 mg/kg bw, the highest dose tested. No LOAEL was established. No**  **evidence of neurotoxicity.** The study is classified as acceptable/guideline as an acute neurotoxicity study in rats (870.6200). **870.6200 Subchronic Neurotoxicity Screening Battery**  **- Rat**  In a subchronic neurotoxicity study (MRID 48542708) , BAS 9210 I (97.08% cy flumtofen) was administered to 10 Wistar rats/sex/group in the diet for 91 day s at doses of 0, 500, 1500, and 5000 ppm (equivalent to 0/0, 30/41 , 89/99, and 293/353 mg/kg bw in males/females). Neurobehavioral assessments (functional observation battery and motor activity

testing) were performed in all animals one week before dosing commenced and also 1, 22, 50, and 85 day s after the start of dosin g . At study termination, 5 animals/sex/group were euthanized and perfused for neuropathological examination and the brain weights of these animals were measured. Of the perfused animals, only

the control and high dose groups were subjected to histopatholog ical evaluation of brain and peripheral nervous s ys tem tissues. The remaining 5 animals/sex/group were sacrificed b y decapitation, subjected to gross necrops y, and the adrenal gland of each animal was weighed and examined microscopically. Body weights and food consumption for all animals on study

were measured weekl y. There were no treatment related effects on mortality , clinical signs, body weight, food consumption, brain weight or neuropathology . Food consumption was elevated in 500 ppm females, and thes e animals also exhibited increased body weights and body weight gains. Consequently , due to the increased body weights, absolute brain weights were elevated in 500 ppm females while relative brain weights remained comparable to controls. Since these findin gs were restricted to the low dose and no dose - response was observed, increased food consumption, body weight, and the corresponding increase in absolute brain weights are not considered treatment - related in 500 ppm females. FOB testing revealed no treatment - related effects. Slightly decreased motor activity was observed in all treated males and in high dose females on Day 1, and this finding is considered to be potentially

treatment - related. However, due to a lack of an y other indications of neurotoxici ty in this study

(altered FOB parameters, clinical observations or neuropathy) a slight depression of motor activity

is likely not indicative of a neurotoxic effect. Although potentially treatment related, the slight decrease in motor activity in males at the low dose was not consideredCyflumetofen Human Health Risk Assessment DP No. D398246

Page **60** of **73** sufficiently

adverse to be considered for the determination of the L OAEL. Absolute and relative adrenal weights were statistically significantly

increased in 1500 ppm females and 5000 ppm males and females. Upon gross necro ps y, the adrenal cortex of all 5000 ppm animals was discoloured to light beige and it was moderately enlarged in 5000 ppm females. Microscopic evaluation revealed diffuse vacuolation of the adrenal cortex in 1500 and 5000 ppm animals of both sexes. The sev erit y of vacuolation appeared to increase with dose. **A NOAEL of 500 ppm (30/41 mg/kg bw/day in males/females) was selected based on the increased adrenal weights in females and the altered adrenal histopathology of both sexes**  **observed at the LOAEL of 1500 ppm (89/99 mg/kg bw/day). No evidence of neurotoxicity.**  The study is classified as acceptable/guideline as a subchronic neurotoxicity study in rats (870.6200; OECD 424). **A.4.8 Metabolism**  **870.7485 Metabolism**  **- Rat**  In a series of metabolism studies , 14 C - cyflumetofen (>98% radiochemical purity), labeled either on the benzene ring in the 4 - tert - but ylphen ylgroup (A - ring) or on the benzene ring in the α , α , α trifluoro - o - tolyl group (B - ring), was administered via gavage in aqueous h ydrox yp rop yl cellulose to 3 - 4 Fischer rats/sex/dose/radiolabel position at dose levels of 3 or 250 mg/kg bw. Rats were sacrificed either at Tmax (1 or 2 hours post - dosing), or at 2 4, 48 or 72 hours after dosing. The 14 C - time course in plasma; the 14 C - excretion in urine, feces and bile; and the distribution to organs and tissues were examined. In addition, the profile of the metabolites in urine, feces and bile was determined. 14 C - cyflumetofen was rapidly absorbed following administration of the low dose, with plasma levels of radioactivity

peaking at 1 hour post - dosing. Absorption was slightly slower following administration of the high dose, with peak plasma levels attained at 2 - 4 hours post - dosing. At the high dose, females demonstrated higher Cmax and AUC values than males for both radiolabels. The AUC values at the high dose were approximately 15 - 16 and 36 - 38 times the AUC at the low dose for males and females, respectively ; these values are much lower than the 83 - fold difference in dose levels, indicating saturation of absorption. The half - lives of elimination from plasma ranged from 12 to 22 hours, with no consistent pattern in terms of differences related to sex, dose or radiolabel position. The half - lives of elimination from whole blood, kidney

and liver were comparable to the elimination rates from plasma, but longer elimination half

- lives were calculated for bone marrow (14 - 30 hours) and adipose tissue (19 - 43 hours). Th e absorption rates for the A - ring group were higher for the low dose group (68% and 71% in males and females, respectively) than for the high dose group (46% for both males and females). For the B - ring groups, the absorption rate was higher in females (78 %) than in males (69%) at the low dose, but higher in males (44%) than in females (35%) at the high dose.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **61** of **73** At 72 hours post - dosing, the total radioactivity recovered in tissues and carcass accounted for approximately

0.4 - 2.5% of the administered dose, with lower proportions recovered in tissues from rats in the high dose group than in the low dose group. For all dose groups, the gastrointestinal tract, carcass, and liver and kidney contained the highest proportions of radioactivity . The remaining tissues generall y contained 0.002% of the administered dose or less at 72 hours. For the low dose groups, biliary , urinary and fecal excretion accounted for approximately 25 - 37%, 29 - 51% and 6 - 17% of the administered dose, respectivel y. For the high dose groups, biliary , urinary

and fecal excretion accounted for approximately 18 - 32%, 11 - 24% and 34 - 41% of the administered dose, respectively . Most of the radioactivity excreted in urine from low dose rats (90 - 96%) was eliminated within 24 hours after dosing, whereas at the high dose, excretion was slower with onl y 74 - 88% of the radioactivity excreted in urine being eliminated with 24 hours of dosing. At both low and high doses, 60 - 89% of the radioactivity excreted in feces was eliminated within 24 hours of dosing. The unchanged parent was not detected in the urine of an y test group. For both radiolabels, metabolite AB - 3 was identified as a major metabolite in the urine of female rats but was a minor urinary metabolite in males. For the A - ring label, metabolite A - 18 was a major metabolite common to both males and females administered low and high doses, while metabolite A - 21 was detected at high levels in the urine of both sexes in the low dose group and males from the high dose group, but was minimal in the urine of females from the high dose group. Minor metabolites common to males and females from the low and high dose groups administered the A - ring label included A - 20, AB - 2, and [A - 6] - GA. For the B - ring label, metabolites [B - 1] - TLA, B - 1, and [B - 1] - MA were major components in urine of both males and females from both the low and high dose groups. Metabolite AB - 2 was a minor metabolite in urine of all test groups except females from the low dose group, in which residues for this metabolite reached 4% of the administer ed dose. In feces, the unchanged parent and metabolites A - 20 and A - 12 were detected in the low dose groups administered the A - ring label, each accounting for approximately 2 - 4% of the administered dose. However, in the corresponding high dose groups, unc hanged parent was detected in feces at 62 - 63% of the administered dose while metabolites A - 12 and A - 20 were detected at approximately 1%. Following administration of the B - ring label, the unchanged parent detected in feces accounted for approximately 2% o f the administered dose for the low dose groups, but increased at the high dose to 66% and 54% of the administered dose for males and females, respectivel y. The only metabolite detected in feces was metabolite B - 1, which was detected at much higher levels in the low dose groups than the high dose groups. The major metabolites detected in the bile from all test groups were the glucuronic acid conjugates of metabolites AB - 1 and AB - 3. Metabolite AB - 2 was also detected at lower levels in the bile from all tes t groups. Unique metabolites identified in the bile of rats administered the A ring or B - ring label included the glucuronic acid conjugate of A - 6 and the glutathione conjugate of B - 1, respectively .Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **62** of **73** 14 C - cyflumetofen was metabolized in the rat primarily by hydrol yt ic cleavage of the trifluoromethylbenzoyl moiety resulting in metabolite B - 1 (trifluoromethylbenzoic acid) and A 18. Another minor pathway included successive hydrox yl ation of the tert - butyl side chain. This series of metabolism studies in th e rat is classified as acceptable/guideline and satisfies the guideline requirement for a metabolism study (OPPTS 870.7485; OECD 417) in rats. **870.7600 Dermal Absorption**  **- Rat**  In a dermal absorption study (MRID 48542724), a dermal absorption of 14 C - BAS 9210 (cyflumetofen) was examined in vivo in male rats after a single dermal application at 2, 20 or 2000 μg/cm 2 doses. A 100 μl of each dose was applied to10 cm 2 skin area to groups of 4 animals each. Each dose was washed after 8h of exposure and groups o f animals were sacrificed at 8h, 24h or 120h. An additional skin wash before sacrifice was given to groups monitored for 24h or 120h. The dermal absorption, as % of applied radioactive dose, increased over monitored time of 5 day s; but decreased with incr ease in dose. The dermal absorption, as sum of excreta, blood and carcass, was 4.93% (8h), 6.48% (24h) and 8.02% (120h) in 2 μg/cm 2 dose groups; 0.63% (8h), 1.27% (24h) and 2.20% (120h) in 20 μg/cm 2 dose groups; and 0.26% (8h), 0.53% (24h) and 0.96% (120h) in at 2000 μg/cm 2 dose groups . Recovery of the applied dose (mass balance) was acceptable at all dose levels (93 - 108 %). The majority of the administered dose was recovered in first skin wash after 8h of exposure at all dose levels (85 - 95%) . The amount of radioactivit y recovered in non - occlusive protective cover was small for mid and high dose groups and up to 25.52% in low dose groups. The amount retained at the application sites was 5.18% (8h), 1.44 % (24h) and 1.00 %(120h) in 2 μg/cm 2 dose grou ps; 4.88% (8h), 2.13 %(24h) and 1.32 % (120h) in 20 μg/cm 2 dose groups; 6.48% (8h), 2.24 %(24h) and 0.45 %(120h) in 2000 μg/cm 2 dose groups. Small amounts were also detected in skin surrounding the test site and in skin strips. As the residues at the ap plication site skin and in skin strips were absorbed over 5 day s, they were included in the total estimate of dermal absorption (Table 3). The residues in the surrounding skin samples were variable, but were lower in 120h groups compared to 8h groups. Ther efore, these residues were also included in the estimate. Thus, the total amount of test substance absorbed over time by

each animal was estimated as the sum of the quantity found in the excreta (urine, feces and cage wash), blood (cells + plasma), carcas s and skin (at the application site + surrounding skin + skin strips). T he estimated dermal absorption were: 11.33% (8h), 10.86% (24h) or 9.5% (120h) in low dose (2 μg/cm 2 ) groups; 7.74 %(8h), 6.09 % (24h) and 3.9 % (120h) in 20 μg/cm 2 groups; and 7.28 %( 8h), 3.02% (24h) and 1.63% (120h) in 2000 μg/cm 2 groups. The test substance doses and exposure time were selected based on the application rate of the concentrated and spray

diluted product expected in the field in actual use conditions. Given the uncerta int y regarding actual deposition under field conditions and worker exposure time frame, it is considered appropriate to derive an estimate of dermal absorption based on the results from the low dose group (2 μg/cm 2 ) sacrificed at 8 hr after a skin wash, as the percent dermal absorption was highest in this dose group. Thus, the estimated dermal absorption is 11%. This value is considered conservative as the residues retained at the skin site and surrounding skin as well as residues found in the skin strips was included in this estimate and it is possible that all of the skin residues may

not become sy stemicall y available.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **63** of **73** This study

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

study (MRID 48542726) , BAS 9210 I(97.08% a.i.) was administered to 8 female Wistar rats/dose in the diet at dose levels of 0, 500, 1500, or 5000 ppm (0, 33, 107, or 349 mg/kg bw/day) for 28 day s. An additional group of 8 female rats was dosed with cyclophosphamide monohydrate in drinking water at a dose level of 4.5 mg/kg bw/day to serve as positive control. Sy stemic toxicity parameters were evaluated, and immunotoxici ty was investigated b y performing an enzyme - linked immunoabsorbant assay (ELISA) to measure serum IgM responses to sheep red blood cells (sRBC) following immunization with SRBC. A statistically

significant increase (p ≤0.01) in absolute and relative adrena l weights was observed in the 1500 and 5000 ppm dose groups. Correlating histopathology was noted as vacuolation of adrenal cortical cells, with severity increasing with dose. In addition, light discolouration and enlargement of the adrenals was noted in the 1500 and 5000 ppm dose groups. There were no treatment related effects on mortality , clinical signs, body weights, body weight gains, or food consumption at any dose level. **The LOAEL for systemic toxicity was 1500 ppm (107 mg/kg bw/day) based upon increased**  **adrenal weights and correlating histopathology. The NOAEL for systemic toxicity is 500 ppm (33 mg/kg bw/day) in female rats.**  There was no evidence of immunotoxicity . No effects of treatment were observed on the humoral immune response as measured by the primary

serum IgM antibody

response to the T dependent antigen, sheep ery throcy tes. Spleen and thy

mus weights were unaffected by treatment. Positive control rats demonstrated an 81% decrease (p ≤0.01) in serum titer compared to concurrent contro ls, demonstrating the ability of this ELISA to detect suppression of the humoral immune response. **The LOAEL for immunotoxicity was not established. The NOAEL for immunotoxicity is 5000 ppm (349 mg/kg bw/day) in female rats.**  This immunotoxicity

study is classified acceptable/guideline and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in the rat.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **64** of **73 A.5**  **Summary of Toxicological Doses and Endpoints for Cyflumetofen Table A.5. Summary of Toxicological Doses and Endpoints**  **for Cyflum etofen**  **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 populations) An acute reference dose has not been established for either the general population or for Females

13 - 49 years of age since there were no appropriate studies that demonstrated evidence of toxicity attributable to a single dose for these populations.

Chronic Dietary (All Populations) NOAEL =

16.5 mg/kg/day UF A= 10x

UF H = 10x FQPA SF= 1x Chronic RfD =

0.17 mg/kg/day cPAD = 0.17 mg/kg/day **Three co -**  **critical studies :** 

90 - day feeding study in rats LOAEL = 1000 ppm (54.5/62.8 mg/kg/day in M/F) based on hematology and organ weight changes in the liver, adrenal, kidney and ovaries; and histopathology effects in the adrenals and the ovaries . NOAEL=300 ppm (16.5/19 mg/kg/day in males/females) Chronic toxicity/carcinogenicity study in rats LOAEL = 1500 ppm (49.5/61.9 mg/kg/day in M/F) based on increased adrenal weights and histopathology. NOAEL=500 ppm (16.5/20.3 mg/kg/day in males/females) Two generation reproduction study in rats Parental: LOAEL = 500 ppm (30.6/46.6 mg/kg/day in M/F) based on increased organ weight and histopathology in adrenals. NOAEL=150 ppm (9.2/13.8 mg/kg/day in males/females) Incidental Oral (Short - and Intermediate Term) NOAEL =

16.5 mg/kg/day UF A= 10x

UF H = 10x FQPA SF= 1x Residential LOC

for MOE = 100 **Same as chronic dietary endpoint**  Dermal (Short - , Intermediate and Long Term) No dermal hazard was identified. No appropriate endpoint was selected for risk assessment. Inhalation (Short - , Intermediate and Long Term) NOAEL =

16.5 mg/kg/day UF A= 10x

UF H = 10x FQPA SF= 1x Occupational

and Residential LOC for MOE = 100 **Same as chronic dietary endpoint** Cancer (oral, dermal, inhalation) CARC Classification: Suggestive Evidence of Carcinogenic Potential. 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 l evel. 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 (a = ac ute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **65** of **73 Appendix**  **B. Metabolism Summary Table**  **B.1 Structures of Cyflumetofen Metabolites**  **Table B.1. Cyflum etofen and Metabolite Structures**  **Comm on Names /**  **Code Chemical Name (IUPAC)**  **Chemical Structure** Cyflumetofen BAS 9210 I OK - 5101 2 - methoxyethyl ( RS ) - 2 - (4 - tert butylphenyl) - 2 - cyano - 3 - oxo - 3 - (α,α,α trifluoro - o - tolyl)propionate **CAS:** 2 - methoxyethyl α - cyano - α - [4 - (1,1 - dimethylethyl)phenyl] - β - oxo - 2 - (trifluoromethyl) benzenepropanoate A - 1 2 - methoxyethyl (RS) - (4 - tert - butylphenyl)

cyanoacetate A - 2 (4 - tert - butylphenyl) acetonitrile A - 12 4 - tert - butylbenzoic acid

A - 18 (4 - tert - butylphenyl) cyanoacetic acid

B - 1 o - trifluoromethylbenzoic acid

B - 3 **CAS:** 2 - (trifluoromethyl) benzamide NC O OH

CF 3 O NH 2Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **66** of **73 Table B.1. Cyflum** **etofen and Metabolite Structures Comm**  **on Names / Code**  **Chemical Name (IUPAC) Chemical Structure**  AB - 1 (RS) - 2 - (4 - tert - butylphenyl) - 3 - oxo - 3 -

(α,α,α - tifluoro - o - tolyl) propiononitrile

AB - 6

AB - 7

AB - 11

AB - 15

AB - 1 Dimer

AU - 16 CF 3 O

NC O O

CF 3 O CN

F 3 C

O NC

O O CN NCO O O O CF 3 O

NC O O OHCyflumetofen Human Health Risk Assessment DP No. D398246

Page **67** of **73 Table B.1. Cyflum**  **etofen and Metabolite Structures Comm**  **on Names / Code**  **Chemical Name (IUPAC) Chemical Structure** 

AU - 17 CF 3 O CN NCO O OCyflumetofen Human Health Risk Assessment DP No. D398246

Page **68** of **73 B.2**  **Tabular Summary of Metabolites and Degradates Table B.2. Tabular Summary of Cyflum** **etofen Metabolites and Degradates Me**  **tabolite Nam e and**  **Structure Matrix**  **Percent TRR (PPM) A Label (Butylphenyl)**  **B Label (Benzoyl) Matrices**  **- Major**  **Residue (>10%TRR)**  **Matrices -** 

**Minor Residue (<10%TRR)**  **Matrices -** 

**Major Residue (>10%TRR)**  **Matrices -** 

**Minor Residue (<10%TRR)**  Cyflumetofen Apple 61.0% (Day 1) 78.2% (Day 7) 53.2% (Day 30) 58.4% (Day 1) 83.8% (Day 7) 64.9% (Day 30) Eggplant 95.0% (Day

1) 66.9 (Day 7) 62.2 (Day 14) 91.2% (Day 1) 70.7% (Day 7) 42.4% (Day 14) Mandarin 89.8% (Day

1) 82.6% (Day 7) 54.0% (Day 30) 88.4% (Day 1) 78.9% (Day 7) 43.9% (Day 30) Rotational Crops Ruminant Feces -

45.6% Fat (abdominal)

– 19.6% Fat (kidney)

– 21.0% Feces

– 7.4%

Rat 1 Feces

–

3.3%

– 63.5% Feces

– 2.5% - 65.7% B - 1 ( 2 - trifluoromethylbenzoic acid) Apple 1.2% (Day 7) 1.8% (Day 30) Eggplant 10.6% (Day 7) 14.8% (Day 14) 16.2% (Conjugate

– Day 14) 2.5% (Day 1)

Mandarin 11.2% (Day 30) 4.7% (Day 1) 6.6% (Day 7) Rotational Crops 0.2% 2 Ruminant Liver

– 32.0% Kidney

– 53.9% Muscle (leg)

– 50.5% Milk

– 4.5%Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **69** of **73 Table B.2. Tabular Summary of Cyflum** **etofen Metabolites and Degradates Me**  **tabolite Nam e and**  **Structure Matrix**  **Percent TRR (PPM) A Label (Butylphenyl)**  **B Label (Benzoyl) Matrices**  **- Major**  **Residue (>10%TRR)**  **Matrices -** 

**Minor Residue (<10%TRR)**  **Matrices -** 

**Major Residue (>10%TRR)**  **Matrices -** 

**Minor Residue (<10%TRR)**  Muscle (back)

– 46.5% Urine

– 47.0% Feces

– 63.9% Bile

– 22.4% Fat (abdominal)

– 40.2% Fat (kidney)

– 21.0% Rat 1 Feces

– 6.0% - 27.0% Urine

– 1.4% - 13.5% (mercapturic acid conjugate) Urine

– 4.3% - 20.2% (thiolactic acid conjugate) Urine

– 2.6% -

9.7%

AB - 6 Apple 1.3% (Day 7) 5.1% (Day 30) 5.3% (Day 30) Eggplant 8.8% (Day 7) 5.1% (Day 14) 3.0% (Day 7) 3.4% (Day 14) Mandarin 1.0% (Day 1) 2.1% (Day 7) 7.5% (Day 30) 1.0% (Day 1) 2.5% (Day 7) 8.6% (Day 30) Rotational Crops Ruminant Rat 1 Apple AB - 7 Apple 6.3% (Day 30) 5.4% (Day 7) 5.3% (Day 30) Eggplant 4.8% (Day 7) 5.1% (Day 14) 2.9% (Day 7) 3.6% (Day 14) Mandarin 0.7% (Day 1) 1.6% (Day 7) 7.1% (Day 30) 0.5% (Day 1) 2.0% (Day 7) 8.5% (Day 30) Rotational Crops Ruminant Rat 1Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **70** of **73 Table B.2. Tabular Summary of Cyflum**  **etofen Metabolites and Degradates Me**  **tabolite Nam e and**  **Structure Matrix**  **Percent TRR (PPM) A Label (Butylphenyl)**  **B Label (Benzoyl) Matrices**  **- Major**  **Residue (>10%TRR)**  **Matrices -** 

**Minor Residue (<10%TRR)**  **Matrices -** 

**Major Residue (>10%TRR)**  **Matrices -** 

**Minor Residue (<10%TRR)**  Notes:

- For plant metabolism studies, rinsate and extract values were summed prior to inclusion in this table.

- Due to rounding of some values with very low residues, accountabilities may be slightly different from those reported in earlier tables. 1 For the rat metabolism s tudy , a range is given from the low dose to the high dose groups 2 B - 1 was seen in the benzoyl labeled spring wheat grain only (30 day PBI) at <0.001ppmCyflumetofen Human Health Risk Assessment DP No. D398246

Page **71** of **73 Appendix C.**  **Physical/Chemical Properties Table C**  **. 1. Physicochemical Properties of the Technical**  **Grade Cyflumetofen Param**  **eter Value**  **Reference** Molecular weight (g/mole) 447.45 MRIDs 48542735 - 41 Phy sical state (21.5°C) White solid (powder) Melting point (°C) 77.9 pH NA Density (g/cm 3 ) (23°C) 1.229 Water solubility ( mg/L at 20°C) 0.0277 Solvent solubility (g/L at 20°C) n - Hexane 5.16 Toluene >500 Dichloromethane >500 Acetone >500 Methanol 98.7 Ethyl acetate >500 Vapor pressure ( mm Hg ) 4.43 x 10 - 8 at 25 oC Dissociation constant (pKa) The structural formula does not indicate dissociation in the relevant pH region (2 to12). The pKa was calculated to be - 4.19. Octanol/water partition coefficient - Lo g(KOW ) 4.3Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **72** of **73 Appendix D.**  **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 the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultur al Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database; the Agricultural Re - entry

Task Force (ARTF) database; and the Residential SOPs (Residential Handler) are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain studies that review may have included review b y the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be found at: http://www.epa.gov/pesticides/science/handler - exposure data.html and http://www.epa.go v/pesticides/science/post - app - exposure - data.html .Cyflumetofen Human Health Risk Assessment DP No. D398246

Page **73** of **73 Appendix**  **E . Residue**  **Summary Table Table**  **E .1. Summary of Residues from Field Trials with Cyflumetofen**  **Crop Matrix**  **Analyte Applic.**  **Rate (lb**  **ai/acre) PHI** 

**(days) n**  ***** **Residues (ppm )** 

**Min. †**  **Max. †**  **LAFT** ***** **HAFT** ***** **Median** ***** **Me an**  ***** **SD** ***** **Citrus** Orange fruit Cyflumetofen 0.355

– 0.366 7 12 0.010 0.159 0.010 0.116 0.073 0.070 0.035 Grapefruit fruit Cyflumetofen 0.357

– 0.364 7 6 <0.010 0.077 0.010 0.072 0.038 0.037 0.021 Lemon fruit Cyflumetofen 0.349 - 0.358 7 5 <0.010 0.141 0.010 0.135 0.021 0.054 0.054 **Pom e Fruits**  Apple fruit 1 Cyflumetofen 0.349 - 0.375 6 - 8 12 <0.010 0.248 0.015 0.163 0.080 0.092 0.048 Pear fruit Cyflumetofen 0.349 - 0.375 6 - 8 5 0.032 0.265 0.049 0.160 0.106 0.098 0.045 **Tree Nuts** Pecan Nutmeat Cyflumetofen 0.350 - 0.365 7 - 8 5 <0.010 <0.010 <0.010 <0.010 0.010 0.010 0 Almond Nutmeat Cyflumetofen 0.354 - 0.356 7 5 <0.010 <0.010 <0.010 <0.010 0.010 0.010 0 Almond Hulls Cyflumetofen 0.354 - 0.356 7 5 0.339 2.046 0.352 1.871 0.0534 0.830 0.610 **Strawberry** Straw berry Cyflumetofen 0.351 - 0.362 1 8 0.038 0.437 0.042 0.365 0.154 0.171 0.098 **Tom ato**  Tomato 2 Cyflumetofen 0.345 - 0.364 3 16 <0.010 0.161 0.013 0.148 0.038 0.053 0.038 Tomato 3 Cyflumetofen 0.345 - 0.364 3 16 <0.019 0.298 0.023 0.274 0.070 0.097 0.071 **Grape** Grape Cyflumetofen 0.350 - 0.361 14 12 0.014 0.439 0.023 0.423 0.156 0.175 0.103 † Values based on total number of samples. Includes samples from decline trials at proposed PHI. * Values based on per - trial averages. LAFT = Lowest Average Field Trial, HAFT = Highest Average Field Trial, SD = Standard Deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ are assumed to be at the LOQ. 1 App le fruit trials consisted of four treated samples (two replicates, one dilute and one concentrate) at each field trial site. Summary statistics are calculated by using the per - trial average of all four samples. 2 Uncorrected residues of cyflumetofen from tomato field trials. 3 Corrected residues of cyflumetofen for residue loss during freezer storage.