TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 1 of 36 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA**  **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM D**  **ATE :**  June 10 , 201 4 **SUBJECT: Trifloxystrobin**  **.** Aggregate Human Health Risk Assessment for the Proposed

New Use s on Chickpea, Dry Peas, and Lentils with Updated Residential Risk Estimates of All Existing Residential Uses (Lawns/Turf; Gardens and Trees) . **PC Code:** 129112 **DP Barcode:** D 413109 **Decision No.:**  478982 **Re gistration**  **No. :**  264 - 1055 **Petition No .**  **:** 3F8180 **Regulatory Action:** Section 3 Registration **Case No.:**  NA **Risk A**  **ss essment Type**  **:** Single Chemical/Aggregate **T XR No.:**  NA **CAS No.:** 141517 - 21 - 7 **MRID No .**  **:** NA **40 CFR:** § 180 . 555 **FROM:** Nancy Keller , Chemist, Risk Assessor

Meheret Negussie, Chemist My ron Ottley , Senior Toxico logist Risk Assessment Branch 3 Health Effects Division (7509P) **THROUGH:** Christine Olinger, Branch Chief

Risk Assessment Branch 3 He alth Effects Division (7509P) **TO:** Marcel Howard

Fungicides Branch (FB) Registration Division (7505P) The Registration Division ( RD ) requested that the Health Effects Division ( HED ) provide an evaluation of the proposed new agricultural use s of trifloxystrobin on chickpea, dry peas, and lentils . A summary

of the findings and an assessment of human health risk resulting from the proposed and registered uses of trifloxystrobin are p ro vided in this document . The toxicology

and hazard database review was conducted by My ron Ottley ; the residue chemistry review and dietary

risk assessment w ere conducted b y Meheret Negussie; the occupational/residential exposure and aggregate risk assessme nt s w ere conducted by Nancy Tsaur .TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 2 of 36 **Table of Contents 1.0**  **Executive Summary ................................**  **................................ ................................**  **.............. 4**  **2.0 HED Recommendations**  **................................ ................................**  **................................ .......**  **6 2.1**  **Data Deficiencies** ................................ ................................ ................................ ............ 6 **2.2 Tolerance Considerations**  ................................ ................................ .............................. 6 **2.2.1 Enforcement Analytical Method**  ................................ ................................ ................... 6 **2.2.3 Revisions to Petitioned**  **- For Tolerances**  ................................ ................................ ........ 7 **2.2.4 International Harmonization**  ................................ ................................ ........................ 7 **2.2.5 Label Recommendation**  ................................ ................................ ................................ . 8 **3. 0**  **Introduction ................................**  **................................ ................................**  **........................... 8**  **3.1 Chemical Identity**  ................................ ................................ ................................ ........... 8 **3.2 Physical/Chemical Characteristics**  ................................ ................................ ............... 9 **3.3 Pesticide Use Pattern**  ................................ ................................ ................................ ...... 9 **3.4 Anticipated Exposure Pathways**  ................................ ................................ ................... 9 **3.5 Consideration of Environmental Justice**  ................................ ................................ .... 10 **4.0 Hazard Characterization and Dose**  **- Response Assessment**  **................................ .............**  **10 4.1**  **Toxicology Studies Available for Analysis** ................................ ................................ . 10 **4.2 Absorption, Distribution, Metabolism and Excretion (ADME)**  .............................. 10 **4.3 Toxicological Effects**  ................................ ................................ ................................ .... 11 **4.4 Safety Factor for Infants and**  **Children (FQPA Safety Factor)** ............................... 12 **4.4.1 Completeness of the Toxicology Database**  ................................ .......................... 12 **4.4.2 Evidence of Neurotoxicity**  ................................ ................................ .................... 12 **4.4.3 Evidence**  **of Sensitivity/Susceptibility in the Developing or Young Animal** .... 12 **4.4.4 Residual Uncertainty in the Exposure Database**  ................................ ................ 13 **4.5 Toxicity Endpoint and Point of Departure Selection**  ................................ ................ 13 **4.5.1 Recommendation for Combining Routes of Exposure for Risk Assessment**  ... 13 **4.5.2 Cancer Classification and Risk Assessment Recommendation**  ........................ 13 **4.5.3 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk**  **Assessment** ................................ ................................ ................................ ........................... 14 **5.0 Dietary Exposure and Risk Assessment**  **................................ ................................**  **............ 15**  **5.1 Residues of Concern**  **Summary and Rationale** ................................ .......................... 15 **5.2 Food Residue Profile**  ................................ ................................ ................................ .... 16 **5.3 Water Residue Profile**  ................................ ................................ ................................ .. 16 **5. 4**  **Dietary Risk Assessment** ................................ ................................ .............................. 17 **5.4.1 Description of Residue Data Used in Dietary Assessment**  ................................ 17 **5.4.2 Acute Dietary Risk Assessment**  ................................ ................................ ........... 18 **5.4.3 Chronic Dietary Risk Assessment**  ................................ ................................ ....... 18 **5.4.4 Cancer Dietary Risk Assessment**  ................................ ................................ ......... 18 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  **................................ 19**  **6.1 Combined Residential Risk Estimates**  ................................ ................................ ........ 20 **6.2 Recommendations for Aggregate Assessment**  ................................ ........................... 20 **6.3 Residential Bystander Post**  **- Application Inhalation Exposure**  ................................ 20 **6.4 Spray Drift**  ................................ ................................ ................................ .................... 21 **7.0 Aggregate Exposure/Risk Characterization**  **................................ ................................**  **..... 21**  **7.1 Acute Aggregate Risk**  ................................ ................................ ................................ ... 21TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 3 of 36 **7.2 Short**  **- Term Aggregate Risk**  ................................ ................................ ........................ 21 **7.3 Intermediate**  **- Term Aggregate Risk**  ................................ ................................ ........... 22 **7.4 Chronic Aggregate Risk**  ................................ ................................ .............................. 22 **7.5 Cancer Aggregate Risk**  ................................ ................................ ................................ 22 **8.0 Cumulative Exposure/Risk Characterization**  **................................ ................................**  **.. 22**  **9.0 Occupational Exposure/Risk Characterization**  **................................ ...............................**  **23 9.1**  **Short -**  **and Intermediate**  **- Term Handler Risk**  ................................ ........................... 23 **9.2 Short**  **- and Intermediate**  **- Term Post**  **- Application Risk**  ................................ ............. 24 **9.2.1 Dermal Post**  **- Application Risk**  ................................ ................................ ............. 24 **9.2. 2**  **Restricted Entry Interval** ................................ ................................ ..................... 25 **9.2.3 Inhalation Post**  **- Application Risk**  ................................ ................................ ........ 25 **10.0 References**  **................................ ................................**  **................................ ............................**  **25 Appendix A.**  **Toxicology Profile and Executive Summaries ................................**  **................... 27**  **A.1 Toxicology Data Requirements**  ................................ ................................ ................... 27 **A.2 Toxicity Profile of Trifloxystrobin Technical**  ................................ ............................ 28 **Appendix B. Physical/Chemical Properties**  **................................ ................................**  **............. 32**  **Appendix C. Review of Human Research**  **................................ ................................**  **................ 32**  **Appendix D. International Residue Limit Status**  **................................ ................................**  **.... 33**  **Appendix E. Residential and Occupational Exposure/Risk Summary Table**  **...................... 34** TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 4 of 36 **1.0 Executive Summary**  Triflox ys trobin is a strobilurin - class broad - spectrum fungicide that controls foliar , soilborne , and seedling fungal diseases in various agricultural cro ps . Itworks by interrupting mitochondrial respiration in plant - pathogenic fungi, thus inhibiting spore g ermination and mycelial growth. In PP#3F8164, Baye r Crop S cience (Bayer) has submitted a label amendment to add chickpea, dry peas, and lentils to the la bel for USF 0728 325 SC Fungicide (EPA Reg. No. 264 - 1055 ), thus petitioning for the associated tolerance s . USF 0728 325 SC Fungicide, henceforth referred to as USF, is a suspension concentrate (SC ) formulation containing 13.7 % active ingredient (ai) by we ight (1.27 lb ai/gal) . Although USF is a mixed active ingredient (MAI) product also containing 16.0% prothioconazole ( 1.49 lb prothioconazole per gallon) , this document only addresses the human health effects of triflox ys trobin. The proposed use of proth ioconazole will be evaluated in a separate document. Since the last risk assessment, the 28 - day dermal study

in rats has been reclassified as showing no adverse s ys temic effects up to the limit dose of 1,000 mg/kg/day because the observed i ncreases in liv er and kidney weights were not accompanied with any histopathological correlates and not considered adverse. Thus, a dermal point of departure (POD) is no longer relevant for human health risk assessment. Proposed Use Profile USF may be applied as a foliar spray via groundboom, aircraft, chemigation, and handheld equipment. Human flagging is also allowed on the label. The proposed maximum single application rate for chickpea, dry peas, and lentils, is 12.0 fl oz product per acre (0.12 lb ai/acre, or 0.012 lb ai/gallon). Annual applications are limited to two per year and may be repeated on a 10 - to 14 - day

interval, up to a maximal seasonal application rate of 0.24 lb ai/acre/ye ar. Exposure Profile Exposure pathways include diet ary (food and drinking water) , non - occupational (residential) and occupational exposure sources. E xposures via diet and drinking water are expected for all durations; residential handler and post - application exposure s are onl y expected for the short - term duration ; and o ccupational handler and post - application exposures are expected for short - and intermediate - term durations. The proposed label requires occupational handlers to wear long pants, long sleeves, shoes, socks, and chemical - resistant gloves. Toxicity/Hazard The toxicology

database for trifloxy strobin is complete. The primary target organ of toxicity

is the liver in dogs, mice, and rats in subchronic and chronic studies. The effects of reduced body weight and food consumption were also found in the majority of the toxicity

studies. There are no susceptibility

concerns regarding developmental or reproductive toxicity , and no evidence of neurotoxicity

or immunotoxicity in the trifloxystrobin toxicology database. The requirement for a subchronic neurotoxicity study has been waived (TXR0056150 , D. Smegal, 01/05/2012 ) , and the requirement for a subchronic inhalation study h as also been waived (TXR0056957, U. Habiba, 0 5/22 /2014) . Trifloxystrobin exhibits low acute mammalian toxicity via oral (Toxici ty Category IV), dermal (Toxicity

Category IV), and inhalation (Toxicity Category IV) routes ofTRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 5 of 36 exposure. Triflox ys trobin is a mild eye and skin irritant, and is a strong dermal sensitizer. Triflox ys trobin is classified as “Not likel y to be Carcinogenic to Humans” b ased on the lack of evidence of carcinogenicity in mice and rats. Trifloxystrobin is not mutagenic in vivo and in vitro . The level of concern (LOC) for all routes and durations of exposure is 100. Dietary Exposure (Food and W ater) and Risk Estimates The acute and chronic dietary exposure and risk estimate s assumed tolerance level residues and 100% crop treated (%CT) for all commodities, and were not of concern . There were no appropriate toxicological effects attributable to a sing le exposure (dose) for the general population; therefore, a dose and endpoint were not identified. An acute endpoint was identified for females 13 - 49 years old. The acute dietary (food + drinking water) risk estimate for females 13 - 49 years old is 1.3% o f the a cute population adjusted dose (aPAD ) at the 95 th percentile . The chronic dietary

(food + drinking water) risk estimates represented 32 % of the chronic population adjusted dose (cPAD) for the general U.S. population and 78 % of the cPAD for all infants <1 ye ar old, the most highl y exposed population subgroup. Residential Exposure and Risk Estimates Although there are no residential exposures associated with the proposed uses, all existing residential exposures have been reassessed to reflect updates to HED’s 2012 Residential Standard Operating Procedures ( SOPs ) along with changes in dermal risk assessment hazard and changes in the policy for body weight assumptions. There are no registered products that would result in residential handler or post - application risk estimates of concern. Short - term residential handler inhalation margins of exposure ( MOEs ) range from 8,100 to 170,000,000 . Short - term post - application MOEs for all residential scenarios range from 730 to 330,000 . Aggregate Exposure Risk Estimates There is onl y potential for short - term aggregate exposure to trifloxystrobin via the diet ary and residential pathway s; residential exposures include inhalation (adults and children) and incidental oral (onl y children 1 to <2 years) . For adults, females age 13 - 49 years old , and children 1 to <2 ye ars old, the short - term aggregate risk estimate s are not of concern ; the MOEs are 300, 30 0, and 120, respectivel y. Occupational Handler Exposures and Risk Estimates The results of the occupational handler exposure and risk assessment indicate that short - and intermediate - term inhalation risk estimate s are not of concern without personal prote ctive equipment (PPE) . Short - and intermediate - term inhalation MOEs range from 6,600 to 150,000 . Note that o nly

engineering control (enclosed cockpit) data are available to assess risks to handlers operating aircrafts. Occupational Post-

A pplication Exposures and Risk Estimates An occupational post - application dermal exposure and risk assessment was not conducted because an adverse s ys temic dermal hazard was not identified for trifloxy strobin. B ased on the Agency's current practices, a quantitative n on - cancer occupational post - application inhalation exposure assessment was not performed for trifloxy strobin at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application i nhalation exposure assessment for trifloxystrobin. The 12 - hour restricted entryTRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 6 of 36 interval ( REI ) listed on the label is adequate to protect agricultural workers from post - applicati on exposures to trifloxystrobin. Dermal Sensitizer Worker Notification Label Recommendation According to 40 CFR 156.210 (b), any produc t that is a dermal sensitizer should bear the following statement on the label: “Notify workers of the application by warning them orally

and by posting warning signs at entrances to treated areas. ” 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 o w - Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ). **2.0 HED**  **Recommendations** HED has examined the toxicology and residue chemistry

database s for trifloxys trobin . Pending submission of a revised Section F (tolerances) , there are no issues that would preclude granting registration for the requested uses of trifloxy strobin on chickpea, dry peas, and lentils, or establishment of the recommended tolerance for c ombined residues of trifloxystro bin and its metabolite CGA - 321113 (see Table 2.2. 2 ). The specific tolerance recommendations are discussed in Section 2.2 . **2.1 Data Deficiencies**  Guideline 875.2100

– Turf Transferable Residues (TTR) Study At this time, EPA is requiring the 40 CFR TTR data because the estimated residential turf post application exposure , using default TTR values for trifloxystrobin, is not minimal in comparison to the level of concern (i.e. the calculated MOE is not greater than 10 times higher than the level of concern ; MOE = 730 compared to the LO C of 100 ). **2.2 Tolerance Considerations**  Tolerances are currentl y established for the combined residues of triflox ys trobin and the free form of its acid metabolite CGA

– 321113 in/on various crop an d livestock commodities ranging from 0.0 1 ppm to 38 ppm [40 CFR §180.555(a)]. **2.2.1 Enforcement Analytical Method**  An adequate gas chromatography method with nitrogen phosphorus detection (GC/NPD), Method AG - 659A, is available for enforcing tolerances for the combined residues of trifloxystrobin and CGA - 321113 in plant and livestock commodities. Samples from the submi tted crop field trials on chickpea and dry peas (seed , forage, and hay) were anal yz ed for residues of triflox ys trobin and CGA - 321113 using a high performance liquid chromatography method with tandem mass spectrometry detection (L C/MS/MS) . Residues of CGA - 321113 were converted to parent equivalents using a molecular weight conversion factor. The method wasTRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 7 of 36 adequatel y validated in conjunction with the analysis of crop field trial samples. The lowest level of method validation (LLMV) is equivalent to the li mit of quantitation (LOQ) which was 0.010 ppm for each anal yte in/on all matrices. **2.2.2 Recommended Tolerances**  A revised Section F needs to be submitted to reflect the recommended tolerances and the correct commodity

definitions as shown below in Table 2.2.2. **Table 2.2. 2**  **. Tolerance Summary for**  **Trifloxystrobin** Commodity Tolerance (ppm) Comments Correct Commodity Definition Proposed Recommended **40 CFR §180. 5**  **55 (a)(**  **1 )**  Pea, dry , seed 0.06 0.0 6 Pea, dry, hay 15 15 Pea, field, hay Pea, dry, vines 4 4 Pea, field, vines Chickpea, seed 0.06 Not Needed Covered by pea, dry, seed. Increase tolerance to harmonize with Canada . Chickpea, hay 15 Not Needed Chickpea, vines 4 Not Needed Lentil, seed 0.06 Not Needed Covered by pea, dry, seed. **2.2.3 Revisions to Petitioned**  **- For Tolerances**  Tolerances for chickpea hay and vines are not needed since both commodities are not significant livestock feed items. The proposed pea, dry , hay and pea, dry , vines commodity definitions need to be revised to pea, field, hay and pea, field, vines to refle ct the correct commodity definitions. The proposed tolerances on chickpea seed and lentil seed are not needed since pea , dry , seed includes these commodities. Based on the Organization for Economic Cooperation and Development (OECD) tolerance calculation spre adsheet, the proposed tolerance for chickpea, seed is 0.04 ppm. However, a tolerance of 0.06 ppm is recommended for harmonization purposes. **2.2. 4**  **International Harmonization** Codex MRL s are expressed in terms of trifloxy strobin for plants ; thus , har monization of MRL s is not possible. The Codex residue definition for l ivestock is the same as the US. The Canadian residue definition s for plants and livestock are the same as the US. There are no Codex MRL s established on the proposed crops. Canadian MRLs exist for dry chickpea, dry

field peas, and dry lentil s at 0.02 ppm. This petition is revi ewed as a workshare with Canada, and tolerances for the proposed crops are harmonized. The International Residue Limit Status is detailed in Appendix D .TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 8 of 36 **2.2.5 Label Recommendation**  According to 40 CFR 156.210 (b), any produc t that is a dermal sensitizer should bear the following statement on the label: “Notify workers of the application by warning them orally

and by posting warning signs at entrances to treated areas.” **3.0 In**  **troduction** Triflox ys trobin is a broad - spectrum preventative fungicide used for control of many plant diseases in various fruit, nut, vegetable, and field crops, including corn and soy bean. It is a strobilurin - class fungicide (also termed methoxyacrylates) that controls foliar, soilborne, and seedling fungal diseases . Itworks by interrupting mitochondrial respiration in plant - pathogenic fungi, thus inhibiting spore germination and myc elial growth. In PP#3F8164, Baye r has submitted a label amendment to add chickpea, dry peas, and lentils to the label for USF (EPA Reg. No. 264 - 1055), thus petitioning for the associated tolerances. USF is an SC formulation containing 13.7% ai b y weight (1.27 lb ai/gal) . **3.1 Chemical Identity**  **Table 3.1. Trifloxystrobin**  **Nom enclature**  Com pound

Common name T rifloxystrobin Com pany experimental name BO17211 or CGA - 279202 IUPAC name methyl (E) - methoxyimino - {(E) - α - [1 - (α,α,α, - trifluoro - m - tolyl) ethylideneaminooxy] - o - tolyl}acetate CAS name methyl (α E) - α - (methoxyimino) - 2 - [[[[(1 E) - 1 - [3 - (trifluoromethyl)phenyl] ethylidene]amino]oxy]methyl]benzeneacetate CAS registry number 141517 - 21 - 7 End - use product (EP) Trifloxystrobin / Prothioconazole USF 0728 325 SC Fungicide; 1.27 lb ai/gal trifloxystrobin and 1.49 lb ai/gal prothioconazole ; EPA Reg. No. 264 - 1055 Com pound (metabolite CGA - 321113)

Common name trifloxystrobin acid Com pany experimental name CGA - 321113 CAS name (α E) - α – (methoxyimino - [2 - [[[(E) - 1 - [3 - (trifluoromethyl)phenyl] ethylidene] amino]oxy]methyl]benzeneacetic acid CAS registry number 252913 - 85 - 2 O N C F 3 N O O

CH 3 O C H 3 CH 3

O N C F 3 N O H O O C H 3 CH 3TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 9 of 36 **3.2 Physical/Chemical Characteristics**  Triflox ys trobin has a low vapor pressure ( 2.55 ×10 - 7 mm Hg at 25 °C); therefore, inhalation due to chemical vaporization is unlikely . Triflox ys trobin has a log octanol/water partition coefficient (log P ow) of 4.5 and is considered soluble in fat . Additionally , trifloxystrobin has a molecular weight of 408.4 g/mol ; therefore, the potential to cross biological barriers, such as the skin, is somewhat limited. More detailed physicochemical properties of trifloxy strobin are summarized in Appendix B. **3.3 Pesticide Use Pattern**  Baye r has submitted an amended labe l for USF (EPA Reg. No. 264 - 1055) . The newl y proposed use pattern is presented i n Table 3.3 . **Table 3.3**  **. Summ ary of**  **Proposed Use**  **Directions for USF 0728 325 SC Fungicide**  **(EPA Reg. No. 264**  **- 1055**  **)** a Application Timing, T ype, and Equipment Single

Maximum Application Rate Maximum

Number of Applications per Year Maximum

Annual Application Rate PHI b Use Directions and Limitations

days **Chickpea, Dry Peas, and Lentil s**  c Broadcast Foliar : ground, aerial, chemigation, or handheld 12 fl oz

product /A 0.1 2 lb ai/A 0.012 lb ai/gal d 2 24 fl oz product /A 0.24 lb ai/A 7 for

Forage 30 for Seed Begin fungicide applications preventatively and continue as needed on a 10 - to 14 - day interval. Use the shorter interval when conditions are favorable for severe disease pressure. a SC = suspension concentrate. b PHI = pre - harvest interval. c EPA Reg. No. 264 - 1055 is a mixed active ingredient (MAI) also containing 16% prothioconazole by weight (1.49 lb prothioconazole per gallon). d The application rate is based on use direction of “a minimum of 10 gallons per acre” recommended for ground equipment . **3.4 Anticipated Exposure Pathways**  Humans may be exposed to trifloxystrobin via food and drinking water because trifloxy strobin may be applied directly

to growing crops , and application may result in trifloxystrobin reaching surface and ground sources o f drinking water. In residential settings, adults and children may be exposed during handler and post - application activities . In occupational setting s , applicators may be exposed while handling the pesticide prior to application, as well as during application. There is also a potential for post - application exposure for workers re - entering treated fields. Several risk assessments have been previousl y prepared for the existing uses of trifloxystrobin . This risk assessment considers all of the aforementioned exposure pathway s based on the proposed new use of trifloxystrobin , but also considers the existing uses as well, particularl y for th e dietary and residential exposure assessment.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 10 of 36 **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 Population s," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well - estab lished 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 co nsumption patterns are compiled by the USDA under the National Health and Nutrition Examination Survey /What We Eat in America (NHANES/WWEIA), and are used in pesticide risk assessments for all registered foo d uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age and ethnic group . Additionally, OPP is able to assess dietary

exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non - dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post - application are evaluated. Further considerations are currentl y in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patter ns among specific subgroups. **4.0 Hazard Characterization and Dose**  **- Response Assessment**  Triflox ys trobin controls fungal diseases by interrupting mitochondrial respiration in plant pathogenic fungi, thus inhibiting spore germination and mycelial growth. Th ere are no mammalian molecular data to specificall y show this mode of action in the test animals. **4.1 Toxicology Studies Available for Analysis**  The toxicology

database of trifloxystrobin provides sufficient information for selecting toxicity endpoints an d points of departure for risk assessment. The available toxicology studies include (1) subchronic oral toxicity studies in rats, mice, and dogs; (2) a 28 - day dermal toxicity

study in rats; (3) developmental toxicity studies in rats and rabbits; (4) a 2 - g eneration reproduction study in rats; (5) chronic toxicity studies in rats and dogs; (6) carcinogenicity studies in rats and mice; (7) a battery

of the required genotoxicity studies; (8) immunotoxicity study in rats; and (9) metabolism studies in rats. At this time, n either a subchronic neurotoxicity study ( T XR0056150, D. Smegal, 01/05/2012 ) nor a subchronic inhalation toxicity study (TXR0056957 , U. Habiba, 0 5/22 /2014 ) is required . **4.2 Absorption, Distribution, Metabolism and Excretion (ADME)**  With low dose oral administration of trifloxystrobin to rats, approximately 56% and 65% of the administered dose was absorbed, with 41% and 47% in the bile of male and female rats, respectivel y. With high dose administration, the absorption was 41% and 27 %, with 35% andTRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 11 of 36 19% in the bile of male and female rats, respectively . The percentage of absorption was similar with either single dose administration or repeated dosing in both sexes. The time to peak blood concentration was 12 - 24 hours. The blood, liv er, and kidney s were found to have the highest residues. Most of the examined tissues had somewhat higher residue levels in the females than in the males (b y up to two - fold). A majority of the administered dose was eliminated in the feces. Less than 0.1 % of the administered dose was found in the expired air. The total tissue and carcass contained 0.3 - 0.5% of the administered dose indicating essentially no tissue accumulation. The parent compound was extensively metabolized to approximately 35 metabolit es. Dermal Absorption D ermal absorption studies are not available for trifloxystrobin. In the past (TXR 0050612, S. Dapson, 04/01/2002 ), the L OAEL of 337 mg/kg/day observed in the oral 28 - day range - finding feeding study in rats (MRID 44496643) was comp ared to the LOAEL of 1000 mg/kg/day observed in the 28 - day

dermal toxicity

study in rats (MRID 44496704) to yield a calculated dermal absorption factor (DAF) of approximately 33 %. Both of the LOAEL s were based on increases in liver weight. However, when the dermal subchronic study was reevaluated by current criteria, the increased liver weights were not considered to be adverse because they were minimal and not confirmed by histopathological correlates. Therefore, the NOAEL for this dermal subchronic study

was set at 1000 mg/kg/day and the LOAEL was not established, which invalidated the comparison with the 28 - day oral range - finding study

and the calculated dermal absorption factor. Dermal penetration study data for other strobilurins such as azox ys trob in, fluoxastrobin and py raclostrobin suggest that dermal absorption of trifloxystrobin is expected to be less than 20%. As mentioned above, the 28 - day dermal toxicity

study showed no adverse dermal or s ys temic effects at dose levels (up to the limit dose of 1000 mg/kg bw/day) where toxicity was seen in comparable oral studies, supporting the expectation that dermal absorption is low. However, in the absence of actual data on triflox ys trobin, a DAF of 100% is used for risk assessment. **4.3 Toxicological**  **Effects** With repeated dos ing , the liver is consistently the target organ for trifloxy strobin . Liver effects characterized b y an increase in liver weights and an increase in incidences of hepatocellular hy pertrophy and/or hepatocellular necrosis were seen in rats, mice, and dogs . The effects of reduced body weights and food consumption were also found in the majority of the toxicity studies. Intestinal disturbances, as indicated by diarrhea and vomiting, were seen in dogs and rats at higher dos e levels relative to those which caused liver and body weight effects. This finding was consistent with those produced b y other members of the strobilurin class. In the rabbit developmental toxicity study , an increase in the incidence of fused sternabrae was seen at a dose 10 times higher than the maternal lowest observed adverse effect level ( LOAEL ) . In the rat reproduction study , both parents and offspring showed decreases in body weight during lactation. The rat and rabbit developmental and the rat r eproduction toxicity data do not demonstrate an increase in susceptibility in the fetus or other offspring.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 12 of 36 Triflox ys trobin was determined not to be carcinogenic in mice or rats following long - term dietary administration. However, it is positive for mutagenicity in Chinese Hamster V79 cells at cy totoxic dose levels while testing negative in the remaining mutagenicity studie s. Triflox ys trobin was not neurotoxic in the acute neurotoxicity study , nor in any

of the repeated dose studies in the available data . The requirement for a subchronic neurotoxicity study was waived (TXR0056150, D. Smegal, 01/05/2014) because there is no evidence of neurotoxicity in the existing trifloxystrobin database or that of other strobilurin pesticides, and because endpoints and Points of Departure (PODs) used for risk assessment are likel y to be protective of neurotoxicity

concerns. Triflox ys trobin exhibits low acute toxicity following single oral, dermal and inhalation exposures (Toxicity Category III or IV) . It is a strong de rmal sensitizer and a mild dermal and eye irritant. **4.4 Safety Factor for Infants and Children (FQPA Safety Factor)**  The triflox ys trobin risk assessment team evaluated the quality of the toxicity

and exposure data and recommended that the FQPA SF be reduc ed to 1 X because 1) the trifloxystrobin database is considered completed for risk assessment; 2) there is no indication of neurotoxicity following trifloxystrobin exposure in single or repeated dose studies; 3) there is no increased quantitative or qualitative susceptibility

to trifloxystrobin in developmental (rats and rabbits) and reproduction (rats) studies , and 4) there are no uncertainties in the exposure database. **4.4.1 Completeness of the Toxicology Database**  The toxicity

database for trifloxystrobin is adequate for selecting toxicity endpoints and points of departure for risk assessment. The selected toxicity endpoints and points of departure for risk assessment are based on the mo st sensitive and relevant dat a. **4.4.2 Evidence of Neurotoxicity**  Adverse effects were not seen up to the limit dose in an acute neurotoxicity study (the requirement for a subchronic neurotoxicity study has been waived as detailed in Section 4.3). There i s no evidence of neurotoxicity in subchronic and chronic toxicity studies (rats, dogs, mice), in developmental toxicity studies (rats, rabbits), or in a reproductive toxicity study (rats). **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  There is no indication of increased quantitative or qualitative susceptibility to trifloxystrobin in rats or rabbits . In the prenatal developmental study in rats, there was no developmental toxicity at and up to the limit dose. In the prenatal developmental study in ra bbits, developmental toxicity was seen at a dose that was higher than the dose caus ing maternal toxicity . In the multigeneration study , offspring and parental LOAEL s are at the same dose level.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 13 of 36 **4.4.4 Residual Uncertainty in the Exposure Database**  The exposure databases are complete or are estimated based on data that reasonably account for potential exposures. The exposure assessments will not underestimate the potential dietary (food and drinking water) or non - dietary exposures for infants and children from the use of trifloxystrobin. The chronic dietary food exposure assessment was conservatively based on 100 % crop treated (CT) assumptions and conservative ground water drinking water modeling estimates. The dietary

drinking water assessment utilizes water concentration values generated by models and associated modeling parameters which are designed to provide conservative, health protective, high - end estimates of water concentrations, and are not likely to be exceeded. In addition, the residential post - application assessment is based upon the residential SOPs employing surrogate study data. These data are re liable and are not expected to underestimate risk to adults or children. The R esidential SOPs are based upon reasonable “worst - case” assumptions and are not expected to underestimate risk. **4.5 Toxicity Endpoint and Point of Departure Selection**  As discu ssed in Section 4.2, in the absence of dermal absorption data on trifloxystrobin a dermal absorption factor of 100% is assumed for this risk assessment. Since no dermal or s ys temic toxicity was observed in the available 28 - day dermal subchronic study up to 1000 mg/kg/day (the limit dose), a dermal hazard has not been identified for risk assessment for the general population, including children. The 28 - day

dermal subchronic study did not assess the potential for developmental toxicity after dermal exposure. However, there is no concern for fused sternebrae noted in rabbit fetuses at 250 mg/kg/day

in a developmental toxicity study , because these effects occurred onl y at maternall y toxic dose levels (maternal LOAEL = 50 mg/kg/day) and there are no susceptibil ity issues. Therefore, a dermal hazard has not been identified for risk assessment for women of child - bearing age. **4.5. 1**  **Recommendation for Combining Routes of Exposure for Risk Assessment** When common toxicity

endpoints are selected for the dermal, oral , and inhalation routes of e xposure they

may be combined together. For short - , intermediate - , and long - term aggregate risk assessments, oral and inhalation routes can be combined due to the selection of a common toxicological endpoint of concern (the oral equivalent was used for inhalation expo sure). However, the dermal route of exposure does not need to be combined with another route of exposure or included in the aggregate risk assessment because there is no identified adverse sy stemic dermal hazard. **4.5.2 Cancer Classification and Risk Assessment Recommendation**  B ased on the absence of significant tumor increases in two adequate rodent carcinogenicity studies , trifloxystrobin is classified as: “Not likel y to be Carcinogenic to Humans . ” Cancer risk as sessments do not need to be conducted.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 14 of 36 **4.5. 3**  **Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment**  The summary

of toxicological doses and endpoints for human health risk assessment are presented below in Table 4.5. 3 . **Table 4.**  **5 .3**  **. Summary of Toxicological Doses and Endpoints for**  **Trifloxystrobin for Use in Dietary**  **, Non**  ****

**Occupational , and Occupational**  **Hum an Health Risk Assessments**  a Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Ac ute Dietary ( Females 13 - 49 Only) NOAEL =

250 mg/kg/day UF A = 10 X

UF H = 10 X FQPA SF = 1 X Ac ute RfD =

2 .5 mg/kg/day aPAD = 2.5 mg/kg/day Developmental - Rabbit

LOAEL = 500 mg/kg/day based on increased fetal skeletal anomalies. Ac ute Dietary ( General Population, including Infants and Children) There were no appropriate toxicological effects attributable to a single exposure (dose) observed

in oral toxicity studies including maternal effects in developmental studies in rats and rabbits. Therefore, a dose and endpoint were not identified for this risk assessment .

Chronic Dietary (All Populations) NOAEL =

3.8 mg/kg/day UF A = 10 X

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

= 0.038 mg/kg/day cPAD = 0.038 mg/kg/day Two - Generation Reproduction

– Rat

Maternal LOAEL = 55.3 mg/kg/day based on decreased body weight and weight gain, decreased food consumption, liver, kidney and spleen effects. Offspring LOAEL = 55.3 mg/kg/day based on decreased pup body weights during lactation. Incidental Oral Short - Term (1 - 30 days) NOAEL =

3.8 mg/kg/day UF A = 10 X

UF H = 10 X FQPA SF = 1 X Residential

LOC for MOE = 100 Two - Generation Reproduction

– Rat

Maternal LOAEL = 55.3 mg/kg/day based on decreased body weight and weight gain, decreased food consumption, liver, kidney and spleen effects. Offspring LOAEL = 55.3 mg/kg/day based on decreased pup body weights during lactation. Dermal All Durations A toxicity endpoint was not identified . Adverse s ystemic toxicity was not seen in 28 - day dermal toxicity in rats at the limit dose (1000 mg/kg/day) . T here are no concerns for developmental or reproductive toxicity (including potential susceptibility issues) or neurotoxicityTRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 15 of 36 **Table 4.**  **5 .3**  **. Summary of Toxicological Doses and Endpoints for**  **Trifloxystrobin for Use in Dietary**  **, Non**  ****

**Occupational , and Occupational**  **Hum an Health Risk Assessments**  a Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Inhalation All Durations NOAEL =

3.8 mg/kg/day UF A = 10 X

UF H = 10 X FQPA SF = 1 X Residential

LOC for MOE = 100 Occupational LOC for MOE = 100 Two - Generation Reproduction

– Rat

Maternal LOAEL = 55.3 mg/kg/day based on decreased body weight and weight gain, decreased food consumption, liver, kidney and spleen effects. Offspring LOAEL = 55.3 mg/kg/day based on decreased pup body weights during lactation. Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant

tumor increases in two adequate rodent carcinogenicity studies. a 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 l ow er environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensi tivity among members of the human population (intraspecies). FQPA SF = Food Quality Protection Act Safety Factor. RfD = reference dose (a = acute, c = chronic). PAD = population adjusted dose (a = acute, c = chronic). MOE = margin of expos ure. LOC = l evel of concern. b Toxicity by the inhalation route is assumed to be equivalent to the oral route. A subchronic inhalation toxicity study is not required for trifloxystrobin at this time ( Hazard and Science Policy Council memo , U. Habiba, TXR005695 7 , 05/22/2014 ). **5.0 Dietary Exposure and Risk Assessment**  **5. 1**  **Residues of Concern Summary and Rationale** The qualitative nature of the residue in plants and livestock commodities is adequatel y understood based on acceptable metabolism studies reflecting direct application of trifloxystrobin to apples, cucumbers, peanuts, sugar beets, and wheat, and metabolism studies on goats and laying hens. HED has concluded that both trifloxystrobin and CGA - 321113 are of concern for both regulatory and risk assessment purposes for both plant and livestock commodities. HED also determined that for livestock commodities, the metabolite L 7a (taurine conjugate of triflox ys trobin) in liver and meat b yproducts should be included in the risk assessment. The residues of concern for dietary risk assessment and the tolerance expression are summarized in Table 5.1. **Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance** 

**Expression** Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Trifloxystrobin and CGA - 321113

Rotational CropTRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 16 of 36 **Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance** 

**Expression** Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Livestock Ruminant Trifloxystrobin and CGA 321113; plus Metabolite L7a in liver and meat byproducts Trifloxystrobin and CGA - 321113 Poultry Trifloxystrobin and CGA - 321113 Drinking Water Trifloxystrobin and CGA - 321113 Not Applicable **5.2 Food Residue Profile**  Adequate crop field trial data have been submitted to support the requested use s on dry peas, chickpeas, and lentils (D P 413711, M. Negussie, 05/18/2014) . The trials reflect the proposed use pattern and the number and locations of the trials are acceptable based on the ChemSAC minutes of 20 March, 2013. Adequate storage stability data are available to support the storage durations an d conditions of samples of dry pea commodities, chickpeas, and lentils from the submi tted crop field trial studies. There are no processed commodities associated with the proposed new uses; therefore, no new processing studies were submitted or reviewed f or this petition. The propos ed use on dry

peas does not result in an increased dietary burden for livestock. The existing tolerances on live stock commodities are adequate. Adequate confined and field rotational crop data are available. HED previously c oncluded that the residues of concern in rotated crops are triflox ys trobin and CGA - 321113. The available data support a 30 - day plant back interval (PBI) for all crops not listed on the label for direct use. **5. 3**  **Water Residue Profile** The environmental fate database is adequate to characterize drinking water exposure for the parent compound. Limited fate data are available for the degradates of trifloxystrobin. The data indicate that triflox ys trobin is non - persistent in soil or water with rapid degradation in aerobic soil. In contrast, the major degradate of concern, CGA - 321113, is persistent in both soil and aquatic environments. Furthermore, CGA - 321113 is expected to be more mobile than the parent compound. Model simulations show that ground water estimated drinking water concentrations (EDWCs) for total toxic residues of triflox ys trobin are greater than surface water EDWCs. In addition to evaluating the EDWCs from the proposed use, EDWCs were reevalu ated for all existing uses with the Pesticide Ro ot Zone Model for Ground Water ( PRZM - GW ) , 1 which models continued use of triflox ys tro bin over many years (DP 413801 , M. Biscoe , 0 1 /28 /201 4 ) . The most conservative EDWC s were based on an existing registered turf use which has the highe st annual use rate (1.33 lb ai/acre) of all the proposed and existing uses of trifloxystrobin . Water residues were incorporated directl y into the acute and chronic dietary assessments in the Dietary Exposure Evaluation Model

– Food Commodity Intake Database ( DEEM - FCID ) food categories of “water, direct, all sources” and “water, indirect, all sources.” Maximum s urface

1 PRZM - GW was approved for standard use in drinking water assessments as a Tier I/II exposure tool (12/2012).TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 17 of 36 water EDWCs using Pesticide Root Zone Model linked with the Exposure Analy sis Modeling Sy stem ( PRZM/EXAMS ) and ground water EDWCs using the PRZM - GW model are r eported in Table 5. 3. The highest estimated peak (acute) concentration of total toxic residues in ground water is 427 μg/L, and the highest estimated (chronic) concentration in ground water is 365 μg/L. **Table 5.3 .**  **Maximum Estim ated Drinking Water**  **Concentrations (EDWCs) of Total Toxic Residues of**

**Trifloxystrobin** a **Surface Water Model** b ( μg/L ) Crop Scenario Peak Exposure Annual Mean Exposure Average Annual Exposure Peak 1 - in - 10 Year Chronic

1 - in - 10 Year 30 - year Annual Average Pennsylvania Turf scenario Aerial Application 29 ppb 23 ppb 19 ppb **Ground Water Model** c ( μg/L ) Crop Scenario Peak Post - Breakthrough Average Wisconsin Corn scenario Ground Application **427 ppb 365 ppb**  a EDWC modeling includes total toxic residue (TTR) of trifloxystrobin and its major degradate, CGA - 32113 , based on 1.33 lb ai/A for turf (Trifloxystrobin Flowable Fungicide, EPA Reg. No. 264 - 989 ) . The highest estimated drinking water concentration are bolded . b Highest EDWCs generated using PRZM/EXAMS model . PCA of 0.91 adjusted for aerial application . c Highest EDWCs generated u sing PRZM - GW 30 - year simulation mo del. **5. 4**  **Dietary Risk Assessment 5.4**  **.1 Description of Residue Data Used in Dietary Assessment**  A cute and chronic dietary (food and drinking water) exposure and risk assessment s were conducted using the DEEM - FCID Version 3.16. This model uses 2003 - 2008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutri tion Examination Survey, What We Eat in America (NHANES/WWEIA). An acute dietary

assessment was conducted assuming tolerance level residues and 100% crop treated (%CT) for all commodities . DEEM version 7.81 default processing factors were assumed except for where tolerances were established for processed commodities . For the dietary assessment, a value of 0.20 ppm fo r the metabolite L 7a was added to the tolerance level for liver ; therefore, meat by products and liver of cattle, goats, horses, and sheep were assessed in the dietary

assessments at 0.3 ppm. The maximum theoretical dietary burden was lower for pork, except for pork liver, than for these other commodities. Therefore, p ork was included in the DEEM at the established tolerance level of 0.05 ppm; pork, liv er was included at 0.16 ppm (DP 267787, L . Cheng, 0 1/17/2002). A separate tolerance was set for grape, raisin; therefore, the processing factor for this commodity was set at 1. For all other processed commodities, DEEM 7.81 default processing factors were used. Residue reduction data on strawberries from a single trial were previousl y provided which demonstrated that residues of triflox ystrobin and CGA 321113 declined in/on strawberries after washing and cooking . The default proc essing factor of 1 was retained. The acute drinking w ater estimate of 427 μg/L was directl y incorporated into the acute assessment.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 18 of 36 A chronic dietary (food and drinking water) exposure and risk assessment was conducted assuming 100% crop treated, tolerance level residues and anticipated residues (ARs) for grapes, apples, oranges, and pears . For the dietary assessment, a value of 0.20 ppm fo r the metabolite L7a was added to the tolerance level f or liver . DEEM version 7.81 default processing factors were assumed except for where tolerances were established for processed commodities . The chronic drinking water estimate of 365 μg/L was directly incorporated into the chronic assessment. **5. 4**  **. 2**  **Acute Dietary Risk Assessment** There were no appropriate toxicological effects attributable to a single exposure (dose) for the general population; therefore, a dose and endpoint were not identified. An acute endpoint was identified for females 13 - 49 year s old. Therefore, an acute dietary assessment was conducted for this population subgroup. The results of the acute dietary (food and drinking water) anal ys is indicate that exposure and risk does not exceed HED’s LOC for females 13 - 49 y ears old. The diet ary exposure for food and water at the 95 th percentile of exposure distribution is estimated at 1 . 3 % of the aPAD for the females 13 - 49 years old. **5. 4**  **. 3**  **Chronic Dietary Risk Assessment**  The results of the chronic dietary (food and drinking water) anal ys is indicate that exposure and risk estimates are not of concern to HED for the U.S. population and all population subgroups. The dietary

exposure for food and water is estimated at 32 % of the cPAD for the general U.S. population and 78% for all infants (<1 year old) , the most highly exposed population subgroup . Drinking water residues make up the majority of the dietary exposure contribution in the chronic risk estimates. The results of the chronic dietary exposure analy s e s are reported in Table 5.4 .5 . **5.4 .4**  **Cancer Dietary Risk Assessment** Triflox ys trobin is classified as “not likel y to be carcinogenic to humans;” therefore, cancer risk was no t assessed . **5 .**  **4 .**  **5 Summary Table**  **Table 5. 4**  **.5 . Summary of Dietary Exposure and Risk for**  **Trifloxystrobin (**  **c PAD =**  **0. 038**  **mg /k** **g/day)** a Population Subgroup Ac ute Dietary Exposure Estimates (Food and Drinking Water) Chronic Dietary Exposure Estimates (Food and Drinking Water) mg/kg/day % aPAD mg/kg/day % cPAD General U.S. Population N/A b 0.012139 32 **All Infants (< 1 year old)**  **0.029751 78**  Children 1 - 2 years old 0.026545 70 Children 3 - 5 years old 0.020721 54 Children 6 - 12 years old 0.012755 34 Youth 13 - 19 years old 0.008879 23TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 19 of 36 **Table 5. 4**  **.5 . Summary of Dietary Exposure and Risk for**  **Trifloxystrobin (**  **c PAD =**  **0. 038**  **mg /k** **g/day)** a Population Subgroup Ac ute Dietary Exposure Estimates (Food and Drinking Water) Chronic Dietary Exposure Estimates (Food and Drinking Water) mg/kg/day % aPAD mg/kg/day % cPAD Adults 20 - 49 years old 0.011282 30 Adults 50 - 99 years old 0.010870 29 Females 13 - 49 years old **0.032259 1.3**  0.010893 29 a The population subgroup s with the greatest exposure are bolded . b N/A = Not Applicable; an acute dietary endpoint was not identified for these population subgroups. **6.0 Residential (Non**  **- Occupational)**  **Exposure/Risk Characterization** There are no proposed residential uses at this time; however, there are existing residential turf and ornamental use s that have been reassessed in this document to reflect updates to HED’s 2012 Residential SOPs along with ch anges in dermal risk assessment hazard and changes in the policy for body weight assumptions (DP413713, N. Tsaur, 05/15/2014). The revision of residential exposures does impact the human health aggregate risk assessment for triflox ys trobin. There are various formulation s registered for residential use on turfgrass and ornamentals, which include water dispersible granules (WG), water soluble packaging (WSP), granules (G), and liquid (L). The currentl y registered end - use products (EPs) available for reside ntial use include: 1. CompassTM Fungicide (EPA Reg. No. 432 - 1371 ) , a WG formulation (Restricted Use), 2. ArmadaTM 50 WP (EPA Reg. No. 432 - 1412 ) , a WSP formulation, 3. CompassTM G Fungicide (EPA Reg. No. 432 - 1432 ) , a G formulation, 4. TartanTM Fungicide (EPA Reg. No. 432 - 1446 ) , an Lformulation, 5. Chipco® 26019T Fungicide (EPA Reg. No. 432 - 1505 ) , an L formulation, and 6. ArmadaTM 50 WDG (EPA Reg. No. 432 - 1513 ) , a WG formulation. Baye r Environmental Science (Bayer) is the registrant of all six products. Two of the labels ( Co mpassTM Fungicide and CompassTM G Fungicide ) are restricted to professional handlers only . However, the use of both products on residential and recreational turf may still result in residential post - application exposure. Furthermore, there are no granular or liquid formulation uses on ornamentals (only WSP and WG are registered for use on residential ornamentals). The reassessment of all registered residential products do not result in any residential handler or post - application risk estimates of concern. Residential h andler exposure is expected to be short term only . Intermediate - term exposures are not likely because of the intermittent nature of applications by

homeowners. The quantitative exposure/risk assessment developed for residential handlers is based on various exposure scenarios that involve mixing/loading/appl yi ng various formulations with manually pressurized handguns, hose - end sprayers, backpack sprayers, and sprinkler cans. Short - term residential handler inhalation MOEs range from 8,100 to 170,000,000 . Short - term incidental - oral post - application MOEs for all residential scenarios range from 730 to 330,000 . Dermal handler risk assessments were not conducted because an adverse s ys temic dermal hazard was not identified for trifloxy strobin. Incidental oral granule ingestion is not applicable because there is no endpoint identified for the acute dietary duration. Appendix E summarizes all assessed residential exposure and risk estimates.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 20 of 36 **6.1 Combined Residential Risk Estimates**  HED combines risk estimates resulting from separate post - application exposure scenarios when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population and when the toxicological effects are similar. Howe ver, the incidental oral scenarios (i.e., hand - to - mouth, object - to - mouth, and soil ingestion) should be considered inter - related and it is likely that they occur interspersed amongst each other across time. Combining all three of these scenarios would be overl y- conservative because of the conservative nature of each individual assessment. Therefore , the hand - to - mouth post application exposure scenario for children 1 to < 2 years old is considered a protective estimate of children’s exposure to pesticides used on turf. **6.2 Recommendations for Aggregate Assessment**  For the purpose of the triflox ys trobin human health risk assessment, a summary of the worst - case residential exposure estimates are provided in Table 6.2. All short - term residential handler and post - application exposure estimates resulted in MOEs greater than 100, and were not of concern. **Table 6. 2**  **. Scenarios Recommended for Aggregate Risk Assessment of Trifloxystrobin (Short**  **- Term** **)** Scenario Dose a MOE mg/kg/day LOC = 100 **Adults** Handler : Inhalation Exposure ( Manually - Pressurized Handwand or Backpack Sprayer Application of Water Dispersible Granule Form ulation to Residential Turf) 0.00047 8,1 00 **Children 1 to < 2 years old**  Post - Application : Hand - to - Mouth Exposure (Liquid Application to Residential Lawn) 0.0052 730 a Handler scenario represents high - end handler exposure (DP413713, N. Tsaur, 05/15/2014) . b Post - application MOE represents high - end incidental oral exposure (DP413713, N. Tsaur, 05/15/2014) . c MOE = NOAEL ÷ Average Daily Dose . Inhalation NOAEL = 3.8 mg/kg/day. Incidental Oral NOAEL = 3.8 mg/kg/day. **6. 3**  **Residential Bystander Post -** **A pplication Inhalation Exposure**  Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for trifloxy strobin at this time primarily because of the low acute inhalation t oxicity

(Toxicity Category IV), low vapor pressure (3.4× 10 - 6 Pa, or 2.55×10 - 7 mm Hg at 25oC) and the low proposed use rate (0. 12 lb ai/A). However, volatilization of pesticides may be a source of post - application inhalation exposure to individuals nearb y pesticide applications. The Agency

sought expert advice and input on issues related to volatiliz ation 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 - application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the

2 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlTRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 21 of 36 Agency may revisit the need for a quantitative post - application inh alation exposure assessment for triflox ys trobin . **6. 4**  **Spray Drift** Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularl y the ca se with aerial application, but to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g. groundboom and airblast) employed for trifloxy strobin The Agency has been working with the Spray Drift Task Force (a task force compose d of various registrants which was developed as a result of a Data Call - In issued by EPA), EPA Regional Offices , and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency ’s Spray Drift website for more information). 3 The Agency is also taking means to qualitatively and qualitatively

address spray

drift as a potential source of exposure in risk assessments for pesticides through existing programs such as Ag Drift and chemical spe cific properties of pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide wi ll be considered concurrently . **7.0 Aggregate Exposur**  **e/Risk Characterization** In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant source s 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 triflox ys trobin, potential exposures from food, drinking water, and residential scenarios were aggregated. **7.1 Acute Aggregate Risk**  There were no appropriate toxicological effects attributable to a single exposure (dose) for the general population; theref ore, a dose and endpoint were not identified for this risk assessment. The aPAD for females 13 - 49 years old was 2.5 mg/kg/day . To assess the aggregate acute risk, EDWCs were incorporated directl y into the dietary exposure anal ys is. Refer to S ection 5.4. 1 for this risk estimate. **7.2 Short**  **- Term Aggregate Risk**  There is potential short - term exposure to trifloxystrobin via dietary (which is considered background exposure) and residential (which is considered primary) pathway s. For adults, these pathway s lead t o exposure via oral (background) as well as dermal and inhalation (primary) routes. For children, these pathway s lead to exposure via the oral (background) as well as incidental oral and dermal (primary) routes. For trifloxystrobin, dermal routes of expo sure are not combined into an aggregate risk estimate because there are no adverse sy stem ic hazards via 3 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmTRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 22 of 36 the dermal route. Thus, only adult inhalation and children incidental oral aggregate MOEs are presented. Table 7.2 shows that all MOEs are greater tha n 100, and aggregate risk estimates are not of concern. The children’s aggregate estimate for incidental oral exposure only incorporates hand - to - mouth oral exposure because it is considered to be a conservative upper bound estimate of oral post - application exposure. Additionally, the dietary exposure estimates (food and water) are conservative. Further refinement using additional anticipated residues and empirical processing factors may

need to be incorporated in future assessments. **Table 7.2**  **. Short**  **- Term Aggregate Risk Calculations**  **for Trifloxystrobin** Population NOAEL LOC a Average Food and Water Exposure Residential

Handler Exposure b Residential

Post Application Exposure c Total

Exposure d Aggregate

MOE (food, water, and residential) e mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day Adult 3.8 100 0.0 12139 0.00047 NA f 0. 012609 300 Children 1 - 2 years old (Oral Exposure) 3.8 100 0. 026545 NA f 0.00 52 0.031745 120 a The LOC is based on inter - and intra - species uncertainty factors which total 100 X. b Residential handler exposure based on adult handler inhalation only, of manually -pressurized handwand or backpack sprayer application of water dispersible granule f orm ulation to residential t

urf ( see Ta

ble 6. 2 ). c Residenti al post - application exposure based on children inc idental oral only , of hand - to - mouth exposure following liquid application to residential lawn (see Table 6.2 ). d Total Exposure = Average Food and Water Exposure + Residential Exposure . e Aggregate MOE = NOAE L / (Avg Food & Water Exposure + Residential Exposure) . f NA = Not Applicable. **7.3 Intermediate**  **- Term Aggregate Risk**  An intermediate - term aggregate risk assessment (1 to 6 months of exposure to trifloxystrobin residues from food, drinking water, and residential pesticide uses) is not expected to occur based on the intermittent nature of homeowner applications, and the short soil half - life (about 2 day s). Therefore, an intermediate - term aggregate risk assessment was not performed. **7.4 Chronic Aggrega**  **te Risk** There is potential chronic exposure via dietary (food and drinking water) exposure. Refer to Section 5.4.2. **7.5 Cancer Aggregate Risk**  Triflox ys trobin is classified as “not likel y to be carcinogenic to humans;” therefore, an aggregate cancer ass essment has not been conducted. **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 a s to trifloxystrobin and any other substances and trifloxystrobin does not appear to produce a toxicTRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 23 of 36 metabolite produced b y other substances. For the purposes of this tolerance action, there fore, EPA has not assumed that trifloxystrobin has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine 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 o f Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. **9.0 Occupational Exposure/Risk**  **Characterization** Occupational handler and post - application exposure may occur b y the dermal and inhalation routes of exposure onl y. For short - and intermediate - term exposure, onl y inhalation exposures were assessed s ince there is no sy stemic hazard from the dermal route of exposure . The results of the occupational handler exposure and risk assessment indicate that short - and intermediate term risk estimates are not of concern ( DP 416655 , N. Tsaur , 0 3 /2 7 /201 4 ). Appendix E summarize s all assessed occupatio nal exposure and risk estimates. **9.1 Short**  **- and Intermediate**  **- Term Handler Risk**  Based on the anticipated use patterns and current labeling, typ es of equipment and techniques that can potentially

be used, occupational handler exposure is expected from the proposed agricultural uses. The quantitative exposure/risk assessment developed for occupational handlers is ba sed on several scenarios which include mixing/loading/appl yi ng the SC formulation of trifloxystrobin. Methods of application include aerial, ch emigation, groundboom, and handheld equipment. Flagging for aerial use is also a potential source of worker exposure. HED classifies exposures from 1 to 30 day s as short - term and exposures from 30 day s to six months as intermediate - term. Exposure durati on is determined b y many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site. For most agricultural uses, it is reasonable to believe that occu pational handlers will not apply the same chemical every day for more than a one month time frame; however, there may be a large agribusiness and/or commercial applicators who may appl y a product over a period of weeks (e.g., completing multiple applicatio ns for multiple clients within a region). The area treated or amount handled is b ased on HED Exp oSAC Policy No. 9.1 (refer to Appendix E for these assumptions for each scenario). Since the PODs for short - and intermediate - term exposure are the same, the short - term assumptions and risk calculations are protective of both durations. It is the policy

of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical - specific data, include the Pesticide Handlers Exposure Database ( PHED ) 1.1, the Agricultural Handlers Exposure Task Force (AHETF ) database , or other registrant - submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA ) . The standard values rec ommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure SurrogateTRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 24 of 36 Reference Table 4 ”, which, along with additional information on HED poli cy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 5

. The results of the occupational handler exposure and risk assessment indicate that short - and intermediate - term inhalation risk estimates are not of concern (i.e . all MOEs ≥ 100 ) at baseline mitigation (no PPE) . Since the short - and intermediate - term PODs are the same, the inhalation MOEs are also the same, ranging 6,600 to 150,000 . Note that o nly engineering control (enclosed cockpit) data are available to assess risks to handlers operating aircrafts. HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the eng ineering control (enclosed cockpits) and baseline attire (long - sleeve shirt, long pants, shoes, and socks); per the Agency ’s Worker Protection Standard stipulations for engineering controls, pilots are not required to wear protective gloves for the duratio n of the application. With this level of protection, there are no risk estimates of concern for applicators. The Agency

matches quantitative occupational exposure assessment with appropriate characterization of exposure potential. While HED presents qua ntitative risk estimates for human flaggers where appropriate, agricultural aviation has changed dramatically over the past two decades. According the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of GPS for sw ath guidance in agricultural aviation has grown steadil y from the mid 1990’s. Over the same time period, the use of human flaggers for aerial pesticide applications has decreased steadily from ~15% in the late 1990’s to onl y 1% in the most recent (2012) NAAA survey . The Agency will continue to monitor all available information sources to best assess and characterize the exposure potential for human flaggers in agricultural aerial applications. **9.2 Short**  **- and Intermediate**  **- Term Post**  **- Application Risk**  HED u ses the term post - application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post - app lication exposure levels vary over time and depend on such things as the ty pe of activity , the nature of the crop o r target that was treated, the ty pe of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatl y reduce the potential for post - application exposure. **9.2.1 Dermal Post**  **- Application Risk**  There is potential for short - and intermediate - term occupational exposure during post - application activities. However, there is no adverse sy stemic dermal hazard for any exposure duration for trifloxystrobin .

4 Available: http://www.epa.gov/opp00001/science/handler - exposure - table.pdf 5 Available: http://www.epa.gov/pesticides/science/handler - exposure - data.htmlTRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 25 of 36 **9.2.2 Restricted Entry Interval**  Triflox ys trobin is classified as Toxicity Category IV via the dermal route. It is a mild irritant to eyes and skin, and it is a strong dermal sensitizer. Ty pically , the REIspecified on the proposed label is based on the acute toxicity of the active ingredient. Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Acute III or IV for acute dermal, eye irritation , and primary skin irrigation are assigned a minimum of 12 hour s for the REI . Thus, the 12 - hour REIon the proposed label is adequate to protect workers. **9.2.3 Inhalation Post**  **- Application Risk**  Based on the Agency's current practices, a quantitative post - application inhalation exposure a ssessment was not performed for trifloxy strobin at this time primaril y because of the low acute inhalation t oxicity

(Toxicity Category IV), low vapor pressure (3.4× 10 - 6 Pa, or 2.55×10 - 7 mm Hg at 25oC) and the low proposed use rate (0. 12 lb ai/A). However, there are multiple potential sources of post - application inhalation exposure to individuals performing post - application activities in previously

treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advi ce and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 6 . 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 occupation al 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 inh alation exposure assessment for trifloxy strob in . Although a quantitative occupational post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post - application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post - application inhalation exposure scenarios. **10 .0**  **Referen ces**  Biscoe , Melanie . 0 1 /2 8 /201 4 . DP Barcode 4 1 3801 . “ Triflox ys trobin : Drinking Water Exposure Assessment in Support of a Proposed New Use on Dry Peas, Chickpeas, and L entils (Reg. Nos. 264 - 776 (technical) and 264 - 1055). ” Negussie, Meheret. 0 3 /18 /201 4 . DP Barcode 4 13711 . “ Triflox ys trobin. Application for Section 3 Registration for Use s on Dry Peas, Chickpeas, and L entils. Summary of Analy tical Chemistry

and Residue Data. ”

6 Available: http://www.epa.gov/ scipoly/SAP/meetings/2009/120109meeting.htmlTRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 26 of 36 Negussie, Meheret. 0 4 / 14 /201 4 . DP Barcode 413712 . “ Triflox ys trobin. Acute and Chronic Aggregate Dietary

(Fo od and Drinking Water) Exposure and Risk Assessment s for Uses on Dry Peas, Chickpeas, and L entils . ” Habiba, Uma . 05/22/2014. TXR Number 00569 5 7 . “ Triflox ys trobin. Summary of Hazard and Science Policy

Council (HASPOC) Meeting on April 24, 2014: Recommendation on the Waiver Request for a 28 - day Inhalation Study . ” Tsaur, Nancy . 0 5 / 14 /201 4 . DP Barcode 413713 . “ Triflox ys trobin. Occupational Exposure and Risk Assessment for the Proposed New Uses on Chickpea, Dry Peas, and Lentils with An Updated Residential Exposure Assessment of All Existing Residential Uses . ”TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 27 of 36 **A ppendix**  **A .**  **Toxicology Profile and Executive Summaries A.1**  **Toxicology Data Requirements** The requirements (40 CFR § 158. 555 ) for food use for trifloxy strobin are in Table A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. **Table A.1.**  **Satisfac tion of Trifloxystrobin Toxicology Data Requirements**  **Study Technical**  **Required Satisfied**  870.1100 Acute Oral Toxicity ................................ ......................... 870.1200 Acute Dermal Toxicity ................................ .................... 870.1300 Acute Inhalation Toxicity ................................ ................ 870.2400 Primary Eye Irritation ................................ ...................... 870.2500 Primary Dermal Irritation ................................ ................ 870.2600 Dermal Sensitization ................................ ....................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent) ................................ ................. 870.3150 Oral Subchronic (nonrodent) ................................ ........... 870.3200 21 - Day

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

Dermal ................................ ................................ 870.3465 90 - Day

Inhalation ................................ ............................ yes yes yes CRa w aivedb yes yes yes

-

- 870.3700a Developmental Toxicity (rodent) ................................ ..... 870.3700b Developmental Toxicity (nonrodent) .............................. 870.3800 Reproduction ................................ ................................ ... yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) ................................ ................ 870.4100b Chronic Toxicity (nonrodent) ................................ .......... 870.4200a Oncogenicity (rat) ................................ ............................ 870.4200b Oncogenicity (mouse) ................................ ..................... 870.4300 Chronic/Oncogenicity ................................ ...................... - yes

- yes yes -

yes

- yes yes 870.5100 Mutagenicity

—Gene Mutation - bacterial ....................... 870.5300 Mutagenicity

—Gene Mutation - mammalian .................. 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations ..... 870.5xxx Mutagenicity

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

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

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

Neurotoxicity Screening Battery (rat) ................. 870.63 00 Develop. Neurotoxicity ................................ ................... no no yes yes CRc -

- yes no d

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

yes yes a C onditionally required . b A subchronic inhalation toxicity study has been waived for trifloxystrobin at this time ( Hazard and Science Policy Council memo , TXR005695 7 , U. Habiba, 05/22 /2014 ). c Conditional requirement pending submission of acceptable guideline acute and subchronic neurotoxicity batteries. d A subchronic neuro toxicity study has been waived for trifloxystrobin at this time ( Hazard and Science Policy Council memo , TXR0056150 , D. Smegal, 01/05/2012)TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 28 of 36 **A.2 Toxicity Profile of Trifloxystrobin Technical**  **Table A.2.1.**  **Trifloxystrobin Acute Toxicity Profile**  **Guideline No. Study Type**  **MRID Results**  **Toxicity Category**  870.1100 Ac ute Oral

– Rats 44496622 44496623 LD 50 > 5 g/kg IV 870.1200 Ac ute Dermal

– Rabbits 44496626 44496627 LD 50 > 2 g/kg IV 870.1300 Ac ute Inhalation

– Rats 44496630 LC 50 > 4.65 mg/L IV 870.2400 Primary Eye Irritation

– Rabbits 44496632 mild irritant III 870.2500 Primary Skin Irritation

– Rabbits 44496635 mild irritant IV 870.2600 Dermal Sensitization

– Guinea Pigs 44496637 44496638 strong sensitizer N/A **Table A.2.2.**  **Trifloxystrobin Subchronic, Chronic and Other Toxicity Profile**  **Guideline No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.3100 28 - Day range finding oral toxicity (rat) 44496643 (1994)

0, 200, 1000, 4000, or 12000 ppm M: 0, 16.5, 84.4, 337, 1,074 mg/kg/day F: 0, 16.4, 84.1, 327, or 1,005 mg/kg/day NOAEL = 84.1 mg/kg/day LOAEL = 327 mg/kg/day base d on decreased body weight and increased relative liver w eight.

870.3100 90 - Day oral toxicity (rat) 44496701 (1995)

Acceptable/Guideline 0, 100, 500, 200 0, or 8000 (F only) ppm M: 0, 6.44, 30.6, or 127 mg/kg/day F: 0, 6.76, 32.8, 133, or 618 mg/kg/day NOAEL = 30.6 mg/kg/day LOAEL =127 mg/kg/day based on d ecreased body weight (males), hypertrophy of hepatocytes (males), and pancreatic atrophy.

870.3100 90 - Day oral toxicity (mouse) 44496641(1994)

Acceptable/Guideline 0, 500, 2000, 7000 ppm M: 0, 76.9, 315, or 1,275 mg/kg/day F: 0, 110, 425, 1649 mg/kg/day NOAEL = 76.9 mg/kg/day LOAEL = 315 mg/kg/day based on increased liver weights and necrosis of hepatocytes . 870.3150 90 - Day oral toxicity (dog) [capsule] 44496702 (1994)

Acceptable/Guideline 0, 5, 30, 150, or 500 mg/kg/day NOAEL = 30 mg/kg/day LOAEL = 150 mg/kg/day based on increased liver weight and hepatocyte hypertrophy; increased incidence of diarrhea and vomiting. 870.3150 2 8 - Day

subchronic range - finding oral toxicity (dog) [capsule] 44496642 (1994)

Unacceptable/non guideline (2 dog/sex/do s e) 0, 20, 50, 150 mg/kg/day NOAEL=50 mg/kg/day LOAEL= 150 mg/kg/day based on increased inc idence of diarrhea and vomiting and body weight reduction .TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 29 of 36 **Table A.2.2.**  **Trifloxystrobin Subchronic, Chronic and Other Toxicity Profile**  **Guideline No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.3200 28 - Day dermal toxicity (rat) 44496703 (1996)

Acceptable/Guideline 0, 10, 100, 1000 mg/kg/day NOAEL = 1 0 00 mg/kg/day . LOAEL > 1000 mg/kg/day ; a LOAEL was not established. The observed increase s in liver and kidney weight s were not accompanied with any histopathological correlates and not considered adverse . 870.3700a Prenatal

developmental in (rat) [gavage] 44496708 (1995)

Acceptable/Guideline 0, 10, 100, 300 mg/kg/day Maternal NOAEL = 10 mg/kg/day . Maternal LOAEL = 100 mg/kg/day based on decreased body weight gain and food consumption . Devel opmental NOAEL = 1000 mg/kg/day (HDT) . 870.3700b Prenatal

developmental in (rabbit) [gavage] 44496709 (1994)

Acceptable/Guideline 0, 10, 50, 250, 500 mg/kg/day Maternal NOAEL = 10 mg/kg/day . Maternal LOAEL of 50 mg/kg/day based on decreased body weights and body weight gain, food consumption and efficiency. Deve lopmental NOAEL = 250 mg/kg/day . Developmental LOAEL = 500 mg/kg/day based **s** keletal anoma lies (fused sternabrae #3 & #4).

870.3800 Multi generational reproduction and fertility effects (rat) 44496710 ( 1997)

Acceptable/Guideline 0, 50, 750, 1500 ppm M: 0, 3.8, 55.3, 110.6 mg/kg/day F: 4.1, 58, 123.1 mg/kg/day Parental NOAEL = 3.8 mg/kg/day . Parental LOAEL = 55.3 mg/kg/day based on decreased body weight and weight gain, decreased food consumption, liver, kidney and spleen effects. Offspring NOAEL= 3 .8 mg/kg/day Offspring LOAEL = 55.3 mg/kg/day based on decreased pup body weights during lactation. Reproductive NOAEL = 110.6 mg/kg/day (HDT) . 870.4100b Chronic toxicity

(dog) [capsule] 44496704 (1997)

Acceptable/Guideline 0. 2, 5, 50, 200 mg/kg/day NOAEL = 5 mg/kg/day . LOAEL = 50 mg/kg/day based on increased clinical signs, increased liver weight and hepatocellular hypertrophy. 870.4200b Carcinogenicity

(mouse) 44496705 (1997)

Acceptable/Guideline 0, 30, 300, 1000, 2000 ppm M: 0, 3.9, 39.4, 131.1, 274 mg/kg/day F: 0, 3.51, 35.7, 124.1, 274 mg/kg/day NOAEL = 39.4 mg/kg/day LOAEL =131.1 mg/kg/day based on liver effects (single cell necros is, hepatocellular hypertrophy). There was non - statistically significant and non dose related increase in lymphoma incidence. Trifloxystrobin i s classified as “Not Likely to be Carcinogenic to Humans. ” 870.4300 Carcinogenicity

chronic toxicity (rat) 44496711 (1997)

Acceptable/Guideline 0, 50, 250, 750, 1500 ppm M:0, 1.95, 9.81,29.7, 62.2 mg/kg/day F: 0, 2.22, 11.37, 34.5, 72.8 mg/kg/day NOAEL = 9.81 mg/kg/day LOAEL= 29.7 mg/kg/day based on decreased b ody weight and body weight gain. No increase in tumor incidence.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 30 of 36 **Table A.2.2.**  **Trifloxystrobin Subchronic, Chronic and Other Toxicity Profile**  **Guideline No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.5100 In vitro bacterial

reverse gene mutation - Salmonella 44496712

44496715 44496716 44496717 Acceptable/Guideline Negative 870.5300 Gene Mutation in

Chinese Hamster Cultured V - 79 44496713

Acceptable/Guideline Positive 870.5385 Structural

Chromosome Aberration - Micronucleus - mo use 44496714

Acceptable/Guideline Negative

870.5385 Structural

Chromosome Aberration - Cy togenetics - Chinese Hamster 44496718

Acceptable/Guideline Negative 870.5500 DNA Repair - Rat

hepatocytes 44496719

Acceptable/Guideline Negative

870.6200a Ac ute oral

neurotoxicity screening battery (rat) Ac ute oral range finding neurotoxicity (rat) 44496640 (1977)

Acceptable/Non guideline 0, 2000 mg/kg/day 44840802 (1997) 0, 1000, 2000, 3500 mg/kg/day (provides supplemental information). Study useful for risk assessment and does not need to be repeated (TXR0056150, D. Smegal, 01/05/2012). NOAEL and LOAEL could not be determined because the data on females were missing . Piloerection and reduced activity were often found in 2000 and 3500 mg/kg test animals, and the effects peaked at 6 to 8 hours post dosing. No mortality and no effects on food consumption and body weights were found.

870.7485 Metabolism &

pharmacokinetics (rat) 44496722 (1997)

44496821 (1996) Acceptable/Guideline 0.5, 100 mg/kg/day Oral administration of trifloxystrobin to rats resulted in 56% and 65% of the administered dose absorbed by male and female rats, respectively. The time to maximal blood concentration was 12 - 24 hours. 41% and 47% of the administered dose was found in the bile of males and females respectively. Hi ghest residues were found in l iver, kidneys, spleen and blood . Majority of the administered radioactivity was eliminated in the feces. Less than 0.1% of the administered dose was found in the expired air. Total tissue and carcass content was 0.3 - 0.5% of the administered dose. Parent compound was extensively metabolized to approximately 35 metabolites.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 31 of 36 **Table A.2.2.**  **Trifloxystrobin Subchronic, Chronic and Other Toxicity Profile**  **Guideline No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results**

870.7800 Immunotoxicity

(male rat) 48856301 (2012)

Acceptable/Guideline 0, 200, 1000, 4000 ppm 0, 14.2, 70.5, 263 mg/kg bw /day Sy stemic NOAEL = 70.5 mg/kg/day Sy stemic LOAEL = 263 mg/kg bw/day based on decreased body weight, body weight gain, and feed consumption. Immunotoxicity NOAEL = 263 mg/kg/day Immunotoxicity LOAEL is not establishedTRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 32 of 36 **A ppendix B.**  **Physical/Chemical Properties Table B.**  **Physico -**  **Chemical Properties of Trifloxystrobin** 

**Parameter Value**  **Reference** Melting Point/Range 72.9oC

MRID 44502801 pH ( 25oC ) 7.7 in 1 % w /w aqueous dispersion Density ( 21oC ) 1.36 g/cm 2 Water S olubility ( 20oC ) 0.00061 g/L Solvent S olubi lity

( g/L at 25 °C) methanol 76

acetone >500 ethyl acetate >500 n - hexane 11 dichloromethane >500 toluene 500 n - octanol 18 Vapor P ressure (25 °C ) 3.4 x 10 - 6 Pa , 2.55 x 10 - 7 mm Hg Dissociation C onstant (pKa) none at pH of 2 - 12 Octanol/Water Partition C oefficient ( 25oC ) Log(KOW) 4.5 UV/Visible Absorption S pectrum 17,500 at 250.7 μm (neutral) 17,300 at 250.2 μm (acidic) 15,900 at 252.3 μm (basic) **Appendix C. Review of Human Research**  This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These studies, which comprise PHED and AHETF, have been determined to require a review of their ethical conduct and have received that review. In this assessment, PHED and AHETF data w ere used to assess mixing, loading, and applying a liquid formulation of trifloxystrobin . Studies reviewed by the Human Studies Review Board : None.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 33 of 36 **Appendix D. International Residue Limit Status**  **Table D.1. Trifloxystrobin**  **Summary of US and International Tolerances and Maximum Residue Limits** Residue Definition **US Canada**  **Mexico** b **Codex** 40 CFR 180.555: Plants and Livestock: sum of trifloxystrobin, benzeneacetic acid, (E , E) - α - (methoxyimino) - 2 - [[[[1 - [3 - (trifluoromethyl) phenyl]ethylidene] amino]oxy]methyl] - , methyl ester, and the free form of its acid metabolite CGA

– 321113, (E , E) - methoxyimino - [2 - [1 - (3 - trifluoromethyl -phenyl) - ethylideneaminooxymethyl] -phenyl]acetic aci d, cal culated as the stoichiometric equivalent of trifloxystrobin Methyl ( α , E) - α - (methoxyimino) - 2 - [[[(E

) - [1 - [3 - (trifluoromethyl)phenyl]eth ylidene]amino]oxy]methyl] benzeneacetate, including the metabolite ( α, E

) - α - (methyoxyimino) - 2 - [[[(E) - [1 - [3 - (trifluromethyl)phenyl]ethy lidene]amino]oxy]methyl]b enzeneacetic acid, expressed as trifloxystrobin Plant: Trifloxystrobin Livestock: sum

of trifloxystrobin and [(E,E) - me thoxyimino - {2 - [1 - (3 - trifluoromethylphenyl) ethylideneaminooxym ethyl] phenyl}ac etic acid] (CGA 321113), expressed as trifloxystrobin. The residue is fat - soluble. Commoditya Toleranc e /Maximum Residue Limit **US Canada**  **Mexico** b **Codex** ppm mg/kg

Pea, dry , seed 0.0 6 0.06 (proposed) (pea field, pea pigeon, chickpea, lentil) seed 0.02 dry (field peas, chickpeas, lentils) Pea, field , hay 15 Pea, field , vines 3 Com pleted: M. Negussie; 02/25/2014 a Includes only commodities of interest for this action. b Mexico adopts US tolerances and/or Codex MRLs for its export purposes.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 34 of 36 **Appendix E. Residential and Occupational**  **Exposure/Risk Summary Table Table E.1.**  **Short -**  **Term Residential Handler Exposure and Risk Estimates for Trifloxystrobin** 

**Application on Residential Turf and Ornam**  **entals** a Exposure Scenario Application Rate b Amount

Handled or Area Treated Dailyc Baseline

Inhalation Unit Exposure d Baseline

Inhalation Dose e Inhalation

Baseline MOE f mg/lb ai mg/kg/day LOC = 100 Liquid Formulation on Turf Manually- Pressurized Handwand 0.034 lb ai/gal 5

gallons 0.018 0.000038 99,000 Hose - End Sprayer 0.34 lb ai/acre 0.50

acres 0.022 0.000047 81,000 Backpack Sprayer 0.034 lb ai/gal 5

gallons 0.14 0.0003 13,000 Sprinkler Can 0.0000078 lb ai/sq ft 1,000

sq ft 0.022 0.0000021 1,800,000 Water Soluble Packaging on Turf Manually- Pressurized Handwand 0.0068 lb ai/gal 5

gallons 0.018 0.0000077 500,000 Hose - End Sprayer 0.34 lb ai/acre 0.50

acres 0.034 0.000072 53,000 Backpack Sprayer 0.068 lb ai/gal 5

gallons 0.018 0.0000077 500,000 Sprinkler Can 0.0000078 1,000 sq ft 0.034 0.0000033 1,100,000 Water Dispersible Granules Formulation on Turf **Manually -**  **Pressurized Handw**  **and 0.0068**  **lb ai/gal 5** 

**gallons 1.1**  **0.00047 8,100**  Hose - End Sprayer 0.34 lb ai/acre 0.50

acres 0.022 0.000047 81,000 **Back pack**  **Sprayer 0.0068**  **lb ai/gal 5** 

**gallons 1.1**  **0.00047 8,100**  Sprinkler Can 0.0000078 lb ai/sq ft 1,000

sq ft 0.022 0.0000021 1,800,000 Water Soluble Packaging on Ornamentals Manually- Pressurized Handwand 0.00000094 lb ai/sq ft 1,200

sq ft 0.018 0.00000025 15,000,000 0.00047 lb ai/gal 5

gallons 0.018 0.00000053 7,200,000 Hose - End Sprayer 0.00000094 lb ai/sq ft 1,200

sq ft 0.034 0.00000048 7,900,000 0.00047 lb ai/gal 11

gallons 0.034 0.0000022 1,700,000 Backpack Sprayer 0.00000094 lb ai/sq ft 1,200

sq ft 0.018 0.00000025 15,000,000 0.00047 lb ai/gal 5

gallons 0.018 0.00000053 7,200,000 Sprinkler Can 0.00000094 lb ai/sq ft 1,200

sq ft 0.034 0.00000048 7,900,000 0.00047 lb ai/gal 5

gallons 0.034 0.000001 3,800,000 Water Dispensable Granules Formulation on Ornamentals Manually- Pressurized Handwand 0.0000011 lb ai/sq ft 1,200

sq ft 1.1 0.000018 210,000 0.0013 lb ai/gal 5

gallons 1.1 0.000089 43,000 Hose - End Sprayer 0.0000011 lb ai/sq ft 1,200

sq ft 0.0014 0.000000023 170,000,000 0.0013 lb ai/gal 11

gallons 0.0014 0.00000025 15,000,000TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 35 of 36 **Table E.1. Short**  **- Term Residential Handler Exposure and Risk Estimates for**  **Trifloxystrobin**

**Application on Residential Turf and Ornam**  **entals** a Exposure Scenario Application Rate b Amount

Handled or Area Treated Dailyc Baseline

Inhalation Unit Exposure d Baseline

Inhalation Dose e Inhalation

Baseline MOE f mg/lb ai mg/kg/day LOC = 100 Backpack Sprayer 0.0000011 lb ai/sq ft 1,200

sq ft 1.1 0.000018 210,000 0.0013 lb ai/gal 5

gallons 1.1 0.000089 43,000 Sprinkler Can 0.0000011 lb ai/sq ft 1,200

sq ft 0.0014 0.000000023 170,000,000 0.0013 lb ai/gal 5

gallons 0.0014 0.00000011 33,000,000 a Bolded values represent the high - end exposure scenario recommended for aggregate risk calculations. b Application Rates based on maximum application rates of registered residential turf and ornamental uses for trifloxystrobin . c Based on HED’s SOPs: Lawns/Turf and Gardens and Trees (January 2012). d Baseline Inhalation: no respirator. e Dose (mg/kg/day) = daily unit exposure (mg/lb ai) × application rate ( lb ai per gallons, square feet, or acres ) × amount handled or area treated ( gallons, square feet, or a cres per day) ÷ body weight (80 kg). No inhalation absorption factor. f MOE = NOAEL ÷ daily dose (mg/kg/ day). ST Inhalation NOAEL = 3.8 mg/kg/day. Level of concern = 100. **Table E**  **.2. Short**  **- Term**  **Residential Post -**  **Application Exposure and Risk Estimates for Trifloxystrobin on**

**Turf and Ornamentals** a Lifestage Post - Application Exposure Scenario Dose b MOE c mg/kg/day Liquid Formulation on Turf max single application rate: 0. 34 lb ai/A **Child 1 to < 2 year**  **s old**  **Oral Hand to Mouth**  **0.0052 730**  Object to Mouth 0.00016 24,000 Soil Ingestion 0.000012 330,000 Granular Formulation on Turf max single application rate: 0. 34 lb ai/A Child 1 to < 2 year s old Oral d Hand to Mouth 0.00051 7,400 Object to Mouth 0.000031 120,000 Soil Ingestion 0.000012 330,000 a Bolded values represent the high - end exposure scenario recommended for aggregate risk calculations. b Hand - to -Mouth Dose = hand residue loading (mg/cm 2 ) × fraction of hand mouthed (0.127) × surface area of 1 hand (150 cm 2 ) × exposure time (1.5 hrs/day) × # of replenishment intervals/hr (4 int/hr) × (1 - ((1 - saliva extraction factor (0.5))^(Number of hand - to - mouth events per hour (13.9 events/hr) ÷ # of replenishment intervals/hr)) ÷ body weight (11 kg). Object- to -Mouth Dose = object residue loading (μg/cm2 ) × unit conversion factor (0.001 mg/μg) × object surface area mouthed / event (10 cm2/event) × exposure time (1.5 hrs/day) × # replenishment intervals/hr (4 int/hr) × (1 - ((1 - saliva extractio n factor (0.50))^(# Object - to - Mouth Events/hr (8.8 events/hr) ÷ # replenishment intervals/hr)) ÷ body weight (11 kg). Soil Ingestion = soil residue (μg/g) × ingestion rate (50 mg/day) × conversion factor (0.000001 g/μg) ÷ body weight (11 kg). c MOE = NOAEL ÷ Daily Dose (mg/kg/day) . In cidental Oral NOAEL= 3.8 mg/kg/day . Level of concern = 100. d Incidental Granule Ingestion is not applicable because there is no endpoint identified for the acute dietary duration.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D413109

Page 36 of 36 **Table E. 3**  **. Occupational Handler E**  **xposure and Risk Estimates for Trifloxystrobin Use on Typical Field**

**Crops** a Exposure Scenario Inhalation Unit Exposure b Maximum

Application Rate c Area Treated or

Amount Handled Dailyd Inhalation

Dose e Inhalation MOE f μg/lb ai lb ai/A Acres mg/kg/day ST/IT LOC = 100

**Mi xer/Loader**  Mixing/Loadi ng Dry Flowables for Aerial and Chemigation Application 0.219 0.12 350 0.000114 33,000 Mixing/Loading Dry Flowables for Groundboom Application 0.12 80 0.0000261 150,000 **Applicator** Applying Sprays for Aerial Application 0.068 0.12 350 0.0000354 110,000 Applying Sprays for Groundboom

Application 0.34 0.12 80 0.0000405 94,000 **Flagger** Flagging for Aerial Application 0.35 0.12 350 0.000183 21,000 **Mi xer/Loader/Applicator**  M/L/A Dry Flowables for Mechanically- Pressurized Handgun

Sprayers 3.9 0.012 lb ai/gal 1000

gallons 0.00058 6,600 a “Typical Field Crops” include chickpea, dry peas, and lentils. b Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); Level of mitigation = Baseline (no respirator) except for aerial applicator which includes engineering controls. c Based on the maximum application rates on the proposed labels (Reg. No. 264 - 1055, USF 0728 325 SC Fungicide). d Exposure Science Advisory Co uncil Policy #9.1. e Inhalation Dose = Inhalation 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 (80 kg). f MOE = NOAEL ( mg/kg/day) ÷ Dose (mg/kg/day). ST/IT Inhalation NOAEL = 3.8 mg/kg/day. Level of concern = 100.