TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 1 of 32 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA**  **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM DATE**  **:** August 2 , 2011 **SUBJECT: Trifloxy**  **strobin.** Human Health Risk Assessment for Proposed New Use on

Imported Coffee . **PC Code:** 129112 **DP Barcode:** 385972 **Decision No.:** 440437 **Re gistration**  **No. :**  NA **Petition No .**  **:** 0E 7789 **Regulatory Action:** Tolerance (no S3) **Risk A**  **ss essment Type**  **:** Single Chemical/Aggregate **Case No.:**  NA **T XR No.:**  NA **CAS No.:** 141517 - 21 - 7 **MRID No .**  **:** NA **40 CFR:** 180. 555 **FROM:** Nancy

Tsaur, Chemist, Risk Assessor Whang Phang , Toxicologist Risk Assessment Branch 3 Health Effects Division (7509P) **THROUGH:** Paula Deschamp, Branch Chief

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

Kish/Janet Whitehurst , Risk Manager Team 22 Fungicides Branch R egistration Division (7505P)TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 2 of 32 **Table of Contents**  **1.0 Executive Summary**  **................................ ................................**  **................................ ...........**  **4 2.0**  **HED Recommendations ................................**  **................................ ................................**  **.... 6**  **2.1 Data Deficiencies (Prior Conditions of Registration)**  ................................ ................. 6 **2.2 Tolerance Considerations**  ................................ ................................ .............................. 6 **2.2.1 Enforcement Analytical Method**  ................................ ................................ ............... 6 **2.2.2 International Harmonization**  ................................ ................................ ..................... 7 **2.2.3 Recommended Tolerances**  ................................ ................................ ......................... 7 **2.3 Label Recommendations**  ................................ ................................ ................................ 7 **3.0 Intr**  **oduction ................................**  **................................ ................................**  **........................ 7**  **3.1 Chemical Identity**  ................................ ................................ ................................ ........... 8 **3.2 Physical/Chemical Characteristics**  ................................ ................................ ............... 8 **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**  ................................ ................................ . 11 **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  ............................. 11 **4.3 Toxicological Effects**  ................................ ................................ ................................ .... 11 **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 Selections**  ................................ .............. 13 **4.5.1 Dose**  **- Response Assessment**  ................................ ................................ ...................... 13 **4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment**  ...... 14 **4.5.3 Cancer**  **Classification and Risk Assessment Recommendation** ............................ 14 **4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk**  **Assessment** ................................ ................................ ................................ ............................... 14 **4.6 Endocrine Disruption**  ................................ ................................ ................................ ... 16 **5.0 Dietary Exposure and Risk Assessment**  **................................ ................................**  **......... 17**  **5.1 Metabolite/Degradate Residue Profile**  ................................ ................................ ....... 17 **5.1.1 Summary of Plant and Animal Metabolism Studies**  ................................ ............. 17 **5.1.2 Summary of Environmental Degradation**  ................................ .............................. 18 **5.1.3 Comparison of Metabolic Pathways**  ................................ ................................ ....... 18 **5.1.4 Residues of Concern Summary and Rationale**  ................................ ...................... 18 **5.2 Food Residue Profile**  ................................ ................................ ................................ .... 19 **5.3 Water Residue Profile**  ................................ ................................ ................................ .. 20 **5.4 Dietary Risk Assessment**  ................................ ................................ .............................. 21 **5.4. 1**  **Acute Dietary Risk Assessment** ................................ ................................ ............... 21 **5.4.2 Chronic Dietary Risk Assessment**  ................................ ................................ ........... 21 **5.4.3 Cancer Dietary Risk Assessment**  ................................ ................................ ............. 22 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  **............................. 22**  **6.1 Residential Handler Exposure**  ................................ ................................ .................... 22 **6.2 Post**  **- Application Exposure**  ................................ ................................ .......................... 23TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 3 of 32 **6.3 Combined Exposure**  ................................ ................................ ................................ ..... 23 **6.4 Residential Bystander Post**  **- Application Inhalation Exposure**  ................................ 24 **6.5 Spray Drift**  ................................ ................................ ................................ .................... 24 **7.0 Aggregate Exposure/Risk Characterization**  **................................ ................................**  **.. 24**  **7.1 Acute Aggregate Risk**  ................................ ................................ ................................ ... 25 **7.2 Short**  **- Term Aggregate Risk**  ................................ ................................ ........................ 25 **7. 4**  **Chronic Aggregate Risk** ................................ ................................ .............................. 26 **7.5 Cancer Aggregate Risk**  ................................ ................................ ................................ 26 **8.0 Cumulative Exposure/Risk Characterization**  **................................ ...............................**  **26 Appendix A.**  **Toxicology Profile and Executive Summaries ................................**  **................ 27**  **A.1 Toxicology Data Requirements**  ................................ ................................ ................... 27 **A.2 Toxicity Profile of Trifloxystrobin Technical**  ................................ ............................ 28 **Appendix B. Metabolism Summary Table**  **................................ ................................**  **............ 31**  **Appendix C. Physical/Chemical Properties**  **................................ ................................**  **........... 31**  **Appendix D. International Residue Limit Summary**  **................................ ...........................**  **32**TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 4 of 32 **1.0 Executive Summary**  Triflox ys trobin belongs to the MAEs (β - methoxyacryl esters) class of fungicides, which are sy nthetic analogs of strobilurin A. It is a broad - spectrum preventative fungicide used for control of many plant diseases in various fruit, nut, vegetable, and field cro ps, including corn and soy bean. In PP# 0 E 77 89 , Bayer Cropscience (Bayer) petitioned for the establishment of a new tolerance for combined residues of the fungicide trifloxy strobin [benzeneacetic acid, (E,E ) - α - (methox yi mino) - 2 - [[[[1 - [3 - (trifluorometh yl )phen yl]ethylidene] amino]oxy]methyl] - methyl ester] and the free form of its acid metabolite CGA - 321113 [( E,E ) - (methox yi mino) - [2 - [1 - (3 - (trifluorometh ylphenyl) - ethylideneaminooxy m ethyl] - phenyl]acetic acid] in/on the following raw agricultural commoditie s (RAC):

Coffee, green bean ................................ ................. 0. 0 2 ppm Pending submission of a revised Section F, there are no residue chemistry issues that would preclude establishment of permanent tolerance s for combined residues of trifloxystrobin and its acid metabolite CGA - 321113 in/on imported coffee . The most recent human health risk assessment was conducted for use on alfalfa (DP# 378917 , B. Hanson , 01 /25 /201 1 ). Other than a waiver for a subchronic 28 - day inhalation toxicity

study , n o new hazard data have been submitted since the issuance of the last human health risk assessment. A summary

of the findings and an assessment of human health risk resulting from the proposed and registered uses of trifloxystrobin are provided in this document and its attachments. The residue chemistry

data submitted in support of this petition we re reviewed by Nancy Tsaur , the toxicology re evaluation was performed b y Whang Phang, and the drinking water assessment was conducted b y James Wolf . Subsequently , the dietary exposure and overall human health risk assessment s were conducted by Nancy Tsaur . Use Profile Baye r submitted a partial English translation of the Sphere® Max draft specimen label to be used on imported coffee grown in L atin America. Sphere® Max is a multiple active ingredient (MAI) suspension concentrate (SC) formulation consisting of 375 g ai/Ltriflo xystrobin and 160 g ai/L cy proconazole. However, this document only addresses the application use pattern of trifloxystrobin. Note: the submitted data are all based on Sphere® 535 SC, an SC end - use product (EP) that is identical to Sphere® Max with regard to the formulation and the MAI mixture composition. Toxicity/Hazard The risk assessment for triflox ys trobin is based on a well - characterized and complete toxicology database, with the exception of acute and subchronic neurotoxicity and immunotoxicity

studies which are now required as part of the toxicology data requirements for registration of a pesti cide (food and non - food uses).TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 5 of 32 With repeated dos ing b y either the oral or dermal route , the liver is consistently the target organ for triflox ys trobin . Trifloxystrobin does not produce malformation in either rat or rabbit developmental toxicity

studies and does not produce reproductive effects. Trifloxystrobin 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 cytotoxic dose levels while testing negative in the remaining mutagenicity studie s. Triflox ys trobin exhibits low acute toxicity following single oral, dermal , and inhalation exposures (Toxicity

Category I II or IV) . Itis a strong dermal sensitizer and a mild dermal and eye irritant. Although acute and subchronic neurotoxicity and immunotoxicity

studies are needed to complete the database, there are no concerns for neurotoxicity or immunotoxicity

based on the results of the existing studies. The FQPA factor was reduced to 1X because triflox ys trobin showed no evidence of increased susceptibility of the young. The acute dietary risk assessment is based on increased incidence of fuse d sternebrae in fetuses observed in a developmental toxicity study in rabbits; therefore, the acute assessment was assessed for females of childbearing age (13 - 49 ye ars old) onl y. The chronic dietary risk assessment is based on decreases in body weight, b ody weight gains, reduced food consumption, and histopathological lesions in the liver, kidney s , and spleen of parental animals in a multi - generation reproduction study in rats. Drinking W

ater The Environmental Fate and Effects Division (EFED) previousl y determined estimated drinking water concentrations (EDWCs) of triflox ys trobin in surface and ground water for use on turf (1.02 lb ai/A) (DP Barcode: 244219, 7/28/1999). The GENEEC surface wate r estimates for acute and chronic exposure concentrations were 47.98 and 4 7.31 μg/L (ppb), respectively . Dietary Exposure An unrefined acute dietary (food plus drinking water) assessment assuming tolerance - level residues and 100% crop treated for all commodities with existing and proposed tolerances yi elded exposure estimates below HED’s level of concern ; a cute dietary exposure utilized 1.9 % of the aPAD for females 13 - 49 years old at the 95 th percentile . A partiall y refined chronic dietary (food + drinking water) assessment assuming mostly tolerance - level residues with some anticipated residues (apples, grapes, and oranges) yielded exposure estimates below HED’s level of concern ; chronic dietary exposure utilized 34 % of the cPAD for the general U.S. p opulation and 64% of the cPAD for children 1 - 2 years old ( the population subgroup with the highest estimated chronic dietary exposure to trifloxystrobin) . Residential Exposure No residential uses are being requested at this time; therefore, no residential risk assessment has been conducted. However, the label for the trifloxystrobin product Compass TM includes residential use on turfgrass and ornamentals. Previously calculated non - occupational post application margins of exposure (MOEs) are greater than 1 00 on the day of application and do not exceed HED ’s level of concern (DP Barcode: D319131, J. Arthur, 7/14/2005). The MOEs ranged from 750 to 220,000 for adult and ch ild residential scenarios .TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 6 of 32 Aggregate Risk Acute, short - term, and chronic aggregate risk estimates resulting from aggregate exposure to trifloxystrobin in food and drinking water, and residential settings are below HED’s level of concern. The estimated acute dietary exposure (food plus drinking water) for females 13 - 49 ye ars old is represent ative of the acute aggregate risk and the estimated chronic dietary exposure assessment (food plus drinking water) is representative of the chronic aggregate risk. For short term (1 to 30 day s) aggregate risk , food plus drinking water and residential expo sures are considered . Residential exposure for dermal and oral routes must be assessed separatel y, since dermal and oral endpoints were different and cannot be combined. The resulting MOEs for all short - term aggregate scenarios for adults and children are below HED’s level of concern ( adult d ermal MOE = 1 1 00, c hildren dermal MOE = 650, c hildren i ncidental o ral MOE = 1 3 0). **2.0 HED**  **Recommendations** Pending submission of a revised Section F, HED recommend s for the establishment of a permanent tolerance fo r the use of trifloxy strobin on imported coffee . Additional data deficiencies based on new guideline requirements have been noted as condition s of registration for prior domestic registrations as outlined in Section 2.1 below. The specific tolerance reco mmendations are discussed in Section 2.2, and the re are no necessary label modifications . **2.1 Data Deficiencies (Prior**  **Conditions of Registration )**  Data Deficiencies Toxicology

[870.3465 28 - Day

Inhalation Toxicity] Toxicology

[ 870. 6200 Neurotoxicity Screening Battery] Toxicology

[870.7800 Immunotoxicity] **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  An adequate gas chromatograph y/nitrogen phosphorus detection (GC/NPD) method based on crop - specific cleanup procedures , Method AG - 659A, is available for enforcing tolerances for the combined residues of trifloxystrobin and CGA - 321113 in crop and livestock commodities. This method was validated b y the Agency and forwarded to the Food and Drug Administration (FDA) for inclusion in the Pesticide Anal yt ical Manual (PAM), Vol. II. The limit of detection (LOD ; the lowest concentration of an anal yt e that can be determined to be statistically different from a blank untreated control sample ) for each anal yt e of this method is 0.0 8 ng injected, and the limit of quantitation ( LOQ ; the lowest anal yt e fortification level at which acceptable recovery through the anal yt ical method was achieved ) is 0.02 ppm . In addition, a newer analytical enforcement method, M ethod No. 200177 , is available . Method No. 200177 employ s identical solvent mixtures and solvent to matrix ratio as Method AG - 659A , deuterated internal standards, and high performance liquid chromatography with an electrosprayTRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 7 of 32 interface and tandem mass spectrometry , operated in the positive ion mode (HPL C/MS/MS) . The LOQ for each analy

te i s 0.01 ppm . **2.2.2 International Harmonization**  There are currently

no established Mexican, Canadian, or Codex maximum residue limits ( MRL s ) or tolerances for trifloxystrobin on coffee (see Appendix D ). **2.2.3 Recommended Tolerances**  As shown in Table 2. 2.3 , the proposed tolerance commodity term has to be corrected in a revised Section F to agree with the Agency ’s Food and Feed Commodity Vocabulary . **TABLE 2.**  **2.3 .**  **Tolerance Summary fo r**  **Trifloxystrobin.** Commodity Tolerance (ppm) Comments Correct Commodity Definition Established Proposed Recommended

40 CFR §180.609(a)(1) Coffee, green, bean a -- 0.0 2 0. 0 2 Coffee, green bean a No domestic registration has been established as of August 2, 2011. The 40 CFR tolerance expression for triflox ys trobin has been properl y revised in accordance with HED’s Interim Guidance on Tolerance Expressions (S. Knizner , 0 5/27/2 0 0 9 ) . **2.3 Label Recommendations**  None. **3.0 In**  **troduction** Triflox ys trobin belongs to the MAEs (β - methoxyacryl esters) class of fungicides, which are sy nthetic analogs of strobilurin A. These fungicides are also designated quinone inhibitors (QoIs) and are assigned to the Fungicide Resistance Actio n Committee (FRAC) Group 11. Triflox ys trobin is a broad - spectrum preventative fungicide used for control of many plant diseases in various fruit s , nut s , vegetable s , and field crops, including corn and soy bean. Baye r is petitioning for a tolerance for residues of trifloxystrobin in/ on imported coffee and has submitted a partial English translation of the draft specimen label to be used in L atin America. The submitted label indicates that up to three bro adcast foliar applications may be made using airblast backpacks at the rate of 0.08 4 to 0.14 lb ai/A/application for a maximum seasonal application rate of 0.25 to 0.27 lb ai/A , with a 30 - day preharvest interval (PHI). Tolerances are currentl y established for the combined residues of triflox ys trobin and its free form acid metabolite CGA

– 321113 in/on various crop and livestock commodities ranging from 0.02 ppm (milk) to 38 ppm (citrus oil) [40 CFR §180.555(a)] .TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 8 of 32 **3.1 Chemical Identity**  The chemical structure and nomenclature of trifloxystrobin and its regulated metabolite are presented in Table 3.1. **TABLE 3.**  **1. Test Compound Nomenclature.** 

**Chemical Structure of Parent Com** **pound Empirical Formula**  C 20 H 19 F 3 N 2 O 4 **Comm on Name**  trifloxystrobin **Company 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 #** 141517 - 21 - 7 **End -**  **Use Products (EPs)**  Sphere® Max (375 g ai/L trifloxystrobin + 160 g ai/L cyproconazole) Sphere® 535 SC (375 g ai/L trifloxystrobin + 160 g ai/L cyproconazole) **Chemical Class** Strobilurin, methoxyacrylates **Known Im purities of Concern**  None

**Chemical Structure of Metabolite CGA**  **- 321113**  **Comm on Name**  trifloxystrobin acid **Company Code** CGA - 321113 **CAS Name** (αE) - α - (methoxyimino) - 2 - [[[[(1 E) - 1 - [3 - (trifluoromethyl)phenyl]ethylidene]amino]oxy]methyl] - benzeneacetic acid **CAS #** 252913 - 85 - 2 **3.2 Physical/Chemical**  **Characteristics** Triflox ys trobin has a low vapor pressure ( 2.55 x 10 - 7 mmHg at 25  C ); therefore, inhalation via chemical vaporization is unlikely . The decline of parent trifloxy strobin (half - life <3 day s ) and 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. 385972

Page 9 of 32 formation of CGA - 321113 appears to be quite rapid; however, the decline of CGA - 321113 is much slower (half

- life >180 day s). The ph ys icochemical properties of trifloxystrobin are summarized in Appendix C. **3.3 Pesticide Use Pattern**  Baye r submitted a partial English translation of the Sphere® Max draft specimen label to be used on imported coffee grown in Latin America. Sphere® Max is a MAI SC formulation consisting of 375 g ai/Ltrifloxystrobin and 160 g ai/Lcy proconazole. However, this document only addresses the application use pattern of trifl oxy strobin . A summary of the directions for use of Sphere® Max on imported coffee are listed in Table 3.3. Note: the submitted data are all based on Sphere® 535 SC, an SC EP that is identical to Sphere® Max with regard to the formulation and the MAI mixture composition. **TABLE 3.3.**  **Summary of Directions for Use of Trifloxystrobin.**  Applic. Timing, Ty pe, and Equip. Form ulation Applic.

Rate Max.

No. Applic. per Season Max.

Seasonal Applic. Rate PHI Use Directions and Limitations lb ai/A lb ai/A days **Coffee, green bean**

Airblast Backpack Suspension

Concentrate Sphere® 535 SC or Sphere® Max 0.084 3 0.25 30 To control Rust (Hemileia vastatrix ) and Cercospora ( Cercospora coffeicola ): The first application should be made preventatively in December in the phase of “start of fruiting,” and the second and third applications should be performed at intervals of 40 - 45 days. 0.13 - 0.14 2 0.26 - 0.27 To control Rust during critical period of disease: The first application should be made preventatively in December in the phase of “start of fruiting” and the second application should be made 60 - 80 day s after the first. Coffee Use Directions: Add methylated soybean oil , 0.25%. Dilute the recommended dose in water: 250 - 500 L/ha. Note: the submitted data are a ll based on Sphere® 535 SC, an SC EP that is identical to Sphere® Max with regard to the formulation an d the MAI mixture composition. **3.4 Anticipated Exposure Pathways**  The Registration Division has requested an assessment of human health risk to support the proposed new use of trifloxystrobin on imported coffee . As a result of existing domestic uses of trifloxystrobin, s everal risk assessments have been previously prepared for the existing uses of trifloxystrobin. This risk assessment considers exposure pathway s based on the proposed new use of triflox ys trobin, but also considers the existing uses as well, particularly for the dietary exposure assessment. Humans may be exposed to trifloxystrobin in food and drinking waterTRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 10 of 32 since trifloxystrobin may be applied directly to growing crops and application may result in trifloxystrobin reaching surface and ground water sources of drinking water. There are also re sidential uses of trifloxy strobin ; thus , there is likely to be exposure in residential or non occupational settings. **3.5 Consideration of Environmental Justice**  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

pesticide ris k assessment, OPP considers a large variety of consumer subgroups according to well - established procedures. In line with OPP policy , HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food an d water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . Additionally , OPP is able to assess dietary

exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non - dietary exposures based on home use of pesticide products and associated risks for adult applicators and fo r 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 patterns among specific subgroups. **4.0 Hazard Characterization and Dose**  **- Response Assessment**  Triflox ys trobin is considered a s ynthetic strobilurin A analog, bel onging to the MAE (β methoxyacryl ester) class of fungicides. The strobilurin pesticidal mode of action is biochemical interference with the mitochondria respiration sy stem in fungi leading to inhibition of spore germination and mycelial growth. More spe cifically , the mode of action consists of interaction with the ubiquinone binding site of the mitochondrial bc1 complex (complex III) in fungal cells, thereb y preventing the oxidation of ubihydroquinone and the transfer of electrons to cy tochrome c. The i nterruption of the elec tron transport chain prevents oxidative phosphorylation, thus causing a severe reduction in the availability of adenosine triphosphate (ATP ; the main energy currency of the cell ) . This shortage of energy has a very

wide range of biochemical consequences, such as the breakdown of essential membrane potentials and concentration gradients and the inhibition of nucleic acid and protein biosy nthesis. Fungal spore germination, mycelial growth and the development of infection structures are thus prevented. However, the available mammalian toxicity data do not provide a clear set of results to demonstrate a similar mode of action on mammals .TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 11 of 32 **4.1 Toxicology Studies Available for Analysis**  Th e toxicology

database of trifloxystrobin provides sufficient information for selecting toxicity endpoints and 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 - generation reproduction study in rats; (5) chronic toxicity studies in rats and dogs; (6) carcinoge nicity studies in rats and mice; (7) a battery

of th e required genotoxicity studies; and (8) metabolism studies in rats. A waiver for a subchronic 28 - day inhalation toxicity study has been submitted and is currentl y under review. **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  With low dose oral administration of triflox ys trobin to rats, approximately 56% and 65% of the a dministered 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%, wi th 35% and 19% in the bile of male and f emale rat s, 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, liver, 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 m ajority of the administered dose was eliminated in the feces. Less than 0.1% of the administered dose was found in the expired air. T he t otal tissue and carcass contained 0.3 - 0.5% of the administered dose indicating essentially no tissue accumu l ation . The p arent compound was extensively metabolized to approximately 35 metabolites. Dermal Absorption A dermal penetration study is not available; however, a 28 - day dermal toxicity study is available for selecting dermal toxicity endpoints and point s of departure for risk assessment. **4.3 Toxicological Effects**  With repeated dos ing b y either the oral or dermal route , the liver is consistently the target organ for triflox ys trobin . L iver effect s were seen in rats, mice, and dogs , characterized by an increase in liver weights and an increase in incidence s of hepatocellular h yp ertro phy and/or hepatocellular necrosis . The effect s of reduced body weights and foo d consumption were also found in the majority of the toxicity

studies. Intestinal disturbance s , as indicated by diarrhea and vomiting, were seen in dogs and rats at higher dos e levels relative to that which caused liver and body weight effects. This finding was consistent with those p roduced 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 LOAEL. In the rat reproduction study , both parents and offspring showed decreases in body weight during lactation. The rat and rabbitTRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 12 of 32 developmental and the rat reproduction toxicity data do not demonstrate an increase in susceptibility

in either fetal animals or offspring. 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 exhibits low acute toxicity following single oral, dermal and inhalation exposures (Toxicity Category III or IV) . It is a strong dermal sensitizer and a mild dermal and eye irritant. The toxicity

of the major acid metabolite, CGA - 321113 (formed b y h ydrolysis of the meth yl ester), has been evaluated in cultured rat hepatocytes and found to be 20 times less cy tot oxic than th e parent compound. **4.4 Safety F**  **actor 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 reduced to 1 X. **4.4 .1**  **Completeness o**  **f the**  **Toxicology Database** T he toxicity

database for trifloxystrobin is adequate for selecting toxicity en dpoints and points of departure for risk assessment. However, 40 CFR Part 158 now require s neurotoxicity and immunotoxicity

testing for pesticide registration . Although neurotoxicity (acute and subchronic) and immunotoxicity

studies are needed to complete the database, the selected toxicity endpoints and points of departure for risk assessment are based on the most sensitive and relevant data. Currently , there are no concerns for neurotoxicity or immunotoxicity based on the results of the existing studies. The toxicological database for triflox ys trobin does not show any evidence of treatment - related effects on the immune sy stem. Further, there i s no evidence of neurotoxicity at the limit dose in an unacceptable acute neurotoxicity study or in the other subchronic and chronic studies in the database. HED does not believe that conducting neuro toxicity or immunotoxicity studies will result in a dose less than the points of departure already used in this risk assessment and an additional database uncertainty factor for potential neurotoxicity and/or immunotoxicity does not need to be applied. A waiver for a subchronic 28 - day inhalation toxicity study has been submitted and is currently under review. **4.4.2 Evidence of N**  **eurotoxicity** There i s no evidence of neurotoxicity in subchronic and chronic toxicity studies (rats, dogs, m ice ), in developmental toxicity studies (rats, rabbits), or in a reproductive toxicity study (rats ) . **4.4.3 Evidence**  **o f Sensitivity/Su**  **sceptibility in the Developing o r Young Animal**  T here 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 the limit dose. In the prenatal developmental study in rabbits, developmental toxicity wasTRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 13 of 32 seen at a dose that was higher than the dos e that caused maternal toxicity . In the multigeneration study , offspring and parental LOAELs are at the same dose level. **4.4.4 Residual**  **Uncertainty in the Exposure Datab ase**  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 triflox ys trobin. The dietary drinking water assessment utilizes water concentration values generated b y model s and associated modeling parameters which are designed to provide conservative, health protective, high - end estimates of wat er concentrations, and are not likely to be exceeded . Inaddition, the residential post - application assessment is based upon the residential SOPs employing surrogate study data. These data are reliable and are not expected to underestimate risk to adults or children. The residential SOPs are based upon reasonable “worst - case” assumptions and are not expected to unde restimate risk. **4.5 Toxicity Endpoint and Point of**  **D eparture Selections**  The triflox ys trobin risk assessment team has examined the toxicity endpoints and points of departure used in the most recent risk assessment and in the context of the currentl y avail able data, the team determined that selections are valid and reflecting the current policy of HED (DP # 378917, B. Hanson, 01/25/2011) . The toxicity endpoints and points of departure are presented in Tables 4.5 .4a and 4.5 .4 b . **4.5.1 Dose**  **- Response Assessment**  As mentioned in Section 4.3, the available toxicology database demonstrate that trifloxystrobin produces liver effects, body weight reduction , and intestinal disturbance which manifests as increased incidence of diarrhea. These three effects are often s een with repeated dosing. Gastro intestinal effects produced by trifloxy strobin seem to occur at higher dose level than the levels where body weight and liver effect s are seen. The only possible effects which could be attributed to a single dose were inc reased fetal skeletal anomalies seen in the rabbit developmental toxicity

study . These effects were selected as the endpoint for acute dietary exposure assessments. The effects selected for the chronic toxicity endpoint from the two - generation reproduct ion study include liver toxicity

and decreases in body weight. The two - generation reproduction study provides the lowest point of departure for risk assessment and is protective of all other toxicity seen in the triflox ys trobin database. The dermal toxic ity

endpoint for dermal exposure assessment i s based on a 28 - day dermal toxicity study where statistically

significant increases in absolute and relative kidney and liver weights were found at 1000 mg/kg/day (LOAEL at the limit dose). The point of departure is 100 mg/kg/day

which is 10X lower than the LOAEL.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 14 of 32 **4.5.2 Recommendation for Combining R** **outes of Exposure for Risk Assessment**  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 exposures cannot be combined with oral o r inhalation exposures for any time period . **4.5.3 Cancer Classification and Risk Assessment Recommendation**  B ased on the absence of significant tumor increases in two adequate rodent carcinogenicity studies , trifloxystrobin is c lassified as : “Not likel y to be Carcinogenic to Humans . ” C ancer risk assessment s do not need to be conducted. **4. 5**  **. 4**  **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 two separate tables: ( 1) Dietary and Non - Occupational E xposures in Table 4.5.4a and ( 2) Occupational E xposures in Table 4.5.4b . **TABLE 4**  **.5. 4**  **a .**  **Summary of Toxicol**  **ogical Doses and Endpoints for Trifloxystrobin**  **for Use in Dietary**

**and Non -**  **Occupational Human Health Risk Assessments .**  **Exposure/ Scenario**  **Point of**

**Departure Uncertainty/** 

**FQPA Safety Factors**  **RfD, PAD,**

**Level of Concern for**  **Risk Assessment**  **Study and Toxicological Effects**  Ac ute Dietary ( Females 13 - 49 Only) NOAEL =

250 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X 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 = 0.0 38 mg/kg/day Two - Generation Reproduction - Rat

LOAEL = 55.3 mg/kg/day based on decreases in body weight, body weight gains, reduced food consumption , and histopathological lesions in the liver, kidneys , and spleen. Oral Short Term (1 - 30 days) and Intermediate Term (1 - 6 mo nths) 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

LOAEL = 55.3 mg/kg/day based on reduced pup body weights during lactation.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 15 of 32 **TABLE 4**  **.5. 4**  **a .**  **Summary of Toxicol**  **ogical Doses and Endpoints for Trifloxystrobin**  **for Use in Dietary**

**and Non -**  **Occupational Human Health Risk Assessments .**  **Exposure/ Scenario**  **Point of**

**Departure Uncertainty/** 

**FQPA Safety Factors**  **RfD, PAD,**

**Level of Concern for**  **Risk Assessment**  **Study and Toxicological Effects**  Dermal Short - Term (1 - 30 days) and Intermediate Term (1 - 6 mo nths) NOAEL =

100 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Residential

LOC for MOE = 100 28 - Day

Dermal - Rat LOAEL = 1000 mg/kg/day based on statistically significant increases in mean absolute and relative liver and kidney weights. Dermal Long - Term (>6 mo nths) NOAEL =

13.8 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Dermal absorption rate = 3 3% Residential

LOC for MOE = 100 Two - Generation Reproduction - Rat

LOAEL = 55.3 mg/kg/day based on decreases in body weight, body weight gains, reduced food consumption , and histopathological lesions in the liver, kidneys , and spleen. Inhalation Short - Term (1 - 30 days), Intermediate Term (1 - 6 mo nths) , and Long - Term (>6 months) NOAEL =

3.8 mg/kg/day UF A = 10 X

UF H = 10 X FQPA SF = 1 X Inhalation absorption rate = 100% Residential

LOC for MOE = 100 Two - Generation Reproduction - Rat

LOAEL = 55.3 mg/kg/day based on decreases in body weight, body weight gains, reduced food consumption , and histopathological lesions in the liver, kidneys , and spleen. Cancer (oral, dermal, inhalation) Trifloxystrobin is classified as “Not Likely Human Carcinogen” based on the lack of evidence

of carcinogenicity in mouse and rat cancer studies. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chro nic). RfD = reference dose. MOE = margin of expo sure. LOC = level of concern.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 16 of 32 **TABLE 4.5.**  **4 b**  **. Summary of Toxicol**  **ogical Doses and Endpoints for Trifloxystrobin**  **for Use in**

**Occupational Hum an Health Risk Assessments**  **. Exposure/**  **Scenario Point of** 

**Departure Uncertainty** 

**Factors Level of** 

**Concern for Risk**  **Assessment Study and Toxicological Effects**  Dermal Short Term (1 - 30 days) Intermediate Term (1 - 6 mo nths) NOAEL =

100 mg/kg/day UF A = 10X

UF H = 10X SF = 1X Occupational

LOC for MOE = 100 28 - Day

Dermal Toxicity Study in Rats LOAEL = 1000 mg/kg/day based on increases in liver and kidney weights. Inhalation Short - Term

(1 - 30 days) and Intermediate Term (1 - 6 mo nths) a NOAEL = 3.8

mg/kg/day UF A = 10 X

UF H = 10 X SF = 1 X Inhalation absorption rate = 100% Occupational

LOC for MOE = 100 Two - generation reproduction - Rat

LOAEL = 55.3 mg/kg/day based on decreases in pup body weights during lactation . Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the abse nce of significant

tumor increases in two adequate rodent carcinogenicity studies. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). SF = safety factor. MOE = margin of expo sure. LOC = level of concern. Based on the available toxicity database and the Agency's current practices, the inhalation risk f or trifloxy strobin was assessed using an oral toxicity study . The Agency

sought expert advice and input on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may , as appropriate, reexamine and develop new policies and procedures for conducting inhalation risk assessments, including route to route extrapolation of toxicity

data. If any

new policies or procedures are developed, the Agency may revisit the need for an inhalation toxicity study for trifloxystrobin and/or reexamin e of the inhalation toxicity

risk assessment. **4.6 Endocrine Disruption**  As required under FFDCA Section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally

oc curring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employ s a two - tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assay s to identify the potential of aTRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 17 of 32 chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal sy stems will proceed to the nex t stage of the EDSP where EPA will determine which, if any , of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify an y adverse endocrine related effects caused by the substance, and establish a quantitative re lationship between the dose and the E, A, or T effect. Between October 2009 and February 2010, EPA i ssued test orders/data call - ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathway s such as food and water, residential activity , and certain post - application agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors. Triflox ys trobin is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p) , the Agency must screen all pesticide chemicals. Accordingl y, EPA anticipates issuing future EDSP orders/data call - ins for all Registration Review cases, including those for which EPA has already opened a Registration Review docket for a pesticide active ingredient. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery , please visit our website: http://www.epa.gov/endo/. **5.0 Dietary Exposure and Risk Assessment**  **Reference s**  **:**

- Trifloxystrobin. Petition for Establishment of a Tolerance on Imported Coffee and its Processed Commodities. Submission of Coffee Field Trials Conducted in Latin America. Summary of Analytical Chemistry and Residue Data . DP# 387200 , Nancy Tsaur , 07 / 08 /201 1 .

- Trifloxystrobin. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Petition for Establishment of a Tolerance on Imported Coffee . DP#387 201 , Nancy Tsaur , 07 / 13/2011 .

- Drinking Water Assessment for Tolerance Petition for New Uses of Trifloxystrobin in Fluopyram/Trifloxystrobin 500 SC Fungicide [EPA Reg. No. 264 -RNON ] . DP#360307, J ames Wolf, 10/ 0 7/2009. **5.1 Metabolite/Degradate Residue Profile**  **5.1.1 Summary of Plant and Animal Metabolism Studies**  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, as well as met abolism studies of lactating goats and poultry . HED has concluded that both trifloxy strobin and its acid metabolite, 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 trifloxy strobin) in liver should also be included in the risk assessment.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 18 of 32 Available confined rotational crop data are adequate to satisfy data requirements and to delineate the nature of the residue in rotated crop commodities. Adequate field rotational crop data are available, including a limited field rotational crop study and extensive field rotational crop studies. Based on the data from the primary plant metabolism studies an d the confined rotational crop study , HED concluded that the residue of concern in plants, including rotational crops, is parent and its fr ee acid metabolite CGA - 321113. Rotational crop restrictions have been established; however, the proposed use on impo rted coffee does not affect rotational crops. **5.1.2 Summary of Environmental Degradation**  The major routes of degradation and dissipation for triflox ys trobin are associated with alkaline catal yz ed h ydrol ys is, microbial - mediated metabolism, photodegradatio n, and soil binding. Hydroly sis of trifloxy strobin is most important under alkaline conditions. Dissipation of trifloxystrobin will also occur in the environment by spray drift, in runoff water and eroded soil. Volatilization is not an important dissipat ion pathway . Triflox ys trobin is expected to have low mobility in the environment. The CGA - 321113 , on the other hand, is expected to be moderately mobile to highly

mobile in the environment. The major degradate b y hydrol ys is, metabolism and photodegradation is CGA - 321113, the free acid degradation product of triflox ys trobin. CGA - 321113 is persistent in aerobic soil, aerobic aquatic and anaerobic aquatic sy stems. The decline of parent trifloxystrobin (half - life <3 day) and formation of CGA - 321113 appears to be quite rapid; however, the decline of CGA - 321113 is much slower (half

- life >180 day s). Due to the rapid degradation, low solubility (0.61 mg/L) , and relativel y low mobility , trifloxystrobin is thought to have a limited potential to contaminate water. Based upon the persistence in aquatic environments and its mobility , CGA - 321113 is not likely to bind with sediment and thus wil l remain in the water column. The greater persistence, mobility , and solubility ( 30.9 mg/L) of CGA - 321113 suggest that the CGA - 321113 degradate is more likel y to reach ground and surface water via leaching and runoff. **5.1.3 Comparison of Metabolic Pathways**  Metabolism of trifloxystrobin has been well characterized in plants, soil, and animals. In plants and soil , photoly

tically induced isomerization of surface residues results in a few minor metabolites not seen in the rat. However, most of the a pplied material remained as parent compound as shown in the apple and cucumber studies. All quantitatively major plant and/or soil metabolites were also seen in the rat. Trifloxystrobin was extensively metabolized in the rat to approximately

35 metabolites as evidenced by the extensive metabolic profiles f rom liver, kidney s , and spleen. **5.1 .4**  **Residues of Concern Summary and Rationale** Table 5.1.4 summarizes the metabolites and degradates included in the risk assessment and the tolerance expression.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 19 of 32 **TABLE 5.1.4**  **. Summary of Metabolites and Degradates to be included in the Risk Assessment and** 

**Tolerance Expression .**  Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Trifloxystrobin and CGA 321113 Trifloxystrobin and CGA 321113 Rotational Crop Livestock Ruminant Trifloxystrobin and CGA 321113; plus Metabolite L7a in liver and meat byproducts Trifloxystrobin and CGA 321113 Swine and Poultry Trifloxystrobin and CGA 321113 Trifloxystrobin and CGA 321113 Drinking Water Trifloxystrobin and CGA 321113 Not Applicable **5 .2**  **Food Residue**  **Profile** Field Trials DER 48219801 (2010 Coffee Field Trials) , PP#0E7789 Triflox ys trobin residues on plants are mainl y surface residues with only limited translocation within the plant. Residue reduction of various crops was previousl y investigated and residues of trifloxystrobin and CGA - 321113 were found to be reduced with washing and cooking. T o support the petition for tolerance , Bayer submitted adequate Latin American field trial data reflecting the proposed use patterns of triflox ys trobin on importe d coffee (application rates of 0.26 - 0.27 lb ai/A ( 2 applications at 0.1 3 - 0.14 lb ai/A/application) with a 30 - day PHI ). The residue declin e studies show that combined residues of trifloxy strobin and trifloxystrobin acid (CGA - 321113) do not increase with ti me . Samples were anal yz ed for residues of trifloxy strobin and triflox ys trobin acid using acceptable methods, and the studies are supported by adequate storage stability

data. The results from these studies are summarized in Table 5.2 a . **TABLE 5.2 a**  **. Summary of Residue Data from** **Crop Field Trials with Trifloxystrobin (Sphere® 535 SC). Commodity**  **Total Applic.**

**Rate PHI**  **Residue Levels (ppm)**  lb ai/A (kg ai/ha) days **n Min.**  **Ma x.**  **HAFT** a **Median Mean**  **Std. Dev.** STMdR STMR **Total Trifloxystrobin** Coffee, Green Beans 0.26 to 0.27

(0.29 to 0.30) 30 19 <0.010 0.013 <0.010 <0.010 <0.010 <0.010 a HAFT = Highest Average Field Trial. These field trial data were used to determine tolerance levels for total trifloxystrobin residues of trifloxystrobin and its acid metabolite CGA - 321113 on c offee . Except for one, all fie ld trial residues (triflox ys trobin and CGA - 321113) for coffee were below the LOQ ( < 0.0 1 ppm) at the 30 - day PHI. Thus, the recommended t olerance was not calculated b y using the OECD method and HED recommends a tolerance of 0.02 ppm for coffee, green bean .TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 20 of 32 Processed Food and Feed DER 48219802 (Coffee Processed Food/Feed Study) , PP#0E7789 Baye r submitted an acceptable processing study t o support this petition for tolerance. The submitted coffee processing study indicates that following the exaggerated (5X) use of Sphere® 535 SC on coffee plants and subsequent processing of green coffee beans (RAC) into the required commodities of dried i nstant or roasted coffee, total triflox ys trobin residues did not concentrate in dried instant coffee (processing factor <1X) or roasted coffee (processing factor <1X). The processing factor determined for trifloxystrobin residue in coffee is less than the maximum theoretical concentration factor of 4.5X cited in the EPA Residue Chemistry Test Guideline OPPTS 860.1520. A c ceptable method s w ere used for quantitation of residues in/on green coffee beans, roasted coffee, and instant coffee . Acceptable storage stability data are also available to support the study . The results from this study are summarized in Table 5.2b. **TABLE 5. 2b.**  **Residue Data from Green Coffee Beans**  **Processing Study with Trifloxystrobin. Processed Commodity**  **Total Rate**  **PHI Residues**  **Processing Factor**  a lb ai/A (g ai/ha) days ppm NA (RAC) b 1.3 (1.5) 28 0.07 0.07 0.06 NA Coffee , Instant NA <0.010 <0.010 <0.010 <1X Coffee , Roasted Beans NA <0.010 <0.010 <0.010 <1X

a Processing Factor = average residue in the processed sample (coffee, instant or coffee, roasted) divided by the average residue in the unprocessed sample (green coffee beans) . b NA = not applicable. RAC = raw agricultural commodity. Meat, Milk, Poultry, and Eggs The potential exists for secondary residues to occur in some livestock commodities from registered uses . There are no livestock feedstuffs associated with the proposed use s on imported coffee . The dietary

burdens for trifloxy strobin residues in livestock diets will not be affected by the subject action; therefore, data requirements pertaining to meat, milk, poultry , and eggs are not relevant to the proposed uses. The dietary burdens were previousl y calculated and estimated at 3.40 and 7.76 ppm for beef and dairy cattle, and 0. 8 0 ppm for poultry and swine (DP#378917, B. Hanson, 01/25/2011). **5.3 Water Residue Profile**  The highest and most protective EDWCs for trifloxystrobin in drinking water are those estimated in the GENEEC Tier I drinking water assessment for turf (3 applications at 0.34 lbs ai /A; 1.02 lb ai/A/year) . The GENEEC estimates for acute and chronic ( 56 - day) average exposure concentrations were 47.98 and 47.31 μg/L (pp b ) for CGA - 321113, respectively (summarized in Table 5.3). The model and its description are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/ .TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 21 of 32 **TABLE 5**  **.3. Summary of Est**  **im ated Surface**  **W ater Concentrations for**  **Trifloxystrobin.**

**Scenario Surface**  **Water Conc., ppb** a Ac ute (1 in 10 year peak) 47.9 8 Chronic, Non - C ancer ( 1 in 10 year annual mean) 47.31 **5.4 Dietary Risk Assessment**  A c onservative acute and a partiall y refined chronic dietary exposure assessment w ere performed for trifloxy strobin . The assumptions included tolerance - level residues for the acute assessment with partial refinements using anticipated residues for the chronic assessment , 100% crop treated, and DEEM default processing factors. For cattle, goats, horses, and sheep, value of 0.20 ppm was added for Metabolite L 7a in addition to the recommended tolerance level for liver; therefore, meat b yp roducts and liver of cattle, goats, horses, and sheep were assessed in the dietary assessment at 0.3 ppm (DP # 318618, B. O’Keefe, 0 8/ 0 7/2006). The maximum theoretical dietary burden was lower for pork. Therefore, pork was included in the DEEM at the established tolerance level of 0.05 ppm; pork, li ver was included at 0.16 ppm ( D P# 267787, L . Cheng, 0 1/17/2002). Residue reduction data on strawberries from a single trial were previousl y provided which demonstrated that residues of trifloxystrobin and CGA - 321113 declined in/on strawberries after washing and cooking; because additional dietary refinements are not needed, the default processin g factor of 1 was retained. The EDWC for acute exposure of 47.98 μ g/ L ( the 1 - in - 10 year peak surface water EDWC for an existing turf use ) and the EDWC for chronic exposure of 47.31 μ g/ L ( 1 - in - 10 year annual mean surface water) were incorporated directl y into the dietary

assessments (DP#360307 , J . Wolf, 10/07/2009 ). **5.4.1 Acute Dietary Risk Assessment**  There were no appropriate toxicological effects attributable to a single exposure (dose) for the general population or any o ther population subgroups other than females 13 - 49 years old ; therefore these population subgroups were not included in this assessment. An acute dietary (food plus drinking water) assessment assuming tolerance - level residues for all commodities with exis ting and proposed tolerances yi elded exposure estimates below HED’s level of concern ; a cute dietary

exposure utilized 1.9 % of the aPAD for females 13 - 49 years old at the 95 th percentile . The result of the acute dietary exposure anal ys is is reported in Table 5.4. 4 . **5.4.2 Chronic Dietary Risk Assessment**  A partially

refined chronic dietary

(food + drinking water) assessment assuming mostly tolerance - level residues with some anticipated residues (apples, grapes, and oranges) yi elded exposure estimates bel ow HED’s level of concern ; chronic dietary exposure utilized 34 % of the cPAD for the general U.S. population and 64 % of the cPAD for children 1 - 2 years old ( the population subgroup with the highest estimated chronic dietary exposure to trifloxystrobin) . T he results of the chronic dietary exposure anal ys e s are reported in Table 5.4. 4 .TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 22 of 32 **5.4.3 Cancer Dietary Risk Assessment**  Triflox ys trobin is classified as “not likel y to be carcinogenic to humans;” therefo re, no cancer risk is expected and cancer risk assessments were not conducted. **5.4. 4**  **Summary Table TABLE**  **5.4.4 .**  **Summary of Dietary Exposure and Risk for Trifloxystrobin**  **.** a Population Subgroup Ac ute Dietary (Food Only) Chronic Dietary (Food and Drinking Water) Dietary Exposure % cPAD* Dietary Exposure % cPAD* mg/kg/day mg/kg/day General U.S. Population

N/A 0.013067 34 All Infants (< 1 year old) 0.016858 44 Children 1 - 2 years old **0.024165 64**  Children 3 - 5 years old 0.020873 55 Children 6 - 12 years old 0.014334 38 Youth 13 - 19 years old 0.011057 29 Adults 20 - 49 years old 0.012222 32 Adults 50+ years old 0.011801 31 Females 13 - 49 years old **0.047424 1.9**  0.012206 32 a Values for the population with the highest risk for each type of risk assessment are **bolded** . b NA = Not Applicable; no acute dietary endpoint was identified for these population subgroups. **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  **References:**

- Occupational and Residential Risk Assessment for Section 3 Petition to Register New Uses of Trifloxystrobin on Barley, Oats, Sweet Corn, and for the Treatment of Sweet Corn Seed. DP#319193, Jack Arthur, 07/14/2005. While it is assumed that most residential use will result in short - term (1 to 30 day s) post application exposures, it is also believed that intermediate - term exposures (> 30 day s to 180 day s) are possible, although unlikel y. **6.1 Residential Handler Exposure**  According to the labels, the currently registered residential produ ct s are restricted to use b y Certified Pest Control Operator s (PCO s ) onl y . Therefore, an assessment for residential handlers was not conducted (DP#319193, J. Arthur, 07/14/2005) .TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 23 of 32 **6.2 Post**  **- Application Exposure**  There is potential for post - application de rmal and oral exposure to homeowners and children in residential areas previously treated with trifloxy strobin from existing registered domestic uses of trifloxystrobin . As a result, risk assessments have been completed for residential post application sc enarios. Use of triflox ys tro bin on turf may result in individuals of varying ages potentially being exposed from activities in areas that have been treated. Potential routes of exposure include dermal (adults and children) and incidental oral ingestion ( children three to less than six years old only). Since no acute hazard has been identified for children, an assessment of episodic granular ingestion was not conducted. All calculated non - occupational post - application MOEs are greater than 100 on th e day of application, and do not exceed HED's level of concern (DP# 319131, J. Arthur, 0 7/14/2005). The MOEs range from 750 to 220,000 for adult and child residential scenarios (i.e., post - application dermal exposure from pesticide residues on lawns, incidental non - dietary ingestion of pesticide residues on lawns from hand - to - mouth transfer, incidental non - dietary ing estion of residues from pesticide - treated turfgrass from object - to - mouth activities, and incidental non - dietary ingestion of soil from pesticide - treated residential areas). The calculated risks represent screening level estimates and are thought to be con servative. Although both short - and intermediate - term exposures were calculated, the residential exposure duration is believed to be mostly short - term based on the use pattern. A summary of the estimated residential post - application exposures and risks i s presented below in Table 6.2. **TABLE 6.2.**  **Short -**  **and Int ermediate**  **- Term Residential Post**  **- A**  **pplication Exposure and Risk Estimates** 

**for Trifloxy**  **strobin .**  Lifestage Post - Application Exposure Scenario Dose 1 MOE 2 mg/kg/day Adult Mowing Turf

High Contact Dermal 0.079 1,300 Child High Contact Dermal 0.13 760

Treated Lawns Hand to Mouth 0.0051 750 Object to Mouth 0.0013 3,000 Incidental Soil Ingestion 0.000017 220,000 1 Dose calculated based on maximum a pplication rate values found on registered label (EPA Reg. No. 66330 - 3 79 ). 2 MOE Baseline Dermal = NOAEL/Dermal Dose . Short - and Intermediate - Term Dermal NOAEL = 100 mg/kg/day. Short - and Intermediate - Term Incidental Oral NOAEL = 3.8 mg/kg/day. **6.3 Combined Exposure**  FQPA requires residential expo sures that could reasonably be expected to occur on the same day be combined and compared to the appropriate toxicity endpoint. Because trifloxystrobin is not applied by

residential handlers, the only multiple - residential exposure scenario involve s children's exposure from dermal and oral routes following turfgrass treatment by a PCO . For incidental oral exposure to children three to less than six ye ars old in residential settings, the three scenarios that would reasonabl y be expected to occur on the same day are incidental ingestion of residues on turf from hand - to - mouth activities, object - to - mouth activities, and directTRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 24 of 32 ingestion of soil. When combined, these dail y exposures total 0.006417 mg/kg/day . When the combined exposure is compared to the short - term incidental oral NOAEL (3.8 mg/kg/day), the MOE = 590. Because the toxicity endpoints for dermal and oral exposure are not the same, risks from these different routes of exposure are not combined . Thus , the combined risk from incidental oral exposures anticipated for children three to less than six ye ars old (i.e. an MOE of 590) does not exceed HED’s level of concern. **6.4 Residential Bystander Post**  **- A** **pplication Inhalation Exposure** Base d on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for triflox ys trobin at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV), low vapor pressure ( 2.55 x 10 - 7 mmHg ), and the low turf use rate ( 0.34 lb ai/A ). However, volatilization of pesticides may be a source of post application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insec ticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report 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 Agency may revisit the need for a quantitative post - application inhalation exposure assessment for trifloxy strobin . **6. 5**  **Spray Drift** Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground a pplication method employed for trifloxy strobin . The Agency

has been working with the Spray Drift Task Force, EPA Regional Offices , and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency ’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by che mical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by

the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy

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

is in p lace, the Agency

may impose further refinements in spray drift management practices to reduce off - target drift with specific products with significant risks associated with drift. **7.0 Aggregate Exposure/Risk Characterization**  In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregateTRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 25 of 32 assessment, exposures from relevant sources are added together and compared to quantitative estimate s 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 trifloxystrobin , 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; therefore, 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 a ssess 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 p athway s lead to exposure via oral (background) as well as dermal and inhalation (primary) routes. For children, these pathway s lead to exp osure vi a the oral (background) as well as incidental oral and dermal (primary) routes. The adult (dermal) and children’s (dermal and oral) aggregate MOEs are greater than 100, which indicates that exposure and risk do not exceed HED’s level of concern. The ch ildren’s a ggregate 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 empiri cal processing fac t or s may need to be incorporated in future assessments. **TABLE 7.2**  **. Short**  **- and Intermediate Term Aggregate Risk Calculations**  **.** Population Short - and Intermediate - Term Scenario NOAEL LOC 1 Average

Food and Water Exposure Residential

Dermal Exposure 2 Residential

Oral Exposure 2 Total

Exposure 3 Aggregate

MOE (food, water, and residential) 4 mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day Adult 100 100 0.0 3067 0.079 NA 5 0.0 92067 1,100 Children 1 - 2 years old (Derma l Exposure ) 100 100 0.0 24165 0.13 NA 0.1 54165 65 0 Children 1 - 2 years old (Oral Exposure ) 3.8 100 0.0 24165 NA 0.00 51 0.0 29265 130 1 Indicate in this footnote the basis for the LOC (inter - and intra - species uncertainty factors total 100 X ) . 2 Residential Dermal and Oral Exposure s cannot be combined (Table 6. 2 ). 3 Total Exposure = Avg Food & Water Exposure + Residential Exposure) . 4 Aggregate MOE = [NOAE L / (Avg Food & Water Exposure + Residential Exposure)] . 5 NA = N o t A

pplicable.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 26 of 32 **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 short soil half

- life (about 2 day s). Therefore, an intermediate - term aggregate risk assessment was not performed. **7. 4**  **Chronic Aggregate 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 assessment has not been conducted. **8.0 Cumulative Exposure/Risk Character**  **ization** Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity , EPA has not made a common mechanism of toxicity finding as to trifloxys trobin and an y other substances and trifloxystrobin does not appear to produce a toxic 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 of Pesticide Programs concerning common mechanism determinations and pro cedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/ .TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 27 of 32 **A ppendix**  **A .**  **Toxicology Profile and Executive Summaries A.1**  **Toxicology Data Requirements** The requirements (40 CFR § 158.340) 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.**  **Satisfication of Trifloxystrobin**  **Toxicology Data Requirem ents**  **. Study**  **Technical Required**  **Satisfied** 870.1100 Acute Oral Toxicity ................................ ......................... 870.1200 Acute Dermal Toxicity ................................ .................... 870.13 00 Acute Inhalation Toxicity ................................ ................ 870 .2400 Primary Eye Irritation ................................ ...................... 870.25 00 Primary Dermal Irritation ................................ ................ 870. 2600 Dermal Sensitization ................................ ........................ yes yes yes yes yes yes yes

yes yes yes yes yes 870.3 100 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 CR 1 CR2 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) ................. 870.6300 Develop. Neurotoxicity ................................ ................... no no yes yes CR3 -

- no no

- 870.7485 Gen eral Metabolism ................................ ........................ 870.7600 Dermal Penetration ................................ .......................... 870.7800 Immunotoxicity ................................ ............................... yes yes yes yes

yes no CR 1 = Conditiona lly

required based on previous domestic registration action ; CR2 = The Agency is in the process of evaluating the SAP report and may, as appropriate, reexamine and develop new policies and procedures for conducting inhalation risk assessments, including route to route extrapolation of toxicity data ; CR3 = Determination of requirement is pending submission of acceptable guideline acute and subchronic neurotoxicity batteries.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 28 of 32 **A.2 Toxicity Profile**  **of Tri floxystrobin 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.**  **Trifloxy strobin**  **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 weight.

870.3100 90 - Day oral

toxicity (rat) 44496701 (1995)

Acceptable 0, 100, 500, 2000, 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 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 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 29 - Day

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

Unacceptable/non guideline (2 dog/sex/dsoe) 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. 385972

Page 29 of 32 **TABLE A.2.2.**  **Trifloxy strobin**  **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 0, 10, 100, 1000 mg/kg/day NOAEL = 100 mg/kg/day . LOAEL = 1000 mg/kg/day based on i ncreased liver and kidney weight. 870.3700a Prenatal

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

Acceptable 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 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. Developmental 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 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, decr eased 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 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 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 - statis tically 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)

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. 870.5100 In vitro bacterial

reverse gene mutation - Salmon ella 44496712

44496715 44496716 44496717 NegativeTRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 30 of 32 **TABLE A.2.2.**  **Trifloxy strobin**  **Subchronic, Chronic and Other Toxicity Profile .**  **Guideline No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.5300 Gene Mutation in

Chinese Hamster Cultured V - 79 44496713 Positive 870.5385 Structural

Chromosome Aberration - Micronucleus - mo use 44496714 Negative

870.5385 Structural

Chromosome Aberration - Cy togenetics - Chinese Hamster 44496718 Negative 870.5500 DNA Repair - Rat

hepatocytes 44496719 Negative

870.6200a Ac ute oral

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

Unacceptable 0, 2000 mg/kg/day 44840802 (1997) 0, 1000, 2000, 3500 mg/kg/day (provides supplemental information). 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 0.5, 100 mg/kg/day Oral admi nistration 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 ma les and females respectively. Highest 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 c arcass 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. 385972

Page 31 of 32 **A ppendix**  **B. M**  **etabolism Summary Table TABLE**  **B. Tabular Summary of Metabolites and Degradates**  **.** Com pany Name Chemical Name Structure 1 trifloxystrobin [parent] methyl (α E) - α - (methoxyimino) - 2 - [[[[(1 E) - 1 - [3 - (trifluoromethyl)phenyl]ethylidene]amino]oxy] methyl]benzeneacetate

CGA - 321113 [acid metabolite] (αE) - α - (methoxyimino) - 2 - [[[[(1 E) - 1 - [3 -

(trifluoromethyl)phenyl]ethylidene]amino]oxy] methyl] - benzeneacetic acid **Appendix C. Physical/Chemical Properties**  **TABLE C.**  **Phy sicochemical Properties of the**  **Technical Grade Test Compound: Trifloxystrobin**  **.**

**Parameter Value**  **Reference** Melting Point/Range 72.9oC MRID 44502801 pH ( 25oC ) 7.7 in 1 % w /w aqueous dispersion MRID 44502801 Density ( 21oC ) 1.36 g/cm 2 MRID 44502801 Water S olubility ( 20oC ) 0.00061 g/L MRID 44502801 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 MRID 44502801 Vapor P ressure (25 °C ) 3.4 x 10 - 6 Pa , 2.55 x 10 - 7 mmHg MRID 44502801 Dissociation C onstant (pKa) none at pH of 2 - 12 MRID 44502801 Octanol/Water Partition C oefficient ( 25oC ) Log(KOW) 4.5 MRID 44502801 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) MRID 44502801 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. 385972

Page 32 of 32 **Appendix D. International Residue Limit Summary**  **Table E**  **. Summary of US and International**  **Tolerances and Maximum Residue Limits.** Residue Definition **US Canada**  **Mexico** 2 **Codex** 40 CFR 180.555: Plants/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 it s acid metabolite CGA

– 321113, ( E,E ) - methoxyimino - [2 - [1 - (3 - trifluoromethyl - phenyl) - ethylideneaminooxymethyl] - phenyl]acetic acid, calculated as the stoichiometric equivalent of trifloxystrobin. methyl (α, E ) - α - (methoxyimin o) - 2 - [[[( E ) - [1 - [3 - (trifluoromethyl)phenyl]ethylide ne]amino]oxy]methyl]benzene acetate, including the metabolite (α, E ) - α - (methoxyimino) - 2 - [[[( E ) - [1 - [3 - (trifluoromethyl)phenyl]ethylide ne] - amino]oxy]methyl]benzene acetic acid, expressed as trifloxystrobin. Plants : trifloxystrobin Livestock : sum of trifloxystrobin and [(E,E) - methoxyimino - {2 - [1 - (3 - trifluoromethylphenyl)eth ylideneaminooxymethyl] phenyl}acetic acid] (CGA 321113), expressed as trifloxystrobin. The residue is fat - soluble. Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) **US Canada**  **Mexico** 2 **Codex** Coffee, green bean 0.02 Com pleted: : M. Negussie; 06/27/2011 1 Includes only commoditie s of interest for this action. 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.