TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 388187/388434

Page 1 of 9 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA**  **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM DATE:**  June 14 , 2012 **SUBJECT: REVISED**  **Trifloxy strobin.**  Human Health Risk Assessment Anal ys is for

Propo sed New Use on Globe Artichokes and Waiver Requests for 28 - Day Inhalation Toxicity

and Subchronic Neurotoxicity Studies. **PC Code:** 129112 **DP Barcode:** 388187, 388434 **Decision No.:** 445968, 445971 **Registration No. :**  264 - 776, 777, 826 **Petition No.:** 1F7845 **Regulatory Action:** Section 3 **Risk Assessment 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 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 Registration Division (7505P) RD requested that HED provide an evaluation of the proposed tolerance for trifloxystrobin in/on artichoke, glo b e . HED concludes that a new human health aggregate risk assessment is not needed for this petition . There are no changes to trifloxystrobin dietary exposure from food and

/or drinking water, no r any changes to residentia l exposure resulting from the proposed tolerance of 1.0 ppm . In addition to the tolerance evaluation, this document address es the responses to two waiver request s for : 28 - Day

Inhalation Exposure Toxicity and Subchronic Neurotoxicity .TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 388187/388434

Page 2 of 9 **Table of Contents 1.0**  **Executive Summary ................................**  **................................ ................................**  **........... 3**  **2.0 HED Recommendations**  **................................ ................................**  **................................ ....**  **3 2.1**  **Data Deficiencies/Conditions of Registration** ................................ .............................. 3 **2.2 Recommended Tolerances**  ................................ ................................ ............................. 4 **3.0 Introduction**  **................................ ................................**  **................................ ........................**  **4 3.1**  **Chemical Ide ntity**  ................................ ................................ ................................ ........... 4 **3.2 Pesticide Use Pattern**  ................................ ................................ ................................ ...... 5 **4.0 Hazard Characterization and Dose**  **- Response Assessment**  **................................ ............**  **6 4.1**  **Safety Factor for Infants and Children (FQPA Safety Factor)** ................................ . 6 **4.1.2 Evidence of Neurotoxicity**  ................................ ................................ .......................... 6 **4. 1.3**  **Evidence of Sensitivity/Susceptibility in the Developing or Young Animal** .......... 7 **4.1.4 Residual Uncertainty in the Exposure Database**  ................................ ..................... 7 **5.0 Dietary Exposure and Risk Assessment**  **................................ ................................**  **........... 7**  **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  **............................... 8**  **7.0 Aggregate Exposure/Risk Characterization**  **................................ ................................**  **.... 8** TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 388187/388434

Page 3 of 9 **1.0 Executive Summary**  In PP# 1 F7845, Bayer Cropscience (Bayer) has 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 methyl] - phenyl]acetic acid] in/on the following raw agricultural commodities (RAC):

Artichoke, globe ................................ ....................... 1.0 ppm The most recent human health risk assessment was conducted for use on imported coffee in which the hazard characterization and toxicity endpoints for risk assessment were reported (DP#379110, N. Tsaur, 02/28/2011) . Since then, a waiver request for a 28 - day inhalation exposure toxicity

stu dy was submitted and denied, and a waiver request for a subchronic neurotoxicity (SCN) study was submitted and accepted. Other then the waiver requests , the hazard characterization and toxicity endpoints for risk assessment remain unchanged. The details of the hazard characterization and the rationale for toxicity endpoint selection will not be repeated in this risk assessment. However, the salient features for the Food Quality Protection Act (FQPA) safety

factor will be summarized . A summary

of the fin dings and a discussion of human health risk resulting from the proposed tolerance of trifloxy strobin are provided in this document . This assessment has been conducted by Nancy Tsaur. **2.0 HED Recommendations**  T here are no data deficiencies that preclude establishment of a permanent tolerance for combined residues of trifloxy strobin in/on globe artichokes . **2.1 Data Deficienc**  **ies /Condition**  **s of Registration**  Toxicology

[870.7800 Immunotoxicity] In 2007, the Agency revised 40CFR Part 158.500 Toxicology data requirements to include functional immunotoxicity testing and granted a 2 - ye ar grace period to allow time for registrants to develop the required data. The registrant has informed the Agency of their intent to sub mit an immunotoxicity study as a condition of registration (the study was scheduled to be conducted in 2011) . Toxicology

[870.3465 28 - Day

Inhalation Toxicity] Prior to 2010, the Agency frequentl y relied on oral toxicity studies to conduct inhalation risk assessments. In December 2009, the Agency sought expert advice and input from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) on issues related to this route to route extrapolation approach in the absence of an inha lation toxicity study (i.e. the use of oral toxicity studies for inhalation risk assessment). Based on the SAP’s recommendations in the March 2, 2010 Final Report ( http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ), the Agency hasTRIFLOXYSTROBIN Human Health Risk Assessment DP No. 388187/388434

Page 4 of 9 increased its focus on the uncertainties associated with route - to - route extrapolation and is presentl y requiring inhalation toxicity studies more frequently . The Agency has concluded that an inhalation toxicity study is required as a condition of registration to fully characterize the risk from inhalation exposure to triflox ys trobin . **2.2 Recommended Tolerances**  **Table 2.2. Tolerance Summary for**  **Trifloxystrobin** Commodity Tolerance (ppm) Comments Correct Commodity Definition Established Proposed Recommended

40 CFR §180.609(a)(1) Artichoke, globe -- 1.0 1.0 **3.0 Introduction**  In 2010 (PP#8F7464), Bayer submitted a petition for tolerance on globe artichokes. Subsequently , HED reviewed the submitted field trial data and concluded that the data did support the proposed tolerance of 1.0 ppm in a previous risk assessment (B. Hanson , DP#360305, 12/09/2010). To support the risk assessment recommendation , both acute and chronic dietary

risk estimates incorporated the proposed tolerance level of 1.0 ppm for globe artichokes (B. Hanson, DP#379505, 09/28/2010) . However, Bayer later with drew the petition for tolerance in/on globe artichokes prior to the establishment of a permanent tolerance. Now , in 2011 (PP# 1F78 45 ), Baye r has submitted a new petition for a tolerance of 1.0 ppm for residues of trifloxy strobin in/on globe artichokes . Wi th the petition, Bayer has submitted amended label s for Flint® Fungicide (EPA Reg. No. 264 - 777) and GemTM 500 SC Fungicide (EPA Reg. No. 264 - 826) to include use on globe artichokes. Flint® is a water dispersible granule (WG) formulation consisting of 50% triflox ys trobin by weight whereas GemTM 500 SC is a s uspension concentrate (SC) formulation consisting of 4.17 lb triflox ys trobin per gallon of product. Along with this petition for tolerance, Bayer has submitted two waiver requests : one for a 28 - day inhalation exposure toxicity study ( Guideline 870.3465 ) , and one for the subchronic neurotoxicity (SCN) study of the neurotoxicity

battery ( Guideline 870.6200b ) . Upon review of the waiver requests, HED determined that a 28 - day inhalation exposure toxicity study will be required based on a weight of evidence app roach : HED considered the trifloxy strobin use pattern, all relevant hazard and exposure information, in addition to the current OPP guidance for waiving inhalation studies. **Therefore, HED concluded**  **to deny the waiver request for the 28 -**  **day inhalation expo sure toxicity study.**  However, regarding the SCN, HED determined that the re is no concern for neurotoxicity for trifloxy strobin based on the available database, limited findings in an acute neurotoxicity (ACN) study, and lack of neurotoxicity in other fungicides of the strobilurin class. **Therefore, HED concluded**  **to grant the waiver request**  **for an SCN study**  (DP#385650, TXR#0056 113 , Sheila Heal y, 01/06 /201 2 ) . **3.1 Chemical Identity** TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 388187/388434

Page 5 of 9 Triflox y strobin is a strobilurin - class fungicide (also termed methox yacryl ates) that controls foliar fungal diseases and soilborne/seedling fungal diseases . It works b y interrupting mitochondrial respiration in plant - pathogenic fungi, thus inhibiting spor e germination and mycelial growth. It 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. Trifloxystrobin is described in Table 3.1. **Table 3.1 .**  **Trifloxy strobin Nom**  **enclature**

Chemical Structure

Em pirical Formula C 20 H 19 F 3 N 2 O 4 Common name trifloxystrobin 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 Products (EPs) Flint® Fungicide (50% ai ); GemTM 500 SC (4.17 lb ai/gallon) Chemical Class Strobilurin, methoxyacrylates Known Impurities of Concern None **3. 2**  **Pesticide Use Pattern** Baye r submitted amended labels for Flint® Fungicide (EPA Reg. No. 264 - 777) and GemTM 500 SC Fungicide (EPA Reg. No. 264 - 826) to include use on globe artichokes. Flint® WG formulation consisting of 50% triflox ys trobin by weight whereas GemTM 500 SC is an SC formul ation consisting of 4.17 lb trifloxystrobin per gallon of product. A summary of the directions for use are listed in Table 3.2. **Table 3. 2**  **. Summ ary of Directions for Use of**  **Trifloxystrobin** Applic. Timing, T ype, and Equip. Form

ulation ( EPA Reg. No. ) Applic.

Rate Max.

No. Applic. per Season Max.

Seasonal Applic. Rate PHI Use Directions and Limitations lb ai/A lb ai/A days

**Peanut** Groundboom, Aerial, Airblast, or Chemigation Flint®

Water Dispersible Granule (264 - 777) 0.10 -

0.125 2 0.25 0 To control Powdery mildew ( Leveillula taurica ). Applications should begin when conditions are favorable for diseases but before infection. RTI = 7 to 10 days. GemTM 500 SC Suspension Concentrate (264 - 826) O N C F 3 N O O

CH 3 O C H 3 C H 3TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 388187/388434

Page 6 of 9 **4.0 Hazard Characterization and Dose**  **- Response**  **Assessment References:** 

- Trifloxy

strobin. Human Health Risk Assessment for Proposed New Use on Imported Coffee . DP# 385972, Nancy J. Tsaur , 0 8 / 02 /20 11 . A detailed hazard characterization with a list of available toxicity studies for trifloxystrobin is presented in the previous risk assessment (DP# 385972 , N . Tsaur , 0 8 / 02 /2011 ). The submitted toxicology

studies are of good qualit y and provide sufficient information to determine whether trifloxystrobin poses a human health hazard. In addition to the existing database , Baye r has submitted two waiver requests: one for a 28 - day inhalation exposure toxicity study (Guideline 870.3465 ), and one for the SCN study of the neurotoxicity

battery (Guideline 870.6200b ). Upon review of the waiver requests, HED determined that a 28 - day

inhalation exposure toxicity study will be required based on a weight of evidence approach: HED considered the triflox ys trobin use pattern, all relevant hazard and exposure information, in addition to the current OPP guidance for waiving inhalation studies. **Therefore, HED concluded**  **to deny the waiver request for the 28 -**  **day inhalation exposure toxicity study.**  However, regarding the SCN, HED determined that there is no concern for neurotoxicity

for trifloxystrobin based on the available database, limited findings in an ACN study , and lack of neurotoxicity in other fungicides of the strobilurin class. **Therefor e, HED**  **concluded to grant the waiver request for an SCN study**  (DP#385650, TXR#0056 113 , Sheila Heal y, 01/06 /201 2 ) . **4.1 Safety Factor for Infants and Children (FQPA Safety Factor)**  The toxicology

and exposure data and have been evaluated and trifloxystrobin has been determined to be safe for infants and children, supporting the reduction of the FQPA safety factor to 1X. **4 .1**  **.1 Completeness of the Toxicology Database**  The toxicity

database for trifloxystrobin is complete with the exception of an immunotoxicity study and a 28 - day

inhalation toxicity

study . A waiver for a subchronic neurotoxicity study has been granted. Although immunotoxicity and inhalation studies are needed to complete the database, the entire trifloxystrobin toxicity database was examined; the database of this chemical shows no indication that this chemical directl y targets the immune s ys tem , and there are no uncertainties with respect to residential inhalation exposures . **4.1.2 Evidence of Neurotoxicity**  There is 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). There is no concern for neurotoxicity for trifloxy strobin based on the availabl e database, limited findings in an ACN study , and lack of neurotoxicity in other fungicides of the strobilurin class .TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 388187/388434

Page 7 of 9 **4. 1**  **.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  There is no indication of increased quantitative or quali tative 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 was seen at a dose that was higher than the dose that caused maternal toxicity . In the multi generation study, offspring and parental LOAELs are at the same dose level. **4. 1**  **.4 Residual Uncertainty in the Exposure Database**  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 trifloxy strobin. The main contribution to total aggregate exposure is from the dietary route. The acute dietary assessment was unrefined, assuming conservative upper bound inputs including 100% crop treated and tolerance - level residues. The chronic dietary assessment was partiall y refined, assuming 100% crop treated and tolerance - level residues for all commodities except for apples, grapes, and oranges where the average field trial residues were used. Although the chronic assessment included these minor refinements , the use of representative field trial data ensures that actual exposures/risks f

rom residues in food will not be underestimated. The dietary drinking water assessment utilizes water concentration values generated b y models and associated modeling parameters which are designed to provide conservative, health protective, high - end estim ates of water concentrations, and are not likel y to be exceeded. In addition, the residential post application exposure assessment is based upon the residential SOPs employing surrogate study data , including con s ervative exposure assumptions based on Day 0 dermal contact to turf treated at the maximum application rate . 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 un derestimate risk. **4. 2**  **Summary of Points of Departure and Endpoints Used in Human Risk Assessment** The summary

of toxicological doses and endpoints supporting this petition remain unchanged and have been summarized in the previous human health risk assessment (DP# 385972 , N. Tsaur, 08/02/2011 ) as well as the most recent Federal Register Notice ( EPA - HQ - OPP - 201 1 - 0456 - 0004, FRN Vol. 76, No. 217 , pp. 69648 , 11 / 09 /2011 ). **5.0 Dietary Exposure and Risk Assessment**  **References:**

- 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# 387201 , Nancy J. Tsaur , 07/13/2011 . T here were no appropriate toxicological effects attributable to a single exposure (dose) for the general population or any other population subgroups other than females 13 - 49 years old . The most recent acute and chronic dietary exposure assessment s conducted for trifloxystrobin included the proposed tolerance for globe artichokes . The results of both acute and chronic dietary exposure anal ys es remain unchanged and are reported in Table 5. 0 . The acute dietaryTRIFLOXYSTROBIN Human Health Risk Assessment DP No. 388187/388434

Page 8 of 9 (food + drinking water) assessment was unrefined , and the chronic dietary (food + drinking water) assessment was partially refined, assuming 100% crop treated and tolerance - level residues for all commodities except for apples, grapes, and oranges where the average field trial residues were used . Triflox ys trobin is classified as “not like ly to be carcinogenic to humans ” and thus cancer risk is not expected. **Table 5.0 . Summ**  **ary of Dietary Exposure and Risk for Trifloxystrobin**  Population Subgroup Ac ute Dietary (Food and Drinking Water) Chronic Dietary (Food and Drinking Water) Dietary Exposure % aPAD* Dietary Exposure % cPAD* mg/kg/day mg/kg/day General U.S. Population N/A 0.013067 34 Children 1 - 2 years old 0.024165 64 Females 13 - 49 years old 0.047424 1.9 0.012206 32 **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. According to the labels, the currently registered residential products are restricted to use b y Certified Pest Control Operators (PCOs) onl y. Therefore, an assessment for residential handlers was not conducted. Additionally , r esidential risk estimates cannot be combined because the toxic effe cts are different via different routes of exposure. Thus, the risk estimates resulting from post - application exposure scenarios remain unchanged from the previous assessment and are summarized in Table 6. 0 . **Table 6. 2**  **. Short**  **- and Intermediate**  **- Term**  **Residential Post -**  **Application Exposure and Risk Estimates for Trifloxystrobin**  Population Post - Application Exposure 1 mg/kg/day Residential Post Application Total Exposure mg/kg/day MOE Dermal Inhalation Oral Adult 0.079 NA NA 0.079 1300 Child 0.13 NA NA 0.13 770

NA NA 0.0051 0.0051 750 1 Post - application exposure represents high end incidental oral exposure for the relevant exposure duration (hand - to - mouth) . **7.0 Aggregate Exposure/Risk Characterization**  The aggregate risk calculation remains unchanged since the last risk assessment because the proposed tolerance for globe artichokes has been previously incorporated into the dietary risk estimates, and residential risk estimates remain unchanged . Chronic exposures via the dietary (food and drinking water) route are summarized in Section 5.0 . Short - and intermediate - term risk estimates are summarized in Table 7.0. An aggregate cancer assessment was not conducted because trifloxystrobin is classified as “n ot likel y t o be carcinogenic to humans .”TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 388187/388434

Page 9 of 9 This assessment has taken into consideration the changes in the new R esidential S tandard O perating P rocedure s (SOPs) to be implemented in January of 2012. HED finds no changes that would affect the aggregate safe ty finding and confirms that there are no risks of concern resulting from setting a tolerance for triflox ys trobin in/on globe artichokes , nor from utilizing the new Residential SOPs to estimate residential exposure and risk . **Table 7. 0**  **. 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 0.03067 0.079 NA 0.092067 1,100 Children (Dermal) 1 - 2 years old 100 100 0.024165 0.13 NA 0.154165 650 Children (Oral) 1 - 2 years old 3.8 100 0.024165 NA 0.0051 0.029265 130 1 LOC = level of concern. 2 Residential Dermal and Oral Exposures cannot be combined (Table 6.2). 3 Total Exposure = Avg Food & Water Exposure + Residential Exposure. 4 Aggregate MOE = [NOAEL / (Avg Food & Water Exposure + Residential Exposure)].