Document ID: EPA-HQ-OPP-2011-0458-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-07-20T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND

\* MERGEFORMAT
                                                           POLLUTION PREVENTION
                                       

MEMORANDUM

DATE:	June 14, 2012

SUBJECT:	REVISED Trifloxystrobin.  Human Health Risk Assessment Analysis for Proposed 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
TXR 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
	Health 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, globe.  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, nor any changes to residential exposure resulting from the proposed tolerance of 1.0 ppm.

In addition to the tolerance evaluation, this document addresses the responses to two waiver requests for: 28-Day Inhalation Exposure Toxicity and Subchronic Neurotoxicity.
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 Identity	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
1.0	Executive Summary

In PP#1F7845, Bayer Cropscience (Bayer) has petitioned for the establishment of a new tolerance for combined residues of the fungicide trifloxystrobin [benzeneacetic acid, (E,E)-α-(methoxyimino)-2-[[[[1-[3-(trifluoromethyl)phenyl]ethylidene] amino]oxy]methyl]-methyl ester] and the free form of its acid metabolite CGA-321113 [(E,E)-(methoxyimino)-[2-[1-(3-(trifluoromethylphenyl)-ethylideneaminooxymethyl]-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 study 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 findings and a discussion of human health risk resulting from the proposed tolerance of trifloxystrobin are provided in this document.  This assessment has been conducted by Nancy Tsaur.

2.0	HED Recommendations

There are no data deficiencies that preclude establishment of a permanent tolerance for combined residues of trifloxystrobin in/on globe artichokes.

2.1	Data Deficiencies/Conditions 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-year grace period to allow time for registrants to develop the required data. The registrant has informed the Agency of their intent to submit 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 frequently 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 inhalation 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 has increased its focus on the uncertainties associated with route-to-route extrapolation and is presently 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 trifloxystrobin.

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 withdrew the petition for tolerance in/on globe artichokes prior to the establishment of a permanent tolerance.

Now, in 2011 (PP#1F7845), Bayer has submitted a new petition for a tolerance of 1.0 ppm for residues of trifloxystrobin in/on globe artichokes.  With the petition, Bayer has submitted amended labels for Flint(R) Fungicide (EPA Reg. No. 264-777) and Gem(TM) 500 SC Fungicide (EPA Reg. No. 264-826) to include use on globe artichokes.  Flint(R) is a water dispersible granule (WG) formulation consisting of 50% trifloxystrobin by weight whereas Gem(TM) 500 SC is a suspension concentrate (SC) formulation consisting of 4.17 lb trifloxystrobin 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 approach: HED considered the trifloxystrobin 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 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#0056113, Sheila Healy, 01/06/2012).

3.1	Chemical Identity

Trifloxystrobin is a strobilurin-class fungicide (also termed methoxyacrylates) that controls foliar fungal diseases and soilborne/seedling fungal diseases.  It works by interrupting mitochondrial respiration in plant-pathogenic fungi, thus inhibiting spore 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 soybean.  Trifloxystrobin is described in Table 3.1.

Table  3.1.  Trifloxystrobin Nomenclature
Chemical Structure

Empirical Formula
C20H19F3N2O4 
Common 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 (αE)-α-(methoxyimino)-2-[[[[(1E)-1-[3-(trifluoromethyl)phenyl]ethylidene]amino]oxy]methyl]benzeneacetate
CAS Registry Number
141517-21-7
End-Use Products (EPs)
Flint(R) Fungicide (50% ai); Gem(TM) 500 SC (4.17 lb ai/gallon)
Chemical Class
Strobilurin, methoxyacrylates
Known Impurities of Concern
None

3.2	Pesticide Use Pattern

Bayer submitted amended labels for Flint(R) Fungicide (EPA Reg. No. 264-777) and Gem(TM) 500 SC Fungicide (EPA Reg. No. 264-826) to include use on globe artichokes.  Flint(R) WG formulation consisting of 50% trifloxystrobin by weight whereas Gem(TM) 500 SC is an SC formulation 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.  Summary of Directions for Use of Trifloxystrobin
                       Applic. Timing, Type, and  Equip.
                          Formulation (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(R)
                           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.
                                       
                                 Gem(TM) 500 SC
                            Suspension Concentrate
                                   (264-826)
                                       
                                       
                                       
                                       

4.0	Hazard Characterization and Dose-Response Assessment

References: 
   oo Trifloxystrobin.  Human Health Risk Assessment for Proposed New Use on Imported Coffee. DP#385972, Nancy J. Tsaur, 08/02/2011.

A detailed hazard characterization with a list of available toxicity studies for trifloxystrobin is presented in the previous risk assessment (DP#385972, N. Tsaur, 08/02/2011).  The submitted toxicology studies are of good quality and provide sufficient information to determine whether trifloxystrobin poses a human health hazard.  

In addition to the existing database, Bayer 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 trifloxystrobin 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.  Therefore, HED concluded to grant the waiver request for an SCN study (DP#385650, TXR#0056113, Sheila Healy, 01/06/2012).

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 directly targets the immune system, 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 trifloxystrobin based on the available database, limited findings in an ACN study, and lack of neurotoxicity in other fungicides of the strobilurin class.

4.1.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no indication of increased quantitative or qualitative susceptibility to trifloxystrobin in rats or rabbits.  In the prenatal developmental study in rats, there was no developmental toxicity at 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 trifloxystrobin.  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 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.  Although the chronic assessment included these minor refinements, the use of representative field trial data ensures that actual exposures/risks from residues in food will not be underestimated.  The dietary drinking water assessment utilizes water concentration values generated by models and associated modeling parameters which are designed to provide conservative, health protective, high-end estimates of water concentrations, and are not likely to be exceeded.  In addition, the residential post-application exposure assessment is based upon the residential SOPs employing surrogate study data, including conservative 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 underestimate 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-2011-0456-0004, FRN Vol. 76, No. 217, pp. 69648, 11/09/2011). 

5.0	Dietary Exposure and Risk Assessment 

References: 
   oo 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.

There 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 assessments conducted for trifloxystrobin included the proposed tolerance for globe artichokes.  The results of both acute and chronic dietary exposure analyses remain unchanged and are reported in Table 5.0.   The acute dietary (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.  Trifloxystrobin is classified as "not likely to be carcinogenic to humans" and thus cancer risk is not expected.

 Table 5.0.  Summary of Dietary Exposure and Risk for Trifloxystrobin
                              Population Subgroup
                                 Acute 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: 
   oo 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 by Certified Pest Control Operators (PCOs) only.  Therefore, an assessment for residential handlers was not conducted.  Additionally, residential risk estimates cannot be combined because the toxic effects 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 "not likely to be carcinogenic to humans." 

This assessment has taken into consideration the changes in the new Residential Standard Operating Procedures (SOPs) to be implemented in January of 2012.  HED finds no changes that would affect the aggregate safety finding and confirms that there are no risks of concern resulting from setting a tolerance for trifloxystrobin 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)].