TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 396514

Page 3 of 9 1.0 Executive Summary

In PP# 1F7845 , Bayer Cropscience (Bayer) has petitioned for the increase of an existing 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):

Almond, hulls

................................ ........................... 9 .0 ppm

In addition, Bayer has petitioned for the removal of an existing tolerance for combined residues of trifloxystrobin in/on vegetable, root, except sugar beet, subgroup 1B, except radi sh (0 .1 ppm)

.

The most recent human health risk assessment was conducted for use on imported coffee in
which t he hazard characterization and toxicity endpoints for risk assessment were reported ( DP 379110, N. Tsaur, 02/28/2011) . Since then, a waiver reque st 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. In addition, an immunotoxicity study has been submitted; preliminary examination of the data found no evidence of immunotoxicity.
T he hazard characterization and toxicity endpoints for risk assessment s associated with this
action remain unchanged. The d etails 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 increase of trifloxystrobin 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 n increased permanent tolerance
for combined residues of trifloxystrobin in/on almond hulls

.

The established tolerance for a lmond has been replaced by the established tolerance for n ut, tree, group 14 , and should be removed. In addition, the established tolerance for v egetable, root, except sugar beet, subgroup 1B, except radish , has been superseded by the established tolerance
for v egetable, root, except sugar beet, subgroup 1B , and should be removed.

2.1 Data Deficienc ies

Toxicology [870.7800 Immunotoxicity] A Part 158.500 functional immunotoxicity study, previously required as a condition of registration, has been received and is currently in review.

Toxicology [870.3465 28

- Day Inhalation Toxicity]TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 396514

Page 4 of 9 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 Adv isory 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, 201 0 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 extrapola tion 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 a Proposed Recommended

40 CFR §180.609(a)(1)

Almond

, hulls 3.0 3.0 9.0

Almond 0.04

-- Remove A separate tolerance for almond is no longer needed because residues in this commodity will be covered by the established tolerance for nut, tree, group 14 at 0.04 ppm.

Vegetable, root, except sugar beet, subgroup 1B, except radish 0.10

-- Remove This tolerance has been replaced by the established tolerance for

v egetable, root, except sugar beet, subgroup 1B

.

a Under 40 CFR §180.555(a)

.

3.0 Introduction

I n PP# 1F7845

, Bayer has submitted a petition for a tolerance increase for trifloxystrobin in/on
almond

, hulls and the removal of tolerance in/on vegetable, root, except sugar beet, subgroup 1B, except radish

. With the petition, Bayer has submitted several draft labels detailing the proposed use pattern for the following tr ifloxystrobin products, two of which are mixed active ingredient (MAI) products : 50% WG formulation (Flint® Fungicide; EPA Reg. No. 264

- 777)

, 4.17 lb ai/gal SC formulation (Gem® 500 SC Fungicide; EPA Reg. No. 264

- 826)

, 25% WG formulation (Gem® Fungicide; E PA Reg. No. 264

- 781)

, 0.49 lb ai/gal SC MAI formulation (DistinguishTM 480 SC Fungicide; EPA Reg. No 264

- 1027; also contains 3.51 lb ai/gal pyrimethanil) , and 25% WG MAI formulation (Adament® 50 WG Fungicide; EPA Reg. No. 264

- 1052; also
contains 25% tebucon azole)

.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 396514

Page 5 of 9 3.1 Chemical Identity

Trifloxy strobin 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

- path ogenic 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. Trifloxy strobin is described in
Table 3.1.

Table 3.1. Trifloxy strobin Nomenclature

Chemical Structure

Empirical Formula C 20 H 19 F 3 N 2 O 4 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 (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

Reference :

- Trifloxystrobin. Application for Section 3 Registration to Increase the Tolerance on Almond Hulls, Reduce the Preharvest Interval for Use on Almond, and Remove the Tolerance for Vegetable, Root, Except Sugar Beet, Subgroup 1B, Except Radish. Summary of Analytical Chemistry and Residue Data

. DP 396514, Amelia Acierto,
05/16/2012

.

Under this action, Bayer is proposing to reduce the p reharvest interval ( PHI ) for almonds from 60 days to 14 days (except as noted for the MAI products )

. The proposed use patterns were compared with the accepted labels for all products; a summary of the u se patterns are presented in Table 3.2 with proposed PHI changes denoted in italicized bold

.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 396514

Page 6 of 9 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 a Use Directions and Limitations

lb ai/A lb ai/A days

Almond

Foliar;
Broadcast or Airblast;
Ground (min. 50 gal/A) or
aerial (min. 10 gal/A) 50% WG

[264

- 777] 4.17 lb ai/gal SC [264

- 826]
25% WG [264

- 781] 0.062

-

0.125 4 0.50 14 Apply at a 7

- to 21

- day RTI. Use of an adjuvant is not specified.

Foliar; Broadcast;
Ground (min. 50 gal/A) or
aerial (min. 15 gal/A) 0.49 lb ai/gal SC

MAI [ 264

- 1027 ] 0.05

-

0.10 3 0.30 30 Apply at a 7

- to 14

- day RTI.
Use of an adjuvant is not specified.

Foliar; Broadcast;
Ground (min. 10 gal/A) or
aerial (min. 5 gal/A) 25% WG MAI

[264

- 1052] 0.062

-

0.125 4 0.50 35 Apply at a 7

- to 14

- day RTI. Use of an adjuvant is not specified.

a PHIs were formerly 60 days for all products.

The differences in the PHIs proposed for the two MAI formulations (30 and 35 days vs. 14 days) are associated with the second active ingredient in each product: minimum PHIs for almond are 30 days for pyrimethanil and 35 days for tebuconazole.

T he labels include separate use directions for pecan, pistachio, and tree nuts (50% WG, 4.17 lb ai/gal SC, and 25% WG formulations), for pistachio (0.49 lb ai/gal SC MAI formulation), and for pistachio and tree nuts (25% WG MAI formulation) ; t hese use patterns remai n unchanged.

The submitted use directions are adequate to allow evaluation of the residue data relative to the proposed reduction in PH I for use on almond; n o additional data are required. A lthough adjuvant use is not specified for almond, the submitted data will support use of nonionic surfactants (NISs) for applications to almonds.

4.0 Hazard Characterization and Dose

- Response Assessment

Reference:

- 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 trifloxy strobin is presented in the previous risk assessment ( DP 385972

, N

. Tsaur , 0 8 / 02 / 2011 ). The submittedTRIFLOXYSTROBIN Human Health Risk Assessment DP No. 396514

Page 7 of 9 toxicology studies are of good quality an d provide sufficient information to determine whether trifloxystrobin poses a human health hazard.

4.1 Safety Factor for Infants and Children (FQPA Safety Factor)

The toxicology and exposure data and have been evaluated and trifloxy strobin 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 an d a 28

- day inhalation toxicity study. A waiver for a subchronic neurotoxicity study has been granted. A preliminary examination of the recently submitted immunotoxicity study data provides no indication that trifloxystrobin affects the immune system and does not alter any of
the PoDs for risk assessment. Although an inhalation stud y is needed to complete the database, there is no potential for residential inhalation exposure ; therefore , there are no uncertainties with respect to inhalation risk.

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 Y oung 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 develop mental 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 Exp osure 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 th e 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 modelingTRIFLOXYSTROBIN Human Health Risk Assessment DP No. 396514

Page 8 of 9 parameters which are designed to provide conservat ive, health protective, high

- end estimates of water concentrations, and are not likely to be exceeded. In addition, t he residential post

application exposure assessment is based upon the residential SOPs employing surrogate study
data , including con s ervat ive exposure assumptions based on Day 0 dermal contact to turf treated at the maximum application rate

. There is no potential for inhalation exposure. These data are reliable and are not expected to underestimate risk to adults or children. The resident ial 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 petiti on remain unchanged and have been summarized in the previous hu man 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

Reference :

- 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 would not be affected by the proposed tolerance increase for almond hulls

. 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 t he 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 avera ge field
trial residues were used

. Trifloxystrobin is classified as “not like ly 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 % a PAD* 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

Reference:

- 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. DP3 19193, Jack Arthur, 07/14/2005.TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 396514

Page 9 of 9 According to the labels, the currently registered residential product s are restricted to use by Certified Pest Control Operators (PCOs) only. Therefore, an assessment for residential handlers
was not conducted. Additionally, r esidential risk estimates cannot be combined because the
toxic effects are different via differen t 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 increase for almond hulls does not change 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 c arcinogenic to humans .”

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 safety finding and co nfirms that there are no risks of concern resulting from setting a higher tolerance of 9.0 ppm for trifloxystrobin in/on almond

, 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 0.013067 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)].