### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 2 of 32 health risk resulting from the proposed and registered uses of trifloxystrobin are p rovided in this

document

. The residue chemistry review and dietary risk assessment w ere conducted by Meheret Negussie; the aggregate risk assessment w as conduct ed by Nancy Keller

.

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 3 of 32 Table of Contents

1.0 Executive Summary

................................ ................................ ................................ .............. 5

2.0 HED Recommendations

................................ ................................ ................................ ....... 7

2. 1 Data Deficiencies

................................ ................................ ................................ ............ 7

2.2 Tolerance Considerations

................................ ................................ .............................. 7

2.2.1 Enforcement Analytical Method

................................ ................................ ................... 7

2.2.3 Revisions to Petitioned

- For Tolerances

................................ ................................ ........ 8

2.2.4 International Harmonization

................................ ................................ ........................ 8

3.0 Introduction

................................ ................................ ................................ ........................... 9

3.1 Chemical Identity

................................ ................................ ................................ ........... 9

3.2 Physical/Chemical Characteristics

................................ ................................ ............. 10

3.3 Pesticide Use Pattern

................................ ................................ ................................ .... 10

3. 4 Anticipated Exposure Pathways

................................ ................................ ................. 11

3.5 Consideration of Environmental Justice

................................ ................................ .... 11

4.0 Hazard Characterization and Dose

- Response Assessment

................................ ............. 12

4.1 Toxicology Studies Available for Analysis

................................ ................................ . 12

4.2 Absorption, Distribution, Metabolism and Excretion (ADME)

.............................. 12

4.3 Toxicological Effects

................................ ................................ ................................ .... 13

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

............................... 14

4.4.1 Completeness of the Toxicology Database

................................ .......................... 14

4.4.2 Eviden ce of Neurotoxicity

................................ ................................ .................... 14

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

.... 14

4.4.4 Residual Uncertainty in the Exposure Database

................................ ................ 14

4.5 Recommendation for Combining Routes of Exposure for Risk Assessment

.......... 14

4.6 Cancer Classificati on and Risk Assessment Recommendation

........................ 15

4.7 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

................................ ................................ ................................ ........................... 15

5.0 Dietary Exposure and Risk Assessment

................................ ................................ ............ 16

5.1 Residues of Concern Summary and Rationale

................................ .......................... 16

5.2 Food Residue Profile

................................ ................................ ................................ .... 17

5.3 Water Residue Profile

................................ ................................ ................................ .. 17

5. 4 Dietary Risk Assessment

................................ ................................ .............................. 18

5.4.1 Description of Residue Data Used in Dietary Assessment

................................ 18

5.4.2 Acute Dietary Risk Assessment

................................ ................................ ........... 19

5.4.3 Chronic Dietary Risk Assessment

................................ ................................ ....... 19

5.4.4 Cancer Dietary Risk Assessment

................................ ................................ ......... 19

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ 20

6.1 Combined Residential Risk Estimates

................................ ................................ ........ 20

6.2 Recommendations for Aggregate Assessment

................................ ........................... 21

6.3 Residential Bystander Post

- Application Inhalation Exposure

................................ 21

6.4 Non

- Occupational Spray Drift Exposure and Risk Estimates

................................ . 21

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ..... 22

7.1 Acute Aggregate Risk

................................ ................................ ................................ ... 22

7.2 Short

- Term Aggregate Risk

................................ ................................ ........................ 22

7.3 Intermediate

- Term Aggregate Risk

................................ ................................ ........... 23

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 4 of 32 7.4 Chronic Aggregate Risk

................................ ................................ .............................. 23

7.5 Cancer Aggregate Risk

................................ ................................ ................................ 23

8.0 Cumulative Exposure/Risk Characterization

................................ ................................ .. 23

9.0 Occupational Exposure/Risk Characterization

................................ ............................... 24

10.0 References

................................ ................................ ................................ ............................ 24 Appendix A. Toxicology Profile and Executive Summaries

................................ ................... 26

A.1 Toxicology Data Requirements

................................ ................................ ................... 26

A.2 Toxicity Profile of Trifloxystrobin Technical

................................ ............................ 27 Appendix B. Physical/Chemical Properties

................................ ................................ ............. 30 Appendix C. Review of Human Research

................................ ................................ ................ 30 Appendix D. Residential Exposure/Risk Summary Table

................................ ...................... 31

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 5 of 32 1.0 Executive Summary

Trifloxystrobin is a strobilurin

- class broad

- spectrum fungicide that controls foliar

, soilborne , and seedling fungal diseases in various agricultural cro ps

. It works by interrupting mitochondrial respiration in plant

- pathogenic fungi, thus inhibiting spore g ermination and mycelial growth.

In PP# 4 F 8288

, Bayer Crop S ci ence (Bayer) has submitted a petition for trifloxystrobin to establish tolerances on leafy greens (crop subgroup 4A), head and stem Brassica vegetables (crop subgroup 5A), leafy Brassica greens (crop subgroup 5B), herbs (crop group 19A), and spices, except black pepper (crop subgr oup 19B); and, to amend the current tolerance on leafy petioles (crop subgroup 4B). In addition, Bayer is proposing to convert the potato tolerance to the tuberous and corm vegetables subgroup (crop subgroup 1C), the grape toleran ce to the small fruit vine climbing (subgroup 13

- 07F), and the strawberry tolerance to the low growing berries (subgroup 13

- 07G), based on the currently approved potato , grape
, and strawberry use s for this active ingredient , respectively . All of these uses are proposed to be added to the end use product

label for Gem ® 500 SC (EPA Reg. No. 264

- 826)

, a suspension concentrate (SC ) formulation containing 42.6 % active ingredient (ai) by weight ( 4.05 lb ai/gal)

.

Since the last risk assessment

, there have been no changes to the hazard characterization o r hazard profile of trifloxystrobin (DP413109, N. Tsaur, 06/03/2014)

.

Proposed Use Profile

Gem 500 SC may be applied as a foliar spray via groundboom, aircraft, chemigation, and handheld equip ment. Human flagging is also allowed on the label. The proposed maximum single application rate for all proposed crops

, is 3.8 fl oz product per acre (0.12 lb ai/acre, or 0.012 lb ai/gallon). Annual applications are limited to two per year and may be re peated on a 5

- to 1 0

- day interval, up to a maximal seasonal application rate of 0.24 lb ai/acre/year.

Exposure Profile Exposure pathways include dietary (food and drinking water) , non

- occupational (residential) and occupational exposure sources for the proposed and existing registered uses of trifloxystrobin

. E xposures via diet and drinking water are expected for all durations; residential handler and post

application exposure s are only expected for the short

- term duration ; and o ccupational han dler and post

- application exposures are expected for short

- and intermediate

- term durations. The proposed label requires occupational handlers to wear long pants, long sleeves, shoes, socks, and

chemical

- resistant gloves.

Toxicity/Hazard The toxicology d a tabase for trifloxystrobin is complete and adequate for risk assessment

. The primary target organ of toxicity in subchronic and chronic studies in dogs, mice, and rats is the liver. The effects of reduced body weight and food consumption were also found in the majority of the toxicity studies. There are no susceptibility concerns regarding developmental or reproductive toxicity , and no evidence of neurotoxicity or immunotoxicity in the trifloxystrobin toxicology database. Trifloxystrobin exhibits low a cute mammalian toxicity via oral (Toxicity Category IV), dermal (Toxicity Category IV), and inhalation (Toxicity Category IV) routes of exposure. Trifloxystrobin is a mild eye and skin irritant, and is a strong dermal sensitizer.

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 6 of 32 T rifloxystrobin is class ified as “Not likely to be Carcinogenic to Humans” b ased on the lack of evidence of carcinogenicity in mice and rats. Trifloxystrobin is not mutagenic in vivo and in

vitro

. The level of concern (LOC) for all routes and durations of exposure is 100.

Diet ary Exposure (Food and Water) and Risk Estimates

The acute and chronic dietary exposure and risk estimate s were not of concern. They were highly conservative since they assumed tolerance level residues, anticipated residues for some crops, 100% crop treat ed ( CT ) , and included mainly default processing factors

. There were no appropriate toxicological effects attributable to a single exposure (dose) for the general population; therefore, a dose and endpoint were not identified. An acute endpoint was identi fied

for females 13

- 49 years old. Acute and chronic dietary exposure and risk estimates are below HED’s LOC for the U.S. population and all population subgroups. The acute dietary (food + drinking water) risk estimate for females 13

- 49 years old is 3 .1 % of the a cute population adjusted dose (a PAD ) at the 95 th 

### percentile . The chronic dietary (food + drinking water ) risk estimates represented 3 4 % of the chronic population adjusted dose (cPAD) for the general U.S. population and 71 % of the cPAD for all infa nts <1 year old, the most highly exposed population subgroup.

Residential Exposure and Risk Estimates Although there are no residential exposures associated with the proposed uses, a ll existing

r esidential exposures were previously assessed according to H ED’s 2012 Residential Standard Operating Procedures ( SOPs ) and to incorporate previous changes to the dermal risk assessment point of departure and changes in the policy for body weight assumptions. There are no registered products that would result in re sidential handler or post

- application risk estimates of

concern. Short

- term residential handler inhalation margins of exposure ( MOEs ) for the existing uses of trifloxystrobin range from 8,100 to 170,000,000

. Short

- term post

- application incidental

oral MOEs for all residential scenarios range from 730 to 330,000

.

Aggregate Exposure Risk Estimates

There is only potential for short

- term aggregate exposure to trifloxystrobin via the diet ary and

residential pathways; residential exposures include inhalation (adults) and incidental oral ( children 1 to <2 years)

. For adults and children 1 to <2 years old, the short

- term aggregate risk estimates are not of concern; the MOEs are 290 and 130 respectively.

Occupational Handler and Post

- Application Exposures and Risk Estimates Although there are occupational exposures associated with all of the proposed uses, existing occupational risk assessments are protective of the proposed uses, and a new occupational risk

assessment was not conducted for this action

. The 12

- hour restricted entry interval ( REI ) listed on the label is adequate to protect agricultural workers from post

- applicati on exposures to trifloxystrobin.

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 Lo w

- Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 7 of 32 2.0 HED Recommendations

HED has examined the toxicology and residue chemistry databases for trifloxys trobin

. Pending submission of a revised Section F (tolerances), there are no issues that would preclude granting registration for the requested uses of trifloxystrobin, or establishment of the recommended

tolerance for combined residues of trifloxystro bin and its metabolite CGA

- 321113 (see Table

2.2. 2 ). The specific tolerance recommendations ar e discussed in Section 2.2

.

2.1 Data Deficiencies

Guideline 875.2100

– Turf Transferable Residues (TTR) Study At this time, EPA is requiring the 40 CFR TTR data because the estimated residential turf post

application exposure

, using default TTR values for trifloxystrobin, is not minimal in comparison to the level of concern (i.e. the calculated MOE is not greater than 10 times higher than the level

of concern ; MOE = 730 compared to the LO C of 100 ).

2.2 Tolerance Considerations

Tolerances are currently established for the combined residues of trifloxystrobin and the free

form of its acid metabolite CGA

– 321113 in/on various crop and livestock commodities ranging

from 0.0 1 ppm to 38 ppm [40 CFR §180.555(a)].

2.2.1 Enforcement Analytical Method

An adequate gas chromatography method with nitrogen phosphorus detection (GC/NPD),

Method AG

- 659A, is available for enforcing tolerances for the combined residues of

trif loxystrobin and CGA

- 321113 in plant and livestock commodities. Samples from the

submitted crop field trials on chickpea and dry peas (seed , forage, and hay) were analyzed for residues of trifloxystrobin and CGA

- 321113 using a high performance liquid chromatography method with tandem mass spectrometry detection (LC/MS/MS) . Residues of CGA

- 321113 were converted to parent equivalents using a molecular weight conversion factor. The method was adequately validated in conjunction with the analysis of crop field trial samples. The lowest

level of method validation (LLMV) is equivalent to the limit of quantitation (LOQ) which was 0.010 ppm for each analyte in/on all matrices.

2.2.2 Recommended Tolerances

A revised Section F needs to be submitted to reflec t the correct commodity definitions as shown

below in Table 2.2.2.

Table 2.2. 2

. Tolerance Summary for Trifloxystrobin

Commodity Tolerance (ppm) Comments Correct Commodity Definition Proposed Recommended

40 CFR §180. 5 55 (a)( 1 )
Leafy greens, subgroup 4A 30 30 Leafy greens subgroup 4A

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 8 of 32 Table 2.2. 2

. Tolerance Summary for Trifloxystrobin

Commodity Tolerance (ppm) Comments Correct Commodity Definition Proposed Recommended

Leafy petioles, subgroup

4B 1 9 9 Leaf petioles subgroup 4B

Head and stem brassica subgroup 5A 2 2 Brassica, head and stem, subgroup

5A

Leafy brassica Subgroup

5B 30 30 Brassica, leafy greens, subgroup

5B

Herb, subgroup 19A 200 200 Herb subgroup 19A

Spice, subgroup 19B, except black pepper 30 30 Dill, seed

Tuberous and corm vegetable subgroup 1C 0.04 0.04 Vegetable, tuberous and corm, subgroup 1C

Small fruit vine climbing subgroup (except fuzzy kiwifruit), subgroup 13

- 07F 2 2.0 2.0 Fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F

Low growing berry, subgroup 13

- 07G 3 1.5 1.5 Berry, low growing, subgroup 13

- 07G

1 A tolerance of 3.5ppm currently exists for l eafy petioles subgroup 4B. This petition is changing the use pattern

fr om a 14

- day pre

- harvest interval ( PHI ) to a 0

- day PHI.

2 The c urrent tolerance on grape (the representative commodity for the subgroup) is being expanded to cover the entire subgroup.

3 The c urrent tolerance on strawberry (the representative commodity for the subgroup) is being expand ed to cover the entire subgroup and raised from the existing 1.1 ppm to 1.5 ppm.



### 2.2.3 Revisions to Petitioned

- For Tolerances

Although HED’s recommended tolerances do not differ from the registra nt’s proposed tolerances, a revised Section F needs to be submitted to reflect the correct commodity

definitions.

Specifically, t he Agency is revising the commodity definitions for the requested tolerances to reflect the common commodity vocabulary curren tly used by the Agency. Specifically, Head and stem brassica subgroup 5A was changed to Brassica , head and stem, subgroup 5A; Leafy brassica Subgroup 5B was changed to Brassica , leafy greens, subgroup 5B; Tuberous and corm vegetable subgroup 1C was chang ed to Vegetable, tuberous and corm, subgroup 1C; Small fruit vine climbing subgroup (except fuzzy kiwifruit), subgroup 13

- 07F was changed to Fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F ; and Low growing berry, subgroup 13

- 07G was changed to Berry , low growing, subgroup 13

- 07G. Bayer requested a tolerance for spice (Crop Subgroup 19B), except black pepper. Because black pepper serves as a representative commodity for S pice

, subgroup 19B, it may no t be excepted from a tolerance (see 40 CFR 180.40(h) ) . Without sufficient data to establish the subgroup tolerance, the Agency is establishing an individual tolerance for the crop for which data was submitted

– dill, seed.

2.2.4 International Harmonization

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 9 of 32 Codex maximum residue limits ( MRLs ) have been established for residues of trifloxystrobin in/on a number of commodities associated with this petition. Codex MRLs are expressed in terms of trifloxystrobin (parent only) while U.S. tolerances are based on the combined residues of trifloxystrobin and its acid metabolite CGA

- 321113, expressed in parent equivalents. Therefore, harmonization is not possible as the Codex MRLs are likely to be too low based on

the U.S. residue definition for toleran ce enforcement.

Canadian MRLs are based on the combined residues of trifloxystrobin and its acid metabolite expressed as parent equivalents, and are therefore harmonized with the U.S. enforcement residue

definition. The Canadian MRLs are consistent with the established tolerances for potato and grape and, therefore, will be consistent with the proposed U.S. tolerances for the tuberous and corm vegetables subgroup and the small vine climbing fruit, except fuzzy kiwifruit, subgroup.

Tolerances will not be harmonized for leafy petioles subgroup 4B as the change in pre

- harvest interval ( PHI ) and subsequent increase in tolerance to 9 ppm will no longer be the same as the Canadian MRL of 3.5 ppm. Similarly, the pro po sed increase in the tolerance for strawberr ies to 1.5 ppm (and subsequent expansion to subgroup 13

- 07G) will no longer be harmonized with the Canadian MRL of 1.1 ppm.

Table 2.2.4 is a summary of the recommended tolerances and a comparison to Codex MRLs.

Table 2.2.4. US Recommended Tolerance/Cod ex MRL Comparison

United States Codex

US Crop Subgroup Recommended Tolerance, ppm Commodity MRL, ppm

Leafy greens subgroup 4A 30 Lettuce, Head 15 Leaf petioles subgroup 4B 9 Celery 1

Brassica , head and stem, subgroup 5A 2 Brussels Sprouts 0.1 Flowerhead brassicas (includes Broccoli: Broccoli, Chinese and Cauliflower) 0.5

Cabbages 0.5

Brassica , leafy greens, subgroup 5B 30 None None

Herb s ubgroup 19A 200 None None
Dill, seed 30 None None Vegetable, tuberous and corm, subgroup

1C 0.04 Potato 0.2

Fruit, s mall fruit vine climbing

, except fuzzy kiwifruit, subgroup 13

- 07F 2.0 Grape 3

Berry, l ow growing, subgroup 13

- 07G 1.5 Strawberry 1



### 3.0 In troduction

Trifloxystrobin is a broad

- spectrum preventative fungicide used for control of many plant diseases in various fruit, nut, vegetable, and field cro ps. It is a strobilurin

- class fungicide that controls foliar, soilborne, and seedling fungal diseases

. It works by interrupting mitochondrial respiration in plant

- pathogenic fungi, thus inhibiting spore germination and mycelial growth.

3.1 Chemical Identity

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 10 of 32 Table 3.1. Trifloxystrobin Nomenclature
Compound

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 product (EP) Gem ® 500 SC Fungicide; 4.05 lb ai trifloxystrobin /gal ; EPA Reg. No. 264

- 826

Compound (metabolite CGA

- 321113)

Common name trifloxystrobin acid

Company experimental name CGA

- 321113

CAS name (α E )

- α

– (methoxyimino

- [2

- [[[( E )

- 1

- [3

- (trifluoromethyl)phenyl] ethylidene] amino]oxy]methyl]benzeneacetic acid

CAS registry number 252913

- 85

- 2



### 3.2 Physical/Chemical Characteristics

Trifloxystrobin has a low vapor pressure ( 2.55 ×10

- 7 

### mm Hg at 25 °C); therefore, inhalation due to chemical vaporization is unlikely. Trifloxystrobin has a log octanol/water partition coefficient (log P
ow 

### ) of 4.5 and is considered soluble in fat . Additionally, trifloxystrobin has a molec ular weight of 408.4 g/mol ; therefore, the potential to cross biological barriers, such as the skin, is

somewhat limited. More detailed physicochemical properties of trifloxystrobin are summarized in Appendix B.

3.3 Pesticide Use Pattern

Bayer has submitted an amended labe l for Gem® 500 SC (EPA Reg. No. 264

- 826 )

. The newly proposed use pattern is presented in Table 3.3

. O
N C F 3

N

O O

C H 3 O
C H 3 C H 3

O
N C F 3

N

O H O O
C H 3 C H 3

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 11 of 32 Table 3.3 . Summary of Proposed Use Directions for Gem® 500 SC Fungicide (EPA Reg. No. 264

- 826 ) a

Application Timing, Type,

and Equipment Single

Maximum Application

Rate Maximum

Number of Applications

per Year Maximum

Annual Application

Rate PHI b

Use Directions and Limitations
days

Leafy Greens (Crop Subgroup 4A), Head and Stem Brassica Vegetables (Crop Subgroup 5A), Leafy Brassica Greens (Crop Subgroup 5B), Herbs (Crop Group 19A), and Spices, Except Black Pepper (Crop Subgroup 19B), Potato and Tuberous and Corm Vegetables Subgroup (Crop Subgroup 1C)

Broadcast

Foliar : ground, aerial, chemigation, or

handheld 3.8 fl oz product /A

0.1 2 lb ai/A

0.012 lb ai/gal c 2 7.6 fl oz product /A

0.24 lb ai/A 5

- 10 Do not apply more than 2 applications per year. Do not exceed 0.24 lb trifloxystrobin per acre per year. The application may be made by ground, chemigation, or aerial

spray equipment. Do not apply within 30 days of harvest. For ground equipment, a

minimum of 10 GPA is recommended. For aerial equipment, a minimum of 5

GPA is recommended.

a SC = suspension concentrate.

b PHI = pre

- harvest interval.

c The a pplication rate is based on use direction of “a minimum of 10 gallons per acre” recommended for ground

equipment.



### 3.4 Anticipated Exposure Pathways

Humans ma y be exposed to trifloxystrobin via food and drinking water because trifloxystrobin may be applied directly to growing crops

, and application may result in trifloxystrobin reaching surface and grou nd sources of drinking water. In residential settings, adults and children may be exposed during handler and post

- application activities . In occupational setting s , applicators may be exposed while handling the pesticide prior to application, as well as during application. There is also a potential for post

- application exposure for workers re

- entering treated fields.

Several risk assessments have been previously prepared for the existing uses of trifloxystrobin

. This risk assessment considers all of the aforementioned exposure pathway s based on the proposed new use of trifloxystrobin , but also considers the existing uses as well, particularly for

th e dietary and residential exposure assessment.

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 Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf )

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on p atterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.

Extensive data on food co nsumption patterns are compiled by the USDA under the National

Health and Nutrition Examination Survey/What We Eat in America (NHANES/WWEIA), and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 12 of 32 analyzed and categorized by subgroups based on age and ethnic group . Additionally, OPP is

abl e 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 ad ult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized so ftware and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Trifloxystrobin controls fungal diseases by interrupting mitochondrial respiration in plant

pathogenic fungi, thus inhibiting spore germination and mycelial growth. There are no mammalian molecular data to specifically show this mode of action in the test animals.

4.1 Toxicology Studies Availa ble for Analysis

The 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 rat s, 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) carcinogenicity studies in rats and mic e; (7) a battery of the required genotoxicity studies; (8) immunotoxicity study in rats; and (9)

metabolism studies in rats. At this time, n either a subchronic neurotoxicity study ( T XR0056150, D. Smegal, 01/05/2012 ) nor a subchronic inhalation toxicity st udy (TXR 0056957

, U. Habiba,

0 5/22 /2014 ) are required

.

4.2 Absorption, Distribution, Metabolism and Excretion (ADME)

With low dose oral administration of trifloxystrobin to rats, approximately 56% and 65% of the administered dose was absorbed, with 41% an d 47% found in the bile of male and female rats, respectively. With high dose administration, the absorption was 41% and 27%, with 35% and

19% in was found in the bile of male and female rats, respectively. The percentage of absorption

was similar with e ither single dose administration or repeated dosing in both sexes. The time to peak blood concentration was 12

- 24 hours. The blood, liver, and kidneys were found to have the highest residues. Most of the examined tissues had somewhat higher residue leve ls in the females than in the males (by up to two

- fold). A majority of the administered dose was eliminated in the feces. Less than 0.1% of the administered dose was found in the expired air.

The total tissue and carcass contained 0.3

- 0.5% of the admini stered dose indicating essentially no tissue accumulation. The parent compound was extensively metabolized to approximately 35

metabolites.

Dermal Absorption

D ermal absorption studies are not available for trifloxystrobin. In the past (TXR 0050612, S. Dapson, 04/01/2002 ), the lowest observed adverse effect level ( LOAEL ) of 337 mg/kg/day

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 13 of 32 observed in the oral 28

- day range

- finding feeding study in rats (MRID 44496643) was compared to the LOAEL of 1000 mg/kg/day observed in the 28

- day dermal toxicity study in rats (MRID 44496704) to yield a calculated dermal absorption factor (DAF) of approximately 33%. Both of the LOAELs were based on increases in liver weight ; h owever, when the dermal subchronic study was reevaluated with current criteria, the increased liver weights were not considered to be adverse because they were minimal and not confirmed by histopathological correlates. Therefore, the no observed adverse effect level ( NOAEL ) for this dermal subchronic study was set at 1000 mg/kg/day and the LOAEL w as not established

.

Dermal penetration study data for other strobilurins such as azoxystrobin, fluoxastrobin and pyraclostrobin suggest that dermal absorption of trifloxystrobin is expected to be less than 20%. As mentioned above, the 28

- day dermal toxic ity study showed no adverse dermal or systemic effects at dose levels (up to the limit dose of 1000 mg/kg bw/day) where toxicity was seen in comparable oral studies, supporting the expectation that dermal absorption is low

.

4.3 Toxicological Effects

With repeated dos ing , the liver is consistently the target organ for trifloxystrobin . Liver effects characterized by an increase in liver weights and an increase d incidence of hepatocellular hypertrophy and/or hepatocellular necrosis were seen in rats, mi ce, and dogs . The effects of reduced body weights and food consumption were also found in the majority of the toxicity studies. Intestinal disturbances, as indicated by diarrhea and vomiting, were seen in dogs and rats at higher dose levels relative to t hose which caused liver and body weight effects. This finding was consistent with those produced by 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 rabbit developmental and the rat reproduction toxicity data do not demonstrate an increase in

s usceptibility in the fetus or other offspring.

Trifloxystrobin was determined not to be carcinogenic in mice or rats following long

- term dietary administration. However, it is positive for mutagenicit y in Chinese Hamster V79 cells at cytotoxic dose levels while testing negative in the remaining mutagenicity studie s.

Trifloxystrobin was not neurotoxic in the acute neurotoxicity study, nor in any of the repeated dose studies in the available data. The requirement for a subchronic neurotoxicity study w as waived (TXR0056150, D. Smegal, 01/05/2014) because there is no evidence of neurotoxicity in the existing trifloxystrobin database or that of other strobilurin pesticides, and because endpoints and Points of Departure (PODs) used for risk assessment are likely to be protective of neurotoxicity concerns.

Trifloxystrobin 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.

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 14 of 32 4. 4 Safety Factor for Infants and Children (FQPA Safety Factor)

The trifloxystrobin risk assessment team evaluated the quality of the toxicity and exposure data and recommended that the FQPA SF be reduced to 1 X because 1) the trifloxystrobin database is

con sidered complete for risk assessment; 2) there is no indication of neurotoxicity following trifloxystrobin exposure in single or repeated dose studies; 3) there is no increased quantitative or qualitative susceptibility to trifloxystrobin in developmental (rats and rabbits) and reproducti ve toxicity (rats) studies ; and 4) there are no uncertainties in the exposure database.

4.4.1 Completeness of the Toxicology Database

T he toxicity database for trifloxystrobin is adequate for selecting toxicity endpoints and points of departure for risk assessment. T he selected toxicity endpoints and points of departure for risk

assessment are based on the mo st sensitive and relevant data.

4.4.2 Evidence of Neurotoxicity

Adverse effects were not seen up to the limit dose in an acute neurotoxicity study (the requirement for a subchronic neurotoxicity study has been waived as detailed in Section 4.3).

There i s no evidence of neurotoxicity in subchronic and chronic toxicity studies (rats, dogs, mice), in developmental t oxicity studies (rats, rabbits), or in a reproductive toxicity study (rats).

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or 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 and up to the limit dose. In the prenatal developmental study in rabbits, developmental toxicity was seen at a dose that was higher than the dose cau s ing maternal toxicity. In the multigeneration study, offspring and parental LOAELs are at the same dose level.

4.4.4 Residual Uncertainty in the Exposure Database

The exposure databases are complete or are estimated based on data that reasonably accou nt for potential exposures. The exposure assessments will not underestimate the potential dietary (food and drinking water) or non

- dietary exposures for infants and children from the use of trifloxystrobin. The chronic dietary food exposure assessment wa s conservatively based on 100%CT assumptions and conservative ground water drinking water modeling estimates. The dietary drinking water assessment utilizes water concentration values generated by models and associated modeling parameters which are design ed to provide conservative, health protective, high

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

- application assessment is based upon the residential SOPs employing surrogate study data. The R esidential SOPs are based upon reasonable “worst

- case” assumptions and are not expected to underestimate risk. These data are reliable and are not expected to underestimate

risk to adults or children.

4.5 Recommendation for Combining Routes of Exposure for Risk Assessment

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 15 of 32 W hen common toxicity endpoints are selected for the dermal, oral, and inhalation routes of

e xposure they may be combined together. For short

- term aggregate risk assessments, oral and

inhalation routes can be combined due to the selec tion of a common toxicological endpoint of concern ( the oral equivalent was used for inhalation expo sure). However, t he dermal route of exposure does not need to be combined with another route of exposure or included in the aggregate risk assessment becau se there is no identified adverse systemic dermal hazard.

4.6 Cancer Classification and Risk Assessment Recommendation

B ased on the absence of significant tumor increases in two adequate rodent carcinogenicity

studies , trifloxystrobin is classified as: “ Not likely to be Carcinogenic to Humans

. ” Cancer risk

assessments do not need to be conducted.

4.7 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

prese nted below in Table 4.7

.

Table 4. 7 Summary of Toxicological Doses and Endpoints for Trifloxystrobin for Use in Dietary

, Non

Occupational , and Occupational Human Health Risk Assessments a

Exposure/

Scenario Point of Departure Uncertainty/ FQPA Safety

Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Acute Dietary ( Females 13

- 49 Only ) NOAEL =

250 mg/kg/day UF A = 10 X

UF H = 10 X FQPA SF = 1 X Acute 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.

Acute Dietary ( General Population, including

Infants and Children) There were no appropriate toxicological effects attributable to a single exposure (dose)

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

.

Chronic Dietary (All Populations) NOAEL = 3.8 mg/kg/day UF A = 10 X

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

= 0.038 mg/kg/day

cPAD =

0.038 mg/kg/day Two

- Generation R eproduction

– Rat

Maternal LOAEL = 55.3 mg/kg/day based

on decreased body weight an d histopathological lesions in the liver, kidney and splee n

.

Offspring LOAEL = 55.3 mg/kg/day based on decreased pup body weights during

lactation.

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 16 of 32 Table 4. 7 Summary of Toxicological Doses and Endpoints for Trifloxystrobin for Use in Dietary

, Non

Occupational , and Occupational Human Health Risk Assessments a

Exposure/

Scenario Point of Departure Uncertainty/ FQPA Safety

Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Incidental

Oral

Short

- Term (1

- 30 days) NOAEL = 3.8 mg/kg/day UF A = 10 X

UF H = 10 X FQPA SF = 1 X Residential

LOC for

MOE = 100 Two

- Generation R eproduction

– Rat

Maternal LOAEL = 55.3 mg/kg/day based

on decreased body weight an d histopathological lesions in the liver, kidney and splee n

.

Offspring LOAEL = 55.3 mg/kg/day based on decreased pup body weights during

lactation.

Dermal All

Durations A toxicity endpoint was not identified . A dverse s ystemic toxicity was not seen in 28

- day dermal toxicity in rats at the limit dose (1000 mg/kg/day) . T here are no concerns for developmental or reproductive toxicity (including potential susceptibility issues) or neurotoxicity

Inhalation

All Durations NOAEL = 3.8 mg/kg/day UF A = 10 X

UF H = 10 X FQPA SF = 1 X Residential

LOC for

MOE = 100

Occupational

LOC for

MOE = 100 Two

- Generation R eproduction

– Rat

Maternal LOAEL = 55.3 mg/kg/day based

on decreased body weight and weight gain,

decreased food consumption, liver, kidney and spleen effects.

Offspring LOAEL = 55.3 mg/kg/day based on decreased pup body weights during

lactation. Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant tumor increases in two adequate rodent carcinogenicity studies.

a Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data

and used to mark the beginning of extrapolation to determine r isk 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 = Food Quality Protection Act Safety Factor. RfD = reference dose (a = acute, c = chronic). PAD = population adjusted dose (a = acute, c = chronic). MOE = margin of expos ure. LOC = level of concern.

b Toxicity by the inhalation route is assumed to be equivalent to the oral route. A subchronic inhalation toxicity

study is not required for trifloxystrobin at this time ( Hazard and Science Policy Council memo , U. Habiba,

TXR 005695 7

, 05/22/2014 ).



### 5.0 Dietary Exposure and Risk Assessment

5. 1 Residues of Concern Summary and Rationale

The qualitative nature of the residue in plants and livestock commodities is adequately understood based on acceptable metabolism studies reflecting direct application of trifloxystrobin to apples, cucumbers, peanuts, sugar beets, and wheat, and metabolism studies on goats and laying hens. HED has concluded that both trifloxystrobin and CGA

- 321113 are of concern for both regulatory and risk assessment purposes for both plant and livestock

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 17 of 32 commodities. HED also determined that for livestock commodities, th e metabolite L7a (taurine conjugate of trifloxystrobin) in liver and meat byproducts should be included in the risk

assessment. The residues of concern for dietary risk assessment and the tolerance expression are

summarized in Table 5.1.

Table 5.1. Summa ry of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

Matrix Residues included in

Risk Assessment Residues included in Tolerance Expression

Plants Primary Crop Trifloxystrobin and CGA

- 321113 Rotational Crop

Livestock Ruminant Trifloxystrobin and CGA

321113; plus Metabolite L7a in liver and meat byproducts Trifloxystrobin

and CGA

- 321113

Poultry Trifloxystrobin and CGA

- 321113

Drinking Water Trifloxystrobin

and CGA

- 321113 Not Applicable



### 5.2 Food Residue Profile

Adequate crop field trial data have been submitted to support the requested uses on all proposed

crops (D P 4 22436

, G. Luta

, 08 / 06 /201 5 ) . The trials reflect the proposed use pattern and the number and locations of the trials are acceptable. Adequa te storage stability data are available to support the storage durations and conditions of samples of all proposed crops from the submi tted crop field trial studies. There are no processed commodities associated with the proposed new uses; therefore, no n ew processing studies were submitted or reviewed for this petition. The proposed use s do not result in an increased dietary burden for livestock. The existing tolerances

on live stock commodities are adequate. Adequate confined and field rotational crop data are available. HED previously concluded that the residues of concern in rotated crops are trifloxystrobin and CGA

- 321113. The available data support a 30

- day plant

- back interval (PBI) for all crops not listed on the label for direct use.

5. 3 Water Residue Profile

The environmental fate database is adequate to characterize drinking water exposure for the parent compound. Limited fate data are available for the degradates of trifloxystrobin. The data indicate that trifloxystrobin is non

- persi stent in soil or water with rapid degradation in aerobic soil. In contrast, the major degradate of concern, CGA

- 321113, is persistent in both soil and aquatic environments. Furthermore, CGA

- 321113 is expected to be more mobile than the parent compound. Model simulations show that ground water estimated drinking water concentrations (EDWCs) for total toxic residues of trifloxystrobin are greater than surface water EDWCs.

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 18 of 32 EDWCs were evaluate d for all proposed uses with the Pesticide Root Zone Model for Gr ound

Water ( PRZM

- GW )

, 1 

### which models continued use of t rifloxyst r o bin over many years (DP 422483

, M. Biscoe

, 03/12/2015 )

. T he most conservative EDWC s were based on an existing

r egistered turf use which has the highe st annual use rate (1.33 lb ai /acre) of all the proposed and existing uses of trifloxystrobin

. Water residues were incorporated directly into the acute and chronic dietary assessments in the Dietary Exposure Evaluation Model

– Food Commodity Intake Database ( DEEM

- FCID ) food categories of “water , direct, all sources” and “water, indirect, all sources.” Maximum s urface water EDWCs using Pesticide Root Zone Model linked with the Exposure Analysis Modeling System ( PRZM/EXAMS ) and ground water EDWCs using the PRZM

- GW model are reported in Table 5. 3. The highest estimated peak (acute) concentration of total toxic residues in ground water is 427 μg/L, and the highest estimated (chronic) concentration in ground water is 365 μg/L.

Table 5.3

. Maximum Estimated Drinking Water Concentrations (EDWCs) of Total Toxic Residues of Trifloxystrobin a

Surface Water Model b ( μg/L )

Crop Scenario Peak Exposure Annual Mean Exposure Average Annual Exposure

Peak

1

- in

- 10 Year Chronic

1

- in

- 10 Year 30

- year Annual Average

Pennsylvania Turf scenario

Aerial Application 29 ppb 23 ppb 19 ppb

Ground Water Model c ( μg/L )

Crop Scenario Peak Post

- Breakthrough Average

Wisconsin Corn scenario Ground Application 427 ppb 365 ppb

a EDWC modeling includes total toxic residue (TTR) of trifloxystrobin and its major degradate, CGA

- 32113

, based

on 1.33 lb ai/A for turf (Trifloxystrobin Flowable Fungicide, EPA Reg. No. 264

- 989 )

. The highest estimated drinking water concentration are bolded

. b Highest EDWCs generated using PRZM/EXAMS model

. PCA of 0.91 adjusted for aerial application

.

c Highest EDWCs generated u sing PRZM

- GW 30

- year simulation model.



### 5. 4 Dietary Risk Assessment

5.4 .1 Description of Residue Data Used in Dietary Assessment

A cute and chronic dietary (food and drinking water) exposure and risk assessment s were conducted using the DEEM

- FCID Version 3.16. This model uses 2003

- 2008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition

Exam ination Survey, What We Eat in America (NHANES/WWEIA).

The acute females 13

- 49 assessment was based on the assumption of tolerance level residues for all commodities while the chronic assessment incorporated some average residues. Both

assessments assume d 100%CT. For the dietary assessments, a value of 0.20 ppm was added to
the recommended tolerance for liver to account for the Metabolite L7a ; therefore, meat byproducts and liver of cattle, goats, horses, and sheep were assessed in the dietary assessment s at 0.3 ppm. The maximum theoretical dietary burden was lower for pork, except for pork liver,

1 PRZM

- GW was approved for standard use in drinking water assessments as a Tier I/II exposure tool (12/2012).

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 19 of 32 than for these other commodities. Therefore, pork was included in the DEEM at the established tolerance level of 0.05 ppm; pork, liver was included at 0.16 pp m (DP267787, L. Cheng, 01/17/2002). A separate tolerance was set for grape, raisin; therefore, the processing factor for this commodity was set at 1. For all other processed commodities, DEEM 7.81 default processing factors were used. Residue reduction data on strawberries from a single trial were previously provided which demonstrated that residues of trifloxystrobin and CGA

- 321113 declined in/on strawberries after washing and cooking. The default processing factor of 1 was retained since the exposure estimates are below HED’s LOC.

The chronic dietary assessment was refined by using average residues for the proposed crop groups and apple, grape, orange, rice, and pear commodities. The averages for the new

commodities were calculated in the memo summar izing the tolerance assessment (DP422436, G.

Luta , 08/06 /2015). A summary of the residue data used to calculate the average residues for rice, apple, grape, and orange, commodities is attached to this memo. Residue data from apple field

trials were used for all pome fruits since averages were higher from apples than pears. The limit of quantitation (LOQ) value was used for all non

- detectable samples.

The acute drinking w ater estimate of 427 μg/L was directly incorporated into the acute

assessment. The chronic drinking water estimate of 365 μg/L was directly incorporated into the

chronic assessment.

5. 4

. 2 Acute Dietary Risk Assessment

There were no appropriate toxicological effects attributable to a single exposure (dose) for the general population; th erefore, a dose and endpoint were not identified and a dietary exposure

assessment was not conducted

. An acute endpoint was identified for females 13

- 49 years old. Therefore, an acute dietary assessment was conducted for this population subgroup.

The re sults of the acute dietary (food and drinking water) analysis indicate that exposure and risk

does not exceed HED’s LOC for females 13

- 49 years old. At the 95 th 

### percentile of exposure, t he dietary exposure estimate for food and drinking water is estimated at 3 .1 % of the aPAD for the

females 13

- 49 years old.

5. 4

. 3 Chronic Dietary Risk Assessment

The results of the chronic dietary (food and drinking water) analysis indicate that exposure and

risk estimates are not of concern to HED for the U.S. population and all population subgroups. The dietary exposure for f ood and drinking water is estimated at 34 % of the cPAD for th e general U.S. population and 71 % for all infants (<1 year old) , the most highly exposed population subgroup. Drinking water residues make up the majority of the dietary exposure

contribution in the chronic risk estimates. The results of the chronic dietary exposure analyses are reported in Table 5.4 .5

.

5.4 .4 Cancer Dietary Risk Assessment

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 20 of 32 Trifloxystrobin is classified as “not likely to be carcinogenic to hu mans;” therefore, cancer risk

was no t assessed

.

5

. 4

. 5 Summary Table

Table 5. 4 .5 . Summary of Dietary Exposure and Risk for Trifloxystrobin ( c PAD = 0. 038 mg/kg/day) a

Population Subgroup Acute Dietary Exposure Estimates (Food and Drinking Water) Chronic Dietary Exposure Estimates (Food and Drinking Water)

mg/kg/day % aPAD mg/kg/day % cPAD

General U.S. Population

N/A b 0.013028 34

All Infants (< 1 year old) 0.026821 71

Children 1

- 2 years old 0.024642 65

Children 3

- 5 years old 0.020301 53

Children 6

- 12 years old 0.013125 34

Youth 13

- 19 years old 0.009489 25

Adults 20

- 49 years old 0.012339 32

Adults 50

- 99 years old 0.012408 33

Females 13

- 49 years old 0.077271 3.1 0.012318 32

a The population subgroup s with the greatest exposure are bolded

. b N/A = Not Applicable; an acute dietary endpoint was not identified for these population subgroups.



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no proposed residential uses at this time; however, there are existing residential turf

and ornamental use s that have been previously assessed (DP413713, N. Tsaur, 05/15/2014).

The assessment of all registered residential products do es not result in any residential handler or

post

- application risk estimates of concern. Residential h andler exposure is expected to be short

term only

. Intermediate

- term exposures are not likely because of the intermittent nature of applicatio ns by homeowners. The quantitative exposure/risk assessment developed for

residential handlers is based on various exposure scenarios that involve mixing/loading/applying various formulations with manually pressurized handguns, hose

- end sprayers, backpack sprayers, and sprinkler cans. Short

- term residential handler inhalation MOEs range from 8,100 to 170,000,000

. Short

- term incidental

- oral post

- application MOEs for all residential scenarios range from 730 to 330,000

. Dermal handler risk assessments were not conducted because an adverse systemic dermal hazard was not identified for trifloxystrobin. Incidental oral granule ingestion is not applicable because there is no endpoint identified for the acute dietary duration applicable to children

. Appendix D summarizes all assessed residential exposure and risk

estimates.

6.1 Combined Residential Risk Estimates

HED combines risk estimates resulting from separate post

- application exposure scenarios when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population and when the toxicological effects are similar. However, the

incidental oral scenarios (i.e., hand

- to

- mouth, object

- to

- mouth, and soil ingestion) should be

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 21 of 32 considered inter

- related and it is likely that they occur interspersed amongst each other across

time. Combining all three of these scenarios would be overly

- conservative because of the

conservative nature of each individual assessment. Therefore , the hand

- to

- mouth post

application exposure scenario for children 1 to < 2 years old is considered a protective estimate of children’s exposure to pesticides used on turf.

6.2 Recommendations for Aggregate Assessment

For the purpose of the trifloxystrobin human health risk assessment, a s ummary of the worst

- case residential exposure estimates are provided in Table 6.2. All short

- term residential handler and

post

- application exposure estimates resulted in MOEs greater than 100, and were not of concern.

Table 6. 2

. Scenarios Recommended for Aggregate Risk Assessment of Trifloxystrobin (Short

- Term)

Scenario Dose a MOE

mg/kg/day LOC = 100

Adults

Handler : Inhalation Exposure ( Manually

- Pressurized Handwand or Backpack Sprayer Application

of Water Dispersible Granule Formulation to Residential Turf) 0.00047 8,1 00

Children 1 to < 2 years old

Post

- Application : Hand

- to

- Mouth Exposure

(Liquid Application to Residential Lawn) 0.0052 730

a Handler scenario represents high

- end handle r exposure (DP413713, N. Tsaur, 05/15/2014)

. b Post

- application MOE represents high

- end incidental oral exposure (DP413713, N. Tsaur, 05/15/2014)

.

c MOE = NOAEL ÷ Average Daily Dose

. Inhalation NOAEL = 3.8 mg/kg/day. Incidental Oral NOAEL = 3.8 mg/kg/day.



### 6. 3 Residential Bystander Post

- A pplication Inhalation Exposure

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 Fe deral Insecticide, 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 has evaluated the SAP re port and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219). During Registration Review, the agency will utilize this analysis to determine i f data (i.e. flux studies, route

- specific inhalation toxicological studies) or fu rther analysis is required for trifloxystrobin

.

6. 4 Non

- Occupational Spray Drift Exposure and Risk Estimates

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application method s (e.g. groundboom and airblast) employed for trifloxystrobin

. The agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offices

, and State Lead Agencies for pesticide regulation

, and

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 22 of 32 other parties to develop the best spray drift management practices (see the agency’s Spray Drift website for more information). 2 

### The agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk asses sm ents for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during

the Registration Review process which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in th e revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

- Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification

of indirect non

- occupa tional exposure to drift.

7.0 Aggregate Exposure/Risk Characterization

HED aggregate s (add s ) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sou rces are added together and compared to quantitative estimates of hazard ( e.g. a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. F or 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; th erefore, a dose and endpoint were not identified for this risk assessment.

The aPAD for females 13

- 49 years old was 2.5 mg/kg/day. To assess the aggregate acute risk, EDWCs were incorporated directly into the dietar y exposure analysis. 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) pathways. For adults, these pathways le ad to exposure via oral (background) as well as dermal and inhalation (primary) routes. For children, these pathways lead to exposure via the oral (background) as well as incidental oral and dermal (primary) routes. For trifloxystrobin, dermal routes of exposure are not combined into an aggregate risk estimate because there are no adverse system ic hazards via the dermal route. Thus, only adult inhalation and children incidental oral aggregate MOEs are presented. Table 7.2 shows that all MOEs are greater than 100, and aggregate risk estimates are

not of concern. The children’s aggregate estimate for incidental oral exposure only incorporates

hand

- to

- mouth oral exposure because it is considered to be a conservative upper bound estimate of oral post

- applic ation exposure. Additionally, the dietary exposure estimates (food and water) are conservative. Further refinement using additional anticipated residues and empirical processing factors may need to be incorporated in future assessments.

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 23 of 32 Table 7.2

. Short

- Term Aggregate Risk Calculations for Trifloxystrobin

Population NOAEL LOC a Average

Food and

Water Exposure Residential

Handler Exposure b Residential

Post

Application Exposure c Total Exposure d Aggregate MOE (food, water, and residential) e mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day

Adult 3.8 100 0.012408 f 0.0004 7 NA g 0. 012 88 290

Children

1

- 2 years old (Oral Exposure) 3.8 100 0.024670 NA g 0.0052 0.029870 13 0

a The LOC is based on inter

- and intra

- species uncertainty factors which total 100 X.

b Residential handler exposure based on adult handler inhalation only, of manually

- pressurized handwand or

backpack sprayer a pplication of water dispersible granule f ormulation to residential t urf ( see Table 6. 2 ).

c Residenti al post

- application exposure based on children inc idental oral only , of hand

- to

- mouth exposure

following liquid application to residential lawn (see Table 6.2 ).

d Total Exposure = Average Food and Water Exposure + Residential Exposure

.

e Aggregate MOE = NOAE L / (Avg Food & Water Exp osure + Residential Exposure)

. f Adult subpopulation of “Adults 50

- 99” was selected from the chronic dietary exposure assessment a s the most

protective adult subpopulation.

g NA = Not Applicable.



### 7.3 Intermediate

- Term Aggregate Risk

An intermediate

- term aggregate risk assessment (1 to 6 months of exposure to trifloxystrobin residues from food, drinking water, and residential pesticide uses) is not expected to occur based

on the intermittent nature of homeowner applications, and the short soil half

- life (a bout 2 days). 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

Trifloxystrobin is classified as “not likely to be carcinogenic to humans;” therefore, an aggregate

cancer assessment has not been conducted.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to trifloxystrobin and any other substances and trifloxystrobin does not appear to produce a toxic metabolite produced by other substances. F or 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

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 24 of 32 me chanism determinations and procedures for cumulating effects from substances found to have

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

9.0 Occupational Exposure/Risk Characterization

Although there are occupational exposures associated with all of the proposed uses, the most

recent occupational risk assessment is protective of the proposed uses, and a new occupational

risk assessment was not conducted fo r this action (DP413713, N. Tsaur, 05/15/2014)

. The most recent assessment was for typical and high acreage field crops treated at a maximum single application rate of 0.12 lb ai/A via ground, aerial, and chemigation equipment . The highest application ra te of the newly proposed crops to be applied to typical and high acreage field crops is also 0.12 lb ai/A. Thus, a new occupational risk assessment is not needed because the previous assessment a lready covers the proposed uses; t he occupational risk estim ates were not
of concern. It should be noted that HED previously required a TTR study to be submitted for the residential use on turf (the lowest MOE of 730 was based on hand

- to

- mouth postapplication to residential turf treated with a liquid formulation o f trifloxystrobin).

Trifloxystrobin is classified as Toxicity Category IV via the dermal route. It is a mild irritant to eyes and skin, and it is a strong dermal sensitizer. Typically, the REI specified on the proposed

label is based on the acute toxici ty of the active ingredient. Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Acute III or IV for acute dermal, eye irritation

, and primary skin irrigation are assigned a minimum of 12 hour s for the REI . Thus, the 12

- hour REI on the proposed label is adequate to protect workers.

10 .0 References

Biscoe, Melanie. 03/12/2015. DP Barcode 422483. “ Trifloxystrobin : Drinking Water Exposure

Assessment in Support of N ew U se s on Several Vegetable and Small Fruit Crop Groups (Leafy Greens, Bra ssica, Herbs, Spices, Tuberous and Corm Vegetables, Small Fruit of Climbing Vines, and Low

- Growing Berries).”

Luta, Gabriela

. 08 / 06 /201 5 . DP Barcode 422436 . “ Trifloxystrobin. Application for Section 3 Registration for Uses on Tuberous and Corm Vegetables (Subgroup 1C), Leafy Greens (Subgroup 4A), Leafy Petioles (Subgroup 4B), Head and Stem Brassica Vegetables (Subgroup 5A), Leafy Brassica Greens (Subgroup 5B), Herbs (Subgroup 19A), and Spices (Subgroup 19B). Summary of Analytic al Chemistry and Residue Data. ”

Luta, Gabriela. 11/17/2015. DP Barcode 428501. “ Trifloxystrobin. Evaluation of Proposed

T olerances for Tuberous and Corm Vegetables (S ubgroup 1C ), Leafy G reens (Subgroup 4A), Leafy P etioles (Subgroup 4B), Head and Stem Brassica Vegetables (Subgroup 5A), Leafy

Brassica Greens (Subgroup 5B), Small Fruit Vine Climbing (Except Fuzzy Kiwifruit) (Subgroup 13

- 07F), Low Growing Berry (Subgroup 13

- 07G), Herbs (Subgroup 19A), and Spices (Subgroup 19B).

Negussie, Meheret. 11 / 24 /20 1 5 . DP Barcode 422978

. “ Trifloxystrobin. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for Uses on

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 25 of 32 Leafy Vegetables, Brassica Vegetables, Herbs, Spices, Crop Subgroup 1C , Small Fruit Vine Climbing (Subgroup 13

- 07F) and Low Growing Berries (Subgroup 13

- 07G).”

Tsaur, Nancy. 06/03 /201 4 . DP Barcode 413109

. “ Trifloxystrobin . Aggre gate Human Health Risk Assessment for the Proposed New Uses on Chickpea, Dry Peas, and Lentils with Updated Residential Risk Estimates of All Existing Residential Uses (Lawns/Turf; Gardens and Trees)

. ”

Tsaur, Nancy. 05/15/2014. DP Barcode 413713. “ Trifloxystrobin. Occu pational Exposure and

Risk Assessment for the Proposed New Uses on Chickpea, Dry Peas, and Lentils with An Updated Resid ential Exposure Assessment of All Existing Residential Uses

. ”

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 26 of 32 A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR § 158. 555 ) for food use for trifloxystrobin are in Table A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1. Satisfac tion of Trifloxystrobin Toxicology Data Requirements

Study Technical Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ..................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes
870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes

yes

yes CR a

w aived b 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 CR c -

- yes

no d

- 870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

yes

yes yes

yes

yes

a C onditionally required

. b A subchronic inhalation toxicity study has been waived for trifloxystrobin at this time ( Hazard and Science Policy

Council memo

, TXR005695 7

, U. Habiba, 05/22 /2014 ).

c Conditional requirement pending submission of acceptable guideline acute and subchronic neurotoxicity batteries.

d A subchronic neuro toxicity study has been waived for trifloxystrobin at this time ( Hazard and Science Policy

Council memo

, TXR0056150

, D. Smegal, 01/05/2012)

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 27 of 32 A.2 Toxicity Profile of Trifloxystrobin Technical

Table A.2.1. Trifloxystrobin Acute Toxicity Profile

Guideline No. Study Type MRID Results Toxicity Category

870.1100 Acute Oral

– Rats 44496622

44496623 LD 50 > 5 g/kg IV

870.1200 Acute Dermal

– Rabbits 44496626

44496627 LD 50 > 2 g/kg IV

870.1300 Acute Inhalation

– Rats 44496630 LC 50 > 4.65 mg/L IV

870.2400 Primary Eye Irritation

– Rabbits 44496632 mild irritant III

870.2500 Primary Skin Irritation

– Rabbits 44496635 mild irritant IV

870.2600 Dermal Sensitization

– Guinea Pigs 44496637

44496638 strong sensitizer N/A

Table A.2.2. Trifloxystrobin Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3100 28

- Day range

finding oral toxicity (rat) 44496643 (1994) 0, 200, 1000, 4000, or 12000 ppm M: 0, 16.5, 84.4, 337, 1,074 mg/kg/day F: 0, 16.4, 84.1, 327, or 1,005 mg/kg/day NOAEL = 84.1 mg/kg/day

LOAEL = 327 mg/kg/day base d on decreased body weight and increased relative liver w eight.

870.3100 90

- Day oral toxicity (rat) 44496701 (1995) Acceptable /Guideline
0, 1 00, 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 /Guideline 0, 500, 2000, 7000 ppm M: 0, 76.9, 315, or 1,275 mg/kg/day F: 0, 110, 425, 1649 mg/kg/day NOAEL = 76.9 mg/kg/day LOAEL = 315 mg/kg/day based on increased liver weights a nd necrosis of hepatocytes

.

870.3150 90

- Day oral toxicity (dog) [capsule] 44496702 (1994) Acceptable /Guideline 0, 5, 30, 150, or 500 mg/kg/day NOAEL = 30 mg/kg/day LOAEL = 150 mg/kg/day based on increased liver weight and hepatocyte hypertrophy; increased incidence of diarrhea and vomiting.

870.3150 2 8

- Day

subchronic

range

- finding oral toxicity (dog) [capsule] 44496642 (1994) Unacceptable/non

guideline (2 dog/sex/do s e) 0, 20, 50, 150 mg/kg/day NOAEL=50 mg/kg/day LOAEL= 150 mg/kg/day based on increased

inc idence of diarrhea and vomiting and body weight

reduction

.

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 28 of 32 Table A.2.2. Trifloxystrobin Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3200 28

- Day dermal toxicity (rat) 44496703 (1996) Acceptable /Guideline 0, 10, 100, 1000 mg/kg/day NOAEL = 1 0 00 mg/kg/day

. LOAEL > 1000 mg/kg/day ; a LOAEL was not

established. I ncrease s in liver and kidney weight s observed at this dose were not accompanied with any histopathological correlates and not considered

adverse

.

870.3700a Prenatal developmental in (rat) [gavage] 44496708 (1995) Acceptable /Guideline
0, 10, 100, 300 mg/kg/day Maternal NOAEL = 10 mg/kg/day

. Maternal LOAEL = 100 mg/kg/day based on decreased body weight gain and food consumption

. Devel opmental NOAEL = 1000 mg/kg/day (HDT)

.

870.3700b Prena tal developmental in (rabbit) [gavage] 44496709 (1994) Acceptable /Guideline 0, 10, 50, 250, 500 mg/kg/day Maternal NOAEL = 10 mg/kg/day

. Maternal LOAEL of 50 mg/kg/day based on decreased body weights and body weight gain, food consumption and efficiency. 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 /Guideline 0, 50, 750, 1500 ppm M: 0, 3.8, 55.3, 110.6 mg/kg/day F: 4.1, 58, 123.1 mg/kg/day Parental NOAEL = 3.8 mg/kg/day

. Parental LOAEL = 55.3 mg/kg/day based on decreased body weight and weight gain, decreased food consumption, liver, kidney and spleen effects. Offspring NOAEL= 3

. 8 mg /kg/day Offspring LOAEL = 55.3 mg/kg/day based on decreased pup body weights during lactation. Reprod uctive NOAEL = 110.6 mg/kg/day (HDT)

.

870.4100b Chronic toxicity (dog) [capsule] 44496704 (1997) Acceptable /Guideline 0. 2, 5, 50, 200 mg/kg/day NOAEL = 5 mg/kg/day

. LOAEL = 50 mg/kg/day based on increased clinical signs, increased liver weight and hepatocellular hypertrophy.

870.4200b Carcinogenicity (mouse) 44496705 (1997) Acceptable /Guideline 0, 30, 300, 1000, 2000

ppm M: 0, 3.9, 39.4, 131.1

, 274 mg/kg/day F: 0, 3.51, 35.7, 124.1, 274 mg/kg/day NOAEL = 39.4 mg/kg/day LOAEL =131.1 mg/kg/day based on liver effects (single cell necros is, hepatocellular hypertrophy).

There was non

- statistically significant and non

- dose related increase in lymphom a incidence. Trifloxystrobin i s classified as “Not Likely to be Carcinogen ic to Humans. ”

870.4300 Carcinogenicity chronic toxicity (rat) 44496711 (1997) Acceptable/Guideline 0, 50, 250, 750, 1500

ppm M:0, 1.95, 9.81,29.7, 62.2 mg/kg/day F: 0, 2.22, 11.3 7, 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

- Salmonella 44496712

44496715

44496716

44496717 Acceptable/Guideline Negative

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 29 of 32 Table A.2.2. Trifloxystrobin 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 Acceptable/Guideline Positive

870.5385 Structural

Chromosome

Aberration

- Micronucleus

-

mouse 44496714 Acceptable/Guideline Negative

870.5385 Structural

Chromosome

Aberration

- Cytogenetics

- Chinese Hamster 44496718 Acceptable/Guideline Negative

870.5500 DNA Repair

- Rat hepatocytes 44496719 Acceptable/Guideline Negative

870.6200a Acute oral neurotoxicity screening battery (rat)

Acute oral range

finding neurotoxicity (rat) 44496640 (1977) Acceptable/Non

guideline 0, 2000 mg/kg/day

44840802 (1997) 0, 1000, 2000, 3500 mg/kg/day (provides supplemental information). Study useful for risk assessment and does not need to be repeated (TXR0056150, D. Smegal, 01/05/2012).

NOAEL and LOAEL could not be determined because the data on females were missing

. Piloerection and reduced activity were often found in 2000 and 3500 mg/kg test animals, and the effects peaked at 6 to 8 hours post dosing. No mortality and no effects on food consumption and body weights were found.

870.7485 Metabolism & pharmacokinetics (rat) 44496722 (1997) 44496821 (1996) Acceptable /Guideline 0.5, 100 mg/kg /day Oral administration of trifloxystrobin to rats
resulted in 56% and 65% of the administered dose absorbed by male and female rats, respectively. The

time to maximal blood concentration was 12

- 24

hours. 41% and 47% of the administered dose was found in the bile of males and females respectively.

Hi ghest residues were found in l iver, kidneys, spleen and blood . Majority of the administered radioactivity was eliminated in the feces. Less than

0.1% of the administered dose was found in the expired air. Total tissue and carcass content was

0.3

- 0.5% of the administered dose. Parent compound was extensively metabol ized to approximately 35 metabolites.

870.7800 Immunotoxicity (male rat) 48856301 (2012) Acceptable/Guideline 0, 200, 1000, 4000 ppm 0, 14.2, 70.5, 263 mg/kg bw/day Systemic NOAEL = 70.5 mg/kg/day Systemic LOAEL = 263 mg/kg bw/day based on

decreased body weight, body weight gain, and feed consumption.

Immunotoxicity NOAEL = 263 mg/kg/day Immunotoxicity LOAEL is not established

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 30 of 32 A ppendix B. Physical/Chemical Properties

Table B. Physico

- Chemical Properties of Trifloxystrobin

Parameter Value Reference Melting Point/R ange 72.9oC

MRID 44502801 pH ( 25oC ) 7.7 in 1 % w/w aqueous dispersion Density ( 21oC ) 1.36 g/cm 2

Water S olubility ( 20oC ) 0.00061 g/L

Solvent S olubi lity ( g/L at 25 °C) methanol 76

acetone >500 ethyl acetate >500

n

- hexane 11 dichloromethane >500

toluene 500

n

- octanol 18

Vapor P ressure (25 °C ) 3.4 x 10

- 6 Pa

, 2.55 x 10

- 7 mm Hg

Dissociation C onstant (pK
a ) none at pH of 2

- 12

Octanol/Water Partition C oefficient ( 25oC ) Log(K OW ) 4.5

UV/Visible Absorption S pectrum 17,500 at 250.7 μm (neutral) 17,300 at 250.2 μm (acidic) 15,900 at 252.3 μm (basic)



### Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies, which comprise the Pesticide Handlers Exposure Databased ( PHED ) and Agricultural Handlers Exposure Task Force ( AHETF )

, have been determined to require a review of their ethical conduct and have received

that review. In this assessment, PHED and AHETF data were used to assess mixing, loading, and applying a liquid formulation of trifloxystrobin

.

Studies reviewed by the Human Studies Review Board : None.

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 31 of 32 Appendix D

. Residential Exposure/Risk Summary Table

Table D .1. Short

- Term Residential Handler Exposure and Risk Estimates for Trifloxystrobin Application on Residential Turf and Ornamentals a

Exposure Scenario Application

Rate b Amount

Handled or

Area Treated Daily c Baseline

Inhalation Unit

Exposure d Baseline

Inhalation Dose e Inhalation

Baseline

MOE f
mg/lb ai mg/kg/day LOC = 100

Liquid Formulation on Turf
Manually

- Pressurized

Handwand 0.034 lb ai/gal 5 gallons 0.018 0.000038 99,000

Hose

- End Sprayer 0.34

lb ai/acre 0.50

acres 0.022 0.000047 81,000

Backpack

Sprayer 0.034 lb ai/gal 5 gallons 0.14 0.0003 13,000

Sprinkler Can 0.0000078 lb ai/sq ft 1,000 sq ft 0.022 0.0000021 1,800,000

Water Soluble Packaging on Turf
Manually

- Pressurized

Handwand 0.0068 lb ai/gal 5 gallons 0.018 0.0000077 500,000

Hose

- End Sprayer 0.34

lb ai/acre 0.50

acres 0.034 0.000072 53,000

Backpack

Sprayer 0.068 lb ai/gal 5 gallons 0.018 0.0000077 500,000

Sprinkler Can 0.0000078 1,000 sq ft 0.034 0.0000033 1,100,000

Water Dispersible Granules Formulation on Turf
Manually

- Pressurized

Handwand 0.0068 lb ai/gal 5 gallons 1.1 0.00047 8,100

Hose

- End Sprayer 0.34

lb ai/acre 0.50

acres 0.022 0.000047 81,000

Backpack Sprayer 0.0068 lb ai/gal 5 gallons 1.1 0.00047 8,100

Sprinkler Can 0.0000078 lb ai/sq ft 1,000 sq ft 0.022 0.0000021 1,800,000

Water Soluble Packaging on Ornamentals

Manually

- Pressurized

Handwand 0.00000094 lb ai/sq ft 1,200 sq ft 0.018 0.00000025 15,000,000

0.00047 lb ai/gal 5 gallons 0.018 0.00000053 7,200,000

Hose

- End Sprayer 0.00000094 lb ai/sq ft 1,200 sq ft 0.034 0.00000048 7,900,000

0.00047 lb ai/gal 11 gallons 0.034 0.0000022 1,700,000

Backpack

Sprayer 0.00000094 lb ai/sq ft 1,200 sq ft 0.018 0.00000025 15,000,000

0.00047 lb ai/gal 5 gallons 0.018 0.00000053 7,200,000

Sprinkler Can 0.00000094 lb ai/sq ft 1,200 sq ft 0.034 0.00000048 7,900,000

0.00047 lb ai/gal 5 gallons 0.034 0.000001 3,800,000

Water Dispensable Granules Formulation on Ornamentals

Manually

- Pressurized

Handwand 0.0000011 lb ai/sq ft 1,200 sq ft 1.1 0.000018 210,000

0.0013 lb ai/gal 5 gallons 1.1 0.000089 43,000

Hose

- End Sprayer 0.0000011 lb ai/sq ft 1,200 sq ft 0.0014 0.000000023 170,000,000

0.0013 lb ai/gal 11 gallons 0.0014 0.00000025 15,000,000

### TRIFLOXYSTROBIN Human Health Risk Assessment DP No. D422974

Page 32 of 32 Table D .1. Short

- Term Residential Handler Exposure and Risk Estimates for Trifloxystrobin Application on Residential Turf and Ornamentals a

Exposure Scenario Application

Rate b Amount

Handled or

Area Treated Daily c Baseline

Inhalation Unit

Exposure d Baseline

Inhalation Dose e Inhalation

Baseline

MOE f
mg/lb ai mg/kg/day LOC = 100

Backpack

Sprayer 0.0000011 lb ai/sq ft 1,200 sq ft 1.1 0.000018 210,000

0.0013 lb ai/gal 5 gallons 1.1 0.000089 43,000

Sprinkler Can 0.0000011 lb ai/sq ft 1,200 sq ft 0.0014 0.000000023 170,000,000

0.0013 lb ai/gal 5 gallons 0.0014 0.00000011 33,000,000

a Bolded values represent the high

- end exposure scenario recommended for aggregate risk calculations.

b Application Rates based on maximum application rates of registered residential turf and ornamental uses for trifloxystrobin

.

c Based on HED’s SOPs: Lawns/Turf and Gardens and Trees (January 2012).

d Baseline Inhalation: no respirator.

e Dose (mg/kg/day) = daily unit exposure (mg/ lb ai) × application rate ( lb ai per gallons, square feet, or acres ) × amount handled

or area treated ( gallons, square feet, or a cres per day) ÷ body weight (80 kg). No inh alation absorption factor.

f MOE = NOAEL ÷ daily dose (mg/ kg/ day). ST Inhalation NOAEL = 3.8 mg/kg/day. Level of concern = 100.

Table D .2. Short

- Term Residential Post

- Application Exposure and Risk Estimates for Trifloxystrobin on

Turf and Ornamentals a

Lifestage Post

- Application Exposure Scenario Dose b MOE c mg/kg/day
Liquid Formulation on Turf max single application rate: 0. 34 lb ai/A

Child 1 to < 2 year s old Oral Hand to Mouth 0.0052 730 Object to Mouth 0.00016 24,000

Soil Ingestion 0.000012 330,000

Granular Formulation on Turf max single application rate: 0. 34 lb ai/A

Child 1 to < 2 year s old Oral d Hand to Mouth 0.00051 7,400 Object to Mouth 0.000031 120,000

Soil Ingestion 0.000012 330,000

a Bolded values represent the high

- end exposure scenario recommended for aggregate risk calculations.

b Hand

- to

- Mouth Dose = hand residue loading (mg/cm 2 ) × fraction of hand mouthed (0.127) × surface area of 1 hand (150 cm 2 )

× exposure time (1.5 hrs/day) × # of replenishment intervals/ hr (4 int/hr) × (1

- ((1

- saliva extraction factor (0.5))^(Number of

hand

- to

- mouth events per hour (13.9 events/hr) ÷ # of replenishment intervals/hr)) ÷ body weight (11 kg). Object

- to

- Mouth Dose = object residue loading (μg/cm 2 ) × unit conversion factor (0. 001 mg/μg) × object surface area mouthed / event (10 cm 2 /event) × exposure time (1.5 hrs/day) × # replenishment intervals/hr (4 int/hr) × (1

- ((1

- saliva extraction factor (0.50))^(# Object

- to

- Mouth Events/hr (8.8 events/hr) ÷ # replenishment intervals/hr)) ÷ body weight (11 kg). Soil Ingestion = soil residue (μg/g) × ingestion rate (50 mg/day) × conversion factor (0.000001 g/μg) ÷ body weight (11 kg).

c MOE = NOAEL ÷ Daily Dose (mg /kg/day)

. Incidental Oral NOAEL= 3.8 mg/kg/day . Level of concern = 100.
d Incidental Granule Ingestion is not applicable because there is no endpoint identified for the acute dietary duration.