Document ID: EPA-HQ-OPP-2013-0504-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-09-03T04:00Z

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

MEMORANDUM

DATE:	June 10, 2014

SUBJECT:	Trifloxystrobin.  Aggregate 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).
 
PC Code:  129112
DP Barcode:  D413109
Decision No.:  478982
Registration No.:  264-1055
Petition No.:  3F8180
Regulatory Action:  Section 3 Registration
Case No.:  NA
Risk Assessment Type:  Single Chemical/Aggregate
TXR No.:  NA
CAS No.:  141517-21-7
MRID No.:  NA
40 CFR:  §180.555

FROM:	Nancy Keller, Chemist, Risk Assessor
	Meheret Negussie, Chemist
	Myron Ottley, Senior Toxicologist
	Risk Assessment Branch 3
	Health Effects Division (7509P)

THROUGH:	Christine Olinger, Branch Chief
	Risk Assessment Branch 3
	Health Effects Division (7509P)

TO:	Marcel Howard
	Fungicides Branch (FB)
		Registration Division (7505P)

The Registration Division (RD) requested that the Health Effects Division (HED) provide an evaluation of the proposed new agricultural uses of trifloxystrobin on chickpea, dry peas, and lentils.  A summary of the findings and an assessment of human health risk resulting from the proposed and registered uses of trifloxystrobin are provided in this document.

The toxicology and hazard database review was conducted by Myron Ottley; the residue chemistry review and dietary risk assessment were conducted by Meheret Negussie; the occupational/residential exposure and aggregate risk assessments were conducted by Nancy Tsaur.

Table of Contents

1.0	Executive Summary	4
2.0	HED Recommendations	6
2.1	Data Deficiencies	6
2.2	Tolerance Considerations	6
2.2.1	Enforcement Analytical Method	6
2.2.3	Revisions to Petitioned-For Tolerances	7
2.2.4	International Harmonization	7
2.2.5	Label Recommendation	8
3.0	Introduction	8
3.1	Chemical Identity	8
3.2	Physical/Chemical Characteristics	9
3.3	Pesticide Use Pattern	9
3.4	Anticipated Exposure Pathways	9
3.5	Consideration of Environmental Justice	10
4.0	Hazard Characterization and Dose-Response Assessment	10
4.1	Toxicology Studies Available for Analysis	10
4.2	Absorption, Distribution, Metabolism and Excretion (ADME)	10
4.3	Toxicological Effects	11
4.4	Safety Factor for Infants and Children (FQPA Safety Factor)	12
4.4.1	Completeness of the Toxicology Database	12
4.4.2	Evidence of Neurotoxicity	12
4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	12
4.4.4	Residual Uncertainty in the Exposure Database	13
4.5	Toxicity Endpoint and Point of Departure Selection	13
4.5.1	Recommendation for Combining Routes of Exposure for Risk Assessment	13
4.5.2	Cancer Classification and Risk Assessment Recommendation	13
4.5.3	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment	14
5.0	Dietary Exposure and Risk Assessment	15
5.1	Residues of Concern Summary and Rationale	15
5.2	Food Residue Profile	16
5.3	Water Residue Profile	16
5.4	Dietary Risk Assessment	17
5.4.1	Description of Residue Data Used in Dietary Assessment	17
5.4.2	Acute Dietary Risk Assessment	18
5.4.3	Chronic Dietary Risk Assessment	18
5.4.4	Cancer Dietary Risk Assessment	18
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	19
6.1	Combined Residential Risk Estimates	20
6.2	Recommendations for Aggregate Assessment	20
6.3	Residential Bystander Post-Application Inhalation Exposure	20
6.4	Spray Drift	21
7.0	Aggregate Exposure/Risk Characterization	21
7.1	Acute Aggregate Risk	21
7.2	Short-Term Aggregate Risk	21
7.3	Intermediate-Term Aggregate Risk	22
7.4	Chronic Aggregate Risk	22
7.5	Cancer Aggregate Risk	22
8.0	Cumulative Exposure/Risk Characterization	22
9.0	Occupational Exposure/Risk Characterization	23
9.1	Short- and Intermediate-Term Handler Risk	23
9.2	Short- and Intermediate-Term Post-Application Risk	24
9.2.1	Dermal Post-Application Risk	24
9.2.2	Restricted Entry Interval	25
9.2.3	Inhalation Post-Application Risk	25
10.0	References	25
Appendix A. 	Toxicology Profile and Executive Summaries	27
A.1	Toxicology Data Requirements	27
A.2	Toxicity Profile of Trifloxystrobin Technical	28
Appendix B.	Physical/Chemical Properties	32
Appendix C.	Review of Human Research	32
Appendix D.	International Residue Limit Status	33
Appendix E.	Residential and Occupational Exposure/Risk Summary Table	34

1.0	Executive Summary

Trifloxystrobin is a strobilurin-class broad-spectrum fungicide that controls foliar, soilborne, and seedling fungal diseases in various agricultural crops.  It works by interrupting mitochondrial respiration in plant-pathogenic fungi, thus inhibiting spore germination and mycelial growth.

In PP#3F8164, Bayer CropScience (Bayer) has submitted a label amendment to add chickpea, dry peas, and lentils to the label for USF 0728 325 SC Fungicide (EPA Reg. No. 264-1055), thus petitioning for the associated tolerances.  USF 0728 325 SC Fungicide, henceforth referred to as USF, is a suspension concentrate (SC) formulation containing 13.7% active ingredient (ai) by weight (1.27 lb ai/gal).  Although USF is a mixed active ingredient (MAI) product also containing 16.0% prothioconazole (1.49 lb prothioconazole per gallon), this document only addresses the human health effects of trifloxystrobin.  The proposed use of prothioconazole will be evaluated in a separate document.

Since the last risk assessment, the 28-day dermal study in rats has been reclassified as showing no adverse systemic effects up to the limit dose of 1,000 mg/kg/day because the observed increases in liver and kidney weights were not accompanied with any histopathological correlates and not considered adverse.  Thus, a dermal point of departure (POD) is no longer relevant for human health risk assessment.

Proposed Use Profile
USF may be applied as a foliar spray via groundboom, aircraft, chemigation, and handheld equipment.  Human flagging is also allowed on the label.  The proposed maximum single application rate for chickpea, dry peas, and lentils, is 12.0 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 repeated on a 10- to 14-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.  Exposures via diet and drinking water are expected for all durations; residential handler and post-application exposures are only expected for the short-term duration; and occupational handler 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 database for trifloxystrobin is complete.  The primary target organ of toxicity is the liver in dogs, mice, and rats in subchronic and chronic studies.  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.  The requirement for a subchronic neurotoxicity study has been waived (TXR0056150, D. Smegal, 01/05/2012), and the requirement for a subchronic inhalation study has also been waived (TXR0056957, U. Habiba, 05/22/2014).  Trifloxystrobin exhibits low acute 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 is classified as "Not likely to be Carcinogenic to Humans" based 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.

Dietary Exposure (Food and Water) and Risk Estimates
The acute and chronic dietary exposure and risk estimates assumed tolerance level residues and 100% crop treated (%CT) for all commodities, and were not of concern.  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 identified for females 13-49 years old.  The acute dietary (food + drinking water) risk estimate for females 13-49 years old is 1.3% of the acute population adjusted dose (aPAD) at the 95[th] percentile.  The chronic dietary (food + drinking water) risk estimates represented 32% of the chronic population adjusted dose (cPAD) for the general U.S. population and 78% of the cPAD for all infants <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, all existing residential exposures have been reassessed to reflect updates to HED's 2012 Residential Standard Operating Procedures (SOPs) along with changes in dermal risk assessment hazard and changes in the policy for body weight assumptions.  There are no registered products that would result in residential handler or post-application risk estimates of concern.  Short-term residential handler inhalation margins of exposure (MOEs) range from 8,100 to 170,000,000.  Short-term post-application 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 dietary and residential pathways; residential exposures include inhalation (adults and children) and incidental oral (only children 1 to <2 years).  For adults, females age 13-49 years old, and children 1 to <2 years old, the short-term aggregate risk estimates are not of concern; the MOEs are 300, 300, and 120, respectively.

Occupational Handler Exposures and Risk Estimates
The results of the occupational handler exposure and risk assessment indicate that short- and intermediate-term inhalation risk estimates are not of concern without personal protective equipment (PPE).  Short- and intermediate-term inhalation MOEs range from 6,600 to 150,000.  Note that only engineering control (enclosed cockpit) data are available to assess risks to handlers operating aircrafts.

Occupational Post-Application Exposures and Risk Estimates
 An occupational post-application dermal exposure and risk assessment was not conducted because an adverse systemic dermal hazard was not identified for trifloxystrobin.  Based on the Agency's current practices, a quantitative non-cancer occupational post-application inhalation exposure assessment was not performed for trifloxystrobin at this time.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for trifloxystrobin.  The 12-hour restricted entry interval (REI) listed on the label is adequate to protect agricultural workers from post-application exposures to trifloxystrobin.

Dermal Sensitizer Worker Notification Label Recommendation
According to 40 CFR 156.210 (b), any product that is a dermal sensitizer should bear the following statement on the label: "Notify workers of the application by warning them orally and by posting warning signs at entrances to treated areas."

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).

2.0	HED Recommendations

HED has examined the toxicology and residue chemistry databases for trifloxystrobin.  Pending submission of a revised Section F (tolerances), there are no issues that would preclude granting registration for the requested uses of trifloxystrobin on chickpea, dry peas, and lentils, or establishment of the recommended tolerance for combined residues of trifloxystrobin and its metabolite CGA-321113 (see Table 2.2.2).  The specific tolerance recommendations are 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 LOC 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 0.01 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 trifloxystrobin 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 reflect the recommended tolerances and 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 §180.555(a)(1)
                                Pea, dry, seed
                                     0.06
                                     0.06

                                 Pea, dry, hay
                                      15
                                      15
Pea, field, hay
                                Pea, dry, vines
                                       4
                                       4
Pea, field, vines
                                Chickpea, seed
                                     0.06
                                  Not Needed
Covered by pea, dry, seed. Increase tolerance to harmonize with Canada.
                                 Chickpea, hay
                                      15
                                  Not Needed

                                Chickpea, vines
                                       4
                                  Not Needed

                                 Lentil, seed
                                     0.06
                                  Not Needed
Covered by pea, dry, seed.

2.2.3	Revisions to Petitioned-For Tolerances

Tolerances for chickpea hay and vines are not needed since both commodities are not significant livestock feed items.  The proposed pea, dry, hay and pea, dry, vines commodity definitions need to be revised to pea, field, hay and pea, field, vines to reflect the correct commodity definitions.  The proposed tolerances on chickpea seed and lentil seed are not needed since pea, dry, seed includes these commodities.  Based on the Organization for Economic Cooperation and Development (OECD) tolerance calculation spreadsheet, the proposed tolerance for chickpea, seed is 0.04 ppm.  However, a tolerance of 0.06 ppm is recommended for harmonization purposes.

2.2.4	International Harmonization

Codex MRLs are expressed in terms of trifloxystrobin for plants; thus, harmonization of MRLs is not possible.  The Codex residue definition for livestock is the same as the US.  The Canadian residue definitions for plants and livestock are the same as the US.  There are no Codex MRLs established on the proposed crops.  Canadian MRLs exist for dry chickpea, dry field peas, and dry lentils at 0.02 ppm.  This petition is reviewed as a workshare with Canada, and tolerances for the proposed crops are harmonized.  The International Residue Limit Status is detailed in Appendix D.

2.2.5	Label Recommendation

According to 40 CFR 156.210 (b), any product that is a dermal sensitizer should bear the following statement on the label: "Notify workers of the application by warning them orally and by posting warning signs at entrances to treated areas."

3.0	Introduction

Trifloxystrobin 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.  It is a strobilurin-class fungicide (also termed methoxyacrylates) 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.  In PP#3F8164, Bayer has submitted a label amendment to add chickpea, dry peas, and lentils to the label for USF (EPA Reg. No. 264-1055), thus petitioning for the associated tolerances.  USF is an SC formulation containing 13.7% ai by weight (1.27 lb ai/gal).

3.1	Chemical Identity

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 (αE)-α-(methoxyimino)-2-[[[[(1E)-1-[3-(trifluoromethyl)phenyl]
ethylidene]amino]oxy]methyl]benzeneacetate
CAS registry number
141517-21-7
End-use product (EP)
Trifloxystrobin/ Prothioconazole USF 0728 325 SC Fungicide; 1.27 lb ai/gal trifloxystrobin and 1.49 lb ai/gal prothioconazole; EPA Reg. No. 264-1055
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 (2.55x10[-7] mm Hg at 25°C); therefore, inhalation due to chemical vaporization is unlikely.  Trifloxystrobin has a log octanol/water partition coefficient (log Pow) of 4.5 and is considered soluble in fat.  Additionally, trifloxystrobin has a molecular 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 label for USF (EPA Reg. No. 264-1055).  The newly proposed use pattern is presented in Table 3.3.

Table 3.3.  Summary of Proposed Use Directions for USF 0728 325 SC Fungicide (EPA Reg. No. 264-1055)[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
                                       
                      Chickpea, Dry Peas, and Lentils[c]
                              Broadcast Foliar: 
                   ground, aerial, chemigation, or handheld
                              12 fl oz product/A
                                       
                                 0.12 lb ai/A
                                       
                              0.012 lb ai/gal[d]
                                       2
                              24 fl oz product/A
                                       
                                 0.24 lb ai/A
                                 7 for Forage
                                       
                                  30 for Seed
Begin fungicide applications preventatively and continue as needed on a 10- to 14-day interval. Use the shorter interval when conditions are favorable for severe disease pressure.
a	SC = suspension concentrate.
b	PHI = pre-harvest interval.
c	EPA Reg. No. 264-1055 is a mixed active ingredient (MAI) also containing 16% prothioconazole by weight (1.49 lb prothioconazole per gallon).
d	The application rate is based on use direction of "a minimum of 10 gallons per acre" recommended for ground equipment.

3.4	Anticipated Exposure Pathways

Humans may 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 ground sources of drinking water.  In residential settings, adults and children may be exposed during handler and post-application activities.  In occupational settings, 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 pathways based on the proposed new use of trifloxystrobin, but also considers the existing uses as well, particularly for the 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 patterns 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 consumption 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 analyzed and categorized by subgroups based on age and ethnic group.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and 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 software 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 Available 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 rats, mice, and dogs; (2) a 28-day dermal toxicity study in rats; (3) developmental toxicity studies in rats and rabbits; (4) a 2-generation reproduction study in rats; (5) chronic toxicity studies in rats and dogs; (6) carcinogenicity studies in rats and mice; (7) a battery of the required genotoxicity studies; (8) immunotoxicity study in rats; and (9) metabolism studies in rats.  At this time, neither a subchronic neurotoxicity study (TXR0056150, D. Smegal, 01/05/2012) nor a subchronic inhalation toxicity study (TXR0056957, U. Habiba, 05/22/2014) is 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% and 47% in the bile of male and female rats, respectively.  With high dose administration, the absorption was 41% and 27%, with 35% and 19% in the bile of male and female rats, respectively.  The percentage of absorption was similar with either single dose administration or repeated dosing in both sexes.  The time to peak blood concentration was 12-24 hours.  The blood, liver, and kidneys were found to have the highest residues.  Most of the examined tissues had somewhat higher residue levels 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 administered dose indicating essentially no tissue accumulation.  The parent compound was extensively metabolized to approximately 35 metabolites. 

Dermal Absorption
Dermal absorption studies are not available for trifloxystrobin.   In the past (TXR 0050612, S. Dapson, 04/01/2002), the LOAEL of 337 mg/kg/day 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.  However, when the dermal subchronic study was reevaluated by current criteria, the increased liver weights were not considered to be adverse because they were minimal and not confirmed by histopathological correlates.  Therefore, the NOAEL for this dermal subchronic study was set at 1000 mg/kg/day and the LOAEL was not established, which invalidated the comparison with the 28-day oral range-finding study and the calculated dermal absorption factor.

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 toxicity 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.  However, in the absence of actual data on trifloxystrobin, a DAF of 100% is used for risk assessment. 

4.3	Toxicological Effects

With repeated dosing, the liver is consistently the target organ for trifloxystrobin.  Liver effects characterized by an increase in liver weights and an increase in incidences of hepatocellular hypertrophy and/or hepatocellular necrosis were seen in rats, mice, 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 those 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 lowest observed adverse effect level (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 susceptibility 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 mutagenicity in Chinese Hamster V79 cells at cytotoxic dose levels while testing negative in the remaining mutagenicity studies.

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 was 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.

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 1X because 1) the trifloxystrobin database is considered completed 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 reproduction (rats) studies , and 4) there are no uncertainties in the exposure database.

4.4.1	Completeness of the Toxicology Database

The toxicity database for trifloxystrobin is adequate for selecting toxicity endpoints and points of departure for risk assessment.  The selected toxicity endpoints and points of departure for risk assessment are based on the most 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 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).

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

There is no indication of increased quantitative or qualitative susceptibility to trifloxystrobin in rats or rabbits.  In the prenatal developmental study in rats, there was no developmental toxicity at 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 causing 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 account 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 was conservatively based on 100% crop treated (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 designed to provide conservative, health protective, high-end estimates of water concentrations, and are not likely to be exceeded.  In addition, the residential post-application assessment is based upon the residential SOPs employing surrogate study data.  These data are reliable and are not expected to underestimate risk to adults or children.  The Residential SOPs are based upon reasonable "worst-case" assumptions and are not expected to underestimate risk.

4.5	Toxicity Endpoint and Point of Departure Selection
 
As discussed in Section 4.2, in the absence of dermal absorption data on trifloxystrobin a dermal absorption factor of 100% is assumed for this risk assessment. Since no dermal or systemic toxicity was observed in the available 28-day dermal subchronic study up to 1000 mg/kg/day (the limit dose), a dermal hazard has not been identified for risk assessment for the general population, including children.

The 28-day dermal subchronic study did not assess the potential for developmental toxicity after dermal exposure.  However, there is no concern for fused sternebrae noted in rabbit fetuses at 250 mg/kg/day in a developmental toxicity study, because these effects occurred only at maternally toxic dose levels (maternal LOAEL = 50 mg/kg/day) and there are no susceptibility issues.  Therefore, a dermal hazard has not been identified for risk assessment for women of child-bearing age.

4.5.1	Recommendation for Combining Routes of Exposure for Risk Assessment

When common toxicity endpoints are selected for the dermal, oral, and inhalation routes of exposure they may be combined together.  For short-, intermediate-, and long-term aggregate risk assessments, oral and inhalation routes can be combined due to the selection of a common toxicological endpoint of concern (the oral equivalent was used for inhalation exposure).  However, the dermal route of exposure does not need to be combined with another route of exposure or included in the aggregate risk assessment because there is no identified adverse systemic dermal hazard.

4.5.2	Cancer Classification and Risk Assessment Recommendation

Based 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.

4.5.3	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

The summary of toxicological doses and endpoints for human health risk assessment are presented below in Table 4.5.3.

Table 4.5.3.	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
                                   UFA = 10X
                                   UFH = 10X
                                 FQPA SF = 1X
                           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
                                   UFA = 10X
                                   UFH = 10X
                                 FQPA SF = 1X
                         Chronic RfD = 0.038 mg/kg/day
                                       
                            cPAD = 0.038 mg/kg/day
Two-Generation Reproduction  -  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.
Incidental Oral 
Short-Term (1-30 days)
                            NOAEL =  3.8 mg/kg/day
                                   UFA = 10X
                                   UFH = 10X
                                 FQPA SF = 1X
                         Residential LOC for MOE = 100
Two-Generation Reproduction  -  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.
Dermal All Durations
A toxicity endpoint was not identified.  Adverse systemic toxicity was not seen in 28-day dermal toxicity in rats at the limit dose (1000 mg/kg/day).  There are no concerns for developmental or reproductive toxicity (including potential susceptibility issues) or neurotoxicity
Inhalation
All Durations
                            NOAEL = 3.8  mg/kg/day
                                   UFA = 10X
                                   UFH = 10X
                                 FQPA SF = 1X
                         Residential LOC for MOE = 100
                                       
                        Occupational LOC for MOE = 100
Two-Generation Reproduction  -  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 risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = 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 exposure.  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, TXR0056957, 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 commodities.  HED also determined that for livestock commodities, the 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.	Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression
                                    Matrix
                             Residues included in
                                Risk Assessment
                             Residues included in
                             Tolerance Expression
                                    Plants
                                 Primary Crop
                        Trifloxystrobin and CGA-321113
                                       
                                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 dry peas, chickpeas, and lentils (DP413711, M. Negussie, 05/18/2014).  The trials reflect the proposed use pattern and the number and locations of the trials are acceptable based on the ChemSAC minutes of 20 March, 2013.  Adequate storage stability data are available to support the storage durations and conditions of samples of dry pea commodities, chickpeas, and lentils from the submitted crop field trial studies.  There are no processed commodities associated with the proposed new uses; therefore, no new processing studies were submitted or reviewed for this petition.  The proposed use on dry peas does not result in an increased dietary burden for livestock.  The existing tolerances on livestock 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-persistent 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.

In addition to evaluating the EDWCs from the proposed use, EDWCs were reevaluated for all existing uses with the Pesticide Root Zone Model for Ground Water (PRZM-GW), which models continued use of trifloxystrobin over many years (DP413801, M. Biscoe, 01/28/2014).  The most conservative EDWCs were based on an existing registered turf use which has the highest 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 surface 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 using PRZM-GW 30-year simulation model.

5.4	Dietary Risk Assessment

5.4.1	Description of Residue Data Used in Dietary Assessment

Acute and chronic dietary (food and drinking water) exposure and risk assessments 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 Examination Survey, What We Eat in America (NHANES/WWEIA).

An acute dietary assessment was conducted assuming tolerance level residues and 100% crop treated (%CT) for all commodities.  DEEM version 7.81 default processing factors were assumed except for where tolerances were established for processed commodities.  For the dietary assessment, a value of 0.20 ppm for the metabolite L7a was added to the tolerance level for liver; therefore, meat byproducts and liver of cattle, goats, horses, and sheep were assessed in the dietary assessments at 0.3 ppm.  The maximum theoretical dietary burden was lower for pork, except for pork liver, 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 ppm (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.  The acute drinking water estimate of 427 ug/L was directly incorporated into the acute assessment.

A chronic dietary (food and drinking water) exposure and risk assessment was conducted assuming 100% crop treated, tolerance level residues and anticipated residues (ARs) for grapes, apples, oranges, and pears.  For the dietary assessment, a value of 0.20 ppm for the metabolite L7a was added to the tolerance level for liver.  DEEM version 7.81 default processing factors were assumed except for where tolerances were established for processed commodities.  The chronic drinking water estimate of 365 ug/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; therefore, a dose and endpoint were not identified.  An acute endpoint was identified for females 13-49 years old.  Therefore, an acute dietary assessment was conducted for this population subgroup.

The results 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.  The dietary exposure for food and water at the 95[th] percentile of exposure distribution is estimated at 1.3% 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 food and water is estimated at 32% of the cPAD for the general U.S. population and 78% 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 is classified as "not likely to be carcinogenic to humans;" therefore, cancer risk was not assessed.

5.4.5	Summary Table

 Table 5.4.5.  Summary of Dietary Exposure and Risk for Trifloxystrobin (cPAD = 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]
                                   0.012139
                                      32
                         All Infants (< 1 year old)
                                       
                                   0.029751
                                      78
                            Children 1-2 years old
                                       
                                   0.026545
                                      70
                            Children 3-5 years old
                                       
                                   0.020721
                                      54
                            Children 6-12 years old
                                       
                                   0.012755
                                      34
                             Youth 13-19 years old
                                       
                                   0.008879
                                      23
                            Adults 20-49 years old
                                       
                                   0.011282
                                      30
                            Adults 50-99 years old
                                       
                                   0.010870
                                      29
                            Females 13-49 years old
                                   0.032259
                                      1.3
                                   0.010893
                                      29
a	The population subgroups 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 uses that have been reassessed in this document to reflect updates to HED's 2012 Residential SOPs along with changes in dermal risk assessment hazard and changes in the policy for body weight assumptions (DP413713, N. Tsaur, 05/15/2014).  The revision of residential exposures does impact the human health aggregate risk assessment for trifloxystrobin.

There are various formulations registered for residential use on turfgrass and ornamentals, which include water dispersible granules (WG), water soluble packaging (WSP), granules (G), and liquid (L).  The currently registered end-use products (EPs) available for residential use include:
   1. Compass(TM) Fungicide (EPA Reg. No. 432-1371), a WG formulation (Restricted Use),
   2. Armada(TM) 50 WP (EPA Reg. No. 432-1412), a WSP formulation,
   3. Compass(TM) G Fungicide (EPA Reg. No. 432-1432), a G formulation,
   4. Tartan(TM) Fungicide (EPA Reg. No. 432-1446), an L formulation,
   5. Chipco(R) 26019T Fungicide (EPA Reg. No. 432-1505), an L formulation, and
   6. Armada(TM) 50 WDG (EPA Reg. No. 432-1513), a WG formulation.
Bayer Environmental Science (Bayer) is the registrant of all six products.  Two of the labels (Compass(TM) Fungicide and Compass(TM) G Fungicide) are restricted to professional handlers only.  However, the use of both products on residential and recreational turf may still result in residential post-application exposure.  Furthermore, there are no granular or liquid formulation uses on ornamentals (only WSP and WG are registered for use on residential ornamentals).

The reassessment of all registered residential products do not result in any residential handler or post-application risk estimates of concern.  Residential handler exposure is expected to be short-term only.  Intermediate-term exposures are not likely because of the intermittent nature of applications 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.  Appendix E 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 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 summary 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
                                     8,100
                        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 handler 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-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for trifloxystrobin at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (3.4x10[-6] Pa, or 2.55x10[-7] mm Hg at 25ºC) and the low proposed use rate (0.12 lb ai/A).  However, volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010.  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for trifloxystrobin.

6.4	Spray Drift

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 methods (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 other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information).   The Agency is also taking means to qualitatively and qualitatively address spray drift as a potential source of exposure in risk assessments for pesticides through existing programs such as Ag Drift and chemical specific properties of 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.

7.0	Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources 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. For trifloxystrobin, potential exposures from food, drinking water, and residential scenarios were aggregated.

7.1	Acute Aggregate Risk

There were no appropriate toxicological effects attributable to a single exposure (dose) for the general population; therefore, a dose and endpoint were not identified for this risk assessment.  The aPAD for females 13-49 years old was 2.5 mg/kg/day.  To assess the aggregate acute risk, EDWCs were incorporated directly into the dietary exposure analysis.  Refer to Section 5.4.1 for this risk estimate.

11.2 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 lead 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 systemic 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-application 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.

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
                                   0.012139
                                    0.00047
                                     NA[f]
                                   0.012609
                                      300
                                   Children
                                 1-2 years old
                                (Oral Exposure)
                                      3.8
                                      100
                                   0.026545
                                     NA[f]
                                    0.0052
                                   0.031745
                                      120
a	The LOC is based on inter- and intra- species uncertainty factors which total 100X.
b	Residential handler exposure based on adult handler inhalation only, of manually-pressurized handwand or backpack sprayer application of water dispersible granule formulation to residential turf (see Table 6.2).
c	Residential post-application exposure based on children incidental 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 = NOAEL / (Avg Food & Water Exposure + Residential Exposure).
f	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 (about 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.  For the purposes of this tolerance action, therefore, EPA has not assumed that trifloxystrobin has a common mechanism of toxicity with other substances.  For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and 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

Occupational handler and post-application exposure may occur by the dermal and inhalation routes of exposure only.  For short- and intermediate-term exposure, only inhalation exposures were assessed since there is no systemic hazard from the dermal route of exposure.  The results of the occupational handler exposure and risk assessment indicate that short- and intermediate-term risk estimates are not of concern (DP416655, N. Tsaur, 03/27/2014).  Appendix E summarizes all assessed occupational exposure and risk estimates.

9.1	Short- and Intermediate-Term Handler Risk

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed agricultural uses.  The quantitative exposure/risk assessment developed for occupational handlers is based on several scenarios which include mixing/loading/applying the SC formulation of trifloxystrobin.  Methods of application include aerial, chemigation, groundboom, and handheld equipment.  Flagging for aerial use is also a potential source of worker exposure.

HED classifies exposures from 1 to 30 days as short-term and exposures from 30 days to six months as intermediate-term.  Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site.  For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for more than a one-month time frame; however, there may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks (e.g., completing multiple applications for multiple clients within a region).  The area treated or amount handled is based on HED ExpoSAC Policy No. 9.1 (refer to Appendix E for these assumptions for each scenario).  Since the PODs for short- and intermediate-term exposure are the same, the short-term assumptions and risk calculations are protective of both durations.

It is the policy of HED to use the best available data to assess handler exposure.  Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include the Pesticide Handlers Exposure Database (PHED) 1.1, the Agricultural Handlers Exposure Task Force (AHETF) database, or other registrant-submitted occupational exposure studies.  Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA).  The standard values recommended for use in predicting handler exposure that are used in this assessment, known as "unit exposures", are outlined in the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table", which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website.

The results of the occupational handler exposure and risk assessment indicate that short- and intermediate-term inhalation risk estimates are not of concern (i.e. all MOEs >= 100) at baseline mitigation (no PPE).  Since the short- and intermediate-term PODs are the same, the inhalation MOEs are also the same, ranging 6,600 to 150,000.  Note that only engineering control (enclosed cockpit) data are available to assess risks to handlers operating aircrafts.

HED has no data to assess exposures to pilots using open cockpits.  The only data available is for exposure to pilots in enclosed cockpits.  Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (long-sleeve shirt, long pants, shoes, and socks); per the Agency's Worker Protection Standard stipulations for engineering controls, pilots are not required to wear protective gloves for the duration of the application.  With this level of protection, there are no risk estimates of concern for applicators.

The Agency matches quantitative occupational exposure assessment with appropriate characterization of exposure potential.  While HED presents quantitative risk estimates for human flaggers where appropriate, agricultural aviation has changed dramatically over the past two decades.  According the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of GPS for swath guidance in agricultural aviation has grown steadily from the mid 1990's.  Over the same time period, the use of human flaggers for aerial pesticide applications has decreased steadily from ~15% in the late 1990's to only 1% in the most recent (2012) NAAA survey.  The Agency will continue to monitor all available information sources to best assess and characterize the exposure potential for human flaggers in agricultural aerial applications.

9.2	Short- and Intermediate-Term Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure).  Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting.  Post-application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties.  In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.

9.2.1	Dermal Post-Application Risk

There is potential for short- and intermediate-term occupational exposure during post-application activities.  However, there is no adverse systemic dermal hazard for any exposure duration for trifloxystrobin.  

9.2.2	Restricted Entry Interval

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 toxicity 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 hours for the REI.  Thus, the 12-hour REI on the proposed label is adequate to protect workers.

9.2.3	Inhalation Post-Application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for trifloxystrobin at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (3.4x10[-6] Pa, or 2.55x10[-7] mm Hg at 25ºC) and the low proposed use rate (0.12 lb ai/A).  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010. The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures to identify the need for, and subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for trifloxystrobin.

Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers.  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.

10.0	References

Biscoe, Melanie. 01/28/2014. DP Barcode 413801. "Trifloxystrobin: Drinking Water Exposure Assessment in Support of a Proposed New Use on Dry Peas, Chickpeas, and Lentils (Reg. Nos. 264-776 (technical) and 264-1055)."

Negussie, Meheret. 03/18/2014. DP Barcode 413711. "Trifloxystrobin.  Application for Section 3 Registration for Uses on Dry Peas, Chickpeas, and Lentils. Summary of Analytical Chemistry and Residue Data."

Negussie, Meheret. 04/14/2014. DP Barcode 413712. "Trifloxystrobin.  Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for Uses on Dry Peas, Chickpeas, and Lentils."

Habiba, Uma. 05/22/2014. TXR Number 0056957. "Trifloxystrobin. Summary of Hazard and Science Policy Council (HASPOC) Meeting on April 24, 2014: Recommendation on the Waiver Request for a 28-day Inhalation Study."

Tsaur, Nancy. 05/14/2014. DP Barcode 413713. "Trifloxystrobin.  Occupational Exposure and Risk Assessment for the Proposed New Uses on Chickpea, Dry Peas, and Lentils with An Updated Residential Exposure Assessment of All Existing Residential Uses."
Appendix 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.	Satisfaction 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]
                                   waived[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
                                      CRc
                                       - 
                                       - 
                                      yes
                                     no[d]
                                       - 
870.7485    General Metabolism	
870.7600    Dermal Penetration	
870.7800    Immunotoxicity	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
a	Conditionally required.
b	A subchronic inhalation toxicity study has been waived for trifloxystrobin at this time (Hazard and Science Policy Council memo, TXR0056957, U. Habiba, 05/22/2014).
c	Conditional requirement pending submission of acceptable guideline acute and subchronic neurotoxicity batteries.
d	A subchronic neurotoxicity study has been waived for trifloxystrobin at this time (Hazard and Science Policy Council memo, TXR0056150, D. Smegal, 01/05/2012)
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
                               LD50 > 5 g/kg
                                      IV
                                   870.1200
Acute Dermal  -  Rabbits
                                   44496626
                                   44496627
                               LD50 > 2 g/kg
                                      IV
                                   870.1300
Acute Inhalation  -  Rats
                                   44496630
                              LC50 > 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 based on decreased body weight and increased relative liver weight.
870.3100

90-Day oral toxicity (rat)
44496701 (1995)
Acceptable/Guideline
0, 100, 500, 2000, or 8000 (F only)  ppm
M: 0, 6.44, 30.6, or 127 mg/kg/day
F: 0, 6.76, 32.8, 133, or  618 mg/kg/day
NOAEL = 30.6 mg/kg/day 
LOAEL =127 mg/kg/day based on decreased 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 and 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

28-Day subchronic range-finding oral toxicity (dog) [capsule]
44496642 (1994)
Unacceptable/non-guideline
(2 dog/sex/dose)
0, 20, 50, 150 mg/kg/day
NOAEL=50 mg/kg/day
LOAEL= 150 mg/kg/day based on increased incidence of diarrhea and vomiting and body weight reduction.
870.3200

28-Day dermal toxicity (rat)
44496703 (1996)
Acceptable/Guideline
0, 10, 100, 1000 mg/kg/day
NOAEL = 1000 mg/kg/day.
LOAEL > 1000 mg/kg/day; a LOAEL was not established.  The observed increases in liver and kidney weights 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.
Developmental NOAEL = 1000 mg/kg/day (HDT).
870.3700b

Prenatal 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 skeletal anomalies (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.
Reproductive 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 necrosis, hepatocellular hypertrophy).
There was non-statistically significant and non-dose related increase in lymphoma incidence.  Trifloxystrobin is classified as "Not Likely to be Carcinogenic 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, 11.37, 34.5, 72.8 mg/kg/day
NOAEL = 9.81 mg/kg/day
LOAEL= 29.7 mg/kg/day based on decreased body 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
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. Highest residues were found in liver, 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 metabolized 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

Appendix B.	Physical/Chemical Properties

Table B.  Physico-Chemical Properties of Trifloxystrobin
                                   Parameter
                                     Value
                                   Reference
Melting Point/Range
72.9ºC
MRID 44502801
pH (25ºC)
7.7 in 1% w/w aqueous dispersion

Density (21ºC)
1.36 g/cm[2]

Water Solubility (20ºC)
0.00061 g/L

Solvent Solubility (g/L at 25°C)
methanol	76
acetone	>500
ethyl acetate	>500
n-hexane	11
dichloromethane	>500
toluene	500
n-octanol	18

Vapor Pressure (25°C)
3.4 x 10[-6] Pa, 2.55 x 10[-][7] mm Hg

Dissociation Constant (pKa)
none at pH of 2-12

Octanol/Water Partition Coefficient (25ºC) Log(KOW)
4.5

UV/Visible Absorption Spectrum
17,500 at 250.7 um (neutral)
17,300 at 250.2 um (acidic)
15,900 at 252.3 um (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 PHED and 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.

Appendix D.	International Residue Limit Status

Table D.1. Trifloxystrobin Summary of US and International Tolerances and Maximum Residue Limits
                              Residue Definition
                                      US
                                    Canada
                                   Mexico[b]
                                     Codex
40 CFR 180.555:
Plants and Livestock:  sum of trifloxystrobin, benzeneacetic acid, (E,E)-α-(methoxyimino)-2-[[[[1-[3-(trifluoromethyl) phenyl]ethylidene] amino]oxy]methyl]-, methyl ester, and the free form of its acid metabolite CGA - 321113, 
(E,E)-methoxyimino-[2-[1-(3-trifluoromethyl-phenyl)-ethylideneaminooxymethyl]-phenyl]acetic acid, calculated as the stoichiometric equivalent of trifloxystrobin
Methyl (α,E)-α-(methoxyimino)-2-[[[(E)-[1-[3-(trifluoromethyl)phenyl]ethylidene]amino]oxy]methyl]benzeneacetate, including the metabolite (α,E)-α-(methyoxyimino)-2-[[[(E)-[1-[3-(trifluromethyl)phenyl]ethylidene]amino]oxy]methyl]benzeneacetic acid, expressed as trifloxystrobin
                                       
Plant: Trifloxystrobin
Livestock: sum of trifloxystrobin and [(E,E)-methoxyimino-{2-[1-(3-trifluoromethylphenyl)ethylideneaminooxymethyl]
phenyl}acetic acid] (CGA 321113), expressed as trifloxystrobin. The residue is fat-soluble.
                                 Commodity[a]
                        Tolerance/Maximum Residue Limit
                                       
                                      US
                                    Canada
                                   Mexico[b]
                                     Codex
                                       
                                      ppm
                                     mg/kg
Pea, dry, seed
                                     0.06
                                     0.06
          (proposed)  (pea field, pea pigeon, chickpea, lentil) seed
                   0.02 dry (field peas, chickpeas, lentils)
                                       
                                       
Pea, field, hay
                                      15
                                       
                                       
                                       
Pea, field, vines
                                       3
                                       
                                       
                                       
Completed:  M. Negussie; 02/25/2014
a	Includes only commodities of interest for this action.
b	Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

Appendix E.	Residential and Occupational Exposure/Risk Summary Table

Table E.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 Exposured
                          Baseline Inhalation Dose[e]
                           Inhalation Baseline MOEf
                                       
                                       
                                       
                                   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
                                   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) x application rate (lb ai per gallons, square feet, or acres) x amount handled or area treated (gallons, square feet, or acres per day) / body weight (80 kg). No inhalation absorption factor.
f	MOE = NOAEL / daily dose (mg/ - kg/ - day). ST Inhalation NOAEL = 3.8 mg/kg/day. Level of concern = 100.	

Table E.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 years 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 years 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]) x fraction of hand mouthed (0.127) x surface area of 1 hand (150 cm[2]) x exposure time (1.5 hrs/day) x # of replenishment intervals/hr (4 int/hr) x (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 (ug/cm[2]) x unit conversion factor (0.001 mg/ug) x object surface area mouthed / event (10 cm[2]/event) x exposure time (1.5 hrs/day) x # replenishment intervals/hr (4 int/hr) x (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 (ug/g) x ingestion rate (50 mg/day) x conversion factor (0.000001 g/ug) / 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.

Table E.3.	Occupational Handler Exposure and Risk Estimates for Trifloxystrobin Use on Typical Field Crops[a]
                               Exposure Scenario
                          Inhalation Unit Exposure[b]
                                    Maximum
                              Application Rate[c]
                    Area Treated or Amount Handled Daily[d]
                              Inhalation Dose[e]
                               Inhalation MOE[f]
                                       
                                   μg/lb ai
                                    lb ai/A
                                     Acres
                                   mg/kg/day
                                ST/IT LOC = 100
                                 Mixer/Loader
      Mixing/Loading Dry Flowables for Aerial and Chemigation Application
                                     0.219
                                     0.12
                                      350
                                   0.000114
                                    33,000
            Mixing/Loading Dry Flowables for Groundboom Application
                                       
                                     0.12
                                      80
                                   0.0000261
                                    150,000
                                  Applicator
                    Applying Sprays for Aerial Application
                                     0.068
                                     0.12
                                      350
                                   0.0000354
                                    110,000
                  Applying Sprays for Groundboom Application
                                     0.34
                                     0.12
                                      80
                                   0.0000405
                                    94,000
                                    Flagger
                        Flagging for Aerial Application
                                     0.35
                                     0.12
                                      350
                                   0.000183
                                    21,000
                            Mixer/Loader/Applicator
       M/L/A Dry Flowables for Mechanically-Pressurized Handgun Sprayers
                                      3.9
                                     0.012
                                   lb ai/gal
                                     1000
                                    gallons
                                    0.00058
                                     6,600
a	"Typical Field Crops" include chickpea, dry peas, and lentils.
b	Based on the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (March 2012); Level of mitigation = Baseline (no respirator) except for aerial applicator which includes engineering controls.
c	Based on the maximum application rates on the proposed labels (Reg. No. 264-1055, USF 0728 325 SC Fungicide).
d	Exposure Science Advisory Council Policy #9.1.
e	Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount  Handled Daily (A or gal/day) / BW (80 kg).
f	MOE = NOAEL ( mg/kg/day) / Dose (mg/kg/day). ST/IT Inhalation NOAEL = 3.8 mg/kg/day. Level of concern = 100.