                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                         WASHINGTON, D.C. 20460      

                                                     OFFICE OF CHEMICAL SAFETY 
                                                       AND POLLUTION PREVENTION


MEMORANDUM

DATE:	March 19, 2013

SUBJECT:	REVISED Trifloxystrobin.  Human Health Assessment Scoping Document in Support of Registration Review.

PC Code:  129112
DP Barcode: D405469
Decision No.: 469960
Registration No.: NA
Petition No.: NA
Regulatory Action: Registration Review
Risk Assessment Type: NA
Case No.: 5072-1
TXR No.: NA
CAS No.: 141517-21-7
MRID No.: NA
40 CFR: 180.555

FROM:	Nancy Tsaur, Chemist		
	Sheila Healy, Ph.D., Toxicologist
	Meheret Negussie, Chemist
	Risk Assessment Branch 3 (RAB3)
	Health Effects Division (7509P)

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

	and

	Dana Vogel, Deputy Director
	Jess Rowland, Acting Associate Director
	Immediate Office (IO)
	Health Effects Division (7509P)

TO:	Moana Appleyard, Chemical Review Manager
	Risk Management and Implementation Branch 5 (RMIB5)	
	Pesticide Re-Evaluation Division (7508P)

Executive Summary

The HED Registration Review Team has evaluated the database for the fungicide trifloxystrobin to determine whether sufficient data are available and whether any updates are needed to support Registration Review.  HED has considered the most recent human-health risk assessments for trifloxystrobin; updates to the toxicity, exposure, and usage databases; and current Agency science policy and risk assessment methodologies to determine the scope of work necessary to support Registration Review.  In addition, HED has conducted an open literature search and determined that new information relevant to the human health risk assessment has not been published.

Trifloxystrobin is a strobilurin-class fungicide that controls foliar fungal diseases and soilborne/seedling fungal diseases.  It works by interrupting mitochondrial respiration in plant-pathogenic fungi, thus inhibiting spore germination and mycelial growth.  Trifloxystrobin is registered for use on a variety of agricultural crops including the following: almonds, artichokes, asparagus, citrus, cucurbit vegetables, fruiting vegetables, grapes, grasses grown for seed, hops, leafy petiole vegetables, pecans, pistachios, pome fruits, potatoes, rice, root vegetables, stone fruits, strawberries, sugar beets, tree nuts, tropical fruits, and wheat.  In addition to agricultural uses, trifloxystrobin is registered for foliar use on sod farms and turfgrass (including landscapes and interiorscapes of residential, recreational, commercial, industrial, and public areas); and ornamentals (grown in greenhouses, shadehouses, and fields).  Furthermore, trifloxystrobin is registered for use as a seed treatment on the following commodities: canola, cotton, cucurbit vegetables, fruiting vegetables, field corn, mustard seed, rapeseed, popcorn, rice, sorghum, sugar beets, wheat, potatoes, peanuts, turf grass, conifers, ornamental flowers, soybeans, beans and peas, and sweet corn.

The toxicology database for trifloxystrobin is incomplete.  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.  The primary target organ of toxicity is the liver in dogs, mice, and rats in subchronic (including dermal) and chronic studies.  The effects of reduced body weight and food consumption were also found in the majority of the toxicity studies.

There is no evidence of developmental or reproductive toxicity in the trifloxystrobin toxicology database.  There is no evidence of neurotoxicity at the limit dose of an acute neurotoxicity study or in the other subchronic and chronic studies in the database; the requirement for a subchronic neurotoxicity study has been waived (TXR0056150, 01/05/2012, D. Smegal).  An immunotoxicity study in rats has been submitted by the registrant and is under review.  Upon preliminary screen, no functional immunotoxicity is observed at the highest dose tested (263 mg/kg/day).  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.

HED's Hazard and Science Policy Committee (HASPOC) determined that a route-specific subchronic inhalation study is required to assess risk from inhalation exposure from occupation use based on a weight-of-evidence (WOE) approach considering all of the available hazard and exposure information for trifloxystrobin, including the Margins of Exposure (MOEs) from the most recent risk assessment. The use of an oral POD resulted in the MOE of 47 for pressurized hand gun applications that is lower than the HED Level of Concern (MOE=1000) therefore, a route specific study was requested to address the uncertainty resulting from the use of an oral study.

The toxicological endpoints and the Food Quality Protection Act (FQPA) safety factor will need to be re-evaluated for the registration review risk assessment, including the results of the inhalation toxicity study.  There are no residual uncertainties in the exposure database.

The residue chemistry database is sufficient to support existing registrations of trifloxystrobin.  The nature of the residue in plants and livestock has been defined.  Adequate field trial data, rotational crop data, and storage stability data are available.  

A new risk assessment will be needed pending review of an inhalation toxicity study.  HED has identified inhalation toxicity as a data gap and will apply an additional 10X safety factor for all inhalation exposures accordingly.  Residential exposure and risk assessments also need to be reassessed based on current Residential Standard Operating Procedures (SOPs).  Occupational exposure assessments need to be reassessed based on current occupational exposure and risk assessment policies.  In addition, the Agency may need to consider off-target movement of pesticides into residential settings.

Introduction

HED has evaluated the existing human health risk assessments for trifloxystrobin to determine whether sufficient data are available and whether a new human health risk assessment is needed to support Registration Review.  HED has considered the most recent risk assessments for trifloxystrobin, updates to its toxicity, exposure and usage databases, and current Agency science policies and risk assessment methods.  The most recent risk assessment for trifloxystrobin was conducted in August 2011 to set a tolerance on imported coffee (DP385972, N. Tsaur, 08/02/2011).

Hazard Identification/Toxicology

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

On January 5, 2012, the HASPOC has determined that a repeat-dose (28-day) inhalation toxicity study is required based on trifloxystrobin's use pattern and exposure scenarios, and the unacceptable MOEs that resulted form the use of an oral POD (TXR0056150).  Since that HASPOC meeting, the registrant has responded with a rebuttal indicating that the MOEs used by the HASPOC were outdated and unreliable.  On November 29, 2012, the HASPOC reviewed and reconsidered the registrant's waiver request and re-affirmed its earlier decision that a route-specific (inhalation) study is required to address the uncertainty of using an oral POD and to assess risk from occupational exposure (DP405845, K. Rury, 01/30/2013, TXR0056527).  A 10X database uncertainty factor (UFDB) will be retained for the lack of this study only for inhalation risk assessments (i.e., MOE of 1000).
 
With repeated dosing by either the oral or dermal route, the liver is consistently the target organ for trifloxystrobin.  Liver effects were seen in rats, mice, and dogs, characterized by an increase in liver weights and an increase in incidences of hepatocellular hypertrophy and/or hepatocellular necrosis.  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 that which caused liver and body weight effects.  This finding was consistent with those produced by other members of the strobilurin class.

Trifloxystrobin is not a developmental toxicant and does not produce reproductive effects.  The rat and rabbit developmental and the rat reproduction toxicity data demonstrate no increase in susceptibility in either fetal animals or pups.

Trifloxystrobin was determined not to be carcinogenic in mice or rats following long-term dietary administration.  It is positive for mutagenicity in Chinese Hamster V79 cells at cytotoxic dose levels while testing negative in the remaining mutagenicity studies.

Trifloxystrobin exhibits low acute toxicity following single oral, dermal and inhalation exposures.  It is a strong dermal sensitizer and a mild dermal and eye irritant.

Conclusions: The toxicology database is adequate for FQPA assessment, with the exception of data on subchronic inhalation.  Submission of a subchronic inhalation study will require reevaluation of toxicity endpoints and safety factors.

Residue Chemistry

There are no residue chemistry deficiencies.  Tolerances are currently established for the combined residues of trifloxystrobin and its free form acid metabolite CGA - 321113 in/on various crop and livestock commodities ranging from 0.02 ppm (milk) to 38 ppm (citrus oil) [40 CFR §180.555(a)].  

The qualitative nature of the residue in plants and livestock commodities is adequately understood based on the data from the primary plant metabolism studies and the confined rotational crop study, as well as metabolism studies on lactating goats and poultry.  HED concluded that the residues of concern in plants (including rotational crops) and livestock commodities are parent and its free acid metabolite CGA-321113 for regulatory and risk assessment purposes (for chemical names and structures, refer to Attachment 1).  HED also determined that for livestock commodities, the metabolite L7a (taurine conjugate of trifloxystrobin) in liver should also be included in the risk assessment.  The toxicity of the metabolites are assumed to be toxicologically equivalent to the parent compound.

An adequate gas chromatography/nitrogen phosphorus detection (GC/NPD) method (Method AG-659A) is available for enforcing tolerances for the combined residues of trifloxystrobin and CGA-321113 in plant and livestock commodities.  This method was validated by the Agency and forwarded to FDA for inclusion in the Pesticide Analytical Manual (PAM), Vol. II.

Adequate multiresidue methods test data are available.  Trifloxystrobin gave adequate responses through protocol C, and was completely recovered from fortified apple samples when analyzed through protocols D and E.  Acid metabolite CGA-321113 was recoverable through protocol B and residues from apples fortified with CGA-321113 were completely recovered through Section 402 E2/C1 (extraction with methylene chloride).  These data were forwarded to the Food and Drug Administration (FDA).

Adequate storage stability data are available to support storage durations for trifloxystrobin.

Conclusions: The chemistry database is complete and adequate for considering dietary risk estimates.  Additional residue and metabolism data are not required for all registered uses of trifloxystrobin.

Dietary Exposure

The residue chemistry and environmental fate data are adequate to assess human exposure.  Although somewhat refined, the acute and chronic dietary food and water exposure assessments are based on reliable data and will not underestimate exposure/risk.

An acute and chronic aggregate dietary (food and drinking water) exposure and risk assessment was conducted on trifloxystrobin using the Dietary Exposure Evaluation Model, DEEM-FCID(TM), Version 2.03, which uses food consumption data from the U.S. Department of Agriculture's Continuing Surveys of Food Intakes by Individuals (CSFII).  The surveys were taken from 1994-1996 and included a supplemental children's survey taken in 1998.  

Residue Data used for Acute and Chronic Dietary Food and Drinking Water Exposure Assessments
There were no appropriate toxicological effects attributable to a single exposure (dose) for the general U.S. population.  However, because a developmental effect that could result from a single dose was identified in the toxicology database, an endpoint was selected for the acute dietary assessment of the population subgroup females 13-49 years old.
 
The acute assessment was based on the assumption of tolerance-level residues for all commodities while the chronic assessment incorporated anticipated residues (ARs) for grapes, apples, and oranges.  ARs were calculated by averaging the residue values over the entire field trial data and using the limit of quantitation for non-detect samples.  Both assessments assumed 100% of the crops were treated.  For the dietary assessments only, a value of 0.20 ppm was added for the Metabolite L7a in addition to the recommended 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.  For pork liver, a value of 0.11 ppm was added to the pork established tolerance (0.05 ppm); thus pork liver was included in the DEEM 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 1X.  For all other processed commodities, DEEM(TM) 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; however, the default processing factor of 1X was retained because further refinements are not needed.

The drinking water estimates include residues of trifloxystrobin and CGA-321113.  The acute drinking water estimate of 47.98 ug/L (ppb) and chronic drinking water estimate of 47.31 ug/L (ppb), provided by the Environmental Fate and Effects Division (EFED), were directly incorporated into the acute and chronic assessment, respectively. 

Acute Dietary (Food and Drinking Water) Exposure Results
The acute dietary risk assessment for trifloxystrobin yielded exposure estimates below HED's level of concern (i.e. <100% aPAD); acute dietary exposure utilized 1.9% of the aPAD for females 13-49 years old at the 95[th] percentile.

Chronic Dietary (Food and Drinking Water) Exposure Results 
The chronic dietary risk assessment for trifloxystrobin yielded exposure estimates below HED's level of concern (i.e. <100% cPAD).  For the general U.S. population the exposure for food and drinking water utilized 34% of the cPAD.  The chronic dietary risk estimate for the highest reported exposed population subgroup, children 1-2 years old, is 64% of the cPAD.  

Trifloxystrobin is classified as "Not Likely to be Carcinogenic to Humans" based on the lack of evidence of carcinogenicity in mouse and rat cancer studies; therefore, no cancer risk is expected and cancer risk assessments were not conducted. 

Conclusions:  Up-to-date drinking water estimates will be needed from EFED based on new modeling policies; therefore, a new dietary assessment for trifloxystrobin will be required for the purpose of registration review.  Furthermore, although a new version of DEEM (Version 3.16) has been released and a new Screening Level Usage Analysis (SLUA) was provided (May 15, 2012) by BEAD, a new dietary risk assessment may not be needed since it is anticipated that these updates will not affect the risk conclusion.  The updated SLUA will lower risk estimates since %CT data were not incorporated in the assessment. 

Residential Exposure 

Registered residential uses include application to residential turfgrass, ornamentals, and recreational turf areas.  The duration of exposure for residential handler and post-application exposures is expected to be short-term (1-30 days) only; intermediate- and long-term exposures are not anticipated.  The level of concern (LOC) for risk estimates is a margin of exposure (MOE) of less than 100 for short-term dermal and oral exposure and 1000 for short-term inhalation exposure.  Existing residential handler and post-application exposure and risk assessments do not show risk estimates of concern.

Turf Transferable Residue (TTR):  In accordance with the updated Part 158 data requirements (2007), a TTR study is required for all occupational (e.g., sod farms, golf courses, parks, and recreational areas) or residential turf uses.  As part of the recent revision to the Health Effects Division's 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment, HED analyzed all available data and selected new liquid and granular default values for the fraction of the application rate available for transfer after a turf application (FAR).  These defaults are 1% for formulations applied as liquids (i.e., emulsifiable concentrates, liquids, wettable powders, dry flowables, etc.) and 0.2% for granular formulations.  Of the available TTR studies submitted to the Agency, the maximum FAR value seen using a liquid product was 6.1% or 6.1 times higher than the default residue transfer value.  The maximum FAR value seen in a TTR study using a granular product was 0.69% or 3.5X the default residue transfer value.  Therefore, for both liquid and granular formulations, a calculated MOE of approximately 10 times higher than the level of concern (e.g., an MOE > 1,000 if the LOC = 100) using the default residue transfer values would provide an adequate margin of safety for any potentially higher residues seen in a chemical-specific TTR study (Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies. 6/7/2012, Exposure Science Advisory Council).  A TTR study is required for trifloxystrobin at this time since the hand-to-mouth MOE is less than 1,000 (MOE = 720) based on default values for the fraction of application rate available for transfer after a turf application.

Residential exposures resulting from off-site transport (e.g. spray drift or volatilization) may occur as a result of applications of trifloxystrobin. The Agency is in the process of evaluating these types of exposures and will examine the need for spray drift and volatilization assessments for trifloxystrobin during registration review.

Conclusion:  There is sufficient information available to assess residential exposure, with the exception of TTR data.  However, all residential exposure scenarios were not assessed adequately based on current HED policy; an up-to-date quantitative residential risk assessment may be needed to account for additional scenarios that were not assessed in the past, or if there is a change in endpoints and safety factors.

Aggregate Risk Assessment

Aggregate assessments consider exposures from food, drinking water, and residential uses.  In the most recent human health risk assessment (DP385972, N. Tsaur, 08/02/2012), short-term aggregate risk estimates were estimated using chronic food and drinking water exposure estimates along with short-term residential exposure estimates.  As previously mentioned, these aggregate risk estimates were below HED's LOC.

Conclusions: There is sufficient information available to assess aggregate human health exposure and risk; however, updated aggregate assessments are required to incorporate changes in residential exposure and risk policies, new data (e.g. a subchronic inhalation toxicity study), and an up-to-date drinking water assessment.

Occupational Exposure 

Trifloxystrobin is registered for several agricultural uses and non-crop areas.  The durations of exposure are expected to be short-term (1-30 days) and intermediate-term (1-6 months); long-term exposures are not anticipated.  The LOC for dermal risk estimates is a MOE of less than 100 for short- and intermediate-term exposure.  The LOC for inhalation risk estimates is a MOE of less than 1000 for short- and intermediate-term exposure.  Occupational handler and post-application exposure and risk assessments have been conducted on a majority of the registered occupational (agricultural and non-crop) uses, resulting in risk estimates that are not of concern.  The current HED policy incorporates new scenarios that were previously unassessed (e.g. handheld equipment for turf and ornamentals).

Based on the Agency's current practices, a quantitative occupational post-application inhalation exposure assessment has not been performed for trifloxystrobin at this time.  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.  The Agency received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the Agricultural Reentry Task Force 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.

Dislodgeable Foliar Residue (DFR):  In accordance with the updated Part 158 data requirements (2007), one or more DFR studies are required when a pesticide has residential or occupational uses that could result in post-application dermal exposure.  As part of the recent revision to the Health Effects Division's 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment, HED analyzed a number of DFR studies and selected a new default value for the fraction of the application rate available to be dislodged after a foliar application (FAR).  This default value is 25% and is based on an analysis of 19 DFR studies where the FAR value ranged from 2% to 89%.  This value is recommended for use in both residential and occupational postapplication assessments.  Of the analyzed DFR studies, the maximum FAR value seen was 89% or 3.6 times higher than the default residue transfer value.  Therefore, the HED has decided that a calculated MOE of approximately 4 times higher than the level of concern (e.g., an MOE > 400 if the LOC = 100) using the default dislodged residue values would provide an adequate margin of safety for any potentially higher residues seen in a chemical-specific DFR study (Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies. 6/7/2012, Exposure Science Advisory Council).  A DFR study is required for trifloxystrobin at this time since some dermal MOEs are less than 400 (the lowest MOEs are 140 for girdling/turning grapes and 270 for tying/training grapes, and 140 for harvesting hops) based on default values for the fraction of application rate available for transfer after a foliar application.

Conclusions: There is sufficient information available to assess occupational handler and post-application exposures, with the exception of DFR data.  However, all occupational exposure scenarios were not assessed adequately based on current HED policies.  An up-to-date quantitative occupational risk assessment may be required to account for the correct registered application rates, the changes in unit exposures, the changes in transfer coefficients (TCs), and any possible changes to endpoints and safety factors.  Updated risk estimates may result in some risks of concern.

Public Health and Pesticide Epidemiology Data 

For this evaluation, both OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk-Pesticides (SENSOR) databases were consulted for pesticide incident data on trifloxystrobin (DP407067, S. Recore, 11/27/2012).  Based on the low frequency and severity of incident cases reported for trifloxystrobin in both IDS and NIOSH SENSOR, there does not appear to be a concern at this time that would warrant further investigation.  The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk assessment.

Tolerance Assessment and International Harmonization

Codex and Canada have established maximum residue limits (MRLs) for trifloxystrobin on various crop commodities.  The U.S. and Canadian tolerance expressions are in harmony whereas Codex is not (plant only).  Residue definition in the U.S. is parent and the metabolite.  
The Codex residue definition is expressed in terms of the parent only for plant commodities and parent and the metabolite for livestock commodities; therefore harmonization of tolerances/ MRLs is not possible.  
 
Most of the available Codex MRL values are not in harmony with the U.S.; the Codex MRLs for beet sugar (dried pulp, molasses, and roots), corn field, citrus fruits, tree nuts, strawberry, and cucurbit vegetables are lower than the U.S. tolerances.  MRL values are harmonized on citrus dry pulp, eggs, grape raisins, hog meat, hog meat byproducts (liver only), poultry meat and meat byproducts, milk, and livestock feedstuffs.  The U.S. tolerances for livestock commodities (meat and meat byproducts) of cattle, goat, hog, horse, and sheep (0.1 ppm) are not harmonized with the Codex value (0.04 ppm).

The U.S. tolerances on fruiting vegetables (0.50 ppm) and root and tubers (subgroup 1B) (0.1 ppm) were established as a crop group/subgroup while Codex MRLs were established on individual crops, peppers (0.3) and tomatoes (0.7) and carrots (0.1) and potatoes (0.02), respectively.  The carrot MRL (0.1 ppm) is the same as the U.S. subgroup 1B tolerance.

There are Codex MRLs on banana, Brussels sprouts, cabbages head, flower head Brassica, leek, and peanut fodder that do not have U.S. equivalent.

The available Canadian MRLs are in harmony with the U.S., except for corn sweet kernel plus cob with husks removed, root and tuber vegetables subgroup 1B, fat, meat, and meat byproducts of cattle, hogs, horses, and sheep.  The U.S. has recommended tolerances for livestock feed commodities, but by policy Canada does not establish MRLs for livestock feed commodities.

There are Canadian MRLs on dry, edible-podded, succulent (beans and peas), mustard seed, and rapeseed; since these are no registered uses in the U.S., there are no U.S. tolerance equivalents.

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 from the Continuing Surveys of Food Intakes by Individuals (CSFII) and/or the What We Eat in America Survey (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, season of the year, ethnic group, and region of the country.  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.

Endocrine Disruptor Screening Program

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals.  Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity.  These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring.  For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups.  As part of its most recent registration decision, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database.  However, as required by FFDCA section 408(p), trifloxystrobin is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).  EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a "naturally occurring estrogen, or other such endocrine effects as the Administrator may designate."  The EDSP employs a two-tiered approach to making the statutorily required determinations.  Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems.  Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine-related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals.  Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients.  Trifloxystrobin is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP.  Accordingly, as part of registration review, EPA will issue future EDSP orders/data call-ins, requiring the submission of EDSP screening assays for trifloxystrobin.  For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website:  http://www.epa.gov/endo/.

Cumulative

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 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/.

Human Studies

The previous risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These studies, which comprise the PHED, the Outdoor Residential Exposure Task Force (ORETF), and the Agricultural Reentry Task Force (ARTF), have been determined to require a review of their ethical conduct, and have received that review.

Data Requirements

Exposure	870.2100 Turf Transferable Residue Dissipation 
A TTR study is required for trifloxystrobin at this time since the hand-to-mouth MOE is less than 1,000 (MOE = 720) based on default values for the fraction of application rate available for transfer after a turf application.

Exposure	870.2100 Dislodgeable Foliar Residue Dissipation 
A DFR study is required for trifloxystrobin at this time since some dermal MOEs are less than 400 (the lowest MOEs are 140 for girdling/turning grapes and 270 for tying/training grapes, and 140 for harvesting hops) based on default values for the fraction of application rate available for transfer after a foliar application.

Toxicology	870.3465 Inhalation Toxicity 
A subchronic inhalation study is required as the use pattern of this chemical indicates inhalation exposure can occur; a waiver for an inhalation toxicity study has not been granted.

References

Memoranda Relevant to Registration Review of Trifloxystrobin
                                    Author
                                    DP/TXR
                                    Barcode
                                     Date
                                     Title
L. Cheng
                                   DP267787
01/17/2002
Trifloxystrobin on Barley, Citrus, Corn (Field and Pop), Pecan, Pistachio, Rice, and Stone Fruit.  Review of Analytical Methods and Residue Data.
K. Rury 
                                  TXR 0056527
01/30/2012
Trifloxystrobin:  Summary of Hazard and Science Policy Council (HASPOC) Meeting of November 29, 2012:  Recommendations on waiver requests for 28-day inhalation study for trifloxystrobin.
D. Smegal
                                  TXR 0056150
01/05/2012
Trifloxystrobin:  Summary of Hazard and Science Policy Council (HASPOC) Meeting of December 8, 2011:  Recommendations on waiver requests for 28-day inhalation and subchronic neurotoxicity studies for trifloxystrobin.
N. Tsaur
                                   DP385972
08/02/2011
Trifloxystrobin.  Human Health Risk Assessment for Proposed New Use on Imported Coffee.
N. Tsaur
                                   DP387201
07/13/2011
Trifloxystrobin.  Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Petition for Establishment of a Tolerance on Imported Coffee.
J. Wolf
                                   DP360307
10/07/2009
Drinking Water Assessment for Tolerance Petition for New Uses of Trifloxystrobin in Fluopyram/Trifloxystrobin 500 SC Fungicide [EPA Reg. No. 264-RNON].


Attachments
   1. Chemical Identity Table
   2. International Residue Limits
   3. Endpoint Selection Table
   4. Toxicology Data Requirements Table
   5. Acute Toxicity profile
   6. Subchronic, Chronic, and Other Toxicity Profile

Attachment 1

                            Chemical Identity Table

Table 1.	Test Compound Nomenclature
Chemical Structure 
of Parent Compound

Empirical Formula
C20H19F3N2O4 
Common Name
trifloxystrobin
Company Experimental Name
BO17211 or CGA-279202
IUPAC Name
methyl (E)-methoxyimino-{(E)-α-[1-(α,α,α-trifluoro-m-tolyl)ethylideneaminooxy]-o-tolyl}acetate
CAS Name
methyl (αE)-α-(methoxyimino)-2-[[[[(1E)-1-[3-(trifluoromethyl)phenyl]ethylidene]amino]oxy]methyl]benzeneacetate
CAS Registry #
141517-21-7
Chemical Class
Strobilurin
Known Impurities of Concern
None
Chemical Structure
of Metabolite CGA-321113 

Common Name
trifloxystrobin acid
Company Code
CGA-321113
CAS Name
(αE)-α-(methoxyimino)-2-[[[[(1E)-1-[3-(trifluoromethyl)phenyl]ethylidene]amino]oxy]methyl]benzeneacetic acid
CAS #
252913-85-2


Attachment 2
                                       
                         International Residue Limits
                                       
Table 2.	Summary of U.S. and International Tolerances and Maximum Residue Limits
                              Residue Definition
                                     U.S.
                                    Canada
                                   Mexico[2]
                                   Codex[3]
40 CFR 180.555: 
Plants/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]benzene acetate, including the metabolite (α,E)-α-(methoxyimino)-2-[[[(E)-[1-[3-(trifluoromethyl)phenyl]ethylidene]-amino]oxy]methyl]benzene acetic acid, expressed as trifloxystrobin.

Plants: 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
                Tolerance (ppm) /Maximum Residue Limit (mg/kg)
                                       
                                     U.S.
                                    Canada
                                   Mexico[2]
                                   Codex[3]
Alfalfa, forage
0.01



Alfalfa, hay
0.01



Almond, hulls
9.0


3
Apple, wet pomace
5.0



Artichoke, globe
1.0



Asparagus
0.07



Banana[1]
0.10


0.05
Barley, grain
0.05
0.05

0.5
Barley, hay
0.3



Barley, straw
5.0


7 barley straw and fodder, dry
Beet, sugar, dried pulp
0.4


0.2 sugar beet pulp, dry
Beet, sugar, molasses
0.2


0.1 sugar beet molasses
Beet, sugar, roots
0.1
0.1 sugar beet roots

0.05 sugar beet
Beet, sugar, tops
4.0



Canistel
0.7
0.7


Cattle, fat
0.1
0.04


Cattle, meat
0.1
0.04

0.05 (fat) (meat from mammals other than marine mammals)
Cattle, meat byproducts
0.1
0.04

0.04  (*) kidney of cattle
0.05 liver of cattle
Citrus, dried pulp
1.0


1 citrus pulp, dry
Citrus, oil
38
38


Coffee, green bean[1]
0.02



Corn, field, forage
6.0



Corn, field, grain
0.05
0.05 field corn

0.02 maize
Corn, field, stover
7


10 maize fodder (dry)
Corn, field, refined oil
0.1
0.1


Corn, pop, grain
0.05
0.05 popcorn grain


Corn, pop, stover
7



Corn, sweet, cannery waste
0.6



Corn, sweet, forage
7.0



Corn, sweet, kernel plus cob with husks removed
0.04
0.04


Corn, sweet, stover
4.0



Egg
0.04
0.04

0.04 (*)
Fruit, citrus, group 10
0.6
0.6 Australian (desert limes, finger limes, round limes), brown river finger limes,  calamondin, citrus citron, citrus hybrids, grapefruits, Japanese summer grapefruit, kumquats, lemons, limes, Mediterranean mandarin, Mount white lime, New Guinea wild lime, oranges, pummelos, Russell river lime, Satsuma mandarins, sweet limes, tachibana oranges, tahiti limes, tangelos, tangerines, tangors,  trifoliate oranges, uniq fruits 

0.5 citrus fruits
1 citrus pulp, dry
Fruit, pome
0.5
0.5 apples, asian pears, crabapples, loquats, mayhaws, pears, quinces

0.7 pome fruits
Fruit, stone, group 12
2
2.0  apricots, nectarines, peaches, plumcots, plums, prune plums, sweet cherries, tart cherries

3 stone fruits
Goat, fat
0.1
0.04


Goat, meat
0.1
0.04

0.05 (fat) (meat from mammals other than marine mammals)
Goat, meat byproducts
0.1
0.04

0.04 (*) kidney of goats
0.05 liver of goats
Grain, aspirated fractions
5.0



Grape
2.0
2.0

3 
Grape, raisin
5.0
5 raisins

5 Dried grapes (=currants, raisins and sultanas
Grass, forage
12



Grass, hay
17



Hog, fat
0.05
0.04


Hog, meat
0.05
0.04

0.05 (fat) (meat from mammals other than marine mammals)
Hog, meat byproducts
0.05
0.04

0.04 (*) kidney of pigs
0.05 liver of pigs
Hop, dried cones
11.0


40 hops, dry
Horse, fat
0.1
0.04


Horse, meat
0.1
0.04

0.05 (fat) (meat from mammals other than marine mammals)
Horse, meat byproducts
0.1
0.04


Leaf petioles subgroup 4B
3.5


1 celery
Mango
0.7
0.7


Milk
0.02
0.02

0.02 (*)
Nut, tree, group 14
0.04
0.04 almond; beech nuts; Brazil nuts; butternuts; cashew nuts; chestnuts; chinquapins; filberts; hickory nuts; macadamia nuts; pecans; walnuts, black and English 

0.02 (*) tree nuts
Oat, forage
0.3



Oat, grain
0.05
0.05


Oat, hay
0.3



Oat, straw
5.0



Papaya
0.7
0.7


Peanut, hay
4.0



Peanut
0.05


0.02 (*)
0.02 (*) tree nuts
Pistachio
0.04
0.04

0.02 (*) tree nuts
Potato
0.04
0.04

0.02 (*) 
Poultry, fat
0.04
0.04


Poultry, meat
0.04
0.04

0.04 (*) (fat)
Poultry, meat byproducts
0.04
0.04

0.04 (*) poultry edible offal
Radish, tops
10



Rice, grain
3.5
3.5 rice

5
7 rice bran unprocessed
Rice, hulls
8



Rice, straw
7.5


10 rice straw and fodder, dry
Sapodilla
0.7
0.7


Sapote, black
0.7
0.7


Sapote, mamey
0.7
0.7


Sheep, fat
0.1
0.04


Sheep, meat
0.1
0.04

0.05 (fat) (meat from mammals other than marine mammals)
Sheep, meat byproducts
0.1
0.04

0.04 (*) kidney of sheep
0.05 liver of sheep
Soybean, forage
10.0



Soybean, hay
25.0



Soybean, seed
0.08
0.08 dry soybeans


Star apple
0.7
0.7


Strawberry
1.1


0.2
Vegetable, cucurbit, group 9
0.50
0.5 balsam apples, balsam pears, cantaloupes, chayote fruit, Chinese cucumbers, Chinese waxgourds, citron melons, cucumbers, edible gourds,  muskmelons (other than those listed in this item) pumpkins,  summer squash, watermelons, west Indian gherkins, winter squash

0.3 Fruitng vegetables, cucurbit
Vegetable, fruiting
0.5
0.5 bell peppers, eggplant, groundcheries, non-bell peppers, pepinos, pepper hybrids, tomatillos, tomatoes 

0.3 Peppers, sweet (including pimento or pimiento)
 0.7 tomato
Vegetable, root, except sugar beet, subgroup 1B
0.1
0.04 potatoes 


0.1 carrot
0.02 potato
Wheat, bran
0.15


0.5 wheat bran, unprocessed
Wheat, forage
0.3



Wheat, grain
0.05
0.05

0.2
Wheat, hay
0.2



Wheat, straw
5


5 wheat straw and fodder, dry





MRLs with NO U.S. equivalent
Dry (adzuki beans, beans,  blackeyed peas, broad beans,  catjang seeds,  chickpeas, cowpea seed,  field peas, guar seeds, kidney beans, lablab beans, lentils, lima beans, moth beans, mung beans, navy beans, pigeon peas, pink beans, pinto beans, rice beans,  southern peas,  tepary beans, urd beans); 
edible podded (dwarf peas, jackbeans, moth beans, peas, pigeon peas, runner beans, snap beans, snow peas, soybeans, sugar snap peas, sword beans, wax beans, yardlong beans); grain lupin; succulent  shelled ( blackeyed peas, broad beans,  cowpeas,  english peas, garden peas, green peas, lima beans, peas, pigeon peas, southern peas

0.02


Mustard seeds (condiment type) 

0.02


Mustard seeds (oilseed type) 

0.02


Rapeseeds (canola)

0.02


Brussels sprouts



0.1
Cabbages, head



0.5
Flowerhead brassicas (includes Broccoli: broccoli, Chinese and Cauliflower



0.5
Leek



0.7
Peanut fodder



5
Completed:  M. Negussie; 10/03/2012
[1]	There are no U.S. registrations for use on banana (as of September 27, 1999) and coffee, green bean (as of January 18, 2012).
2	Mexico adopts U.S. tolerances and/or Codex MRLs for its export purposes.
3	* = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

                                                                               
Attachment 3

           Summary of Endpoints, Points of Departure, and Toxicology
                     Data Requirements for Trifloxystrobin

Table 3.1.	Summary of Toxicological Doses and Endpoints for Trifloxystrobin for Use in Dietary and Non-Occupational Human Health Risk Assessments
                              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 Toxicity-Rat
LOAEL = 500 mg/kg/day based upon 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 study-Rat
LOAEL = 55.3 mg/kg/day based on decreases in body weight, body weight gains, reduced food consumption, and histopathological lesions in the liver, kidneys, and spleen.
Oral Short-Term (1-30 days) and Intermediate-Term (1-6 months)
NOAEL =  3.8 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF = 1X
Residential LOC for MOE = 100
Two-Generation reproduction study-Rat
LOAEL = 55.3 mg/kg/day based on reduced pup body weights during lactation.
Dermal Short-Term (1-30 days) and Intermediate-Term (1-6 months)
NOAEL =  100 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF = 1X
Residential LOC for MOE = 100
28-Day Dermal Toxicity Study-Rat
LOAEL = 1000 mg/kg/day based on increases in mean absolute and relative liver and kidney weights.
Dermal 
Long-Term
(>6 months)


NOAEL = 3.8 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF = 1X

Dermal absorption rate = 33%
Residential LOC for MOE = 100

Two-Generation reproduction study-Rat
LOAEL = 55.3 mg/kg/day based on decreases in body weight, body weight gains, reduced food consumption, and histopathological lesions in the liver, kidneys, and spleen.
Inhalation Short-Term (1-30 days), Intermediate-Term (1-6 months), and Long-Term (>6 months)
NOAEL = 3.8  mg/kg/day
UFA = 10X
UFH = 10X
UF  = 10X
FQPA SF = 1X
Residential LOC for MOE = 1000
Two-Generation reproduction study-Rat
LOAEL = 55.3 mg/kg/day based on decreases in body weight, body weight gains, reduced food consumption, and histopathological lesions in the liver, kidneys, and spleen.
Cancer (oral, dermal, inhalation)
Trifloxystrobin is classified as "Not Likely Human Carcinogen" based on the lack of evidence of carcinogenicity in mouse and rat cancer studies.		
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 = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable

Table 3.2.	Summary of Toxicological Doses and Endpoints for Trifloxystrobin for Use in Occupational Human Health Risk Assessments
                              Exposure/ Scenario
                              Point of Departure
                              Uncertainty Factors
                     Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Dermal Short-Term (1-30 days) Intermediate-Term (1-6 months)
NOAEL = 100 mg/kg/day
UFA = 10X
UFH = 10X
SF = 1X
Occupational LOC for MOE = 100

28-Day Dermal Toxicity Study-Rat
LOAEL = 1000 mg/kg/day based on increases in mean absolute and relative liver and kidney weights.
Inhalation Short-Term (1-30 days) and Intermediate-Term (1-6 months) a
NOAEL = 3.8  mg/kg/day
UFA = 10X
UFH = 10X
UF   = 10X
SF = 10X
Occupational LOC for MOE = 1000
Two-Generation reproduction study-Rat
LOAEL = 55.3 mg/kg/day based on decreases in body weight, body weight gains, reduced food consumption, and histopathological lesions in the liver, kidneys, and spleen.
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.
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).  UFL = use of a LOAEL to extrapolate a NOAEL.  SF = safety factor.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.
Attachment 4

                         Toxicology Data Requirements

The requirements (40 CFR 158.500) for food uses of trifloxystrobin are in Table 4.  Use of the new guideline numbers does not imply that the new guideline protocols were used.

Table 4.  Summary of Toxicological Data Requirements for Trifloxystrobin 
                                     Test
                                   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
                                      No-
                                      Yes
                                      Yes
                                      Yes
                                      Yes
                                       -
                                      No
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	
870.5385    Mutagenicity -- Mammalian Bone Marrow 
                                          Chromosome Aberration Aberrations
870.5550    Mutagenicity -- Unscheduled DNA Synthesis	
                                      Yes
                                      Yes
                                       
                                      Yes
                                      Yes
                                      Yes
                                      Yes
                                       
                                      Yes
                                      Yes
870.6200a  Acute Neurotoxicity Screening Battery (rat)	
870.6200b  90-Day Neurotoxicity Screening Battery (rat)	
870.6300    Developmental Neurotoxicity	
                                      Yes
                                     No[1]
                                      No
                                    Yes[1]
                                      --
                                      No
870.7485    General Metabolism	
870.7600    Dermal Penetration	
870.7800    Immunotoxicity	
                                      Yes
                                      No
                                      Yes
                                      Yes
                                      --
                                      Yes
1	TXR0056150, 01/05/2012, D. Smegal. Trifloxystrobin:  Summary of Hazard and Science Policy Council (HASPOC) Meeting of December 8, 2011:  Recommendations on waiver requests for 28-day inhalation and subchronic neurotoxicity studies for trifloxystrobin.Attachment 5

                            Acute Toxicity Profile
                                       
Table 5.	Acute Toxicity Profile Data on Trifloxystrobin 
                                 Guideline No.
                                  Study Type
                                     MRID
                                    Results
                               Toxicity Category
                                   870.1100
Acute Oral  -  Rats
                                   44496622
                                   44496623
                                LD50 > 5g/kg
                                      IV
                                   870.1200
Acute Dermal  -  Rabbits
                                   44496626
                                   44496627
                                LD50 > 2g/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

Attachment 6
                                       
                Subchronic, Chronic, and Other Toxicity Profile
                                       
Table 6.	Subchronic, Chronic, and Other Toxicity Profile Data on Trifloxystrobin.
                                 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
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
0, 500, 2000, 7000 ppm
M: 0, 76.9, 315, or 1275 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 
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

29-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 
0, 10, 100, 1000 mg/kg/day
NOAEL = 100 mg/kg/day.
LOAEL = 1000 mg/kg/day based on increased liver and kidney weight.
870.3700a

Prenatal developmental in (rat) [gavage]
44496708  (1995)
Acceptable
0, 10, 100, 1000 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 
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 anomolies (fused sternabrae #3 & #4).
870.3800

Multi-generational reproduction and fertility effects
(rat)
44496710 (1997)
Acceptable
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  (highest dose tested: HDT) 
870.4100b

Chronic toxicity (dog) [capsule]
44496704 (1997)
Acceptable
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
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 was classified as "Not Likely Human Carcinogen."
870.4300

Carcinogenicity chronic toxicity
(rat)
44496711 (1997)
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
Negative.
870.5300
Gene Mutation in Chinese Hamster Cultured V-79
44496713
Positive at cytotoxic concentration levels.
870.5385
Structural Chromosome Aberration -Micronucleus - mouse
44496714
Negative.
870.5385
Structural Chromosome Aberration -Cytogenetics - Chinese Hamster
44496718
Negative.
870.5500
DNA Repair-Rat hepatocytes
44496719
Negative.
870.6200a

Acute oral neurotoxicity screening battery (rat)

Acute oral range-finding neurotoxicity (rat)


44496640 (1977)
Unacceptable
0, 2000 mg/kg/day


44840802 (1997)
0, 1000, 2000, 3500 mg/kg/day (provides supplemental information).
NOAEL and LOAEL could not be determined.

Limited results which include mortality, in-life observation, body weight, food consumption, & FOB only. No histological examination.  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.
870.6200b

Subchronic neurotoxicity screening battery (rat )
Waived.
870.7485
Metabolism & pharmacokinetics (rat)
44496722 (1997)
44496821 (1996)
Acceptable 
0.5, 100 mg/kg/day
Oral administration of trifloxystrobin to rats resulted in 56% and 65% of the administered dose was 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. 

