Page 1 of 25 **UNITED STA**

**TES ENVIRONMENTA L PROTECTION A** **GENCY WA** **SHINGTON, 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:** 129 112 **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 , Chem ist Sheila Heal y , Ph.D., Toxicologist Meheret Negussie , Chemist Risk Assessment Branch 3 (RAB 3 ) 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 Implementatio n Branch 5 (RMIB 5 ) Pesticide Re

- Evaluation Div ision (7508P)Page 2 of 25

**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 datab ases ; 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. Triflox ys trobin is a strobilurin

- class fungici de that controls foliar fungal diseases and soilborne/seedling fungal diseases

. It works b y interrupting mitochondrial respiration in plant

pathogenic fun gi, thus inhibiting spore germination and mycelial growth

. Triflox ys trobin 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, triflox ys trobin is register ed 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 , conifer s, ornamental flowers , soy beans , beans and peas , and sweet corn. The toxicology

database for trifloxy strobin is incomplete. Triflox ys trobin exhibits low acute mammalian toxicity

via oral (Toxicity

Category I V), dermal (Toxicity

Category IV), and inhalation (Toxicity

Category IV) routes of exposure. Triflox ys trobin 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 effect s 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 i s no evidence of neurotox icity 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). T rifloxystrobin is classified as “Not likely to be Carcinogenic to Humans” b ased on the lack of evidence of carcinogenicity in mice and rats. Triflox ys trobin 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 andPage 3 of 25

exposure information for trifloxystrobin, including the Margins of Exposure ( MOEs ) from the mo st 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

. T he toxicological e ndpoints and the Food Quality Protection Act ( FQPA ) safety factor will need to be re

- evaluated for the registration rev iew risk assessment, including the results of the inhalation toxicity study . There are no residual uncertainties in the exposure database

. The residue chemistry

database i s 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 accordingl y. Residential exposure and risk assessments also need to be reassessed based on current Residential Standard Operating Procedures (SOPs). O ccupational exposure assessments need to be reassessed based on current occupational exposure and risk assessment polic ies. 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 trifloxy strobin 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 201 1 to set a tolerance on imported coffee ( DP385972, N. Tsaur , 08/02/2011 ). **Hazard Identification/ Toxicology**  Triflox ys trobin is a strobilurin

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

. It works b y interrupti ng 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 p attern and exposure scenarios, and the unacceptable MOEs that resulted form the use of an oral POD ( TXR 0056150 )

. 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 ( DP 405845, K. Rury , 01/30/2013, TXR 0056527 ). APage 4 of 25

10X database uncertainty factor (UF DB ) will be retained for the lack of this study onl y for inhalation risk assessments (i.e., MOE of 1000)

. With repeated d os ing b y either the oral or dermal route , the liver is consistently the target organ for triflox ys trobin . L iver effects were seen in rats, mice, and dogs, characterized by an increase in liver weights and an increase in incidences of hepatocellular hyp ertrophy 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 d ose levels relative to that which caused liver and body weight effects. This finding was consistent with those produced b y other members of the strobilurin class. Triflox ys trobin 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. Triflox ys trobin 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 cy totoxic dose levels while testing negative in the remaining mutagenicity studies **.** Triflox ys trobin exhibits low acute toxicity following single oral, dermal and inhalation exposures. Itis 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. S ubmi s sion 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 adequatel y un derstood based on the data from the primary plant metabolism studies and the confined rotational crop study, as well as metabolism studies o n lactating goats and poultry . HED concluded that the residues of concern in plants (including rotational crops) an d livestock commodities are parent and its free acid metabolite CGA

- 321113 for regulatory and risk assessment purposes (f

or chemical names and structure s , refer to Attachment 1 ) . HED also determined that for livestock commodities, the metabolite L 7a (taurine conjugate of trifloxystrobin) in liver should also be in cluded in the risk assessment. The toxicity of the metabolites are assumed to be toxicologically equivalent to the parent compound. An adequate gas chromatograph y/nitrogen phosphorus detect ion (GC/NPD) method (Method AG

- 659A) is available for enforcing tolerances for the combined residues of trifloxystrobin andPage 5 of 25

CGA

- 321113 in plant and livestock commodities. This method was validated by the Agency

and forwarded to FDA for inclusion in the Pe sticide Analy tical Manual (PAM), Vol. II. Adequate multiresidue methods test data are available. Triflox ys trobin gave adequate responses through protocol C, and was completel y recovered from fortified apple samples when anal yz ed through protocols D and E . Acid metabolite CGA

- 321113 was recoverable through protocol B and residues from apples fortified with CGA

- 321113 were completel y 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 triflox ys trobin. 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. Althou gh somewhat refined, the acute and chronic dietary food and water exposure as sessments 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 trifloxy strobin using the Dietary Exposure Evaluation Model, DEEM

- FCIDTM, Version 2.03, which uses food consumption data from the U.S. Department of Agriculture’s Continuing Survey s of Food Intakes by Individuals (CSFII). The survey s were taken from 1994

- 1996 and include d 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 b y 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 re commended tolerance level for liver; therefore, meat by products 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 liv er was inclu ded in the DEEM at 0.16 ppm (DP 267787, L. Cheng , 0 1/17/2002 )

. A separate tolerance was set for grape, raisin; therefore, the processing factor for this commodity was set at 1 X . For all other processed commodities, DEEMTM 7.81Page 6 of 25

defa ult processing factors were used. Residue reduction data on strawberries from a single trial were previousl y provided which demonstrated that residues of triflox ys trobin and CGA

- 321113 declined in/on strawberries after washing and cooking; however , the de fault processing factor of 1 X was retained because further refinements are not needed

. The drinking water es timates include residues of trifloxystrobin and CGA

- 321113. The acute drinking water estimate of 47.98 μg/L (ppb) and chronic drinking water estimate of 47.31 μg/L (ppb) , provided b y the Environmental Fate and Effects Division (EFED), were directl y incorporated into the acute and chronic assessment , respectivel y . Acute Dietary ( Food and Drinking Water) Exposure Results The acute dietary

risk assessment for trifloxy strobin yi elded exposure estimates below HED’s level of concern (i.e. <100% aPAD) ; a cute dietary exposure utilized 1.9% of the aPAD for females 13

- 49 years old at the 95 th percentile. Chronic Dietary ( Food an d Drinking Water) Exposure Results The chronic dietary

risk assessment for trifloxy strobin yi elded exposure estimates below HED’s level of concern (i.e. <100% c PAD) . F or 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 subgrou p, children 1

- 2 years old, is 64 % of the cPAD. Triflox ys trobin is classified as “N ot L ikel y to be C arcinogenic to Humans” based on the lack of evidence of c arcinogenicity 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 p urpose of registration review. Furthermore, although a new version of DEEM (Version 3. 16 ) has been released and a new Screening Level Usage Anal ys is (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 Exposur e**  Registered residential use s 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 day s) 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 r esidential handler and post

- application exposure and risk assessment s 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 EffectsPage 7 of 25

Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment, HED anal yz ed 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 (F AR). 1 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 F AR value s een using a liquid product was 6.1% or 6.1 times higher than the default residue transfer value. The maximum F AR 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 granu lar 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 s een 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 trifloxy strobin at this time sin ce 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 volatilizati on) may occur as a result of applications of triflox ys trobin. The Agency is in the process of evaluating these ty pes of exposures and will examine the need for spray drift and volatilization assessments for triflox ys trobin during registration review. Conc lusion: There is sufficient information available to assess residential exposure , with the exception of TTR data . However, all residential exposure scenarios were not assessed adequatel y based on current HED policy ; an up - to
- date quantitative resi dential 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**  A ggregate assessments consider exposures from food, drinking water, and residential uses. In the most recent human heal th risk assessment ( DP 385972 , N. Tsaur, 08/02/2012 ), short

- term aggregate risk estimate s were estimated using chronic food and drinking w ater exposure estimates along with short

- term residential exposure estimates . As previously mentioned, these aggregate risk estimate s 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 E**  **xpos ure**  Triflox ys trobin is registered for several agricultural uses and non

- crop areas. The durations of exposure are expected to be short

- term (1

- 30 day s) and intermediate

- term (1

- 6 months); long

-
1 http://www.epa.gov/pesticides/science/residential

- exposure - sop.htmlPage 8 of 25

term exposures are not anticipated. The LOC for dermal risk estim ates 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. O ccupational 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 equipm ent 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. T he 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 b y 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 Ag ency 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 anal yz ed 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 a pplication (F AR). This default value is 25 % and is based on an anal ysis of 19 DFR studies where the F AR value ranged from 2% to 89%. This value is recommended for use in both residential and occupational postapplication assessments. Of the anal yz ed DFR studies, the maximum F AR 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) u sing 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 trifloxy strobin at this time since some dermal MOE s 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 occup ational handler and post

application exposure s , with the exception of DFR data . However, all occupational exposurePage 9 of 25

scenarios were not assessed adequatel y 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 risk s of concern. **Public Health and Pesticide Epidemiology Data**  For this evaluation, both OPP Incident Data S ys tem (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NI OSH) Sentinel Event Notification Sy stem for Occupatio nal Risk

- Pesticides (SENSOR) databases were consulted for pesticide incide nt data on trifloxy strobin ( DP407067 , S. Recore, 11/27 /20 12 ). Based on the low frequency and severity

of incident cases reported for trifloxystrobin in both IDS and NIOSH SENSOR, th ere 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 analy sis will be included in the risk assessment. **Tolerance Assessment and International Harmonization**  Codex and Canada have established maximum residue limits (MRL s) for trifloxystrobin on various crop commodities. The U.S. and Canadian tolerance expressions are in harmony whereas Codex is not (plant only). Res idue 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 / MRL s is not possible. Most of the available Codex MRLvalues are not in harmony with the U.S.; the Codex MRL s 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. MRLvalues are harmonized on citrus dry pulp, eggs, grape raisins, hog meat, hog meat b yproducts (liver only), poultry meat and meat by products, milk, and livestock feedstuffs. The U.S. tolerances for livestock commodities (meat and meat b yproducts) of cattle, g oat, 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 MRL s were esta blished on individual crops, peppers (0.3) and tomatoes (0.7) and carrots (0.1) and potatoes (0.02), respectivel y. The carrot MRL(0.1 ppm) is the same as the U.S. subgroup 1B tolerance. There are Codex MRL s on banana, Brussels sprouts, cabb ages head, fl ower head Brassica , leek, and peanut fodder that do not have U.S. equivalent

. The available Canadian MRL s are in harmon y with the U.S., except for corn sweet kernel plus cob with husks removed, root and tuber vegetables subgroup 1B, fat, meat, and meat by products of cattle, hogs, horses, and sheep. The U.S. has recommended tolerances for livestock feed commodities, but by

policy Canada does not establish MRL s for livestock feed commodities.Page 10 of 25

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 equivalent s . **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 L ow - 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 subgro ups 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 Survey s 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 anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . Additionally , OPP is able to assess d ietary 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 applicato rs 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 mo dels that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. **Endocrine Disruptor Screening Program** As required b y 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 carc inogenicity, neurotoxicity , developmental, reproductive, and general or s ys temic toxicity . These studies include endpoints which may

be susceptible to endocrine influence, including effects on endocrine target organ histopathology , organ weights, estrus c yclicity , 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 differe nt 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 b y a “naturally occurring estrogen, or other such endocrine effects as the AdministratorPage 11 of 25

may designate.” The EDSP employs a two
- tiered approach to making the statutorily required determinations. Tier 1 con sists of a battery of 11 screening assay s to identify the potential of a chemical substance to interact with the estrogen, androgen, or th yroid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have the potential t o interact with E, A, or T hormonal sy stems 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 an y adverse endocrine

- relat ed 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 tes t orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Triflox ys trobin is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP . Accordingl y, as part of registration review, EPA will issue future EDSP orders/data call

- ins, requiring the submission of EDSP screening assay s for trifloxy strobin . For further information on the status of the EDSP, the policies and procedures, the lis t 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 an y other substances and trifloxystrobin does not appear to produce a toxic metabolite produced b y 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 eff orts to determine which chemicals have a common mechanism of toxicity

and to evaluate the cumulative effects of such chemicals, see the policy statements released b y EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedur es 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 assessment s rely in part on data from studies in which adult human subjects were intentionall y 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 trifloxy strobin 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.Page 12 of 25

Exposure 870.2100 Dislodgeable Foliar Residue Diss ip ation A DFR study is required for trifloxy strobin at this time since some dermal MOE s are less than 400 (the lowest MOEs are 140 for girdling/turning grapes and 270 for tyi ng/training grapes, and 140 for harvesting hops) based on default values for the fraction of application rate available for transfer after a foliar application. Toxicolog y 870.3465 Inhalation Toxicity A subchronic inhalation study is required as the us e 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 DP 267787 0 1/17/2002 Triflox ys trobin on Barley , Citrus, Corn (Field and Pop), Pecan, Pistachio, Rice, and Stone Fruit. Review of Anal yt ical Methods and Residue Data. K. Rury TXR

0056527 0 1/ 30 /2012 Triflox ys trobin **:** 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 01/05/20 12 Triflox ys trobin **:** 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 DP 385972 0 8/02/2011 Triflox ys trobin. Human Health Risk Assessment for Proposed New Use on Imported Coffee. N. Tsaur DP 387 201 0 7 / 13 /2011 Triflox ys trobin. 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 DP 360307 10/ 0 7/2009 Drinking Water Assessment for Tolerance Petition for New Uses of Triflox ys trobin in Fluopy ram/Trifloxy strobin 500 SC Fungicide [EPA Reg. No. 264
- RNON].Page 13 of 25

**Attachment s**  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 Profil e **Attachment 1 Chemical Identity Table**  **Table 1.**  **Test Compound Nomenclat ure** 

**Chemical Structure of Parent Com** **pound**

**Empirical Formula** C 20 H 19 F 3 N 2 O 4 **Comm on Name**  trifloxystrobin **Company Experimental Name** BO17211 or CGA

- 279202 **IUPAC Name** methyl (E)

- methoxyimino

- {(E)

- α - [1

- (α,α,α

- trifluoro

- m tolyl)ethylideneaminooxy]

- o - tolyl}acetate **CAS Name** methyl (α E)

- α - (methoxyimino)

- 2
- [[[[(1 E)

- 1
- [3

- (trifluoromethyl)phenyl]ethylidene]amino]oxy]methyl]benzeneacetate **CAS Registry #** 141517
- 21
- 7 **Chemical Class** Strobilurin **Known Im purities of Concern**  None

**Chemical Structure of Metabolite CGA**  **- 321113** 

**Comm on Name**  trifloxystrobin acid **Company Code** CGA

- 321113 **CAS Name** (αE)

- α - (methoxyimino)

- 2
- [[[[(1 E)

- 1
- [3

- (trifluoromethyl)phenyl]ethylidene]amino]oxy]methyl]benzeneacetic acid **CAS #** 252913
- 85
- 2 O N C F 3
N O O

CH 3 O C H 3 CH 3

O N C F 3
N O H O O C H 3 CH 3Page 14 of 25

**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, calc ulated as the stoichiometric equivalent of trifloxystrobin. methyl (α, E)

- α - (methoxyimino)

- 2
- [[[(E)

- [1

- [3

- (trifluoromethyl)phenyl]ethyliden e]amino]oxy]methyl]benzene acetate, including the metabolite (α, E)

- α - (methoxyimino)

- 2
- [[[(E)

- [1

- [3

- (trifluoromethyl)ph enyl]ethyliden e]

- amino]oxy]methyl]benzene acetic acid, expressed as trifloxystrobin. Plants: trifloxystrobin Livestock: sum of trifloxystrobin and [(E , E)

- me thoxyimino

- {2

- [1

- (3

- trifluoromethylphenyl) ethylideneaminooxyme thyl] 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, mo lasses 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 maizePage 15 of 25

**Table 2. Summary of**  **U.S. and International Tolerances and Maximum Residue Limits**  Residue Definition U.S. Canada Mexico 2 Codex 3 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, t angerines, tangors , tri foliate 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, dryPage 16 of 25

**Table 2. Summary of**  **U.S. and International Tolerances and Maximum Residue Limits**  Residue Definition U.S. Canada Mexico 2 Codex 3 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 Soy bean, forage 10.0 Soy bean, hay 25.0 Soy bean, seed 0.08 0.08 dry soybeans Star apple 0.7 0.7 Straw berry 1.1 0.2Page 17 of 25

**Table 2. Summary of**  **U.S. and International Tolerances and Maximum Residue Limits**  Residue Definition U.S. Canada Mexico 2 Codex 3 Vegetable, cucurbit, group 9 0.50 0.5 balsam apples, balsam pears, cantaloupes, chayote fruit, Chinese cucumbers, Chinese wa xgourds, citron melons, cucumbers, edible gourds, muskmelons (other than those listed in this item) pumpkins, summer squash, watermelons, we st 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 w heat straw and fodder, dry MRLs with NO U.S. equivalent Dry (adzuki beans, beans, blackeyed peas, broad beans, catjang seeds, chickpeas, cow

pea 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 ( bla ckeyed peas, broad beans, cow

peas, english peas, garden peas, green peas, lima beans, peas, pigeon peas, southern peas 0.02Page 18 of 25

**Table 2. Summary of**  **U.S. and International Tolerances and Maximum Residue Limits**  Residue Definition U.S. Canada Mexico 2 Codex 3 Mustard seeds (condiment ty pe) 0.02 Mustard seeds (oilseed ty pe) 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 Com pleted: 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 Code x MRLs for its export purposes. 3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed pos tharvest 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.Page 19 of 25

**Attachment 3**  **Summary of Endpoints, Points of De parture, and**  **Toxicology Data Requirements for Trifloxystrobin**  **Table 3**  **. 1.**  **Summary of Toxicol ogical 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**

Ac ute Dietary ( Females 13

- 49 Only) NOAEL =

250 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Ac ute 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. Ac ute Dietary ( General Population, including Infants and Children) There were no appropriate toxicological effects attributable to a single exposure (dose)

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

.

Chronic Dietary (All Populations) NOAEL =

3.8 mg/kg/day UF A = 10X

UF H = 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 liv er, kidneys, and spleen. Oral Short

Term (1

- 30 days) and Intermediate

Term (1

- 6 mo nths) NOAEL =

3.8 mg/kg/day UF A = 10X

UF H = 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 mo nths) NOAEL =

100 mg/kg/day UF A = 10X

UF H = 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 UF A = 10X

UF H = 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.Page 20 of 25

**Table 3**  **. 1.**  **Summary of Toxicol ogical 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**
Inhalation Short

- Term (1

- 30 days), Intermediate

Term (1

- 6 mo nths) , and Long
- Term (>6 mo nths) NOAEL =

3.8 mg/kg/day UF A = 10X

UF H = 10X UF = 10X FQPA SF = 1X Residential

LOC for MOE = 100 0 Two - Generation reproduction study

- Rat

LOAEL = 55.3 mg/kg/day based on decreases in body weight, body weight gains, reduced food consumption, and histop athological 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 eff ect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Sa fety 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 Toxicol**  **ogical Doses and Endpoints for Trifloxystrobin for Use in** 

**Occupational Hum an 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 mo nths) NOAEL =

100 mg/kg/day UF A = 10X

UF H = 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 mo nths) a NOAEL = 3.8

mg/kg/day UF A = 10 X

UF H = 10 X UF = 10X SF = 1 0 X Occupational

LOC for MOE = 100 0 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 carc inogenicity 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. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human po pulation (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. SF = safety factor. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.Page 21 of 25

**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.Page 22 of 25

**Attachment 5**  **Acute Toxicity Profile Table 5**  **. Acute Toxicity Profile Data on Trifloxystrobin**  **Guideline No. Study Type**  **MRID Results**  **Toxicity Category**  870.1100 Ac ute Oral

– Rats 44496622 44496623 LD 50 > 5g/kg IV 870.1200 Ac ute Dermal

– Rabbits 44496626 44496627 LD 50 > 2g/kg IV 870.1300 Ac ute Inhalation

– Rats 44496630 LC 50 > 4.65 mg/L IV 870.2400 Primary Eye Irritation

– Rabbits 44496632 mild irritant III 870.2500 Primary Skin Irritation

– Rabbits 44496635 mild irritant IV 870.2600 Dermal Sensitization

– Guinea Pigs 44496637 44496638 strong sensitizer N/A **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 d ecreased 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/d ay based on increased liver weight and hepatocyte hypertrophy; increased incidence of diarrhea and vomiting.Page 23 of 25

**Table 6 .**  **Subchronic, Chronic, and Other Toxicity Profile Data on Trifloxystrobin**  **. Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results** 
870.3150 29
- Day

subchronic range - finding oral toxicity (dog) [capsule] 44496642 (1994)

Unacceptable/non

guideline (2 dog/sex/d os e) 0, 20, 50, 150 mg/kg/day NOAEL = 50 mg/kg/day LOAEL = 150 mg/kg/day based on increased inc idence of diarrhea and vomiting and body weight reduction

. 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 i ncreased liver and kidney weight.

870.3700a Prenatal

developmental in (rat) [gavage] 44496708 (1995)

Acceptable 0, 10, 100, 10 00 mg/kg/day Maternal NOAEL = 10 mg/kg/day

. Maternal LOAEL = 100 mg/kg/day based on decreas ed 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 **s** keletal anomolies (fused sternabrae #3 & #4).

870.3800 Multi

generational r eproduction 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 m g/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, hepatocel lular hypertrophy)

. There was non - statistically significant and non

dose related increase in lymphoma incidence. Trifloxystrobin was classified as “Not Likely Human Carcinogen

. ”Page 24 of 25

**Table 6 .**  **Subchronic, Chronic, and Other Toxicity Profile Data on Trifloxystrobin**  **. Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results** 

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 Ham ster Cultured V

- 79 44496713 Positive at cytotoxic concentration levels

.

870.5385 Structural

Chromosome Aberration

- Micronucleus

- mo use 44496714 Negative

.

870.5385 Structural

Chromosome Aberration

- Cy togenetics

- Chinese Ham ster 44496718 Negative

.

870.5500 DNA Repair

Rat hepatocytes 44496719 Negative

.

870.6200a Ac ute oral

neurotoxicity screening battery (rat) Ac ute 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.
870.6200 b Subchronic

neurotoxicity screening battery (rat ) Waived

.Page 25 of 25

**Table 6 .**  **Subchronic, Chronic, and Other Toxicity Profile Data on Trifloxystrobin**  **. Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results** 

870.7485 Metabolism &

pharmacokineti cs (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.