UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, DC 20460

OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM D AT E : 1 / 07 / 10 S UBJECT : Flumioxazin. Human Health Risk Assessment for the Proposed Aquatic Use and

Proposed Food Us e s on Cucurbit Vegetables, Leaf Petioles, and Hops

. PC Code: 129034 DP Num : D359142 Decision No.: 402046 Registration No. : 59639 - 161 , 59639 - 99, 59639 - 119 Petition Nos.: 8F7438, 8E7462 Regulatory Action: Section 3 Registration Risk Assess Ty

pe: Single Chemical Aggregate Case No.: NA T XR No.: NA CAS No.: 103361 - 09 - 7 MRID No.: NA 40 CFR: §180.568 F ROM : W . Cutchin, Acting Senior Branch Scientist

Alternative Risk Integration and Assessment (ARIA ) Team Risk Integration, Minor Use and Emergency Response Branch (RIMUERB) Registration Division (RD ; 7505P) T HROUGH : C hristina Swartz, Chief

Risk Assessment Branch II (RAB II ) Health Effects Division (HED ; 7509P) T O : L. Nolan / D. Rosenblatt

RIMUERB/RD (7505P)Page 2 of 64

ARIA/RIMUERB of RD of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. RD of OPP has requested that ARIA evaluate hazard and exposure data and conduct dietary , occupational, residential and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from proposed and currentl y registered uses of the active ingredient flumioxazin. Valent has submitte d a petition to establish a t olerance as a result of the aquatic uses of flumioxazin, formulated as a 51% water - dispers ible granular (WDG) formulation, in freshwater fish . The Interregional Research Project No. 4 (IR - 4) has also submitted petitions to est ablish tolerances as a result of the uses of flumioxazin , formulated as two 51% WDG formulations in/on cucurbit vegetables, leaf petioles, and hops . In this document, ARIA has conducted an assessment of the human exposure and risks resulting from these proposed uses and all currentl y registered uses. The overall risk assessment , dietary risk assessment , and residue chemistry assessment were provided by W. Cutchin , the water exposure assessment by L . L i u (Environmental Fate and Effects Division (EFED)) and the occupational exposure assessment s by M. Dow (ARIA) and S . Wang ( HED, Risk Assessment Branch II (RAB II ) ) .Page 3 of 64 TABLE OF CONTENTS 1.0 EXECUTIVE SUMMARY ................................ ................................ ................................ .... 5 2.0 INGREDIENT PROFILE ................................ ................................ .............................. 12 2.1 Summary of Proposed Uses ................................ ................................ ............................ 13 2.2 Structure and Nomenclature ................................ ................................ ......................... 14 2.3 Physical and Chemical Properties : ................................ ................................ ................ 14 3.0 HAZARD CHARACTERIZATION ................................ ................................ .................. 15 3.1 H azard and Dose - Response Characterization ................................ .............................. 15 3.1.1 Database Summary ................................ ................................ ............................. 15 3.1.1.1 Studies available and considered ................................ ................................ ... 15 3.1.1.2 Mode of action, metabolism, toxicokinetic data ................................ ........... 15 3.1.1.3 Sufficiency of studies/data ................................ ................................ .............. 15 3.1.2 Toxicological Effects ................................ ................................ ........................... 16 3.1.3 Dose - response ................................ ................................ ................................ ...... 17 3.1.4 FQ PA ................................ ................................ ................................ .................... 18 3.2 Absorption, Distribution, Metabolism, Excretion (ADME) ................................ ........ 18 3.3 FQ PA Considerations ................................ ................................ ................................ ..... 18 3.3.1 Adequacy o f the Toxicity Database ................................ ................................ ... 18 3.3.2 Evidence of Neurotoxicity ................................ ................................ .................. 18 3.3.3 Developmental Toxicity Studies ................................ ................................ ......... 19 3.3.4 Reproductive Toxicity Study ................................ ................................ ............. 19 3.3.5 Additional Information from Literature Sources ................................ ............ 19 3.3.6 Pre - and/or Post - natal Toxicity ................................ ................................ ........... 19 3.3.6.1 Determination of Susceptibility ................................ ................................ ..... 19 3.3.6.2 Degree of Concern Analysis and Res idual Uncertainties ............................ 20 3.3.7 Recommendation for a Developmental Neurotoxicity Study .......................... 20 3.4 FQ PA Safety Factor for Infants and Ch ildren ................................ ............................. 20 3.5 Hazard Identification and Toxicity Endpoint Selection ................................ .............. 21 3.5.1 Acute Reference Dose (aRfD) - Females age 13 - 49 ................................ .............. 21 3.5.2 Acute Reference Dose (aRfD) - General Population ................................ ........ 22 3.5.3 Chronic Reference Dose (cRfD) ................................ ................................ ......... 22 3.5.4 Incidental Oral Exposure (Short - and Intermediate - Term) ........................... 22 3.5.5 Dermal Absorption ................................ ................................ ............................. 23 3.5.6(b) Dermal Exposure (Short - , Intermediate - and Long - Term) for Adults ...... 23 3.5.7 Inhalation Exposure (Short - and Intermediate - Term) ................................ ... 24 3.5.8 Inhalation Exposure (Long - Term) ................................ ................................ .... 25 3.5.9 Level of Concern for Margin of Exposure ................................ ........................ 25 3.5.10 Recommendation for Agg regate Exposure Risk Assessments ........................ 26 3.5.11 Classification of Carcinogenic Potential ................................ ........................... 26 3.6 Endocrine Disruption ................................ ................................ ................................ ..... 28 4.0 PUBLIC HEALTH AND PESTICIDE EPIDEMIOLOGY DATA ........................... 29 5.0 DIETARY EXPOSURE/RISK CHARACTERIZATION ................................ .......... 29 5.1 Pesticide Metabolism and Environmental Degradation ................................ .............. 29 5.1.1 Metabolism in Primary Crops and Livestock Commodities. .......................... 29 5.1.2 Metabolism in Rotational Crops ................................ ................................ ........ 29Page 4 of 64

5.1.3 Analytical Methodology ................................ ................................ ...................... 30 5.1.4 Multiresidue Methods ................................ ................................ ......................... 31 5.1.5 Storage Stability ................................ ................................ ................................ .. 31 5.1.6 Magnitude of the Residue ................................ ................................ ................... 31 5.1.7 Magnitu de of the Residue in Meat, Milk, Poultry, and Eggs .......................... 32 5.1.8 Confined and Field Rotational Crops ................................ ............................... 32 5.1.9 Pesticide Metabolites a nd Degradates of Concern ................................ ........... 33 5.1.10 Drinking Water Residue Profile ................................ ................................ ........ 33 5.2 Dietary Exposure and Risk ................................ ................................ ............................ 34 5.2.1 Acute Dietary Exposure/Risk ................................ ................................ ............. 34 5.2.2 Chronic Dietary Exposure/Risk ................................ ................................ ......... 34 5.2.3 Cancer D ietary Risk ................................ ................................ ........................... 35 6.0 RESIDENTIAL (NON - OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION ................................ ................................ ................................ ........... 35 6.1 Other (Spray Drift, etc.) ................................ ................................ ................................ . 39 7.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION ....... 39 7.1 Acute Aggregate Risk ................................ ................................ ................................ ..... 39 7.2 Short - and Intermediate - Term Aggregate Risk ................................ ........................... 40 7.3 Chronic Aggregate Risk ................................ ................................ ................................ . 42 7.4 Cancer Risk ................................ ................................ ................................ ..................... 42 8.0 CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT ............................ 42 9.0 OCCUPATIONAL EXPOSURE/RISK PATHWAY ................................ .................. 42 9.1 Short -/Intermediate -/Long - Term Handler Risk ................................ .......................... 43 9.2 Short -/Intermediate -/Long - Term Post - application Risk ................................ ............. 51 9.3 Restricted Entry Interval (REI) ................................ ................................ .................... 52 10.0 TOLERANCE SUMMARY ................................ ................................ ........................... 52 11.0 DATA NEEDS AND LABEL RECOMMENDATIONS ................................ ............. 53 11.1 Toxicology ................................ ................................ ................................ ........................ 53 11.2 Residue Chemistry ................................ ................................ ................................ .......... 54 11.3 Occupational and Residential Exposu re ................................ ................................ ....... 54 12.0 REFERENCES ................................ ................................ ................................ ................ 54 Appendix A: Toxicology Assessment ................................ ................................ ....................... 56 A .1 Toxicology Data Requirements ................................ ................................ ...................... 56 A.2 Toxicity Profiles ................................ ................................ ................................ ............... 57 A.3 Data Requirements ................................ ................................ ................................ ......... 61 Appendix B: Metabolism Assessment ................................ ................................ ...................... 64 Appendix C: Review of Human Research ................................ ................................ ............... 64Page 5 of 64

1.0 EXECUTIVE SUMMARY Background This document is a human health risk assessment to support an aquatic use (PP#: 8F7438 ) and Section 3 request s for crop uses (PP#: 8E7462 ) and for the establishment of permanent flumioxazin tolerances in/on freshwater fish, cucurbit vegetables , leaf petioles, and hops . Flumioxazin , 2 - [7 - fluoro - 3,4 - dihydro - 3 - oxo - 4 - (2 - propy nyl) - 2H - 1,4 - benzoxazin - 6 - yl ] - 4,5,6,7 - tetrah ydro - 1 H

- isoindole - 1,3(2H

) - dione, is an herbicide of the N - phenylphthalimide class (Group 14) that is currentl y used for pre - and pos t - emergence control of susceptible weeds in a variety of fruit, vegetable and other field crops . Its mode of action is as an inhibitor of protoporph yrinogen oxidase (PPO); it is active against certain grasses, broadleaf weeds, and sedges (including aquati c species ) . The most recent human health risk assessment for flumioxazin was conducted in conjunction with a request for the establishment of tolerances for residues on field corn ( PP#: 7F7243 , DP Num : D 342248 , B. Hanson , 4 /8/0 8 ). This document includ es revised dietary (food and drinking water), non - occupational, occupational (handler and post - application), residue chemistry , and aggregate assessments. Proposed Uses The registrant, Valent, propose s a use of Clipper Herbicide ( EPA Reg. No 59639 - 161 ) , a WDG formulation containing flumioxazin at 51% , for management of aquatic weeds in bayous, canals, fresh water ponds, l akes, marshes and reservoirs. The proposed maximum rates are 0.3825 lb ai/A for surface and aerial applications, and 8.62 lb ai/A for subsurface application. IR - 4 is seeking the registration of flumioxazin on cucurbit vegetables, leaf petioles, and hops . The end - use products (EPs) relevant to this registration request are ValorTM Herbicide (EPA Reg. No. 59639 - 99) and ChateauTM Herbicide (EPA Reg. No. 59639 - 119). The products are WDG formulations containing 51% flumioxazin. Valor and Chateau are proposed for uses with ground equipment for a pre - emergence or pre - transplant application and followed by a second application to row middles at a total of 0.25 lb ai/A on cucurbit vegetables; for a pre - transplant soil application at 0.094 - 0.188 lb ai/A on leaf pe tioles; and for 0.375 lb ai/A with a 30 - day pre harvest interval (PHI) on hops . Toxicology and Dose-

Response The toxicology

database for flumioxazin is not complete because several studies newl y required in accordance with the 12/2007 update of the Part 158 Guidelines for toxicology have not yet been submitted. These include rat acute and subchronic neurotoxicity studies, as well as an immunotoxicity

study . Despite these missing studies, the toxicity database is considered to be adequate for the purpose of dose and endpoint selection for the current risk assessment, and for characterizing toxic effects associated with flumioxazin.Page 6 of 64

Flumioxazin has mild or no acute toxicity (categories III or IV) when administered orall y, dermally , or by

inhalation. It h as little or no toxicity with re spect to eye or skin irritation (categories III or IV). In addition, f lumioxazin is not a dermal sensitizer. Subchronic and chronic toxicity

studies demonstrated that toxic ity associated with flumioxazin include anemia, an d effe cts on the liver and the cardiovascular s ys tem. Developmental effects were observed in developmental rat studies but not in developmental rabbit studies . These effects were fetal cardiovascular anomalies , especiall y ventricular septal defects. Hem atologic (hematopoietic) effects of anemia were noted in rats, consisting of alterations in hemoglobin parameters. In creased renal toxicity in male rats was also reported following chronic exposure. In creased absolute and relative liver weights and/or in creased alkaline phosphatase values were observed in dogs. Flumioxazin administered orally and dermall y to rats in developmental studies resulted in cardiovascular anomalies , the most serious being ventricular septal defects. The same effects occurred b y both dermal and oral routes of administration, with the oral being observed at 10 and the dermal at 100 mg/kg/day . A mechanistic oral developmental study

in rats indicated that a single dose of 400 mg/kg caused the ventricular septal defects when administe red on gestation day 12, but not when given on day s 11 or 13 or 14 or 15. In the 2 - generation reproduction study, s ys temic effects (clinical signs and mortality as well as a decrease in body weight/gain and food consumption) were noted at approximately 19 and 23 mg/kg/day

in males and females, respectively ; however, effects on the offspring (decrease in the number of live born and decreased pup body weights , decreased mating index, and testicular atroph y in F1 males ) occurred at lower doses (approximately 13 and 15 mg/kg/day). Based on the lack of evidence of carcinogenicity in mice and rats, flumioxazin is classified as “not likel y t o be carcinogenic to humans.” The endpoint selected for acute dietary risk assessment was based on the cardiovascular effec ts , ventricular septal defects in fetuses , observed in oral developmental and supplemental pre - natal studies in rats. The endpoint is only applicable to females of childbearing age (i.e., females 13 - 49) . No acute dietary

endpoint (i.e., toxic effect resu lting from a single dose) applicable to the general population or any other population subgroups was identified in the submitted studies . The endpoint selected for chronic dietary risk assessment for all population subgroups was increased chronic nephropathy in males and decreased hematological parameters in females observed in a 2 - year chronic/carcinogenicity study in rats. This endpoint and dose are the lowest of an y long - term studies submitted for flumioxazin, and are also protective of the offspring e ffects seen in the 2 - generation reproduction study. A no observable adverse effects level (NOAEL ) of 30.0 mg/kg/day was selected from a rat dermal developmental toxicity study for short - and intermediate - term dermal risk assessments for adults potentially exposed to flumioxazin . The NOAEL was based on a biologically significant increase in cardiovascular abnormalities, particularl y ventricular septal defects observed at the lowest observed adverse effects level (LOAEL) of 100 mg/kg/day . Since the dermal endpoint and dose w ere selected from a dermal study , an absorption factor was not used in the dermal assessments . However, for children potentially exposed to flumioxazin via thePage 7 of 64

dermal route, the offspring effects in the rat reproduction study were chose n for risk assessment, and a dermal absorption factor was used to account for route - to - route extrapolation. For both short - and intermediate - term incidental oral exposure and risk assessments, the endpoint and dose were selected from the reproductive toxi city study in rat, based on the offspring/reproductive effects, including decreased live born pups and decreased pup body weights observed at the LOAEL of 12.7 mg/kg/day. The dose for risk assessment was the NOAEL of 6.3 mg/kg/day . The study was consider ed to be the most appropriate for the route of exposure (oral), the duration, short - and intermediate - term, and because the endpoint is relevant for the potentiall y exposed population, children. For short - term inhalation exposure, a NOAEL of 3.0 mg/kg/day was selected from an oral developmental study

in rats, based on a biologically significant increase in cardiovascular abnormalities, particularly ventricular septal defects, at the L OAEL of 10 mg/kg/day . For intermediate - term inhalation exposure, a NOAEL of 2.0 mg/kg/day was selected from a 2 - ye ar chronic rat study , based on increased chronic nephropathy in males, and decreased hematological parameters in females , observed at the LOAEL of 18 mg/kg/day . Since the doses and endpoints for inhalation risk as sessments were selected from oral studies, a 100% inhalation absorption factor was used for risk assessment. Both qualitative and q

uantitative susceptibility

w ere observed in the rat developmental toxicity studies, in which the effects on fetuses occurre d at doses which did not cause maternal toxicity . In addition, qualitative and quantitative susceptibility w ere observed in the rat reproduction study , in which offspring effects were observed at lower doses than those which caused parental/s ys temic toxic ity , and in which the offspring effects were considered to be more severe . Although there w ere both qualitative and quantitative susceptibility , HED concluded the 10X FQPA Safety Factor could be removed (reduced to1X) . Th is conclusion was based on the lo w degree of concern for the observed susceptibility because the observed effects were adequatel y characterized and the doses and endpoints selected for risk assessment are sufficientl y protective of the fetal/offspring susceptibility . In addition, there w ere no concerns for neurotoxicity based on the submitted data, and a developmental neurotoxicity study is not required. Although there are missing studies, including acute and subchronic neurotoxicity and immunotoxicity

studies, there is no evidence in th e submitted data to indicate flumioxazin directly impacts the nervous sy stem or the immune s ystem. Finally, the exposure assessment is conservative, and therefore potential risks to infants and children have not been underestimated. Since the FQPA factor was reduced to 1X, and there were no other database uncertainty factors retained for missing data or the lack of a NOAEL, the level of concern (LOC) for both residential and occupational exposure and risk is margin of exposure (MOE) of 100, based on the s tandard 10X uncertainty factors retained for interspecies extrapolation and intraspecies variability. Endocrine Dis ruptor Screening Program (EDSP) Between October 2009 and February 2010, EPA is issuing test orders/data call - ins for endocrine testing for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9Page 8 of 64

inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathway s such as food and water, residential activity , and certain post - application agricultural scenarios , and should not be construed as a list of known or likely endocrine disruptors. Flumioxazin is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDC A sec. 408(p) the Agency must screen all pesticide chemicals. Accordingl y, EPA anticipates issuing future EDSP test orders/data call - ins for all pesticide active ingredients. For further information on the status of the EDSP, the policies and procedures , the list of 67 chemicals, the test guidelines and the Tier 1 screening battery , please visit our website: http://www.epa.gov/endo/. Residue Chemistr

y With the exception of the aquatic use and the need for a restriction on the use of adjuvants , the pro posed application labels are acceptable. Based on occupational exposure concerns associated with the aquatic use , ARIA/HED recommends that the water depth for subsurface application sh ould not go beyond 7 feet ( a 7 foot deep water column requires 7.55 lb ai/A/application) . Updated label s are required . The nature of flumioxazin residues in plants and animals is adequatel y understood based on previously

submitted studies. In primary and rotated crops, the residue of concern is the parent compound , flumiox azin . For ruminants, the residues of concern are parent, 3 - OH - flumioxazin, 4 - OH - flumioxazin, plus Metabolites B, C, and F. For poultry , the residues of concern are parent, 3 - OH - flumioxazin, 4 - OH - flumioxazin, and 4 - OH - S - 53482 - SA. For purposes of this pet ition, ARIA has waived the requirement for a fish metabolism study and has concluded that the residues of concern in fish include flumioxazin and its major degradates in water, APF and 482 - HA. For tolerance enforcement in fish tissues , Valent has submitte d a liquid chromatograph y with tandem mass spectroscopy/mass spectroscop y detector (LC - MS/MS) method (GPL - MTH - 066) for determining residues of flumioxazin, APF and 482 - HA. The validated limit of quantitation (LOQ) is 0.01 ppm for each anal yt e in fish. Th is method has undergone a successful independent laboratory

validation (ILV) trial and appears to be acceptable for data collection and tolerance enforc ement ; however, additional information/data are required before the method can be recommended as an enfo rcement method (See Sec. 11, below) . In addition, FDA multiresidue testing data are required for the metabolite/degradates 482 - HA and APF, and reference standards must be provided for the EPA National Pesticide Standards Repository . An adequate gas chrom atography /nitrogen - phosphorus detection (GC/NPD) method, Valent Method RM - 30 - A - 1, is available for enforcing tolerances for residues of flumioxazin per se in/on plant commodities. The reported method LOQ and limits of detection ( LOD) for flumioxazin in/on plant commodities are 0.02 and 0.01 ppm, respectivel y.Page 9 of 64

Acceptable data collection methods were used in the submitted studies based on acceptable concurrent method recoveries. The submitted fish residue study is adequate and supports the proposed aquati c use. R esidues of flumioxazin, APF and 482 - HA were determined in the water and edible fish tissues over a 28 - day period of exposure to residues at 2x the application rate. Total flumioxazin residues were highest at the earliest sampling interval (4 hour s) , ranging from 0.85 - 2.52 ppm. Total residues declined rapidl y b y Day 3 and then remained relatively steady up to Day

28 (0.063 - 0.204 ppm). Total flumioxazin residues did not bioaccumulate over the 28 day study . When extrapolated to reflect the 1x use rate, the estimated total residues would support the proposed 1.5 ppm tolerance for residues in freshwater fish. Because applications to flowing water, intertidal or estuarine areas and to water used for crawfish farming are prohibited , residue data and t olerances are not required for shellfish or saltwater fishes. The submitted residue data for cucumber and summer squash are adequate. In addition, residue field trial data on cantaloupe, the representative crop for muskmelon subgroup 9A were submitted previously

in support of the tolerance using the same use pattern. The data indicate that a tolerance for residues on cucurbits should be established at 0.03 ppm. ARIA recommends for the proposed flumioxazin tolerance on cucurbit v egetables, group 9 , at 0. 03 ppm. C oncurrentl y, with the establishment of the tolerance on cucurbit vegetables, the existing tolerance on muskmelon subgroup 9A should be removed. The submitted residue data for celery are adequate. Since celery is the representative crop for leaf p etioles, subgroup 4B, the data is adequate to support the requested tolerance. ARIA recommends for the proposed flumioxazin tolerance on leaf petioles, subgroup 4B, at 0.02 ppm. The submitted residue data for hops are adequate. Following Agency policy , a tolerance of 0.05 ppm would be appropriate on hops . ARIA recommends for a tolerance of 0.05 ppm for the residues of flumioxazin on hops. A revised Section F is required. However, since adjuvants were not used in the submitted residue field trials, the labels should prohibit such uses on cucurbit vegetables, leaf petioles, and hops. A p reviously

submitted confined rotational crop study is adequate for the proposed uses on the requested field corn commodities. Based on the results of the confined accumulation study , the existing rotational crop plantback intervals (PBIs) are acceptable and rotational crop field trials and tolerances are not necessary . Dietary Risk (Food and Drinking Water) The drinking water residues for flumioxazin (flumioxazin, 482 - HA, and APF) used in the dietary risk assessment were provided by EFED and incorporated directly into the dietary

assessments The estimated drinking water concentration (EDWC) for flumioxazin residues (used in both the acute and chronic dietary anal ys es) was 0.048 ppm.Page 10 of 64

The acute dietary

exposure anal ys is for flumioxazin is an unrefined assessment , assuming 100% crop treated and tolerance level residues , upper bound estimates of potential drinking water residues, and using DEEM  default processing factors ( Version 7.81 ) for processed commodities (with the exception of tomato , which used the empirical processing factor of 1x ). The acute dietary

endpoint is applicable only to the population subgro up females 13 - 49 years old . An acute dietary

endpoint for th e general population , including infants and children was not identified. The estimated acute dietary exposure (food and drinking water) for females 13 - 49 ye ars old occupies 9 % of the aPAD and does not exceed ARIA ’s level of concern. Similarly , the chroni c dietary exposure anal ys is for flumioxazin is an unrefined assessment , with the same food residue and drinking water assumptions as the acute anal ys is . The chronic dietary endpoint applies to all population subgroups , including infants and children. The estimated chronic dietary

exposure (food and water) from flumioxazin does not exceed ARIA ’s level of concern for an y population subgroup. Food and water exposure occupies 7 % of the cPAD for the US population and 19% of the cPAD for all infants (<1 year o ld) , the subgroup with the highest exposure. Non - Occupational and Residential Risk Flumioxazin is not registered for use b y homeowners for weed control in residential areas. However, HED recently

reviewed a proposed u se of BroadStarTM Herbicide for use by commercial applicators for control of weeds on walkway s, parking lots and non - grass y areas in home landscapes. Although the product is not intended for use by homeowners , HED assumed homeowners could buy

the product if available in garden centers and o ther retail outlets . T herefore , residential handlers were assessed for both dermal and inhalation exposure , and the risks were not of concern (i.e., MOEs were significantly greater than the level of concern, and MOE of 100) . No postapplication scenarios were assessed because children and adults are not expected to come into contact with flumioxazin following application to parking lots, walkway s, and non - grass y areas. There is also the potential fo r non - occupational exposure associated with swimming in treated water for recreational purposes. ARIA used the standard approach used for assessing exposure and risk for recreational swimmers. The exposure estimates are considered to be reasonable high - end estimates based on observations from chemical - specific field studies and professional judgment . Swimmer assessments based on the proposed use pattern indicate d that all MOEs are above the level of concern , with MOEs ranging from 2 ,300 to 8 4, 0 00. Aggregate Risk When aggregating exposures and risks from various sources, ARIA ha s considered both the route and duration of exposure. Potential residential exposure scenarios include adult and child swimmers, and adult handlers appl yi ng flumioxazin for weed control. When these short - term exposures were combined with background (chronic) dietary exposure from food and drinking water, aggregate risks were not of concern, with MOEs ranging from 900 to 1300. The lowest MOE was associated with children’s combined exposure from the diet (food and water) and fromPage 11 of 64

swimming in water treated with flumioxazin. ARIA notes that both the adult and children’s short - term aggregate risk assessments are conservative based on the use of the SWIMMODEL to determine potential exposure from recreational swimming. Acute and chronic a ggregate risks are the same as dietary

risks which incorporated exposure from both food and drinking water. These risks were not of concern. Occupational Exposure and Risk Based on the product use information, there is a potential for occupational expos ure from handling (mixing/loading/applying) flumioxazin for the aquatic uses . A MOE of 100 or more is sufficient to protect occupational pesticide handlers . Except for the short - term total MOE for the subsurface application (MOE = 94 ), all short - term tot al MOEs and intermediate - term dermal & inhalation MOEs for the handlers performing the proposed uses on aquatic weeds are greater than 100 (110 ~ 43,000) and therefore, the risks do not exceed HED’s level of concern. The rate of 8.62 lb ai/A results a sho rt - term total MOE of 94 when assessed using baseline protection plus glov es as required on the label. The short - term total MOE calculated for the next highest application rate (7.55 lb ai/A) used in the subsurface application is 110. Based on this result and given the serious nature of the toxicological endpoint, ARIA/HED recommends that the water depth for subsurface application shall not go beyond 7 feet ; an updated label is required. Workers may also be exposed to flumioxazin during mixing, loading, and application activities associated with agricultural crops. Occupational handler assessments indicate that all MOEs are above the levels of concern at the baseline level (total MOEs = 210 to 4,400 ). The post application MOEs for commodities were not de termined because the exposures to flumioxazin for workers performing post - application activities on these commodities are expected to be negligible. The 12 - hour restricted entry interval (REI) appearing on the label is appropriate for this chemical. Environment

al Justice Potential areas of environmental justice concern, 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 con sumer subgroups according to well - established procedures. In line with OPP policy , HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by

Individuals (CSFII) and are used in pesticide risk assessments for all registe red food uses of a pesticide. These data are anal yz ed 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 expos ure assessments are performed when conditions or circumstances warrant. WheneverPage 12 of 64

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 currentl y in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to b ys tanders and farm workers as well as lifestyl e and traditional dietary patterns among specific subgroups. Cumulative Exposure and Risk 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 flumioxazin and any

other substances , and flumioxazin does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that flumioxazi n has a common mechanism of toxicity with other substances. Review of Human Research This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These studies (liste d in Appendix C ) have been determined to require a review of their ethical conduct, and have received that review. Additional Data Needs and Recommendations Pending the resolution of the requirements listed in Section 1 1 , ARIA recommends in favor of establishing the tolerances as listed in Table 10. 0. 2.0 INGREDIENT PROFILE Flumioxazin is an herbicide of the N - phenylphthalimide class (Group 14) that is currentl y used for pre - and post - emergence control of susceptible weeds in a variety of fruit, vegetable and other field crops. It s mode of action is as an inhibitor of protoporph yrinogen oxidase ( PPO ) ; it is active against certain grasses, broadleaf weeds, and sedges. Tolerances are currentl y established for residues of flumioxazin in/ on various plant commodities, at levels ranging from 0.02 to 0.70 ppm (40 CFR §180.568[a]). Temporary t olerances associated with a Section 18 emergency exemption have also been established on alfalfa forage and hay at 0.13 and 0.45 ppm, respectivel y (40 C FR 180.568[b]). Valent and IR - 4, wish to amend the product labels for ValorTM Herbicide , ChateauTM Herbicide , and Clipper Herbicide . The products are WDG formulation s containing flumioxazin at 51% to incorporate new aquatic uses and uses on cucurbit vegetable, leaf petioles, and hops. T h e nomenclature and ph ys icochemical properties of flumioxazin are presented below in Tables 2.2 and 2 .3 .Page 13 of 64

2.1 Summary of Proposed Use s Table 2.1 . Summ ary of Proposed Use Pattern of Flumioxazin. Applic. Timing, Type, and Equip. Form

ulation [EPA Reg. No .] Applic.

Rate (lb ai/A) Max.

No. Applic. per Season Max.

Seasonal Applic. Rate (lb ai/A) RTI 1 PHI (days) Use Directions and

Limitations Aquatic W eeds and A lgae Surface application --- broad spray using backpack or handgun sprayer, airboat, or other equipment C lipperTM

51% WDG [59639 - 1 61 ] 0.3825 2 0.765 28 NA Treat up to half of the water body and wait 10 to 14 d ays before treating the remaining area. Do not re - treat the same section of water within 28 days of application . A erial application --- helicopte r, airplane 0.3825 2 0.765 28 NA Subsurface application --- hoses trailing behind a boat 8.62 (8 foot deep water column) 2 17.24 28 NA

Cucurbit Vegetables Group 9 Ground equipment ValorTM

51% WDG [59639 - 99] ChateauTM 51% WDG [59639 - 119] 0 .125 2 0.250 21±2 after transplant 28±2 after emergence NS 2 Fist shielded application to

row middles 14±2 before crop emergence or transplant. Apply at 10 - 40 gal/A. Leaf Petioles Subgroup 4B Ground equipment ValorTM

51% WDG [59639 - 99] ChateauTM 51% WDG [5 9639 - 119] 0.094 -

0.188 1 0.094 - 0.188 NA NS Apply to soil surface before transplant. Apply at 20 - 40 gal/A. Hops Ground equipment ValorTM

51% WDG [59639 - 99] ChateauTM 51% WDG [59639 - 119] 0.375 2 0.750 30±3 30±3 Apply to lower 30in of plant extending to 18 in from row . Apply at 10 - 40 gal/A.

1 Retreatment Interval. 2 NS = not specified.Page 14 of 64

Conclusion : Based on occupational exposure and risk concerns, ARIA recommends that the water depth for subsurface application shall not go beyond 7 feet ( a 7 foot deep wat er column requires 7.55 lb ai/A/application to achieve the desired 400 ppb water concentration) . An updated aquatic application label is required . In addition , since adjuvants were not used in the submitted residue field trials, the labels should prohibi t such uses on cucurbit vege tables, leaf petioles, and hops; updated labels are required. 2.2 Structure and Nomenclature Table 2.2 . Flumioxazin Nomenclature. Com pound N N O F

C H 2 O

O O C C H Common name Flumioxazin Com pany experimental name VC - 1152 IUPAC name N - (7 - fluoro - 3,4 - dihydro - 3 - oxo - 4 - prop - 2 - ynyl - 2H - 1,4 - benzoxazin - 6 - yl)cyclohex 1 - ene - 1,2 - dicarboxamide CAS name 2 - [7 - fluoro - 3,4 - dihydro - 3 - oxo - 4 - (2 - propy nyl) - 2H - 1,4 - benzoxazin - 6 - yl] - 4,5,6,7 - tetrahydro - 1 H

- isoindole - 1,3(2H

) - dione CAS registry number 103361 - 09 - 7 End - use p roduct (EP) ValorTM Herbicide (EPA Reg. No 59639 - 99), ChateauTM Herbicide (EPA Reg. No 59639 - 1 99), and Clipper Herbicide (EPA Reg. No 59639 - 161) . All p roducts are WDG formulations containing 51% flumioxazin . 2.3 Physical and Chemical Properties : Table 2 .3 . Physicochemical Properties of Flumioxazin. Parameter Value Reference Melting point/range 202 - 204°C EPA Fact Sheet for Flumioxazin issued April 12, 2001. pH 7.29 at 25°C Density 1.51 g/ml at 20°C Water solubility (25°C) 1079 mg/L Solvent solubility Not available Vapor pressure 2.41 x10 - 6 mm Hg Dissociation constant, pKa None Octanol/water partition coefficient, Log(KOW) 2.55 at 20°C UV/visible absorption spectrum λ218 , ε = 14700 (pH

 1.9) λ216 , ε = 43600 (pH

 6.8) λ216 ε = 51200 (pH 10.0)

 , MRID No. 44295004Page 15 of 64

3.0 HAZARD CHARACTERIZATION 3.1 Hazard and Dose - Response Characterization 3.1.1 Database Summary 3.1.1 .1 Studies ava ilable and considered The following toxicity studies have been submitted in support of registered and proposed uses of flumioxazin: Acute - oral, dermal, inhalation, eye irritation, dermal irritation, skin sensitization; Subchronic - Dermal 21 - day rat; Ora l 28 - day

mouse, oral 90 - day

rat, oral 90 - day

dog; Chronic - Oral dog and rat; Carcinogenicity- Rat and mouse; Reproductive/developmental - Oral Pre - natal developmental rat, oral pre - natal developmental rabbit, dermal pre - natal developmental rat, 2 - generation reproduction rat ; Other - Mutagenicity

screens, metabolism and pharmacokinetic studies, dermal penetration rat, and a Special Study: Rat Developmental: Critical Time for Defects. 3.1.1.2 Mode of action, metabolism, toxicokinetic data Flumioxazin is an herbicide of the N - phenylphthalimide class (Group 14) that is currentl y used for pre - and post - emergence control of susceptible weeds in a variety of fruit, vegetable and other field crops. It s mode of action is as an inhibitor of the enzy me PPO; it is active again st certain grasses, broadleaf weeds, and sedges. In mammals, the inhibition of the enzy me can interfere with porph yrin component of heme. Metabolism studies in rats indicated that there was extensive biliary excretion following oral administration of flumioxazin. Itis noted that 4 - 5 times more radioactivity is excreted in feces than in urine. Radioactivity excretion in urine was statistically significantly elevated in females (38.8 - 42.8%, low dose; 22.9 - 23.4%, high dose) vs. males (28.1 - 30.8%, low dose ; 12.8 - 13.0%, high dose). Highest levels of residues were found in blood cells (35.9 - 48.8 ppb, low dose and 2823 - 3040 ppb, high dose), which were much higher than the plasma levels (0.5 - 0.7 ppb, low dose and 53 - 37 ppb, high dose). 3.1.1.3 Sufficiency of studie s/data The toxicology

database for flumioxazin is not complete because several studies newl y required in accordance with the 12/2007 update of the Part 158 Guidelines for toxicology have not yet been submitted. These include acute and subchronic neurotox icity studies, as well as an immunotoxicity

study . Despite these missing studies, the toxicity database is considered to be adequate for the purpose of assessment of susceptibility , dose and endpoint selection for the current risk assessment, and for characterizing toxic effects associated with flumioxazin .Page 16 of 64

3.1 .2 Toxicological Effects The toxicity

profile of flumioxazin may be found in Appendix A. Ingeneral, the s ubchronic and chronic toxicity

studies demonstrated that toxic effects associated with flumioxazin include anemia, and effects on the liver and the cardiovascular sy stem. Developmental effects were observed in developmental rat studies but not in developmental rabbit studies. Hematologic (hematopoietic) effects of anemia were noted in rats, c onsisting of alterations in hemoglobin parameters. Increased renal toxicity in male rats was also reported following chronic exposure. Acute Toxicity : Flumioxazin has mild or no acute toxicity (categories III or IV) when administered orall y, dermally , o r b y inhalation. It is also classified as Toxicity Category I II or IVfor primary

eye and skin irritation. Flumioxazin is not a dermal sensitizer. Reproductive and Developmental Toxicity : The pre - and post - natal toxicity database for flumioxazin includ e s the rat and rabbit developmental toxicity studies and the two - generation reproduction toxicity

study in rats. There is quantitative evidence of increased susceptibility of rat fetuses to in - utero exposure to flumioxazin in the oral and dermal developme ntal studies. In both studies, there was an increased incidence in fetal cardiovascular anomalies (especially ventricular septal defects). In the oral study, no maternal effects were seen at the highest dose tested (30 mg/kg/day); however , the effects in the fetuses were observed at 10 mg/kg/day . In the dermal study , no maternal effects were noted at the highest dose tested (300 mg/kg/day) but the effects in fetuses were observed at 100 mg/kg/day . In the 2 - generation rat reproduction study , parental eff

ects (red substance in vagina and increased mortality in females as well as decreases in male and female body weights, body weight gains and food consumption) were noted at 18.9 mg/kg/day

in males at the highest dose tested (HDT) and 22.7 mg/kg/day in fema les (HDT). The observed reproduction/offspring effects were a decrease in the number of liveborn , a decrease in pup body weights , and a decrease in mating index at 12.7 mg/kg/day for males and 15.1 mg/kg/day

for females. In addition, testicular atrophy w as observed in the F1 males at 12.7 mg/kg/day . The effects observed in the fetuses and offspring in the developmental and reproductive toxicity studies occurred at lower doses than those which cause d maternal and/or parental effects, which is considered t o be evidence of an increase in quantitative susceptibility . An additional rat developmental study

was submitted in which a single dose of 400 mg/kg/day was administered to pregnant rats on gestation day s (GDs) 11, 12, 13 or 14. The results of the study indicated that a single dose on gestation day 12 was the cause of the ventricular septal defect observed in the rat developmental toxicity studies. A number of mechanist ic studies were submitted by the Registrant to further describe the hematopoietic and fetal effects , and to determine the relationship between these effects . The r egistrant postulated that the anemia observed in rats leads to fetal anemia and subsequent fetal hy poxia, followed by suppressed liver function and a decrease in protein s ynthesi s. T he decreased protein sy

nthesis w as proposed to result in wavy ribs and changes in osmotic forces leading to edema observed in the fetus. Concurrently , the fetus would compensate for the anemia b y pumping a greater volume of blood leading to the obser ved enlargement of the heart.Page 17 of 64

Th e registrant further postulated that the ventricular septal defect was produced by mechanical distortion of the heart. The two other signs of developmental toxicity reported, growth retardation and fetal death were also co nsidered to be related to the h ypoxia produced b y the anemic condition in the fetus. After evaluating the data, the Agency concluded the mechanistic studies were not sufficientl y robust to support the registrant’s proposed mechanism of toxicity . However, since doses and endpoints for risk assessment were chosen to be protective of the cardiovascular (acute dose and endpoint) and hematopoietic (chronic dose and endpoint) effects, the lack of a conclusion regarding the mechanism of toxicity does not result in the need for additional uncertainty factors. There was no evidence (quantitative or qualitative) of susceptibility following in - utero oral exposure in rabbits. No developmental toxicity was seen at th e HDT (3 x the l imit - d ose). The absence of effects in rabbits was supported by literature studies indicating rabbits are less susceptible to the effects of PPO inhibitors. Neurotoxicity : HED concluded there is no concern for neurotoxicity resulting from exposure to flumioxazin. None of the acute, subchronic, chronic, developmental or reproduction studies indicated an effect on the nervous s ys tems. Based on the lack of concern for neurotoxicity , HED concluded a developmental toxicity study (DNT) was not required. Nonetheless, the acute and chronic neuro toxicity

studies are now required for all pesticide active ingredients, in accordance with 40 CFR, Part 158 (Updated, 12/2007). Carcinogenicity: In accordance with the 1999 Proposed Guidelines for Carcinogen Risk Assessment , HED determined that flumioxaz in was “not likely to be a human carcinogen.” Flumioxazin did not induce significant increases in any tumor type in either rats or mice under the conditions of the studies and it did not induce any mutagenic activity in the required battery of mutgenicity studies . 3.1. 3 Dose - response V entricular septal defects in the rat oral and dermal developmental toxicity studies were seen in the absence of maternal toxicity . Therefore to be protective of potential developmental effects from exposure to pregnant f emales , the adults’ dermal and inhalation risk assessments were based on these effects. In addition, since the developmental effect was demonstrated to occur on gestation day

12, it was considered to be a single - dose effect and served as the basis for the acute dietary risk assessment for females 13 - 49. In addition, offspring effects observed in the rat reproductive toxicity

study ( decreased number of females with liveborn and mean number of pups/litter on lactation day 1, decreased pup body weight, testi cular atroph y in F1 males and decreased mating index ) served as the basis for assessing potential risks to children from dermal and incidental oral exposure. No acute dietary endpoint was identified in the database for children or the general population. Based on the submitted studies, the rat appeared to be the most sensitive species, and the risk assessments (all durations and routes of exposure) were based on effects observed in rats. Long -Page 18 of 64

term dosing in the chronic/carcinogenicity study did not yield evidence of carcinogenicity. However, after long - term dosing, effects on blood parameters and the kidney were observed and these effects were used for risk assessment purposes. The dose of 2 mg/kg/day selected from the chronic rat study

for chronic diet ary risk assessment was the lowest dose observed in the toxicity database. 3.1. 4 FQ PA HED evaluated the toxicology data base of flumioxazin and determined that it was adequate to characterize the potential for pre - natal or post - natal risks to infants and children , despite the previously

mentioned data gaps (i.e., acute and subchronic neurotoxicity , immunotoxicity ) . The scientific quality of the flumioxazin database is relatively high , and the toxicity

profile can be characterized for most effects, including potential carcinogenic, mutagenic and developmental/reproductive . 3.2 Absorption, Distribution, Metabolism, Excretion (ADME) The absorption, distribution, metabolism and excretion (ADME) of flumioxazin was investigated in rats following single oral d oses of radiolabeled flumioxazin. Metabolism studies in rats indicated that there was extensive biliary excretion following oral administration of flumioxazin. G.I. tract absorption of flumioxazin may amount to over 90% of the dose. Total recovery of ra dioactivity

in feces and urine, 7 day s after dosing, accounted for 96.5 - 100.7% of the dose in all test groups. It was noted that 4 - 5 times more radioactivity is excreted in feces than in urine. Radioactivity

excretion in urine was statisticall y significantl y el evated in females (38.8 - 42.8%, low dose; 22.9 - 23.4%, high dose) vs. males (28.1 - 30.8%, low dose; 12.8 - 13.0%, high dose). Highest levels of residues were found in blood cells (35.9 - 48.8 ppb, low dose and 2823 - 3040 ppb, high dose), which were much hi gher than the plasma levels (0.5 - 0.7 ppb, low dose and 53 - 37 ppb, high dose). Thin layer chromatography analy sis of feces and urine revealed up to 35 putative metabolites. In addition to untransformed parent compound, 7 metabolites were identified in uri ne and feces. Identified compounds amounted to 37.5 - 46.1% of the dose at the low dose treatments and to 70.7 - 71.5% of the dose at the high dose. 3.3 FQ PA Considerations 3.3.1 Adequacy of the Toxicity Database The submitted toxicology studies are consid ered adequate to support a determination of the need for additional uncertainty factors to account for potential pre - and postnatal susceptibility . 3.3.2 Evidence of Neurotoxicity N o neurotoxicity studies are available for flumioxazin. However, none of the ac ute, subchronic, chronic, developmental or reproduction studies indicated an effect on the nervous s ys tem. HED concluded that there is no concern for neurotoxicity resulting from exposure to flumioxazin. In accordance with the updated Part 158 Toxicology Data Requirements, 12/2007, acute andPage 19 of 64

subchronic neurotoxicity

studies must be submitted . 3.3.3 Developmental Toxicity Studies Acceptable gavage developmental toxicity studies are available in both the rat and rabbit, and in addition a dermal developmental to xicity study in the rat was submitted. In the rat developmental studies, developmental effects, including cardiovascular abnormalities, were observed in fetuses at doses which did not cause maternal toxicity . In the oral study , maternal doses of 30 mg/kg did not result in maternal toxicity , whereas the developmental LOAEL was 10 mg/kg/day , with a NOAELof 3 mg/kg/day . In the dermal study , no maternal effects were observed at dermal dose s of up to 300 mg/kg/day , whereas the developmental L OAEL was 100 mg/kg/day , with a NOAELof 30 mg/kg/day . A special study was conducted which demonstrated that the developmental effects were most prominent when dosing with flumioxazin occurred on gestation day 12. In the rabbit developmental study , maternal effects were limited to decreased body weight and food consumption at the high dose of 3000 mg/kg/day, with no developmental/fetal effects (i.e., developmental LOAEL no t determined). 3.3.4 Reproductive Toxicity Study In the rat reproductive toxicity study , reproductive eff

ects in the offspring were observed at lower doses than those which caused effects in the parental animals. The s ys temic /parental LOAEL was 18.9/22.7 m g/kg/day (males/fe males) based on increased clinical signs , increased mortality and liver effects, and d ecreased food consumption during lactation in females ; and decreased body weight/weight gain in males and females . The s ys temic /parental NOAE L for these effects was 12.7/15.1 mg/k g/day (males / females) . Reproductive parameters were affected in both generations of offspring. These effects were more pronounced at the 18.9/22.7 mg/kg/day

dose level, and were observed to a lesser extent at the next lowest dose, the LOAEL of 12.7/15.1 mg/kg/day

(males/females). Reproductive/offspring e ffects were decreased number of females with liveborn and mean number of pups/litter on lactation day 1, decreased pup body weight, testicular atroph y in F1 males and decreased mating index. The reproductive/offspring NOAEL was 6.3/7.6 mg/kg/day (mal es / females). 3.3.5 Additiona l Information from Literature Sources No additional literature sources were consulted in conjunction with evaluating the currently proposed agricultural and aquatic uses. 3.3.6 Pre - and/or Post - natal Toxicity 3.3.6.1 Determination of Susceptibility Ba sed upon the oral as well as the dermal developmental rat studies, due to cardiovascular anomalies (ventricular septal defect) which occurred at doses which did not cause maternal toxicity , there is evidence of increased qualitative and quantitative suscep tibility of fetuses. The rat reproduction study demonstrated evidence of qualitative and quantitative post - natalPage 20 of 64

susceptibility because reproductive effects in offspring were observed at doses lower than those which cause parental/sy stemic toxicity , and w ere also considered to be more severe than the parental/s ys temic effects . 3.3.6.2 Degree of Concern Analysis and Residual Uncertainties Since there is evidence of increased qualitative and quantitative susceptibility of the young following exposure to flumioxazin in the oral and dermal developmental toxicity studies in the rat and in the rat reproduction study , a d egree of c oncern analy sis was performed to: 1) determine the level of concern for the effects observed when considered in the context of all av ailable toxicity

data; and 2) identify

any residual concerns after establishing toxicity endpoints and traditional uncertainty factors to be used in the risk assessment. If residual concerns are identified, HED examines whether these residual concerns can be addressed by a special FQPA safety factor and, if so, the size of the factor needed. While the toxicity

database is not complete, due to the lack of neurotoxicity and immunotoxicity studies, the database is adequate for the purpose of evaluating susceptibility . There was no evidence in an y of the submitted studies that flumioxazin affects the nervous system or directly targets the immune sy stem. HED’s degree of concern for the susceptibility observed in the rat developmental and reproductive studies is low, because the regulatory endpoints for flumioxazin are based on clear NOAELs for developmental and offspring effects that are protective of the increased susceptibility

seen in the developmental and reproduction studies, and there are no residual con cerns for these effects . 3.3.7 Recommendation for a Developmental Neurotoxicity Study There was n o evidence of neurotoxicity in an y of the submitted studies , including chronic (rat, mouse or dog), 90 day

(rat, mo u se or dog), 4 week (mouse), 21 - day rat de rmal, 2 - generation rat reproduction and developmental (oral rat, dermal rat or oral rabbit). In addition, the developmental effects observed in the rat, cardiovascular anomalies, are not related to developmental effects of the central or peripheral nervou s s ys tems. Therefore, a DNT study is not required. 3.4 FQ PA Safety Factor for Infants and Children HED recommend s the 10X FQPA Safety Factor (as required by

the Food Quality

Protection Act) be reduced t o 1X (i.e., removed) for all population subgroups for all exposure durations in assessing the risk posed by flumioxazin . Although increased prenatal and postnatal qualitative and quantitative susceptibility w ere seen in rats, there is low concern for this susceptibility and no residual uncertainties for pre - and/or post - natal toxicity because: 1) The onl y missing toxicity data for flumioxazin are the newl y required neurotoxicity and immunotoxicity

studies; however, no additional uncertainty factor is needed in the absence of these studies because there is no evidence in the available studies indicating that flumioxazinPage 21 of 64

targets the nervous s ys tem or the immune sy stem. Further, HED has concluded a developmental neurotoxicity

study is not required. 2) Although increased prenatal and postnatal qualitative and quantitative susceptibility was seen in rats, HED concluded that there is a low concern and no residual uncertainties for pre - and/or postnatal toxicity

because the developmental toxicity NOAELs/LOAELs are well characterized after oral and dermal exposure; the offspring toxicity NOAEL and LOAE L are well characterized ; and the doses and endpoints have been selected from the developmental and reproductive toxicity

studies for risk assessment for the relevant exposed populations, i.e., pregnant females and chi ldren, with the exception of the chronic dietary endpoint, for which a chronic study was chosen for endpoint selection. 3) The exposure assessment is conservative, based on tolerance - level residues in food and drinking water and upper - bound estimates of p otential residential/aggregate exposure; therefore, the potential risk for infants and children will not be underestimated . 3.5 Hazard Identification and Toxicity Endpoint Selection The available toxicity

database was evaluated for endpoint selection for acute and chronic dietary risk assessments; residential exposures including dermal and incidental oral exposure for children and dermal and inhalation exposure for adults; and for occupational exposures via the dermal and inhalation routes. HED notes that al though long - term dermal and inhalation doses and endpoints were considered and selected , there are no long - term exposures expected for these routes based on the existing and proposed use patterns. 3.5.1 Acute Reference Dose (aRfD) - Females age 13 - 49 Study Selected: Pre - natal Developmental Toxicity Study - Rat MRID No s .: 42684930 (pilot study ); 42684925 (main study); 42884006 ; 42694931 and 42684932 (studies demonstrating critical time to effects). Dose and Endpoint for Risk Assessment : NOAEL = 3 mg/kg/day , Endpoint = cardiovascular effects , speci fic ally

ventricular septal defects in fetuses , seen at the LOAEL of 10 mg/kg/day Comments about Study

/Endpoint/Uncertainty Factors : The end point selected is appropriate because the critical effect, cardiovascular abnormalities observed in fetuses, has been demonstrated to be the result of a single dose, with dosing on gestation day 12 being the most critical time period for the effect. The a pplication of the endpoint and dose to the population of potentially

pregnant females is protective of fetal effects. A clear NOAEL and LOAEL were identified for the fetal abnormalities; therefore no additional uncertainty factors (other than the standard 10X for interspecies extrapolation and 10X for intraspecies variability) are needed. Furthermore, the FQPA factor has been reduced to 1X. Therefore, the acute reference dose and acute population adjusted dose are calculated as follows: Ac ute RfD = Acut e PAD = 3 mg/kg/day (NOAEL) = 0.03 mg/kg/dayPage 22 of 64 100 (UF) 3.5.2 Acute Reference Dose (aRfD) - General Population No appropriate endpoint s were sel ected because there were no toxic effects relevant to the general population (including infants and children) identified in the database which could result from a single dose. 3.5.3 Chronic Reference Dose (cRfD) Study Selected: Combined chronic carcinogenicity - rat MRID No.: 4429502 8 Dose and Endpoint for Risk Assessment: NOAEL = 2.0 mg/kg/day , Endpoint = increased chronic nephropath y in males and decreased hematological parameters in females (Hgb, MCV, MC H, and MCHC) seen at the LOAEL of 18 mg/kg/day . Comments about Study

/Endpoint/Uncertainty Factors: The duration and route of exposure, in the rat study

are applicable to the chronic dietary route (oral) and duration (long term to lifetime) of exposure. In addition, the rat is the most sensitive species; in the one - ye ar dog study , liver effects were observed at the LOAEL of 1000 mg/kg/day , with a NOAEL of 100 mg/kg/day . In the carcinogenicity study in the mouse, no systemic effects were seen at the high est dose tested. Finally , the NOAEL selected from the rat study is the lowest observed in the submitted studies, and is protective of all other effects, including the offspring effects in the reproductive toxicity study . Since the FQPA factor has been re duced to 1X, and there are no other uncertainty factors needed, the standard 100X (10X for interspecies extrapolation and 10X for intraspecies variability) UF has been applied to attain the chronic reference dose and population adjusted dose, which are equ ivalent.

Chronic RfD = Chronic PAD = 2 mg/kg/day (NOAEL) = 0.02 mg/kg/day 100 (UF) 3.5.4 Incidental Oral Exposure (Short - and Intermediate - Term) Study Selected: Reproduction and fertility effects - rat MRID No.: 42684934 and 42684936 (pilot studies); 42684935 (main study) Dose and Endpoint for Risk Assessment: NOAEL = 6.3 mg/kg/day , Endpoint = decreased live born pups and d ecreased pup body weight , and testicular atroph y in F1 males seen at the LOAEL of 12.7 mg/kg/day . Comments about Study

/Endpoint/Uncertainty Factors: The endpoint and dose have been selected from an oral study , which is appropriate for assessing the inci dental oral pathway of exposure. In addition the endpoint, offspring effects in a reproductive study, is relevant for thePage 23 of 64

exposed population (infants and children) and therefore the risk assessment will be protective for the qualitative and quantitative s usceptibility observed in the reproductive study . Since the FQPA factor has been reduced to 1X, and a clear NOAEL and LOAEL were identified in the study , the standard UFs of 100X (10X for interspecies extrapolation and 10X for intraspecies variability) de fine the LOC for risk assessment as an MOE of 100 for residential exposure and risk assessments. 3.5.5 Dermal Absorption Study Selected: Dermal penetration - rat MRID No.: 42684944 Dermal absorption following applicati on of 200 and 800 mg/kg was 3.9 % and 8.0% , respectivel y, by

48 hours after initiation of treatment for 6 hours. Blood levels at 6 - 24 hours after dermal dosing with 200 mg/kg were similar to those obtained at 2 - 6 hours after oral dosing with 1 mg/kg. Bloo d levels at 6 - 24 hours after dermal dosing with 800 mg/kg were similar to those obtained at 2 - 6 hours after oral dosing with 30 mg/kg. For the purpose of risk assessment, an upper - bound estimate of 8 % dermal absorption should be used. 3.5.6(a) Dermal Exp osure (Short, Intermediate - Term) for Children Study Selected: Reproduction and fertility effects - rat MRID No.: 42684934 and 42684936 (pilot studies); 42684935 (main study) Dose and Endpoint for Risk Assessment: NOAEL = 6.3 mg/kg/day , Endpoint = decrea sed live born pups and decreased pup body weight, and testicular atrophy in F1 males seen at the LOAEL of 12.7 mg/kg/day . Comments about Study

/Endpoint/Uncertainty Factors: The endpoint and dose have been selected from the oral reproductive toxicity stu dy in the rat; the route - specific dermal study was not appropriate because reproductive parameters were not measured in the dermal study in rats. In addition the endpoint, offspring effects in a reproductive study , is relevant for the exposed population ( infants and children) and therefore the risk assessment will be protective for the qualitative and quantitative susceptibility observed in the reproductive study . Since the FQPA factor has been reduced to 1X, and a clear NOAEL and LOAEL were identified in the study , the standard UFs of 100X (10X for interspecies extrapolation and 10X for intraspecies variability) define the LOC for risk assessment as an MOE of 100 for residential e xposure and risk assessments. 3.5.6 (b) Dermal Exposure (Short - , Intermediat e - and Long - Term) for Adults Study Selected: Dermal Developmental Study (Rat)Page 24 of 64

MRID No.: 42684929 (pilot); 42684926 (main study) Dose and Endpoint for Risk Assessment: Dermal NOAEL = 30 mg/kg/day , Endpoint = cardiovascular effects, specificall y ventricular septal defects , in fetuses observed at the LOAEL of 100 mg/kg/day . Comments about Study

/Endpoint/Uncertainty Factors : The study is appropriate for dermal risk assessment because the most critical toxic effect, ventricular septal defect in fetuses, was evaluated following exposure via the dermal route. This study is appropriate for all durations because of the developmental toxicity concerns. The oral NOAEL selected for chronic diet ary risk assessment is ty

pically used to assess long - term dermal risk. However, for flumioxazin, the developmental NOAEL was selected for all dermal exposures, including long - term, since the use of the oral NOAEL of 2.0 mg/kg/day (chronic RfD) with an 8% dermal absorption factor yielded a dermal equivalent dose of 25 mg/kg/day (2.0/0.08 = 25), which is essentially comparable to the selected dermal NOAEL of 30 mg/kg/day . Since the FQPA factor has been reduced to 1X, and a clear NOAEL and LOAEL were identif ied in the study , the standard UFs of 100X (10X for interspecies extrapolation and 10X for intraspecies variability) define the LOC for risk assessment as an MOE of 100 for both residential and occupational exposure and risk assessments. 3.5.7 Inhalation Exposure (Short - and Intermediate - Term) Study Selected: Oral Developmental Study (Rat) MRID No.: 42684930 (pilot study); 42684925 (main study); 42884006 Dose and Endpoint for Risk Assessment: NOAEL = 3 mg/kg/day , Endpoint = cardiovascular effects , specifically ventricular septal defects , in fetuses seen at the LOAEL of 10 mg/kg/day . Comments about Study

/Endpoint/Uncertainty Factors: Inthe absence of an inhalation study with flumioxazin, HED selected the endpoint from an oral study . The developmental study was considered to be the most appropriate because the duration is relevant for short - term exposure, and because selection of the endpoint from the study ensures the risk asse ssment is protective of potential developmental effects. Furthermore, although the selection of the dose and endpoint are considered to be conservative for short - and intermediate - term exposure durations, the selection of the developmental effects allows for aggregation of dermal and inhalation exposure for both residential and occupational scenarios. Since an oral study was selected for the inhalation route, an inhalation absorption factor of 100% should be applied during risk assessment. Because the FQ PA factor has been reduced to 1X, and a clear NOAEL and LOAEL were identified in the study , the standard UFs of 100X (10X for interspecies extrapolation and 10X for intraspecies variability) define the LOC for risk assessment as an MOE of 100 for both resi dential and occupational exposure and risk assessments.Page 25 of 64

3.5.8 Inhalation Exposure (Long - Term) Study Selected: 2 - Year Chronic/Carcinogenicity S tudy (Rat) MRID No.: 44295028 Dose and Endpoint for Risk Assessment: NOAEL = 2 m g/kg/day , Endpoint = increased chron ic nephropath y in males and decreased hematological parameters in females (Hgb, MCV, MCH, and MCHC) seen at the LOAEL of 18 mg/kg/day. Comments about Study

/Endpoint/Uncertainty Factors: Inthe absence of an inhalation study for flumioxazin, HED selected an oral study. The duration of exposure in the chronic rat study is applicable long - term durations of exposure. In addition, the rat is the most sensitive species; in the one - ye ar dog study, liver effects were observed at the LOAEL of 1000 mg/kg/day, with a NOAEL of 100 mg/kg/day . In the carcinogenicity study in the mouse, no sy stemic effects were seen at the highest dose tested. F urthermore , the selected NOAEL is the lowest observed in the submitted studies, and is protective of all other effects, including the offspring effects in the reproductive toxicity

study . Since a route - specific inhalation study is not available, an inhalation absorption factor of 100% should be used for risk assessment purposes. Finally , because the FQPA factor has been reduc ed to 1X, and a clear NOAEL and LOAEL were identified in the study , the standard UFs of 100X (10X for interspecies extrapolation and 10X for intraspecies variability) define the LOC for risk assessment as an MOE of 100 for both residential and occupational exposure and risk assessments. 3.5. 9 Level of Concern for Margin of Exposure Table 3.5.9 Summ ary of Levels of Concern for Risk Assessment.

Duration Route Short - Term Intermediate - Ter m Long - Term Occupational (Worker) Exposure Derm al 100 100 N/A Inhalation 100 100 N/A Residential (Non - Dietary) Exposure Oral 100 100 N/A Derm al 100 100 N/A Inhalation 100 100 N/A For Occupational Exposure: A MOE of 100 is required. This is base d on the conventional uncertainty

factor of 100X (10X for intraspecies extrapolation and 10X for interspecies variation) .Page 26 of 64

For Residential Exposure: A MOE of 100 is required. This is based on the conventional uncertainty factor of 100X (10X for intraspecie s extrapolation and 10X for interspecies variation). 3.5. 10 Recommendation for Aggregate Exposure Risk Assessments As per FQPA, 1996, when there are potential residential exposures to a pesticide, aggregate risk assessment must consider exposures from three major sources: food, drinking water and residential (oral, dermal and inhalation) exposure pathway s . In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED ha s considered both the route and duration of exposure. For the purpose of occupational exposures, the dermal and inhalation exposures can be aggregated because the same endpoint, fetal effects, was selected for risk assessment. Likewise, children’s dermal and oral exposures associated with swimming in treated water can be aggre gated due to the same offspring effects being used to assess dermal and oral risks. Residential handlers’ dermal and inhalation risks can also be aggregated, as can adults’ post application exposure from swimming. These combined occupational and residential exposures should be combined with background exposure from food and water determined in the chronic dietary exposure assessment. 3.5.11 Classification of Carcinogenic Potential HED classified flumioxaz in as “not likely to be a carcinogen to humans ; ” therefore, there is no cancer risk associated with the existing or proposed uses of flumioxazin . 3.5.1 2 Summary of Toxicological Doses and Endpoints for Flumioxazin for Use in Human Risk Assessments Table 3. 5 .1 2 a Summ ary of Toxicological Doses and Endpoints for Flumioxazin for Use in Dietary and Non Occupational Hum an Health Risk Assessments Exposure/ Scenario Point of

Departure (POD) Uncerta inty

/FQPA Safety Factors RfD, PAD, Level of

Concern for Risk Assessment Study and Toxicological Effects Acute Dietary Females 13 - 49 only NOAEL = 3

mg/kg/day UF A=10x

UF H =10x FQPA SF=1x Acute RfD = Acute PAD

= 0.03 mg/kg/day Oral Developmental and Supp lemental Pre - natal Studies (Rat) LOAEL = 10 mg/kg/day, based on cardiovascular effects in fetuses . 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= 2.0

mg/kg/day UF A=10x

UF H =10x FQPA SF=1x Chronic RfD = Chronic PAD

= 0.0 2 mg/kg/day 2 - Year Chronic/Carcinogenicity Study (Rat) LOAEL = 18 mg/kg/day, based on increased chronic nephropathy in males and decreased hematological parametersPage 27 of 64

Table 3. 5 .1 2 a Summ ary of Toxicological Doses and Endpoints for Flumioxazin for Use in Dietary and Non Occupational Hum an Health Risk Assessments Exposure/ Scenario Point of

Departure (POD) Uncerta inty

/FQPA Safety Factors RfD, PAD, Level of

Concern for Risk Assessment Study and Toxicological Effects

in females . Incidental Oral - Short - (1 - 30 d ays) and Intermed iate Term (1 - 6 months ) NOAEL= 6.3

mg/kg/day UF A=10x

UF H =10x FQPA SF = 1X LOC for MOE = 100 2 - Generation Reproduction Study (Rat) LOAEL = 12.7 mg/kg/day, based on decreased pup body weight and testicular atrophy in F1 males. Dermal

– C hildren Short - (1 - 30 days) and Intermediate Term (1 - 6 months) NOAEL = 6.3

mg/kg/day DAF = 8% UF A=10x

UF H =10x FQPA SF = 1X LOC for MOE = 100 2 - Generation Reproduction Study (Rat) LOAEL = 12.7 mg/kg/day, based on decreased pup body weight and testicular atrophy in F1 males. Dermal - Adults ( All durations) NOAEL= 30

mg/kg/day UF A=10x

UF H =10x FQPA SF = 1X LOC for MOE = 100 Dermal Developmental Study (Rat) LOAEL = 100 mg/kg/day, based on cardiovascular effects in fetuses . Inhalation Short - (1 - 30 days) and Intermediate Term (1 - 6 months) NOAEL = 3

mg/kg/day (inhalation absorption rate = 100%) UF A=10x

UF H =10x FQPA SF = 1X LOC for MOE = 100 Oral Developmental Study (Rat) LOAEL = 10 mg/kg/day, based on cardiovascular effects in fetuses . I nhalation Long - Term (> 6 months) Inhalation NOAEL= 2

mg/kg/day (inhalation absorption rate = 100%) UF A=10x

UF H =10x FQPA SF = 1X LOC for MOE = 100 2 - Year Chronic/Carcinogenicity Study (Rat) LOAEL = 18 mg/kg/day, based on increased chronic nephropathy in males and decr eased hematological parameters in females . Cancer (oral, dermal, inhalation) “Not likely to be a carcinogen for humans,” based on the lack of carcinogenicity in a 2 - year rat study, an 18 -

month mouse study, and a battery of mutagenic studies. Point of D eparture (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 adv erse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (intraspecies). UF H = potential variation in sensitivity among members of the human population (interspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short - term study for long - term

risk assessment. UF DB = to account for the absence of key data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. NA = not applicable. Table 3. 5 . 1 2 b Summ ary of Toxicological Doses and Endpoints for Flumioxazin for Use in Occupational Human Health Risk Assessments Exposure/ S cenario Point of

Departure Uncertainty

Factors Level of Concern for Risk

Assessment Study and Toxicological Effects Dermal - All Durations NOAEL=

30 mg/kg/day UF A = 10X

UF H = 10X LOC for MOE = 100 Dermal Developmental Study in Rats LOAEL = 100 mg/kg/day based on cardi ovascular effects in fetuses.Page 28 of 64

Table 3. 5 . 1 2 b Summ ary of Toxicological Doses and Endpoints for Flumioxazin for Use in Occupational Human Health Risk Assessments Exposure/ S cenario Point of

Departure Uncertainty

Factors Level of Concern for Risk

Assessment Study and Toxicological Effects Inhalation Short and Intermediate Term (1 - day up to 6 months ) NOAEL= 3.0

mg/kg/day (inhalation absorption rate = 100%) UF A = 10X

UF H = 10X LOC for MOE = 100 Oral Developmental Study in Rats LOAEL = 10 mg/kg/day based on cardi ovascular effects in fetuses. Inhalation Long Term Inhalation (>6 months) NOAEL = 2.0

mg/kg/day (inhalation absorption rate = 100%) UF A = 10X

UF H = 10X LOC for MOE = 100 2 - Year Chronic/Carcinogenicity Study (Rat) LOAEL = 18 mg/kg/d ay , based on increased chronic nephropathy in males and decreased hematological parameters in females Cancer (oral, dermal, inhalation) “Not likely to be a carcinogen for humans,” based on the lack of carcinogenicity in a 2 - year rat study, an 18 - month

mo use study, and a battery of mutagenic 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 enviro nmentally 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 (intraspecies). UF H = potential variation in sensitivity amon g members of the human population (interspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short - term study for long - term

risk assessment. UF DB = to account for the absence of key data (i.e., lack of a critical study). MOE = margin o f exposure. LOC = level of concern. NA = not applicable. 3. 6 Endocrine Disruption As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide a ctive 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 employ s a two - tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assay s to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal sy stems. Chemicals that go through Tie r 1 screening and are found to have the potential to 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 related effects caused by the substance, and establish a dose - response relationship between the dose and the E, A, or T effect. Between October 2009 and February 2010, EPA is issuing test orders/data call - ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathway s such as food and water, residential activity , and certain post - application agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors. Flumioxazin is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticidePage 29 of 64

chemicals. Accordingl y, EPA anticipates issuing future EDSP test orders/data call - ins for all pesticide active ingredients. For further information on the status of the EDSP, the policies an d procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery , please visit our website: http://www.epa.gov/endo/. 4.0 PUBLIC HEALTH AND PESTICIDE EPIDEMIOLOGY DATA T here are no new public health data or pesticide epidemiology data to report at this time. 5.0 DIETARY EXPOSURE/RISK CHARACTERIZATION 5.1 Pesticide Metabolism and Environmental Degradation 5.1.1 Metabolism in Primary Crops and Livestock Commodities. The nature of the res idue has been adequatel y delineated for both plant and animal commodities. In plants, the major metabolic pathway is hydrolysis of the imide moiety to produce the metabolites THPA and APF. The THPA is then hydrated to produce 1 - OH - HPA. The residue of co ncern in plants, for both tolerance expression and risk assessment purposes , is the parent compound only . The results of the ruminant and poultry metabolism studies with both phenyl - and THP - labeled flumioxazin show that the major metabolic pathways are hydrol ys is of the imide moiety , hydrox yl ation of the cyclohexene ring, and the equivalent of addition of sulfonic acid to the alkene function. The residues of concern in ruminants for risk assessments are the parent, 3 - OH flumioxazin, 4 - OH - flumioxazin, and metabolites B, C, and F. In poultry , the residues of concern are parent, 3 - OH - flumioxazin, 4 - OH - flumioxazin, and 4 - OH - S - 53482 - SA ( P P#: 1F06296 , DP Num : D 284045 , W . Drew , 5/24 /04) . For purposes of this petition, ARIA/HED has waived the requirement for a fish metabolism study and has concluded that the residues of concern in fish include flumioxazin and its major degradates in water, APF and 482 - HA. 5.1.2 Metabolism in Rotational Crops The previousl y submitted confined rotational crop study ( DP Num: D 259593, D . Dotson, 3/12/01 ) is adequate for the proposed uses on the requested field corn commodities. Following an application of [14C]flumioxazin at 0.96 lb ai/A, total radioactive residues (TRR) were 0.004 - 0.057 ppm in RACs from representative rotational crops planted 30 day s post - treatment (60 day s for lettuce, because of phy totoxicity). Extraction and anal ys is of plant samples with TRRs >0.01 ppm indicated that the majority of extractable 14C - residues were comprised of unknown polar components each present at ≤0.015 ppm. L ow levels of flumioxazin (≤0.003 ppm) were detected in carrot tops and wheat chaff and straw, along with trace amounts (<0.001 ppm) of the metabolites 482 - HA, IMOXA, and 482 - CA.Page 30 of 64

HED has concluded that the residue of concern in rotational crops is the parent compound only . Based on the results of the confined accumulation study , HED concluded that the existing rotational crop PBI s are acceptable, and that field trials and tolerances in rotated crops are not necessary . 5.1.3 Analytical Methodology An adequate GC/NPD method is available for enforcing tolerances of flumioxazin in plant commodities (MRID No. 43935509, Valent Residue Method #RM - 30A - 1, Determination of Flumioxazin Residues in Crops , J. Garbus, 1/8/ 96). This method has undergone a succ essful ILV trial and a successful PMV trial by the Agency . The reported method LOQ and LOD for flumioxazin are 0.020 and 0.010 ppm, respectively . For tolerance enforcement in fish tissues , Valent has submitted a L C - MS/MS method (GPL MTH - 066) for determin ing residues of flumioxazin, APF and 482 - HA. For this method, residues are extracted with acetonitrile (ACN) and aqueous ACN, each containing either 1% formic acid for extraction of parent and APF or 1% ammonium hydroxide for extraction of 482 - HA. Extrac ted residues are diluted with water and analyzed directly by L C - MS/MS using external standards for quantitation. The validated LOQ is 0.01 ppm for each anal yt e in fish. This method has undergone a successful ILV trial and appears to be acceptable for enf orcing tolerances; however, additional information/data are required before the method can be recommended as an enforcement method (See Sec. 11, below) . Residues of flumioxazin in/on cucumber, summer squash, and celery were quanti fied by GC/NPD. The harv ested RAC samples were analyzed by Cornell Anal yt ica l Laboratory using the Method, Residue Analysis of Flumioxazin on Cucumber by GC/NPD Detection, Version #6 , adapted and modified from Determination of Flumioxazin Residues in Crops; Residue Method RM - 30A - 1. Valent USA Corporation (Revised January 1996). Residues were extracted with acetone:water (4:1, v:v). The residues were partitioned into dichloromethane (DCM), concentrated to dry

ness, and further purified b y partitioning in hexane/ACN. The residue s in the ACN phase were evaporated to dry ness, re - dissolved in hexane:ethyl acetate (2:1, v:v), and cleaned up on a Florisil column eluted with hexane:ethyl acetate (2:1, v:v). The residues were evaporated to dry

ness, re - constituted in acetone, and anal yz ed b y GC/NPD. The LLMV for residues of flumioxazin in/on cucumbers, summer squash celery was 0.02 ppm. The anal yt ical method was adequate for data collection purposes Residues of flumioxazin in/on hops RAC samples (dried cones) were quantified by GC/MSD using Valent method RM - 30A - 3, Determination of Flumioxazin Residues in Crops , modified by the anal yt ical laboratory , IR - 4 Western Region Leader Laboratory , University of California, Department of Environmental Toxicology , Davis, CA. The residues were partitioned into DCM, concentrated to dry

ness, re - dissolved in hexane:ethyl acetate (2:1, v:v), and cleaned up on a Florisil column eluted with hexane:ethyl acetate (2:1, v:v). The residues were evaporated to dry ness, re - dissolved in hexane:ethyl acetate (1: 1, v:v) and further purified on a tandem NH 2 carbon SPE column eluted with hexane:ethyl acetate (1:1, v:v). The residues in the eluate were evaporated to dry

ness, re - constituted in acetone, and anal yz ed b y GC/MSD in the selective ionPage 31 of 64

monitoring (SIM) mode . The LLMV for residues of flumioxazin on hops samples was 0.02 ppm. The anal yt ical method was adequate for data collection purposes Residues of flumioxazin and its two hydrox y metabolites (3 - OH - flumioxazin and 4 - OH flumioxazin) were determined in milk and tissues using two related liquid chromatograph y with tandem mass spectroscopy/mass spectroscop y ( LC /MS/MS ) methods, Valent Methods RM 30MK for milk and RM - 30T for tissues. Recoveries from milk, cream and skim milk averaged 84 - 92% (± 1 - 9%) for flumioxaz in, 89 - 95% (± 8 - 11%) for 3 - OH - flumioxazin, and 84 - 93% (± 6 - 10%) for 4 - OH - flumioxazin. Recoveries from tissues averaged 77 - 88% (± 3 - 12%) for flumioxazin, 85 - 102% (± 12 - 25%) for 3 - OH - flumioxazin, and 96 - 102% (± 17 - 20%) for 4 - OH flumioxazin. For both method s, the validated LOQ is 0.02 ppm for each analy te, and the reported LOD is 0.01 ppm. 5.1. 4 Multiresidue Methods Data depicting the anal ys is of flumioxazin through FDA Multiresidue Protocols were submitted and will be forwarded to FDA for review. The multiresidue method testing data indicate that flumioxazin is not recovered through Sections 304 and 402 of PAM, Vol. I (DP Num: D 259493, D. Dotson, 3/12 /01). However, anal yt ical reference standards and multiresidue method testing dat a are not available for APF and 482 - HA. 5.1.5 Storage Stability During the fish magnitude of residue study, tissue samples were stored frozen for 8 - 14 day s prior to extraction for anal ys is. As samples were stored frozen for <30 day s prior to extraction and anal ys is, storage stability data is not required to support the fish residue study . The available storage stability

data are adequate and support the sample storage durations incurred in the cucumber, summer squash, celery , and hop field trials. 5.1.6 Mag nitude of the Residue Fish The submitted fish residue study is adequate and supports the proposed aquatic use. Juvenile bluegill sunfishes (

Lepomis macrochirus ) and channel catfish ( Ictalurus punctatus ) were treated under static water conditions with flumioxazin at an initial concentration of 800 ppb (2x maximum proposed rate), and residues of flumioxazin, APF and 482 - HA were determined in the water and edible fish tissues over a 28 - day period of exposure. In edible fish tissues, the distribution and de cline of residues were similar for both test species, although residue levels were generally

higher in catfish than in bluegills. Total flumioxazin residues were highest at the earliest sampling interval (4 hours) in both catfish (2.52 ppm) and bluegills (0.85 ppm). Total residues declined rapidl y by Day 3 and then remained relativel y steady up to Day 28 in both bluegills (0.063 - 0.075 ppm) and catfish (0.098 - 0.204 ppm). At the earliest sampling interval, total residues in both species were comprised prim arily of parent (55 - 65%) and 482 - HA (34 - 45%), with trace amounts of APF (<1%), but b y Day 28, total residues were distributed equall yPage 32 of 64

between parent (38 - 39%), 482 - HA (26 - 27%) and APF (34 - 39%). Total flumioxazin residues did not bioaccumulate in either tes t species over the 28 day study . When extrapolated to reflect the 1x use rate, the estimated total residues in bluegills (0.43 ppm) and catfish (1.26 ppm) would support the proposed 1.5 ppm tolerances for freshwater fish. Because applications are prohibi ted to flowing water, intertidal or estuarine areas and to water used for crawfish farming, residue data and tolerances are not required for shellfish or saltwater fishes. Plants The submitted residue data for cucumber and summer squash are adequate. In addition, residue field trial data on cantaloupe, the representative crop for muskmelon subgroup 9A were submitted previously

in support of the tolerance using the same use pattern. The only cucurbit vegetable residue data set containing quantifiable res idues is cucumber. The data indicate that a tolerance for residues on cucurbits should be established at 0.03 ppm. ARIA recommends for the proposed flumioxazin tolerance on cucurbit vegetables, group 9 at 0.03 ppm. Concurrently , with the establishment of the tolerance on cucurbit vegetables, the existing tolerance on muskmelon subgroup 9A should be removed. The submitted residue data for celery are adequate. No residues of flumioxazin above the LOQ of 0.02 ppm were found on celery . Since celery is the representative crop for leaf petioles, subgroup 4B, the data is adequate to support the requested tolerance. ARIA recommends for the proposed flumioxazin tolerance on leaf petioles, subgroup 4B, at 0.02 ppm. The submitted residue data for hops are adequat e. The submitted data is adequate to support a tolerance on hops. However, the proposed tolerance was calculated with the MRLspreadsheet using half the LLMV value. Following Agency policy , using the LLMV value in place of the residue result lower than LOQ, the MRLspreadsheet indicates a tolerance of 0.05 ppm would be appropriate. ARIA recommends for a tolerance of 0.05 ppm for the residues of flumioxazin on hops. A revised Section F is required. S ince adjuvants were not used in the submitted residue field trials, the labels should prohibit such uses on cucurbit vegetables, leaf petioles, and hops. There are no processed food or feed items of regulable interest associated with the raw agricultural commodities in the current petition s . 5.1.7 Magnitude of t he Residue in Meat, Milk, Poultry, and Eggs None of the commodities in this petition, fish, cucurbit vegetables, leaf petioles, and hops are associated with livestock feed items of regulable interest . ARIA concludes that tolerances for meat, milk, poultry, and eggs are not required for the purpose of this petition. 5.1.8 Confined and Field Rotational Crops Current label directions for both 51% WDG formulations of flumioxazin specify the following general rotational crop restriction: Do not plant any crop exc ept cotton, peanut, soy bean andPage 33 of 64

sugarcane earlier than 30 day s after application of flumioxazin. In addition, the labels also specify a variety of PBIs for different field crops depending on the application rate. For the highest use rate on an y rotated c rop (0.38 lb ai/A), the specified PBIs are 9 months for cotton, field corn, peanut, rice, sorghum, so ybean, sunflower, tobacco and wheat, and 18 months for all other field crops. 5.1.9 Pesticide Metabolites and Degradates of Concern Table 5.1.9. Summary of M etabolites and Degradates to be included in the Risk Assessment and Tolerance Expression Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Flumioxazin Flumioxazin

Rotational Crop Flumioxazin Flumioxazin Livestock Ruminant Flumioxazin; 3 - OH flumioxazin, 4 - OH flumioxazin, and metabolites B, C, and F. Not Applicable *

Swine Flumioxazin; 3 - OH flumioxazin, 4 - OH flumioxazin, and metabolites B, C, and F. Not Applicable * Poultry Flumioxazin and 3 - O H flumioxazin, 4 - OH flumioxazin, and 4 - OH - S 53482 - SA. Not Applicable * Drinking Water Flumioxazin , 482 - HA and APF Not Applicable * Tolerances have not been required for livestock commodities to date . 5.1.10 Drinking Water Residue Profile The EDWC for flumio xazin residues (flumioxazin, 482 - HA, and APF) used in this dietary risk assessment was obtained from EFED’s environmental risk assessment for flumioxazin, Drinking Water Assessment for: (1) IR - 4 Registration for Flumioxazin to be used on Asparagus, Dry Bea n, Bushberry Subgroup 13B, Fruiting Vegetable Subgroup 8, Melon Subgroup 9A, Okra and Tree Nut Subgroup 14; and (2) Section 3 Registration for Use on Field Corn and Alfalfa ; DP Num : D 336195, D 342249 , and D 331732; L . Liu; 9/25 /07. The h ydrol ys is study for flumioxazin indicates that flumioxazin forms the metabolite 482 - HA, which can further hydrolyze to the metabolites APF and THPA. The rates of the two hydrol yt ic reactions are very pH dependent, but flumioxaz in (parent compound) is not very stable at any

l ikel y environmental pH. Data also indicates that THPA and APF are likely to be very mobile. Although THPA can comprise a major portion of the total residue in water, it does not possess the phenyl ring and is thusPage 34 of 64

considered significantly

less toxic than parent, APF, and 482 - HA. Thus, THPA has not been included in the residue of concern for drinking water. Therefore, parent flumioxazin and the metabolites 482 - HA and APF are the residues of concern in drinking water. The EDWC for flumioxazin residues (us ed in both the acute and chronic dietary anal ys es) was 0.048 ppm, the concentration in groundwater as estimated b y the SCI - GROW model. SCI - GROW is an empirical model for predicting pesticide levels in groundwater; the value from SCI - GROW is considered an upper bound concentration estimate, and thus conservative. In order to be conservative with the estimates, the groundwater EDWC (0.048 ppm), which is greater than the surface water EDWC (0.034 ppm), was used in both dietary anal ys es. Table 5.1.10 summari zes the drinking water concentrations provided by EFED. The model and its description are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/ . Table 5.1.10 . E DW Cs for F lumioxazin and its D egradates in S urface W ater and G roundwater at pH 7. 1 Compound Average 56 - Day

Conc. in Surface Water Peak Conc. in

Surface Water Conc. in

Groundwater Flumioxazin negligible 1.03 ppb negligible 482 - HA 4.84 ppb 6.87 ppb 45.27 ppb APF 12.85 ppb 26.46 ppb 2.66 ppb THPA 19.50 ppb 27.67 ppb 182.28 ppb 1 Total EDWC = Flumioxazin + 482 - HA + APF 5.2 Dietary Exposure and Risk 5.2.1 Acute Dietary Exposure/Risk The anal ys is summarized in Table 5.2 .2 (below) is based on tolerance - level res idues in all RACs (modified by

DEEM  processing factors, Version 7.81, for processed commodities), and 100% CT assumptions. Dietary exposure via drinking water was also included in this assessment. Even with the conservative assumptions utilized, the ris k estimate is well below ARIA’s level of concern. The onl y population subgroup anal yz ed is females 13 - 49 (onl y subgroup with an identified acute dietary

endpoint) , which has an exposure estimate of 0.0027 34 mg/kg/day at the 95th percentile, and utilizes 9 % of the aPAD. 5.2.2 Chronic Dietary Exposure/Risk The anal ys i s summarized in Table 5.2 .2 (below) are based on tolerance - level residues in all RACs (modified by

DEEM  processing factors, Version 7.81, for processed commodities), and 100% CT assumptions. Dietary exposure via drinking water was also included in these assessments. Even with the conservative assumptions utilized, the risk estimates are well below ARIA’s level of concern. The most highl y exposed population subgroup is all infants <1, which has an exposure estimate of 0.0037 61 mg/kg/day , and utilizes 19 % of the cPAD.Page 35 of 64

TABLE 5.2.2. Summary of Dietary Exposure and Risk for Flumioxazin. Population Subgroup 1 DEEM Acute Dietary Analysis, 95 th Percentile DEEM Chronic Dietary Analysis

aPAD (m g/kg) Exposure

(m g/kg/day) % aPAD cPAD (m g/kg/day) Exposure

(m g/kg/day) % cPAD General U.S. Population NA 2 0.02 0.001 307 7 All Infants (< 1 year old) 0.02 0.0037 61 19 Children 1 - 2 years old 0.02 0.0022 89 11 Children 3 - 5 years old 0.02 0.0021 20 11 Children 6 - 12 years old 0.02 0.001433 7 Youth 13 - 19 years old 0.02 0.000980 5 Adults 20 - 49 years old 0.02 0.001165 6 Adults 50+ years old 0.02 0.00122 5 6 Females 13 - 49 years old 0.03 0. 0027 34 9 0.02 0.0011 6 5 6 1 Values for the population with the highest risk for each type of risk assessment are bolded . 2 NA = Not Applicable; no acute dietary endpoint was identified for these population subgroups 5.2.3 Cancer Dietary Risk HED classified flumioxazin as “not likely to be a human carcinogen . ” T herefore, quantification of human cancer risk was not necessary . 6.0 RESIDENTIAL (NON - OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION HED has reviewed two proposed use patterns that could potential ly result in residential (non occupational) exposure. First , a new use site, to include walkway s, parking lots and non - grass y areas around residential dwellings was assessed for residential handlers. Although the product is not intended for use b y homeowners, the label does not specificall y prohibit use by reside ntial handlers. However, based on the use sites, no postapplication exposure for adults or children was expected or assessed. Residential handler risks were not of concern (refer to the 8/11/09 S. Oonnithan memo for details (DP Num: D362611). The result s of the handler exposure and risk assessment are presented below , in Table 6.1 . Table 6.1 Short - termRisk to Hom eowners From the Use of BroadStar Granules on Non - crop Areas Within Residential Settings 1Page 36 of 64

Exposure Scenario Appl.

rate , lb AI/A

Dermal unit exp. (mg AI /lb) Inhal.

unit exp. (mg AI/lb) Dermal

dose (mg/kg/day) 2 / Dermal MOE Inhal. dose

(mg/kg/ day) 2 / Inhal. MOE Total

MOE 3 Applying granules with push - type spreader 4 0.375 0.67 0.00088 0.00209/ 14,000 2.75E - 06 /

1 x 10 6 14,000 Applying granules with a hand shaker 5 0.375 3.5 0.045 0.01094 / 2700 1.41E - 04 /

21,000 2, 4 00 1. Inputs used for the exposure and MOE calculations are : (1) area treated per day = 0.5 Acres (from HED's ExpoSAC Policy No. 12, (2) body wt. of handlers, (3) Inhalation absorp., (4) short - term dermal NOAEL, (5) short term inhalation NOAEL. 2. Dermal dose (mg/kg/day) = (appl. rate * area treated/day * dermal unit exp.) / body wt. Inhalation exposure (mg/kg/day) = (appl. rate * area treated/day * inhalation unit exp. * inhalation absorption rate) / body wt. 3. Total MOE = 1 / [( 1/dermal MOE) + (1/inhal. M OE)]. Dermal MOE = dermal NOAEL / dermal exposure. Inhalation MOE = inhalation NOAEL/ inhalation exposure. The short - term derma l and inhalation MOEs were combined because of the common endpoints (i.e., developmental effects) for both exposure routes. 4. The unit exposures (geometric means) represent homeowners applying granules with push - ty pe drop/rotary spreader while wearing T - shirt and short s (ORETF Study No. OMA 003, 2003). 5. The unit exposures are for homeowners applying granules with a shaker c an (S. Recore, D296625, 5/6/04). The area treated/day with a shaker - can was taken as 0.5 Acres, which is on the higher side. In conjunction with the proposed use for control of aquatic weeds, th ere is a potential for non occupational/residential post - ap plication exposure to treated water for recreational purposes (i.e., swimming) because there is no post - application holding restriction against such use. HED used the SWIMODELto assess short - term post - application exposures/risks for children and adults exposed to flumioxazin - treated water. The SWIMODEL uses well - accepted screening exposure assessment equations to calculate the total worst - case exposure for swimmers expressed as a mass - based intake value (mg/event). The formula the model uses to calculate the dermal dose of the swimmer is as follows: ADR = CW * SA * ET * Kp * CF1 Where: ADR = Absorbed Dose Rate (mg/day) CW = Concentration of ai in pool water (mg/L) SA = Surface Area exposed (cm 2 ) ET = Exposure Time (hours/day) Kp = permeability

coef ficient (cm/hr) CF1 = volume unit Conversion Factor (L/1,000 cm 3 ) Dermall y absorbed dose rate, normalized to body weight, is calculated as: ADRnorm = ADR / BW Where:Page 37 of 64

ADRnorm = Absorbed Dose Rate, normalized to body weight (mg/kg/day) BW = Body Weight (k g) The formula used to calculate incidental oral dose is as follows: PDR = CW * IgR * ET Where: PDR = Potential Dose Rate (mg/day) CW = Concentration of ai in pool water (mg/L) IgR = In gestion Rate of pool water (L/hour) ET = Exposure Time (hours/day) Potential dose rates, normalized to body weight, are calculated as: PDRnorm = PDR / BW Where: PDRnorm = Potential Dose Rate, normalized to body weight (mg/kg/day) BW = Body Weight (kg) The assumptions and factors used in the risk calculations are consis tent with current EPA policy for completing residential exposure assessments (SOPs for Residential Exposure Assessment). The SWIMODEL was applied incorporating the assumptions and factors of the SOPs for Residential Exposure Assessments. The values used in the assessment include:

 It is assumed that 100% of the application concentration is available in the water for dermal contact. This is believed to be a reasonable assumption because biocides are ty picall y maintained in water at specified levels.  For s ubsequent day s after application, it may be assumed that the pesticide will not dissipate because it is usually desirable to maintain a specified level of biocide in the water.  The skin surface area of adults is assumed to be 21,000 cm2 cited in the Reside ntial SOPs. This is the 95 th percentile value for females (EPA Exposure Factors Handbook, 1997).  The body

weight for children is assumed to be 22 kg as cited in the Residential SOPs. This is a mean value for 6 year old children.  The skin surface area for children is assumed to be 9,000 cm 2 as cited in the Residential SOPs. This is the 90 th percentile value for male and female children.  The exposure time is assumed to be 3 hours per day . This is the 90 th percentile value for time spent swimming in a fres hwater pool. (EPA Child Specific Exposure Factors Handbook, 2002).Page 38 of 64

 The body

weight for adult short - term exposures is assumed to be 60 kg (due to the use of a developmental endpoint in the risk assessment) .  Post - application risks are based on maximum appli cation rates specific on the label. The maximum concentration of 0.4 mg/liter (400 ppb) was used to assess exposures.  Post - application inhalation exposure was not required as the active ingredient flumioxazin has a vapor pressure less than 10 - 6 mm Hg and is non - volatile, thus exposure is negligible and was not calculated.  The permeability

coefficient of flumioxazin (Kp) is 0.00085 cm/hr.  The assumed mean inhalation rates are 1.7 m 3 /hour for adults and 1.2 m 3 /hour for children, based on a moderate activity level (U.S. EPA, 1996). These rates were not needed in the present assessment due to the low vapor pressure noted above.  The assumed mean ingestion rate for adult and children swimmers is 0.05 L/hour (U.S EPA, 1989; Dang 1996) and as cited in the Resident ial SOP. All short - term post - application MOEs are greater than 100 and therefore are not of concern. HED notes that the children’s exposures were assessed using the NOAEL and endpoint fro m the reproductive toxicity

study , in which offspring effects were observed. For adults, however, HED used the oral and developmental NOAELs and endpoints for risk assessment, in order to be protective of potential fetal effects. In addition, the use of the developmental effects observed via the dermal and oral routes allowed for combining exposure and risk from both routes of exposure. HED notes that the SWIMODEL provides an upper - bound assessment for exposure associated with aquatic weed control, since it is representative of potential exposure to competitive swimmers in pools. A summary of the MOEs is presented in Table 6. 2 . Table 6. 2 . Flumioxazin Recreational Swimmer Exposure s and Risks . Exposed Person Route of

Exposure Water

Concentration (m g/L) Dose

(m g/kg/day) NOAEL

(m g/kg/day) MOE Child - 22 kg Oral 0 .4 0.002727 6.3 2,300

Dermal 0.4 0.000417 6.3 15 ,000 Adult - 60 kg Oral 0.4 0.001 3 3 , 00 0

Dermal 0.4 0.000357 30 84,000 For children’s exposures, the NOAEL and endpoint were selected from the reproductive study in rats . No additional corrections were made for dermal absorption, based on the use of the permeability coefficient . MOE = NOAEL/Dose For adult exposure, the NOAELs were selected from route - specific studies , the dermal and oral developmental toxicity studies in rats . MOE = NOAEL/Dose. Th e exposure s calculated using th e SWIMODEL are based on some central tendency (i.e., ingestion rate, body weight) and some upper - percentile assumptions (i.e., exposure duration, application rate, surface area), and are assumed to be representative of high - e nd exposure. The uncertainties associated with this assessment stem from the assumptions regarding dissipation of chemical residue in the water, and the use of an assumed permeability coefficient. The dose estimates are considered to be reasonable high - e nd estimates based on observations from chemical - specific field studies and professional judgment. A MOE of 100 or more is sufficientPage 39 of 64

to protect swimmers . Swimmer assessments indicate that all MOEs are above the levels of concern , with MOEs ranging from 3 , 0 0 0 to 84,000 . 6.1 Other (Spray Drift, etc.) Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for flumioxazin. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. On a chemical b y chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submi tted by the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriatel y apply

the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y air, orchard airblast and gro und hydraulic methods. After the policy is in place, the Agency

may impose further refinements in spray drift management practices to reduce off - target drift with specific products with significant risks associated with drift. 7.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION In accordance with the FQPA, HED must consider and aggregate flumioxazin pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED consider s both the route and duration of exposure , and also determines which scenarios are likely to co - occur . Flumioxazin exposures can occur through food and drinking water (all populations), swimming in treated waters (adults an d children), and, potentially , appl yi ng (handler only) a granular formu lation around residences (adults only). In the current risk assessment, HED considered both the handler and postapplication (swimmer) assessments to be very conservative; in addition, HED concluded that co - occurrence of these exposure scenarios is unlikel y. Therefore, short t erm aggregate assessments were conducted for food and water plus handlers, and food and water plus swimmers (see below). 7.1 Acute Aggregate Risk There were no appropriate toxicological effects attributable to a single exposure (dos e) for the general population; therefore, a dose and endpoint were not identified for this risk assessment. The aPAD for females 13 - 49 years was 0.03 mg/kg/day . T he aggregate acute risk is equivalent to the dietary

(food and water) risk shown in Section 5.2.1 ; acute aggregate risk is below the level of concern.Page 40 of 64

7.2 Short - and Intermediate - Term Aggregate Risk Intermediate - term aggregate risks were not calculated, since endpoints for short - and intermediate - term risk assessments were the same, and since res idential exposure durations are expected to be short - term in nature. For calculating short - term aggregate risks for adults (residential handler and swimming) , the 1/MOE approach was used because a route - specific study was used to select the endpoint for d ermal risk assessment (developmental dermal toxicity study , fetal cardiovascular abnormalities). For children’s risks from swimming, both the dermal and oral routes were assessed based on an endpoint selected from an oral study (offspring effects in the r eproductive toxicity), so the exposures were simply combined, along with the contribution from food and water. The specific equations and calculations used are described below : Residential Handlers Aggregate Exposure and Risk Aggregate MOE =

____________ ____ 1 _______________ 1/MOE Dermal + 1/MOE Inhalat i on + Dietary Where the dermal MOE was presented in T able 6.1, and the MOE for Inhalation + dietary exposure was calculated as follows: MOE Inhalation + Dietary =

___________Oral N OAEL

________ Inhalation Exp. + Dietary Exposure Chronic dietary

exposure for the general US population was used, since it was higher than the other adult subpopulations (Table 5.2.2, 0.001307 mg/kg/day) MOE Inhalation + Dietary =

______ 3 ___ = 207 0 0.000141 + 0.001307 Aggregate MOE =

______ 1

______

1/2700 + 1/2070

= 1170 (1200 after rounding) Adult Swimmers Aggregate Exposure and Risk Aggregate MOE =

________________ 1 _______________ 1/MOE Dermal + 1/MOE Oral + Dietary Where the dermal MOE was presented in T able 6.2 and the MOE for o ral + dietaryPage 41 of 64

exposure was calculated as follows: MOE Oral + Dietary =

___________Oral NOAEL

________ Oral Exp osure + Dietary

Exposure Chroni c dietary

exposure for the general US population was used, since it was higher than the other adult subpopulations (Table 5.2.2, 0.001307 mg/kg/day) MOE Oral + Dietary = ______ 3 ___ = 1300 0.001 + 0.001307 Aggregate MOE =

_____ _ 1

__ ______ 1/ 84,000 + 1/ 1300

= 1280 (1300 after rounding) Children Swimmers Aggregate Exposure and Risk Aggregate Exposure = Oral Dose + Dermal Dose + Chronic Dietary Exposure

= 0. 002727 + 0.000417 + 0.003761

= 0.006905 mg/kg/day Wher e Oral and Dermal Doses were taken from Table 6.2 , and the chronic dietary exposure for all infants, the highest exposed subpopulation, was taken from Table 5.2.2. Aggregate MOE =

____ NOAEL

______ Aggregate Exposure Aggregate MOE =

____ 6. 3

_ mg/kg/day

__ = 912 (900 after rounding) 0.006905 mg/kg/day Both adults’ and children’s short - term aggregate exposure and risk are below HED’s level of concern, since combined exposure through dietary (food + water) and residential (handlers and postapplication swimmers) resulted in MOEs greater than 100, ranging from a minimum of 900 for children swimmers to 1300 for adult swimmers. The residential aggregate exposure assessment is conservative and health protective, since upper - bound estimates of both residenti al and dietary

exposure were used to calculate aggregate exposure and risk.Page 42 of 64

7.3 Chronic Aggregate Risk Because there are no long - term (chronic) exposures associated with the residential pathway , the chronic aggregate risk is equivalent to chronic dietary (food plus water) risk . Refer to section 5.2.2 for the chronic aggregate risk estimates , which are not of concern . 7.4 Cancer Risk HED classified flumioxazin as "not likely” to be a human carcinogen. Therefore, there is no cancer risk associated with flumi oxazin exposure. 8.0 CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT 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 flumioxazin and any

other substances and flumioxazin does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that flumioxazin 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 b y EPA’s Office of Pesticide Programs concernin g common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. 9.0 OCCUPATION AL EXPOSURE/RISK PATHWAY Based on the product use information, there is a potential for occupational exposure from handling (mixing/loading/applying) flumioxazin for the aquatic uses :  Mixing/L oading Dry Flowable for Aerial Applications (Scenario 1)  Applying Spray s with Helicopter or Fix - Wing Airplane (Scenario 2)  Flagging during Aerial Applications (Scenario 3)  Mixing/L oading Dry Flowable for Boom Mounted Airboat Application (Scenario 4)  Applying Spray s with Boom Mounted Airboat (Scenario 5)  Mixing/L oadin g/Applying for Spray s with Boom Mounted Airboat (Scenario 6)  Mixing/L oading/Applying for Spray s with Low Pressure Handwand Sprayer (Scenario 7)  Mixing/L oading/Applying for Spray s with Backpack Sprayer (Scenario 8)  Mixing/L oading/Applying for Spray s with Ri ght of Way Sprayer (Scenario 9)  Mixing/L oading/Applying for Sub - Surface Application --- hoses trailing behind a boat (Scenario 10)Page 43 of 64

Based upon the proposed new use patterns for cucurbit vegetables, leaf petiole vegetables, and hops , the methods of applicatio n are b y ground - boom sprayer which includes hooded or directed spray s. The most highl y exposed occupational pesticide handlers for these uses are:

 Mixing/L oad ers using open pour loading of granules  Applicators using open - cab, ground - boom sprayers. It should be noted that HED and RD do not have study data regarding the loading of water dispersible granules, per se . However, the data for loaders using open - pour loading o f dry flowable (DF) formulation are considered appropriate surrogates. 9.1 Short -/Intermediate -/Long - Term Handler Risk Aquatic Uses Equations/Calculations The following equations were used to calculate handler exposure and risk: Dermal Dose (mg/kg/day) = Rate (lb ai/A) x UE (mg/lb ai) x Acres Treated (A/day) BW (kg) Inhalation Dose (mg/kg/day) = Rate (lb ai/acre) x UE (mg/lb ai) x Acres Treated (A/day) BW (kg) Where: Rate (Application Rate) = Maximum application rate on product label (lb ai/acre) UE (Unit Exposure) = Exposure value derived from August 1998 PHED Surrog ate Exposure Table (mg/lb ai handled) Acres Treated = Maximum number of acres treated per day (a cres/day) BW = Body weight (kg) Dermal MOE = NOAEL (30 mg/kg/day) (Short - & Intermediate - Term) D ermal Dose (mg/kg/day) Short - Term Inhalation MOE = NOAEL (3 mg/kg/day) Inhalation Dose (mg/kg/day) Intermediate - Te rm Inhalation MOE = NOAEL (2 mg/kg/day) Inhalation Dose (mg/kg/day) Short - Term Total MOE = _______________

_ 1_ _______________Page 44 of 64 (1/ Dermal MOE) + (1/ Inhalation MOE) Application Rate The maximum application rates given in the label were used for all exposure assessments. The maximum rates are 0.3825 lb ai/A for surface & aerial applications, and 8.62 lb ai/A (note: an 8 foot deep water column requires this rate to achieve a desired 400 ppb water concentration, and a 7 foot deep water column requires 7.55 lb ai/A to achieve a d esired 400 ppb water concentration) for subsurface application. Area or the Amount Treated Based on HED’s Exposure Science Advisory Council Policy

Number 9.1, and the values used in a previous assessment (D P Num : D 316596, T. Dole, 2005), the following ac res per day treated were assumed:

 350 acres/day

for aerial applications;  10 acres/day

for surface applications (D P Num: D 316596, T. Dole, 2005); and  30 acres/day

for subsurface application ( D P Num : D 316596, T. Dole, 2005). Body Weight The femal e body weight (60 kg) was used for all assessments because: (1) NOAELs are identified from a developmental study with fetal effects, or (2) it produces a more conservative exposure estimate which can be protective to all workers (both females and males). Exposure Frequency No data on the number of exposure day s per ye ar was provided . For this risk assessment, HED assumes that most handlers would be exposed for less than 30 day s per ye ar (short - term exposure). However, commercial pesticide handlers could be exposed for more than 30 day s but less than 6 months (intermediate - term exposure). L ong - term exposure is not expected. Unit Exposures Based on the PHED Version 1.1 as presented in the August 1998 PHED Surrogate Exposure Guide, the unit exposures use d in the handlers’ exposure/risk assessment are:

 Dermal unit exposure for mixing/loading dry flowables = 0.066 mg/lb ai  Inhalation unit exposure for mixing/loading dry flowables = 0.77 μg/lb ai  Dermal unit exposure for applying with helicopter or airpl ane = 0.0050 mg/lb ai  Inhalation unit exposure for appl yi ng with helicopter or airplane = 0.068 μg/lb ai  Dermal unit exposure for flagging = 0.011 mg/lb ai  Inhalation unit exposure for flagging = 0.35 μg/lb aiPage 45 of 64

 Dermal unit exposure for applying with airboat - boom = 0.014 mg/lb ai  Inhalation unit exposure for appl yi ng with airboat - boom = 0.74 μg/lb ai  Dermal unit exposure for mixing/loading/appl yi ng with airboat - boom = 0.37 mg/lb ai  Inhalation unit exposure for mixing/loading/appl ying with airboat - boom = 1.3 μ g/lb ai  Dermal unit exposure for mixing/loading/appl yi ng with low - pressure handwand sprayer = 0.43 mg/lb ai (gloves)  Inhalation unit exposure for mixing/loading/appl ying with low - pressure handwand sprayer = 30 μg/lb ai  Dermal unit exposure for mixing/loading/appl yi ng with backpack sprayer = 2.5 mg/lb ai (gloves)  Inhalation unit exposure for mixing/loading/appl ying with backpack sprayer = 30 μg/lb ai  Dermal unit exposure for mixing/loading/appl yi ng with right - of - way sprayer = 1.3 mg/lb ai  Inhalation unit exposure for mixing/loading/appl ying with right - of - way sprayer = 3.9 μg/lb ai  Dermal unit exposure for mixing/loading/appl yi ng for subsurface application = 0.066 mg/lb ai  Inhalation unit exposure for mixing/loading/appl ying for subsurface application = 0.77 μg/lb ai PHED was designed b y a task force of representatives from the U.S. EPA, Health Canada, the California Department of Pesticide Regulation, and member companies of the American Crop Protection Association. PHED is a software sy stem consisting of two parts

– a database of measured exposure values for workers involved in the handling of pesticides under actual field conditions and a set of computer algorithms used to subset and statistically summarize the selected data. Currentl y, the database contain s values for over 1,700 monitored individuals (i.e., replicates). Users select criteria to subset the PHED database to reflect the exposure scenario being evaluated. The subsetting algorithms in PHED are based on the central assumption that the magnitude of handler exposures to pesticides is primarily a function of activity

(e.g., mixing/loading, applying), formulation ty pe (e.g., wettable powders, granulars), application method (e.g., aerial, ground - boom), and clothing scenarios (e.g., gloves, double layer clothing). Once the data for a given exposure scenario have been selected, the data are normalized (i.e., divided by) b y the amount of pesticide handled resulting in standard unit exposures (milligrams of exposure per pound of active ingredient handled). Following normalization, the data are statistically

summarized. The distribution of exposure values for each body part (e.g., chest, upper arm) is categorized as normal, lognormal, or “other” (i.e., neither normal nor lognormal). A central tendency

v alue is then selected from the distribution of the exposure values for each body part. These values are the arithmetic mean for normal distributions, the geometric mean for lognormal distributions, and the median for all “other” distributions. Once selec ted, the central tendency values for each body

part are composited into a “best fit” exposure” value representing the entire body.Page 46 of 64

There are three basic risk mitigation approaches considered appropriate for controlling occupational exposures. These inclu de administrative controls, the use of personal protective equipment or PPE, and the use of engineering controls. Occupational handler exposure assessments are often completed by HED using baseline, PPE, and engineering controls. [Note: Administrative controls available generall y involve altering application rates for handler exposure scenarios. These are typically not utilized for completing handler exposure assessments.] The baseline clothing level scenario for occupational exposure scenarios is general ly an individual wearing long pants, a long - sleeved shirt, no chemical resistant gloves, and no respirator. The first level of mitigation generall y applied is PPE. PPE may involve the use of an additional layer of clothing, chemical - resistant gloves, and a respirator. The next level of mitigation considered in the risk assessment process is the use of appropriate engineering controls which, b y design, attempt to eliminate the possibility of human exposure. Examples of commonly

used engineering controls include enclosed tractor cabs and cockpits, closed mixing/loading/transfer systems, and water - soluble packets. Except for scenarios 7, 8, & 10, the handler exposure/risk were evaluated at baseline level (handlers wearing long pants, a long - sleeved shirt, no gloves, and no respirator). For all scenarios except sub - surface use, mitigation controls (i.e. PPE and engineering controls) were not needed for the MOE to be greater than or equal to the level of concern (MOE = 100). Handlers’ Exposure and Risk Exc ept for the short - term total MOE for the subsurface application (MOE = 94 ), all short - term total MOEs and intermediate - term dermal & inhalation MOEs for the handlers performing the proposed uses on aquatic weeds are greater than 100 (110 ~ 43,000) and ther efore, the risks do not exceed HED’s level of concern. The short - term total MOE calculated for the next highest application rate (7.55 lb ai/A) used in the subsurface application is 110. Based on this result and given the serious nature of the toxicologi cal endpoint, HED recommends that the water depth for subsurface application shall not go beyond 7 feet (a 7 foot deep water column requires 7.55 lb ai/A to achieve desired 400 ppb water concentration, while an 8 foot deep water column requires 8.62 lb ai/A to achieve desired 400 ppb water concentration). The rate of 8.62 lb ai/A results a short - term total MOE of 94 when assessed using baseline protection plus gloves as required on the label. Summaries of the exposures/risks for flumioxazin occup ational handlers are presented in Tables 9.1.a and 9.1.b . The handler exposure estimates in this assessment are based on a central tendency estimate of unit exposure and an upper - percentile assumption for the application rate, and are assumed to be repr esentative of high - end exposures. The uncertainties associated with this assessment stem from the use of surrogate exposure data (e.g., differences in use scenario and data confidence), and assumptions regarding that amount of chemical handled. The estim ated exposures are believed to be reasonable high - end estimates based on observations from field studies and professional judgment.Table 9.1.a . Non - Cancer Short - TermRisk for Flumioxazin Handlers for Aquatic Uses.

Exposure Scenario (Scenario #) Mitig ation Level a Dermal

Unit Exposure b (m g/lb ai) Inhalation

Unit Exposure c (μg/lb ai) Crop Application Rate (lb ai/A) Am ount

Treated d (A/day) Daily

Dermal Dose e (m g/k g/day) Daily

Inhalation Dose f (m g/k g/day) Dermal

MOE g Inhalation

MOE h Total

M OE i Mixer/Loader Dry Flowables for Aerial Application (1) Baseline 0.066 0.77 Aquatic Weeds 0.3825 350 0.1473 0.00172 204 1,744 180 Dry Flowables for Airboat Application (4 ) Baseline 0.066 0.77 Aquatic Weeds 0.3825 10 <0.1473 <0.00172 >204 >1,74 4 >180 Applicator Sprays with Helicopter/ Fix - Wing Airplane (2) En. Control 0.0050 0.068 Aquatic Weeds 0.3825 350 0.0112 0.00015 2,679 20,000 2,400 Sprays with Boom Mounted Airboat (5) Baseline 0.014 0.74 Aquatic Weeds 0.3825 10 0.00089 0.000047 33,70 8 63,830 22,000

Mixer/Loader/Applicator Sprays with Boom Mounted Airboat (6) Baseline 0.37 1.3 Aquatic Weeds 0.3825 10 0.0236 0.000083 1,271 36,145 1,200 Sprays with Low - Press Handwand (7) Baseline + gloves 0.43 30 Aquatic Weeds 0.3825 10 <0.1594 0.0019 >188 >1,579 >170 Sprays with Back Pack Sprayer (8) Baseline + gloves 2.5 30 Aquatic Weeds 0.3825 10 0.1594 0.0019 188 1,579 170 Sprays with Right - of

Way (9) Baseline 1.3 3.9 Aquatic Weeds 0.3825 10 <0.1594 <0.0019 >188 >1,579 >170 Sub - Surface Application (10) Baseline + gloves 0.066 0.77 Aquatic Weeds 8.62

7.55 30 0.2845 0.2492 0.0033

0.0029 105

120 909

1034 94

110 Flagger Flagging during Aerial Application (3) Baseline 0.011 0.35 Aquatic Weeds 0.3825 350 0.0245 0.00078 1,224 3,846 930 a Baseline consists of long - sleeve shirt, long pants, shoes, and socks and no respirator. PPE consists of long - sleeve shirt, long pants, shoes, socks, chemical - resistant gloves, and no respirator. b Baseline Dermal Unit Exposure represents long pants, long sleeved s hirt, no gloves, open mixing/loading, and open cab tractors, as appropriate. c Baseline I

nhalation Exposure represents no respiratory protection , open mixing/loading, and open cab tractors, as appropriate. d Daily acres treated values are from EPA esti mates of acreage that could be treated or volume handled in a single day for each exposure scenario of concern, based on the application method

and formulation/packaging type ; and also based on values used in D 316596 ( T. Dole 2005 ) . e Daily dermal dose (m g/kg/d) = unit dermal exposure (mg/lb ai) * application rate (lb ai/acre) * daily acres treated / body weight (60 kg). f Daily inhalation dose (mg/kg/d) = unit exposure (μg/lb ai) * (1mg/1000 μg) conversion * application rate (lb ai/acre) * daily acres treated / body weight (60 kg). g Dermal MOE = NOAEL ( 30 mg/kg/d) / daily dermal dose. UF = 100. h Inhalation MOE = NOAEL ( 3 mg/kg/d) / daily inhalation dose. UF = 100. i Total MOE = 1 / 1 / Dermal MOE + 1/ I nhalation MOE . UF = 100.Page 48 of 64

Table 9.1.b . No n - Cancer Interm ediate - Term Risk for Flumioxazin Handlers for Aquatic Uses. Exposure Scenario (Scenario #) Mitigation Level a Dermal

Unit Exposure b (m g/lb ai) Inhalation

Unit Exposure c (μg/lb ai) Crop Application Rate (lb ai/A) Am ount

Treated d (A/d ay) Daily

Dermal Dose e (m g/k g/day) Daily

Inhalation Dose f (m g/k g/day) Dermal

MOE g Inhalation

MOE h Total

MOE i Mixer/Loader Dry Flowables for Aerial Application (1) Baseline 0.066 0.77 Aquatic Weeds 0.3825 350 0.1473 0.00172 200 1,200 NA Dry Flowables for Airboat Application (4 ) Baseline 0.066 0.77 Aquatic Weeds 0.3825 10 <0.1473 <0.00172 >200 >1,200 NA Applicator Sprays with Helicopter/ Fix - Wing Airplane (2) En. Control 0.0050 0.068 Aquatic Weeds 0.3825 350 0.0112 0.00015 2,700 13,000 NA Sprays with Boom Mounted Airboat (5) Baseline 0.014 0.74 Aquatic Weeds 0.3825 10 0.00089 0.000047 34,000 43,000 NA

Mixer/Loader/Applicator Sprays with Boom Mounted Airboat (6) Baseline 0.37 1.3 Aquatic Weeds 0.3825 10 0.0236 0.000083 1,300 24,000 NA Sprays with Low - Press Handwand (7) Baseline + gloves 0.43 30 Aquatic Weeds 0.3825 10 <0.1594 0.0019 >190 >1,100 NA Sprays with Back Pack Sprayer (8) Baseline + gloves 2.5 30 Aquatic Weeds 0.3825 10 0.1594 0.0019 190 1,100 NA Sprays with Right - of

Way (9) Baseline 1.3 3.9 Aquatic Weeds 0.3825 10 <0.1594 <0.0019 >190 >1,100 NA Sprays for Sub - Surface Application (10) Baseline 0.066 0.77 Aquatic Weeds 8.62

7.55 30 0.2845 0.2492 0.0033

0.0029 110

120 610

690 NA Flagger Flagging during Aerial Application (3) Baseline 0.011 0.35 Aquatic Weeds 0.3825 350 0.0245 0.00078 1,200 2,600 NA a Baseline consists of long - sleeve shirt, long pants, shoes, and socks and no respirator. PPE consists of long - sleeve shirt, long pants, shoes, socks, chemical - resistant glov es, and no respirator. b Baseline Dermal Unit Exposure represents long pants, long sleeved shirt, no gloves, open mixing/loading, and open cab tractor s, as appropriate. c Baseline I

nhalation Exposure represents no respiratory protection , open mixing/loading, and open cab tractors, as appropriate. d Daily acres treated values are from EPA estimates of acreage that could be treated or volume handled in a single day for each exposure scenario of concern, based on the application method

and formulation/pack aging type ; and also based on values used in D 316596 ( T. Dole 2005 ) . e Daily dermal dose (mg/kg/d) = unit dermal exposure (mg/lb ai) * application rate (lb ai/acre) * daily acres treated/body wei ght (60 kg). f Daily inhalation dose (mg/kg/d) = unit expos ure (μg/lb ai) * (1mg/1000 μg) conversion * application rate (lb ai/acre) * daily acres treated / body weight (60 kg). g Dermal MOE = NOAEL ( 30 mg/kg/d) / daily dermal dose. UF = 100. h Inhalation MOE = NOAEL ( 2 mg/kg/d) / daily inhalation dose. UF = 1 00. i Total MOE is not applicable since the intermediate - term dermal and inhalation NOAELs are based on different toxicological endpoints .Cucumber Vegetables, Leaf Petioles, and Hops

ARIA/RD believes handlers will be exposed to short - term duration expo sures (1 - 30 day s). Depending on crop, there are one or two applications per year as described in the proposed supplemental product labels and the IR - 4 submission. ARIA/RD expects that ground applications will be conducted b y private, (i.e., grower) applic ators. Particularl y for ground applications, p rivate ( i.e., grower) applicators may perform all functions, that is, mix, load and appl y the material. Standard HED procedure directs that although the same individual may perform all those tasks, they

shall be assessed separatel y. The available exposure data for combined mixer/loader/applicator scenarios are limited in comparison to the monitoring of these two activities separately . These exposure scenarios are outlined in the Pesticide Handler Exposure Database (PHED) Surrogate Exposure Guide (August 1998). HED has adopted a methodology to present the exposure and risk estimates separately for the job functions in some scenarios and to present them as combined in other cases. Most exposure scenarios for hand - held equipment (such as hand wands, backpack sprayers, and push - ty pe granular spreaders) are assessed as a combined job function. With these ty pes of hand held operations, all handling activities are assumed to be conducted by the same individual. T he available monitoring data support this and HED presents them in this way . Conversel y, for equipment ty pes such as fixed - wing aircraft, groundboom tractors, or air - blast sprayers, the applicator exposures are assessed and presented separately from those of the mixers and loaders. By separating the two job functions, HED determines the most appropriate levels of personal protective equipment (PPE) for each aspect of the job without requiring an applicator to wear unnecessary PPE that might be required fo r a mixer/loader ( e.g., chemical resistant gloves may only be necessary

during the pouring of a liquid formulation). No chemical specific data were available with which to assess potential exposure to pesticide handlers. The estimates of exposure to pe sticide handlers are based upon surrogate study data available in the PHED (v. 1.1, 1998). For pesticide handlers, it is HED standard practice to present estimates of dermal exposure for “baseline” that is, for workers wearing a single layer of work cloth ing consisting of a long sleeved shirt, long pants, shoes plus socks and no protective gloves as well as for “baseline” and the use of protective gloves or other PPE as might be necessary . PPE for the two products was discussed earlier. The toxicologic al endpoints used herein for risk assessment are listed in Table 3.5.12b, above. A short - term duration (1 - 30 day s ) dermal toxicological endpoint was identified from a dermal developmental study

in the rat. The NOAEL is 30.0 mg ai/kg bw/day and the effec ts seen were cardiovascular effects, especiall y ventricular septal defects in fetuses. The level of concern for occupational exposures is for MOE < 100. Since the toxicological endpoint was identified from a dermal study, dermal exposure is not corrected for dermal absorption. Also, since the effects were identified from a developmental study with fetal toxicological effects, a 60 kg body weight is used to calculate average daily exposure. The short - term inhalation toxicological NOAEL is 3.0 mg ai/kg bw/day . The endpoint was identified from an oral developmental study in the rat. The effects seen were the same as those noted in the dermal study ( i.e., cardiovascular effects , especiall y ventricular septal defects inPage 50 of 64

fetuses ) . Since the toxic effects were identified from a developmental study with fetal effects, a 60 kg bw is used to calculate exposure. HED and RD assume 100 % absorption via the inhalation route of exposure. MOE s are calculated separately and as “combined” MOEs. The dermal and inhal ation NOAELs are different, therefore, the combined MOE is calculated as 1/(1/MOE dermal + 1/MOE inhalation ). Flumioxazin is classified as "not likel y" to be a human carcinogen based on the lack of carcinogenicity

in a 2 - ye ar rat study, an 18 - month mouse study , and a battery of mutagenic studies . Therefore there is no cancer risk for flumioxazin . Table 9.1 .c. Summary of Exposure & Risk for Occupational Handlers Applying Flumioxazin Unit Exposure 1 mg ai/lb handled Applic. Rate 2 lb ai/unit Units Treate d 3 Avg. Daily Exposure 4 mg ai/kg bw/day MOE 5 Com bined MOE 6 Mixer/Loader Using Open Pour Loading of Dry Flowable (Hops) Dermal: SLNoGlove 0.066 SLWithGlove 0.066 Inhal. 0.00077 0.375 lb ai/A 40

A/day Dermal:

SLNoGlove 0.0165 SLWithGlove 0.0165 Inhal. 0.00019 1,818 1,818 15,789 1,630

1,630 Mixer/Loader Using Open Pour Loading of Dry Flowable (Leaf Petiole) Dermal: SLNoGlove 0.066 SLWithGlove 0.066 Inhal. 0.00077 0.188 lb ai/A 200

A/day Dermal:

SLNoGlove 0.0414 SLWithGlove 0.0414 Inhal. 0.000483 725 725 6,211 649

649 Applicator Using Open - cab Ground - boom Sprayer Dermal: SLNoGlove 0.014 SLWithGlove 0.014 Inhal. 0.00074 0.375 lb ai/A 40

A/day Dermal :

SLNoGlove 0.0035 SLWithGlove 0.0035 Inhal. 0.00019 8,571 8,571 15,789 5,555

5,555 Applicator Using Open - cab Ground - boom Sprayer Dermal: SLNoGlove 0.014 SLWithGlove 0.014 Inhal. 0.00074 0.188 lb ai/A 200

A/day Dermal:

SLNoGlove 0.0088 SLWithGlove 0.0088 Inhal. 0.000464 3,409 3,409 6,465 2,233

2,233 1. Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”, Estimates of Worker Exposure from The Pesticide Handler Exposure Databa se Version 1.1, August 1998. Inhal. = Inhalation. Units = mg ai/pound of active ingredient handled 2. Applic. Rate. = Taken from the proposed draft labels 3. Units Treated are taken from “Standard Values for Daily Acres Treated in Agriculture”; SOP N o. 9.1. Science Advisory Council for Exposure; Revised 5 July 2000; 4. Average Daily Dose (ADD) = Unit Exposure * A pplic. Rate * Units Treated  Body Weight (60 kg since NOAELs are identified from a developmental study with fetal effects). 5. MOE = M argin of Exposure = No Observ ed Adverse Effect Level (NOAEL)  ADD. NOAEL = 30.0 mg ai/kg bw/day for short - term dermal; 3.0 mg ai/kg bw/day for short - term inhalation) . 6. Combined MOE = 1 ÷ (1 ÷ MOE Dermal + 1 ÷ MOE Inhalat io n) Conclusion: A MOE of 100 i s adequate to protect occupational pesticide handlers from exposures to flumioxazin. Except for the short - term total MOE for the subsurface application (MOE = 94; application rate for 8 foot deep water column = 8.62 lb ai/A), all short - term total MOEs and intermediate - term dermal & inhalation MOEs for handlers performing the proposed uses on aquatic weeds and terrestrial crops are greater than 100 and therefore, the risks do not exceed ARIA/HED’s level of concern. The short - term total MOE calculated for the next highestPage 51 of 64

aquatic application rate of 7.55 lb ai/A (the application rate for 7 foot deep water column in the subsurface application) is 110. Based on this result and given the serious nature of the toxicological endpoint, HED recommends that the wat er depth for subsurface application shall not go beyond 7 feet

. Pending the receipt of an updated aquatic application label, the proposed new uses do not exceed ARIA/HE Ds level of concern. 9.2 Short -/Intermediate -/Long - Term Post - application Risk Occupatio nal post - application exposures are not expected for the proposed aquatic uses. It is possible for agricultural workers to have post - application exposure s to pesticide residues during the course of ty

pical terrestrial agricultural activities. HED in conjunction with the Agricultural Re - entry

Task Force (ARTF) has identified a number of post - application agricultural activities that may occur and which may

result in post - application exposures to pesticide residues. HED has also identified Transfer Coefficie nts (TC) (cm2/hr) relative to the various activities which express the amount of foliar contact over time, during each of the activities identified . For the proposed new crop use sites, the highest appropriate TC is 1 , 5 00 cm2/hr which results from "scouti ng" (i.e., crop advisors) in peanut, leaf petiole vegetables and cucurbit vegetables. The TC for scouting hops in the earlier parts of the season is 1,300 cm 2 /hr . One might typicall y expect high exposures in late season hops, however, the directions for application to hops indicates application to the hop yard floor for sucker control and are made earlier in the season. Therefore, a s a “screening” level assessment, RD herein uses a TC of 1 , 5 00 cm2/hr. The TCs used in this assessment are from an interim TC Standard Operating Procedure (SOP) developed b y HED’s ExpoSAC using proprietary data from the ARTF database (SOP # 3.1). It is the intention of HED’s ExpoSAC that this SOP will be periodicall y updated to incorporate additional information about agricul tural practices in crops and new data on transfer coefficients. Much of this information will originate from exposure studies currently being conducted by

the ARTF, from further analy sis of studies already submitted to the Agency , and from studies in the published scientific literature. Lacking compound specific dislodgeable foliar residue (DFR) data, HED assumes 20 % of the application rate is available as DFR on day zero after application. This is adapted from the ExpoSAC SOP No. 003 (7 May 1998 - Revi sed 7 August 2000). The following convention may be used to estimate post - application exposure. Average Dail y Dose (ADD) (mg ai /kg bw/day) = DFR μg/cm 2 * TC cm 2 /hr * hr/day * 0.001 mg/μg * 1/ 6 0 kg bw and where: Surrogate Dislodgeable Foliar Resid ue (DFR) = application rate * 20% available as dislodgeable residue * (1 - D) t * 4.54 x 10 8 μg/lb * 2.47 x 10 - 8 A/cm 2

.Page 52 of 64

0. 188 lb ai /A * 0.20 * (1 - 0) 0 * 4.54 x 10 8 μg/lb * 2.47 x10 - 8 A/cm2 = 0. 42 μg/cm 2 , therefore, 0. 42 μg/cm 2 * 1 , 5 00 cm 2/hr * 8 hr/day * 0.001 mg/μg  6 0 kg bw = 0.0 84 mg/kg bw/day . MOE = NOAEL  ADD then 30 mg/kg bw/day  0.0 84 mg/kg bw/day = 357. 0. 375 lb ai /A * 0.20 * (1 - 0) 0 * 4.54 x 10 8 μg/lb * 2.47 x10 - 8 A/cm2 = 0. 84 μg/cm 2 , therefore, 0. 84 μg/cm 2 * 1 , 5 00 cm 2/hr * 8 hr/day * 0.0 01 mg/μg  6 0 kg bw = 0. 168 mg/kg bw/day . MOE = NOAEL  ADD then 30 mg/kg bw/day  0. 168 mg/kg bw/day = 178. Conclusion: A MOE of 100 is adequate to protect agricultural workers from post - application exposures. Since the estimated MOEs are > 100, the p roposed use s do not exceed ARIA ’s level of concern. 9.3 Restricted Entry Interval (REI) Flumioxazin is classified in Acute Toxicity Category I II for acute dermal toxicity and for eye irritation. It is classified in Acute Toxicity Category IV for acute inha lation toxicity and for dermal irritation. It is not a dermal sensitizer. The interim worker protection standard (WPS) REI of 12 hours is adequate to protect agricultural workers from postapplication exposures to flumioxazin. The product labels both lis t 12 hour REI s. 10.0 TOLERANCE SUMMARY Flumioxazin tolerances are established under 40 CFR §180.568. Tolerances for residues in/on plant commodities are listed in 40 CFR §180.568[a] and are expressed in terms of flumioxazin per se . Tolerances rangin g from 0.02 to 0.70 ppm have been established in/on the commodities of almonds, cotton, pome fruits (group 11), stone fruits (group 12), garlic, grape, onion, peanut, peppermint, pistachio, shallot, soy bean, spearmint, strawberry , sugarcane, and tuberous/c orm vegetables (subgroup 1C). Time - limited tolerances in/on alfalfa forage and hay , with a 12/ 31/09 expiration date, are also listed in 40 CFR §180.568[b]. No tolerances have been estab lished in meat, milk, poultry , or eggs. HED/ARIA notes that the resi due definition for the tolerance expression for CFR § 180.568 (a) General should be as follows: “Tolerances are established for residues of flumioxazin, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only

flumioxazin, 2 - [7 - fluoro -Page 53 of 64

3,4 - dihydro - 3 - oxo - 4 - (2 - propy nyl) - 2H - 1,4 - benzoxazin - 6 - yl ] - 4,5,6,7 - tetrahydro - 1H - isoindole 1,3(2H) - dione.” HED /ARIA notes that once the anal yt ical method def iciencies have been resolved for fish, the residue definition for the tolerance expression for fish should be as follows: “Tolerances are established for residues of flumioxazin, including its metabolites and degradates, in or on the commodities in the tab le below. Compliance with the tolerance levels specified below is to be determined b y measuring only the sum of flumioxazin, 2 - [7 - fluoro - 3,4 - dihydro - 3 - oxo - 4 - (2 - propy nyl) - 2H - 1,4 - benzoxazin - 6 - yl ] - 4,5,6,7 - tetrahydro - 1H - isoindole - 1,3(2H) - dione, and its metabo lites APF (3 - oxo - 4 - prop - 2y nyl - 6 - amino - 7 - fluoro - 3,4 - dihydro - 1,4 - benzoxazin) and 482 - HA (N - (7 - fluoro - 3,4 - dihdy ro - 3 - oxo - 4 - prop - 2 - yn yl - 2H - 1,4 - benzoxazin - 6 - yl)cyclohex - 1 - ene - 1 - carboxamide - 2 - carbox yl ic acid), calculated as the stoichiometric equivalent of flumio xazin, in or on the commodity .” There are no Codex, Canadian or Mexican MRL s for flumioxazin; therefore, there are no issues of international harmonization raised b y this action. Table 10.0. Tolerance Summary for Flumioxazin. Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments;

Correct Commodity Definition Fish, freshwater 1.5 1.5 Cucurbit vegetables , group 9 0.03 0.03 Leaf petioles , subgroup 4B 0.02 0.02 Hops, dried cones 0.07 0.05 Melon subgroup 9A 0.02 rem ove With the es tablishment of the tolerance on cucurbit vegetables, the existing tolerance on muskmelon subgroup 9A should be removed. 11.0 DATA NEEDS AND LABEL RECOMMENDATIONS 11.1 Toxicology The following toxicology studies should be submitted as a condition of r egistration

–

 870.7800 Immunotoxicity

– in accordance with the 12/2007 updated Part 158 Toxicology Data Requirements, an immunotoxicity study is required.

 870.6200 Neurotoxicity

– in accordance with the 12/2007 updated Part 158 Toxicology Data Requireme nts, acute and subchronic neurotoxicity studies are required .Page 54 of 64

11.2 Residue Chemistry The following residue chemistry deficiencies must be resolved prior to establishment of the tolerance for residues in fish:

 An updated aquatic application label is required (see Section 11.3 below).

 T he labels should prohibit the use of adjuvants on cucurbit vegetables, leaf petioles, and hops. Updated labels are required.

 A confirmatory

method is required for the proposed enforcement method for fish (GPL MTH - 066).

 FDA multiresidue method testing data are required for 482 - HA and APF.

 Reference standards for 482 - HA and APF must be submitted to the EPA National Pesticide Standards Repository . The following should be submitted to support the recommended tolerance fo r residues in hops:

 A revised Section F is required for a tolerance of 0.05 ppm for the residues of flumioxazin on hops. 11.3 Occupational and Residential Exposure ARIA/HED recommends that the water depth for subsurface application sh ould not go beyond 7 feet ( a 7 foot deep water column requires 7.55 lb ai/A/application to achieve desired 400 ppb water concentration) . An updated aquatic application label is required. 12.0 REFERENCES Dietary Exposure Memorandum Flumioxazin . Acute and Chronic Dietary ( Food and W

ater) Exposure Assessments for the Petition Proposing Tolerances for Residues of Flumioxazin on Fish, Cucurbit Vegetables, Leaf Petioles, and Hops . DP Num: D 367978 , W. Cutchin, 8/11/09. Drinking Water Memorandum Section 3 Registration for Use on Field Corn and Alfalfa . DP Num : D 336195, D 342249, D 331732; L . Liu; 9/25/ 07. Product Chemistry Memorandum EPA Fact Sheet for Flumioxazin.Page 55 of 64

Residue Chemistry Data Reviews Flumioxazin. Petition for the Establishment of Permanent Tolerances on Cucurbit Ve getables, Leaf Petioles, and Hops. Summary of Analytical Chemistry and Residue Data. PP#8E7462, DP Num : D 359142 , W. Cutchin, 12/14/09 O ccupational and Residential Exposure Memorandum Flumioxazin - Occupational Exposure/Risk Assessment for the Proposed U ses of Flumioxazin on Cucurbit Vegetables (Crop Group 9), Leaf Petiole Vegetables (Crop Group 4B), Hops, and Peanut. DP Num: D 359690, M. Dow, 1/5/09 . Flumioxazin : Occupational and Residential Exposure/Risk Assessment of Flumioxazin for Section 3 Registration of a New Use on Aquatic Weeds . DP Num : D 3 58360 , S . Wang , 4/20/09 . Flumioxazin: Occupational and Residential Exposure Assessment for the Registration of New Uses for BroadStar Herbicide . DP Num: D362611 , S. Oonnithan, 8/11/09. Flumioxazin: Addendum to the Residential Exposure Assessment of Flumioxazin for Seciotn 3 Registration of a New Use on Aquatic Weeds . DP Num: D 372257, C. Swartz, 12/14/09.Page 56 of 64

Appendix A: Toxicology Assessment A.1 Toxicology Data Requ irements The requirements (40 CFR 158.340) for food use for flumioxazin are in Table A. 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. Test Technical Re quired 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 ye s 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 no yes

yes yes no no 870.3700a Developmental Tox icity (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 1

yes yes 1 yes yes 870.5100 Mutagenicity

—Gene Mutation - bacterial ..................... 870.53 75 Mutagenicity

—Gene Mutation

– CHO cells ................. 870.5 395 Mutagenicity

— In vivo rat bone marrow ....................... 870. 5550 Mutagenicity —Other Genotoxic Effects - UDS assay ... yes yes yes yes yes

yes yes yes 870.6100a Acute Delayed Neurotox. (hen) ................................ ..... 870.6100b 90 - Day

Neurotoxicity (hen) ................................ .......... 870.6200a Acute Neurotox. Screening Battery (rat) ....................... 870.6200b 90 - Day

Neuro. Screening Battery (rat) .......................... 87 0.6300 Develop. Neuro ................................ ............................. no no yes yes no -

- no no

- 870.7485 General Metabolism ................................ ...................... 870.7600 Dermal Penetration ................................ ........................ 870.7 8 00 Immunotoxicity ................................ ............................. y es yes yes yes

yes no Special Studies for Ocular Effects

Ac ute Oral (rat) ................................ ........................... Subchronic Oral (rat) ................................ .................. Six - mo nth Oral (dog) ................................ .................. no -

1 Requirements for 870.4100a and 870.4200a are satisfied by the receipt of an acceptable/guideline com bined chronic/carcinogenicity study in rats (870.4300.)Page 57 of 64

A.2 Toxicity Profiles Table A.2.1 Acute To xicity Profile for Flumioxazin Guideline No. Study T ype MRID(s) Results Toxicity Category 870.1100 Ac ute oral [rat] 42684911 LD 50 >5000 mg/kg M & F IV 870.1200 Ac ute dermal [rat] 42684913 LD 50 >2000 mg/kg III 870.1300 Ac ute inhalation [rat] 42684915 LC 5 0 =3.93 mg/L IV 870.2400 Ac ute eye irritation [rabbit] 42684917 Not an ocular irritant III 870.2500 Ac ute dermal irritation [rabbit] 42684917 Non - irritating IV 870.2600 Skin sensitization [guinea pig] 42684921 Non - sensitizer N/APage 58 of 64

Table A.2.2 Subchronic , Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.3100 90 - Day

oral toxicity - rat 42684923

dose levels: 0, 2.3, 20.7, 69.7, and 243.5 mg/kg/day (M) and 0, 2.2, 21.7, 71.5, and 229.6 mg/kg/ day (F) NOAEL = 69.7 (M), 71.5 (F) mg/kg/day LOAEL = 243.5 (M), 229.6 (F) mg/kg/day based on a decrease in MCV both sexes; increase in platelets F only. 870.3100 90 - Day

oral toxicity - rat 42683922

dose levels: 0, 1.9, 19.3, 65.0, and 196.7 mg/kg/day (M ) and 0, 2.2, 22.4, 72.9, and 218.4 mg/kg/day (F) NOAEL = 65.0 (M), 72.9 (F) mg/kg/day LOAEL = 196.7 (M), 218.4 (F) mg/kg/day based on hematology changes.

870.3100 90 - Day

oral toxicity - mouse MRID unknown (referred

to in 79 - week study, MRID 44295018 ) dose levels: 0, 143, 429, or 1429 (M & F) mg/kg/day NOAEL = 429 mg/kg/day LOAEL = 1429 mg/kg/day based on increased liver weight in males.

870.3100 4 - Week oral

toxicity - mouse 44307301 (see MRID

44295018 DER#2) dose levels: 0, 151.5, 419.9 or 1366.5 (M) and 0, 164.5, 481.6 or 1698.3 (F) mg/kg/day NOAEL = 151.5 (M), 164.5 (F) mg/kg/day LOAEL = 419.9 (M), 481.6 (F) mg/kg/day based on increased absolute &/or relative liver weights in M & F. 870.3150 90 - Day

capsule - dog 4268 4924

dose levels of 0, 1 0, 100, or 1000 mg/kg/day NOAEL = 10 mg/kg/day LOAEL = 100 mg/kg/day based on dose dependent increase in total cholesterol, phospholipid & alkaline phosphatase activity . 870.3200 21 - Day

dermal toxicity - rat 44295016

dose levels: 1, 100, 300, or 1000 mg/kg/day NOAEL = mg/kg/day: 1000 (LIMIT DOSE) LOAEL = mg/kg/day: >1000 based on no effects. 870.3250 90 - Day

dermal toxicity (species) Study Not Submitted 870.3465 90 - Day

inhalation toxicity (species) Study Not Submitted 870.3700a Pre - natal

develop mental - rat (oral) (1)42684930 (pilot study);

42684925 (main study); (2) 42884006 dose levels: 0, 1, 3, 10 and 30 mg/kg/day Maternal NOAEL = 30 mg/kg/day (HDT) LOAEL = >30 mg/kg/day (HDT) Developmental NOAEL = 3 mg/kg/day LOAEL = 10 mg/kg/day based on cardiovascular effects (especially ventricular septal defects).Page 59 of 64

Table A.2.2 Subchronic , Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.3700a Pre - natal

developmental - rat (derm al) 42684929 (pilot);

42684926 (main study) dose levels: 0, 30, 100, and 300 mg/kg/day Maternal NOAEL = 300 mg/kg/day (HDT) LOAEL = >300 mg/kg/day (HDT) Developm ental NOAEL = 30 mg/kg/day LOAEL = 100 mg/kg/day based on cardiovascular effects (especially ventricular septal defects). 870.3700b Pre - natal

developmental - rabbit (oral) 42684927 (range - finding);

42684928 (main study) dose levels: 0, 300 , 1000, or 3000 mg/kg/day Maternal NOAEL = 1000 mg/kg/day LOAEL = 3000 mg/kg/day (HDT) based on decrease in body weight and food consumption during dosing Developm ental NOAEL = 3000 mg/kg/day (HDT) LOAEL = >3000 mg/kg/day 870.3800 Reproduction and

fertil ity effects - rat) 42684934 and 42684936

(pilot studies); 42684935 (main study) dose levels: 0, 3.2, 6.3, 12.7, and 18.9 mg/kg/day (M) and 0, 3.8, 7.6, 15. 1, and 22.7 mg/kg/day (F) Parental/Systemic NOAEL = 12.7 (M), 15.1 (F) mg/kg/day; LOAEL = 18.9 (M) , 22.7 (F) mg/kg/day based on increase in clinical signs (red substance in vagina) and increased female mo rtality as well as decreased body weight, body weight gain and food consumption. Reproductive NOAEL = 18.9 (HDT) (M), 22.7 (HDT) (F) mg/kg/day; LOAEL = >18.9 (HDT) (M), >22.7 (HDT) (F) mg/kg/day Offspring NOAEL = 6.3 (M), 7.6 (F) mg/kg/day; LOAEL = 12.7 (M), 15.1 (F) mg/kg/day based on a decrease in the number of liveborn , a decrease in pup body weight , a decrease in the mating index, and testicular atrophy of F1 males . 870.4100b 12 - Month capsule -

dog 44295017

dose levels: 0, 10, 100 or 1000 mg/kg/day NOAEL = 100 mg/kg/day (M & F) LOAEL = 1000 mg/kg/day (M &F), (LIMIT DOSE) based on the following for males and females: increased absolute and relativ e liver weights; 300% increase in alkaline phosphatase values 870.4100 a Chronic toxicity

( species ) [ ] NOAEL = [ ] mg/kg/day LOAEL = [ ] mg/kg/day based on [ ]. 870.4200 b Carcinogenicity -

mo use 44295018

dose levels: 0, 31.1, 314.9 or 754.1 mg/kg/day i n males and 0, 36.6, 346.4, or 859.1 mg/kg/day in females NOAEL = 754.1 (M), 859.1 (F) mg/kg/day (LIMIT DOSE); LOAEL = no systemic effects at LIMIT DOSE in males or females No evidence of carcinogenicity

870. 4300 Com

bined chronic carcinogenicity - rat 4 4295028

dose levels: 0, 1.8, 18.0, and 36.5 mg/kg/day in male rats and 0, 2.2, 21.8, and 43.6 mg/kg/day in female rats NOAEL = 1.8 (M), 2.2 (F) mg/kg/day LOAEL = 18.0 (M), 21.8 (F) mg/kg/day based on increased chronic nephropathy in males and decreased hematological parameters in females (Hgb, MCV, MCH and MCHC). No evidence of carcinogenicityPage 60 of 64

Table A.2.2 Subchronic , Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ Classification /Doses Results Gene Mutation 870.5100 Gene mutation in S.

typhimurium and E. coli 42684938

dose levels: with or without metabolic activation to 0, 50, 100, 200, 500, 1000, or 2000 μg/plate Neither cytotoxic nor mutagenic up to 2000 μg/plate. There were reproducible increases in revertant colonies of S. typhimurium strains TA 1538 and TA98 in S9 activated phases of the preliminary cytotoxicity and both mutation assays. [Results are considered to be equivocal.] Gene Mutation 870.5375 Gene mutation in

chinese hamster ovary cells 42684939

nonactivated levels, 30, 100, 200, and 500 μM (11, 35, 70, and 177 μg/mL, respectively) Precipitation at  200 μM. Cytotoxicity at 500 μM. Positive +S9  100 μM and negative at 30 - 500 μM - S9. Aberrations were chromatid breaks and exchanges. 870.5395 In vivo rat bone

marrow 42684940

dose levels: 1250, 2500, or 5000 mg/kg Negative in male (up to 5000 mg/kg) and female rats (up to 4400 mg/kg) w hen te sted orally. 870.5550 UDS assay 42684941 dose levels: by oral gavage to 5000 mg/kg or 12 hours post exposure to 1250 or 2500 mg/kg Negative up to 5000 mg/kg.Page 61 of 64

Table A.2.2 Subchronic , Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 8 70.6200a Ac ute neurotoxicity

screening battery Data Gap 870.6200b Subchronic

neurotoxicity screening battery Data Gap 870.6300 Developmental

neurotoxicity Not required. 870.7485 Metabolism and

pharmacokinetics - rat (oral) 426 8 4943

single oral dose of 1 mg/kg or 100 mg/kg, Gastrointestinal tract absorption >90% at 1 mg/kg and up to 50% at 100 mg/kg. At least 97% recovery in feces and urine 7 days after dosing. Highest levels of residues (36 - 49 ppb) in blood cells at low

dose and 2800 - 3000 ppm at high dose (RBC levels > plasma). In addition to untransformed parent, 7 metabolites identif ied in urine and feces (38 - 46% for low dose and about 71% at high dose). 870.7600 Dermal penetration

- rat 42684944

dose levels: 200 or 800 mg/kg bw Females dosed with 200 or 800 mg/kg b.w. Dermal absorption for 200 and 800 mg/kg was 3.9 % and 8.0% , respectively, by 48 hours after initiation of treatment for 6 hours. Blood levels at 6 - 24 hours after dermal dosing with 200 mg/kg were similar to those obtained at 2 - 6 hours after oral dosing with 1 mg/kg. Blood levels at 6 - 24 hours after dermal dosin g with 800 mg/kg were similar to those obtained at 2 - 6 hours after oral dosing with 30 mg/kg. 870.7800 Immunotoxicity Data Gap Non guideline Special Study -

Rat Developmental: Critical Time for Defects 42694931, 42684932

single dose:400 mg/kg bw Pregnant females were administered 400 mg/kg by gavage on gestation day 11 or 12 or 13 or 14 or 15. Day 12 administration showed: largest incidence of embryonic death, lowest fetal body weights and greatest incidence of ventricular septal defects. A. 3 Data R equirements Guideline Number: 870.6200 Study Title : Neurotoxicity Battery (Acute and Subchronic Studies) Rationale for Requiring the Data This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non - food uses). The Neurotoxicity Screening Battery (OPPTS 870.6200) is designed to evaluate the potential adverse effects on the nervous system from exposure to pesticide chemicals. The Agency believes that thePage 62 of 64

Guideline Number: 870.6200 Study Title : Neurotoxicity Battery (Acute and Subchronic Studies) guideline studies are ina dequate in their assessment of behavioral effects and do not use optimal methods to evaluate the potential toxicity to the nervous tissue structure and function. To detect and characterize these potential effects more fully, a battery of more sensitive tes ting is required. The objective of this neurotoxicity battery testing is to evaluate the incidence and severity of the functional and/or behavioral effects, the level of motor activity, and the histopathology of the nervous system. The acute neurotoxicity study is required to detect possible effects resulting from a single exposure. The subchronic neurotoxicity study is intended to detect possible effects resulting from repeated or long - term exposures. Practical Utility of the Data How will the data be used? The acute and subchronic neurotoxicity studies provide critical scientific information needed to characterize potential hazard to the human population on the nervous system from pesticide exposure. These studies can provide data on a wide range of functional tests for evaluating neurotoxicity including sensory effects, neuromuscular effects, learning and memory and histopathology of the nervous system For example, animal studies with organophosphorous chemicals have shown neurotoxi city to be the primary toxic endpoints (e.g., cholinesterase inhibition) of concern s in rodents and non - rodents. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a pri mary data source for reliable reference dose calculation. The Agency has established an oral reference dose (RfD) for assessing dietary risks for a number of chemicals (e.g., organophos p hates and carbamates) where neurotoxicity was the most sensitive endpo int of concern. How could the data impact the Agency's future decision - making? If the acute or subchronic neurotoxicity studies show that flumioxazin poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the r isk assessment s for flumioxazin may need to be revised to reflect the magnitude of potential risk derived from the new data. If the Agency does not have this data, a 10X database uncertainty factor may be applied when conducting a risk assessment using the currently available studies. Guideline Number: 870.7800 Study Title : Immunotoxicity Rationale for Requiring the Data This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non - food uses). The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is designed to evaluate the potential of a repeated chemical exposure to produce adverse effect s (i.e., suppression) on the immune system. Immunosuppression is a deficit in the ability of the immune system to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly complex, studies assessing functional immunotoxic endpoints are helpful in fully characterizing a pesticide’s potential immunotoxicity. These data will be used in combination with data from hematology, lymphoid organ w eights, and histopathology in routine chronic or subchronic toxicity studies to characterize potential immunotoxic effects. Practical Utility of the Data How will the data be used?Page 63 of 64

Guideline Number: 870.7800 Study Title : Immunotoxicity These animal studies can be used to select endpoints and doses for us e in risk assessment of all exposure scenarios and are considered a primary data source for reliable reference dose calculation. For example, animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations of TCD D (2,3,7,8 - tetrachlorodibenzo - p - dioxin) among developmental, reproductive, and endocrinologic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (I RIS, 1997). How could the data impact the Agency's future decision - making? If the immunotoxicity study shows that the test material poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessments fo r the test material may need to be revised to reflect the magnitude of potential risk derived from the new data. If the Agency does not have this data, a 10X database uncertainty factor may be applied for conducting a risk assessment from the available s tudies.Page 64 of 64

Appendix B: Metabolism Assessment Not included. Appendix C : Review of Human Research No MRID - PHED Surrogate Exposure Guide