Page 1 of 67 UNITED STATES ENVIRONMENTA L PROTECTION A GENCY

WASHINGTON, D.C. 20460 OFFICE OF PREVENTION, PESTICIDE AND TOXIC SUBSTANCES MEMORANDUM Date: 3 /31 /2010 SUBJECT: Fluazinam. Human Health Risk Assessment for the Proposed Uses on Apples,

Carrots, Lettuce, and the Bulb Onion Subgroup (3
- 07A), and a Request for a Reduced Tolerance on the Bushberry S ubgroup ( 13
- 07B)
. PC Code: 129098 DP Barcodes: D365940, D365945, D371444 Decision Nos.: 411458, 412727 Registration No. : 71512
- 1 Petitions: 8E7506, 9E7570, and 9F7571 Regulatory Action: Section 3 Registration Risk Assessment Type: Single Chemical Aggregate Case No.: NA T XR No.: NA CAS No.: 79622
- 59
- 6 MRID Nos.: NA 40 CFR: §180.574
FROM: Douglas Dotson, Ph.D., Chemist

Karl yn Middleton, Toxicologist Zaida Figueroa, Industrial Hygienist Risk Assessment Branch II Health Effects Division (7509P) THROUGH: Richard Loranger, Senior Scientist

Christina Swartz, Branch Chief Risk Assessment Branch II Health Effects Division (7509P) TO: Laura Nollen/Barbara Madden, RM Team 5, RIMUERB

John Bazuin/ Tony

Kish, PM Team 22, Fungicide Branch Registration Division (7505P)Page 2 of 67 T able of Contents 1.0 Executive Summary
................................ ................................ ................................ .......... 4 2.0 Ingredient Profile
................................ ................................ ................................ ............ 1 2 2.1 Summary

of Registered/Proposed Uses
................................ ................................ 12 2.2 Structure and Nomenclature
................................ ................................ ................. 14 2.3 Phy sical and Chemical Properties
................................ ................................ ......... 1 4 3.0 Hazard Characterization/Assess ment ................................ ................................ ........... 15 3.1 Hazard and Dose
- Response Characterization
................................ ....................... 1 5 3.1.1 Database Summary
................................ ................................ ................... 15 3.1.1.1 Studies Available and Considered
................................ ............. 16 3.1.1.2 Mode of A ction
................................ ................................ .......... 1 6 3.1.2 Toxicological Effects
................................ ................................ ................ 16 3.1.3 Dose
- response ................................ ................................ ........................... 17 3.2 Absorption, Distribution, Metabolism, Excreti on (ADME)
................................ . 18 3.3 FQPA Considerations
................................ ................................ ........................... 19 3.3.1 Evidence of Neurotoxicity
................................ ................................ ........ 1 9 3.3.2 Developmental Toxicity Studies
................................ ............................... 20 3.3.3 Reproductive Toxicity Study
................................ ................................ .... 20 3.3.4 Additional Information from L iterature Sources
................................ ...... 21 3.3.5 Pre
- and/or Postnatal Toxicity
................................ ................................ ... 21 3.3. 5 .1 D etermination of Susceptibility
................................ ................. 21 3.3.5 .2 Degree of Concern Analysis and Residual Uncertainties
.......... 21 3.4 FQPA Safet y Factor for Infants and Children
................................ ...................... 22 3.5 Hazard Identification and Toxicity Endpoint Selection
................................ ........ 2 3 3.5.1 Acute Reference Dose (aRfD)
- Females 1 3
- 49
................................ ....... 23 3.5.2 Acute Reference Dose (aRfD)
- General Population
................................ 23 3.5.3 Chronic Reference Dose (cRfD)
................................ ............................... 24 3.5.4 Dermal Absorption
................................ ................................ .................... 25 3.5.5 Dermal Exposure (Short
- and Intermediate
- Term)
................................ ... 25 3.5.6 Inhalation Exposure (Short
- and Intermediate
- Term)
............................... 2 6 3.5.7 Le vel of Concern for Margin of Exposure
................................ ................ 27 3.5.8 Recommendation for Aggregate Exposure Risk Assessments
................. 27 3.5.9 Classification of Carcinogenic Potential
................................ ................. 27 3.5.10 Summary

of Toxicological Doses and Endpoints for F luazinam
........... 28 3.6 Endocrine disruption
................................ ................................ ............................. 29 4.0 Public Health and Pesticide Epidemiology Data
................................ .......................... 30 5.0 Dietary Exposure/Risk Characterization
................................ ................................ ..... 30 5.1 Pesticide Metabolism and Environmental Degradation
................................ ............. 30 5.1.1 Metabolism in Primary Crops
................................ ................................ ... 30 5.1.2 Metabolism in Rotational Crops
................................ ............................... 31 5.1.3 Metabolism in L ives tock
................................ ................................ ........... 31 5.1.4 Analy

tical Methodology
................................ ................................ ........... 31 5.1.5 Environmental Degradation
................................ ................................ ...... 32 5.1.6 Comparative Metabolic Profile
................................ ................................ . 3 4 5.1.7 Toxicity

Profile of Major Metabolites and Degradates of Concern
......... 3 4Page 3 of 67 5.1.8 Pesticide Metabolites and Degradates of Concern
................................ .... 3 5 5.1.9 Drinki ng Water Residue Profile
................................ ................................ 36 5.1.10 Food Residue Profile
................................ ................................ ............... 36 5.1.11 International Residue Limits
................................ ................................ ... 39 5.2 Dietary

Exposure and Risk
................................ ................................ ........................ 39 5.2.1 Acute Dietary

Exposure/Risk
................................ ................................ ..... 39 5.2.2 Chronic Dietary

Exposure/Risk
................................ ................................ .. 39 5.2.3 Cancer Dietary

Risk
................................ ................................ .................... 40 5.3 Anticipated Residue and Percent Crop Treated (%CT) Information
.......................... 40 6.0 Residential (Non - Occupational) Exposure/Risk Characterization
............................ 40 7.0 Aggregate Risk Assessments and Risk Characterization
................................ ............ 41 7.1 Acute Aggregate Risk
................................ ................................ ........................... 41 7.2 Short
- Term Aggregate Risk
................................ ................................ .................. 41 7.3 Intermediate
- Term Aggregate Risk
................................ ................................ ...... 41 7.4 Long
- Term Aggregate Risk
................................ ................................ .................. 41 7.5 Cancer Risk
................................ ................................ ................................ ........... 42 8.0 Cumulative Risk Characterization/Assessment
................................ ........................... 42 9.0 Occupational Exposure/Risk Pathway
................................ ................................ .......... 42 9.1 Agricultural Handler Exposure and Risk
................................ .............................. 42 9
. 1 .1 Data and Assumptions for Handle r Exposure Scenarios
............................ 43 9
. 1 .2 Handler Exposure and Risk
................................ ................................ ........ 45 9.2 Postapplication Exposure and Risk
................................ ................................ ....... 50 9
. 2 .1 Data and Assumptions for Postapplication Exposure Scenarios
................ 50 9
. 2 .2 Postapplication Exposure and Risk
................................ ............................. 54 9
. 2
. 3 Postapplication Risk Characterization
................................ ........................ 54 10.0 Data Needs and Label Re commendations
................................ ................................ .... 55 10.1 Toxicology
................................ ................................ ................................ ............ 55 10.2 Residue Chemistry
................................ ................................ ................................ 55 10.3 Occupational and Residential Exposure
................................ ............................... 57 References:
................................ ................................ ................................ ................................ ... 58 Appendix A: Toxicology Assessment
................................ ................................ ....................... 59 A.1 Toxicology

Data Requirements
................................ ................................ ................ 59 A.2 Toxicity

Profiles
................................ ................................ ................................ ........ 60 A. 3 Executive Summaries
................................ ................................ ................................ 65 Appendix B: Tolerance Summary Table
................................ ................................ ................. 66Page 4 of 67

1.0 Executive Summary The active ingredient (ai) , fluazinam, is a preventive contact fungicide with a multi
- site mode of action. It disrupts the production of energy at s everal metabolic sites within the fungal cell. Interregional Research Project #4 (IR
- 4) has submitted petitions (PP# s 8 E7 506 and 9 E7 570 ) proposing the use of OMEGA ® 500F , a soluble
- concentrate formulation containing 40% fluazinam on head lettuce, leaf lettuce, carrots, and the Onion, bulb, subgroup, 3
- 07A. In addition, IS K Biosciences Corporation submitted a tolerance petition for the use of fluazinam on apples ( PP# 8 E7 506)
. Finally , IR
- 4 submitted a request to rev ise the established 7.0
- ppm tolerances f

or fluazinam residues in/on the B ushberry subgroup ( 13B ) and other bushberry t yp e crops . IR
- 4 requested that the revised tolerance be established for the updated Bushberry subgroup 13
- 07B. T his document assesses the toxicology database, the residue chemi stry aspects, the dietary , residential, and occupational exposures and risks that would result f rom the proposed uses of the product. OMEGA ® 500F may be applied as a foliar spray using aerial, chemigation, groundboom, and airblast equipment. Based on the product labels, handler exposures are expected to be short
- and intermediat e - term in duration. Toxicology In subchronic and chronic oral and dermal toxicity studies in rats, dogs , and mice, the liver appeared to be the primary target organ . Liver effec ts included changes in clinical chemistry , increased absolute and/or relative liver weights, gross lesions, and a variety of histopathological lesions. Treatment
- related effects were also observed in other organs in subchronic and chronic oral, dermal , and inhalation studies in rats, dogs , and mice, but these effects were not regularl y noted in all three species or in a ll studies in a given species. In a developmental toxicity study in rats there was evidence of increased qualitative susceptibility

(sk eletal abnormalities/facial/palate clefts in fetuses vs. decreases in body weight gain/food consumption in maternal animals) of fetuses to fluazinam; however, there was no evidence of increased quantitative susceptibility . There was no evidence of increas ed quantitative or qualitative susceptibility in a developmental toxicity study in rabbits or in a 2
- generation reproduction study in rats. In an acute neurotoxicity

study in rats, there were decreases in motor activity and soft stools at high doses (10 00 mg/kg/day) ; h owever, i n two subchronic neurotoxicity studies (evaluated together) there were no signs of neurotoxicity observed at doses up to 280 mg/kg/day . A neurotoxic lesion described as vacuolation of the white matter of the central nervous s ys tem was observed in studies in mice and dogs . T his lesion was found to be reversible and is attributed to an impurity

( Impurity
- 5). Based on the level of this impurity in technical grade fluazinam, the risk assessment for the parent compound is protective o f effects from the impurity
.Page 5 of 67

A developmental neurotoxicity study in rats and a series of special studies were submitted that address the issues of increased susceptibility in the developmental toxicity study and the presence of neurotoxic lesions observe d in the toxicological database. As a result, there are no residual uncertainties with regard to pre
- and/or postnatal toxicity , and no additional safet y factors are needed. HED recommen ds that the FQPA S afety F actor be reduced to 1 x for dietary and derm al exposure risk assessments. For inhalation exposure risk assessment, a 10x safety factor has been retained to account for the lack of histopathology evaluation in a 7
- day

inhalation study (currentl y used for risk assessment) and the use of the study in evaluating intermediate
term (6 months) inhalation exposure
. Additionally , a subchronic (28
- day) inhalation toxicity study is required. The Cancer Assessment Review Committee (CARC) classified fluazinam as having “ Suggestive evidence of carcinogenic ity , but not sufficient to asse ss human carcinogenic potential. ” The CARC determined that quantification of human cancer risk using a linear low
- dose (Q1*) extrapolation approach is not required , and the cRfD (0.011 mg/kg/day) is protective of potential c ancer effects. As a result of new data requirements in the 40 CFR Part 158 for conventional pesticide registration, an immunotoxicity study is required for fluazinam. HED has concluded that the available data show no evidence of effects on the immune sy s tem. Therefore, a database uncertainty factor is not needed for the absence of this study
. Metabolic Profile The nature of fluazinam residues in plants is adequately understood based on metabolism studies on potatoes, peanuts, and grapes. The Agency pr eviously concluded that the residue of concern in peanuts and root and tuber vegetables is fluazinam per se for purposes of both dietary risk assessment and tolerance enforcement . For all other crops, the residues of concern include both fluazinam and its metabolite AMGT for purposes of dietary risk assessment. For setting tolerances, the residues of concern in plants include fluazinam and AMGT for wine grapes, but only fluazinam for all other plant commodities. The nature of fluazinam residues in rotati onal crops is adequatel y understood. Based on the absence of metabolites containing the intact fluazinam nucleus, HED has determined that the residue of concern in rotational crops is the parent compound, and that rotational crop tolerances are not requir ed for fluazinam. The available confined field rotational crop study supports the 30
- day plant
- back interval (PBI) that is currentl y listed on the label for crops without direct uses of fluazinam. The nature of the residue in livestock is also understood based on acceptable goat and hen metabolism studies. The fluazinam residues of regulatory interest in animal commodities are parent plus the metabolites AMPA and DAPA and their sulfamate conjugates.Page 6 of 67

R esidues in D rinking W ater T he environmental fate studies for fluazinam indicate that the parent compound forms transformation compounds that , in most cases , are similar in structure to the parent . F luazinam does not undergo degradation. Instead, it undergo es transformation into a series of products, al l of which resemble the parent by way of their chemical structure. For modeling of drinking water residues , the E nvironmental F ate and E ffects Division (EFE D ) assumed that the phy sicochemical characteristics were similar for both the parent and its produc ts ( i.e. the total toxic residue approach ). Residue Chemistry

Profile An adequate gas chromatograph y with electron capture detection ( GC/ECD ) method (6148
- 91
- 0170
- MD
- 001 ) is available for determination of fluazinam residues in crop matrices. The method was deemed to be suitable for tolerance enforcement after it successfully completed the routes required for an enforcement method including radiovalidation, independent laboratory validation (ILV), and tolerance method validation (TMV). Samples collected from the magnitude of the residue and storage stability studies were anal yz ed for residues of fluazinam using various GC/ECD methods based on, and revised slightly from, the plant enforcement method. The GC/ECD methods are adequate for data collection bas ed on acceptable method recovery data. The lowest limit of method validation (LLMV) was 0.01 ppm in all tested commodities except in carrots where the LLMV was 0.02 ppm. An enforcement method for determination of AMGT, a residue in the tolerance for wine grapes, is also available. PTRLMethod 1676W was the data
- collection method used for the analy sis of samples collected from the dairy

cattle feeding study
. The method is written for LC/MS/MS analy sis of fluazinam, AMPA, and DAPA in bovine milk and tissu es, and for GC/MS analysis of DAPA in milk only
. The limit of quantitation was 0.01 ppm for each analy te in milk, muscle, fat, liver , and kidney
. Preliminary

method validation data showed that Method 1676W adequatel y recovered residues of fluazinam, AMP A, and DAPA in milk, muscle, and fat. However, poor and/or marginal recoveries were obtained for AMPA and DAPA residues in kidney and liver. Method 1676W was marginall y validated by an independent laboratory during the third trial and following modificat ions to make the method more rugged. For the purpose of developing an animal enforcement method, radiovalidation data are required to determine whether the method can detect aged residues. HED forwarded Method 1676W to ACB/BEAD for a tolerance method val idation (TMV) because the method encountered difficulties in the ILV (e.g., three attempts for successful validation and/or marginal recoveries with wide variability and high coefficient of variation). ACB/BEAD reported that the lab that performed the ILV made major modifications to the original method. As a result, HED requested that the registrant submit a revised method that incorporated the revisions made by the ILV lab. I SK Biosciences revised the method and re
submitted it. ACB/BEAD performed a cursory review of the revised method. The registrant incorporated the modifications made by the ILV lab. However, the revision eliminated the cleanup steps that were in the original method, and the only recovery data for the revised method were data provid ed b y the ILV lab. ACB/BEAD was concerned that the elimination of the cleanup steps could lead to dirty samples which would, in turn, lead to analy tical problems, such as interference. ACB/BEAD performed no further validation of the method. As the revis edPage 7 of 67

method contains major revisions to the original method, and ACB/BEAD believes it is very likely that the revised method still is not adequate for sample analy sis or tolerance enforcement, HED recommends that the registrant submit an ILV o f the revised m ethod. Adequate FDA multiresidue method ( MRM) testing data are available for fluazinam and its metabolite AMGT. As fluazinam is partially recovered through Sections 302, 303, and 304 of PAM Volume I , the M RM s can serve as a confirmatory procedure for residues of fluazinam. The FDA MRM methods are not suitable for determining residues of AMGT. Multiresidue method testing data are required for the regulated metabolites, AMPA and DAPA, in animals. Adequate storage stability data are available to support the storage conditions and durations of samples collected from the magnitude of the residue studies on apples, carrots, lettuce, and onions. The residue data from the cattle feeding study are not adequate to satisfy data requirements. The feeding study data (adjusted for residue decline) along with the calculated dietary burdens for beef cattle (0.04 ppm) and dairy cattle ( 1.27 ppm) indicate that tolerances are needed for the combined residues of fluazinam and its metabolites DAPA and AMPA in the fat and meat by products of cattle and other ruminants at 0.0 5 ppm to support the proposed use s on apples and carrots and the established tolerances on potatoes and peanuts . However, no tolerances are required for milk and meat of ruminants , a s the expected combined residues in these matrices are below the combined method limit of quantitation (LOQ) of 0.03 ppm for the regulated compounds. Based on the transfer coefficients for livestock tissues and the relativel y low dietary burden for swine of 0.003 ppm for fluazinam, tolerances for hog commoditie s are not needed. A poultry feeding study

is not required at this time because of the low dietary burden for poultry (0.005 ppm ). The submitted field trial data for fluazinam on head lettuce, leaf lettuce, bulb onions, carrots, and apples are acceptable and support the proposed uses. Adequate numbers of trials were conducted in the appropriate geographic regions at ~1x the maximum proposed rate using a representative FlC formulation, and the approp riate samples were collected from each test at the proposed PHI. However, no residue data were provided on AMGT residues in lettuce. Although AMGT residue data on lettuce are still required for purposes of dietary risk assessment, the available data supp ort tolerances of 0.0 2 ppm for head lettuce and 2.0 ppm for leaf lettuce
. HED accounted for AMGT residues in lettuce in the current risk assessment using a ratio obtained from plant metabolism data. The field trial data also support a tolerance of 0.20 p pm for the B ulb onion subgroup ( 3
- 07A)
. The tolerance spreadsheet ( Guidance for Setting Pesticide Tolerances Based on Field Trial Data SOP) was used for determini ng appropriate tolerance levels. Because of data deficiencies associated with Method 1676W, the cattle feeding study , and the apple processing study , HED does not recommend in favor of tolerances for apple and carrot commodities. After reevaluating the available residue data for blueberries, HED conclude s that the residue data for fluazinam from the blueberry field trials are distributed lognormall y. As a result, the recommended tolerance for the revised Bushberry subgroup , 13
- 07B is 7.0 ppm, which is equivalent to the current tolerance for Subgroup 13B.Page 8 of 67

The apple processing study is not adequat e to satisfy data requirements. Inapples, the metabolite AMGT is a residue of concern for risk assessment. In the processing study there were no quantifiable residues of AMGT in raw apples. In several of the field trials that were performed, however, r aw apples contained AMGT residues at, or above, the limit of quantitation. In a few cases, residues of AMGT were comparable to those of the parent fluazinam. Canadian and U.S. residue chemistry guidelines both stipulate that in the processing study , if r esidues in the raw agricultural commodity ( RAC ) are below the LO Q, but quantifiable residue s occurred in the RAC in field trials performed at the maximum requested label rate, that the processing study should be conducted at exaggerated rates in order to e nsure that quantifiable residues will be present in the RAC . Quantifiable residues are needed in the RAC in order to determine a reliable concentration factor. As a result, the processing study needs to be repeated at a sufficientl y high rate that residu es of both parent and AMGT are quantifiable in the RAC. In the event that the potential for ph yt otoxicity exists, the application rate does not need to be greater than the rate at which phy

to to xicity occurs. Tolerance Harmonization There are currently

n o established Codex, Canadian, or Mexican maximum residue limits (MRL s) for fluazinam on apple s , carrot s , lettuce, onions , or berry crops. Therefore, there are no harmonization issues for the requested tolerances. Dietary Expos ure HED performed the acut e and chronic dietary exposure anal ys es based on conservative assumptions. Both assessments incorporate 100% crop treated (CT) assumptions and modeled estimated drinking water concentrations (EDWCs) . The acute assessment is based on tolerance level resid

ues . The chronic assessment is based on an average field trial value for apples and tolerance level residues for all other commodities. HED considers the resulting acute and chronic exposure and risk estimates t o be high
- end and very conservative. The a cute risk estimates are below HED’s level of concern for all population subgroups, including those comprised of infants and children. Generall y, HED is concerned when risk estimates exceed 100% of the population
- adjusted dose (PAD). The acute risk estimate for the general U.S. population is 4.1 % of the acute PAD (aPAD). The population subgroup with the highest risk estimate is F emales 13
- 49 years of age, which uses 20 % of the aPAD. The c hronic risk estimates are also below HED’s level of concern for all population subgroups. The risk estimate for the general U.S. population is 14 % of the chronic PAD (cPAD). The population subgroup with the highest risk estimate is All Infants less than one ye ar old, which uses 40 % of the c PAD. The CARC determined that the cRfD is protective of cancer effects. As a result, a dietary exposure assessment for cancer risk is not necessary
. Residential Exposure Fluazinam has n o residential uses , and no occupational uses at residential sites are being requested in this pet ition; therefore, no residential risk assessment has been conducted.Page 9 of 67

Aggregate Exposure The acute aggregate risk of exposure to fluazinam is equivalent to the acute dietary risk. Acute d ietary risk estimates are not of concern for the general U.S. pop ulation or any population subgroup. There are no residential uses for fluazinam; therefore, no short
- or intermediate
- term aggregate risk assessments were performed. As there are no residential uses for fluazinam, di etary (food + water) consumption is th e only source of exposure to fluazinam that is expected to result in chronic exposure. Therefore, the long
- term aggregate exposure and risk estimates are equivalent to the chronic dietary exposure and risk estimates. The c hronic aggregate risk estimates are below HED’s level of concern for all population subgroups. The CARC determined that the cRfD is protective of cancer effects. Cancer risk resulting from exposure to fluazinam is not of concern. Occupational Handler Risk No chemical
- specific handler exposure data were submitted in support of this registration. HED data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 was used to assess handler exposures (HED Science Advisory Council for Exposure (ExpoSAC) , SOP No. 7, January 1999)
. The maximum application rate for each exposure scenario is presented as the worst
- case scenario. All handler scenarios resulted in MOEs greater than the level of concern (MOEs > 100 for dermal and > 1,000 for inhalation) wi th some level of risk mitigatio n. HED recommends that all label requirements for PPE are followed and expanded to all handlers. Occupational Postapplication Risk Based on the Agency ’ s current practices, a quantitative postapplication inhalation exposure assessment i s not being perf ormed for fluazinam at this time. However, volatilization of pesticides m ight be a potential source of postapplication inhalation exposure to individuals in close proximity to locations where pesticide applications are made . The Agency sought expert advi ce and input on issues related to volatilization of pesticides from its FIFRA Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipol y/ SAP/meetings/2009/120109meeting.html). The Agency is in the process of evaluating the SAP report and m ight , as appropriate, develop policies and procedures to identify

the need for and the way to incorporate postapplication inhalation exposure into the Agency ’ s risk assessments. If new polici es or procedures are put into place, the Agency

m ight revisit the need for a quantitative postapplication inhalation exposure assessment for fluazinam
. C hemical
- specific dislodgeable foliar residue (DFR) studies on apples (MRID 45584203) and peanuts (MRID 46991302) were submitted and reviewed by HED
. For this assessment, peanut DFR data w ere used as surrogate data to assess postapplication exposure for lettuce, onions , and carrots.Page 10 of 67

The restricted entry

interval (REI) for fluazinam is based on the acute t oxicity of technical material. Fluazinam is classified as Toxicity Category Ifor eye irritation. Under the Worker Protection Standard (WPS) for Agricultural Pesticides, active ingredients classified as acute T oxicity C ategory

Ifor any of these routes are assigned a 48
- hour REI. Postapplication MOEs were estimated for “Day 0” exposure (i.e., the day of application). In cases where the MOE was less than the level of concern ( LOC ) of 100 on Day 0, residue dissipation data/assumptions were used to deter mine the day

for which the risk would be not of concern (i.e., MOE of 100 or greater). Based on HED’s postapplication exposure calculations, the dermal risks for a

pples and onions, and for certain activities on carrots were greater than 100 within 48 hour s, which is in accordance with the current label REI. Apple and onion postapplication dermal risks were 100 or greater within 12 hours of application
. C arrot postapplication dermal risks were 1 00 or greater within 48 hours of application for low to medium contact activities (i.e. h and weeding, irrigation, and scouting )
. However, carrots did not reach a MOE of 100 or greater for high contact activities (i.e., hand harvesting) until day 6. Furthermore, lettuce did not reach a MOE of 100 or greater for med ium contact activities (i.e., irrigation, scouting) until day 8 and for high contact activities (i.e., hand harvesting) until day

12 . Risks from these activities are of concern until the specified intervals have elapsed
. HED recommends that the Registrat ion Division ensure that the appropriate REI is provided on all registered labels. Environmental Justice Considerations Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in ac cordance 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 con siders a large variety of consumer subgroups according to well
- established procedures. In line with OPP policy , HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake s by

Individuals (CSFII) and are used in pesticide ri sk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by

subgroups based on age, season of the year, ethnic group, and region of the country . Additionally , OPP is able to assess dietary exposure to smaller, s pecialized subgroups , and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, nondietary

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 postapplication are evaluated. Further considerations are currentl y under evaluation as OPP has committed resources and expertise to the development of specialized software models and the refinement of curre nt methodologies and policies that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. To ensurePage 11 of 67

that this risk assessment is consistent with scientific standards and policies un der development, HED m ight refine the risk assessment components for all registered uses in the future. Review of Human Research This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pestic ide or other chemical. These studies, which comprise the Pesticide Handlers Exposure Database (PHED) and the Agricultural Reentry Task Force (ARTF) Database, have been determined to require a review of their ethical conduct, have received that review, and have been determined to be ethical. Conclusions/Recommendations HED concludes that there is a reasonable certainty that no harm will result to the general U.S. population, any

population subgroup, or occupational workers through the establishment of the recommended tolerances on head lettuce, leaf lettuce, or the Bulb onion subgroup (3
- 07A). HED recommends in favor of the establishment of the following tolerances: lettuce, head at 0.02 ppm; lettuce, leaf, at 2.0 ppm; and Onion, bulb, subgroup 3
- 07A, at 0.20 ppm. Refer to Table B.1., in Appendix B for a complete list of the proposed and recommended tolerances associated with these tolerance petitions. HED recommends that the tolerance expressions for fluazinam be revised as stated in Appendix B. An an al yt ical reference standard for the AMGT metabolite is not available. RD should request that the registrant submit this standard to the EPA’s National Pesticide Repository as soon as possible. Although residues in or on apples, carrots, and animal commo dities were included in this risk assessment, HED cannot recommend in favor of tolerances for these commodities at the present time because of deficiencies in the livestock residue anal yt ical method, the cattle feeding study, and the apple processing study
. These data deficiencies are outlined in Section 10.0, Data Needs and Label Recommendations, and are discussed in detail in Sections 5.1.4 and 5.1.10 of this document. Prior to the establishment of tolerances, RD should request that the registrant provi de the following: (1) A revised Section F in which a tolerance of 0.2 ppm is proposed for Onion, bulb, subgroup 3
- 07A, and a tolerance of 7.0 ppm is proposed for Bushberry , subgroup 13
- 07B (2) R evised labels in which the use directions for all the subject crops (including apples and carrots) include a prohibition against addition of adjuvants to the spray mixture (3) R evised labels that specify the appropriate REI sPage 12 of 67

(4) R evised labels in which the required PPE is expanded to all handlers (i.e., w orkers cond ucting flagger
- related activities should wear the same PPE as applicators in order to reduce exposures )
. These requirements are outlined in greater detail in Section 10.0, Data Needs and Label Recommendations. HED recommends that the following data be ma de conditions of registration : (1) F ield trial data for AMGT residues in lettuce (2) An immunotoxicity

study for fluazinam (3) A subchronic (28
- day) inhalation toxicity study for fluazinam. These requirements are outlined in greater detail in Section 10. 0, Data Needs and Label Recommendations. 2.0 Ingredient Profile Fluazinam (Omega 500F Agricultural Fungicide) is a non
- sy stemic, preventive, contact fungicide of the phen yl
- py ridinamine class, with a multi
- site mode of action. It disrupts the production of energy

at several metabolic sites within the fungal cell. Fluazinam is a protectant fungicide . That is, when applied to plants, it remains primarily on the plant surface, is not taken up to any extent by the plant, and is not translocated within the plant. 2.1 Summary of Registered/Proposed Uses Fluazinam is currentl y registered in the U.S. for use on ginseng, peanuts, potatoes, turnip greens, Crop Group 5 (

Brassica leafy

vegetables), Subgroup 6A (except pea), S ubgroup 6B (except pea), Subgroup 6C (except pea), the Bushberry subgroup (13B), and other bushberries that are included in Subgroup 13
- 07B but not 13B. Tolerances range from 0.01 ppm for the Brassica leafy vegetables and turnip greens to 7.0 ppm for the Bushberry subgroup and other bushberries. In addition, there is a tolerance of 3.0 ppm for residues in/on wine grapes (no U.S. registration). These tolerances are listed in 40 CFR 180.574. The current tolerance petitions include apples, carrots, head le ttuce, leaf lettuce, and the Bulb onion subgroup (3
- 07 A ). Inaddition, IR
- 4 submitted a request to rev ise the established 7.0
- ppm tolerance for fluazinam residues in/on the B ushberry

subgroup ( 13B ) and other bushberry ty pe crops by

reducing it to 4.5 ppm
. IR
- 4 requested that the revised tolerance of 4.5 ppm be established for the updated Bushberry subgroup 13
- 07B. IR
- 4 and ISK Biosciences are proposing the use of a formulation containing 4.17 pounds per gallon (lb/gal) of fluazinam (Omega 500F Agricultur al Fungicide; EPA Registration No. 71512
- 1) on the proposed crops. This end
- use product (EP) is formulated as a flowable
suspension concentrate (F lC ) . Copies of the proposed labels were provided, and the proposed uses on the requested crops are summariz ed in Table 2.1 , below.Page 13 of 67

Table 2.1. Summ ary of Directions for Use of Fluazinam. Applic. Timing; Type; and Equipment Form ulation [EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Direc tions and

Limitations 1 Apple Broadcast foliar applications prior to or during disease development; Ground and aerial equipment 4.17 lb/gal FlC [71512
- 1] 0.33
-

0.45 10 4.50 28 Apply in a minimum of 5 gal/A (both ground and aerial equipment). The minimum RTI is 7 days. Bulb Onion Subgroup 3 - 07A Broadcast foliar applications prior to or during disease development; Ground equipment 4.17 lb/gal FlC [71512
- 1] 0.52 6 3.12 7 Apply in a minimum of 5 gal/A. The minimum RTI is 7 days. Carrot Directed band to the crop prior to or during disease development; Ground equipment 4.17 lb/gal FlC [71512
- 1] 0.52 4 2.08 (im plied) 7 Apply in a minimum

of 30 gal/A. The minimum RTI is 7 days. Lettuce (Head and Leaf) Broadcast or banded foliar application or soil dren ch application at thinning; Ground equipment 4.17 lb/gal FlC [71512
- 1] 0.52
-

0.99 1 1.0 50
- head lettuce; 30
- leaf lettuce Apply in a minimum

of 50 gal/A.

1 A 48
- hour restricted entry interval is specified. T he current (and proposed) product label for the 4.17 lb/gal FlC formulation specifies that a pplications are allowed through the following types of irrigations s ys tems: center pivot, motorized lateral move, traveling gun, solid set or portable (wheel move, side roll, end tow, or hand move). The label contains the following rotational crop restriction s : a ll crops on the label may be replanted immediately after treatment . A ll other crops can be replanted 30 day s after the last application.Page 14 of 67

2.2 Structure and Nomenclature TABLE 2.2 . Test Compound Nomenclature Com pound Chemical Structure

N N H C F 3 Cl

Cl C F 3 N O 2 O 2N

Em pirical Formula C 13 H 4 Cl 2 F 6N 4 O 4 Molecular Weight 465.1 Common Name Fluazinam Com pany Experimental Names Fluazinam, IKF
- 1216 IUPAC Name 3
- chloro
-N
- (3
- chloro
- 5
- trifluoromethyl
- 2
- py ridyl)
- α,α,α - trifluoro
- 2,6
- dinitro
p - toluidine CAS Name 3
- chloro
-N
- [3
- chloro
- 2,6
- dinitro
- 4
- (trifluoromethyl)phenyl]
- 5
- (trifluoromethyl)
- 2
- py

ridinamine CAS Number 79622
- 59
- 6 End
- use Product/(EP) Omega® 500F (USA); Allegro ® 500F (Canada)
2.3 Physical and Chemical Properties TABLE 2.3 Physicochemical Properties of Fluazinam

Param eter Value Reference Melting Point/Range 115
- 117°C The e
- Pesticide Manual (13 th Edition) Version 3.1 pH 5.85 MRID # 43521001 Density (25°C) 1.02 g/cm3 LSS 2000_1973_2LS_rev Water Solubility (25°C) (pH buffered to 5) 0.131 mg/L (pH buffered to 7) 0.157 mg/L (pH buffered to 9) 3.384 mg/L LSS 2000_1973_2LS_revPage 15 of 67

TABLE 2.3 Physicochemical Properties of Fluazinam

Param eter Value Reference Solvent Solubility (25°C) Solvent Solubility (g/L ) LSS 2000 _1973_2LS_rev acetone dichloromethane ethyl acetate ethyl ether hexane methanol octanol toluene 853 675 722 231 8 192 41 451 Vapor Pressure Tem p (°C) Vap. Press. (Pa) LSS 2000_1973_2LS_rev 25 35 45 2.3 x 10 - 5

1.3 x 10 - 4 6.7 x 10 - 5 Dissociation Con stant (pKa) Average pKa = 7.22 in 50% ethanol/water (v/v) LSS 2000_1973_2LS_rev Octanol/Water Partition Coefficient (Log KOW ) 1.08 x 10 4 (Log Kow = 4.03) LSS 2000_1973_2LS_rev UV/Visible Absorption Spectrum pH λmax (nm) Regulatory Note REG2003
- 12 5 7 >10 238

239, 342 260, 343, 482

3.0 Hazard Characterization/Assessment 3.1 Hazard and Dose - Response Characterization 3.1.1 Datab ase Summary T he toxicity

profile for fluazinam can be characterized for potential carcinogenic, mutagenic, developmental, and reproductive effects. However, an immunotoxicity study is required as a result of new data requ irements in the 40 CFR Part 158 for conventional pesticide registration. Additionally , a subchronic (28
- day) inhalation toxicity study is required. A 7
- day

inhalation toxicity study was used for short
- and intermediate
- term inhalation risk assessments; however, this study did not include histopathology evaluation. As a result, a 10x safety factor has been retained to account for the lack of histopathology evaluation , as well as the use of the 7
- day study for intermediate
- term (6 months) inhalation exp osure risk assessment. Th e submitt al of the required subchronic inhalation study could potentially result in the removal of the database uncertainty factor.Page 16 of 67

3.1.1.1 Studies Available and Considered (Animal, Human, General Literature) The following s tudies were submitted: 1. Subchronic toxicity studies in rats and dogs, 2. Chronic/carcinogenicity study in rats, 3. Carcinogenicity study in mice, 4. Chronic toxicity study in dogs, 5. Developmental toxicity studies in rats and rabbits, 6
. Reproduc tion study

in rats 7. Acute, subchronic, and developmental neurotoxicity studies in rats 8. Dermal toxicity study in rats 9. Mutagenicity

battery (including Bacterial reverse assay , Mammalian cell mutation, In vitro chromosome aberration, Micronucleus ass ay , and unscheduled DNA sy nthesis in cultured mammalian cells) 10. Metabolism study in rats. 3.1.1.2 Mode of action Fluazinam is a preventive contact fungicide with a multi
- site mode of action. It disrupts the production of energy

at several metabo lic sites within the fungal cell. Fluazinam is a protectant fungicide . That is, when applied to plants, it remains primarily on the plant surface. It is not taken up to an y extent by the plant, and is not translocated within the plant as ar e s ys temic fungicides. 3.1.2 Toxicological Effects T he liver appeared to be a primary target organ i n subchronic and chronic oral and dermal toxicity studies in rats, dogs , and mice. Signs of liver toxicity included changes in clinical chemistry (e.g. increased se rum alkaline phosphatase, increased aspartate aminotransferase), increased absolute and/or relative liver weights, increased incidences of gross lesions (e.g. pale, enlarged, pitted, mottled, accentuated markings), and a variety of histopathological lesion s. Microscopic liver le sions included eosinophilic/ basophilic hepatocy

tes, rarefied or vacuolated hepatocy tes, altered hepatocy

tic foci, hepatocy

tic single cell necrosis, hy pertrophy , fatty changes, increased brown pigmented macrophages, sinusoidal chroni c inflammation, pericholangitis, and bile duct hy perplasia. Treatment
- related effects were also observed in other organs in subchronic and chronic oral, dermal , and inhalation studies in rats, dogs , and mice, but these effects were not regularl y noted in all three species or in all studies in a given species. In rats, effects observed w ere decreased body weight gain and food consumption, mild anemi a, increased serum cholesterol, phospholipid, and aspartate aminotransferase, testicular atroph y, increas ed testicular and lung weights, pancreatic exocrine atrophy , increased alveolar adenomatosis, epithelialization and macrophages, thy

roid gland follicular cell hy perplasia, and an increased incidence of th yroid gland follicular cell tumors in male rats, but not in female rats. In dogs, effects included increased salivation, nasal dry ness, grey mottling of the retina, mild anemia, increased serum alkaline phosphatase and gastric ly mphoid hy

perplasia. In mice, increased mortality (at highPage 17 of 67

doses), decreased b ody

weight gain, increased glucose, increased kidney weights, cy stic thy

roid follicules, and an increased incidence of both benign and malignant hepatocellular liver tumors (males) were seen. In a developmental toxicity study in rats there was evidence o f increased qualitative susceptibility

of fetuses to fluazinam; however, there was no evidence of increased quantitative susceptibility
. Fetal exposure of 250 mg/kg/day resulte d in decreases in body weights and placental weights, increased incidences of f acial/palate clefts, diaphragmatic hernia , and delayed ossification in several bone ty pes. There was also greenish amniotic fluid and increases in late resorptions, as well as postimplantation loss. Maternal effects observed at the same dose level were d ecreases in body weight gain and food consumption, increases in water consumption and urogenital staining. There was no evidence of increased quantitative or qualitative susceptibility in a developmental toxicity study in rabbits or in a 2
- generation reproduction study in rats. In an acute oral neurotoxicity study in rats, decreases in motor activity and soft stools were observed on the day

of dosing at 1000 mg/kg/day . These effects were considered to be due to sy stemic toxicity

and not a result of frank neurotoxicity . In two subchronic neurotoxicity studies in rats that were evaluated together there were no signs of neurotoxicity observed up to a dose of 280 mg/kg/day . A neurotoxic lesion described as vacuolation of the white matter of the central ner vous s ys tem (CNS) was observed initially in long
- te rm (1
- 2 year) chronic studies in mice and dogs
. This vacuolation was also observed later upon careful re
- examination of the CNS , i n shorter
- term (4
- week to 90
- day) subchronic studies in mice and dogs. Th is lesion was observed during the histopathology examination of several tissues of the CNS and occurred most frequentl y in the brain (sections of cerebrum and/or sections of cerebellum, pons, medulla, and midbrain) and less frequently in the cervical spinal cord. This lesion is reversible and is attributed to an impurity , Impurit y 5 ( see section 3.3.2.). F luazinam is classified as having “Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential.” This class ification is based on increases in thy roid gland follicular cell tumors in male rats and increases in hepatocellular tumors in male mice
. The Agency has determined that quantification of human cancer risk using a linear low
- dose (Q1*) extrapolation approa ch is not required and the cRfD (0.011 mg/kg/day) is protective of potential cancer effects. 3.1.3 Dose - response Although treatment
- related effects were noted in other organs, liver toxicity was the primary effect noted in the toxicology database for f

luazinam. L iver effects were observed in the majority of toxicity

studies in rats. In subchronic studies, effects included increased liver weights, increased aspartate aminotransferase, and liver pathology (fatt y change) at doses ≥ 9.7 mg/kg/day . Effect s were mainly observed at the highest doses tested (HDT) . F or those studies with liver toxicity

noted in mid
- doses, higher doses did not result in a significant increase in liver toxicity . However, chronic exposure did result in more severe liver toxicity (pigmented macrophages and vacuolation) at lower doses (3.8 mg/kg/day). Similar effects (including adenomas) were observed in mice after chronic exposure at ≥ 126 mg/kg/day , with severit y of toxic effects increasing with dose. Additionally , liver effec ts were also noted in toxicity studiesPage 18 of 67

in dogs and rabbits. In dogs, increased liver weights and alkaline phosphatase, along with hy perplasia were observed at the HDT of 100 mg/kg/day after subchronic exposure. After chronic exposure, liver effects were limited to increased alkaline phosphatase at the HDT of 50 mg/kg/day . Significant liver toxicity (hy pertroph y, necrosis, brown pigment, apoptosis, etc.) was also noted in adult anim als in a developmental rabbit study at ≥ 7 mg/kg/day
. As the liver was the target organ for fluazinam in several studies, liver toxicity observed in a carcinogenicity

study in mice was selected for chronic dietary exposure risk assessment. The chronic reference dose of 0.011 mg/kg/day was calculated based on liver effects observed at the LOAEL of 10 mg/kg/day (NOAEL=1.1 mg/kg/day). For acute dietary exposure of females 13
- 49 , toxic effects relevant to females and attributable to a single dose were sele cted. Increased incidences of total litter resorptions and fetal skeletal abnormalities were observed in a developmental toxicity

study in rabbits at the LOAELof 12 mg/kg/day (NOAEL= 7 mg/kg/day). As a result, the developmental study was used to calculate the acute reference dose (aRfD) of 0.07 mg/kg/day . Developmental effects were also observed in the young in developmental rat studies; however, they

occurred at much higher doses ( ≥ 250 mg/kg/day) than developmental effects seen in rabbits. In a repro duction study , offspring effects were limited to decreased body weight gain. For the general population, the aRfD of 0.5 mg/kg/day was based on a LOAEL of 1000 mg/kg/day

(NOAEL=50mg/kg/day) from an acute neurotoxicity study in rats; adverse effects seen were decreases in motor activity and soft stools on the day of dosing. These effects were not observed in subchronic neurotoxicity studies. For short
- and intermediate
- term dermal and inhalation risk assessments, route specific studies were used based on liver effects. For dermal, a 21
- day dermal toxicity study in rats was used based on effects observed at the LOAEL of 100 mg/kg/day

(NOAEL=10 mg/kg/day)
. For inhalation, a 7
- day inhalation study

in rats was used with a LOAEL of 3.87 mg/kg/day (NOAEL of 1 .38 mg/kg/day). 3.2 Absorption, Distribution, Metabolism, Excretion (ADME) Overall recovery

of the administered radioactivity (reported in MRID Nos. 43521006, 43521007, and 435 21008) was acceptable (93
- 10 4 %). Excretion via the urine was minor. AMPA mercapturate and DAPA, the major urinary metabolites, represented only 0.05
- 0.39% of the administered dose. Radioactivity in the feces represented most of the administered dose (8 9
- 100%) as determined b y review of MRID s 43521006, 43521007, and 43521008. I dentified fecal metabolites, however, represented from 11.20
- 68.59% of the administered dose. For all dose groups, most of the fecal radioactivity appeared to reside with unextract able components in the post - extraction solids (PES). Further anal ys is of the PES components using base hydrol ys is indicated that most of this radioactivity could be attributed to hydrol ys is products of AMPA and DAPA. PES radioactivity was also greatest f or the low
- dose group which was consistent with the lower overall accounting of identified metabolites for this group. Approximately 20
- 25% of the aqueous phase of the fecal extraction was identified as a cy steine conjugate of DAPA and represented <1% of the administered dose. With the exception of the low
- dose group, parent compound represented most of the identified radioactivity in the feces. AMPA and DAPA were identified in the feces from all dose groups but these metabolites never represented more t han 5% of the administered dose (except for high
- dose female rats where AMPA accounted for 10.22%).Page 19 of 67

DAPA glucuronide and AMPA mercapturate were the major biliary metabolites , but they represented < 4% of the administered dose. Total biliary radioactivi ty , however , represented 25
- 34% of the administered dose (MRIDs 43521006, 43521007, and 43521008). Anal ys is of chromato grams indicated that numerous other metabolites were present in the bile , but individually were of insufficient quantit y to allow for c haracterization. Metabolite profiles from administration of different label positions (py ridyl and phen yl ) indicated that there was no metabolic cleavage of the ring structures. Minor quantitative differences in metabolite recovery were observed betwee n genders , but not of sufficient magnitude to suggest biologicall y relevant differences in the metabolism of IKF
- 1216
. 3.3 FQ PA Considerations 3.3.1 Evidence of Neurotoxicity N o evidence of neurotoxicity was observ ed in an acute neurotoxicity study (MRID 44807210) in rats up to 1000 mg/kg/day. S ys temic effects observed were decreases in motor activity and soft stools on the day

of dosing. In two subchronic neurotoxicity studies (MRIDs 44807217 and 44807218), evalu ated together, no signs of neurotoxicity or s ys temic effects were observed at doses up to 280 mg/kg/day . A neurotoxic lesion described as vacuolation of the white matter of the CNS was observed initially in long
- term (1
- 2 year) chronic studies in mice and dogs . This vacuolation was also observed later upon careful re
- examination of the CNS, in shorter
- term (4
- week to 90
- day) subchronic studies in mice and dogs. This lesion was observed during histopathological examination of several tissues of the CNS an d occurred most frequentl y in the brain (sections of cerebrum and/or sections of cerebellum, pons, medulla, and midbrain) and less frequentl y in the cervical spinal cord. Although this lesion was also observed in control animals, the increased incidence and/or severity of the lesion in treated animals was clearl y treatment related and dose
- related. Further investigation of this lesion in a series of special studies demonstrated the same lesion could also be induced in rats. In the special studies, the fo llowing observations were made: 1. Fluazinam, per se , was not responsible for the induction of this lesion. An anal ys is of the effects of impurities present in technical grade fluazinam revealed that one single impurity , Impurity 5, was solely

responsible for the appearance of white matter vacuolation. 2. No significant differences in susceptibility or in incidence or severity of vacuolation of the white matter of the CNS were observed among species (mice, dogs, or rats). Similarly , no significant differences were attributed to sex. 3. White matter vacuolation in the CNS was reversible. Electron microscopy of the white matter (cerebellum) of mice treated with technical grade fluazinam indicated that treatment
related effects were confined to the myelin sheaths. L arge vacuoles were observed in the intramyelin sheaths because of the accumulation of fluid between the sheaths. The nucleus and mitochondria in oligodendroglia were observed to remain intact, which suggest ed that there was no damage to these cells. The m yelin sheaths appeared to recover completel y during a recovery

period of up to 56 days.Page 20 of 67

4. There appears to be a non
- linear dose
- response with a clear threshold below which no effect occurs. It was concluded that a LOAEL of 0.1 mg/kg/ day and a NOAELof 0.02 mg/kg/day for CNS effects could be established for Impurity 5
. A developmental neurotoxicity study (MRID 46534401) was submitted that address es the concerns regarding the white matter vacuolation observed in the subchronic and chronic studies in mice and dogs, as well as the increased qualitative susceptibility seen in the developmental rat study . In the study, there was no evidence of vacuolation of the brain or any other treatment
related pathology

seen in dams or pups up to 50 mg/kg/day . Treatment
- related effects observed in pups were decreases in body weight and body

weight gain (lactation), and delayed preputial separation seen in the absence of maternal toxicity
. As previously

stated, the brain lesions (vacuolation of the brain and nerve tissue) observed are attributed to Impurit y 5. The level of Impurity 5 in the DNT study

was 0.09%. At the current maximum concentration of Impurity 5 in technical grade fluazinam of 0.1% (M emo , D272455 , I. Gairola, 5/18/2001), the NOAE L for CNS effects of 0.02 mg/kg/day for Impurity 5 is equivalent to a NOAEL for CNS effects of 20 mg/kg/day for technical grade fluazinam. The aRfDs (0.07 and 0.5 mg/kg/day) and cRfD (0.011 mg/kg/day), as well as risk assessments for dermal (10 mg/kg/day) and inhalation (1.38 mg/kg/day + additional 10x safety factor) exposures are set at doses much lower than 20 mg/kg/day . Therefore, they are protective of any possible neurotoxic effects resulting from exposure to Impurity 5. Based on the results of the developmental neurotoxicity study and the overall weight of the evidence, additional neurotoxicity studies are not needed. 3.3.2 Developmental Toxicity Studies In a developmental toxicity study in rats, dec reased body

w eight gain and food consumption, a s well as increased water consumption and urogenital staining were observed in maternal animals at the LOAEL of 250 mg/kg/day (NOAEL= 50 mg/kg/day). Additionally , at 250 mg/kg/day , developmental effects obser ved were decreases in fetal body and placental weights, increases in facial and palate clefts, diaphragmatic he rnia, and delayed ossification. There were also slight increases in late resorptions and postimpl antation loss . In the developmental toxicity s tudy in rabbits, maternal effects included decreases in food consumption and liver histopathology at the LOAEL of 7 mg/kg/day

(NOAEL=4 mg/kg/day). In fetuses, skeletal anomalies and an increased incidence of total litter resorptions were noted at 12 mg/kg/day (NOAEL=7 mg/kg/day). 3.3.3 Reproductive Toxicity Study In a 2
- generation reproduction study in rats, liver pathology

(periacinar hepatocy

tic fatty changes) was observed in parental F 1 males at the L OAEL of 9.7 mg/kg/day (NOAEL=1.9 mg/kg/day). Rep roductive toxicity was seen in F 1 females (F 2 litters) at the LOAEL of 53.6 mg/kg/day

(NOAEL=10.6 mg/kg/day) as a decreased number of implantation sites and decreased litter sizes up to day

4 post partum. At the L OAEL of 42.12 mg/kg/day (NOAEL=8.4Page 21 of 67

mg/kg/d ay), developmental effects observed were limited to decreased body weight gain during lactation for both F 1 and F 2 pups. 3.3.4 Additional Information from Literature Sources A PubMed literature search identified the existence of an open literat ure article that suggests that fluazinam might have immunotoxic potential. The reference for this article is: A. Draper, et al., 2003, Occupational Asthma from Fungicides Fluazinam and Chlorothalonil, Occupational and Environmental Medicine 60:76
- 77. Fluazinam is a skin sensitizer; thus, it is a potential inhalation allergen with the potential to cause asthma. Although the cited study demonstrates that fluazinam causes asthmatic sy mptoms, the asthma effect might be related to the sensitization potential for this chemical. Consequently , asthmatic sy

mptoms might only

be detected in a small population of people who might develop hy persensitivity

as a result of chronic exposure to small amounts of the chemical in an industrial setting. Therefore, the devel opment of asthma in the general population is not anticipated. Furthermore, the product label requires that mixer/loaders wear dust/mist or NIOSH approved respirators . HED recommends that this requirement be expanded to all handlers of fluazinam
. 3.3. 5 Pre - and/or Postnatal Toxicity 3.3.5.1 Determination of Susceptibility E vidence of i ncreased qualitative susceptibility of fetuses to fluazinam was observed in the developmental toxicity

study in rats. In this study , increased incidences of facial/palate clefts and other rare deformities in the fetuses were observed in the presence of minimal maternal toxicity . A developmental neurotoxicity study in rats was submitted to address the increased susceptibility , as well as the presence of neurotoxic lesions observed after fluazinam exposure. In the developmental neurotoxicity study , decreases in body weight and body

weight gain and a delay in comp letion of balano
- preputial separation were observed in pups. These effects were seen in the absence of maternal effects, suggesting increased quantitative susceptibility of the offspring. 3.3.5 .2 Degree of Concern Analysis and Residual Uncertainties for Pre - and/or Postnatal Susceptibility The purposes of the Degree of Concern anal ys is are: (1) to determine the level of concern for the effects observed when considered in the context of all available toxicity data; and (2) to identify any residual uncertainties after establishing toxicity endpoints and traditional uncertainty factors to be used in the risk assessment. I f residual uncertainties are identified, then HED determines whether these residual uncertainties can be addressed by a FQPA safet y factor and, if so, the size of the factor needed. Although there is qualitative evidence of increased susceptibility in young in the developmental toxicity study in rats, th ere are no residual uncertainties with regard to pre
- and/or postnatalPage 22 of 67

toxicity following in utero exposure to rats or rabbits and pre and/or post
- natal exposures to rats. Considering the overall toxicity profile and the doses and endpoints selected for ri sk assessment for fluazinam, the degree of concern for the effects observed in the study is low. There is a clear NOAEL for the fetal effects seen, the effects occurred in the presence of maternal toxicity , and they were onl y s een at the highest dose test ed. Additionally , the NOAEL of 50 mg/kg/day identified in this developmental toxicity study in rats is significantl y higher than the NOAEL used ( 7 mg/kg/day) to establish the acute Reference Dose (aRfD) of 0.07 mg/kg/day (females 13
- 49); thus, the aRfD is protective of an y potential developmental effects. In creased quantitative evidence of susceptibility was observed in a developmental neurotoxicity study in rats (MRID 46534401). In pups, there were decreases in body weight and body

weight gain during lactation, and delayed preputial separation observed at 10 mg/kg/day (NOAEL=2 mg/kg/day). Although the NOAEL of 2 mg/kg/day is lower than that used for the aRfD for females 13
- 49 (7 mg/kg/day), the effects noted in the developmental neurotoxicity study ar e attributable to multiple doses and are considered to be post - natal effects. Therefore, the study endpoint is not appropriate for acute dietary exposures. The cRfD of 0.011 mg/kg/day is based on a lower NOAEL of 1.1 mg/kg/day , and is considered to be protective of potential developmental effects. 3.4 FQ PA Safety Factor for Infants and Children After evaluating the toxicological and exposure data, the fluazinam risk assessment team recommends that the FQPA SF be reduced to 1x for dietary and dermal e xposure risk assessments based on the following:

 The toxicological database for fluazinam is complete in regard to pre
- and postnatal toxicity and neurotoxicity
.
 The degree of concern is low regarding the q ualitative susceptibility observed in the dev el opmental toxicity

study and neurotoxic lesions in studies in rats, mice , and dogs. Additionally , there are no r esidual uncertainties with regard to pre
- and/or postnatal toxicity or neurotoxicity , and no additional factors are needed.

 An immunotoxicity study is now required as a r esul t of new data requirements in the 40 CFR Part 158 for conventional pesticide registration . However, based on the available data fluazinam shows no evidence of treatment
- related effects on the immune sy stem. T he Agency

doe s not believe that conducting a study will result in a lower p oint of d eparture (P o D) than that currentl y selected for overall risk assessment and , therefore, a database uncertainty

factor (UF DB ) is not needed to account for the lack of th e study
.
 The ac ute and chronic dietary exposure assessment s are based on the assumption that 100% of all commodities wi th fluazinam tolerances will be treated with fluazinam. In addition, the acute assessment is based on tolerance level residues for all commodities and the chronic assessment is based on tolerance level residues for all commodities except apples, for which the average field trial value was used. These assumptions result in very high
- end estimates of dietary exposure.Page 23 of 67

 Estimated drinking water concentratio ns in both the acute and chronic dietary exposure assessments are based on values generated by model s and modeling parameters that are designed to provide conservative, health protective, high
- end estimates of water concentrations.

 No residential uses are registered or proposed at this time. A 7
- day inhalation study

is currentl y being used for short
- and intermediate
- term inhalation risk assessments. A 10x database safety factor has been retained for these scenarios to account for the lack of histopath ology evaluation in the inhalation study , as well as its use in evaluating intermediate
- term (6 months) inhalation exposure
. 3.5 Hazard Identification and Toxicity Endpoint Selection 3.5.1 Acute Reference Dose (aRfD) - Females age 13 - 49 Study Selected: Developmental toxicity study in rabbits MRID No: 46578987 Dose and Endpoint for Risk Assessment : NOAEL= 7 mg/kg/day Unc ertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability) Comments about Study/Endpoint/Uncertainty Factors: A developmental toxicity study in rabbits was used to select the dose and endpoint for establishing the aRfD of 0.07 mg/kg/day
. The NOAEL of 7 mg/kg/day and the LOAEL of 12 mg/kg/day were based on increased incidence of total litter resorptions and a possibly increased incidence of fetal skeletal abnormalities (including kinked tail tip, fused or incompletely ossified s ternebrae, and abnormalities of head bones). The skeletal abnormalities observed are considered to be effects that could occur after a single dose of fluazinam; thus, the route and duration of exposure are appropriate for this population. Uncertainty fac tors (100x) include: 10x interspecies extrapolation and 10x intraspecies variability.

Acute RfD (fem ales 13 - 49) = ) ( 100 / / 7 UF day kg mg = 0.07 m g/kg/day

3.5.2 Acute Reference Dose (aRfD) - General Population Study Selected: Acute neurotoxicity study in rats MRID No: 44807210 Dose and Endpoint for Risk Assessment : NOAEL= 50 mg/kg/day Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability) Study/Endpoint/Uncertainty Factors: An acute oral neurotoxicity study in rats was used to select the dose and endpoint for establishing the aRfD of 0.5 mg/kg/day . The NOAEL of 50Page 24 of 67

mg/kg/day

and the LOAELof 1000 mg/kg/day were based on soft stools and decreased motor activity
. Because of the large dose spread in this study between the NOAEL (50 mg/kg/day) and the L OAEL (1000 mg/kg/day), the true NOAEL is probably much higher than 50 mg/kg/day
. This study , however, provides the best data available for determining an acute RfD for the general population (including infants a nd children) in that the route and duration of exposure are appropriate for this population. Uncertainty factors (100x) include: 10x interspecies extrapolation and 10x intraspecies variability.

Acute RfD ( general population ) = ) ( 100 / / 50 UF day kg mg = 0 .5 m g/kg/day

3.5.3 Chronic Reference Dose (cRfD) Studies Selected: A 2
- y ear carcinogenicity study in mice and a 1
- year chronic oral study in dogs (co
- critical studies) were selected to establish the cRfD. The 2
- Year carcinogenicity study in mice, rather than the 1
- ye ar chronic oral study in dogs, was used to establish the RfD because the treatment
- related effects at the LOAEL in the mouse study were related to liver toxicity (the regularl y observed target organ for fluazinam in many studies) , wher eas the effects at the LOAEL in the dog study

(increased incidence of nasal dry ness in females and increased incidence/severity

of gastric ly

mphoid hy

perplasia in males and females) were unrelated to liver toxicity . The NOAELs in the mouse and dog studies were similar. The L OAEL s in the mouse and dog studies were also similar. The NOAELs in the mouse study were 1.12 mg/kg/day

in males and 1.16 mg/kg/day in females
. In the dog study , the NOAEL was the same for males and females: 1 mg/kg/day . The LOAELs in the mouse study were 10.72 mg/kg/day

in males and 11.72 mg/kg/day

in females . In the dog study , the L OAEL was the same for males and females: 1 0 mg/kg/day
. 1 st Study: 2
- Year carcinogenicity study in mice MRID No: 42208405, 44807220, 44807212 Dose and Endpoint for Risk Assessment : NOAEL= 1.12 mg/kg/day Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability) Study/Endpoint/Uncertainty Factors: A 2
- year carcinogenicity study in mice was one of two co - critic al studies used in selecting the dose and endpoint for establishing the cRfD of 0.11 mg/kg/day . The NOAEL of 1.12 mg/kg/day and the LOAEL of 10.72 mg/kg/day were based on increased incidences of brown pigmented macrophages in the liver of both sexes, increased incidences of eosinophilic vacuolated hepatocy tes in males, and increased liver weights in females . The route and duration of exposure are appropriate for this population. Uncertainty factors (100x) include: 10x interspecies extrapolation and 10x i ntraspecies variability. 2 nd Study: 1
- Year chronic oral toxicity study in dogs MRID No s : 42270603, 44807219 Dose and Endpoint for Risk Assessment : NOAEL= 1 mg/kg/day Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variab ility)Page 25 of 67

Study/Endpoint/Uncertainty Factors: A 1
- Year chronic oral toxicity study in dogs was one of two co - critical studies used in selecting the dose and endpoint for establishing the cRfD of 0.11 mg/kg/day
. The NOAEL of 1 mg/kg/day and the LOAEL of 10 mg/kg/day were based on marginal increases in the incidence of nasal dry ness in females and the incidence/severity of gastric ly mphoid hy

perplasia in both sexes. The route and duration of exposure are appropriate for this population. Uncertainty factors (100x) include: 10x interspecies extrapolation and 10x intraspecies variability
. Chronic RfD = ) ( 100 / / 1
. 1 UF day kg mg = 0.011 m g/kg/day
Comments: A 2
- ye ar chronic feeding/carcinogenicity study in rats (MRID s 42248620 and 44807223) was also considered for establishing the cRfD based on a lower NOAEL of 0.38 mg/kg/day . The next highest dose level tested in this study was 3.8 mg/kg/day

in males and 4.9 mg/kg/day

in females (a 10 fold higher dose). A second 2
- ye ar chronic feeding study in rats (MRID s 448 39901 and 44807213) was subsequently performed with 2 intermediate dose levels. The doses used in the study were 0, 1.0, 1.9, and 3.9 mg/kg/day for males; 0, 1.2, 2.4, and 4.9 mg/kg/day

for females. The NOAEL observed in the second study was 1.9 mg/kg/day for males and 4.9 mg/kg/day

for females, which is higher than the NOAEL (1.1 mg/kg/day) selected for establishing the chronic RfD. Therefore, this study was not chosen for risk assessment. 3.5.4 Dermal Absorption A dermal absorption study is not available for fluazinam. A dermal absorption factor of 25% was estimated b y comparing the LOAEL from a 21
- day dermal toxicity

study in rats (42270602) to the L OAEL from a 4
- week range
- finding feeding study in rats (448072 13) based on a common endpoint (liver toxicity ). In the dermal toxicity

study , liver effects observed were increased aspartate aminotransferase (AST) and increased cholesterol levels in males at the LOAEL of 100 mg/kg/day (NOAEL=10 mg/kg/day). In the ran ge - finding study , effects included increased serum phospholipids in females, increased total cholesterol in males and females, increased relative liver weights in females, liver hy pertrophy in males, as well as decreased body weight gain and decreased food consumption in females at the L OAEL of 26.4 mg/kg/day

in males (25.9 mg/kg/day in females) and the NOAEL of 5.1 mg/kg/day in males (5.3 mg/kg/day

in females). Estimated Dermal = Oral L OAEL x 100 = 25 mg/kg/day x 100 = 25% Absorption Factor D ermal LOAEL 100 mg/kg/day 3.5.5 Dermal Exposure (Short - and Intermediate - Term) Study Selected: 21
- Day dermal toxicity study in rats MRID No: 42270602 Dose and Endpoint for Risk Assessment : NOAEL= 10 mg/kg/day Uncertainty Factor: 100x ( 10x interspecies extrapolation, 10x intraspecies variability)Page 26 of 67

Study/Endpoint/Uncertainty Factors: A 21
- day dermal toxicity study in rats was used to select the dose and endpoint for short
- and intermediate
- term dermal exposure. The NOAEL of 10 mg/kg/day and the LOAEL of 100 mg/kg/day were based on increased AST and increased cholesterol levels in males. The route and duration of exposure are appropriate for this population. Uncertainty factors (100x) include: 10x interspecies extrapolation and 10x intra species variability
. Comments: Developmental effects were noted in developmental toxicity studies at ≥ 12 mg/kg/day ; however, a s the endpoint chosen for dermal risk assessments is based on a lower NOAEL (10 mg/kg/day) it is considered to be protective of potential developmental effects. 3.5.6 Inhalation Exposure (Short - and Intermediate - Term) Study Selected: 7
- Day

range - finding inhalation study in rats (test material: Frowncide WP, containing 51.9% fluazinam) MRID No: 42248621 Dose and Endpoint f

or Risk Assessment : NOAEL= 1.38 mg/kg/day Uncertainty Factor: 100 0 x (10x interspecies extrapolation, 10x intraspecies variability , 10x database uncertainty

factor) Study/Endpoint/Uncertainty Factors: A 7
- day range - finding inhalation study in rats was us ed to select the dose and endpoint for short
- and intermediate
- term exposure. The NOAEL of 0.011 mg/L (2.76 mg/kg/day in males and 2.97 mg/kg/day in females) and the L OAEL of 0.032 mg/L (7.93 mg/kg/day

in males and 8.50 mg/kg/day in females) were based on sli ghtly increased testicular weights (males) and slightl y i ncreased liver weights (females). The test material used in the inhalation study was not technical grade fluazinam, but a formulation containing approximately 5 2 % fluazinam ( Frowncide WP) . Cons equently, the NOAEL from the study (0.011 mg/L or 2.76 mg/kg/day in males and 2.97 mg/kg/day in females) was reduced by half to account for this decreased concentration (i.e. adjusted NOAEL = 1.38 mg/kg/day for males and 1.48 mg/kg/day for females) . As a result, for inhalation risk assessment a NOAEL of 1.38 mg/kg/day

was used. A histopathology examination was not performed in the study , and it is possible that the true NOAEL could be lower than that demonstrated in the study
. A safet y factor of 10x was retained to account for the lack of histopathology evaluation in the inhalation studies. This factor also addresses the use of a short
- term (7 day) study to evaluate intermediate
- term inhalation exposure. Uncertainty factors (1000x) include: 10x interspe cies extrapolation, 10x intraspecies variability , and 10x database uncertainty factor . The 7
- day range - finding inhalation study is the most appropriate route to use for evaluating inhalation risk. The target organ in the study is the liver, as seen in se veral other studies in the toxicology database. The submitt al of the required subchronic inhalation study m ight result in the removal of the 10x database uncertainty factor. Comments: Developmental effects were noted in developmental toxicity studies at ≥ 12 mg/kg/day ; however, as the endpoint chosen for inhalation risk assessments is based on a lower NOAEL (1.38 mg/kg/day) it is considered to be protective of potential developmental effects.Page 27 of 67

3.5.7 Level of Concern for Margin of Exposure Table 3.5. 7 . Summary of Levels of Concern for Risk Assessment. Rout e Short - Term (1 - 30 Days ) Intermediate - Ter m (1 - 6 Months) Long - Term (> 6 Months) Occupational (Worker) Exposure Dermal 100 100 N/A Inha lation 1000 1000 N/A 3.5.8 Recommendation for Aggregate Exposure Risk Assessments As per the Food Quality Protection Act (FQPA, 1996), EPA must aggregate (add) exposure from food, drinking water, and residential exposures. When there are potential residential exposures, EPA must consider exposure from three major routes: oral, dermal, and inhalation. As there are no registered or proposed residential uses for fluazinam, a residential exposure assessment is not needed; furthermore, the aggregate assessment is limited to risk resulting from the dietary (food + water) route of exposure. When conducting occupational risk assessments, HED combines dermal and inhalation exposures if th e toxicity

studies demonstrate the toxicological effects are the same for both exposure routes. In previous fluazinam risk assessments, HED did not combine dermal and inhalation exposures. For the current assessment, HED considered combining exposure fro m these routes because the effects observed at the LOAEL were related to liver toxicity in the route - specific dermal and inhalation toxicity studies
. However, the toxic effects were not identical in these studies. Inthe dermal study , liver effects inclu ded increased cholesterol and aspartate aminotransferase (AST) levels , which were observed at the mid and high doses. However, at the mid
- dose, which was originally considered to be a LOEL (lowest observed effect level), the increases were relativel y mild and would likely be dismissed if re
- evaluated under current policy . T hese effects would be considered to be treatment - related but not adverse. The high dose tested in the dermal toxicity study is more reflective of a true LOAEL because more pronounced li ver effects were seen ( i.e., significantly increased liver weights, AST, and cholesterol, a s well as hy

pertroph y). In the inhalation study , the liver effects were limited to increased liver weights and were also mild; however, in the absence of histopatho logy evaluations these effects were considered to be adverse, and they served as the basis for the LOAEL. Additionally , a 10x safety factor was retained for the inhalation route of exposure to account for the lack of histopathology data in the inhalation toxicity study
. As the endpoints selected for both dermal and inhalation exposure assessments are considered to be very conservative, combining exposure from these routes is not considered to be appropriate for the current assessment. 3 .5.9 Classificat ion of Carcinogenic Potential In accordance with EPA’s Draft Guidelines for Carcinogen Risk Assessment (July , 1999), the Cancer Assessment Review Committee (CARC) classified fluazinam as having “ Suggestive evidence of carcinogenicity , but not sufficient to assess human carcinogenic potential , ” based on increases in thy

roid gland follicular cell tumors in male rats and increases in hepatocellularPage 28 of 67

tumors in male mice (HED Doc. No.: 014512, March 29, 2001)
. The Agency has determined that quantification of human cancer risk using a linear low
- dose (Q1*) extrapolation approach is not required , and the cRfD of 0.011 mg/kg/day is protective of potential cancer effects. The cancer classification was based on the following weight
- of
- evidence considerations: (i) There was some evidence that fluazinam induced an increase in thy roid gland follicular cell tumors in male rats, but not in female rats at ≥ 100 ppm (3.8 mg/kg/day). In one study in mice, there was clear evidence that an increased incid ence of hepatocellular tumors observed in male mice was treatment related at 1000 ppm (107 mg/kg/day). In another study in mice, there was some equivocal evidence that fluazinam m ight have induced an increase in hepatocellular tumors in the male mice at ≥ 3000 ppm (377 mg/kg/day). Increases in hepatocellular tumors observed in the female mice in the latter study were not statistically

significant and some occurred at an excessivel y t oxic dose level. The th yroid gland follicular cell tumors of concern were seen onl y in the male rats , and the hepatocellular tumors of concern were seen only in the male mice. (ii) Fluazinam was negative in mutagenicity assay s. 3.5.10 Summary of Toxicological Doses and Endpoints for Fluazinam for Use in Human Risk Assessments Table 3.5a Toxicological Doses and Endpoints for Fluazinamfor Use in Dietary and Non - Occupational Hum an Health Risk Assessments Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD, Level

of Concern for Risk Assessment Study and Toxicological Effects Ac ute Dietary (General population) NOAEL= 50

mg/kg/day UF A= 10x

UF H =10x FQPA SF=1x Total UF=100x Ac ute RfD =0.5

mg/kg/day aPAD = 0.5 mg/kg/day Ac ute Neurotoxicity
- Rats.

LOAEL = 1000 mg/kg/day based on decreased motor activity and soft stools on day of dosing. Ac ute Dietary (Females 13
- 49 years of age) NOAEL

(developmental) = 7 mg/kg/day UF A= 10x

UF H =10x FQPA SF=1x Total UF=100x Ac ute RfD =0.07

mg/kg/day aPAD = 0.07 mg/kg/day Developmental Toxicity
- Rabbits.

Developmental LOAEL = 12 mg/kg/day based on increased incidence of total litter resorptions and possibly increased incidence of fetal skeletal abnormalities. Chronic Dietary (All Populations) NOAEL= 1.1

mg/kg/day UF A= 10x

UF H =10x FQPA SF=1x Total UF=100x Chronic RfD

=0. 011 mg/kg/day cPAD = 0.011 mg/kg/day Carcinogenicity
- Mice.

LOAEL = 10.7 mg/kg/day based on liver histopathology and increased liver weight. Cancer (oral, dermal, inhalation) Classification: “Suggestive Evidence of Carcinogenicity, but not sufficient to assess human

carcinogenic potential
. ” The cRfD is protective of cancer effects.

. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor . UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = refer ence dose. N/A = not applicable.Page 29 of 67

Table 3.5b Summary of Toxicological Doses and Endpoints for Fluazinamfor Use in Occupational Hum an Health Risk Assessments Exposure/ Scenario Point of Departure Uncertainty Factors Level of

Concern for Risk Assessment Study and Toxicological Effects

Dermal Short
- Term (1
- 30 days); Intermediate
Term (1
- 6 mo nths) NOAEL (systemic)

10 mg/kg/day UF A=10x

UF H =10x Occupational

LOC for MOE = 100 21
- Day dermal, rats. Sy stemic LOAEL = 100 mg/kg/day based on increased cholest erol, increased aspartate aminotransferase. Inhalation Short
- Term (1
- 30 days) Inhalation study

NOAEL= 1.38 mg/kg/day UF A=10x

UF H =10x UF DB =10x IAF=100% Occupational

LOC for MOE = 1000 7
- Day inhalation, rats. LOAEL = 3.97 mg/kg/day based on increased l iver weight s (females) and increased testicular weights. Inhalation Intermediate
Term (1
- 6 mo nths) Inhalation study

NOAEL= 1.38 mg/kg/day UF A=10x

UF H =10x UF DB /UF S =10x IAF=100% Occupational

LOC for MOE = 1000 7
- Day inhalation, rats. LOAEL = 3.97 mg/kg/day based on increased liver weight s (females) and increased testicular weights. Cancer (oral, dermal, inhalation) Classification: “Suggestive evidence of carcinogenicity, but not sufficient to assess human

carcinogenic potential
. ” The cRfD is protec tive of cancer effects. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members o f the human population (intraspecies). 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 histopathological examination). MOE = margin of exposure. LOC = level of concern. IAF=inhalation absorption factor. 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 pes ticide active and other ingredients) m ight 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 t o 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 th yroid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 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 to 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/d ata 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 sPage 30 of 67

such as food and water, residential ac tivity , and certain post
- application agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors. Fluazinam 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 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 p olicies and procedures, the list of 67 chemicals, the test guidelines , and the Tier 1 screening battery , please visit EPA’s website: http://www.epa.gov/endo/
. 4.0 Public Heal th and Pesticide Epidemiology Data No public health/epidemio l ogy data were used in developing this risk assessment. 5.0 Dietary Exposure/Risk Characterization 5.1 Pesticide Metabolis m and Environmental Degradation 5.1.1 Metabolism in Primary Crops The nature of the residue in plants has been adequately delineated, based on acceptable potato, peanut, and grape metabolism studies that were reviewed previousl y (D257115; William Cutchin; 5/21/2001). The metabolism of fluazinam appears to be similar in potatoes, peanuts, and grapes. Fluazinam undergoes reduction of one of the nitro groups to an amine, forming AMPA. AMPA can then be conjugated with glutathione, with subsequent degradation of the glutathione moiety to cysteine. The AMPA
- cysteine conjugate then undergoes transamination, reduction, and conjugation with glucose to form AMGT. In addition, both rings of fluazinam appear to be labile to ring cleavage . Sub sequent degradation of the rings into small fragments occurs and these fragments can then be incorporated into a variety of natural plant components. HED concluded that the residue of concern ( ROC ) in peanuts as well as root and tuber vegetables (for both tolerance expression and dietary risk assessment purposes) i s the parent compound only

(D272624; William Cutchin; 4/23/2001). In wine grapes, both parent and AMGT are included in the ROC for tolerance expression and risk assessment. Additionally , HED determined that data generated for potential new uses on other crops (with the exception of root and tuber, and bulb vegetables) should include anal ys es for both pare nt and AMGT. The residues of regulatory

interest in primary

crops are listed in Table 5.1. b
. The registrant submitted an apple metabolism study (MRID 46991301); however, HED has not reviewed it. In the event that the registrant resolves the data deficie ncies associated with the apple petition and re
- submits it, the apple metabolism study should be reviewed.Page 31 of 67

5.1.2 Metabolism in Rotational Crops Regulatory

requirements pertaining to fluazinam residues in rotational crops have been fulfilled, and the rotational crop restrictions on the proposed label are adequate. An adequate confined rotational crop study was previously reviewed ( Memo, D212612, G . Herndon, 9/5/1995) in conjunction with a time
- limited tole rance petition for use on peanuts. The available data indicate that neither fluazinam nor any of its structurall y related metabolites are likely to be detectable in rotational root crops or leafy vegetables planted ≥30 day s (≥68 day s for small grains and all other crops) following a 2.0 lb ai/A soil application of fluazinam. 5 .1.3 Metabolism in Livestock The nature of the residue in livestock is also understood, based on adequate goat and hen metabolism studies ( Memo, D257115 , W
. Cutchin; 5/21/2001). The metabolism of [ 14 C]
- fluazinam in ruminants and poultry is similar, and involves reduction of one or both nitro groups on the phen ylring to form AMPA, MAPA, or DAPA. Fluazinam also undergoes dehalogenation and hydroxylation of the chlorine on the phen ylring to form HYPA. These compounds can then undergo conjugation with glutathione, and subsequent degradation of the glutathione component yi elds a variety of polar compounds. Although the ring structure of the parent molecule remains intact, fluazinam per se was only a minor component ( ≤2.7% TRR) of the [ 14 C]
- residues in poultry tissues and eggs, and was not detected in ruminant tissues or milk. HED h as determined that the fluazinam residues of regulatory interest in animals are parent plus the metabolites AMPA and DAPA as well as their sulfamate conjugates. 5.1.4 Analytical Methodology Tolerance Enforcement Method for Plant Commodities Th e tolerance
- enforcement method for fluazinam in crops is entitled: Fluazinam: Method for the Analysis in Peanut Nut Mea t (Method 6148
- 9 4
- 0170
- MD
- 001). The method is based on gas chromatograph y with electron capture detection ( GC/ECD ) and is adequate for enforcement of tolerance s in crop matrices. The method was deemed to be suitable for tolerance enforcement after it successfull y completed the routes required for an enforcement method including radiovalidation, independent laboratory validation (ILV), and tolerance method validation (TMV). Samples collected from the magnitude of the residue in plants and storage stability studies were anal yz ed for residues of fluazinam using various GC/ECD methods based on, and revised slightl y from, the plant enforceme nt method. The GC/ECD methods are adequate for data collection based on acceptable method recovery data. The lowest limit of method validation (LLMV) was 0.01 ppm in all tested commodities except in carrots where the LLMV was 0.02 ppm. An enforcement me thod for determination of AMGT, a residue in the tolerance expression for wine grapes, is also available. HED recommended in a previous memorandum (Memo, D335640, W. Drew, 8/22/07) that a previousl y submitted HPL C/UV method undergo an ILV trial, and potentially , a TMV trial by the ACB. This method is based on Method Evaluation forPage 32 of 67

the Analysis of AMGT in Grapes (MRID 45593101). HED has agreed to accept the recovery data generated b y IR
- 4 for AMGT residues in blueberries as the ILV. Tolerance Enforcement Method for Animal Commodities An enforcement method for determination of the fluazinam residues of concern in livestock commodities is not available. PTRL Method 1676W was the data
- collection method used for the anal ys is of samples collected from the da iry cattle feeding study. The method is written for LC/MS/MS analy sis of fluazinam, AMPA, and DAPA in bovine milk and tissues, and for GC/MS analy sis of DAPA in milk only . The limit of quantitation was 0.01 ppm for each anal yt e in milk, muscle, fat, live r , and kidney . Preliminary method validation data showed that Method 1676W adequatel y recovered residues of fluazinam, AMPA, and DAPA in milk, muscle, and fat. However, poor and/or marginal recoveries were obtained for AMPA and DAPA residues in kidney and liver. Method 1676W was marginally validated by an independent laboratory during the third trial and following slight modifications to make the method more rugged. For the purpose of developing an animal enforcement method, radiovalidation data are re quired to determine whether the method can detect aged residues. HED forwarded Method 1676W to ACB/BEAD for a tolerance method validation (TMV) because the method encountered difficulties in the ILV (e.g., three attempts for successful validation and/or m arginal recoveries with wide variability

and high coefficient of variation). ACB/BEAD reported that the lab that performed the ILV made major modifications to the original method. As a result, HED requested that the registrant submit a revised method that incorporated the revisions made by the ILV lab. ISK Biosciences revised the method and re
- submitted it. ACB/BEAD performed a cursory review of the revised method. The registrant incorporated the modifications made by the ILV lab. However, the revisio n eliminated the cleanup steps that were in the original method, and the only

recovery data for the revised method were data provided b y the ILV lab. ACB/BEAD was concerned that the elimination of the cleanup steps could lead to dirty samples which would, in turn, lead to analy tical problems, such as interference. ACB/BEAD performed no further validation of the method. As the revised method contains major revisions to the original method, and ACB/BEAD believes it is very likel y that the revised method st ill is not adequate for sample analy sis or tolerance enforcement, HED recommends that the registrant submit an ILV for the revised method. 5.1.5 Environmental Degradation Reference: Tier I Estimated Drinking Waters Concentrations (EDWCs) of Fluazinam and its Transformation Products for the Use in the Human Health Risk Assessment for the Registration o f the Following New F ood Uses : Lettuce, Apples, Carrots and Bulb Vegetables ( Crop Subgroup 3
- 07A) , D360713, J. Melendez, 2/24/2010 Based on the propertie s of fluazinam , applications are likel y to reach the target ( i.e., the crop), but drift is also possible. Fluazinam has a low vapor pressure and a moderate Henry ’s Law constant. As a result of the fact that it appears to show relativel y short half lives in aquatic media and it binds to soils, EFED believes that the chemical would not volatilize substantially
.Page 33 of 67

F luazinam appears to degrade at moderate to low rates in aerobic soils . However, in high pH solutions or in aquatic media, both aerobic and anaerobic , it is more rapidly transformed into other compounds of similar backbone structure. Fluazinam can be photolyzed relatively rapidl y (2.5 day s) to form a tricyclic compound (G
- 504). The total fluazinam residues , fluazinam and its transformation produ cts (DCPA, CAPA, DAPA , AMPA, and HYPA ) are persistent in most environments ( stable to hydroly sis at all pHs, aerobic aquatic metabolism 51
- 71 day s, relatively stable in anaerobic aquatic environment) and are likely to reach aquatic media as a totality thro ugh runoff. As fluazinam does not substantially alter its backbone structure in the environment, but instead, goes through a slight transformation of functional groups, EFED considered parent and transformation products together when making assessments. P arent fluazinam and two transformation products, HYPA and CAPA, have relativel y low mobility , indicating a relatively low potential for groundwater contamination
. At this time, EFED has two newl y submitted terrestrial field dissipation studies that are i n review. Fluazinam shows a potential to bioaccumulate in fish (BCF=1220 x for whole fish; ≥67% of residues depurated in 21 day s). The fate and transport characterization is summarize d in Table 5.1.a. Table 5.1. a. Summary of Fluazinam Environmental D eg radate s

STUDY TYPE DEGRADATE and MAXIMUM CONCENTRATION SOURCE CAPA, G - 504, HYPA AMPA, MAPA, DAPA, DCPA (% applied) Hydrolysis CAPA 34% at 28 days pH 7; 84
- 85% at 20 days at pH 9 – – MRID: 4 2208412
. Aqueous Photolysis G
- 504 was 14.0
- 17.1% by 7
- 10 days _ – MRID: 4 44807312, 43521009, 45584204
. Soil Photolysis HYPA, detected > dark control AMPA detected > dark control – MRID: 4 4807313, 45584204
. Aerobic Soil Metabolism HYPA, MAPA and DAPA detected (in the SL soils, applied at 1 kg/ha) MRID: 4 220 8413, 42208414
. Anaerobic Soil Metabolism HYPA was 11.0% at 60 days for the SL flooded at 30 days MAPA was 29.8% at 14

days for the SL flooded at zero time – MRID: 4 2208413, 42208414
. Aerobic Aquatic Metabolism CAPA 12.6 % at 72 hr DAPA: 19.0% by 240 hr DCPA: 11.3% at 24 hr MRID: 4 4807314
. Anaerobic Aquatic Metabolism AMPA 24.2% at 0.2 day DAPA: 32.7% at day 30 SDS
- 67200 39.6% by day 14 MRID: 4 3521010
. Terrestrial Field Dissipation MAPA, CAPA, and HYPA were monitored; however, there were problems with the storage stability data for the degradates. MRID: 44807318, 44807320, 44807316, 44807319, 44807317
.Page 34 of 67

5.1.6 Comparative Metabolic Profile Data depicting the metabolism of fluazinam in plants and animals, as well as data on environmental degradat es, have been submitted to the Agency
. In rats, fluazinam metabolism involves hydrox yl ation followed by conjugation. T he major urinary metabolites identified were AMPA mercapturate and DAP A at 0.05
- 0.39% of administered dose (AD). Radioactivity in the f eces represented most of the AD (8 9
- 100%); however, metabolites identified represented onl y 11
- 6 9 % the AD. Fecal radioactivity (all dose groups) appeared to reside with unextractable components in the post
- extraction solids (PES), which upon further anal y sis was attributed to hydrol ys is products of AMPA and DAPA. Approximately 20
- 25% of the aqueous phase of the fecal extraction was identified as a cy steine conjugate of DAPA and represented <1% of the AD
. With the exception of the low
- dose group (greatest PES radioactivity), parent compound represented most of the identified radioactivity in the feces. AMPA and DAPA were identified in the feces from all dose groups but these metabolites never represented more than 5% of the AD (except for high
- dose female rats where AMPA accounted for 10%). DAPA glucuronide and AMPA mercapturate were the major biliary metabolites (<4% of the AD). The metabolism of [ 14 C]
- fluazinam in ruminants and poultry is similar, and involves reduction of one or both nitro groups on the phen ylring to form AMPA, MAPA, or DAPA. Fluazinam also undergoes dehalogenation and hydroxylation of the chlorine on the phenyl ring to form HYPA. These compounds c an then undergo conjugation with glutathione, and subsequent degradation of the glutathione component yields a variety of polar compounds. Although the ring structure of the parent molecule remains intact, fluazinam per se was onl y a minor component ( ≤2.7% TRR) of the [ 14 C]
- residues in poultry tissues and eggs, and was not detected in ruminant tissues or milk
. In plants, fluazinam undergoes reduction of one of the nitro groups to an amine, forming AMPA. AMPA can then b e conjugated with glutathione, with subsequent degradation of the glutathione moiety to cy steine. The AMPA
- cy steine conjugate then undergoes transamination, reduction, and conjugation with glucose to form AMGT. In addition, both rings of fluazinam appear to be labile to ring cleavage, and subsequent degradation of the rings into small fragments occurs. T h ese fragments can then be incorporated into a variet y of natural plant components. The primary

metabolites in the plant and livestock metabolism studie s are accounted for in the rat metabolism study . The reduction products, AMPA and DAPA, and their hydroly sis or conjugation products are the primary metabolites in plants, ruminants, poultry , and rats. 5.1.7 Toxicity Profile of Major Metabolites a nd Degradates of Concern There is no toxicology

information available on fluazinam metabolites and degradates .Page 35 of 67

5.1.8 Pesticide Metabolites and Degradates of Concern Table 5.1. b Summary of Metabolites and Degradates to be included in the Risk A ssessment

and Tolerance Expression Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop : grapes Parent fluazinam and AMGT Parent fluazinam and AMGT

Primary Crop : peanuts, root /tuber vegetables , bulb vegetables Parent fluazinam Parent fluazinam Primary Crop : all others Parent fluazinam and AMGT Parent fluazinam Rotational Crop N/A Note: Tolerances are not required based on the absence of residues in rotational crops at the requested plant back interval. Livestock Ruminant Parent fluazinam, AMPA, and DAP A , and their sulfate conjugates Parent fluazinam, AMPA, and DAP A, and their sulfate conjugates Poultry Parent fluazinam, AMPA, and DAP A, and their sulfate conjugates Pare nt fluazinam, AMPA, and DAP A, and their sulfate conjugates Drinking Water Fluazinam , CAPA, DAPA , DCPA , HYPA , and AMPA Not Applicable For this current risk assessment, HED continues to consider the residues of concern to be those that have been establi shed previously
. At a meeting held on 11/28/2000, HED concluded that the residue of concern (ROC) in potatoes and peanuts (for both tolerance expression and dietary risk assessment purposes) was the parent compound only ( Memo, D272624 , W
. Cutchin , 4/23/20 01). HED has extended this determination to bulb vegetables as well. Inwine grapes, both parent and AMGT were included in the ROC for tolerance expression and risk assessment. Additionally , HED determined that data generated for potential new uses on o ther crops (with the exception of root and tuber and bulb vegetables) should include anal ys es for both parent and AMGT. The fluazinam residues of regulatory interest in animals were determined by HED to be parent plus the metabolites AMPA and DAPA and their sulfamate conjugates. E stimated drinking water concentrations (E DWCs) were calculated for t otal f luazinam r esidues because the environmental fate studies indicated that the parent compound forms transformation compoun ds (CAPA, DAPA, DCPA, HYPA, and AMPA) which are similar in structure to the parent (under most conditions ) . Given that HED is unable to conclude that all these degradates are significantl y less toxic than the parent, the drinking water assessment is based on total residues of fluazinam and its major degradates.Page 36 of 67

5.1.9 D rinking Water Residue Profile The drinking water residue values used in the dietary risk assessment s w ere provided b y the Environmental Fate and Effects Division (EFED; D360713 , J. Meléndez, 2 /24/2010 ) and incorporated directl y into th e dietary assessment s into the food categories “water, direct, all sources” and “water, indirect, all sources.” The residues of concern in drinking water for risk assessment are parent fluazinam and its transformation products, including DC PA, CAPA, DAPA , AMPA, and HYPA. The acute and chronic EDWC s are based on ground application of fluazinam to apples. The values are provided in Table 5.1.c , below. The groundwater value was generated using the Screening Concentration in Groundwater (SCI
- GROW) Model and the surface water values were generated using the FQPA Index Reservoir Screening Tool (FIRST) Model. The surface water estimates were used for both the acute and chronic assessments because they

were higher than the groundwater value. For the acute assessment, a value of 117 ppb was used. This value includes both parent and degradates. For the chronic assessment, a value of 19.8 ppb was used. This value also includes both parent and degradates. For more information about EFED’s drinkin g water models, see http://www.epa.gov/oppefed1/models/water/).

Table 5.1. c. Maximum Tier I Estimated Drinking Water Concentrations Drinking Water Source (Model Used) USE (Rate Modeled) Max imum Estimated Drinking Water Concentration (EDWC ; p pb) Groundwater (SCI
- GROW) Total Residues of Fluazinam (including parent) Apples (4.5 lb a.i./A/season) Ac ute and Chronic 0. 216 Surface Water (FIRST) Total Residues of Fluazinam (including parent) App les (4.5 lb a.i./A/season) Ac ute 117* Chronic 19
. 8 * This value exceeds the solubility of fluazinam at pH 7 (71 ppb), but is lower than the solubility at pH 11. 5.1.10 Food Residue Profile Reference: Fluazinam. Petitions for the Establishment of Tolerances and Registration of New Uses on Apples, Carrots, Lettuce, and Bulb Onion Subgroup (3
- 07A), and a Request for a Reduced Tolerance on Bushberry S ubgroup ( 13
- 07B) . Summary of Anal yt ical Chemistry

and Residue Data, D36 084 0 ; D. D otson, 3/31 /2010 D ata Collection Anal yt ical Methods Samples collected from the magnitude of the residue and storage stability studies were anal yz ed for residues of fluazinam using various GC/ECD methods based on, and revised slightly from, the plant enforcement method (Method (6148
- 94
- 0170
- MD
- 001, discussed above). The GC/ECD methods are adequate for data collection based on acceptable method recovery data. The lowest limit of method validation (LLMV) was 0.01 ppm in all tested commodities except in carrots where the LLMV was 0.02 ppm.Page 37 of 67

An enforcement method for determination of AMGT, a residue in the tolerance expression for wine grapes, is also available. HED recommended in a previous memorandum (Memo, D335640, W. Drew, 8/22/07) that a previousl y submitted HPL C/UV method undergo an ILV trial, and potentially , a TMV trial by the ACB. This method is based on Method Evaluation for the Analysis of AMGT in Grapes (MRID 45593101). HED has agreed to accept the recovery data generated b y IR
- 4 for AMGT residues in blueberries as the ILV. PTRLMethod 1676W was the data
- collection method used for the analy sis of samples collected from the dairy

cattle feeding study
. The method is written for LC/MS/MS analy sis of fluazinam, AMPA, and DAPA in bovine milk and tissues, and for GC/MS analy sis of DAPA in milk only
. The limit of quantitation was 0.01 ppm for each analy te in milk, muscle, fat, liver , and kidney
. Preliminary

method validation data showed that Method 1676W adequatel y recovered residues of fluazinam, AMPA, and DAPA in mil k, muscle, and fat. However, poor and/or marginal recoveries were obtained for AMPA and DAPA residues in kidney and liver. Method 1676W was marginall y validated by an independent laboratory during the third trial and following slight modifications to mak e the method more rugged. For the purpose of developing an animal enforcement method, radiovalidation data are required to determine whether the method can detect aged residues. HED forwarded Method 1676W to ACB/BEAD for a tolerance method validation (TM V) because the method encountered difficulties in the ILV (e.g., three attempts for successful validation and/or marginal recoveries with wide variability and high coefficient of variation). ACB/BEAD reported that the lab that performed the ILV made major modifications to the original method. As a result, HED requested that the registrant submit a revised method that incorporated the revisions made by the ILV lab. I SK Biosciences revised the method and re
submitted it. ACB/BEAD performed a cursory revie w of the revised method. The registrant incorporated the modifications made by the ILV lab. However, the revision eliminated the cleanup steps that were in the original method, and the only recovery data for the revised method were data provided b y the I LV lab. ACB/BEAD was concerned that the elimination of the cleanup steps could lead to dirty samples which would, in turn, lead to analy tical problems, such as interference. ACB/BEAD performed no further validation of the method. As the revised method c ontains major revisions to the original method, and ACB/BEAD believes it is very likely that the revised method still is not adequate for sample analy sis or tolerance enforcement, HED recommends that the registrant submit an ILV for the revised method. St orage Stability Adequate storage stability data are available to support the storage conditions and durations of samples collected from the magnitude of the residue studies on apples, carrots, lettuce, and onions. As residues of fluazinam were found to b e stable in tested crop matrices, storage stability corrections do not need to be applied to the recommended tolerances for fluazinam residues in/on apples, carrots, lettuce, and onions. Storage stability data for the fluazinam metabolite AMGT in apple co mmodities were also submitted, and showed that residues in wet apple pomace were reasonably stable for 12 months, but declined to an average corrected recovery of 58
- 63% at the 19
- month interval, 61% at the 32
- month interval, and 33% at the 37
- month interv al. The submitted storage stability data for bovine milk, meat, and meat b yproducts showed mixed results. However, HED is not currently recommending in favor of tol erances for animal commodities.Page 38 of 67

Residues in Meat, Milk, Poultry , and Eggs The residue d ata from the cattle feeding study are not adequate to satisfy data requirements. The feeding study data (adjusted for residue decline) along with the calculated dietary burdens for beef cattle (0.04 ppm) and dairy cattle ( 1
. 27 ppm) indicate that tolerance s are needed for the combined residues of fluazinam and its metabolites DAPA and AMPA in the fat and meat by products of cattle and other ruminants at 0.0 2 ppm to support the proposed use s on apples and carrots and the established tolerances on potatoes and peanuts . However, no tolerances are required for milk and meat of ruminants
. Based on the transfer coefficients for livestock tissues and the relativel y low dietary burden for swine of 0.003 ppm for fluazinam, tolerances for hog commoditie s are not need ed. A poultry feeding study

is not required at this time because of the low dietary

burden for poultry

(0.005 ppm ). Magnitude of the Residue in Plants The submitted field trial data for fluazinam on head lettuce, leaf lettuce, bulb onions, carrots, and apples are acceptable and support the proposed uses. Adequate numbers of tests were conducted in the appropriate geographic regions at ~1x the maximum proposed rate, and the appropriate samples were collected from each test at, or close to, the proposed P HI . Samples from all the field trials were anal yz ed for fluazinam residues using an adequate GC/ECD method, and the storage stability

data support the sample storage durations for these crops. However, no residue data were provided on AMGT residues in le ttuce. Although AMGT residue data on lettuce are still required for purposes of dietary risk assessment, the available data support tolerances of 0.0 2 ppm for head lettuce and 2.0 ppm for leaf lettuce
. HED accounted for AMGT residues in lettuce in the current risk assessment by using a ratio obtained from plant metabolism data. The field trial data also support a tolerance of 0.20 ppm for the Bulb onion subgroup ( 3
- 07A). The tolerance spreadsheet ( Guidance for Setting Pesticide Tolerances Based on Field Trial Data SOP) was used for determining appropriate tolerance levels. Because of data deficiencies associated with Method 1676W, the cattle feeding study, and the apple processing study, HED does not recommend in favor of tolerances for apple and carrot commodities. Processing Studies The registrant submitted a processing study for apples. This study is not adequate to satisfy data requirements. In apples, the metabolite AMGT is a residue of concern for risk assessment. In the processing study there were no quantifiable residues of AMGT in raw apples. In several of the field trials that were performed, however, raw apples contained AMGT residues at, or above, the limit of quantitation. In a few cases, residues of AMGT were comparable to those of th e parent fluazinam. Canadian and U.S. residue chemistry guidelines both stipulate that in the processing study , if residues in the raw agricultural commodity ( RAC ) are below the LOQ, but quantifiable residue s occurred in the RAC in field trials performed at the maximum requested label rate, that the processing study should be conducted at exaggerated rates in order to ensure that quantifiable residues will be present in the RAC . Quantifiable residues are needed in the RAC in order to determine a reliable concentration factor. As a result, the processing study needs to be repeated at a sufficiently high rate that residues of both parent and AMGT arePage 39 of 67

quantifiable in the RAC. In the event that the potential for phy totoxicity exists, the application rate doe s not need to be greater than the rate at which phy to to xicity occurs. Rotational Crop Studies Regulatory

requirements pertaining to fluazinam residues in rotational crops have been fulfilled, and the rotational crop restrictions on the proposed label are adequate. 5.1.11 International Residue Limits There are currently

no established Codex, Canadian, or Mexican maximum residue limits (MRL s) for fluazinam on apple s , carrot s , lettuce, onions , or berry crops . Therefore, there are no harmonization issues for the requested tolerances. 5.2 Dietary Exposure and Risk Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model DEEM
- FCIDTM, Version 2.03 which use s food consumption data from the U.S. Department of Agriculture’s Continuing Survey s of Food Intakes by Individuals (C SFII) from 1994
- 1996 and 1998. 5.2.1 Acute Dietary Exposure/Risk The acute anal ys is is based on tolerance
- level residues for all commodities and uses high
- end residue estimates for the metabolite AMGT. In addition, the acute assessment assumes 100% crop treated and incorporates modeled estimated drinking water concentrations (EDWCs) that account for both parent fluazinam and its transformation products. Therefore, the resulting exposure and risk estimates are considered to be very conservative. The acute risk estimates are below HED’s level of conce rn for all population subgroups, including those comprised of infants and children. Generally , HED is concerned when risk estimates exceed 100% of the PAD. The acute risk estimate for the general U.S. population is 4.1 % of the aPAD. The population subgroup with the highest risk estimate is Females 13
- 49, which uses 20 % of the aPAD. 5.2.2 Chronic Dietary Exposure/Risk The chronic anal ys is is based on tolerance
- level residues for all commodities except app les. For apples, the average field trial value was used. As with the acute assessment, it assumes high
- end estimates for AMGT, 100% crop treated, and incorporates modeled EDWCs that account for both parent and transformation products. Again, the resulti ng exposure and risk estimates are considered to be conservative. Chronic risk estimates are below HED’s level of concern for all population subgroups. The risk estimate for the general U.S. population is 14 % of the cPAD. The most highl y exposed populat ion subgroup is All Infants (<1 ye ar old), which uses 40 % of the cPAD.Page 40 of 67

5.2.3 Cancer Dietary Risk The CARC determined that the cRfD is protective of cancer effects. As a result, a dietary exposure assessment for c ancer risk is unnecessary .
Table 5.2 . Summary of Acute and Chronic Exposure and Risk Estimates for Fluazinam Population Subgroup Ac ute Assessment (95 th Percentile) Chronic Assessment

aPAD, mg/day Exposure Estimate,

mg/day % aPad cPAD, mg/day Exposure Estimate,

mg/day % cP AD U.S. Population 0.5 0.020332 4.1 0.011 0.001530 14 All infants 0.5 0.086600 17 0.011 0.0044 11 40 Children 1
- 2 y

rs 0.5 0.098940 20 0.011 0.004064 37 Children 3
- 5 y

rs 0.5 0.063647 13 0.011 0.002789 25 Children 6
- 12 y

rs 0.5 0.0 22625 4.5 0.011 0.001374 1 3 Youth 13
- 19 y

rs 0.5 0.013076 2.6 0.011 0.000813 7. 4 Adults 20
- 49 y

rs 0.5 0.012952 2.6 0.011 0.001346 12 Adults 50+ yrs 0.5 0.012761 2.6 0.011 0.001488 14 Fem ales 13 - 49 yrs 0.07 0.0141 24 20 0.011 0.001394 13 Actual dietary exposures and risks from fluazinam will likely be much lower than the values generated in the acute and chronic analy ses. The anal ys es indicate that dietary exposure considerations would not preclude establishing the proposed tolerances for fluazinam. 5 .3 Anticipated Residue and Percent Crop Treated (%CT) Information Anticipated Residues The acute anal ys is is based on tolerance
- level residues for all commodities, and the chro nic anal ys is is based on tolerance
- level residues for all commodities except apples. For apples, the average field trial value was used. Both assessments assume high
- end estimates for AMGT and incorporate modeled EDWCs that account for both parent and tr ansformation products. Percent Crop Treated The acute and chronic assessments are both based on the assumption that 100% of all crops with fluazinam tolerances will be treated with fluazinam. 6.0 Residential (Non - Occupational) Exposure/Risk Charact erization Currently , there are no registered or proposed r esidential uses for fluazinam ; thus, there is no exposure via this pathway and an assessment was not conducted
.Page 41 of 67

Spray Drift Spray drift is alway s a potential source of exposure to residents livin g in close proximity to spraying operations. This situation is particularly the case with aerial application. However, to a lesser extent, spray

drift resulting from the ground application of fluazinam could also be a potential source of exposure. The A gency has been working with the Spray Drift Task Force (a membership of U.S. pesticide registrants), EPA Regional Offices, State Lead Agencies for pesticide regulation, and other parties to develop the best spray drift management practices. 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 submitted by

the Spray

Drift Task Force, and is developing a policy on how to app ly appropriatel y the data and the AgDRIFT computer model to its risk assessments for pesticides applied by

air, orchard airblast, and ground hydraulic methods. After the policy is in place, the Agency might impose further refinements in spray drift manage ment practices to reduce off
target drift risks associated with pesticide application.
7.0 Aggregate Risk Assessments and Risk Characterization 7.1 Acute Aggregate Risk A cute aggregate risk consists of risks resul ting from exposure to residues in food and drinking water alone. The acute dietary exposure anal ys is included both food and drinking water. As a result, the acute aggregate risk assessment is equivalent to the acute dietary risk assessment discussed in S ection 5.2.1, above. All risk estimates are below HED’s level of concern. 7.2 Short - Term Aggregate Risk Short
- term exposures result from residential uses. As there are no residential uses for fluazinam , short
- term aggregate risk assessments were not conducted
. 7.3 Intermediate - Term Aggregate Ris k Intermediate
- term exposures result from residential uses. As there are no residential uses for fluazinam , intermediate
- term aggregate risk assessments were not conducted
. 7.4 Long - Term Aggregate Risk The chronic aggregate risk assessment consists of risks resulting from exposure to residues in food, drinking water, and residues resulting from residential applications. As there are no residential uses for fluazinam , chronic aggregate risk consists of risks resulting from exposure to residues in food and drinking water alone. The chronic dietary exposure analy sis included both food and drinking water. As a result, the chronic aggregate risk assessment is equivalent to the chronic dietary

risk assessment discussed in Section 5.2.2, above . All risk estimates are below HED’s level of concern.Page 42 of 67

7.5 Cancer Risk The CARC determined that the cRfD is protective of canc er effects. Cancer risk resulting from exposure to fluazinam is not of concern. 8.0 Cumulative Risk Characterization/Assessment Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering whether to establish, modify , or revoke a tolerance, the Agency consider “ available information concerning the cumulative effects” of a particular pesticide's residues and “ other substances that have a common mechanism of toxicity .” Unlike other pesticides for which EPA has followed a cumulative risk approa ch based on a common mechanism of toxicity , EPA has not made a common mechanism of toxicity finding as to fluazinam and any

other substances , and fluazinam does not appear to produce a toxic metabolite produced b y other substances. For the purposes of thi s tolerance action, therefore, EPA has not assumed that fluazinam has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. 9.0 Occupational Exposure/Risk Pathway Reference: Fluazinam: Occupational and Residential Risk Assessment for Proposed Use of Fluazinam on Apples, Carrots, Lettuce (He ad and Leaf), and Onions (Bulb), D371446, Z. Figueroa, 3 / 3 0 /2010
. 9.1 Agricultural Handler Exposure and Risk The proposed occupational uses of fluazinam are for control of certain fungi in apples , carrots, lettuce (head and leaf), and onions (bulb). This document assesses occupational exposures and risks from the proposed uses of the product OMEGA ® 500F , a soluble
- concentrate formulation containing 40% ai fluazinam. OMEGA ® 500F may be applied as a foliar spray using aerial, chemigatio n, groundboom, and airblast equipment. Based on the product labels, handler exposures are expected to be short
- and intermediate
- term in duration. Application methods, maximum application rates, and use sites are summarized in Table 2.1
. The quantitat ive exposure/risk assessment for occupational handlers is based on the use pattern and the following exposure scenarios:Page 43 of 67

Mixer/L oaders 1. Mixing/loading liquid concentrates to support aerial applications , 2. Mixing/loading liquid concentrates to support chem igation applications, 3. Mixing/loading liquid concentrates to support groundboom applications , 4. Mixing/loading liquid concentrates to support airblast applications , Applicators 5. Applying spray s with aircraft (enclosed cockpit) , 6. Applying spray s with groundboom equipment , 7. Applying spray s with airblast equipment, and Flaggers 8. Flagging to support aerial spray applications
. 9 .1.1 Data and Assumptions for Handler Exposure Scenarios Unit Exposures : Chemical
- specific data for assessing exposure during pesticid e handling activities were not submitted to the Agency

in support of th ese tolerance petitions
. Itis HED policy to use data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 to assess handler exposures for regulatory

actions when chemical
- specific data are not available (HED ExpoSAC , SOP N o. 7 , January

1999)
. For flaggers, the unit exposure value for the first level of mitigation (i.e., single layer, gloves) is considered to be of low confidence because of the small number of replicates us ed in determining the unit exposure value. Mitigation Approaches : There are three basic risk mitigation approaches considered appropriate for controlling occupational exposure. These include administrative controls, use of personal protective equipment (PPE), and the use of engineering controls. Occupational handler exposure assessments were completed by HED using baseline, PPE, and engineering controls. The baseline clothing level for occupational exposure scenarios is generall y an individual wearing long pants, a long
- sleeved shirt, shoes, socks, no chemical
- resistant gloves, and no respirator. The first level of mitigation generally applied is PPE, which may include addition of chemical resistant
- gloves, an additional layer of clothing, and/or a res pirator. The next layer 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 inclu de enclosed cockpits or tractor cabs, closed mixing/loading s ys tems, and water
- soluble packets. The proposed label has PPE recommendations th at include:

 Applicators and other handlers wear coveralls worn over long
- sleeved shirt, long pants, socks, protect ive eyewear , and chemical
- resistant gloves and footwear ;Page 44 of 67  Mixer/loaders or handlers conducting cleaning activities wear a chemical
- resistant apron ; and,
 Mixer/loaders wear a dust/mist or NI OSH approved respirator. Baseline clothing level was used as a starting point to calculate handler exposures. Depending on the need for additional dermal or inhalation protection, additional PPE is added to obtain an MOE higher than the LOC. However, HED recommends that all label requirements be followed and expanded t o all handlers. Because of the low confidence there is in the unit exposure data for flaggers, workers conducting flagger
- related activities should wear the same PPE as the applicators in order to reduce exposures. Acres Treated : The acres treated p er day for each scenario are shown in Table 9.1 . The values are b ased on HED Expo SAC SOP No. 9.1 and the equipment used. Application Rate : Maximum application rates for all proposed uses are shown in Table 9.1
. Body Weight : T he average adult body

we ight of 70 kg was used for short
- and intermediate
- term dermal and inhalation calculations because the effects were not sex
- specific. Absorption Factor s : A dermal absorption factor was not used in the calculation of the dermal dose in this instance becau se the toxicity

endpoint is derived from a dermal study rather than extrapolated from an oral study
. As the short
- and intermediate
- term inhalation POD was based on an inhalation study , no inhalation absorption factor is necessary to estimate inhalation e xposure s for short
- and intermediate
- term durations. Equations and Calculations: Daily Exposure: Dail y handler exposures are estimated for each applicable handler task with the application rate, the amount of acres treated or gallons applied in a day , and the applicable unit exposure using the following formula: Daily Exposure (mg ai/day) = Unit Exposure (μg ai/lb ai handled) x Application Rate (lbs ai/A or gal ) x Daily Amount Handled ( A or gal/day) x Conversion Factor (mg/1,000 μg)Page 45 of 67 Where: Dai ly Exposure = Amount (mg ai/day) deposited on the surface of the skin that is

available for dermal absorption or amount inhaled that is available for inhalation absorption, Unit Exposure = Unit exposure value (μg ai/day), Application Rate = Normalized application rate based on a logical unit treatment (lb ai/acre), and Daily Amount Handled = Normalized application area based on a logical unit treatment such as acres or gallons (A/day or gal/day). Daily Dose: Dail y d ose (inhalation or dermal) was calculated b y normalizing the daily dermal or inhalation exposure value by body weight. Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day)/Body Weight (kg) Where: Average Daily Dose = Absorbed dose received fr om exposure to a pesticide in a given scenario (mg pesticide active ingredient/kg body weight/day), Daily Exposure = Amount (mg ai/day) deposited on the surface of the skin that is available for dermal absorption or amount inhaled that is available for inhalation absorption, and Body Weight = Body weight determined to represent the population of interest in a risk

assessment. Margin of Exposure (MOE): The dail y dermal dose and dail y inhalation dose received b y occupatio nal handlers w ere compared to the appropriate POD (i.e., NOAEL) to assess the risk to occupational handlers for each exposure route. All MOE values were calculated separatel y for dermal and inhalation exposure levels using the following formula: MOE = NOAEL (mg/kg/day)

Average Daily Dose (mg/kg/day) Where: MOE = Margin of exposure value used by HED to represent risk or how close a chemical exposure is to being of concern (unitless), ADD = Average daily dose (ADD) is absorbed dose rec eived from exposure to pesticide, and NOAEL = Dose level in a toxicity study, where no observed adverse effects occurred in the

study.
9 .1.2 Handler Exposure and Risk HED’s level of concern for the MOE is defined b y the uncertainty factors that are applied to the assessment. HED applies a 10 x factor to account for interspecies extrapolation and a 10 x factor to account for intraspecies sensitivity
. The uncertainty factor that has been applied to occupational risk assessments is 100 x for short
- and intermediate
- term dermal exposures . AnPage 46 of 67

additional 10 x uncertainty factor was added to short
- and intermediate inhalation exposures , because of the absence of key data (i.e., lack of a histopathological examination)
. As discussed in Section 3.5.8, although liver effects were observed in both the dermal and inhalation route
- specific toxicity studies, both endpoints are considered to be very conservative , and combining exposures from these routes is not considered to be necessary . Nevertheless, HED di d calculate the combined risk estimate for the worker with the highest exposure (i.e., the mixer/loader for aerial or chemigation treatment of lettuce). The total risk estimate was determined using the aggregate risk index approach because there are diffe rent levels of concern for the two routes . This risk estimate was greater than one and , therefore , not of concern. As a result , the dermal and inhalation risk estimate s as shown in Table 9.1 were not combined. Summaries of the risks for occupational handlers are included in Table 9.1 . The maximum application rate for each exposure scenario is presented as the worst
- case scenario. All handler scenarios resulted in MOEs greater than the level of concern (MOEs > 100 for dermal and > 1,000 for inhalation) at some level of risk mitigation. Dermal For the scenarios listed below, short
- and intermediate
- term dermal MOEs did not exceed HED’s level of concern (MOEs > 100) at the baseline attire level of mitigation (long
- sleeved shirt, long pants, shoes, and socks):

• Applying spray s with groundboom equipment to carrots, onions, and lettuce;
• Flagging for aerial spray applications for apples, carrots, onions, and lettuce; and
• Applying spray s via airblast equipment to apples. For the scenarios listed below, sh ort - and intermediate
- term dermal MOEs exceeded HED’s level of concern (MOEs < 100) at the baseline attire level of mitigation (long
- sleeve shirt, long pants, shoes, and socks). However , MOEs were greater than 100 and not of concern to HED with baseline attire plus chemical
- resistant gloves:

• mixing/loading liquid concentrates for aerial applications to carrots, apples, and onions;
• mixing/loading liquid concentrates for chemigation applications to carrots, apples, and onions;
• mixing/loading liquid concentrates for groundboom applications to carrot s , onion s , and lettuce; and
• mixing/loading liquid concentrates for airblast applications to apples
. For the scenarios listed below, short
- and intermediate
- term dermal MOEs exceeded HED’s level of concern (MOEs < 100) with the use of baseline attire plus chemical
- resistant gloves
. However, MOEs were greater than 100 and not of concern to HED with the double layer body attire (coveralls worn over long
- sleeve shirt and long pants) plus chemical
- resistant gloves:

• m ixing/loading liquid concentrates for aerial applications to lettuce (MOE = 90 with baseline + gloves; MOE = 120 with double layer attire +gloves); andPage 47 of 67

• mixing/loading liquid concentrates for chemigation applications to lettuce (MOE = 90 with baseline + gl oves; MOE = 120 with double layer attire + gloves). Only engineering control (enclosed cockpit) data are available to assess dermal risks to handlers operating aircraft. The dermal risks do not exceed HED’s level of concern for pilots using enclosed cock

pits and wearing baseline attire. Inhalation For the scenarios listed below, short
- and intermediate
- term inhalation risks did not exceed HED’s level of concern ( MOEs > 1, 00 0 ) at the baseline level of mitigation (no respirator):

• mixing/loading liquid concentrates for groundboom applications to carrots, onions, and lettuce;
• mixing/loading liquid concentrates for airblast applications to apples ; • applying spray s with groundboom equipment to carrots, onions, and lettuce;
• applying spray s with airblast equipment to apples; and
• flagging for aerial spray applications to apples, carrots, and onions
. For the scenarios listed below, short
- and intermediate
- term inhalation risks exceeded HED’s level of concern (MOEs < 1,000) at the baseline level of mitigation
. However , MOEs were greater than 1000 and not of concern to HED with a quarter - face dust/mist respirator :

• mixing/loading liquid concentrates for aerial applications to carrots, apples, onions, and lettuce;
• mixing/loading liquid concentrates for chemigati on applications to carrots, apples, onions, and lettuce; and
• flagging for aerial spray applications to lettuce. Only engineering control (enclosed cockpit) data are available to assess short
- and intermediate
term inhalation risks to handlers operating ai rcraft. The short
- and intermediate
- term inhalation risks do not exceed HED’s level of concern for pilots using enclosed cockpits and wearing no respirator.Page 48 of 67

Table 9.1 . Short - and Intermediate - Term Occupational Handler Derm al and Inhalation Exposure and Risk for Fluazinam

Exposure Scenario Crop or

Target App

Rate a (lb ai/A) Acres

Treated Daily b Unit Exposure c ,d MOEs Dermal LOC = 100 Inhalation LOC = 1 ,0 00 Baseline Dermal mg/lbai PPE
- G

Dermal mg/lb ai PPE
- G,

DL Dermal mg/lb ai Baseline

Inhalation μg/ lb ai 80%

PPE
- R Inhalation Baseline

Dermal e PPE
- G

Dermal e PPE
- G, DL

Dermal e Baseline

Inhalation f 80%

PPE
- R Inhalation f Mixer/Loader Mixing/Loading Li quid Concentrates for Aerial Applications Carrot, Onion 0.5 2 350 2.9 0.023 0.017 1.2 0.24 1.3 170 230 44 0 2 ,2 00

Apple 0.45 350 2.9 0.023 0.017 1.2 0.24 1.5 190 260 510 2,500 Lettuce 0.99 350 2.9 0.023 0.017 1.2 0.24 0.7 90 120 230 1,200

Mixing/Loading Li quid Concentrates for Chemigation Applications Carrot, Onion 0.5 2 350 2.9 0.023 0.017 1.2 0.24 1.3 17 0 230 440 2,200

Apple 0.45 350 2.9 0.023 0.017 1.2 0.24 1.5 190 260 510 2,500

Lettuce 0.99 350 2.9 0.023 0.017 1.2 0.24 0.7 90 120 230 1,200 Mixing/Loading Li quids Concentrates for Gr oundboom Applications Carrot, Onion 0.5 2 80 2.9 0.023 0.017 1.2 0.2 4 5.8 730 990 1,900 9,700

Lettuce 0.99 80 2.9 0.023 0.017 1.2 0.24 3 380 520 1,000 5,100 Mixing/Loading Li quid Concentrates for Airblast Applications Apple 0.45 40 2.9 0.023 0.017 1.2 0.24 13 1,700 2,300 4,500 22,000 Applicator Applying Sprays via Aerial Equipment Carrot, Onion 0.5 2 350 0.005 (eng. control) No Data No Data 0.068 (eng. control) No Data 770 (eng. control) No Data No Data 7,800 (eng. control) No Data Apple 0.45 350 0.005 (eng. control) No Data No Data 0.068 (eng. control) No Data 890 (eng. control) No Data No Data 9,000 (eng. control) No DataPage 49 of 67

Table 9.1 . Short - and Intermediate - Term Occupational Handler Derm al and Inhalation Exposure and Risk for Fluazinam

Exposure Scenario Crop or

Target App

Rate a (lb ai/A) Acres

Treated Daily b Unit Exposure c ,d MOEs Dermal LOC = 100 Inhalation LOC = 1 ,0 00 Baseline Dermal mg/lbai PPE
- G

Dermal mg/lb ai PPE
- G,

DL Dermal mg/lb ai Baseline

Inhalation μg/ lb ai 80%

PPE
- R Inhalation Baseline

Dermal e PPE
- G

Dermal e PPE
- G, DL

Dermal e Baseline

Inhalation f 80%

PPE
- R Inhalation f
Lettuce 0.99 350 0.005 (eng. control) No Data No Data 0.068 (eng. control) No Data 400 (eng. control) No Data No Data 4,100 (eng. control) No Data Applying Sprays via Groundboom Equipment Carrot , Onion 0.5 2 80 0.014 0.014 0.011 0.74 0.148 1 , 200 1,200 1,500 3,100 16,000

Lettuce 0.99 80 0.014 0.014 0.011 0.74 0.148 630 630 800 1,600 8,200 Applying Sprays via Airblas t Equipment Apple 0. 45 40 0.36 0 0.24 0 0.22 0 4.5 0 0.9 00 110 160 180 1,200 6,000 F lagger g Flagging for Aerial Sprays Applications Carrot, Onion 0.5 2 350 0.011 0.012 0.01 0 0.35 0.07 0 350 320 350 1,500 7,600

Apple 0. 45 350 0.011 0.012 0.01 0 0.35 0.07 0 400 370 400 1 , 800 8,800 Lettuce 0.99 350 0.011 0.012 0.01 0 0.35 0.07 0 180 170 180 800 4,000

a. Application Rates based on proposed uses on label s for fluazinam. b. Science Advisory Council Policy No. 9.1 c. Unit Exposures based on PHED Version 1.1. Engineering control unit exposure for applying sprays via aerial equipment = enclo sed cockpit. d
. Baseline Dermal: Long
- sleeve shirt, long pants, and no gloves
. Baseline plus Gloves Dermal (PPE
- G): Baseline plus chemical
- resistant gloves. DL is the addition of double layer body attire. Baseline I nhalation: No respirator
. PPE

– R 80% = A quarter
- face dust/mist respirator (that provides a 5
- fold (80%) protection factor)
. Those risks specified as engineering control (eng. control) represent enclosed cockpit application. e . Dermal MOE = NOAEL (1 0 mg/kg/day) / dermal daily dose (mg/ kg/day). Level of concern = 100. Dermal Dose (mg/kg/day) = d aily unit exposure (mg/lb ai) x application rate (lb ai/acre) x acres treated / body weight ( 7 0 kg). f. Inhalation MOE = NOAEL (1.38 mg/kg/day) / inhalation daily dose (mg/kg/day). Level of concern = 1000. Inhalation Dose (mg/kg/day) daily unit exposure (μg/lb ai) x application rate (lb ai/acre) x acres treated / body weight (70 kg). g. The PPE
- G unit exposure for flaggers is considered to be of low confidence because of the small number of replicates used in determining the unit exposure value
. HED recommends that all handlers follow label PPE.Page 50 of 67

9 .2 Postapplication Exposure and Risk 9 .2.1 Data and Assumptions for Postapplication Exposure Scenarios Inhalation Based on the Age ncy ’ s current practices, a quantitative postapplication inhalation exposure assessment i s not being performed for fluazinam at this time. However, volatilization of pesticides m ight be a potential source of postapplication inhalation exposure to individua ls in close proximity to locations where pesticide applications are made . The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipol y/ SAP/meetings/2009/120109meeting.html). The Agency is in the process of evaluating the SAP report and m ight , as appropriate, develop policies and procedures to identify

the need for and the w ay to incorporate postapplication inhalation exposure into the Agency ’ s risk assessments. If new policies or procedures are put into place, the Agency

m ight revisit the need for a quantitative postapplication inhalation exposure assessment for fluazinam
. Dermal Chemical
- specific dislodgeable foliar residue (DFR) studies on apples (MRID 45584203) and peanuts (MRID 46991302) were submitted and reviewed b y HED. The peanut dislodgeable foliar residue (DFR) data w ere previousl y used as surrogate data to ass ess post application exposure for all crops when no crop
- specific DFR data w ere available ( Memo, D346976 , M. Collantes, 2/27 /2008). As indicated below , a linear regression anal ys is was conducted of the individual foliar residue values collected immediatel y after the last application through the last day of sampling for peanuts (42 DAT) , which resulted in a regression (R2 ) of 0.962. Regressions close in value to 1 .0 are a good indication of direct correlation between actual and predicted residues
. For this assessment, p eanut DFR data w ere used as surrogate data to assess postapplication exposure for lettuce, onions , and carrots. The apple DFR data w ere used to assess postapplication exposure for apples. A summary of each study is provided below. In ad dition to the DFR data, maximum dermal transfer coefficients from the Science Advisory Council for Exposure Policy

Number 3.1: Agricultural Transfer Coefficients, August 2000, (summarized in Table 9.2.a, below) and the following assumptions were used in th e postapplication assessment:

 Max Application Rate = 0.5 2 lb ai/A for carrots and onions; 0.45 lb ai/A for apples; 0.99 lb ai/A for lettuce  Exposure Duration = 8 hours per day  Body Weight = 70 kg, and  Dermal Absorption = Not applicablePage 51 of 67

Table 9 .2. a . Anticipated Postapplication Activities and Dermal Transfer Coefficients Proposed Crops Policy Crop

Group Category Exposure

Potential Transfer

Coefficients (cm 2 /hr) Activities
Carrots Vegetable, “root” Lo w 300 hand weeding, irrigation, and scouting High 2,500 hand harvest Onion Vegetable, “root” Lo w 300 hand weeding, irrigation, and scouting
Lettuce Vegetable, leafy Lo w 500 hand weeding, thinning Medium 1,500 irrigation, scouting High 2,500 hand harvest
Apple Tree , “fruit”

deciduous Lo w 1 ,000 hand weeding, irrigation, and scouting High 1 , 5 00 hand harvesting, propping, training, hand pruning Very High 3,000 thinning

 Summary of Dislodgeable Foliar Residue Study on Peanut ( MRID 45584201 ) This study

was d esigned to determine the dissipation of dislodgeable foliar residues (DFR) of fluazinam applied to peanut fields located in Sampson County near Garner, North Carolina (EPA Region 2). Two applications of Fluazinam 500F, a flowable liquid formulation contai ning 41.5% fluazinam as the ai, were made to peanut crops. The target application rate was 0.7 9 lbs ai/A for each application which was the maximum label use rate. The total application rate for both applications was 1.58 lb ai/A. Applications were made as a foliar broadcast spray

at a spray

volume of about 20 gallons per acre (GPA). Samples were collected before the first application and at the following time periods thereafter: immediately , 7 day s , 14 day s , and 21 day s . Samples were also collected at the following time periods after the second (final) application : immediately , 8 hours , and 1, 2, 4, 7, 10, 14, 21, 28, 35, and 42 day s. At each sampling interval, triplicate samples were collected from the control plot and from the treated plot. Field
- fortified samples using leaf samples from the control plot were prepared on day s 7, 14, and 35 after the second application to evaluate the stability of the field samples during shipping and storage. Fluazinam residue values were not corrected for field fortification or concurrent percent recoveries b y the Registrant. The DFR residues were corrected by HED using the average field fortification recovery from the fortification level closest to the DFR value (63.2% for low level fortification and 62.2% for high level fortification).Page 52 of 67

The highest average DFR value occurred immediately after the first application (1.56 μg/cm 2 ). The residues then declined to 0.0085 μg/cm2 by 21 day s after the first application (21DAT1). The average residues after the final a pplication were highest immediately after that application (1.29 μg/cm 2 ). Following the second application, residues declined to 0.013 μg/cm 2 by 42 day s after treatment (42 DAT2). All residue values remained above the LOQ out to the last day

of sampling. Rainfall occurred throughout the entire sampling period, with the first rainfalls after application occurring 3 days after the first application and 3 day s after the last application. A linear regression analysis was conducted using the natural logari thm of the individual foliar residue values collected immediatel y after the last application through the last day of sampling (42 DAT). The estimated half
- life life value for fluazinam was 6.30 day s (R2 = 0.962). Upon review of the data, HED determined that f or day s 0
- 2, the actual measured (raw) DFR data w ere more protective than the predicted D FR values , which would potentially under estimate residue value s and risk of exposure. Therefore, measured DFR values were used to assess post application exposure for day s 0 through 2
.
 Summary of Dislodgeable Foliar Residue Study on Apple ( MRID 4558420 3) This study

was designed to determine the dissipation of dislodgeable foliar residues (DFR) of fluazinam applied to apple trees at a test site in Concord, Ohio. Fluazinam 500F, a flowable liquid formulation containing 41.1% fluazinam as the ai, was applied as a foliar directed spray using an airblast sprayer to two plots consisting of five apple trees each. One plot received a single application at the reported recommended rate (0.4 lb ai/A) and the other plot received a single application at three times the reported recommended rate (1.2 lb ai/A). A third plot was used to collect untreated (control) samples. Samples were collected prior to the application and at intervals from 1 hr to 35 day s after the application. At each sampling interval, triplicate samples were collected from the control plot and from the treated plots. Field
- fortified samples and storage stability samples were not prepared for this study
. HED and the r egistrant calculated DFR values in μg/cm2 by dividing the corrected residue found in each sample b y the total surface area of each sample (400 cm2 ). Residue values that dropped below the limit of quantitation (LOQ) were assigned a value of 1⁄2L OQ. For both treatment plots, the highest average residue was observed 1 h our after application (0.071 μg/cm 2 for the 1 x plot and 0.086 for the 3 x plot). The average residue dropped to below the LOQ (0.00005 μg/cm 2 ) by day 28 for the 1 x plot and day 35 for the 3 x plot. A significant drop in residues between the Day 2 and Day

4 sampling intervals was seen in both plots. From d ay

2 to d ay 4, the average residue dropped from 0.053 μg/cm2 to 0.0086 μg/cm 2 in the 1 x plot and from 0.056 μg/cm 2 t o 0.0059 μ g/cm 2 in the 3 x plot.Page 53 of 67

A linear regression analysis was conducted using the natural logarithm of the individual foliar residue values. The estimated half
- life values for fluazinam from the 1 x and 3 x plots were 3.06 day s (R2 = 0.937) and 2.93 day s (R2 = 0 .931), respectively
. The significant drop in day 4 residues was the result of a heav y thunderstorm with at least 0.33 inches of rain that occurred on the night before the d ay 4 sampling interval
. The rainfall did not significantl y affect the overall diss ipation curve, but it did result in predicted residues on day 0 (0.045 μg/cm 2 for 1 x rate and 0.046 μg/cm 2 for 3 x rate) that were lower than the actual residue on day

0 (0.071 μg/cm 2 for 1 x rate and 0.086 for 3 x rate). For purposes of this assessment, HED chose to use the actual residues on day 0, rather than the predicted residues on day 0. HED believes that this analy sis provides a more realistic assessment of actual residue decline. Equations/Calculations: The following equations were used to calculate risks for workers performing postapplication activities: Adjusted DFR (μg/cm2 ) = Study DFR (μg/cm2 ) x crop application rate (lb ai/A) Study application rate (lb ai/A) Daily Dermal D ose t (mg/kg
- day) = DFR t (μg/cm2 ) x 1E
- 3 mg/μg x T c (cm 2 /hr) x DA x ET (hrs) BW (kg) Where, t = number of days after application day (days) DFR t = dislodgeable foliage residue on day t (μg/cm2 ) Tc = transfer coefficient (cm 2 /hr) DA = dermal absorption factor (unitless) ET = exposure time (hr/day) BW = body weight (kg)Page 54 of 67

9 .2.2 Postapplication Exposure and Risk The postapplication exposure associated with the use of fluazinam is summarized in Table 9.2.b
. Table 9.2.b . Occupational Postapplication Exposure and Risk for Fluazinam
Crop Activity Application Rate (lb ai/A) Transfer

Coefficient a (cm2 /hr) Norm alized

DFR b (μg/cm2 ) Short - and Intermediate - Term

Daily Derm al Dose c (m g/kg/day) MOE

on Day 0 d Days after Application until MOE ≥100
Carrots H and weeding,

irrigation, and scouting 0.52 300 0.860 0.0295 340 0 H and harvest 2,500 0. 340 0.0971 41 6 Onions hand weeding,

irrigation, and scouting 0.52 300 0.860 0.0295 340 0

Lettuce H and weeding,

thinning 0.99 500 1.637 0.0939 110 0 I rrigation, scouting 1,500 0.520 0.0892 35 8 H and harvest 2,500 0.330 0.0943 21 12

Apples H and weeding,

irrigation, and scoutin g 0.45 1,000 0.080 0.0091 1100 0 H and harvesting, propping, training, hand pruning 1,500 0.080 0.0137 730 0
T hinning 3,000 0.080 0.0274 360 0

a. Transfer coefficients and associated activities from ExpoSAC Policy Memo #003.1 “Agricultural Transfe r Coefficients , ” 8/17/2000. b. DFR = Dislodgeable Foliar Residue from the submitted studies , adjusted to compensate for difference in application rates (AR) between study and actual label application rates
. c. Daily Dermal Dose = [(DFR x Tc x Dermal A bsor ption x 8
- hr Exposure Time)] / [(CF: 1000 μg/mg) x (70
- kg Body Weight)]. d. MOE = NOAEL/Daily Dose (Short
- and intermediate
- term Dermal NOAEL = 1 0 mg/kg/day). 9.2.3 Postapplication Risk Characterization The restricted entry

interval (REI) for fluazi nam is based on the acute toxicity of technical material. Fluazinam is classified as Toxicity Category Ifor eye irritation. Under the Worker Protection Standard for Agricultural Pesticides, active ingredients classified as acute toxicity category Ifor an y of these routes are assigned a 48
- hour REI.Page 55 of 67

Postapplication MOEs were estimated for “Day 0” exposure (i.e., the day of application). In cases where the MOE was less than the LOC of 100 on Day 0, residue dissipation data/assumptions were used to dete rmine the day for which the risk would be not of concern (i.e., MOE of 100 or greater). Based on HED’s postapplication exposure calculations, the dermal risks for all proposed crops were greater than 100 within 48 hours, which is in accordance with the current label REI.

• Apple and onion postapplication dermal risks were 100 or greater within 12 hours of application;
• C arrot postapplication dermal risks were 100 or greater within 48 hours of application for low to medium contact activities (i.e. h and weeding, irrigation, and scouting )
. However, carrots did not reach a MOE of 100 or greater for high contact activities (i.e., hand harvesting) until day 6. Furthermore, lettuce did not reach a MOE of 100 or greater for medium contact activities (i.e., ir

rigation, scouting) until day 8 and for high contact activities (i.e., hand harvesting) until day

12 . Risks from these activities are of concern until the specified intervals have elapsed
. HED recommends that the Regist ration Division ensure that the app ropriate REI is provided on all registered labels. 1 0.0 Data Needs and Label Recommendations 10.1 Toxicology As a result of new data requirements in the 40 CFR Part 158 for conventional pesticide re gistration, an immunotoxicity study is required for fluazinam. Additionally , a subchronic (28
- day) inhalation toxicity

study is required. HED recommends that these studies be made a condition of registration for the proposed uses. 10.2 Residue Chem istry No major deficiencies were noted in the current petition s that would preclude establishing permanent tolerance s for fluazinam residues of concern on head lettuce; leaf lettuce; Onion, bulb, subgroup 3
- 07A; and Bushbe rry , subgroup 13
- 07B. In addition, the deficiency listed below for lettuce field trials needs to be resolved as a condition of registration. A revised Section F is needed as detailed below (860.1550). Because of major data deficiencies, HED does not rec ommend in favor of the establishment of tolerances for apples or carrots. HED also does not recommend in favor of tolerances for animal commodities. The data deficiencies associated with the apple and carrot petitions are discussed below.Page 56 of 67

List of Defic iencies 860.1200 Directions for Use

• The use directions for all the subject crops (lettuce, onions, bushberries, apples, and carrots) should include a prohibition against addition of adjuvants to the spray mixture. The following deficiency applies t o both existing and proposed uses of fluazinam 860.1650 Submittal of Analy tical Reference Standards

• An anal yt ical reference standard for the AMGT metabolite is not available. RD should request that the registrant submit this standard to the EPA’s National Pesticide Repository

as soon as possible. List of Deficiencies b y Petition PP# 8E7506 (L ettuce, Onion, Bushberry Subgroup ) 860.1500 Crop Field Trials

• Samples from the lettuce field trial need to be analyzed for residues of AMGT. The resid ue data should also be supported by data depicting the frozen storage stability of AMGT in the lettuce samples. HED recommends that these data be made a condition of registration for the use on lettuce. 860.1550 Proposed Tolerances

• The registrant sho uld submit a r evised section F in which a tolerance of 0.2 ppm is proposed for Onion, bulb, subgroup 3
- 07A, and a tolerance of 7.0 ppm is proposed for Bushberry , subgroup 13
- 07B.Page 57 of 67

PP# s 9E7570 (Carrots) and 9F7571 (Apples) 860.1340 Residue Anal yt ical Methods

• At the present time, an analy tical method is not available for enforcement of fluazinam tolerances in animal commodities. The registrant should submit an ILV of the revised method. This method needs to be adequate for anal ys is of parent fluazinam as well as the metabolites AMPA and DAPA in animal commodities for which tolerances will be established.

• If the registrant resolves the data deficiencies associated with the apple and carrot petitions and re
- submits the tolerance petitions, multiresid ue method testing data will be required for the regulated animal metabolites, AMPA and DAPA. 860.1480 Meat, Milk, Poultry , and Eggs

• The residue data from the cattle feeding study are not adequate to satisfy data requirements. To support tolerances fo r apples and carrots, the registrant needs to submit a new cattle feeding study . When this study is repeated, the samples need to be anal yz ed as soon as possible after sacrifice in order to minimize degradation of residues. 860.1520 Processed Food and Fe ed (Applies Only to Apple Petition)

• The apple processing study is not adequate to satisfy data requirements. T he processing study

needs to be repeated at a sufficiently high rate that residues of both parent and AMGT are quantifiable in the RAC. In the event that the potential for ph yt otoxicity exists, the application rate does not need to be greater than the rate at which phy to to xicity occurs.

10.3 Occupational and Residential Exposure HED recommends that the Regis tration Division ensure that the appropriate REIis provided on all registered labels. HED also recommends that the PPE required on the label be expanded to all handlers. Workers conducting flagger
- related activities should wear the same PPE as applicato rs in order to reduce exposures.Page 58 of 67

REFERENCES : Fluazinam: Human Health Risk Assessment for Proposed Use on Edible
- Podded Beans, Shelled Succulent and Dried Beans, Brassica Le af y Vegetables, Bushberries, and Ginseng. PC Code: 129098, Petition No: 6E7139, DP Barcode: D334949 , K. Bailey , et al., 8/22/2007 Fluazinam. Petitions for the Establishment of Tolerances and Registration of New Uses on Apples, Carrots, Lettuce, and Bulb Onion Subgroup (3
- 07A), and a Request for a Reduced Tolerance on Bushberry S ubgroup ( 13
- 07B) . Summary of Anal yt ical Chemistry

and Residue Data, D360840, D. Dotson, 3 / 31 /2010 Fluazinam : Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action on Apples, Carrots , Head L ettuce, Leaf Lettuce, and the Bulb Onion Subgroup (3
- 07A), D374522, D. Dotson, 3 / 31 /2010 Tier I Estimated Drinking Waters Concentrations (EDWCs) of Fluazinam and its Transformation Products for the Use in the Human Health Risk Assessment for the R egistration o f the Following New F ood Uses : Lettuce, Apples, Carrots and Bulb Vegetables ( Crop Subgroup 3
- 07A) , D360713, J. Melendez, 2/24/2010 Fluazinam: Occupational and Residential Risk Assessment for Proposed Use of Fluazinam on Apples, Carrots, Lettu ce (Head and Leaf), and Onions (Bulb) , D371446, Z. Figueroa, 3 / 3 0 /2010Page 59 of 67 Appendix A: Toxicology Assessment A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for a food use for fluazinam are in Table A. 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. Table A.1 Test Tec hnical Required Satisfied 870.1100 Ac ute Oral Toxicity
................................ ........................ 870.1200 Ac ute Dermal Toxicity
................................ ................... 870.1300 Ac ute Inhalation Toxicity
................................ ............... 870.2400 Primary Eye Irritation
................................ ..................... 870.2500 Primary Dermal Irritation
................................ ............... 870.2600 Dermal Sensitization
................................ ...................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent)
................................ ................ 870.3150 Oral Subchronic (nonrodent)
................................ .......... 870.3200 21/28
- Day Dermal
................................ .......................... 870.3250 90
- Day

Dermal
................................ ............................... 870.3465 28
- Day

Inhalation
................................ ........................... yes yes yes no yes yes

yes yes

--- no 870.3700a Developmental Toxicity (r odent)
................................ ... 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 Chr onic/Oncogenicity
................................ .................... yes yes yes yes yes yes

yes yes yes yes 870.5100 Mutagenicity

—Gene Mutation
- bacterial
...................... 870.5300 Mutagenicity

—Gene Mutation
- mammalian
................. 870.5375 Mutagenicity

— Structural Chromosomal Aberrations
.... 870.5395 Mutagenicity

—Mammalian Erythrocy te Micronucleus
. yes yes yes yes yes

yes yes yes 870.6100a Ac ute Delayed Neurotox icity . (hen)
............................... 870.6100b 90
- Day

Neurotoxicity (hen)
................................ ........... 870.6200a Ac ute Neurotoxicity Screening Battery (rat)
.................. 870.6200b 90 Day Neurotoxicity Screening Battery (rat)
................ 870. 6300 Develop. Neuro toxicity
................................ .................. no no yes yes yes ---

--- yes yes yes 870.7485 General Metabolism
................................ ....................... 870.7600 Dermal Penetration
................................ ......................... yes no yes

--- 870.7800 Immunotoxicity................................................ yes noPage 60 of 67

A.2 T oxicity Profiles
Table A.2. a. Acute T oxicity Data on Fluazinam Technical Guideline No./ Study Type Test Substance MRID No. Results Toxicity Category 870.1100 Ac ute oral toxicity rats Technical grade fluazinam

(lot #109; 95.3%) 42248603 M: LD50 = 4500 mg/kg F: LD50 = 4100 mg/kg III
Te chnical grade fluazinam (lot #8412
- 20; 95.3%) 42248602 M: LD50 >5000 mg/kg F: LD50 >5000 mg/kg IV Technical grade fluazinam (lot #1/87; 97.9%) 42248604 M: LD50 >5000 mg/kg F: LD50 >5000 mg/kg IV 870.1200 Ac ute dermal toxicity rats Technical grade f luazinam (lot #8303
- 2; 98.5%) 42248605 M: LD50 >2000 mg/kg F: LD50 >2000 mg/kg III

870.1300 Ac ute inhalation toxicity rats Technical grade fluazinam

(lot #109; 95.3%) 42270601 M: LC50 = 0.463 mg/L F: LD50 = 0.476 mg/L II

870.2400 Ac ute eye irrit ation rabbits Technical grade fluazinam

(lot # SNPE B
- 1216, No. 1006; 97.9%) 42248606 Extremely irritating. Corneal opacity did NOT reverse in 21 days. I

870.2500 Acute dermal irritation rabbits Technical grade fluazinam

(lot # SNPE B
- 1216, No. 100 6; 97.9%) 42248607 Slightly irritating IV

870.2600 Dermal sensitization guinea pigs Technical grade fluazinam

(lot # 1030/91; 96.7%) 42274401 Positive NA Ultra
- purified fluazinam (lot #Y910401; 100%) 42248608 Negative NAPage 61 of 67

Table A . 2. b. A cu te Toxicity Data on Fluazinam (F ormulation) Guideline No./ Study Type Test Substance MRID No. Results Toxicity Category 870.1100 Ac ute oral toxicity rats Omega 500F (40% fluazinam) 42974907 M: LD 50 >5000 mg/kg F: LD 50 >5000 mg/kg IV
870.120 0 Ac ute dermal toxicity rabbits Omega 500F (40% fluazinam) 42974908 M: LD 50 >2000 mg/kg F: LD 50 >2000 mg/kg III
870.1300 Ac ute inhalation toxicity rats Fluazinam 50% WP (1) (51.3% fluazinam) 42311001 M: LC 50 = 3.0 mg/L F: LD 50 = 3.4 mg/L IV

87 0.2400 Ac ute eye irritation rabbits Omega 500F (40% fluazinam) 42974910 Slightly irritating III
870.2500 Acute dermal irritation rabbits Omega 500F (40% fluazinam) 42974911 Moderately irritating II
870.2600 Dermal sensitization guinea pigs Ome ga 500F (40% fluazinam) 42974912 Positive NA
(1) Study satisfies requir ement for testing on Omega 500FPage 62 of 67

Table A.2. c . Subchronic, Chronic , and Other Toxicity Studies Guideline No. Study Type MRID No./ (year)

Classification /Doses Results 870.3100 90
- Day oral toxicity rats 42248610 (1984);

44807214 (1998) Acceptable/guideline M : 0, 0.15, 0.77, 3.8, 38 mg/kg/day; F: 0, 0.17, 0.86, 4.3, 44 mg/kg/day NOAEL: Males: 3.8 mg/kg/day; Females: 4.3 mg/kg/day LOAEL Males = 38 mg/kg/day; Females = 4 4 mg/kg/day based on increased liver weights and liver histopathology in males, and increased lung and uterus weights in females.
870.3150 90
- Day oral toxicity dogs 42248611 (1991);

44807215 (1998) Acceptable/guideline M & F: 0, 1, 10, 100 mg/kg/day N OAEL = 10 mg/kg/day LOAEL = 100 mg/kg/day based on retinal effects, increased relative liver weight, liver histopathology and possible increased serum alkaline phosphatase in females and possible marginal vacuolation of the cerebral w hite matter (equivocal ) 870.3200 21
- Day dermal toxicity rats 42270602 (1985)

Acceptable/guideline M & F: 0, 10, 100, 1000 mg/kg/day Systemic NOAEL = 10 mg/kg/day LOAEL = 100 mg/kg/day based on increased AST and cholesterol levels in clinical chemistry determinations (males ) Derm al NOAEL = not identified LOAEL = 10 mg/kg/day based on erythema, acanthosis, and dermatitis
870.3250 90
- Day dermal toxicity NA NA
870.3465 90
- Day inhalation toxicity NA NA
870.3700a Prenatal developmental toxicity rats 42248613 (1985)

A cceptable/guideline F: 0,10, 50, 250 mg/kg/day Maternal NOAEL = 50 mg/kg/day LOAEL = 250 mg/kg/day based on decreased body weight gain and food consumption and increased water consumption and urogenital staining Developm ental NOAEL = 50 mg/kg/day LOAEL = 250 mg/kg/day based on decreased fetal body weights and placental weights, increased facial/cleft palates, diaphragmatic hernia, and delayed ossification in several bone types, greenish amniotic fluid and possible increased late resorptions and postimplant ation loss 870.3700b Prenatal developmental toxicity rabbits 42248616 (1988)

Acceptable/guideline F: 0, 2, 4, 7, 12 mg/kg/day Materna l NOAEL = 4 mg/kg/day LOAEL = 7 mg/kg/day based on decreased food consumption and increased liver histopathology. Devel opm enta l NOAEL = 7 mg/kg/day LOAEL = 12 mg/kg/day based on an increase in total litter resorptions and possible fetal skeletal abnormalitiesPage 63 of 67

Table A.2. c . Subchronic, Chronic , and Other Toxicity Studies Guideline No. Study Type MRID No./ (year)

Classification /Doses Results 870.3700b Prenatal developmental toxicity rabbits 42248615 (1985);

42248614 (1984); 42248617 (1984) Unacceptabl e/guideline F: 0, 0.3, 1, 3 mg/kg/day Materna l NOAEL = 3 mg/kg/day LOAEL = not identified (>3 mg/kg/day) Developm enta l NOAEL = 3 mg/kg/day LOAEL = not identified (>3 mg/kg/day) 870.3800 Reproduction and fertility effects rats 42248619 (1987);

42208406 (1985); 42248618 (1986) Acceptable/guideline F 0 males: 0, 1.5, 7.3, 36.6 mg/kg/day F 0 females: 0, 1.7, 8.4, 42.1 mg/kg/day F 1 males: 0, 1.9, 9.7, 47.3 mg/kg/day F 1 females: 0, 2.2, 10.6, 53.6 mg/kg/day Parental/Systemic NOAEL = 1.9 mg/kg/day LOAEL = 9.7 mg/kg/day based on liver pathology in F 1 males Reproductive NOAEL = 10.6 mg/kg/day LOAEL = 53.6 mg/kg/day based on decreased number of im plantation sites and decreased litter sizes to day 4 post
partum for F 1 females (F 2 litters). Offspring NOAEL = 8.4 mg/kg/day LOAEL = 42.1 mg/kg/day based on reduced F 1 and F 2 pup body weight gains during lactation.
870.4100a Chronic toxicity rats 44839901 (1993)

Acceptable/guideline M: 0, 1.0, 1.9, 3.9 mg/kg/day F: 0, 1.2, 2.4, 4.9 mg/kg/day NOAEL = Males: 1.9 mg/kg/d ay ; Females: 4.9 mg/kg/day LOAEL = Males: 3.9 mg/kg/day; Females: not identified (>4.9 mg/kg/day) based on increased testicular atrophy in males and no effects in females 870.4100b Chronic toxicity dogs 42270603 (1987);

44807219 (1998) Acceptable/guide line M & F: 0, 1, 10, 50 mg/kg/day NOAEL = 1 mg/kg/day LOAEL = 10 mg/kg/day based on gastric lymphoid hyperplasia in both sexes and nasal dryness in females
870.4300 Com bined chronic toxicity/carcino
genicity rats 42248620 (1988);

44807223 (1999); 4515 0201 (2000) Acceptable/guideline M: 0, 0.04, 0.38, 3.8, 40 mg/kg/day F: 0, 0.05, 0.47, 4.9, 53 mg/kg/day NOAEL = Males: 0.38 mg/kg/day; Females: 0.47 mg/kg/day LOAEL = Males: 3.8 mg/kg/day; Females: 4.9 mg/kg/day based on liver toxicity in both sexes, pan creatic exocrine atrophy in females and testicular atrophy in males. Som e evidence of carcinogenicity (thyroid gland follicular cell tum ors) in male rats, but not in fem ales
. 870.4200b Carcinogenicity mice 42208405 (1988); 4807220

(1996) Acceptable/gui deline M: 0, 0.12, 1.1, 10.7, 107 mg/kg/day F: 0, 0.11, 1.2, 11.7, 117 mg/kg/day NOAEL = Males:1.1 mg/kg/day; Females: 1.2 mg/kg/day LOAEL = Males: 10.7 mg/kg/day; Females: 11.7 mg/kg/day based on increased incidences of brown macrophages in the liver of both sexes, eosinophilic vacuolated hepatocytes in males, and increased liver weight in females Clear evidence of carcinogenicity (hepatocellular tum ors) in male mice, but not in fem ales 870.4200b Carcinogenicity mice 44807222 (1996);

44807221 (1998); 45201301 (2000) Acceptable/guideline NOAEL = Males:<126 mg/kg/day, Females: <162 mg/kg/day LOAEL = Males: 126 mg/kg/day; Females: 162 mg/kg/day based on increased liver weights and liver andPage 64 of 67

Table A.2. c . Subchronic, Chronic , and Other Toxicity Studies Guideline No. Study Type MRID No./ (year)

Classification /Doses Results M: 0, 126, 377, 964 mg/kg/day F: 0, 162, 453, 1185 mg/kg/day b rain histopathology in both sexes Equivocal/some evidence of carcinogenicity (hepatocellular tum ors) in male mice, but not in fem ales 870.5100 Bacterial reverse mutation assay (Ames test) 42270605 (1988)

Acceptable/Guideline Up to 2 μg/plate for S. typhimurium strains and up to 250 μg/plate for E. coli (
- S9). Up to 100 μg/plate for S. typhimurium strains and up to 500 μg/plate for E. coli (+ S9) Negative with and without S9 up to cytotoxic concentrations.

870.5100 Bacteri al reverse mutation assay (Ames test) 42270604 (1989)

Acceptable/Guideline Up to 1μg/plate for S. typhimurium strains and up to 250 μg/plate for E. coli (
- S9) and up to 100 μg/plate for S. typhimurium strains and up to 500 μg/plate for E. coli (+S9) Neg ative with and without S9 up to cytotoxic concentrations.

870.5300 In vitro mammalian gene mutation assay 45261801 (2000)

Acceptable/guideline Up to 9 μg/ml (+S9), up to 0.3 μg/ml (
- S9) Negative with S9 activation up to 9 μg/ml. Negative without S9 activation up to 0.3 μg/ml. Com pound tested to cytotoxic concentrations. 870.5300 In vitro mammalian gene mutation assay 45156902 (1986)

Acceptable/guideline Up to 5 μg/ml (+/
- S9) Negativ e with and without S9 activation up to 5 μg/ml. Com pound tested to cytotoxic concentrations. 870.5375 In vitro mammalian chromosome aberration (CHL cells) 42270606 (1988)

Acceptable/guideline Up to 9.5 μg/ml (+S9) up to 4 μg/ml (
- S9) Negative with and without S9 up to cytotoxic concentrations. Cells harvested at 24 and 48 hours in nonactivated studies and at 24 hours in activated studies.
870.5395 Mammalian erythrocyte micronucleus test 44807224 (1999)

Acceptable/guideline 500, 1000, 2000 mg/kg ( oral gavage) Negative at 24 hour sacrifice (500, 1000, 2000 mg/kg). Negative at 24, 48, and 72 hour sacrifices (2000 mg/kg).
870.5550 UDS in primary rat hepatocytes 45156901 (1984)

Unacceptable/guideline 0.05 to 6.25 μg/ml Negative; however there were several serious study deficiencies: treatment time shorter than recommended, no data supporting the claim of cytotoxicity, data variability for major endpoints. 870.5550 Differential killing/growth 42270607 (1988)

Unacceptable /guideline 0.003 to 0.3 μg/disk (
- S9) Negative, however only one replicate plate/dose was used.Page 65 of 67

Table A.2. c . Subchronic, Chronic , and Other Toxicity Studies Guideline No. Study Type MRID No./ (year)

Classification /Doses Results inhibition in B. subtilis 0.3 to 30 μg/disk (+S9) 870.6200a Ac ute neurotoxicity screening battery rats 44807210 (1995)

Acceptable/guideline M & F: 0, 50, 1000, 2000 mg/kg Systemic NOAEL = 50 mg/kg LOAEL = 1000 mg/kg based on soft stools and decreased mo tor activity on day of dosing. Neurotoxicity NOAEL = 2000 mg/kg LOAEL = not identified (>2000 mg/kg) 870.6200b Subchronic neurotoxicity screening battery rats 44807217 (1998);

44 807218 (1998) Acceptable/guideline M :0, 21, 69, 74, 149, 233 mg/kg/day; F: 0, 23, 81, 89, 175, 280 mg/kg/day Neurotoxicity NOAEL = Males: 233 mg/kg/day; Females: 280 mg/kg/day LOAEL = not identified (Males: >233 mg/kg/day; Females: > 280 mg/kg/day)

8 70.6300 Developmental neurotoxicity 46534401, 47018301 and

47037001. Acceptable/Non
- Guideline 0, 2, 10 or 50 mg/kg/day Maternal: NOAEL not established. No toxicity at highest dose tested. Developmental: NOAEL = 2 mg/kg/day. LOAEL = 10 mg/kg/day based on decreased pup weight and gain and delayed balano
- preputial separation.

870.7485 Metabolism and pharmacokinetics rats 44807233 (1995);

43521004 thru 43521008, 43553001 (1993
- 1995) Acceptable/guideline 0.5, 50 mg/kg Only 33
- 40% of the administered dose was absorbed. Most of the administered dose was recovered in the feces (>89%). Excretion via the urine was minor (<4%). Total biliary radioactivity, however, represented 25
- 34% of the administered dose, indicating considerable enterohep atic circulation.

A.3 Executive Summaries For the executive summaries of the toxicology studies submitted for fluazinam, refer to the previous risk assessment that HED prepared for fluazinam (Memo, D 334949 , K
. Baile y , 8/22/2007).Page 66 of 67 Appendix B : Tolerance Summary Table Table B.1. Tolerance Summary for Fluazinam Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity Definition
PP#8E7506 Bushberry, subgroup 13
- 07B 4.5 7.0 Adequate blueberry residue data are available. The recommended tolerance for Subgroup 13
- 07B is the same as that for Subgroup 13B (i.e., 7.0 ppm) The established individual tolerances for aronia berry, buffalo currant, Chilean guava, European barberry, h ighbush cranberry, edible honeysuckle, edible jostaberry, Juneberry, lingonberry, native currant, salal, and sea buckthorn should be deleted because they are included under the revised Bushberry subgroup, 13
- 07B. Onion, bulb, subgroup 3
- 07A 0.15 0.20 Adequate bulb onion residue data are available. Lettuce, head 0.02 0.02 Adequate head lettuce residue data are available. Lettuce, leaf 2.0 2.0 Adequate leaf lettuce residue data are available. PP#9E7570 Carrot, roots 0.8 None * Adequate carrot residue data are available. HED’s tolerance generator directs that the tolerance for this data set should be 0.70 ppm. PP#9F7571 Apples 1.7 None * Adequate apple residue data are available. HED’s tolerance generator directs that the tolerance for this data set sh ould be 1.50 ppm. The USEPA and Canada’s PMRA agreed to establish the tolerance at 2.0 ppm at such time as the data deficiencies are resolved. Apple, pomace, wet 5.0 None * Adequate apple processing data are not available. Cattle, fat 0.03 None An adequate cattle feeding study is not available. Based on the results of the inadequate study, the maximum expected residues in meat byproducts and fat is 0.0 5 ppm . This value can be used as a very conservative residue value for the dietary exposure assessment. Based on the results of the inadequate feeding study, tolerances will probably not be needed f or milk and meat of cattle , goat, horse, and sheep
. Cattle, kidney 0.03 Not required Cattle, liver 0.03 Not required Cattle, meat 0.03 Not required Cattl e, meat byproducts 0.03 None Goat, fat 0.03 None Goat, kidney 0.03 Not required Goat, liver 0.03 Not required Goat, meat 0.03 Not required Goat, meat byproducts 0.03 None Horse, fat 0.03 None Horse, kidney 0.03 Not required Horse, liver 0.0 3 Not required Horse, meat 0.03 Not required Horse, meat byproducts 0.03 None Milk 0.03 Not requiredPage 67 of 67

Table B.1. Tolerance Summary for Fluazinam Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity Definition Sheep, fat 0.03 None Sheep, kidney 0.03 Not required Sheep, liver 0.03 Not required Sheep, meat 0.03 Not required Sheep, meat byproducts 0. 03 None * HED is recommending against the establishment of tolerances on apples and carrots because of deficiencies in the livestock residue analy tical method, the cattle feeding study , and the apple processing study
.
HED recommends that 40CFR §180 .574(a)(1) be amended b y replacing the tolerance expression with the following: “Tolerances are established for residues of f luazinam ( 3
- chloro
-N

- [3
- chloro
2,6
- dinitro
- 4
- (trifluoromethyl)phenyl]
- 5
- (trifluoromethyl)
- 2
- py ridinamine ), including its metabolit es 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

fluazinam.” HED further recommends that 40CFR §180.610(a)(2) be amended by replacing the tolerance expression with the following: “Tolerances are established for residues of fluazinam, 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 b y measuring onl y fluazinam and its metabolite AMGT ( 3
- [[4
- amino
- 3
- [[3
- chloro
- 5
- (triflu oromethyl)
- 2
- py ridinyl]amino]
- 2
- nitro
- 6
- (trifluorometh yl ) phen yl ]thio]
- 2
- (beta
- D
- glucop yr anosyloxy) propionic acid) .”