Page 1 of 40 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 OFFICE OF PREVENTION, PESTICIDES , AND TOXIC SUBSTANCES MEMORANDUM Date: 7 - APRIL - 20 10 SUBJECT: C yazofamid . Human Health Risk Assessment for Proposed Uses on Brassica

(Cole) Leafy

V egetables Crop Group 5, Turnip Greens, Spinach, and Hops . PC Code: 085651 DP Barcode: D370671 Decision No.: 420982 Registration No. : 71512 - 3 Petition No.: 9E7615 Regulatory Action: Section 3 Registration Risk Assessment Type: Single Chemical/A ggregate Case No.: NA T XR No.: NA CAS No.: 120116 - 88 - 3 MRID No.: NA 40 CFR: § 180.6 01 FROM: Nancy

J. Tsaur, Risk Assessor Amelia Acierto, Chemist Kristin Rury , Biologist, ORE Assessor Whang Phang, Toxicologist Risk Assessment Branch 3 (RAB3) Health Effects Division ( 7509P) THROUGH: Paula Deschamp, Branch Chief

Risk Assessment Branch 3 (RAB3) Health Effects Division (7509P) TO : Laura Nollen/Barbara Madden , Risk Management Team 05

Risk Integration, Minor Use and Emergency Response Branch ( RIMUE RB ) Registration Division (7505P)Page 2 of 40

Introduction This document addresses a petition submitted to the Agency regarding cyazofamid . The Interregional Research Project No. 4 (IR - 4) of Rutgers, New Jersey , has submitted a petition (PP# 9E7615 ) to regist er the agricultural end - use product, Ranman® 400SC Fungicide, for use on the B rassica (c ole) leafy

vegetable crop group ( crop group, CG 5), turnip greens, spinach, and hops . The Health Effects Division (HED) of the Office of Pesticide Programs (OPP) is charged w ith estimating the risk to human health from exposure to pesticides. The Registration Division (RD) of OPP has requested that HED evaluate hazard and exposure data and conduct dietary , occupational, residential, and aggregate exposure assessments, as need ed, to estimate the risk to human health that will result from the proposed new uses of cyazofamid. Ranman® 400SC is a 3 4. 5% active ingredient (ai) suspension concentrate (SC) containing the fungicide cyazofamid ( 4 - chloro - 2 - cyano -N,N - dimethyl - 5 -

p - tolyli midazole - 1 - sulfonamide ) . IR - 4 is proposing the following tolerances for use of Ranman® 400SC in/on Brassica (cole) leafy vegetables (CG 5) , turnip greens, spinach, and hops : Comm odity Proposed Tolerance (ppm) Brassica , head & stem, crop , sub group 5A 1.2 Brassica , leafy greens, crop, subgroup 5B 12.0 Turnip Greens 12.0 Spinach 9.0 Hops 10.0 Note to RM: HED recommends modification of the tolerance expressions for cyazofamid according to the new compliance/measurement policy (Interim Guidance on Toler ance Expressions, Steve Knizner, May 27, 2009). HED recommends that the tolerance defin ition entries in 40 CFR §180.601 be revised and that tolerances for the listed commodities be established, as follows: (a) General. (1) Tolerances are established for residues of the fungicide cyazofamid, 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 only the sum of 4 - chloro - 2 - cyano -N,N

- dimethyl - 5 - (4 - methylphenyl) - 1 H - imidazole - 1 - sulfonamide and its metabolite, 4 - chloro - 5 - (4 - methylphen yl ) - 1 H - imidazole - 2 - carbonitrile, calculated as the stoichiometric equivalent of cyazofamid, in or on the commodity . Brassi ca, head and s tem, subgroup 5A ................................ 1.2 ppm B ras sica, leafy

greens, subgroup 5B ................................ .. 12.0 ppm Turnip greens ................................ ................................ ..... 1 2.0 ppm Spinach ................................ ................................ ................. 9.0 ppm Hops ................................ ................................ ................... 10.0 ppm Note to RM: Zero - day

data were not provided with the concurrent storage stability study on leaf lettuce and tomato; IR- 4 is reminded that storage stability st udies should always include a 0 -Page 3 of 40

day sampling interval to establish the residue levels present at the time samples are placed into storage and such data should be submitted in future petitions [see OPPTS 860.1380(d)(6)(i)]. This document contains only thos e aspects of the risk assessment wh ich are affected b y the IR - 4 petition to establish tolerances in/on Brassica (cole) leafy vegetables, turnip greens, spinach, and hops. This document provides a summary of the findings from the data evaluation and subsequent assessment of human health risk resulting from these requests. T he occupational exposure data review for the tolerance petition was performed b y Kristin Rury (RAB3), the residue chemistry

data review and dietary

exposure assessment were completed by Amelia Acierto (RAB3) , and the overall human health risk assessment w as conducted by Nancy J. Tsaur (RAB3); additionall y, the drinking water assessment was conducted b y José Meléndez of OPP’s Environmental Fate and Effects Division (EFED). The most recent human - health risk assessment was conducted in conjunction with a request for use of cyazofamid on fruiting vegetables, okra, grapes east of the Rockies, vegetable greenhouse transplants, and commercial application on residential turf and residential ornam entals (DP#356837, N. Tsaur, 05/20/2009) . The detailed hazard characterization, dose response considerations (explanation of selected endpoints) , absorption, distribution, metabolism, e xcretion (ADME) determinations, FQPA safety factor determination , mode of action, and toxicological effects can be found in a previous risk assessment (DP# 342612 , K . O’Rourke , 03/ 19/20 08).Page 4 of 40 Table of Contents 1.0 EXECUTIVE SUMMARY ................................ ................................ ................................ . 5 2.0 INGREDIENT PROFILE ................................ ................................ ................................ ... 8 2.1 Summary of Proposed Uses ................................ ................................ .......................... 8 2.2 Structure and Nomenclature ................................ ................................ ..................... 10 2.3 Physical and Chemical Properties ................................ ................................ ............. 11 3.0 HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS ............................... 11 3.1 FQ PA Considerations ................................ ................................ ................................ . 12 3.2 Dose - Response Assessment ................................ ................................ ........................ 13 3.3 Endocrine Disruption ................................ ................................ ................................ . 15 4.0 DIETARY EXPOSURE/RISK CHARACTERIZATION ................................ ............. 16 4.1 Pesticide Metabolism ................................ ................................ ................................ .. 16 4.2 Analyti cal Methodology ................................ ................................ .............................. 17 4.3 Food Residue Profile ................................ ................................ ................................ ... 17 4.4 International Residue Limits ................................ ................................ ..................... 20 4.5 Drinking Water Residue Profile ................................ ................................ ................ 20 4.6 Dietary Exposure and Risk ................................ ................................ ........................ 21 4.7 Cancer Dietary Exposure and Risk ................................ ................................ ........... 24 5.0 NON - OCCUPATIONAL/RESIDENTIAL EXPOSURE/RISK PATHWAY .............. 24 6.0 AGGREGATE RISK ASSESSMENTS and RISK CHARACTERIZATION ............. 25 6.1 Acute Aggregate Risk Assessment (Food and Drinking Water) ............................ 26 6.2 Short - and Intermediate - Term Aggregate Risk Assessment ................................ .. 26 6.3 Chronic Aggregate Risk Assessment (Food and Drinking Water) ........................ 27 6.4 Cancer Aggregate Risk Assessment ................................ ................................ .......... 27 7.0 CUMULATIVE RISK ................................ ................................ ................................ ....... 27 8.0 OCCUPATIONAL EXPOSURE ................................ ................................ ...................... 27 8.1 Occupational Handler Exposure and Risk ................................ ............................... 27 8.2 Occupational Postapplication Exposure and Risk ................................ ................... 30 9.0 DATA NEEDS AND LABEL RECOMMENDATIONS ................................ ................ 31 9.1 Chemistry ................................ ................................ ................................ ..................... 31 9.2 Toxicology ................................ ................................ ................................ .................... 31 APPENDIX A. Codes, Chemical Names, and Chemical Structu re of Cyazofamid and

Identified Metabolites ................................ ................................ ................ 32 APPENDIX B. International Residue Limit Status ................................ ........................... 33 APPENDIX C.1. Toxicity Profile of Cyazofamid Technical ................................ ................ 34 APPENDIX C.2. Acute Toxicity of Cyazofamid ................................ ................................ .... 38 APPENDIX D. Rationale for Immunotoxicity Data Requireme nt ................................ ... 39 APPENDIX E. Rationale for Subchronic Toxicity Data Requirement ............................ 40Page 5 of 40

1.0 EXECUTIVE SUMMARY Cyazofamid is a fungicide which b elongs to a novel chemical class based on the cyanoimidazole moiety . Cyazofamid is a broad spectrum fungicide active against oomycete fungi (such as Phytophthora, Plasmopara, Pseudoperonospora, and Pythium ) and Plasmodiophoromycetes ( Plasmodiospora brassi cae ). It specificall y interferes with the cytochrome bc 1 complex (ubiquinol cy

tochrome c oxidoreductase) in the mitochondrial respiratory chain of oomycetes fungi. Background The most recent human health risk assessment for cyazofamid was conducted in May of 200 9 for Section 3 registration on fruiting vegetables, okra, grapes east of the Rockies, vegetable greenhouse transplants, and commercial application on residential t urf and residential ornamentals ( D P# 35 6837 , N. Tsaur , 0 5 /20 /20 0 9 ). There are currently no established Codex Alimentarius or Mexican maximum residue limits (MRL s) for residues of cyazofamid in/on plant or livestock commodities. Canada has established MRL s for residues of c yazofamid in/on seve ral commodities, but has not established maximum residue limits for the commodities of this petition (See Appendix B ) . Proposed Use Profile Brassica and Turnip Greens : Ranman® 400SC is proposed for minor uses on B rassica crop subgroup 5A and 5B , as well a s turnip greens, as a single post transplant soil drench applied to the base of the plants at the rate of 0.118 lb ai/A. Broadcast foliar applications of cyazofamid may be applied at a maximum a pplication rate of 0.072 lb ai/A/application on Brassica leaf y vegetables and turnip greens with no more than six (1 soil + 5 broadcast) applications per crop. Cyazofamid may

be applied during transplantation of Brassica leafy vegetables and turnip greens at a rate of up to 0.665 lb ai per 100 gallons and via soil incorporation at a rate of 0.52 lb ai/A. The maximum seasonal application rate for cyazofamid is 39.5 fl oz per acre per growing season (1.28 lb ai/A/season) for Brassica leafy vegetables and turnip greens. Spinach & Hops : Cyazofamid may be applied to sp inach and hops at a maximum application rate of 0.071 lb ai/Acre. For spinach, no more than five applications of Ranman® 400SC may be applied per crop. For hops, no more than six applications of Ranman® 400SC may be applied per crop. The maximum seasonal application rate is 13.75 fl oz per acre (0.36 lb ai/A) per growing season for spinach and 16.5 fl oz per acre (0.43 lb ai/A) per growing season for hops. Handlers may

apply Ranman® 400SC using aerial, groundboom, chemigation, or airblast equipment. Hazard Assessment Cyazofamid has a low order of acute toxicity via the oral, dermal, and inhalation route s of exposure. It produces minimal but reversible eye irritation , is a slight dermal irritant, and is a weak dermal sensitizer. The propensity of c yazofamid to be a slight dermal irritant and a weak sensitizer might be due to the sulf onamide moiety in the compound. Following repeated administration in more than one species, cyazofamid seems to have mild or low toxicity . In rats, the kidney is the majo r target organ following subchronic dosing. NoPage 6 of 40

adverse kidney

effects or other toxicity

findings were observed following chronic exposures. Skin lesions were observed in male mice onl y, likely due to sy stemic allergy . In dogs, there were no major toxici ty

findings. In the acute neurotoxicity study , there were no indications of treatment - related adverse neurotoxicity . The pre - and post - natal toxicology database for cyazofamid includes rat and rabbit developmental toxicity

studies and a two - generation reproduction toxicity study in rats. There was some evidence of increased susceptibility following in utero exposure to rats in the prenatal developmental toxicity

study ; the increased incidence of bent ribs in the high dose fetuses was considered adverse and was used for setting th e developmental NOAEL/LOAEL (no observed adverse effect level/lowe st observed adverse effect level). HED considers this approach conservative and highly

protective because bent ribs are a reversible developmental anoma ly rather than a malformation. C yazofamid is classified as “not likely to be carcinogenic to humans” based on the lack of evidence of carcinogenicity in both the rat and the mouse studies . Additionally , cyazofamid does not appear to have mutagenicity potential, bas ed on several negative in vivo and in vitro studies. Dose Response Assessment and Food Quality Protection Act (FQPA) Decision HED has examined the toxicology data and determined that there are no concerns or residual uncertainties for pre - and or postnata l toxicity . On this basis, the FQPA s afety factor should be removed ( i.e. reduced to 1X ) for all potential exposure scenarios of cyazofamid. Furthermore, HED does not believe that conducting either a functional immunotoxicity study or an acute neurotoxic ity

study will result in lower NOAELs than the regulatory doses for risk assessment, and an additional factor (UF DB ) for database uncertainty is not needed to account for lack of these studies. Additionally , the cyazofamid risk assessment team evaluated the quality of the exposure data, and based on these data, agreed that the FQPA SF could be reduced to 1X . Drinking W

ater Assessment The highest acute (peak) and chronic (mean) estimated drinking water concentrations (EDWCs) were estimated for surface water using the PRZM/EXAMS model. For the purpose of this unrefined dietary

assessment, HED used the highest calculated EDWCs for surface water based on the conservative screening - level estimates : 136 ppb for the acute analy sis and 133 ppb for the chronic analy sis. This approach may significantly

overestimate dietary

exposure to cyazofamid from drinking water. Dietary Exposure Estimates For the acute anal ys is, an acute endpoint was not identified for the general population including infants and children, b ecause no effects were observed which could be attributed to a single - dose exposure. D ietary (food and drinking water) exposure of females 13 - 49 years old is well below HED’s level of concern (LOC) at the 95 th percentile of exposure. Combined dietary exp osure from food and drinking water is estimated at 0.01214 mg/kg/day , equivalent to 1 .2 % of the acute Population Adjusted Dose (aPAD). For the chronic anal ys is, dietary (food and drinking water) exposure is estimated at 0. 004945 mg/kg/day ( <1% of the chro nic Population Adjusted Dose (cPAD)) for the general U.S. population and 0. 01108 mg/kg/day (1.2 % of the cPAD) for infants <1 year old, the populationPage 7 of 40

subgroup with the highest estimated chronic dietary exposure to cyazofamid ; both cPADs are below HED’s LOC . Residential Exposure Estimates Non - occupational handler exposure is not expected from residential turf and ornamentals because application is limited to licensed and certified operators . However, postapplication exposure is possible for children and ad ults . Non - occupational scenarios were previously assessed and the MOEs were estim ated for “Day 0" exposure (i.e. the day

of application). All postapplication MOEs , including the children’s aggregate, are greater than 100, and therefore, are not of concer

n to HED (DP#356837, N. Tsaur, 05/20/2009). Aggregate Exposure Scenarios and Risk Conclusions Human health aggregate risk assessments have been conducted for acute aggregate exposure (food + drinking water), short - /intermediate - term aggregate exposure (fo od + residential exposure + drinking water), and chronic aggregate exposure (food + drinking water) scenarios. A cancer aggregate risk assessment was not performed because cyazofamid is classified as “not likely to be carcinogenic to humans . ” All potenti al exposure pathway s were assessed in the aggregate risk assessment. MOEs for aggregate exposure range from 1, 0 0 0 to 1,500 . None of the aggregate expo sure and risk estimates are not of concern to HED . Occupational Exposure Estimates No chemical - specific handler exposure data were submitted to support the agricultural uses petition (PP# 9E7615 ) . In accordance with HED policy, occupational handler exposures were estimated using the Pesticide Handlers Exposure Database (PHED) Surrogate Exposure Guide (revis ed August, 1998). The results of the handler occupational exposure and risk assessment for the proposed agricultural uses indicate that risks are not of concern with baseline clothing, or when gloves are worn. The total short/intermediate - term MOEs range from 23,000 to 220,000; which are greater than the LOC of 100, and are not of concern to HED. The results of the occupational postapplication exposure and risk assessment indicate that the MOEs are greater than 100 on the day of application and therefore , are not of concern to the Agency . Under the Worker Protection Standard (WPS) for Agricultural Pesticides, active ingredients classified as acute to xicity categories III or IV for dermal and inhalation routes are assigned a 12 - hour restricted reentry int erval ( REI ) . Therefore, the 12 - hour REIthat appears on the proposed label is adequate. Environmental Justice Considerations Potential areas of environmental justice concern, to the extent possible, were considered in the human - health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http://www. eh.doe.gov/nepa/tools/guidance/Volume1/2 - 6 - EO_12898envjustice.pdf). OPP ty picall y considers the highest potential exposures from the legal use of a pesticide when conducting human health risk assessments including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., and people who may

be exposed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best available information.Page 8 of 40

Review of Human Research This risk assessment relies in part on data from PHED studies in which adult human subjects were intentionall y exposed to a pesticide or other chemical. These studies have been determined to require a review of their ethical conduct, have receive d that review , and have been determined to be ethical . 2.0 INGREDIENT PROFILE Cyazofamid is a broad - spectrum fungicide ai that controls oomycete fungi (such as Phytophthora , Plasmopara , Pseudoperonospora , and Pythium ) and Plasmodiophoromycetes ( Plasmodiospora brassicae ). It inhibits all stages of fungal development in the life cycle of Phytophthora infestans which causes late blight disease i n potatoes and tomatoes, and inhibits the germination and formation of zoosporang ia, germination of cy tospores, zoospore mobility , and mycelial growth. It controls downy mildew i n cucurbit vegetables and grapes. Ranman® 400 SC ( EPA Reg. No. 71512 - 3) is proposed for minor use in the control of club root ( Pasmodiophora brassiceae ) an d downy mildew (Peronospora parasitica ) in Brassica vegetables and turnip greens , white rust ( Albugo occidentalis ) disease in spinach; and down y mildew ( Pseudoperonospora humuli ) in hops. 2.1 Summary of Proposed Uses IR - 4 submitted a Section B specifyi ng the proposed uses of Ranman® 400SC, along with a specimen label reflecting general use directions (PP#9E7615) . A summary of the proposed use directions for cyazofamid is presented below in Table 2.1 . Ranman® 400SC is proposed for minor uses on B rass ica crop subgroup 5A and 5B , as well as turnip greens, as a single post transplant soil drench applied to the base of the plants at the rate of 0.118 lb ai/A followed by multiple ( five) foliar applications at a target rate of 0. 072 lb ai/A/application with a maximum seasonal foliar application rate of 0.3 60 lb ai/A or a total application rate of 0.478 lb ai/A/season (1 soil drench + 5 foliar applications). Soil drench application was not proposed for spinach or hops. The formulated product is proposed for use on spinach as five foliar spray s at the target rate of 0.07 1 lb ai/A/application with a maximum seasonal rate of 0.36 lb ai/A and six foliar applications on hops at the target rate of 0.071 lb ai/A/application with a maximum seasonal rate of 0.426 lb ai/A. Re - treatment intervals (RTIs) of 7 to 10 days are proposed for all the crops, starting when disease is first detected or when weather or disease pressure is expected to initiate a disease epidemic . Preharvest intervals (PHI s) are proposed at day 0 for the B rassica leafy vegetables , turnip greens, and spinach , and 3 day s for hops. Except for hops, Silwet L - 77, a non - ionic organosilicone surfactant, is recommended to be tank mixed at a 4:3 ratio for all foliar spray s.Page 9 of 40

Table 2.1 . Summary of Directio ns for Use of Ranm an® 400SC (EPA Reg. No. 71512 - 3) . Applic. Timing, Type, and Equip. Applic. Rate

fl oz (lb ai/A) Max. No.

Applic. per Season Max.

Seasonal Applic. Rate fl oz (lb ai/A) RT I

(days) PHI (days) Use Directions and Limitations Crop Group 5, B rassica (Cole) Leafy V egetables: b roccoli; Chinese broccoli (gai lon); broccoli raab (rapini); Brussels sprouts; cabbage; Chinese cabbage (bok choy); Chinese cabbage (napa); Chinese mustard (gai choy); cauliflower; cavalo broccolo; collards; kale; kohlrab i;

mizuna; mustard greens; mustard spinach; rape greens; Tu rnip G reens 1,2,3,4 Transplant Soil Drench (for control of Club root disease) 12.9 to 25.75

(0.333 - 0. 665 / 100 gal) 1 25.75 (0.665 lb ai/100 gal ) NA NA Soil drench immediately after transplant : make a single application within the rate range listed and apply 1.7 fl. oz per plant as transplant water. Soil Incorporation (for control of Club root disease) 2 20

(0.52) 1 20 (0.52) NA NA Apply in a water volume of at least 50 gal per acre. Transpla nt the seedlings into the treated band. If planting into a bed, a broadcast application can be made prior to forming the bed. Foliar (For the control of Downy mildew disease) 3 2.75

(0.072) 5 13.75 (0.36) 7 to 10 0 Begin spray when disease is first seen or weather and downy mildew disease pressure are expected to initiate a disease epidemic. Use longer interval for preventive or low disease pressure. Do not apply more than six (1 soil + 5 foliar) applications of RANMAN® 400SC per season. Spinach Foliar (For control of white rust disease) 5 2.1 to 2.75

(0.054 to 0.071) 5 13.75 (0.36) 7 to 10 0 Begin spray when disease is first seen or weather and white rust disease pressure are expected to initiate a disease epidemic. Use longer interval for preventi ve or low disease pressure. Hops Foliar ( f or control of Downy mildew ease) 6 2.1 to 2.75

(0.054 to 0.0 (0.0 71) 6 16.5 (0.426) 7 to 10 3 Begin spray when disease is first seen or weather and downy mildew disease pressure are expected to initiate a disease epidemic. Use longer interval for preventive or low disease pressure. Use water sp r ay

of at least 100 gal/A .Page 10 of 40 1 Resistance management : Do not apply more than six (1 soil + 5 foliar) applications of Ranman® 400SC per crop. Alternate foliar sprays of Ranman® 400SC with a fungicide with a different mode of action. DO NOT make mo re than three consecutive applications of Ranman® 400SC followed by at least three applications of fungicides having different modes of action before applying additional Ranman® 4 00SC. 2 Soil Incorporation: Alternatively, if desired and for soil with low infiltration rates, apply 20 fl oz per acre in a minimum bandwidth of 9 inches along the planting row and incorporate to a soil depth of 6 to 8 inches with a precision incorporat or in the same operation. 3 Use of an organosilicone and a nonionic surfactant is recommended when disease infection is severe at water volumes up to 60 gal/A. 4 Restrictions: Do not apply more than 39.5 fl oz per acre per crop growing season [1 soil ap plication at 25.75 fl oz/A and 5 foliar applications at 2.75 fl oz/A/application (13.75 fl oz/A)] . 5 Resistance management : Do not apply more than five applications of Ranman® 400SC per crop. Alternate foliar sprays of Ranman® 400SC with a fungicide with a different mode of action. DO NOT make more than three consecutive applications of Ranman® 400SC followed by at least three applications of fungicides having different mo des of action before applying additional Ranman® 400SC. 6 Resistance management : Do not apply more than six applications of Ranman® 400SC per crop. Alternate foliar sprays of Ranman® 400SC with a fungicide with a different mode of action. DO NOT make more than three consecutive applications of Ranman® 400SC followed by at least three ap plications of fungicides having different mo des of action before applying additional Ranman® 400SC . The submitted use directions are sufficient to allow evaluation of the submitted residue data relative to the proposed uses. The use direction s are acco rding to the proposed supplemental label. HED notes that soil incorporation of Ranman® 400 SC at the rate of 20 fl oz per acre before transplant is included i n the supplemental label as an alternative to the post - transplant soil drench application. N o data have been submitted to support the soil incorporation method. However, HED notes that incorporation of Ranman® 400 SC into the soil (before transplant) is already on the current label and has been used on crop field studies from earlier petitions (PP #8E7427). No further data are required. 2.2 Structure and Nomenclature The chemical structure and nomenclature of the technical grade of cyazofamid and its metabolite CCIM ( 4 - chloro - 5 -

p - tolylimidazole - 2 - carbonitrile) are shown in Table 2.2 . Table 2.2 . Test Compound Nomenclature. Com pound Chemical Structure

N N C H3 Cl CN S O 2 N ( C H3 ) 2 Common name Cyazofamid Com pany experimental name N/A IUPAC name 4 - chloro - 2 - cyano -N, N - dimethyl - 5 -

p - tolylimidazole - 1 - sulfonamide CAS name 4 - chloro - 2 - cyano -N,N - dimethyl - 5 - (4 - methylphenyl) - 1 H - imid azole - 1 - sulfonamide CAS registry number 120116 - 88 - 3 End - use product (EP) Ranman® 400SC Agricultural Fungicide (EPA Reg. No. 71512 - 3)Page 11 of 40

Table 2.2 . Test Compound Nomenclature. Com pound Chemical Structure of metabolite

N H N C H3 Cl CN Common name CCIM IUPAC name 4 - chloro - 5 - p - tolylimidazole - 2 - carbonitrile CA S name 4 - chloro - 5 - (4 - me thylphenyl) - 1 H - imidazole - 2 - carbonitrile 2.3 Physical and Chemical Properties The phy sicochemical properties of the technical grade of cyazofamid are shown in Table 2.3 . Table 2.3 . Physicochemical Properties of the Technical Grade Cyazofamid. Parameter Value Reference Melting point (°C) 152.7 PMRA Regulatory Note REG2006 - 05 on Cyazofamid, 12/6/06 pH 4.9 e - Pesticide Manual, 13 th Edition Density at 20 °C (g/mL) 1.446 Water solubility (at 20 °C) pH Solubility (mg/L) REG2006 - 05 5 7 9 0.121

0.107 0.109 Solvent solubility (at 21.2°C) Solvent Solubility (g/L) Acetone Ethyl acetate Methanol Dichloromethane Toluene Hexane n - Octanol Acetonitrile 2 - Propanol 43.1

16.19 1.74 94.82 6.0 0.03 0.04 29.446 0.43 Vapor pressure at 25°C <1. 33 x 10 - 5 Pa Dissociation constant (pKa) Does not dissociate in water. No pKa in the pH range of 2 - 12. Octanol/water partition coefficient LogK OW = 3.2 KOW = 1.585 x 10 3 UV/visible absorption spectrum pH Λ max (nm) 2 7 10 285

279 287 3.0 HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS References:

- Cyazofamid [IFK

- 916]

– Report of the Hazard Identification Assessment Review Committee. Ghazi Dannan, 03/03/20 04.

- Cyazofamid. Human Health Risk Ass essment for Proposed Uses on Fruiting Vegetables and Okra, Grapes East of the Rocky Mountains, Vegetable Greenhouse Transplants, and Commercial Application on Residential TurfPage 12 of 40

and Residential Ornamentals . Nancy J. Tsaur , DP# 356837 , 0 5 /20 /20 09 .

- Hu man Health Risk Assessment to Support the Registration of Cyazofamid for Use on Carrot . Kelly O’Rourke, DP#342612, 03/19/2008. The toxicology

database for cyazofamid is sufficient to characterize the hazard, to conduct FQPA assessment, and to select toxicity endpoi nts for risk assessment. Data quality is acceptable and meets the criteria set in the OPPTS guidelines and 40 CFR § 158.500. However, under the current data requirement guidelines, functional immunotoxicity data (OPPTS 8 7 0.7800) shall be require d as a con dition of registration. To address the issue of the immunotoxicity

data gap and the associated database uncertainty factor, RAB3 has examined the entire database of cyazofamid and concluded that the toxicology database of this chemical does not show any

e vidence of biologicall y relevant structural effects o n the immune sy stem that relate to this chemical. The overall weight of evid ence suggests that this chemical does not directly target the immune sy stem . HED does not believe that conducting a functional immunotoxicity

study will result in a lower NOAELthan the regulatory dose s for risk assessment, and an additional factor for database uncertainty (UF DB ) is not needed to account for lack of this study . A ddition ally , a subchronic neurotoxicity study is not available. Under the current rules (40 CFR § 158.500), a subchronic neurotoxicity study is required. However, based on the available data, conducting a subchronic neurotoxicity study is unlikely to result in a lower NOAEL than the available relevant t oxicity results because the acute neurotoxicity study , which tested dose levels as high as 2000 mg/kg, shows no neurotoxic effects with gavage do s ing. Neurotoxicity is also not demonstrated in subchronic, chronic, reproduction, or developmental toxicity s tudies. At this time, the lack of a subchronic neurotoxicity study does not present an y uncertainty for evaluating the toxicity

of cyazofamid. Therefore, a database uncertainty factor (UF DB ) for lack of a subchronic neurotoxicity

is not needed. The de tailed hazard characterization, dose response considerations (explanation of selected endpoints) , absorption, distribution, metabolism, excretion (ADME) determinations, FQPA safety factor determination , mode of action, and toxicological effects can be foun d in a previous risk assessment (DP# 342612 , K . O’Rourke , 03/ 19/2008). 3.1 FQ PA Considerations Based on the hazard and exposure data, the HED cyazofamid risk assessment team recommend s that the FQPA SF be reduced to 1X . The recommendation is based on the following:

 The toxicology

database for cyazofamid is complete for the purposes of this risk assessment and for the characterization of potential pre - and postnatal risks to infants and children. Recent changes to 40 C FR § 158.500 now require subchronic neurotoxicity and immunotoxicity

studies from the pesticide registrant. Although both of these studies have yet to be submitted, as discussed in Section 3.0, the available toxicology data do not show neurotoxicity

or immunotoxicity ; therefore, a database uncertainty factor for the lack of these studies is not needed.Page 13 of 40

 The prenatal developmental toxicity study in rabbits and the two - generation reproduction study did not show an y i ndication of increased susceptibility (qual itative or quantitative). For both studies the highest tested dose was at or greater than the limit dose (1,000 mg/kg/day). However, in the rat developmental toxicity study , there was quantitative evidence of in utero susceptibility ; increases in fetuses with bent ribs were seen at 1,000 mg/kg/day

(top dose) in the absence of maternal toxicity . The developmental NOAEL was 100 mg/kg/day

and the maternal NOAEL was 1,000 mg/kg/day . HED believes that bent ribs are a reversible developmental anomal y rather th an a malformation and a clear NOAEL is established for this effect. In addition, using this endpoint for setting the developmental NOAEL/L OAEL in the rat study is a conservative approach.

 The available data do not demonstrate neurotoxicity .  The dietary

exposure assessments (food and w ater), which emplo yed tolerance - level resides, 100% crop treated, high - end estimates of water concentrations (EDWCs), are conservative and high - end assessments . They do not underestimate the potential dietary exposures. The calculated residential risks represent conservative estimates of exposure because maximum application rates are used to define residue levels. Exp osures are unlikely to be under estimated because the assessment is a screening - level assessment. 3.2 D ose - Response Assessment Table s 3.2 a and 3.2b summarize the toxicological endpoints for cyazofamid for use in dietary and occupational human health risk assessments, respectivel y. In addition to the detailed overview from a previous assessment, a study (28 - d ay dose - range finding study in rats , Guideline 870.3100 ) has been added to the toxicity profile in Appendix C . Also, a new toxicological endpoint has been selected with respect to short - /intermediate - term incident al oral exposures for children 3 to <6 ye ars old as shown in Table 3. 2 a . Please refer to the listed references for further extensive details and refer to Appendix C for the toxicity profile tables. Aside from consideration of the 28 - d ay oral range - findin g study in the rat for selection of an incidental oral endpoint , the hazard characterization and endpoint selection from the previous risk assessment are applied directl y to this section. Table 3.2a. Toxicological Doses and Endpoints for Cyazofamid for Use in Dietary and Non - Occupational

Hum an Health Risk Assessments . Exposure/ Scenario Point of

Departure (PoD) Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects Ac ute Dietary (General Populati on, including Infants and Children) No adverse effects were observed which could be attributed to a single - dose exposure for the

general population . Ac ute Dietary (Females 13 - 49 years of age) NOAEL = 100

mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Ac ute Rf D = 1.0 mg/kg/day Rat Prenatal Developmental Toxicity

(MRID 45408933) LOAEL = 1,000 mg/kg/day based on developmental toxicity findings of increased incidence of bent ribs.Page 14 of 40

Table 3.2a. Toxicological Doses and Endpoints for Cyazofamid for Use in Dietary and Non - Occupational

Hum an Health Risk Assessments . Exposure/ Scenario Point of

Departure (PoD) Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects Chronic Dietary (All Populations) NOAEL= 94.8

mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Chronic RfD

= 0.948 mg/kg/day 18 - Month Mouse Oral Carcinogenicity

(MRID 45408932) LOAEL = 985 mg/kg/day based on increased skin lesions. Incidental Oral Short - Term

(1 - 30 days) and Intermediate Term (1 - 6 mo nths) NOAEL= 30

mg/kg/day UF A = 10X

UF H = 1 0X FQPA SF = 1X Residential

LOC for MOE = 100 90 - Day oral toxicity study in rats. LOAEL= 295 mg/kg based on i ncreased number of basophilic tubules of the kidneys, increased urinary volume, pH, & protein. This toxicity endpoint is also supported by th e r esults of a 28 - day

oral dose range - finding study in rats. In this study, at 370 mg/kg/day or above increased incidence of basophilic tubules in the kidneys was found. Dermal Short Term (1 - 30 days) and Intermediate Term (1 - 6 mo nths) For CHILDREN:

No toxi city was found at 1000 mg/kg in a 28 - day dermal toxicity study ; therefore, in the absence of hazard identified for this population, a risk assessment is not necessary. For ADULTS: NOAEL = 100 mg/kg/day (Dermal Absorption Rate = 37%) UF A = 10X

UF H = 10X F QPA SF = 1X Ac ute RfD =

1.0 mg/kg/day Rat Prenatal Developmental Toxicity

(MRID 45408933) LOAEL = 1,000 mg/kg/day based on developmental toxicity findings of increased incidence of bent ribs. Inhalation Short Term (1 - 30 days) and Intermediate Term (1 - 6 months) No residential exposure is expected via inhalation route. Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant

tumor increases in two adequate rodent carcinogenicity studie s. Point of Departure (Po D) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (inter species). UF H = potential variation in sensitivity among members of th e human population (intra species ). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.Page 15 of 40

Table 3.2 b . Summary of Toxic ologic al Doses and Endpoints for C yaz ofamid for Use in Occupational Hum an

Health Risk Assessments . Exposure/ Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk Assessment Study and Toxicological Effects Dermal Short Term (1 - 30 days) and Intermediate Term (1 - 6 mo nth s) Oral Study

NOAEL= 100 mg/kg/day (Dermal Absorption Rate = 37%) UF A = 10X

UF H = 10 X Occupational LOC

for MOE = 100 Rat Prenatal Developmental Toxicity

(MRID 45408933) LOAEL = 1,000 mg/kg based on developmental toxicity findings of increased incidence of bent ribs. Dermal Long Term (>6 mo nths) NOAEL=

94.8 mg/kg/day (Dermal Absorption Rate = 37%) UF A = 10X

UF H = 10X Occupational LOC

for MOE = 100 18 - Month Mouse Oral Carcinogenicity

(MRID 45408932) LOAEL = 985 mg/kg/day based on increased skin lesions. Inh alation Short - Term

(1 - 30 days) and Intermediate Term (1 - 6 mo nths) NOAEL=

100 mg/kg/day UF A = 10X

UF H = 10X Occupational LOC

for MOE = 100 Rat Prenatal Developmental Toxicity

(MRID 45408933) LOAEL = 1,000 mg/kg based on developmental toxicity findings of i ncreased incidence of bent ribs. Inhalation Long - Term

(>6 mo nths) NOAEL=

94.8 mg/kg/day UF A = 10X

UF H = 10X Occupational LOC

for MOE = 100 18 - Month Mouse Oral Carcinogenicity

(MRID 45408932) LOAEL = 985 mg/kg/day based on increased skin lesions. Cancer ( oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant

tumor increases in two adequate rodent carcinogenicity studies. Point of Departure (P o D) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect l evel. UF = uncertainty factor. UF A = extrapolation from animal to human (inter species). UF H = potential variation in sensitivity among member s of the human population (intra species ). MOE = margin of exposure. LOC = level of concern. N/A = not applicable. 3. 3 Endocrine Disruption As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally

occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employ s a two - tiered approach to making the statutorily requi red determinations. Tier 1 consists of a battery of 11 screening assay s to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal sy stems. Chemicals that go through 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 identi fy an y adverse endocrine related effects caused by the substance, and establish a dose - response relationship between the dose and the E, A, or T effect.Page 16 of 40

Between October 2009 and February 2010, EPA issued test orders/data call - ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathway s such as food and water, residential activity , and certain post - application a gricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors. Cyazofamid 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 policies and procedures, the list of 6 7 chemicals, the test guidelines and the Tier 1 screening battery , please visit our website: http://www.epa.gov/endo/. 4 .0 DIETARY EXPOSURE/RISK CHARACTERIZATION References:

- Cyazofamid. Tolerance Pe tition for Uses on Brassica (Cole) Leafy Vegetables Crop Group 5, Turnip Greens, Spinach, and Hops. Summary of Analytical Chemistry and Residue Data . DP# 371162 , Amelia Acierto , 0 2 /24 /20 10 .

- Cyazofamid: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for Tolerance Petition and Proposed Section 3 Amendment Registration for Uses on Brassica (Cole) Leafy Vegetables Crop Group 5, Turnip Greens, Spinach, and Hops . D P# 371163 , Amelia Acierto, 03/ 08 /20 10 .

- Cyazofamid - Meeting Report of the Metabolism Assessment Review Committee (MARC) . DP#298915, Amelia Acierto, 02/18/20 04. The exposure pathway s resulting from use of this chemical are dietary (food and drinking water), residential, and occupational. 4 .1 Pesticide Metabol ism Nature of the Residue

– Plants The nature of the residue in plants is adequatel y understood based on previously submitted metabolism studies on grape, potato, and tomato. HED concluded that, for the risk assessment and tolerance expression, parent and CCIM are the residues of concern for plant commodities (DP#298915, A. Acierto , 02/18/2004) . Nature of the Residue

– Livestock T he current uses of cyazofamid fall under 40 CFR § 180.6(a)(3) ( i.e. there is no reasonable expectation of finite residues in livestock commodities). The nature of residues in livestock is adequatel y understood based on the previousl y submitted goat and hen metabolism studies. Based on the available ruminant metabolism studies in goats, HED rec ommended the following metabolites be anal yz ed f or future cattle feeding studies : cyazofamid, CCIM, CCBA ( 4 - (4 - chloro - 2 - cyanoimidazol - 5 - yl )benzoic acid ; see Appendix A ), CCBA - cy steine conjugate. Confined Accumulation in Rotational Crops No confined accumu lation in rotational crop study was submitted with this petition. However, studies were submitted in conjunction with an earlier petition (PP#1F06305). The results ofPage 17 of 40

these data showed that cyazofamid and structurall y related metabolites are not expected to be present at a level greater than 0.01 ppm in/on three representative rotational crop commodities at a plant - back interval of 30 day s. Therefore, HED has concluded that a rotational crop plant - back interval (PBI) of 30 day s would be appropriate for the cyazofamid end - use labels. 4 .2 Analytical Methodology Residue Analytical Methods

– Plants An acceptable anal yt ical method is available for enforcement purposes. An adequate data collection method, “Independent Lab oratory Validation of the Residue Method for IKF - 916 and CCIM in T omatoes ” , Document Number 013033 - 0, Py xant Lab s Inc, with slight modification , was used to determine the residues of cyazofamid and CCIM. Quantitation of the residues of cyazofamid and CCIM was achieved by liquid chromatography

/mass spectrometry

/mass spectrometry

(LC/MS/MS). Storage Stability Adequate storage stability data are available to support the storage durations and conditions of samples of cabbage, mustard greens, spinach and hops. Although the concurrent recoveries were acceptable for broccoli, the storage stability data were erratic which, according to the petitioner , may have been due to the spiking solution that appeared to have degraded (separated) during frozen storage . There are sufficient data from the representative crop group 5 to support the storage stability data for broccoli. No additional storage stability study is required. 4 .3 Food Residue Profile T olerances have been establis hed in 40 CFR §180.601 (a) for the combined residues of cyazofamid and CCIM expressed as cyazofamid in/on carrot , roots at 0.09 ppm, okra at 0.40 ppm, potato at 0.02 ppm, vegetable , cucurbit , group 9 at 0.10 ppm, and vegetable, fruiting, group 8 at 0. 4 0 ppm . In addition, tolerances with regional registrations are established in 40 CFR §180.601 (c) in/on grape at 1.5 ppm. The current request for registration is for a proposed use on Brassica (cole) leafy

vegetables, turnip greens, spinach, and hops. Crop Fi eld Trial Data To support this petition , crop field trial data from broccoli, cabbage, mustard greens, spinach, and hops were submitted. The crop field trial data submitted are adequate to support the proposed new minor use s of cyazofamid in/on B rassica v egetables, turnip greens, spinach , and hops . All raw agricultural commodities were analyzed for residues of cyazofamid and CCIM using the LC/MS/MS method which was validated prior to and concurrently with field samples. Results of the crop field trials are summarized in Table 4 .3 a .Page 18 of 40

T able 4 .3 a. Summary of Residue Data from Crop Field Trials with Cyazofamid . Commodity Analyte Total Application Rate (lbs ai/A) PHI

(days) Residue Levels (ppm)

n Min. Max. HAFT 1 Median 2 (STMdR) Mean 2

(STMR) Standard

Deviation 2 Broccoli Broccoli Flower Head Cyazofamid 0.479

– 0.552 0 12 0.18 0.91 0.84 0.36 0.41 0.22

CCIM NA 3 0 12 < 0.01 < 0.01 0.005 0.005 0.005 0 Cabbage Cabbage Head with Wrapper Leaves Cyazofamid 0.467

– 0.531 0 18 0.12 0.87 0.75 0.27 0.32 0.21

CCIM NA 3 0 18 < 0.01 0.025 0.02 0.01 0.01 0.01 Mustard Greens Mustard Greens (leaves) Cyazofamid 0.472

– 0.503 0 18 1.3 6.8 6.3 3.7 3.9 1.7 Mustard Greens (leaves) Cyazofamid 0.477 1 2 1.2 1.4 1.3 1.3 1.3 0.14 Mustard Greens (leaves) Cyazofamid 0.477 3 2 0. 33 0.38 0.36 0.36 0.36 0.035 Mustard Greens (leaves) Cyazofamid 0.477 6 2 0.061 0.066 0.064 0.064 0.064 0.0035 Mustard Greens (leaves) Cyazofamid 0.477 7 2 0.022 0.024 0.023 0.023 0.023 0.0014 Mustard Greens (leaves) CCIM NA 0 18 0.030 0.19 0.18 0.053 0 .081 0.053 Mustard Greens CCIM NA 1 2 0.019 0.019 0.019 0.019 0.019 0 (leaves) CCIM NA 3 2 <0.01 0.012 0.009 0.009 0.009 0.005 Mustard Greens CCIM NA 6 2 <0.01 <0.01 0.005 0.005 0.005 0 (leaves) CCIM NA 7 2 <0.01 <0.01 0.005 0.005 0.005 0 Spinach Leav es Spinach Leaves Cyazofamid 0.347 - 0.366 0 20 1.4 6.5 6.4 3.1 3.2 1.4 Spinach Leaves Cyazofamid 0.365 1 2 1.6 2.5 2.1 2.1 2.1 0.64 Spinach Leaves Cyazofamid 0.365 3 2 1.2 1.2 1.2 1.2 1.2 0 Spinach Leaves Cyazofamid 0.365 4 2 0.90 1.0 0.95 0.95 0.95 0 .071 Spinach Leaves Cyazofamid 0.365 6 2 0.69 0.82 0.76 0.76 0.76 0.092 Spinach Leaves CCIM NA 0 20 0.027 0.15 0.14 0.073 0.075 0.038 Spinach Leaves CCIM NA 1 2 0.023 0.031 0.027 0.027 0.027 0.01 Spinach Leaves CCIM NA 3 2 0.012 0.015 0.0135 0.0135 0.0 135 0.0021 Spinach Leaves CCIM NA 4 2 0.013 0.016 0.0145 0.0145 0.0145 0.0021 Hops Hop Cones Cyazofamid 0.425 - 0.443 2 - 4 6 2.5 6.9 6.3 3.2 4.0 1.9

CCIM NA 2 - 4 6 0.13 0.45 0.435 0.245 0.27 0.14 1 Highest Average Field Trial . 2 For residue values <LO Q, half of the LOQ (0.005 ppm) was used to calculate the median, mean, HAFT, and standard deviation . 3 Not Applicable.Page 19 of 40

T he submitted crop field trials are adequate to support the proposed minor uses. The studies were conducted consis tent ly with standard agricultural practices as per proposed use pattern. The number and geographic distribution of the supervised crop field trials are adequate. Tolerances HED recommends modification of the tolerance expression for cyazofamid accordin g to the new compliance/measurement policy ( Interim Guidance on Tolerance Expressions , Steve Knizner, 05/27/2009) to read as follows: “HED recommends that the tolerance definition entry in 40 CFR § 180.601 be revised as follows: (a) General. Tolerances are established for residues of the fungicide cyazofamid, i ncluding its metabolites and de gradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only

the sum of 4 - chloro - 2 - cyano -N,N

- dimethyl - 5 - (4 - methylphen yl ) - 1 H - imidazole - 1 - sulfonamide and its metabolite, 4 - chloro - 5 - (4 - methylphenyl) - 1 H - imidazole - 2 - carbonitrile, calculated as the stoichiometric equivalent of cyazofamid, in or on the commodity .” The Agency ’s SOP “ Guidelin es for Setting Pesticide Tolerances Based on Field Trial Data” was utilized for determining the appropriate to lerance level for each commodity . As the minimum and maximum recommended t olerances differ b y less than 5X , a crop group tolerance is appropriat e for the Brassica h ead and s tem, crop s ubgroup 5A. Although cabbage belongs to both crop subgroup 5A and 5B, the tolerance of 12.0 ppm is appropriate for Brassica , l eaf y greens, crop s ubgroup 5B based on mustard greens, the representative crop. HED ha s concluded that turnip greens will be moved from the leaves of root and tuber vegetables crop group (group 2) to the Brassica leafy vegetables crop group 5, subgroup 5B: (m emorandum, B. Schneider, 6/14/2002). However, until the regulations have been fin alized in the Federal Register, a separate tolerance is needed for turnip greens at the same level as the Brassica , leafy

greens, crop s ubgroup 5B at 12.0 ppm. The recommended tolerances for spinach and hops are 9 ppm and 10.0 ppm, respectivel y. The reco mmended tolerances are listed in Table 4 .3b .Page 20 of 40

Table 4 .3b . Tolerance Summary for Cyazofamid. Commodity Proposed Tolerance (ppm Existing

Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity Definition 40 CFR 180. 601 (a) Brassica , head & stem, crop subgroup 5A 1.2 1.2 Brassica , leafy greens, crop subgroup 5B 12.0 12.0 H ops 10.0 10.0 S pinach 9.0 9.0 Turnip greens 12.0 12.0 Until the regulations have been finalized in the Federal Register to move turnip greens from the leaves of root and tuber vegetables crop group (group 2) to the Brassica leafy greens subgroup 5B, a separate tolerance is needed at the same level as the Brassica , Leafy Greens, Subgroup 5B. 1 1 Memorandum, B. Schneider, 6/14/2002 . 4 .4 International Residue Limits Canada has established MRL s for residues of c yazofamid in/on several commodities, but has not established maximum residue limits for the commodities of this petition. No MRL s for residues of c yazofamid have been established by the Codex Alimentarius Commission . 4 . 5 Drinking Water Residue Profile Reference:

- Estimated Drinking Water Concentrations of Parent Cyazofamid and its Degradates of Concern CCIM, CCIMA M and CTCA, for Use in Human Health Risk Assessment: New Uses on Brassica (Cole) Leafy Vegetables & Turnip Greens (Crop Group 5), Spinach, and Hops . DP# 370673 , José L. Meléndez , 0 3/ 01 /2010 . The Agency

used screening - level water exposure models in the die tary exposure anal ys is and risk assessment for cyazofamid in drinking water. These simulation models take into account data on the ph ys ical, chemical, and fate/transport characteristics of cyazofamid. The Tier 2 linked PRZM/EXAMS model s were used in pred icting the surface water concentrations, and the Tier 1 regression model SCI - GROW was used in predicting ground water concentrations. The primary use of these models by

the Agency

at this stage is to provide a coarse screen for determining that pesticide residues (and metabolites) in water are not of concern. Further information regarding EPA drinking water models used in pesticide exposure assessment can be found at : http://www.epa.gov/oppefed1/mo dels/water/ . Environmental Profile Available environmental fate studies suggest cyazofamid is not very mobile and quickl y degrades into a number of degradation products under different environmental conditions. HED concluded that cyazofamid and the me tabolites designated as CCIM, CCIM - AM ( 4 - chloro - 5 - p tolylimidazole - 2 - carboxamide ; see Appendix A), and CTCA ( 4 - chloro - 5 - p - tolylimidazole - 2 - carbox yl ic acid ; see Appendix A) are considered to be the major residues in water and should be included in the drinking water risk assessment. Among the three major degradates forPage 21 of 40

cyazofamid (CCIM, CCIM - AM and CTCA), the two terminal ones are CCIM and CTCA. CCIM is expected to be the major terminal degradate in water bodies with low biological activity because it form s as a result of abiotic hydrol ys is of the parent. In contrast, CTCA is expected to be the major terminal degradate in biologicall y active soils and water/sediment sy stems. Both CCIM and CTCA are stable to abiotic hydrol ys is and susceptible to leaching, but onl y CCIM is highl y susceptible to biodegradation. Given these fate characteristics, cyazofamid and/or its degradates could potentially reach surface water via spray drift or runoff under certain environmental conditions, but the potential for it to reach ground water is very low. CCIM and/or CTCA could potentially be the terminal degradates in surface water bodies affected by spray drift and/or runoff depending on the level of biological activity . However, onl y CTCA has a high potential to contaminat e ground water due to its high persistence and mobility . Estimated Drinking W

ater Concentrations (EDW Cs) The screening level surface water and ground water concentrations were estimated using linked PRZM/EXAMS models and the SCI - GROW model, resp ectively . The maximum EDWCs that m ay occur are due to the use of cyazofamid on turf and ornamentals , and are presented in Table 4 .5 for the following scenarios: 1. The parent, assuming application of the maximum rate as parent; 2. Each of the degradates CCIM, CCIM - AM, and CTCA , assuming application of the molar equivalent of the parent for each of the degradate s by dividing the rate between the degradates based on molecular ratios and adjusted maximums found in fate studies; and 3. The terminal degradate CTCA , assuming app lication of 100% molar conversion of the parent into this terminal degradate CTCA. Table 4 .5. Maximum Surface/Ground W ater EDWCs for Cyazofamid and each of its Major

Degradates (fromuse on Turf and Ornam entals) . Scenario Chemical Surface water EDWCs (p pb) Ground W ater EDWC (ppb) Acute (1 - in - 10 yr. peak) Chronic (1 - in - 10 yr. m ean) 1 st Scenario Parent 14.4 0.38 0.012 2 nd Scenario CCIM 17.1 12.1 0.00061

CCIM - AM 6.7 6.3 0.0027 CTCA 16.7 11.0 0.52 3 rd Scenario CTCA 136 133 2.18 The highes t acute (peak) and chronic (mean) EDWCs were estimated for surface water using the PRZM/EXAMS model. For the purpose of this Tier 1 dietary assessment, HED used the highest calculated screening EDWCs for surface water based on the 3 rd modeling scenario: 1 36 ppb for the acute anal ys is and 133 ppb for the chronic analy sis. This approach may significantl y overestimate dietary

exposure to cyazofamid from drinking water. 4 .6 D ietary Exposure and Risk Reference:

- Cyazofamid: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for an IR - 4 Proposed Section 3 Registration Amendment to Add Uses in/on Fruiting Vegetables, Okra, and Grapes . DP#357 043 , Amelia Acierto, 03 /25 /2009.Page 22 of 40

Cyazo famid acute and chronic dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model software w ith the Food Commodity Intake Database (DEEM FCIDTM, Version 2.03), which incorporates consumption data from USDA’s Continuing Survey s of Food Intakes b y Individuals (CSFII), 1994 - 1996 and 1998. The 1994 - 96, 98 data are based on the reported consumption of more than 20,000 individuals over two non - consecutive survey day s. Foods “as consumed” ( e.g. apple pie) are linked to EPA - defined food commodities (e.g. apples, peeled fruit - cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S, baked) usi ng publicly

available recipe translation files developed jointly by USDA/ARS and EPA. For chronic exposure assessment, consumption data are averaged for the entire U.S. population and within population subgroups, but for acute exposure assessment are retained as individual consumption events. Based on anal ys is of the 1994 - 96, 98 CSFII consumption data, which took into account dietary

patterns and survey

respondents, HED concluded that it is most appropriate to report risk for the following population subgroups: the general U.S. population, all infants (<1 ye ar old), children 1 - 2, children 3 - 5, children 6 - 12, youth 13 - 19, adults 20 - 49, females 13 - 49, and adults 50+ years old. For both the acute and chronic anal ys es, the drinking water EDWC was incorporated directl y as a point estimate in the DEEM anal ys is to assess exposure to cyazofamid from drinking water. Acute Dietary Exposure and Risk For acute exposure assessments, individual one - day food consumption data are used on an individual - by- individual basis . The reported consumption amounts of each food item can be multiplied by

a residue point estimate and summed to obtain a total daily pesticide exposure for a deterministic exposure assessment, or “matched” in multiple random pairings with residue values and then summed in a probabilistic assessment. The resulting distribution of exposures is expressed as a percentage of the aPAD on both a user ( i.e. onl y those who reported eating relevant commodities/food forms) and a per - capita ( i.e. those who reported eating the relevant commodities as well as those who did not) basis. In accordance with HED policy, per capita exposure and risk are reported for all tiers of anal ysis. However, for unrefined and less refined assessments , an y significant differences in u ser vs. per capita exposure and risk are specificall y identified and noted in the risk assessment. Since an acute endpoint was not identified for the general population including infants and children and the FQPA SF has been reduced to 1X, the acute popul ation - adjusted - dose or acute PAD is equal to the acute RfD. The acute PAD was used for assessing acute dietary risk. An acute dietary

exposure anal ys is ( food + drinking water) was conducted via DEEM - FCIDTM for cyazofamid for females 13 - 49 years old only, since an acute endpoint of concern was not identified for the general U.S. population . Based on the assumptions of tolerance - level residues ( all processing factors set to 1X , based on the results of processing studies) , 100% crop - treated, and screening - level EDWC s , acute dietary exposure of females 13 - 49 years old is well below HED’s LOC (i.e. <100% of the aPAD of 1.0 mg/kg). The combined dietary exposure from food and drinkin g water is estimated at 0. 01214 mg/kg/day (equivalent to 1.2 % of the aPAD) at the 95 th percentile of exposure, the appropriate regulatory statistic for dietary assessments. Itis noted that estimated a c ute dietary exposure of females 13 - 49 years old is al so well below HED’s LOC at the 99 th and 99.9 th percentiles, as shown in Table 4 .6 a .Page 23 of 40

Table 4 . 6 a. Results of Acute Dietary Exposure Analysis for Food and Drinking Water at the 95 th

Percentile of Exposure using DEEM FCID . Population Subgroup aPAD

(m g/kg/day) 95th Percentile 99th Percentile 99.9th Percentile

Exposure (m g/kg/day) %

aPAD Exposure (m g/kg/day) %

aPAD Exposure (m g/kg/day) %

aPAD Females 13 - 49 years old 1.0 0. 0121 4 1.2 0.0 2448 2.5 0.0 5974 6.0 Chronic Dietary Exposure and Risk For chronic die tary

exposure assessments, an estimate of the residue level in each food or food form ( e.g. orange or orange juice) on the food commodity residue list is multiplied by the average dail y consumption estimate for that food/food form to produce a residue intake estimate. The resulting residue intake estimate for each food/food form is summed with the residue intake estimates for all other food/food forms on the commodity residue list to arrive at the total average estimated exposure. Exposure is expressed in mg/kg body weight/day and as a percent of the cPAD. This procedure is performed for each population subgroup. The chronic RfD of 0.95 mg/kg/day is derived from a NOAEL of 94.8 mg/kg/day based on increased incidence of skin lesions in males at 985 mg/kg/day (LOAEL) in the mouse carcinogenicity

study . A 100 - fold uncertainty factor (10X inter species extrapolation and 10X intraspecies variability) is required. Since the FQPA SF has been reduced to 1X, the chronic PAD is equal to the chronic RfD. The chron ic PAD was used for assessing chronic risk. A chronic dietary

exposure anal ys is was conducted via DEEM - FCIDTM for cyazofamid. The assumptions of this dietary exposure assessment are tolerance - level residues ( all processing factors set to 1 X , based on the results of processing studies) , 100% crop - treated, and screening level EDWC. Cyazofamid chronic dietary (food + drinking water) exposure estimates are well below HED’s LOC for the general U.S. population and each of the population subgroups , as shown in T able 4 . 6 b . Dietary exposure was estimated at 0.004945 mg/kg/day for the general U.S. population (<1% of the cPAD) and 0. 01 1079 mg/kg/day (1. 2 % of the cPAD) for the most highl y exposed population subgroup (infants <1 year old). Table 4 . 6 b . Summary of C hronic Dietary Exposure and Risk for Cyazofamid . 1 Population Subgroup Exposure (mg/kg/day) % cPAD General U.S. Population 0.004945 <1 All Infants (< 1 year old) 1 0.011079 1.2 Children 1 - 2 years old 0.010749 1 Children 3 - 5 years old 0.008556 <1 Childr en 6 - 12 years old 0.004916 <1Page 24 of 40

Table 4 . 6 b . Summary of C hronic Dietary Exposure and Risk for Cyazofamid . 1 Population Subgroup Exposure (mg/kg/day) % cPAD Youth 13 - 19 years old 0.003393 <1 Adults 20 - 49 years old 0.004351 <1 Adults 50+ years old 0.004884 <1 Females 13 - 49 years old 0.004302 <1 1 The population subgroup with the highest estimated chronic dietary (food + drinking water) exposure and risk is indicated by bold text. 4 .7 Cancer Dietary Exposure and Risk A cancer dietary

assessment was not conducted because cyazofamid has been classified as “not likely to be carci nogenic to humans . ” 5 .0 NON - OCCUPATIONAL/RESIDENTIAL EXPOSURE/RISK PATHWAY Reference s :

- Cyazofamid. Occupational and Residential Exposure Assessment for Section 3 Registration of Cyazofami d for Commercial Use on Residential Turf and Ornamentals . DP# 365261 , Nancy J. Tsaur, 03 /27 /2009.

- Occupational and Residential Risk Assessment to Support Request for Registration of Cyazofamid on Non Residential Turf and Ornamentals. DP#332425, K elly O’Rourke, 10/12/2006 . This document presents the assessment of proposed agricultural uses of cyazofamid. No residential uses are being requested at this time; therefore, no residential handler exposure and risk assessment has been conducted in this document. Cyazofamid is currently commercially registered to treat p ythium diseases on residential turf and p ythium, phy tophthora and downy mildew diseases on ornamental plants in residential landscapes (DP#365261 , N. Tsaur, 0 3/27/20 09). In addition, cyazofamid is commercially registered to treat py

thium and downy mildew diseases on professionally managed turf areas, and p ythium, phy tophthora, and downy mildew diseases on ornamental plants in landscapes and in commercial greenhouses and nurseries (DP#332425, K. O’Ro urke, 10/12/20 06). Application of cyazofamid by home - owners to residential turf is prohibited by the label . However, residential exposure for both adults and children 3 to <6 ye ars old are expected following commercial application on residential turf and ornamentals. The dermal post application MOE for adults was found to be 1,100. Since the MOE is greater than 100, it is no t of risk concern for HED. Post application exposure for children was analyzed and found to be 1,600, which is greater than 100, and not of risk concern to HED ( DP#365261, N. Tsaur, 0 3/27/20 09). Post application exposure was also anal yz ed for recreational golfers or players of various sports who use turf areas following cyazofamid exposure. The dermal MOEs for postapplication exp osure for recreational golfers or sports playe rs were greater than 100 (330 to 14,000) and , therefore , are not of risk concern to HED ( DP#332425, K. O’Rourke, 10/12 /20 0 6 ).Page 25 of 40

Based on the currentl y registered uses of cyazofamid and past ORE assessments, there are no residential risk concerns to the Agency of cyazofamid exposure. Table 5 .0 summarizes children’s aggregate exposure and risk estimates previously calculated from residential lawns ( DP#365261, N. Tsaur, 3/27/2009) . Table 5 . 0. Children’s Aggregat e Exposure and Risk Estimates from Residential Lawn s . Children’s Scenarios TTR/GR/SR0 (ug/cm2 or g) 1 PDR0 - norm

(m g/k g/day) 2 Short - Term

MOE 3 Total

Short - Term MOE 4 (1) Hand - to - Mouth 0.57 0.015 2 , 0 00 1,600 (2) Mouthing Grass 2.29 0.0038 8 ,000 (3) Soi l Ingestion 7.66 0.000051 590 ,000 1 TTR=turf transferable residue on day “0"; GR=grass residue on day “0"; SR0 =soil residue on day “0". 2 PDR0norm=potential dose rate on day “0”. 3 MOE = NOAEL/PDR; where Short - /Intermediate - term NOAEL Incidental O ral = 30 mg/kg/day. 4 Total MOE = 1/ [(1/MOE Hand - to - Mouth) + (1/MOE Grass ) + (1/MOE Soil )] Spray Drift Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is parti cularly

the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for cyazofamid. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices , and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The A gency has completed its evaluation of the new data base submitted b y the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriatel y apply the data and the AgDRIFT computer model to its risk assessm ents for pesticides applied b y air, orchard airblast , and ground h ydraulic methods. After the policy is in place, the Agency

may impose further refinements in spray

drift management practices to reduce off - target drift and risks associated with aerial as well as other application types where appropriate. Note: A s indicated in this assessment, cyazofamid is directly applied to residential lawns and ornamentals and does not result in exposures of concern. It is unlikel y that the potential for risk of exp osure to spray

drift from these uses would be higher than that estimated for contact with treated turf. 6 .0 AGGREGATE RISK ASSESSMENTS and RISK CHARACTERIZATION Aggregate exposure risk as sessments were performed for the following scenarios: acute aggregate exposure (food + drinking water), short - /intermediate - term aggregate exposure (food + residential exposure + drinking water), and chronic aggregate exposure (food + drinking water). A c ancer aggregate risk assessment was not performed because cyazofamid is classified as “not likely to be carcinogenic to humans”. All potential exposure pathway s were assessed in the aggregate risk assessment. Dietary (food and drinking water) and residential exposures were considered, as necessary , because there is a potential for individuals to be exposed concurrentl yPage 26 of 40

through these routes. 6 .1 Acute Aggregate Risk Assessment (Food and Drinking Water) An acute aggregate risk assessment is required for the population subgroup of concern, females 13 - 49 ye ars old. An appropriate endpoint for the general population was not identified; therefore, a corresponding assessment is not require d. For the population of concern, the acute dietary (food and drinking water) risk assessment reported in Section 4 .6 represents acute aggregate risk . The dietary route alone is relevant for acute exposure and risk assessment. 6 .2 Short - and Intermediat e - Term Aggregate Risk Assessment The short - /intermediate - term aggregate risk assessment estimates that risks are likel y to result from exposure to cyazofamid residues from food, drinkin g water, and residential pesticide uses. Short - term and intermediate - term risks have been assessed together because both scenarios have the same endpoints and PODs. High - end estimates of residential exposure are used, while average values are used for fo od and drinking water exposure (i.e. chronic exposures). A short - /intermediate - term risk assessment is required for adults and children because there are potential postapplication exposures from the use on residential lawns and ornamentals . The results o f the short/intermediate - term aggregate asses sments are presented in Table 6 .2 . HED is generall y not concerned if the MOEs remain above the LOC, which for this assessment , is 100. The MOEs for all scenarios are ≥ 100, and therefore, are not of concern to the Agency . Table 6 .2. Short - Term and/or Inter me diate - TermAggregate Risk Calculations . Population Short - or Interm ediate - Term Scenario

LOC for Aggregate Risk 1 MOE

food & water 2 MOE

oral 3 MOE

derm al 4 MOE

inhalation 5 Aggregate MOE

(food and residential) 6 General U.S. Population 100 2 0 , 0 00 NA 1,100 NA 1, 00 0 Children 3 - 5 years old 1 2 , 0 00 1,600 NA NA 1,400 Children 6 - 12 years old 20,0 00 1,600 NA NA 1,500 1 LOC is an MOE = 100. 2 MOE food = [(short - or intermediate - term oral NOAEL) /(chronic dietary exposure)], NOAEL = 100 mg/kg/day (See Ta ble 4 .6b for dietary exposure). 3 MOE oral = [(short - or intermediate - term oral NOAEL)/(hand - to - mo uth residential exposure)] NOAEL = 30 mg/kg/day (See Table 5 .0 for children’s oral exposure ). 4 MOE dermal = [(short - o r intermediate - term dermal NOAEL)/(high - end dermal residential exposure)] NOAE L = 100 mg/kg/day (See DP#356837 , Table 5.2.2) . 5 MOE inhalation is not applicable for postapplication activities. 6 Aggregate MOE (food and residential) = 1/ [(1/MOE Food) + (1/M OE Oral ) + (1/MOE Dermal ) + (1/MOE Inhalation)]Page 27 of 40

6 .3 Chronic Aggregate Risk Assessment (Food and Drinking Water) The chronic aggregate risk assessment takes into account average exposure estimates from dietary consumption of cyazofamid (food and drinking water) and residential uses. Based on the cyazofamid use pattern, no long - term resi dential exposures are expected. Therefore, the chronic aggregate risk assess ment is based on exposure from food and drinking water only , as presented previously in this memorandum (Section 4 .6 ). 6 .4 Cancer Aggregate Risk Assessment HED classified cyazofamid as “not likely to be carcinogenic to humans”. Thus, an aggregate cancer risk assessment was not performed for cyazofamid. 7 .0 CUMULATIVE RISK Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanis m of toxicity , EPA has not made a common mechanism of toxicity finding as to cyazofamid and any

other substances and cyazofamid does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefor e, EPA has not assumed that cyazofamid 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 chemic als, 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/. 8 .0 OCCUPATIONAL EXPOSURE Reference:

- Amendment: Cyazofamid: Occupational and Residential Exposure Assessment for Proposed Field U ses of C yazofamid on Brassica Leafy Vegetables, Turnip Greens, Spinach and Hops. DP# 377618 , Kristin Rury, 04 / 0 6 /2010 . Cyazofamid can be applied to Brassica leafy vegetables , turnip greens, and spinach using groundboom, aerial, and chemigation application equipment. Additionally, cyazofamid can be applied to hops with airblast equipment. Workers may be exposed to cyazofamid during mixing, loading, application, and postapplication activities. Based on the prop osed application regimen, short - / intermediate - term exposure may occur. Chronic exposure (greater than or equal to 6 months of continuous exposure) is not expected. 8 .1 Occupational Handler Exposure and Risk No chemical - specific handler exposure data were submitted in support of this registration for the IR - 4 petition ( PP#9E7615 ) for tolerances on Brassica (cole) leafy vegetable crop group (CG 5), turnip greens, spinach, and hops . Itis the pol icy of HED to use data from PHED Version 1.1 as presented in PHED Surrogate Exposur e Guide (8/98) to assess handler exposures for regulatory actions when chemical - specific monitoring data are not available (HED E xpoSAC SOP #7, dated 1/28/99).Page 28 of 40

The results of the handler occupational exposure and risk assessment for the proposed agricultural uses indicate that risks are not of concern with baseline clothing, or when gloves are worn . The total short/intermediate - t erm MOEs range from 23,000 to 22 0 ,000; which are greater than the LOC of 100, and are not of concern to HED . Exposure assumptio ns and MOEs for occupational handlers of Ranman® 400SC are summarized in Table 8 .1 a . The average adult body

weight of 60 kg was used for estimating dermal and inhalation dose, since the selected toxicological endpoint is based on developmental effects (fe males 13+ years old) . Since the short - and intermediate - term dermal endpoint was based on an oral study , a dermal absorption factor of 37% and an inhalation absorption factor of 100% were used to estimate dermal exposure for short - and intermediate - term d urations. HED’s LOC for the MOE is defined by the uncertainty

factors that are applied to the assessment. HED applies a 10X factor to account for interspecies extrapolation and a 10X factor to account for intraspecies sensitivity . The total uncertainty factor that has been applied to the non - cancer risk assessment for cyazofamid is 100 for occupational exposure. Occupational exposure and risk resulting in MOEs greater than or equal to 100 will not be of concern to HED. Summaries of the risks for occu pational handlers are included in Table 8.1 . The maximum application rate for each exposure scenario is presented as the worst case scenario. All handler scenarios resulted in combined dermal and inhalation MOEs greater than the LOC (MOEs ≥ 100) at some level of risk mitigation. The inhalation risks to handlers are not a concern at baseline (no respirator) for any of the handler scenarios where baseline data are available. Only engineering control (enclosed cockpit) data are available to assess inhalation risks to handlers operating aircraft. The inhalation risks are not a concern for pilots using enclosed cockpits and wearing no respirator. The dermal and combined (dermal and inhalation) risks to handlers are not a concern with baseline attire ( i.e. long - sleeve d shirt, long pants, shoes, and socks) where baseline data are available. Onl y engineering control (enclosed cockpit) data are available to assess dermal (and therefore combined risks) to handlers operating aircraft. The dermal and combined ri sks are not a concern for pilots using enclosed cockpits and wearing baseline attire. Also, only baseline plus chemical - resistant glove data are available to assess dermal risks (and therefore combined risks) to handlers mixing/loading/appl yi ng with handgun equipment. The dermal and combined risks are not a concern for these scenarios when baseline attire is worn with the addition of chemical resistant gloves . The minimum level of personal protective equipment ( PPE ) f or handlers is based on acute toxicity for the end - use products. RD is responsible for ensuring that PPE listed on the label is in compliance with WPS.Page 29 of 40

Table 8.1. Agricultural Handler Exposure and Risk for Cyazofamid . Exposure Scenario Crop or Target App Rate a (lb ai/A) Acres Treated Daily b Unit Exposure c Dose (m g/kg/Day) MOEs Baseline Dermal (mg/lb ai) PPE - G Dermal (mg/lb ai) Baseline inhalation (μ g/lb ai) Baseline

Dermal d,h PPE - G

Dermal i Baseline

Inhalation e Baseline

Dermal f PPE - G

Dermal Baseline

Inhalation g Combined

Baseline Dermal + Inhalation

j Combined PPE - G + Baseline Inhalationk Mixer/Loader Mixing/Loading to Support Aerial Treatments Brassica Leafy

Vegetables, Turnip Greens 0.072 350 2.9 0.023 1.2 0.45 0.004 0. 000504 220 2 8 , 000 198 ,000 220 24,000 Spinach, Hops 0.071 350 2.9 0.023 1.2 0.44 0.004 0. 000497 2 30 28,400 201 ,000 220 25,000 Mixing/Loading to S upport C hemigation Treatments Brassica Leafy

Vegetables, Turnip Greens 0.072 350 2.9 0.023 1.2 0.45 0.004 0. 000504 22 0 28,000 198 ,000 220 24,000 Spinach 0.071 350 2.9 0.023 1 .2 0.44 0.004 0. 000497 2 30 28, 400 201 ,000 220 25,000 Mixing/Loading to Support Groundboom Applications Brassica Leafy Vegetables, Turnip Greens 0.52 80 2.9 0.023 1.2 0.74 0.006 0.000832 130 17,000 120,000 130 15,000 Spinach 0.071 80 2.9 0.023 1.2 0.10 0 . 00081 0. 00011 98 0 124, 000 880 ,000 980 110,000 Mixing/Loading to Support Airblast Applications Hops 0.07 1 40 2.9 0.023 1.2 0. 051 0. 00040 0. 000057 2,000 245,000 1,760,000 2,000 220,000 Applicator Applying Sprays via Aerial Equipment Brassica Leafy Vegetables, Turnip Greens 0.072 350 0.005 no data 0.068 0.000 78 No Data 0. 000029 128,700 N/A 3,501 ,000 120,000 No Data Spinach, Hops 0.071 350 0.005 no data 0.068 0.00 77 No Data 0.0 000028 131,000 N/A 3,551 ,000 130,000 N o Data Applying Sprays via Gr oundboom Equipment Brassica Leafy Vegetables, Turnip Greens 0.52 80 0.014 0.014 0.74 0.0036 0.0036 0.001 28,000 28,000 195,000 24,000 24,000 Spinach 0.071 80 0.014 0.014 0.74 0.000 49 0.000 49 0.0 000 70 204,000 204,000 1,427 ,000 180,000 180,000 Applying Sprays via Ai rblast Applications Hops 0.07 1 40 0.36 0.24 1.5 0.0063 0.0042 0.000071 15,900 23,800 1,400,000 16,000 23,000 Flagger Flagging for Aerial Sprays Brassica Leafy

Vegetables, Turnip Greens 0.072 350 0.011 0.012 0.35 0. 0017 0.00 18 0. 00014 59, 000 54, 400 690 ,00 0 55,000 50,000 Spinach, Hops 0.071 350 0.011 0.012 0.35 0.00 17 0 .0019 0. 00015 58,500 53,600 680 ,000 54,000 50,000Page 30 of 40

a Application Rates based on proposed uses for cyazofamid product Ranman® 400SCTM (EPA Registration No. 71512 - 3) . b Exposure Science Advisory Council Policy # 9.1 (when rates given in gallons 40 gal/day ÷ 100 gal/A = 0.4 A/day) . c Unit Exposures based on PHED Version 1.1. Engineering control unit exposure for applying sprays via aerial equipment = enclosed cockpit. d Dermal Dose (mg/kg/day) = daily unit exposure (mg/ lb ai) x application rate (lb ai/acre) x acres treated x dermal absorption factor (37%) / body weight (60 kg adult female). e Inhalation Dose (mg/kg/day) daily uni t exposure (μg/ lb ai) x application rate (lb ai/acre) x acres treated x inhalation absorption (100%) / body weight (60 kg adult female). f Dermal MOE = NOAEL (100 mg/kg/day) / dermal daily dose (mg/kg/ day). Level of concern = 100. g Inhalation MOE = NOAEL (100 mg/kg/day) / inhalation daily dose (mg/kg/ day). Level of concern = 100. h Baseline Dermal: l ong - sleeve d shirt, long pants, and no gloves; Baseline Inhalation: no respirator. i Baseline plus Gloves Dermal: Baseline plus chemical - resistant glo ves. j Combined Baseline Dermal + Inhalation MOE = 1 / (1/Baseline Dermal MOE) + (1/Baseline Inhalation MOE). k Combined PPE - G + Baseline Inhalation MOE = 1 / (1/PPE - G Dermal MOE) + (1/Baseline Inhalation MOE). Those risks specified as engineering control represent enclosed cockpit application l The higher application rate of 0.52 lb ai/A is due to soil incorporation for Brassica leafy vegetables and turnip greens. 8 .2 Occupational Postapplication Exposure and Risk The proposed a gricultural uses of cyazofamid on Brassica (cole) leafy vegetables, turnip greens, spinach, and hops involve various postapplication activities including hand harvesting, hand pruning, thinning, training, tyi ng, etc. Wo rkers performing typical postapplication activities may receive exposure to cyazofamid residues. The cyazofamid technical material has been classified in Toxicity Category III for acute dermal and primary

skin irritation, and Category IV for primary

e ye irritation. Per WPS , a 12 - hr REIis required for chemicals classified under Toxicity Category III/ IV. Based on the postapplication dermal risk estimates, the labeled 12 - hr REI is protective of re - entry workers. Cyazofamid is also intended for non - agr icultural use sites to which the WPS does not apply , and correctl y contains language cautioning unprotected persons to keep out of treated areas until spray s have dried . Dermal: Chemical - specific dislodgeable foliar residue (DFR) studies on tomatoes (MRID#45409118), grapes (MRID#45409118) and squash (MRID#45409119) were submitted for a previous action on cyazofamid. These studies were reviewed and found to be acceptable for risk assessment purposes (D285682, K. O’Rourke, 3/23/04). A summary of each study is provided below. In ad dition to the DFR data, maximum dermal transfer coefficients from ExpoSAC SOP # 3.1 (Agricultural Transfer Coefficients, August 2000 ) and the following assumptions were used in the postapplication assessment:

 Max Application R ate = 0.5 2 lb ai/A for Brassica leafy vegetable soil incorporation at transplanting, 0.071 lb ai/A for spinach and hops.  Exposure Duration = 8 hours per day ,  Body Weight = 60 kg for adult female, and  Dermal Absorption = 37%. The postapplication expo sure associated with agricultural crops is summarized in Table 8 . 2 . All scenarios resulted in MOEs greater than 100 on day 0 (12 hours after application) and , therefore , are not of concern to HED.Page 31 of 40

Table 8 .2 . Posta pplication Exposure and Risk for Cyazofam id. Crop Grouping/ Crop Activity Proposed Application Rate (lb ai/A) Transfer

Coefficient (cm2 /hr) Days

A fter Treatment Chemical S pecific DFR Data Normalized

DFR (ug/cm2 ) 1 Daily

Dermal Dose (m g/k g/day) 2 MOE 3

(LOC = 100) Brassica Leafy Vegetable s, Turnip Greens Thinning, H and Pruning,

Irrigation, Hand Harvesting, T opping, Thinning, Tying 0 .52 5000 0 Tomato DFR 0. 017 0. 004 2 3 ,000 Spinach Hand Harvesting, H and

P runing, Thinning 0.071 2500 0 Tomato DFR 0.128 0.016 6,300 Hops Hand Harvesting,

Mechanical Har

vesting, Stripping, Training 0.071 2000 0 Grape DFR 0.160 0.016 6,300 1 DFR values were obtained from the DFR studies: To mato DFR: average measured value from “Day 3" was used as a surrogate for Day 0 because it was higher than both

the predicted and me asured Day 0 values. The DFR was adjusted for the difference in application rate used in the study ( i.e. 0.071 lb ai/A compared to the maximum 0.078 lb ai/A rate proposed for fruiting vegetables and okra), and Grape DFR: average measured Day 0 value from the grape DFR data was used - with an adjustment for the difference

in application rate used in the study ( i.e. 0.089 lb ai/A compared to the maximum 0.071 lb ai/A rate proposed for grapes). 2 Daily Dermal Dose = [DFR (μg/cm 2 ) x Tc x 0.001 mg/μg x 8 hrs/day x DA]  (body weight (60 kg adult female)). 3 MOE = NOAEL/Daily Dose (Adult Dermal NOAEL = 100 mg/kg/day). 9 .0 DATA NEEDS AND LABEL RE COMMENDATIONS 9 .1 Chemistry 860.1550 Propos ed Tolerance s : The petitioner should submit a revised Section F reflecting the recommended tolerances and commodity definitions presented in Table 4 . 3b . 9 .2 Toxicology

 Based on the available toxicity database and the Agency's current practices, the inhalation risk for cyazofamid was assessed using an oral toxicity study . The Agency

sought expert advice and input on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity

studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may , as appropriate, reexamine and develop new policies and procedures for conducting inhalation risk assessments, including route to route extrapolation of toxicity data. If an y new policies o r procedures are developed, the Agency may revisit the need for an inhalation toxicity study for cyazofamid and/or a reexamination of the inhalation toxicity risk assessment.  A s part of the new 40 CFR §158 Guidelines, a functional immunotoxicity study in rats and/or mice is required ( Guideline 870.7800 ) ; see Appendix D .  A s part of the new 40 CFR §158 Guidelines, a s ubchronic neurotoxicity study is required (Guideline 870.6200 ) ; see Appendix E .Page 32 of 40

APPENDIX A . Codes, Chemical Names , and Chemical Structure of Cy azofamid and

Identified Metabolites Table A. Identification of Compounds fromthe Cyazofamid Metabolism Studies. Common name/ code/matrix Chemical name Chemical structure Cyazofamid/ IKF - 916 4 - chloro - 2 - cyano -N,N - dimethyl - 5 - (4 - methylphenyl) - 1 H

- imidazole - 1 - sulfonamide N N C H 3 Cl CN S O 2 N ( C H 3 ) 2 CCIM 4 - chloro - 5 - p - tolylimidazole - 2 - carbonitrile

N H N C H 3 Cl CN CCBA 4 - (4 - chloro - 2 - cyanoimidazol - 5 - yl)benzoic acid N H N Cl CN O H O CCIM - AM 4 - chloro - 5 - p - tolylimidazole - 2 - carboxamide

N H N C H 3 Cl O N H 2 CTCA 4 - chloro - 5 - p - tolylimidazole - 2 - carboxylic acidPage 33 of 40

APPENDIX B . International Residue Limit Status 

## INTERNATIONAL RESIDUE LIMIT STATUS Chemical Name: 4 - Chloro - 2 - cyano -N,N

dimethyl - 5 - (4 - methylph enyl) - 1 H

imidazole - 1 - sulfonamide Common Name: Cyazofamid □ Proposed tolerance □ Reevaluated tolerance X Other Recommended Date: 03/06/2010

Codex Status (Maximum Residue Limits) U. S. Tolerances √ No Codex proposal step 6 or above □ No Codex proposal ste p 6 or above for the crops requested Petition Number: PP# 9 E7 615 DP#: 371163 Other Identifier: Residue definition (step 8/CXL): N/A Revie wer/Branch: A.Acierto/RAB3 Residue definition: Com bined residues of cyazofamid, 4 - chloro - 2 - cyano -N,N

- dimethyl - 5 - (4 - methylphenyl) - 1 H - imidazole - 1 - sulfonamide and its metabolite, CCIM, 4 - chloro - 5 - (4 - me thylphenyl) - 1 H - imidazole - 2 - carbonitrile, expressed as cyazofamid Crop (s) MRL (mg/kg) Crop(s) Tolerance (ppm) Brassica , head & stem, crop subgroup 5A 1.2 Brassica , leafy greens, crop subgroup 5B 12.0 Turnip greens 12.0 Spinach 9.0 Hops 10.0 Limits for Canada Limits for Mexico □ No Limits √ No Limits for the crops requested √ No Limits □ No Limits for the crops requested Residue definition: 4 - chloro - 2 - cyano -N,N - dimethyl - 5 - (4 - methylphenyl) - 1 H

- imidazole - 1 - sulfonamide, including the metabolite 4 - chloro - 5 - (4 - methylphenyl) - 1 H - imidazole - 2 - carbonitrile Residue definition: N/A Mexico adopts Codex MRLs or US tolerances for its export purposes. Crop(s) MRL (mg/kg) Crop(s) MRL (mg/kg)

Notes/Special Instructions: S. Funk, 0 3/ 0 6/2010Page 34 of 40

APPENDIX C .1. Toxicity Profile of Cyazofamid Technical Table C .1. Toxicity Profile of Cyazofamid [IKF - 916] Technical. Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 870.3100 28 - Day dose - range finding study in rats 45408927 0, 50, 500, 5000, & 20,000 ppm Male: 0, 3.8, 38.5, 370, & 1488 mg/kg/day Female: 0, 3.6, 37.1, 389, & 1535 mg/kg/day NOAEL = 38.5 [M] mg/kg/day LOAEL = 370 [M] mg/kg/day based on increased number of basophilic tubules was noted in the kidneys of males. 870.3100 90 - Day oral toxicity in rats 45408928 (1999) Acceptable/guideline Males: 0, 10, 50, 500, or 5,000 ppm 0, 0.6, 2.9, 29.5, or 294.5 mg/kg/day Females: 0, 50, 500, 5,000, or 20,000 ppm 0, 3.3, 33.3, 337.6, or 1,359.0 mg/kg/day NOAEL = 29.5 [M] mg/kg/day LOAEL = 295 [M] mg/kg/day based on increased number of “basophilic kidney tubules,” and increased urinary volume, pH, and protein.

870.3100 90 - Day oral toxicity in mice Study not available. Study not available. 870.3150 90 - Day oral toxicity in dogs 45408929 (2001) Acceptable/guideline 0, 40, 200, or 1,000 mg/kg/day NOAEL = 1,000 [M/F] mg/kg/day LOAEL = not observed. 870.3200 28 - Day dermal toxicity in rats 45408930 (1997) Acceptable/guideline 0, 250, 500, or 1,000 mg/kg/day NOAEL = 1,000 [M/F] mg/kg/day LOAEL = not observed. 870.3250 90 - Day dermal toxicity Study not available. 870.3465 90 - Day inhalation toxicity Study not available. 870.3700a Prenatal developmental in rats 45430404 (1999) Acceptable/guideline 0, 30, 100, or 1,00 0 mg/kg/day Maternal NOAEL = 1,000 mg/kg/day LOAEL = not observed . Developm ental NOAEL = 100 mg/kg/day LOAEL = 1,000 mg/kg/day based on increased incidence of bent ribs. 870.3700b Prenatal developmental in rabbits 45408934 (1999) Acceptable/guideline 0, 30, 100, or 1,000 mg/kg/day Maternal NOAEL = 1,000 mg/kg/day LOAEL = not observed . Developm ental NOAEL = 1,000 mg/kg/day LOAEL = not observed .Page 35 of 40

Table C .1. Toxicity Profile of Cyazofamid [IKF - 916] Technical. Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 870.3800 Reproduction and fertility effects in rats 45408935 (1998) Acceptable/guideline 0, 200, 2,000, or 20,0 00 ppm F 0 M: 11 - 22, 108 - 213, and 1114 - 2185 mg/kg/day F 0 F: 14 - 21, 137 - 219, and 1416 - 2179 mg/kg/day F 1 M: 11 - 27, 107 - 267, and 1117 - 2714 mg/kg/day F 1 F: 14 - 27, 135 - 267, and 1451 - 2678 mg/kg/day Parental/Systemic NOAEL = 1114/ 1416 [M/F] mg/kg/day LOAEL = not observed . Reproductive NOAEL = 1114/ 1416 [M/F] mg/kg/day LOAEL = not observed . Offspring NOAEL = 1114/ 1416 [M/F] mg/kg/day LOAEL = not observed .

870.4100a Chronic toxicity in rats 45408936 (1999) Acceptable/guideline Males: 0, 10, 50, 500, or 5,000 pp m 0, 0.35, 1.7, 17.1, or 171.1 mg/kg/day Females: 0, 50, 500, 5,000, or 20,000 ppm 0, 2.0, 20.2, 207.8, or 856.0 mg/kg/day NOAEL = 171/ 856 [M/F] mg/kg/day LOAEL = not observed.

870.4100b Chronic toxicity in dogs 45408931 (2001) Acceptable/guideline 0, 40, 200, 1,000 mg/kg/day NOAEL = 200 [M/F] mg/kg/day LOAEL = 1,000 [M/F] mg/kg/day based on increased cysts in parathyroids in males. 870.4200 Carcinogenicity rats 45408936 (1999) Acceptable/guideline NOAEL = 171/ 856 [M/F] mg/kg/day LOAEL = not observe d. No evidence of carcinogenicity . 870.4300 Carcinogenicity mice 45408932 (1999) Acceptable/guideline NOAEL = 94.8 [M] mg/kg/day LOAEL = 985 [M] mg/kg/day based on increased incidence of skin lesions including hair loss, body sores, dermatitis, ulceratio n, and acanthosis. No evidence of carcinogenicity . Gene Mutation 870.5100 Bacterial reverse mutation assay 45408937 (1998) Acceptable/ guideline (ai) N egative ± S9 up to 5,000 μg/plate by standard plate and tube preincubation (not cytotoxic but there was precipitation at ≥1,500 μg/plate. Gene Mutation 870.5300 Mammalian cell culture 45409002 (1998) Acceptable/ guideline (ai) Negative ± S9 up to cytotoxic and precipitating concentration of 100 μ g/mL . Cy togenetics 870.5375 Chromosomal aberrations 45409003 (1996) Acceptable/ guideline (ai) Negative ± S9 for clastogenic/aneugenic activity up to cytotoxic and precipitating 200 μ g/mL . Cy togenetics 870.5395 Micronucleus test on mo use 45409004 (1996) Acceptable/ guideline (ai) Negative up to the highest dose t ested ( limit dose) 2,000 mg/kg.Page 36 of 40

Table C .1. Toxicity Profile of Cyazofamid [IKF - 916] Technical. Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results Other Effects 870.5500 Bacterial DNA repair test (Rec - assay) 45409005 (1998) Acceptable/ guideline (ai) Negative ± S9 up to limit of solubility at 8,000 μ g/disc . 870.6200a Ac ute neurotoxicity screening battery 45434601 (2 000) Acceptable/guideline 0, 80, 400, or 2000 mg/kg NOAEL = 2000 [M/F] mg/kg/day LOAEL = not observed. The HIARC concluded that the slight increase ( ≈ 5%) in motor activity at day 14 among the mid and high - dose males is marginal and should not be considere d an adverse finding. 870.6200b Subchronic neurotoxicity screening battery Study not available.

870.6300 Developmental neurotoxicity Study not available. 870.7485 Metabolism and pharmacokinetics in rats 45409006 - 45409009 and 45434602 (1998 - 1999) Ac ceptable/guideline Dose: 0.5, 1,000, or 14 day 0.5 mg/kg repeat non - labeled followed by 0.5 mg/kg [phenyl - U 14 C] - or [ 14 C - Imidazole] IKF - 916. Biliary excretion study: 0.5 or 1,000 mg/kg [phenyl - U 14 C] - or [ 14 C Imidazole] IKF - 916. There was rapid absorption (irrespective of dose t cmax = 0.25 - 0.5 hrs) and rapid elimination at the low dose (t 1/2 4.4 - 5.8 hrs) while there was saturated absorption with prolonged elimination (t 1/2 of 7.6 - 11.6 hrs) at the high - dose. The extent of absorption (as per cent of admi nistered dose) was highly dose dependent being nearly 75% at the low dose and only about 5% at the high dose. Both the urine and feces were major routes of excretion at the low dose with most of the urinary radioactivity being a metabolite named CCBA (4 - ( 4 - chloro - 2 - cyanoimidazol - 5 - yl)benzoic acid). The biliary elimination was highly variable at the low dose ( ≈ 12 - 39% of the administered low dose) and negligible (<2%) in the high - dose groups. Urinary or biliary excretion in the high - dose groups was low (ea ch ≈ 2%) with most of the radioactivity being CCBA. Irrespective of the dosing regimen, mo st of the recovered fecal radioactivity was unchanged parent compound; the major fecal metabolites were CCBA and 4 - chloro - 5 - p tolylimidazole - 2 - carbonitrile (CCIM) ea ch of which being less than 5% of the administered dose. Tissue burdens at t 1/2 , tma x , and at 168 hours post dose indicated rapid clearance and low tissue burdens suggesting little or no bioaccumulation or sequestration. 870.7600 Dermal penetration Study not available.Page 37 of 40

Table C .1. Toxicity Profile of Cyazofamid [IKF - 916] Technical. Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results Special study: In Vitro Metabolism of IKF - 916 and CCIM in Blood and Stomach Contents 45409010 (1999) Acceptable/non - guideline The in vitro biodegradation of [ 14 C - Bz]IKF - 916 or [ 14 C - Bz)CCIM by rat blood or rat stomach contents wa s examine d. The results indicated that, during the 60 - minute incubation period, IKF - 916 underwent degradation to CCIM ( ≈ 30%) in blood but was stable in stomach contents while CCIM wa s unaffected in either medium. The results also suggest that CCIM could be produc ed in rats following IKF - 916 entering the blood compartment but not necessarily in the stomach compartment. Special study: In Vitro Metabolism of CCIM in S9 Fraction 45409011 (1999) Acceptable/non - guideline The in vitro metabolism of 14 C - CCIM was followe d up to five minutes in the presence of rat liver S9. The results suggested that CCIM was rapidly and completely metabolized within 5 minutes to at least three metabolites with the major one being CHCN (4 - chloro - 5(4 - hydroxymethyl - phenyl) - imidazole - 2 - carbo nitrile) which accounted for 77 - 94% of the radioactivity. Lower concentrations were found of CCBA (3 - 13%) and one or more unknown metabolites. It was concluded that CCIM produced in the intestines or blood would be rapidly and completely metabolized by the liver. Special study: In Vitro Study to Identify Metabolites Absorbed Through the Intestinal Mucosa After Incubation with IKF - 916 and CCIM 45409012 (1999) Acceptable/non - guideline Using in vitro isolated rat intestinal segments containing [ 14 C]IKF - 916 or [ 14 C]CCIM, 2.6% of IKF - 916 and 10.4% of CCIM was transferred from the lumen (mucosal side) to the exterior (serosal side) of the gut segment. Of the IKF - 916 that was absorbed and transferred to the buffer solution, approximately 60% had undergone biotr ansformation/degradation to CCIM, CCBA and three additional products. Also, CCIM appeared to be degraded to two metabolites not observed for intestine preparations containing IKF 916. Based on the findings of this study, cyazofamid seems to be poorly abs orbed from the intestinal lumen although its conversion to CCIM or other metabolites may increase overall transfer across the gut wall.Page 38 of 40

Table C .1. Toxicity Profile of Cyazofamid [IKF - 916] Technical. Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results Special study: Com parative metabolism of [ 14 C]IKF 916 or [ 14 C]CCIM in rats 45409013 (1999) Acceptable/non - guideline Rat s were given a single gavage dose of 0.46 mg/kg of [ 14 C - Bz]IKF - 916 or 0.33 mg/kg of [ 14 C Bz]CCIM and, after 30 minutes, blood, liver, stomach (plus contents), and duodenum (plus contents) were collected and analyzed for radioactivity and metabolites. Foll owing a single gavage dose of CCIM, the metabolites CCBA and CHCN, in addition to unchanged CCIM, were detected in the plasma and liver. The same metabolites, as well as CCIM, were also detected in plasma and liver following administration of IKF 916. The refore, orally administered IKF - 916 is converted to CCIM and subsequently to CCBA and CHCN. APPENDIX C .2. Acute Toxicity of Cyazofamid Table C.2. Acute Toxicity of Cyazofamid – Technical. Guideline No. Study Type MRID No. Results Toxicity Category 870.1100 Ac ute Oral

– Rat 45408910 LD 50 > 5000 mg/kg [M/F] IV 870.1200 Ac ute Dermal

– Rat 45408911 LD 50 > 2000 mg/kg [M/F] III 870.1300 Ac ute Inhalation

– Rat 45408912 LC 50 > 5.5mg/L [M/F] IV 870.2400 Primary Eye Irritation

–

Rabbit 45408913 Grade 2 conjunctival redness and discharge that resolved by 24 hours IV 870.2500 Primary Skin Irritation

– Rabbit 45408914 Very slight to well defined erythema that cleared by 7 days III 870.2600 Dermal Sensitization

(Guinea Pig Maximization test) 45408915 Positive (weak sensitizer) -Page 39 of 40

APPENDIX D . Rationale for Immunotoxicity Data Requirement Guideline Number: 870.7800 Study Title : Immunotoxicity Rationale fo r Requiring the Data This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non - food uses). The Immunotoxicity

Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is designed to evaluate the potential of a repeated chemical exposure to produce adverse effects ( i.e. suppression) on the immune sy stem. Immunosuppression is a deficit in the ability of the immune sy stem to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired Respiratory

Sy ndrome (SARS), or neoplasia. Because the immune s ys tem is highly complex, studies assessing functional immunotoxic endpoints are helpful in fully characteriz ing a pesticide’s potential immunotoxicity . These data will be used in combination with data from hematology , l ymphoid organ weights, and histopathology in routine chronic or subchronic toxicity studies to characterize potential immunotoxic effects . Prac tical Utility of the Data How will the data be used? These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a primary data source for reliable reference dose calculation. For example, animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8 - tetrachlorodibenzo p - dioxin) among developmental, reproductive, and endocrinologic toxicities. Additionally , the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRI S, 1997). How could the data impact the Agency's future decision - making? If the immunotoxicity

study shows that the test materi al poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessments for the test material may

need to be revised to reflect the magnitude of potential risk derived from the new data. If the Agency

doe s not have this data, a 10X database uncertainty factor may be applied for conducting a risk assessment from the available studies.Page 40 of 40

APPENDIX E. Rationale for Subchronic Toxicity Data Requirement Guideline Number: 870.6200 Study Title : Neurotoxicity Battery ( Subchronic Study) Rationale for Requiring the Data This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non - food uses). The Neurotoxicity

Screening Battery

(OPPTS 870.6200) is designed to evaluate the potential adverse effects on the nervous s ys tem from exposure to pesticide chemicals. The Agency

believes that the guideline studies are inadequate in their as sessment of behavioral effects and do not use optimal methods to evaluate the potential toxicity to the nervous tissue structure and function. To detect and characterize these potential effects more fully , a battery

of more sensitive testing is required. T he objective of this neurotoxicity

battery testing is to evaluate the incidence and severity of the functional and/or behavioral effects, the level of motor activity , and the histopathology of the nervous s ys tem. The acute neurotoxicity study is required t o detect possible effects resulting from a single exposure. The subchronic neurotoxicity study is intended to detect possible effects resulting from repeated or long - term exposures. Practical Utility of the Data How will the data be used? The acute an d subchronic neurotoxicity studies provide critical scientific information needed to characterize potential hazard to the human population on the nervous sy stem from pesticide exposure. These studies can provide data on a wide range of functional tests fo r evaluating neurotoxicity including sensory

effects, neuromuscular effects, learning and memory

and histopathology

of the nervous s ys tem . For example, animal studies with organophosphorous chemicals have shown neurotoxicity to be the primary toxic endpoi nts ( e.g. cholinesterase inhibition) of concern in rodents and non - rodents. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a primary data source for reliable referen ce dose calculation. The Agency has established an oral reference dose (RfD) for assessing dietary risks for a number of chemicals ( e.g. organophop hates and carbamates) where neurotoxicity

was the most sensitive endpoint of concern. How could the data imp act the Agency's future decision - making? If the acute or subchronic neurotoxicity studies show that cyazofamid poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessment for cyazofamid may need t o be revised to reflect the magnitude of potential risk derived from the new data. If the Agency

does not have this data, a 10X database uncertainty factor may be applied when conducting a risk assessment using the currently available studies.