Page 1 of 30 **UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON, D.C. 20460 OFFICE OF CHEMICAL**  **SAFETY AND POLLUTION PREVENTION**  **MEMORANDUM Date:**  August 3 , 2010 **SUBJECT: C**  **yazofamid .**  Human Health Risk Assessment for Proposed Section 18 Use on

Basil . **PC Code:**  085651 **DP Barcode:** D376500 **Decision No s**  **.:** 431716 **Registration No. :**  71512 - 3 **Petition No.:** 10IL02 **Regulatory Action:** Section 18 **Risk Assessment Type:** Single Chemical/Aggregate **Case No.:** NA **T XR No.:**  NA **CAS No.:** 120116 - 88 - 3 **MRID No.:** NA **40 CFR:** 180.6 01 **FROM:** Breann Hanson, Biologist

Alternative Risk Integration and Assessment (ARIA) Team Risk Integration, Minor Use and Emergency Response Branch (RIMUERB) Registration Division (RD ; 7505P) **THROUGH:** William Cutchin, Acting Senior Branch Scientist

ARIA RIMUERB/RD (7505P) **AND:** Barry

O’Keefe, Biologist Paula Deschamp, Branch Chief Risk Assessment Branch 3 (RAB3) Health Effects Division (7509P) **TO** : Marcel Howard/ Barbara Madden/Dan Rosenblatt , Risk Management Team 05

RIMUERB RD; 7505PPage 2 of 30 **Table of Contents 1.0**  **EXECUTIVE SUMMARY** ................................ ................................ ................................ . 3 **2.0 INGREDIENT PROFILE**  ................................ ................................ ................................ ... 6 **2.1 Structure and Nomenclature**  ................................ ................................ ....................... 7 **2.2 Physical and Chemical Properties**  ................................ ................................ ............... 7 **2.3 Summary of Proposed Uses**  ................................ ................................ .......................... 8 **3.0 HAZARD CHARACTERIZATION**  ................................ ................................ .................. 8 **3.1 Endocrine Disruption**  ................................ ................................ ................................ . 11 **4.0 DIETARY EXPOSURE/RISK CHARACTERIZATION**  ................................ ............. 12 **4.1 Pesticide Residue Profile**  ................................ ................................ ............................ 12 **4.2 Food Residue Profile**  ................................ ................................ ................................ ... 12 **4.3 Drinking Water Residue Profile**  ................................ ................................ ................ 13 **4.4 Dietary Exposure and Risk**  ................................ ................................ ........................ 14 **5. 0**  **NON -**  **OCCUPATIONAL/RESIDENTIAL EXPOSURE/RISK PATHWAY** .............. 16 **6.0 AGGREGATE RISK ASSESSMENTS and RISK CHARACTERIZATION**  ............. 17 **6.1 Acute Aggregate Risk Assessment (Food and Drinking Water)**  ............................ 17 **6.2 Short**  **- and Intermediate**  **- Term Aggregate Risk Assessment**  ................................ .. 17 **6.3 Chronic Aggregate Risk Assessment (Food and Drinking Water)**  ........................ 18 **7.0 CUMULATIVE RISK**  ................................ ................................ ................................ ....... 18 **8.0 OCCUPATIONAL EXPOSURE**  ................................ ................................ ...................... 19 **8.1 Occupational Post**  **- Application Exposure and Risk**  ................................ ................ 20 **9.0 DATA NEEDS AND LABEL RECOMMENDATIONS**  ................................ ................ 20 **9.1 Toxicology**  ................................ ................................ ................................ .................... 20 **10.0 ATTACHMENTS**  ................................ ................................ ................................ .............. 21 **Appendix A: Tolerance Setting** ................................ ................................ ......................... 22 **Ap pendix B:**  **Review of Human Research** ................................ ................................ ....... 22 **Appendix C. Codes, Chemical Names, and Chemical Structure of Cyazofamid and Identified Metabol**  **ites** ................................ ................................ ................................ ........ 22 **Appendix D. Toxicity Profile of Cyazofamid Technical**  ................................ .............. 23 **Appendix E. Acute Toxicity of Cyazofamid**  ................................ ................................ . 28 **Appendix F. Rationale for Immunotoxicity Data Requirement**  ................................ . 29 **Appendix G. Rationale for Subchronic Toxicity Data Require**  **ment** ......................... 30Page 3 of 30

**1.0 EXECUTIVE SUMMARY**  Introduction The Illinois Department of Agriculture (IDA) has submitted a Section 18 Tolerance Exemption request (PP# 10IL02) to establish a time - limited tolerance for the agricultural end - use product Ranman ® 400SC Fungicide to control down y mildew ( Peronospora balbahrii ) on basil . T his document provides a summary of the findings from the data evaluation and subsequent assessment of human health risk resulting from th is request. The hazard assessment and characterization were conducted b y Breann Hanson ( ARIA ) , the dietary exposure assessment was performed b y Roger Chesser (ARIA) and the occupational exposure data review for the tolerance petition was performed b y Mark Dow (Inert Ingredients Assessment Branch). ISK Biosciences Corporation has proposed, and ARIA concurs, that the tolerance in/on fresh basil be set at 12 ppm , based on currently existing tolerances on other leafy green commodities. ARIA recommends that the tolerance be set at 144 ppm for dried basil (derived from multiplying the recommended tolerance for basil, fresh (12 ppm ) by a maximum theoretical concentration factor of 12X . Background Cyazofamid (4 - chloro - 2 - cyano -N,N - dimethyl - 5 -

p - tolylimidazole - 1 - sulfonamide) is a fungicide which belongs to a novel chemical class based on the cyanoimidazole moiety . C yazofamid is a broad spectrum fungicide active against oomycete fungi (such as Phytophthora, Plasmopara, Pseudoperonospora, and Pythium ) and Plasmodiophoromycetes ( Plasmodiospora brassicae ). It specificall y interferes with the cy tochrome bc 1 complex (ubiquinol cy tochrome c oxidoreductase) in the mitochondrial respiratory chain of oomycetes fungi. The most recent human - health risk assessment was conducted in conjunction with a request for use of cyazofamid on Brassica ( cole ) leafy vegetables , turnip greens , spinach , and h ops (DP Barcode : 370671 , N. Tsaur , 0 4/7/2010 ). Proposed Use on Basil Ranman ® 400 SC is a soluble concentrate formulation which contains 3.33 lb active ingredient (ai) cyazofamid per gallon. Applications will be made by ground sprayers. The requested rate of application is 0.071 lb ai/A with a maximum of 6 applications/A/year (0. 43 lb ai/A/year). Cyazofamid will be used in rotation with 2 other fungicides having different modes of action. The total acreage expected to be treated is 500 acres which will require approximately 215 lb ai cyazofamid. The use season is June 1

– Octob er 15. The retreatment interval is 1 day. There is a 0 day pre - harvest interval indicated by the primary

registrant, FMC. Hazard Assessment For the purposes of this Section 18, the toxicology data base is adequate . Cyazofamid has a low order of acute toxicity

via the oral, dermal, and inhalation routes of exposure. It produces minimal but reversible eye irritation, is a slight dermal irritant, and is a weak dermal sensitizer. The propensit y of c yazofamid to be a slight dermal irritant and a weak sens itizer might be due to the sulfonamide moiety

in the compound.Page 4 of 30

Following repeated administration in more than one species, cyazofamid seems to have mild or low toxicity . In rats, the kidney is the major target organ following subchronic dosing. No adverse kidney

effects or other toxicity

findings were observed following chronic exposures. In mice, s kin lesions likely

due to sy stemic allergy , were observed in the males only . In dogs, there were no major toxicity

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. Cyazofamid is classified as “not likely to be carcinogenic to humans” based on the lack of evidenc e of carcinogenicity in both the rat and the mouse studies. Additionally , cyazofamid does not appear to have mutagenicity potential, based on several negative in vivo and in vitro studies. Dose Response Assessment and Food Quality Protection Act (FQPA) D ecision HED has examined the toxicology data and determined that there are no concerns or residual uncertainties for pre - and or postnatal toxicity . On this basis, the FQPA safety factor should be removed ( i.e. reduced to 1X) for all potential exposure sc enarios of cyazofamid. Furthermore, HED does not believe that conducting either a functional immunotoxicity study or an acute neurotoxicity

study will result in lower NOAELs than the regulatory doses for risk assessment, and an additional factor (UF DB ) fo r 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) EDWCs were estimated for surface water using the PRZM/EXAMS model. For the purpose of this dietary assessment, ARIA used the highest calculated screening estimated drinking water concentrations ( EDWCs ) for surface water based on the conservative screen - level estimates : 136 ppb for the acute analy sis and 133 ppb for the chronic analy sis. This approach may substantiall y overestimate dietary exposure to cyazofamid from drinking water. Dietary Exp osure Estimates For the acute anal ys is, an acute endpoint was not identified for the general population including infants and children, because 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 the Agency ’s level of concern at the 95 th percentile of exposure. Combined dietary exposure from food and drinking water is estimated at 0.0122 29 mg/kg/day , equivalent to 1.2 % of the acute Population Adju sted Dose (aPAD).Page 5 of 30

For the chronic anal ys is, dietary (food and drinking water) exposure is estimated at 0 .0 05118 mg/kg/day

for the general U.S. population (<1% of the chronic Population Adjusted Dose ( cPAD) ) and 0.011 594 mg/kg/day (1. 2 % of the cPAD) for infants 1

–2 year s old, the population subgroup with the highest estimated chronic dietary exposure to cyazofamid. These aPADs and cPADs are well below the Agency ’s level of concern. Residential Exposure Estimates No non - occupational or residential expo sures are expected from this proposed use on basil. Residential exposure to c ya zofamid has previously been assessed for use on commerciall y treated residential turf and ornamentals . No n - occupational handler exposure s are not expected ; h owever, post - appli cation exposure is possible for children and adults . Non - occupational/ residential Margins of Exposure ( MOEs ) were estimated for “Day 0" exposure (i.e., the day of application). The post - application children’s aggregate M OE (including incidental oral exposures) is 1, 600 . All MOEs , including the children’s aggregate, are greater than 100, and therefore, are not of concern to the Agency . 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 (food + 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 potential exposure pathway s were assessed in the aggregate risk assessment. MOEs for aggregate exposure range from 1,100 to 1,500 . None of the aggregate expo sure and risk estimates exceed the Agency ’s level of concern. Occupational Exposure Estimates No chemical specific data were available with which to assess potential exposure to pesticide handlers. In accordance with HED policy , occupational handler exposures were estimated using the Pesticide Handlers Exposure Database (PHED) Surrogate Exposure Guide (revised August, 1998). MOEs range d from 980 to 179,000 ; which are greater than the level of concern ( LOC ) of 100, and are not of concern to the Agency . The results of the occupational post - application exposure and risk assessment indicate that the MOE is greater than 100 and therefore, is 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 interval ( REI ) . Therefore, the 12 - hour REI that 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_12898envjustic e.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 obtainPage 6 of 30

drinking water from sources near agricultural areas, the varia bility 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 avai lable information. 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 received that review , and have been determined to be ethical . Recommendations ARIA has compared the proposed Section 18 label for RANMAN 400SC with the labeled use rates for the existing uses on other leafy green commodities ; no changes are required on the proposed label. No risks of concern have been identified for the emergency exemption use of cyazofamid on basil; therefore, ARIA recommends for granting the exemption and establishing time - limited tolerances for residues of cyazofamid. Time - limited t olerances are established for residues of the fungicide cyazofamid, including its metabolites and degradates, in or on the commoditie s noted 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 . basil, fresh ................................ ................................ ................................ ..... 12 ppm basil, dried ................................ ................................ ................................ ... 144 ppm **2.0 INGREDIENT PROFILE**  The chemical structure and nomenclature of cyazofamid are presented in Table 2.1. The phy sicochemical properties of the technical grade cyazofamid are presented in Table 2.2. A summary of the proposed uses is presented in Table 2.3.Page 7 of 30

**2.1 Structure and Nomenclature**  The chemical structure and nomenclature of the technical grade of cyazofamid and its metabolite CCIM are shown in Table 2. 1 . **Table 2.1.**  **Test Com pound Nom**  **enclature.** Com pound Chemical Structure

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 - imidazole - 1 - sulfonamide CAS registry number 120116 - 88 - 3 End - use product (EP) Ranman® 400SC Agricultural Fungicide (EPA Reg. No. 71512 - 3) Com pound Chemical Structure of metabolite

Common name CCIM IUPAC name 4 - chloro - 5 - p - tolylimidazole - 2 - carbonitrile CAS name 4 - chloro - 5 - (4 - me thylphenyl) - 1 H - imidazole - 2 - carbonitrile **2. 2**  **Physical and Chemical Properties** The phy sicochemical properties of the technical grade of cyazofamid are shown in Table 2. 2 . **Table 2.**  **2 .**  **Physicochem ical Properties of the Technical Grade Cyazofam** **id.** 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 N N C H3 Cl CN S O 2 N ( C H3 ) 2

N H N C H 3 Cl C NPage 8 of 30

**Table 2.**  **2 .**  **Physicochem ical Properties of the Technical Grade Cyazofam** **id.** Parameter Value Reference 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 pK a 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 **2.3 Summary of Proposed Uses**  **Table 2.3. Summ ary of Proposed Use Pattern for Applying Cyazofam** **id to Basil in Illinois.** Form ulation Ranman ® 400 SC; Reg. No. 71512 - 3; 3.33 lb ai/gal s.c.. Pest Downy mildew; Peronospora belbahrii Method of Applic. ground - boom Applic. Rate 0.071 lb ai/A Max. No. Applications 6 per acre per year Max. Am't/Yr 0.43 lb ai/A/yr Total Acres Treated Approximately 500 A Total A.I. Required 215 lb ai at the maximum rate of application Applic. Interval 1 day Preharvest Interval 0 days Restricted Entry Interval 12 hours Manufacturer FMC **3.0 HAZARD CHARACTERIZATION**  The toxicology

database for cyazofamid is sufficient to characterize the hazard, to conduct FQPA assessment, and to select toxicity endpoints 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 780.7800) shall be require d as a condition of registration. To address the issue of the immunotoxicity data gap and the associated database uncertainty factor, RAB3 has examined the entire database ofPage 9 of 30

cyazofamid and concluded that the toxicology database of this chemical does not show any evidence of biologically

relevant effects on the immune sy stem that related to this chemical. The overall weight of evid ence suggests that this chemical does not directly target the immune sy stem . The Agency

does not believe that conducting a functional immunotoxicity study will result in a lower NOAEL than the regulatory dose for risk assessment, and an additional factor (UF DB ) for database uncertainty is not needed to account for lack of this study . In addition, 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 toxicity 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 subchr onic, chronic, reproduction, or developmental toxicity studies. 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 uncertaint y factor (UF DB ) for lack of a subchronic neurotoxicity study is not needed. The hazard characterization, dose response considerations, abso rption, distribution, metabolism, e xcretion (ADME) determinations, FQPA safet y factor determination , mode of action, and toxicological effects are detailed in a previous risk assessment (DP Barcode: 342612 , K . O’Rourke , 03/ 19 /20 08). Based on the hazard and exposure data, the HED cyazofamid risk assessment team recommend ed that the FQPA SF be reduced to 1x . Tables 3.0.a and 3.0.b summarize the toxicological endpoints for cyazofamid for use in dietary and occupational human health risk assessments, respectivel y. **Table 3. 0.**  **a. Toxicological Doses and Endpoints for Cyazofam** **id 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 Population, 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 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 incidenc e of bent ribs. 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.Page 10 of 30

**Table 3. 0.**  **a. Toxicological Doses and Endpoints for Cyazofam** **id 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**

Incidental Oral Short - Term

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

mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Residential

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

oral dose - range - finding study in rats. In this study, at 370 mg/kg/day or above increas ed 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 toxicity 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 FQPA 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 mo nths) 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 studies. Point of Departure (PoD) = A data point or an estimated point that is derived from o bserved 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 = unc ertainty factor. UF A = extrapolation from animal to human (intraspecies). UF H = potential variation in sensitivity among members of the human population (interspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chroni c). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. **Table 3. 0.b**  **. Summary of Toxicological Doses and Endpoints for Cyazofam** **id 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 nths) Oral Study

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

UF H = 10X SF = 1X 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.Page 11 of 30

**Table 3. 0.b**  **. Summary of Toxicological Doses and Endpoints for Cyazofam** **id for Use in Occupational Hum an** 

**Health Risk Assessments.** Dermal Long Term (>6 mo nths) NOAEL=

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

UF H = 10X SF = 1X Occupational LOC

for MOE = 100 18 - Month Mouse Oral Carcinogenicity

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

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

100 mg/kg/day UF A = 10X

UF H = 10X SF = 1X 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. Inhalation Long - Term

(>6 mo nths) NOAEL=

94.8 mg/kg/day UF A = 10X

UF H = 10X SF = 1X 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 (PoD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (intraspecies). UF H = potential variation in sensitivity among members of the human population (interspecies ). SF = safety factor. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. **3. 1**  **Endocrine Disruption** As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certa in 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 emplo ys a two - tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assay s to identify the potential of a chemical substance to interact with the estrogen, androgen, or th yroid (E, A, or T) hormonal sy st ems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal sy stems will proceed to the next stage of the EDSP where EPA will determine which, if any , of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify an y adverse endocrine related effects caused by the substance, and establish a dose - response relationship between the dose and the E, A, or T effect. Between October 2009 and February 2010, EPA is sued 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 wat er, residential activity , and certain post - application agricultural 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 t o be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticidePage 12 of 30

chemicals. Accordingl y, EPA anticipates issuing future EDSP test orders/data call - ins for all pesticide active ingredients . For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery , please visit our website: http://www.epa.gov/endo/. **4 .0**  **DIETARY EXPOSURE/RISK CHARACTERIZATION 4**  **.1 Pesticide Residue Profile**  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; for the risk assessment and tolerance expression, parent and CCIM are the residues of concern for plant commodities. 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; b ased on the available ruminant metabolism studies in goats, the following metabolites should be anal yz ed for future cattle feeding studies: cyazofamid, CCIM, CCBA ( 4 - (4 - chloro - 2 - cyanoimidazol - 5 - yl )benzoic acid ; CCBA - cysteine conjugate. Confined Accumulation in Rotational Crops No confined accumulation in rotational crop study was submitted with this petition. However, studies were submitted in conjunction with an ea rlier petition (PP#1F06305). The results of these data showed that cyazofamid and structurall y related metabolites are not expected to be present at a level greater than 0.01 ppm at a plant - back interval of 30 day s. Therefore, a rotational crop plant - back interval (PBI) of 30 day s is appropriate for cyazofamid end - use labels. Residue Analytical Methods

– Plants An acceptable anal yt ical method is available for enforcement purposes. An adequate data collection method, “Independent Laboratory 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, can be used to determine the residues of cyazofamid and CCIM. The method is expected to b e suitable for anal ys is of basil. **4.2 Food Residue Profile**  There are no data available depicting residues of cyazofamid in fresh or dried basil. As a surrogate, ARIA had translated data from Brassica , l eaf y greens, crop s ubgroup 5B (Table 4 . 2 ). These d ata support the recommended tolerance of 12 ppm in/on fresh basil. A conservative tolerance of 144 ppm in/on basil, dried is recommended to accommodate a maximum theoretical concentration factor of 12X.Page 13 of 30

**Table 4**  **. 2**  **Summary of Food Residue**  **Considerations** Parameter Proposed Use on Basil Translated Residue Data Chemical Cyazofmaid Cyazofamid Form ulation Ranman® 400SC

Fungicide Ranman® 400SC Fungicide Crop Basil Brassica , leafy greens, crop subgroup 5B Ty pe of Application ground - boom sprays Transplant Soil

Drench Soil Incorporation Broadcast foliar Number of Applications 6 1 1 5 Timing/Retreat ment Interval 1 day N/A N/A 7 - 10 days Individual Application Rate 0.071 lb ai/A 0.333 - 0. 665 lb ai/ 100 gal 0.52 lb ai/A 0.072 lb ai/A Seasonal Application Rate 0.43 lb ai/A/yr 0.665 lb ai/100 gal 0.52 lb ai/A 0.36 lb ai/A Pre - harvest Interval 0 days N/A N/A 0 day Restrictions Non - ionic

surfactant may be used. Non - ionic surfactant may be used. Residue Data Source Section 18 10IL02 DP Barcode: 370671, N. Tsaur, 0 4/ 0 7/2010 Performing Laboratory Not Applicable Field Trial Studies Canada has established MRL s for residues of c ya zofamid in/on several commodities, but has not established maximum residue limits for basil . No MRL s for residues of c yazofamid have been established by

the Codex Alimentarius Commission ( email, S. Funk, 0 6/ 0 7/2010) . **4 .**  **3 Drinking Water Residue Profile**  The maximum seasonal application proposed for the Section 18 use on basil is less than or equal to currentl y registered use rates. As such, a previously modeled Tier I drinking water assessment conducted b y EFED for the established cyazofamid uses (DP Barcode : 370673, J. Meléndez, 0 3/ 0 1/2010) was used in this assessment. The assessment included cyazofamid and the metabolites designated as CCIM, CCIM - AM ( 4 - chloro - 5 - p - tol yl imidazole - 2 - carboxamide ), and CTCA ( 4 - chloro - 5 -

p - tolylimidazole - 2 - carbox yl ic acid) in drinking water . The maximum EDWCs that m ay occur are due to the use of cyazofamid on turf and ornamentals, presented in Table 4 . 3 , 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 degradates by dividing the rate between the degradates based on molecular ratios and adjusted maximums found in fate studies; andPage 14 of 30

3. The terminal degradate CTCA, a ssuming application of 100% molar conversion of the parent into this terminal degradate CTCA. **Table 4**  **. 3**  **. Resulting Maximum Surface/Groundwater EDWCs for Cyazofam** **id and each of its Major**

**Degradates (from use on Turf and Ornam**  **entals) .**  **Scenario Chemical**  **Surface water EDWCs (ppb) Ground Water**  **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 highest acute (peak) and chronic (mean) EDWCs were estimated for surface water using the PRZM/EXAMS model. For the purpose of the Tier 1 dietary assessment, ARIA used the highest calculated screening EDWCs for surface water : 136 ppb for the acute analy sis and 133 ppb for the chronic anal ys is. This approach may significantly

overestimate dietary

exposure to cyazofamid from drinking water. **4 .**  **4 D**  **ietary Exposure and Risk** Cyazofamid acute and chronic dietary exposure assessm ents were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM FCIDTM, Version 2.03) . 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. A cancer dietary assessment was not conducted because cyazofamid has been classified as “not likely to be carcinogenic to humans.” Acute and Chronic Dietary Exposure and Risk An acute endpoint was not identified for the general population including infants and children, because no effects were observed which could be attributed to a single - dose exposure. However, for females 13 to 49 years old, the acute RfD of 1.0 mg/kg/day i s derived from the d evelopmental toxicity

NOAEL of 100 mg/kg/day based on increased incidence of bent ribs at the developmental LOAELof 1,000 mg/kg/day in the rat prenatal developmental toxicity study . A 100 - fold uncertainty

factor (10X inter - species extrapolation and 10X intra - species variabilit y) is required. Since the FQPA SF has been reduced to 1X, the acute population - adjusted - dose or acute PAD is equal to the acute RfD. The acute PAD was used for assessing acute dietary risk. The chronic RfD of 0.9 5 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 intra - species v ariability) is required. Since the FQPA SF has been reduced to 1X, the chronic PAD is equal to the chronic RfD. The chronic PAD was used for assessing chronic risk. The unrefined acute and chronic analy ses assumed that cyazofamid residues are present in/on all registered food commodities at tolerance levels and that 100% of all commodities are treated. Adequate processing data are available for grapes (MRID 45409028) and tomatoes (MRID 45409031). A previously submitted potato processing study is not sc ientifically

acceptablePage 15 of 30

(MRID 45409033) . The results of these studies indicate that residues in processed commodities will exceed the raw agricultural commodity (RAC) tolerances in certain cases ( DP Barcode: 285680; A. Acierto; 2/20/20 04 ) . Therefore, pro cessing factors were set to 1x , ex cept that default processing factors were used for dried tomatoes, tomato juice, dry potatoes, and potato flour. There were no processing data for basil. A cute dietary (food and drinking water) exposure of females 13 - 49 years old is well below the Agency ’s level of concern (i.e., <100% of the aPAD of 1.0 mg/kg/day). The combined dietary exposure from food and drinking water is estimated at 0.0122 29 mg/kg/day (equivalent to 1 .2 % of the aPAD), at the 95 th percentile of expo sure. It is noted that estimated acute dietary exposure of females 13 - 49 years old is also well below the Agency ’s level of concern at the 99 th an d 99.9 th percentiles of exposure as shown in Table 4 .4.a, below . **Table 4.4.a. Results of Acute Dietary Exposure Analysis for Food and Drinking Water at the 95**  **th Percentile of**  **Exposure using DEEM FCIDTM. 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 0.012229 1.2 0.025266 2.5 0.060021 6.0 C hronic dietary

(food + drinking water) exposure estimates are well below the Agency ’s level of concern for the general U.S. population and each of the population subgroups. Dietary exposure was estimated at 0.0051 18 mg/kg/day for the U.S. population (<1% of the cPAD) and 0.011 594 mg/kg/day

(1. 2 % of the cPAD) for the most highl y exposed population subgroup ( children 1

– 2 ye ars old) . The estimated exposures/risks for food and drinking water are summarized in Table 4.4.b, below, for all populations.

**Table 4.4.b**  **. Summary of Chronic Dietary Exposure and Risk for Cyazofamid 1**  **Population Subgroup Exposure**  **(m g/kg/day)**  **% cPAD**  General U.S. Population 0.005118 <1 All Infants (< 1 year old) 0.011214 1.2 **Children 1 -**  **2 years old 0.011594**  **1.2** Children 3 - 5 years old 0.009133 1 Children 6 - 12 years old 0.005201 <1 Youth 13 - 19 years old 0.003560 <1 Adults 20 - 49 years old 0.004467 <1 Adults 50+ years old 0.004958 <1Page 16 of 30 **Table 4.4.b**  **. Summary of Chronic Dietary Exposure and Risk for Cyazofamid 1**  **Population Subgroup Exposure**  **(m g/kg/day)**  **% cPAD**  Females 13 - 49 years old 0.004413 <1 1 The population subgroup with the highest estimated chronic dietary (food + drinking water) exposure and risk is indicated by bold text. **5 .0**  **NON -**  **OCCUPATIONAL/RESIDENTIAL EXPOSURE/RISK PATHWAY** 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 currentl y commerciall y registered to treat p ythium diseases on residential turf and phy thium, phy

tophthora and down y mildew diseases on ornamental plants in residential landscapes (DP Barcode: 365261 , N. Tsaur, 0 3/27/ 20 09). In addition, cyazofamid is c ommerciall y registered to treat py thium and downy

mildew diseases on professionally managed turf areas, and py thium, phy tophthora, and downy

mildew diseases on ornamental plants in landscapes and grown in commercial greenhouses and nurseries (DP Barcode: 3 32425, K. O’Rourke, 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 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 anal yz ed and found to be 1,600, which is greater than 100, and not of risk concern to HED (DP Barcode: 365261, N. Tsaur, 0 3/27/2009). Post - application exposure was also anal yz ed for recreational golfers or players of various sports who use turf areas following cyazofamid expo sure. The dermal MOEs for post - application exposure for recreational golfers or sports playe rs were greater than 100 (330 to 14,000) and therefore not of risk concern to HED (DP Barcode: 332425, K. O’Rourke, 0 3/27/20 09). 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 Barcode: 365261, N. Tsaur, 03 /27/2009). **Ta ble**  **5 .**  **0. Children’s Aggregate Exposure and Risk Estimates from Residential Lawn**  **s. Children’s Scenarios**  **TTR/GR/SR 0**  **(ug/cm 2**  **or g) 1**  **PDR 0**  **- 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) Soil 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".Page 17 of 30 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 )] Other Exposure Sources (Spray Drift) Spray drift is alway s a potential source of exposure to residents nearby to spraying op erations. This is particularly

the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for 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 Agency 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 assessments for pesticides applied by 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 a ssociated with aerial as well as other application types where appropriate. Note: As 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 exposure 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 assessments 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 cancer aggregate risk assessment was not pe rformed 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 y 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 required. For the population of concern, the acute dietary (food and drinking water) risk assessment reported in Section 4 .4 represents acute aggregate risk . The dietary route alone is relevant for acute exposure and risk assessment. **6 .2**  **Short -**  **and Intermediate -**  **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, drinking water, and residential pesticide uses.Page 18 of 30

Short - term and intermediate - term risks have been assessed together because both scenarios have the same endpoints and PODs. High - end estimat es of residential exposure are used, while average values are used for food and drinking water exposure (i.e. chronic exposures). A short - /intermediate - term risk assessment is required for adults and children because there are potential post - application e xposures from the use on residential lawns and ornamentals . The results of 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 Interm ediate**  **- Term Aggregate 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 20,000 NA 1,100 NA 1,100 Children 3 - 5 years old 11,000 1,600 NA NA 1,400 Children 6 - 12 years old 19,000 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 3 MOE oral = [(short - or intermediate - term oral NOAEL)/(hand - to - mo uth residential exposure)] NOAEL = 30 mg/kg/day . (See Table 5 . 0 fo r children’s oral exposure ). 4 MOE dermal = [(short - or intermediate - term dermal NOAEL)/(high - end dermal residential exposure)] NOAE L = 100 mg/kg/day. ( See DP Barcode: 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/MOE Oral ) + (1/MOE Dermal ) + (1/MOE Inhalation)] **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 assessment is based on exposure from food and drinking water only , as presented previously in this memorandum ( Section 4 . 4 ) . **7 .0**  **CUMULATIVE RISK** Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering whether to establish, modify , or revoke a tolerance, the Agency consider "available information concerning the cumulative effects” of a particular pesticide's residues and "other substances that have a common mechanism of toxicity .” Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity , EPA has not made a common mechanism of toxicity finding asPage 19 of 30

to cyazofamid and any

other substances and cyazofamid does not appear to produ ce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, 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 chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating e ffects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. **8 .0**  **OCCUPATIONAL EXPOSURE** ARIA believes the most highl y exposed occupational p esticide handlers will be mixer/loaders preparing stock spray

solution and applicators using ground boom sprayers. Open cab sprayers are assumed. A dermal point of departure for short - and intermediate - term exposures was identified from a prenatal deve lopmental study in the rat; a NOAEL of 100 mg/kg/day was identified for occupational exposures. Since the study was an oral study , the toxicological team identified a dermal absorption factor of 37%. The UF is for MOEs < 100 that is, 10X for interspecies variation and 10X for intraspecies variation. The Agency also identified short - and intermediate term inhalation toxicological endpoints. They are identified from the same study and cite the same toxicological effects and the same NOAEL. HED/ARIA assum es 100% absorption via the inhalation route of exposure. See Table 8 .0, below, for a summary of estimated exposures and risks to occupational pesticide handlers from applying cyazofamid to basil.

1. Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”, Estimates of Worker Exposure from The Pesticide Handler Exposure Database Version 1.1, August 1998. Dermal = Single Layer Work Clothing **No Gloves** ; Single Layer Work Clothing **With Gloves** ; Inhal. = Inhalation. Units = mg ai/pound of active ingredient handled. Single layer of work clothing = long - sleeved shirt, long pants, shoes plus socks. 2. App lic. Rate = Taken from Illinois Dept. Agric. Section 18 Request 3. Units Treated are taken from “Standard Values for Daily Acres Tre ated in Agriculture”; ExpoSAC SOP No. 9.1. Revised 25 September 2001 ; 4. Average Daily Dose = Unit Exposure * A pplic. Rate * Units Treated * 37 % dermal absorption  60 kg Body Weight 5. MOE = Margin of Exposure = NOAEL  ADD. NOAEL = 100 mg/kg bw /day. ADD = Dermal Avg. Daily Exposure + Inhalation Avg. Daily Exposure. **Table 8**  **.0. Summary of Exposure & Risk to Occupational Handlers From** **Application of Cyazofam id to Basil**  **Unit Exposure 1**  mg ai/lb handled **Applic. Rate 2**  lb ai/unit **Units**

**Treated 3**  **Avg. Daily Exposure 4** 

mg ai/kg bw/day **MOE 5**  **Mixer/Loader -**  **Liquid -**  **Open Pour** Dermal: SLNoGlove 2.9 SLWithGlove 0.023 Inhal. 0.0012 0.071 lb ai/A 80 A/day Dermal: SLNoGlove 0.102 SLWithGlove 0.00081 Inhal. 0.000114 No Glove 980 With Glove 108,000 **Applicator –**  **Ground**

**- boom**  **- Open**  **- cab**  Dermal: SLNoGlove 0.014 SLWithGlove 0.014 Inhal. 0.00074 0.071 lb ai/A 80 A/day Dermal: SLNoGlove 0.00049 SLWithGlove 0.00049 Inhal. 0.00007 No Glove 179,000 With Glove 179,000Page 20 of 30

A MOE of 100 is adequate to protect occupational pesticide handlers from exposures to cyazofamid . The estimated MOEs are all > 100. Therefore the proposed use do es not exceed the Agency ’s level of concern. **8 .1**  **Occupational Post**  **- Application Exposure and Risk**  The following convention is used to est imate post - application exposure: Average Daily Dose (ADD) (mg a.i./kg bw/day) = DFR μg/cm 2 * TC cm2 /hr * hr/day * 0.001 mg/μg * 1/60 kg bw and where: Surrogate Dislodgeable Foliar Residue (DFR) = application rate * 20% available as dislodgeable residue * 4.54 x 10 8 μg/lb * 2.47 x 10 - 8 A/cm2

. 0.071 lb a.i./A * 0.20 * 4.54 x 10 8 μg/lb * 2.47 x10 - 8 A/cm2 = 0.349 μg/cm2 , therefore, 0.349 μg/cm2 * 2,500 cm2 /hr * 8 hr/day * 0.001 mg/μg * 0.37 (37 % dermal absorption)  60 kg bw = 0.0087 mg/kg bw/day. **MOE = NOAEL**  **ADD** then 100 mg/kg bw/day  0.0087 mg/kg bw/day = **460.** A MOE of 100 is adequate to protect agricultural workers from post - application exposures . The most conservative estimate (i.e., highest exposure/risk) of post - application exposure results in MOEs > 100. Therefore, th e proposed risk does not exceed the Agency ’s level of concern. **8 .2**  **Restricted Entry Interval (REI)** The interim Worker Protection Standard (WPS) REI is 12 hours for active ingredients classified in Acute Toxicity

C ategory I II or IV for acute dermal toxicity , acute inhalation toxicity skin irritation potential, and eye irritation potential. The product label lists a REI of 12 hours. **9 .**  **0 DATA NEEDS AND**  **LABEL RE COMMENDATIONS**  **9 .1**  **Toxicology**

 Based on low volatility , low inhalation toxicity (Category

IV), and inhalation MOEs > 1,000 for the proposed uses in this risk assessment, cy azofamid qualifies for a waiver of the 28 - day

inhalation toxicity

study for the proposed uses [HED Standard Operating Procedure (SOP) 2002.01: Guidance: Waiver Criteria for Multiple - Exposure Inhalation Toxicity Studies, 08/15/02]. **The requirement for the 28 -**  **day inhalation toxicity study is waived for this action only**  . I f in the future, requests for new uses or formulations are submitted that may

result in a significant change in either the toxicity pr ofile or exposure scenarios, HED will reconsider this data requirement.  A s part of the new 40CFR §158 Guidelines, a functional immunotoxicity study in rats and/or mice is required (Guideline 870.7800); see Appendix C .Page 21 of 30

 A s part of the new 40CFR §158 Guidelin es, a subchronic neurotoxicity study is required (Guideline 870.6200); see Appendix D . **1 0**  **.0 ATTACHMENTS**  Appendix A: Tolerance Setting Appendix B: Review of Human Research Appendix C. Codes, Chemical Names, and Chemical Structure of C yazofamid and I dentified Metabolites Appendix D . Toxicity

Profile of Cyazofamid Technical Appendix E. Acute Toxicity of C yazofamid Appendix F : Rationale for Immunot oxicity Data Requirement Appendix G : Rationale for Subchronic Neurotoxicity Data Requirement **REFERENCES :**  Dietary (Food and Drinking Water) Assessment Cyazofamid: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for a Section 18 Registration Action f or Use of Cyazofamid on Basil . DP Barcode: 376585, R. Chesser, 5/25/2010. Drinking Water Assessment Estimated Drinking W

ater Concentrations of Parent Cyazofamid and its Degradates CCIM, CCIM - AM and CTCA for Use in Human Health Risk Assessment (Use on Fru iting Vegetables, Crop Group 8 + Okra, and Grapes, East of the Rocky Mountains) . DP Bar c ode: 356836, J . Meléndez , 3/24/2009. Hazard Characterization Assessment Cyazofamid [IFK

- 916]

– Report of the Hazard Identification Assessment Review Committee. G . Dannan, 3/03/20 04. Metabolism Assessment Cyazofamid - Meeting Report of the Metabolism Assessment Review Committee (MARC) . DP Barcode: 298915, A. Acierto, 2/18/20 04. Occupational Assessment CY AZOFAMID

– Human, Non -Dietary Exposure/Risk Assessment for the Section 18 Requested Use of Cyazofamid on Basil in Illinois . DP Barcode: 376858, M. Dow, 4/27/2010. Previous Risk Assessment Cyazofamid. Human Health Risk Assessment for Proposed Uses on Brassica (Cole) Leafy Vegetables Crop Group 5, Turnip Greens, Spinach, and Hops . DP Barcode: 370671 , N. Tsaur, 4/7/2010.Page 22 of 30

**A ppendix**  **A : Tolerance Setting**  **Table A.1**  **. Tolerance Summary for**  **Cyazofam id**  **.** Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity Definition **Proposed Time**  **- lim**  **ited Tolerances**  Basil, fresh --- 12 Recommended tolerance translated from Brassica , leafy greens, crop subgroup 5B Basil, dried --- 144 Recommended tolerance for basil, fresh, multiplied by a maximum theoretical concentration factor of 12X. **Appendix B**  **: Review of Human Research**  The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency , and the National Agricultural Chemicals Association, released February , 1995. **Appendix C. Codes, Chemical Names**  **, and Chemical Structure of Cyazofamid**  **and Identified Metabolites**  **Table C. Identification of Com** **pounds from the 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 C N 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 OPage 23 of 30

**Table C. Identification of Com** **pounds from the Cyazofamid Metabolism**  **Studies.** Common name/ code/matrix Chemical name Chemical structure 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 acid

**Appendix D. Toxicity Profile of Cyazofamid Technical**  **Table D. Toxicity Profile of Cyazofam id**  **[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 ki dney 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.Page 24 of 30

**Table D. Toxicity Profile of Cyazofam id**  **[IKF -**  **916] Technical Guideline No./**  **Study Type MRID No. (year)/**  **Classification/Doses Results**  870.3465 90 - Day inhalation toxicity Study not available. 870.3700a Prenatal developmental in rats 45430404 (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 = 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. 870.3800 Reproduction and fertility effects in rats 45408935 (1998)

Acceptable/guideline 0, 200, 2,000, or 20,000 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/System ic**  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 ppm 0, 0.35, 1.7, 17.1, or 171.1 mg/kg/day Females: 0, 50, 500, 5,000, o r 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 observed. **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, ulceration, and acanthosis. **No evidence of carcinogenicity.**Page 25 of 30

**Table D. Toxicity Profile of Cyazofam id**  **[IKF -**  **916] Technical Guideline No./**  **Study Type MRID No. (year)/**  **Classification/Doses Results**  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 tested (limit dose) 2,000 mg/kg. 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 (2000)

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 considered an adverse finding. 870.6200b Subchronic ne urotoxicity screening battery Study not available.

870.6300 Developmental neurotoxicity Study not available.Page 26 of 30

**Table D. Toxicity Profile of Cyazofam id**  **[IKF -**  **916] Technical Guideline No./**  **Study Type MRID No. (year)/**  **Classification/Doses Results**  870.7485 Metabolism and pharmacokinetics in rats 45409006 - 45409009 and 45434602

(1998 - 1999) Acceptable/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 administered 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 (each ≈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) each of which being less than 5% of the administ ered 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. 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 examined. 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 produced in rats following IKF - 916 entering the blood compartment but not necessarily in the stomach compartment.Page 27 of 30

**Table D. Toxicity Profile of Cyazofam id**  **[IKF -**  **916] Technical Guideline No./**  **Study Type MRID No. (year)/**  **Classification/Doses Results**  Special study: In Vitro Metabolism of CCIM in S9 Fraction 45409011 (1999)

Acceptable/non - guideline The in vitro metabolism of 14 C - CCIM was followed 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 - carbonitrile) 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 t o 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 biotransformation/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 absorbed from the intestinal lumen although i ts conversion to CCIM or other metabolites may increase overall transfer across the gut wall. Special study: Com parative metabolism of [ 14 C]IKF - 916 or [ 14 C]CCIM in rats 45409013 (1999)

Acceptable/non - guideline Rats 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. Following a single gavage dose of CCIM, the me tabolites 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. Therefore, orally administered IKF - 916 is converted to CCIM and subsequently to CCBA and CHCN.Page 28 of 30

**Appendix E. Acute Toxicity of Cyazofamid Table**  **E. Acute Toxicity of Cyazofam** **id –**  **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 29 of 30

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

Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity

testing and is designed to evaluate the potential of a repeated chemical exposure to produce adverse 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 . **Practical 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 material 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

does not have this data, a 10X database uncertaint y factor may be applied for conducting a risk assessment from the available studie s.Page 30 of 30

**Appendix G. 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 assessment of behavioral effects and do not use optimal methods to evaluate the potential toxicity to the nervous tissue str

ucture and function. To detect and characterize these potential effects more fully , a battery

of more sensitive testing is required. The objective of this neurotoxicity

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

effects, neuromuscular effects, learning and memory

and histopathology

of the nervous s ys tem. For example, animal studies with organophosphorous chemicals have shown neurotoxicity to be the primary toxic endpoints (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 reference dose calculation. The Agency has established an oral reference dose (RfD) for assessing dietary risks for a number of c hemicals (e.g. organophophates and carbamates) where neurotoxicity

was the most sensitive endpoint of concern. **How could the data impact 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 to be revised to reflect the magnitude of potential risk derived from the new data. If the Agency

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