Document ID: EPA-HQ-OPP-2011-0697-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-01-27T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                                       
                            WASHINGTON, D.C.  20460
                                       
                                                           OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION
MEMORANDUM

Date:		August 3, 2010

SUBJECT:	Cyazofamid.  Human Health Risk Assessment for Proposed Section 18 Use on Basil.

PC Code:  085651
DP Barcode:  D376500  
Decision Nos.: 431716
Registration No.: 71512-3
Petition No.: 10IL02 
Regulatory Action:  Section 18 
Risk Assessment Type:  Single Chemical/Aggregate
Case No.: NA
TXR No.:  NA
CAS No.:  120116-88-3
MRID No.:  NA
40 CFR: 180.601

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; 7505P

		

                                       
                               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
Appendix B: Review of Human Research	22
Appendix C. Codes, Chemical Names, and Chemical Structure of Cyazofamid and Identified Metabolites	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 Requirement	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[(R)] 400SC Fungicide to control downy mildew (Peronospora balbahrii) on basil.  This document provides a summary of the findings from the data evaluation and subsequent assessment of human health risk resulting from this request.  The hazard assessment and characterization were conducted by Breann Hanson (ARIA), the dietary exposure assessment was performed by Roger Chesser (ARIA) and the occupational exposure data review for the tolerance petition was performed by 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.  Cyazofamid is a broad spectrum fungicide active against oomycete fungi (such as Phytophthora, Plasmopara, Pseudoperonospora, and Pythium) and Plasmodiophoromycetes (Plasmodiospora brassicae).  It specifically interferes with the cytochrome bc1 complex (ubiquinol cytochrome 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 hops (DP Barcode: 370671, N. Tsaur, 04/7/2010).  

Proposed Use on Basil
Ranman[(R)] 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  -  October 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 propensity of cyazofamid to be a slight dermal irritant and a weak sensitizer might be due to the sulfonamide 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 major target organ following subchronic dosing. No adverse kidney effects or other toxicity findings were observed following chronic exposures.  In mice, skin lesions likely due to systemic 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 the developmental NOAEL/LOAEL (no observed adverse effect level/lowest observed adverse effect level).  HED considers this approach conservative and highly protective because bent ribs are a reversible developmental anomaly rather than a malformation.

Cyazofamid 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, based 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 postnatal toxicity.  On this basis, the FQPA safety 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 neurotoxicity study will result in lower NOAELs than the regulatory doses for risk assessment, and an additional factor (UFDB) 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 Water 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 analysis and 133 ppb for the chronic analysis.  This approach may substantially overestimate dietary exposure to cyazofamid from drinking water.  

Dietary Exposure Estimates
For the acute analysis, 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.  Dietary (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 0.012229 mg/kg/day, equivalent to 1.2% of the acute Population Adjusted Dose (aPAD).  

For the chronic analysis, dietary (food and drinking water) exposure is estimated at 0.005118 mg/kg/day for the general U.S. population (<1% of the chronic Population Adjusted Dose (cPAD)) and 0.011594 mg/kg/day (1.2% of the cPAD) for infants 1 - 2 years 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 exposures are expected from this proposed use on basil.  Residential exposure to cyazofamid has previously been assessed for use on commercially treated residential turf and ornamentals.  Non-occupational handler exposures are not expected; however, post-application 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 MOE (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 pathways were assessed in the aggregate risk assessment.  MOEs for aggregate exposure range from 1,100 to 1,500.  None of the aggregate exposure 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 ranged 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 toxicity 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 Low-Income Populations," (http://www.eh.doe.gov/nepa/tools/guidance/Volume1/2-6-EO_12898envjustice.pdf).  OPP typically 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.

Review of Human Research
This risk assessment relies in part on data from PHED studies in which adult human subjects were intentionally 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 tolerances are established for residues of the fungicide cyazofamid, including its metabolites and degradates, in or on the commodities 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-methylphenyl)-1H-imidazole-1-sulfonamide and its metabolite, 4-chloro-5-(4-methylphenyl)-1H-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 physicochemical properties of the technical grade cyazofamid are presented in Table 2.2. A summary of the proposed uses is presented in Table 2.3. 

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 Compound Nomenclature.
Compound
Chemical Structure
                                       
Common name
Cyazofamid
Company 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)-1H-imidazole-1-sulfonamide
CAS registry number
120116-88-3
End-use product (EP)
Ranman(R) 400SC Agricultural Fungicide (EPA Reg. No. 71512-3)
Compound
Chemical Structure of metabolite
                                       
Common name
CCIM
IUPAC name
4-chloro-5-p-tolylimidazole-2-carbonitrile
CAS name
4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile

2.2	Physical and Chemical Properties

The physicochemical properties of the technical grade of cyazofamid are shown in Table 2.2.

Table 2.2.  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 
                                 LogKOW = 3.2
                              KOW = 1.585 x 10[3]
                                       
UV/visible absorption spectrum
                                      pH
                                  Λmax (nm)
                                       

                                       2
                                       7
                                      10
                                      285
                                      279
                                      287
                                       

2.3	Summary of Proposed Uses

Table 2.3.  Summary of Proposed Use Pattern for Applying Cyazofamid to Basil in Illinois.
Formulation
Ranman[(R)] 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 required 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 of cyazofamid and concluded that the  toxicology database of this chemical does not show any evidence of biologically relevant effects on the immune system that related to this chemical. The overall weight of evidence suggests that this chemical does not directly target the immune system. 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 (UFDB) 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 dosing. Neurotoxicity is also not demonstrated in subchronic, chronic, reproduction, or developmental toxicity studies. At this time, the lack of a subchronic neurotoxicity study does not present any uncertainty for evaluating the toxicity of cyazofamid. Therefore, a database uncertainty factor (UFDB) for lack of a subchronic neurotoxicity study is not needed.  

The hazard characterization, dose response considerations, absorption, distribution, metabolism, excretion (ADME) determinations, FQPA safety factor determination, mode of action, and toxicological effects are detailed in a previous risk assessment (DP Barcode: 342612, K. O'Rourke, 03/19/2008).  Based on the hazard and exposure data, the HED cyazofamid risk assessment team recommended 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, respectively.  

Table 3.0.a.	Toxicological Doses and Endpoints for Cyazofamid for Use in Dietary and Non-Occupational Human 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
Acute 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
Acute Dietary
(Females 13-49 years of age)
NOAEL = 100 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF = 1X
Acute 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.
Chronic Dietary (All Populations)
NOAEL= 94.8 mg/kg/day
UFA = 10X
UFH = 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 months)
NOAEL= 30 mg/kg/day 
UFA = 10X
UFH = 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   increased incidence of basophilic tubules in the kidneys was found.  
Dermal Short-Term (1-30 days) and Intermediate-Term (1-6 months)
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%)
UFA = 10X
UFH = 10X
FQPA SF = 1X

Acute 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 studies.
Point of Departure (PoD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (intraspecies).  UFH = potential variation in sensitivity among members of the human population (interspecies).  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.

Table 3.0.b.	Summary of Toxicological Doses and Endpoints for Cyazofamid for Use in Occupational Human 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 months)
Oral Study NOAEL= 100 mg/kg/day (Dermal Absorption Rate = 37%)
UFA = 10X
UFH = 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.
Dermal Long Term (>6 months)
NOAEL= 94.8 mg/kg/day
(Dermal Absorption Rate = 37%)
UFA = 10X
UFH = 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 months)
NOAEL= 100 mg/kg/day

UFA = 10X
UFH = 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 months)
NOAEL= 94.8 mg/kg/day
UFA = 10X
UFH = 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 observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (intraspecies).  UFH = 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 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 employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems.  Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems 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 any 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 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 pathways such as food and water, residential activity, and certain post-application agricultural scenarios.  This list should not be construed as a list of known or likely endocrine disruptors.

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.  Accordingly, 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 adequately 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
The 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 adequately understood based on the previously submitted goat and hen metabolism studies; based on the available ruminant metabolism studies in goats, the following metabolites should be analyzed 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 earlier petition (PP#1F06305).  The results of these data showed that cyazofamid and structurally related metabolites are not expected to be present at a level greater than 0.01 ppm at a plant-back interval of 30 days.  Therefore, a rotational crop plant-back interval (PBI) of 30 days is appropriate for cyazofamid end-use labels.  

Residue Analytical Methods  -  Plants
An acceptable analytical method is available for enforcement purposes.  An adequate data collection method, "Independent Laboratory Validation of the Residue Method for IKF-916 and CCIM in Tomatoes", Document Number 013033-0, Pyxant Labs Inc, with slight modification, can be used to determine the residues of cyazofamid and CCIM.  The method is expected to be suitable for analysis 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, leafy greens, crop subgroup 5B (Table 4.2).  These data 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.

Table 4.2  Summary of Food Residue Considerations
Parameter
                             Proposed Use on Basil
                           Translated Residue Data 
Chemical
                                  Cyazofmaid
                                  Cyazofamid
Formulation
                           Ranman(R) 400SC Fungicide
                           Ranman(R) 400SC Fungicide
Crop
                                     Basil
                   Brassica, leafy greens, crop subgroup 5B
Type 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, 04/07/2010
Performing Laboratory
                                Not Applicable
                              Field Trial Studies

Canada has established MRLs for residues of cyazofamid in/on several commodities, but has not established maximum residue limits for basil.   No MRLs for residues of cyazofamid have been established by the Codex Alimentarius Commission (email, S. Funk, 06/07/2010). 

4.3	Drinking Water Residue Profile

The maximum seasonal application proposed for the Section 18 use on basil is less than or equal to currently registered use rates.  As such, a previously modeled Tier I drinking water assessment conducted by EFED for the established cyazofamid uses (DP Barcode: 370673, J. Meléndez, 03/01/2010) was used in this assessment.  The assessment included cyazofamid and the metabolites designated as CCIM, CCIM-AM (4-chloro-5-p-tolylimidazole-2-carboxamide), and CTCA (4-chloro-5-p-tolylimidazole-2-carboxylic acid) in drinking water.

The maximum EDWCs that may 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; and
      3.         The terminal degradate CTCA, assuming application of 100% molar conversion of the parent into this terminal degradate CTCA.

Table 4.3.	Resulting Maximum Surface/Groundwater EDWCs for Cyazofamid and each of its Major 	Degradates (from use on Turf and Ornamentals).
Scenario
Chemical
                           Surface water EDWCs (ppb)
                            Ground Water EDWC (ppb)

                                    Acute 
                              (1-in-10 yr. peak)
                                    Chronic
                               (1-in-10 yr. mean)
                                       
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 analysis and 133 ppb for the chronic analysis.  This approach may significantly overestimate dietary exposure to cyazofamid from drinking water.  

4.4	Dietary Exposure and Risk

Cyazofamid acute and chronic dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID(TM), Version 2.03).  For both the acute and chronic analyses, the drinking water EDWC was incorporated directly as a point estimate in the DEEM analysis 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 is derived from the developmental toxicity NOAEL of 100 mg/kg/day based on increased incidence of bent ribs at the developmental LOAEL of 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 variability) 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 0.95 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 intra-species variability) 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 analyses 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 scientifically acceptable (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; 2/20/2004).  Therefore, processing factors were set to 1x, except that default processing factors were used for dried tomatoes, tomato juice, dry potatoes, and potato flour. There were no processing data for basil.

Acute 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 0.012229 mg/kg/day (equivalent to 1.2% of the aPAD), at the 95[th] percentile of exposure.  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] and 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 FCID(TM).
                              Population Subgroup
                                aPAD (mg/kg/day)
                                95th Percentile
                                99th Percentile
                               99.9th Percentile
 
 
                              Exposure (mg/kg/day)
                                     % aPAD
                              Exposure (mg/kg/day)
                                     % aPAD
                              Exposure (mg/kg/day)
                                     % aPAD
 Females 13-49 years old 
                                      1.0
 0.012229
                                      1.2
                                    0.025266
                                      2.5
                                    0.060021
                                      6.0
 
Chronic 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 0.005118 mg/kg/day for the U.S. population (<1% of the cPAD) and 0.011594 mg/kg/day (1.2% of the cPAD) for the most highly exposed population subgroup (children 1  -  2 years 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
                                  (mg/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       
                                     <1
Females 13-49 years old
                                0.004413       
                                     <1
       1The 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 currently commercially registered to treat pythium diseases on residential turf and phythium, phytophthora and downy mildew diseases on ornamental plants in residential landscapes (DP Barcode: 365261, N. Tsaur, 03/27/2009).  In addition, cyazofamid is commercially registered to treat pythium and downy mildew diseases on professionally managed turf areas, and pythium, phytophthora, and downy mildew diseases on ornamental plants in landscapes and grown in commercial greenhouses and nurseries (DP Barcode: 332425, K. O'Rourke, 10/12/2006).    

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 not 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 Barcode: 365261, N. Tsaur, 03/27/2009).

Post-application exposure was also analyzed for recreational golfers or players of various sports who use turf areas following cyazofamid exposure.  The dermal MOEs for post-application exposure for recreational golfers or sports players were greater than 100 (330 to 14,000) and therefore not of risk concern to HED (DP Barcode: 332425, K. O'Rourke, 03/27/2009).

Based on the currently 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).

	Table 5.0.  Children's Aggregate Exposure and Risk Estimates from Residential Lawns.
                            Children's Scenarios
                        TTR/GR/SR0 (ug/cm[2] or g) [1]
                                   PDR0-norm
                                (mg/kg/day) [2]
                              Short-Term MOE [3]
                                     Total
                              Short-Term MOE [4]
(1) Hand-to-Mouth
                                     0.57
                                     0.015
                                     2,000
                                     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".
2 PDR0norm=potential dose rate on day "0".
3 MOE = NOAEL/PDR; where Short-/Intermediate-term NOAELIncidental Oral = 30 mg/kg/day.
[4] Total MOE = 1/ [(1/MOEHand-to-Mouth) + (1/MOEGrass) + (1/MOESoil)]
  
Other Exposure Sources (Spray Drift)
Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for 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 by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast, and ground hydraulic methods.  After the policy is in place, the Agency 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: As indicated in this assessment, cyazofamid is directly applied to residential lawns and ornamentals and does not result in exposures of concern.  It is unlikely 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 performed because cyazofamid is classified as "not likely to be carcinogenic to humans".  All potential exposure pathways 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 concurrently 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 years 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 likely to result from exposure to cyazofamid residues from food, drinking 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 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 exposures from the use on residential lawns and ornamentals.  The results of the short/intermediate-term aggregate assessments are presented in Table 6.2.  HED is generally 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 Intermediate-Term Aggregate Risk Calculations 
                                       
                                  Population
                     Short- or Intermediate-Term Scenario
                                       
                               LOC for Aggregate
                                    Risk[1]
                                      MOE
                              food & water[2]
                                      MOE
                                    oral[3]
                                      MOE
                                   dermal[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-mouth residential exposure)] NOAEL = 30 mg/kg/day. (See Table 5.0 for children's oral exposure).
[4] MOE dermal = [(short- or intermediate-term dermal NOAEL)/(high-end dermal residential exposure)] NOAEL = 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/MOEFood) + (1/MOEOral) + (1/MOEDermal) + (1/MOEInhalation)]

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 residential 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 as to cyazofamid and any other substances and cyazofamid does not appear to produce a toxic metabolite produced by 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 effects 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 highly exposed occupational pesticide 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 developmental 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 assumes 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.  
Table 8.0. Summary of Exposure & Risk to Occupational Handlers From Application of Cyazofamid 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
179,000

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.  Applic. Rate = Taken from Illinois Dept. Agric. Section 18 Request
3.  Units Treated are taken from "Standard Values for Daily Acres Treated in Agriculture"; ExpoSAC SOP  No. 9.1.   Revised 25 September 2001;
4.  Average Daily Dose = Unit Exposure * Applic. 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.

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 does not exceed the Agency's level of concern.

8.1	Occupational Post-Application Exposure and Risk

The following convention is used to estimate post-application exposure:  

Average Daily Dose (ADD) (mg a.i./kg bw/day) = DFR ug/cm[2] * TC cm[2]/hr * hr/day * 0.001 mg/ug * 1/60 kg bw 

 and where:

Surrogate Dislodgeable Foliar Residue (DFR) = application rate * 20% available as dislodgeable residue * 4.54 x 10[8] ug/lb * 2.47 x 10[-8] A/cm[2].  

0.071 lb a.i./A * 0.20  * 4.54 x 108 ug/lb *  2.47 x10[-8] A/cm² = 0.349 ug/cm[2] , therefore,

0.349 ug/cm[2] * 2,500 cm[2]/hr * 8 hr/day * 0.001 mg/ug * 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, the 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 Category III 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 RECOMMENDATIONS

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, cyazofamid 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.  If in the future, requests for new uses or formulations are submitted that may result in a significant change in either the toxicity profile or exposure scenarios, HED will reconsider this data requirement.
   * As part of the new 40CFR §158 Guidelines, a functional immunotoxicity study in rats and/or mice is required (Guideline 870.7800); see Appendix C.
   * As part of the new 40CFR §158 Guidelines, a subchronic neurotoxicity study is required (Guideline 870.6200); see Appendix D.

 10.0	ATTACHMENTS

Appendix A: 	Tolerance Setting
Appendix B:	Review of Human Research 
Appendix C.  Codes, Chemical Names, and Chemical Structure of Cyazofamid and Identified Metabolites
Appendix D.  Toxicity Profile of Cyazofamid Technical
Appendix E.  Acute Toxicity of Cyazofamid
Appendix F:	Rationale for Immunotoxicity 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 for Use of Cyazofamid on Basil.  DP Barcode: 376585, R. Chesser, 5/25/2010.

Drinking Water Assessment
Estimated Drinking Water Concentrations of Parent Cyazofamid and its Degradates CCIM, CCIM-AM and CTCA for Use in Human Health Risk Assessment (Use on Fruiting Vegetables, Crop Group 8 + Okra, and Grapes, East of the Rocky Mountains).  DP Barcode: 356836, J. Meléndez, 3/24/2009.

Hazard Characterization Assessment
Cyazofamid [IFK-916]  -  Report of the Hazard Identification Assessment Review Committee.  G. Dannan, 3/03/2004.

Metabolism Assessment
Cyazofamid - Meeting Report of the Metabolism Assessment Review Committee (MARC).  DP Barcode: 298915, A. Acierto, 2/18/2004.

Occupational Assessment
CYAZOFAMID  -  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.

Appendix A: Tolerance Setting

Table A.1. 	Tolerance Summary for Cyazofamid.
Commodity
                                   Proposed 
                                Tolerance (ppm)
                                 Recommended 
                                Tolerance (ppm)
Comments; Correct Commodity Definition
                       Proposed Time-limited 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 Compounds 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)-1H-imidazole-1-sulfonamide

CCIM

4-chloro-5-p-tolylimidazole-2-carbonitrile

CCBA

4-(4-chloro-2-cyanoimidazol-5-yl)benzoic acid

CCIM-AM

4-chloro-5-p-tolylimidazole-2-carboxamide

CTCA
4-chloro-5-p-tolylimidazole-2-carboxylic acid

Appendix D.	Toxicity Profile of Cyazofamid Technical

Table D.  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 1,000 mg/kg/day
Maternal NOAEL = 1,000 mg/kg/day
LOAEL =  not observed.
Developmental 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.
Developmental 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
F0 M: 11-22, 108-213, and 1114-2185 mg/kg/day
F0 F: 14-21, 137-219, and 1416-2179 mg/kg/day
F1 M: 11-27, 107-267, and 1117-2714 mg/kg/day
F1 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 ppm 
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 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.
Gene Mutation
870.5100
Bacterial reverse mutation assay
45408937 (1998)
Acceptable/ guideline
(ai)
Negative +- S9 up to 5,000 ug/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 ug/mL.
Cytogenetics 
870.5375 Chromosomal aberrations
45409003 (1996)
Acceptable/ guideline
(ai)
Negative +- S9 for clastogenic/aneugenic activity up to cytotoxic and precipitating 200 ug/mL.
Cytogenetics 
870.5395
Micronucleus test on mouse
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 ug/disc.
870.6200a
Acute 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 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)
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 tcmax = 0.25-0.5 hrs) and rapid elimination at the low dose (t1/2 4.4-5.8 hrs) while there was saturated absorption with prolonged elimination (t1/2 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, most 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 administered dose.  Tissue burdens at t1/2, tmax, 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 was 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 was 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.
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 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 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 its conversion to CCIM or other metabolites may increase overall transfer across the gut wall.
Special study:
Comparative 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 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. Therefore, orally administered IKF-916 is converted to CCIM and subsequently to CCBA and CHCN.

Appendix E.  Acute Toxicity of Cyazofamid

Table E.  Acute Toxicity of Cyazofamid  -  Technical.
                                 Guideline No.
                                  Study Type
                                   MRID No.
                                    Results
                               Toxicity Category
                                   870.1100
                              Acute Oral  -  Rat
                                   45408910
                           LD50> 5000 mg/kg [M/F]
                                      IV
                                   870.1200
                             Acute Dermal  -  Rat
                                   45408911
                          LD50 > 2000 mg/kg [M/F]
                                      III
                                   870.1300
                           Acute Inhalation  -  Rat
                                   45408912
                           LC50 > 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)
                                       -

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 system. Immunosuppression is a deficit in the ability of the immune system to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia.  Because the immune system is highly complex, studies assessing functional immunotoxic endpoints are helpful in fully characterizing a pesticide's potential immunotoxicity.  These data will be used in combination with data from hematology, lymphoid organ 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 (IRIS, 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 uncertainty factor may be applied for conducting a risk assessment from the available studies.

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 system 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 structure 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 system. The acute neurotoxicity study is required to detect possible effects resulting from a single exposure. The subchronic neurotoxicity study is intended to detect possible effects resulting from repeated or long-term exposures.
 
                         Practical Utility of the Data
How will the data be used?

The acute and subchronic neurotoxicity studies provide critical scientific information needed to characterize potential hazard to the human population on the nervous system from pesticide exposure.  These studies can provide data on a wide range of functional tests for evaluating neurotoxicity including sensory effects, neuromuscular effects, learning and memory and histopathology of the nervous system.  For example, animal studies with organophosphorous chemicals have shown 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 chemicals (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 uncertainty factor may be applied when conducting a risk assessment using the currently available studies.