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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
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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
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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 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®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.
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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 95th 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). 
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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 
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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. 
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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® 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, 13th Edition

Density at 20°C (g/mL) 1.446

N

N

H3C

Cl

CN

SO2N(CH3)

2

N

H

N

H3C

Cl

CN
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Table 2.2. Physicochemical Properties of the Technical Grade Cyazofamid.

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 10-5Pa

Dissociation constant (pKa) Does not dissociate in water. No pKain 

the pH range of 2-12.

Octanol/water partition 

coefficient 

LogKOW = 3.2

KOW = 1.585 x 103

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®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 
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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.
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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

Incidental Oral 

Short-Term (1-30 

days) and 

IntermediateTerm (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 ShortTerm (1-30 days) 

and IntermediateTerm (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 ShortTerm (1-30 days) 

and IntermediateTerm (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 ShortTerm (1-30 

days) and 

IntermediateTerm (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.
Page 11 of 30

Table 3.0.b. Summary of Toxicological Doses and Endpoints for Cyazofamid for Use in Occupational Human 

Health Risk Assessments.

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 

IntermediateTerm (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 
Page 12 of 30

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.
Page 13 of 30

Table 4.2 Summary of Food Residue Considerations

Parameter Proposed Use on 

Basil

Translated Residue Data

Chemical Cyazofmaid Cyazofamid

Formulation Ranman® 400SC 

Fungicide

Ranman® 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/Retreatment Interval1 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
Page 14 of 30

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 (DEEMFCIDTM, 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
Page 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; 2/20/2004). 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 95th 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 99th and 99.9th

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 95th Percentile of 

Exposure using DEEM FCIDTM.

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 Cyazofamid1

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
Page 16 of 30

Table 4.4.b. Summary of Chronic Dietary Exposure and Risk for Cyazofamid1

Population Subgroup

 Exposure

(mg/kg/day)

% cPAD

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/cm2or 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

(2) Mouthing Grass 2.29 0.0038 8,000 1,600

(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 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. 
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 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

Risk1

MOE

food & water2

MOE

oral3

MOE

dermal4

MOE 

inhalation5

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 
Page 19 of 30

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 intermediateterm 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. 

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.

Table 8.0. Summary of Exposure & Risk to Occupational Handlers From Application of Cyazofamid to Basil 

Unit Exposure1

mg ai/lb handled

Applic. Rate2

lb ai/unit

Units 

Treated3

Avg. Daily Exposure4

mg ai/kg bw/day

MOE5

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
Page 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 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 μg/cm2* 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 108μg/lb * 2.47 x 10-8 A/cm2. 

0.071 lb a.i./A * 0.20 * 4.54 x 108 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, 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.
Page 21 of 30

 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.
Page 22 of 30

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

N

N

H3C

Cl

CN

SO2N(CH3)

2

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

N

H

N

H3C

Cl

CN

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

acid

N

H

N

Cl

CN

HO

O
Page 23 of 30

Table C. Identification of Compounds 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

H C3

Cl

O

NH2

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.
Page 24 of 30

Table D. Toxicity Profile of Cyazofamid [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.

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.
Page 25 of 30

Table D. Toxicity Profile of Cyazofamid [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)

Negative ± 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 μg/mL.

Cytogenetics 

870.5375 

Chromosomal 

aberrations

45409003 (1996)

Acceptable/ guideline

(ai)

Negative ± S9 for clastogenic/aneugenic activity up 

to cytotoxic and precipitating 200 μg/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 

μg/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 midand 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.
Page 26 of 30

Table D. Toxicity Profile of Cyazofamid [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- U14C]- or 

[

14C-Imidazole] IKF-916.

Biliary excretion study: 0.5 or 1,000 

mg/kg [phenyl- U14C]- or [14CImidazole] 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 dosedependent 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-ptolylimidazole-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 [14C-Bz]IKF-916 or 

[

14C-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.
Page 27 of 30

Table D. Toxicity Profile of Cyazofamid [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 14C-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 [14C]IKF-916 or [14C]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 IKF916. 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 

[

14C]IKF-916 or 

[

14C]CCIM in rats

45409013 (1999)

Acceptable/non-guideline

Rats were given a single gavage dose of 0.46 mg/kg 

of [14C-Bz]IKF-916 or 0.33 mg/kg of [14CBz]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 IKF916. 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 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) -
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 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-tetrachlorodibenzop-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.
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 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.