UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM / 

Date: November 9, 2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Cyazofamid. Human Health Risk Assessment for Prop,6sed New Uses on Use 

on Crop Subgroup 19A, Peppers and Tomatoes Grown in Greenhouses, and on 

Bulb Vegetables Crop Group 03-07. 

PC Code: 085651 DP Barcodes: 426778 

Decision Nos.: 500747 Registration Nos.: 71512-2, 71512-3 

Petition Nos.: 5E8350, 5F8352 Regulatory Action: Section 3 Registration 

Risk Assessment Type: Single Chemical, Aggregate Case No.: 7056 

TXR No.: NA CAS No.: 120116-88-3 

MRID No.: NA 40 CFR: §180.601 

FROM: Cassi Walls, Ph.D., Senior Biologist ~ "1. ucJi.& 

William 

Sarah S. 

D. 

Gallagher, 

Wassell, 

Ph.D., 

Chemist Biologi Nl/t t -:;:-( ~~ 

Risk Assessment Branch 1 ffYt:i 

Kristin Rury, Biologist 

Risk Assessment Branch 3 

'Health Effects Division (HED) (7509P) 

THROUGH: Christine L. Olinger, Branch Chief /0 · Risk Assessment Branch 3 ~ 

• Health Effects Division (7509P) 

TO: Barbara Madden/Laura Nollen, Risk Manager Team 05 

Risk Integration, Minor Use, and Emergency Response Branch (RIMUERB) 

and 

Lindsay Roe, Risk Manager 

Fungicide Branch 

Registration Division (7505P) 

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. Two separate petitions have been submitted for proposed 

new cyazofamid uses: (1) the Inter-Regional Research Project Number 4 (IR-4) proposed new 

uses on herb subgroup 19A (field and greenhouse) and on tomatoes and peppers grown in 

greenhouses; and (2) ISK Biosciences Corporation (ISK Biosciences) proposed new use on bulb 

vegetable group 03-07. The Registration Division (RD) of OPP has requested that HED evaluate 

hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure 

Page 1 of37 
Cyazofamid Human Health Risk Assessment DP No. D426778 

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assessments, as needed, to estimate the risk to human health that will result from the proposed 

uses of cyazofamid. A summary of the findings and an assessment of human health risk 

resulting from the proposed and registered uses of cyazofamid are provided in this document. 

The HED team members contributing to this risk assessment include Cassi Walls (risk 

assessment and dietary assessment), Kristin Rury (occupational and residential assessments), 

Sarah Gallagher (hazard assessment), and William Wassell (residue chemistry). The drinking 

water assessment was conducted by José Meléndez of the Environmental Fate and Effects 

Division (EFED). 

 
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1.0 Executive Summary ............................................................................................................. 5

2.0 HED Recommendations ...................................................................................................... 8

2.1 Data Deficiencies ............................................................................................................ 8

2.2 Tolerance Considerations .............................................................................................. 8

2.2.1 Enforcement Analytical Method ........................................................................... 8

2.2.2 Recommended Tolerances...................................................................................... 8

2.2.3 Revisions to Petitioned-For Tolerances ................................................................ 9

2.2.4 International Harmonization ................................................................................. 9

2.3 Label Recommendations ............................................................................................... 9

3.0 Introduction .......................................................................................................................... 9

3.1 Chemical Identity ........................................................................................................... 9

3.2 Physical/Chemical Characteristics ............................................................................. 10

3.3 Pesticide Use Pattern ................................................................................................... 11

3.4 Anticipated Exposure Pathways ................................................................................. 12

3.5 Consideration of Environmental Justice ................................................................... 12

4.0 Hazard Characterization and Dose-Response Assessment ............................................ 13

4.1 Toxicology Studies Available for Analysis ................................................................. 13

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME) ............................. 13

4.2.1 Dermal Absorption Factor ................................................................................... 14

4.3 Summary of Toxicological Effects .............................................................................. 14

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 15

4.4.1 Completeness of the Toxicology Database .......................................................... 15

4.4.2 Evidence of Neurotoxicity .................................................................................... 15

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal .... 15

4.4.4 Residual Uncertainty in the Exposure Database................................................ 15

4.5 Toxicity Endpoint and Point of Departure Selections .............................................. 16

5.0 Dietary Exposure and Risk Assessment ........................................................................... 18

5.1 Residues of Concern Summary and Rationale .......................................................... 18

5.2 Food Residue Profile .................................................................................................... 19

5.3 Water Residue Profile.................................................................................................. 20

5.4 Dietary Risk Assessment ............................................................................................. 21

5.4.1 Description of Residue Data Used in Dietary Assessment ................................ 21

5.4.2 Acute Dietary Risk Assessment ........................................................................... 21

5.4.3 Chronic Dietary Risk Assessment ....................................................................... 22

5.4.4 Summary Table ..................................................................................................... 22

6.0 Residential and Other Nonoccupational Exposure/Risk Characterization .................. 22

6.1 Residential Risk Estimates for Use in Aggregate Assessment ................................. 23

6.2 Non-Occupational Spray Drift Exposure and Risk Estimates ................................. 23

6.3 Non-Occupational Bystander Post-Application Inhalation Exposure and Risk 

Estimates ............................................................................................................................. 24

7.0 Aggregate Exposure/Risk Characterization .................................................................... 24

7.1 Acute Aggregate Risk .................................................................................................. 24

7.2 Short-Term Aggregate Risk ........................................................................................ 24

7.3 Chronic Aggregate Risk .............................................................................................. 25

8.0 Cumulative Exposure/Risk Characterization ................................................................. 25

9.0 Occupational Exposure/Risk Characterization .............................................................. 25
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9.1 Short-/Intermediate-Term Handler Risk .................................................................. 25

9.2 Short- and Intermediate-Term Post-Application Risk ............................................. 29

9.2.1 Dermal Post-application Risk .................................................................................... 29

9.2.2 Inhalation Post-application Risk ............................................................................... 29

10.0 References ........................................................................................................................... 30

Appendix A. Toxicology Profile ................................................................................................ 31

A.1 Toxicology Data Requirements ................................................................................... 31

A.2 Toxicity Profiles ........................................................................................................... 32

Appendix B. Identification of Compounds from the Cyazofamid Metabolism Studies ...... 37
Cyazofamid Human Health Risk Assessment DP No. D426778 

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1.0 Executive Summary 

Use Profile: 

Cyazofamid (4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonamide) 

is currently registered for food use under FIFRA section 3 on basil, beans (succulent), Brassica

(subgroups A and B), carrot roots, hops, leafy greens (subgroup 4A), turnip greens, cucurbits 

(group 9), fruiting vegetables (group 8-10), and tuberous and corm (subgroup 1C). Permanent 

tolerances for residues of cyazofamid and its metabolite CCIM (4-chloro-5-(4-methylphenyl)-

1H-imidazole-2-carbonitrile) are established in 40 CFR §180.601 at levels ranging from 0.02 

ppm on potato to 90 ppm on dried basil and a regional registration tolerance on grapes at 1.5 

ppm. Cyazofamid is also currently registered for use on several residential and non-agricultural 

use sites including turf areas associated with golf courses, sod farms, seed farms, college and 

professional sports fields, residential and commercial lawns, and on ornamental plants in 

landscapes and those grown in commercial greenhouses and nurseries. 

Two separate petitions have been submitted for proposed uses of cyazofamid: (1) IR-4 new uses 

Herb Subgroup 19A (field and greenhouse) and on tomatoes and peppers grown in greenhouses; 

and (2) ISK Biosciences proposed a new use on Bulb Vegetable Group 03-07. The proposed 

uses will be added to the RANMAN® 400 SC end-use product label (EPA Reg. No. 71512-3) 

which is a soluble concentrate containing 34.5% cyazofamid by weight (3.33 lb ai per gallon). 

The proposed maximum single application rates range from 0.039 lb ai/A to 0.078 lb ai/A. 

RANMAN® 400 SC may be applied using ground, aerial, chemigation, and handheld spray 

equipment. Most of the proposed uses allow for repeat applications on a 7-10 day schedule. The 

product label requires occupational handlers to wear long sleeves, long pants, shoes, socks, and 

chemical-resistant gloves, and has a restricted-entry interval (REI) of 12 hours. 

Exposure Profile: 

Exposures to cyazofamid are expected to occur over acute, short-, intermediate-, and long-term 

(chronic) durations. The proposed agricultural uses result in new exposures in both food and 

drinking water. There are currently existing residential uses that result in non-occupational 

exposure from handler and post-application activities. In occupational settings, exposure is also 

expected during handler and post-application activities. 

Hazard Identification:

Cyazofamid belongs to a chemical class based on the cyanoimidazole and sulfonamide moieties. 

It specifically interferes with the cytochrome bc1 complex (ubiquinol cytochrome c

oxidoreductase) in the mitochondrial respiratory chain of oomycetes fungi. The mechanism of 

toxicity in mammals is not clear. Following repeated administration in more than one species, 

cyazofamid seems to have mild or low toxicity. The kidney appeared to be the primary target 

organ. Skin lesions were only observed in male mice, likely due to systemic allergy. In dogs, 

there were no major toxicity findings. In the acute neurotoxicity study, there were no indications 

of treatment-related adverse neurotoxicity. 

There was some evidence of increased quantitative susceptibility following in utero exposure to 

rats in the prenatal developmental toxicity study; the marginal increased incidence of bent ribs in 

the high-dose fetuses was considered adverse; however, this effect was not used for the 
Cyazofamid Human Health Risk Assessment DP No. D426778 

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determination of endpoints since bent ribs are a developmental variation rather than a 

malformation and the effect was only seen at the limit dose, which is not relevant for risk 

assessment. The Food Quality Protection Act (FQPA) safety factor is reduced to 1X for all 

population subgroups and exposure scenarios. 

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 be mutagenic, based on several negative in vivo and in vitro studies. 

Cyazofamid has low 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. 

Dietary Exposure (Food/Water): 

Acute: An acute dietary exposure assessment was not conducted since there was no adverse 

effect observed for a single dose for cyazofamid. 

Chronic: An unrefined chronic dietary (food and drinking water) assessment was conducted for 

existing and proposed uses of cyazofamid. The assessment included tolerance level residues for 

all crops and assumed that 100% of the crops were treated with cyazofamid (100% CT). Default 

processing factors were used. The groundwater estimated drinking water concentration (EDWC) 

of 211 μg/L from the PRZM-GW modeling was incorporated directly into the dietary 

assessment. 

 

The chronic dietary (food and drinking water) exposure to cyazofamid is below HED’s level of 

concern (LOC) [i.e., <100% of the chronic Population Adjusted Dose (cPAD)] for the general 

U.S. population and all population subgroups. The chronic dietary exposure estimates are 1.1% 

of the cPAD for the general U.S. population and 2.0% of the cPAD for children 1-2 years old, 

the most highly exposed population subgroup. 

Residential Exposure: 

There are no proposed residential uses of cyazofamid and the existing residential uses were 

evaluated previously using the 2012 Residential Standard Operating Procedures (SOPs). Since 

the incidental oral and inhalation points of departure (PODs) have changed since the previous 

assessment, the residential scenarios for aggregate assessment have been re-evaluated here. The 

short-term adult residential exposure estimates for inclusion in the aggregate risk assessment 

result from mixing/loading/applying liquid cyazofamid to turf using a hose-end sprayer 

(inhalation MOE = 120,000, level of concern; LOC = 100). The residential exposures for 

inclusion in the aggregate risk assessment for children 1-2 years old from post-application handto-mouth exposure on turf results in an MOE of 19,000. 

Aggregate Exposure: 

Acute: Acute aggregate exposure is equivalent to acute dietary risk (e.g., food and drinking 

water exposure) where an acute dietary exposure assessment was not conducted since there was 

no adverse effect observed for a single dose for cyazofamid. 
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Short-Term: There is potential short-term aggregate exposure to cyazofamid for adults from 

dietary exposure (which is considered background exposure) and residential dermal and 

inhalation exposures from handling cyazofamid. However, since no hazard was identified for 

the dermal route of exposure, short-term aggregate risk estimate included dietary and inhalation 

exposures only. The short-term aggregate MOE for adults is 14,000 and not of concern to HED. 

The short-term aggregate exposure to cyazofamid for children 1 to <2 years old is from dietary 

exposure (which is considered background exposure) and incidental oral exposure from hand to 

mouth activities on treated turf. The short-term aggregate MOE for children 1 to <2 years old is 

6,100 and not of concern to HED. 

Intermediate-Term: Intermediate-term exposure is not expected for the residential exposure 

pathway. Therefore, the intermediate-term aggregate risk estimate would be equivalent to the 

chronic dietary exposure estimate, which is not of concern. 

Chronic: Chronic aggregate exposure is equivalent to chronic dietary risk (e.g., food and 

drinking water exposure) where the estimates are not of concern. 

Occupational Exposure: 

Occupational Handler Exposures: 

There are no occupational handler risk estimates of concern for the proposed uses of cyazofamid 

at baseline attire (i.e., long sleeves, long pants, shoes, and socks with no personal-protective 

equipment; PPE), and engineering controls for aerial applications (i.e., enclosed cockpits). The 

occupational handler inhalation risk estimates ranged from 71,000 to 600,000,000 (LOC = 100). 

Occupational Post-application Exposures: 

A quantitative occupational dermal post-application risk assessment was not conducted for 

cyazofamid because no dermal hazard or developmental toxicity was identified in the toxicity 

database. Based on the Agency's current practices, a quantitative non-cancer occupational postapplication inhalation exposure assessment was not performed for cyazofamid at this time. If 

new policies or procedures are put into place, the Agency may revisit the need for a quantitative 

occupational post-application inhalation exposure assessment for cyazofamid. 

Restricted-Entry Interval (REI): 

The REI of 12 hours on the product label is considered appropriate to protect agricultural 

workers from post-application exposures. 

Review of Human Research: 

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include Pesticide 

Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task 

Force (AHETF) database; the Residential SOPs (Lawns & Turf), and other registrant-submitted 

exposure monitoring studies (MRID 44339801), are (1) subject to ethics review pursuant to 40 

CFR 26, (2) have received that review, and (3) are compliant with applicable ethics 

requirements. For certain studies, the ethics review may have included review by the Human 
Cyazofamid Human Health Risk Assessment DP No. D426778 

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Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be 

found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

Environmental Justice Considerations: 

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

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.archives.gov/federal-register/executive-orders/pdf/12898.pdf). 

2.0 HED Recommendations 

HED has examined the residue chemistry, toxicity, and exposure databases for cyazofamid and 

concluded that, provided a revised Section B/proposed label is submitted, there are no 

deficiencies that would preclude setting tolerances and granting a Section 3 registration for 

proposed uses on herb (subgroup 19A; field and greenhouse), tomatoes and peppers grown in 

greenhouses, and on bulb vegetables (group 03-07). 

2.1 Data Deficiencies 

There are no data gaps or deficiencies in the toxicology, exposure, or residue chemistry 

databases for the proposed uses. However, a revised Section B/proposed label are required for 

submission. 

2.2 Tolerance Considerations 

2.2.1 Enforcement Analytical Method

Adequate enforcement methods are available to determine residues of cyazofamid and its 

metabolite CCIM (4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile) in various 

commodities. An enforcement method for non-fatty commodities is available, FDA’s 

Multiresidue Protocol D (without cleanup). The method completely recovers (>80% recovery) 

cyazofamid and its metabolite CCIM. In addition, the high-performance liquid chromatography 

method with ultraviolent light detection (HPLC/UV) method (MRID 45409020; revised in 

MRID 46550401) is acceptable for use as a single analyte enforcement method provided a 

confirmatory method such as the liquid chromatography method with tandem mass-spectrometric 

detection (LC/MS/MS) method is used. 

2.2.2 Recommended Tolerances

HED has reviewed the available residue data and has determined the appropriate tolerance levels 

for residues of cyazofamid and its metabolite CCIM (Table 2.2.2.). The tolerance expression is 

as follows: 

(a) General. Tolerances are established for residues of the fungicide cyazofamid, 

including its metabolites and degradates, in or on the commodities in the following table. 
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Compliance with the tolerance levels specified in the following table is to be determined 

by measuring only the sum of 4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1Himidazole-1-sulfonamide and its metabolite, 4-chloro-5-(4-methylphenyl)-1H-imidazole2-carbonitrile, calculated as the stoichiometric equivalent of cyazofamid, in or on the 

following commodities: 

Table 2.2.2. Tolerance Summary for Cyazofamid. 

Commodity Proposed Tolerance 

(ppm) 

HED-Recommended 

Tolerance (ppm) 

Comments 

(correct commodity definition) 

Herb, Subgroup 19A 90 90 

Bulb Vegetables, 

Group 3-07 2.0 2.0 

Established tolerances for cyazofamid residues in/on basil, fresh and dried can be deleted once 

the tolerance for residues herbs, subgroup 19A is established. 

2.2.3 Revisions to Petitioned-For Tolerances

There are no revisions to the petitioned for tolerances. 

2.2.4 International Harmonization

There are no Codex and Mexican maximum residue limits (MRLs) established for cyazofamid 

in/on the commodities included in this petition. Canadian MRLs are established for residues of 

cyazofamid and its metabolite in/on fresh basil at 30 ppm and dried basil at 90 ppm. Both of 

these MRLs should be considered harmonized as the tolerance for residues of cyazofamid and its 

metabolite CCIM in herb, subgroup 19A includes these commodities. 

2.3 Label Recommendations 

The proposed label for use on bulb vegetables, group 3-07 includes the following restriction: 

Ranman® 400SC can be applied on herbs grown in a greenhouse. This statement needs to be 

removed from the directions for use on bulb vegetables group 3-07 as it inappropriate for that 

section of the label. 

3.0 Introduction

Cyazofamid is a broad-spectrum fungicide active against oomycete fungi (such as Phytophthora, 

Plasmopara, Pseudoperonospora, and Pythium) and Plasmodiophoromycetes (Plasmodiophora

brassicae). It inhibits all stages of fungal development in the life cycle, specifically interfering 

with the cytochrome bc1 complex in the mitochondrial respiratory chain of oomycete fungi. 

3.1 Chemical Identity

The chemical structure, and nomenclature of cyazofamid and its metabolite CCIM are presented 

in Table 3.1. Structures of other metabolites and degradates are shown in Appendix B. 
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Table 3.1. Cyazofamid Nomenclature.

Parent Chemical Structure 

Empirical Formula C13H13ClN4 O2S 

Common Name cyazofamid 

Company Experimental Name NA 

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 

Chemical Class imidazole, sulfonamide 

Known Impurities of Concern None 

Metabolite Chemical Structure 

Common name CCIM 

IUPAC name 4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile 

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

CAS Registry Number 120118-14-1 

3.2 Physical/Chemical Characteristics

Cyazofamid has a low vapor pressure (1.33 × 10-5 Pa at 25 °C or 9.98 × 10-8 mm Hg at 25 °C); 

therefore, inhalation via chemical vaporization is unlikely. Cyazofamid has a log octanol/water 

partition coefficient (log Pow) of 3.2 and is considered relatively insoluble in water. Additionally, 

cyazofamid has a molecular weight of 327.79 amu; therefore, the potential to cross biological 

barriers, such as the skin, is somewhat limited. More detailed physicochemical properties of 

cyazofamid are summarized in Table 3.2. 

Table 3.2. Physicochemical Properties of Technical Grade Cyazofamid. 

Parameter Value Reference 

Melting point/range 152.7 °C Pesticide Fact Sheet – Cyazofamid 

pH 4.9 at 25 °C September 2004 

Density (at 25 °C) 1.38 g/cm3

Water solubility (at 25 °C) 0.107 mg/L at pH 7 

Solvent solubility (at 21.2 °C) 0.003 g/100 mL in hexane 

0.174 g/100 mL in methanol 

3.095 g/100 mL in acetonitrile 

10.212 g/100 mL in dichloromethane 

0.600 g/100 mL in toluene 

1.649 g/100 mL in ethyl acetate 

4.564 g/100 mL in acetone 

0.004 g/100 mL in octanol 

Vapor pressure <1.33 x 10-5 Pa at 25, 30, 35 °C 

Dissociation constant, pKa No pKa evident at pH range 2-12. 

N

N

H3C

Cl

CN

SO2N(CH3)2

N

H

N

H3C

Cl

CN
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Table 3.2. Physicochemical Properties of Technical Grade Cyazofamid. 

Parameter Value Reference 

Octanol/water partition coefficient Log Pow = 3.2 

UV/visible absorption pH 

2 

7 

10 

Λmax (nm) 

285 

279 

287 

Memo, 04/25/2012, N. Dodd, 

D396051 

3.3 Pesticide Use Pattern

The proposed use pattern associated with the two petitions (PP#5E8350 and PP#5F8352) is 

shown in Table 3.3 

Table 3.3. Summary of Proposed Directions for Use of Cyazofamid. 

Applic. Type, 

Equip. & 

Timing 

End-Use 

Product 

Applic. Rate Max. No. 

Apps. per 

Season 

Max. Seasonal 

Applic. Rate 

Preharvest 

Interval

(days) 

Use 

Directions 

and 

Limitations 

Herb, Subgroup 19A 

Foliar application 

by ground and 

aerial equipment. 

Apps should start 

before disease 

infects crop. 

Ranman®

400SC 

EPA Reg. No. 

71512-3 

2.75 to 3.0 

fl oz /A 

0.071 to 0.078 

lb ai/A 

9 27 fl. oz/A 

0.7 lb ai/A 0 See below 

Tomato Greenhouse Transplants 

Soil-drench 

application at the 

time of planting 

or at any time 

thereafter up until 

1 week before 

transplanting. 

Ranman®

400SC 

EPA Reg. No. 

71512-3 

3 fl oz/100 

gallons water 

0.078 lb ai/100 

gallons water 

1 

(implied) 

3 fl oz/100 

gallons water 

0.078 lb ai/100 

gallons water 

0 See below 

Bell Peppers Greenhouse-grown 

Soil-drench 

application at the 

time of planting 

or up to first fruit 

set. 

Ranman®

400SC 

EPA Reg. No. 

71512-3 

3.2 fl oz/100 

gallons water 

0.083 lb ai/100 

gallons water 

2 

(implied) 0.35 lb ai/A 0 See below 

Bulb Vegetable, Group 3-07 

Foliar application 

by ground and 

aerial equipment. 

Apps should start 

when disease 

conditions are 

favorable. 

Ranman®

400SC 

EPA Reg. No. 

71512-3 

2.75 to 3.0 

fl oz/A 

0.071 to 0.078 

lb ai/A 

6 16.5 fl oz/A 

(0.43 lb ai/A) 0 See below 

The following rotational crop restrictions are included on the Ranman® 400SC label: Crops on 

this label may be planted immediately after the last treatment. Do not plant other crops not 

registered for this product within 30 days after the last application. 
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The following restrictions are included on the label for applications to herbs, subgroup 19A: 

Make applications on a 7- to 10-day schedule beginning when disease conditions are favorable 

for disease development. The product can be used on herbs grown in a greenhouse. Ranman®

400SC should be tanked mixed with an organosilicone surfactant (OSS) when disease infection 

is severe, or a non-ionic surfactant (NIS) or a blend of OSS and a NIS when disease infection is 

moderate or light. Ranman® 400SC may be applied through sprinkler irrigation equipment. 

 

The following restrictions are included on the label for applications to tomato greenhouse 

transplants: Apply fungicide solution as a drench to thoroughly wet the growing medium. Do 

not use any surfactant with this drench application. Cyazofamid is also registered for foliar 

applications at rates of 0.054 to 0.071 lb ai/A with a maximum seasonal use rate of 16.5 oz/A 

(0.43 lb ai/A). The crop field trials for tomatoes utilized both the transplant application and 

directed foliar applications. 

The following restrictions are included on the label for applications to bell peppers greenhouse 

grown: Apply the first application at transplanting or up to first fruit set, using 5 fl oz of drench 

solution per plant. A second drench application may be necessary after 42 days at the rate of 8.5 

fl oz (0.22 lb ai). Do not use surfactant with these drench applications. 

The following restrictions are included on the label for applications to bulb vegetables, group 3-

07: For control of downy mildew make applications on a 7- to 10-day schedule. Ranman®

400SC should be tanked mixed with an OSS and a NIS when disease infection is moderate or 

light. The product may be applied trough sprinkler irrigation equipment. 

3.4 Anticipated Exposure Pathways 

Humans may be exposed to cyazofamid in food and drinking water, since cyazofamid may be 

applied directly to growing crops and application may result in cyazofamid reaching surface and 

ground water sources of drinking water. There are also residential uses of cyazofamid; thus, 

there is likely to be exposure in residential or non-occupational settings. In both residential and 

occupational settings, applicators may be exposed while handling the pesticide prior to 

application, as well as during application. There is also a potential for post-application exposure 

for residents and occupational workers re-entering treated areas. 

Several risk assessments have been previously prepared for the existing uses of cyazofamid. 

This risk assessment considers all of the aforementioned exposure pathways based on the 

proposed new uses of cyazofamid, but also considers the existing uses as well, particularly for 

the dietary exposure assessment. 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

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.archives.gov/federal-register/executive-orders/pdf/12898.pdf). As a part of every 

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to 
Cyazofamid Human Health Risk Assessment DP No. D426778 

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well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water 

consumption, and activities in and around the home that involve pesticide use in a residential 

setting. Extensive data on food consumption patterns are compiled by U.S. Department of 

Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We Eat in 

America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food 

uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season 

of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas post-application are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise to the 

development of specialized software and models that consider exposure to bystanders and farm 

workers as well as lifestyle and traditional dietary patterns among specific subgroups. 

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicological database for cyazofamid is adequate for hazard characterization, toxicity 

endpoint selection, and FQPA SF consideration. The HED Hazard and Science Policy Council 

(HASPOC) concluded using a weight-of-evidence approach that the subchronic inhalation study 

is not required at this time (Memo, J. Van Alstine, 11-JULY-2012, TXR# 0056341). Since the 

last risk assessment, immunotoxicity and subchronic neurotoxicity studies have been submitted 

and the results were incorporated into the current assessment. Appendix A includes a summary 

of the cyazofamid toxicological database. Cyazofamid was evaluated for the following: 

(1) Subchronic and chronic oral toxicity in rats, mice, and dogs; 

(2) Subchronic dermal toxicity in rats; 

(3) Developmental toxicity in rats and rabbits; 

(4) Reproductive and postnatal toxicity in rats; 

(5) Carcinogenicity in mice and rats; 

(6) Subchronic neurotoxicity in rats; 

(7) Immunotoxicity in rats; 

(8) Genotoxicity and mutagenicity studies; and 

(9) Absorption, distribution, metabolism, excretion (ADME) studies. 

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

Absorption of orally administered cyazofamid (0.5 or 1,000 mg/kg) was rapid irrespective of the 

dose (tmax = 0.25 or 0.5 hrs, respectively). Elimination was found to be rapid 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 (expressed as percent of administered dose) was 

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 
Cyazofamid Human Health Risk Assessment DP No. D426778 

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radioactivity found as metabolite CCBA (4-(4-chloro-2-cyanoimidazol-5-yl)benzoic acid). 

Results of biliary excretion experiments showed biliary elimination of the radiolabel to be 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 rats of 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 CCIM, each of which being less than 5% of the administered dose. Tissue 

burdens at t1/2, tmax, and at 168 hours post dose were indicative of rapid clearance and low tissue 

burdens suggesting little or no bioaccumulation or sequestration. 

4.2.1 Dermal Absorption Factor 

There are no dermal penetration studies available for cyazofamid. There was no dermal hazard 

identified in the toxicological database. As a result, a dermal absorption factor is not needed 

because a quantitative dermal assessment was not performed. 

4.3 Summary of Toxicological Effects 

Cyazofamid belongs to a chemical class based on the cyanoimidazole and sulfonamide moieties. 

Cyazofamid is a broad-spectrum fungicide active against oomycete fungi and 

Plasmodiophoromycetes. It specifically interferes with the cytochrome bc1 complex (ubiquinol 

cytochrome c oxidoreductase) in the mitochondrial respiratory chain of oomycetes fungi. The 

mechanism of toxicity in mammals is not clear. The available toxicity studies show that 

cyazofamid has low toxicity in rats, rabbits, and dogs. The target organ in rats is the kidney, 

with an increased incidence of basophilic tubules, increased urinary volume, pH, and protein 

noted in male rats after subchronic exposure. Female rats were less sensitive, with only a 

marginal increase in urinary volume, and pH. These findings were noted in a 90-day oral 

toxicity study, and similar findings were noted in the 28-day oral toxicity range-finding study in 

rats. In the two-generation reproductive study in rats, there was an increased incidence of 

nephropathy in the high-dose male rats as compared to the controls; however, only a small 

number of animals were observed to have basophilic tubules. Basophilic tubules are indicative 

of a regenerative process, but they can be more difficult to identify in older animals (i.e., tubular 

basophilia can be obscured by nephropathy or included as part of the nephropathy constellation). 

No kidney effects were observed in the chronic oral toxicity study in rats; however, this study 

did not test up to doses as high as those eliciting kidney effects in the subchronic and twogeneration reproduction toxicity studies. The only relevant finding in the dog was an incidence 

of parathyroid cysts in males at the limit dose in the chronic study. 

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. The 

prenatal developmental study in rats showed evidence of increased quantitative susceptibility 

following in utero exposure as a marginally increased incidence of bent ribs was noted in fetuses 

at the limit dose, whereas no maternal toxicity was noted. 

No adverse effects were seen in a route-specific dermal toxicity study. Skin lesions were 

observed in males following oral exposure in the mouse carcinogenicity study, and are thought to 
Cyazofamid Human Health Risk Assessment DP No. D426778 

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be caused by an allergic reaction to systemic exposure because they did not occur following 

exposure via the dermal route. 

Cyazofamid was categorized as having low 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. 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) 

The RAB1 risk assessment team for cyazofamid determined that the FQPA SF should be reduced 

to 1X for all exposure scenarios. The toxicity database is complete and dietary and residential 

exposure analyses are unlikely to underestimate exposure. No effects were seen in neurotoxicity 

studies. Although there is evidence of quantitative susceptibility in the developmental rat study, 

the effects are well-characterized with clearly established NOAEL/lowest-observed adverseeffect level (LOAEL) values and selected endpoints address the observed effects. 

4.4.1 Completeness of the Toxicology Database

The existing toxicological database for cyazofamid is adequate for FQPA evaluation. 

Developmental toxicity studies in rats and rabbits, a two-generation reproduction study in rats, 

and neurotoxicity studies in rats are available for FQPA consideration. The submitted toxicology 

studies are of good quality and are sufficient to select endpoints for risk assessment and to 

determine whether cyazofamid poses a human health hazard. 

4.4.2 Evidence of Neurotoxicity 

The available toxicity database for cyazofamid does not show any evidence of neurotoxicity, 

including the acute and subchronic neurotoxicity studies. 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

The developmental rabbit and two-generation reproduction toxicity study in rats did not show 

any evidence of increased susceptibility developmental or offspring, respectively. However, 

there was increased quantitative susceptibility in the rat developmental study; concentrations up 

to the limit dose did not cause maternal systemic toxicity, but there was an increased incidence 

of bent ribs. Concern is low based on the following: (1) the increase was marginal, (2) bent ribs 

are considered a variation rather than a malformation, (3) the effect was only seen at the limit 

dose, (4) there is a clear NOAEL for the effect, and (5) the selected endpoints address any 

concerns for this effect. 

4.4.4 Residual Uncertainty in the Exposure Database

The exposure databases are complete or are estimated based on data that reasonably account for 

potential exposures. New 2012 Residential SOPs were used to assess post-application exposure 

to children including incidental oral exposure. The residential post-application assessment 

assumes maximum application rates and conservative day zero hand-to-mouth activities. All of 
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the exposure estimates are based on conservative high-end assumptions and are not likely to 

underestimate risk. 

The dietary exposure assessments (food and drinking water), which assumed tolerance-level 

residues, 100% crop treated and high-end EDWCs, are conservative, high-end assessments. 

They do not underestimate the potential dietary exposures. The calculated residential risks 

represent conservative estimates of exposure because maximum application rates are used to 

define residue levels. Exposures are unlikely to be underestimated because the assessment is a 

screening-level assessment. 

4.5 Toxicity Endpoint and Point of Departure Selections 

Since the last risk assessment (N. Tsaur et al.; 28-JUN-2012; D456373), all of the endpoints, 

except chronic dietary, have been updated. Table 4.5 summarizes the toxicological doses and 

endpoints selected for dietary, non-occupational, and occupational risk assessments. The 

rationale for the dose/endpoint selection is also described below. 

Acute dietary (all populations): An endpoint was not selected to evaluate acute dietary exposures. 

Previously, the prenatal developmental study in rats was used to evaluate acute dietary exposures 

for females 13-49 years old; however, effects (increased incidence of bent ribs) were only seen at 

the LOAEL of 1000 mg/kg/day, which is not considered a relevant dose for human health risk 

assessment. Additionally, there is low concern for this effect since bent ribs are a developmental 

variation rather than a malformation, the increased incidence was only marginally increased over 

historical and concurrent controls, and similar effects were not seen in the rabbit developmental 

study. There were no other effects seen in the database attributable to a single dose. 

Chronic dietary (all populations): The 18-month mouse carcinogenicity study was selected for 

this exposure scenario since the endpoints of concern were seen following long-term dietary 

exposure. The LOAEL of 985 mg/kg/day (NOAEL = 94.8 mg/kg/day) was based on increased 

incidence of skin lesions in males. This study is appropriate for the route and duration of 

exposure. This endpoint is considered conservative given the effect was seen at approximately 

the limit dose; however, itis protective of all effects seen following chronic exposure to 

cyazofamid including the kidney effects which had a comparable NOAEL. The chronic 

population-adjusted dose (cPAD) of 0.948 mg/kg/day is based on the NOAEL of 94.8 mg/kg/day 

and a 100-fold uncertainty factor (10X for interspecies extrapolation, 10X for intraspecies 

extrapolation, and 1X for FQPA SF).

Short- and intermediate-term incidental oral: Co-critical 90-day and chronic oral toxicity 

studies in rats were selected for the short-and intermediate term incidental oral exposure. In the 

90-day oral toxicity study, there was increased incidence of basophilic tubules in the kidneys, 

increased urinary volume, pH, and protein in males at the LOAEL of 295 mg/kg/day (NOAEL = 

29.5 mg/kg/day). This observation was also supported by the 28-day oral toxicity study in rats 

where similar findings were seen in males at the LOAEL of 370 mg/kg/day (NOAEL = 38.5 

mg/kg/day). A NOAEL of 171 mg/kg/day was selected as the POD based on the following: (1) 

no kidney effects were seen up to 171 mg/kg/day in male rats, the highest dose tested, and (2) the 

large gap between the NOAEL and LOAEL values from the subchronic rat studies appears to be 

due to dose selection. In the two-generation reproductive study, there was an increased incidence 
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of nephropathy for male rats in the high-dose group as compared to the control. In the chronic 

study, the high background incidence of nephropathy in all groups may have obscured detection 

of renal effects. However, there was no difference in incidence of nephropathy between the 

control and high-dose group in male rats in a lifetime dietary feeding study; but this is most likely 

due to the fact that the study only tested up to 171 mg/kg/day and did not test high enough doses 

to see the effects on the kidneys as seen in other studies. These studies are appropriate for the 

route and duration of exposure and are protective of all other findings noted in the toxicological 

database. The LOC for incidental oral exposures is 100 (10X for interspecies extrapolation, 10X 

for intraspecies extrapolation, and 1X for FQPA SF). 

Short-and intermediate-term dermal: A dermal endpoint was not selected for evaluating dermal 

risk. There were no adverse effects observed in the route-specific dermal toxicity study up to the 

limit dose. Previously, the prenatal developmental study in rats was used to evaluate short- and 

intermediate-term dermal exposures; however, the effect (increased incidence of bent ribs) was 

only seen at the LOAEL of 1000 mg/kg/day. Additionally, an upper bound dermal absorption 

factor (DAF) of 37% was derived by extrapolation using the LOAEL of 370 mg/kg/day from the 

28-day oral toxicity study and the NOAEL of 1000 mg/kg/day from the dermal toxicity study. 

Using this value, it is estimated that dermal exposure would need to be approximately 2.7-fold 

higher than the limit dose to elicit the effect seen in the rat developmental study (1000 / 0.37 = 

2703 mg/kg/day). Therefore, developmental effects are not a concern via the dermal route. Since 

there were no adverse effects seen in the route-specific dermal toxicity study up to the limit dose 

(1000 mg/kg/day) and no concerns for developmental or offspring effects. Skin lesions including 

hair loss, body sores, dermatitis, ulceration, and acanthosis were observed in the carcinogenicity 

study in mice; however, these were not considered relevant for a dermal assessment because they 

were only seen via the oral route of exposure and are thought to be the result of a systemic 

allergic reaction. 

Short- and intermediate-term inhalation: Since a subchronic inhalation study is not required at 

this time for cyazofamid (Memo, J. Van Alstine, 11-JULY-2012, TXR# 0056341), an oral study 

was selected for assessing risks via the inhalation route. This toxicity endpoint was established 

based on the same combination of studies used for the incidental oral endpoint (90-day and 

chronic oral toxicity studies in rats) with the NOAEL of 171 mg/kg/day and the LOAEL of 295 

mg/kg/day. These studies are appropriate for the duration of exposure and are protective of all 

effects seen following subchronic exposure to cyazofamid. The LOC for inhalation exposures is 

100 (10X for interspecies extrapolation, 10X for intraspecies extrapolation, and 1X for FQPA 

SF). For this endpoint, inhalation exposure is assumed to be equivalent to toxicity by the oral 

route of exposure. 

Cancer: Cyazofamid is classified as “not likely to be carcinogenic to humans” based on the lack of 

evidence for carcinogenicity in mice and rats and a lack of mutagenic potential (Memo, G. Dannan, 

15-APR-2004, TXR# 0052428). Therefore, a quantitative cancer risk assessment is not necessary. 
Cyazofamid Human Health Risk Assessment DP No. D426778 

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Table 4.5. Summary of Toxicological Doses and Endpoints for Cyazofamid for Use in Dietary, NonOccupational, and Occupational Human Health Risk Assessments.a 

Exposure/ 

Scenario POD 

Uncertainty/ 

FQPA Safety 

Factors 

RfD, PAD, 

LOC for 

Risk 

Assessment 

Study and Toxicological Effects

Acute Dietary 

(All 

Populations) 

No appropriate toxicological effect attributable to a single dose was observed. Therefore, a 

dose and endpoint were not identified for this risk assessment. 

Chronic 

Dietary (All 

Populations) 

NOAEL = 

94.8 

mg/kg/day 

UFA = 10X 

UFH = 10X 

FQPA SF = 1X 

Chronic RfD 

= 0.948 

mg/kg/day 

cPAD = 

0.948 

mg/kg/day 

18-Month Mouse Oral Carcinogenicity 

LOAEL = 985 mg/kg/day based on 

increased skin lesions. 

Incidental 

Oral ShortTerm (1-30 

days) and 

IntermediateTerm (1-6 

months) 

NOAEL = 

171 

mg/kg/day 

UFA = 10X 

UFH = 10X 

FQPA SF = 1X 

Residential 

LOC for 

MOE = 100 

Co-critical 90-Day and chronic oral toxicity 

studies in rats. 

LOAEL= 295 mg/kg based on increased 

incidence of basophilic tubules in the 

kidneys, increased urinary volume, pH, & 

protein. 

Dermal ShortTerm (1-30 

days) and 

IntermediateTerm (1-6 

months) 

No hazard was identified for dermal exposure; therefore, a quantitative dermal assessment is 

not needed. 

Inhalation 

Short- Term 

(1-30 days) 

and 

IntermediateTerm (1-6 

months) 

Oral 

NOAEL = 

171 

mg/kg/day 

UFA = 10X 

UFH = 10X 

FQPA SF = 1X 

Residential 

LOC for 

MOE = 100 

Occupationa

l LOC for 

MOE = 100 

Co-critical 90-Day and chronic oral toxicity 

studies in rats. 

LOAEL= 295 mg/kg based on increased 

incidence of basophilic tubules in the 

kidneys, increased urinary volume, pH, & 

protein. 

Cancer (oral, 

dermal, 

inhalation) 

Classification: “Not likely to be Carcinogenic to Humans” based on the absence of treatmentrelated tumors in two adequate rodent carcinogenicity studies. 

a 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 (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population-adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = 

level of concern. N/A = not applicable. 

5.0 Dietary Exposure and Risk Assessment 

5.1 Residues of Concern Summary and Rationale 

The residues of concern for dietary risk assessment and the tolerance expression are summarized 

in Table 5.1. Although potato and carrot commodities may be significant feed items for cattle, 

currently registered and newly proposed uses fall under 40 CFR § 180.6(a)(3) (i.e. there is no 
Cyazofamid Human Health Risk Assessment DP No. D426778 

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reasonable expectation of finite residues in livestock commodities). Based on the available 

ruminant metabolism studies in goats, HED recommends that the following metabolites should 

be analyzed for future cattle feeding studies: cyazofamid, CCIM, CCBA, CCBA-cysteine 

conjugate. In addition, there are no poultry or swine feed items. 

Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance 

Expression.a 

Matrix Residues Included in Risk Assessment Residues Included in 

Tolerance Expression 

Plants Parent and CCIM Parent and CCIM 

Livestock 

No decision (For future cattle feeding studies, the MARC 

recommended that the petitioner analyze parent, CCIM, CCBA, 

and CCBA-cysteine conjugate.) 

No decision 

Rotational crops Parent only Parent only 

Water Parent, CCIM, CCIM-AM, and CTCA N/A 

a Currently registered and proposed uses fall under 40 CFR § 180.6(a)(3) (i.e. there is no reasonable expectation of 

finite residues in livestock commodities). In addition, there are no poultry or swine feed items. (Note: there is a 

restriction against use on cowpea used for livestock feed on the label.) 

5.2 Food Residue Profile 

Crop Field Trials 

To support the newly proposed uses, IR-4 has submitted field trials of cyazofamid on chives, 

greenhouse-grown tomatoes, and peppers while ISK Biosciences Corporation submitted field 

trial data for cyazofamid on green onion and dry bulb onion. There are adequate data for risk 

assessment and tolerance assessment. In the residue decline studies, combined residues of 

cyazofamid and its metabolite, CCIM, were quantifiable, generally declining with increasing 

sampling interval. Furthermore, the residue data are supported by adequate storage stability data. 

The results from the crop field trial studies are summarized in Table 5.2. 

Table 5.2. Summary of Residues from Field Trials with Cyazofamid.

Crop Matrix Analyte 

Total 

Application 

Rate 

lb ai/A 

(g ai/ha) 

PHI 

(days) n1 

Combined Residues (ppm parent equivalents) 

Min.2 Max.2 LAFT3 HAFT3 Median3 Mean3 SD3

Chives 

Field Trials 

Chives, fresh Cyazofamid 0.698-0.712 0 6 0.751 3.56 0.832 3.30 1.44 1.81 1.01 

CCIM4 6 0.0357 0.305 0.0363 0.294 0.0781 0.127 0.110 

Combined5 6 0.838 3.60 0.922 3.32 1.51 1.93 0.999 

Chives, dried Cyazofamid 0.698-0.712 0 5 2.91 12.6 2.91 12.6 8.44 7.71 4.46 

CCIM4 5 0.378 5.62 0.378 5.62 1.39 2.23 2.19 

Combined5 5 3.29 17.0 3.29 17.0 11.6 9.94 5.79 

Greenhouse Trials 

Chives, fresh Cyazofamid 0.687-0.713 0 3 0.489 3.48 0.674 3.34 0.931 1.65 1.47 

CCIM3 3 <0.01 0.0725 <0.01 0.0662 0.0618 0.0460 0.0313 

Combined 3 <0.499 3.55 <0.684 3.40 0.993 1.69 1.49 

Combined Field and Greenhouse Trials

Chives, fresh Cyazofamid 0.687-0.713 0 9 0.489 3.56 0.674 3.34 1.22 1.75 1.09 
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Table 5.2. Summary of Residues from Field Trials with Cyazofamid.

Crop Matrix Analyte 

Total 

Application 

Rate 

lb ai/A 

(g ai/ha) 

PHI 

(days) n1 

Combined Residues (ppm parent equivalents) 

Min.2 Max.2 LAFT3 HAFT3 Median3 Mean3 SD3

CCIM4 9 <0.01 0.305 <0.01 0.294 0.0658 0.100 0.0973 

Combined5 9 <0.499 3.60 <0.684 3.40 1.33 1.85 1.09 

Greenhouse Tomato 

Tomato, 

greenhouse 

Cyazofamid 0.425-0.433 0-1 4 0.0331 0.324 0.0349 0.295 0.0562 0.111 0.124 

CCIM4 <0.01 0.0350 <0.01 0.0330 0.01 0.0158 0.0115 

Combined5 <0.0431 0.359 <0.0449 0.328 0.0662 0.126 0.136 

Greenhouse Peppers 

Greenhouse 

peppers 

Combined5 40 

mg ai/plant 

1.41x10-3

oz ai/plant 

0 2 <0.02 <0.02 <0.02 <0.02 <0.02 <0.02 0 

Onion

Onion, green Cyazofamid 0.407-0.426 

(455-477) 

0 5 0.362 1.15 0.463 1.085 0.541 0.667 0.263 

CCIM4 0.0159 0.0283 0.0165 0.0272 0.0182 0.0197 0.0043 

Combined5 0.390 1.17 0.490 1.10 0.559 0.687 0.261 

Onion, dry 

bulb 

Cyazofamid 0.415-0.433 

(465-485) 

0 10 0.0292 0.868 0.0322 0.861 0.0479 0.135 0.256 

CCIM4 <0.01 0.0353 <0.01 0.0349 0.01 0.0125 0.0079 

Combined5 <0.0392 0.902 <0.0422 0.895 0.0579 0.147 0.264 1 n = number of field trials. 

2 Values based on residue levels for individual samples. 3 Values based on per-trial average residue levels. LAFT = lowest average field trial, HAFT = highest average field trial, SD =

standard deviation. (LAFT and HAFT were not reported for dried chives because only one sample was collected at each site.) 

The LAFT, HAFT, median, mean, and standard deviation, values <LOQ are assumed to be at the LOQ (0.01 ppm). Data reflect 

conversion of quantifiable residues of CCIM to parent equivalents by the study reviewer. 4 Residues of CCIM were converted to parent equivalents by the study reviewer. 5 Combined residues of cyazofamid and CCIM. 

Processing Studies

Processed food or feeds are not derived from bulb vegetables, group 3-07 and herb, subgroup 

19A. Processed foods and feeds are derived from tomatoes. Processing data for cyazofamid 

in/on tomato (MRID 45409031) were previously submitted (Memo, 02/20/2004, A. Acierto, 

D285680). In conjunction with this review, it was determined that tolerances for residues of 

cyazofamid and its metabolite CCIM in/on tomato processed commodities are not needed. 

Meat, Milk, Poultry, and Eggs 

There are no feed items associated with bulb vegetables, group 3-07, herbs, subgroup 19A, 

tomato, and pepper. Livestock feeding studies are not required for cyazofamid. There is no 

dietary exposure of livestock to cyazofamid and there are no concerns for secondary residues in 

livestock commodities. 

5.3 Water Residue Profile 

Available environmental fate studies suggest cyazofamid is not very mobile and quickly 

degrades into a number of degradation products under different environmental conditions. HED 

concluded that cyazofamid and the metabolites designated as CCIM, CCIM-AM (4-chloro-5-ptolylimidazole-2-carboxamide), and CTCA (4-chloro-5-p-tolylimidazole-2-carboxylic acid) are 
Cyazofamid Human Health Risk Assessment DP No. D426778 

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considered to be the major residues in water and should be included in the drinking water risk 

assessment. Among the three major degradates for cyazofamid (CCIM, CCIM-AM and CTCA), 

the two terminal ones are CCIM and CTCA. CCIM is expected to be the major terminal 

degradate in water bodies with low biological activity because it forms as a result of abiotic 

hydrolysis of the parent. In contrast, CTCA is expected to be the major terminal degradate in 

biologically active soils and water/sediment systems. Both CCIM and CTCA are stable to 

abiotic hydrolysis and susceptible to leaching, but only CCIM is highly susceptible to 

biodegradation. Given these fate characteristics, cyazofamid and/or its degradates could 

potentially reach surface water via spray drift or runoff under certain environmental conditions, 

but the potential for it to reach ground water is very low. CCIM and/or CTCA could potentially 

be the terminal degradates in surface water bodies affected by spray drift and/or runoff 

depending on the level of biological activity. However, only CTCA has a high potential to 

contaminate ground water due to its high persistence and mobility. 

Table 5.3 summarizes the EDWCs. The non-cancer chronic value of 211 ppb was directly 

entered into the exposure model to assess the contributions from drinking water. EDWCs in 

groundwater were modeled using PRZM-GW for residues from use on turf and ornamentals, 

which had the highest seasonal rates among the proposed and registered uses. EDWCs in surface 

water as modeled by Tier 1 PRZM/EXAMS were lower. The models and their descriptions are 

available online at: http://www.epa.gov/oppefed1/models/water/. 

Table 5.3. Maximum Estimated Drinking Water Concentrations for Cyazofamid, CCIM, CCIM-AM and 

CTCA. Maximum EDWCs Are Based on the Use on Turf and Ornamentals. 

Drinking Water 

Source (Model Used) 

Use (rate modeled per 

year) 

Estimated Drinking Water Concentration (EDWC) 

(ppb) (Species) 

Groundwater 

(PRZM-GW) 

Ornamentals (3.12 lb 

ai/A/yr) 

Acute (CTCA) 2241

Chronic (CTCA) 2111

Surface water 

(PRZM/EXAMS) 

Turf & Ornamentals 

(3.0 & 3.12 lb ai/A/yr, 

respectively) 

Acute (cyazofamid, CCIM, CCIM-AM) 38.22

Chronic (CTCA) 133.52

Cancer/Chronic (CTCA) 77.32

1. For groundwater, acute and chronic exposure is based on modeling the degradate CTCA. 

2. For surface water, acute exposure is based on modeling of the parent cyazofamid plus the degradates CCIM 

and CCIM-AM. Chronic exposure is based on modeling of the degradate CTCA. 

5.4 Dietary Risk Assessment 

Conservative dietary exposure analyses using DEEM-FCIDTM indicate that acute and chronic 

dietary risk estimates for cyazofamid exposure from food and drinking water are well below 

HED’s LOC (i.e. <100% of the population adjusted dose). 

5.4.1 Description of Residue Data Used in Dietary Assessment

Chronic dietary (food + drinking water) assessments were conservative, assuming that residues 

in all crops were at tolerance levels and that 100% of the crops were treated. 

5.4.2 Acute Dietary Risk Assessment
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No acute dietary toxicity endpoint could be identified based on the toxicology data currently 

available for cyazofamid; therefore, a quantitative acute assessment was not performed. 

5.4.3 Chronic Dietary Risk Assessment

The chronic dietary (food and drinking water) exposure assessment for the general U.S. 

population resulted in a risk estimate of 1.1% of the cPAD. The chronic dietary risk estimate for 

the highest reported exposed population subgroup, children (1-2 years old), was 2.0% of the 

cPAD. The results of the chronic dietary exposure analysis are reported in Table 5.4.4 below. 

5.4.4 Summary Table

Table 5.4.4. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Cyazofamid. 

Population Subgroup 

Chronic Dietary 

Dietary Exposure 

(mg/kg/day) % cPAD a

General U.S. Population 0.010631 1.1 

All Infants (<1 year old) 0.015810 1.7 

Children 1-2 years old 0.018609 2.0 

Children 3-5 years old 0.015997 1.7 

Children 6-12 years old 0.010164 1.1 

Youth 13-19 years old 0.007809 <1% 

Adults 20-49 years old 0.010452 1.1 

Adults 50+ years old 0.010256 1.1 

Females 13-49 years old 0.010436 1.1 

a cPAD (chronic population adjusted dose) = 0.95 mg/kg/day. The population subgroup with the greatest exposure 

is in bold. 

6.0 Residential and Other Nonoccupational Exposure/Risk Characterization

There are no proposed residential uses at this time; and the existing residential uses have been 

previously reassessed to reflect updates to HED’s 2012 Residential SOPs1

 along with policy 

changes for body weight assumptions (K. Rury, D397215, 06/18/2012). However, since the 

previous assessment, the incidental oral, dermal, and inhalation PODs were reevaluated and 

changed. Therefore, the child incidental oral and adult inhalation scenarios for aggregate risk 

assessment have been updated for purposes of aggregating with dietary exposures for the 

cyazofamid risk assessment (K. Rury, D429457 and D429458, 10/XX/2015). There are no risks 

of concern for the existing residential uses of cyazofamid. A turf transferrable residue (TTR) 

 

1

 Available: http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/standard-operating-proceduresresidential-pesticide
Cyazofamid Human Health Risk Assessment DP No. D426778 

Page 23 of 37

study is available for cyazofamid and deemed acceptable (MRID 46571104); therefore, 

additional TTR data are not required at this time. 

6.1 Residential Risk Estimates for Use in Aggregate Assessment 

Table 6.1 reflects the residential risk estimates that are recommended for use in the aggregate 

assessment for cyazofamid. 

 The recommended residential exposure for use in the adult aggregate assessment reflects 

mixing/loading/applying with a hose-end sprayer to turf. 

 The recommended residential exposure for use in the children 1 to <2 years old aggregate 

assessment reflects and hand-to-mouth exposures from post-application exposure to 

treated turf. 

For additional information on the registered residential scenarios of cyazofamid, see K. Rury, 

D397215, 06/18/2012. 

Table 6.1. Recommendations for the Residential Exposures for the Cyazofamid Aggregate Assessment. 

Lifestage Exposure Scenario Dose (mg/kg/day)1 MOE2

Dermal3 Inhalation Oral3 Total Dermal Inhalation Oral Total 

Adult 

Mixing/Loading/Applying 

with a Hose-end Sprayer 

to Turf 

N/A4 0.0014 N/A 0.0014 N/A4 1,200,000 N/A 1,200,000 

Children 

1 to <2 

years old 

Post-application hand-tomouth exposure on turf N/A4 N/A 0.0089 0.0089 N/A4 N/A 19,000 19,000 

1 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed. Total = dermal + inhalation + incidental oral 

(where applicable). 

2 MOE = the MOEs associated with the highest residential doses. Total = 1 ÷ [(1/Dermal MOE) + (1/Inhalation MOE) + (1/Incidental 

Oral MOE)], where applicable. 

3 Dermal and incidental oral (hand-to-mouth) exposures were calculated using available chemical-specific TTR and DFR studies for 

turf and garden scenarios, respectively. Post-application risk estimates for contact with treated gardens/trees were calculated using an 

available DFR study on with tomatoes (MRID 45409118), and the post-application risk estimates for contact with treated turf was

calculated using the available TTR study (MRID 46571104). 

4 No toxicity was found at 1,000 mg/kg in a 28-day dermal toxicity study and no developmental effects were seen in the toxicity

database; therefore a dermal exposure assessment has not been conducted. 

6.2 Non-Occupational Spray Drift Exposure and Risk Estimates 

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a 

potential source of exposure from the ground application methods (e.g., groundboom and 

airblast) employed for cyazofamid. The agency has been working with the Spray Drift Task 

Force (a task force composed of various registrants which was developed as a result of a Data 

Call-In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation 

and other parties to develop the best spray drift management practices (see the agency’s Spray 

Drift website for more information).2

 The agency has also developed a policy on how to 

appropriately consider spray drift as a potential source of exposure in risk assessments for 

pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during 

the Registration Review process which ensures that all uses for that pesticide will be considered 

 

2

 Available: http://www2.epa.gov/reducing-pesticide-drift
Cyazofamid Human Health Risk Assessment DP No. D426778 

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concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures 

For Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating 

Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification 

of indirect non-occupational exposure to drift. 

6.3 Non-Occupational Bystander Post-Application Inhalation Exposure and Risk 

Estimates 

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The agency sought expert advice and input on issues 

related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the 

SAP’s final report on March 2, 2010 

(http://archive.epa.gov/scipoly/sap/meetings/web/html/120109meeting.html). The agency has 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-2014-0219). 

During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux 

studies, route-specific inhalation toxicological studies) or further analysis is required for 

cyazofamid. 

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g. a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure. For cyazofamid, potential exposures from food, drinking water, and 

residential scenarios were aggregated. 

7.1 Acute Aggregate Risk 

A quantitative acute aggregate risk assessment was not conducted since an appropriate acute 

point of departure was not established for cyazofamid. 

7.2 Short-Term Aggregate Risk 

There is potential short-term exposure to cyazofamid via the dietary (which is considered 

background exposure) and residential (which is considered primary) pathways. For adults, these 

pathways lead to exposure via the oral (background) and inhalation (primary) routes. For 

children, these pathways lead to exposure via the oral (background) and incidental oral (primary) 

routes. All aggregate risk estimates (MOEs) are greater than 100, which indicates that exposure 

and risk do not exceed HED’s LOC. The adult and children short-term aggregate dietary and 

residential MOEs are 14,000 and 6,100, respectively. 
Cyazofamid Human Health Risk Assessment DP No. D426778 

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Table 7.2. Short-Term Aggregate Risk Calculations.

Population 

Short- or Intermediate-Term Scenario 

NOAEL 

mg/kg/day LOC1 

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day 

Residential 

Exposure 

mg/kg/day3 

Total 

Exposure 

mg/kg/day4 

Aggregate 

MOE (food, 

water, and 

residential)5 

Adult 171 100 1.71 0.010452 0.0014 0.012 14,000 

Children 

1-2 years old 171 100 1.71 0.018609 0.0089 0.028 6,100 

1

 LOC includes the standard 10X inter- and 10X intra- species uncertainty factors and FQPA 1X totaling 100. 2

 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC. 

3

 Residential Exposure see Table 6.1. 

4

 Total Exposure = Avg Food & Water Exposure + Residential Exposure). 5

 Aggregate MOE = [NOAEL / (Avg Food & Water Exposure + Residential Exposure)]. 

7.3 Chronic Aggregate Risk 

Chronic exposure is not expected for the adult or child residential exposure pathway. Therefore, 

the chronic aggregate risk estimate would be equivalent to the chronic dietary exposure estimate. 

Refer to Section 5.4.3. 

8.0 Cumulative Exposure/Risk Characterization

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/ 

9.0 Occupational Exposure/Risk Characterization

9.1 Short-/Intermediate-Term Handler Risk 

HED evaluated occupational exposures from the proposed uses of cyazofamid. Application 

methods, maximum application rates, and use sites are summarized in Table 3.3. Based on 

application rates and label information, short- and intermediate-term exposures are expected for 

occupational handlers. However, the cyazofamid short- and intermediate-term PODs are the 

same for both durations; therefore this assessment is protective of both short- and intermediateterm exposures. Although a greenhouse use could result in agricultural production over the 

entire year (similar to a long-term exposure of six months to one year); the proposed cyazofamid 

labels recommend alternating with a different fungicide chemical or mode of action before 

continuous repeated applications; therefore it is unlikely that an individual will be exposed 
Cyazofamid Human Health Risk Assessment DP No. D426778 

Page 26 of 37

continually for greater than six months. The proposed labels require occupational handlers to 

wear long pants, long sleeved shirts, chemical resistant gloves, shoes, and socks. 

Inhalation risk estimates for the proposed uses of cyazofamid were not of concern at baseline 

with no PPE (no respirator) and with engineering control for aerial applications (i.e., enclosed 

cockpits). Short- and intermediate-term risk estimates for occupational handlers are presented in 

Table 9.1.1. The occupational handler inhalation MOEs ranged from 71,000 to 600,000,000. 
Cyazofamid Human Health Risk Assessment DP No. D426778 

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Table 9.1.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Cyazofamid. 

Exposure Scenario Crop or Target1 LOC 

Inhalation 

Unit 

Exposure 

(μg/lb ai)2

Maximum 

Application 

Rate3

Area Treated or 

Amount Handled 

Daily4

 Mixer/Loader 

Mixing/Loading Liquids for Aerial and 

Chemigation Application 

Nursery (Ornamentals, Vegetables, Trees, 

Container Stock) 

100 0.219 0.078 lb ai/A 

60 acres 

Field Crop, Typical 350 acres 

Mixing/Loading Liquids for Chemigation 

Application 

Greenhouse (Ornamentals, Vegetables, 

Container Stock) 60 acres 

Mixing/Loading Liquids for Groundboom 

Application 

Field-Grown Ornamental Crops 40 acres 

Nursery (Ornamentals, Vegetables, Trees, 

Container Stock) 60 acres 

Greenhouse (Ornamentals, Vegetables, 

Container Stock) 60 acres 

Field Crop, Typical 80 acres 

Applicator 

Applying Sprays via Aerial Equipment 

Nursery (Ornamentals, Vegetables, Trees, 

Container Stock) 100 0.0049 0.078 lb ai/A 60 acres 

Field Crop, Typical 350 acres 

Applying Sprays via Groundboom Equipment 

Field-Grown Ornamental Crops 

100 0.34 0.078 lb ai/A 

40 acres 

Nursery (Ornamentals, Vegetables, Trees, 

Container Stock), Greenhouse 

(Ornamentals, Vegetables, Container Stock)

60 acres 

Field Crop, Typical 80 acres 

Flagger 

Flagging for Aerial Applications 

Nursery (Ornamentals, Vegetables, Trees, 

Container Stock) 100 0.35 0.078 lb ai/A 60 acres 

Field Crop, Typical 350 acres 

Mixer/loader/Applicator 

Mixing/Loading/Applying Liquids with a 

Backpack Sprayer (Broadcast) 

Greenhouse (Ornamentals, Vegetables, 

Container Stock) 100 140 0.0016 lb ai/gal 40 gals 

Nursery (Ornamentals, Vegetables, Trees, 

Container Stock) 100 69.1 0.0016 lb ai/gal 40 gals 

Mixing/Loading/Applying Liquids with a Nursery (Ornamentals, Vegetables, Trees, 100 2.58 0.0016 lb ai/gal 40 gals 
Cyazofamid Human Health Risk Assessment DP No. D426778 

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Table 9.1.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Cyazofamid. 

Exposure Scenario Crop or Target1 LOC 

Inhalation 

Unit 

Exposure 

(μg/lb ai)2

Maximum 

Application 

Rate3

Area Treated or 

Amount Handled 

Daily4

Backpack Sprayer (Soil Directed) Container Stock), 

Mixing/Loading/Applying Liquids with a 

Manually Pressurized Handgun 

Nursery (Ornamentals, Vegetables, Trees, 

Container Stock), Greenhouse 

(Ornamentals, Vegetables, Container Stock)

100 30 0.0016 lb ai/gal 40 gals 

Mixing/Loading/Applying Liquids with a 

Mechanically Pressurized Handgun 

(Broadcast) 

Greenhouse (Ornamentals, Vegetables, 

Container Stock) 100 120 0.0016 lb ai/gal 1,000 gals 

Nursery (Ornamentals, Vegetables, Trees, 

Container Stock), Field Crop, Typical 3.9 

Mixing/Loading/Applying Liquids with a 

Mechanically Pressurized Handgun (Ground 

Directed) 

Greenhouse (Ornamentals, Vegetables, 

Container Stock) 100 120 0.00083 lb ai/gal 1,000 gals 

Nursery (Ornamentals, Vegetables, Trees, 

Container Stock), Field Crop, Typical 8.68 

1 For all proposed crops/use site, the proposed application rate on Bulb Vegetables Group 3-07 and Herb Subgroup 19A were used as the worst-case estimate of exposu

directed handheld equipment uses, where the drench rate for bell peppers was used as the worst-case estimate of exposure; these risk estimates presented here are prot

2 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September 2015); Level of mitigation: Baseline and Engineering Controls f

cockpits). 

3 Based on product label (Reg. No. 71512-3). 

4 Exposure Science Advisory Council Policy #9.1. 5 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A 

6 Inhalation MOE = Inhalation NOAEL (171 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).
Cyazofamid Human Health Risk Assessment DP No. D426778 

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9.2 Short- and Intermediate-Term Post-Application Risk 

9.2.1 Dermal Post-application Risk 

An occupational post-application dermal assessment was not completed for cyazofamid because 

no short- or intermediate-term dermal hazard was identified in the toxicity database. DFR 

studies are available in the cyazofamid exposure database (MRID 45409118 and 45409119); 

therefore, additional studies are not required at this time. 

Although a greenhouse use could result in agricultural production over the entire year (similar to 

a long-term exposure of six months to one year); the proposed cyazofamid labels recommend 

alternating with a different fungicide chemical or mode of action before continuous repeated 

applications; therefore, it is unlikely that an individual will be exposed to cyazofamid continually 

for greater than six months. Although the half-life for cyazofamid residues are relatively long 

(2.6 – 47.8 days), continuous long-term exposures are not expected because of the following: (1) 

because of the need to alternate fungicides with different modes of action, especially in 

greenhouses, it is unlikely that the same individual would be exposed to cyazofamid residues 

continuously for greater than six months; (2) the use directions for cyazofamid require repeat 

applications on a 7-10 day schedule, therefore, it is unlikely that an individual would be exposed 

to cyazofamid residues continuously for greater than six months; and (3) because crops are 

grown in varying stages in a greenhouse continuously throughout the year, it unlikely that the 

same person would be performing the same task, contacting the same residues continuously 

throughout six months; the individual tasks would likely rotate with the greenhouse growth 

schedules. 

Restricted Entry Interval 

Cyazofamid is classified as Toxicity Category III via the dermal route and Toxicity Category III 

for skin irritation potential. It is a weak skin sensitizer. Short- and intermediate-term postapplication risk estimates were not a concern on day 0 (12 hours following application) for all 

post-application activities. Under 40 CFR §156.208 (c) (2), ai’s classified as Acute III or IV for 

acute dermal, eye irritation and primary skin irritation are assigned a 12-hour REI. Therefore, 

the [156 subpart K] Worker Protection Statement interim proposed REI of 12 hours is adequate 

to protect agricultural workers from post-application exposures to cyazofamid. HED would 

recommend a REI of 12 hours. This is the REI listed on the product label, and is considered 

protective of post-application exposure. 

9.2.2 Inhalation Post-application Risk 

There are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

pesticides. The agency sought expert advice and input on issues related to volatilization of 

pesticides from its FIFRA SAP in December 2009, and received the SAP’s final report on March 

2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQ-
Cyazofamid Human Health Risk Assessment DP No. D426778 

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OPP-2014-0219). During Registration Review, the agency will utilize this analysis to determine 

if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is 

required for cyazofamid. 

In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the 

Agency will continue to identify the need for and, subsequently, the way to incorporate 

occupational post-application inhalation exposure into the agency's risk assessments. 

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios. 

The Worker Protection Standard for Agricultural Pesticides contains requirements for protecting 

workers from inhalation exposures during and after greenhouse applications through the use of 

ventilation requirements [40 CFR 170.110, (3) (Restrictions associated with pesticide 

applications)]. 

10.0 References 

Meléndez, J., 10/06/15 DP426776, Estimated Drinking Water Concentrations of Cyazofamid and 

its Degradates of Concern CCIM, CCIM-AM and CTCA, for Use in Human Health Risk 

Assessment: Petitions for the Use on Herb (Subgroup 19A), Greenhouse Tomato, Greenhouse 

Pepper, and Bulb Vegetables (Group 03-07) 

Rury, K., 10/XX/15, DP429457 and DP429458, Cyazofamid. Occupational and Residential 

Exposure Assessment for a Proposed Use on Crop Subgroup 19A, Peppers and Tomatoes Grown 

in Greenhouses, and on Bulb Vegetables Crop Group 03-07. 

Wassell W., 10/XX/15, DP426632 and DP426778, Cyazofamid. Petitions for the Establishment 

of Registrations and Tolerances for Residues in/on Herb, Subgroup 19A, Bulb Vegetables, 

Group 3-07, and data to support use on Tomato and Peppers in Greenhouses. Summary of 

Analytical Chemistry and Residue Data. 

Walls, C., 10/19/15, DP430735, Cyazofamid Acute and Chronic Aggregate Dietary (Food and 

Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action on Crop 

Subgroup 19A and on Bulb Vegetables Crop Group 03-07.
Cyazofamid Human Health Risk Assessment DP No. D426778 

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Appendix A. Toxicology Profile 

A.1 Toxicology Data Requirements

The requirements (40 CFR §158.340) for food use for cyazofamid are in Table 1. Use of the new guideline numbers 

does not imply that the new (1998) guideline protocols were used 

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity ....................................................... 

870.1200 Acute Dermal Toxicity .................................................. 

870.1300 Acute Inhalation Toxicity .............................................. 

870.2400 Primary Eye Irritation .................................................... 

870.2500 Primary Dermal Irritation .............................................. 

870.2600 Dermal Sensitization ..................................................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.3100 Oral Subchronic (rodent) ............................................... 

870.3150 Oral Subchronic (nonrodent) ......................................... 

870.3200 21-Day Dermal .............................................................. 

870.3250 90-Day Dermal .............................................................. 

870.3465 90-Day Inhalation .......................................................... 

yes 

yes 

no 

no 

yes

yes 

yes 

- 

-

yes1

870.3700a Developmental Toxicity (rodent) .................................. 

870.3700b Developmental Toxicity (nonrodent) ............................ 

870.3800 Reproduction ................................................................. 

yes 

yes 

yes 

yes 

yes 

yes 

870.4100a Chronic Toxicity (rodent) .............................................. 

870.4100b Chronic Toxicity (nonrodent) ........................................ 

870.4200a Oncogenicity (rat) .......................................................... 

870.4200b Oncogenicity (mouse) ................................................... 

870.4300 Chronic/Oncogenicity ................................................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.5100 Mutagenicity—Gene Mutation - bacterial ..................... 

870.5300 Mutagenicity—Gene Mutation - mammalian ................ 

870.5375 Mutagenicity—Structural Chromosomal Aberrations ... 

870.5395 Mutagenicity—Other Genotoxic Effects ....................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.6100a Acute Delayed Neurotoxicity (hen) ............................... 

870.6100b 90-Day Neurotoxicity (hen) .......................................... 

870.6200a Acute Neurotoxicity Screening Battery (rat) ................. 

870.6200b 90-Day Neurotoxicity Screening Battery (rat) .............. 

870.6300 Develop. Neurotoxicity ................................................. 

 no 

no 

yes 

yes 

no 

- 

 - 

yes 

yes 

 - 

870.7485 General Metabolism ...................................................... 

870.7600 Dermal Penetration ........................................................ 

870.7800 Immunotoxicity ............................................................. 

yes 

no 

yes 

yes 

- 

yes 

Special Studies for Ocular Effects 

Acute Oral (rat) ................................................................................ 

Subchronic Oral (rat)........................................................................ 

Six-month Oral (dog) ....................................................................... 

no 

no 

no 

- 

- 

- 

1 = HED HASPOC concluded that the subchronic inhalation study was not required at this time (J. Van Alstine, 

7/11/12, TXR#0056341). 
Cyazofamid Human Health Risk Assessment DP No. D426778 

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A.2 Toxicity Profiles

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) -

Subchronic, Chronic, and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ Classification 

/Doses

Results

870.3100 

28-Day dose-range 

finding study in rats 

45408927 (1999) 

Acceptable/non-guideline 

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 dose related 

increase in the incidence of basophilic kidney tubules in 

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 

incidence of basophilic kidney tubules, and increased 

urinary volume, pH, and protein. 

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. 
Cyazofamid Human Health Risk Assessment DP No. D426778 

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Subchronic, Chronic, and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ Classification 

/Doses

Results

870.3465 

28-Day inhalation 

toxicity 

Waived (HASPOC; TRX# 0056341; 7/11/12) 

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 = 108/ 1416 [M/F] 

mg/kg/day. 

LOAEL = M: 1114 mg/kg/day based on increased 

incidence of nephropathy; F: not observed. 

Reproductive NOAEL = 1114/ 1416 [M/F] mg/kg/day. 

LOAEL = not observed. 

Offspring NOAEL = 1117/ 1451 [M/F] mg/kg/day. 

LOAEL = Not observed. 

Note: No histopathology conducted on the kidneys of 

pups. 

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 

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. 

No evidence of carcinogenicity.
Cyazofamid Human Health Risk Assessment DP No. D426778 

Page 34 of 37

Subchronic, Chronic, and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ Classification 

/Doses

Results

870.4300 

Carcinogenicity mice 

45408932 (1999) 

Acceptable/guideline 

Males: 0, 9.5, 94.8, or 984.9 

mg/kg/day 

Females: 0, 12.2, 124.3, or 1203.4 

mg/kg/day 

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 

Negative ± S9 up to 5,000 μg/plate by standard plate 

and tube pre-incubation (not cytotoxic but there was 

precipitation at ≥1,500 μg/plate. 

Gene Mutation 

870.5300 

Mammalian cell culture 

45409002 (1998) 

Acceptable/ guideline 

Negative ± S9 up to cytotoxic and precipitating 

concentration of 100 μg/mL. 

Cytogenetics 

870.5375 

Chromosomal 

aberrations 

45409003 (1996) 

Acceptable/ guideline 

Negative ± S9 for clastogenic/aneugenic activity up to 

cytotoxic and precipitating concentration of 200 μg/mL. 

Cytogenetics 

870.5395 

Micronucleus test on 

mouse 

45409004 (1996) 

Acceptable/ guideline 

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 

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. 

870.6200b 

Subchronic 

neurotoxicity screening 

battery 

48891702 (2012) 

Acceptable/guideline 

Males: 0, 34, 134, or 1,356 

mg/kg/day 

Females: 0, 39, 156, or 1,539 

mg/kg/day 

Systemic/Neurotoxicity: 

NOAEL = 1356 mg/kg/day. 

LOAEL = not observed. 

870.6300 

Developmental 

neurotoxicity 

Study not available. 
Cyazofamid Human Health Risk Assessment DP No. D426778 

Page 35 of 37

Subchronic, Chronic, and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ Classification 

/Doses

Results

870.7485 

Metabolism and 

pharmacokinetics in 

rats 

45409006- 45409009 and 45434602 

(1998- 1999) 

Acceptable/guideline 

Dose: 0.5, 1,000, or 14 day 0.5 

mg/kg repeat non-labeled followed 

by 0.5 mg/kg [phenyl- U-14C]- or 

[

14C-Imidazole] IKF-916. 

Biliary excretion study: 0.5 or 1,000 

mg/kg [phenyl- U-14C]- 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 highdose. The extent of absorption (as percent 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, CCBA. 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 

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. 

870.7800 

Immunotoxicity 

48891701 (2012) 

Acceptable/guideline 

0, 136, 599, or 1381 mg/kg/day 

Systemic/Immunotoxicity: 

NOAEL = 1381 mg/kg/day. 

LOAEL = not observed. 

Special study: 

In Vitro Metabolism of 

IKF-916 and CCIM in 

Blood and Stomach 

Contents 

MRID 45409010 (1999) 

Acceptable/non-guideline 

The in vitro biodegradation of [14C-Bz]IKF-916 or [14CBz)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. 
Cyazofamid Human Health Risk Assessment DP No. D426778 

Page 36 of 37

Subchronic, Chronic, and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ Classification 

/Doses

Results

Special study: 

In Vitro Metabolism of 

CCIM in S9 Fraction 

MRID 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-chloro5(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 IKF916 and CCIM 

MRID 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 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 

[

14C]IKF-916 or 

[

14C]CCIM in rats 

MRID 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 [14C-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.
Cyazofamid Human Health Risk Assessment DP No. D426778 

Page 37 of 37

Appendix B. 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 

N

N

H C3

Cl

CN

SO2N(CH3)2

N

H

N

H C3

Cl

CN

N

H

N

Cl

CN

HO

O

N

H

N

H C3

Cl

O

NH2