Page 1 of 40

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

PREVENTION, PESTICIDES,

AND TOXIC SUBSTANCES

MEMORANDUM

Date: 7-APRIL-2010

SUBJECT: Cyazofamid. Human Health Risk Assessment for Proposed Uses on Brassica

(Cole) Leafy Vegetables Crop Group 5, Turnip Greens, Spinach, and Hops.

PC Code: 085651 DP Barcode: D370671 

Decision No.: 420982 Registration No.: 71512-3

Petition No.: 9E7615 Regulatory Action: Section 3 Registration

Risk Assessment Type: Single Chemical/Aggregate Case No.: NA

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

MRID No.: NA 40 CFR: §180.601

FROM: Nancy J. Tsaur, Risk Assessor

Amelia Acierto, Chemist

Kristin Rury, Biologist, ORE Assessor

Whang Phang, Toxicologist

Risk Assessment Branch 3 (RAB3)

Health Effects Division (7509P)

THROUGH: Paula Deschamp, Branch Chief 

Risk Assessment Branch 3 (RAB3)

Health Effects Division (7509P)

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

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

Registration Division (7505P)
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Introduction

This document addresses a petition submitted to the Agency regarding cyazofamid. The

Interregional Research Project No. 4 (IR-4) of Rutgers, New Jersey, has submitted a petition 

(PP#9E7615) to register the agricultural end-use product, Ranman® 400SC Fungicide, for use on

the Brassica (cole) leafy vegetable crop group (crop group, CG 5), turnip greens, spinach, and 

hops. The Health Effects Division (HED) of the Office of Pesticide Programs (OPP) is charged 

with estimating the risk to human health from exposure to pesticides. The Registration Division 

(RD) of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, 

occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to 

human health that will result from the proposed new uses of cyazofamid. 

Ranman® 400SC is a 34.5% active ingredient (ai) suspension concentrate (SC) containing the 

fungicide cyazofamid (4-chloro-2-cyano-N,N-dimethyl-5-p-tolylimidazole-1-sulfonamide). IR-4

is proposing the following tolerances for use of Ranman® 400SC in/on Brassica (cole) leafy

vegetables (CG 5), turnip greens, spinach, and hops:

Commodity Proposed Tolerance (ppm)

Brassica, head & stem, crop, subgroup 5A 1.2

Brassica, leafy greens, crop, subgroup 5B 12.0

Turnip Greens 12.0

Spinach 9.0

Hops 10.0

Note to RM: HED recommends modification of the tolerance expressions for cyazofamid 

according to the new compliance/measurement policy (Interim Guidance on Tolerance 

Expressions, Steve Knizner, May 27, 2009). HED recommends that the tolerance definition 

entries in 40 CFR §180.601 be revised and that tolerances for the listed commodities be 

established, as follows:

(a) General. 

(1) Tolerances are established for residues of the fungicide cyazofamid, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance 

with the tolerance levels specified below is to be determined by measuring only the sum 

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

its metabolite, 4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile, calculated as 

the stoichiometric equivalent of cyazofamid, in or on the commodity.

Brassica, head and stem, subgroup 5A ................................ 1.2 ppm 

Brassica, leafy greens, subgroup 5B.................................. 12.0 ppm

Turnip greens..................................................................... 12.0 ppm

Spinach................................................................................. 9.0 ppm

Hops................................................................................... 10.0 ppm

Note to RM: Zero-day data were not provided with the concurrent storage stability study on leaf 

lettuce and tomato; IR-4 is reminded that storage stability studies should always include a 0-
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day sampling interval to establish the residue levels present at the time samples are placed 

into storage and such data should be submitted in future petitions [see OPPTS 

860.1380(d)(6)(i)].

This document contains only those aspects of the risk assessment which are affected by the IR-4 

petition to establish tolerances in/on Brassica (cole) leafy vegetables, turnip greens, spinach, and 

hops. This document provides a summary of the findings from the data evaluation and 

subsequent assessment of human health risk resulting from these requests. The occupational 

exposure data review for the tolerance petition was performed by Kristin Rury (RAB3), the

residue chemistry data review and dietary exposure assessment were completed by Amelia 

Acierto (RAB3), and the overall human health risk assessment was conducted by Nancy J. Tsaur 

(RAB3); additionally, the drinking water assessment was conducted by José Meléndez of OPP’s 

Environmental Fate and Effects Division (EFED).

The most recent human-health risk assessment was conducted in conjunction with a request for 

use of cyazofamid on fruiting vegetables, okra, grapes east of the Rockies, vegetable greenhouse 

transplants, and commercial application on residential turf and residential ornamentals

(DP#356837, N. Tsaur, 05/20/2009). The detailed hazard characterization, dose response 

considerations (explanation of selected endpoints), absorption, distribution, metabolism, 

excretion (ADME) determinations, FQPA safety factor determination, mode of action, and 

toxicological effects can be found in a previous risk assessment (DP#342612, K. O’Rourke, 

03/19/2008).
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Table of Contents

1.0 EXECUTIVE SUMMARY ................................................................................................. 5

2.0 INGREDIENT PROFILE................................................................................................... 8

2.1 Summary of Proposed Uses.......................................................................................... 8

2.2 Structure and Nomenclature ..................................................................................... 10

2.3 Physical and Chemical Properties............................................................................. 11

3.0 HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS............................... 11

3.1 FQPA Considerations................................................................................................. 12

3.2 Dose-Response Assessment ........................................................................................ 13

3.3 Endocrine Disruption ................................................................................................. 15

4.0 DIETARY EXPOSURE/RISK CHARACTERIZATION ............................................. 16

4.1 Pesticide Metabolism .................................................................................................. 16

4.2 Analytical Methodology.............................................................................................. 17

4.3 Food Residue Profile................................................................................................... 17

4.4 International Residue Limits..................................................................................... 20

4.5 Drinking Water Residue Profile................................................................................ 20

4.6 Dietary Exposure and Risk ........................................................................................ 21

4.7 Cancer Dietary Exposure and Risk........................................................................... 24

5.0 NON-OCCUPATIONAL/RESIDENTIAL EXPOSURE/RISK PATHWAY .............. 24

6.0 AGGREGATE RISK ASSESSMENTS and RISK CHARACTERIZATION............. 25

6.1 Acute Aggregate Risk Assessment (Food and Drinking Water) ............................ 26

6.2 Short- and Intermediate-Term Aggregate Risk Assessment .................................. 26

6.3 Chronic Aggregate Risk Assessment (Food and Drinking Water) ........................ 27

6.4 Cancer Aggregate Risk Assessment .......................................................................... 27

7.0 CUMULATIVE RISK....................................................................................................... 27

8.0 OCCUPATIONAL EXPOSURE...................................................................................... 27

8.1 Occupational Handler Exposure and Risk............................................................... 27

8.2 Occupational Postapplication Exposure and Risk................................................... 30

9.0 DATA NEEDS AND LABEL RECOMMENDATIONS................................................ 31

9.1 Chemistry..................................................................................................................... 31

9.2 Toxicology.................................................................................................................... 31

APPENDIX A. Codes, Chemical Names, and Chemical Structure of Cyazofamid and 

Identified Metabolites................................................................................ 32

APPENDIX B. International Residue Limit Status........................................................... 33

APPENDIX C.1. Toxicity Profile of Cyazofamid Technical ................................................ 34

APPENDIX C.2. Acute Toxicity of Cyazofamid.................................................................... 38

APPENDIX D. Rationale for Immunotoxicity Data Requirement................................... 39

APPENDIX E. Rationale for Subchronic Toxicity Data Requirement............................ 40
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1.0 EXECUTIVE SUMMARY

Cyazofamid is a fungicide which belongs to a novel chemical class based on the cyanoimidazole 

moiety. Cyazofamid is a broad spectrum fungicide active against oomycete fungi (such as

Phytophthora, Plasmopara, Pseudoperonospora, and Pythium) and Plasmodiophoromycetes 

(Plasmodiospora brassicae). It specifically interferes with the cytochrome bc1 complex 

(ubiquinol cytochrome c oxidoreductase) in the mitochondrial respiratory chain of oomycetes 

fungi. 

Background

The most recent human health risk assessment for cyazofamid was conducted in May of 2009 for 

Section 3 registration on fruiting vegetables, okra, grapes east of the Rockies, vegetable 

greenhouse transplants, and commercial application on residential turf and residential 

ornamentals (DP#356837, N. Tsaur, 05/20/2009). There are currently no established Codex

Alimentarius or Mexican maximum residue limits (MRLs) for residues of cyazofamid in/on plant 

or livestock commodities. Canada has established MRLs for residues of cyazofamid in/on 

several commodities, but has not established maximum residue limits for the commodities of this 

petition (See Appendix B).

Proposed Use Profile

Brassica and Turnip Greens: Ranman® 400SC is proposed for minor uses on Brassica crop 

subgroup 5A and 5B, as well as turnip greens, as a single post transplant soil drench applied to 

the base of the plants at the rate of 0.118 lb ai/A. Broadcast foliar applications of cyazofamid 

may be applied at a maximum application rate of 0.072 lb ai/A/application on Brassica leafy 

vegetables and turnip greens with no more than six (1 soil + 5 broadcast) applications per crop. 

Cyazofamid may be applied during transplantation of Brassica leafy vegetables and turnip 

greens at a rate of up to 0.665 lb ai per 100 gallons and via soil incorporation at a rate of 0.52 lb 

ai/A. The maximum seasonal application rate for cyazofamid is 39.5 fl oz per acre per growing 

season (1.28 lb ai/A/season) for Brassica leafy vegetables and turnip greens.

Spinach & Hops: Cyazofamid may be applied to spinach and hops at a maximum application 

rate of 0.071 lb ai/Acre. For spinach, no more than five applications of Ranman® 400SC may be 

applied per crop. For hops, no more than six applications of Ranman® 400SC may be applied 

per crop. The maximum seasonal application rate is 13.75 fl oz per acre (0.36 lb ai/A) per 

growing season for spinach and 16.5 fl oz per acre (0.43 lb ai/A) per growing season for hops.

Handlers may apply Ranman® 400SC using aerial, groundboom, chemigation, or airblast

equipment. 

Hazard Assessment

Cyazofamid has a low order of acute toxicity via the oral, dermal, and inhalation routes of 

exposure. It produces minimal but reversible eye irritation, is a slight dermal irritant, and is a 

weak dermal sensitizer. The propensity of cyazofamid to be a slight dermal irritant and a weak 

sensitizer might be due to the sulfonamide moiety in the compound.

Following repeated administration in more than one species, cyazofamid seems to have mild or 

low toxicity. In rats, the kidney is the major target organ following subchronic dosing. No 
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adverse kidney effects or other toxicity findings were observed following chronic exposures. 

Skin lesions were observed in male mice only, 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.

The pre- and post-natal toxicology database for cyazofamid includes rat and rabbit 

developmental toxicity studies and a two-generation reproduction toxicity study in rats. There 

was some evidence of increased susceptibility following in utero exposure to rats in the prenatal 

developmental toxicity study; the increased incidence of bent ribs in the high dose fetuses was 

considered adverse and was used for setting the developmental NOAEL/LOAEL (no observed 

adverse effect level/lowest observed adverse effect level). HED considers this approach 

conservative and highly protective because bent ribs are a reversible developmental anomaly

rather than a malformation.

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

evidence of carcinogenicity in both the rat and the mouse studies. Additionally, cyazofamid does 

not appear to have mutagenicity potential, based on several negative in vivo and in vitro studies.

Dose Response Assessment and Food Quality Protection Act (FQPA) Decision

HED has examined the toxicology data and determined that there are no concerns or residual 

uncertainties for pre- and or postnatal toxicity. On this basis, the FQPA safety factor should be 

removed (i.e. reduced to 1X) for all potential exposure scenarios of cyazofamid. Furthermore, 

HED does not believe that conducting either a functional immunotoxicity study or an acute 

neurotoxicity study will result in lower NOAELs than the regulatory doses for risk assessment, 

and an additional factor (UFDB) for database uncertainty is not needed to account for lack of 

these studies. Additionally, the cyazofamid risk assessment team evaluated the quality of the 

exposure data, and based on these data, agreed that the FQPA SF could be reduced to 1X.

Drinking Water Assessment

The highest acute (peak) and chronic (mean) estimated drinking water concentrations (EDWCs) 

were estimated for surface water using the PRZM/EXAMS model. For the purpose of this 

unrefined dietary assessment, HED used the highest calculated EDWCs for surface water based 

on the conservative screening-level estimates: 136 ppb for the acute analysis and 133 ppb for the 

chronic analysis. This approach may significantly overestimate dietary exposure to cyazofamid 

from drinking water. 

Dietary Exposure Estimates

For the acute analysis, an acute endpoint was not identified for the general population including 

infants and children, because no effects were observed which could be attributed to a single-dose 

exposure. Dietary (food and drinking water) exposure of females 13-49 years old is well below 

HED’s level of concern (LOC) at the 95th percentile of exposure. Combined dietary exposure 

from food and drinking water is estimated at 0.01214 mg/kg/day, equivalent to 1.2% of the acute 

Population Adjusted Dose (aPAD).

For the chronic analysis, dietary (food and drinking water) exposure is estimated at 0.004945 

mg/kg/day (<1% of the chronic Population Adjusted Dose (cPAD)) for the general U.S. 

population and 0.01108 mg/kg/day (1.2% of the cPAD) for infants <1 year old, the population 
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subgroup with the highest estimated chronic dietary exposure to cyazofamid; both cPADs are 

below HED’s LOC.

Residential Exposure Estimates

Non-occupational handler exposure is not expected from residential turf and ornamentals

because application is limited to licensed and certified operators. However, postapplication 

exposure is possible for children and adults. Non-occupational scenarios were previously

assessed and the MOEs were estimated for “Day 0" exposure (i.e. the day of application). All

postapplication MOEs, including the children’s aggregate, are greater than 100, and therefore, 

are not of concern to HED (DP#356837, N. Tsaur, 05/20/2009).

Aggregate Exposure Scenarios and Risk Conclusions

Human health aggregate risk assessments have been conducted for acute aggregate exposure 

(food + drinking water), short-/intermediate-term aggregate exposure (food + residential 

exposure + drinking water), and chronic aggregate exposure (food + drinking water) scenarios. 

A cancer aggregate risk assessment was not performed because cyazofamid is classified as “not 

likely to be carcinogenic to humans.” All potential exposure pathways were assessed in the 

aggregate risk assessment. MOEs for aggregate exposure range from 1,000 to 1,500. None of 

the aggregate exposure and risk estimates are not of concern to HED.

Occupational Exposure Estimates

No chemical-specific handler exposure data were submitted to support the agricultural uses 

petition (PP#9E7615). In accordance with HED policy, occupational handler exposures were 

estimated using the Pesticide Handlers Exposure Database (PHED) Surrogate Exposure Guide 

(revised August, 1998). The results of the handler occupational exposure and risk assessment for 

the proposed agricultural uses indicate that risks are not of concern with baseline clothing, or 

when gloves are worn. The total short/intermediate-term MOEs range from 23,000 to 220,000; 

which are greater than the LOC of 100, and are not of concern to HED.

The results of the occupational postapplication exposure and risk assessment indicate that the 

MOEs are greater than 100 on the day of application and therefore, are not of concern to the 

Agency. Under the Worker Protection Standard (WPS) for Agricultural Pesticides, active 

ingredients classified as acute toxicity categories III or IV for dermal and inhalation routes are 

assigned a 12-hour restricted reentry interval (REI). Therefore, the 12-hour REI that appears on 

the proposed label is adequate.

Environmental Justice Considerations

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

human-health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/nepa/tools/guidance/Volume1/2-6-EO_12898envjustice.pdf). OPP 

typically considers the highest potential exposures from the legal use of a pesticide when 

conducting human health risk assessments including, but not limited to, people who obtain 

drinking water from sources near agricultural areas, the variability of diets within the U.S., and

people who may be exposed when harvesting crops. Should these highest exposures indicate 

potential risks of concern, OPP further refines the risk assessments to ensure that the risk 

estimates are based on the best available information.
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Review of Human Research

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

were intentionally exposed to a pesticide or other chemical. These studies have been determined 

to require a review of their ethical conduct, have received that review, and have been determined 

to be ethical.

2.0 INGREDIENT PROFILE

Cyazofamid is a broad-spectrum fungicide ai that controls oomycete fungi (such as 

Phytophthora, Plasmopara, Pseudoperonospora, and Pythium) and Plasmodiophoromycetes 

(Plasmodiospora brassicae). It inhibits all stages of fungal development in the life cycle of 

Phytophthora infestans which causes late blight disease in potatoes and tomatoes, and inhibits 

the germination and formation of zoosporangia, germination of cytospores, zoospore mobility, 

and mycelial growth. It controls downy mildew in cucurbit vegetables and grapes. 

Ranman® 400 SC (EPA Reg. No. 71512-3) is proposed for minor use in the control of club root 

(Pasmodiophora brassiceae) and downy mildew (Peronospora parasitica) in Brassica

vegetables and turnip greens, white rust (Albugo occidentalis) disease in spinach; and downy 

mildew (Pseudoperonospora humuli) in hops. 

2.1 Summary of Proposed Uses

IR-4 submitted a Section B specifying the proposed uses of Ranman® 400SC, along with a 

specimen label reflecting general use directions (PP#9E7615). A summary of the proposed use 

directions for cyazofamid is presented below in Table 2.1. 

Ranman® 400SC is proposed for minor uses on Brassica crop subgroup 5A and 5B, as well as 

turnip greens, as a single post transplant soil drench applied to the base of the plants at the rate of 

0.118 lb ai/A followed by multiple (five) foliar applications at a target rate of 0.072 lb 

ai/A/application with a maximum seasonal foliar application rate of 0.360 lb ai/A or a total 

application rate of 0.478 lb ai/A/season (1 soil drench + 5 foliar applications). Soil drench 

application was not proposed for spinach or hops. The formulated product is proposed for use on 

spinach as five foliar sprays at the target rate of 0.071 lb ai/A/application with a maximum 

seasonal rate of 0.36 lb ai/A and six foliar applications on hops at the target rate of 0.071 lb 

ai/A/application with a maximum seasonal rate of 0.426 lb ai/A. Re-treatment intervals (RTIs) 

of 7 to 10 days are proposed for all the crops, starting when disease is first detected or when 

weather or disease pressure is expected to initiate a disease epidemic. Preharvest intervals 

(PHIs) are proposed at day 0 for the Brassica leafy vegetables, turnip greens, and spinach, and 3 

days for hops. Except for hops, Silwet L-77, a non-ionic organosilicone surfactant, is 

recommended to be tank mixed at a 4:3 ratio for all foliar sprays. 
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Table 2.1. Summary of Directions for Use of Ranman® 400SC (EPA Reg. No. 71512-3).

Applic. 

Timing, Type, 

and Equip.

Applic. Rate 

fl oz

(lb ai/A)

Max. No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate

fl oz (lb ai/A)

RTI

(days)

PHI

(days)

Use Directions and Limitations

Crop Group 5, Brassica (Cole) Leafy Vegetables: 

broccoli; Chinese broccoli (gai lon); broccoli raab (rapini); Brussels sprouts; cabbage; Chinese cabbage (bok choy); 

Chinese cabbage (napa); Chinese mustard (gai choy); cauliflower; cavalo broccolo; collards; kale; kohlrabi; 

mizuna; mustard greens; mustard spinach; rape greens; Turnip Greens 1,2,3,4

Transplant Soil 

Drench (for 

control of Club 

root disease) 

12.9 to 25.75

(0.333-0.665/

100 gal)

1

25.75

(0.665 lb 

ai/100 gal)

NA NA

Soil drench immediately after 

transplant: make a single 

application within the rate range 

listed and apply 1.7 fl. oz per 

plant as transplant water. 

Soil 

Incorporation 

(for control of 

Club root 

disease) 2

20

(0.52) 1

20

(0.52) NA NA

Apply in a water volume of at 

least 50 gal per acre. Transplant 

the seedlings into the treated 

band. If planting into a bed, a 

broadcast application can be 

made prior to forming the bed.

Foliar (For the 

control of 

Downy mildew 

disease) 3

2.75

(0.072) 5

13.75

(0.36) 7 to 10 0

Begin spray when disease is first 

seen or weather and downy 

mildew disease pressure are 

expected to initiate a disease 

epidemic. 

Use longer interval for preventive 

or low disease pressure.

Do not apply more than six (1 

soil + 5 foliar) applications of 

RANMAN® 400SC per season.

Spinach

Foliar (For 

control of 

white rust 

disease) 5

2.1 to 2.75 

(0.054 to 

0.071)

5

13.75

(0.36) 7 to 10 0

Begin spray when disease is first 

seen or weather and white rust 

disease pressure are expected to 

initiate a disease epidemic. 

Use longer interval for preventive 

or low disease pressure.

Hops

Foliar (for 

control of 

Downy mildew 

ease) 6

2.1 to 2.75 

(0.054 to 0.0

(0.071)

6

16.5

(0.426) 7 to 10 3

Begin spray when disease is first 

seen or weather and downy 

mildew disease pressure are 

expected to initiate a disease

epidemic. 

Use longer interval for preventive 

or low disease pressure.

Use water spray of at least 100 

gal/A.
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1

 Resistance management: Do not apply more than six (1 soil + 5 foliar) applications of Ranman® 400SC per 

crop. Alternate foliar sprays of Ranman® 400SC with a fungicide with a different mode of action. DO NOT make 

more than three consecutive applications of Ranman® 400SC followed by at least three applications of fungicides 

having different modes of action before applying additional Ranman® 400SC.

2

 Soil Incorporation: Alternatively, if desired and for soil with low infiltration rates, apply 20 fl oz per acre in a 

minimum bandwidth of 9 inches along the planting row and incorporate to a soil depth of 6 to 8 inches with a 

precision incorporator in the same operation. 

3 Use of an organosilicone and a nonionic surfactant is recommended when disease infection is severe at water 

volumes up to 60 gal/A. 

4 Restrictions: Do not apply more than 39.5 fl oz per acre per crop growing season [1 soil application at 25.75 fl 

oz/A and 5 foliar applications at 2.75 fl oz/A/application (13.75 fl oz/A)].

5 Resistance management: Do not apply more than five applications of Ranman® 400SC per crop. Alternate foliar 

sprays of Ranman® 400SC with a fungicide with a different mode of action. DO NOT make more than three 

consecutive applications of Ranman® 400SC followed by at least three applications of fungicides having different 

modes of action before applying additional Ranman® 400SC.

6 Resistance management: Do not apply more than six applications of Ranman® 400SC per crop. Alternate foliar 

sprays of Ranman® 400SC with a fungicide with a different mode of action. DO NOT make more than three 

consecutive applications of Ranman® 400SC followed by at least three applications of fungicides having different 

modes of action before applying additional Ranman® 400SC.

The submitted use directions are sufficient to allow evaluation of the submitted residue data 

relative to the proposed uses. The use directions are according to the proposed supplemental 

label. HED notes that soil incorporation of Ranman® 400 SC at the rate of 20 fl oz per acre 

before transplant is included in the supplemental label as an alternative to the post-transplant soil 

drench application. No data have been submitted to support the soil incorporation method. 

However, HED notes that incorporation of Ranman® 400 SC into the soil (before transplant) is 

already on the current label and has been used on crop field studies from earlier petitions 

(PP#8E7427). No further data are required. 

2.2 Structure and Nomenclature

The chemical structure and nomenclature of the technical grade of cyazofamid and its metabolite 

CCIM (4-chloro-5-p-tolylimidazole-2-carbonitrile) are shown in Table 2.2.

Table 2.2. Test Compound Nomenclature.

Compound Chemical Structure

N

N

H3C

Cl

CN

SO2N(CH3)

2

Common name Cyazofamid

Company experimental name N/A

IUPAC name 4-chloro-2-cyano-N, N-dimethyl-5-p-tolylimidazole-1-sulfonamide

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

CAS registry number 120116-88-3

End-use product (EP) Ranman® 400SC Agricultural Fungicide (EPA Reg. No. 71512-3)
Page 11 of 40

Table 2.2. Test Compound Nomenclature.

Compound Chemical Structure of metabolite

N

H

N

H3C

Cl

CN

Common name CCIM

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

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

2.3 Physical and Chemical Properties

The physicochemical properties of the technical grade of cyazofamid are shown in Table 2.3.

Table 2.3. Physicochemical Properties of the Technical Grade Cyazofamid.

Parameter Value Reference

Melting point (°C) 152.7 PMRA Regulatory Note REG2006-

05 on Cyazofamid, 12/6/06

pH 4.9 e-Pesticide Manual, 13th Edition

Density at 20°C (g/mL) 1.446

Water solubility (at 20°C) pH Solubility (mg/L) REG2006-05

5

7

9

0.121

0.107

0.109

Solvent solubility (at 21.2°C) Solvent Solubility (g/L)

Acetone

Ethyl acetate

Methanol

Dichloromethane

Toluene

Hexane

n-Octanol

Acetonitrile

2-Propanol

43.1

16.19

1.74

94.82

6.0

0.03

0.04

29.446

0.43

Vapor pressure at 25°C <1.33 x 10-5Pa

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

the pH range of 2-12.

Octanol/water partition 

coefficient 

LogKOW = 3.2

KOW = 1.585 x 103

UV/visible absorption spectrum pH Λmax (nm)

2

7

10

285

279

287

3.0 HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS

References:

- Cyazofamid [IFK-916] – Report of the Hazard Identification Assessment Review Committee. Ghazi Dannan, 

03/03/2004.

- Cyazofamid. Human Health Risk Assessment for Proposed Uses on Fruiting Vegetables and Okra, Grapes East 

of the Rocky Mountains, Vegetable Greenhouse Transplants, and Commercial Application on Residential Turf 
Page 12 of 40

and Residential Ornamentals. Nancy J. Tsaur, DP#356837, 05/20/2009.

- Human Health Risk Assessment to Support the Registration of Cyazofamid for Use on Carrot. Kelly O’Rourke, 

DP#342612, 03/19/2008.

The toxicology database for cyazofamid is sufficient to characterize the hazard, to conduct 

FQPA assessment, and to select toxicity endpoints for risk assessment. Data quality is 

acceptable and meets the criteria set in the OPPTS guidelines and 40 CFR §158.500. However, 

under the current data requirement guidelines, functional immunotoxicity data (OPPTS 

870.7800) shall be required as a condition of registration. To address the issue of the

immunotoxicity data gap and the associated database uncertainty factor, RAB3 has examined the 

entire database of cyazofamid and concluded that the toxicology database of this chemical does 

not show any evidence of biologically relevant structural effects on the immune system that 

relate to this chemical. The overall weight of evidence suggests that this chemical does not 

directly target the immune system. HED does not believe that conducting a functional 

immunotoxicity study will result in a lower NOAEL than the regulatory doses for risk 

assessment, and an additional factor for database uncertainty (UFDB) is not needed to account for 

lack of this study.

Additionally, a subchronic neurotoxicity study is not available. Under the current rules (40 CFR 

§158.500), a subchronic neurotoxicity study is required. However, based on the available data, 

conducting a subchronic neurotoxicity study is unlikely to result in a lower NOAEL than the 

available relevant toxicity results because the acute neurotoxicity study, which tested dose levels 

as high as 2000 mg/kg, shows no neurotoxic effects with gavage dosing. Neurotoxicity is also 

not demonstrated in subchronic, chronic, reproduction, or developmental toxicity studies. At this 

time, the lack of a subchronic neurotoxicity study does not present any uncertainty for evaluating 

the toxicity of cyazofamid. Therefore, a database uncertainty factor (UFDB) for lack of a 

subchronic neurotoxicity is not needed. 

The detailed hazard characterization, dose response considerations (explanation of selected 

endpoints), absorption, distribution, metabolism, excretion (ADME) determinations, FQPA

safety factor determination, mode of action, and toxicological effects can be found in a previous 

risk assessment (DP#342612, K. O’Rourke, 03/19/2008). 

3.1 FQPA Considerations

Based on the hazard and exposure data, the HED cyazofamid risk assessment team recommends

that the FQPA SF be reduced to 1X. The recommendation is based on the following:

 The toxicology database for cyazofamid is complete for the purposes of this risk 

assessment and for the characterization of potential pre- and postnatal risks to infants and 

children. Recent changes to 40 CFR §158.500 now require subchronic neurotoxicity and 

immunotoxicity studies from the pesticide registrant. Although both of these studies 

have yet to be submitted, as discussed in Section 3.0, the available toxicology data do not 

show neurotoxicity or immunotoxicity; therefore, a database uncertainty factor for the 

lack of these studies is not needed.
Page 13 of 40

 The prenatal developmental toxicity study in rabbits and the two-generation reproduction 

study did not show any indication of increased susceptibility (qualitative or quantitative). 

For both studies the highest tested dose was at or greater than the limit dose (1,000 

mg/kg/day). However, in the rat developmental toxicity study, there was quantitative 

evidence of in utero susceptibility; increases in fetuses with bent ribs were seen at 1,000 

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

was 100 mg/kg/day and the maternal NOAEL was 1,000 mg/kg/day. HED believes that 

bent ribs are a reversible developmental anomaly rather than a malformation and a clear 

NOAEL is established for this effect. In addition, using this endpoint for setting the 

developmental NOAEL/LOAEL in the rat study is a conservative approach. 

 The available data do not demonstrate neurotoxicity.

 The dietary exposure assessments (food and water), which employed tolerance-level 

resides, 100% crop treated, high-end estimates of water concentrations (EDWCs), are 

conservative and high-end assessments. They do not underestimate the potential dietary

exposures. The calculated residential risks represent conservative estimates of exposure 

because maximum application rates are used to define residue levels. Exposures are 

unlikely to be underestimated because the assessment is a screening-level assessment.

3.2 Dose-Response Assessment

Tables 3.2a and 3.2b summarize the toxicological endpoints for cyazofamid for use in dietary

and occupational human health risk assessments, respectively. In addition to the detailed 

overview from a previous assessment, a study (28-day dose-range finding study in rats, 

Guideline 870.3100) has been added to the toxicity profile in Appendix C. Also, a new 

toxicological endpoint has been selected with respect to short-/intermediate-term incidental oral 

exposures for children 3 to <6 years old as shown in Table 3.2a. Please refer to the listed 

references for further extensive details and refer to Appendix C for the toxicity profile tables. 

Aside from consideration of the 28-day oral range-finding study in the rat for selection of an

incidental oral endpoint, the hazard characterization and endpoint selection from the previous 

risk assessment are applied directly to this section. 

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

Human Health Risk Assessments.

Exposure/

Scenario

Point of 

Departure

(PoD)

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including Infants 

and Children)

No adverse effects were observed which could be attributed to a single-dose exposure for the 

general population.

Acute Dietary

(Females 13-49 

years of age)

NOAEL = 100 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Acute RfD = 

1.0 mg/kg/day

Rat Prenatal Developmental Toxicity 

(MRID 45408933)

LOAEL = 1,000 mg/kg/day based on 

developmental toxicity findings of 

increased incidence of bent ribs.
Page 14 of 40

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

Human Health Risk Assessments.

Exposure/

Scenario

Point of 

Departure

(PoD)

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Chronic Dietary 

(All Populations)

NOAEL= 94.8 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Chronic RfD 

= 0.948

mg/kg/day

18-Month Mouse Oral Carcinogenicity 

(MRID 45408932)

LOAEL = 985 mg/kg/day based on 

increased skin lesions.

Incidental Oral 

Short-Term (1-30 

days) and 

IntermediateTerm (1-6 

months)

NOAEL= 30 

mg/kg/day 

UFA = 10X

UFH = 10X

FQPA SF = 1X

Residential 

LOC for 

MOE = 100

90-Day oral toxicity study in rats. 

LOAEL= 295 mg/kg based on 

increased number of basophilic tubules 

of the kidneys, increased urinary 

volume, pH, & protein. This toxicity 

endpoint is also supported by the results 

of a 28-day oral dose range-finding study 

in rats. In this study, at 370 mg/kg/day or 

above increased incidence of basophilic 

tubules in the kidneys was found. 

Dermal ShortTerm (1-30 days) 

and IntermediateTerm (1-6 

months)

For CHILDREN:

No toxicity was found at 1000 mg/kg in a 28-day dermal toxicity study; therefore, in the 

absence of hazard identified for this population, a risk assessment is not necessary.

For ADULTS:

NOAEL = 100 

mg/kg/day

(Dermal 

Absorption 

Rate = 37%)

UFA = 10X

UFH = 10X

FQPA SF = 1X

Acute RfD = 

1.0 

mg/kg/day

Rat Prenatal Developmental Toxicity 

(MRID 45408933)

LOAEL = 1,000 mg/kg/day based on 

developmental toxicity findings of 

increased incidence of bent ribs.

Inhalation ShortTerm (1-30 days) 

and IntermediateTerm (1-6 

months)

No residential exposure is expected via inhalation route.

Cancer (oral, 

dermal, 

inhalation)

Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant 

tumor increases in two adequate rodent carcinogenicity studies.

Point of Departure (PoD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (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.
Page 15 of 40

Table 3.2b. Summary of Toxicological Doses and Endpoints for Cyazofamid for Use in Occupational Human 

Health Risk Assessments.

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal ShortTerm (1-30 

days) and 

IntermediateTerm (1-6 

months)

Oral Study 

NOAEL= 

100 

mg/kg/day 

(Dermal 

Absorption 

Rate = 37%)

UFA = 10X

UFH = 10X

Occupational LOC 

for MOE = 100

Rat Prenatal Developmental Toxicity 

(MRID 45408933)

LOAEL = 1,000 mg/kg based on 

developmental toxicity findings of 

increased incidence of bent ribs.

Dermal Long 

Term (>6 

months)

NOAEL= 

94.8 

mg/kg/day

(Dermal 

Absorption 

Rate = 37%)

UFA = 10X

UFH = 10X

Occupational LOC 

for MOE = 100

18-Month Mouse Oral Carcinogenicity 

(MRID 45408932)

LOAEL = 985 mg/kg/day based on 

increased skin lesions.

Inhalation 

Short-Term (1-

30 days) and 

IntermediateTerm (1-6 

months)

NOAEL= 

100 

mg/kg/day

UFA = 10X

UFH = 10X

Occupational LOC 

for MOE = 100

Rat Prenatal Developmental Toxicity 

(MRID 45408933)

LOAEL = 1,000 mg/kg based on 

developmental toxicity findings of 

increased incidence of bent ribs.

Inhalation 

Long-Term (>6 

months)

NOAEL= 

94.8 

mg/kg/day

UFA = 10X

UFH = 10X

Occupational LOC 

for MOE = 100

18-Month Mouse Oral Carcinogenicity 

(MRID 45408932)

LOAEL = 985 mg/kg/day based on 

increased skin lesions.

Cancer (oral, 

dermal, 

inhalation)

Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant 

tumor increases in two adequate rodent carcinogenicity studies.

Point of Departure (PoD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of 

concern. N/A = not applicable.

3.3 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including pesticide active 

and other ingredients) may have an effect in humans or wildlife similar to an effect produced by

a “naturally occurring estrogen, or other such endocrine effects as the Administrator may

designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect.
Page 16 of 40

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first 

group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors.

Cyazofamid is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/.

4.0 DIETARY EXPOSURE/RISK CHARACTERIZATION

References: 

- Cyazofamid. Tolerance Petition for Uses on Brassica (Cole) Leafy Vegetables Crop Group 5, Turnip Greens, 

Spinach, and Hops. Summary of Analytical Chemistry and Residue Data. DP#371162, Amelia Acierto, 

02/24/2010.

- Cyazofamid: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments 

for Tolerance Petition and Proposed Section 3 Amendment Registration for Uses on Brassica (Cole) Leafy 

Vegetables Crop Group 5, Turnip Greens, Spinach, and Hops. DP#371163, Amelia Acierto, 03/08/2010.

- Cyazofamid - Meeting Report of the Metabolism Assessment Review Committee (MARC). DP#298915, Amelia 

Acierto, 02/18/2004.

The exposure pathways resulting from use of this chemical are dietary (food and drinking water), 

residential, and occupational.

4.1 Pesticide Metabolism

Nature of the Residue – Plants

The nature of the residue in plants is adequately understood based on previously submitted 

metabolism studies on grape, potato, and tomato. HED concluded that, for the risk assessment 

and tolerance expression, parent and CCIM are the residues of concern for plant commodities

(DP#298915, A. Acierto, 02/18/2004). 

Nature of the Residue – Livestock

The current uses of cyazofamid fall under 40 CFR §180.6(a)(3) (i.e. there is no reasonable 

expectation of finite residues in livestock commodities). The nature of residues in livestock is 

adequately understood based on the previously submitted goat and hen metabolism studies.

Based on the available ruminant metabolism studies in goats, HED recommended the following 

metabolites be analyzed for future cattle feeding studies: cyazofamid, CCIM, CCBA (4-(4-

chloro-2-cyanoimidazol-5-yl)benzoic acid; see Appendix A), CCBA-cysteine conjugate.

Confined Accumulation in Rotational Crops

No confined accumulation in rotational crop study was submitted with this petition. However, 

studies were submitted in conjunction with an earlier petition (PP#1F06305). The results of 
Page 17 of 40

these data showed that cyazofamid and structurally related metabolites are not expected to be 

present at a level greater than 0.01 ppm in/on three representative rotational crop commodities at 

a plant-back interval of 30 days. Therefore, HED has concluded that a rotational crop plant-back 

interval (PBI) of 30 days would be appropriate for the cyazofamid end-use labels. 

4.2 Analytical Methodology

Residue Analytical Methods – Plants

An acceptable analytical method is available for enforcement purposes. An adequate data 

collection method, “Independent Laboratory Validation of the Residue Method for IKF-916 and 

CCIM in Tomatoes”, Document Number 013033-0, Pyxant Labs Inc, with slight modification,

was used to determine the residues of cyazofamid and CCIM. Quantitation of the residues of 

cyazofamid and CCIM was achieved by liquid chromatography/mass spectrometry/mass 

spectrometry (LC/MS/MS).

Storage Stability

Adequate storage stability data are available to support the storage durations and conditions of 

samples of cabbage, mustard greens, spinach and hops. Although the concurrent recoveries were 

acceptable for broccoli, the storage stability data were erratic which, according to the petitioner,

may have been due to the spiking solution that appeared to have degraded (separated) during 

frozen storage.

There are sufficient data from the representative crop group 5 to support the storage stability data 

for broccoli. No additional storage stability study is required. 

4.3 Food Residue Profile

Tolerances have been established in 40 CFR §180.601(a) for the combined residues of 

cyazofamid and CCIM expressed as cyazofamid in/on carrot, roots at 0.09 ppm, okra at 0.40 

ppm, potato at 0.02 ppm, vegetable, cucurbit, group 9 at 0.10 ppm, and vegetable, fruiting, group 

8 at 0.40 ppm. In addition, tolerances with regional registrations are established in 40 CFR 

§180.601(c) in/on grape at 1.5 ppm. The current request for registration is for a proposed use on 

Brassica (cole) leafy vegetables, turnip greens, spinach, and hops.

Crop Field Trial Data

To support this petition, crop field trial data from broccoli, cabbage, mustard greens, spinach, 

and hops were submitted. The crop field trial data submitted are adequate to support the 

proposed new minor uses of cyazofamid in/on Brassica vegetables, turnip greens, spinach, and 

hops.

All raw agricultural commodities were analyzed for residues of cyazofamid and CCIM using the 

LC/MS/MS method which was validated prior to and concurrently with field samples. Results of 

the crop field trials are summarized in Table 4.3a.
Page 18 of 40

Table 4.3a. Summary of Residue Data from Crop Field Trials with Cyazofamid.

Commodity Analyte

Total 

Application 

Rate

(lbs ai/A)

PHI 

(days)

Residue Levels (ppm)

n Min. Max. HAFT1 Median2

(STMdR)

Mean2

(STMR)

Standard 

Deviation2

Broccoli

Broccoli Flower 

Head

Cyazofamid 0.479–0.552 0 12 0.18 0.91 0.84 0.36 0.41 0.22

CCIM NA30 12 < 0.01 < 0.01 0.005 0.005 0.005 0

Cabbage

Cabbage Head 

with Wrapper 

Leaves

Cyazofamid 0.467–0.531 0 18 0.12 0.87 0.75 0.27 0.32 0.21

CCIM NA30 18 < 0.01 0.025 0.02 0.01 0.01 0.01

Mustard Greens

Mustard Greens

(leaves) Cyazofamid 0.472 – 0.503 0 18 1.3 6.8 6.3 3.7 3.9 1.7

Mustard Greens

(leaves) Cyazofamid 0.477 1 2 1.2 1.4 1.3 1.3 1.3 0.14

Mustard Greens

(leaves) Cyazofamid 0.477 3 2 0.33 0.38 0.36 0.36 0.36 0.035

Mustard Greens

(leaves) Cyazofamid 0.477 6 2 0.061 0.066 0.064 0.064 0.064 0.0035

Mustard Greens

(leaves) Cyazofamid 0.477 7 2 0.022 0.024 0.023 0.023 0.023 0.0014

Mustard Greens

(leaves) CCIM NA 0 18 0.030 0.19 0.18 0.053 0.081 0.053

Mustard Greens CCIM NA 1 2 0.019 0.019 0.019 0.019 0.019 0

(leaves) CCIM NA 3 2 <0.01 0.012 0.009 0.009 0.009 0.005

Mustard Greens CCIM NA 6 2 <0.01 <0.01 0.005 0.005 0.005 0

(leaves) CCIM NA 7 2 <0.01 <0.01 0.005 0.005 0.005 0

Spinach Leaves

Spinach Leaves Cyazofamid 0.347 - 0.366 0 20 1.4 6.5 6.4 3.1 3.2 1.4

Spinach Leaves Cyazofamid 0.365 1 2 1.6 2.5 2.1 2.1 2.1 0.64

Spinach Leaves Cyazofamid 0.365 3 2 1.2 1.2 1.2 1.2 1.2 0

Spinach Leaves Cyazofamid 0.365 4 2 0.90 1.0 0.95 0.95 0.95 0.071

Spinach Leaves Cyazofamid 0.365 6 2 0.69 0.82 0.76 0.76 0.76 0.092

Spinach Leaves CCIM NA 0 20 0.027 0.15 0.14 0.073 0.075 0.038

Spinach Leaves CCIM NA 1 2 0.023 0.031 0.027 0.027 0.027 0.01

Spinach Leaves CCIM NA 3 2 0.012 0.015 0.0135 0.0135 0.0135 0.0021

Spinach Leaves CCIM NA 4 2 0.013 0.016 0.0145 0.0145 0.0145 0.0021

Hops

Hop Cones Cyazofamid 0.425-0.443 2-4 6 2.5 6.9 6.3 3.2 4.0 1.9

CCIM NA 2 - 4 6 0.13 0.45 0.435 0.245 0.27 0.14

1 Highest Average Field Trial.

2

For residue values <LOQ, half of the LOQ (0.005 ppm) was used to calculate the median, mean, HAFT, and 

standard deviation.

3 Not Applicable.
Page 19 of 40

The submitted crop field trials are adequate to support the proposed minor uses. The studies 

were conducted consistently with standard agricultural practices as per proposed use pattern. 

The number and geographic distribution of the supervised crop field trials are adequate.

Tolerances

HED recommends modification of the tolerance expression for cyazofamid according to the new 

compliance/measurement policy (Interim Guidance on Tolerance Expressions, Steve Knizner,

05/27/2009) to read as follows:

“HED recommends that the tolerance definition entry in 40 CFR §180.601 be revised as follows: 

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

metabolites and degradates, in or on the commodities in the table below. Compliance with the 

tolerance levels specified below is to be determined by measuring only the sum of 4-chloro-2-

cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonamide and its metabolite, 4-

chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile, calculated as the stoichiometric 

equivalent of cyazofamid, in or on the commodity.”

The Agency’s SOP “Guidelines for Setting Pesticide Tolerances Based on Field Trial Data” was 

utilized for determining the appropriate tolerance level for each commodity. 

As the minimum and maximum recommended tolerances differ by less than 5X, a crop group 

tolerance is appropriate for the Brassica head and stem, crop subgroup 5A. Although cabbage 

belongs to both crop subgroup 5A and 5B, the tolerance of 12.0 ppm is appropriate for Brassica, 

leafy greens, crop subgroup 5B based on mustard greens, the representative crop. 

HED has concluded that turnip greens will be moved from the leaves of root and tuber 

vegetables crop group (group 2) to the Brassica leafy vegetables crop group 5, subgroup 5B: 

(memorandum, B. Schneider, 6/14/2002). However, until the regulations have been finalized in 

the Federal Register, a separate tolerance is needed for turnip greens at the same level as the 

Brassica, leafy greens, crop subgroup 5B at 12.0 ppm.

The recommended tolerances for spinach and hops are 9 ppm and 10.0 ppm, respectively. The 

recommended tolerances are listed in Table 4.3b.
Page 20 of 40

Table 4.3b. Tolerance Summary for Cyazofamid.

Commodity Proposed 

Tolerance 

(ppm

Existing 

Tolerance 

(ppm)

Recommended 

Tolerance 

(ppm)

Comments; Correct Commodity Definition

40 CFR 180.601 (a)

Brassica, head & stem, 

crop subgroup 5A 1.2 1.2

Brassica, leafy greens, 

crop subgroup 5B

12.0 12.0

Hops 10.0 10.0

Spinach 9.0 9.0

Turnip greens 12.0 12.0 Until the regulations have been finalized in 

the Federal Register to move turnip greens 

from the leaves of root and tuber vegetables 

crop group (group 2) to the Brassica leafy 

greens subgroup 5B, a separate tolerance is 

needed at the same level as the Brassica, 

Leafy Greens, Subgroup 5B.1

1Memorandum, B. Schneider, 6/14/2002.

4.4 International Residue Limits

Canada has established MRLs for residues of cyazofamid in/on several commodities, but has not 

established maximum residue limits for the commodities of this petition. No MRLs for residues 

of cyazofamid have been established by the Codex Alimentarius Commission. 

4.5 Drinking Water Residue Profile

Reference: 

- Estimated Drinking Water Concentrations of Parent Cyazofamid and its Degradates of Concern CCIM, CCIMAM and CTCA, for Use in Human Health Risk Assessment: New Uses on Brassica (Cole) Leafy Vegetables &

Turnip Greens (Crop Group 5), Spinach, and Hops. DP#370673, José L. Meléndez, 03/01/2010.

The Agency used screening-level water exposure models in the dietary exposure analysis and 

risk assessment for cyazofamid in drinking water. These simulation models take into account 

data on the physical, chemical, and fate/transport characteristics of cyazofamid. The Tier 2 

linked PRZM/EXAMS models were used in predicting the surface water concentrations, and the 

Tier 1 regression model SCI-GROW was used in predicting ground water concentrations. The 

primary use of these models by the Agency at this stage is to provide a coarse screen for 

determining that pesticide residues (and metabolites) in water are not of concern. Further 

information regarding EPA drinking water models used in pesticide exposure assessment can be 

found at: http://www.epa.gov/oppefed1/models/water/. 

Environmental 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; see Appendix A), and CTCA (4-chloro-5-p-tolylimidazole-2-

carboxylic acid; see Appendix A) are considered to be the major residues in water and should be 

included in the drinking water risk assessment. Among the three major degradates for 
Page 21 of 40

cyazofamid (CCIM, CCIM-AM and CTCA), the two terminal ones are CCIM and CTCA. 

CCIM is expected to be the major terminal degradate in water bodies with low biological activity

because it 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. 

Estimated Drinking Water Concentrations (EDWCs)

The screening level surface water and ground water concentrations were estimated using linked 

PRZM/EXAMS models and the SCI-GROW model, respectively. The maximum EDWCs that 

may occur are due to the use of cyazofamid on turf and ornamentals, and are presented in Table 

4.5 for the following scenarios:

1. The parent, assuming application of the maximum rate as parent;

2. Each of the degradates CCIM, CCIM-AM, and CTCA, assuming application 

of the molar equivalent of the parent for each of the degradates by dividing the 

rate between the degradates based on molecular ratios and adjusted 

maximums found in fate studies; and

3. The terminal degradate CTCA, assuming application of 100% molar 

conversion of the parent into this terminal degradate CTCA.

Table 4.5. Maximum Surface/Ground Water EDWCs for Cyazofamid and each of its Major 

Degradates (from use on Turf and Ornamentals).

Scenario Chemical

Surface water EDWCs (ppb)

Ground Water 

EDWC (ppb)

Acute 

(1-in-10 yr. peak)

Chronic

(1-in-10 yr. mean)

1

st

 Scenario Parent 14.4 0.38 0.012

2

nd

 Scenario 

CCIM 17.1 12.1 0.00061

CCIM-AM 6.7 6.3 0.0027

CTCA 16.7 11.0 0.52

3

rd

 Scenario CTCA 136 133 2.18

The highest acute (peak) and chronic (mean) EDWCs were estimated for surface water using the 

PRZM/EXAMS model. For the purpose of this Tier 1 dietary assessment, HED used the highest 

calculated screening EDWCs for surface water based on the 3

rd modeling scenario: 136 ppb for 

the acute analysis and 133 ppb for the chronic analysis. This approach may significantly 

overestimate dietary exposure to cyazofamid from drinking water. 

4.6 Dietary Exposure and Risk

Reference: 

- Cyazofamid: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments 

for an IR-4 Proposed Section 3 Registration Amendment to Add Uses in/on Fruiting Vegetables, Okra, and 

Grapes. DP#357043, Amelia Acierto, 03/25/2009.
Page 22 of 40

Cyazofamid acute and chronic dietary exposure assessments were conducted using the Dietary

Exposure Evaluation Model software with the Food Commodity Intake Database (DEEMFCIDTM, Version 2.03), which incorporates consumption data from USDA’s Continuing Surveys 

of Food Intakes by Individuals (CSFII), 1994-1996 and 1998. The 1994-96, 98 data are based on 

the reported consumption of more than 20,000 individuals over two non-consecutive survey

days. Foods “as consumed” (e.g. apple pie) are linked to EPA-defined food commodities (e.g. 

apples, peeled fruit - cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S, baked) 

using publicly available recipe translation files developed jointly by USDA/ARS and EPA. For 

chronic exposure assessment, consumption data are averaged for the entire U.S. population and 

within population subgroups, but for acute exposure assessment are retained as individual 

consumption events. Based on analysis of the 1994-96, 98 CSFII consumption data, which took 

into account dietary patterns and survey respondents, HED concluded that it is most appropriate 

to report risk for the following population subgroups: the general U.S. population, all infants (<1 

year old), children 1-2, children 3-5, children 6-12, youth 13-19, adults 20-49, females 13-49, 

and adults 50+ years old.

For both the acute and chronic analyses, the drinking water EDWC was incorporated directly as 

a point estimate in the DEEM analysis to assess exposure to cyazofamid from drinking water.

Acute Dietary Exposure and Risk

For acute exposure assessments, individual one-day food consumption data are used on an 

individual-by-individual basis. The reported consumption amounts of each food item can be 

multiplied by a residue point estimate and summed to obtain a total daily pesticide exposure for a 

deterministic exposure assessment, or “matched” in multiple random pairings with residue values 

and then summed in a probabilistic assessment. The resulting distribution of exposures is 

expressed as a percentage of the aPAD on both a user (i.e. only those who reported eating 

relevant commodities/food forms) and a per-capita (i.e. those who reported eating the relevant 

commodities as well as those who did not) basis. In accordance with HED policy, per capita 

exposure and risk are reported for all tiers of analysis. However, for unrefined and less refined 

assessments, any significant differences in user vs. per capita exposure and risk are specifically 

identified and noted in the risk assessment.

Since an acute endpoint was not identified for the general population including infants and 

children and the FQPA SF has been reduced to 1X, the acute population-adjusted-dose or acute 

PAD is equal to the acute RfD. The acute PAD was used for assessing acute dietary risk.

An acute dietary exposure analysis (food + drinking water) was conducted via DEEM-FCIDTM 

for cyazofamid for females 13-49 years old only, since an acute endpoint of concern was not 

identified for the general U.S. population. Based on the assumptions of tolerance-level residues 

(all processing factors set to 1X, based on the results of processing studies), 100% crop-treated, 

and screening-level EDWCs, acute dietary exposure of females 13-49 years old is well below 

HED’s LOC (i.e. <100% of the aPAD of 1.0 mg/kg). The combined dietary exposure from food 

and drinking water is estimated at 0.01214 mg/kg/day (equivalent to 1.2% of the aPAD) at the 

95th percentile of exposure, the appropriate regulatory statistic for dietary assessments. It is 

noted that estimated acute dietary exposure of females 13-49 years old is also well below HED’s 

LOC at the 99th and 99.9th percentiles, as shown in Table 4.6a.
Page 23 of 40

Table 4.6a. Results of Acute Dietary Exposure Analysis for Food and Drinking Water at the 95th

Percentile of Exposure using DEEM FCID.

Population 

Subgroup

aPAD 

(mg/kg/day)

95th Percentile 99th Percentile 99.9th Percentile

Exposure 

(mg/kg/day)

% 

aPAD

Exposure 

(mg/kg/day)

% 

aPAD

Exposure 

(mg/kg/day)

% 

aPAD

Females 13-49 

years old 1.0 0.01214 1.2 0.02448 2.5 0.05974 6.0

Chronic Dietary Exposure and Risk

For chronic dietary exposure assessments, an estimate of the residue level in each food or foodform (e.g. orange or orange juice) on the food commodity residue list is multiplied by the 

average daily consumption estimate for that food/food form to produce a residue intake estimate. 

The resulting residue intake estimate for each food/food form is summed with the residue intake 

estimates for all other food/food forms on the commodity residue list to arrive at the total 

average estimated exposure. Exposure is expressed in mg/kg body weight/day and as a percent 

of the cPAD. This procedure is performed for each population subgroup.

The chronic RfD of 0.95 mg/kg/day is derived from a NOAEL of 94.8 mg/kg/day based on 

increased incidence of skin lesions in males at 985 mg/kg/day (LOAEL) in the mouse 

carcinogenicity study. A 100-fold uncertainty factor (10X interspecies extrapolation and 10X 

intraspecies variability) is required. Since the FQPA SF has been reduced to 1X, the chronic 

PAD is equal to the chronic RfD. The chronic PAD was used for assessing chronic risk.

A chronic dietary exposure analysis was conducted via DEEM-FCIDTM for cyazofamid. The 

assumptions of this dietary exposure assessment are tolerance-level residues (all processing 

factors set to 1X, based on the results of processing studies), 100% crop-treated, and screeninglevel EDWC. Cyazofamid chronic dietary (food + drinking water) exposure estimates are well 

below HED’s LOC for the general U.S. population and each of the population subgroups, as 

shown in Table 4.6b. Dietary exposure was estimated at 0.004945 mg/kg/day for the general 

U.S. population (<1% of the cPAD) and 0.011079 mg/kg/day (1.2% of the cPAD) for the most 

highly exposed population subgroup (infants <1 year old). 

Table 4.6b. Summary of Chronic Dietary Exposure and Risk for Cyazofamid.

1

Population Subgroup

Exposure

(mg/kg/day)

% cPAD

General U.S. Population 0.004945 <1

All Infants (< 1 year old)10.011079 1.2

Children 1-2 years old 0.010749 1

Children 3-5 years old 0.008556 <1

Children 6-12 years old 0.004916 <1
Page 24 of 40

Table 4.6b. Summary of Chronic Dietary Exposure and Risk for Cyazofamid.

1

Population Subgroup

Exposure

(mg/kg/day)

% cPAD

Youth 13-19 years old 0.003393 <1

Adults 20-49 years old 0.004351 <1

Adults 50+ years old 0.004884 <1

Females 13-49 years old 0.004302 <1

1 The population subgroup with the highest estimated chronic dietary (food + drinking water)

 exposure and risk is indicated by bold text.

4.7 Cancer Dietary Exposure and Risk

A cancer dietary assessment was not conducted because cyazofamid has been classified as “not 

likely to be carcinogenic to humans.”

5.0 NON-OCCUPATIONAL/RESIDENTIAL EXPOSURE/RISK PATHWAY

References: 

- Cyazofamid. Occupational and Residential Exposure Assessment for Section 3 Registration of Cyazofamid for 

Commercial Use on Residential Turf and Ornamentals. DP#365261, Nancy J. Tsaur, 03/27/2009.

- Occupational and Residential Risk Assessment to Support Request for Registration of Cyazofamid on NonResidential Turf and Ornamentals. DP#332425, Kelly O’Rourke, 10/12/2006.

This document presents the assessment of proposed agricultural uses of cyazofamid. No 

residential uses are being requested at this time; therefore, no residential handler exposure and 

risk assessment has been conducted in this document. Cyazofamid is currently commercially

registered to treat pythium diseases on residential turf and pythium, phytophthora and downy

mildew diseases on ornamental plants in residential landscapes (DP#365261, N. Tsaur, 

03/27/2009). In addition, cyazofamid is commercially registered to treat pythium and downy

mildew diseases on professionally managed turf areas, and pythium, phytophthora, and downy

mildew diseases on ornamental plants in landscapes and in commercial greenhouses and 

nurseries (DP#332425, K. O’Rourke, 10/12/2006). 

Application of cyazofamid by home-owners to residential turf is prohibited by the label. 

However, residential exposure for both adults and children 3 to <6 years old are expected 

following commercial application on residential turf and ornamentals. The dermal post 

application MOE for adults was found to be 1,100. Since the MOE is greater than 100, it is not 

of risk concern for HED. Postapplication exposure for children was analyzed and found to be 

1,600, which is greater than 100, and not of risk concern to HED (DP#365261, N. Tsaur, 

03/27/2009).

Post application exposure was also analyzed for recreational golfers or players of various sports 

who use turf areas following cyazofamid exposure. The dermal MOEs for postapplication 

exposure for recreational golfers or sports players were greater than 100 (330 to 14,000) and,

therefore, are not of risk concern to HED (DP#332425, K. O’Rourke, 10/12/2006).
Page 25 of 40

Based on the currently registered uses of cyazofamid and past ORE assessments, there are no 

residential risk concerns to the Agency of cyazofamid exposure. Table 5.0 summarizes 

children’s aggregate exposure and risk estimates previously calculated from residential lawns

(DP#365261, N. Tsaur, 3/27/2009).

Table 5.0. Children’s Aggregate Exposure and Risk Estimates from Residential Lawns.

Children’s Scenarios TTR/GR/SR0

(ug/cm2or g) 1

PDR0-norm

(mg/kg/day) 2

Short-Term 

MOE 3

Total

Short-Term MOE 4

(1) Hand-to-Mouth 0.57 0.015 2,000

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

(3) Soil Ingestion 7.66 0.000051 590,000

1 TTR=turf transferable residue on day “0"; GR=grass residue on day “0"; SR0=soil residue on day “0".

2

PDR0norm=potential dose rate on day “0”.

3 MOE = NOAEL/PDR; where Short-/Intermediate-term NOAELIncidental Oral = 30 mg/kg/day.

4 Total MOE = 1/ [(1/MOEHand-to-Mouth) + (1/MOEGrass) + (1/MOESoil)]

Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for cyazofamid. The 

Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices. The Agency is now requiring interim mitigation measures for aerial 

applications that must be placed on product labels/labeling. The Agency has completed its 

evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. 

pesticide registrants, and is developing a policy on how to appropriately apply the data and the 

AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast,

and ground hydraulic methods. After the policy is in place, the Agency may impose further 

refinements in spray drift management practices to reduce off-target drift and risks associated 

with aerial as well as other application types where appropriate. 

Note: As indicated in this assessment, cyazofamid is directly applied to residential lawns and 

ornamentals and does not result in exposures of concern. It is unlikely that the potential for risk 

of exposure to spray drift from these uses would be higher than that estimated for contact with 

treated turf.

6.0 AGGREGATE RISK ASSESSMENTS and RISK CHARACTERIZATION

Aggregate exposure risk assessments were performed for the following scenarios: acute 

aggregate exposure (food + drinking water), short-/intermediate-term aggregate exposure (food + 

residential exposure + drinking water), and chronic aggregate exposure (food + drinking water). 

A cancer aggregate risk assessment was not performed because cyazofamid is classified as “not 

likely to be carcinogenic to humans”. All potential exposure pathways were assessed in the 

aggregate risk assessment. Dietary (food and drinking water) and residential exposures were 

considered, as necessary, because there is a potential for individuals to be exposed concurrently 
Page 26 of 40

through these routes.

6.1 Acute Aggregate Risk Assessment (Food and Drinking Water)

An acute aggregate risk assessment is required for the population subgroup of concern, females 

13-49 years old. An appropriate endpoint for the general population was not identified; 

therefore, a corresponding assessment is not required. For the population of concern, the acute 

dietary (food and drinking water) risk assessment reported in Section 4.6 represents acute 

aggregate risk. The dietary route alone is relevant for acute exposure and risk assessment.

6.2 Short- and Intermediate-Term Aggregate Risk Assessment

The short-/intermediate-term aggregate risk assessment estimates that risks are likely to result 

from exposure to cyazofamid residues from food, drinking water, and residential pesticide uses. 

Short-term and intermediate-term risks have been assessed together because both scenarios have 

the same endpoints and PODs. High-end estimates of residential exposure are used, while 

average values are used for food and drinking water exposure (i.e. chronic exposures).

A short-/intermediate-term risk assessment is required for adults and children because there are 

potential postapplication exposures from the use on residential lawns and ornamentals. The 

results of the short/intermediate-term aggregate assessments are presented in Table 6.2. HED is 

generally not concerned if the MOEs remain above the LOC, which for this assessment, is 100. 

The MOEs for all scenarios are ≥ 100, and therefore, are not of concern to the Agency.

Table 6.2. Short-Term and/or Intermediate-Term Aggregate Risk Calculations.

Population

Short- or Intermediate-Term Scenario

LOC for 

Aggregate

Risk1

MOE

food & water2

MOE

oral3

MOE

dermal4

MOE 

inhalation5

Aggregate MOE

(food and 

residential)

6

General U.S. 

Population

100

20,000 NA 1,100 NA 1,000

Children 3-5 

years old 12,000 1,600 NA NA 1,400

Children 6-12 

years old 20,000 1,600 NA NA 1,500

1 LOC is an MOE = 100.

2 MOE food = [(short- or intermediate-term oral NOAEL)/(chronic dietary exposure)], NOAEL = 100 mg/kg/day

(See Table 4.6b for dietary exposure).

3 MOE oral = [(short- or intermediate-term oral NOAEL)/(hand-to-mouth residential exposure)] NOAEL = 30

mg/kg/day (See Table 5.0 for children’s oral exposure).

4 MOE dermal = [(short- or intermediate-term dermal NOAEL)/(high-end dermal residential exposure)] NOAEL = 

100 mg/kg/day (See DP#356837, Table 5.2.2).

5 MOE inhalation is not applicable for postapplication activities.

6 Aggregate MOE (food and residential) = 1/ [(1/MOEFood) + (1/MOEOral) + (1/MOEDermal) + (1/MOEInhalation)]
Page 27 of 40

6.3 Chronic Aggregate Risk Assessment (Food and Drinking Water)

The chronic aggregate risk assessment takes into account average exposure estimates from 

dietary consumption of cyazofamid (food and drinking water) and residential uses. Based on the 

cyazofamid use pattern, no long-term residential exposures are expected. Therefore, the chronic 

aggregate risk assessment is based on exposure from food and drinking water only, as presented 

previously in this memorandum (Section 4.6). 

6.4 Cancer Aggregate Risk Assessment

HED classified cyazofamid as “not likely to be carcinogenic to humans”. Thus, an aggregate 

cancer risk assessment was not performed for cyazofamid.

7.0 CUMULATIVE RISK

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to cyazofamid and any other substances and cyazofamid does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that cyazofamid has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

8.0 OCCUPATIONAL EXPOSURE

Reference: 

- Amendment: Cyazofamid: Occupational and Residential Exposure Assessment for Proposed Field Uses of 

Cyazofamid on Brassica Leafy Vegetables, Turnip Greens, Spinach and Hops. DP#377618, Kristin Rury, 

04/06/2010.

Cyazofamid can be applied to Brassica leafy vegetables, turnip greens, and spinach using 

groundboom, aerial, and chemigation application equipment. Additionally, cyazofamid can be 

applied to hops with airblast equipment. Workers may be exposed to cyazofamid during mixing, 

loading, application, and postapplication activities. Based on the proposed application regimen, 

short-/intermediate-term exposure may occur. Chronic exposure (greater than or equal to 6 

months of continuous exposure) is not expected.

8.1 Occupational Handler Exposure and Risk

No chemical-specific handler exposure data were submitted in support of this registration for the 

IR-4 petition (PP#9E7615) for tolerances on Brassica (cole) leafy vegetable crop group (CG 5), 

turnip greens, spinach, and hops. It is the policy of HED to use data from PHED Version 1.1 as 

presented in PHED Surrogate Exposure Guide (8/98) to assess handler exposures for regulatory

actions when chemical-specific monitoring data are not available (HED ExpoSAC SOP #7, dated 

1/28/99).
Page 28 of 40

The results of the handler occupational exposure and risk assessment for the proposed 

agricultural uses indicate that risks are not of concern with baseline clothing, or when gloves are 

worn. The total short/intermediate-term MOEs range from 23,000 to 220,000; which are greater 

than the LOC of 100, and are not of concern to HED. Exposure assumptions and MOEs for 

occupational handlers of Ranman® 400SC are summarized in Table 8.1a.

The average adult body weight of 60 kg was used for estimating dermal and inhalation dose, 

since the selected toxicological endpoint is based on developmental effects (females 13+ years 

old). Since the short- and intermediate-term dermal endpoint was based on an oral study, a 

dermal absorption factor of 37% and an inhalation absorption factor of 100% were used to 

estimate dermal exposure for short-and intermediate-term durations. 

HED’s LOC for the MOE is defined by the uncertainty factors that are applied to the assessment. 

HED applies a 10X factor to account for interspecies extrapolation and a 10X factor to account 

for intraspecies sensitivity. The total uncertainty factor that has been applied to the non-cancer 

risk assessment for cyazofamid is 100 for occupational exposure. Occupational exposure and 

risk resulting in MOEs greater than or equal to 100 will not be of concern to HED.

Summaries of the risks for occupational handlers are included in Table 8.1. The maximum 

application rate for each exposure scenario is presented as the worst case scenario. All handler 

scenarios resulted in combined dermal and inhalation MOEs greater than the LOC (MOEs ≥ 100) 

at some level of risk mitigation. 

The inhalation risks to handlers are not a concern at baseline (no respirator) for any of the 

handler scenarios where baseline data are available. Only engineering control (enclosed cockpit) 

data are available to assess inhalation risks to handlers operating aircraft. The inhalation risks 

are not a concern for pilots using enclosed cockpits and wearing no respirator.

The dermal and combined (dermal and inhalation) risks to handlers are not a concern with 

baseline attire (i.e. long-sleeved shirt, long pants, shoes, and socks) where baseline data are 

available. Only engineering control (enclosed cockpit) data are available to assess dermal (and 

therefore combined risks) to handlers operating aircraft. The dermal and combined risks are not 

a concern for pilots using enclosed cockpits and wearing baseline attire. Also, only baseline plus 

chemical-resistant glove data are available to assess dermal risks (and therefore combined risks) 

to handlers mixing/loading/applying with handgun equipment. The dermal and combined risks 

are not a concern for these scenarios when baseline attire is worn with the addition of chemicalresistant gloves.

The minimum level of personal protective equipment (PPE) for handlers is based on acute 

toxicity for the end-use products. RD is responsible for ensuring that PPE listed on the label is in 

compliance with WPS.
Page 29 of 40

Table 8.1. Agricultural Handler Exposure and Risk for Cyazofamid.

Exposure Scenario Crop or Target

App 

Ratea

(lb 

ai/A)

Acres 

Treated 

Dailyb

Unit Exposurec Dose (mg/kg/Day) MOEs

Baseline 

Dermal 

(mg/lb 

ai)

PPE-G 

Dermal 

(mg/lb 

ai)

Baseline 

inhalation 

(μg/lb ai)

Baseline 

Dermald,h

PPE-G 

Dermali

Baseline 

Inhalatione

Baseline 

Dermalf

PPE-G 

Dermal

Baseline 

Inhalationg

Combined 

Baseline 

Dermal + 

Inhalationj

Combined 

PPE-G + 

Baseline 

Inhalationk

Mixer/Loader

Mixing/Loading to 

Support Aerial 

Treatments

Brassica Leafy 

Vegetables, 

Turnip Greens

0.072 350 2.9 0.023 1.2 0.45 0.004 0.000504 220 28,000 198,000 220 24,000

Spinach, Hops 0.071 350 2.9 0.023 1.2 0.44 0.004 0.000497 230 28,400 201,000 220 25,000

Mixing/Loading to 

Support Chemigation 

Treatments

Brassica Leafy 

Vegetables, 

Turnip Greens

0.072 350 2.9 0.023 1.2 0.45 0.004 0.000504 220 28,000 198,000 220 24,000

Spinach 0.071 350 2.9 0.023 1.2 0.44 0.004 0.000497 230 28,400 201,000 220 25,000

Mixing/Loading to 

Support Groundboom 

Applications

Brassica Leafy 

Vegetables, 

Turnip Greens

0.52 80 2.9 0.023 1.2 0.74 0.006 0.000832 130 17,000 120,000 130 15,000

Spinach 0.071 80 2.9 0.023 1.2 0.10 0.00081 0.00011 980 124,000 880,000 980 110,000

Mixing/Loading to 

Support Airblast 

Applications

Hops 0.071 40 2.9 0.023 1.2 0.051 0.00040 0.000057 2,000 245,000 1,760,000 2,000 220,000

Applicator

Applying Sprays via 

Aerial Equipment

Brassica Leafy 

Vegetables, 

Turnip Greens

0.072 350 0.005 no data 0.068 0.00078 No Data 0.000029 128,700 N/A 3,501,000 120,000 No Data

Spinach, Hops 0.071 350 0.005 no data 0.068 0.0077 No Data 0.0000028 131,000 N/A 3,551,000 130,000 No Data

Applying Sprays via 

Groundboom Equipment

Brassica Leafy 

Vegetables, 

Turnip Greens

0.52 80 0.014 0.014 0.74 0.0036 0.0036 0.001 28,000 28,000 195,000 24,000 24,000

Spinach 0.071 80 0.014 0.014 0.74 0.00049 0.00049 0.000070 204,000 204,000 1,427,000 180,000 180,000

Applying Sprays via 

Airblast Applications Hops 0.071 40 0.36 0.24 1.5 0.0063 0.0042 0.000071 15,900 23,800 1,400,000 16,000 23,000

Flagger

Flagging for Aerial 

Sprays

Brassica Leafy 

Vegetables, 

Turnip Greens

0.072 350 0.011 0.012 0.35 0.0017 0.0018 0.00014 59,000 54,400 690,000 55,000 50,000

Spinach, Hops 0.071 350 0.011 0.012 0.35 0.0017 0.0019 0.00015 58,500 53,600 680,000 54,000 50,000
Page 30 of 40

a Application Rates based on proposed uses for cyazofamid product Ranman® 400SCTM (EPA Registration No. 71512-3).

b Exposure Science Advisory Council Policy # 9.1 (when rates given in gallons 40 gal/day ÷ 100 gal/A = 0.4 A/day).

c Unit Exposures based on PHED Version 1.1. Engineering control unit exposure for applying sprays via aerial equipment = 

enclosed cockpit.

d Dermal Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x application rate (lb ai/acre) x acres treated x dermal absorption 

factor (37%) / body weight (60 kg adult female).

e Inhalation Dose (mg/kg/day) daily unit exposure (μg/lb ai) x application rate (lb ai/acre) x acres treated x inhalation 

absorption (100%) / body weight (60 kg adult female). 

f Dermal MOE = NOAEL (100 mg/kg/day) / dermal daily dose (mg/kg/day). Level of concern = 100.

g Inhalation MOE = NOAEL (100 mg/kg/day) / inhalation daily dose (mg/kg/day). Level of concern = 100.

h Baseline Dermal: long-sleeved shirt, long pants, and no gloves; Baseline Inhalation: no respirator.

i Baseline plus Gloves Dermal: Baseline plus chemical-resistant gloves.

j Combined Baseline Dermal + Inhalation MOE = 1 / (1/Baseline Dermal MOE) + (1/Baseline Inhalation MOE).

k Combined PPE-G + Baseline Inhalation MOE = 1 / (1/PPE-G Dermal MOE) + (1/Baseline Inhalation MOE). Those risks 

specified as engineering control represent enclosed cockpit application

l The higher application rate of 0.52 lb ai/A is due to soil incorporation for Brassica leafy vegetables and turnip greens.

8.2 Occupational Postapplication Exposure and Risk

The proposed agricultural uses of cyazofamid on Brassica (cole) leafy vegetables, turnip greens, 

spinach, and hops involve various postapplication activities including hand harvesting, hand 

pruning, thinning, training, tying, etc. Workers performing typical postapplication activities may

receive exposure to cyazofamid residues. 

The cyazofamid technical material has been classified in Toxicity Category III for acute dermal 

and primary skin irritation, and Category IV for primary eye irritation. Per WPS, a 12-hr REI is 

required for chemicals classified under Toxicity Category III/IV. Based on the postapplication 

dermal risk estimates, the labeled 12-hr REI is protective of re-entry workers. Cyazofamid is 

also intended for non-agricultural use sites to which the WPS does not apply, and correctly 

contains language cautioning unprotected persons to keep out of treated areas until sprays have 

dried.

Dermal: Chemical-specific dislodgeable foliar residue (DFR) studies on tomatoes 

(MRID#45409118), grapes (MRID#45409118) and squash (MRID#45409119) were submitted 

for a previous action on cyazofamid. These studies were reviewed and found to be acceptable 

for risk assessment purposes (D285682, K. O’Rourke, 3/23/04). A summary of each study is 

provided below. In addition to the DFR data, maximum dermal transfer coefficients from 

ExpoSAC SOP #3.1 (Agricultural Transfer Coefficients, August 2000) and the following 

assumptions were used in the postapplication assessment:

 Max Application Rate= 0.52 lb ai/A for Brassica leafy vegetable soil incorporation

at transplanting, 0.071 lb ai/A for spinach and hops.

 Exposure Duration = 8 hours per day,

 Body Weight = 60 kg for adult female, and 

 Dermal Absorption = 37%.

The postapplication exposure associated with agricultural crops is summarized in Table 8.2. All 

scenarios resulted in MOEs greater than 100 on day 0 (12 hours after application) and, therefore,

are not of concern to HED.
Page 31 of 40

Table 8.2. Postapplication Exposure and Risk for Cyazofamid.

Crop 

Grouping/

Crop

Activity

Proposed 

Application 

Rate

(lb ai/A)

Transfer 

Coefficient

(cm2/hr)

Days 

After 

Treatment

ChemicalSpecific 

DFR Data

Normalized 

DFR 

(ug/cm2)

1

Daily 

Dermal 

Dose 

(mg/kg/day)2

MOE3

(LOC = 100)

Brassica

Leafy 

Vegetables, 

Turnip Greens

Thinning, Hand Pruning, 

Irrigation, Hand 

Harvesting, Topping, 

Thinning, Tying

0.52 5000 0

Tomato 

DFR 0.017 0.004 23,000

Spinach Hand Harvesting, Hand 

Pruning, Thinning 0.071 2500 0

Tomato 

DFR 0.128 0.016 6,300

Hops

Hand Harvesting, 

Mechanical Harvesting, 

Stripping, Training

0.071 2000 0

Grape 

DFR 0.160 0.016 6,300

1 DFR values were obtained from the DFR studies: 

Tomato DFR: average measured value from “Day 3" was used as a surrogate for Day 0 because it was higher than both 

the predicted and measured Day 0 values. The DFR was adjusted for the difference in application rate 

used in the study (i.e. 0.071 lb ai/A compared to the maximum 0.078 lb ai/A rate proposed for fruiting 

vegetables and okra), and

Grape DFR: average measured Day 0 value from the grape DFR data was used - with an adjustment for the difference 

in application rate used in the study (i.e. 0.089 lb ai/A compared to the maximum 0.071 lb ai/A rate 

proposed for grapes).

2 Daily Dermal Dose = [DFR (μg/cm2

) x Tc x 0.001 mg/μg x 8 hrs/day x DA]  (body weight (60 kg adult female)).

3 MOE = NOAEL/Daily Dose (Adult Dermal NOAEL = 100 mg/kg/day).

9.0 DATA NEEDS AND LABEL RECOMMENDATIONS

9.1 Chemistry

860.1550 Proposed Tolerances: The petitioner should submit a revised Section F reflecting the 

recommended tolerances and commodity definitions presented in Table 4.3b.

9.2 Toxicology

 Based on the available toxicity database and the Agency's current practices, the inhalation 

risk for cyazofamid was assessed using an oral toxicity study. The Agency sought expert 

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

oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, 

and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency

received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in 

the process of evaluating the SAP report and may, as appropriate, reexamine and develop 

new policies and procedures for conducting inhalation risk assessments, including route to 

route extrapolation of toxicity data. If any new policies or procedures are developed, the 

Agency may revisit the need for an inhalation toxicity study for cyazofamid and/or a 

reexamination of the inhalation toxicity risk assessment.

 As part of the new 40 CFR §158 Guidelines, a functional immunotoxicity study in rats and/or 

mice is required (Guideline 870.7800); see Appendix D.

 As part of the new 40 CFR §158 Guidelines, a subchronic neurotoxicity study is required

(Guideline 870.6200); see Appendix E.
Page 32 of 40

APPENDIX A. Codes, Chemical Names, and Chemical Structure of Cyazofamid and 

Identified Metabolites

Table A. Identification of Compounds from the Cyazofamid Metabolism Studies.

Common name/ 

code/matrix

Chemical name Chemical structure

Cyazofamid/

IKF-916

4-chloro-2-cyano-N,N-dimethyl-5-(4-

methylphenyl)-1H-imidazole-1-sulfonamide

N

N

H3C

Cl

CN

SO2N(CH3)

2

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

N

H

N

H C3

Cl

CN

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

acid

N

H

N

Cl

CN

HO

O

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

N

H

N

H C3

Cl

O

NH2

CTCA 4-chloro-5-p-tolylimidazole-2-carboxylic acid
Page 33 of 40

APPENDIX B. International Residue Limit Status

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name: 4-

Chloro-2-cyano-N,Ndimethyl-5-(4-

methylphenyl)-1Himidazole-1-sulfonamide

Common Name:

Cyazofamid

□ Proposed tolerance

□ Reevaluated tolerance

X Other Recommended

Date: 03/06/2010

Codex Status (Maximum Residue Limits) U. S. Tolerances

√ No Codex proposal step 6 or above

□ No Codex proposal step 6 or above for the crops 

requested

Petition Number: PP#9E7615

DP#: 371163

Other Identifier: 

Residue definition (step 8/CXL): N/A Reviewer/Branch: A.Acierto/RAB3

Residue definition: Combined residues of cyazofamid, 

4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-

1H-imidazole-1-sulfonamide and its metabolite, CCIM, 

4-chloro-5-(4-methylphenyl)-1H-imidazole-2-

carbonitrile, expressed as cyazofamid 

Crop (s) MRL (mg/kg) Crop(s) Tolerance (ppm)

Brassica, head & stem, crop 

subgroup 5A

1.2

Brassica, leafy greens, crop 

subgroup 5B

12.0

Turnip greens 12.0

Spinach 9.0

Hops 10.0

Limits for Canada Limits for Mexico

□ No Limits

√ No Limits for the crops requested

√ No Limits

□ No Limits for the crops requested

Residue definition: 4-chloro-2-cyano-N,N-dimethyl-5-

(4-methylphenyl)-1H-imidazole-1-sulfonamide, 

including the metabolite 4-chloro-5-(4-methylphenyl)-

1H-imidazole-2-carbonitrile 

Residue definition: N/A

Mexico adopts Codex MRLs or US tolerances for its 

export purposes.

Crop(s) MRL (mg/kg) Crop(s) MRL (mg/kg)

Notes/Special Instructions:

S. Funk, 03/06/2010
Page 34 of 40

APPENDIX C.1. Toxicity Profile of Cyazofamid Technical

Table C.1. Toxicity Profile of Cyazofamid [IKF-916] Technical.

Guideline No./

Study Type

MRID No. (year)/

Classification/Doses Results

870.3100

28-Day dose-range 

finding study in rats

45408927

0, 50, 500, 5000, & 20,000 ppm

Male: 0, 3.8, 38.5, 370, & 1488 

mg/kg/day

Female: 0, 3.6, 37.1, 389, & 1535 

mg/kg/day

NOAEL = 38.5 [M] mg/kg/day

LOAEL = 370 [M] mg/kg/day based on increased 

number of basophilic tubules was noted in the 

kidneys of males.

870.3100

90-Day oral toxicity in 

rats

45408928 (1999)

Acceptable/guideline

Males: 0, 10, 50, 500, or 5,000 ppm 

0, 0.6, 2.9, 29.5, or 294.5 mg/kg/day 

Females: 0, 50, 500, 5,000, or 20,000 

ppm 0, 3.3, 33.3, 337.6, or 1,359.0 

mg/kg/day

NOAEL = 29.5 [M] mg/kg/day

LOAEL = 295 [M] mg/kg/day based on increased 

number of “basophilic kidney tubules,” and 

increased urinary volume, pH, and protein.

870.3100

90-Day oral toxicity in 

mice

Study not available. Study not available.

870.3150

90-Day oral toxicity in 

dogs

45408929 (2001)

Acceptable/guideline

0, 40, 200, or 1,000 mg/kg/day

NOAEL = 1,000 [M/F] mg/kg/day

LOAEL = not observed.

870.3200

28-Day dermal toxicity 

in rats

45408930 (1997)

Acceptable/guideline

0, 250, 500, or 1,000 mg/kg/day

NOAEL = 1,000 [M/F] mg/kg/day

LOAEL = not observed.

870.3250

90-Day dermal toxicity

Study not available.

870.3465

90-Day inhalation 

toxicity

Study not available.

870.3700a

Prenatal developmental 

in rats

45430404 (1999)

Acceptable/guideline

0, 30, 100, or 1,000 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.
Page 35 of 40

Table C.1. Toxicity Profile of Cyazofamid [IKF-916] Technical.

Guideline No./

Study Type

MRID No. (year)/

Classification/Doses Results

870.3800

Reproduction and 

fertility effects in rats

45408935 (1998)

Acceptable/guideline

0, 200, 2,000, or 20,000 ppm

F0 M: 11-22, 108-213, and 1114-

2185 mg/kg/day

F0 F: 14-21, 137-219, and 1416-2179 

mg/kg/day

F1 M: 11-27, 107-267, and 1117-

2714 mg/kg/day

F1 F: 14-27, 135-267, and 1451-2678 

mg/kg/day

Parental/Systemic NOAEL = 1114/ 1416 [M/F] 

mg/kg/day

LOAEL = not observed.

Reproductive NOAEL = 1114/ 1416 [M/F] 

mg/kg/day

LOAEL = not observed.

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

LOAEL = not observed.

870.4100a

Chronic toxicity in rats

45408936 (1999)

Acceptable/guideline

Males: 0, 10, 50, 500, or 5,000 ppm 

0, 0.35, 1.7, 17.1, or 171.1 

mg/kg/day 

Females: 0, 50, 500, 5,000, or 20,000 

ppm 0, 2.0, 20.2, 207.8, or 856.0 

mg/kg/day

NOAEL = 171/ 856 [M/F] mg/kg/day

LOAEL = not observed.

870.4100b

Chronic toxicity in dogs

45408931 (2001)

Acceptable/guideline

0, 40, 200, 1,000 mg/kg/day

NOAEL = 200 [M/F] mg/kg/day

LOAEL = 1,000 [M/F] mg/kg/day based on 

increased cysts in parathyroids in males.

870.4200

Carcinogenicity rats

45408936 (1999)

Acceptable/guideline

NOAEL = 171/ 856 [M/F] mg/kg/day

LOAEL = not observed.

No evidence of carcinogenicity.

870.4300

Carcinogenicity mice

45408932 (1999)

Acceptable/guideline

NOAEL = 94.8 [M] mg/kg/day

LOAEL = 985 [M] mg/kg/day based on increased 

incidence of skin lesions including hair loss, body 

sores, dermatitis, ulceration, and acanthosis.

No evidence of carcinogenicity.

Gene Mutation

870.5100

Bacterial reverse 

mutation assay

45408937 (1998)

Acceptable/ guideline

(ai)

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

plate and tube preincubation (not cytotoxic but 

there was precipitation at ≥1,500 μg/plate.

Gene Mutation

870.5300

Mammalian cell culture

45409002 (1998)

Acceptable/ guideline

(ai)

Negative ± S9 up to cytotoxic and precipitating 

concentration of 100 μg/mL.

Cytogenetics 

870.5375 Chromosomal 

aberrations

45409003 (1996)

Acceptable/ guideline

(ai)

Negative ± S9 for clastogenic/aneugenic activity up 

to cytotoxic and precipitating 200 μg/mL.

Cytogenetics 

870.5395

Micronucleus test on 

mouse

45409004 (1996)

Acceptable/ guideline

(ai)

Negative up to the highest dose tested (limit dose) 

2,000 mg/kg.
Page 36 of 40

Table C.1. Toxicity Profile of Cyazofamid [IKF-916] Technical.

Guideline No./

Study Type

MRID No. (year)/

Classification/Doses Results

Other Effects 

870.5500

Bacterial DNA repair 

test (Rec-assay)

45409005 (1998)

Acceptable/ guideline

(ai)

Negative ± S9 up to limit of solubility at 8,000 

μg/disc.

870.6200a

Acute neurotoxicity 

screening battery

45434601 (2000)

Acceptable/guideline

0, 80, 400, or 2000 mg/kg

NOAEL = 2000 [M/F] mg/kg/day

LOAEL = not observed.

The HIARC concluded that the slight increase 

(≈5%) in motor activity at day 14 among the midand high-dose males is marginal and should not be 

considered an adverse finding.

870.6200b

Subchronic 

neurotoxicity screening 

battery

Study not available.

870.6300

Developmental 

neurotoxicity

Study not available.

870.7485

Metabolism and 

pharmacokinetics in rats

45409006- 45409009 and 45434602 

(1998- 1999)

Acceptable/guideline

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

mg/kg repeat non-labeled followed 

by 0.5 mg/kg [phenyl- U14C]- or 

[

14C-Imidazole] IKF-916.

Biliary excretion study: 0.5 or 1,000 

mg/kg [phenyl- U14C]- or [14CImidazole] IKF-916. 

There was rapid absorption (irrespective of dose 

tcmax = 0.25-0.5 hrs) and rapid elimination at the 

low dose (t1/2 4.4-5.8 hrs) while there was saturated 

absorption with prolonged elimination (t1/2 of 7.6-

11.6 hrs) at the high-dose. The extent of absorption 

(as per cent of administered dose) was highly dosedependent being nearly 75% at the low dose and 

only about 5% at the high dose. Both the urine and 

feces were major routes of excretion at the low 

dose with most of the urinary radioactivity being a 

metabolite named CCBA (4-(4-chloro-2-

cyanoimidazol-5-yl)benzoic acid). The biliary 

elimination was highly variable at the low dose 

(≈12-39% of the administered low dose) and 

negligible (<2%) in the high-dose groups. Urinary 

or biliary excretion in the high-dose groups was 

low (each ≈2%) with most of the radioactivity 

being CCBA. Irrespective of the dosing regimen, 

most of the recovered fecal radioactivity was 

unchanged parent compound; the major fecal 

metabolites were CCBA and 4-chloro-5-ptolylimidazole-2-carbonitrile (CCIM) each of 

which being less than 5% of the administered dose. 

Tissue burdens at t1/2, tmax, and at 168 hours post 

dose indicated rapid clearance and low tissue 

burdens suggesting little or no bioaccumulation or 

sequestration.

870.7600

Dermal penetration

Study not available.
Page 37 of 40

Table C.1. Toxicity Profile of Cyazofamid [IKF-916] Technical.

Guideline No./

Study Type

MRID No. (year)/

Classification/Doses Results

Special study: 

In Vitro Metabolism of 

IKF-916 and CCIM in 

Blood and Stomach 

Contents

45409010 (1999)

Acceptable/non-guideline

The in vitro biodegradation of [14C-Bz]IKF-916 or 

[

14C-Bz)CCIM by rat blood or rat stomach contents 

was examined. The results indicated that, during 

the 60-minute incubation period, IKF-916 

underwent degradation to CCIM (≈30%) in blood 

but was stable in stomach contents while CCIM 

was unaffected in either medium. The results also 

suggest that CCIM could be produced in rats 

following IKF-916 entering the blood compartment 

but not necessarily in the stomach compartment.

Special study: 

In Vitro Metabolism of 

CCIM in S9 Fraction

45409011 (1999)

Acceptable/non-guideline

The in vitro metabolism of 14C-CCIM was followed 

up to five minutes in the presence of rat liver S9. 

The results suggested that CCIM was rapidly and 

completely metabolized within 5 minutes to at least 

three metabolites with the major one being CHCN 

(4-chloro-5(4-hydroxymethyl-phenyl)-imidazole-2-

carbonitrile) which accounted for 77-94% of the 

radioactivity. Lower concentrations were found of 

CCBA (3-13%) and one or more unknown 

metabolites. It was concluded that CCIM produced 

in the intestines or blood would be rapidly and 

completely metabolized by the liver.

Special study:

In Vitro Study to 

Identify Metabolites 

Absorbed Through the 

Intestinal Mucosa After 

Incubation with IKF-916 

and CCIM

45409012 (1999)

Acceptable/non-guideline

Using in vitro isolated rat intestinal segments 

containing [14C]IKF-916 or [14C]CCIM, 2.6% of 

IKF-916 and 10.4% of CCIM was transferred from 

the lumen (mucosal side) to the exterior (serosal 

side) of the gut segment. Of the IKF-916 that was 

absorbed and transferred to the buffer solution, 

approximately 60% had undergone 

biotransformation/degradation to CCIM, CCBA 

and three additional products. Also, CCIM 

appeared to be degraded to two metabolites not 

observed for intestine preparations containing IKF916. Based on the findings of this study, 

cyazofamid seems to be poorly absorbed from the 

intestinal lumen although its conversion to CCIM 

or other metabolites may increase overall transfer 

across the gut wall.
Page 38 of 40

Table C.1. Toxicity Profile of Cyazofamid [IKF-916] Technical.

Guideline No./

Study Type

MRID No. (year)/

Classification/Doses Results

Special study:

Comparative 

metabolism of [14C]IKF916 or [14C]CCIM in 

rats

45409013 (1999)

Acceptable/non-guideline

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

of [14C-Bz]IKF-916 or 0.33 mg/kg of [14CBz]CCIM and, after 30 minutes, blood, liver, 

stomach (plus contents), and duodenum (plus 

contents) were collected and analyzed for 

radioactivity and metabolites. Following a single 

gavage dose of CCIM, the metabolites CCBA and 

CHCN, in addition to unchanged CCIM, were 

detected in the plasma and liver. The same 

metabolites, as well as CCIM, were also detected in 

plasma and liver following administration of IKF916. Therefore, orally administered IKF-916 is 

converted to CCIM and subsequently to CCBA and 

CHCN.

APPENDIX C.2. Acute Toxicity of Cyazofamid

Table C.2. Acute Toxicity of Cyazofamid – Technical.

Guideline No. Study Type MRID No. Results Toxicity 

Category

870.1100 Acute Oral – Rat 45408910 LD50> 5000 mg/kg [M/F] IV

870.1200 Acute Dermal – Rat 45408911 LD50 > 2000 mg/kg [M/F] III

870.1300 Acute Inhalation – Rat 45408912 LC50 > 5.5mg/L [M/F] IV

870.2400 Primary Eye Irritation –

Rabbit 45408913 Grade 2 conjunctival redness and discharge that resolved by 24 hours IV

870.2500 Primary Skin Irritation 

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

870.2600

Dermal Sensitization 

(Guinea Pig 

Maximization test)

45408915 Positive (weak sensitizer) -
Page 39 of 40

APPENDIX D. Rationale for Immunotoxicity Data Requirement

Guideline Number: 870.7800

Study Title: Immunotoxicity

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements 

for registration of a pesticide (food and non-food uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional 

immunotoxicity testing and is designed to evaluate the potential of a repeated chemical 

exposure to produce adverse effects (i.e. suppression) on the immune system. 

Immunosuppression is a deficit in the ability of the immune system to respond to a 

challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired 

Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly

complex, studies assessing functional immunotoxic endpoints are helpful in fully

characterizing a pesticide’s potential immunotoxicity. These data will be used in 

combination with data from hematology, lymphoid organ weights, and histopathology in 

routine chronic or subchronic toxicity studies to characterize potential immunotoxic

effects. 

Practical Utility of the Data

How will the data be used?

These animal studies can be used to select endpoints and doses for use in risk assessment 

of all exposure scenarios and are considered a primary data source for reliable reference 

dose calculation. For example, animal studies have demonstrated that immunotoxicity in 

rodents is one of the more sensitive manifestations of TCDD (2,3,7,8-tetrachlorodibenzop-dioxin) among developmental, reproductive, and endocrinologic toxicities. 

Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide 

(TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making?

If the immunotoxicity study shows that the test material poses either a greater or a 

diminished risk than that given in the interim decision’s conclusion, the risk assessments 

for the test material may need to be revised to reflect the magnitude of potential risk 

derived from the new data.

If the Agency does not have this data, a 10X database uncertainty factor may be applied 

for conducting a risk assessment from the available studies.
Page 40 of 40

APPENDIX E. Rationale for Subchronic Toxicity Data Requirement

Guideline Number: 870.6200

Study Title: Neurotoxicity Battery (Subchronic Study)

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements 

for registration of a pesticide (food and non-food uses). 

The Neurotoxicity Screening Battery (OPPTS 870.6200) is designed to evaluate the 

potential adverse effects on the nervous system from exposure to pesticide chemicals. 

The Agency believes that the guideline studies are inadequate in their assessment of 

behavioral effects and do not use optimal methods to evaluate the potential toxicity to the 

nervous tissue structure and function. To detect and characterize these potential effects 

more fully, a battery of more sensitive testing is required. The objective of this 

neurotoxicity battery testing is to evaluate the incidence and severity of the functional 

and/or behavioral effects, the level of motor activity, and the histopathology of the 

nervous system. The acute neurotoxicity study is required to detect possible effects 

resulting from a single exposure. The subchronic neurotoxicity study is intended to 

detect possible effects resulting from repeated or long-term exposures.

Practical Utility of the Data

How will the data be used?

The acute and subchronic neurotoxicity studies provide critical scientific information 

needed to characterize potential hazard to the human population on the nervous system 

from pesticide exposure. These studies can provide data on a wide range of functional 

tests for evaluating neurotoxicity including sensory effects, neuromuscular effects, 

learning and memory and histopathology of the nervous system. For example, animal 

studies with organophosphorous chemicals have shown neurotoxicity to be the primary

toxic endpoints (e.g. cholinesterase inhibition) of concern in rodents and non-rodents. 

These animal studies can be used to select endpoints and doses for use in risk assessment 

of all exposure scenarios and are considered a primary data source for reliable reference 

dose calculation. The Agency has established an oral reference dose (RfD) for assessing 

dietary risks for a number of chemicals (e.g. organophophates and carbamates) where 

neurotoxicity was the most sensitive endpoint of concern.

How could the data impact the Agency's future decision-making?

If the acute or subchronic neurotoxicity studies show that cyazofamid poses either a 

greater or a diminished risk than that given in the interim decision’s conclusion, the risk 

assessment for cyazofamid may need to be revised to reflect the magnitude of potential 

risk derived from the new data.

If the Agency does not have this data, a 10X database uncertainty factor may be applied

when conducting a risk assessment using the currently available studies.