CYAZOFAMID Human Health Risk Assessment DP No. D397213

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

DATE: June 28, 2012

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

Greens (Crop Subgroup 4A), Succulent-Podded and Succulent-Shelled Beans, 

Basil, Tuberous and Corm Vegetables (Subgroup 1C), and Fruiting Vegetables 

(Crop Group 8-10) with Updated Residential Risk Estimates of All Existing 

Residential Uses.

PC Code: 085651 DP Barcode: 397213

Decision No.: 456373 Registration Nos.: 71512-3

Petition No.: 1E7929 Regulatory Action: Section 3 Registration

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

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

MRID No.: NA 40 CFR: §180.601

FROM: Nancy Tsaur, Chemist, Risk Assessor

Nancy Dodd, Chemist

Kristin Rury, Biologist

Whang Phang, PhD, Senior Toxicologist

Risk Assessment Branch 3

Health Effects Division (7509P)

THROUGH: Paula Deschamp, Branch Chief

Risk Assessment Branch 3

Health Effects Division (7509P)

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

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

Registration Division (7505P)

RD requested that HED provide an evaluation of proposed new uses and tolerances for 

cyazofamid in/on leafy greens (crop subgroup 4A), succulent-podded and succulent-shelled 

beans, basil, tuberous and corm vegetables (subgroup 1C), and fruiting vegetables (crop group 8-

10). A summary of the findings and an assessment of human health risk resulting from the 

proposed and registered uses of cyazofamid are provided in this document and its attachments. 

This assessment has incorporated the updated 2012 Residential Standard Operating Procedures 

(SOPs).
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The residue chemistry data review and the dietary exposure assessment were completed by 

Nancy Dodd. The occupational and residential exposure updates were completed by Kristin 

Rury, and the aggregate human health risk assessment was conducted by Nancy Tsaur. The 

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

Effects Division (EFED).

Table of Contents

1.0 Executive Summary............................................................................................................. 4

2.0 HED Recommendations...................................................................................................... 6

2.1 Data Deficiencies ............................................................................................................ 6

2.2 Tolerance Considerations.............................................................................................. 7

2.2.1 Enforcement Analytical Method ............................................................................... 7

2.2.2 International Harmonization..................................................................................... 7

2.2.3 Recommended Tolerances......................................................................................... 8

2.2.4 Revisions to Petitioned-For Tolerances.................................................................... 8

2.3 Label Recommendations......... Error! Bookmark not defined.Error! Bookmark not 

defined.

3.0 Introduction.......................................................................................................................... 8

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

3.2 Physical/Chemical Characteristics ............................................................................... 9

3.3 Pesticide Use Pattern...................................................................................................... 9

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

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

4.0 Hazard Characterization and Dose-Response Assessment............................................ 12

4.1 Summary of Toxicological Effects.............................................................................. 13

4.2 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 14

4.2.1 Completeness of the Toxicology Database.............................................................. 14

4.2.2 Evidence of Neurotoxicity........................................................................................ 14

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal........ 14

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

4.3 Toxicity Endpoint and Point of Departure Selections.............................................. 15

5.0 Dietary Exposure and Risk Assessment........................................................................... 17

5.1 Residues of Concern Summary and Rationale.......................................................... 17

5.2 Food Residue Profile .................................................................................................... 17

5.3 Water Residue Profile.................................................................................................. 19

5.4 Dietary Risk Assessment.............................................................................................. 20

5.4.1 Description of Residue Data Used in Dietary Assessment.................................... 20

5.4.2 Acute Dietary Risk Assessment............................................................................... 20

5.4.3 Chronic Dietary Risk Assessment........................................................................... 20

5.4.4 Cancer Dietary Risk Assessment............................................................................. 20

5.4.5 Summary Table......................................................................................................... 20

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................... 21

6.1 Residential Handler Exposure .................................................................................... 21

6.2 Post-Application Exposure.......................................................................................... 24

6.3 Combined Exposure..................................................................................................... 24
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6.4 Residential Bystander Post-Application Inhalation Exposure ................................ 25

6.5 Spray Drift.................................................................................................................... 25

7.0 Aggregate Exposure/Risk Characterization.................................................................... 26

7.1 Acute Aggregate Risk................................................................................................... 26

7.2 Short-Term Aggregate Risk........................................................................................ 26

7.3 Intermediate-Term Aggregate Risk ........................................................................... 27

7.4 Chronic Aggregate Risk .............................................................................................. 27

7.5 Cancer Aggregate Risk ................................................................................................ 27

8.0 Cumulative Exposure/Risk Characterization ................................................................. 27

9.0 Occupational Exposure/Risk Characterization .............................................................. 27

9.1 Short- and Intermediate-Term Handler Risk ........................................................... 27

9.2.1 Dermal Post-Application Risk................................................................................. 28

9.2.2 Inhalation Post-Application Risk............................................................................ 29

Appendix A. Toxicology Profile and Executive Summaries................................................ 31

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

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

Appendix B. Physical/Chemical Properties and Metabolic Profile .................................... 37

Appendix C. Review of Human Research ............................................................................. 38

Appendix D. Occupational Exposure and Risk Estimates Summary Table ...................... 39

Appendix E. International Residue Limit Summary ........................................................... 43
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1.0 Executive Summary

In PP#1E7929, the Interregional Research Project No. 4 (IR-4) of Rutgers, New Jersey, has 

petitioned for the establishment of new tolerances for combined residues of the fungicide 

cyazofamid, 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/on the following raw agricultural commodities

(RACs):

Bean, succulent ........................................................ 0.4 ppm

Bean, succulent, shelled......................................... 0.07 ppm

Leafy greens subgroup 4A ...................................... 9.0 ppm

Basil, fresh leaves ..................................................... 30 ppm

Basil, dried leaves..................................................... 80 ppm

Vegetable, tuberous and corm, subgroup 1C......... 0.02 ppm

Vegetable, fruiting, group 8-10.............................. 0.40 ppm

Pending submission of a revised Section B label with resolutions identified in Section 2.1, there 

are no toxicology or residue chemistry issues that would preclude granting unconditional 

registration for the requested uses of cyazofamid or for the establishment of permanent

tolerances for the combined residues of cyazofamid.

The most recent human health risk assessment, conducted for use on Brassica (cole) leafy

vegetables, turnip greens, spinach, and hops, reported the hazard characterization and toxicity 

endpoints for risk assessment (D370671, N. Tsaur, 04/07/2010). Since the last risk assessment, 

the registrant has agreed to submit immunotoxicity and subchronic neurotoxicity studies by the 

end of July 2012. Aside from the two outstanding studies, the hazard characterization and 

toxicity endpoints for risk assessment remain unchanged. Furthermore, HED has waived the 

data requirement for inhalation toxicity since the last risk assessment (TXR0056341). The 

detailed rationale for toxicity endpoint selection will not be repeated in this risk assessment. A

brief hazard characterization along with the salient features for the Food Quality Protection Act 

(FQPA) safety factor will be summarized.

Proposed Use Profile

Broadcast application of cyazofamid may be applied at the maximum single application rate of 

0.078 lb ai/A (3.0 fl oz/A) to field-grown basil and basil grown in greenhouses; and at 0.072 lb 

ai/A (2.75 fl oz/A) to leafy greens (subgroup 4A), succulent-podded and shelled beans, tuberous 

and corm vegetables (subgroup 1C), and fruiting vegetables (crop group 8-10). At-planting 

applications to tuberous and corm vegetables (subgroup 1C) may be made at the maximum 

single rate of 0.16 lb ai/A (6.1 fl oz/A), and soil drench applications (based on 60 gallons of 

water per acre) may be made to fruiting vegetables (crop group 8-10) at the maximum single 

application rate of 0.047 lb ai/A (1.8 fl oz/A). Cyazofamid may also be applied to greenhouse 

transplant tomatoes with a soil drench application at a maximum application rate of 1 pint of 

solution per square foot (0.0085 lb ai/A). 
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Occupational handlers may apply Ranman® 400SC using ground, aerial, and chemigation 

equipment for broadcast application. For soil drench applications, cyazofamid may be applied 

using chemigation and handheld equipment.

Exposure Profile

Exposures to cyazofamid are expected to occur for short-, intermediate-, and long-term (chronic) 

durations. The proposed agricultural uses result in new exposures in both food and drinking 

water. There are also existing residential uses that result in non-occupational exposure from 

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

during handler and post-application activities.

Toxicity/Hazard

Cyazofamid has low acute toxicity via the oral, dermal, and inhalation routes of exposure. It 

produces minimal but reversible eye irritation, is a slight dermal irritant, and is a weak dermal 

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

might be due to the sulfonamide moiety in the compound.

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

low toxicity. The kidney appeared to be affected the most. 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 be mutagenic, based on several negative in vivo and in vitro studies.

Dietary Exposure (Food and Water) and Risk Estimates

The residue chemistry data and environmental fate data are adequate to assess human exposure. 

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

dietary exposures to cyazofamid from food and drinking water are well below the Agency’s level 

of concern (LOC). Both acute and chronic dietary (food + drinking water) assessments were 

conservative, assuming that residues in all crops were at tolerance levels and that 100% of the 

crops were treated. An acute dietary (food + drinking water) exposure assessment was only 

performed for females 13-49 years old since an acute endpoint of concern was not identified for 

the general population. The acute dietary risk estimate for females 13-49 years old at the 95th

percentile of exposure was 2.5% of the aPAD. The chronic dietary (food and drinking water) 

exposure assessment for the general U.S. population resulted in <1% of the cPAD. The chronic 
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dietary risk estimate for the highest reported exposed population subgroup, children (1-2 years 

old), was 1.5% of the cPAD. Cyazofamid is classified as “not likely to be carcinogenic to 

humans;” therefore, no cancer risk is expected. 

 

Residential Exposure and Risk Estimates

All existing residential exposures have been reassessed to reflect updates to HED’s 2012 

Residential SOPs along with policy changes for body weight assumptions. There are no 

registered products that would lead to any residential handler or post-application risk estimates 

of concern. Short-term residential handler (margins of exposure) MOEs range from 2,400 to 

59,000. Short-term post-application MOEs for adults and children range from 660 to 570,000.

Residential Aggregate Exposure Risk Estimates

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

considered background exposure) and residential (which is considered primary) pathways. All

MOEs are greater than 100, which indicates that exposure and risk do not exceed HED’s LOC. 

The adult and children short-term aggregate (dietary and residential) MOEs are 390 and 2,200, 

respectively. Acute aggregate risk for females 13-49 is expected to be equivalent to the acute 

exposure via the dietary pathway. Intermediate-term and chronic aggregate risk are expected to 

be equivalent to chronic exposure via the dietary pathway.

Occupational Exposure and Risk Estimates

There is potential for short- and intermediate-term occupational exposure to cyazofamid during 

handling activities (e.g. mixing, loading, application). There are no risk estimates of concern at 

the baseline level of personal protective equipment (PPE); all short-term combined (dermal and 

inhalation) handler risk estimates resulted in MOEs ranging from 200 to 140,000.

There is potential for short- and intermediate-term occupational exposure during post-application 

activities. There are no risk estimates of concern on day 0 (12 hours after application); all 

scenarios resulted in MOEs greater than the LOC of 100 (ranging from 9,500 to 1,200,000) on 

day 0 (12 hours after application). Based on a quantitative post-application assessment, the 12-

hour restricted entry interval (REI) on the proposed label is appropriate. Post-application 

inhalation exposures and risk estimates were not quantitatively assessed.

2.0 HED Recommendations

Pending submission of a revised Section B label with resolutions identified in Section 2.1, there 

are no toxicology or residue chemistry issues that would preclude granting unconditional 

registration for the requested uses of cyazofamid or establishment of the tolerances for the

combined residues of cyazofamid listed in Section 2.2.3.

2.1 Requirements Prior to Registration

The following changes are required prior to establishing a tolerance or allowing a registration:

860.1200 Directions for Use
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 The Ranman® 400SC label should be amended to prohibit applications to cowpea grown 

for livestock feeds because no residue data are available for cowpea forage and hay. The 

statement “Do not apply to cowpea used for livestock feed” should be added to the label. 

Cowpea is a succulent shelled bean.”

 The label indicates that Ranman® 400SC should be tank mixed with an organosilicone 

surfactant, non-ionic surfactant, or a blend of an organosilicone and non-ionic surfactant. 

The label should be revised to specify that an organosilicone surfactant can be used on 

basil, snap beans, lima beans, pepper, potato, spinach and tomato, and either a nonionic 

surfactant or an organosilicone surfactant can be used on head and leaf lettuce. 

860.1480 Meat, Milk, Poultry, and Eggs

 Tolerances for residues of cyazofamid in poultry and swine commodities are not required 

provided that application to cowpea used for livestock feed is prohibited on the label. 

870.7800 Immunotoxicity

 The registrant has informed the Agency of their intent to submit an immunotoxicity study

by the end of July 2012.

870.6100b Subchronic Neurotoxicity

 The registrant has informed the Agency of their intent to submit a subchronic 

neurotoxicity study by the end of July 2012.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

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

metabolite CCIM in lettuce, basil, snap bean, lima bean, pepper, potato, spinach, and tomato. An 

enforcement method for non-fatty commodities is FDA’s Multiresidue Protocol D (without 

cleanup), which completely recovers (>80% recovery) cyazofamid and metabolite CCIM. In 

addition, the HPLC/UV method is acceptable for use as a single analyte enforcement method 

provided a confirmatory method such as the LC/MS/MS data collection method (a modified 

version of the method in MRID 45409020) is used.

2.2.2 International Harmonization

There are no Codex or Mexican maximum residue limits (MRLs) on the proposed crops. Canada 

has a tolerance of 0.02 ppm on potatoes, which is the same level as the U.S. tolerance for

vegetable, tuberous and corm, subgroup 1C which includes potatoes. Canada also has a 

tolerance of 0.2 ppm on tomatoes, which is less than the recommended U.S. tolerance of 0.9 ppm 

for vegetable, fruiting, group 8-10 which includes tomatoes. This variation is because Canada 

has set a single commodity tolerance on tomatoes while the U.S. tolerance is based on the

highest value for the representative crops of the entire fruiting vegetable crop group.
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The tolerance definition for the U.S. and Canada are the same. Both the U.S. and Canada 

include parent and the metabolite, 4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile, in 

the tolerance expression. The International Residue Limit Status is attached in Appendix E.

2.2.3 Recommended Tolerances

Table 2.2.3 summarizes the HED recommendations for establishing tolerances.

Table 2.2.3. Tolerance Summary for Cyazofamid

Commodity

Tolerance (ppm) Comments

Established Proposed Recommended Correct Commodity Definition a

40 CFR §180.609(a)(1)

Bean, succulent --- 0.4 0.5

none

Bean, succulent, shelled --- 0.07 0.08

Leafy greens subgroup 4A --- 9.0 10

Basil, fresh leaves 30 30

Basil, dried leaves --- 80 90

Vegetable, tuberous and 

corm, subgroup 1C --- 0.02 0.02

Vegetable, fruiting, group 

8-10 --- 0.40 0.9

a See Section 2.2.4 “Revisions to Petitioned-For Tolerance.”

When the above tolerances are established, the existing tolerances on spinach, potato, fruiting 

vegetable group 8, and okra can be removed as requested by the petitioner.

2.2.4 Revisions to Petitioned-For Tolerances

The revisions to petitioned-for tolerances for the following commodities are due to the 

Organization for Economic Cooperation and Development (OECD) tolerance calculation 

procedures: bean,succulent (0.4 ppm to 0.5 ppm); bean, succulent, shelled (0.07 ppm to 0.08 

ppm); leafy greens subgroup 4A (9 ppm to 10 ppm); and basil, dried leaves (80 ppm to 90 ppm).

The vegetable, fruiting, group 8-10 tolerance must be revised from 0.40 to 0.9 ppm. The OECD 

calculation procedures using average field trials of existing data result in values of 0.2 ppm for 

tomato, 0.4 ppm for bell pepper, and 0.9 ppm for nonbell pepper. Thus, the highest value of 0.9 

ppm is recommended as the crop group tolerance.

3.0 Introduction

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

Plasmopara, Pseudoperonospora, and Pythium) and Plasmodiophoromycetes (Plasmodiospora

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

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

In PP#1E7929, IR-4 has petitioned for new tolerances for combined residues of the fungicide 

cyazofamid on the RACs listed in Table 2.2.3. Concomitantly, IR-4 is proposing that the new 
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uses be added to the currently registered label for Ranman® 400SC (EPA Reg. No. 71512-3), 

consisting of 34.5% ai at 3.33 lb ai/gal.

3.1 Chemical Identity

Table 3.1 summarizes the residue profile for the parent cyazofamid and its major metabolite, 

CCIM. Structures of other metabolites and degradates are shown in Appendix B, Table B-2.

Table 3.1. Cyazofamid Nomenclature

Parent Chemical Structure

Empirical Formula C13H13ClN4 O2S

Common Name cyazofamid

Company Experimental Name NA

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

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

sulfonamide

CAS Registry Number 120116-88-3

Chemical Class imidazole, sulfonamide

Known Impurities of Concern None

Metabolite Chemical Structure

Common name CCIM

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

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

3.2 Physical/Chemical Characteristics

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

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

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

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

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

cyazofamid are summarized in Appendix B, Table B-1.

3.3 Pesticide Use Pattern

Cyazofamid is currently registered for use on a variety of field crops including the following: 

Brassica leafy vegetables, carrots, hops, potatoes, spinach, turnip greens, cucurbits, and fruiting 

vegetables. The proposed uses of Ranman® 400SC are presented in Table 3.3.

Table 3.3. Summary of Proposed Directions for Use of Ranman® 400SC (EPA Reg. No. 71512-3)

N

N

H3C

Cl

CN

SO2N(CH3)

2

N

H

N

H3C

Cl

CN
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Applic. Timing, 

Type, and Equip.

Applic. 

Rate

Max. 

No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate

PHI

Use Directions and Limitations a

lb ai/A lb ai/A days

Basil

Post-emergence.

Foliar broadcast 

sprays using 

ground, aerial, or 

sprinkler irrigation 

equipment. Can be 

grown in a 

greenhouse.

0.072-

0.078 9 0.7 0

Normal water volume is 50-75 gals water per acre.

For downy mildew on basil, make applications on 

a 7 to 10 day schedule.

Beans, Succulent Podded and Succulent Shelled

Cicer arietinum (chickpea, garbanzo bean); Lupinus spp. (including sweet lupine, white sweet lupine, white 

lupine, and grain lupine); Phaseolus spp. (including kidney bean, lima bean, mung bean, navy bean, pinto bean, 

snap bean, and waxbean); Vicia faba (broad bean, fava bean); Vigna spp. (including asparagus bean, blackeyed 

pea and cowpea)

Post-emergence.

Foliar broadcast 

sprays using 

ground, aerial, or 

sprinkler irrigation 

equipment.

0.072 6 0.43 0

Normal water volumes are 20-60 gals water per 

acre.

For downy mildew on lima beans: Make 

applications on a 7 to 10 day schedule.

For cottony leak control: Make the initial 

application at full bloom (1st pods) and repeat on a 

7-14-day schedule.

For Phytophthora blight control: Make the 1st

application at 100% bloom-pin pod development 

and a 2nd application at late pin-small pod 

development and repeat every seven days.

Fruiting Vegetables (Crop Group 8-10)

African eggplant; bush tomato; bell pepper; cocona; currant tomato; eggplant; garden huckleberry; goji berry; 

groundcherry; martynia; naranjilla; okra; pea eggplant; pepino; nonbell pepper; roselle; scarlet eggplant; sunberry; 

tomatillo; tomato; tree tomato; cultivars, varieties, and/or hybrids of these

Post-emergence. 

Broadcast foliar or 

soil drench to the 

base of the plants 

at transplanting or 

in transplant water. 

Ground, aerial, or 

sprinkler irrigation 

equipment. 

Tomatoes for 

transplant can be 

grown in the 

greenhouse. A soil 

drench can be 

applied to 

tomatoes in the 

greenhouse.

0.054-

0.072

Soil 

drench: 

0.078 lb 

ai/100 

gals 

water

6 0.43 0

Normal water volumes are 30-60 gals water per 

acre.

For late blight control, make applications on a 7 to 

10 day schedule.

For Phytophthora blight control, apply to the base 

of the plants at the time of transplanting. 

Alternatively, apply in transplant water at the time 

of transplanting. Apply 0.072 lb ai/A in transplant 

water in a water volume of at least 50 gals/A for 

the initial application. Apply on a 7 to 10 day 

schedule.

Tomato Greenhouse Transplant Production: For 

control of Pythium spp., make a single fungicide 

application to the seeding tray at the time of 

planting or at any time thereafter up until 1 week 

before transplanting. Apply the fungicide solution 

as a drench to thoroughly wet the growing 

medium (1 pt of solution per square foot if the 

growing medium is 4 inches deep). Do not use a 
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Table 3.3. Summary of Proposed Directions for Use of Ranman® 400SC (EPA Reg. No. 71512-3)

Applic. Timing, 

Type, and Equip.

Applic. 

Rate

Max. 

No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate

PHI

Use Directions and Limitations a

lb ai/A lb ai/A days

surfactant with this drench application.

Leafy Greens, Crop Subgroup 4A

Amaranth (leafy amaranth, Chinese spinach, tampala); arugula (Roquette); chervil; edible-leaved chrysanthemum; 

garland chrysanthemum; corn salad; garden cress; upland cress (yellow rocket, winter cress); dandelion; dock 

(sorrel); endive (escarole); lettuce (head and leaf); orach; parsley; garden purslane; winter purslane; radicchio (red 

chicory); spinach; New Zealand spinach; vine spinach (Malabar spinach, Indian spinach).

Post-transplant; 

Post-seeding; Postemergence.

Foliar broadcast or 

soil drench band 

spray using 

ground, aerial, or 

sprinkler irrigation 

equipment.

0.072 b6 0.43 0

Downy mildew: Apply at 7-14-day intervals.

Pythium: Make first application as a band to the 

soil as a directed, post- transplant or post-seeding 

application; alternatively, apply in transplant 

water at the time of transplant as a soil drench in 

at least 50 gals water per acre. Apply at 7 to 10 

day intervals.

Normal water volumes are 20-60 gals water per 

acre.

Tuberous and Corm Vegetables, Crop Subgroup 1C

Arracacha; arrowroot; Chinese artichoke; Jerusalem artichoke; edible canna; bitter cassava; sweet cassava; chayote 

(root); chufa; dasheen (taro); ginger; leren; potato; sweet potato; tanier; turmeric; yam bean; true yam

Post-emergence 

foliar sprays using 

ground, aerial, or 

sprinkler irrigation 

equipment.

Can also be atplanting, in-furrow

at planting, or layby/ hilling

Foliar: 

0.036-

0.072 b

At 

planting: 

0.42 fl 

oz per 

1000 

linear 

feet

(0.16 lb 

ai/A 

based on 

a 36” 

row

spacing)

Lay-by/ 

Hilling: 

0.072

10 0.72 b7

Normal water volumes are 20-50 gals water per 

acre.

For foliar blight, make applications on a 7 to10 

day schedule.

For tuber and corm rot control, make the last 2 to 

3 applications prior to harvest at the rate of 0.072 

lb ai/A applied weekly.

For pink rot, Phythium root and crown rot control 

at planting, apply 0.42 fl oz product per 1000 

linear foot of row in-furrow at planting using a 

minimum of 5 gals water per acre. Apply in a 6-8 

inch band directly over the seed pieces prior to 

furrow closure. Mefenoxam can be added as a 

tank mix.

For additional control of Pythium root and crown 

rot, in combination with an at-planting, in-furrow

application, apply as a broadcast spray at 0.072 lb 

ai/A in a minimum of 20 gals of finished spray 

solution per acre at hilling.

a Use directions and limitations: 

The plantback interval is 0 days for crops on the label and 30 days for other crops. 

Spray volumes will usually range from 20-100 gals per acre for dilute sprays and 5-10 gals/A for concentrate 

sprays and aerial sprays. Aerial sprays should be made in a minimum of 5 gals of water per acre.
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Alternate 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. 

Ranman® 400SC should be tank mixed with an organosilicone surfactant, non-ionic surfactant, or a blend of an 

organosilicone and a non-ionic surfactant. 

b 2.75 fl oz product /A = 0.0715 lb ai/A and 27.5 fl oz product /A= 0.715 lb ai/A. HED rounds up to 0.072 and 

0.72, respectively, as per HED’s Hot Sheet #10.

3.4 Anticipated Exposure Pathways

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

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

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

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

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

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

for residents and occupational workers re-entering treated areas. 

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

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

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

the dietary exposure assessment. 

3.5 Consideration of Environmental Justice

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

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

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

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. 

Further considerations are currently in development as OPP has committed resources and 

expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment
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The cyazofamid hazard characterization is detailed in a previous risk assessment (D342612, K. 

O’Rourke, 03/19/2008). New toxicity data have not been submitted since the last risk 

assessment (D370671, N. Tsaur, 04/07/2010). HED has waived the data requirement for 

inhalation toxicity since the last risk assessment (TXR#0056307). All available toxicity studies 

are listed in Appendix A.

4.1 Summary of Toxicological Effects

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

Cyazofamid is a broad spectrum fungicide active against oomycete fungi and 

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

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

mechanism of toxicity in mammals is not clear.

The available toxicity studies show that following repeated administration in more than one 

species, cyazofamid seems to have mild or low toxicity. The kidney seemed to be affected the 

most following 13 weeks of dietary feeding in male rats which had increased microscopic kidney

lesions characterized as an “increased number of basophilic tubules, graded as slight” with 

associated mild increases in urinary output, protein, and pH. Female rats of the same study were 

less sensitive, with the only change being a marginal increase in urine volume and pH. 

However, there were no adverse kidney effects or any other toxicity findings following lifetime 

dietary feeding at concentrations up to 171.1 mg/kg/day and 856.0 mg/kg/day in male and female 

rats, respectively.

Skin lesions (likely due to systemic allergy) were observed in males in the mouse carcinogenicity 

study. The skin lesions occurred at a relatively high dose (985 mg/kg/day) and were 

characterized by hair loss, body sores, dermatitis, ulceration and acanthosis (hyperplasia). The 

sulfonamide moiety in the cyanoimidazole ring might have rendered cyazofamid a weak 

allergen. Cyazofamid’s allergenic properties are supported by the fact that cyazofamid is a slight

dermal irritant (Toxicity Category III) in the primary rabbit skin test and is a positive weak 

sensitizer in the guinea pig skin maximization test. In addition, sulfonamide antimicrobial drugs 

(e.g., sulfamethoxazole) have been known to cause idiosyncratic drug reactions including 

delayed type skin reactions (benign rash and potentially lethal toxidermias).

The dog is not the most sensitive species. With the exception of increased parathyroid cysts in

male dogs at the highest dose (1000 mg/kg/day) in the chronic (one-year) study, there were no 

major toxicity findings in the 13-week and one-year dog studies up to a dose of 1,000 mg/kg/day.

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 did 

not show mutagenicity potential, based on several negative in vivo and in vitro studies. 

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

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

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

sensitizer might be due to the sulfonamide moiety in the compound. 
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4.2 Safety Factor for Infants and Children (FQPA Safety Factor)

The FQPA safety factor is reduced to 1X; consideration of the toxicology database leads to no 

additional concerns for infants and children.

4.2.1 Completeness of the Toxicology Database

The toxicological database for cyazofamid is complete except for the immunotoxicity and 

subchronic neurotoxicity studies. The registrant has agreed to submit both studies by the end of 

July 2012. Furthermore, HED has waived the data requirement for inhalation toxicity since the 

last risk assessment (TXR#0056307). The submitted toxicology studies are of good quality. 

They are sufficient to select endpoints for risk assessment and to determine whether cyazofamid

poses a human health hazard.

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

system. The overall weight of evidence suggests that cyazofamid does not directly target the 

immune system. HED does not believe that conducting a functional immunotoxicity study will 

result in a lower no observed adverse effect level (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.

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 2,000 mg/kg, shows no neurotoxic effects with gavage 

dosing. Neurotoxicity is also not seen 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. 

4.2.2 Evidence of Neurotoxicity

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

the acute neurotoxicity study, there were no indications of treatment-related adverse 

neurotoxicity findings including clinical signs, qualitative or quantitative neurobehavioral 

effects, brain weight, or gross/microscopic pathology. 

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

The available studies used to evaluate pre- and post-natal exposure susceptibility do not indicate

increased susceptibility of developing rats or rabbits to cyazofamid. 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. In the prenatal developmental toxicity study

in rabbits, there were no maternal or developmental effects at any dose up to the limit dose of 
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1,000 mg/kg/day. In the two-generation reproduction study, the highest dose tested (>1,000 

mg/kg/day) did not cause maternal systemic toxicity nor did it elicit reproductive or offspring 

toxicity. 

4.2.4 Residual Uncertainty in the Exposure Database

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

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

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

assumes maximum application rates and conservative day zero hand-to-mouth activities. All of 

the exposure estimates are based on conservative high-end assumptions and are not likely to 

underestimate risk.

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

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

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

The calculated residential risks represent conservative estimates of exposure because maximum 

application rates are used to define residue levels. Exposures are unlikely to be underestimated 

because the assessment is a screening-level assessment.

4.3 Toxicity Endpoint and Point of Departure Selections

There are no changes to the previous dose-response assessment. A summary of the toxicological 

endpoints for cyazofamid for use in dietary and occupational human health risk assessments is 

presented in Table 4.3.

Table 4.3. Summary of Toxicological Doses and Endpoints for Cyazofamid for Use in Dietary, NonOccupational, and Occupational Human Health Risk Assessments a

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children) and 

None: There is no indication of an adverse effect attributable to a single dose. An aRfD was not 

established.

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

aPAD = 1.0 

mg/kg/day

Rat Prenatal Developmental Toxicity

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

developmental toxicity findings of increased 

incidence of bent ribs.
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Table 4.3. Summary of Toxicological Doses and Endpoints for Cyazofamid for Use in Dietary, NonOccupational, and Occupational Human Health Risk Assessments a

Exposure/ 

Scenario

Point of 

Departure

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

cPAD = 

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 

factor = 

37%

UFA = 10X

UFH = 10X

FQPA SF = 1X

Residential 

LOC for 

MOE = 100

Occupational 

LOC for 

MOE = 100

Rat Prenatal Developmental Toxicity (MRID 

45408933)

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

developmental toxicity findings of increased 

incidence of bent ribs.

Inhalation 

Short- Term

(1-30 days)

and 

IntermediateTerm (1-6 

months)

NOAEL= 

100 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Residential 

LOC for 

MOE = 100

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.

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.

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

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

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

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

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

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

level of concern. N/A = not applicable.
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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.

5.0 Dietary Exposure and Risk Assessment 

5.1 Residues of Concern Summary and Rationale

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

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

currently registered and newly proposed uses fall under 40 CFR § 180.6(a)(3) (i.e. there is no 

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

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

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

conjugate. In addition, there are no poultry or swine feed items. (These conclusions assume that

the recommended restriction against use on cowpea used for livestock feed is added to the label.)

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

Expression a

Matrix Residues Included in Risk Assessment Residues Included in

Tolerance Expression

Plants Parent and CCIM Parent and CCIM

Livestock

No decision (For future cattle feeding studies, the MARC 

recommended that the petitioner analyze parent, CCIM, CCBA, 

and CCBA-cysteine conjugate.)

No decision

Rotational crops Parent only Parent only

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

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

finite residues in livestock commodities). In addition, there are no poultry or swine feed items. (These 

conclusions assume that the recommended restriction against use on cowpea used for livestock feed is added to 

the label.)

5.2 Food Residue Profile

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

beans, snap beans, head lettuce, and leaf lettuce. There are adequate data for risk assessment and 

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

metabolite, CCIM, were quantifiable, generally declining with increasing sampling interval. 

The results from these studies are summarized in Table 5.2.
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Crop Field Trials

Provided the requested revisions are made to the Ranman® 400SC label, the field trials are 

adequate to establish tolerances on all the proposed commodities at levels recommended in Table 

2.2.3. Detectable residues may occur in food. Field trial decline studies show that residues in 

agricultural commodities decline with increasing preharvest intervals.

Table 5.2. Summary of Residue Data from Field Trials with Cyazofamid a,b

Crop Matrix Analyte

Applic. 

Rate

(lb ai/acre)

PHI 

(days) n

Residues (ppm)

Min. Max. LAFT HAFT Median Mean SD

BASIL Proposed Use = 0.7 lb ai/acre total application rate, 0-day PHI

Basil, fresh 

(leaves and 

stems) c

Cyazofamid 

+ CCIM

0.693-

0.721 0 6 2.4 15 2.6 14 8.5 8.4 5.1

Basil, dried 

(leaves and 

stems) c

Cyazofamid 

+ CCIM

0.693-

0.721 0 4 11 46 11 43 30 28 13

BEAN, LIMA Proposed Use = 0.43 lb ai/acre total application rate, 0-day PHI

Bean, lima 

(succulent 

seeds)

Cyazofamid 

+ CCIM

0.427-

0.523 0-1 6 <0.02 <0.057 <0.02 <0.050 0.020 0.025 0.012

BEAN, SNAP Proposed Use = 0.43 lb ai/acre total application rate, 0-day PHI

Bean, snap

(pods with 

seeds)

Cyazofamid 

+ CCIM

0.426-

0.507 0 8 <0.022 <0.23 <0.029 <0.21 0.12 0.12 0.072

LETTUCE, HEAD Proposed Use = 0.43 lb ai/acre total application rate, 0-day PHI

Lettuce, head 

(head with 

wrapper 

leaves)

Cyazofamid 

+ CCIM

0.419-

0.506 0 11 <0.06 2.0 <0.080 1.8 0.65 0.83 0.61

LETTUCE, LEAF Proposed Use = 0.43 lb ai/acre total application rate, 0-day PHI

Lettuce, leaf 

(leaves)

Cyazofamid 

+ CCIM

0.427-

0.587 0 11 <0.49 4.6 <0.54 4.5 1.8 2.1 1.3

a Except for sample min/max, values reflect per trial averages; n = no. of field trials.

b LAFT = Lowest Average Field Trial; HAFT = Highest Average Field Trial; SD = Standard Deviation. For 

computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ are assumed to be at the 

LOQ.

c Data for fresh basil include field trials and greenhouse trials. Data for dried basil reflect field trials.

Processing Studies

Additional processing studies are not required. The previously submitted tomato and potato 

processing studies are adequate to show that residues in tomato and potato processed 

commodities will not concentrate above the tolerance levels for the raw agricultural 

commodities; therefore, separate tolerances on the processed commodities of tomato and potato 

are not required.

Storage Stability

The available storage stability data are adequate to support the storage durations and conditions 

of the field trial samples. Except for residues of the metabolite CCIM in fresh basil, the data are 

adequate to conclude that residues of cyazofamid and CCIM in the field trial samples were stable 
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during frozen storage. Residues of CCIM in fresh basil declined by 46% after 284 days (9.3 

months) of freezer storage; therefore, residues in fresh basil in the field trials were corrected for 

loss of CCIM in storage. 

Meat, Milk, Poultry, and Eggs

The results of the goat metabolism study indicate that tolerances for residues of cyazofamid in 

ruminant commodities are not required for the purpose of this petition since there is no 

reasonable expectation that finite residues will occur in ruminant commodities [40 CFR 

§180.6(a)(3)]. 

Tolerances for residues of cyazofamid in poultry and swine commodities are not required 

provided that application to cowpea used for livestock feed is prohibited on the label. With that 

label prohibition, there are no poultry or swine feed items associated with the proposed or 

registered uses, and the proposed and registered uses fall under 40 CFR §180.6(a)(3) for poultry

commodities.

Rotational Crops

Since the results of the confined rotational crop study showed that cyazofamid and structurally

related metabolites are each expected to be present at a level less than 0.01 ppm at a plantback 

interval of 30 days, no field rotational crop studies are required. The rotational crop plantback 

interval of 0 days for crops which are on the label and 30 days for other crops is appropriate.

5.3 Water Residue Profile

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

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

concluded that cyazofamid and the metabolites designated as CCIM, CCIM-AM (4-chloro-5-ptolylimidazole-2-carboxamide), and CTCA (4-chloro-5-p-tolylimidazole-2-carboxylic acid) are 

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

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

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

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

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

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

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

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

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

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

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

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

contaminate ground water due to its high persistence and mobility. 

Table 5.3 summarizes the EDWCs. The acute value of 136.2 ppb and the non-cancer chronic 

value of 133.5 ppb were directly entered into the exposure model to assess the contributions from 

drinking water. EDWCs in surface water were modeled using Tier 2 PRZM/EXAMS (Pesticide 

Root Zone Model/Exposure Analysis Modeling System) for residues from use on turf and 
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ornamentals, which had the highest seasonal rates among the proposed and registered uses. 

EDWCs in ground water as modeled by Tier 1 SCI-GROW (Screening Concentration in Ground 

Water) were lower. The models and their descriptions are available online at: 

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

Table 5.3. Surface/Ground Water EDWCs for Cyazofamid and its Major Degradates.

Scenario Chemical

Surface Water EDWCs (ppb) Ground Water 

Ac EDWC (ppb) ute

(1-in-10 yr. peak)

Chronic

(1-in-10 yr. mean)

1

st

 Scenario Parent 14.362 0.377 0.01180

2

nd

 Scenario CCIM 17.106 12.094 0.00061

CCIM-AM 6.699 6.312 0.00270

3

rd

 Scenario CTCA 136.242 133.458 2.18000

5.4 Dietary Risk Assessment

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

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

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

5.4.1 Description of Residue Data Used in Dietary Assessment

Both acute and chronic dietary (food + drinking water) assessments were conservative, assuming

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

5.4.2 Acute Dietary Risk Assessment

An acute dietary (food + drinking water) exposure assessment was only performed for females 

13-49 years old since an acute endpoint of concern was not identified for the general population. 

The acute dietary risk estimate for females 13-49 years old at the 95th percentile of exposure was 

2.5% of the aPAD. The results of the acute dietary exposure analysis are reported in Table 5.4.5. 

5.4.3 Chronic Dietary Risk Assessment

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

population resulted in a risk estimate of <1% of the cPAD. The chronic dietary risk estimate for 

the highest reported exposed population subgroup, children (1-2 years old), was 1.5% of the 

cPAD. The results of the chronic dietary exposure analysis are reported in Table 5.4.5.

5.4.4 Cancer Dietary Risk Assessment

Cyazofamid is classified as “not likely to be carcinogenic to humans;” therefore, no cancer risk is 

expected. 

5.4.5 Summary Table of Dietary Risk Assessments
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Table 5.4.6. Summary of Dietary Exposure and Risk for Cyazofamid a

Population Subgroup

Acute Dietary 95th Percentile

(Food and Drinking Water)

Chronic Dietary Exposure Estimates

(Food and Drinking Water)

mg/kg/day % cPAD

General U.S. Population

NA b

0.008157 <1%

All Infants (< 1 year old) 0.012989 1.4

Children 1-2 years old 0.014334 1.5

Children 3-5 years old 0.012279 1.3

Children 6-12 years old 0.008139 <1%

Youth 13-19 years old 0.006274 <1%

Adults 20-49 years old 0.007733 <1%

Adults 50+ years old 0.007855 <1%

Females 13-49 years old 0.024799 2.5 0.007725 <1%

a aPAD (acute population adjusted dose) = 1.0 mg/kg/day. cPAD (chronic population adjusted dose) = 0.95 

mg/kg/day. The population subgroup with the greatest exposure is in bold.

b NA = Not applicable.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no proposed residential uses at this time; however, cyazofamid is registered for use on 

several residential and non-agricultural use sites. Cyazofamid 400SC Turf and Ornamentals 

Fungicide (EPA Reg. No. 71512-13) may be used on turf areas associated with golf courses, sod 

farms, seed farms, college and professional sports fields, residential and commercial lawns, and 

on ornamental plants in landscapes and those grown in commercial greenhouses and nurseries. 

While the label says “application by homeowners to residential turf is prohibited,” the label does 

not identify this product as a restricted use; therefore, a residential handler exposure assessment 

was performed to be protective of potential residential handler exposure. Residential exposure 

and risks from use on gardens, trees, and turf have been reassessed to reflect updates to the 2012 

HED Residential SOPs along with policy changes for body weight assumptions. All residential 

handler risk estimates range from 2,400 to 59,000 and all residential post-application risk 

estimates ranged from 660 to 570,000; and therefore, are not of concern to HED. This revision 

of residential exposures impacts the human health aggregate risk assessment for cyazofamid.

Based on the Agency's current practices, a quantitative residential post-application inhalation 

exposure assessment was also not performed for cyazofamid at this time primarily because of the 

low acute inhalation toxicity (Toxicity Category IV) and low vapor pressure of cyazofamid (9.98 

x 10-8 mm Hg at 25 oC). If new policies or procedures are developed, the Agency may revisit the 

need for a quantitative post-application inhalation exposure assessment for cyazofamid.

6.1 Residential Handler Exposure

Residential handler exposure is expected to be short-term. Intermediate-term exposures are not 

likely because of the intermittent nature of applications by homeowners. Additionally, 

homeowners are assumed to complete all elements of an application without use of any 

protective equipment.
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The quantitative exposure/risk assessment developed for residential handlers is based on the 

following exposure scenarios:

1. Mixing/Loading/Applying for Sprays Using Manually-Pressurized Handwand, 

2. Mixing/Loading/Applying for Sprays with Back-Pack Sprayer,

3. Mixing/Loading/Applying for Sprays with Hose-end Sprayer, and

4. Mixing/Loading/Applying for Application with a Sprinkler Can.

The maximum application rate for each exposure scenario is presented as the worst case 

scenario. All residential risk estimates are not of concern to HED (MOEs ranged from 2,400 to 

59,000). A summary of the short-term risk estimates (dermal and inhalation) for residential 

handlers are included in Table 6.1.
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Table 6.1. Short-Term Residential Handler Exposure and Risk Estimates for Cyazofamid

Exposure Scenario Target 

MOE

Dermal 

Unit 

Exposure

Inhalation 

Unit 

Exposure 

Maximum 

Application

Rate a

Area Treated or 

Amount 

Handled Daily b

Dermal Inhalation Total

Dose c

MOE d Dose cMOE d MOE e

μg/lb ai mg/kg/day mg/kg/day

Mixer/Loader/Applicator

Manually Pressurized Hand 

wand to Gardens and Trees 100 63 0.018 0.0016 lb ai/gal 5 gallons 0.0027 37,000 0.0000021 48,000,000 37,000

Manually Pressurized Hand 

wand to Gardens and Trees 100 63 0.018 0.000036 lb ai/sq ft 1200 sq ft 0.015 6,900 0.000011 8,900,000 6,900

Hose-End Sprayer to Gardens 

and Trees 100 58 0.0014 0.000036 lb ai/sq ft 1200 sq ft 0.013 7,500 0.00000087 110,000,000 7,500

Hose-End Sprayer to Gardens 

and Trees 100 58 0.0014 0.0016 lb ai/gal 11 gallons 0.0055 18,000 0.00000036 280,000,000 18,000

Hose-End Sprayer to Turf 100 13.4 0.022 1.02 lb ai/A 0.5 acres 0.037 2,700 0.00016 620,000 2,700

Manually Pressurized 

Handwand to Turf 100 63 0.018 0.012 lb ai/gal 5 gallons 0.020 5,100 0.000015 6,500,000 5,100

Backpack Sprayer to Gardens 

and Trees 100 130 0.14 0.000036 lb ai/sq ft 1200 sq ft 0.030 3,300 0.000087 1,100,000 3,300

Backpack Sprayer to Gardens 

and Trees 100 130 0.14 0.0016 lb ai/gal 5 gal 0.0056 18,000 0.000016 6,2000,000 18,000

Sprinkler Can to Gardens and 

Trees 100 58 0.0014 0.000036 lb ai/sq ft 1200 sq ft 0.013 7,500 0.00000087 110,000,000 7,500

Sprinkler Can to Gardens and 

Trees 100 58 0.0014 0.0016 lb ai/gal 5 gal 0.0025 40,000 0.00000016 620,000,000 40,000

Sprinkler Can to Lawns and 

Turf 100 13.4 0.022 0.000023 lb ai/sq ft 1000 sq ft 0.0017 59,000 0.0000075 13,000,000 59,000

Backpack Sprayer to Lawns and 

Turf 100 130 0.14 0.012 lb ai/gal 5 gal 0.041 2,500 0.00012 840,000 2,400

a Application Rates based on proposed uses for cyazofamid (Cyazofamid 400SC Turf and Ornamentals Fungicide, EPA Reg. No. 71512-13).

b Amount Treated or Amount Handled Daily taken from Exposure Science Advisory Council (ExpoSAC) 2012 Residential SOPs.

c Dose = Dermal/Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or 

gallons/day) x AF (37% for dermal) / BW (69 kg).

d Dermal or Inhalation MOE = NOAEL (100 mg/kg/day) / Dose (mg/kg/day).

e Total MOE = NOAEL (mg/kg/day) / (Dermal Dose + Inhalation Dose) OR Total MOE = 1/ [(1/Dermal MOE) + (1/Inhalation MOE)].
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6.2 Post-Application Exposure

Adults and children performing physical post-application activities on turf (e.g. golfing, mowing)

may receive dermal exposure to cyazofamid residues. Young children 1 to <2 years old may

also receive incidental oral post-application exposure to cyazofamid from treated turf.

Table 6.2 presents the residential post-application dermal and incidental oral MOE values 

calculated for the appropriate lifestages after application of cyazofamid to gardens, trees, and 

residential turf. A dermal risk estimate for children was not conducted because there is no 

dermal toxicity for children up to the limit dose of 1000 mg/kg/day in a 28-day dermal toxicity

study. Post-application risk estimates were not of concern to HED for any of the scenarios 

assessed (MOEs range from 660 to 570,000).

Table 6.2. Short-Term Residential Post-Application Exposure and Risk Estimates for Cyazofamid.

Lifestage Post-Application Exposure Scenario Dose a

MOEs b

mg/kg/day

Adult

Gardens/Trees

Liquid Formulation

1.56 lb ai/A Dermal 

Contact with gardens 0.15 660

Contact with trees 0.017 6,000

Adult Turf

Liquid Formulation

1.02 lb ai/A

Physical Activities on Turf 0.095 1,100

Mowing 0.0019 52,000

Golfing 0.0074 13,000

Child 1-2 years old Oral

Incidental Oral Hand to Mouth 0.0089 3,400

Incidental Oral Object to Mouth 0.00042 72,000

Incidental Oral Soil Ingestion 0.000053 570,000

a Dermal Dose = TTR/DFR (μg/cm2) × CF1 (0.001 mg/μg) × TC (cm2/hr) × Exposure Time (hrs) ÷ body weight (kg). TC for 

physical activities on turf: 180,000 cm2/hr for adults and 49,000 cm2/hr for children 1-2 years old. TCs for mowing: 5,500 

cm2/hr for adults and 4,500 cm2/hr for children 11 to < 16 years old. TCs for golfing: 300 cm2/hr for adults, 4,400 cm2/hr for 

children 11 to < 16 years old, and 2,900 cm2/hr for children 6 to < 11 years old. Exposure times for physical activities on turf: 

1.5 hrs for adults and children. Exposure time for mowing: 1 hr. Exposure time for golfing: 4 hrs. Body weight for adult: 69

kg. Body weight for children 11 to < 16 years old: 57 kg. Body weight for children 6 to < 11 years old: 32 kg. Body weight for 

children 1 to < 2: 11 kg.

Hand-to-Mouth Dose = hand residue loading (mg/cm2) × fraction of hand mouthed (0.127) × surface area of 1 hand (150 cm2) 

× exposure time (1.5 hrs/day) × # of replenishment intervals/hr (4 int/hr) × (1-((1-saliva extraction factor (0.5))^(Number of 

hand-to-mouth events per hour (13.9 events/hr) ÷ # of replenishment intervals/hr)) ÷ body weight (11 kg).

Object-to-Mouth Dose = object residue loading (μg/cm2) × unit conversion factor (0.001 mg/μg) × object surface area mouthed

/ event (10 cm2/event) × exposure time (1.5 hrs/day) × # replenishment intervals/hr (4 int/hr) × (1-((1- saliva extraction factor 

(0.50))^(# Object-to-Mouth Events/hr (8.8 events/hr) ÷ # replenishment intervals/hr)) ÷ body weight (11 kg).

Soil Ingestion = soil residue (μg/g) × ingestion rate (50 mg/day) × conversion factor (0.000001 g/μg) ÷ body weight (11 kg).

b MOE = NOAEL (mg/kg/day) ÷ Daily Dose (mg/kg/day). ST Dermal NOAEL= 100 mg/kg/day. ST Oral NOAEL = 30 mg/kg/day.

6.3 Combined Exposure

Based on the residential use profile and the 2012 Revised Residential SOPs, exposure duration is 

expected to be short-term only. HED combines risk values resulting from separate postapplication exposure scenarios when it is likely they can occur simultaneously based on the usepattern and the behavior associated with the exposed population. Since exposure to treated 

gardens and turf could occur within the same day, the handler and post-application exposures 

from dermal contact with treated gardens and turf were combined for adults. For children, the 

most conservative post-application exposure estimate is hand-to-mouth incidental oral exposure 

from treated turf. All residential handler and post-application exposure estimates resulted in 
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MOEs greater than 100, and were not of concern. Table 6.3 presents a summary of the worst 

case residential exposure estimates for adults and children.

Table 6.3. Short-Term Residential Exposures for the Cyazofamid Residential Risk Calculations

Population

Handler Exposure a

Residential 

Handler Total 

Exposure b MOE

Post-Application Exposure b

Residential 

PostApplication

Total 

Exposure c

MOE

Dermal Inhalation Dermal Inhalation Oral

mg/kg/day mg/kg/day

Adult 0.041 0.00012 0.041 2,400 0.15 0.095 NA 0.25 400

Child NA NA 0.0089 0.0069 3,400

a Handler exposure represents high end handler exposure of existing registered uses (see Table 6.2).

b Post-application exposure represents high end incidental oral exposure for existing registered uses (see Table 6.2).

c MOE = NOAEL (mg/kg/day) ÷ Daily Dose (mg/kg/day). ST Dermal NOAEL = 100 mg/kg/day. ST Oral NOAEL = 30 mg/kg/day.

6.4 Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for cyazofamid at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV), low vapor pressure (9.98 x 10-8 mm Hg at 25 oC), and 

the low proposed use rate (0.16 lb ai/A). However, volatilization of pesticides may be a source 

of post-application inhalation exposure to individuals nearby pesticide applications. The Agency

sought expert advice and input on issues related to volatilization of pesticides from its Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, 

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

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

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate post-application inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are developed, the 

Agency may revisit the need for a quantitative post-application inhalation exposure assessment 

for cyazofamid.

6.5 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 the previouslyregistered uses of cyazofamid. The Agency has been working with the Spray Drift Task Force, 

EPA Regional Offices, and State Lead Agencies for pesticide regulation and other parties to 

develop the best spray drift management practices. The Agency is now requiring interim 

mitigation measures for aerial applications that must be placed on product labels/labeling. The 

Agency has completed its evaluation of the new data base submitted by the Spray Drift Task

Force, a membership of U.S. pesticide registrants, and is developing a policy on how to 

appropriately apply the data and the AgDRIFT computer model to its risk assessments for 

pesticides applied by air, orchard airblast, and ground hydraulic methods. After the policy is in 

place, the Agency may impose further refinements in spray drift management practices to reduce 
CYAZOFAMID Human Health Risk Assessment DP No. D397213

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off-target drift and risk estimates associated with aerial as well as other application types where 

appropriate.

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

performed to address pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for flaggers. This exposure scenario is representative of a

worst-case inhalation (drift) exposure and may be considered protective of most outdoor 

agricultural and commercial post-application inhalation exposure scenarios.

7.0 Aggregate Exposure/Risk Characterization

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

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

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

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

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

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

residential scenarios were aggregated.

7.1 Acute Aggregate Risk

Acute exposures were only considered for females 13-49 years old because an adverse effect 

attributable to a single dose was not identified for the general population. However, acute

exposure is not expected for the adult residential exposure pathway. Therefore, the acute 

aggregate risk estimate for females 13-49 years old would be equivalent to the acute dietary

exposure estimate. Refer to Section 5.4.2.

7.2 Short-Term Aggregate Risk

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

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

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

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

dermal (primary) routes. All aggregate risk estimates (MOEs) are greater than 100, which 

indicates that exposure and risk do not exceed HED’s LOC. The adult and children short-term 

aggregate dietary and residential MOEs are 390 and 2,200, respectively.

Table 7.2 Short-Term Aggregate Risk Calculations

Population

Short-Term Scenario

LOC for 

Aggregate 

Risk a

Dietary

MOE b

MOE Oral 

Residential 

Exposure c

Combined MOE (Dermal 

and Inhalation) Residential 

Exposure d

Aggregate MOE 

(food, water, and 

residential) e

Adult 100 11,600 NA 400 390

Children

1-2 years old 100 6,600 3,400 NA 2,200

a LOC = 100 (based on inter- and intra- species uncertainty factors totaling 100X).

b MOE dietary = short-term oral NOAEL ÷ chronic dietary exposure. NOAEL = 94.8 mg/kg/day. 
CYAZOFAMID Human Health Risk Assessment DP No. D397213

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c MOE oral = short-term oral NOAEL ÷ hand-to-mouth residential exposure. NOAEL = 30 mg/kg/day. Residential 

exposure for children 1-2 years old = incidental oral only for children (See Table 6.3).

d MOE dermal = short-term dermal NOAEL ÷ high end dermal residential exposure. NOAEL = 100 mg/kg/day.

Residential exposure for adults = post-application combined dermal and inhalation (See Table 6.3).

e MOE Aggregate Adult = 1 ÷ [(1/MOE dietary) + (1/MOE combined dermal and inhalation)].

MOE Aggregate Children 1-2 years old = 1 ÷ [(1/MOE dietary) + (1/incidental oral)].

7.3 Intermediate-Term Aggregate Risk

Intermediate-term exposure is not expected for the adult residential exposure pathway. 

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

dietary exposure estimate. Refer to Section 5.4.3.

7.4 Chronic Aggregate Risk

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

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

Refer to Section 5.4.3.

7.5 Cancer Aggregate Risk

Cyazofamid is classified as “not likely to be carcinogenic to humans;” therefore, an aggregate 

cancer assessment was not conducted.

8.0 Cumulative Exposure/Risk Characterization

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

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

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

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

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

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

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

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

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

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

9.0 Occupational Exposure/Risk Characterization

9.1 Short- and Intermediate-Term Handler Risk

Ranman® 400SC may be applied as a foliar spray via groundboom, aircraft, and chemigation. 

The proposed use pattern is summarized in Table 3.3. Handler exposure is expected to be shortor intermediate-term based on information provided on the proposed label. The personal 

protective equipment (PPE) label requirements include: long-sleeved shirt, long pants, shoes plus 

socks, and chemical-resistant gloves made of any waterproof material, such as nitrile, butyl, 

neoprene and/or barrier laminate.
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The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following exposure scenarios:

Mixer/Loaders

1. Mixing/Loading liquids to support groundboom applications, 

2. Mixing/Loading liquids to support aerial and chemigation applications,

Flaggers

3. Flagging to support aerial application,

Applicators

4. Applying sprays with groundboom equipment, and

5. Applying sprays with aerial equipment.

No handler exposures are expected from applying sprays via chemigation systems.

Ranman® 400SC is not expected to be applied using handheld equipment to field-grown 

tuberous and corm vegetables, fruiting vegetables, or succulent shelled and succulent podded 

beans. Furthermore, because a minimum of 60 gallons of solution is recommended to treat basil 

in greenhouses, cyazofamid is also not expected to be applied using handheld equipment. As a 

conservative estimate of exposure, and to be protective of smaller-scale tomato transplant 

operations, a mixer/loader/applicator assessment has been conducted for greenhouse tomato 

transplants for the following exposure scenarios:

1. Mixing/Loading/Applying with a manually-pressurized handwand;

2. Mixing/Loading/Applying with a backpack sprayer; and

3. Mixing/Loading/Applying with a mechanically-pressurized handgun. 

Summaries of the risk estimates for occupational handlers are included in Appendix D, Table D1. At baseline, without any required PPE, all combined (dermal and inhalation) handler risk 

estimates are not of concern (greater than the LOC of 100); all short- and intermediate-term 

handler risk estimates resulted in MOEs ranging from 200 to 140,000.

9.2 Short- and Intermediate-Term Post-Application Risk

Agricultural workers performing typical post-application activities (e.g. scouting, hand weeding)

may receive exposure to cyazofamid residues.

9.2.1 Dermal Post-Application Risk

The post-application exposure estimates are partially based on surrogate data. Default transfer 

coefficients (TCs) are considered to be central tendency. Maximum application rates were used 

in this assessment. Overall, the post-application risk estimates are characterized as being central 

to high-end estimates. 

The registrant previously submitted chemical-specific dislodgeable foliar residue (DFR) studies 

on tomatoes, grapes, and squash. These data have been reviewed and the results were used for 

risk assessment purposes. The predicted DFR values have been used in this assessment to 

estimate dermal exposure to treated vegetables in accordance with current HED exposure 

assessment policy. 
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Based on the proposed use pattern, the squash DFR study was used to assess post-application 

exposure risks from contact with treated leafy greens, basil, and tuberous and corm vegetables. 

These crops are low-growing, with mostly broad leaves. The tomato DFR study was used to 

assess post-application exposure risks from contact with treated fruiting vegetables. The grape 

DFR study was used to assess post-application exposure risks from contact with treated beans, as 

both commodities can grow on vines, and have small leaves. 

All scenarios resulted in MOEs greater than the LOC of 100 (ranging from 9,500 to 1,200,000) 

on day 0 (12 hours after application) and, therefore, are not of concern to HED. The postapplication exposure scenarios associated with the proposed uses are summarized in Appendix 

D, Table D-2.

Even though post-application exposure to potatoes while hand harvesting was not assessed, the 

resulting MOE for foliar contact to treated tomatoes was 45,000. Even if soil residues were 10X

higher than the estimated foliar residues, hand harvesting would not result in risks of concern, 

even using the at-planting application rate. Therefore, HED believes the occupational postapplication assessment for foliar contact to tuberous and corm vegetables would be protective of 

hand harvesting potatoes due to the conservative nature of the application rate (0.16 lb ai/A vs. 

0.072 lb ai/A), the conservative TC (1900 cm2/hr), and environmental fate properties.

Restricted Entry Interval

Typically, under the Worker Protection Standard for Agricultural Pesticides, active ingredients 

classified as acute toxicity categories III or IV for these routes are assigned a 12-hour REI. 

Based on the quantitative post-application assessment, the 12-hour REI that appears on the 

proposed label is adequate to protect agricultural workers from post-application exposures to 

cyazofamid.

9.2.2 Inhalation Post-Application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for cyazofamid at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV), low vapor pressure (9.98 x 10-8 mm Hg at 25 oC) and 

the low proposed use rates (<0.16 lb ai/A, at-planting). However, there are multiple potential 

sources of post-application inhalation exposure to individuals performing post-application 

activities in previously treated fields. These potential sources include volatilization of pesticides 

and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert 

advice and input on issues related to volatilization of pesticides from its Federal Insecticide, 

Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and 

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

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

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 
CYAZOFAMID Human Health Risk Assessment DP No. D397213

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procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for cyazofamid.

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

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

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

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

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

inhalation exposure scenarios.

The Worker Protection Standard for Agricultural Pesticides contains requirements for protecting 

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

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

applications)]. 

10.0 References

Dodd, Nancy. 04/25/2012. DP Barcode 396051. “Cyazofamid. Petition for the Establishment of 

Permanent Tolerances and Registration for Use on Basil, Succulent Beans, the Fruiting 

Vegetable Group 8-10, the Leafy Greens Subgroup 4A, and the Tuberous and Corm 

Vegetable Subgroup 1C. Summary of Analytical Chemistry and Residue Data.”

Dodd, Nancy. 04/30/2012. DP Barcode 397214. “Cyazofamid Acute and Chronic Aggregate 

Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 

Registration Action on Basil, Succulent Beans, the Fruiting Vegetable Group 8-10, the Leafy

Greens Subgroup 4A, and the Tuberous and Corm Vegetable Subgroup 1C.”

Meléndez, José. 02/10/2012. DP Barcode 396052. “Estimated Drinking Water Concentrations of 

Cyazofamid and its Degredates of Concern CCIM, CCIM-AM and CTCA, for Use in Human 

Health Risk Assessment: IR-4 Petition for the Use on Succulent Beans, Chelled Beans, Leafy

Greens Subgroup 4A, Basil (Fresh and Dried Leaves), Tuberous and Corm Vegetables 

Subgroup 1C, and Fruiting Vegetables Group 8-10.”

O’Rourke, Kelly. 03/19/2008. DP Barcode 342612. “Human Health Risk Assessment to Support 

the Registration of Cyazofamid for Use on Carrot.”

Rury, Kristin. 06/18/2012. DP Barcode 397215. “Cyazofamid. Occupational Exposure 

Assessment for Proposed Uses on Leafy Greens, Subgroup 4A; Succulent-Podded and 

Succulent-Shelled Beans; Basil; Vegetable, Tuberous and Corm, Subgroup 1C; and 

Vegetables, Fruiting, Crop Group 8-10 with An Updated Residential Exposure Assessment 

of All Existing Residential Uses.”

Tsaur, Nancy. 04/07/2010. DP Barcode 370671. “Cyazofamid. Human Health Risk Assessment 

for Proposed Uses on Brassica (Cole) Leafy Vegetables Crop Group 5, Turnip Greens, 

Spinach, and Hops.”
CYAZOFAMID Human Health Risk Assessment DP No. D397213

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR § 158.500) for food use for cyazofamid are in Table A.1. Use of the 

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

Table A.1. Satisfication of Cyazofamid Toxicology Data Requirements

Study Technical

Required Satisfied

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

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

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

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

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

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

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

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

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

yes

yes

yes

CR1

CR2

yes

yes

yes

-

-

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

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

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

yes

yes

yes

yes

yes

yes

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

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

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

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

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

870.5375 Mutagenicity—Structural Chromosomal Aberrations.....

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

yes

yes

yes

yes

yes

yes

yes

yes

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

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

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

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

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

yes

no

yes

yes

no

yes

-

yes

no

-

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

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

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

yes

CR1

yes

yes

-

no

Special Studies for Ocular Effects

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

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

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

CR1= Conditionally required; CR2= 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; * = needs to be upgraded.
CYAZOFAMID Human Health Risk Assessment DP No. D397213

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A.2 Toxicity Profiles

Table A.2-1. Cyazofamid Acute Toxicity Profile

Guideline 

No. Study Type MRID Results

Toxicity 

Categor

y

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 > 5.5 mg/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) -

Table A.2-2. Toxicity Profile of Cyazofamid [IKF-916] Technical

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses Results

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.
CYAZOFAMID Human Health Risk Assessment DP No. D397213

Page 33 of 43

Table A.2-2. Toxicity Profile of Cyazofamid [IKF-916] Technical

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses Results

870.3700a

Prenatal 

developmental in 

rats

45430404 (1999)

Acceptable/guideline

0, 30, 100, or 1,000 mg/kg/day

Maternal NOAEL = 1,000 mg/kg/day

LOAEL = not observed

Developmental NOAEL = 100 mg/kg/day

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

incidence of bent ribs.

870.3700b

Prenatal 

developmental in 

rabbits

45408934 (1999)

Acceptable/guideline

0, 30, 100, or 1,000 mg/kg/day

Maternal NOAEL = 1,000 mg/kg/day

LOAEL = not observed

Developmental NOAEL = 1,000 mg/kg/day

LOAEL = not observed

870.3800

Reproduction and 

fertility effects in 

rats

45408935 (1998)

Acceptable/guideline

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

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

1114-2185 mg/kg/day

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

1416-2179 mg/kg/day

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

1117-2714 mg/kg/day

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

1451-2678 mg/kg/day

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

mg/kg/day

LOAEL = not observed

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

LOAEL = not observed

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

LOAEL = not observed

870.4100a

Chronic toxicity in 

rats

45408936 (1999)

Acceptable/guideline

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

ppm

0, 0.35, 1.7, 17.1, or 171.1 

mg/kg/day

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

20,000 ppm 0, 2.0, 20.2, 207.8, 

or 856.0 mg/kg/day

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

LOAEL = not observed.

870.4100b

Chronic toxicity in 

dogs

45408931 (2001)

Acceptable/guideline

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

NOAEL = 200 [M/F] mg/kg/day

LOAEL = 1,000 [M/F] mg/kg/day based on increased 

cysts in parathyroids in males.

870.4200

Carcinogenicity 

rats

45408936 (1999)

Acceptable/guideline

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

LOAEL = not observed.

No evidence of carcinogenicity

870.4300

Carcinogenicity 

mice

45408932 (1999)

Acceptable/guideline

NOAEL = 94.8 [M] mg/kg/day

LOAEL = 985 [M] mg/kg/day based on increased 

incidence of skin lesions including hair loss, body sores, 

dermatitis, ulceration, and acanthosis.

No evidence of carcinogenicity

Gene Mutation

870.5100

Bacterial reverse 

mutation assay

45408937 (1998)

Acceptable/ guideline

(ai)

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

and tube preincubation (not cytotoxic but there was 

precipitation at ≥1,500 μg/plate.
CYAZOFAMID Human Health Risk Assessment DP No. D397213

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Table A.2-2. Toxicity Profile of Cyazofamid [IKF-916] Technical

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses Results

Gene Mutation

870.5300

Mammalian cell 

culture

45409002 (1998)

Acceptable/ guideline

(ai)

Negative ± S9 up to cytotoxic and precipitating 

concentration of 100 μg/mL

Cytogenetics

870.5375 

Chromosomal 

aberrations

45409003 (1996)

Acceptable/ guideline

(ai)

Negative ± S9 for clastogenic/aneugenic activity up to 

cytotoxic and precipitating 200 μg/mL

Cytogenetics

870.5395

Micronucleus test 

on mouse

45409004 (1996)

Acceptable/ guideline

(ai)

Negative up to the highest dose tested (limit dose) 

2,000 mg/kg

Other Effects

870.5500

Bacterial DNA 

repair test (Recassay)

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 slight increase (∼45%) in motor activity at day 14 

among the mid- and high-dose males is marginal and 

should not be considered an adverse finding.

870.6200b

Subchronic 

neurotoxicity 

screening battery

Study not available.

870.6300

Developmental 

neurotoxicity

Study not available.
CYAZOFAMID Human Health Risk Assessment DP No. D397213

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Table A.2-2. Toxicity Profile of Cyazofamid [IKF-916] Technical

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses Results

870.7485

Metabolism and 

pharmacokinetics 

in rats

45409006- 45409009 and 

45434602 (1998- 1999)

Acceptable/guideline

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

mg/kg repeat non-labeled 

followed by 0.5 mg/kg [phenylU14C]- or [14C-Imidazole] 

IKF-916.

Biliary excretion study: 0.5 or 

1,000 mg/kg [phenyl- U14C]-

or [14C-Imidazole] IKF-916.

There was rapid absorption (irrespective of dose tcmax = 

0.25-0.5 hrs) and rapid elimination at the low dose (t1/2

4.4-5.8 hrs) while there was saturated absorption with 

prolonged elimination (t1/2 of 7.6-11.6 hrs) at the highdose. The extent of absorption (as per cent of 

administered dose) was highly dose-dependent being 

nearly 75% at the low dose and only about 5% at the 

high dose. Both the urine and feces were major routes 

of excretion at the low dose with most of the urinary 

radioactivity being a metabolite named CCBA (4-(4-

chloro-2-cyanoimidazol-5-yl)benzoic acid). The biliary 

elimination was highly variable at the low dose (∼12-

39% of the administered low dose) and negligible (<2%) 

in the high-dose groups. Urinary or biliary excretion in 

the high-dose groups was low (each ∼2%) with most of 

the radioactivity being CCBA. Irrespective of the 

dosing regimen, most of the recovered fecal 

radioactivity was unchanged parent compound; the 

major fecal metabolites were CCBA and 4-chloro-5-ptolylimidazole-2-carbonitrile (CCIM) each of which 

being less than 5% of the administered dose. Tissue 

burdens at t1/2, tmax, and at 168 hours post dose indicated 

rapid clearance and low tissue burdens suggesting little 

or no bioaccumulation or sequestration.

870.7600

Dermal penetration Study not available.

Special study:

In Vitro

Metabolism of 

IKF-916 and 

CCIM in Blood 

and Stomach 

Contents

MRID 45409010 (1999)

Acceptable/non-guideline

The in vitro biodegradation of [14C-Bz]IKF-916 or [14CBz)CCIM by rat blood or rat stomach contents was 

examined. The results indicated that, during the 60-

minute incubation period, IKF-916 underwent 

degradation to CCIM (∼30%) in blood but was stable in 

stomach contents while CCIM was unaffected in either 

medium. The results also suggest that CCIM could be 

produced in rats following IKF-916 entering the blood 

compartment but not necessarily in the stomach 

compartment.

Special study:

In Vitro

Metabolism of 

CCIM in S9 

Fraction

MRID 45409011 (1999)

Acceptable/non-guideline

The in vitro metabolism of 14C-CCIM was followed up 

to five minutes in the presence of rat liver S9. The 

results suggested that CCIM was rapidly and completely 

metabolized within 5 minutes to at least three 

metabolites with the major one being CHCN (4-chloro5(4-hydroxymethyl-phenyl)-imidazole-2-carbonitrile) 

which accounted for 77-94% of the radioactivity. 

Lower concentrations were found of CCBA (3-13%) 

and one or more unknown metabolites. It was 

concluded that CCIM produced in the intestines or 

blood would be rapidly and completely metabolized by 

the liver.
CYAZOFAMID Human Health Risk Assessment DP No. D397213

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Table A.2-2. Toxicity Profile of Cyazofamid [IKF-916] Technical

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses Results

Special study:

In Vitro Study to 

Identify 

Metabolites 

Absorbed Through 

the Intestinal 

Mucosa After 

Incubation with 

IKF-916 and 

CCIM

MRID 45409012 (1999)

Acceptable/non-guideline

Using in vitro isolated rat intestinal segments containing 

[

14C]IKF-916 or [14C]CCIM, 2.6% of IKF-916 and 

10.4% of CCIM was transferred from the lumen 

(mucosal side) to the exterior (serosal side) of the gut 

segment. Of the IKF-916 that was absorbed and 

transferred to the buffer solution, approximately 60% 

had undergone biotransformation/degradation to CCIM, 

CCBA and three additional products. Also, CCIM 

appeared to be degraded to two metabolites not 

observed for intestine preparations containing IKF-916. 

Based on the findings of this study, cyazofamid seems 

to be poorly absorbed from the intestinal lumen 

although its conversion to CCIM or other metabolites 

may increase overall transfer across the gut wall.

Special study:

Comparative 

metabolism of 

[

14C]IKF-916 or 

[

14C]CCIM in rats

MRID 45409013 (1999)

Acceptable/non-guideline

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

[

14C-Bz]IKF-916 or 0.33 mg/kg of [14C-Bz]CCIM and, 

after 30 minutes, blood, liver, stomach (plus contents), 

and duodenum (plus contents) were collected and 

analyzed for radioactivity and metabolites. Following a 

single gavage dose of CCIM, the metabolites CCBA and 

CHCN, in addition to unchanged CCIM, were detected 

in the plasma and liver. The same metabolites, as well 

as CCIM, were also detected in plasma and liver 

following administration of IKF-916. Therefore, orally 

administered IKF-916 is converted to CCIM and 

subsequently to CCBA and CHCN.
CYAZOFAMID Human Health Risk Assessment DP No. D397213

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Appendix B. Physical/Chemical Properties and Metabolic Profile

Table B-1. 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 

Log KOW = 3.2

KOW = 1.585 x 103

UV/visible absorption spectrum pH Λmax (nm)

2

7

10

285

279

287

Table B-2. Identification of Compounds from the Cyazofamid Metabolism Studies

Common Name/ 

Code/Matrix

Chemical Name Chemical Structure

Cyazofamid/

IKF-916

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

methylphenyl)-1H-imidazole-1-sulfonamide

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

N

N

H3C

Cl

CN

SO2N(CH3)

2

N

H

N

H C3

Cl

CN
CYAZOFAMID Human Health Risk Assessment DP No. D397213

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Table B-2. Identification of Compounds from the Cyazofamid Metabolism Studies

Common Name/ 

Code/Matrix

Chemical Name Chemical Structure

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

acid

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

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

Appendix C. Review of Human Research

Studies reviewed for ethical conduct:

MRID 44972201 – ORETF data 

PHED Surrogate Exposure Guide 

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

intentionally exposed to a pesticide or other chemical. These studies, which comprise the 

Pesticide Handler Exposure Database (PHED) and the Outdoor Residential Exposure Task Force 

(ORETF), have been determined to require a review of their ethical conduct and have received 

that review. In this assessment, ORETF data were used to assess loading/applying with a push 

type spreader (data from MRID 44972201) and PHED data were used to assess loading/applying 

with a belly grinder.

 

Studies reviewed by the Human Studies Review Board:

None.

N

H

N

Cl

CN

HO

O

N

H

N

H C3

Cl

O

NH2
CYAZOFAMID Human Health Risk Assessment DP No. D397213

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Appendix D. Occupational Exposure and Risk Estimates Summary Table

Table D-1. Short- and Intermediate-Term Agricultural Handler Exposure and Risk Estimates for Cyazofamid

Exposure 

Scenario Crop or Target

App 

Rate 1

Amount 

Treated Daily

Unit Exposure 3 Combined Dose 5 MOE 6

lb ai/A

or

lb ai/gal

Baseline 

Dermal 

PPE-G 

Dermal

Baseline 

Inhalation

Baseline 

Dermal + 

Baseline 

Inhalation

PPE-G 

Dermal + 

Baseline 

Inhalation

Combined 

Baseline 

Dermal + 

Inhalation

Combined 

PPE-G + 

Baseline 

Inhalation μg/lb ai

mg/kg/day

Mixer/Loader

M/L to 

Support 

Aerial 

Application

Leafy Greens, Succulent-Podded and 

Succulent-Shelled Beans, Tuberous 

and Corm Vegetables, and Fruiting 

Vegetables

0.072 350 acres 220 37.6 0.219 0.030 0.0052 3,400 19,000

Basil 0.078 350 acres 220 37.6 0.219 0.032 0.0056 3,100 18,000

M/L to 

Support 

Chemigation 

Leafy Greens, Succulent-Podded and 

Succulent-Shelled Beans, Tuberous 

and Corm Vegetables, and Fruiting 

Vegetables

0.072 350 acres 220 37.6 0.219 0.030 0.0052 3,400 19,000

Basil 0.078 350 acres 220 37.6 0.219 0.033 0.0056 3,100 18,000

Tuberous and Corm Vegetables At 

Planting 0.16 350 acres 220 37.6 0.219 0.066 0.015 1,500 8,700

Fruiting Vegetables Soil Drench 0.047 350 acres 220 37.6 0.219 0.019 0.0034 5,100 30,000

M/L to 

Support 

Groundboom 

Application

Leafy Greens, Succulent-Podded and 

Succulent-Shelled Beans, Tuberous 

and Corm Vegetables, and Fruiting 

Vegetables

0.072 80 acres 220 37.6 0.219 0.0068 0.0012 15,000 85,000

Basil 0.078 80 acres 220 37.6 0.219 0.0074 0.0013 14,000 78,000

Tuberous and Corm Vegetables At 

Planting 0.16 80 acres 220 37.6 0.219 0.015 0.0026 6,600 38,000

Fruiting Vegetables Soil Drench 0.047 80 acres 220 37.6 0.219 0.0044 0.00077 22,000 130,000

Applicator
CYAZOFAMID Human Health Risk Assessment DP No. D397213

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Table D-1. Short- and Intermediate-Term Agricultural Handler Exposure and Risk Estimates for Cyazofamid

Exposure 

Scenario Crop or Target

App 

Rate 1

Amount 

Treated Daily

Unit Exposure 3 Combined Dose 5 MOE 6

lb ai/A

or

lb ai/gal

Baseline 

Dermal 

PPE-G 

Dermal

Baseline 

Inhalation

Baseline 

Dermal + 

Baseline 

Inhalation

PPE-G 

Dermal + 

Baseline 

Inhalation

Combined 

Baseline 

Dermal + 

Inhalation

Combined 

PPE-G + 

Baseline 

Inhalation μg/lb ai

mg/kg/day

Applying 

Sprays via 

Aerial 

Equipment

Leafy Greens, Succulent-Podded and 

Succulent-Shelled Beans, Tuberous 

and Corm Vegetables, and Fruiting 

Vegetables

0.072 350 acres 5 N/A 0.068 0.00070 N/A 140,000 N/A

Basil 0.078 350 acres 5 N/A 0.068 0.00076 N/A 130,000 N/A

Applying 

Sprays via 

Groundboom 

Equipment

Leafy Greens, Succulent-Podded and 

Succulent-Shelled Beans, Tuberous 

and Corm Vegetables, and Fruiting 

Vegetables

0.072 80 acres 78.6 16.1 0.34 0.0025 0.00053 41,000 190,000

Basil 0.078 80 acres 78.6 16.1 0.34 0.0027 0.00057 38,000 180,000

Leafy Greens, Succulent-Podded and 

Succulent-Shelled Beans, Tuberous 

and Corm Vegetables, and Fruiting 

Vegetables

0.16 80 acres 78.6 16.1 0.34 0.0055 0.0012 18,000 86,000

Fruiting Vegetables Soil Drench 0.047 80 acres 78.6 16.1 0.34 0.0016 0.00034 62,000 290,000

Flagger

Flagging for 

Aerial Sprays

Leafy Greens, Succulent-Podded and 

Succulent-Shelled Beans, Tuberous 

and Corm Vegetables, and Fruiting 

Vegetables

0.072 350 acres 11 12 0.35 0.0016 0.0018 62,000 57,000

Basil 0.078 350 acres 11 12 0.35 0.0018 0.0019 57,000 53,000

Mixer/Loader/Applicator

Manually 

Pressurized 

Handwand

Tomato Greenhouse Transplant Soil 

Drench 0.0085 40 gallons 100,000 430 30 0.21 0.0011 480 93,000

Backpack 

Sprayer

Tomato Greenhouse Transplant Soil 

Drench 0.0085 40 gallons 8,260 8,260 2.58 0.017 0.017 5,800 5,800
CYAZOFAMID Human Health Risk Assessment DP No. D397213

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Table D-1. Short- and Intermediate-Term Agricultural Handler Exposure and Risk Estimates for Cyazofamid

Exposure 

Scenario Crop or Target

App 

Rate 1

Amount 

Treated Daily

Unit Exposure 3 Combined Dose 5 MOE 6

lb ai/A

or

lb ai/gal

Baseline 

Dermal 

PPE-G 

Dermal

Baseline 

Inhalation

Baseline 

Dermal + 

Baseline 

Inhalation

PPE-G 

Dermal + 

Baseline 

Inhalation

Combined 

Baseline 

Dermal + 

Inhalation

Combined 

PPE-G + 

Baseline 

Inhalation μg/lb ai

mg/kg/day

Mechanically 

Pressurized 

Handgun

Tomato Greenhouse Transplant Soil 

Drench 0.0085 625 gallons 4,310 4,310 3,931 0.49 0.49 200 200

a Application Rates based on proposed uses for cyazofamid (Ranman® 400SC, EPA Reg. No. 71512-3).

b Amount Treated Daily taken from Exposure Science Advisory Council (ExpoSAC) Policy No. 9.1.

c UEs = Unit Exposures based on PHED Version 1.1. Level of mitigation = Baseline (no gloves, no respirator) or PPE (gloves, no respirator).

d Dose (mg/kg/day) = daily unit exposure (μg/lb ai) × application rate (lb ai/acre or gal) × area treated or amount handled/day (acres/day or gal/day) x conversion factor (1 

mg/1,000 μg) × absorption factor (%) ÷ body weight (69 kg). Dermal absorption factor = 37%. No inhalation absorption factor.

e Combined Dose = Dermal Dose (mg/kg/day) + Inhalation Dose (mg/kg/day).

f Combined MOE = NOAEL ÷ Combined Dose (mg/kg/day). ST/IT Dermal/Inhalation NOAEL = 100 mg/kg/day. ST/IT level of concern = 100.

Table D-2. Post-Application Exposure and Risk Estimates for Cyazofamid on Day of Application (Day 0)

Crop 

Proposed 

Application 

Rate Activity

Transfer 

Coefficient a

ChemicalSpecific 

DFR Data b

Normalized 

DFR c

Daily 

Dermal 

Dose d

Short- and 

IntermediateTerm MOE e

lb ai/A cm2/hr μg/cm2 mg/kg/day

Leafy Greens 0.072

Irrigation (hand set) 1900

Squash DFR

0.061 0.0049 20,000

Irrigation (non-hand set), Mechanical Weeding 0 0.061 N/A N/A

Scouting 210 0.061 0.00055 180,000

Hand Harvesting 1100 0.061 0.0029 35,000

Thinning plants, Hand Weeding 70 0.061 0.000018 550,000

Transplanting 230 0.061 0.00060 170,000

Succulent-Podded and Succulent-Shelled Beans

Beans, Snap and Pea, Green 0.072

Irrigation (hand set) 1900

Grape DFR

0.129 0.0105 9,500

Irrigation (non-hand set), Mechanical 

Harvesting, Mechanical Weeding, Fertilizing 0 0.129 N/A N/A

Scouting 210 0.129 0.0012 86,000

Hand weeding 70 0.129 0.00039 260,000

Hand Harvesting 1100 0.129 0.0061 16,000

Tuberous and Corm Vegetables

Potato 0.16 Irrigation (hand set) 1900 Squash DFR 0.027 0.0022 45,000
CYAZOFAMID Human Health Risk Assessment DP No. D397213

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Table D-2. Post-Application Exposure and Risk Estimates for Cyazofamid on Day of Application (Day 0)

Crop 

Proposed 

Application 

Rate Activity

Transfer 

Coefficient a

ChemicalSpecific 

DFR Data b

Normalized 

DFR c

Daily 

Dermal 

Dose d

Short- and 

IntermediateTerm MOE e

lb ai/A cm2/hr μg/cm2 mg/kg/day

Irrigation (non-hand set), Mechanical Weeding, 

Mechanical Harvesting 0 0.027 N/A N/A

Scouting 210 0.027 0.00025 400,000

Hand Weeding 70 0.027 0.000082 1,200,000

Hand Harvesting Alternate 

Guidance f 0.027 See Footnote f

Fruiting Vegetables

Eggplant 0.072

Hand Harvesting 550

Tomato 

DFR

0.069 0.0016 61,000

Tying/Training 550 0.069 0.0016 61,000

Scouting, Hand Weeding, Hand Pruning, Fruit 

Thinning 90 0.069 0.00027 380,000

Eggplant, Okra, Bell Pepper, 

Chili Pepper, Tomato

0.072

Irrigation, Hand Set 1900 0.069 0.0056 18,000

Irrigation (Non Hand Set), Mechanical Weeding, 

Mechanical Harvesting 0 0.069 N/A N/A

Eggplant, Okra, Tomato Transplanting 230 0.069 0.00068 150,000

Okra, Bell Pepper, Chili 

Pepper, Tomato

Hand Harvesting and/or Tying/Training 1100 0.069 0.0033 31,000

Scouting 210 0.069 0.00062 160,000

Hand Weeding 70 0.069 0.00021 480,000

Chili Pepper, Tomato Hand Pruning 70 0.069 0.00021 480,000

Basil (Mint as surrogate)

Basil (Mint as surrogate) 0.078

Irrigation (hand set) 1900

Squash DFR

0.056 0.0046 22,000

Irrigation (non-hand set), Mechanical 

Harvesting, Transplating 0 0.056 N/A N/A

Scouting 1100 0.056 0.0027 38,000

Weeding, Hand 70 0.056 0.00017 590,000

a Transfer Coefficient taken from Exposure Science Advisory Council (ExpoSAC) Policy No. 3.2: Agricultural Transfer Coefficients (March, 2012).

b Chemical-Specific DFR Values calculated from original DFR studies on tomatoes (MRID 45409118), squash (MRID 45409119), and grapes (MRID 45409118).

c Normalized DFR = Study DFR (μg/cm2× Application Rate DFR (lb ai/A) ÷ Proposed Application Rate (lb ai/A).

d Daily Dermal Dose (mg/kg/day) = Normalized DFR (μg/cm2) × TC (cm2/hr) × exposure time (8 hrs) × dermal abs factor (37%) × CF (1000 μg/mg) ÷ body weight (69 kg).

e MOE = NOAEL (mg/kg/day) ÷ Daily Dermal Dose (mg/kg/day). ST/IT Dermal NOAEL = 100 mg/kg/day. LOC = 100.

f Exposure to cyazofamid while hand harvesting potatoes is likely to be from treated soil. However, TCs are only available for exposure following foliar application. HED 

believes the foliar post-application assessment would be protective of hand harvesting following cyazofamid application to potatoes due to the conservative nature of the 

application rate (0.16 lb ai/A vs. a 0.072 lb ai/A) and the TC (1900 cm2/hr). 
CYAZOFAMID Human Health Risk Assessment DP No. D397213

Page 43 of 43

Appendix E. International Residue Limit Summary

Table E. Summary of U.S. and International Tolerances and Maximum Residue Limits 

Residue Definition

U.S. Canada Mexico b Codex

40 CFR 180.601:

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

methylphenyl)-1H-imidazole-1-sulfonamide and 

its metabolite, 4- chloro-5-(4-methylphenyl)-1Himidazole-2-carbonitrile, calculated as the 

stoichiometric equivalent of cyazofamid

4-chloro-2-cyano-N,N-dimethyl5-(4-methylphenyl)-1Himidazole-1-sulfonamide, 

including the metabolite

4-chloro-5-(4-methylphenyl)-1Himidazole-2-carbonitrile

None

Tolerance or Maximum Residue Limit

Commodity a U.S. Canada Mexico b Codex

ppm mg/kg

Bean, succulent 0.5

Bean, succulent, shelled 0.08

Leafy greens subgroup 4A 10

Basil, fresh leaves 30

Basil, dried leaves 90

Vegetable, tuberous and corm, 

subgroup 1C 0.02 0.02 potatoes

Vegetable, fruiting, group 8-10 0.9 0.2 tomatoes

Completed: M. Negussie, 02/02/2012.

a Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and 

not those proposed by the applicant.

b Mexico adopts U.S. tolerances and/or Codex MRLs for its export purposes.