UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: November 21, 2014 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Cyazofamid. Human Health Assessment Scoping Document in Support of Registration 

Review. 

PC Code: 085651 

Decision No.: 495518 

Petition No.: NA 

Risk Assessment Type: NA 

TXRNo.: NA 

MRIDNo.:NA 

DP Barcode: D422931 

Registration No.: NA 

Regulatory Action: Registration Review 

Case No.: NA 

CAS No.: 120116-88-3 

40 CFR: § 180.60 I 

FROM: Cassi Walls, Senior Biologist ~ ;2.. l...J:°'~ Nancy 

Whang 

Dodd, 

Phang

Chemist 

, Senior To

~ 

xicologist

~ 

/¥~ 

Kristin Rury, Biologist V-~ 

Risk Assessment Branch III (RA~ 

Health Effects Division (7509P) 

Office of Pesticide Programs 

THROUGH: Christine Olinger, Branch Chie~ & /; Risk Assessment Branch III (RAB3) o~-­

Health Effects Division (7509P) 

Office of Pesticide Programs 

TO: Jose Gayoso 

Chemical Review Manager 

Risk Management and Implementation Branch II (RMIB2) 

Pesticide Re-Evaluation Division (PRD) (7508P) 

Office of Pesticide Programs 

Executive Summary 

Attached is the Health Effects Division's (HED's) human health risk assessment scoping 

document for the fungicide cyazofarnid to support Registration Review. To evaluate the scope 

of work necessary to support Registration Review, HED has considered recent risk assessments 

for cyazofamid, updates to its toxicity, exposure and usage databases, and the latest Agency 

science policy and risk assessment methodologies. The most recent risk assessment for 

cyazofamid was conducted in 2012 for numerous new uses (D397213, N. Tsaur, 06/28/2012). 

Page 1 of 25 
Cyazofamid is currently registered for use on numerous agricultural crops; golf course turf, sod 

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

ornamentals in greenhouses, fields, and residential areas. 

The toxicology database for cyazofamid is complete and adequate for risk assessment. On 

January 8, 2015, HED's Hazard and Science Policy Council (HASPOC), based on a weight of 

evidence approach considering all the available hazard and exposure information granted a 

waiver for the subchronic neurotoxicity and the immunotoxicity studies that are required under 

the 2007 40 CFR toxicology data requirements (TXR No. 0056341 ). 

Based on the toxicology database, cyazofamid has no consistent target organ of toxicity. In 

repeated dose studies, the kidney was the target organ of cyazofamid toxicity in rats. In dogs, 

there were no major toxicity findings. Based on the available data, there are no concerns for 

neurotoxicity, immunotoxicity, or mutagenicity. 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. 

Based on the available data, toxicity endpoints and points of departure (PODs) have been 

selected for acute dietary (for females 13-49 years of age), chronic dietary, short- and 

intermediate-term incidental oral, short-and intermediate-term dermal (for adults), and short- and 

intermediate-term inhalation exposure scenarios. Since no observed effects could be attributed 

to a single dose, an acute endpoint for acute dietary exposure was not established for the general 

population. Dermal absorption is 37%. The 1 OX Food Quality Protection Act (FQPA) Safety 

Factor was removed (i.e, IX) because there are no residual uncertainties for pre- and post-natal 

toxicity and there are no residual uncertainties in the exposure database. 

The residue chemistry database is sufficient to support the current registrations of cyazofamid. 

The nature of the residue in plants and livestock has been adequately defined. Adequate field 

trial/processing data, rotational crop data, enforcement methods are available. The storage 

stability data are under review. 

New dietary exposure and aggregate risk assessments are not anticipated during Registration 

Review, unless there are significant increases to the drinking water exposure estimates that need 

to be incorporated. 

New residential handler and post-application exposure and risk assessments are not anticipated to 

be needed during Registration Review. However, occupational handler and post-application 

exposure and risk assessments are needed during Registration Review to account for recent 

changes in exposure assessment assumptions, including body weight, amount treated, and 

transfer coefficients. 

The Agency will examine the need for spray drift and volatilization assessments during 

Registration Review for cyazofamid based on the potential for exposure to bystanders from 

agricultural applications. 

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Page 3 of 25

Introduction

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

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

Phytophthora, Plasmopara, Pseudoperonospora, and Pythium) and Plasmodiophoromycetes 

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

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

fungi. 

The most recent human health risk assessment for cyazofamid was finalized in 2012 for 

numerous new uses (D397213, N. Tsaur, 06/28/12). Cyazofamid is currently registered on a 

variety of food crops including, potatoes, basil, peppers, cucumber, squash, eggplant, tomatoes, 

broccoli, cabbage, and ornamental plants and turf. Homeowners may apply cyazofamid to

residential turf and ornamental plants. Cyazofamid end use products are formulated as soluble 

concentrates. Applications can be made with ground, aerial, chemigation, and hand held spray 

equipment. Refer to Attachment 1 (Table 1) for the chemical identity of cyazofamid. 

Hazard Identification/Toxicology

The toxicology database for cyazofamid is adequate for risk assessment, except for the 

immunotoxicity and subchronic neurotoxicity studies. All other toxicity data requirements for 

conventional pesticide registration under the current 40 CFR §158.500 have been satisfied. All 

studies needed to assess susceptibility concerns, such as developmental and reproduction studies, 

were submitted. On January 8, 2015, the HASPOC granted waiver for the subchronic 

neurotoxicity and the immunotoxicity studies (TXR#0056341). The acute neurotoxicity study 

tested up to the limit dose (2000 mg/kg) did not yield any neurotoxic effect, and the existing data 

did not suggest cyazofamid to affect the parameters generally related to immunotoxicity.

Cyazofamid belongs to a chemical class based on the cyanoimidazole moiety. 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. However, the toxicology database indicates cyazofamid has relatively low toxicity via 

all routes of administration (see Attachment 5 for the complete toxicity profile tables for 

cyazofamid). In some studies the adverse effects were seen at relatively high dose levels, some 

of which were either approaching the limit dose or at the limit dose. Cyazofamid has no specific 

target organ of toxicity. For example in rats, cyazofamid was found to produce kidney effects 

characterized by an increase in the incidence of basophilic kidney tubules in the 28-day and 90-

day oral toxicity studies. However, similar kidney finding was not observed following life time 

exposure at doses approaching the limit dose (1000 mg/kg/day). In the mouse carcinogenicity 

study, skin lesions were found following repeated life time oral dosing at the limit dose (1000 

mg/kg/day). In the dog 1-year study, the overall toxicity produced by cyazofamid seemed to be 

limited to an increase in the incidence of parathyroid cysts in the high dose males (1000 

mg/kg/day).

 

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 
Page 4 of 25

weak dermal sensitizer. 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.

The database for FQPA assessment is complete. 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 no evidence of increased susceptibility following 

pre-natal exposure to rabbits at the Limi Dose (1000 mg/kg/day) or following pre and post natal 

exposure to rats at the Limit Dose in a two generation reproduction study. In the pre-natal 

developmental toxicity study in rats, evidence for increased susceptibility manifested as 

increased incidences of fetuses with bent ribs was at the Limit Dose in the absence of any 

maternal toxicity. The concern for this effect, however, is low since the effects were seen only at 

the Limit Dose (i.e, no dose response) and the observed effects are reversible anomaly rather 

than frank malformation. Thus, there are no residual uncertainty for pre-natal toxicity. 

Consequently the 10X FQPA Safety Factor is removed (i.e, 1X).

Refer to Attachment 4 for a summary of the toxicity endpoints and PODs for cyazofamid and 

Attachment 5 for the complete toxicity profile tables for cyazofamid. 

Conclusions: The toxicology database of cyazofamid is adequate for risk assessment. Additional 

toxicity data are not required during Registration Review.

Dietary Exposure

The nature of the residue in plants and livestock has been adequately defined. Adequate 

metabolism studies on grape, potato, tomato, goat and hen are available. The residues of concern 

for the dietary risk assessment and the tolerance expression are parent and CCIM in plants, and 

parent only in rotational crops. The residues of concern in water are parent, CCIM, CCIM-AM, 

and CTCA. No livestock tolerances have been established. 

 

Adequate enforcement methods are available. Cyazofamid and the metabolite CCIM are 

completely recovered (>80% recovery) in non-fatty commodities using FDA’s Multiresidue 

Protocol D (without cleanup). The multiresidue method can be used as an enforcement method.

In addition, a high performance liquid chromatography/ultraviolet (HPLC/UV) detection method 

(MRID 45409020; revised in MRID 46550401) is acceptable for use as a single analyte 

enforcement method provided a confirmatory method such as liquid chromatography with 

tandem mass spectrometry (LC/MS/MS) is used. 

Adequate field trial and processing data are available to support the established tolerances. The 

storage stability data are currently under review.

Adequate rotational crop data are available. A confined accumulation in rotational crops study 

indicated that cyazofamid and structurally related metabolites are not expected to be present at a 

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

interval of 30 days. The study supports the 30-day plantback interval currently on the labels. 

Based on the confined rotational crop study, a field accumulation in rotational crops study is not 

required and rotational crop tolerances are not needed.
Page 5 of 25

The registered uses fall under 40 CFR §180.6(a)(3) for livestock commodities, i.e., although it is 

not possible to establish with certainty whether finite residues will be incurred, there is no 

reasonable expectation of finite residues in livestock commodities. For ruminants, this 

conclusion is based on a goat metabolism study and a low calculated dietary burden. For poultry 

and swine, there are no livestock feed items associated with the registered uses (Table 1 

Feedstuffs, June 2008). 

Acute and chronic dietary (food and drinking water) exposure assessments were conducted. The 

assessments were conservative, i.e., based on the assumption that residues in all crops were at the 

tolerance levels and that 100% of the crops were treated. The acute assessment was conducted 

for females 13-49 years old only, since an acute endpoint was not identified for the general US 

population. Both the acute estimated drinking water concentration (EDWC) of 136.2 ppb and 

the chronic EDWC of 133.5 ppb were modeled using Tier 2 PRZM/EXAMS (Pesticide Root 

Zone Model/Exposure Analysis Modeling System) for residues in surface water from use on turf 

and ornamentals, which yielded the highest acute and chronic EDWCs considering all 

registered/proposed uses. The acute and chronic dietary assessments show that the acute and 

chronic dietary risk estimates are below HED’s level of concern (i.e., <100% of the acute or 

chronic population adjusted doses (aPAD or cPAD). The acute dietary risk estimate for females 

13-49 years old at the 95th percentile of exposure was 2.5% of the aPAD. For the general US

population, the exposure for food and drinking water utilized <1% of the cPAD. The chronic 

dietary risk estimate for the highest reported exposed population subgroup, children (1-2 years 

old), utilized 1.5% of the cPAD. 

A cancer dietary risk assessment was not conducted since cyazofamid is classified as “not likely 

to be carcinogenic to humans.”

Conclusions: A new dietary exposure assessment is not anticipated to be needed during 

Registration Review unless there are significant increases to the drinking water exposure 

estimates.

Residential Exposure

Cyazofamid is currently registered for use in residential settings on turf and ornamental plants. 

There is potential for short-term residential exposure to cyazofamid during handling (mixing, 

loading, and applying) and post-application activities. 

Residential Handlers 

The Cyazofamid 400SC label (EPA Reg. No. 71512-13) indicates that it is allowed for use 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 previously performed to 

be protective of potential homeowner exposure. Previous residential exposure and risk 

assessments for cyazofamid were conducted at the maximum registered application rate and 
Page 6 of 25

incorporated the revised 2012 Residential SOPs (K. Rury, D397215, 06/18/2012). Applications 

can be made using handheld spray equipment to turf and ornamentals. Residential handler total 

(dermal + inhalation) margins of exposure (MOEs) ranged from 2,400 to 59,000. 

Residential Post-Application 

Short-term dermal and incidental oral exposure and risk estimates were reassessed using the 

2012 Residential SOPs in the last cyazofamid ORE assessment (K. Rury, D397215, 06/18/2012). 

A dermal risk estimate for children was not conducted because there is no dermal toxicity up to 

the limit dose of 1,000 mg/kg/day in a 28-day dermal toxicity study; therefore, in the absence of 

hazard identified for this population, a risk assessment is not necessary. However, a dermal risk 

assessment for adults is required to protect for effects on the developing fetus because 

developmental toxicity (increased incidence of bent ribs) was seen at 1,000 mg/kg/day. 

Chemical-specific DFR studies on tomatoes, squash, and grapes were submitted for a previous 

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

assessment. Furthermore, a turf transferrable residue (TTR) study using the modified California 

roller is available so the residue values have been incorporated into the most-recent postapplication exposure assessment to treated turf in place of default assumptions and inputs for the 

initial fraction of residue available for transfer. 

Post-application MOEs were not of concern for any of the registered residential uses of 

cyazofamid. The short-term adult dermal post-application MOEs range from 660 to 52,000. The 

short-term incidental oral MOEs for children 1 to <2 years old range from 3,400 to 570,000. 

Spray Drift or Volatilization

Residential bystander exposures resulting from off-site transport (e.g., spray drift or 

volatilization) may occur as a result of applications of cyazofamid. The potential for spray drift 

will be evaluated for each pesticide during the Registration Review process which ensures that 

all uses for that pesticide will be considered concurrently. The approach is outlined in the 

revised (2012) Standard Operating Procedures for Residential Risk Assessment (SOPs) –

Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of 

Spray Drift. This document outlines the quantification of indirect non-occupational exposure to 

drift. In terms of volatilization, the agency has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analysis is required for cyazofamid.

Conclusions: There are registered residential uses of cyazofamid that have been assessed using 

the maximum application rates and revised 2012 Residential SOPs. Therefore, a residential 

handler and post-application assessment is not required during Registration Review. However, 

the Agency will examine the need for a volatilization assessment, as well as evaluate the 

potential cyazofamid exposure from spray drift during Registration Review.
Page 7 of 25

Aggregate Risk Assessment

Aggregate assessments consider exposures from food, drinking water, and residential uses. 

Since there are residential uses of cyazofamid, aggregate risk considers residential handler and 

post-application exposures, food, and drinking water.

In the most recent human health risk assessment (D397213, N. Tsaur, 06/28/2012), an acute 

aggregate risk assessment, which is equivalent to the acute dietary risk assessment, was not of 

concern to HED. Only females 13-49 years old were assessed, since an acute endpoint of 

concern was not identified for the general population.

A short-term aggregate risk assessment was conducted for adults and children. For adults, the 

pathways leading to aggregate exposure include oral dietary (background), dermal, and 

inhalation (primary) routes. For children, the pathways leading to aggregate exposure include

oral dietary (background), incidental oral, and dermal (primary) routes. The adult and children 

short-term aggregate dietary and residential MOEs are 390 and 2,200, respectively (LOC = 100).

Chronic exposure from the residential pathway is not anticipated based on the current 

cyazofamid use pattern. Therefore, the chronic aggregate risk (food and drinking water) is 

equivalent to the chronic dietary (food and drinking water) exposure estimate, which was not of 

concern to HED.

Conclusions: Aggregate exposure to cyazofamid is currently not of concern to HED. New 

aggregate assessments are not anticipated to be needed during Registration Review, unless 

changes in uses, procedures, or EDWCs occur.

Occupational Exposure

Cyazofamid is registered for use on numerous agricultural crops; on golf course turf, sod farms, 

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

ornamentals in greenhouses and fields. There is potential for short- and intermediate-term 

occupational exposure to cyazofamid during handling (mixing, loading, and applying) and postapplication activities.

Occupational Handlers

The registered cyazofamid labels require occupational handlers to wear long sleeved shirts, long 

pants, shoes, socks, and chemical resistant gloves. Applications can be made using ground, 

aerial, chemigation, and handheld spray equipment. Although some of the updated occupational 

exposure assessment policies and body weight assumptions were incorporated into previous 

cyazofamid exposure assessments, updated occupational handler and post-application 

assessments will be needed for occupational handlers of cyazofamid for the following use sites: 

carrots, cucurbits, grapes, hops, ornamentals, and turf. However, an updated occupational 

handler exposure assessment on sod would be protective of the assessment for cyazofamid use 

on carrots, cucurbits, and ornamentals, but an additional exposure assessment on grapes and hops 

would be needed to account for exposure from airblast application methods. All current 

occupational handler MOEs are not of concern (MOE > 100). 
Page 8 of 25

Occupational Post-Application

Occupational post-application short- and intermediate-term dermal and inhalation exposures are 

possible for workers contacting treated crops. Dislodgeable foliar residue (DFR) studies are 

available for cyazofamid, and were incorporated into the most recent exposure assessment (K. 

Rury, D297215, 06/18/2012). That assessment incorporated changes in transfer coefficients and 

body weight assumptions; however, previous post-application assessments for carrots, cucurbits, 

grapes, hops, ornamentals, and turf did not incorporate updated exposure assessment policies. 

Therefore, an updated occupational post-application exposure assessment will be required during 

Registration Review for cyazofamid use on carrots, cucurbits, grapes, hops, ornamentals, and 

turf. All current occupational post-application MOEs are not of concern (MOE > 100). 

Conclusions: There is sufficient information available to assess occupational handler and postapplication exposures. There are also acceptable DFR and TTR studies available to evaluate the 

post-application exposure to cyazofamid. Updated occupational handler and post-application 

exposure assessments will be conducted during Registration Review for cyazofamid use on 

carrots, cucurbits, grapes, hops, ornamentals, and turf. 

Public Health and Pesticide Epidemiology Data

Based on the low frequency and severity of incident cases reported for cyazofamid in both the 

OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National 

Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System 

for Occupational Risk-Pesticides (SENSOR), there does not appear to be a concern at this time 

that would warrant further investigation. For the Main IDS, from January 1, 2009 to August 12, 

2014, there were 0 incidents reported for the single chemical only in the database. In Aggregate 

IDS, from January 1, 2009 to August 12, 2014, there were 2 incidents reported involving 

cyazofamid. These incidents were classified as minor severity. Overall, there are few incidents 

involving cyazofamid reported to IDS. 

A query of the Sentinel Event Notification System for Occupational Risk (SENSOR)-Pesticides 

database for 1998-2010 identified 0 cases involving cyazofamid. 

The Agricultural Health Study (AHS) is a high quality, prospective epidemiology study 

evaluating the link between pesticide use and various health outcomes including cancer. The 

AHS includes private and commercial pesticide applicators and their spouses. If there are AHS 

findings relevant to a particular pesticide going through registration review, the Agency will 

ensure they are considered in the problem formulation/scoping phase of the process and, if 

appropriate, fully reviewed in the risk assessment phase of the process. The AHS includes 

information on use of 50 different pesticide active ingredients commonly used in agriculture. 

Cyazofamid is not included in the AHS, and therefore, this study does not provide information 

for this report.

The Agency will continue to monitor the incident information and if a concern is triggered, 

additional analysis will be included in the risk assessment.
Page 9 of 25

Conclusion: Based on the low frequency and low severity of incident cases reported for 

cyazofamid in both IDS and SENSOR-Pesticides databases, there does not appear to be a 

concern at this time that would warrant further investigation. The Agency will continue to 

monitor the incident information and if a concern is triggered, additional analysis will be 

included in the risk assessment.

Tolerance Assessment and International Harmonization

Tolerances are established for plant commodities under 40 CFR §180.601 for residues of 

the fungicide cyazofamid, including its metabolites and degradates. Compliance with the 

specified tolerance levels is to be determined by measuring only the sum of 4-chloro-2-cyanoN,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. The tolerances on plants include permanent Section 3 tolerances, a Section 18 

emergency exemption tolerance, and a tolerance with regional registration. The plant tolerance 

levels range from 0.02 ppm to 144 ppm. No livestock tolerances are established.

As shown in Attachment 2, there are no Codex maximum residue limits (MRLs) established for 

cyazofamid; therefore, there is no harmonization issue with Codex at this time. 

The US and Canadian tolerance expressions include the same analytes. For commodities with 

both US and Canadian tolerances, the Canadian tolerance levels are generally the same as the US 

tolerance levels, with some exceptions.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, will be considered in the 

registration review, in accordance with US 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 under the NHANES/WWEIA and are 

used in pesticide risk assessments for all registered food uses of a pesticide. These data are 

analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is 

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

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

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

for toddlers, youths, and adults entering or playing on treated areas post-application are 

evaluated. Further considerations are currently in development as OPP has committed resources 

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

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

subgroups.
Page 10 of 25

Cumulative

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 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/.

Human Studies

The risk assessments which have been previously conducted for cyazofamid relied in part on 

data from studies in which adult human subjects were intentionally exposed to a pesticide to 

determine their dermal and inhalation exposure. Many such studies, involving exposure to many 

different pesticides, comprise generic pesticide exposure databases such as the Pesticide 

Handlers Exposure Database (PHED), the Outdoor Residential Exposure Task Force (ORETF), 

and the Agricultural Reentry Task Force (ARTF) Database. EPA has reviewed all the studies 

supporting these multi-pesticide generic exposure databases, and has found no clear and 

convincing evidence that the conduct of any of them was either fundamentally unethical or 

significantly deficient relative to the ethical standards prevailing at the time the research was 

conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of 

Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued 

reliance on these studies.

Data Deficiencies

No toxicological data, residue chemistry, or occupational and residential exposure data are 

needed to support the registered uses of cyazofamid at this time.
Page 11 of 25

References

Recent Memoranda Relevant to Registration Review of Cyazofamid

Author DP/TXR # Date Title

Risk Assessment

W. Wassell D292390 4/27/04 Human Health Risk Assessment to Support the Registration of 

Cyazofamid for use on Potatoes, Tomatoes, Cucurbits, and 

Imported Wine. First Food Use for Cyazofamid.

K.O’Rourke D332426 10/12/06 Human Health Risk Assessment to Support the Registration of 

Cyazofamid for use on Non-Residential Turf and Ornamentals.

K. O’Rourke D342612 3/19/08 No. 7E7244, DP # Human Health Risk Assessment to Support the 

Registration of Cyazofamid for Use on Carrot (PC Code: 085651, 

Petition 342612).

N. Tsaur D356837 5/20/09 Cyazofamid. Human Health Risk Assessment for Proposed Uses 

on Fruiting Vegetables and Okra, Grapes East of the Rocky 

Mountains, Vegetable Greenhouse Transplants, and Commercial 

Application on Residential Turf and Residential Ornamentals.

N. Tsaur D366114 6/3/09 Cyazofamid. Amendment to D356837, D356878 Human Health 

Risk Assessment for Proposed Uses on Fruiting Vegetables and 

Okra, Grapes East of the Rocky Mountains, Vegetable Greenhouse 

Transplants, and Commercial Application on Residential Turf and 

Residential Ornamentals.

N. Tsaur D370671 4/7/10 Cyazofamid. Human Health Risk Assessment for Proposed Uses 

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

Spinach, and Hops.

B. Hanson D376500 8/3/10 Cyazofamid. Human Health Risk Assessment for Proposed 

Section 18 Use on Basil.

N. Tsaur D397213 6/28/12 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.

Residue Chemistry

A. Acierto D323339 2/8/07 PP# 1F06305. Cyazofamid. Data Submitted to Satisfy Conditional 

Registration Requirements for Use on Cucurbits, Potatoes, 

Tomatoes, and Imported Wine Grapes. Summary of Analytical 

Chemistry and Residue Data.

A. Acierto D285680 10/1/04 PP# 1F06305. Cyazofamid. Petition for the Establishment of 

Permanent Tolerances for use on Cucurbits, Potatoes, Tomatoes, 

and Imported Wine Grapes. Summary of Analytical Chemistry and 

Residue Data. PC Code: 085601. DP Barcode: 285680.

A. Acierto D343419 3/6/08 Cyazofamid. PP# 7E7244: Petition for the Establishment of a 

Tolerance for the Combined Residues of Cyazofamid and its 

Metabolite CCIM, in/on Carrot, Roots. Summary of Analytical 

Chemistry and Residue Data.

A. Acierto D357042 3/18/09 Cyazofamid. Amend Section 3 Registration to Add Uses on 

Fruiting Vegetables, Okra, Grape (East of the Rocky Mountains), 

and Greenhouse Vegetable Transplants. Summary of Analytical 

Chemistry and Residue Data.

N. Dodd D396051 4/25/12 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, 
Page 12 of 25

Recent Memoranda Relevant to Registration Review of Cyazofamid

Author DP/TXR # Date Title

and the Tuberous and Corm Vegetable Subgroup 1C. Summary of 

Analytical Chemistry and Residue Data.

Dietary Exposure Assessment

N. Dodd D397214 4/30/12 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. 

Occupational and Residential Exposure Assessment

K. Rury D397215 06/18/2012 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.

Incident Report

S. Recore D423509 10/28/2014 Cyazofamid: Tier I Review of Human Incidents

Toxicology

G. Dannan TXR# 005428 04/15/2004 Report of the Hazard Identification Assessment Review Committee

K. Rury TXR#0056341 Cyazofamid: Summary of Hazard and Science Policy Council 

(HASPOC) Recommendations on the requirement of the 28 day 

inhalation study.
Page 13 of 25

Attachments

1. Chemical Identity Table

2. Physicochemical Properties of Technical Grade Cyazofamid Table

3. Tolerance/MRL Summary Table

4. Endpoint Selection Tables

5. Toxicity Profile Tables
Page 14 of 25

Attachment 1

Chemical Identity Table

Cyazofamid Nomenclature.

Chemical structure

Common name Cyazofamid

Company experimental name IKF-916

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

Identification of Compounds from the Cyazofamid Metabolism Studies

Common Name/ 

Code/Matrix

Chemical Name Chemical Structure

Cyazofamid/

IKF-916

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

methylphenyl)-1H-imidazole-1-sulfonamide

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

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

acid

N

N

H C3

Cl

CN

SO2N(CH3)

2

N

N

H3C

Cl

CN

SO2N(CH3)

2

N

H

N

H3C

Cl

CN

N

H

N

Cl

CN

HO

O
Page 15 of 25

Identification of Compounds from the Cyazofamid Metabolism Studies

Common Name/ 

Code/Matrix

Chemical Name Chemical Structure

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

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

N

H

N

H C3

Cl

O

NH2
Page 16 of 25

Attachment 2

Physicochemical Properties of Technical Grade Cyazofamid Table

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 10-5 Pa

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

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
Page 17 of 25

Attachment 3

Tolerance/MRL Tables

Cyazofamid (085651; Date of Request 11/4/14)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex

40 CFR §180.601 (a) General. 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

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

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

sulfonamide, including the 

metabolite 4-chloro-5-(4-

methylphenyl)-1H-imidazole-2-

carbonitrile

None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico1 Codex

Basil, dried leaves 90 90

Basil, fresh leaves 30 30

Bean, succulent 0.5 0.5 edible-podded (jackbeans, moth 

beans, runner beans, snap beans, sword 

beans, wax beans, yardlong beans)

Bean, succulent shelled 0.08 0.08 succulent shelled (blackeyed 

peas, broad beans, cowpeas, lima 

beans, southern peas)

Brassica, head and stem, 

subgroup 5A

1.2 0.02 broccoli, brussels sprouts,

cabbages, cauliflowers, Chinese 

broccoli, Chinese mustard cabbages,

kohlrabies, napa Chinese cabbages

Brassica, leafy greens, 

subgroup 5B

12.0

Carrot, roots 0.09 0.09

Hop dried cones 10.0

Leafy greens subgroup 4A 10 10 amaranth, arugula, corn salad, 

dandelion leaves, dock, edible leaved 

chrysanthemum, endives, fresh chervil 

leaves, fresh parsley leaves, garden 

cress, garden purslane , garland 

chrysanthemum, head lettuce, leaf 

lettuce, Malabar spinach, New Zealand 

spinach, orach radicchio, spinach 

upland cress, winter purslane

Turnip, greens 12.0

Vegetable, cucurbit, group 9 0.10 0.1 balsam apples, balsam pears, 

cantaloupes, chayote fruit, Chinese 

cucumbers, Chinese waxgourds, citron 

melons, cucumbers, edible gourds, 

muskmelons (other than those listed in 

this item) pumpkins, summer squash, 

watermelons, west Indian gherkins, 

winter squash

Vegetable, fruiting, group 8-10 0.9 0.02 bell peppers, non-bell peppers

0.2 tomatoes
Page 18 of 25

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex

Vegetable, tuberous and corm, 

subgroup 1C

0.02 0.02 potatoes

MRLs with NO US Equivalent

Fat of cattle 0.02

Fat of goats 0.02

Fat of horses 0.02

Fat of sheep 0.02

Meat byproducts of cattle 0.02

Meat byproducts of goats 0.02

Meat byproducts of horses 0.02

Meat byproducts of sheep 0.02

Meat of cattle 0.02

Meat of goats 0.02

Meat of horses 0.02

Meat of sheep 0.02

Milk 0.02

Completed: M. Negussie; 11/05/14

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

(b) Section 18 emergency exemptions. Time-limited tolerances are established for residues of the 

fungicide cyazofamid, including its metabolites and degradates, in or on the commodities in the following 

table. Compliance with the tolerance levels specified in the following table is to be determined by 

measuring only the sum of cyazofamid, 4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1Himidazole-1-sulfonamide and its metabolite CCIM, 4-chloro-5-(4-methylphenyl)-1H-imidazole-2-

carbonitrile, calculated as the stoichiometric equivalent of cyazofamid, resulting from use of the pesticide 

under FIFRA section 18 emergency exemptions. The tolerances expire and are revoked on the date 

specified in the table.

Commodity Parts per million

Expiration/revocation 

date Canada

Basil, dried 144 12/31/14 90

(c) Tolerances with regional registrations. Tolerances with regional registrations are established for 

residues of the fungicide cyazofamid, including its metabolites and degradates, in or on the commodities 

in the following table. Compliance with the tolerance levels specified in the following table is to be 

determined by measuring only the sum of 4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1Himidazole-1-sulfonamide and its metabolite, 4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile, 

calculated as the stoichiometric equivalent of cyazofamid, in or on the following commodities:

Commodity Parts per million Canada

Grape 1.5 1.2
Page 19 of 25

Attachment 4

Toxicological Doses and Endpoints for Cyazofamid for Use in Dietary and Non-Occupational Human Health Risk 

Assessments

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)

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

population

Acute Dietary

(Females 13-49 

years of age)

NOAEL = 100 

mg/kg/day

UFA= 10x

UFH= 10x

FQPA SF= 1x

Acute RfD = 

1.0 mg/kg/day

Rat Prenatal Developmental Toxicity 

(MRID 45408933)

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

developmental toxicity findings of increased 

incidence of bent ribs.

Chronic Dietary 

(All Populations)

NOAEL= 94.8 

mg/kg/day

UFA= 10x

UFH= 10x

FQPA SF= 1x

Chronic RfD = 

0.948

mg/kg/day

Mouse Oral Carcinogenicity (MRID 

45408932)

LOAEL = 985 mg/kg/day based on 

increased skin lesions.

Incidental Oral 

Short-Term (1-30 

days) and 

Intermediate-Term 

(1-6 months)

NOAEL= 171

mg/kg/day 

UFA= 10x

UFH= 10x

FQPA SF= 1x

Residential 

LOC for MOE 

= 100

90-Day oral toxicity study in rats. LOAEL= 

295 mg/kg based on 

Increased number of basophilic tubules of 

the kidneys, increased urinary volume, pH, 

& protein. This toxicity endpoint is also 

supported by the results of a 28-day oral 

dose- range- finding study in rats. In this 

study, at 370 mg/kg/day or above increased 

incidence of basophilic tubules in the 

kidneys was found. 

Dermal ShortTerm (1-30 days) 

and IntermediateTerm (1-6 months)

For CHILDREN:

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

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

For ADULTS:

NOAEL = 100 

mg/kg/day

(Dermal 

Absorption Rate 

= 37%)

UFA= 10x

UFH= 10x

FQPA SF= 1x

Acute RfD = 

1.0 mg/kg/day

Rat Prenatal Developmental Toxicity (MRID 

45408933)

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

developmental toxicity findings of increased 

incidence of bent ribs.

Inhalation ShortTerm (1-30 days) 

and IntermediateTerm (1-6 months)

No residential exposure is expected via inhalation route.

Cancer (oral, 

dermal, inhalation)

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

increases in two adequate rodent carcinogenicity studies.

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

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

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

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

sensitivity among members of the human population (interspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

date (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c 

= chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.
Page 20 of 25

Summary of Toxicological Doses and Endpoints for Cyazofamid for Use in Occupational Human Health Risk 

Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal ShortTerm (1-30 

days) and 

IntermediateTerm (1-6 

months)

Oral Study 

NOAEL= 

100 

mg/kg/day 

(Dermal 

Absorption 

Rate = 37%)

UFA=10x

UFH=10x

Occupational LOC 

for MOE = 100

Rat Prenatal Developmental Toxicity (MRID 

45408933)

LOAEL = 1,000 mg/kg based on 

developmental toxicity findings of increased 

incidence of bent ribs.

Dermal Long 

Term (>6 

months)

NOAEL= 

94.8 

mg/kg/day

(Dermal 

Absorption 

Rate = 37%)

UFA=10x

UFH=10x

Occupational LOC 

for MOE = 100

18-Month Mouse Oral Carcinogenicity (MRID 

45408932)

LOAEL = 985 mg/kg/day based on increased 

skin lesions.

Inhalation ShortTerm (1-30 

days) and 

IntermediateTerm (1-6 

months)

NOAEL= 

100 

mg/kg/day

UFA=10x

UFH=10x

Occupational LOC 

for MOE = 100

Rat Prenatal Developmental Toxicity (MRID 

45408933)

LOAEL = 1,000 mg/kg based on 

developmental toxicity findings of increased 

incidence of bent ribs.

Inhalation LongTerm (>6 

months)

NOAEL= 

94.8 

mg/kg/day

UFA=10x

UFH=10x

Occupational LOC 

for MOE = 100

18-Month Mouse Oral Carcinogenicity (MRID 

45408932)

LOAEL = 985 mg/kg/day based on increased 

skin lesions.

Cancer (oral, 

dermal, 

inhalation)

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

increases in two adequate rodent carcinogenicity studies.

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

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

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

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

sensitivity among members of the human population (interspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

date (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.
Page 21 of 25

Attachment 5

Toxicity Profile for Cyazofamid

Acute Toxicity of Cyazofamid Technical

Guideline 

No. Study Type MRID No. Results Toxicity Category

870.1100 Acute Oral – Rat 45408910 LD50> 5000 mg/kg [M/F] IV

870.1200 Acute Dermal – Rat 45408911 LD50 > 2000 mg/kg [M/F] III

870.1300 Acute Inhalation – Rat 45408912 LC50 > 5.5mg/L [M/F] IV

870.2400 Primary Eye Irritation –

Rabbit 45408913 Grade 2 conjunctival redness and discharge that resolved by 24 hours IV

870.2500 Primary Skin Irritation 

– Rabbit 45408914 Very slight to well defined erythema that cleared by 7 days III

870.2600

Dermal Sensitization 

(Guinea Pig 

Maximization test)

45408915 Positive (weak sensitizer) -

Toxicity Profile of Cyazofamid Technical.

Guideline No./ Study 

Type

MRID No. (year)/ Classification 

/Doses

Results

870.3100

28-Day dose-range 

finding study in rats

45408927

Acceptable/non-guideline

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

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

mg/kg/day

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

mg/kg/day

NOAEL = 38.5 [M] mg/kg/day

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

increase in the incidence of basophilic kidney tubules in 

males.

870.3100

90-Day oral toxicity in 

rats

45408928 (1999)

Acceptable/guideline

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

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

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

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

mg/kg/day

NOAEL = 29.5 [M] mg/kg/day

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

number of “basophilic kidney tubules,” and increased 

urinary volume, pH, and protein.

870.3150

90-Day oral toxicity in 

dogs

45408929 (2001)

Acceptable/guideline

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

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

LOAEL = not observed.
Page 22 of 25

Toxicity Profile of Cyazofamid Technical.

Guideline No./ Study 

Type

MRID No. (year)/ Classification 

/Doses

Results

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.

870.3465

28-Day inhalation 

toxicity

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

870.3700a

Prenatal developmental 

in rats

45430404 (1999)

Acceptable/guideline

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

Maternal NOAEL = 1,000 mg/kg/day

LOAEL = not observed

Developmental NOAEL = 100 mg/kg/day

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

incidence of bent ribs.

870.3700b

Prenatal developmental 

in rabbits

45408934 (1999)

Acceptable/guideline

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

Maternal NOAEL = 1,000 mg/kg/day

LOAEL = not observed

Developmental NOAEL = 1,000 mg/kg/day

LOAEL = not observed

870.3800

Reproduction and 

fertility effects in rats

45408935 (1998)

Acceptable/guideline

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

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

2185 mg/kg/day

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

mg/kg/day

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

2714 mg/kg/day

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

mg/kg/day

Parental/Systemic NOAEL = 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
Page 23 of 25

Toxicity Profile of Cyazofamid Technical.

Guideline No./ Study 

Type

MRID No. (year)/ Classification 

/Doses

Results

870.4300

Carcinogenicity mice

45408932 (1999)

Acceptable/guideline

NOAEL = 94.8 [M] mg/kg/day

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

incidence of skin lesions including hair loss, body sores, 

dermatitis, ulceration, and acanthosis.

No evidence of carcinogenicity

Gene Mutation

870.5100

Bacterial reverse 

mutation assay

45408937 (1998)

Acceptable/ guideline

(ai)

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

and tube preincubation (not cytotoxic but there was 

precipitation at ≥1,500 μg/plate.

Gene Mutation

870.5300

Mammalian cell culture

45409002 (1998)

Acceptable/ guideline

(ai)

Negative ± S9 up to cytotoxic and precipitating 

concentration of 100 μg/mL

Cytogenetics 

870.5375 

Chromosomal 

aberrations

45409003 (1996)

Acceptable/ guideline

(ai)

Negative ± S9 for clastogenic/aneugenic activity up to 

cytotoxic and precipitating 200 μg/mL

Cytogenetics 

870.5395

Micronucleus test on 

mouse

45409004 (1996)

Acceptable/ guideline

(ai)

Negative up to the highest dose tested (limit dose) 

2,000 mg/kg 

Other Effects 

870.5500

Bacterial DNA repair 

test (Rec-assay)

45409005 (1998)

Acceptable/ guideline

(ai)

Negative ± S9 up to limit of solubility at 8,000 μg/disc

870.6200a

Acute neurotoxicity 

screening battery

45434601 (2000)

Acceptable/guideline

0, 80, 400, or 2000 mg/kg

NOAEL = 2000 [M/F] mg/kg/day

LOAEL = not observed.

The HIARC concluded that the slight increase (∼45%) 

in motor activity at day 14 among the mid- and highdose males is marginal and should not be considered an 

adverse finding.

870.6200b

Subchronic 

neurotoxicity screening 

battery

Study not available.

870.6300

Developmental

neurotoxicity

Study not available.
Page 24 of 25

Toxicity Profile of Cyazofamid Technical.

Guideline No./ Study 

Type

MRID No. (year)/ Classification 

/Doses

Results

870.7485

Metabolism and 

pharmacokinetics in 

rats

45409006- 45409009 and 45434602 

(1998- 1999)

Acceptable/guideline

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

mg/kg repeat non-labeled followed 

by 0.5 mg/kg [phenyl- U14C]- or 

[

14C-Imidazole] IKF-916.

Biliary excretion study: 0.5 or 1,000 

mg/kg [phenyl- U14C]- or [14CImidazole] IKF-916. 

There was rapid absorption (irrespective of dose tcmax = 

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

4.4-5.8 hrs) while there was saturated absorption with 

prolonged elimination (t1/2 of 7.6-11.6 hrs) at the 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-p-tolylimidazole-2-carbonitrile (CCIM) each 

of which being less than 5% of the administered dose. 

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

indicated rapid clearance and low tissue burdens 

suggesting little or no bioaccumulation or sequestration.

870.7600

Dermal penetration

Study not available.

Special study: 

In Vitro Metabolism of 

IKF-916 and CCIM in 

Blood and Stomach 

Contents

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.
Page 25 of 25

Toxicity Profile of Cyazofamid Technical.

Guideline No./ Study 

Type

MRID No. (year)/ Classification 

/Doses

Results

Special study: 

In Vitro Metabolism of 

CCIM in S9 Fraction

MRID 45409011 (1999)

Acceptable/non-guideline

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

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

results suggested that CCIM was rapidly and completely 

metabolized within 5 minutes to at least three 

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

which accounted for 77-94% of the radioactivity. 

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

and one or more unknown metabolites. It was 

concluded that CCIM produced in the intestines or 

blood would be rapidly and completely metabolized by 

the liver.

Special study:

In Vitro Study to 

Identify Metabolites 

Absorbed Through the 

Intestinal Mucosa After 

Incubation with IKF916 and CCIM

MRID 45409012 (1999)

Acceptable/non-guideline

Using in vitro isolated rat intestinal segments containing 

[

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

10.4% of CCIM was transferred from the lumen 

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

segment. Of the IKF-916 that was absorbed and 

transferred to the buffer solution, approximately 60% 

had undergone biotransformation/degradation to CCIM, 

CCBA and three additional products. Also, CCIM 

appeared to be degraded to two metabolites not 

observed for intestine preparations containing IKF-916. 

Based on the findings of this study, cyazofamid seems 

to be poorly absorbed from the intestinal lumen 

although its conversion to CCIM or other metabolites 

may increase overall transfer across the gut wall.

Special study:

Comparative 

metabolism of 

[

14C]IKF-916 or 

[

14C]CCIM in rats

MRID 45409013 (1999)

Acceptable/non-guideline

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

[

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

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

and duodenum (plus contents) were collected and 

analyzed for radioactivity and metabolites. Following a 

single gavage dose of CCIM, the metabolites CCBA 

and CHCN, in addition to unchanged CCIM, were 

detected in the plasma and liver. The same metabolites, 

as well as CCIM, were also detected in plasma and liver 

following administration of IKF-916. Therefore, orally 

administered IKF-916 is converted to CCIM and 

subsequently to CCBA and CHCN.