### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

MEMORANDUM

/
Date: November 9, 2015 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

SUBJECT: Cyazofamid. Human Health Risk Assessment for Prop

, 6sed New Uses on Use

on Crop Subgroup 19A, Peppers and Tomatoes Grown in Greenhouses, and on Bulb Vegetables Crop Group 03-07.

PC Code: 085651 DP Barcodes: 426778
Decision Nos.: 500747 Registration Nos.: 71512-2, 71512-3
Petition Nos.: 5E8350, 5F8352 Regulatory Action: Section 3 Registration
Risk Assessment Type: Single Chemical, Aggregate Case No.: 7056

TXR No.: NA CAS No.: 120116-88-3
MRID No.: NA 40 CFR: §180.601

FROM: Cassi Walls, Ph.D., Senior

## Biologist**~** "1. 

# ucJi.&

Sarah S. Gallagher, Ph.D.,

### Biologi**t ~~**  William D. Wassell, Chemist 

# Nl/t

- :;:-(

Risk Assessment Branch 1 ffYt:i
Kristin Rury, Biologist
Risk Assessment Branch 3

' Health Effects Division (HED) (7509P)

THROUGH: Christine L. Olinger, Branch Chief 

# / 0

· Risk Assessment Branch 3

### ~ • Health Effects Division (7509P)

TO: Barbara Madden/Laura Nollen, Risk Manager Team 05
Risk Integration, Minor Use, and Emergency Response Branch (RIMUERB)
and Lindsay Roe, Risk Manager Fungicide Branch Registration Division (7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human
health from exposure to pesticides. Two separate petitions have been submitted for proposed

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

uses on herb subgroup 19A (field and greenhouse) and on tomatoes and peppers grown in greenhouses; and (2) ISK Biosciences Corporation (ISK Biosciences) proposed new use on bulb vegetable group 03-07. The Registration Division (RD) of OPP has requested that HED evaluate
hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure

Page 1 of37Cyazofamid Human Health Risk Assessment DP No. D426778

Page 2 of 37 

### assessments, as needed, to estimate the risk to human health that will result from the proposed uses of cyazofamid. A summary of the findings and an assessment of human health risk resulting from the proposed and registered uses of cyazofamid are provided in this document. The HED team members contributing to this risk assessment include Cassi Walls (risk assessment and dietary assessment), Kristin Rury (occupational and residential assessments), Sarah Gallagher (hazard assessment), and William Wassell (residue chemistry). The drinking water assessment was conducted by José Melénd ez of the Environmental Fate and Effects Division (EFED).Cyazofamid Human Health Risk Assessment DP No. D426778

Page 3 of 37 

### 1.0 Executive Summary ............................................................................................................. 5
2.0 HED Recommendations ...................................................................................................... 8
2.1 Data Deficiencies ............................................................................................................ 8
2.2 Tolerance Considerations .............................................................................................. 8
2.2.1 Enforcement Analytical Method ........................................................................... 8
2.2.2 Recommended Tolerances ...................................................................................... 8
2.2.3 Revisions to Petitioned-For Tolerances ................................................................ 9
2.2.4 International Harmonization ................................................................................. 9
2.3 Label Recommendations ............................................................................................... 9
3.0 Introduction .................................................................................................................. ........ 9
3.1 Chemical Identity ........................................................................................................... 9
3.2 Physical/Chemical Characteristics ............................................................................. 10
3.3 Pesticide Use Pattern ................................................................................................... 11
3.4 Anticipated Exposure Pathways ................................................................................. 12
3.5 Consideration of Environmental Justice ................................................................... 12
4.0 Hazard Characterization and Dose-Response Assessment ............................................ 13
4.1 Toxicology Studies Available for Analysis ................................................................. 13
4.2 Absorption, Distribution, Metabolism, and Excretion (ADME) ............................. 13
4.2.1 Dermal Absorption Factor ................................................................................... 14
4.3 Summary of Toxicological Effects .............................................................................. 14
4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 15
4.4.1 Completeness of the Toxicology Database .......................................................... 15 4.4.2 Evidence of Neurotoxicity .................................................................................... 15
4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal .... 15
4.4.4 Residual Uncertainty in the Exposure Database ................................................ 15
4.5 Toxicity Endpoint and Point of Departure Selections .............................................. 16
5.0 Dietary Exposure and Risk Assessment ........................................................................... 18
5.1 Residues of Concern Summary and Rationale .......................................................... 18
5.2 Food Residue Profile .................................................................................................... 19
5.3 Water Residue Profile .................................................................................................. 20
5.4 Dietary Risk Assessment ............................................................................................. 21
5.4.1 Description of Residue Data Used in Dietary Assessment ................................ 21
5.4.2 Acute Dietary Risk Assessment ........................................................................... 21
5.4.3 Chronic Dietary Risk Assessment ....................................................................... 22
5.4.4 Summary Table ..................................................................................................... 22
6.0 Residential and Other Nonoccupational Exposure/Risk Characterization .................. 22
6.1 Residential Risk Estimates fo r Use in Aggregate Assessment ................................. 23 6.2 Non-Occupational Spray Drift Exposure and Risk Estimates ................................. 23 6.3 Non-Occupational Bystander Post-Applicat ion Inhalation Exposure and Risk

Estimates ..................................................................................................................... ........ 24
7.0 Aggregate Exposure/Risk Characterization .................................................................... 24
7.1 Acute Aggregate Risk .................................................................................................. 24
7.2 Short-Term Aggregate Risk ........................................................................................ 24
7.3 Chronic Aggregate Risk .............................................................................................. 25
8.0 Cumulative Exposure/Risk Characterization ................................................................. 25
9.0 Occupational Exposure/Risk Characterization .............................................................. 25Cyazofamid Human Health Risk Assessment DP No. D426778

Page 4 of 37 

### 9.1 Short-/Intermediate-Term Handler Risk .................................................................. 25
9.2 Short- and Intermediate-T erm Post-Application Risk ............................................. 29
9.2.1 Dermal Post-application Risk .................................................................................... 29
9.2.2 Inhalation Post-application Risk ............................................................................... 29
10.0 References .................................................................................................................... ....... 30 Appendix A. Toxicology Profile ............................................................................................... . 31
A.1 Toxicology Data Requirements ................................................................................... 31
A.2 Toxicity Profiles ........................................................................................................... 32 Appendix B. Identification of Compounds from the Cyazofamid Metabolism Studies ...... 37Cyazofamid Human Health Risk Assessment DP No. D426778

Page 5 of 37 

### 1.0 Executive Summary

Use Profile: Cyazofamid (4-chloro-2-cyano- N,N -dimethyl-5-(4-methylphenyl)-1 H -imidazole-1-sulfonamide) is currently registered for food use under FI FRA section 3 on basil, beans (succulent), Brassica (subgroups A and B), carrot roots, hops, leafy greens (subgroup 4A ), turnip greens, cucurbits (group 9), fruiting vegetables (group 8-10), and tuberous and corm (subgroup 1C). Permanent tolerances for residues of cyazofamid and its metabolite CCIM (4-chloro-5-(4-methylphenyl)-
1 H -imidazole-2-carbonitrile) are established in 40 CFR §180.601 at levels ranging from 0.02 ppm on potato to 90 ppm on dried basil and a re gional registration tole rance on grapes at 1.5 ppm. Cyazofamid is also currently registered for use on several reside ntial and non-agricultural use sites including turf areas associated with gol f courses, sod farms, seed farms, college and professional sports fields, resi dential and commercial lawns, and on ornamental plants in landscapes and those grown in commer cial greenhouses and nurseries.

Two separate petitions have been submitted for pr oposed uses of cyazofamid: (1) IR-4 new uses Herb Subgroup 19A (field and greenhouse) and on tomatoes and peppers grown in greenhouses; and (2) ISK Biosciences proposed a new use on Bulb Vegetable Group 03-07. The proposed
uses will be added to the RANMAN ® 

### 400 SC end-use product la bel (EPA Reg. No. 71512-3) which is a soluble concentrate containing 34.5% cyazofamid by weight (3.33 lb ai per gallon). The proposed maximum single application rates range from 0.039 lb ai/A to 0.078 lb ai/A.
RANMAN ® 

### 400 SC may be applied using ground, aer ial, chemigation, and handheld spray equipment. Most of the proposed uses allow for repeat applications on a 7-10 day schedule. The product label requires occupational handlers to wear long sleeves, long pants, shoes, socks, and chemical-resistant gloves, and has a restrict ed-entry interval (REI) of 12 hours.

Exposure Profile: Exposures to cyazofamid are expected to occur over acute, short-, interm ediate-, and long-term (chronic) durations. The proposed agricultural uses result in new exposures in both food and drinking water. There are curr ently existing residential uses that result in non-occupational exposure from handler and post-appl ication activities. In occupati onal settings, exposure is also expected during handler and post-application activities.

Hazard Identification: Cyazofamid belongs to a chemical class based on the cyanoimidazole and sulfonamide moieties. It specifically interferes with the cytochrome bc 1 

### complex (ubiquinol cytochrome c oxidoreductase) in the mitochondria l respiratory chain of oomycet es fungi. The mechanism of toxicity in mammals is not clear. Following re peated administration in more than one species, cyazofamid seems to have mild or low toxicity. The kidney appeared to be the primary target organ. Skin lesions were only observed in male mice, likely due to systemic allergy. In dogs, there were no major toxicity findings. In the acute neurotoxicity study, th ere were no indications
of treatment-related ad verse neurotoxicity.

There was some evidence of increased quantitative susceptibility following in utero exposure to rats in the prenatal developmental toxicity study; the marginal increased incidence of bent ribs in the high-dose fetuses was considered adverse; however, this effect was not used for theCyazofamid Human Health Risk Assessment DP No. D426778

Page 6 of 37 

### determination of endpoints since bent ribs ar e a developmental variation rather than a malformation and the effect was only seen at th e limit dose, which is not relevant for risk assessment. The Food Quality Protection Act (FQP A) safety factor is reduced to 1X for all population subgroups and expos ure scenarios.

Cyazofamid is classified as “not likely to be carcinogenic to humans” based on the lack of evidence of carcinogenicity in bo th the rat and the mouse studies . Additionally, cyazofamid does not appear to be mutagenic, based on several negative in vivo and in vitro studies.

Cyazofamid has low acute toxicity via the oral, de rmal, and inhalation routes of exposure. It produces minimal but reversible ey e 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 sulfonami de moiety in the compound.

Dietary Exposure (Food/Water): Acute: An acute dietary exposure assessment was not conducted since there was no adverse effect observed for a single dose for cyazofamid.

Chronic: An unrefined chronic dietary (food an d drinking water) assessment was conducted for existing and proposed uses of cyazofamid. The assessment included tolerance level residues for all crops and assumed that 100% of the crops were treated with cyazofamid (100% CT). Default processing factors were used. The groundwater estimated drinki ng water concentration (EDWC) of 211 μg/L from the PRZM-GW modeling was incorporated directly into the dietary

assessment.

The chronic dietary (food and dr inking water) exposure to cyazofamid is below HED’s level of concern (LOC) [i.e., <100% of the chronic Popul ation Adjusted Dose (cPAD)] for the general U.S. population and all population subgroups. Th e chronic dietary exposure estimates are 1.1% of the cPAD for the general U.S. population a nd 2.0% of the cPAD for children 1-2 years old, the most highly exposed population subgroup.

Residential Exposure : There are no proposed residential uses of cyazo famid and the existing residential uses were evaluated previously using the 2012 Residential Standard Operati ng Procedures (SOPs). Since the incidental oral and inhalation points of de parture (PODs) have changed since the previous assessment, the residential scenarios for aggregate assessment have been re-evaluated here. The short-term adult residential exposure estimates for inclusion in the aggregate risk assessment result from mixing/loading/applying liquid cy azofamid to turf using a hose-end sprayer (inhalation MOE = 120,000, level of concern; LO C = 100). The residential exposures for inclusion in the aggregate risk assessment for children 1-2 years old from post-application handto-mouth exposure on turf resu lts in an MOE of 19,000.

Aggregate Exposure: Acute: Acute aggregate exposur e is equivalent to acute diet ary risk (e.g., food and drinking water exposure) where an acute dietary exposur e assessment was not conducted since there was
no adverse effect observed for a single dose for cyazofamid.Cyazofamid Human Health Risk Assessment DP No. D426778

Page 7 of 37 

### Short-Term: There is potential short-term a ggregate exposure to cyazofamid for adults from dietary exposure (which is considered bac kground exposure) and residential dermal and inhalation exposures from handli ng cyazofamid. However, sin ce no hazard was identified for the dermal route of exposure, short-term aggreg ate risk estimate include d dietary and inhalation exposures only. The short-term aggregate MOE fo r adults is 14,000 and not of concern to HED.

The short-term aggregate exposure to cyazofamid fo r children 1 to <2 years old is from dietary exposure (which is considered background exposure) and incidental oral exposure from hand to
mouth activities on treated turf. The short-term aggregate MOE for children 1 to <2 years old is 6,100 and not of concern to HED.

Intermediate-Term: Intermediate-term exposure is not expected for th e residential exposure pathway. Therefore, the intermediate-term aggreg ate risk estimate would be equivalent to the chronic dietary exposure estimate, which is not of concern.

Chronic: Chronic aggregate exposure is equi valent to chronic diet ary risk (e.g., food and drinking water exposure) where th e estimates are not of concern.

Occupational Exposure: Occupational Handler Exposures: There are no occupational handler risk estimates of concern for the proposed uses of cyazofamid at baseline attire (i.e ., long sleeves, long pants, shoes, a nd socks with no personal-protective equipment; PPE), and engineering controls for aerial applications (i.e., encl osed cockpits). The occupational handler inhalati on risk estimates ranged from 71,000 to 600,000,000 (LOC = 100).

Occupational Post-application Exposures: A quantitative occupational dermal post-applic ation risk assessment was not conducted for cyazofamid because no dermal hazard or developmen tal toxicity was identified in the toxicity database. Based on the Agency's current prac tices, a quantitative non-c ancer occupational postapplication inhalation exposure assessme nt was not performed for cyazofamid at this time. If new policies or procedures are put into place, th e Agency may revisit the need for a quantitative occupational post-application inhalati on exposure assessment for cyazofamid.

Restricted-Entry Interval (REI) : The REI of 12 hours on the product label is cons idered appropriate to protect agricultural workers from post-application exposures.

Review of Human Research: This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pest icide or other chemical. Thes e data, which include Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1) ; the Agricultural Handler Exposure Task Force (AHETF) database; the Residential SOPs (Lawns & Turf), and other registrant-submitted exposure monitoring studies (MRID 44339801), are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethi cs review may have included review by the HumanCyazofamid Human Health Risk Assessment DP No. D426778

Page 8 of 37 

### Studies Review Board. Descriptions of data s ources, as well as guidanc e on their use, can be
found at http://www.epa.gov/pesticides/scien ce/handler-exposure-data.html and http://www.epa.gov/pesticides/scien ce/post-app-exposure-data.html.

Environmental Justice Considerations: Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions
to Address Environmental Just ice in Minority Populations an d Low-Income Populations," (http://www.archives.gov/federal-regi ster/executive-orders/pdf/12898.pdf).

2.0 HED Recommendations

HED has examined the residue chemistry, toxici ty, and exposure databases for cyazofamid and concluded that, provided a revised Section B/proposed label is submitted, there are no deficiencies that would preclude setting tolera nces and granting a Section 3 registration for proposed uses on herb (subgroup 19A; field and greenhouse), tomatoes and peppers grown in greenhouses, and on bulb vegetables (group 03-07).

2.1 Data Deficiencies

There are no data gaps or deficiencies in the toxicology, exposure, or residue chemistry databases for the proposed uses. However, a re vised Section B/proposed label are required for
submission.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate enforcement methods are available to determine residues of cyazofamid and its metabolite CCIM (4-chloro-5-(4-methylphenyl)-1 H -imidazole-2-carbonitrile) in various
commodities. An enforcement method for non- fatty commodities is available, FDA’s Multiresidue Protocol D (without cleanup). The method complete ly recovers (> 80% recovery) cyazofamid and its metabolite CCIM. In additio n, the high-performance liquid chromatography method with ultraviolent light detecti on (HPLC/UV) method (MRID 45409020; revised in MRID 46550401) is acceptable for use as a si ngle analyte enforcement method provided a confirmatory method such as the liquid chroma tography method with tandem mass-spectrometric detection (LC/MS/MS) method is used.

2.2.2 Recommended Tolerances

HED has reviewed the available residue data and has determined the appropriate tolerance levels for residues of cyazofamid and its metabolite CCIM (Table 2.2.2.). The tolerance expression is
as follows:

(a) General. Tolerances are established for residues of the fungicide cyazofamid, including its metabolites and de gradates, in or on the commod ities in the following table.Cyazofamid Human Health Risk Assessment DP No. D426778

Page 9 of 37 

### 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)-1 H

imidazole-1-sulfonamide and its meta bolite, 4-chloro-5-(4-methylphenyl)-1 H-imidazole2-carbonitrile, calculated as the stoichiometr ic equivalent of cyazofamid, in or on the following commodities:

Table 2.2.2. Tolerance Summary for Cyazofamid.

Commodity Proposed Tolerance (ppm) HED-Recommended Tolerance (ppm) Comments ( correct commodity definition ) Herb, Subgroup 19A 90 90

Bulb Vegetables, Group 3-07 2.0 2.0



### Established tolerances for cyazofamid residues in /on basil, fresh and dried can be deleted once the tolerance for residues herbs, subgroup 19A is established.

2.2.3 Revisions to Petitioned-For Tolerances

There are no revisions to the petitioned for tolerances.

2.2.4 International Harmonization

There are no Codex and Mexican maximum residu e limits (MRLs) established for cyazofamid in/on the commodities included in this petition. Canadian MRLs are established for residues of cyazofamid and its metabolite in/on fresh basil at 30 ppm and dried basil at 90 ppm. Both of
these MRLs should be considered harmonized as the tolerance for residues of cyazofamid and its metabolite CCIM in herb, subgroup 19A includes these commodities.

2.3 Label Recommendations

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

Ranman ® 

### 400SC can be applied on herbs grown in a greenhouse. This statement needs to be removed from the directions for use on bulb vegeta bles group 3-07 as it inappropriate for that
section of the label.

3.0 Introduction

Cyazofamid is a broad-spectrum fungicid e active against oomycete fungi (such as Phytophthora, Plasmopara, Pseudoperonospora, and Pythium ) and Plasmodiophoromycetes ( Plasmodiophora
brassicae ). It inhibits all stages of fungal development in the life cycle, specifically interfering with the cytochrome bc 1 

### complex in the mitochondrial resp iratory chain of oomycete fungi.

3.1 Chemical Identity

The chemical structure, and nomenclature of cy azofamid and its metabolite CCIM are presented
in Table 3.1. Structures of other metabolit es and degradates are shown in Appendix B.Cyazofamid Human Health Risk Assessment DP No. D426778

Page 10 of 37 Table 3.1. Cyazofamid Nomenclature.

Parent Chemical Structure

Empirical Formula C 13 H 13 ClN 4 O 2 S 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)-1 H -imidazole-1-
sulfonamide CAS Registry Number 120116-88-3 Chemical Class imidazole, sulfonamide Known Impurities of Concern None

Metabolite Chemical Structure

Common name CCIM IUPAC name 4-chloro-5-(4-methylphenyl)-1 H- imidazole-2-carbonitrile
CAS name 4-chloro-5- p -tolylimidazole-2-carbonitrile CAS Registry Number 120118-14-1



### 3.2 Physical/Chemical Characteristics

Cyazofamid has a low vapor pressure (1.33 × 10 -5 

### Pa at 25 °C or 9.98 × 10 -8 

### mm Hg at 25 °C); therefore, inhalation via chemi cal vaporization is unlikely. Cy azofamid has a log octanol/water partition coefficient (log P ow 

### ) 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 detail ed physicochemical properties of cyazofamid are summarized in Table 3.2.

Table 3.2. Physicochemical Properties of Technical Grade Cyazofamid.

Parameter Value Reference Melting point/range 152.7 °C Pesticide Fact Sheet – Cyazofamid September 2004 pH 4.9 at 25 °C Density (at 25 °C) 1.38 g/cm 3
Water solubility (at 25 °C) 0.107 mg/L at pH 7 Solvent solubility (at 21.2 °C) 0.003 g/100 mL in hexane 0.174 g/100 mL in methanol 3.095 g/100 mL in acetonitrile 10.212 g/100 mL in dichloromethane 0.600 g/100 mL in toluene 1.649 g/100 mL in ethyl acetate 4.564 g/100 mL in acetone 0.004 g/100 mL in octanol
Vapor pressure <1.33 x 10 -5 Pa at 25, 30, 35 °C Dissociation constant, pK
a No pK a evident at pH range 2-12. N N

C H 3 Cl

CN

SO 2 N(CH 3 ) 2

N H N

C H 3 Cl

CNCyazofamid Human Health Risk Assessment DP No. D426778

Page 11 of 37 Table 3.2. Physicochemical Properties of Technical Grade Cyazofamid.

Parameter Value Reference Octanol/water partition coefficient Log P
ow = 3.2 UV/visible absorption pH
2
7
10 Λ max (nm)
285
279
287 Memo, 04/25/2012, N. Dodd,
D396051



### 3.3 Pesticide Use Pattern

The proposed use pattern associated with th e two petitions (PP#5E8350 and PP#5F8352) is
shown in Table 3.3

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

Applic. Type, Equip. & Timing End-Use
Product Applic. Rate Max. No. Apps. per

Season Max. Seasonal Applic. Rate Preharvest
Interval

(days) Use
Directions
and
Limitations Herb, Subgroup 19A Foliar application

by ground and aerial equipment. Apps should start

before disease

infects crop. Ranman ®

400SC EPA Reg. No.
71512-3 2.75 to 3.0
fl oz /A
0.071 to 0.078
lb ai/A 9 27 fl. oz/A
0.7 lb ai/A 0 See below

Tomato Greenhouse Transplants
Soil-drench application at the time of planting

or at any time thereafter up until

1 week before transplanting. Ranman ®

400SC EPA Reg. No.
71512-3 3 fl oz/100 gallons water
0.078 lb ai/100 gallons water 1 (implied) 3 fl oz/100 gallons water
0.078 lb ai/100 gallons water 0 See below

Bell Peppers Greenhouse-grown
Soil-drench application at the time of planting or up to first fruit

set. Ranman ®

400SC EPA Reg. No.
71512-3 3.2 fl oz/100 gallons water
0.083 lb ai/100 gallons water 2 (implied) 0.35 lb ai/A 0 See below

Bulb Vegetable, Group 3-07 Foliar application

by ground and aerial equipment. Apps should start

when disease
conditions are

favorable. Ranman ®

400SC EPA Reg. No.
71512-3 2.75 to 3.0
fl oz/A
0.071 to 0.078
lb ai/A 6 16.5 fl oz/A (0.43 lb ai/A) 0 See below



### The following rotational crop restri ctions are included on the Ranman ® 

### 400SC label: Crops on this label may be planted immediately after the last treatment. Do not plant other crops not registered for this product within 30 days after the last application.Cyazofamid Human Health Risk Assessment DP No. D426778

Page 12 of 37 

### The following restrictions are in cluded on the label for applica tions to herbs, subgroup 19A: Make applications on a 7- to 10-day schedule beginning when di sease conditions are favorable for disease development. The product can be used on herbs grown in a greenhouse. Ranman ® 

### 400SC should be tanked mixed with an organosilic one surfactant (OSS) wh en disease infection is severe, or a non-ionic surfactan t (NIS) or a blend of OSS and a NIS when disease infection is moderate or light. Ranman ® 

### 400SC may be applied through spri nkler irrigation equipment.

The following restrictions are included on the label for app lications to tomato greenhouse transplants: Apply fungicide so lution as a drench to thoroughl y wet the growing medium. Do not use any surfactant with this drench application. Cyazofa mid is also registered for foliar applications at rates of 0.054 to 0.071 lb ai/A with a maximum seasonal use rate of 16.5 oz/A (0.43 lb ai/A). The crop field trials for tomatoes utilized both the tran splant application and directed foliar applications.

The following restrictions are in cluded on the label for applica tions to bell peppers greenhouse grown: Apply the first application at transplanting or up to first fru it set, using 5 fl oz of drench solution per plant. A second drench application may be necessary af ter 42 days at the rate of 8.5 fl oz (0.22 lb ai). Do not use surfactant with these drench applications.

The following restrictions are incl uded on the label for applications to bulb vegetables, group 3- 07: For control of downy mildew make appli cations on a 7- to 10-day schedule. Ranman ®



### 400SC should be tanked mixed with an OSS and a NIS when diseas e infection is moderate or light. The product may be applied trough sprinkler irrigation equipment.

3.4 Anticipated Exposure Pathways

Humans may be exposed to cyazofamid in food a nd drinking water, since cyazofamid may be applied directly to growing cr ops and application may result in cyazofamid reaching surface and ground water sources of drinking water. There ar e 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 e xposed 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 worker s re-entering treated areas.

Several risk assessments have been previously prepared for the existing uses of cyazofamid.
This risk assessment considers all of the af orementioned exposure pathways based on the proposed new uses of cyazofamid, but also consider s the existing uses as well, particularly for the dietary exposure assessment.

3.5 Consideration of Environmental Justice

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions
to Address Environmental Just ice in Minority Populations an d Low-Income Populations," (http://www.archives.gov/federal -register/executive-orders/pdf/ 12898.pdf). As a part of every pesticide risk assessment, OPP considers a larg e variety of consumer subgroups according toCyazofamid Human Health Risk Assessment DP No. D426778

Page 13 of 37 

### well-established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by U.S. Department of Agriculture’s (USDA’s) National Health and Nu trition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pestic ide risk assessments for all registered food uses of a pesticide. These da ta are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the countr y. 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-diet ary exposures based on home use of pesticide products and associated ri sks for adult applicators and for toddlers, youths, and adults entering or playing on treated ar eas 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 traditi onal dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicological database for cyazofamid is adequate for hazard char acterization, toxicity endpoint selection, and FQPA SF consideration. The HED Hazar d and Science Policy Council (HASPOC) concluded using a weig ht-of-evidence approach that the subchronic inhalation study is not required at this time (Memo, J. Van Alstine, 11-JULY-2012, TXR# 0056341). Since the last risk assessment, immunotoxicity and subchr onic neurotoxicity studies have been submitted and the results were incorporated into the cu rrent assessment. Appendix A includes a summary of the cyazofamid toxicologica l database. Cyazofamid was evaluated for the following:

(1) Subchronic and chronic oral toxicity in rats, mice, and dogs; (2) Subchronic dermal toxicity in rats; (3) Developmental toxicity in rats and rabbits; (4) Reproductive and postna tal toxicity in rats; (5) Carcinogenicity in mice and rats; (6) Subchronic neurotoxicity in rats; (7) Immunotoxicity in rats; (8) Genotoxicity and mutagenicity studies; and (9) Absorption, distribution, metabolis m, excretion (ADME) studies.

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

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

### = 0.25 or 0.5 hrs, respectively). Eliminati on was found to be rapid at the low dose (t 1/2 

### 4.4-5.8 hrs), while there was saturated abso rption with prolonged elimination (t 1/2 

### of 7.6-11.6 hrs) at the high-dose. The extent of absorption (expressed as percent of administered dose) was dose-dependent, being nearly 75% at the low dose and only about 5% at the high dose. Both the urine and feces were major routes of excreti on at the low dose with most of the urinaryCyazofamid Human Health Risk Assessment DP No. D426778

Page 14 of 37 

### radioactivity found as metabolite CCBA (4-(4-chloro-2-cyan oimidazol-5-yl)benzoic acid). Results of biliary excretion experi ments showed biliary elimination of the radiolabel to be highly variable at the low dose (~12-39% of the admini stered low dose) and ne gligible (<2%) in the high-dose groups. Urinary or biliary excretion in rats of the high-dose groups was low (each ~2%) with most of the radioactivity being CCBA. Irrespective of the dosing regimen, most of the recovered fecal radioactivity was unchanged parent compound; the major fecal metabolites were CCBA and CCIM, each of which being less th an 5% of the administered dose. Tissue
burdens at t 1/2 

### , t max 

### , and at 168 hours post dose were indicativ e of rapid clearance and low tissue burdens suggesting little or no bi oaccumulation or sequestration.

4.2.1 Dermal Absorption Factor

There are no dermal penetrati on studies available for cyazofamid. There was no dermal hazard identified in the toxicological database. As a result, a dermal absorption factor is not needed because a quantitative dermal assessment was not performed.

4.3 Summary of Toxicological Effects

Cyazofamid belongs to a chemical class based on the cyanoimidazole and sulfonamide moieties. Cyazofamid is a broad-spectrum fungic ide active against oomycete fungi and Plasmodiophoromycetes. It specifically interferes with the cytochrome bc 1 

### complex (ubiquinol cytochrome c oxidoreductase) in the mitochondrial resp iratory chain of oomycetes fungi. The mechanism of toxicity in mammals is not clear. The available toxicity studies show that cyazofamid has low toxicity in rats, rabbits, and dogs. The target organ in rats is the kidney,
with an increased incidence of basophilic tubules, increased ur inary volume, pH, and protein
noted in male rats after subchr onic exposure. Female rats were less sensitive, with only a marginal increase in urinary volume, and pH. These findings were not ed in a 90-day oral toxicity study, and similar findings were noted in the 28-day oral toxicity range-finding study in rats. In the two-generation re productive study in rats, there wa s an increased incidence of nephropathy in the high-dose male rats as comp ared to the controls; however, only a small
number of animals were observed to have bas ophilic tubules. Basophili c tubules are indicative of a regenerative process, but they can be more difficult to identify in ol der animals (i.e., tubular basophilia can be obscured by nephropa thy or included as part of th e nephropathy constellation). No kidney effects were observed in the chronic oral toxicity study in rats; however, this study did not test up to doses as hi gh as those eliciting kidney effects in the subchronic and twogeneration reproduction toxicity st udies. The only relevant findi ng in the dog was an incidence of parathyroid cysts in males at the limit dose in the chronic study.

The pre- and post-natal toxicology databa se for cyazofamid includes rat and rabbit developmental toxicity studies and a two-gene ration reproduction toxicity study in rats. The prenatal developmental study in rats showed ev idence of increased quantitative susceptibility following in utero exposure as a marginally increased incide nce of bent ribs was noted in fetuses at the limit dose, whereas no mate rnal toxicity was noted.

No adverse effects were seen in a route-specif ic dermal toxicity study. Skin lesions were observed in males following oral exposure in th e mouse carcinogenicity study, and are thought toCyazofamid Human Health Risk Assessment DP No. D426778

Page 15 of 37 

### be caused by an allergic reaction to systemic exposure because they did not occur following exposure via the dermal route.

Cyazofamid was categorized as having low acute toxicity via the oral, dermal, and inhalation routes of exposure. It produces minimal but revers ible eye irritation, is a slight dermal irritant,
and is a weak dermal sensitizer.

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

The RAB1 risk assessment team for cyazofamid de termined that the FQPA SF should be reduced to 1X for all exposure scenarios. The toxicity database is complete a nd dietary and residential exposure analyses are unlikely to underestimate expos ure. No effects were seen in neurotoxicity studies. Although there is eviden ce of quantitative susceptibility in the developmental rat study,
the effects are well-characterized with clea rly established NOAEL/lowest-observed adverseeffect level (LOAEL) values and selected endpoints address the observed effects.

4.4.1 Completeness of the Toxicology Database

The existing toxicological database for cy azofamid is adequate for FQPA evaluation. Developmental toxicity studies in rats and rabbits, a two-genera tion reproduction study in rats, and neurotoxicity studies in rats are available for FQPA consideration. The submitted toxicology studies are of good quality and are sufficient to select endpoints for risk assessment and to determine whether cyazofamid poses a human health hazard.

4.4.2 Evidence of Neurotoxicity

The available toxicity database for cyazofamid does not show any evid ence of neurotoxicity, including the acute and subchr onic neurotoxicity studies.

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

The developmental rabbit and two-generation repr oduction toxicity study in rats did not show any evidence of increased susceptibility deve lopmental or offspring, respectively. However, there was increased quan titative susceptibil ity in the rat developmenta l study; concentrations up to the limit dose did not cause maternal systemic toxicity, but there was an increased incidence
of bent ribs. Concern is low based on the followi ng: (1) the increase was marginal, (2) bent ribs
are considered a variation rather than a malformation, (3) the e ffect was only seen at the limit dose, (4) there is a clear NOAEL for the effect , and (5) the selected endpoints address any
concerns for this effect.

4.4.4 Residual Uncertainty in the Exposure Database

The exposure databases are complete or are estim ated based on data that reasonably account for potential exposures. New 2012 Residential SOPs we re used to assess post-application exposure to children including incidental oral exposure. The resident ial post-applica tion assessment assumes maximum application rates and conserva tive day zero hand-to-mouth activities. All ofCyazofamid Human Health Risk Assessment DP No. D426778

Page 16 of 37 

### the exposure estimates are based on conservative high-end assumptions and are not likely to
underestimate risk.

The dietary exposure assessments (food and drin king water), which assumed tolerance-level residues, 100% crop treated and high-end EDWC s, are conservative, high-end assessments. They do not underestimate the potential dietary exposures. The calculated residential risks represent conservative estimates of exposure be cause maximum application rates are used to define residue levels. Exposures are unlikely to be underestimated because the assessment is a screening-level assessment.

4.5 Toxicity Endpoint and Point of Departure Selections

Since the last risk assessment (N. Tsaur et al. ; 28-JUN-2012; D456373), all of the endpoints, except chronic dietary, have b een updated. Table 4.5 summarize s the toxicological doses and endpoints selected for dietary, non-occupational, and occupational risk assessments. The rationale for the dose/endpoint select ion is also described below.

Acute dietary (all populations): An endpoint was not selected to evaluate acute dietary exposures. Previously, the prenatal developm ental study in rats was used to evaluate acute dietary exposures for females 13-49 years old; however , effects (increased incidence of bent ribs) were only seen at the LOAEL of 1000 mg/kg/day, which is not consid ered a relevant dose for human health risk assessment. Additionally, there is low concern for this effect since bent ribs are a developmental variation rather than a malformation, the increas ed incidence was only ma rginally increased over
historical and concurrent contro ls, and similar effects were not seen in the rabbit developmental study. There were no other effects seen in th e database attributab le to a single dose.

Chronic dietary (all populations): The 18-month mouse carcinogenicity study was selected for this exposure scenario since the endpoints of concern were seen following long-term dietary exposure. The LOAEL of 985 mg/kg/day (NOA EL = 94.8 mg/kg/day) was based on increased
incidence of skin lesions in males. This st udy is appropriate for th e route and duration of exposure. This endpoint is considered conservati ve given the effect was seen at approximately the limit dose; however, itis protective of all effects seen following chronic exposure to cyazofamid including the kidney effects whic h had a comparable NOAEL. The chronic population-adjusted dose (cPAD) of 0.948 mg/kg/day is based on the NOAEL of 94.8 mg/kg/day and a 100-fold uncertainty factor (10X for inte rspecies extrapolation, 10X for intraspecies extrapolation, and 1X for FQPA SF).

Short- and intermediate-t erm incidental oral: Co-critical 90-day a nd chronic oral toxicity
studies in rats were selected for the short-and intermediate term in cidental oral exposure. In the 90-day oral toxicity study, ther e was increased incidence of ba sophilic tubules in the kidneys, increased urinary volume, pH, and protein in males at the LOAEL of 295 mg/kg/day (NOAEL = 29.5 mg/kg/day). This observation was also suppor ted by the 28-day oral t oxicity study in rats where similar findings were seen in male s at the LOAEL of 370 mg/kg/day (NOAEL = 38.5 mg/kg/day). A NOAEL of 171 mg /kg/day was selected as the POD based on the following: (1) no kidney effects were seen up to 171 mg/kg/day in male rats, the highest dose tested, and (2) the large gap between the NOAEL and LOAEL values fr om the subchronic rat studies appears to be due to dose selection. In the two-generation re productive study, there was an increased incidenceCyazofamid Human Health Risk Assessment DP No. D426778

Page 17 of 37 

### of nephropathy for male rats in the high-dose group as compared to the control. In the chronic study, the high background incidence of nephropat hy in all groups may have obscured detection of renal effects. However, there was no diffe rence in incidence of nephropathy between the control and high-dose group in male ra ts in a lifetime dietary feedi ng study; but this is most likely due to the fact that the study only tested up to 171 mg/kg/day and did not test high enough doses to see the effects on the kidneys as seen in othe r studies. These studies are appropriate for the route and duration of exposure and are protective of all other findi ngs noted in the toxicological database. The LOC for incidental oral exposures is 100 (10X for interspecies extrapolation, 10X for intraspecies extrapolati on, and 1X for FQPA SF).

Short-and intermediate-term dermal: A dermal endpoint was not selected for evaluating dermal
risk. There were no adverse eff ects observed in the route-specific dermal toxicity study up to the limit dose. Previously, the prenat al developmental study in rats wa s used to evaluate short- and intermediate-term dermal exposures ; however, the effect (increased incidence of bent ribs) was only seen at the LOAEL of 1000 mg/kg/day. Additionally, an upper bound dermal absorption factor (DAF) of 37% was derived by extrapolat ion using the LOAEL of 370 mg/kg/day from the 28-day oral toxicity study and the NOAEL of 10 00 mg/kg/day from the dermal toxicity study. Using this value, it is estimated that dermal exposure would need to be approximately 2.7-fold higher than the limit dose to elic it the effect seen in the ra t developmental study (1000 / 0.37 = 2703 mg/kg/day). Therefore, developmental effects are not a concern via the dermal route. Since
there were no adverse effects seen in the route- specific dermal toxicity study up to the limit dose (1000 mg/kg/day) and no concerns for developmental or offspring effects. Skin lesions including hair loss, body sores, dermatitis, ulceration, and a canthosis were observed in the carcinogenicity study in mice; however, these were not considered relevant for a dermal assessment because they were only seen via the oral route of exposure and are thought to be th e result of a systemic allergic reaction.

Short- and intermediate-term inhalation: Since a subchronic inhalati on study is not required at this time for cyazofamid (Memo, J. Van Al stine, 11-JULY-2012, TXR# 0056341), an oral study was selected for assessing risks via the inhalation route. This toxicity endpoint was established
based on the same combination of studies used for the incidental oral endpoint (90-day and chronic oral toxicity studies in rats) with the NOAEL of 171 mg/kg/day and the LOAEL of 295 mg/kg/day. These studies are appropriate for th e duration of exposure a nd are protective of all effects seen following subchronic exposure to cy azofamid. The LOC for inhalation exposures is 100 (10X for interspecies extrapolation, 10X for intraspecies extrapolat ion, and 1X for FQPA SF). For this endpoint, inhalation exposure is assumed to be equiva lent to toxicity by the oral route of exposure.

Cancer: Cyazofamid is classified as “not likely to be carcinogenic to humans” based on the lack of evidence for carcinogenicity in mice and rats and a lack of mutagenic potential (Memo, G. Dannan, 15-APR-2004, TXR# 0052428). Therefore, a quantitati ve cancer risk assessment is not necessary.Cyazofamid Human Health Risk Assessment DP No. D426778

Page 18 of 37Table 4.5. Summary of Toxicological Doses and Endpoints for Cyazofamid for Use in Dietary, NonOccupational, and Occupational Human Health Risk Assessments. a

Exposure/
Scenario POD Uncertainty/ FQPA Safety
Factors RfD, PAD,
LOC for

Risk
Assessment Study and Toxicological Effects

Acute Dietary (All Populations) No appropriate toxicological eff ect attributable to a single dose was observed. Therefore, a dose and endpoint were not identified for this risk assessment.

Chronic Dietary (All Populations) NOAEL =
94.8 mg/kg/day UF A = 10X
UF H = 10X FQPA SF = 1X Chronic RfD
= 0.948 mg/kg/day

cPAD =

0.948 mg/kg/day 18-Month Mouse Oral Carcinogenicity LOAEL = 985 mg/kg/day based on
increased skin lesions.

Incidental
Oral ShortTerm (1-30 days) and
IntermediateTerm (1-6 months) NOAEL =
171 mg/kg/day UF A = 10X
UF H = 10X FQPA SF = 1X Residential
LOC for
MOE = 100 Co-critical 90-Day and chronic oral toxicity
studies in rats. LOAEL= 295 mg/kg based on increased incidence of basophilic tubules in the kidneys, increased urinary volume, pH, & protein.

Dermal ShortTerm (1-30 days) and
IntermediateTerm (1-6 months) No hazard was identified for dermal exposure; therefore, a quantitative dermal assessment is
not needed.

Inhalation
Short- Term (1-30 days)
and
IntermediateTerm (1-6 months) Oral
NOAEL =
171 mg/kg/day UF A = 10X
UF H = 10X FQPA SF = 1X Residential
LOC for
MOE = 100 Occupationa

l LOC for
MOE = 100 Co-critical 90-Day and chronic oral toxicity
studies in rats. LOAEL= 295 mg/kg based on increased incidence of basophilic tubules in the kidneys, increased urinary volume, pH, & protein.

Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of treatmentrelated tumors in two adequate rodent carcinogenicity studies.

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

and used to mark the beginning of extrapolation to determ ine risk associated with lower environmentally relevant human exposures. NOAEL = no-observed adverse-effect level. LOAEL = lowest-observed adverse-effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intra species). FQPA SF = FQPA Safety Factor. PAD = population-adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.



### 5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

The residues of concern for dietary risk asse ssment and the tolerance expression are summarized in Table 5.1. Although potato and carrot commoditi es may be significant feed items for cattle, currently registered and newl y proposed uses fall under 40 CFR § 180.6(a)(3) (i.e. there is noCyazofamid Human Health Risk Assessment DP No. D426778

Page 19 of 37 

### 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 cattl e feeding studies: cyazofam id, CCIM, CCBA, CCBA-cysteine conjugate. In addition, there are no poultry or swine feed items.

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

Matrix Residues Included in Risk Assessment Residues Included in Tolerance Expression

Plants Parent and CCIM Parent and CCIM

Livestock No decision (For future cattle feeding studies, the MARC recommended that the petitioner analyze parent, CCIM, CCBA, and CCBA-cysteine conjugate.) No decision

Rotational crops Parent only Parent only

Water Parent, CCIM, CCIM-AM, and CTCA N/A a Currently registered and proposed uses fall under 40 CFR § 180.6(a)(3) (i.e. there is no reasonable expectation of

finite residues in livestock commodities). In addition, ther e are no poultry or swine feed items. (Note: there is a restriction against use on cowpea used for livestock feed on the label.)



### 5.2 Food Residue Profile

Crop Field Trials To support the newly proposed uses, IR-4 has submitted field trials of cyazofamid on chives, greenhouse-grown tomatoes, and peppers while ISK Biosciences Corporation submitted field trial data for cyazofamid on green onion and dry bulb onion. There are adequate data for risk
assessment and tolerance assessment. In the re sidue decline studies, co mbined residues of cyazofamid and its metabolite, CCIM, were quan tifiable, generally declining with increasing sampling interval. Furthermore, the residue data are supported by adequate storage stability data. The results from the crop field trial studies are summari zed in Table 5.2.

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

Crop Matrix Analyte Total Application
Rate
lb ai/A (g ai/ha) PHI (days) n 1 Combined Residues (ppm parent equivalents)

Min. 2 Max. 2 LAFT 3 HAFT 3 Median 3 Mean 3 SD 3

Chives

Field Trials Chives, fresh Cyazofamid 0.698-0.712 0 6 0. 751 3.56 0.832 3.30 1.44 1.81 1.01

CCIM 4 6 0.0357 0.305 0.0363 0.294 0.0781 0.127 0.110

Combined 5 6 0.838 3.60 0.922 3.32 1.51 1.93 0.999 Chives, dried Cyazofamid 0.698-0.712 0 5 2.91 12.6 2.91 12.6 8.44 7.71 4.46

CCIM 4 5 0.378 5.62 0.378 5.62 1.39 2.23 2.19

Combined 5 5 3.29 17.0 3.29 17.0 11.6 9.94 5.79

Greenhouse Trials Chives, fresh Cyazofamid 0.687-0.713 0 3 0. 489 3.48 0.674 3.34 0.931 1.65 1.47

CCIM 3 3 <0.01 0.0725 <0.01 0.0662 0.0618 0.0460 0.0313

Combined 3 <0.499 3.55 <0.684 3.40 0.993 1.69 1.49

Combined Field and Greenhouse Trials Chives, fresh Cyazofamid 0.687-0.713 0 9 0. 489 3.56 0.674 3.34 1.22 1.75 1.09Cyazofamid Human Health Risk Assessment DP No. D426778

Page 20 of 37 Table 5.2. Summary of Residues from Field Trials with Cyazofamid.

Crop Matrix Analyte Total Application
Rate
lb ai/A (g ai/ha) PHI (days) n 1 Combined Residues (ppm parent equivalents)

Min. 2 Max. 2 LAFT 3 HAFT 3 Median 3 Mean 3 SD 3

CCIM 4 9 <0.01 0.305 <0.01 0.294 0.0658 0.100 0.0973

Combined 5 9 <0.499 3.60 <0.684 3.40 1.33 1.85 1.09

Greenhouse Tomato
Tomato, greenhouse Cyazofamid 0.425-0.433 0-1 4 0.0331 0. 324 0.0349 0.295 0.0562 0.111 0.124

CCIM 4 <0.01 0.0350 <0.01 0.0330 0.01 0.0158 0.0115

Combined 5 <0.0431 0.359 <0.0449 0.328 0.0662 0.126 0.136 Greenhouse Peppers

Greenhouse

peppers Combined 5 40 mg ai/plant

1.41x10 -3 oz ai/plant 0 2 <0.02 <0.02 <0.02 <0.02 <0.02 <0.02 0

Onion Onion, green Cyazofamid 0.407-0.426 (455-477) 0 5 0.362 1.15 0.463 1.085 0.541 0.667 0.263

CCIM 4 0.0159 0.0283 0.0165 0.0272 0.0182 0.0197 0.0043

Combined 5 0.390 1.17 0.490 1.10 0.559 0.687 0.261 Onion, dry
bulb Cyazofamid 0.415-0.433 (465-485) 0 10 0.0292 0.868 0.0322 0.861 0.0479 0.135 0.256

CCIM 4 <0.01 0.0353 <0.01 0.0349 0.01 0.0125 0.0079

Combined 5 <0.0392 0.902 <0.0422 0.895 0.0579 0.147 0.264

1 n = number of field trials.

2 Values based on residue le vels for individual samples.

3 Values based on per-trial average residue levels. LAFT = lowest average field trial, HAFT = highest average field trial, SD = standard deviation. (LAFT and HAFT were not reported for dried chives because only one sample was collected at each site.) The LAFT, HAFT, median, mean, and standard deviation, values <LOQ are assumed to be at the LOQ (0.01 ppm). Data reflect conversion of quantifiable residues of CCIM to parent equivalents by the study reviewer.

4 Residues of CCIM were converted to pa rent equivalents by the study reviewer.

5 Combined residues of cyazofamid and CCIM.



### Processing Studies
Processed food or feeds are not derived from bulb vegetables, group 3-07 and herb, subgroup
19A. Processed foods and feeds are derived from tomatoes. Processing data for cyazofamid in/on tomato (MRID 45409031) were previously submitted (Memo, 02/20/2004, A. Acierto, D285680). In conjunction with this review, it wa s determined that tole rances for residues of cyazofamid and its metabolite CCIM in/on tomato processed commodities are not needed.

Meat, Milk, Poultry, and Eggs
There are no feed items associated with bulb vegetables, group 3-07, herbs, subgroup 19A, tomato, and pepper. Livestock feeding studies are not required for cyazofamid. There is no dietary exposure of livestock to cyazofamid and there are no con cerns for secondary residues in
livestock commodities.

5.3 Water Residue Profile

Available environmental fate studies suggest cyazofamid is not very mobile and quickly degrades into a number of degradation products under different environmental conditions. HED concluded that cyazofamid and the metabolite s designated as CCIM, CCIM-AM (4-chloro-5- p

tolylimidazole-2-carboxamide), and CTCA (4-chloro-5- p -tolylimidazole-2-carboxylic acid) areCyazofamid Human Health Risk Assessment DP No. D426778

Page 21 of 37 

### considered to be the major residues in water a nd 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. CCI M 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 cont rast, CTCA is expected to be the major terminal degradate in biologically active soils and wate r/sediment systems. Both CCIM and CTCA are stable to abiotic hydrolysis and susceptible to leachi ng, but only CCIM is highly susceptible to biodegradation. Given these fate characterist ics, cyazofamid and/or its degradates could potentially reach surface water via spray drift or runoff under ce rtain 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 wate r bodies affected by spray drift and/or runoff depending on the level of biological activity. However, only CTCA ha s a high potential to contaminate ground water due to its high persistence and mobility.

Table 5.3 summarizes the EDWCs. The non-can cer chronic value of 211 ppb was directly entered into the exposure model to assess the c ontributions from drinking water. EDWCs in groundwater were modeled using PRZM-GW for residues from use on turf and ornamentals, which had the highest seasonal rates among the propos ed and registered uses . EDWCs in surface water as modeled by Tier 1 PRZM/EXAMS were lowe r. The models and their descriptions are
available online at: http://www.epa.gov/oppefed1/models/water/

.

Table 5.3. Maximum Estimated Drinking Water Co ncentrations for Cyazofamid, CCIM, CCIM-AM and
CTCA. Maximum EDWCs Are Based on the Use on Turf and Ornamentals. Drinking Water Source (Model Used) Use (rate modeled per year) Estimated Drinking Water Concentration (EDWC) (ppb) (Species)
Groundwater (PRZM-GW) Ornamentals (3.12 lb ai/A/yr) Acute (CTCA) 224 1 Chronic (CTCA) 211 1

Surface water (PRZM/EXAMS) Turf & Ornamentals (3.0 & 3.12 lb ai/A/yr, respectively) Acute (cyazofamid, CCIM, CCIM-AM) 38.2 2 Chronic (CTCA) 133.5 2 Cancer/Chronic (CTCA) 77.3 2

1. For groundwater, acute and chronic exposure is based on modeling the degradate CTCA.
2. For surface water, acute exposure is based on modeling of the parent cyazofamid plus the degradates CCIM and CCIM-AM. Chronic exposure is based on modeling of the degradate CTCA.



### 5.4 Dietary Risk Assessment

Conservative dietary exposure analyses using DEEM-FCIDTM indicate that acute and chronic dietary risk estimates for cyazofamid exposur e from food and drinki ng water are well below HED’s LOC (i.e. <100% of th e population adjusted dose).

5.4.1 Description of Residue Data Used in Dietary Assessment

Chronic dietary (food + drinking water) assessments were conservative, assuming that residues in all crops were at tolerance levels and that 100% of the crops were treated.

5.4.2 Acute Dietary Risk AssessmentCyazofamid Human Health Risk Assessment DP No. D426778

Page 22 of 37 

### No acute dietary toxicity endpoint could be identified based on the toxicology data currently available for cyazofamid; therefore, a quantit ative acute assessment was not performed.

5.4.3 Chronic Dietary Risk Assessment

The chronic dietary (food and drinking water) exposure assessment for the general U.S. population resulted in a risk estim ate of 1.1% of the cPAD. The chronic dietary risk estimate for the highest reported exposed popul ation subgroup, children (1-2 years old), was 2.0% of the
cPAD. The results of the chroni c dietary exposure analysis are re ported in Table 5.4.4 below.

5.4.4 Summary Table

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

Population Subgroup Chronic Dietary

Dietary Exposure (mg/kg/day) % cPAD a

General U.S. Population 0.010631 1.1

All Infants (<1 year old) 0.015810 1.7

Children 1-2 years old 0.018609 2.0

Children 3-5 years old 0.015997 1.7

Children 6-12 years old 0.010164 1.1

Youth 13-19 years old 0.007809 <1%

Adults 20-49 years old 0.010452 1.1

Adults 50+ years old 0.010256 1.1

Females 13-49 years old 0.010436 1.1
a cPAD (chronic population adjusted dose) = 0.95 mg/kg/day. The population subgroup with the greatest exposure

is in bold.



### 6.0 Residential and Other Nonoccupation al Exposure/Risk Characterization

There are no proposed residential uses at this time; and the exis ting residential uses have been previously reassessed to reflect updates to HED’s 2012 Residential SOPs 1 

### along with policy changes for body weight assumptions (K. Ru ry, D397215, 06/18/2012). However, since the previous assessment, the incidental oral, derm al, and inhalation PODs were reevaluated and changed. Therefore, the child incidental oral and adult inhalation scenarios for aggregate risk assessment have been updated for purposes of aggregating with diet ary exposures for the cyazofamid risk assessment (K. Rury, D 429457 and D429458, 10/XX/2015). There are no risks of concern for the existing residential uses of cyazofamid. A turf transferrable residue (TTR)

1 Available: http://www2.epa.gov/pesticide-sc ience-and-assessing-pesticide-risk s/standard-operating-proceduresresidential-pesticideCyazofamid Human Health Risk Assessment DP No. D426778

Page 23 of 37 

### study is available for cyazofamid and deemed acceptable (MRID 46571104); therefore,
additional TTR data are not re quired at this time.

6.1 Residential Risk Estimates for Use in Aggregate Assessment

Table 6.1 reflects the residential risk estimates that are recomme nded for use in the aggregate assessment for cyazofamid.

 The recommended residential exposure for use in the adult aggregate assessment reflects mixing/loading/applying with a hose-end sprayer to turf.

 The recommended residential exposure for use in the children 1 to <2 years old aggregate assessment reflects and hand-to-mouth exposur es from post-application exposure to
treated turf.

For additional information on the registered resi dential scenarios of cy azofamid, see K. Rury, D397215, 06/18/2012.

Table 6.1. Recommendations for the Residential Ex posures for the Cyazofamid Aggregate Assessment.

Lifestage Exposure Scenario Dose (mg/kg/day) 1 MOE 2

Dermal 3 Inhalation Oral 3 Total Dermal Inhalation Oral Total

Adult Mixing/Loading/Applying with a Hose-end Sprayer
to Turf N/A 4 0.0014 N/A 0.0014 N/A 4 1,200,000 N/A 1,200,000

Children
1 to <2 years old Post-application hand-tomouth exposure on turf N/A 4 N/A 0.0089 0.0089 N/A 4 N/A 19,000 19,000

1 Dose = the highest dose for each applicable lifestage of all re sidential scenarios assessed. Total = dermal + inhalation + i ncidental oral (where applicable). 2 MOE = the MOEs associated with the highest residential doses. Total = 1 ÷ [(1/Dermal MOE) + (1/Inhalation MOE) + (1/Incident al Oral MOE)], where applicable. 3 Dermal and incidental oral (hand-to-mout h) exposures were calculated using availabl e chemical-specific TTR and DFR studies fo r turf and garden scenarios, resp ectively. Post-application risk estimates for c ontact with treated gardens/trees were calculate d using an available DFR study on with tomatoes (MRID 45409118), and the post-a pplication risk estimates for contact with treated turf was calculated using the available TTR study (MRID 46571104). 4 No toxicity was found at 1,000 mg/kg in a 28-day dermal toxicity study and no developmental effects were seen in the toxicity database; therefore a dermal exposure asse ssment has not been conducted.



### 6.2 Non-Occupational Spray Drift Exposure and Risk Estimates

Spray drift is a potential source of exposure to those nearby pest icide applications. This is particularly the case with aerial application, but, to a lesser exte nt, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for cyazofamid

. The agency has been working with the Spray Drift Task Force (a task force composed of various regist rants which was developed as a result of a Data Call-In issued by EPA), EPA Regi onal Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drif t management practices (see the agency’s Spray Drift website for more information). 2 

### The agency has also developed a policy on how to appropriately consider spray drif t as a potential source of expo sure in risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during
the Registration Review process which ensures that all uses fo r that pesticide will be considered

2 Available: http://www2.epa.gov/redu cing-pesticide-driftCyazofamid Human Health Risk Assessment DP No. D426778

Page 24 of 37 

### concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs) - Resi dential Exposure Asse ssment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect non-occupationa l exposure to drift.

6.3 Non-Occupational Bystander Post-App lication Inhalation Exposure and Risk
Estimates

Volatilization of pes ticides may be a source of post-ap plication inhala tion exposure to individuals nearby pesticide applic ations. The agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the SAP’s final report on March 2, 2010 (http://archive.epa.gov/scipoly/sap/meetings/w eb/html/120109meeting.html). The agency has evaluated the SAP report and has developed a Vo latilization Screening Tool and a subsequent Volatilization Screening Anal ysis (http://www.regulations .gov/#!docketDetail;D=EPA-HQOPP-2014-0219). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for cyazofamid.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g. a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED consider s both the route and duration of exposure. For cyazofamid, potenti al exposures from food, drinking water, and residential scenarios were aggregated.

7.1 Acute Aggregate Risk

A quantitative acute aggregate ri sk assessment was not conducted since an appropriate acute point of departure was not established for cyazofamid.

7.2 Short-Term Aggregate Risk

There is potential short-term exposure to cyazo famid 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 (bac kground) and inhalation (p rimary) routes. For children, these pathways lead to exposure via the oral (background) and incidental oral (primary) routes. All aggregate risk estimates (MOEs) ar e greater than 100, which indicates that exposure
and risk do not exceed HED’s LOC. The adult and children short-term aggregate dietary and residential MOEs are 14,000 and 6,100, respectively.Cyazofamid Human Health Risk Assessment DP No. D426778

Page 25 of 37 Table 7.2. Short-Term Agg regate Risk Calculations.

Population Short- or Intermediate-Term Scenario

NOAEL mg/kg/day LOC 1 Max
Allowable Exposure 2 mg/kg/day Average
Food and

Water Exposure mg/kg/day Residential Exposure mg/kg/day 3 Total Exposure mg/kg/day 4 Aggregate MOE (food, water, and residential) 5

Adult 171 100 1.71 0.010452 0.0014 0.012 14,000
Children 1-2 years old 171 100 1.71 0.018609 0.0089 0.028 6,100

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

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

3 Residential Exposure see Table 6.1.

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

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



### 7.3 Chronic Aggregate Risk

Chronic exposure is not expected for the adult or child residential exposur e pathway. Therefore, the chronic aggregate risk estimate would be equiva lent to the chronic diet ary exposure estimate.
Refer to Section 5.4.3.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has fo llowed 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 th e cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and proc edures for cumulating effects from substances found to have
a common mechanism on EPA’s website at http://www.epa.gov/pestic ides/cumulative/

9.0 Occupational Exposure/Risk Characterization

9.1 Short-/Intermediate-Term Handler Risk

HED evaluated occupational exposures from the proposed uses of cyazofamid. Application methods, maximum application rates, and use sites are summarized in Table 3.3. Based on application rates and label information, short- an d intermediate-term exposures are expected for occupational handlers. However, the cyazofami d short- and intermediate-term PODs are the same for both durations; therefore this assessment is protective of both s hort- and intermediateterm exposures. Although a greenhouse use co uld result in agricultu ral production over the entire year (similar to a long-term exposure of si x months to one year); the proposed cyazofamid labels recommend alternating with a different f ungicide chemical or mode of action before continuous repeated applications; therefore it is unlikely that an individual will be exposedCyazofamid Human Health Risk Assessment DP No. D426778

Page 26 of 37 

### continually for greater than six months. The proposed labels require occupational handlers to wear long pants, long sleeved shirts, chemical resistant gloves, shoes, and socks.

Inhalation risk estimates for the proposed uses of cyazofamid were not of concern at baseline with no PPE (no respirator) and with engineering control for aerial applic ations (i.e., enclosed cockpits). Short- and intermediate-term risk es timates for occupational handlers are presented in Table 9.1.1. The occupational handler inhalation MOEs ranged from 71,000 to 600,000,000.Cyazofamid Human Health Risk Assessment DP No. D426778Page 27 of 37Table 9.1.1. OccupationalHandler Non-Cancer Exposure andRisk Estimates for Cyazofamid.Exposure ScenarioCrop or Target1LOCInhalationUnitExposure(μg/lb ai)2MaximumApplicationRate3Area Treated orAmount HandledDaily4InhalationDose (mg/kg/day)5MOE6(LOC = 100)Mixer/LoaderMixing/Loading Liquids for Aerial andChemigation ApplicationNursery (Ornamentals, Vegetables, Trees,Container Stock)100 0.219 0.078 lb ai/A60 acres 0.0000128 13,000,000Field Crop, Typical 350 acres 0.0000748 2,300,000Mixing/Loading Liquids for ChemigationApplicationGreenhouse (Ornamentals, Vegetables,Container Stock)60 acres 0.0000128 13,000,000Mixing/Loading Liquids for GroundboomApplicationField-Grown Ornamental Crops 40 acres 0.00000854 20,000,000Nursery (Ornamentals, Vegetables, Trees,Container Stock)60 acres 0.0000128 13,000,000Greenhouse (Ornamentals, Vegetables,Container Stock)60 acres 0.0000128 13,000,000Field Crop, Typical 80 acres 0.0000171 10,000,000ApplicatorApplying Sprays via Aerial EquipmentNursery (Ornamentals, Vegetables, Trees,Container Stock)100 0.0049 0.078 lb ai/A60 acres 0.000000286 600,000,000Field Crop, Typical 350 acres 0.00000168 100,000,000Applying Sprays via Groundboom EquipmentField-Grown Ornamental Crops100 0.34 0.078 lb ai/A40 acres 0.0000133 13,000,000Nursery (Ornamentals, Vegetables, Trees,Container Stock), Greenhouse(Ornamentals, Vegetables, Container Stock)60 acres 0.0000199 8,600,000Field Crop, Typical 80 acres 0.0000265 6,500,000FlaggerFlagging for Aerial ApplicationsNursery (Ornamentals, Vegetables, Trees,Container Stock)100 0.35 0.078 lb ai/A60 acres 0.0000205 8,300,000Field Crop, Typical 350 acres 0.000112 1,400,000Mixer/loader/ApplicatorMixing/Loading/Applying Liquids with aBackpack Sprayer (Broadcast)Greenhouse (Ornamentals, Vegetables,Container Stock)100 140 0.0016 lb ai/gal 40 gals 0.000112 1,500,000Nursery (Ornamentals, Vegetables, Trees,Container Stock)100 69.1 0.0016 lb ai/gal 40 gals 0.0000553 3,100,000Mixing/Loading/Applying Liquids with a Nursery (Ornamentals, Vegetables, Trees,100 2.58 0.0016 lb ai/gal 40 gals 0.00000206 83,000,000Cyazofamid Human Health Risk Assessment DP No. D426778Page 28 of 37Table 9.1.1. OccupationalHandler Non-Cancer Exposure andRisk Estimates for Cyazofamid.Exposure ScenarioCrop or Target1LOCInhalationUnitExposure(μg/lb ai)2MaximumApplicationRate3Area Treated orAmount HandledDaily4InhalationDose (mg/kg/day)5MOE6(LOC = 100)Backpack Sprayer (Soil Directed) Container Stock),Mixing/Loading/Applying Liquids with aManually Pressurized HandgunNursery (Ornamentals, Vegetables, Trees,Container Stock), Greenhouse(Ornamentals, Vegetables, Container Stock)100 30 0.0016 lb ai/gal 40 gals 0.000024 7,100,000Mixing/Loading/Applying Liquids with aMechanically Pressurized Handgun(Broadcast)Greenhouse (Ornamentals, Vegetables,Container Stock)1001200.0016 lb ai/gal 1,000 gals0.0024 71,000Nursery (Ornamentals, Vegetables, Trees,Container Stock), Field Crop, Typical3.9 0.000174 980,000Mixing/Loading/Applying Liquids with aMechanically Pressurized Handgun (GroundDirected)Greenhouse (Ornamentals, Vegetables,Container Stock)1001200.00083 lbai/gal1,000 gals0.00125 140,000Nursery (Ornamentals, Vegetables, Trees,Container Stock), Field Crop, Typical8.68 0.000090 1,900,0001 For all proposed crops/use site, the proposed application rateon Bulb Vegetables Group 3-07 and Herb Subgroup 19A were usedas the worst-case estimate ofexposure, except for the grounddirected handheld equipment uses, where the drench rate for bellpeppers was used as the worst-case estimate of exposure; theserisk estimates presented here are protective of all proposed uses.2 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September 2015); Level of mitigation:Baseline and Engineering Controlsfor aerial applications (enclosedcockpits).3Based on product label (Reg. No. 71512-3).4 Exposure Science Advisory Council Policy #9.1.5 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW (80 kg).6 Inhalation MOE = Inhalation NOAEL (171 mg/kg/day) ÷ InhalationDose (mg/kg/day).Cyazofamid Human Health Risk Assessment DP No. D426778

Page 29 of 37 

### 9.2 Short- and Intermediate-T erm Post-Application Risk

9.2.1 Dermal Post-application Risk

An occupational post-application dermal assessm ent was not completed for cyazofamid because
no short- or intermediate-term dermal hazard wa s identified in the toxicity database. DFR studies are available in the cyazofami d exposure database (MRID 45409118 and 45409119); therefore, additional studies are not required at this time.

Although a greenhouse use could result in agricultura l production over the entire year (similar to a long-term exposure of six months to one y ear); the proposed cyazofamid labels recommend alternating with a different fungi cide chemical or mode of action before continuous repeated applications; therefore, it is un likely that an individual will be exposed to cyazofamid continually for greater than six months. Although the hal f-life for cyazofamid resi dues are relatively long (2.6 – 47.8 days), continuous long-term exposures are not expected because of the following: (1) because of the need to alternate fungicides wi th different modes of action, especially in greenhouses, it is unlikely that the same individual would be exposed to cyazofamid residues continuously for greater than six months; (2) th e use directions for cy azofamid require repeat applications on a 7-10 day schedule, therefore, it is unlikely that an individual would be exposed to cyazofamid residues continuously for greater than six months; and (3) because crops are grown in varying stages in a greenhouse conti nuously throughout the ye ar, it unlikely that the same person would be performing the same tas k, contacting the same residues continuously throughout six months; the individual tasks woul d likely rotate with the greenhouse growth
schedules.

Restricted Entry Interval

Cyazofamid is classified as Toxicity Category II I via the dermal route and Toxicity Category III for skin irritation potential. It is a weak skin sensitizer. Short- a nd intermediate-term postapplication risk estimates were not a concern on day 0 (12 hours following application) for all post-application activ ities. Under 40 CFR §156.208 (c ) (2), ai’s classified as Acute III or IV for acute dermal, eye irritation and pr imary skin irritation are assigne d a 12-hour REI. Therefore, the [156 subpart K] Worker Protection Statemen t interim proposed REI of 12 hours is adequate to protect agricultural workers from post-application exposures to cyazofamid. HED would
recommend a REI of 12 hours. This is the REI listed on the product labe l, and is considered protective of post-app lication exposure.

9.2.2 Inhalation Post-application Risk

There are multiple potential sources of post-app lication inhalation exposure to individuals performing post-applicati on activities in previously treated fields. These potential sources
include volatilization of pesticides and resuspension of dusts and/or particulat es that contain pesticides. The agency sought expert advice an d input on issues relate d to volatilization of pesticides from its FIFRA SAP in December 2009, a nd received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings /2009/120109meeting.html). The agency has evaluated the SAP report and has developed a Vo latilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/ #!docketDetail;D=EPA-HQ-Cyazofamid Human Health Risk Assessment DP No. D426778

Page 30 of 37 

### OPP-2014-0219 ). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for cyazofamid.

In addition, the Agency is continuing to eval uate the available post- application inhalation exposure data generated by the Ag ricultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation expos ure into the agency's risk assessments.

Although a quantitative occupational post-applic ation inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resultin g from application of pesticides outdoors is likely to result in higher exposure than post -application exposure. Therefore, it is expect ed that these handler inhalation exposure estimates would be protec tive of most occupatio nal post-application inhalation exposure scenarios.

The Worker Protection Standard for Agricultural Pesticides contains requ irements for protecting workers from inhalation exposures during and af ter greenhouse applications through the use of ventilation requirements [40 CFR 170.110, (3) (Restrictions a ssociated with pesticide applications)].

10.0 References

Meléndez, J., 10/06/15 DP426776, Estimated Drinking Water Concentrations of Cyazofamid and its Degradates of Concern CCIM, CCIM-AM and CTCA, for Use in Human Health Risk Assessment: Petitions for the Use on He rb (Subgroup 19A), Greenhouse Tomato, Greenhouse Pepper, and Bulb Vegetables (Group 03-07)

Rury, K., 10/XX/15, DP429457 and DP429458, Cyazofamid. Occupational and Residential Exposure Assessment for a Proposed Use on Crop Subgroup 19A, Peppers and Tomatoes Grown in Greenhouses, and on Bulb Vegetables Crop Group 03-07.

Wassell W., 10/XX/15, DP426632 and DP426778, Cyazofamid. Petitions for the Establishment of Registrations and Tolerances for Residue s in/on Herb, Subgroup 19A, Bulb Vegetables, Group 3-07, and data to support use on Tomato and Peppers in Greenhouses. Summary of Analytical Chemistry and Residue Data.

Walls, C., 10/19/15, DP430735, Cyazofamid Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action on Crop Subgroup 19A and on Bulb Vegetables Crop Group 03-07.Cyazofamid Human Health Risk Assessment DP No. D426778

Page 31 of 37 

### Appendix A. Toxicology Profile

A.1 Toxicology Data Requirements The requirements (40 CFR §158.340) for food use for cyazofam id are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used

Study Technical Required Satisfied 870.1100 Acute Oral Toxicity ....................................................... 870.1200 Acute Dermal Toxicity ..................................................
870.1300 Acute In halation Toxicity ..............................................
870.2400 Primar y Eye Irr itation

.................................................... 870.2500 Primar y Dermal Irr itation

.............................................. 870.2600 Derm al Sensiti zation ..................................................... yes
yes
yes
yes
yes
yes yes
yes
yes
yes
yes
yes 870.3100 Oral Su bchronic (rodent) ...............................................
870.3150 Oral Su bchronic (nonr odent) ......................................... 870.3200 21-Day Dermal .............................................................. 870.3250 90-Day Dermal ..............................................................
870.3465 90-D ay Inhala tion .......................................................... yes
yes

no

no
yes yes
yes

-

- yes 1 870.3700a Developmental Toxicity (rodent) .................................. 870.3700b Developmental Toxicity (nonrodent) ............................
870.3800 Reproduc tion ................................................................. yes
yes
yes yes
yes
yes 870.4100a Chronic T oxicity (rodent) ..............................................
870.4100b Chronic Toxi city (nonrodent) ........................................ 870.4200a Oncoge nicity (ra t) .......................................................... 870.4200b Oncogenicity (mouse) ...................................................
870.4300 Chroni c/Oncogeni city ................................................... yes
yes
yes
yes
yes yes
yes
yes
yes
yes 870.5100 Mutagenicity—G ene Mutation - bacterial ..................... 870.5300 Mutagenicity—Gene Mutation - mammalian ................ 870.5375 Mutagenicity—Struc tural Chromosomal Aberrations ... 870.5395 Mutagenicity—O ther Genotoxic Effects ....................... yes
yes
yes
yes yes
yes
yes
yes 870.6100a Acute Delayed Neurotoxicity (hen) ............................... 870.6100b 90-Day Neurotoxicity (hen) .......................................... 870.6200a Acute Neurotoxicity Screening Battery (rat) ................. 870.6200b 90-Day Neurotoxicity Screening Battery (rat) .............. 870.6300 Develop. Neurotoxicity ................................................. no

no
yes
yes

no -

- yes
yes

-
870.7485 Gene ral Metabo lism ......................................................
870.7600 Derm al Penetr ation ........................................................ 870.7800 Immunotoxicity ............................................................. yes

no
yes yes

- yes Special Studies for Ocular Effects Acute Oral (rat) ................................................................................
Subchronic Or al (rat)........................................................................ Six-month Oral (dog) ....................................................................... no

no

no -

-

- 1 = HED HASPOC concluded that the subchronic inhalation study was not required at this time (J. Van Alstine, 7/11/12, TXR#0056341).Cyazofamid Human Health Risk Assessment DP No. D426778

Page 32 of 37 

### A.2 Toxicity Profiles

Acute Toxicity of C yazofamid Technical

Guideline
No. Study Type MRID No. Results Toxicity Category

870.1100 Acute Oral – Rat 45408910 LD 50 > 5000 mg/kg [M/F] IV

870.1200 Acute Dermal – Rat 45408911 LD 50 > 2000 mg/kg [M/F] III

870.1300 Acute Inhalation – Rat 45408912 LC 50 > 5.5mg/L [M/F] IV

870.2400 Primary Eye Irritation –
Rabbit 45408913 Grade 2 conjunctival redness and discharge that resolved by 24 hours IV

870.2500 Primary Skin Irritation
– Rabbit 45408914 Very slight to well defined erythema that cleared by 7 days III

870.2600 Dermal Sensitization (Guinea Pig Maximization test) 45408915 Positive (weak sensitizer) -

Subchronic, Chronic, and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/ Classification
/Doses Results

870.3100 28-Day dose-range finding study in rats 45408927 (1999) Acceptable/non-guideline 0, 50, 500, 5000, & 20,000 ppm Male: 0, 3.8, 38.5, 370, & 1488 mg/kg/day Female: 0, 3.6, 37.1, 389, & 1535 mg/kg/day NOAEL = 38.5 [M] mg/kg/day. LOAEL = 370 [M] mg/kg/day based on dose related increase in the incidence of basophilic kidney tubules in
males.

870.3100 90-Day oral toxicity in

rats 45408928 (1999) Acceptable/guideline Males: 0, 10, 50, 500, or 5,000 ppm 0, 0.6, 2.9, 29.5, or 294.5 mg/kg/day Females: 0, 50, 500, 5,000, or 20,000 ppm 0, 3.3, 33.3, 337.6, or 1,359.0 mg/kg/day NOAEL = 29.5 [M] mg/kg/day. LOAEL = 295 [M] mg/kg/day based on increased incidence of basophilic kidney tubules, and increased urinary volume, pH, and protein.

870.3150 90-Day oral toxicity in dogs 45408929 (2001) Acceptable/guideline 0, 40, 200, or 1,000 mg/kg/day NOAEL = 1,000 [M/F] mg/kg/day.
LOAEL = not observed.

870.3200 28-Day dermal toxicity
in rats 45408930 (1997) Acceptable/guideline 0, 250, 500, or 1,000 mg/kg/day NOAEL = 1,000 [M/F] mg/kg/day.
LOAEL = not observed.Cyazofamid Human Health Risk Assessment DP No. D426778

Page 33 of 37 Subchronic, Chronic, and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/ Classification
/Doses Results

870.3465 28-Day inhalation toxicity Waived (HASPOC; TRX# 0056341; 7/11/12)

870.3700a Prenatal developmental
in rats 45430404 (1999) Acceptable/guideline 0, 30, 100, or 1,000 mg/kg/day Maternal NOAEL = 1,000 mg/kg/day.
LOAEL = not observed. Developmental NOAEL = 100 mg/kg/day. LOAEL = 1,000 mg/kg/day based on increased
incidence of bent ribs.

870.3700b Prenatal developmental
in rabbits 45408934 (1999) Acceptable/guideline 0, 30, 100, or 1,000 mg/kg/day Maternal NOAEL = 1,000 mg/kg/day.
LOAEL = not observed. Developmental NOAEL = 1,000 mg/kg/day.
LOAEL = not observed.

870.3800 Reproduction and fertility effects in rats 45408935 (1998) Acceptable/guideline 0, 200, 2,000, or 20,000 ppm

F 0 M: 11-22, 108-213, and 1114- 2185 mg/kg/day

F 0 F: 14-21, 137-219, and 1416-2179 mg/kg/day

F 1 M: 11-27, 107-267, and 1117- 2714 mg/kg/day

F 1 F: 14-27, 135-267, and 1451-2678 mg/kg/day Parental/Systemic NOAEL = 108/ 1416 [M/F] mg/kg/day. LOAEL = M: 1114 mg/kg/day based on increased incidence of nephropathy; F: not observed. Reproductive NOAEL = 1114/ 1416 [M/F] mg/kg/day.
LOAEL = not observed. Offspring NOAEL = 1117/ 1451 [M/F] mg/kg/day.
LOAEL = Not observed. Note: No histopathology conducted on the kidneys of

pups.

870.4100a Chronic toxicity in rats 45408936 (1999) Acceptable/guideline Males: 0, 10, 50, 500, or 5,000 ppm 0, 0.35, 1.7, 17.1, or 171.1 mg/kg/day Females: 0, 50, 500, 5,000, or 20,000 ppm 0, 2.0, 20.2, 207.8, or 856.0 mg/kg/day NOAEL = 171/ 856 [M/F] mg/kg/day.
LOAEL = not observed.

870.4100b Chronic toxicity in dogs 45408931 (2001) Acceptable/guideline 0, 40, 200, 1,000 mg/kg/day NOAEL = 200 [M/F] mg/kg/day. LOAEL = 1,000 [M/F] mg/kg/day based on increased cysts in parathyroids in males.

870.4200 Carcinogenicity rats 45408936 (1999) Acceptable/guideline Males: 0, 10, 50, 500, or 5,000 ppm 0, 0.35, 1.7, 17.1, or 171.1 mg/kg/day Females: 0, 50, 500, 5,000, or 20,000 ppm 0, 2.0, 20.2, 207.8, or 856.0 mg/kg/day NOAEL = 171/ 856 [M/F] mg/kg/day.
LOAEL = not observed. No evidence of carcinogenicity.Cyazofamid Human Health Risk Assessment DP No. D426778

Page 34 of 37 Subchronic, Chronic, and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/ Classification
/Doses Results

870.4300 Carcinogenicity mice 45408932 (1999) Acceptable/guideline Males: 0, 9.5, 94.8, or 984.9 mg/kg/day Females: 0, 12.2, 124.3, or 1203.4 mg/kg/day NOAEL = 94.8 [M] mg/kg/day. LOAEL = 985 [M] mg/kg/day based on increased incidence of skin lesions including hair loss, body sores, dermatitis, ulceration, and acanthosis. No evidence of carcinogenicity.

Gene Mutation
870.5100
Bacterial reverse mutation assay 45408937 (1998) Acceptable/ guideline Negative ± S9 up to 5,000 μ g/plate by standard plate and tube pre-incubation (not cytotoxic but there was precipitation at ≥ 1,500 μ g/plate.

Gene Mutation
870.5300
Mammalian cell culture 45409002 (1998) Acceptable/ guideline Negative ± S9 up to cytotoxic and precipitating
concentration of 100 μ g/mL.

Cytogenetics
870.5375
Chromosomal
aberrations 45409003 (1996) Acceptable/ guideline Negative ± S9 for clastogenic/an eugenic activity up to cytotoxic and precipitating concentration of 200 μ g/mL.

Cytogenetics
870.5395
Micronucleus test on

mouse 45409004 (1996) Acceptable/ guideline Negative up to the highest dose tested (limit dose) 2,000 mg/kg.

Other Effects
870.5500 Bacterial DNA repair test (Rec-assay) 45409005 (1998) Acceptable/ guideline Negative ± S9 up to limit of solubility at 8,000 μ g/disc.

870.6200a Acute neurotoxicity screening battery 45434601 (2000) Acceptable/guideline 0, 80, 400, or 2000 mg/kg NOAEL = 2000 [M/F] mg/kg/day.
LOAEL = not observed.

870.6200b
Subchronic neurotoxicity screening battery 48891702 (2012) Acceptable/guideline Males: 0, 34, 134, or 1,356 mg/kg/day Females: 0, 39, 156, or 1,539 mg/kg/day Systemic/Neurotoxicity: NOAEL = 1356 mg/kg/day.
LOAEL = not observed.

870.6300 Developmental neurotoxicity Study not available.Cyazofamid Human Health Risk Assessment DP No. D426778

Page 35 of 37 Subchronic, Chronic, and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/ Classification
/Doses Results

870.7485
Metabolism and pharmacokinetics in

rats 45409006- 45409009 and 45434602 (1998- 1999) Acceptable/guideline Dose: 0.5, 1,000, or 14 day 0.5 mg/kg repeat non-labeled followed by 0.5 mg/kg [phenyl- U- 14 C]- or [ 14 C-Imidazole] IKF-916. Biliary excretion study: 0.5 or 1,000 mg/kg [phenyl- U- 14 C]- or [ 14 CImidazole] IKF-916. There was rapid absorption (irrespective of dose t
cmax = 0.25-0.5 hrs) and rapid elimination at the low dose (t 1/2 4.4-5.8 hrs) while there was saturated absorption with prolonged elimination (t 1/2 of 7.6-11.6 hrs) at the highdose. The extent of absorption (as percent of administered dose) was highly dose-dependent being nearly 75% at the low dose and only about 5% at the high dose. Both the urine and feces were major routes of excretion at the low dose with most of the urinary radioactivity being a metabolite, CCBA. The biliary elimination was highly variable at the low dose (

∼ 12- 39% of the administered low dose) and negligible (<2%) in the high-dose groups. Urinary or biliary excretion in the high-dose groups was low (each

∼ 2%), with most of the radioactivity being CCBA. Irrespective of the dosing regimen, most of the
recovered fecal radioactiv ity was unchanged parent compound; the major fecal metabolites were CCBA and CCIM each of which being less than 5% of the
administered dose. Tissue burdens at t 1/2 , t max , and at 168 hours post dose indicated rapid clearance and low tissue burdens suggesting little or no bioaccumulation or sequestration.

870.7600 Dermal penetration Study not available.

870.7800 Immunotoxicity 48891701 (2012) Acceptable/guideline 0, 136, 599, or 1381 mg/kg/day Systemic/Immunotoxicity: NOAEL = 1381 mg/kg/day.
LOAEL = not observed.

Special study:

In Vitro Metabolism of
IKF-916 and CCIM in
Blood and Stomach
Contents MRID 45409010 (1999) Acceptable/non-guideline The in vitro biodegradation of [ 14 C-Bz]IKF-916 or [ 14 CBz)CCIM by rat blood or rat stomach contents was
examined. The results indi cated 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 nece ssarily in the stomach compartment.Cyazofamid Human Health Risk Assessment DP No. D426778

Page 36 of 37 Subchronic, Chronic, and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/ Classification
/Doses Results

Special study:

In Vitro Metabolism of
CCIM in S9 Fraction MRID 45409011 (1999) Acceptable/non-guideline The in vitro metabolism of 14 C-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 threemetabolites 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 [ 14 C]IKF-916 or [ 14 C]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 transf er across the gut wall.

Special study: Comparative
metabolism of [ 14 C]IKF-916 or [ 14 C]CCIM in rats MRID 45409013 (1999) Acceptable/non-guideline Rats were given a single gavage dose of 0.46 mg/kg of [ 14 C-Bz]IKF-916 or 0.33 mg/kg of [ 14 C-Bz]CCIM and, after 30 minutes, blood, liver, stomach (plus contents), and duodenum (plus conten ts) were collected and analyzed for radioactivity and metabolites. Following a single gavage dose of CCIM, the metabolites CCBA and CHCN, in addition to unchanged CCIM, were detected in the plasma and liver. The same metabolites, as well as CCIM, were also detected in plasma and liver following administration of IKF-916. Therefore, orally
administered IKF-916 is converted to CCIM and subsequently to CCBA and CHCN.Cyazofamid Human Health Risk Assessment DP No. D426778

Page 37 of 37 

### Appendix B. Identification of Compounds from the Cyazofamid Metabolism Studies

Common Name/
Code/Matrix Chemical Name Chemical Structure

Cyazofamid/
IKF-916 4-chloro-2-cyano- N,N -dimethyl-5-(4- methylphenyl)-1 H -imidazole-1-sulfonamide

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

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

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

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

C H 3 Cl

CN

SO 2 N(CH 3 ) 2

N H N

C H 3 Cl

CN

N H N Cl

CN O H

O

N H N

C H 3 Cl

O

NH 2